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Tarsal-carpal coalition syndrome is a rare, inherited bone disorder that affects primarily the hands and feet. Several individual bones make up each wrist (carpal bones) and ankle (tarsal bones). In tarsal-carpal coalition syndrome, the carpal bones fuse together, as do the tarsal bones, which causes stiffness and immobility of the hands and feet. Symptoms of the condition can become apparent in infancy, and they worsen with age. The severity of the symptoms can vary, even among members of the same family.
In this condition, fusion at the joints between the bones that make up each finger and toe (symphalangism) can also occur. Consequently, the fingers and toes become stiff and difficult to bend. Stiffness of the pinky fingers and toes (fifth digits) is usually noticeable first. The joints at the base of the pinky fingers and toes fuse first, and slowly, the other joints along the length of these digits may also be affected. Progressively, the bones in the fourth, third, and second digits (the ring finger, middle finger, and forefinger, and the corresponding toes) become fused. The thumb and big toe are usually not involved. Affected individuals have increasing trouble forming a fist, and walking often becomes painful and difficult. Occasionally, there is also fusion of bones in the upper and lower arm at the elbow joint (humeroradial fusion). Less common features of tarsal-carpal coalition syndrome include short stature or the development of hearing loss.
## Frequency
This condition is very rare; however, the exact prevalence is unknown.
## Causes
Tarsal-carpal coalition syndrome is caused by mutations in the NOG gene, which provides instructions for making a protein called noggin. This protein plays an important role in proper bone and joint development by blocking (inhibiting) signals that stimulate bone formation. The noggin protein attaches (binds) to proteins called bone morphogenetic proteins (BMPs), which keeps the BMPs from triggering signals for the development of bone.
NOG gene mutations that cause tarsal-carpal coalition syndrome reduce the amount of functional noggin protein. With decreased noggin function, BMPs abnormally stimulate bone formation in joint areas, where there should be no bone, causing the bone fusions seen in people with tarsal-carpal coalition syndrome.
Mutations in the NOG gene are involved in several disorders with overlapping signs and symptoms. Because of a shared genetic cause and overlapping features, researchers have suggested that these conditions, including tarsal-carpal coalition syndrome, represent a spectrum of related conditions referred to as NOG-related-symphalangism spectrum disorder (NOG-SSD).
### Learn more about the gene associated with Tarsal-carpal coalition syndrome
* NOG
## Inheritance Pattern
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.
*[v]: View this template
*[t]: Discuss this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Tarsal-carpal coalition syndrome | c1861306 | 6,800 | medlineplus | https://medlineplus.gov/genetics/condition/tarsal-carpal-coalition-syndrome/ | 2021-01-27T08:24:52 | {"gard": ["9225"], "mesh": ["C566089"], "omim": ["186570"], "synonyms": []} |
Pork–cat syndrome
SpecialtyImmunology
Pork–cat syndrome is an allergy to pork, usually after adolescence, that is caused by exposure to cats. Although first described in 1994,[1][2][3] it was first documented in the U.S. by Scott Commins and Thomas Platts-Mills during their research on alpha-gal allergy.[4]
It is called "pork–cat syndrome" because "almost all people with the condition are cat owners, and many have multiple cats. Some develop an allergic response to cat serum albumin (protein made by a cat’s liver) that cross-reacts with albumin in pork when someone consumes it, and can lead to severe or even fatal allergic reactions when pork is consumed."[4]
## References[edit]
1. ^ Abreu, Carmo; Gomes, Raquel; Bartolome Borja, Bial-Arístegui; Falcão, Helena; Cunha, Leonor (30 March 2015). "Pork-cat syndrome?". Clin Transl Allergy. 5 (Suppl 3): P164. doi:10.1186/2045-7022-5-S3-P164. PMC 4412402.
2. ^ "Pork-Cat Syndrome an Under-Recognized Allergy".
3. ^ Posthumus, Jonathon; James, Hayley R; Lane, Charles J; Matos, Luis A; Platts-Mills, Thomas A E; Commins, Scott P (24 March 2017). "Initial Description of Pork-Cat Syndrome in the United States". J Allergy Clin Immunol. 131 (3): 923–925. doi:10.1016/j.jaci.2012.12.665. PMC 3594363. PMID 23352634.
4. ^ a b "Allergic reactions to pork may be prompted by a protein made in the liver of cats".
## External links[edit]
Classification
D
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Pork–cat syndrome | None | 6,801 | wikipedia | https://en.wikipedia.org/wiki/Pork%E2%80%93cat_syndrome | 2021-01-18T18:51:33 | {"wikidata": ["Q30314380"]} |
A number sign (#) is used with this entry because of evidence that primary coenzyme Q10 deficiency-7 (COQ10D7) is caused by homozygous or compound heterozygous mutation in the COQ4 gene (612898) on chromosome 9q34.
Description
Primary coenzyme Q10 deficiency-7 is an autosomal recessive disorder resulting from mitochondrial dysfunction. Most patients have onset of severe cardiac or neurologic symptoms soon after birth, usually resulting in death. Rare patients may have later onset with a more protracted course. Tissue samples from affected individuals show decreased levels of coenzyme Q10 (CoQ10) (summary by Brea-Calvo et al., 2015).
For a general phenotypic description and a discussion of genetic heterogeneity of primary coenzyme Q10 deficiency, see COQ10D1 (607426).
Clinical Features
Brea-Calvo et al. (2015) reported 6 patients from 4 unrelated families with a severe mitochondrial disorder associated with decreased CoQ10 levels. Two Italian sibs, born of unrelated parents, presented at birth with hypotonia, bradycardia, and respiratory insufficiency. One sib was confirmed to have increased serum lactate and left ventricular hypoplasia with septum hypertrophy and a patent ductus arteriosus. An unrelated patient from a second family died of hypertrophic cardiomyopathy on the first day of life, and 2 sibs from a third family had neonatal respiratory distress, cerebellar hypoplasia, and fatal epileptic encephalopathy without cardiac involvement. The last patient, an 18-year-old man with early normal development, had experienced onset of progressive motor deterioration at 10 months of age. He lost ambulation at age 6 years, developed seizures at age 12 years, and thereafter had a slowly progressive downhill course with swallowing impairment and cognitive decline. He also had a sensorimotor polyneuropathy, cerebellar atrophy, and nonspecific abnormal signal intensities on brain MRI. Skeletal muscle samples from most patients showed decreased activity of coupled complexes in the electron transport chain; however, samples from 1 patient showed increased activity of the electron transport chain. Laboratory studies showed increased serum lactate in all patients and increased urinary levels of 2-OH glutaric acid in 3 patients.
Chung et al. (2015) reported 6 girls from 4 unrelated families with severe COQ10D7 resulting in death in the first days or weeks of life or in infancy (range, 36 hours to 19 months of age). The patients presented soon after birth with hypotonia, respiratory insufficiency, feeding difficulties, and lactic acidosis. Common clinical abnormalities included encephalopathy with EEG abnormalities, neonatal seizures, cerebellar atrophy, and hypertrophic cardiomyopathy. Muscle biopsy performed on 1 patient showed decreased activity of mitochondrial respiratory complexes II and III and decreased CoQ10 levels. Neuropathologic examination of 2 patients showed neuronal loss and astrocytosis in the cerebellum, brainstem, basal ganglia, and thalamus, as well as microdysgenesis.
Inheritance
The transmission pattern of COQ10D7 in the families reported by Brea-Calvo et al. (2015) was consistent with autosomal recessive inheritance.
Cytogenetics
Salviati et al. (2012) reported a boy with a severe encephalomyopathic disorder, including poor growth, hypotonia, and delayed psychomotor development with moderate mental retardation and an inability to walk at age 3 years, associated with a de novo heterozygous 3.9-Mb deletion of chromosome 9q34; the deleted region included at least 80 genes, 1 of which was COQ4. Laboratory studies showed a reduction of mitochondrial respiratory complexes II and III in fibroblasts and a decrease of coenzyme Q content (43% of control), consistent with coenzyme Q deficiency (607426). Supplementation of coenzyme Q in patient fibroblasts resulted in correction of the complex II and III deficiencies. A 50% knockdown of COQ4 mRNA in HeLa cells resulted in an approximately 50% decrease in COQ4 protein, and haploinsufficiency of Coq4 in yeast caused a reduction in complex II and III activity. Oral supplementation with coenzyme Q using ubiquinone and subsequently ubiquinol in the patient resulted in clinical improvement. Salviati et al. (2012) maintained that haploinsufficiency for the COQ4 gene in this patient caused the CoQ deficiency, while noting that the disorder is usually inherited as an autosomal recessive trait.
Molecular Genetics
In 5 patients from 4 unrelated families with COQ10D7, Brea-Calvo et al. (2015) identified 6 different homozygous or compound heterozygous mutations in the COQ4 gene (612898.0001-612898.0006). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. In vitro functional expression studies in Coq4-null yeast showed that all the mutations resulted in a severe defect in oxidative growth, consistent with a pathogenic effect. Patient fibroblasts showed reduced COQ4, and patient skeletal muscle samples showed reduced CoQ10 content.
In 6 girls from 4 unrelated families with COQ10D7, Chung et al. (2015) identified biallelic missense mutations in the COQ4 gene (see, e.g., 612898.0003; 612898.0007-612898.0008). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. Two unrelated patients, both of Ashkenazi Jewish descent, shared the same mutation (R240C; 612898.0003), consistent with a founder effect in this population. Functional studies of the variant and studies of patient cells were not performed. The severe phenotype suggested that COQ4 is an essential component of the complex required for CoQ10 biosynthesis.
INHERITANCE \- Autosomal recessive GROWTH Other \- Intrauterine growth retardation (in some patients) CARDIOVASCULAR Heart \- Bradycardia (in some patients) \- Hypertrophic cardiomyopathy (in some patients) \- Left ventricular hypoplasia (in some patients) Vascular \- Patent ductus arteriosus (in some patients) RESPIRATORY \- Respiratory insufficiency, neonatal ABDOMEN Gastrointestinal \- Swallowing difficulties SKELETAL Spine \- Scoliosis (1 patient) MUSCLE, SOFT TISSUES \- Hypotonia, neonatal \- Skeletal muscle biopsy shows decreased activity of coupled complex activity in the electron transport chain \- Increased activity of coupled complex activity in the electron transport chain (1 patient) \- Decreased coenzyme Q10 levels NEUROLOGIC Central Nervous System \- Epileptic encephalopathy (in some patients) \- Regression of psychomotor development (1 patient) \- Loss of ambulation (1 patient) \- Seizures (in some patients) \- Cerebellar hypoplasia (in some patients) Peripheral Nervous System \- Sensorimotor polyneuropathy (1 patient) LABORATORY ABNORMALITIES \- Increased serum lactate \- Increased urinary 2-OH glutaric acid (in some patients) MISCELLANEOUS \- Prenatal onset or onset at birth \- Most patients die in the first days of life MOLECULAR BASIS \- Caused by mutation in the homolog of the S. cerevisiae coenzyme Q4 gene (COQ4, 612898.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| COENZYME Q10 DEFICIENCY, PRIMARY, 7 | c4225392 | 6,802 | omim | https://www.omim.org/entry/616276 | 2019-09-22T15:49:25 | {"doid": ["0070244"], "omim": ["616276"], "orphanet": ["457185"], "synonyms": ["COQ4-related neonatal encephalomyopathy"], "genereviews": ["NBK410087"]} |
A number sign (#) is used with this entry because Mowat-Wilson syndrome (MOWS) is caused by de novo heterozygous mutation in the ZEB2 gene (605802) on chromosome 2q22.
Description
Mowat-Wilson syndrome is an autosomal dominant complex developmental disorder; individuals with functional null mutations present with mental retardation, delayed motor development, epilepsy, and a wide spectrum of clinically heterogeneous features suggestive of neurocristopathies at the cephalic, cardiac, and vagal levels. Mowat-Wilson syndrome has many clinical features in common with Goldberg-Shprintzen syndrome (609460) but the 2 disorders are genetically distinct (Mowat et al., 2003). Goldberg-Shprintzen syndrome is caused by mutation in the KIAA1279 gene (609367) located on 10q.
Clinical Features
Mowat et al. (1998) described 6 unrelated children with a distinctive facial phenotype in association with mental retardation, microcephaly, and short stature. Four of the children presented with Hirschsprung disease in the neonatal period; a fifth child was diagnosed with Hirschsprung disease after years of constipation. One of the 4 patients had an interstitial deletion of chromosome 2 del(2)(q21q23). All the patients described by Mowat et al. (1998) were isolated cases, suggesting a contiguous gene syndrome or a dominant single gene disorder involving a locus for HSCR located at 2q22-q23.
Among more than 200 cases of Hirschsprung disease, Wakamatsu et al. (2001) found that 5 patients presented with Hirschsprung disease associated with microcephaly, mental retardation, epilepsy, and characteristic facial features. These 5 patients were all isolated cases, and 3 of them were complicated by congenital heart disease, including patent ductus arteriosus and/or ventricular septal defect. All patients had normal birth weights; microcephaly, hypertelorism, convergent strabismus, and wide nasal bridge were observed in all cases, with facial features similar to those previously reported by Mowat et al. (1998). Deafness, pigmentation defects, iris coloboma, ptosis, and cleft palate were not observed. Patient 1 also had a t(2;13)(q22;q22) translocation.
Yamada et al. (2001) demonstrated that Hirschsprung disease was absent in 6 patients with mutations in the ZFHX1B gene who otherwise had features similar to previously reported mutation-positive patients (see, e.g., 605802.0002). All mutations were de novo and occurred in 1 allele. The wide spectrum of features suggested neurocristopathies at the cephalic, cardiac, and vagal levels.
Yoneda et al. (2002) reported a 48-year-old woman, born of nonconsanguineous parents, who had late infantile-onset mental retardation and developed megacolon in adulthood. Although the patient had no typical clinical features of Hirschsprung disease-mental retardation syndrome, a deletion identified in exon 3 of the ZFHX1B gene (605802.0011). She was noted to have mental retardation in childhood but received a full education in elementary school. She sometimes had constipation but did not require medication until age 48 years, when she presented with severe constipation and was found to have megacolon. This patient thus appeared to represent an intermediate stage between the full-blown Hirschsprung disease-mental retardation syndrome and Hirschsprung disease-mental retardation syndrome without Hirschsprung disease.
Amiel et al. (2001) found large-scale ZFHX1B deletions or truncating mutations in 8 of 19 patients with Hirschsprung disease and mental retardation. They found frequent features such as hypospadias and agenesis of the corpus callosum. One of the patients with a deletion mutation had previously been reported by Tanaka et al. (1993) to have Goldberg-Shprintzen syndrome. Amiel et al. (2001) stated that 2 other patients reported to have Goldberg-Shprintzen syndrome (Hurst et al., 1988, patient 3; Ohnuma et al., 1997) most likely had Mowat-Wilson syndrome.
Ohnuma et al. (1997) described a Japanese boy who was noted during the neonatal period to have hypotonia and poor sucking. Emergency colostomy was performed at the age of 6 days because of severe constipation, abdominal distention, and congenital megacolon. Histologic findings of a rectal biopsy showed aganglionosis of the submucosal plexus and confirmed short segment Hirschsprung disease. The patient was referred at the age of 15 months because of epilepsy. He had sparse scalp hair, a sloping forehead, sparse eyebrows, telecanthus, broad nasal bridge, large ears, and pointed chin, ventricular septal defect, hypospadias with bifid scrotum, cutaneous syndactyly between the second and third fingers, and rocker-bottom feet. A brain CT revealed prominent sulci and dilatation of ventricles, indicating brain atrophy or hypoplasia. Brain MRI showed loss of parenchymal volume, especially of the white matter, thin and hypoplastic corpus callosum with absent rostrum, genu, and configuration. The anterior commissure was absent.
Zweier et al. (2002) analyzed the ZFHX1B gene in 5 patients, 3 of whom had Hirschsprung disease syndrome, 2 with and 1 without the facial phenotype described by Mowat et al. (1998), and 2 of whom had the distinct facial gestalt without Hirschsprung disease. Zweier et al. (2002) excluded large deletions in all 5 patients and found truncating ZFHX1B mutations (605802.0007-605802.0010) in all 4 patients with the characteristic facial phenotype but not in the patient with syndromic Hirschsprung disease without the distinct facial appearance. Zweier et al. (2002) suggested calling the clinical entity of this distinct facial appearance, mental retardation, and variable MCAs the 'Mowat-Wilson syndrome.'
Wilson et al. (2003) presented clinical data and mutation analyses from a series of 23 patients with Hirschsprung disease-mental retardation syndrome, of whom 21 had proven ZFHX1B mutations or deletions and 15 were previously unpublished. Two patients with the typical features (1 with and 1 without HSCR) did not have detectable abnormalities of ZFHX1B. Wilson et al. (2003) emphasized that this syndrome can be recognized by the facial phenotype in the absence of either HSCR or other congenital anomalies, and that it needs to be considered in the differential diagnosis of dysmorphism with severe mental retardation and presence or absence of epilepsy. They provided numerous photographs illustrating the facial dysmorphism changes with age. Young children tend to have an open-mouthed smiling expression with an uplifted face. The eyebrows are horizontal and wedge-shaped (medially broad) and widely separated. In later childhood, the nasal tip lengthens and depresses, overhanging the philtrum. The upper half of the nasal profile becomes convex, tending to produce an aquiline profile. The chin lengthens and prognathism develops.
Zweier et al. (2003) stated that in addition to severe mental retardation, recognizable facial gestalt, pre- or postnatal microcephaly, and postnatal growth retardation, features of Mowat-Wilson syndrome include seizures (82%) and malformations such as HSCR (67.6%), congenital heart defects (47%), and agenesis of the corpus callosum (35%). Because HSCR occurs in only approximately two-thirds of patients with Mowat-Wilson syndrome, and patients with and without HSCR can be recognized by other features, especially their distinct facial gestalt, Zweier et al. (2003) supported Mowat-Wilson syndrome as a more appropriate designation. Deletion sizes and breakpoints in these patients vary widely from 300 kb to at least 11 Mb, thus ruling out a true microdeletion syndrome. Parental origin had been determined in 4 patients, and was paternal in all. Patients with deletions were very similar to those with truncating mutations. There was no correlation between the phenotype and size of deletion up to 5 Mb; however, 1 patient with a larger deletion of approximately 11 Mb had early seizures with a lethal course and hypoplasia of the big toes as additional features. Zweier et al. (2003) described 4 patients with Mowat-Wilson syndrome; in 2 the diagnosis was made because of HSCR and associated features, and in the other 2 because of mental retardation associated with the distinct facial gestalt in the absence of HSCR.
Adam et al. (2006) presented detailed clinical features of 12 patients with Mowat-Wilson syndrome. All had a characteristic facial feature of a prominent nasal tip with the columella extending below the ala nasi. Other common facial features included cupped ears with fleshy, upturned lobules, deep-set eyes, hypertelorism, medially flared and broad eyebrows, and pointed chin. Adam et al. (2006) also noted that patients had malpositioning of the teeth and delayed tooth eruption, recurrent otitis media, postnatal growth deficiency in both height and weight, accessory nipples, long, tapering fingers, severely impaired or absent speech, happy demeanor, and pulmonary artery and valve anomalies. Only 6 of the 12 patients had Hirschsprung disease, suggesting that it is not required for the diagnosis.
Strenge et al. (2007) reported a girl with Mowat-Wilson syndrome, confirmed by genetic analysis, who had multiple congenital cardiovascular anomalies, including patent ductus arteriosus, ventricular septal defect, coarctation of the aorta, and a pulmonary artery sling. She also had subglottic stenosis and distal tracheal stenosis. Although she had constipation, she did not have Hirschsprung disease, which the authors noted was not required for diagnosis. Other major clinical features included microcephaly, mental retardation, speech impairment, epilepsy, and characteristic facial phenotype with hypertelorism, downslanting palpebral fissures, broad eyebrows, lateral sparseness, prominent nasal tip, pointed chin, ears with upturned lobules, and a high-arched palate.
Cecconi et al. (2008) reported 2 sisters with Mowat-Wilson syndrome confirmed by genetic analysis. Both showed agenesis of the corpus callosum on prenatal screening at about 20 weeks' gestation. One girl had normal cardiac features, whereas the other had a complex heart malformation with aortic coarctation and valvular stenosis, pulmonary valve stenosis, and multiple septal defects. As neither parent was affected, the authors postulated germline somatic mosaicism.
Garavelli et al. (2009) studied 19 Italian patients with Mowat-Wilson syndrome, including 6 previously reported patients (Garavelli et al., 2003; Cerruti Mainardi et al., 2004; Silengo et al., 2004; Zweier et al., 2005), all of whom had the typical facial gestalt. Garavelli et al. (2009) provided photographs demonstrating changes in the characteristic facies with age. In older children, the face appeared more elongated, with a prominent jaw; the eyebrows tended to become heavier, broad, and horizontal, usually subdivided by a middle longitudinal line and an element of sparseness. The nasal tip lengthened and became more depressed, and the columella was prominent, giving rise to the appearance of a short philtrum, and the nasal profile became more convex. In adolescents and adults, the nasal tip overhung the philtrum, the face tended to lengthen with prognathism, and a long, pointed or 'chisel-shaped' chin might be observed. The uplifted ear lobes did not change much over time, except for the central depression becoming less remarkable. Garavelli et al. (2009) also reviewed the published clinical findings in MOWS patients with ZEB2 mutations.
Cordelli et al. (2013) performed a retrospective study of the seizure phenotype of 22 Italian patients with genetically confirmed MOWS. The patients ranged in age from 2 to 22 years. The mean age at seizure onset was 14.5 months (range, 1-108 months), and all patients presented initially with a focal seizure, often associated with fever, manifest variably as hypomotor, versive, or focal clonic. This type was followed by a high prevalence of atypical absence seizures later in childhood. Focal seizures were more frequent during drowsiness or sleep. At onset of seizures, EEG was normal or showed only mild slowing of background activity. However, most patients later showed spike and wave discharges, predominantly frontal, that were sometimes continuous during sleep. The seizures were difficult to control with medication; only 9 patients achieved remission with multiple medications.
Bourchany et al. (2015) reported 4 unrelated patients with Mowat-Wilson syndrome and mutations in the ZEB2 gene who all exhibited eye malformations. Ocular anomalies included microphthalmia, microcornea, irregular border of pupil, corectopia, focal iris atrophy, goniodysgenesis, iris and retinal coloboma, atrophy or absence of the optic nerve, hyphema, and deep refraction troubles, sometimes associated with severely reduced vision. All eye malformations were asymmetric and often unilateral, and all eye segments were involved. Noting that eye abnormalities were rarely reported in MOWS, the authors studied the location of ZEB2 mutations in 12 MOWS patients with ocular malformations, but did not discern any genotype/phenotype correlations. They also noted that the sibs described by McGaughran et al. (2005) exhibited intrafamilial variability, with 1 sib having an aplastic optic nerve with central chorioretinal coloboma of the left eye, and the other sib having no eye malformations.
### Neuropsychologic Features
Evans et al. (2012) evaluated behavior of 61 MOWS patients using a checklist filled out by parents or caregivers. The data were compared to those from 122 individuals with intellectual disability (ID) from other causes. Patients with MOWS tended to have significantly increased oral behaviors such as chewing or eating non-food items and teeth grinding, increased rate of repetitive behaviors, underreactivity to pain, and happy or elated mood compared to those with other ID causes. Patients with MOWS were significantly less likely to appear depressed, cry easily, not show affection, or remain alone compared to those with other ID causes. The overall MOWS behavioral phenotype was suggestive of a happy affect and sociable demeanor. However, those with MOWS displayed similarly high levels of behavioral problems as those with ID from other causes, with over 30% showing clinically significant levels of behavioral or emotional disturbances such as disruptive behavior, communication disturbances, and anxiety. It was not possible to ascertain IQ levels.
### Neuroimaging
Garavelli et al. (2017) reviewed brain MRIs of 54 Mowat-Wilson patients with a proven ZEB2 defect, compared them with features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations. Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of the corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia and cortical and cerebellar malformations. Most features were underrepresented in the literature. The literature review included 56 cases in whom MRI had been performed and evaluated in detail.
Inheritance
Most patients with Mowat-Wilson syndrome have de novo heterozygous mutations in the ZEB2 gene (summary by Ghoumid et al., 2013). However, rare affected sibs have been reported, suggesting germline somatic mosaicism in 1 of the parents (McGaughran et al., 2005; Cecconi et al., 2008).
Cecconi et al. (2008) reported 2 sisters with Mowat-Wilson syndrome confirmed by genetic analysis. As neither parent was affected, the authors postulated germline somatic mosaicism. Including previous reports, Cecconi et al. (2008) estimated that the recurrence rate of Mowat-Wilson syndrome could be as high as 2.3% (4 of 175; range, 0.6-5.7%).
Population Genetics
The prevalence of Mowat-Wilson syndrome is estimated to be 1 per 50,000-70,000 live births (summary by Ghoumid et al., 2013).
Cytogenetics
Engenheiro et al. (2008) reported 2 unrelated patients with Mowat-Wilson syndrome associated with cytogenetic abnormalities resulting in disruption of the ZEB2 gene. One patient had an interstitial 0.6-Mb deletion at chromosome 2q22 including the entire ZEB2 gene that was detected by array comparative genomic hybridization (CGH) at age 13 years after conventional cytogenetic analysis reported a normal karyotype. The other patient had a complex balanced chromosomal rearrangement, t(2;12;18)(q22.3;12q22;q21.33), detected by cytogenetics early in childhood. The 2q22 breakpoint was later found to be in intron 2 of the ZEB2 gene when the patient was about 19 years old. The other breakpoints in this patient were not known to disrupt any genes. Engenheiro et al. (2008) noted that both patients were only properly diagnosed with Mowat-Wilson syndrome after initial cytogenetic findings were investigated further, suggesting that the syndrome may be underdiagnosed.
Molecular Genetics
In 4 of 5 patients with Hirschsprung disease associated with microcephaly, mental retardation, epilepsy, and characteristic facial features of Mowat-Wilson syndrome, Wakamatsu et al. (2001) identified pathogenic changes in the ZEB2 gene, including 1 deletion and 3 mutations (see, e.g., 605802.0001-606802.0003). No mutation was identified in ZEB2 in the fifth patient. All of the mutations occurred de novo.
In 3 patients originally described by Mowat et al. (1998), Cacheux et al. (2001) identified mutations in the ZEB2 gene (see, e.g., 605802.0004).
Horn et al. (2004) reported 2 unrelated patients with Mowat-Wilson syndrome diagnosed on the basis of the characteristic facial features; neither patient had HSCR. Both were found to have deletions in the ZFHX1B gene, confirming the diagnosis.
Ishihara et al. (2004) identified 5 novel nonsense and frameshift mutations in the ZFHX1B gene in patients with Mowat-Wilson syndrome and characterized the clinical features and molecular basis of a total of 27 cases with mutations or deletions in ZFHX1B. Two novel features, pulmonary artery sling and vaginal septum, were observed in 2 patients, 1 with a frameshift and 1 with a nonsense mutation, respectively. Repeated vomiting attacks were seen in 5 patients; the authors suggested that the attacks were possibly related to epilepsy, as they were controlled by anticonvulsants in 1 patient. Two of their patients with large deletions (10.42 Mb and 8.83 Mb) had significantly delayed psychomotor development, and 1 of them also had a cleft palate and complicated heart disease, features not previously reported in patients with Mowat-Wilson syndrome.
McGaughran et al. (2005) described a sister and brother with phenotypic Mowat-Wilson syndrome in whom they identified a 1-bp deletion in the ZFHX1B gene (605802.0013). The mutation was not found in the unaffected parents' lymphocyte-derived DNA, suggesting germline mosaicism in the sibs. McGaughran et al. (2005) stated that this was the first report of a sib recurrence of Mowat-Wilson syndrome.
Zweier et al. (2006) reported a 5-year-old boy with facial features of Mowat-Wilson syndrome but who exhibited an unusually mild phenotype and in whom they identified heterozygosity for a splice site mutation in the ZFHX1B gene (605802.0014). The patient had medially flared broad eyebrows, hypertelorism, pointed nose and chin, and prominent, mildly uplifted earlobes, but the overall facial gestalt was less striking than that of most MOWS patients. His psychomotor development was much better than expected for classic MOWS; by age 4 he spoke in full sentences and had sphincter control. Except for increased disposition to seizures on EEG and body measurements at the 3rd centile, he had no other anomalies frequently observed in MOWS such as agenesis or hypoplasia of the corpus callosum, congenital heart defects, urogenital anomalies, Hirschsprung disease, or constipation.
Heinritz et al. (2006) described a 2.5-year-old boy with a de novo heterozygous missense mutation in the ZFHX1B gene (605802.0015) who had the overall facial phenotype of Mowat-Wilson syndrome, but with cleft lip and palate and lacking the characteristic eyebrows. The patient also had brachytelephalangy, which the authors stated had never been described before in Mowat-Wilson syndrome.
Dastot-Le Moal et al. (2007) stated that more than 110 different mutations in the ZEB2 gene had been described. Nonsense mutations accounted for approximately 41% of the known punctual mutations and have been localized mainly in exon 8. No obvious genotype-phenotype correlations have been observed.
De Pontual et al. (2006) genotyped the RET (164761) locus in 30 patients with Mowat-Wilson syndrome who were known to have mutations in the ZFHX1B gene; no significant differences in SNP distribution of the nonsyndromic HSCR-predisposing RET haplotype (ATA) were observed between MOWS patients with and without HSCR. De Pontual et al. (2006) concluded that there are both RET-dependent and RET-independent HSCR cases and suggested that at least 1 more modifier gene must be involved.
Genotype/Phenotype Correlations
The majority of ZEB2 mutations identified in patients with Mowat-Wilson syndrome lead to haploinsufficiency through premature termination or large gene deletions. In 3 unrelated patients with a mild form of MOWS, Ghoumid et al. (2013) identified 3 different heterozygous missense mutations in the ZEB2 gene (see, e.g., S1071P, 605802.0016 and H1045R, 605802.0017). All 3 mutations occurred in the conserved C-terminal zinc finger cluster domain. In vitro functional expression studies showed that these 3 mutant proteins lost the ability to bind to the E-cadherin (CDH1; 192090) promoter and to repress transcription of this target gene, consistent with a loss of function and without a dominant-negative effect. However, these mutant mRNAs showed significant phenotypic rescue of morpholino knockout zebrafish embryos: complete rescue with S1071P (84%) and partial rescue with H1045R (55%), indicating that they are hypomorphic alleles; wildtype mRNA showed 81% rescue. The patients had mild facial gestalt of MOWS and moderate intellectual disability, but no microcephaly, heart defects, or HSCR. The variable embryonic rescue correlated with the severity of the patients' phenotype.
INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature HEAD & NECK Head \- Microcephaly \- Pointed chin Ears \- Cupped ears \- Fleshy upturned lobules Eyes \- Hypertelorism \- Iris coloboma \- Ptosis \- Deep-set eyes \- Downslanting palpebral fissures \- Convergent strabismus \- Broad eyebrows \- Medially flared eyebrows \- Broad eyebrows \- Medially flared eyebrows \- Ptosis \- Downslanting palpebral fissures \- Deep-set eyes \- Hypertelorism \- Convergent strabismus \- Microphthalmia \- Microcornea \- Irregular border of pupil \- Corectopia \- Cataract \- Iris coloboma \- Chorioretinal coloboma \- Atrophy or absence of optic nerve Nose \- Wide nasal bridge \- Prominent nasal tip \- Columella extends below the ala nasi Mouth \- Submucous cleft palate \- Drooling Teeth \- Widely spaced teeth \- Malpositioned teeth \- Delayed tooth eruption CARDIOVASCULAR Heart \- Ventricular septal defect \- Atrial septal defect \- Pulmonic valve stenosis Vascular \- Patent ductus arteriosus \- Pulmonary artery stenosis \- Pulmonary artery sling CHEST External Features \- Pectus excavatum \- Pectus carinatum Breasts \- Accessory nipple ABDOMEN External Features \- Abdominal distention Gastrointestinal \- Constipation \- Megacolon \- Vomiting \- Barium enema shows transition zone between aganglionic contracted segment and dilated proximal bowel GENITOURINARY External Genitalia (Male) \- Hypospadias \- Bifid scrotum Internal Genitalia (Male) \- Cryptorchidism SKIN, NAILS, & HAIR Hair \- Broad eyebrows \- Medially flared eyebrows NEUROLOGIC Central Nervous System \- Mental retardation, moderate to severe \- Delayed motor development \- Seizures \- Severely impaired or absent speech \- Learning problems \- Hypotonia \- Hypoplasia of the corpus callosum \- Agenesis of the corpus callosum \- Corpus callosum anomalies \- Hippocampal abnormalities \- Enlarged cerebral ventricles \- White matter abnormalities (in some patients) \- Large basal ganglia (in some patients) \- Cortical malformations (in some patients) \- Cerebellar malformations (in some patients) Behavioral Psychiatric Manifestations \- Happy demeanor \- Repetitive behaviors \- Oral behaviors LABORATORY ABNORMALITIES \- Absent enteric ganglia beginning at rectum and extending proximally by varying degrees MISCELLANEOUS \- Prevalence of 1 in 50,000-70,000 live births \- Milder phenotype associated with aberrant function of a single domain of the ZEB2 protein rather than complete haploinsufficiency of ZEB2 MOLECULAR BASIS \- Caused by mutation in the zinc finger E box-binding homeobox 2 gene (ZEB2, 605802.0001 ) ▲ Close
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| MOWAT-WILSON SYNDROME | c1856113 | 6,803 | omim | https://www.omim.org/entry/235730 | 2019-09-22T16:27:09 | {"doid": ["0060485"], "mesh": ["C536990"], "omim": ["235730"], "orphanet": ["2152", "261537", "261552"], "synonyms": ["Alternative titles", "MICROCEPHALY, MENTAL RETARDATION, AND DISTINCT FACIAL FEATURES, WITH OR WITHOUT HIRSCHSPRUNG DISEASE", "HIRSCHSPRUNG DISEASE-MENTAL RETARDATION SYNDROME"], "genereviews": ["NBK1412"]} |
A number sign (#) is used with this entry because vascular-type Ehlers-Danlos syndrome (EDSVASC) is caused by heterozygous mutation in the COL3A1 gene (120180) on chromosome 2q32.
Biallelic mutation in the COL3A1 gene causes polymicrogyria with or without vascular EDS (PMGVEDS; 618343).
Description
The vascular type of Ehlers-Danlos syndrome is characterized by the major complications of arterial and bowel rupture, uterine rupture during pregnancy, and the clinical features of easy bruising, thin skin with visible veins, and characteristic facial features (summary by Leistritz et al., 2011). Joint hypermobility is largely limited to the digits, and skin hyperextensibility is minimal or absent (McKusick, 1972).
Clinical Features
Superti-Furga et al. (1988) provided the first description of a mutation in the COL3A1 gene in type IV EDS. The proband was 22 years old; his father was affected with the same disorder and had died at age 34 years. He had been hospitalized for bleeding in the anterior abdominal wall and retroperitoneally following minor trauma. He went into cardiac arrest; open-chest cardiac massage resulted in avulsion of the heart from the superior vena cava with massive intrathoracic bleeding and death.
Type III procollagen is stored in dermal fibroblasts which show markedly dilated endoplasmic reticulum. Byers et al. (1979) emphasized the heterogeneity of EDS IV. Of 2 patients only 1 showed dilated endoplasmic reticulum. Probably a defect in type III collagen is a common feature. One of their patients showed keloid formation, a seemingly paradoxical feature that McKusick (1979) also observed in this disorder. One patient had had spontaneous pneumothorax as well as spontaneous rupture of the bowel.
Pope et al. (1980) reported an apparent dominant form of EDS IV (in father and daughter). The acrogeric appearance of the skin of the hands was particularly striking in the 37-year-old father. A third patient (their patient 1) had severe acrogeric EDS IV. At age 7 she had been presented at the Section of Dermatology of the Royal Society of Medicine (Morris, 1957). At age 25 she suffered spontaneous rupture of the splenic artery and 3 years later had rupture of a left renal artery aneurysm. At age 29 she showed the typical facies and hand changes of acrogeria. The skin over the nose and ears was tight like that in scleroderma. Acroosteolysis was present. Chemical studies showed striking deficiency of type III collagen in all 3 cases. See 120180.0015.
In an 18-year-old girl whom they considered to have EDS I, De Paepe et al. (1987) found large, irregular collagen fibers by light microscopy of skin biopsies, with the same finding in the affected father. Electron microscopy showed variation in the diameter and shape of collagen fibrils as well as slight dilatation of the rough endoplasmic reticulum of fibroblasts in father and daughter. In both instances, the findings in the unaffected mother were normal. Synthesis of type III collagen was reduced to 50% of normal in the father and daughter. The patient had perhaps a greater tendency to bruising than do many EDS I patients. The abnormality in type III collagen suggested the diagnosis of EDS IV.
Fox et al. (1988) described a man who developed a spontaneous pulsating tinnitus in his left ear at the age of 20.5 years; he discovered accidentally that this noise could be stopped by firm pressure over the left side of the neck. Left-sided periorbital swelling, reddening of the conjunctiva, and ocular pain developed 6 months later, with left-sided pulsatile proptosis and a loud vascular bruit over the left orbit. Signs of EDS IV included thin nose and lips, hyperextensible joints, lax or thin skin with prominent venous markings, and small linear telangiectases on the trunk. There was a history of rectal bleeding attributed to multiple colonic diverticula. The patient was found to have a deficiency of type III collagen. The carotid-cavernous fistula was closed by means of a balloon catheter. Fox et al. (1988) referred to 5 previously reported cases of the Ehlers-Danlos syndrome presenting as spontaneous carotid-cavernous fistula.
In a group of 14 families, Rudd et al. (1983) identified 20 women with EDS IV. The diagnosis was confirmed in at least 1 member of each family by demonstration of reduced production of type III collagen by dermal fibroblasts in vitro. Of the 20 women, 10 had been pregnant and 5 had died of pregnancy-related complications. The overall risk of death in each pregnancy was 25% in this series. Pregnancy-related complications included rupture of bowel, aorta, vena cava or uterus, vaginal laceration, and postpartum uterine hemorrhage. Nine of the families had 29 affected persons in an autosomal dominant pedigree pattern; the remaining 5 families had a single case. Pope and Nicholls (1983) took a less pessimistic view of pregnancy in EDS IV.
Byard et al. (1990) ascribed the 'sudden infant death syndrome' in a previously healthy 5-month-old female infant to type IV Ehlers-Danlos syndrome leading to spontaneous subarachnoid hemorrhage. The skin and aorta at postmortem showed a deficiency of type III collagen. There was no parental consanguinity and no family history of EDS, and both parents were aged 25. There were no gross features of EDS IV and the diagnosis was based exclusively on the finding that type III collagen in aorta and skin was reduced. Sherry et al. (1992) described a 16-year-old boy with EDS IV who developed a hepatoportal fistula 9 days after sigmoid colectomy and colostomy were performed for spontaneous rupture of the colon. The fistula was successfully occluded angiographically with a transcatheter coil
In 2 patients with inherited EDS IV, Superti-Furga et al. (1992) demonstrated evidence of microangiopathy of skin capillaries with microbleedings, microaneurysms, and increased transcapillary diffusion.
In a series of 10 patients, Lewkonia and Pope (1985) found several with peripheral joint contractures and 3 who had acroosteolysis involving both fingers and toes. The simulation of chronic inflammatory joint disease was pointed out. Newton and Carpenter (1959) also reported acroosteolysis in EDS but it is not clear that the mother and daughter that they reported had type IV. They pointed out that the dislocation of the thumbs and other fingers may contribute to the simulation of rheumatoid arthritis.
Yost et al. (1995) described a 27-year-old man with EDS type IV who had recurrent and eventually fatal pulmonary hemorrhages. This had apparently not been previously described. North et al. (1995) reviewed the cerebral vascular complications in 202 individuals with molecularly confirmed type IV Ehlers Danlos syndrome. Of these, 19 individuals had cerebral vascular complications which included intracranial aneurysms, spontaneous carotid cavernous sinus fistulas, and dissection of cervical arteries. The mean age at presentation of the cerebral vascular complication was 28.3 years ranging from 17 to 48.
Phan et al. (1998) described a 39-year-old man with known EDS IV who presented with massive spontaneous hemothorax due to ruptured internal mammary artery aneurysm. He had first presented in his twenties with right renal infarction; 3 years later he underwent partial left nephrectomy for left renal infarction, and an aneurysm of the left renal artery was excised and the artery replaced. In addition to joint hypermobility, he had elastosis perforans serpiginosa. Emergency anterolateral thoracotomy for ligation of an abnormally fragile left internal mammary artery proximal to the aneurysm and drainage of an extensive hemothorax was accomplished successfully and postoperative recovery was uneventful.
Commenting on the report of Pepin et al. (2000), Barabas (2000) stated that in his experience, teenage boys are at high risk for arterial rupture, which is often fatal. He suggested that this may be because during the prepubertal growth spurt the defective collagen is further weakened. He stated further that patients who undergo surgery are prone to arterial rupture in the postoperative period. Pepin et al. (2000) had commented that preexisting aneurysms are only occasionally documented in patients who have arterial ruptures. Barabas (2000) suggested that this is because the patients with EDS type IV do not have true aneurysms. Aneurysms, if present, follow arterial tears and are walled-in hematomas or pseudoaneurysms. Barabas (2000) also drew attention to the danger of varicose vein surgery in unrecognized cases of EDS type IV, since the extreme fragility of all blood vessels can lead to loss of a limb or even loss of life.
Kroes et al. (2003) described a mother and son with EDS type IV and unusual congenital anomalies. The mother had amniotic band-like constrictions on one hand, a unilateral clubfoot, and macrocephaly owing to normal-pressure hydrocephalus; the son had esophageal atresia and hydrocephalus. The family was also anomalous in that protein analysis of collagen III in cultured fibroblasts of the mother showed no abnormalities; however, DNA analysis of the COL3A1 gene revealed a pathogenic mutation (120180.0031) in both the mother and the son. The relationship between the COL3A1 mutation and the congenital anomalies was not clear. The experience emphasized the importance of performing both collagen protein analysis and DNA analysis of COL3A1.
In 16 patients with EDS type IV and 16 age-, gender-, and blood pressure-matched controls, Boutouyrie et al. (2004) measured circumferential wall stress in an elastic (common carotid) and a muscular (radial) artery. In the carotid artery, steady circumferential wall stress was 43% higher in EDS patients than in controls, pulsatile circumferential wall stress was 22% higher, and carotid intima-media thickness was 32% lower (p less than 0.001 for all findings). Carotid internal diameter and radial artery parameters were not significantly different between the 2 groups. Boutouyrie et al. (2004) concluded that the abnormally low intima-media thickness of elastic arteries in EDS IV patients generates higher wall stress, which may increase the risk of arterial dissection and rupture.
Germain and Herrera-Guzman (2004) provided an extensive review of EDS IV.
Murray et al. (2014) reported pregnancy-related complications and deaths in women with vascular Ehlers-Danlos syndrome. Pregnancy-related deaths occurred in 30 (5.3%) of 565 deliveries. There was no difference in Kaplan-Meier survival curves between parous and nulliparous women with vascular EDS. Interviews with 39 women indicated that 46% of deliveries were uncomplicated. The most common complications were third- or fourth-degree lacerations in 20% and preterm delivery in 19%. Life-threatening complications occurred in 14.5% of deliveries and included arterial dissection/rupture (9.2%), uterine rupture (2.6%), and surgical complications (2.6%). There were 5 maternal deaths (6.5%) in 76 deliveries.
Pepin et al. (2014) reviewed clinical records from 1,231 individuals with vascular EDS and found median survival of 51 years; this was influenced by gender (lower in men) and by the type of mutation. Aortic aneurysm, dissection, or rupture was the leading single vascular complication (22%) recorded, leading to death in 68% of patients. Coronary artery aneurysm, dissection, or rupture was described in 25 individuals (9 males and 16 females); the mean age of the event was 30.8 years (25.0 for males and 33.5 for females). Twenty-seven carotid cavernous sinus fistulae were described (22 in females, 5 in males), with mean age of event at 30.9 years. Lethal cerebral vascular accidents without detailed description were reported in 15 of the 38 individuals who suffered 'intracranial' events. There were 181 bowel perforations described in this cohort: 117 (65%) colon or bowel perforations; 52 (29%) sigmoid colon; 8 (4%) small bowel; and 4 (2%) esophagus or stomach. Four birth defects occurred with a significantly greater frequency than the currently estimated prevalence in the United States (p less than 0.01, Z-test). Clubfoot or unilateral or bilateral defect was recorded in 8% of study subjects. Congenital hip dislocation, limb deficiency, and amniotic band were recorded in roughly 1% of patients, which was well above the estimated US prevalence. Pepin et al. (2014) identified 295 individuals less than 18 years of age with vascular EDS; 174 (60%) were tested in the presence of a positive family history. Of those 174, 13% had experienced a major complication, and the mean age of testing was 8 years. Among individuals less than 18 years of age with a negative family history, the proportion ascertained on the basis of a major complication was greater (52%), and the age of testing was older (mean of 11.5 years). In the absence of a positive family history or a major complication, the features most commonly identified as the reason for testing were easy bruising, thin skin, and joint hypermobility, in combination with clubfoot.
Biochemical Features
In studies of cell strains from 8 cases of EDS IV, Superti-Furga et al. (1989) found evidence in 7 of structural defects in half of the type III procollagen chains synthesized, such as deletions or amino acid substitutions, which cause delayed formation and destabilization of the collagen triple helix and, as a consequence, reduced secretion of the molecule. In 3 of the families the inheritance was demonstrably autosomal dominant. One patient who had been thought to have a recessively inherited form of EDS IV (Pope et al., 1977) was found to have normal mRNA levels in the cells and secretion of a small amount of normal type III collagen, compatible with heterozygosity for a mutation in the COL3A1 gene. Because type III procollagen is a homotrimer, a structural defect in one-half of newly synthesized pro-alpha-1(III) chains will result in assembly of one-eighth normal and seven-eighths abnormal procollagen molecules. The mutant procollagen molecules described by Superti-Furga and Steinmann (1988) and Superti-Furga et al. (1986, 1988) had decreased thermal stability, were less efficiently secreted, and were not normally processed.
Steinmann et al. (1989) found that serum levels of procollagen type III aminopropeptide, a peptide released during conversion of type III procollagen to collagen, were abnormally low in 6 of 10 patients with EDS IV and low-normal in 4 other such patients. The serum levels correlated with the amount of type III procollagen secreted by the patients' cultured fibroblasts. Byers et al. (1981) reviewed the state of knowledge about collagen defects in the several forms of the Ehlers-Danlos syndrome.
Other Features
Byers et al. (1979) demonstrated a predominance of collagen fibers of small diameter in EDS IV with or without intracellular accumulation. Dilation of the endoplasmic reticulum is a normal finding in plasma cells, where immunoglobin is the storage material. It is an abnormal finding in hepatocytes in alpha-1-antitrypsin deficiency (613490), and in chondrocytes in pseudoachondroplasia (177170) (Maynard et al., 1972) and metaphyseal dysostosis, presumably of the Murk Jansen type (156400) (Cooper et al., 1973).
Temperature effects on the rate of synthesis and/or the stability of the collagen would account well for the acrogeric appearance of the hands and face with pinched nose and atrophic skin over the ears that is displayed by some patients (see fig. 6-10, p. 311, in McKusick, 1972).
Superti-Furga and Steinmann (1989) expanded the possibility that this disorder is a temperature-dependent condition and that the atrophic changes of the skin on the hands, ears, and nose can be so explained. The suggestion was based on their demonstration that the structurally abnormal type III procollagen, which is retained within fibroblasts at 37 degrees C, can be secreted sufficiently when the temperature is lowered to 32 degrees C or below. They suggested that the presence of defective molecules in the extracellular space leads to disorganization of collagen fibrils and therefore to more pronounced skin changes in the areas of lower skin temperature.
Voermans et al. (2009) performed a cross-sectional study on the presence of neuromuscular symptoms among 40 patients with various forms of EDS. Ten patients each were analyzed with classic type I EDS (130000), vascular EDS, hypermobility EDS (130020), and TNX-deficient EDS (606408). Overall, those with classic EDS and TNX-deficient EDS reported the most neuromuscular involvement, with muscle weakness, hypotonia, myalgia, easy fatigability, and intermittent paresthesias, although patients in all groups reported these features. Physical examination showed mild to moderate muscle weakness (85%) and reduction of vibration sense (60%) across all groups. Nerve conduction studies demonstrated axonal polyneuropathy in 5 (13%) of 39 patients. Needle electromyography showed myopathic EMG features in 9 (26%) and a mixed neurogenic-myopathic pattern in 21 (60%) of 35 patients. Muscle ultrasound showed increased echo intensity in 19 (48%) and atrophy in 20 (50%) of 40 patients. Mild myopathic features were seen on muscle biopsy of 5 (28%) of 18 patients. Patients with the hypermobility type EDS caused by TNXB haploinsufficiency were least affected. Voermans et al. (2009) postulated that abnormalities in muscle or nerve extracellular matrix may underlie these findings.
Prontera et al. (2010) reported a 42-year old Italian man with a complex EDS phenotype caused by a 13.7-Mb de novo heterozygous deletion of chromosome 2q23.3-q31.2 resulting in deletion of the COL3A1, COL5A2 (120190), and myostatin (MSTN; 601788) genes. Loss of function mutations in COL3A1 and COL5A2 cause EDS types IV and I, respectively. Haploinsufficiency for MSTN results in overgrowth of skeletal muscle. Due to the monosomy for MSTN, the patient had 'an exceptional constitutional muscular mass,' without muscle weakness, myalgia, or easy fatigability. He also had no generalized joint hypomobility or recurrent joint dislocation; symptoms of EDS were limited to recurrent inguinal hernias and mild mitral valve prolapse. Prontera et al. (2010) hypothesized that haploinsufficiency for the MSTN allele exerted a protective effect again EDS clinical manifestations in this patient. The findings also indicated that there is direct involvement of muscle damage in EDS and that care of muscle function in these patients may be beneficial.
Inheritance
Barabas (1972) reported a family in which the mother and a 16-year-old brother died of aortic rupture and the proband had frequent hematomata and at least one intraperitoneal bleed. The transmission pattern was consistent with autosomal dominant inheritance. Barabas (1975), whose name along with Sack's is applied eponymically to this condition, later reported 3 sporadic and 2 familial cases. In 1 family the mother was affected and died of a tear in her abdominal aorta following her fourth pregnancy. The eldest boy died at the age of 16 of similar complications. A daughter 'has survived several major arterial catastrophes.' The inheritance appeared to be dominant in the other family also.
Byers (1980) identified 4 autosomal dominant families. In 1 kindred a father and his son and daughter were affected; the father and daughter died of catastrophes. Several members of the next generation are also affected. Two autosomal dominant forms may exist: one with and one without dilated endoplasmic reticulum. These may be allelic disorders, however; in AAT deficiency, similar forms with and without accumulation are observed.
Superti-Furga et al. (1989) supported the view that the great majority of cases of EDS IV have autosomal dominant inheritance.
Mapping
Although the lod score (1.8 at 0.0 recombination) did not achieve the level of 3.0, Schwartz et al. (1985) could conclude from linkage studies with a COL3A1 probe that the collagen III gene is probably mutant in a 3-generation family with EDS IV. Tsipouras et al. (1986) reported further on the study presented in abstract by Schwartz et al. (1985). Findings in 2 kindreds indicated linkage. The lod score was 2.10 at theta = 0.00 in their family A and 0.30 at theta = 0.00 in their family B. Biochemically, the defect was somewhat different in the 2 families. Linkage analysis in a large Belgian family segregating autosomal dominant Ehlers-Danlos syndrome type IV was consistent with linkage of the EDS IV phenotype to the COL3A1 locus. However, no abnormality was detected in the type III collagen produced by the patients, and immunofluorescent and tissue analysis demonstrated significant amounts of type III collagen in the tissues.
De Paepe et al. (1988) described a kindred with EDS IV in 11 members of 3 generations with numerous examples of male-to-male transmission. Deficiency in the synthesis of type III collagen was identified in cultured skin fibroblasts. By use of a RFLP associated with the COL3A1 gene, tight linkage was found between the gene and the disease; no definite recombinant was identified.
Molecular Genetics
Superti-Furga and Steinmann (1988) and Superti-Furga et al. (1986, 1988) showed that a patient with severe, dominantly inherited EDS IV had a deletion of 3.3 kb in the triple-helical coding domain of 1 of the 2 genes for the pro-alpha-chains of type III collagen. His cultured skin fibroblasts contained equal amounts of normal length mRNA and of mRNA shortened by approximately 600 bases, and synthesized both normal and shortened procollagen chains. In procollagen molecules containing 1 or more shortened chains, a triple helix was formed with a length of only about 780 amino acids. The mutant procollagen molecules had decreased thermal stability, were less efficiently secreted, and were not normally processed. This was the first description of the molecular lesion in the COL3A1 gene in a case of EDS type IV.
In affected members of the family reported by Fox et al. (1988), Richards et al. (1992) described a gly847-to-glu mutation of the COL3A1 gene (120180.0014). This family included an unaffected member who was mosaic for the mutation. Kontusaari et al. (1992) described mosaicism for a mutation in the COL3A1 gene in the asymptomatic mother of a patient with EDS type IV (120180.0015). Milewicz et al. (1993) found heterozygosity for a 2-kb deletion in the COL3A1 gene in a severely affected teenaged girl whose asymptomatic father was mosaic for the same deletion. Milewicz et al. (1993) gave a useful summary of the numerous autosomal dominant or X-linked recessive disorders in which this phenomenon has been observed.
Gilchrist et al. (1999) identified a gly571-to-ser substitution in the triple helical domain of the products of one COL3A1 allele (120180.0026) in a large family with a milder phenotype than that typically associated with EDS IV. Clinical presentation in some of the affected members occurred at a later age than usual. Longevity was longer than that seen in many families, and there was less pregnancy-associated morbidity or mortality than that found in some families. The authors suggested that some clinical aspects of EDS IV may be related to the nature of the mutation and its effect on the behavior of the protein.
Palmeri et al. (2003) characterized 7 members of a family with EDS IV. The index patient, a young woman with an acrogeric face, suffered chronic muscle pain and cramps, Achilles tendon retraction, finger flexion contractures, and seizures. The mother had similar features and had experienced an ischemic stroke at the age of 43 years. A gly883-to-val mutation in the COL3A1 gene (120180.0033) was identified in both. Angiography of the cerebral vessels in the mother revealed coiling on both internal carotids in the extracranial tract, which mimicked fibromuscular dysplasia as reported by Schievink and Limburg (1989). The phenotypically normal maternal grandmother was found to be mosaic for this mutation. The maternal grandfather and a maternal aunt each had an abdominal aortic aneurysm, the rupture of which was the cause of death in the latter at 40 years of age; the aneurysm in the grandfather was presumably an incidental finding, with a cause different from the vascular disease that the other members of the family inherited from the mosaic maternal grandmother.
### Ehlers-Danlos Syndrome Type IV Variant
Kontusaari et al. (1990) studied a 37-year-old female captain in the U. S. Air Force who had a family history of sudden death due to rupture of thoracic or abdominal aortic aneurysms. She had mild hyperextensibility of joints and apparent arachnodactyly, with a hand-to-height ratio of 10.9% (upper limit of normal). She had a tendency to bruise easily, and the surgeon who had previously removed her appendix noted that her tissues seemed friable and bled easily, with the loss of 1 liter of blood during that operation. She had no history of joint dislocations, her skin had normal texture without unusual extensibility, and she did not have subluxation of the lens on slit-lamp examination. Analysis of the COL3A1 gene revealed heterozygosity for a missense mutation (G619R; 120180.0002) that was also found in pathology specimens from her mother and a maternal aunt, who died at age 34 years and 55 years, respectively, of aortic aneurysms.
In a 34-year-old man with a history of thin skin and easy bruisability, who died of massive intrathoracic and intraabdominal hemorrhage, Kontusaari et al. (1990) identified heterozygosity for a splice site mutation in the COL3A1 gene (120180.0004). At autopsy, no distinct aneurysm or bleeding point was identified, but microscopic sections of aorta revealed an apparent decrease in and disorganization of elastic fibers, and all the abdominal soft tissues appeared to be unusually friable. The proband's father and 1 brother had died of rupture of abdominal and thoracic aneurysms, respectively.
Genotype/Phenotype Correlations
Schwarze et al. (2001) studied 4 patients with EDS IV who presented with vascular aneurysm or rupture and were found to be haploinsufficient for a COL3A1 allele. They noted that in contrast to the severe phenotype in these patients, mice that are haploinsufficient for COL3A1 have no identified phenotype and individuals with null mutations in the dominant protein of a tissue, i.e., COL1A1 and COL2A1, have milder phenotypes than those caused by mutations that alter protein sequence. Schwarze et al. (2001) suggested that the major effect of many of these dominant mutations in the 'minor' collagen genes may be expressed through protein deficiency rather than through incorporation of structurally altered molecules into fibrils.
Leistritz et al. (2011) reviewed the clinical and family histories of medical complications in 54 individuals from 19 families with COL3A1-null mutations. Compared with individuals with missense or exon-skipping mutations, they found that life span was extended, the age of first complication was delayed by almost 15 years, and major complications were limited to vascular events. Families were ascertained after a complication in a single individual, but only 28% of relatives, some of whom had reached their seventies or eighties without incident, had a complication and only 30% had minor clinical features of vascular Ehlers-Danlos syndrome type IV. Leistritz et al. (2011) concluded that null mutations of COL3A1 have reduced penetrance compared with missense and splicing mutations, and the phenotype seems to be limited almost entirely to vascular events.
Pepin et al. (2014) reviewed clinical records for details of vascular, bowel, and organ complications in 1,231 individuals (630 index cases and 601 relatives) with vascular EDS. Missense and splice site mutations accounted for more than 90% of the 572 alterations that the authors identified in COL3A1. Median survival was 51 years but was influenced by gender (lower in men) and by the type of mutation. Although vascular EDS appears to be genetically homogeneous, allelic heterogeneity is marked, and the natural history varies with gender and type of mutation in COL3A1. Pepin et al. (2014) concluded that these findings indicate that when counseling families, confirmation of the presence of a COL3A1 mutation and its nature can help evaluate the risks of complications. These data are also important factors in both the selection and allocation of individuals to appropriate arms in clinical trials to assess the effects of interventions. Among the 410 unique mutation sites identified by Pepin et al. (2014), 69 had more than 1 family with the same mutation. Among these, 4 sites (c.1662+1G-A, IVS24+1G-A (32), c.547G-A, p.Gly183Ser, p.Gly16Ser in the triple helical domain (18), c.755G-T, p.Gly252Val, c.1347+1G-A, IVS20+1G-A (9), and Gly85Val in the triple helical domain (8)) accounted for 30% of recurrent mutations. There were 17 additional sites with more than 2 unrelated families with the same mutation. By mutation type, Pepin et al. (2014) found that survival was highest among patients with null mutations; second, by more severe and splice acceptor site mutations; third, by glycine substitution mutations; and fourth, by splice donor site mutations. The hazard ratio for a glycine change to any other amino acid was higher than that for null mutations.
Diagnosis
Steinmann et al. (1989) suggested that determination of serum levels of procollagen type III aminopropeptide is a simple test for diagnosis and might be especially helpful in making the diagnosis in children.
Johnson et al. (1995) were successful in demonstrating mutations in all 13 patients with typical or acrogeric EDS IV using denaturing gradient gel electrophoresis (DGGE) in the study of PCR-amplified cDNA from the C-terminal domain of type III collagen.
Autio et al. (1997) pictured the characteristic facial appearance, as well as the thin transparent skin over the anterior aspect of the chest and upper arms, of an EDS IV patient. They suggested B-mode ultrasonic techniques, in place of skin biopsy, as a useful noninvasive method for demonstrating thin skin. In addition, they concluded that the measurement of procollagen propeptides in body fluids is a valuable noninvasive method helpful in the diagnosis and classification of EDS. They confirmed the diagnosis of EDS IV in a patient by measuring type III amino-terminal procollagen propeptide levels in the skin interstitial fluid, i.e., suction blister fluid (SBF), and serum and the type I amino-terminal procollagen propeptide level in SBF. The serum concentration of the type III propeptide has been shown to be abnormally low or in the low normal range in EDS IV patients and well-correlated with the ability of the patient's cultured fibroblasts to secrete type III procollagen. In the patient reported, the serum concentration of the type III propeptide was low; however, the elimination of the type III propeptide molecule from the serum is a constant process and may be altered by factors such as abnormal liver function. Thus, the concentration of the type III propeptide in the SBF more accurately reflects an individual's synthesis of type III collagen. This value was abnormally low in the reported patient. In turn, the concentration of the type I propeptide in the SBF was normal.
Pepin et al. (2000) reviewed the clinical and family histories and the medical and surgical complications of 220 index patients with biochemically confirmed Ehlers-Danlos syndrome type IV and 199 of their affected relatives. They identified the underlying COL3A1 mutation in 135 index patients. Complications were rare in childhood; 25% of the index patients had a first complication by the age of 20 years, and more than 80% had at least 1 complication by the age of 40. The calculated median survival of the entire cohort was 48 years. Most deaths resulted from arterial rupture. Bowel rupture, which often involved the sigmoid colon, accounted for about one-quarter of complications but rarely led to death. Complications of pregnancy led to death in 12 of the 81 women who became pregnant. The types of complications were not associated with specific mutations in COL3A1. The authors urged that the diagnosis of EDS IV be considered in young people who come to medical attention because of uterine rupture during pregnancy or arterial or visceral rupture.
INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature HEAD & NECK Face \- Thin lips Ears \- Lobeless ears Eyes \- Keratoconus Nose \- Pinched, thin nose Mouth \- Periodontal disease \- Early loss of teeth \- Thin lips CARDIOVASCULAR Heart \- Mitral valve prolapse Vascular \- Intracranial aneurysm RESPIRATORY Lung \- Spontaneous pneumothorax \- Hemoptysis ABDOMEN External Features \- Inguinal hernia Gastrointestinal \- Spontaneous rupture of bowel GENITOURINARY Internal Genitalia (Female) \- Uterine rupture associated with pregnancy \- Uterine prolapse \- Cervical insufficiency Bladder \- Bladder prolapse SKELETAL Hands \- Hypermobility of distal interphalangeal joints \- Acroosteolysis Feet \- Clubfoot \- Acroosteolysis SKIN, NAILS, & HAIR Skin \- Fragile skin \- Easy bruisability \- Cigarette-paper scars \- Atrophic skin over ears \- Prominent venous markings \- Absent-mild skin hyperextensibility \- Skin changes worse in areas of lower skin temperature \- Molluscoid pseudotumors \- Acrogeria (skin over hands and feet are thin and finely wrinkled) Hair \- Alopecia of scalp PRENATAL MANIFESTATIONS Delivery \- Premature delivery because of cervical insufficiency or membrane fragility LABORATORY ABNORMALITIES \- Type III collagen defect MISCELLANEOUS \- Death usually occurs before 5th decade \- Autosomal recessive inheritance has been reported in 1 family (as of April 2011) MOLECULAR BASIS \- Caused by mutation in the collagen III, alpha-1 polypeptide gene (COL3A1, 120180.0001 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| EHLERS-DANLOS SYNDROME, VASCULAR TYPE | c0268338 | 6,804 | omim | https://www.omim.org/entry/130050 | 2019-09-22T16:41:48 | {"doid": ["14756"], "mesh": ["D004535"], "omim": ["130050"], "orphanet": ["286"], "synonyms": ["Alternative titles", "EHLERS-DANLOS SYNDROME, TYPE IV, AUTOSOMAL DOMINANT", "EDS IV", "EHLERS-DANLOS SYNDROME, ARTERIAL TYPE", "EHLERS-DANLOS SYNDROME, ECCHYMOTIC TYPE", "EHLERS-DANLOS SYNDROME, SACK-BARABAS TYPE"], "genereviews": ["NBK1494"]} |
Isolated congenital digital clubbing is a rare genodermatosis disorder characterized by enlargement of the terminal segments of fingers and toes with thickened nails without any other abnormality.
## Epidemiology
Prevalence is unknown.
## Clinical description
Isolated congenital digital clubbing is often painless and usually symmetrical and bilateral. Sometimes, some fingers or toes are spared, but the thumbs are almost always involved.
## Etiology
It results from proliferation of the connective tissues between the nail matrix and the distal phalanx and abnormal function of the nail matrix. The condition can be caused by autosomal recessive mutation of the HPGD gene (4q34-q35), but autosomal dominant forms without a known genetic cause have also been reported.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Isolated congenital digital clubbing | c0345408 | 6,805 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=217059 | 2021-01-23T17:27:29 | {"mesh": ["D010004"], "omim": ["119900"], "umls": ["C0345408"], "icd-10": ["Q68.1"], "synonyms": ["Isolated congenital acropachy", "Isolated congenital nail clubbing"]} |
Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome is a rare disorder that primarily affects the development of the brain. Affected individuals are born with an unusually large brain and head size (megalencephaly). The head and brain continue to grow rapidly during the first 2 years of life. MPPH syndrome is also associated with a brain abnormality called bilateral perisylvian polymicrogyria (BPP). The surface of the brain normally has many ridges or folds, called gyri. In people with BPP, an area of the brain called the perisylvian region develops too many gyri, and the folds are irregular and unusually small. Other brain abnormalities, including a buildup of fluid in the brain (hydrocephalus), have also been reported in people with MPPH syndrome.
The problems with brain development cause a variety of neurological signs and symptoms. People with MPPH syndrome have delayed development and intellectual disability that ranges from mild to severe. About half of affected individuals develop recurrent seizures (epilepsy) beginning early in childhood. People with MPPH syndrome also have difficulty coordinating movements of the mouth and tongue (known as oromotor dysfunction), which leads to drooling, difficulty swallowing (dysphagia), and a delay in the production of speech (expressive language).
About half of people with MPPH syndrome have an extra finger or toe on one or more of their hands or feet (polydactyly). The polydactyly is described as postaxial because it occurs on the same side of the hand or foot as the pinky finger or little toe.
The brain abnormalities characteristic of MPPH syndrome are also found in a closely related condition called megalencephaly-capillary malformation syndrome (MCAP). However, MCAP includes abnormalities of small blood vessels in the skin (capillary malformations) and several other features that are not usually part of MPPH syndrome.
## Frequency
MPPH syndrome appears to be a rare disease. About 60 affected individuals have been described in the medical literature.
## Causes
MPPH syndrome can be caused by mutations in the AKT3, CCND2, or PIK3R2 gene. The proteins produced from all three genes are involved in a chemical signaling pathway called the PI3K-AKT-mTOR pathway. This signaling influences many critical cell functions, including the creation (synthesis) of new proteins, cell growth and division (proliferation), and the survival of cells. The PI3K-AKT-mTOR pathway is essential for the normal development of many parts of the body, including the brain.
Mutations in the AKT3, CCND2, or PIK3R2 gene increase the activity of their respective proteins or prevent the proteins from being broken down when they should. As a result, chemical signaling through the PI3K-AKT-mTOR pathway is enhanced, which increases cell growth and division. In the brain, the increased number of cells leads to rapid and abnormal brain growth starting before birth. The rapid growth disrupts the structure and function of the developing brain. It is less clear how increased PI3K-AKT-mTOR signaling contributes to polydactyly, although the extra digits are probably related to abnormal cell proliferation in the developing hands and feet. CCND2 and PIK3R2 gene mutations are more likely to cause polydactyly than are AKT3 gene mutations.
### Learn more about the genes associated with Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome
* AKT3
* CCND2
* PIK3R2
## Inheritance Pattern
This condition is considered autosomal dominant, which means one copy of the altered gene in each cell is sufficient to cause the disorder.
Almost all cases of this condition result from new (de novo) gene mutations that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. These cases occur in people with no history of the disorder in their family.
In a small number of cases, people with MPPH syndrome have inherited the altered gene from an unaffected parent who has a mutation only in their sperm or egg cells. This phenomenon is called germline mosaicism.
Rarely, the condition can also result from somatic mosaicism, in which some of an affected person's cells have a gene mutation and others do not. The genetic changes, which are called somatic mutations, arise randomly in one cell during embryonic development. As cells continue to divide, only cells arising from the first abnormal cell will have the mutation.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome | c1863924 | 6,806 | medlineplus | https://medlineplus.gov/genetics/condition/megalencephaly-polymicrogyria-polydactyly-hydrocephalus-syndrome/ | 2021-01-27T08:24:46 | {"gard": ["10341"], "mesh": ["C566381"], "omim": ["603387", "615937", "615938"], "synonyms": []} |
Giggle incontinence, giggle enuresis or enuresis risoria is the involuntary release of urine in response to giggling or laughter. The bladder may empty completely or only partially.[1]
Giggle incontinence is more common in children than adults, typically appearing at ages 5 to 7,[2] and is most common in girls near the onset of puberty.[3] The condition tends to improve with age, with fewer episodes during the teenage years,[2] but may persist into adulthood.[3] A survey of 99 student nurses indicated that about 25% had experienced such a wetting event during their lifetime, and about 10% were still susceptible in their late teens.[1]
Giggle incontinence is a special form of urge incontinence,[4] and is not the same as stress incontinence, which is generally brought on by participating in vigorous sport.[3]
## Contents
* 1 Cause
* 2 Social consequences
* 3 Treatment
* 4 See also
* 5 References
## Cause[edit]
Involuntary urination, the bladder's normally relaxed detrusor muscle contracts to squeeze urine from the bladder. One study, of 109 children diagnosed with giggle incontinence at Schneider Children's Hospital in New York, concluded that the cause of giggle incontinence is involuntary contraction of the detrusor muscle induced by laughter.[5] Because the complaint is difficult to reproduce under controlled conditions, its triggering mechanism is not clearly understood,[6] but may be related to cataplexy, a sudden transient episode of loss of muscle tone often triggered by strong emotions.[7]
## Social consequences[edit]
Episodes of giggle incontinence are embarrassing and socially incapacitating, diminishing the quality of life. Those having the condition learn to adapt by avoiding activities that may bring on laughter.[3] Other approaches include limiting fluid intake, trying to remain seated, and concealing leakage by wearing absorbent pads and dark clothing.[8]
## Treatment[edit]
Favorable response to treatment with the ADHD drug methylphenidate (Ritalin) has been reported,[3][7][9] but this treatment option is not acceptable to all patient families.[9] Dr. Lane Robson, of The Children's Clinic in Calgary, Alberta, says "If a child is having a wetting episode once a month, medicating them daily is probably not a good treatment. If it's a daily issue, you may have to make that decision."[8]
## See also[edit]
* Urinary incontinence
## References[edit]
1. ^ a b Glahn, B. E. (1979). "Giggle Incontinence (Enuresis Risoria). A Study and an Aetiological Hypothesis". British Journal of Urology. 51 (5): 363–366. doi:10.1111/j.1464-410X.1979.tb02887.x. PMID 533593.
2. ^ a b Cooper, Christopher S (2010). "Voiding Dysfunction Clinical Presentation". Medscape. Retrieved June 3, 2011.
3. ^ a b c d e Carlin & Leong (2002). Female Pelvic Health and Reconstructive Surgery. Informa Healthcare. ISBN 978-0-8247-0822-1. Retrieved May 30, 2011.
4. ^ Liedl et al & Viktrup; et al. (2005, 2004). "Urinary Incontinence: Causes and Diagnostic Work-Up". Urology-Textbook.com. Retrieved June 3, 2011. Check date values in: `|date=` (help)
5. ^ Chandra, M; Saharia, R; Shi, Q; Hill, V (2002). "Giggle incontinence in children: a manifestation of detrusor instability". The Journal of Urology. 168 (5): 2184–7, discussion 2187. doi:10.1016/s0022-5347(05)64350-9. PMID 12394756.
6. ^ Abrams, Paul (2006). "Giggle Incontinence". Urodynamics. Birkhäuser. p. 129. ISBN 978-1-85233-924-1.
7. ^ a b Kher, Schnaper & Makker (2006). Clinical pediatric nephrology. Informa Healthcare. p. 520. ISBN 978-1-84184-447-3. Retrieved May 30, 2011.
8. ^ a b "Developing - School - Giggle Incontinence". ParentsCanada.com. Archived from the original on October 5, 2011. Retrieved May 30, 2011.
9. ^ a b Berry, Amanda K.; Zderic, Stephen; Carr, Michael (2009). "Methylphenidate for Giggle Incontinence". The Journal of Urology. 182 (4): 2028–32. doi:10.1016/j.juro.2009.04.085. PMID 19695642.
* v
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* See Template:Glomerular disease
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* urgency
* frequency
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Eponymous
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* Brewer infarcts
* Lloyd's sign
* Mathe's sign
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Giggle incontinence | None | 6,807 | wikipedia | https://en.wikipedia.org/wiki/Giggle_incontinence | 2021-01-18T18:51:57 | {"wikidata": ["Q5560285"]} |
Diabetic retinopathy
Other namesdiabetic eye disease, DED
Image of fundus showing scatter laser surgery for diabetic retinopathy
Pronunciation
* ˌrɛtɪnˈɑpəθi[1]
SpecialtyOphthalmology
SymptomsMay have no symptoms; blurry vision, vision loss, blindness
CausesLong-term poor control of diabetes mellitus
Diabetic retinopathy, also known as diabetic eye disease (DED),[2] is a medical condition in which damage occurs to the retina due to diabetes mellitus. It is a leading cause of blindness in developed countries.[3]
Diabetic retinopathy affects up to 80 percent of those who have had diabetes for 20 years or more.[4] At least 90% of new cases could be reduced with proper treatment and monitoring of the eyes.[5] The longer a person has diabetes, the higher his or her chances of developing diabetic retinopathy.[6] Each year in the United States, diabetic retinopathy accounts for 12% of all new cases of blindness. It is also the leading cause of blindness in people aged 20 to 64.[7]
## Contents
* 1 Signs and symptoms
* 2 Risk factors
* 3 Pathogenesis
* 3.1 Proliferative diabetic retinopathy
* 4 Diagnosis
* 4.1 Screening
* 5 Management
* 5.1 Laser photocoagulation
* 5.1.1 Modified grid
* 5.1.2 Panretinal
* 5.2 Medications
* 5.2.1 Intravitreal triamcinolone acetonide
* 5.2.2 Intravitreal anti-VEGF
* 5.2.3 Topical medications
* 5.3 Surgery
* 6 Research
* 6.1 Light treatment
* 6.2 C-peptide
* 6.3 Stem cell therapy
* 6.4 Blood pressure control
* 6.5 Fundoscopic image analyses
* 7 See also
* 8 References
* 9 Further reading
* 10 External links
## Signs and symptoms[edit]
Normal vision
The same view with diabetic retinopathy.
Emptied retinal venules due to arterial branch occlusion in diabetic retinopathy (fluorescein angiography)
Diabetic retinopathy often has no early warning signs. Even macular edema, which can cause rapid vision loss, may not have any warning signs for some time. In general, however, a person with macular edema is likely to have blurred vision, making it hard to do things like read or drive. In some cases, the vision will get better or worse during the day.
The first stage, called non-proliferative diabetic retinopathy (NPDR), has no symptoms. Patients may not notice the signs and have 20/20 vision. The only way to detect NPDR is by fundus examination by direct or indirect ophthalmoscope by a trained ophthalmologist, fundus photography can be used for objective documentation of the fundus findings, in which microaneurysms (microscopic blood-filled bulges in the artery walls) can be seen. If there is reduced vision, fluorescein angiography can show narrowing or blocked retinal blood vessels clearly (lack of blood flow or retinal ischemia).
Macular edema, in which blood vessels leak their contents into the macular region, can occur at any stage of NPDR. Its symptoms are blurred vision and darkened or distorted images that are not the same in both eyes. Ten percent (10%) of diabetic patients will have vision loss related to macular edema. Optical Coherence Tomography can show areas of retinal thickening due to fluid accumulation from macular edema.[8]
In the second stage, abnormal new blood vessels (neovascularisation) form at the back of the eye as part of proliferative diabetic retinopathy (PDR); these can burst and bleed (vitreous hemorrhage) and blur the vision, because these new blood vessels are fragile. The first time this bleeding occurs, it may not be very severe. In most cases, it will leave just a few specks of blood, or spots floating in a person's visual field, though the spots often go away after a few hours.
These spots are often followed within a few days or weeks by a much greater leakage of blood, which blurs the vision. In extreme cases, a person may only be able to tell light from dark in that eye. It may take the blood anywhere from a few days to months or even years to clear from the inside of the eye, and in some cases the blood will not clear. These types of large hemorrhages tend to happen more than once, often during sleep.
On funduscopic exam, a doctor will see cotton wool spots, flame hemorrhages (similar lesions are also caused by the alpha-toxin of Clostridium novyi), and dot-blot hemorrhages.
## Risk factors[edit]
All people with diabetes are at risk – those with Type I diabetes and those with Type II diabetes. The longer a person has had diabetes, the higher their risk of developing some ocular problem. Between 40 and 45 percent of Americans diagnosed with diabetes have some stage of diabetic retinopathy.[9] After 20 years of diabetes, nearly all patients with Type I diabetes and >60% of patients with Type II diabetes have some degree of retinopathy; however, these statistics were published in 2002 using data from four years earlier, limiting the usefulness of the research. The subjects would have been diagnosed with diabetes in the late 1970s, before modern fast-acting insulin and home glucose testing.
Prior studies had also assumed a clear glycemic threshold between people at high and low risk of diabetic retinopathy.[10][11]
Published rates vary between trials, the proposed explanation being differences in study methods and reporting of prevalence rather than incidence values.[12]
During pregnancy, diabetic retinopathy may also be a problem for women with diabetes. NIH recommends[13] that all pregnant women with diabetes have dilated eye examinations each trimester.
People with Down syndrome, who have extra chromosome 21 material, almost never acquire diabetic retinopathy. This protection appears to be due to the elevated levels of endostatin,[14] an anti-angiogenic protein, derived from collagen XVIII. The collagen XVIII gene is located on chromosome 21.
## Pathogenesis[edit]
Illustration depicting diabetic retinopathy
Diabetic retinopathy is the result of damage to the small blood vessels and neurons of the retina. The earliest changes leading to diabetic retinopathy include narrowing of the retinal arteries associated with reduced retinal blood flow; dysfunction of the neurons of the inner retina, followed in later stages by changes in the function of the outer retina, associated with subtle changes in visual function; dysfunction of the blood-retinal barrier, which protects the retina from many substances in the blood (including toxins and immune cells), leading to the leaking of blood constituents into the retinal neuropile.[15] Later, the basement membrane of the retinal blood vessels thickens, capillaries degenerate and lose cells, particularly pericytes and vascular smooth muscle cells. This leads to loss of blood flow and progressive ischemia, and microscopic aneurysms which appear as balloon-like structures jutting out from the capillary walls, which recruit inflammatory cells; and advanced dysfunction and degeneration of the neurons and glial cells of the retina.[15][16] The condition typically develops about 10–15 years after receiving the diagnosis of diabetes mellitus.
An experimental study suggests that pericyte death is caused by blood glucose persistently activating protein kinase C and mitogen-activated protein kinase (MAPK), which, through a series of intermediates, inhibits signaling through platelet-derived growth factor receptors — signaling that supports cellular survival, proliferation, and growth. The resulting withdrawal of this signaling leads to the programmed cell death (apoptosis) of the cells in this experimental model.[17]
In addition, excessive sorbitol in diabetics is deposited on retina tissue and it is also proposed to play a role in diabetic retinopathy.[18]
Small blood vessels – such as those in the eye – are especially vulnerable to poor blood sugar (blood glucose) control. An overaccumulation of glucose damages the tiny blood vessels in the retina. During the initial stage, called nonproliferative diabetic retinopathy (NPDR), most people do not notice any change in their vision. Early changes that are reversible and do not threaten central vision are sometimes termed simplex retinopathy or background retinopathy.[19]
Some people develop a condition called macular edema. It occurs when the damaged blood vessels leak fluid and lipids onto the macula, the part of the retina that lets us see detail. The fluid makes the macula swell, which blurs vision.
### Proliferative diabetic retinopathy[edit]
As the disease progresses, severe nonproliferative diabetic retinopathy enters an advanced or proliferative (PDR) stage, where blood vessels proliferate/grow. The lack of oxygen in the retina causes fragile, new, blood vessels to grow along the retina and in the clear, gel-like vitreous humour that fills the inside of the eye. Without timely treatment, these new blood vessels can bleed, cloud vision, and destroy the retina. Fibrovascular proliferation can also cause tractional retinal detachment. The new blood vessels can also grow into the angle of the anterior chamber of the eye and cause neovascular glaucoma.
Nonproliferative diabetic retinopathy shows up as cotton wool spots, or microvascular abnormalities or as superficial retinal hemorrhages. Even so, the advanced proliferative diabetic retinopathy (PDR) can remain asymptomatic for a very long time, and so should be monitored closely with regular checkups.
## Diagnosis[edit]
Diabetic retinopathy is detected during an eye examination that includes:
* Visual acuity test: Uses an eye chart to measure how well a person sees at various distances (i.e., visual acuity).
* Pupil dilation: The eye care professional places drops into the eye to dilate the pupil. This allows him or her to see more of the retina and look for signs of diabetic retinopathy. After the examination, close-up vision may remain blurred for several hours.
* Ophthalmoscopy or fundus photography: Ophthalmoscopy is an examination of the retina in which the eye care professional: (1) looks through a slit lamp biomicroscope with a special magnifying lens that provides a narrow view of the retina, or (2) wearing a headset (indirect ophthalmoscope) with a bright light, looks through a special magnifying glass and gains a wide view of the retina. Hand-held ophthalmoscopy is insufficient to rule out significant and treatable diabetic retinopathy. Fundus photography generally captures considerably larger areas of the fundus, and has the advantage of photo documentation for future reference, as well as availing the image to be examined by a specialist at another location and/or time.
* Fundus Fluorescein angiography (FFA): This is an imaging technique which relies on the circulation of fluorescein dye to show staining, leakage, or non-perfusion of the retinal and choroidal vasculature.
* Retinal vessel analysis detects abnormalities of the autoregulation of small retinal arteries and veins in diabetic patients even before the manifestation of diabetic retinopathy.[20] Such an impairment of retinal responsiveness is seen as one of the earliest markers of vascular dysfunction in diabetes possibly indicating subsequent risk of stroke.[21]
* Optical coherence tomography (OCT): This is an optical imaging modality based upon interference, and analogous to ultrasound. It produces cross-sectional images of the retina (B-scans) which can be used to measure the thickness of the retina and to resolve its major layers, allowing the observation of swelling.
The eye care professional will look at the retina for early signs of the disease, such as:
1. leaking blood vessels,
2. retinal swelling, such as macular edema,
3. pale, fatty deposits on the retina (exudates) – signs of leaking blood vessels,
4. damaged nerve tissue (neuropathy), and
5. any changes in the blood vessels.
If macular edema is suspected, FFA and sometimes OCT may be performed.
Diabetic retinopathy also affects microcirculation thorough the body. A recent study[22] showed assessment of conjunctival microvascular hemodynamics such as vessel diameter, red blood cell velocity and wall shear stress can be useful for diagnosis and screening of diabetic retinopathy. Furthermore, the pattern of conjunctival microvessels was shown to be useful for rapid monitoring and diagnosis of different stages of diabetic retinopathy.[23]
Google is testing a cloud algorithm that scans photos of the eye for signs of retinopathy. The algorithm still requires FDA approval.[24]
According to a DRSS user manual, poor quality images (which may apply to other methods) may be caused by cataract, poor dilation, ptosis, external ocular condition, or learning difficulties. There may be artefacts caused by dust, dirt, condensation, or smudge.[25]
### Screening[edit]
In the UK, screening for diabetic retinopathy is part of the standard of care for people with diabetes.[26] After one normal screening in people with diabetes, further screening is recommended every two years.[27] In the UK, this is recommended every year.[28] Teleophthalmology has been employed in these programs.[29] In The U.S, a current guideline for diabetic retinopathy is recommendation of annual dilated exams for all patients with diabetes. There are barriers to recommended screening that is contributing to the disparity. Such as the patient factor which includes education about diabetic retinopathy and the availability of the treatment. The health care system also contributes to the disparities in diabetic screening, which includes insurance coverage, long waiting time for the appointment and difficulty scheduling appointments which makes the person less likely to screen. Provider factors also influence the barrier to screening which is a lack of awareness of the screening guidelines, skills or having the right tools to perform eye exams which can affect the diagnosis and treatment. A cross-sectional study showed that when physicians treating black patients had more difficulty providing proper subspecialty care and diagnostic imaging for the patients.[30]
There is evidence to support interventions to improve attendance for diabetic retinopathy screening.[31] These might be specifically targeted at diabetic retinopathy screening, or could be general strategies to improve diabetes care.
## Management[edit]
There are three major treatments for diabetic retinopathy, which are very effective in reducing vision loss from this disease.[32] In fact, even people with advanced retinopathy have a 95 percent chance of keeping their vision when they get treatment before the retina is severely damaged.[33] These three treatments are laser surgery, injection of corticosteroids or anti-VEGF agents into the eye, and vitrectomy.
Although these treatments are very successful (in slowing or stopping further vision loss), they do not cure diabetic retinopathy. Caution should be exercised in treatment with laser surgery since it causes a loss of retinal tissue. It is often more prudent to inject triamcinolone or anti-VEGF drugs. In some patients it results in a marked increase of vision, especially if there is an edema of the macula.[32]
Although commonly used in some parts of the world, it is unclear whether herbal medicine (for example, Ruscus extract and Radix Notoginseng extract) are of benefit to people with diabetic retinopathy.[34]
Avoiding tobacco use and correction of associated hypertension are important therapeutic measures in the management of diabetic retinopathy.[35]
Obstructive sleep apnea (OSA) has been associated with a higher incidence of diabetic eye disease due to blood desaturation caused by intermittent upper airway obstructions. Treatment for OSA can help reduce the risk of diabetic complications.[36]
The best way of preventing the onset and delaying the progression of diabetic retinopathy is to monitor it vigilantly and achieve optimal glycemic control.[37]
Since 2008 there have been other therapies (e.g. kinase inhibitors and anti-VEGF) drugs available.[38]
### Laser photocoagulation[edit]
Laser photocoagulation can be used in two scenarios for the treatment of diabetic retinopathy. It can be used to treat macular edema by creating a Modified Grid at the posterior pole[39] and it can be used for panretinal coagulation for controlling neovascularization. It is widely used for early stages of proliferative retinopathy. There are different types of lasers but there is limited evidence available on their benefits and harms to treat proliferative diabetic retinopathy.[40]
#### Modified grid[edit]
A 'C' shaped area around the macula is treated with low intensity small burns. This helps in clearing the macular edema.
#### Panretinal[edit]
Panretinal photocoagulation, or PRP (also called scatter laser treatment), is used to treat proliferative diabetic retinopathy (PDR). The goal is to create 1,600 – 2,000 burns in the retina with the hope of reducing the retina's oxygen demand, and hence the possibility of ischemia. It is done in multiple sittings.
In treating advanced diabetic retinopathy, the burns are used to destroy the abnormal blood vessels that form in the retina. This has been shown to reduce the risk of severe vision loss for eyes at risk by 50%.[4]
Before using the laser, the ophthalmologist dilates the pupil and applies anaesthetic drops to numb the eye. In some cases, the doctor also may numb the area behind the eye to reduce discomfort. The patient sits facing the laser machine while the doctor holds a special lens on the eye. The physician can use a single spot laser, a pattern scan laser for two dimensional patterns such as squares, rings and arcs, or a navigated laser which works by tracking retinal eye movements in real time.[41][42] During the procedure, the patient will see flashes of light. These flashes often create an uncomfortable stinging sensation for the patient. After the laser treatment, patients should be advised not to drive for a few hours while the pupils are still dilated. Vision will most likely remain blurry for the rest of the day. Though there should not be much pain in the eye itself, an ice-cream headache like pain may last for hours afterwards.
Patients will lose some of their peripheral vision after this surgery although it may be barely noticeable by the patient. The procedure does however save the center of the patient's sight. Laser surgery may also slightly reduce colour and night vision.
A person with proliferative retinopathy will always be at risk for new bleeding, as well as glaucoma, a complication from the new blood vessels. This means that multiple treatments may be required to protect vision.
### Medications[edit]
#### Intravitreal triamcinolone acetonide[edit]
Triamcinolone is a long acting steroid preparation. Treating people with DME with intravitreal injections of triamcinolone may lead to a small degree of improvement in visual acuity when compared to eyes treated with placebo injections.[43] When injected in the vitreous cavity, the steroid decreases the macular edema (thickening of the retina at the macula) caused due to diabetic maculopathy, and that may result in an increase in visual acuity. The effect of triamcinolone is not permnanent and may last up to three months, which necessitates repeated injections for maintaining the beneficial effect.[citation needed] Best results of intravitreal Triamcinolone have been found in eyes that have already undergone cataract surgery.[citation needed] Complications of intravitreal injection of triamcinolone may include cataract, steroid-induced glaucoma, and endophthalmitis.[43]
#### Intravitreal anti-VEGF[edit]
There are good results from multiple doses of intravitreal injections of anti-VEGF drugs such as bevacizumab.[44] A 2017 systematic review update found moderate evidence that aflibercept may have advantages in improving visual outcomes over bevacizumab and ranibizumab, after one year.[45] Present recommended treatment for diabetic macular edema is Modified Grid laser photocoagulation combined with multiple injections of anti-VEGF drugs. There is evidence that sustained delivery systems for anti-VEGF medications can reduce the chances of endophthalmitis development by reducing the number of intravitreal injections necessary for treatment. Hydrogels have shown great promise for this platform.[46]
#### Topical medications[edit]
There is little evidence for the role of topical medications in the treatment of macular edema, for example, topical non‐steroidal anti‐inflammatory agents.[47]
### Surgery[edit]
Instead of laser surgery, some people require a vitrectomy to restore vision. A vitrectomy is performed when there is a lot of blood in the vitreous. It involves removing the cloudy vitreous and replacing it with a saline solution.
Studies show that people who have a vitrectomy soon after a large hemorrhage are more likely to protect their vision than someone who waits to have the operation. Early vitrectomy is especially effective in people with insulin-dependent diabetes, who may be at greater risk of blindness from a hemorrhage into the eye.
Vitrectomy is often done under local anesthesia. The doctor makes a tiny incision in the sclera, or white of the eye. Next, a small instrument is placed into the eye to remove the vitreous and insert the saline solution into the eye.
Patients may be able to return home soon after the vitrectomy, or may be asked to stay in the hospital overnight. After the operation, the eye will be red and sensitive, and patients usually need to wear an eyepatch for a few days or weeks to protect the eye. Medicated eye drops are also prescribed to protect against infection. There is evidence which suggests anti-VEGF drugs given either prior to or during vitrectomy may reduce the risk of posterior vitreous cavity haemorrhage.[48] Vitrectomy is frequently combined with other modalities of treatment.
## Research[edit]
### Light treatment[edit]
A medical device comprising a mask that delivers green light through the eyelids while a person sleeps was under development in 2016.[49][50] The light from the mask stops rod cells in the retina from dark adapting, which is thought to reduce their oxygen requirement, which in turn diminishes new blood vessel formation and thus prevents diabetic retinopathy.[49] As of 2016 a large clinical trial was underway.[49] As of 2018, the results from the clinical trial showed no long-term therapeutic benefit from using the mask in diabetic retinopathy patients.No “long-term therapeutic benefit” from £250 mask
### C-peptide[edit]
C-peptide had shown promising results in treatment of diabetic complications incidental to vascular degeneration.[51] Creative Peptides,[52] Eli Lilly,[53] and Cebix[54] all had drug development programs for a C-peptide product. Cebix had the only ongoing program until it completed a Phase IIb trial in December 2014 that showed no difference between C-peptide and placebo, and it terminated its program and went out of business.[55][56]
### Stem cell therapy[edit]
Clinical trials are under way or are being populated in preparation for study at medical centers in Brazil, Iran and the United States. Current trials involve using the patients' own stem cells derived from bone marrow and injected into the degenerated areas in an effort to regenerate the vascular system.[57]
### Blood pressure control[edit]
A Cochrane review examined 15 randomized controlled trials to determine whether interventions that sought to control or reduce blood pressure in diabetics had any effects of diabetic retinopathy.[58] While the results showed that interventions to control or reduce blood pressure prevented diabetic retinopathy for up to 4–5 years in diabetics, there was no evidence of any effect of these interventions on progression of diabetic retinopathy, preservation of visual acuity, adverse events, quality of life, and costs.[58]
### Fundoscopic image analyses[edit]
Distribution in percentage of pre-processing techniques from 2011–2014 [59]
Diabetic retinopathy is diagnosed entirely by recognizing abnormalities on retinal images taken by fundoscopy. Color fundus photography is mainly used for staging the disease. Fluorescein angiography is used to assess the extent of retinopathy that aids in treatment plan development. Optical coherence tomography (OCT) is used to determine the severity of edema and treatment response.[60]
Because fundoscopic images are the main sources for diagnosis of diabetic retinopathy, manually analyzing those images can be time-consuming and unreliable, as the ability of detecting abnormalities varies by years of experience.[61] Therefore, scientists have explored developing computer-aided diagnosis approaches to automate the process, which involves extracting information about the blood vessels and any abnormal patterns from the rest of the fundoscopic image and analyzing them.[59]
## See also[edit]
* Diabetic diet
* Purtscher's retinopathy, a disease with similar abnormalities in the eye, usually caused by trauma.
* Retinal regeneration[62]
## References[edit]
1. ^ "Retinopathy | Definition of Retinopathy by Oxford Dictionary on Lexico.com also meaning of Retinopathy". Lexico Dictionaries | English.
2. ^ Li, Jeany Q.; Welchowski, Thomas; Schmid, Matthias; Letow, Julia; Wolpers, Caroline; Pascual-Camps, Isabel; Holz, Frank G.; Finger, Robert P. (January 12, 2020). "Prevalence, incidence and future projection of diabetic eye disease in Europe: a systematic review and meta-analysis". European Journal of Epidemiology. 35 (1): 11–23. doi:10.1007/s10654-019-00560-z. PMID 31515657 – via PubMed.
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30. ^ 1\. Nsiah-Kumi, P., Ortmeier, S. R., & Brown, A. E. (2009). Disparities in Diabetic Retinopathy Screening and Disease for Racial and Ethnic Minority Populations—A Literature Review. Journal of the National Medical Association, 101(5), 430–438. doi: 10.1016/s0027-9684(15)30929-9
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This article incorporates text from a publication in the public domain: "Facts About Diabetic Retinopathy". National Eye Institute, National Institutes of Health (NEI/NIH). June 2012. Archived from the original on 12 May 2014. Retrieved 13 June 2002.
## Further reading[edit]
* Solomon SD, Chew E, Duh EJ, Sobrin L, Sun JK, VanderBeek BL, Wykoff CC, Gardner TW (March 2017). "Diabetic Retinopathy: A Position Statement by the American Diabetes Association". Diabetes Care. 40 (3): 412–418. doi:10.2337/dc16-2641. PMC 5402875. PMID 28223445.
## External links[edit]
* Diabetic retinopathy resource guide courtesy of National Eye Institute, National Institutes of Health (NEI/NIH)
* Diabetic Eye Disease National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIDDK/NIH)
* NHS Diabetic Eye Screening Programme
Classification
D
* ICD-10: H36 (E10.3 E11.3 E12.3 E13.3 E14.3)
* ICD-9-CM: 250.5
* MeSH: D003930
* DiseasesDB: 29372
External resources
* MedlinePlus: 000494
* eMedicine: oph/414 oph/415
Wikimedia Commons has media related to Diabetic retinopathy.
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Authority control
* NDL: 00935390
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Diabetic retinopathy | c0011884 | 6,808 | wikipedia | https://en.wikipedia.org/wiki/Diabetic_retinopathy | 2021-01-18T19:00:56 | {"mesh": ["D003930"], "umls": ["C0011884"], "icd-10": ["E10.3", "E11.3", "E14.3", "E12.3", "E13.3", "H36"], "wikidata": ["Q631361"]} |
A rare disorder of calcium homeostasis characterized by variable degrees of hypocalcemia with abnormally low levels of parathyroid hormone (PTH) and persistant normal or elevated calciuria.
## Epidemiology
Prevalence is unknown, but the disease is likely to be underdiagnosed as the hypocalcemia may remain asymptomatic.
## Clinical description
Clinical expression and age of onset are extremely variable (depending on the degree of hypocalcemia), ranging from completely asymptomatic patients (in whom the diagnosis is made by chance during a routine exam) to patients with limited symptoms (cramps, asthenia, paresthesias) and patients with severe symptoms (i.e. recurrent seizures). In addition to hypocalcemia, hypercalciuria or relative hypercalciuria (hypercalciuria within the normal range, but relatively high in the presence of hypocalcemia) is present. Hyperphosphatemia, hypomagnesemia and hypermagnesuria are also common. Nephrocalcinosis and impaired renal function have been reported and cases of AD hypocalcemia with classical features of Bartter syndrome (BS; see this term) have been described (referred to as BS with hypocalcemia; see this term). Serum levels of PTH are normal or low. In addition to regulation by PTH, environmental factors also influence calcium homeostasis and may explain why an initially well-controlled hypocalcemia may become symptomatic at various stages of life.
## Etiology
AD hypocalcemia is caused by activating mutations of the gene CASR (3q21.1), encoding the calcium-sensing receptor (CaSR). CaSR plays a key role in the regulation of calcium-phosphate metabolism by controlling PTH secretion and urinary calcium excretion in response to variations in serum calcium levels. Gain-of-function CASR mutations result in increased sensitivity of parathyroid and renal cells to calcium levels, leading to hypocalcemia being perceived as normal. Activating mutations in GNA11 (19p13.3) have also been described.
## Diagnostic methods
Diagnosis is made through analysis of calcium levels in the serum and urine and PTH levels, Molecular analysis of CaSR followed by GNA11 confirms diagnosis.
## Differential diagnosis
Differential diagnosis includes all other causes of hypoparathyroidism as well as BS in patients with renal salt wasting.
## Antenatal diagnosis
Antenatal diagnosis is possible.
## Genetic counseling
Genetic counseling may be proposed but patients should be informed about the wide variability in clinical presentation.
## Management and treatment
Treatment to normalize calcemia levels should be considered with caution, as any increase in calcium levels (even within the normal range) will be perceived by renal cells as hypercalcemia and lead to increased urinary calcium excretion, and possibly to nephrocalcinosis and renal failure. Treatment should aim towards finding a balance between the clinical signs of hypocalcemia and maintenance of calcium homeostasis, without being iatrogenic. Urine calcium levels should be monitored in order to avoid hypercalciuria rather than adapting treatment towards hypocalcemia. In asymptomatic and mildly symptomatic patients, treatment may not be necessary. Special care must be given to children as chronic hypocalcemia has deleterious effects on intellectual development. Treatment is based on administration of 1-alpha hydroxylated vitamin D (doses ranging from 0.5 to 1.5 micrograms/day in adults; higher doses are sometimes required in children). Careful monitoring of calciuria and regular kidney ultrasound are required. In cases where calcium homeostasis is difficult to achieve, exogenous PTH administered by infusion pump can be proposed.
## Prognosis
The prognosis is variable, depending on the severity of the hypocalcemia and the possible consequences of inadequate treatment.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
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*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Autosomal dominant hypocalcemia | c3715128 | 6,809 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=428 | 2021-01-23T18:21:32 | {"gard": ["2877"], "omim": ["601198", "615361"], "icd-10": ["E20.8"], "synonyms": ["AD hypocalcemia"]} |
Early-onset myopathy with fatal cardiomyopathy (EOMFC) is an inherited muscle disease that affects the skeletal muscles, which are used for movement, and the heart (cardiac) muscle. This condition is characterized by skeletal muscle weakness that becomes apparent in early infancy. Affected individuals have delayed development of motor skills, such as sitting, standing, and walking. Beginning later in childhood, people with EOMFC may also develop joint deformities called contractures that restrict the movement of the neck and back. Scoliosis, which is an abnormal side-to-side curvature of the spine, also develops in late childhood.
A form of heart disease called dilated cardiomyopathy is another feature of EOMFC. Dilated cardiomyopathy enlarges and weakens the cardiac muscle, preventing the heart from pumping blood efficiently. Signs and symptoms of this condition can include an irregular heartbeat (arrhythmia), shortness of breath, extreme tiredness (fatigue), and swelling of the legs and feet. The heart abnormalities associated with EOMFC usually become apparent in childhood, after the skeletal muscle abnormalities. The heart disease worsens quickly, and it often causes heart failure and sudden death in adolescence or early adulthood.
## Frequency
EOMFC appears to be a rare disorder, although its prevalence is unknown. It has been reported in a small number of families of Moroccan and Sudanese descent.
## Causes
EOMFC is caused by mutations in the TTN gene. This gene provides instructions for making a protein called titin, which plays an important role in skeletal and cardiac muscle function.
Within muscle cells, titin is an essential component of structures called sarcomeres. Sarcomeres are the basic units of muscle contraction; they are made of proteins that generate the mechanical force needed for muscles to contract. Titin has several functions within sarcomeres. One of this protein's most important jobs is to provide structure, flexibility, and stability to these cell structures. Titin also plays a role in chemical signaling and in assembling new sarcomeres.
The TTN gene mutations responsible for EOMFC lead to the production of an abnormally short version of titin. The defective protein disrupts the function of sarcomeres, which prevents skeletal and cardiac muscle from contracting normally. These muscle abnormalities underlie the features of EOMFC, including skeletal muscle weakness and dilated cardiomyopathy.
### Learn more about the gene associated with Early-onset myopathy with fatal cardiomyopathy
* TTN
## Inheritance Pattern
This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Early-onset myopathy with fatal cardiomyopathy | c2673677 | 6,810 | medlineplus | https://medlineplus.gov/genetics/condition/early-onset-myopathy-with-fatal-cardiomyopathy/ | 2021-01-27T08:25:53 | {"mesh": ["C567129"], "omim": ["611705"], "synonyms": []} |
"Punch drunk" redirects here. For other uses, see Punch drunk (disambiguation).
Neurodegenerative disease caused by repeated head injuries
Chronic traumatic encephalopathy
Other namesTraumatic encephalopathy syndrome, dementia pugilistica,[1] punch drunk syndrome
A normal brain (left) and one with CTE (right)
SpecialtyNeurology, psychiatry, sports medicine
SymptomsBehavioral problems, mood problems, problems with thinking[1]
ComplicationsBrain damage, dementia,[2] aggression, depression, suicide[3]
Usual onsetYears after initial injuries[2]
CausesRepeated head injuries[1]
Risk factorsContact sports, military, domestic abuse, repeated banging of the head[1]
Diagnostic methodAutopsy[1]
Differential diagnosisAlzheimer's disease, Parkinson's disease[3]
TreatmentSupportive care[3]
FrequencyUncertain[2]
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repeated blows to the head. It can include behavioral problems, mood problems, and problems with thinking.[1][2] The disease often gets worse over time and can result in dementia.[2] It is unclear if the risk of suicide is altered.[1]
Most documented cases have occurred in athletes involved in striking-based combat sports, such as boxing, kickboxing, and Muay Thai, hence its original name dementia pugilistica (Latin for "fistfighter's dementia"), and contact sports such as American football, Australian rules football, professional wrestling, ice hockey, rugby, and association football (soccer),[1][4] but also in semi-contact sports such as baseball. Other risk factors include being in the military, prior domestic violence, and repeated banging of the head.[1] The exact amount of trauma required for the condition to occur is unknown, and as of 2020 definitive diagnosis can only occur at autopsy.[1] The disease is classified as a tauopathy.[1]
There is no specific treatment for the disease.[3] Rates of CTE have been found to be about 30% among those with a history of multiple head injuries;[1] however, population rates are unclear.[2] Research in brain damage as a result of repeated head injuries began in the 1920s, at which time the condition was known as dementia pugilistica or "punch drunk syndrome".[1][3] It has been proposed that the rules of some sports be changed as a means of prevention.[1]
## Contents
* 1 Signs and symptoms
* 2 Cause
* 3 Pathology
* 4 Diagnosis
* 4.1 Imaging
* 5 Prevention
* 6 Management
* 7 Epidemiology
* 8 History
* 9 Research
* 10 See also
* 11 References
## Signs and symptoms[edit]
Symptoms of CTE, which occur in four stages, generally appear eight to ten years after an individual experiences repetitive mild traumatic brain injuries.[5]
First-stage symptoms are confusion, disorientation, dizziness, and headaches. Second-stage symptoms include memory loss, social instability, impulsive behavior, and poor judgment. Third and fourth stages include progressive dementia, movement disorders, hypomimia, speech impediments, sensory processing disorder, tremors, vertigo, deafness, depression and suicidality.[citation needed]
Additional symptoms include dysarthria, dysphagia, cognitive disorders such as amnesia, and ocular abnormalities, such as ptosis.[6] The condition manifests as dementia, or declining mental ability, problems with memory, dizzy spells or lack of balance to the point of not being able to walk under one's own power for a short time and/or Parkinsonism, or tremors and lack of coordination. It can also cause speech problems and an unsteady gait. Patients with CTE may be prone to inappropriate or explosive behavior and may display pathological jealousy or paranoia.[7]
## Cause[edit]
See also: Chronic traumatic encephalopathy in sports
Most documented cases have occurred in athletes with mild repetitive brain trauma (RBT) over an extended period of time. Specifically contact sports such as boxing, American football, Australian Rules Football, wrestling, Mixed martial arts, ice hockey, rugby, and association football.[1][4] In association football (soccer), whether this is just associated with prolific headers or other injuries is unclear as of 2017.[8] Other potential risk factors include military personnel (repeated exposure to concussions charges or large caliber ordnance), domestic violence, and repeated banging of the head.[1] The exact amount of trauma required for the condition to occur is unknown although it is believed that it would take many years to develop it.[1]
## Pathology[edit]
The neuropathological appearance of CTE is distinguished from other tauopathies, such as Alzheimer's disease. The four clinical stages of observable CTE disability have been correlated with tau pathology in brain tissue, ranging in severity from focal perivascular epicenters of neurofibrillary tangles in the frontal neocortex to severe tauopathy affecting widespread brain regions.[9]
The primary physical manifestations of CTE include a reduction in brain weight, associated with atrophy of the frontal and temporal cortices and medial temporal lobe. The lateral ventricles and the third ventricle are often enlarged, with rare instances of dilation of the fourth ventricle.[10] Other physical manifestations of CTE include anterior cavum septi pellucidi and posterior fenestrations, pallor of the substantia nigra and locus ceruleus, and atrophy of the olfactory bulbs, thalamus, mammillary bodies, brainstem and cerebellum.[11] As CTE progresses, there may be marked atrophy of the hippocampus, entorhinal cortex, and amygdala.[5]
On a microscopic scale, the pathology includes neuronal loss, tau deposition, TAR DNA-binding Protein 43 (TDP 43)[9] deposition, white matter changes, and other abnormalities. The tau deposition occurs as dense neurofibrillary tangles (NFT), neurites, and glial tangles, which are made up of astrocytes and other glial cells[10] Beta-amyloid deposition is a relatively uncommon feature of CTE.[citation needed]
A small group of individuals with CTE have chronic traumatic encephalomyopathy (CTEM), which is characterized by symptoms of motor-neuron disease and which mimics amyotrophic lateral sclerosis (ALS). Progressive muscle weakness and balance and gait problems (problems with walking) seem to be early signs of CTEM.[10]
Exosome vesicles created by the brain are potential biomarkers of TBI, including CTE.[12]
Loss of neurons, scarring of brain tissue, collection of proteinaceous senile plaques, hydrocephalus, attenuation of the corpus callosum, diffuse axonal injury, neurofibrillary tangles, and damage to the cerebellum are implicated in the syndrome. The condition may be etiologically related to Alzheimer's disease.[13] Neurofibrillary tangles have been found in the brains of dementia pugilistica patients, but not in the same distribution as is usually found in people with Alzheimer's.[14] One group examined slices of brain from patients having had multiple mild traumatic brain injuries and found changes in the cells' cytoskeletons, which they suggested might be due to damage to cerebral blood vessels.[15]
Increased exposure to concussions and sub-concussive blows is regarded as the most important risk factor, which can depend on the total number of fights, number of knockout losses, the duration of career, fight frequency, age of retirement, and boxing style.[16]
## Diagnosis[edit]
Diagnosis of CTE cannot be made in living individuals. A clear diagnosis is possible during an autopsy.[17] Though there are signs and symptoms some researchers associate with CTE, there is no definitive test to prove the existence in a living person. Signs are also very similar to that of other neurological conditions such as Alzheimer's.
The lack of distinct biomarkers is the reason CTE cannot typically be diagnosed while a person is alive. Concussions are non-structural injuries and do not result in brain bleeding, which is why most concussions cannot be seen on routine neuroimaging tests such as CT or MRI.[18] Acute concussion symptoms (those that occur shortly after an injury) should not be confused with CTE. Differentiating between prolonged post-concussion syndrome (PCS, where symptoms begin shortly after a concussion and last for weeks, months, and sometimes even years) and CTE symptoms can be difficult. Research studies are currently examining whether neuroimaging can detect subtle changes in axonal integrity and structural lesions that can occur in CTE.[5] Recently, more progress in in-vivo diagnostic techniques for CTE has been made, using DTI, fMRI, MRI, and MRS imaging; however, more research needs to be done before any such techniques can be validated.[10]
PET tracers that bind specifically to tau protein are desired to aid diagnosis of CTE in living individuals. One candidate is the tracer [18F]FDDNP, which is retained in the brain in individuals with a number of dementing disorders such as Alzheimer's disease, Down syndrome, progressive supranuclear palsy, corticobasal degeneration, familial frontotemporal dementia, and Creutzfeldt–Jakob disease.[19] In a small study of 5 retired NFL players with cognitive and mood symptoms, the PET scans revealed accumulation of the tracer in their brains.[20] However, [18F]FDDNP binds to beta-amyloid and other proteins as well. Moreover, the sites in the brain where the tracer was retained were not consistent with the known neuropathology of CTE.[21] A more promising candidate is the tracer [18F]-T807, which binds only to tau. It is being tested in several clinical trials.[21]
A putative biomarker for CTE is the presence in serum of autoantibodies against the brain. The autoantibodies were detected in football players who experienced a large number of head hits but no concussions, suggesting that even sub-concussive episodes may be damaging to the brain. The autoantibodies may enter the brain by means of a disrupted blood-brain barrier, and attack neuronal cells which are normally protected from an immune onslaught.[22] Given the large numbers of neurons present in the brain (86 billion), and considering the poor penetration of antibodies across a normal blood-brain barrier, there is an extended period of time between the initial events (head hits) and the development of any signs or symptoms. Nevertheless, autoimmune changes in blood of players may consist the earliest measurable event predicting CTE.[23]
According to 2017 study on brains of deceased gridiron football players, 99% of tested brains of NFL players, 88% of CFL players, 64% of semi-professional players, 91% of college football players, and 21% of high school football players had various stages of CTE. Players still alive are not able to be tested.[24]
### Imaging[edit]
Although the diagnosis of CTE cannot be determined by imaging, the effects of head trauma may be seen with the use of structural imaging.[25] Imaging techniques include the use of magnetic resonance imaging, nuclear magnetic resonance spectroscopy, CT scan, single-photon emission computed tomography, Diffusion MRI, and Positron emission tomography (PET).[25] One specific use of imaging is the use of a PET scan is to evaluate for tau deposition, which has been conducted on retired NFL players.[26]
## Prevention[edit]
Prevention of CTE in sport is not an idealistic goal because repetitive concussions increase the risk for this condition.[27] Prevention techniques are also difficult because diagnosis of the condition can only be during a postmortem autopsy.[25] The initial onset of this condition can not yet be determined, and therefore creating techniques for prevention poses a challenge.[citation needed]
Some common preventative methods have been the use of helmets and mouth-guards; though neither has significant research to support its use[citation needed], both have been shown to reduce direct head trauma.[27] Although there is no significant research to support the use of helmets to reduce the risk of concussions, there is evidence to support that helmet use reduces impact forces. Mouth guards have been shown to decrease dental injuries, but again have not shown significant evidence to reduce concussions.[25] A growing area of practice is improved recognition and treatment for concussions and other head trauma, since repeated impacts are thought to increase the likelihood of CTE development, removal from sport during these traumatic incidences is essential.[25] Proper return-to-play protocol after possible brain injuries is also important in decreasing the significance of future impacts.[25]
Another factor that has been implemented and continues to be an area of debate is changing the rules of many contact sports to make them effectively safer.[25] Examples of these rules are the evolution of tackling technique rules in American football, such as the banning of helmet-first tackles, and the addition of rules to protect defenseless players. Likewise, another growing area of debate is better implementation of rules already in place to protect athletes.[25]
Because of the concern that boxing may cause CTE, there is a movement among medical professionals to ban the sport.[7] Medical professionals have called for such a ban as early as the 1950s.[6]
## Management[edit]
No cure currently exists for CTE, and because it can't be tested for until an autopsy is performed, people can't know if they have it.[28] Treatment is supportive as with other forms of dementia.[29] Those with CTE-related symptoms may receive medication and non-medication related treatments.[30]
## Epidemiology[edit]
Rates of disease have been found to be about 30% among those with a history of multiple head injuries.[1] Population rates, however, are unclear.[2]
Professional level athletes are the largest group with CTE, due to frequent concussions and sub-concussive impacts from play in contact sport.[31] These contact-sports include American football, Australian rules football,[32] ice hockey, Rugby football (Rugby union and Rugby league),[33] boxing, kickboxing, mixed martial arts, association football,[34][33] and wrestling.[35] In association football, only prolific headers are known to have developed CTE.[34]
Cases of CTE were also recorded in baseball.[36]
According to 2017 study on brains of deceased gridiron football players, 99% of tested brains of NFL players, 88% of CFL players, 64% of semi-professional players, 91% of college football players, and 21% of high school football players had various stages of CTE.[37]
Other individuals diagnosed with CTE were those involved in military service, had a previous history of chronic seizures, were domestically abused, or were involved in activities resulting in repetitive head collisions.[38][25][39]
Although a definite cause for Chronic Traumatic Encephalopathy is unknown the research has started to point towards the development of many separate mild traumatic brain injuries. One of the only ways to diagnose an individual with chronic traumatic encephalopathy is to perform an autopsy of the brain following death so the amount of cases among the general population is unknown. According to an article authored by Gardner and Yaffe entitled “Epidemiology of mild traumatic brain injury and neurodegenerative disease”, there has only been one reported case of chronic traumatic encephalopathy in an adolescent athlete when he died suddenly and for no apparent reason so the coroner completed a full autopsy.[40] Chronic traumatic encephalopathy is not only seen in athletes that have suffered many mild traumatic brain injuries. It is also seen in people who served tours in the military or people who have been in multiple car accidents (Gardner & Yaffe, 2015[40]). Some issues that are seen in the ability to conduct an epidemiological study on chronic traumatic encephalopathy is the lack of agreement on the criteria for CTE, differing definitions of the disease, measurements of exposure to mild traumatic brain injuries are hard to achieve, and recall bias (Gardner & Yaffe, 2015).[40] According to the largest modern autopsy series that included a total of 85 patients composed of athletes and military veterans and there was identifiable evidence that 80% had CTE (Gardner & Yaffe, 2015).[40]
As stated above CTE is usually only diagnosed after death. Therefore, “descriptions of the clinical features of CTE are based almost entirely on interviews with family members of deceased individuals who were diagnosed with CTE after death” (CDC, 2019). Many people do notice changes of their loved ones when they are getting close to the end. They notice changes in their thinking, feeling, movement and behavior. The CDC has found links in people who have CTE are usually diagnosed with depression or anxiety first (CDC, 2019). The CDC does state they are not certain which symptoms are directly related to CTE because many of these symptoms can also be found in people with CTE.
Concussion or mild traumatic brain injury (mTBI) is one of the most common neurologic disorders accounting for approximately 90% of all brain injuries sustained (Saulle M, Greenwald BD, 2012).[41] CTE is common among the athletic population because of the high prevalence of concussions; “estimated 1.6–3.8 million sport-related concussion annually in the USA” (Saulle M, Greenwald BD, 2012).[41] This number could be higher because many people do not report their symptoms or may not even know they could have a concussion. This could be due to athletes not wanting to be taken out of the game or pressure by the coach/ family members to continue with playing. Also, athletes who have had concussions before may underreport their symptoms to the athletic trainer because they know it takes about six weeks to return back to play from a concussion. “In a 2009 review of CTE, McKee et al. found that 51 neuropathologically diagnosed cases of CTE 46 (90%) occurred in athletes. Specifically, athletes participating in American football, boxing, soccer, and hockey comprise the majority of cases” (Saulle M, Greenwald BD, 2012).[41] It is unclear the incidence of CTE as well as at what age it can start. Many researchers do think CTE is based on sport, position, length of career, number of head injuries, age of first head injury and genetics.
Family members of people that suffered from CTE may notice a change in their loved ones personality. Behavioral changes, memory deficits, cognitive impairments and executive dysfunction are associated with CTE (Daniel H, Daneshvar, 2015).[42] These effects slowly progress over decades. The long term effects of Traumatic Brain Injuries are becoming more understood due to research. As for CTE, there are large gaps of knowledge when it comes to the incidence and prevalence (Daniel H, Daneshvar, 2015).[42] To close these knowledge gaps more research needs to be done on generic risk factors, prior history of head, age of exposure and much more (Daniel H, Daneshvar, 2015).[42]
## History[edit]
CTE was originally studied in boxers in the 1920s as dementia pugilistica. DP was first described in 1928 by a forensic pathologist, Dr. Harrison Stanford Martland, who was the chief medical examiner of Essex County in Newark, New Jersey in a Journal of the American Medical Association article, in which he noted the tremors, slowed movement, confusion and speech problems typical of the condition.[43] The initial diagnosis of dementia pugilistica was derived from the Latin word for boxer pugil (akin to pugnus ‘fist’, pugnāre ‘to fight’).[44][45]
Other terms for the condition have included chronic boxer's encephalopathy, traumatic boxer's encephalopathy, boxer's dementia, pugilistic dementia, chronic traumatic brain injury associated with boxing (CTBI-B), and punch-drunk syndrome.[3]
The seminal work on the disease came from British neurologist Macdonald Critchley, who in 1949 wrote a paper titled "Punch-drunk syndromes: the chronic traumatic encephalopathy of boxers."[46] CTE was first recognized as affecting individuals who took considerable blows to the head, but was believed to be confined to boxers and not other athletes. As evidence pertaining to the clinical and neuropathological consequences of repeated mild head trauma grew, it became clear that this pattern of neurodegeneration was not restricted to boxers, and the term chronic traumatic encephalopathy became most widely used.[47][48]
In the early 2000s, American football player Mike Webster died following unusual and unexplained behavior. In 2005 Nigerian-American neuropathologist Bennet Omalu along with colleagues in the Department of Pathology at the University of Pittsburgh, published their findings in a paper which he titled "Chronic Traumatic Encephalopathy in a National Football League Player", followed by a paper on a second case in 2006 describing similar pathology.[citation needed]
In 2008, the Sports Legacy Institute joined with the Boston University School of Medicine (BUSM) to form the Center for the Study of Traumatic Encephalopathy (CSTE).[49] Brain Injury Research Institute (BIRI) also studies the impact of concussions.[50][51]
In 2014, Patrick Grange of Albuquerque was the first US soccer player with CTE at autopsy. He was well-known for his heading and had died in 2012.[52]
## Research[edit]
In 2005, forensic pathologist Bennet Omalu, along with colleagues in the Department of Pathology at the University of Pittsburgh, published a paper, "Chronic Traumatic Encephalopathy in a National Football League Player", in the journal Neurosurgery, based on analysis of the brain of deceased former NFL center Mike Webster. This was then followed by a paper on a second case in 2006 describing similar pathology, based on findings in the brain of former NFL player Terry Long.[citation needed]
In 2008, the Center for the Study of Traumatic Encephalopathy (CSTE) at Boston University at the BU School of Medicine started the CSTE brain bank at the Bedford Veterans Administration Hospital to analyze the effects of CTE and other neurodegenerative diseases on the brain and spinal cord of athletes, military veterans, and civilians[9] To date, the CSTE Brain Bank is the largest CTE tissue repository in the world.[10] On 21 December 2009, the National Football League Players Association announced that it would collaborate with the CSTE at the Boston University School of Medicine to support the Center's study of repetitive brain trauma in athletes.[53] Additionally, in 2010 the National Football League gave the CSTE a $1 million gift with no strings attached.[54][55] In 2008, twelve living athletes (active and retired), including hockey players Pat LaFontaine and Noah Welch as well as former NFL star Ted Johnson, committed to donate their brains to CSTE after their deaths.[49][56] In 2009, NFL Pro Bowlers Matt Birk, Lofa Tatupu, and Sean Morey pledged to donate their brains to the CSTE.[57] In 2010, 20 more NFL players and former players pledged to join the CSTE Brain Donation Registry, including Chicago Bears linebacker Hunter Hillenmeyer, Hall of Famer Mike Haynes, Pro Bowlers Zach Thomas, Kyle Turley, and Conrad Dobler, Super Bowl Champion Don Hasselbeck and former pro players Lew Carpenter, and Todd Hendricks. In 2010, professional wrestlers Mick Foley, Booker T and Matt Morgan also agreed to donate their brains upon their deaths. Also in 2010, MLS player Taylor Twellman, who had to retire from the New England Revolution because of post-concussion symptoms, agreed to donate his brain upon his death. As of 2010, the CSTE Brain Donation Registry consists of over 250 current and former athletes.[58] In 2011, former North Queensland Cowboys player Shaun Valentine became the first rugby league player to agree to donate his brain upon his death, in response to recent concerns about the effects of concussions on Rugby League players, who do not use helmets. Also in 2011, boxer Micky Ward, whose career inspired the film The Fighter, agreed to donate his brain upon his death. In 2018, NASCAR legend Dale Earnhardt, Jr., who retired in 2017 citing multiple concussions, became the first auto racing competitor agreeing to donate his brain upon his death.
In related research, the Center for the Study of Retired Athletes, which is part of the Department of Exercise and Sport Science at the University of North Carolina at Chapel Hill, is conducting research funded by National Football League Charities to "study former football players, a population with a high prevalence of exposure to prior Mild Traumatic Brain Injury (MTBI) and sub-concussive impacts, in order to investigate the association between increased football exposure and recurrent MTBI and neurodegenerative disorders such as cognitive impairment and Alzheimer's disease (AD)".[59]
In February 2011, Dave Duerson committed suicide,[60] leaving text messages to loved ones asking that his brain be donated to research for CTE.[61] The family got in touch with representatives of the Boston University center studying the condition, said Robert Stern, the co-director of the research group. Stern said Duerson's gift was the first time of which he was aware that such a request had been made by someone who had committed suicide that was potentially linked to CTE.[62] Stern and his colleagues found high levels of the protein tau in Duerson's brain. These elevated levels, which were abnormally clumped and pooled along the brain sulci,[9] are indicative of CTE.[63]
In July 2010, NHL enforcer Bob Probert died of heart failure. Before his death, he asked his wife to donate his brain to CTE research because it was noticed that Probert experienced a mental decline in his 40s. In March 2011, researchers at Boston University concluded that Probert had CTE upon analysis of the brain tissue he donated. He is the second NHL player from the program at the Center for the Study of Traumatic Encephalopathy to be diagnosed with CTE postmortem.[64]
BUSM has also found indications of links between amyotrophic lateral sclerosis (ALS) and CTE in athletes who have participated in contact sports. Tissue for the study was donated by twelve athletes and their families to the CSTE Brain Bank at the Bedford, Massachusetts VA Medical Center.[65]
In 2013, President Barack Obama announced the creation of the Chronic Effects of Neurotrauma Consortium or CENC, a federally funded research project devised to address the long-term effects of mild traumatic brain injury in military service personnel (SM's) and Veterans.[66][67][68] The CENC is a multi-center collaboration linking premiere basic science, translational, and clinical neuroscience researchers from the DoD, VA, academic universities, and private research institutes to effectively address the scientific, diagnostic, and therapeutic ramifications of mild TBI and its long-term effects.[69][70][71][72][73] Nearly 20% of the more than 2.5 million U.S. Service Members (SMs) deployed since 2003 to Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) have sustained at least one traumatic brain injury (TBI), predominantly mild TBI (mTBI),[74][75] and almost 8% of all OEF/OIF Veterans demonstrate persistent post-TBI symptoms more than six months post-injury.[76][77] Unlike those head injuries incurred in most sporting events, recent military head injuries are most often the result of blast wave exposure.[78][citation needed] After a competitive application process, a consortium led by Virginia Commonwealth University was awarded funding.[69][70][71][72][79][80] The project principal investigator for the CENC is David Cifu, Chairman and Herman J. Flax professor[81] of the Department of Physical Medicine and Rehabilitation (PM&R) at Virginia Commonwealth University (VCU) in Richmond, Virginia, with co-principal investigators Ramon Diaz-Arrastia, Professor of Neurology, Uniformed Services University of the Health Sciences,[72] and Rick L. Williams, statistician at RTI International. In 2017, Aaron Hernandez, a former professional football player and convicted murderer, committed suicide while in prison. His family donated his brain to BU's CTE Center. Ann McKee, the head of Center, concluded that "Hernandez had Stage 3 CTE, which researchers had never seen in a brain younger than 46 years old".[82]
## See also[edit]
* Acquired brain injury
* Brain damage
* Concussions in American football
* Concussions in rugby union
* Health issues in American football
* Traumatic brain injury
## References[edit]
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Classification
D
* ICD-10: G93.8
* MeSH: D000070627
* v
* t
* e
Neurotrauma
Traumatic brain injury
* Intracranial hemorrhage
* Intra-axial
* Intraparenchymal hemorrhage
* Intraventricular hemorrhage
* Extra-axial
* Subdural hematoma
* Epidural hematoma
* Subarachnoid hemorrhage
* Brain herniation
* Cerebral contusion
* Cerebral laceration
* Concussion
* Post-concussion syndrome
* Second-impact syndrome
* Dementia pugilistica
* Chronic traumatic encephalopathy
* Diffuse axonal injury
* Abusive head trauma
* Penetrating head injury
Spinal cord injury
* Anterior spinal artery syndrome
* Brown-Séquard syndrome
* Cauda equina syndrome
* Central cord syndrome
* Paraplegia
* Posterior cord syndrome
* Spinal cord injury without radiographic abnormality
* Tetraplegia (Quadriplegia)
Peripheral nerves
* Nerve injury
* Peripheral nerve injury
* classification
* Wallerian degeneration
* Injury of accessory nerve
* Brachial plexus injury
* Traumatic neuroma
* v
* t
* e
Trauma
Principles
* Polytrauma
* Major trauma
* Traumatology
* Triage
* Resuscitation
* Trauma triad of death
Assessment
Clinical prediction rules
* Revised Trauma Score
* Injury Severity Score
* Abbreviated Injury Scale
* NACA score
Investigations
* Diagnostic peritoneal lavage
* Focused assessment with sonography for trauma
Management
Principles
* Advanced trauma life support
* Trauma surgery
* Trauma center
* Trauma team
* Damage control surgery
* Early appropriate care
Procedures
* Resuscitative thoracotomy
Pathophysiology
Injury
* MSK
* Bone fracture
* Joint dislocation
* Degloving
* Soft tissue injury
* Resp
* Flail chest
* Pneumothorax
* Hemothorax
* Diaphragmatic rupture
* Pulmonary contusion
* Cardio
* Internal bleeding
* Thoracic aorta injury
* Cardiac tamponade
* GI
* Blunt kidney trauma
* Ruptured spleen
* Neuro
* Penetrating head injury
* Traumatic brain injury
* Intracranial hemorrhage
Mechanism
* Blast injury
* Blunt trauma
* Burn
* Penetrating trauma
* Crush injury
* Stab wound
* Ballistic trauma
* Electrocution
Region
* Abdominal trauma
* Chest trauma
* Facial trauma
* Head injury
* Spinal cord injury
Demographic
* Geriatric trauma
* Pediatric trauma
Complications
* Posttraumatic stress disorder
* Wound healing
* Acute lung injury
* Crush syndrome
* Rhabdomyolysis
* Compartment syndrome
* Contracture
* Volkmann's contracture
* Embolism
* air
* fat
* Chronic traumatic encephalopathy
* Subcutaneous emphysema
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Chronic traumatic encephalopathy | c4082769 | 6,811 | wikipedia | https://en.wikipedia.org/wiki/Chronic_traumatic_encephalopathy | 2021-01-18T19:01:29 | {"mesh": ["D000070627"], "icd-10": ["G93.8"], "wikidata": ["Q5114004"]} |
A number sign (#) is used with this entry because hereditary motor and sensory neuropathy type IIC (HMSN2C) is caused by heterozygous mutation in the TRPV4 gene (605427) on chromosome 12q24.
Congenital distal spinal muscular atrophy (600175) and scapuloperoneal spinal muscular atrophy (SPSMA; 181405) are allelic disorders with overlapping phenotypes.
Description
HMSN2C, also known as Charcot-Marie-Tooth disease type 2C (CMT2C), is an autosomal dominant form of peripheral axonal neuropathy with diaphragmatic and vocal cord paresis. Age at onset and severity is variable (Dyck et al., 1994; summary by Klein et al., 2011).
Clinical Features
Dyck et al. (1994) described 2 kindreds with an autosomal dominant inherited disorder characterized by a variable degree of muscle weakness of limbs, vocal cords, and intercostal muscles and by asymptomatic sensory loss, beginning in infancy or childhood in severely affected persons. Life expectancy in the patients was shortened because of respiratory failure. Because nerve conduction velocities were normal and the disorder represented an inherited axonal neuropathy, Dyck et al. (1994) classified the condition as a form of hereditary motor and sensory neuropathy type II (HMSN IIC). Klein et al. (2003) reexamined one of the kindreds with CMT2C reported by Dyck et al. (1994) and identified 5 additional affected members.
Chen et al. (2010) reported follow-up of 1 of the families reported by Dyck et al. (1994). The 47-year-old proband developed acute respiratory stridor at age 6 months, requiring a permanent tracheostomy for partial vocal cord paresis at age 3 years. At age 6 years, she had no movement of the right cord and slight movement of the left cord, with a raspy but understandable voice; she developed a slowly progressive peripheral neuropathy at age 7. As an adult, she had weakness and atrophy of intrinsic hand muscles, weakness of the ankle muscles, areflexia, and distal sensory loss in the hands and feet. Her daughter developed severe stridor associated with vocal cord paresis at age 8 months, followed by mild peripheral neuropathy at age 6, and bilateral foot drop at age 26. Both mother and daughter had proportional short stature and used wheelchairs, but could walk short distances with assistance, The daughter also had a congenital strabismus with partial right third nerve deficit and a history of sleep apnea. The father of the mother had no stridor or wheezing, but onset of a peripheral neuropathy at about age 45.
Donaghy and Kennett (1999) described a white British family with axonal HMSN II in which 1 member developed a recurrent laryngeal nerve palsy at the age of 41 years, having had symptomatic polyneuropathy for 4 years and an abducens nerve palsy. McEntagart et al. (2005) provided more clinical details on the family reported by Donaghy and Kennett (1999). The proband presented at age 43 years with a 4-year history of diminished manual dexterity, difficulty walking, and a 2-year history of dysphonia. He had distal amyotrophy, pes cavus, a left lateral rectus palsy, and a left vocal cord paralysis. His mother and older sister were both asymptomatic but showed distal muscle weakness on examination. Electrophysiologic testing on all 3 family members showed an axonal polyneuropathy.
McEntagart et al. (2005) reported a family with 7 affected members spanning 4 generations; 6 were available for examination. The proband presented at birth with sloping shoulders and developed bilateral foot drop in childhood and hoarse voice in adolescence. At age 55 years, he was wheelchair-bound and needed assistance in all activities of daily living due to impaired manual dexterity and gait. He required respiratory assistance for hypercapnic respiratory failure and obstructive sleep apnea. He had severe distal amyotrophy and wasting of the shoulder girdle muscles. Laryngoscopy showed bilateral vocal cord paralysis. Other affected family members were less severely affected. One other member had onset at birth, and the others had onset ranging from 12 to 62 years.
McEntagart et al. (2001) noted that HMSN IIC shows considerable overlap with HMN VII (158580), but is distinguished by the presence of sensory involvement.
Landoure et al. (2010) studied 2 families with HMSN2C, one of which was the family reported by Dyck et al. (1994). There was marked intrafamilial variability of disease onset and severity. One individual had mild late-onset weakness, whereas her daughter had severe quadriparesis and respiratory failure. Axonal neuropathy was more motor than sensory, resulting in progressive weakness of distal limb, diaphragm, and laryngeal muscles. While few affected individuals complained of sensory loss, all had reduced or absent reflexes. Other prominent features included bilateral sensorineural hearing loss, bladder urgency and incontinence, and worsening of hand muscle weakness with cold. Muscle and nerve biopsies in a severely affected individual showed marked neurogenic atrophy of the gastrocnemius muscle, indicating severe loss of muscle innervations, and modest loss of sensory axons.
Chen et al. (2010) reported a 3-generation family in which 6 individuals had autosomal dominant HMSN2C confirmed by genetic analysis (S542Y; 605427.0022). There was phenotypic variability regarding severity of distal muscle weakness and distal sensory loss, but all had peripheral neuropathy, areflexia, and proportional short stature. All except 1 had vocal cord paresis, resulting in difficulty breathing and hoarse voice. Motor nerve conduction velocities were not abnormal, indicating an axonal neuropathy. Radiographic analysis of 1 patient showed reduced height of the vertebral bodies, and another had dolichocephaly. Chen et al. (2010) noted that TRPV4 mutations have also been found in patients with skeletal involvement (see, e.g., brachyolmia type 3; 113500), and suggested that the short stature observed in this family expanded and unified the phenotypic features associated with mutations in this gene.
Aharoni et al. (2011) reported a 3-generation family of Ashkenazi/Sephardic Jewish origin with variable expression of HMSN2C due to a heterozygous TRPV4 mutation (R315W; 605427.0008). Five mutation carriers in 1 family were studied. The proband was a girl who presented at birth with inspiratory stridor, clubfeet, congenital hip dislocation, and knee contractures. She had absent reflexes and bilateral vocal cord paresis requiring tracheostomy. In childhood, she showed delayed motor development, progressive distal amyotrophy and weakness, weakness of the shoulder girdle, scoliosis, and pectus excavatum. Neurophysiologic studies showed an axonal sensorimotor neuropathy. Two of her affected brothers also presented with stridor in infancy and showed a similar phenotype, but without electrophysiologic examination. The mother showed a milder phenotype; she reported being unathletic as a child and having a hoarse voice. In her thirties, she developed slowly progressive fatigue associated with mild distal muscle atrophy in the lower limbs. She had poor reflexes and minimal distal temperature sensitivity. Electrophysiologic studies showed a sensorimotor neuropathy. One mutation carrier in this family was clinically unaffected at age 14 years, although deep tendon reflexes were difficult to elicit.
Landoure et al. (2012) reported a family in which 3 individuals had HMSN2C. This family had previously been reported as family 3 in Landoure et al. (2010). The patients had progressive distal limb muscle weakness and atrophy, hoarse voice, and stridor on exertion. Nerve conduction studies confirmed an axonal neuropathy with phrenic nerve involvement. Two patients had scoliosis and 1 had sensorineural hearing loss, but none had skeletal dysplasia.
Mapping
In 1 large pedigree with HMSN IIC, Dyck et al. (1994) found no linkage to DNA markers located near the CMT1A (HMSN IA) (118220) locus on 17p (PMP22; 601097) or the CMT1B (HMSN IB) (118200) locus on chromosome 1q (MPZ; 159440).
Using a genomewide scan and multipoint linkage analysis in the large kindred with HMSN IIC reported by Dyck et al. (1994), Klein et al. (2003) found linkage to a region at 12q23-q24 between D12S1645 and D12S1583 (maximum lod = 5.17). Haplotype analysis narrowed the region to approximately 5.0 cM. The authors noted that ataxin-2 (ATX2; 601517), the gene responsible for spinocerebellar ataxia type-2 (SCA2; 183090) localizes to this region, but no triplet repeat expansions or point mutations within the repeat expansion were identified. The same chromosomal region is associated with scapuloperoneal spinal muscular atrophy (SPSMA; 181405) and congenital distal spinal muscular atrophy (600175).
McEntagart et al. (2005) confirmed linkage of CMT2C to 12q23-q24 by combined analysis of 2 unrelated affected families, one of whom was originally reported by Donaghy and Kennett (1999) (multipoint lod score of 2.1 at marker D12S1583). The data refined the disease interval to a 3.9-Mb region between D12S105 and D12S1340. The dHMN2 locus (158590) on chromosome 12q24 was clearly excluded in 1 family, and mutation in the ATX2 gene was excluded in both families.
Heterogeneity
Landoure et al. (2010) excluded linkage to chromosome 12q24.11 in a family (family 4) with CMT2C, suggesting genetic heterogeneity.
Molecular Genetics
In affected members of the family reported by McEntagart et al. (2005), Auer-Grumbach et al. (2010) identified a heterozygous mutation in the TRPV4 gene (R315W; 605427.0008). Auer-Grumbach et al. (2010) identified the R315W mutation in 4 members of another family with HMSN2C. In that family, the R315W mutation was also identified in another patient with congenital distal spinal muscular atrophy (600175) and in 2 patients with scapuloperoneal spinal muscular atrophy (SPSMA; 181405). A second mutation in the TRPV4 gene (R316C; 605427.0010) was found by Auer-Grumbach et al. (2010) in 3 members of a third family with HMNS2C, and in 1 member of a fourth family with HMSN2C. Again, 2 members of the fourth family with the R316C mutation had a phenotype consistent with SPSMA. The findings indicated that these 3 are allelic disorders with overlapping phenotypes.
In affected members of the family reported by Dyck et al. (1994), Deng et al. (2010) and Landoure et al. (2010) independently identified a heterozygous mutation in the TRPV4 gene (R269H; 605427.0009). Functional studies suggested that the mutation resulted in a gain of function. Landoure et al. (2010) noted that Trpv4-knockout mice (Gevaert et al., 2007) show sensorineural hearing loss and impairment of bladder voiding, suggesting that some clinical manifestations of HMSN2C may be due to loss of TRPV4 function as well as toxic gain of function.
Chen et al. (2010) identified a heterozygous mutation in the TRPV4 gene (R315W; 605427.0008) in a mother and daughter with HMSN2C reported by Dyck et al. (1994).
In affected members of the family reported by Donaghy and Kennett (1999) and in an unrelated patient with HMSN2C, Klein et al. (2011) identified different heterozygous mutations in the TRPV4 gene (R232C, 605427.0025 and R316H, 605247.0026, respectively). Both mutations occurred in conserved residues in the ankyrin-repeat domain. In vitro functional expression studies showed that both mutant proteins had the same subcellular localization as wildtype in HEK293 cells and localized to the plasma membrane similar to wildtype in HeLa cells. In HEK293 cells, the mutant proteins caused increased agonist-induced channel activity and increased basal intracellular calcium concentrations compared to wildtype. HeLa cells expressing the mutant protein showed increased cell death, which could be suppressed by the TRPV antagonist ruthenium red. Klein et al. (2011) concluded that CMT2C-related mutations in this gene cause a dominant gain of function rather than haploinsufficiency.
In 3 members of a family with HMSN2C, Landoure et al. (2012) identified a heterozygous mutation in the TRPV4 gene (R186Q; 605427.0033). The mutation was found by exome sequencing and confirmed by Sanger sequencing. This family had previously been reported as family 3 in Landoure et al. (2010), but the primers used in that study did not identify the TRPV4 mutation. Functional expression studies in HEK293 cells showed that the R186Q mutant protein resulted in increased calcium levels and increased cell death, suggesting abnormal constitutive TRPV4 activity.
INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature (in some patients) HEAD & NECK Ears \- Hearing loss, sensorineural Eyes \- Abducens nerve palsy \- Oculomotor nerve palsy RESPIRATORY \- Respiratory failure due to intercostal muscle and diaphragm involvement \- Obstructive sleep apnea \- Stridor Larynx \- Vocal cord paresis GENITOURINARY Bladder \- Urinary urgency \- Urinary incontinence SKELETAL Spine \- Scoliosis Feet \- Pes cavus \- Hammertoes MUSCLE, SOFT TISSUES \- 'Sloping' shoulders due to muscle atrophy \- Shoulder girdle muscle atrophy \- Neurogenic atrophy seen on muscle biopsy NEUROLOGIC Peripheral Nervous System \- Distal limb muscle weakness due to peripheral neuropathy \- Distal limb muscle atrophy due to peripheral neuropathy \- Both upper and lower limb involvement \- Wasting of hand muscles often occurs early \- Impaired manual dexterity \- Proximal limb muscles may be involved in severe cases \- Foot drop \- Intercostal muscle involvement \- Diaphragm involvement \- Vocal cord paresis \- Areflexia \- Hyporeflexia \- Distal sensory impairment \- Decreased or absent distal sensory nerve action potential (SNAP) \- Normal motor nerve conduction velocity (NCV) (greater than 38 m/s) \- Decreased compound muscle action potentials (CMAP) VOICE \- Hoarse voice due to vocal cord paresis MISCELLANEOUS \- Phenotypic variability \- Variable age at onset (range birth to 60 years) \- Earlier onset associated with increased severity \- Worsening of hand weakness with cold (in some) \- Clinical overlap with distal hereditary motor neuropathy type VII (dHMN VII, 158580 ) \- Incomplete penetrance MOLECULAR BASIS \- Caused by mutation in the transient receptor potential cation channel, subfamily V, member 4 gene (TRPV4, 605427.0008 ) ▲ Close
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| HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC | c1853710 | 6,812 | omim | https://www.omim.org/entry/606071 | 2019-09-22T16:10:50 | {"doid": ["0110182"], "mesh": ["C565261"], "omim": ["606071"], "orphanet": ["99937"], "synonyms": ["Alternative titles", "HMSN IIC", "CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2C", "CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2C"], "genereviews": ["NBK201366", "NBK1358"]} |
Genetic condition; specifically, the most common form of dwarfism
Achondroplasia
Jason "Wee Man" Acuña, an American actor and stunt performer with achondroplasia
Pronunciation
* /eɪˌkɒndrəˈpleɪziə, ə-, -ˈpleɪʒiə, -ˈpleɪʒə/[1][2]
SpecialtyMedical genetics
SymptomsShort arms and legs, enlarged head, prominent forehead[3]
ComplicationsEar infections, hyperlordosis, back pain, spinal stenosis, hydrocephalus[3]
CausesGenetic (autosomal dominant mutation in the FGFR3 gene)[3]
Risk factorsPaternal age[4][3]
Diagnostic methodBased on symptoms, genetic testing if uncertain[5]
Differential diagnosisHypochondroplasia, thanatophoric dysplasia, cartilage-hair hypoplasia, pseudoachondroplasia[5]
TreatmentSupport groups, growth hormone therapy, treatment of complications[5]
Prognosis10-year shorter life expectancy[5]
Frequency1 in 27,500 people[3]
Achondroplasia is a genetic disorder whose primary feature is dwarfism.[3] In those with the condition, the arms and legs are short, while the torso is typically of normal length.[3] Those affected have an average adult height of 131 centimetres (4 ft 4 in) for males and 123 centimetres (4 ft) for females.[3] Other features include an enlarged head and prominent forehead.[3] Complications can include sleep apnea or recurrent ear infections.[3] The disorder does not generally affect intelligence.[3]
Achondroplasia is caused by a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene that results in its protein being overactive.[3] The disorder has an autosomal dominant mode of inheritance, meaning only one mutated copy of the gene is required for the condition to occur.[6] About 80% of cases result from a new mutation, which originates in the father's sperm.[5] The rest are inherited from a parent with the condition.[3] The risk of a new mutation increases with the age of the father.[4] In families with two affected parents, children who inherit both affected genes typically die before birth or in early infancy from breathing difficulties.[3] The condition is generally diagnosed based on the symptoms but may be confirmed by genetic testing.[5]
Treatments may include support groups and growth hormone therapy.[5] Efforts to treat or prevent complications such as obesity, hydrocephalus, obstructive sleep apnea, middle ear infections or spinal stenosis may be required.[5] Life expectancy of those affected is about 10 years less than average.[5] Achondroplasia is the most common cause of dwarfism[4] and affects about 1 in 27,500 people.[3] The shortest known adult with the condition is Jyoti Amge, at 62.8 centimetres (2 ft 0.7 in).[7]
## Contents
* 1 Signs and symptoms
* 2 Causes
* 3 Diagnosis
* 3.1 Radiologic findings
* 4 Treatment
* 5 Complications
* 5.1 Children
* 5.2 Adults
* 6 Epidemiology
* 7 Animals
* 8 Research
* 9 See also
* 10 References
* 11 External links
## Signs and symptoms[edit]
* Disproportionate dwarfism
* Shortening of the proximal limbs (called rhizomelic shortening)
* Short fingers and toes with trident hands
* Large head with prominent forehead frontal bossing
* Small midface with a flattened nasal bridge
* Spinal kyphosis (convex curvature) or lordosis (concave curvature)
* Varus (bowleg) or valgus (knock knee) deformities
* Frequent ear infections (due to Eustachian tube blockages), sleep apnea (which can be central or obstructive), and hydrocephalus
## Causes[edit]
Achondroplasia is caused by a mutation in fibroblast growth factor receptor 3 (FGFR3) gene.[8] This gene is mainly responsible for making the protein, fibroblast growth factor receptor 3. This protein contributes to the production of collagen and other structural components in tissues and bones.[9] When the FGFR3 gene is mutated it interferes with how this protein interacts with growth factors leading to complications with bone production. Cartilage is not able to fully develop into bone, causing the individual to be disproportionately shorter in height.
In normal development FGFR3 has a negative regulatory effect on bone growth. In achondroplasia, the mutated form of the receptor is constitutively active and this leads to severely shortened bones. The effect is genetically dominant, with one mutant copy of the FGFR3 gene being sufficient to cause achondroplasia, while two copies of the mutant gene are invariably fatal (recessive lethal) before or shortly after birth (known as a lethal allele). This occurs due to respiratory failure from an underdeveloped ribcage.[3] A person with achondroplasia thus has a 50% chance of passing dwarfism to each of their offspring. People with achondroplasia can be born to parents that do not have the condition due to spontaneous mutation.[10]
Achondroplasia can be inherited through autosomal dominance. In couples where one partner has achondroplasia there is a 50% chance of passing the disorder onto their child every pregnancy. In situations where both parents have achondroplasia there is a 50% chance the child will have achondroplasia, 25% chance the child will not, and a 25% chance that the child will inherit the gene from both parents resulting in double dominance and leading to severe or lethal bone dysplasia.[11]
Studies have demonstrated that new gene mutations for achondroplasia are exclusively inherited from the father and occur during spermatogenesis; it has been theorized that sperm carrying the mutation in FGFR3 have a selective advantage over sperm with normal FGFR3.[4] The frequency of mutations in sperm leading to achondroplasia increase in proportion to paternal age, as well as in proportion to exposure to ionizing radiation.[12] The occurrence rate of achondroplasia in the children of fathers over 50 years of age is 1 in 1,875, compared to 1 in 15,000 in the general population.[13] Research by urologist Harry Fisch of the Male Reproductive Center at Columbia Presbyterian Hospital in 2013 indicated that in humans this defect may be exclusively inherited from the father and becomes increasingly probable with paternal age, specifically males reproducing after 35.[14]
There are two other syndromes with a genetic basis similar to achondroplasia: hypochondroplasia and thanatophoric dysplasia.
## Diagnosis[edit]
Detail of Las Meninas by Diego Velázquez (1656), showing Maribarbola and Nicolasito Pertusato (right), achondroplastic dwarfs in the entourage of Infanta Margarita
Achondroplasia can be detected before birth by prenatal ultrasound. A DNA test can be performed before birth to detect homozygosity, wherein two copies of the mutant gene are inherited, a lethal condition leading to stillbirths. Clinical features include megalocephaly, short limbs, prominent forehead, thoracolumbar kyphosis and mid-face hypoplasia.[15] Complications like dental malocclusion, hydrocephalus and repeated otitis media can be observed.[15] The risk of death in infancy is increased due to the likelihood of compression of the spinal cord with or without upper airway obstruction.
### Radiologic findings[edit]
A skeletal survey is useful to confirm the diagnosis of achondroplasia. The skull is large, with a narrow foramen magnum, and relatively small skull base. The vertebral bodies are short and flattened with relatively large intervertebral disk height, and there is congenitally narrowed spinal canal. The iliac wings are small and squared, with a narrow sciatic notch and horizontal acetabular roof.[16][17] The tubular bones are short and thick with metaphyseal cupping and flaring and irregular growth plates.[16] Fibular overgrowth is present. The hand is broad with short metacarpals and phalanges, and a trident configuration. The ribs are short with cupped anterior ends.[16] If the radiographic features are not classic, a search for a different diagnosis should be entertained. Because of the extremely deformed bone structure, people with achondroplasia are often "double jointed". The diagnosis can be made by fetal ultrasound by progressive discordance between the femur length and biparietal diameter by age. The trident hand configuration can be seen if the fingers are fully extended.
Another distinct characteristic of the syndrome is thoracolumbar gibbus in infancy.
## Treatment[edit]
There is no known cure for achondroplasia even though the cause of the mutation in the growth factor receptor has been found. Although used by those without achondroplasia to aid in growth, human growth hormone does not help people with achondroplasia, which involve a different hormonal pathway. Usually, the best results appear within the first and second year of therapy.[18] After the second year of growth hormone therapy, beneficial bone growth decreases,[19] so the therapy is not a satisfactory long-term treatment.[18]
An experimental drug called Vosoritide has shown promise in stage 3 human trials, although its long-term effects are unknown.[20]
The controversial surgery of limb-lengthening will increase the length of the legs and arms of someone with achondroplasia.[21]
## Complications[edit]
### Children[edit]
Children with achondroplasia often have less muscle tone; because of this it is common for them to have delayed walking and motor skills. It is also common for children to have bowed legs, scoliosis, lordosis, arthritis, issues with joint flexibility, breathing problems, ear infections, and crowded teeth.[22] These issues can be treated with surgery, braces, or physical therapy.
Hydrocephalus is a severe effect associated with achondroplasia in children. This condition occurs when cerebrospinal fluid is not able to flow in and out of the skull because of how the spine narrows.[23] This fluid build up is associated with an enlarged head, vomiting, lethargy, headaches, and irritability.[24] A shunt surgery is commonly performed to treat this condition, but an endoscopic third ventriculostomy can also be done.[25]
### Adults[edit]
Adults with achondroplasia often face issues with obesity and sleep apnea. It is also typical for adults to suffer from numbness or tingling in their legs because of nerve compression.
Pregnancy in women with achondroplasia is considered higher risk. Women with achondroplasia generally have their babies delivered through C-sections to prevent complications that could occur with a natural birth.[26]
## Epidemiology[edit]
Achondroplasia is one of several congenital conditions with similar presentations, such as osteogenesis imperfecta, multiple epiphyseal dysplasia tarda, achondrogenesis, osteopetrosis, and thanatophoric dysplasia. This makes estimates of prevalence difficult, with changing and subjective diagnostic criteria over time. One detailed and long-running study in the Netherlands found that the prevalence determined at birth was only 1.3 per 100,000 live births.[27] Another study at the same time found a rate of 1 per 10,000.[27]
## Animals[edit]
Based on their disproportionate dwarfism, some dog breeds traditionally have been classified as "achondroplastic". This is the case for the dachshund, basset hound, corgi and bulldog breeds.[28][29][30] Data from whole genome association studies in short-limbed dogs reveal a strong association of this trait with a retro-gene coding for fibroblast growth factor 4 (FGF4).[31] Therefore, it seems unlikely that dogs and humans are achondroplastic for the same reasons. However, histological studies in some achondroplastic dog breeds have shown altered cell patterns in cartilage that are very similar to those observed in humans exhibiting achondroplasia.[32]
A similar form of achondroplasia was found in a litter of piglets from a phenotypically normal Danish sow. The dwarfism was inherited dominant in the offspring from this litter. The piglets were born phenotypically normal, but became more and more symptomatic as they reached maturity.[33] This involved a mutation of the protein collagen, type X, alpha 1, encoded by the COL10A1 gene. In humans a similar mutation (G595E) has been associated with Schmid metaphyseal chondrodysplasia (SMCD), a relatively mild skeletal disorder that is also associated with dwarfism.
The now-extinct Ancon sheep was created by humans through the selective breeding of common domestic sheep with achondroplasia. The average-sized torso combined with the relatively smaller legs produced by achondroplasia was valued for making affected sheep less likely to escape without affecting the amount of wool or meat each sheep produced.[34]
## Research[edit]
As of 2019[update], tentative evidence has found that the experimental peptide drug vosoritide increases growth velocity in those with achondroplasia. The drug inhibits the activity of FGFR3.[35]
## See also[edit]
* Achondroplasia in children
* List of radiographic findings associated with cutaneous conditions
## References[edit]
1. ^ "Achondroplasia". Oxford Dictionaries UK Dictionary. Oxford University Press. Retrieved 20 January 2016.
2. ^ "Achondroplasia". Merriam-Webster Dictionary.
3. ^ a b c d e f g h i j k l m n o p "Achondroplasia". Genetics Home Reference. May 2012. Retrieved 12 December 2017.
4. ^ a b c d Horton, William A; Hall, Judith G; Hecht, Jacqueline T (July 2007). "Achondroplasia". The Lancet. 370 (9582): 162–172. doi:10.1016/S0140-6736(07)61090-3. PMID 17630040. S2CID 208788746.
5. ^ a b c d e f g h i Pauli, RM; Adam, MP; Ardinger, HH; Pagon, RA; Wallace, SE; Bean, LJH; Mefford, HC; Stephens, K; Amemiya, A; Ledbetter, N (2012). "Achondroplasia". GeneReviews. PMID 20301331.
6. ^ "Achondroplasia". Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. 2016. Retrieved 12 December 2017.
7. ^ "New world's shortest woman: It's official – Jyoti Amge from India is new record holder". Guinness World Records. 13 December 2011. Retrieved 12 December 2017.
8. ^ "Learning About Achondroplasia". National Human Genome Research Institute (NHGRI). Retrieved 26 September 2018.
9. ^ Reference, Genetics Home. "FGFR3 gene". Genetics Home Reference. Retrieved 26 September 2018.
10. ^ Richette P, Bardin T, Stheneur C (2007). "Achondroplasia: From genotype to phenotype". Joint Bone Spine. 75 (2): 125–30. doi:10.1016/j.jbspin.2007.06.007. PMID 17950653.
11. ^ "Achondroplasia". Retrieved 26 September 2018.
12. ^ Wyrobek AJ, Eskenazi B, Young S, Arnheim N, Tiemann-Boege I, Jabs EW, Glaser RL, Pearson FS, Evenson D (2006). "Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm". Proceedings of the National Academy of Sciences of the United States of America. 103 (25): 9601–9606. Bibcode:2006PNAS..103.9601W. doi:10.1073/pnas.0506468103. PMC 1480453. PMID 16766665.
13. ^ Kovac, Jason R; Addai, Josephine; Smith, Ryan P; Coward, Robert M; Lamb, Dolores J; Lipshultz, Larry I (November 2013). "The effects of advanced paternal age on fertility". Asian Journal of Andrology. 15 (6): 723–728. doi:10.1038/aja.2013.92. PMC 3854059. PMID 23912310.
14. ^ Harry Fisch (24 September 2013). The Male Biological Clock: The Startling News About Aging, Sexuality, and Fertility in Men. Simon and Schuster. pp. 11–. ISBN 978-1-4767-4082-9.
15. ^ a b Beattie, R.M.; Champion, M.P., eds. (2004). Essential questions in paediatrics for MRCPCH (1st ed.). Knutsford, Cheshire: PasTest. ISBN 978-1-901198-99-7.
16. ^ a b c EL-Sobky, TA; Shawky, RM; Sakr, HM; Elsayed, SM; Elsayed, NS; Ragheb, SG; Gamal, R (15 November 2017). "A systematized approach to radiographic assessment of commonly seen genetic bone diseases in children: A pictorial review". J Musculoskelet Surg Res. 1 (2): 25. doi:10.4103/jmsr.jmsr_28_17. S2CID 79825711.
17. ^ "Achondroplasia Pelvis". Archived from the original on 22 October 2007. Retrieved 28 November 2007.
18. ^ a b Vajo, Zoltan; Francomano, Clair A.; Wilkin, Douglas J. (1 February 2000). "The Molecular and Genetic Basis of Fibroblast Growth Factor Receptor 3 Disorders: The Achondroplasia Family of Skeletal Dysplasias, Muenke Craniosynostosis, and Crouzon Syndrome with Acanthosis Nigricans". Endocrine Reviews. 21 (1): 23–39. doi:10.1210/edrv.21.1.0387. PMID 10696568.
19. ^ Aviezer, David; Golembo, Myriam; Yayon, Avner (30 June 2003). "Fibroblast Growth Factor Receptor-3 as a Therapeutic Target for Achondroplasia - Genetic Short Limbed Dwarfism". Current Drug Targets. 4 (5): 353–365. doi:10.2174/1389450033490993. PMID 12816345.
20. ^ Savarirayan, Ravi; Tofts, Louise; Irving, Melita; Wilcox, William; Bacino, Carlos A.; Hoover-Fong, Julie; Font, Rosendo Ullot; Harmatz, Paul; Rutsch, Frank; Bober, Michael B.; Polgreen, Lynda E.; Ginebreda, Ignacio; Mohnike, Klaus; Charrow, Joel; Hoernschemeyer, Daniel; Ozono, Keiichi; Alanay, Yasemin; Arundel, Paul; Kagami, Shoji; Yasui, Natsuo; White, Klane K.; Saal, Howard M.; Leiva-Gea, Antonio; Luna-González, Felipe; Mochizuki, Hiroshi; Basel, Donald; Porco, Dania M.; Jayaram, Kala; Fisheleva, Elena; Huntsman-Labed, Alice; Day, Jonathan (5 September 2020). "Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial". The Lancet. 396 (10252): 684–692. doi:10.1016/S0140-6736(20)31541-5. PMID 32891212. S2CID 221472752.
21. ^ Kitoh H, Kitakoji T, Tsuchiya H, Katoh M, Ishiguro N (2007). "Distraction osteogenesis of the lower extremity in patients that have achondroplasia/hypochondroplasia treated with transplantation of culture-expanded bone marrow cells and platelet-rich plasma". J Pediatr Orthop. 27 (6): 629–34. doi:10.1097/BPO.0b013e318093f523. PMID 17717461. S2CID 42226362.
22. ^ "Dwarfism". kidshealth.org. Retrieved 26 September 2018.
23. ^ "Achondroplasia | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 26 September 2018.
24. ^ Kieffer, Sara. "Achondroplasia | Johns Hopkins Pediatric Neurosurgery". Retrieved 26 September 2018.
25. ^ "Hydrocephalus – Diagnosis and treatment – Mayo Clinic". www.mayoclinic.org. Retrieved 26 September 2018.
26. ^ Services, Department of Health & Human. "Dwarfism". Retrieved 26 September 2018.
27. ^ a b Online Mendelian Inheritance in Man (OMIM): ACHONDROPLASIA; ACH - 100800
28. ^ "WebMD".
29. ^ Jones, T.C.; Hunt, R.D. (1979). "The musculoskeletal system". In Jones, T.C.; Hunt, R.D.; Smith, H.A. (eds.). Veterinary Pathology (5th ed.). Philadelphia: Lea & Febiger. pp. 1175–6. ISBN 978-0812107890.
30. ^ Willis M.B. (1989). "Inheritance of specific skeletal and structural defects". In Willis M.B. (ed.). Genetics of the Dog. Great Britain: Howell Book House. pp. 119–120. ISBN 978-0876055519.
31. ^ Parker HG, VonHoldt BM, Quignon P, et al. (August 2009). "An expressed fgf4 retrogene is associated with breed-defining chondrodysplasia in domestic dogs". Science. 325 (5943): 995–8. Bibcode:2009Sci...325..995P. doi:10.1126/science.1173275. PMC 2748762. PMID 19608863.
32. ^ Braund KG, Ghosh P, Taylor TK, Larsen LH (September 1975). "Morphological studies of the canine intervertebral disc. The assignment of the beagle to the achondroplastic classification". Res. Vet. Sci. 19 (2): 167–72. doi:10.1016/S0034-5288(18)33527-6. PMID 1166121.
33. ^ Nielsen VH, Bendixen C, Arnbjerg J, et al. (December 2000). "Abnormal growth plate function in pigs carrying a dominant mutation in type X collagen". Mamm. Genome. 11 (12): 1087–92. doi:10.1007/s003350010212. PMID 11130976. S2CID 2786778.
34. ^ Gidney, Louisa (May–June 1019). "Earliest Archaeological Evidence of the Ancon Mutation in Sheep from Leicester, UK". International Journal of Osteoarchaeology. 15 (27): 318–321. doi:10.1002/oa.872. ISSN 1099-1212.
35. ^ Savarirayan, Ravi (4 July 2019). "C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia". New England Journal of Medicine. 381 (1): 25–35. doi:10.1056/NEJMoa1813446. PMID 31269546.
## External links[edit]
Classification
D
* ICD-10: Q77.4
* ICD-9-CM: 756.4
* OMIM: 100800
* MeSH: D000130
* DiseasesDB: 80
External resources
* MedlinePlus: 001577
* eMedicine: article/1258401-overview
* Patient UK: Achondroplasia
* Orphanet: 15
Look up achondroplasia in Wiktionary, the free dictionary.
* Achondroplasia at Curlie
* Pauli RM (1998). "Achondroplasia". In Pagon RA, Bird TD, Dolan CR, et al. (eds.). GeneReviews. Seattle WA: University of Washington, Seattle. PMID 20301331. NBK1152.
* v
* t
* e
Osteochondrodysplasia
Osteodysplasia//
osteodystrophy
Diaphysis
* Camurati–Engelmann disease
Metaphysis
* Metaphyseal dysplasia
* Jansen's metaphyseal chondrodysplasia
* Schmid metaphyseal chondrodysplasia
Epiphysis
* Spondyloepiphyseal dysplasia congenita
* Multiple epiphyseal dysplasia
* Otospondylomegaepiphyseal dysplasia
Osteosclerosis
* Raine syndrome
* Osteopoikilosis
* Osteopetrosis
Other/ungrouped
* FLNB
* Boomerang dysplasia
* Opsismodysplasia
* Polyostotic fibrous dysplasia
* McCune–Albright syndrome
Chondrodysplasia/
chondrodystrophy
(including dwarfism)
Osteochondroma
* osteochondromatosis
* Hereditary multiple exostoses
Chondroma/enchondroma
* enchondromatosis
* Ollier disease
* Maffucci syndrome
Growth factor receptor
FGFR2:
* Antley–Bixler syndrome
FGFR3:
* Achondroplasia
* Hypochondroplasia
* Thanatophoric dysplasia
COL2A1 collagen disease
* Achondrogenesis
* type 2
* Hypochondrogenesis
SLC26A2 sulfation defect
* Achondrogenesis
* type 1B
* Autosomal recessive multiple epiphyseal dysplasia
* Atelosteogenesis, type II
* Diastrophic dysplasia
Chondrodysplasia punctata
* Rhizomelic chondrodysplasia punctata
* Conradi–Hünermann syndrome
Other dwarfism
* Fibrochondrogenesis
* Short rib – polydactyly syndrome
* Majewski's polydactyly syndrome
* Léri–Weill dyschondrosteosis
* v
* t
* e
Cell surface receptor deficiencies
G protein-coupled receptor
(including hormone)
Class A
* TSHR (Congenital hypothyroidism 1)
* LHCGR (Luteinizing hormone insensitivity, Leydig cell hypoplasia, Male-limited precocious puberty)
* FSHR (Follicle-stimulating hormone insensitivity, XX gonadal dysgenesis)
* GnRHR (Gonadotropin-releasing hormone insensitivity)
* EDNRB (ABCD syndrome, Waardenburg syndrome 4a, Hirschsprung's disease 2)
* AVPR2 (Nephrogenic diabetes insipidus 1)
* PTGER2 (Aspirin-induced asthma)
Class B
* PTH1R (Jansen's metaphyseal chondrodysplasia)
Class C
* CASR (Familial hypocalciuric hypercalcemia)
Class F
* FZD4 (Familial exudative vitreoretinopathy 1)
Enzyme-linked receptor
(including
growth factor)
RTK
* ROR2 (Robinow syndrome)
* FGFR1 (Pfeiffer syndrome, KAL2 Kallmann syndrome)
* FGFR2 (Apert syndrome, Antley–Bixler syndrome, Pfeiffer syndrome, Crouzon syndrome, Jackson–Weiss syndrome)
* FGFR3 (Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia, Muenke syndrome)
* INSR (Donohue syndrome
* Rabson–Mendenhall syndrome)
* NTRK1 (Congenital insensitivity to pain with anhidrosis)
* KIT (KIT Piebaldism, Gastrointestinal stromal tumor)
STPK
* AMHR2 (Persistent Müllerian duct syndrome II)
* TGF beta receptors: Endoglin/Alk-1/SMAD4 (Hereditary hemorrhagic telangiectasia)
* TGFBR1/TGFBR2 (Loeys–Dietz syndrome)
GC
* GUCY2D (Leber's congenital amaurosis 1)
JAK-STAT
* Type I cytokine receptor: GH (Laron syndrome)
* CSF2RA (Surfactant metabolism dysfunction 4)
* MPL (Congenital amegakaryocytic thrombocytopenia)
TNF receptor
* TNFRSF1A (TNF receptor associated periodic syndrome)
* TNFRSF13B (Selective immunoglobulin A deficiency 2)
* TNFRSF5 (Hyper-IgM syndrome type 3)
* TNFRSF13C (CVID4)
* TNFRSF13B (CVID2)
* TNFRSF6 (Autoimmune lymphoproliferative syndrome 1A)
Lipid receptor
* LRP: LRP2 (Donnai–Barrow syndrome)
* LRP4 (Cenani–Lenz syndactylism)
* LRP5 (Worth syndrome, Familial exudative vitreoretinopathy 4, Osteopetrosis 1)
* LDLR (LDLR Familial hypercholesterolemia)
Other/ungrouped
* Immunoglobulin superfamily: AGM3, 6
* Integrin: LAD1
* Glanzmann's thrombasthenia
* Junctional epidermolysis bullosa with pyloric atresia
EDAR (EDAR hypohidrotic ectodermal dysplasia)
* PTCH1 (Nevoid basal-cell carcinoma syndrome)
* BMPR1A (BMPR1A juvenile polyposis syndrome)
* IL2RG (X-linked severe combined immunodeficiency)
See also
cell surface receptors
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Achondroplasia | c0001080 | 6,813 | wikipedia | https://en.wikipedia.org/wiki/Achondroplasia | 2021-01-18T18:41:24 | {"gard": ["8173"], "mesh": ["D000130"], "umls": ["C0001080"], "icd-9": ["756.4"], "orphanet": ["15"], "wikidata": ["Q340594"]} |
A number sign (#) is used with this entry because susceptibility to malignant hyperthermia-5 (MHS5) is caused by heterozygous mutation in the CACNA1S gene (114208) on chromosome 1q32.
For a phenotypic description and a discussion of genetic heterogeneity of malignant hyperthermia, see MHS1 (145600).
Mapping
In a collaborative study in 3 pedigrees in Europe, in which disease status was classified according to the European in vitro contracture test (IVCT), Robinson et al. (1997) performed a genomewide screen and found that at least 2 further loci exist for MH susceptibility. One of these was located on 5p (601888). The other was located on 1q, between markers D1S422 and D1S1660. Between these 2 markers had already been localized a candidate gene, CACNL1A3 (CACNA1S; 114208), assigned to 1q32. This gene had been previously identified as the site of mutations causing hypokalemic periodic paralysis (170400). The MH family linked to 1q was from Grenoble, France.
Molecular Genetics
In affected members of a large French family with MHS, Monnier et al. (1997) identified a heterozygous mutation in the CACNA1S gene (114208.0004).
INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Tachycardia during anesthesia \- Hypercapnia during anesthesia \- Extrasystoles during anesthesia MUSCLE, SOFT TISSUES \- Contracture response to halothane on muscle biopsy testing \- Contracture response to caffeine on muscle biopsy testing NEUROLOGIC Central Nervous System \- Hyperthermia MISCELLANEOUS \- Two families have been reported (last curated December 2016) MOLECULAR BASIS \- Caused by mutation in the calcium channel, voltage-dependent, L type, alpha-1S subunit (CACNA1S, 114208.0004 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| MALIGNANT HYPERTHERMIA, SUSCEPTIBILITY TO, 5 | c0024591 | 6,814 | omim | https://www.omim.org/entry/601887 | 2019-09-22T16:14:10 | {"mesh": ["D008305"], "omim": ["601887"], "orphanet": ["423"], "synonyms": ["Alternative titles", "MHS5"], "genereviews": ["NBK1146"]} |
Neuroma
Solitary circumscribed neuroma
SpecialtyOncology
A neuroma (/njʊəˈroʊmə/; plural: neuromata or neuromas) is a growth or tumor of nerve tissue.[1] Neuromas tend to be benign (i.e. not cancerous); many nerve tumors, including those that are commonly malignant, are nowadays referred to by other terms.
Neuromas can arise from different types of nervous tissue, including the nerve fibers and their myelin sheath, as in the case of genuine neoplasms (growths) like ganglioneuromas and neurinomas.
The term is also used to refer to any swelling of a nerve, even in the absence of abnormal cell growth. In particular, traumatic neuroma results from trauma to a nerve, often during a surgical procedure. Morton's neuroma affects the foot. Neuromas can be painful, or sometimes, as in the case of acoustic neuromas, can give rise to other symptoms.
## Contents
* 1 Neoplasms
* 2 Other nerve swellings
* 3 Etymology
* 4 References
* 5 External links
## Neoplasms[edit]
* Acoustic neuroma \- a slow-growing, benign tumor of the acoustic nerve.[2] Symptoms, which most often start after the age of 30, can include dizziness, headache, vertigo, loss of balance, ringing sensations, and numbness.[3]
* Ganglioneuroma \- a tumor of the sympathetic nerve fibers arising from neural crest cells.[4]
* Pacinian neuroma \- a very rare, painful, benign hyperplastic tumor of Pacinian corpuscles (mechanoreceptors responsible for sensitivity to vibration and pressure), sometimes linked to a history of local trauma.[5]
## Other nerve swellings[edit]
Some of the benign varieties of neuroma, in the broadest sense of the term, are not neoplasms.
* Traumatic neuroma follows different forms of nerve injury (often as a result of surgery). They occur at the end of injured nerve fibres as a form of ineffective, unregulated nerve regeneration; it occurs most commonly near a scar, either superficially (skin, subcutaneous fat) or deep (e.g., after a cholecystectomy). They are often very painful. Synonyms include scar neuroma, amputation neuroma, or pseudoneuroma.
* Morton's neuroma (a mononeuropathy of the foot) is another example of the more general usage of the term neuroma. Some prefer the term "Morton's metatarsalgia", thus avoiding the term neuroma and its association with tumors.[6]
## Etymology[edit]
The stem neuro- originates from the Greek word for nerve (νεῦρον), while the suffix -oma (-ωμα) denotes swelling.[7] The stem does not imply that neuromas necessarily arise from neurons; neuromas generally arise from non-neuronal nerve tissues. The word was originally used to refer to any nerve tumor, but its meaning has evolved.[7]
## References[edit]
1. ^ "Neuroma". Dorland's Illustrated Medical Dictionary (32nd ed.). Oxford University Press. 2011. p. 5287. ISBN 978-1-4557-0985-4. Retrieved 25 August 2013.
2. ^ "Acoustic Neuroma". NHS Choices. Retrieved 30 August 2013.
3. ^ "Acoustic neuroma". PubMed Health. A.D.A.M. Medical Encyclopedia. NLM. Retrieved 21 December 2014.
4. ^ Gross, Kenneth (2006-09-25). "Ganglioneuroma". Retrieved 2007-05-09.
5. ^ Zanardi F, Cooke RM, Maiorana A, Curti S, Farioli A, Bonfiglioli R, Violante FS, Mattioli S (2011). ""Is this case of a very rare disease work-related?" A review of reported cases of Pacinian neuroma". Scand J Work Environ Health. 37 (3): 253–8. doi:10.5271/sjweh.3132. PMID 21082159.
6. ^ "Morton's metatarsalgia". GPnotebook.
7. ^ a b "neuroma". Oxford English Dictionary (Online ed.). Oxford University Press. (Subscription or participating institution membership required.)
## External links[edit]
Classification
D
* ICD-O: 9570/0
* MeSH: D009463
* v
* t
* e
Tumours of the nervous system
Endocrine
Sellar:
* Craniopharyngioma
* Pituicytoma
Other:
* Pinealoma
CNS
Neuroepithelial
(brain tumors,
spinal tumors)
Glioma
Astrocyte
* Astrocytoma
* Pilocytic astrocytoma
* Pleomorphic xanthoastrocytoma
* Subependymal giant cell astrocytoma
* Fibrillary astrocytoma
* Anaplastic astrocytoma
* Glioblastoma multiforme
Oligodendrocyte
* Oligodendroglioma
* Anaplastic oligodendroglioma
Ependyma
* Ependymoma
* Subependymoma
Choroid plexus
* Choroid plexus tumor
* Choroid plexus papilloma
* Choroid plexus carcinoma
Multiple/unknown
* Oligoastrocytoma
* Gliomatosis cerebri
* Gliosarcoma
Mature
neuron
* Ganglioneuroma: Ganglioglioma
* Retinoblastoma
* Neurocytoma
* Dysembryoplastic neuroepithelial tumour
* Lhermitte–Duclos disease
PNET
* Neuroblastoma
* Esthesioneuroblastoma
* Ganglioneuroblastoma
* Medulloblastoma
* Atypical teratoid rhabdoid tumor
Primitive
* Medulloepithelioma
Meninges
* Meningioma
* Hemangiopericytoma
Hematopoietic
* Primary central nervous system lymphoma
PNS:
* Nerve sheath tumor
* Cranial and paraspinal nerves
* Neurofibroma
* Neurofibromatosis
* Neurilemmoma/Schwannoma
* Acoustic neuroma
* Malignant peripheral nerve sheath tumor
Other
* WHO classification of the tumors of the central nervous system
Note: Not all brain tumors are of nervous tissue, and not all nervous tissue tumors are in the brain (see brain metastasis).
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Neuroma | c0027858 | 6,815 | wikipedia | https://en.wikipedia.org/wiki/Neuroma | 2021-01-18T18:49:22 | {"mesh": ["D009463"], "umls": ["C0027858", "C0273482"], "wikidata": ["Q1981345"]} |
Isovaleric acidemia (IVA) occurs when the body cannot breakdown certain parts of the proteins found in food. This can cause a build-up of toxic substances which can lead to bouts of serious illness known as metabolic crises. There are two types of IVA. The acute, neonatal type has more severe symptoms that begin in the newborn period. In the chronic, intermittent type symptoms appear during childhood and can come and go. Symptoms include poor feeding, tremor, vomiting, low muscle tone, and lack of energy (lethargy). These may get worse over time and lead to coma and possibly death. One characteristic sign of IVA is an odor of sweaty feet during illness. IVA occurs due to variants in the IVD gene and is inherited in an autosomal recessive pattern. Diagnosis of IVD is based on the symptoms, clinical exam, and blood and urine testing. The results of genetic testing may help confirm the diagnosis. Treatment is focused on managing the symptoms and involves a special protein-restricted diet and medications that rid the body of excess isovaleric acid.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Isovaleric acidemia | c0268575 | 6,816 | gard | https://rarediseases.info.nih.gov/diseases/465/isovaleric-acidemia | 2021-01-18T17:59:42 | {"mesh": ["C538167"], "omim": ["243500"], "umls": ["C0268575"], "orphanet": ["33"], "synonyms": ["Isovaleric acid CoA dehydrogenase deficiency", "IVA", "Isovaleryl CoA carboxylase deficiency", "IVD deficiency"]} |
This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (August 2019)
Urticarial dermatoses are distinct from urticaria, which examples being drug-induced urticaria, eosinophilic cellulitis and bullous pemphigoid. It is important to distinguish urticaria from urticarial dermatoses. The individual wheals of urticaria are ‘here today and gone tomorrow’ (i.e. they last less than 24 hours), whereas with urticarial dermatoses, the individual lesions last for days or longer.[1]
## See also[edit]
* Urticaria
* List of cutaneous conditions
## References[edit]
1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 264. ISBN 1-4160-2999-0.
This dermatology article is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Urticarial dermatoses | None | 6,817 | wikipedia | https://en.wikipedia.org/wiki/Urticarial_dermatoses | 2021-01-18T19:06:45 | {"wikidata": ["Q7901361"]} |
Ads for abortion clinics in East London, South Africa
Abortion in South Africa is legal on request in the first trimester of pregnancy, and in special circumstances afterwords. Abortion was legal only under very limited circumstances until 1 February 1997, when the Choice on Termination of Pregnancy Act (Act 92 of 1996) came into force, providing abortion on demand for a variety of cases.
## Contents
* 1 Legal position
* 2 Statistics
* 3 See also
* 4 Literature
* 5 References
## Legal position[edit]
In South Africa, a woman of any age can get an abortion on request with no reasons given if she is less than 13 weeks pregnant. If she is between 13 and 20 weeks pregnant, she can get the abortion if (a) her own physical or mental health is at stake, (b) the baby will have severe mental or physical abnormalities, (c) she is pregnant because of incest, (d) she is pregnant because of rape, or (e) she is of the personal opinion that her economic or social situation is sufficient reason for the termination of pregnancy. If she is more than 20 weeks pregnant, she can get the abortion only if her or the fetus' life is in danger or there are likely to be serious birth defects.[1]
A woman under the age of 18 will be advised to consult her parents, but she can decide not to inform or consult them if she so chooses. A woman who is married or in a life-partner relationship will be advised to consult her partner, but she can decide not to inform or consult him/her. An exception is that if the woman is severely mentally ill or has been unconscious for a long time, where consent of a life-partner, parent or legal guardian is required.
The Constitution does not explicitly mention abortion, but two sections of the Bill of Rights mention reproductive rights. Section 12(2)(a) states that, "Everyone has the right to bodily and psychological integrity, which includes the right [...] to make decisions concerning reproduction," while section 27(1)(a) states "Everyone has the right to have access to [...] health care services, including reproductive health care." In the case of Christian Lawyers Association v Minister of Health an anti-abortion organisation challenged the validity of the Choice on Termination of Pregnancy Act on the basis that it violated the right to life in section 11 of the Bill of Rights; the Transvaal Provincial Division of the High Court dismissed their argument, ruling that constitutional rights only apply to born people and not to fetuses.[2][3]
In general, only medical doctors may perform abortions. Nurses who have received special training may also perform abortions up to the 12th week of pregnancy. A medicine-induced abortion can be performed by any medical doctor at his/her premises up to 7 weeks from the first day of the last menstrual period. The usual method is a dose of an antiprogestin, followed by a dose of a prostaglandin analogue two days later.[4]
Health workers are under no obligation to perform or take active part in an abortion if they do not wish to; however, they are obligated by law to assist if it is required to save the life of the patient, even if the emergency is related to an abortion.[5] A health worker who is approached by a woman for an abortion may decline if they choose to do so, but are obligated by law to inform the woman of her rights and refer her to another health worker or facility where she can get the abortion.[6]
Abortion can be had for free at certain state hospitals or clinics, although sometimes only if the woman is referred by a health worker.[5] Most abortion centres will insist on providing pre- and post-abortion counselling, and the woman can legally demand it, but it is not a legal requirement that abortion centres provide it.
## Statistics[edit]
There has since the legalisation of abortion on demand been a decrease in deaths from backstreet abortions, but the number of deaths following abortions are still quite high according to statistics gathered in Gauteng province—5% of maternal deaths following childbirth are abortion related, and 57% of these are related to illegal abortions.[7]
A 2003 study in Soweto showed the following: the rate of abortions for women older than 20 years decreased from 15.2% in 1999 to 13.2% in 2001, the rate for women aged 16–20 decreased from 21% to 14.9%, and the rate for women aged 13–16 decreased from 28% to 23%. In 2001, 27% of abortions were second-trimester.[7]
## See also[edit]
* Abortion by country
* Abortion debate
* Abortion law
* Law of persons in South Africa
* Religion and abortion
* Choice on Termination of Pregnancy Act, 1996
* History of Abortion Law Debate
* Birth control in Africa
## Literature[edit]
* Susanne M. Klausen: Abortion under Apartheid. Oxford, Oxford University Press, 2015. ISBN 9780199844494
## References[edit]
1. ^ Choice on Termination of Pregnancy Act, Act 92 of 1996 Archived September 30, 2007, at the Wayback Machine
2. ^ Christian Lawyers Association of SA and Others v Minister of Health and Others 1998 (4) SA 1113 (T) (10 July 1998), Transvaal Provincial Division
3. ^ "This Day in History: 10 July 1998". South African History Online. Archived from the original on 28 October 2018. Retrieved 27 August 2011.
4. ^ "Abortion.pdf" (PDF). Archived from the original (PDF) on 2007-03-06. Retrieved 2007-03-04.
5. ^ a b Choice On Termination Of Pregnancy Archived April 27, 2007, at the Wayback Machine
6. ^ Termination of Pregnancy (TOP)
7. ^ a b Dawes, A. (Ed.) (2003). The state of children in Gauteng. A report for the office of the Premier, Gauteng Provincial Government. Archived July 26, 2011, at the Wayback Machine Pretoria: Child Youth and Family Development, Human Sciences Research Council. Page 82, 157, 161
* v
* t
* e
Abortion
Main topics
* Definitions
* History
* Methods
* Abortion debate
* Philosophical aspects
* Abortion law
Movements
* Abortion-rights movements
* Anti-abortion movements
Issues
* Abortion and mental health
* Beginning of human personhood
* Beginning of pregnancy controversy
* Abortion-breast cancer hypothesis
* Anti-abortion violence
* Abortion under communism
* Birth control
* Crisis pregnancy center
* Ethical aspects of abortion
* Eugenics
* Fetal rights
* Forced abortion
* Genetics and abortion
* Late-term abortion
* Legalized abortion and crime effect
* Libertarian perspectives on abortion
* Limit of viability
* Malthusianism
* Men's rights
* Minors and abortion
* Natalism
* One-child policy
* Paternal rights and abortion
* Prenatal development
* Reproductive rights
* Self-induced abortion
* Sex-selective abortion
* Sidewalk counseling
* Societal attitudes towards abortion
* Socialism
* Toxic abortion
* Unsafe abortion
* Women's rights
By country
Africa
* Algeria
* Angola
* Benin
* Botswana
* Burkina Faso
* Burundi
* Cameroon
* Cape Verde
* Central African Republic
* Chad
* Egypt
* Ghana
* Kenya
* Namibia
* Nigeria
* South Africa
* Uganda
* Zimbabwe
Asia
* Afghanistan
* Armenia
* Azerbaijan
* Bahrain
* Bangladesh
* Bhutan
* Brunei
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* United States
Oceania
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* Paraguay
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Law
* Case law
* Constitutional law
* History of abortion law
* Laws by country
* Buffer zones
* Conscientious objection
* Fetal protection
* Heartbeat bills
* Informed consent
* Late-term restrictions
* Parental involvement
* Spousal consent
Methods
* Vacuum aspiration
* Dilation and evacuation
* Dilation and curettage
* Intact D&X
* Hysterotomy
* Instillation
* Menstrual extraction
* Abortifacient drugs
* Methotrexate
* Mifepristone
* Misoprostol
* Oxytocin
* Self-induced abortion
* Unsafe abortion
Religion
* Buddhism
* Christianity
* Catholicism
* Hinduism
* Islam
* Judaism
* Scientology
* Category
* v
* t
* e
Law of South Africa
Main areas
* Constitutional law
* Administrative law
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* Labour law
* Company and Insolvency
* Competition law
* Commercial law
* Property
* Lease
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* Delict
* Agency
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* Insurance
Specific issues
* Abortion
* Bill of Rights
* Chapter nine institutions
* Freedom of religion
* Gun laws
* Human rights
* Internet censorship
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* Prostitution
* Protection of State Information Bill
* Slums Act
Specific laws
* Marine Living Resources Act, 18 of 1998
* National Environmental Management Act, 107 of 1998
* National Environmental Management: Biodiversity Act, 10 of 2004
* National Environmental Management: Integrated Coastal Management Act, 24 of 2008
* National Environmental Management: Protected Areas Act, 57 of 2003
Category
* v
* t
* e
Abortion in Africa
Sovereign states
* Algeria
* Angola
* Benin
* Botswana
* Burkina Faso
* Burundi
* Cameroon
* Cape Verde (Cabo Verde)
* Central African Republic
* Chad
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* South Africa
* South Sudan
* Sudan
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States with limited
recognition
* Sahrawi Arab Democratic Republic
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Dependencies and
other territories
* Canary Islands / Ceuta / Melilla (Spain)
* Madeira (Portugal)
* Mayotte / Réunion (France)
* Saint Helena / Ascension Island / Tristan da Cunha (United Kingdom)
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Abortion in South Africa | None | 6,818 | wikipedia | https://en.wikipedia.org/wiki/Abortion_in_South_Africa | 2021-01-18T18:32:38 | {"wikidata": ["Q859701"]} |
Automatic tachycardia
Junctional tachycardia (rate about 115/min) dissociated from a slightly slower sinus tachycardia (rate about 107/min). Junctional tachycardia is both an SVT and an automatic tachycardia
An automatic tachycardia is a cardiac arrhythmia which involves an area of the heart generating an abnormally fast rhythm, sometimes also called enhanced automaticity. These tachycardias, or fast heart rhythms, differ from reentrant tachycardias (AVRT and AVNRT) in which there is an abnormal electrical pathway which gives rise to the pathology. Most automatic tachycardias are supraventricular tachycardias (SVT). It is important to recognise an automatic tachycardia because the treatment will be different to that for a reentrant tachycardia. The most useful clue will be the presence of 'warm up' and 'cool down'. This means that whereas a reentrant tachycardia will both begin and end abruptly as cardiac conduction utilises then ceases to utilise the accessory pathway, an automatic tachycardia will rise and fall gradually in rate as the automatic focus increases and decreases its automatic rate of electrical discharge.[1]
## Contents
* 1 Types
* 2 Treatment
* 3 See also
* 4 References
## Types[edit]
* Sinus tachycardia may be considered an automatic tachycardia, since the sinoatrial node (SAN) is discharging at an abnormally fast rate.
* Atrial ectopic tachycardia, in which the focus or foci are in the atria of the heart, is an automatic tachycardia.
* Atrial fibrillation may be considered an automatic tachycardia.
* Junctional ectopic tachycardia, in which the focus is in the atrioventricular node (AVN), and
* Accelerated idioventricular rhythm, involving a ventricular focus, are also examples. Idioventricular tachycardia is notable because it is the only automatic tachycardia which is not an SVT.
## Treatment[edit]
Treatment depends on the origin of the automatic tachycardia, however the mainstay of treatment is either antidysrhythmic medication or cardiac pacing. Specifically overdrive pacing may be used for all forms of automatic tachycardia; a pacemaker assumes control of the heart rhythm in overdrive pacing. In some cases ablation of the ectopic focus may be necessary.
## See also[edit]
* Cardiac ectopy
* Clinical cardiac electrophysiology
* Electrical conduction system of the heart
* Supraventricular tachycardia
## References[edit]
1. ^ Lister B et al. Paediatric BASIC: Basic Assessment and Support in Paediatric Intensive Care. Department of Anaesthesia and Intensive Care of The Chinese University of Hong Kong, Hong Kong 2016.
* v
* t
* e
Cardiovascular disease (heart)
Ischaemic
Coronary disease
* Coronary artery disease (CAD)
* Coronary artery aneurysm
* Spontaneous coronary artery dissection (SCAD)
* Coronary thrombosis
* Coronary vasospasm
* Myocardial bridge
Active ischemia
* Angina pectoris
* Prinzmetal's angina
* Stable angina
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* Unstable angina
Sequelae
* hours
* Hibernating myocardium
* Myocardial stunning
* days
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* weeks
* Aneurysm of heart / Ventricular aneurysm
* Dressler syndrome
Layers
Pericardium
* Pericarditis
* Acute
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* Pericardial effusion
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Myocardium
* Myocarditis
* Chagas disease
* Cardiomyopathy
* Dilated
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* Tachycardia-induced
* Restrictive
* Loeffler endocarditis
* Cardiac amyloidosis
* Endocardial fibroelastosis
* Arrhythmogenic right ventricular dysplasia
Endocardium /
valves
Endocarditis
* infective endocarditis
* Subacute bacterial endocarditis
* non-infective endocarditis
* Libman–Sacks endocarditis
* Nonbacterial thrombotic endocarditis
Valves
* mitral
* regurgitation
* prolapse
* stenosis
* aortic
* stenosis
* insufficiency
* tricuspid
* stenosis
* insufficiency
* pulmonary
* stenosis
* insufficiency
Conduction /
arrhythmia
Bradycardia
* Sinus bradycardia
* Sick sinus syndrome
* Heart block: Sinoatrial
* AV
* 1°
* 2°
* 3°
* Intraventricular
* Bundle branch block
* Right
* Left
* Left anterior fascicle
* Left posterior fascicle
* Bifascicular
* Trifascicular
* Adams–Stokes syndrome
Tachycardia
(paroxysmal and sinus)
Supraventricular
* Atrial
* Multifocal
* Junctional
* AV nodal reentrant
* Junctional ectopic
Ventricular
* Accelerated idioventricular rhythm
* Catecholaminergic polymorphic
* Torsades de pointes
Premature contraction
* Atrial
* Junctional
* Ventricular
Pre-excitation syndrome
* Lown–Ganong–Levine
* Wolff–Parkinson–White
Flutter / fibrillation
* Atrial flutter
* Ventricular flutter
* Atrial fibrillation
* Familial
* Ventricular fibrillation
Pacemaker
* Ectopic pacemaker / Ectopic beat
* Multifocal atrial tachycardia
* Pacemaker syndrome
* Parasystole
* Wandering atrial pacemaker
Long QT syndrome
* Andersen–Tawil
* Jervell and Lange-Nielsen
* Romano–Ward
Cardiac arrest
* Sudden cardiac death
* Asystole
* Pulseless electrical activity
* Sinoatrial arrest
Other / ungrouped
* hexaxial reference system
* Right axis deviation
* Left axis deviation
* QT
* Short QT syndrome
* T
* T wave alternans
* ST
* Osborn wave
* ST elevation
* ST depression
* Strain pattern
Cardiomegaly
* Ventricular hypertrophy
* Left
* Right / Cor pulmonale
* Atrial enlargement
* Left
* Right
* Athletic heart syndrome
Other
* Cardiac fibrosis
* Heart failure
* Diastolic heart failure
* Cardiac asthma
* Rheumatic fever
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Automatic tachycardia | None | 6,819 | wikipedia | https://en.wikipedia.org/wiki/Automatic_tachycardia | 2021-01-18T19:05:57 | {"wikidata": ["Q28454409"]} |
Abarognosis
Other namesBaragnosis, baroagnosis[1]
Abarognosis () is type of cortical sensory defect[2] consisting of a loss of barognosis, the ability to detect the weight of an object held in the hand or to tell the difference in weight between two objects,[3] or more succinctly "Loss of the ability to sense weight".[4] This deficit may be caused by damage to the parietal lobe.[5]
The term is from Greek "a" not, "baros" weight, "gnosis" knowledge.
## Contents
* 1 References
* 1.1 Notes
* 1.2 Sources
* 2 External links
## References[edit]
Look up abarognosis in Wiktionary, the free dictionary.
### Notes[edit]
1. ^ Dorland 2011, baragnosis
2. ^ Black 1995, pg. 14
3. ^ abarognosis, Drugs.com, retrieved 2013-03-21
4. ^ "abarognosis", The American Heritage® Stedman's Medical Dictionary, Houghton Mifflin, retrieved 2013-03-21
5. ^ Campbell 2012, pg. 554
### Sources[edit]
* Black, Peter McLaren; Rossitch, Eugene (1995), "Neurological Diagnosis", Neurosurgery: An Introductory Text (Google eBook), Oxford University Press, ISBN 9780195044492, retrieved 2013-02-21
* Buck, Carol J. (2013), "Section Index to Diseases and Injuries", 2013 ICD-9-CM for Physicians (Google preview), Vol. 2 (Professional ed.), Elsevier Health Sciences, ISBN 9781455775033, retrieved 2013-03-21
* Campbell, William W. (2012), "36: Sensory Localization", DeJong's The Neurologic Examination (Google eBook) (7th ed.), Lippincott Williams & Wilkins, ISBN 9781469817521, retrieved 2013-03-21
* Dorland (2011), Dorland's Illustrated Medical Dictionary (Google eBook) (32nd ed.), Elsevier Health Sciences, ISBN 9781455709854, retrieved 2013-03-21
## External links[edit]
Classification
D
* ICD-9-CM: 781.99
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Abarognosis | None | 6,820 | wikipedia | https://en.wikipedia.org/wiki/Abarognosis | 2021-01-18T18:38:08 | {"wikidata": ["Q305575"]} |
A rare, genetic lipodystrophy characterized by abnormal subcutaneous fat distribution, resulting in excess accumulation of fat in the face, neck, shoulders, axillae, trunk and pubic region, and loss of subcutaneous fat from the lower extremities. Variable common additional features are progressive adult onset myopathy, insulin resistance, diabetes, hypertriglyceridemia, hepatic steatosis, and vitiligo.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| LIPE-related familial partial lipodystrophy | c4014869 | 6,821 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=435660 | 2021-01-23T18:04:57 | {"omim": ["615980"], "icd-10": ["E88.1"], "synonyms": ["FPLD6", "LIPE-related FPLD"]} |
A rare, hereditary, pheochromocytoma/paraganglioma tumor arising from neuroendocrine chromaffin cells of the adrenal medulla (pheochromocytoma) or from any paraganglia from the skull base to the pelvic floor (paraganglioma). Clinical manifestations are often linked to excess catecholamines production causing sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, palpitations, pallor and apprehension or anxiety. Hereditary pheochromocytoma/paraganglioma tumors tend to present at younger ages, to be multi-focal, bilateral, and recurrent, or to have multiple synchronous neoplasms.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Hereditary pheochromocytoma-paraganglioma | c1861848 | 6,822 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=29072 | 2021-01-23T18:45:26 | {"gard": ["11984"], "mesh": ["C565335"], "omim": ["115310", "168000", "171300", "601650", "605373", "614165", "618464", "618475"], "icd-10": ["C74.1", "C75.5", "D35.0", "D35.6"], "synonyms": ["Familial pheochromocytoma-paraganglioma"]} |
Plantar reflex
Babinski response/Babinski sign (pathological)
The reflex occurs upon stroking of the sole of the foot with a blunt object such as a pen. If the reflex occurs in adults as illustrated at bottom it may be due to nerve damage or disease.
ICD-9-CM796.1
MedlinePlus003294
The plantar reflex is a reflex elicited when the sole of the foot is stimulated with a blunt instrument. The reflex can take one of two forms. In healthy adults, the plantar reflex causes a downward response of the hallux (flexion). An upward response (extension) of the hallux is known as the Babinski response or Babinski sign, named after the neurologist Joseph Babinski. The presence of the Babinski sign can identify disease of the spinal cord and brain in adults, and also exists as a primitive reflex in infants.[1]
While first described in the medical literature by Babinski in 1896,[2] the reflex has been identified in art at least as early as Botticelli's Madonna and Child With an Angel, painted in the mid-15th century.[3]
## Contents
* 1 Methods
* 2 Interpretation
* 2.1 In infants
* 2.2 Pathways
* 3 Relationship to Hoffmann's reflex
* 4 Babinski-like responses
* 4.1 Abnormal reflexes seen as flexion of toes
* 5 References
## Methods[edit]
Pathological Babinski's sign in adult
The lateral side of the sole of the foot is rubbed with a blunt instrument or device so as not to cause pain, discomfort, or injury to the skin; the instrument is run from the heel along a curve to the toes[4] (metatarsal pads). Many reflex hammers taper at the end of the handle to a point which was used for testing the plantar response in the past; due to the tightening of infection control regulation this is no longer recommended. Either a single use device or the thumb nail should be used.[citation needed]
There are three responses possible:
* Flexor: the toes curve down and inwards, and the foot inverts; this is the response seen in healthy adults.
* Indifferent: there is no response.
* Extensor: the hallux dorsiflexes, and the other toes fan out; this is Babinski's sign, which indicates damage to the central nervous system if elicited in an adult, but normal reflex if elicited in infants (see below).
As the lesion responsible for the sign expands, so does the area from which the afferent Babinski response may be elicited. The Babinski response is also normal while asleep and after a long period of walking.
## Interpretation[edit]
Babinski's sign in a healthy newborn
The Babinski sign can indicate upper motor neuron lesion constituting damage to the corticospinal tract. Occasionally, a pathological plantar reflex is the first and only indication of a serious disease process and a clearly abnormal plantar reflex often prompts detailed neurological investigations, including CT scanning of the brain or MRI of the spine, as well as lumbar puncture for the study of cerebrospinal fluid.
The phrase "negative Babinski sign" is sometimes used for the normal flexor plantar response.[5]
### In infants[edit]
Main article: Primitive reflexes
Infants will usually show an extensor response. In one study of 256 healthy infants, the response to testing was extensor in 73.8%, flexor in 8.9%, and equivocal in 17.3%[6] This extensor response occurs because the corticospinal pathways that run from the brain down the spinal cord are not fully myelinated at this age, so the reflex is not inhibited by the cerebral cortex. The extensor response usually disappears – giving way to the flexor response – by 12 months of age.[7] Its persistence beyond age 2–3 indicates a problem in the brain or spinal cord.[8][9]
### Pathways[edit]
* Afferent: Nociception detected in the S1 dermatome and travels up the tibial nerve to the sciatic nerve to roots of L5,S1 and synapse in the anterior horn to elicit the motor response.
* Efferent: Motor response back through the L5,S1 roots to the sciatic nerve to its bifurcation. Toe flexors are innervated by the tibial nerve. Toe extensors (extensor hallucis longus, extensor digitorum longus) are innervated by the deep peroneal nerve. Loss of normal adult descending pyramidal control of the reflex arc to suppress extensor withdrawal results in the upgoing toes in the plantar reflex known as Babinski's sign.[10]
## Relationship to Hoffmann's reflex[edit]
Main article: Hoffmann's reflex
The Hoffmann's reflex is sometimes described as the upper limb equivalent of the Babinski sign[11] because both indicate upper motor neuron dysfunction. Mechanistically, they differ significantly; the finger flexor reflex is a simple monosynaptic spinal reflex involving the flexor digitorum profundus that is normally fully inhibited by upper motor neurons. The pathway producing the plantar response is more complicated, and is not monosynaptic.
## Babinski-like responses[edit]
The plantar reflex can be elicited in a number of ways, which were described in the late 19th and early 20th century. These have their own eponyms.[12][13][14]
* Bing sign – multiple pinpricks on the dorsum of the foot
* Cornell sign – scratching along the inner side of the extensor hallucis longus tendon
* Chaddock sign – stroking the lateral malleolus
* Gonda sign – flexing and suddenly releasing the 4th toe
* Gordon sign – squeezing the calf muscle
* Moniz sign – forceful passive plantar flexion of the ankle
* Oppenheim sign – applying pressure to the medial side of the tibia
* Schaeffer sign – squeezing the Achilles tendon
* Silva sign – pinching the rectus femoris muscle[14]
* Stransky sign – vigorously abducting and suddenly releasing the little toe
* Strümpell sign – patient attempts to flex the knee against resistance
* Throckmorton reflex – percussion over the metatarsophalangeal joint of the big toe
### Abnormal reflexes seen as flexion of toes[edit]
* Bekhterev-Mendel reflex – flexion of the 2nd to 5th toes on percussion of the dorsum of the foot
* Rossolimo sign – exaggerated flexion of the toes induced by rapid percussion on the tips of the toes
## References[edit]
1. ^ synd/366 at Who Named It?
2. ^ Comptes rendus de la Société de Biologie, Vol. 48, 1896, p. 207, http://gallica.bnf.fr/ark:/12148/bpt6k6459605g/f225.image
3. ^ Massey, E. W.; Sanders, L. (1 January 1989). "Babinski's Sign in Medieval, Renaissance, and Baroque Art". Archives of Neurology. 46 (1): 85–88. doi:10.1001/archneur.1989.00520370087025.
4. ^ "plantar reflex" at Dorland's Medical Dictionary
5. ^ Larner, A. J. (2006). A Dictionary of Neurological Signs. Springer. pp. 50–. ISBN 978-0-387-26214-7.
6. ^ Gupta, A; Gupta, Piyush (July 2003). "Neonatal plantar response revisited". Journal of Paediatrics and Child Health. 39 (5): 349–351. doi:10.1046/j.1440-1754.2003.00172.x.
7. ^ "Neonatal reflexes". Retrieved 24 May 2017.
8. ^ "Medline plus: Babinski reflex". Retrieved 24 May 2017.
9. ^ Neelon, Francis A; Harvey, Elisabeth (January 21, 1999). "The Babinski Sign". N Engl J Med. 340 (3): 196. doi:10.1056/NEJM199901213400305. PMID 9895399.
10. ^ Futagi, Y; Suzuki, Y (August 2010). "Neural mechanism and clinical significance of the plantar grasp reflex in infants". Pediatric Neurology. 43 (2): 81–6. doi:10.1016/j.pediatrneurol.2010.04.002. PMID 20610116.
11. ^ Harrop JS, Hanna A, Silva MT, Sharan A (2007). "Neurological manifestations of cervical spondylosis: an overview of signs, symptoms, and pathophysiology". Neurosurgery. 60 (1 Supp1 1): S14–20. doi:10.1227/01.NEU.0000215380.71097.EC. PMID 17204875.
12. ^ Kumar, SP; Ramasubramanian, D (December 2000). "The Babinski sign--a reappraisal". Neurology India. 48 (4): 314–8. PMID 11146592.
13. ^ Walker, H. Kenneth; Hall, W. Dallas; Schlossberg, J. Willis Hurst; illustrations by Leon; Boyter, Charles H. (1990). "Chapter 73 The Plantar Reflex". In Walker, H. Kenneth (ed.). Clinical methods : the history, physical, and laboratory examinations (3rd ed.). Boston: Butterworths. ISBN 978-0-409-90077-4. "Table 73.1 Variants of the Babinski Sign"
14. ^ a b Silva Rosas, Carlos (2013). Semiología y Fundamentos de la Neurología Clínica (First ed.). AMOLCA. pp. 66–67. ISBN 978-958-8760-73-5.
* v
* t
* e
Reflexes
Cranial nerve
* midbrain: Pupillary light reflex
* Accommodation reflex
pons/medulla: Jaw jerk reflex
* Corneal reflex
* Caloric reflex test/Vestibulo-ocular reflex/Oculocephalic reflex
* Pharyngeal (gag) reflex
Stretch reflexes
* Arm: Biceps reflex C5/C6
* Brachioradialis reflex C6
* Triceps reflex C7/C8
Leg: Patellar reflex L2-L4
* Ankle jerk reflex S1/S2
* Plantar reflex L5-S2
Primitive reflexes
* Galant
* Gastrocolic
* Grasp
* Moro
* Rooting
* Stepping
* Sucking
* Tonic neck
* Parachute
Superficial reflexes
* Abdominal reflex
* Cremasteric reflex
Cardiovascular
* Bainbridge reflex
* Bezold–Jarisch reflex
* Coronary reflex
* Diving reflex
* Oculocardiac reflex
Baroreflex
* Reflex bradycardia
* Reflex tachycardia
Respiratory
* Churchill–Cope reflex
Other
* List
* Acoustic reflex
* H-reflex
* Golgi tendon reflex
* Optokinetic
* Startle response
* Withdrawal reflex (Crossed extensor reflex)
* Symmetrical tonic neck reflex
* v
* t
* e
Symptoms and signs relating to the nervous system
Neurological examination · Cranial nerve examination
Central nervous system
Head
* Battle's sign
* Kernig's sign
* Macewen's sign
* Myerson's sign
* Stroop test
* Hirano body
Other
* increased intracranial pressure
* Cushing's triad
* Lhermitte's sign
* Charcot's neurologic triad
Peripheral nervous system
Reflexes
Combination
* Jendrassik maneuver
Legs
* Plantar reflex
* Chaddock reflex
* Oppenheim's sign
* Westphal's sign
Arms
* Hoffmann's sign
Other
Arms
* Froment's sign
* carpal tunnel syndrome
* Tinel sign
* Phalen maneuver
Legs
* Gowers' sign
* Hoover's sign
* Lasègue's sign
* Trendelenburg's sign
Torso
* Beevor's sign
General
* Pain stimulus
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Plantar reflex | c0750948 | 6,823 | wikipedia | https://en.wikipedia.org/wiki/Plantar_reflex | 2021-01-18T18:47:29 | {"mesh": ["D001405"], "wikidata": ["Q506923"]} |
A number sign (#) is used with this entry because of evidence that a mutation of the TNFRSF10B gene (603612.0001), alone or in combination with other genes, can cause squamous cell carcinoma of the head and neck. Mutations in the ING1 gene (601566) have been found in a small but significant number of cases of squamous cell carcinoma of the head and neck. Somatic mutation in the PTEN gene (601728) has also been found in cases of HNSCC.
Pathogenesis
The transforming growth factor beta family of 25-kD polypeptides (TGFB1, 190180; TGFB2, 190220; TGFB3, 190230) are potent inhibitors of epithelial cell growth. Acquisition of cellular resistance to growth inhibitors, such as TGFB1, may represent an important step in tumor development. Human and murine epidermal keratinocytes secrete TGFB1, which appears to act as an autocrine inhibitor of growth. TGFB1 inhibits cell division by causing cells to arrest at the transition of G1 to S phase and stimulates keratinocyte differentiation. The acquisition of resistance to TGFB1 appears to represent an important step in the genesis of squamous cell carcinomas, as only transformed keratinocytes that have escaped from the negative control by TGFB1 seem to give rise to invasive carcinomas. Furthermore, most squamous carcinoma cell lines of the respiratory, digestive, and genital tracts are refractory to the antiproliferative action of TGFB1 in vitro. By use of somatic cell genetics, Reiss et al. (1993) studied the basis of the resistance of squamous carcinoma cell lines to TGFB1. Stable hybrid cell lines were obtained by fusing a TGFB1-resistant hypopharyngeal squamous carcinoma cell line with a papilloma virus 16-immortalized, TGFB1-sensitive, human foreskin keratinocyte cell line. TGFB1 type II receptor (TGFBR2; 190182) mRNA was detected in all sensitive and resistant cell lines studied. TGFB1 resistance of the squamous carcinoma cell line appeared to be recessive and due to the loss of 1 or more postreceptor elements of the signaling pathway. The gene encoding this (or these) element(s) may be located in the distal portion of chromosome 18q, as this was the sole chromosomal region of homozygous deletion in the resistant cell lines.
Nawroz et al. (1996) stated that microsatellite DNA alterations are an integral part of neoplastic progression and there is evidence that senescent tumor cells release DNA into the circulation. The investigators reported results from PCR-based microsatellite analysis of paired samples of lymphocyte and serum DNA from 21 patients with primary head and neck squamous cell carcinoma. Microsatellite alterations were defined as the appearance of new alleles (new size forms) or loss of heterozygosity (LOH) at each of 12 markers, including IFNA (147660), CHRNB1 (100710), FGA (134820), and DRPLA (607462). Nawroz et al. (1996) reported that 6 out of 21 patients had 1 or more microsatellite alterations in serum that precisely matched the alteration in tumor DNA. All 6 patients had advanced disease and 5 patients had nodal metastases. The authors concluded that analysis of serum and plasma DNA may be useful for assessment of tumor burden, metastatic status, and overall prognosis.
Koybasi et al. (2004) measured endogenous long-chain ceramides in 32 human HNSCC and 10 nonsquamous head and neck carcinoma tumor tissues, and found that C(18:0)-ceramide was selectively downregulated in the majority of HNSCC tumor tissues but not in the nonsquamous tumor tissues or in adjacent noncancerous tissues from HNSCC patients. Overexpression of the homolog of S. cerevisiae lag1 gene (LASS1; 606919) in an HNSCC cell line resulted in a 2-fold increase in levels of C(18:0)-ceramid e to concentrations similar to those of normal head and neck tissues and was associated with a 70 to 80% inhibition of cell growth. Koybasi et al. (2004) concluded that LASS1 and C(18:0)-ceramide have a biologic role in the regulation of growth of head and neck squamous cell carcinomas.
Diagnosis
Roepman et al. (2005) showed that DNA microarray gene expression profiling can detect lymph node metastases for primary head and neck squamous cell carcinomas that arise in the oral cavity and oropharnyx. The predictor, established with a set of 82 tumors, outperformed current clinical diagnosis when independently validated. The 102 predictor genes offered unique insight into the processes underlying metastasis. The results showed that the metastatic state can be deciphered from the primary tumor gene expression pattern and that treatment can be substantially improved.
Mapping
### Immortality of Squamous Cell Carcinoma
Most advanced squamous cell carcinomas are immortal. Forsyth et al. (2002) noted that analyses of the immortal phenotype had shown several genetic alterations to be important to the process, including dysfunction of p53 (191170), INK4A (600160), and a gene on chromosome 3p that represses telomerase activity. LOH of other chromosomes, including chromosome 4, had also been observed. To test for a functional cancer mortality gene on chromosome 4, Forsyth et al. (2002) introduced a complete or fragmented copy of the chromosome into squamous cell carcinoma cell lines by microcell-mediated chromosome transfer (MMCT). In those lines with LOH on chromosome 4, the process caused a delayed crisis, but chromosomes 3, 6, 11, and 15 were without effect. MMCT of chromosomal fragments into BICR6 mapped the mortality gene to the region 4cen-q23. Mutation analysis of the introduced chromosome in immortal segregants narrowed the candidate interval to 2.7 Mb spanning the markers D4S423 and D4S1557. The results suggested the existence of a gene on chromosome 4 whose dysfunction contributes to the continuous proliferation of squamous cell carcinomas and indicated that this gene operates independently of telomeres, p53, and INK4A.
Molecular Genetics
### Mutation in the TNFRSF10B Gene
Pai et al. (1998) performed sequence analysis of all 10 coding exons of the TNFRSF10B gene (603612.0001) in 20 primary head and neck cancers with allelic loss of 8p. To screen for a subset of mutations localized to the functional cytoplasmic death domain, they sequenced this region in an additional 40 primary head and neck cancers. They found 2 alterations, including a 2-bp insertion at a minimal repeat site (603612.0001), introducing a premature stop codon and resulting in a truncated protein. Sequence analysis of normal tissue from the patient showed that the truncating mutation was also present in the germline, and that the tumor did not have a p53 mutation.
### Mutation in the ING1 Gene
In tumor tissue of squamous cell carcinoma of the head and neck, Gunduz et al. (2000) identified missense mutations in the ING1 gene (see, for example, 601566.0001).
### Mutation in the PTEN Gene
In a study of 52 HNSCC tumor samples, Poetsch et al. (2002) found an ala121-to-gly mutation (A121G; 601728.0031) in the PTEN gene in 1 oropharyngeal and 1 laryngeal carcinoma.
### Role of MicroRNAs
Cervigne et al. (2009) examined microRNA (miR) expression changes in 43 sequential progressive oral leukoplakia samples from 12 patients and 4 nonprogressive leukoplakias from 4 different patients. The findings were validated using quantitative RT-PCR in an independent cohort of 52 progressive dysplasias and oral squamous cell carcinomas (OSCCs), and 5 nonprogressive dysplasias. Global miR expression profiles distinguished progressive leukoplakia/OSCC from nonprogressive leukoplakias/normal tissues. Of 109 miRs which were highly expressed exclusively in progressive leukoplakia and invasive OSCC, miR21 (611020), miR181b (612744), and miR345 expression was consistently increased and associated with increases in lesion severity during progression. The authors hypothesized that overexpression of miR21, miR181b, and miR345 may play an important role in malignant transformation.
### Mutation in Genes Involved in Squamous Differentiation
To explore the genetic origins of head and neck squamous cell carcinoma, Agrawal et al. (2011) used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53 (191170), CDKN2A (600160), PIK3CA (171834), and HRAS (171834), Agrawal et al. (2011) identified mutations in NOTCH1 (190198). Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type. Seven of 21 patients with NOTCH1 mutations had 2 independent mutations presumably on different alleles. After TP53, NOTCH1 was the most frequently mutated gene found in the combined discovery and prevalence sets, with alterations present in 15% of patients.
Stransky et al. (2011) independently analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; HPV was detectable by sequencing DNA from infected tumors. In addition to identifying known HNSCC genes, their analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (i.e., NOTCH1; IRF6, 607199; and TP63, 603273), implicating its dysregulation as a major driver of HNSCC carcinogenesis.
The Cancer Genome Atlas Network (2015) profiled 279 HNSCCs to provide a comprehensive landscape of somatic genomic alterations. They showed that HPV-associated tumors are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3 (601896), and amplification of the cell cycle gene E2F1 (189971). Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumors with favorable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8 (601763), NOTCH1, and TP53. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1 (606681), WNT pathway genes AJUBA (JUB; 609066) and FAT1 (600976), and activation of oxidative stress factor NFE2L2 (600492), mainly in laryngeal tumors.
### Mutation in the FBXW7 Gene
Among 120 primary HNSCCs, Agrawal et al. (2011) identified 6 mutations in FBXW7. Two were indels and the other 4 were missense; none was homozygous. The FBXW7 mutations observed were in a hotspot known to block the degradation of active NOTCH1. Agrawal et al. (2011) noted that FBXW7 mutations had not been observed in HNSCC, although they are frequent in other tumor types.
Lab \- Beta family transforming growth factor resistance Inheritance \- Autosomal recessive ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| SQUAMOUS CELL CARCINOMA, HEAD AND NECK | c1168401 | 6,824 | omim | https://www.omim.org/entry/275355 | 2019-09-22T16:21:30 | {"doid": ["5520"], "mesh": ["D000077195"], "omim": ["275355"], "orphanet": ["502363", "494547", "494550", "500464", "502366", "500478", "500481"], "synonyms": ["Squamous cell carcinoma of the nasal cavity and sinuses"]} |
Benign familial neonatal seizures (BFNS) is a condition characterized by recurrent seizures in newborn babies. The seizures begin around day 3 of life and usually go away within 1 to 4 months. The seizures can involve only one side of the brain (focal seizures) or both sides (generalized seizures). Many infants with this condition have generalized tonic-clonic seizures (also known as grand mal seizures). This type of seizure involves both sides of the brain and affects the entire body, causing muscle rigidity, convulsions, and loss of consciousness.
A test called an electroencephalogram (EEG) is used to measure the electrical activity of the brain. Abnormalities on an EEG test, measured during no seizure activity, can indicate a risk for seizures. However, infants with BFNS usually have normal EEG readings. In some affected individuals, the EEG shows a specific abnormality called the theta pointu alternant pattern. By age 2, most affected individuals who had EEG abnormalities have a normal EEG reading.
Typically, seizures are the only symptom of BFNS, and most people with this condition develop normally. However, some affected individuals develop intellectual disability that becomes noticeable in early childhood. A small percentage of people with BFNS also have a condition called myokymia, which is an involuntary rippling movement of the muscles. In addition, in about 15 percent of people with BFNS, recurrent seizures (epilepsy) will come back later in life after the seizures associated with BFNS have gone away. The age that epilepsy begins is variable.
## Frequency
Benign familial neonatal seizures occurs in approximately 1 in 100,000 newborns.
## Causes
Mutations in two genes, KCNQ2 and KCNQ3, have been found to cause BFNS. Mutations in the KCNQ2 gene are a much more common cause of the condition than mutations in the KCNQ3 gene.
The KCNQ2 and KCNQ3 genes provide instructions for making proteins that interact to form potassium channels. Potassium channels, which transport positively charged atoms (ions) of potassium into and out of cells, play a key role in a cell's ability to generate and transmit electrical signals.
Channels made with the KCNQ2 and KCNQ3 proteins are active in nerve cells (neurons) in the brain, where they transport potassium ions out of cells. These channels transmit a particular type of electrical signal called the M-current, which prevents the neuron from continuing to send signals to other neurons. The M-current ensures that the neuron is not constantly active, or excitable.
Mutations in the KCNQ2 or KCNQ3 gene result in a reduced or altered M-current, which leads to excessive excitability of neurons. Seizures develop when neurons in the brain are abnormally excited. It is unclear why the seizures stop around the age of 4 months. It has been suggested that potassium channels formed from the KCNQ2 and KCNQ3 proteins play a major role in preventing excessive excitability of neurons in newborns, but other mechanisms develop during infancy.
About 70 percent of people with BFNS have a mutation in either the KCNQ2 or the KCNQ3 gene. Researchers are working to identify other gene mutations involved in this condition.
### Learn more about the genes associated with Benign familial neonatal seizures
* KCNQ2
* KCNQ3
## Inheritance Pattern
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the mutation from one affected parent. A few cases result from new mutations in the KCNQ2 gene. These cases occur in people with no history of benign familial neonatal seizures in their family.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Benign familial neonatal seizures | c2751195 | 6,825 | medlineplus | https://medlineplus.gov/genetics/condition/benign-familial-neonatal-seizures/ | 2021-01-27T08:25:42 | {"gard": ["1519"], "mesh": ["C567743"], "omim": ["121200", "121201"], "synonyms": []} |
## Summary
### Clinical characteristics.
MYH9-related disorders (MYH9RD) are characterized by large platelets (i.e., >40% of platelets >3.9 μm in diameter) and thrombocytopenia (platelet count <150 x 109/L), both of which are present from birth. MYH9RD is variably associated with young-adult onset of progressive sensorineural hearing loss, presenile cataract, elevation of liver enzymes, and renal disease manifesting initially as glomerular nephropathy. Before identification of the gene in which mutation is causative, MYH9, individuals with MYH9RD were diagnosed as having Epstein syndrome, Fechtner syndrome, May-Hegglin anomaly, or Sebastian syndrome based on the combination of different clinical findings at the time of diagnosis. However, the realization that they all are due to heterozygous pathogenic variants in MYH9 and that the clinical findings often worsen throughout life as a result of late onset of non-hematologic manifestations has led the four conditions to be regarded as one disorder, now known as MYH9RD.
### Diagnosis/testing.
The diagnosis is established by the finding of typical MYH9 protein aggregates in neutrophils detected through immunofluorescence analysis of a peripheral blood smear and/or by the identification of a heterozygous pathogenic variant in MYH9. Absence of MYH9 protein aggregates in neutrophils excludes the diagnosis of MYH9RD.
### Management.
Treatment of manifestations: For active hemorrhage, application of local measures, desmopressin (DDAVP), and antifibrinolytic agents are used; platelet transfusion is necessary for: hemorrhages not controlled by the above treatments, life-threatening bleeding, or hemorrhages at critical sites. Hearing loss, renal complications, and cataract are managed in a standard fashion; individuals with severe/profound deafness benefit from cochlear implantation.
Prevention of primary manifestations: Platelet transfusion, desmopressin, antifibrinolytic drugs, or eltrombopag can be used to reduce the risk of bleeding prior to surgery or invasive procedures; oral contraceptives may be effective in preventing or treating menorrhagia; regular dental care to prevent gingival bleeding.
Surveillance: In those with bleeding episodes, blood count at least every six months to identify anemia. In all affected individuals, annual urinalysis (including 24-hour protein or protein [albumin]/creatinine ratio on a spot urine sample) and measurement of serum concentration of creatinine prior to onset of renal disease; serum liver enzyme measurements and audiometric and ophthalmologic evaluations every three years.
Agents/circumstances to avoid: Drugs that inhibit platelet function or blood coagulation; ototoxic, nephrotoxic, and hepatotoxic drugs should be used only after careful assessment of risk versus benefit; hazardous noise and activities with high risk of injury should be avoided.
Evaluation of relatives at risk: Screen at-risk newborns with molecular genetic testing if the family-specific pathogenic variant is identified; otherwise assess platelet count and size.
Pregnancy management: Deliveries should be managed as they are in women with other forms of thrombocytopenia; a platelet count of ≥50 x 109/L is generally recommended for safe delivery.
### Genetic counseling.
MYH9RD is inherited in an autosomal dominant manner. Approximately 35% of affected individuals represent simplex cases, half of whom have a documented de novo pathogenic variant. Each offspring of an individual with MYH9RD has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known.
## Diagnosis
The MYH9-related disorders (MYH9RD) were thought to be separate conditions involving congenital macrothrombocytopenia prior to the understanding of their shared molecular genetic basis.
### Suggestive Findings
MYH9-related disorders (MYH9RD) should be suspected in individuals with the following clinical and laboratory findings.
Clinical findings
* Manifestations of thrombocytopenia
* Easy bruising
* Spontaneous mucocutaneous bleedings
* Excessive bleeding after hemostatic challenges (major or minor surgery, deliveries, treatment with antiplatelet drugs).
* Sensorineural hearing loss. See Hereditary Hearing Loss and Deafness Overview for discussion of audiologic methods to detect hearing loss.
* Glomerular nephropathy with possible renal failure (see Laboratory Findings below).
* Presenile cataract (occurring in early or middle life detected on slit lamp evaluation).
* Family history consistent with autosomal dominant inheritance.
Note: Lack of a family history of MYH9RD does not preclude the diagnosis.
Laboratory findings
* Routine blood cell counts demonstrate thrombocytopenia (platelet count <150 x 109/L [normal: 150 to 400 x 109/L])
* Microscopic assessment of a peripheral blood smear after conventional staining (such as May-Grünwald-Giemsa) demonstrates:
* Large platelets (mean platelet diameter >3.7 μm and/or >40% of platelets with diameter >3.9 µm [about half a red blood cell])
Note: Electronic cell counters do not recognize the largest platelets of individuals with MYH9RD and therefore underestimate both platelet count and size in these subjects.
* Döhle-like bodies (faint, light blue basophilic inclusion bodies similar to the Döhle bodies that may be found in persons with an infection) in the cytoplasm of neutrophils
Note: Döhle-like bodies are present in 42%-84% of individuals with MYH9RD. They may escape detection because they are very faint and/or small [Kunishima et al 2003, Seri et al 2003].
* Immunofluorescence of a peripheral blood smear demonstrates typical MYH9 protein aggregates in the cytoplasm of neutrophils. These aggregates are:
* Present from birth;
* Detectable in all affected individuals with a heterozygous MYH9 pathogenic variant [Kunishima et al 2003, Savoia et al 2010, Kitamura et al 2013, Pecci et al 2014a].
Note: In neutrophils of unaffected individuals, MYH9 protein is uniformly distributed.
* Elevated liver enzymes (serum alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST] and occasionally serum gamma-glutamyltransferase [GGT])
* Urinalysis demonstrating proteinuria and microhematuria
Note: Proteinuria is the earlier sign of kidney involvement
* Elevated serum creatinine concentration (indicating progression to renal failure and risk for end-stage renal disease [ESRD])
### Establishing the Diagnosis
The diagnosis of MYH9RD is established in a proband with typical MYH9 protein aggregates in neutrophils detected through immunofluorescence analysis of a peripheral blood smear and/or by the identification of a heterozygous pathogenic variant in MYH9 (see Table 1).
Molecular testing approaches can include single-gene testing and use of a multigene panel.
Single-gene testing. Sequence analysis of MYH9 is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
Tiered approaches to sequence analysis and exon numbering may vary among laboratories (see Molecular Genetics for exon numbering information).
* Tier 1. Of the 40 coding exons of MYH9, sequence first the five exons in which pathogenic variants are found in 84% of cases. Pathogenic missense variants at amino acid residues 96 (exon 1), 702 (exon 17), 1165 (exon 27), 1424 (exon 31), and 1841 (exon 39), or nonsense and frameshift pathogenic variants in exon 41 have been found in 79% of affected individuals (see Table 2).
* Tier 2. When pathogenic variants are not detected in Tier 1 testing, the analysis is extended to exons 2, 11, 25, 26, 32, 33, 35, and 38, in which the remaining 16% of pathogenic variants have been identified [Balduini et al 2011].
* Tier 3. In individuals without an identifiable pathogenic variant in Tier 1 or Tier 2 testing, sequence analysis of all coding exons is performed.
A multigene panel that includes MYH9 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
### Table 1.
Molecular Genetic Testing Used in MYH9-Related Disorders
View in own window
Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
MYH9Sequence analysis 3, 498% 5, 6
Gene-targeted deletion/duplication analysis 7Unknown 8
1\.
See Table A. Genes and Databases for chromosome locus and protein.
2\.
See Molecular Genetics for information on allelic variants detected in this gene.
3\.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4\.
Sequence analysis may be performed with a tiered approach that focuses initially on exons in which pathogenic variants are most commonly found, then on exons in which pathogenic variants have previously been identified, and finally on the remainder of the gene.
5\.
Affected individuals: those with an aggregate distribution of MYH9 protein in neutrophils [Savoia et al 2010]
6\.
No MYH9 pathogenic variants have been detected in individuals of two case series (36 and 39 subjects, respectively) with clinical findings suggestive of MYH9RD but without MYH9 protein aggregates detected through immunofluorescence [Savoia et al 2010, Kitamura et al 2013].
7\.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
8\.
Because a large deletion of 1220 nucleotides leading to an in-frame removal of exon 25 has been identified in MYH9 [Kunishima et al 2008b], gene-targeted deletion/duplication analysis may be appropriate in families with a strong clinical history and no identifiable MYH9 pathogenic variant on sequence analysis.
## Clinical Characteristics
### Clinical Description
In all individuals with an MYH9-related disorder (MYH9RD), macrothrombocytopenia is present at birth. Mean platelet diameter was 4.5 μm (95% confidence interval, 4.2-4.8) in 125 persons with MYH9RD and 2.6 μm (95% confidence interval, 2.4-2.7) in 55 healthy controls [Noris et al 2014a]. Thrombocytopenia ranges from mild to severe and remains stable in an individual throughout life. Platelet counts at the lower limit of normal range have been reported in a few individuals with MYH9RD. Thus, large platelets are the only finding shared among all affected individuals.
Presence and severity of spontaneous bleeding tendency correlate with the degree of thrombocytopenia. Most affected individuals have no spontaneous bleeding or only easy bruising. About 28% of persons with MYH9RD have spontaneous mucocutaneous bleeding, including epistaxis, gum bleeding, or menorrhagia [Pecci et al 2014a]. Life-threatening bleeding is rare.
The noncongenital manifestations of MYH9RD can develop anytime between infancy and adulthood. The overall annual rates per 100 affected persons are 1.71 for sensorineural hearing loss, 0.77 for nephropathy, and 0.57 for cataract [Pecci et al 2014a] (i.e., for example, 0.57% of individuals with MYH9RD develop cataract every year). Alteration of liver enzymes has been found in about 50% of individuals with MYH9RD who have been evaluated [Pecci et al 2012a].
Sensorineural hearing loss. Onset of hearing loss is distributed evenly from the first to sixth decade. Of those who develop hearing loss, 36% do so before age 20 years, 33% between ages 20 and 40 years, and 31% after age 40 years. Once diagnosed, hearing loss frequently progresses over time, although it remains stable in a minority of affected individuals [Verver et al 2016]. Hearing loss interfering with activities of daily living is present in 90% of those individuals who have an abnormal audiometric examination [Pecci et al 2014a].
Glomerular nephropathy presents with proteinuria and microhematuria. However, in MYH9RD, hematuria may result from thrombocytopenia rather than glomerular disease; therefore, proteinuria is the more reliable indicator of glomerular involvement. The mean age at onset is 27 years. Of those who develop renal disease, 72% are diagnosed before age 35 years. In most affected individuals with nephropathy, kidney damage is progressive and evolves to end-stage renal disease (ESRD). Among those with nephropathy, the overall annual rate for 100 affected persons for progression to ESRD is 6.79. After a median follow-up of 36 months, 64% of 61 affected individuals with nephropathy developed renal failure and 43% developed ESRD [Pecci et al 2014a].
Cataract. The mean age of onset of cataract is 37 years, although congenital forms have been reported. In most cases, cataract is bilateral and progresses over time.
Elevated liver enzyme levels. Elevated AST and/or ALT (possibly associated with increased GGT) usually remains stable over time. In some affected individuals, normalization of enzyme levels has been observed. Progression to impairment of liver function has not been reported in any affected individual [Pecci et al 2012a, Favier et al 2013a].
### Genotype-Phenotype Correlations
Identification of the family-specific MYH9 pathogenic variant can help assess the risk of developing the noncongenital features of the disease.
Affected individuals with pathogenic variants involving the head domain of the MYH9 protein have more severe thrombocytopenia compared to those with pathogenic variants affecting the tail domain. The risk of developing kidney damage, hearing loss, and cataract also depends on the specific MYH9 pathogenic variant [Pecci et al 2014a]. See Molecular Genetics, Normal gene product for domain structure, Molecular Genetics, Pathogenic variants, and Table 2.
* Pathogenic variants in the codon for arginine residue 702, which is located in the short functional SH1 helix of the head domain, are associated with the most severe phenotype. Individuals with Arg702 substitutions (Table 2) present with severe thrombocytopenia (platelet count usually <50 x 109/L) and all are expected to develop nephropathy and hearing loss before age 40 years. Moreover, nephropathy usually progresses rapidly to ESRD in these individuals.
* The p.Asp1424His substitution is associated with an intermediate to high risk of developing the noncongenital manifestations of the disease. Most affected individuals with the p.Asp1424His variant develop kidney damage before age 60 years; all are expected to develop hearing loss within 60 years; the risk for cataracts is higher than in those with other genotypes.
* Pathogenic variants involving the residues at the interface between the SH3-like motif and the motor domain or those resulting in substitutions of the arginine residue 1165 (see Table 2) are associated with a high risk for hearing loss (all are expected to develop hearing loss before age 60 years) and a low risk for nephropathy and cataract.
* The p.Asp1424Asn and p.Glu1841Lys substitutions, as well as the nonsense or frameshift pathogenic variants resulting in alterations of the non-helical tailpiece (see Table 2), are associated with low risk of developing the noncongenital manifestations of the disease. In individuals with these pathogenic variants, thrombocytopenia usually remains the only manifestation of the disease throughout life [Pecci et al 2014a].
To date, no significant genotype-phenotype correlations have been identified for the occurrence of liver enzyme alteration [Pecci et al 2012a].
### Penetrance
Penetrance is complete for the following congenital findings:
* Large platelets
* MYH9 aggregates in neutrophils
Except for a few individuals in whom platelet count was just above the conventional cut-off value for thrombocytopenia (150 x 109/L), thrombocytopenia is a congenital manifestation of the disease.
Expressivity varies for onset and severity of sensorineural deafness, glomerular nephropathy, presenile cataract, and alterations of liver enzymes.
### Nomenclature
In the past, the conditions included in MYH9RD were known as
* Epstein syndrome
* Fechtner syndrome
* May-Hegglin anomaly
* Sebastian syndrome (Sebastian platelet syndrome)
These four disorders, characterized by thrombocytopenia with giant platelets, were classified on the basis of morphologic aspects of Döhle-like bodies and different combinations of the other manifestations of MYH9RD: hearing loss, glomerular nephropathy, and cataract. However, because the phenotype of a person with an MYH9 pathogenic variant often evolves over time, the diagnosis of an individual can change over time based on the appearance of a new finding or findings. Moreover, the four syndromes do not define all the possible manifestations deriving from heterozygous MYH9 pathogenic variants. Finally, members of the same family may have different phenotypes and receive different diagnoses within the spectrum of MYH9RD. For these reasons, MYH9RD has been proposed as a new nosologic entity that includes all individuals with heterozygous MYH9 pathogenic variants independent of their neutrophil phenotype (i.e., presence of morphologic aspects of Döhle-like bodies) and clinical phenotype (late-onset non-hematologic manifestations) [Seri et al 2003].
### Prevalence
MYH9RD is considered a very rare disease. The Italian Registry for MYH9RD includes 180 Italian affected individuals, indicating that the prevalence of the disorder in Italy is at least 3:1,000,000. Because mild forms are discovered incidentally and severe forms are often misdiagnosed as other disorders, the actual prevalence is expected to be higher.
MYH9RD has been diagnosed worldwide and there is no evidence of variation in prevalence across ethnic populations.
## Differential Diagnosis
MYH9-related disorder (MYH9RD) should be suspected in all individuals with congenital thrombocytopenia and giant platelets. It should also be considered when macrothrombocytopenia is discovered incidentally in infancy or adulthood and no previous blood counts are available to determine if the macrothrombocytopenia is congenital or acquired.
Absence of thrombocytopenia in other family members does not exclude MYH9RD because the frequency of de novo pathogenic variants is high (~35% of probands) [Balduini et al 2011].
The differential diagnosis of MYH9RD should take into consideration acquired and congenital forms of thrombocytopenia as well as collagen IV-related nephropathies.
Acquired thrombocytopenia. Differentiating MYH9RD from acquired forms of thrombocytopenia may be difficult and several individuals with MYH9RD have been misdiagnosed with idiopathic (autoimmune) thrombocytopenic purpura (ITP). This led to administration of treatments (immunosuppressive drugs and splenectomy) that are ineffective in individuals with MYH9RD. Whenever a family history of thrombocytopenia is absent or unclear, evaluation of peripheral blood slides is a simple and effective tool to distinguish individuals with MYH9RD from those with ITP, as platelets are significantly larger in persons with MYH9RD than in those with ITP. In particular, a mean platelet diameter >3.7 µm distinguishes MYH9RD from ITP with 86% sensitivity and 87% specificity. Otherwise, a proportion of platelets with diameter >3.9 µm (about half a red blood cell) higher than 40% differentiates MYH9RD from ITP with 85% sensitivity and 87% specificity [Noris et al 2014a].
Congenital thrombocytopenia. The following inherited thrombocytopenias presenting with large platelets should be considered in the differential diagnosis of MYH9RD:
* Bernard-Soulier syndrome (BSS) (OMIM 231200), an autosomal recessive nonsyndromic thrombocytopenia resulting from pathogenic variants in the genes coding for platelet glycoproteins (GP) GPIbα, GPIbβ, and GPIX, which together with subunit GPV constitute the von Willebrand factor receptor, GPIb/IX/V. Platelets in BSS can be as large as in MYH9RD. Bernard-Soulier syndrome is recognized by (1) failure of platelets to agglutinate in vitro after stimulation with ristocetin, and (2) absence or severe reduction of the GPIb/IX/V complex on the platelet surface detected by flow cytometry. More than 200 cases with a molecular diagnosis have been reported in the literature.
* Gray platelet syndrome (OMIM 139090), a very rare autosomal recessive nonsyndromic thrombocytopenia resulting from pathogenic variants in NBEAL2. The hallmark of Gray platelet syndrome is the finding of "pale" platelets on peripheral blood films as a result of lack of alpha granules. Electron microscopy of platelets or the finding of biallelic pathogenic variants in NBEAL2 confirms the diagnosis. Approximately 30 families have been reported in the literature.
* GATA1-related X-linked cytopenia, another rare condition characterized by a mild to moderate hemolytic anemia sometimes associated with hemoglobin changes similar to heterozygous beta-thalassemia. An estimated fourteen families have been reported in the literature.
Collagen IV-related nephropathies, including X-linked and autosomal (dominant and recessive) forms of Alport syndrome and thin basement membrane nephropathy. Whereas the latter is characterized mainly by persistent microscopic hematuria, which rarely progresses to renal failure, Alport syndrome is associated with renal disease that evolves from microscopic hematuria to proteinuria, progressive renal insufficiency, and ESRD. It is also characterized by extrarenal abnormalities including progressive sensorineural hearing loss (usually present by late childhood or early adolescence), anterior lenticonus, maculopathy, corneal endothelial vesicles, and recurrent corneal erosion. Platelet defects have not been described in either Alport syndrome or thin basement membrane nephropathy. Therefore, whenever nephropathies are associated with macrothrombocytopenia, MYH9RD should be strongly considered.
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with an MYH9-related disorder (MYH9RD), the following evaluations are recommended:
* Microscopic assessment of platelet count (phase contrast microscopy by a counting chamber) to determine the degree of thrombocytopenia
* In individuals with bleeding episodes, complete blood count to evaluate for anemia
* In individuals with anemia, serum concentration of iron and ferritin level to evaluate for iron deficiency
* Audiometric evaluation
In those with severe to profound deafness, speech recognition tests
* Measurement of serum concentration of AST, ALT, and GGT
* Urinalysis, including measurement of 24-hour protein or protein (or albumin)/creatinine ratio on a spot urine sample, and measurement of serum concentration of creatinine
* In individuals with established renal involvement, testing appropriate to the severity of renal disease
* Ophthalmologic examination
* Consultation with a clinical geneticist and/or genetic counselor
### Treatment of Manifestations
Bleeding tendency
* Local measures are the first-line treatment for mucocutaneous bleeding and often are sufficient to control mild or moderate bleeding. Local measures include packing or endoscopic cauterization of the bleeding site for treatment of epistaxis; suturing for treatment of accidental or surgical wounds; and compression and application of gauzes soaked in tranexamic acid for bleeding from superficial wounds. Mouthwash with tranexamic acid may control gingival bleeding.
* Transfusions of platelet concentrates are currently used to transiently increase platelet count. Platelet transfusions have associated risks of possible alloimmunization and subsequent refractoriness to platelet infusions, infectious diseases, and acute reactions. Thus, platelet transfusions should be limited to treatment for active hemorrhages that cannot be otherwise managed, life-threatening bleedings, and/or hemorrhages at critical sites; platelet concentrates may also be used as prophylaxis prior to surgery or other major hemostatic stresses. When available, platelets from HLA-matched donors should be used to prevent or overcome alloimmunization.
* Eltrombopag. A Phase II study in 12 persons with MYH9RD and severe thrombocytopenia demonstrated that eltrombopag, an oral drug mimicking the natural hormone that stimulates platelet production, increased platelet counts and abolished bleeding tendency in most instances [Pecci et al 2010]. Thereafter, short-term eltrombopag courses have been successfully used in one affected adult prior to major surgery and in one child with MYH9RD and severe thrombocytopenia [Pecci et al 2012b, Favier et al 2013b]. At the present time, this drug is approved in the US and Europe only for individuals with some forms of acquired thrombocytopenia.
* Antifibrinolytic agents. Some authors recommend the systemic administration of antifibrinolytic agents, such as tranexamic or epsilon-aminocaproic acid, to treat mild or moderate mucocutaneous bleeding [Bolton-Maggs et al 2006, Althaus & Greinacher 2009].
* Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) shortened bleeding time in some individuals with MYH9RD [Balduini et al 1999]. Successful surgery after prophylaxis with DDAVP has been reported [Pecci et al 2014b]. As not all affected individuals respond to the treatment, a test dose is recommended to identify those who will benefit from this treatment either in future bleeding episodes or in prevention of bleeding at the time of invasive procedures.
Deafness. A total of 11 individuals with an established diagnosis of MYH9RD and severe to profound deafness have received cochlear implantations [Pecci et al 2014b, Nabekura et al 2015]. Ten of them benefited from cochlear implants; nine of them obtained restoration of practically normal hearing and verbal communication abilities.
Glomerular nephropathy
* Four affected individuals with renal involvement had their proteinuria greatly reduced by treatment with angiotensin receptor blockers and/or angiotensin-converting enzyme inhibitors [Pecci et al 2008]. It is premature to conclude whether this therapeutic approach prevents or delays the development of ESRD.
* Dialysis or kidney transplantation is required in individuals with ESRD.
Cataracts. Cataract surgery remedies clouding of the lens.
Elevation of liver enzymes does not require any specific treatment.
### Prevention of Primary Manifestations
Thrombocytopenia cannot be prevented; however, the risk of bleeding can be significantly reduced through education regarding drugs that affect platelet function (see Agents/Circumstances to Avoid).
Affected individuals should be prepared for surgery or other invasive procedures with platelet transfusions, desmopressin, antifibrinolytic drugs, or eltrombopag according to the individual's platelet count and history of bleeding.
Oral contraceptives are often effective in preventing or controlling menorrhagia; however, oral contraceptives increase the risk of thrombosis, which has also been described in individuals with MYH9RD. Thus, the balance between risks and benefits associated with use of oral contraceptives should be considered [Heller et al 2006, Nishiyama et al 2008, Girolami et al 2011].
Regular dental care and good oral hygiene are essential to prevent gingival bleeding.
### Surveillance
The following evaluations should be considered at the suggested maximum intervals:
Every six months. blood count in individuals with bleeding episodes to identify anemia; more frequent counts are appropriate in cases of recurrent profuse bleeding.
Every year
* Urinalysis (including measurement of 24-hour protein or protein (or albumin)/creatinine ratio on spot urine sample)
* Measurement of serum concentration of creatinine
* For individuals with an established renal defect, referral to a nephrologist
Every three years
* Audiometric evaluation. Once hearing loss is identified, the frequency of follow-up evaluations is determined by the treating hearing specialists.
* Ophthalmologic evaluation. Once cataract is identified, the frequency of evaluations is determined by the treating ophthalmologist.
* Measurement of serum AST, ALT and GGT
* In individuals with alterations of liver enzymes, alternative causes of liver damage should be investigated.
* If alternative causes are excluded, the frequency of the liver enzyme measurements depends on the severity of the alteration.
### Agents/Circumstances to Avoid
Bleeding tendency
* Agents. Drugs that inhibit platelet function or blood coagulation:
* Nonsteroidal anti-inflammatory drugs (NSAIDs), especially aspirin, which are strong inhibitors of platelet aggregation
* Other substances that interfere with platelet function including some antibiotics; cardiovascular, psychotropic, and oncologic drugs; drugs that affect platelet cAMP; some anesthetics; antihistamines; and radiographic contrast agents
Note: (1) Drugs that impair platelet function should be prescribed only after a careful assessment of the risks versus the benefits. (2) Physicians should try to avoid prescribing any other drugs that increase the risk of bleeding in individuals with MYH9RD. (3) Individuals with MYH9RD can develop thromboembolic events [Girolami et al 2011]. The use of antithrombotic agents (such as heparin) must be carefully balanced against the risks according to the overall clinical picture of each affected individual.
* Circumstances. In individuals with moderate to severe thrombocytopenia, avoidance of activities at high risk of trauma (e.g., contact sports)
Hearing loss
* Agents. Ototoxic drugs (e.g., aminoglycoside antibiotics, salicylates in large quantities, loop diuretics, some drugs used in chemotherapy regimens). These should be used only after a careful assessment of the risks versus the benefits.
* Circumstances. Exposure to hazardous noise. If noise exposure cannot be avoided, use ear devices (e.g., earplugs, headphones) to attenuate intense sound.
Nephropathy
* Agents that can damage renal function, including radiocontrast, antibiotics, NSAIDs, diuretics, and oncologic drugs. The balance between benefit and risk of such agents should be carefully considered, especially in individuals with established kidney involvement or with MYH9 pathogenic variants associated with high risk for kidney damage.
Cataract
* Agents. Glucocorticoids and radiation therapy, which predispose to development of cataracts
Elevation of liver enzymes
* Agents. In affected individuals with liver enzyme elevation, assessment of risks versus benefits before use of potentially hepatotoxic drugs
### Evaluation of Relatives at Risk
It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.
* Assessing platelet count and size in a newborn at risk for MYH9RD identifies those at risk for bleeding.
* If the family-specific pathogenic variant is known, molecular genetic testing can be used to evaluate at-risk family members so that early diagnosis can inform treatment.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Pregnancy Management
Deliveries should be managed as they are in women with other forms of thrombocytopenia (MYH9RD is not usually associated with defects of platelet function). As expected, pregnant women whose thrombocytopenia and bleeding history before pregnancy are more severe have a higher incidence of delivery-related bleeding. In general, a platelet count of ≥50 x 109/L is recommended for safe delivery. Vaginal deliveries in women with severe thrombocytopenia should be considered at increased risk for neonatal intracranial bleeding [Noris et al 2014b].
### Therapies Under Investigation
Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| MYH9-Related Disorders | c1854520 | 6,826 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK2689/ | 2021-01-18T21:12:55 | {"mesh": ["C535507"], "synonyms": []} |
A number sign (#) is used with this entry because autosomal dominant dyskeratosis congenita-2 (DKCA2) and autosomal recessive dyskeratosis congenita-4 (DKCB4) are caused by heterozygous and homozygous or compound heterozygous mutation, respectively, in the TERT gene (187270) on chromosome 5p15.
Description
Dyskeratosis congenita is a multisystem disorder caused by defective telomere maintenance. Features are variable and include bone marrow failure, pulmonary and liver fibrosis, and premature graying of the hair (summary by Armanios et al., 2005).
For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (127550).
Clinical Features
Armanios et al. (2005) reported a 3-generation family in which at least 6 members had autosomal dominant dyskeratosis congenita without skin manifestations. Common but variable features included gray forelock or premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, liver fibrosis, and abnormal dentition. Anticipation of clinical features was observed, and all affected individuals showed increased frequency of short telomeres compared to unaffected family members. Molecular analysis excluded the TERC gene (602322) and identified a pathogenic heterozygous mutation in the TERT gene (187270.0007).
Basel-Vanagaite et al. (2008) reported an Iraqi Jewish family with autosomal dominant dyskeratosis congenita-2. Affected males presented with thrombocytopenia, and later developed aplastic anemia, premature graying of the hair, and pulmonary and hepatic fibrosis. One patient developed cardiac fibrosis and another developed dilated cardiomyopathy. Anticipation for these features was observed. Whereas all 6 males of the family were severely affected, 2 female mutation carriers had only premature gray hair; however, all mutation carriers had a similar shortening of telomere length.
### Autosomal Recessive Dyskeratosis Congenita 4
Marrone et al. (2007) reported 2 unrelated patients, both born of consanguineous parents, with autosomal recessive dyskeratosis congenita-4. A 13-year-old Libyan girl had poor growth, bone marrow failure, reticulated pigmentation of the skin, leukoplakia, and nail dysplasia. Her parents had mild manifestations, such as dysplastic toenails and hyperpigmented skin. The second patient was a 3-year-old girl, born of consanguineous Iranian-Jewish parents, who had early bone marrow failure, leukoplakia, failure to thrive, cerebellar hypoplasia, microcephaly, and developmental delay. Telomere lengths were severely shortened in the patient and at the low-normal level in each parent. Marrone et al. (2007) noted that the presence of developmental delay and cerebellar hypoplasia in the second patient was consistent with a clinical diagnosis of Hoyeraal-Hreidarsson syndrome, which is a severe variant of DKC.
Du et al. (2008) reported a 31-year-old Scottish man with DKCB4 who had a severe phenotype, including short stature, elfin appearance, esophageal stricture, leukoplakia of the buccal mucosa, anus, and penis, abnormal pigmentation, hyperkeratosis of his palms, ridged fingernails, avascular necrosis of both hips, tooth loss, chronic diarrhea, learning difficulties, pulmonary infiltrates, and progressive bone marrow failure. Laboratory studies showed very short telomeres, and genetic analysis showed a homozygous mutation in the TERT gene (187270.0014).
Pathogenesis
Batista et al. (2011) showed that even in the undifferentiated state, induced pluripotent stem cells (iPSCs) from dyskeratosis congenita patients harbor the precise biochemical defects characteristic of each form of the disease and that the magnitude of the telomere maintenance defect in iPSCs correlates with clinical severity. In iPSCs from patients with heterozygous mutations in TERT, the telomerase reverse transcriptase, a 50% reduction in telomerase levels blunts the natural telomere elongation that accompanies reprogramming. In contrast, mutation of dyskerin (DKC1; 300126) in X-linked dyskeratosis congenita severely impairs telomerase activity by blocking telomerase assembly and disrupts telomere elongation during reprogramming. In iPSCs from a form of dyskeratosis congenita caused by mutations in TCAB1 (also known as WRAP53, 612661), telomerase catalytic activity is unperturbed, yet the ability of telomerase to lengthen telomeres is abrogated, since telomerase mislocalizes from Cajal bodies to nucleoli within the iPSCs. Extended culture of DKC1-mutant iPSCs leads to progressive telomere shortening and eventual loss of self-renewal, indicating that a similar process occurs in tissue stem cells in dyskeratosis congenita patients. Their findings in iPSCs from dyskeratosis congenita patients led Batista et al. (2011) to conclude that undifferentiated iPSCs accurately recapitulate features of a human stem cell disease and may serve as a cell culture-based system for the development of targeted therapeutics.
Molecular Genetics
In all 6 affected members of a family with autosomal dominant dyskeratosis congenita, Armanios et al. (2005) identified a heterozygous mutation in the TERT gene (K902N; 187270.0007).
In affected members of an Iraqi Jewish family with DKCA2, Basel-Vanagaite et al. (2008) identified a heterozygous mutation in the TERT gene (R631Q; 187270.0011).
### Autosomal Recessive Dyskeratosis Congenita 4
Marrone et al. (2007) identified homozygous TERT mutations (187270.0012 and 187270.0013) in patients with a severe form of autosomal recessive dyskeratosis congenita-4.
INHERITANCE \- Autosomal dominant \- Autosomal recessive GROWTH Height \- Short stature Other \- Failure to thrive (seen in recessive form) HEAD & NECK Head \- Microcephaly (seen in recessive form) Mouth \- Leukoplakia (seen in recessive form) \- Bluish discoloration of the tongue (seen in recessive form) Teeth \- Abnormal dentition \- Tooth loss (seen in recessive form) CARDIOVASCULAR Heart \- Cardiac fibrosis \- Dilated cardiomyopathy RESPIRATORY Lung \- Pulmonary fibrosis ABDOMEN Liver \- Liver fibrosis Gastrointestinal \- Esophageal stricture (seen in recessive form) \- Chronic diarrhea (seen in recessive form) SKELETAL \- Osteoporosis Limbs \- Avascular necrosis of the hip (seen in recessive form) SKIN, NAILS, & HAIR Skin \- Reticulated pigmentation (seen in recessive form) \- Leukoplakia (seen in recessive form) \- Hyperkeratosis of the palms (seen in recessive form) Nails \- Nail dystrophy (seen in recessive form) Hair \- Gray forelock \- Premature graying NEUROLOGIC Central Nervous System \- Learning difficulties (seen in recessive form) \- Developmental delay (seen in recessive form) \- Cerebellar hypoplasia (seen in recessive form) HEMATOLOGY \- Bone marrow failure \- Pancytopenia \- Aplastic anemia \- Thrombocytopenia \- Leukopenia LABORATORY ABNORMALITIES \- Shortened telomeres \- Decreased telomerase activity MISCELLANEOUS \- Two autosomal dominant families have been reported (as of May 2011) \- Highly variable phenotype and severity, even within families \- Variable penetrance and expressivity \- Age at onset ranges from childhood to adulthood \- Genetic anticipation \- Patients with the autosomal recessive disorder have a more severe phenotype MOLECULAR BASIS \- Caused by mutation in the telomerase reverse transcriptase gene (TERT, 187270.0007 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| DYSKERATOSIS CONGENITA, AUTOSOMAL DOMINANT 2 | c1846142 | 6,827 | omim | https://www.omim.org/entry/613989 | 2019-09-22T15:56:47 | {"doid": ["0070016"], "mesh": ["C536068"], "omim": ["613989"], "orphanet": ["3322", "1775"], "genereviews": ["NBK22301"]} |
A number sign (#) is used with this entry because of evidence that cerebrooculofacioskeletal syndrome-3 (COFS3) is caused by homozygous mutation in the ERCC5 gene (133530) on chromosome 13q33.
Biallelic mutations in the ERCC5 gene can also cause Xeroderma pigmentosum, group G and/or Cockayne syndrome (278780).
Description
Cerebrooculofacioskeletal syndrome is a severe, progressive neurologic disorder characterized by prenatal onset of arthrogryposis, microcephaly, and growth failure. Postnatal features include severe developmental delay, congenital cataracts (in some), and marked UV sensitivity of the skin. Survival beyond 6 years of age is rare. COFS represents the severe end of the spectrum of disorders caused by mutations in nucleotide excision repair (NER) genes, with Cockayne syndrome and xeroderma pigmentosum being milder NER-related phenotypes (summary by Drury et al., 2014).
For a phenotypic description and a discussion of genetic heterogeneity of cerebrooculofacioskeletal syndrome, see COFS1 (214150).
Clinical Features
Hamel et al. (1996) and Nouspikel et al. (1997) studied a male who was born to healthy first-cousin Moroccan parents and had extremely severe early-onset Cockayne syndrome leading to death at 7 months of age. Graham et al. (2001) referred to the case reported by Hamel et al. (1996) as one of cerebrooculofacioskeletal syndrome. The patient showed prenatal-onset growth deficiency, severe microcephaly, microphthalmia with no cataracts, cleft palate, cutaneous photosensitivity, and brain atrophy with no calcifications. Skin fibroblasts showed extreme cellular sensitivity to UV, comparable to that in classic XP.
Drury et al. (2014) reported a family of Pakistani ancestry in which 5 fetuses conceived to 3 pairs of first cousins presented with abnormal ultrasound findings in the second trimester, including contractures and microcephaly. All pregnancies were terminated and underwent autopsy. Variable intracerebral findings included 2 instances of ventriculomegaly, 2 of delayed cerebral sulcation, and 2 of cerebellar hypoplasia/posterior fossa abnormalities. The 1 fetus that survived beyond 24 weeks developed progressive edema. None of the fetuses had cataracts.
Inheritance
The transmission pattern of COFS3 in the family reported by Drury et al. (2014) was consistent with autosomal recessive inheritance.
Mapping
By linkage analysis of a consanguineous Pakistani kindred in which 5 fetuses were affected with COFS, Drury et al. (2014) found linkage to a 9.3-Mb region on chromosome 13q32.3-q33.3 (lod score of 5.0).
Molecular Genetics
In a boy, born of consanguineous Moroccan parents, with COFS originally reported by Hamel et al. (1996), Nouspikel et al. (1997) identified a homozygous truncating mutation in the ERCC5 gene (133530.0003).
In 4 fetuses from a large consanguineous Pakistani kindred with COFS3, Drury et al. (2014) identified a homozygous truncating mutation in the ERCC5 gene (133530.0016) predicting the loss of the C terminus. The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed.
INHERITANCE \- Autosomal recessive GROWTH Other \- Intrauterine growth retardation HEAD & NECK Head \- Microcephaly Face \- Micrognathia Ears \- Low-set ears Eyes \- Microphthalmia (in some patients) Mouth \- Cleft palate (in some patients) SKELETAL \- Arthrogryposis Hands \- Clenched fists Feet \- Rocker bottom feet \- Talipes equinovarus SKIN, NAILS, & HAIR Skin \- Sun sensitivity MUSCLE, SOFT TISSUES \- Edema NEUROLOGIC Central Nervous System \- Lack of psychomotor development \- Immature cerebral sulcation (in some patients) \- Posterior fossa abnormalities (in some patients) PRENATAL MANIFESTATIONS Movement \- Decreased fetal movements LABORATORY ABNORMALITIES \- Increased cellular UV sensitivity MISCELLANEOUS \- Early death \- One consanguineous Pakistani family and 1 unrelated patient have been reported (last curated September 2015) MOLECULAR BASIS \- Caused by mutation in the excision repair, complementing defective, in Chinese hamster, 5 gene (ERCC5, 133530.0003 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| CEREBROOCULOFACIOSKELETAL SYNDROME 3 | c0009207 | 6,828 | omim | https://www.omim.org/entry/616570 | 2019-09-22T15:48:31 | {"mesh": ["D003057"], "omim": ["616570"], "orphanet": ["191", "1466"]} |
Pancolitis
This condition affects the large intestine.
Pancolitis, in its most general sense, refers to inflammation of the entire colon. This can be caused by a variety of things. Pancolitis or universal colitis is frequently used in a more specific fashion to denote a very severe form of ulcerative colitis. This form of ulcerative colitis is spread throughout the entire large intestine including the right colon, the left colon, the transverse colon, descending colon, and the rectum. A diagnosis can be made using a number of techniques but the most accurate method is direct visualization via a colonoscopy.[1] Symptoms are similar to those of ulcerative colitis but more severe and affect the entire large intestine. Patients with ulcerative colitis generally exhibit symptoms including rectal bleeding as a result of ulcers, pain in the abdominal region, inflammation in varying degrees, and diarrhea (often containing blood). Pancolitis patients exhibit these symptoms and may also experience fatigue, fever, and night sweats.[2][3] Due to the loss of function in the large intestine patients may lose large amounts of weight from being unable to procure nutrients from food.[4] In other cases the blood loss from ulcers can result in anemia which can be treated with iron supplements. Additionally, due to the chronic nature of most cases of pancolitis, patients have a higher chance of developing colon cancer.
Pancolitis is a kind of inflammatory bowel disease (IBD) that affects the entire internal lining of the colon. The precise causes of this inflammatory disorder are unclear, although physicians currently believe that autoimmune diseases and genetic predispositions might play a role in its progress. Genes that are known to put individuals at risk for Crohn’s disease have been shown to also increase risk of other IBD including pancolitis.[5] Furthermore, an individual may also develop pancolitis if ulcerative colitis of only a small portion of the colon is left untreated or worsens.[3] Current treatment of pancolitis is focused on forcing the disease into remission, a state where the majority of the symptoms subside. Ultimately, the goal is to reach an improved quality of life, reduction in need for medicine, and minimization of the risk of cancer.[3][6] Medication utilized in treatment includes anti-inflammatory agents and corticosteroids to alleviate inflammation and immunomodulators which act to suppress the immune system. Immunomodulators are used in severe cases of ulcerative colitis and often utilized to treat patients with pancolitis who have shown little improvement with anti-inflammatories and corticosteroids.[2][3][5] However, in this case it can further expose the patient to other diseases due to the compromised immune system. A final option of treatment is available in the form of surgery. Generally, this option is reserved for only the cases in which cancer development is highly suspected or major hemorrhaging from ulcers occurs. In this case the entire colon and rectum are removed which both cures the pancolitis and prevents any chance of colon cancer. Patients who undergo surgery either must have their stool collect in a reservoir made in place of the rectum or have the end of the small intestine attached to the anus. In the latter case the diseased portion of the anus must be removed, but the muscles are left intact, allowing bowel movement to still take place.[7]
## References[edit]
1. ^ Bennett, A. L.; Buckton, S.; Lawrance, I.; Leong, R. W.; Moore, G.; Andrews, J. M. (2015-12-01). "Ulcerative colitis outpatient management: development and evaluation of tools to support primary care practitioners". Internal Medicine Journal. 45 (12): 1254–1266. doi:10.1111/imj.12872. ISSN 1445-5994. PMID 26256445.
2. ^ a b Hoy, Sheridan M. (2015-04-29). "Budesonide MMX®: A Review of Its Use in Patients with Mild to Moderate Ulcerative Colitis". Drugs. 75 (8): 879–886. doi:10.1007/s40265-015-0396-8. ISSN 0012-6667. PMID 25920500.
3. ^ a b c d "Ulcerative Colitis Symptoms, Diet, Treatment & Medication". Retrieved 2016-06-27.
4. ^ "Ulcerative colitis". 2016-03-17. Retrieved 2016-06-27.
5. ^ a b Franke, Andre; Balschun, Tobias; Sina, Christian; Ellinghaus, David; Häsler, Robert; Mayr, Gabriele; Albrecht, Mario; Wittig, Michael; Buchert, Eva (2010). "Genome-wide association study for ulcerative colitis identifies risk loci at 7q22 and 22q13 (IL17REL)". Nature Genetics. 42 (4): 292–294. doi:10.1038/ng.553. PMID 20228798.
6. ^ "Ulcerative Colitis in Adults | American College of Gastroenterology". www.gi.org. Retrieved 2016-06-27.
7. ^ Vella, M., Masood, M. R., & Hendry, W. S. (2007). Surgery for ulcerative colitis. Surgeon (Edinburgh University Press), 5(6), 356-362.
## External links[edit]
* UC
* Description of UC
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Pancolitis | c0868908 | 6,829 | wikipedia | https://en.wikipedia.org/wiki/Pancolitis | 2021-01-18T19:02:09 | {"umls": ["C0868908"], "icd-9": ["556.6"], "icd-10": ["K51.0"], "wikidata": ["Q7130382"]} |
Familial anetoderma is an extremely rare genetic skin disease characterized by loss of elastin tissue leading to localized areas of flaccid skin and a family history of the disorder.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Familial anetoderma | c4518793 | 6,830 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=228277 | 2021-01-23T19:04:30 | {"icd-10": ["L90.8"], "synonyms": ["Hereditary anetoderma", "Hereditary macular atrophy"]} |
Hypomyelination-congenital cataract is characterized by the onset of cataract either at birth or in the first two months of life, delayed psychomotor development by the end of the first year of life and moderate intellectual deficit.
## Epidemiology
The syndrome has been described in 10 children from five different families.
## Clinical description
Progressive weakness of the muscles in the lower limbs was also reported.
## Etiology
The progressive neurological degeneration is caused by hypomyelination of the central and peripheral nervous systems. The syndrome is caused by mutations in hyccin, a recently identified nuclear membrane protein encoded by the FAM126A gene (7p15.3).
## Genetic counseling
It is transmitted as an autosomal recessive trait.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Hypomyelination-congenital cataract syndrome | c1864663 | 6,831 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=85163 | 2021-01-23T17:14:27 | {"gard": ["11980"], "mesh": ["C567166"], "omim": ["610532"], "umls": ["C1864663"], "icd-10": ["G37.8"]} |
Tricho–rhino–phalangeal syndrome type 2
Other namestrichorhinophalangeal syndrome with exostosis[1]
Tricho–rhino–phalangeal syndrome type 2 (also known as Langer-Giedion syndrome) is a genetic disorder consisting of fine and sparse scalp hair, thin nails, pear-shaped broad nose, and cone-shaped epiphyses of the middle phalanges of some fingers and toes.[2]:578[3]
It has been associated with TRPS1.[4]
## See also[edit]
* Skin lesion
* List of cutaneous conditions
## References[edit]
1. ^ "Trichorhinophalangeal syndrome type II". Genetics Home References. NIH. Retrieved 19 March 2019.
2. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
3. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 716. ISBN 978-1-4160-2999-1.
4. ^ Momeni P, Glöckner G, Schmidt O, et al. (January 2000). "Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I". Nat. Genet. 24 (1): 71–4. doi:10.1038/71717. PMID 10615131. S2CID 21447066.
## External links[edit]
Classification
D
* OMIM: 190350
* v
* t
* e
Genetic disorders relating to deficiencies of transcription factor or coregulators
(1) Basic domains
1.2
* Feingold syndrome
* Saethre–Chotzen syndrome
1.3
* Tietz syndrome
(2) Zinc finger
DNA-binding domains
2.1
* (Intracellular receptor): Thyroid hormone resistance
* Androgen insensitivity syndrome
* PAIS
* MAIS
* CAIS
* Kennedy's disease
* PHA1AD pseudohypoaldosteronism
* Estrogen insensitivity syndrome
* X-linked adrenal hypoplasia congenita
* MODY 1
* Familial partial lipodystrophy 3
* SF1 XY gonadal dysgenesis
2.2
* Barakat syndrome
* Tricho–rhino–phalangeal syndrome
2.3
* Greig cephalopolysyndactyly syndrome/Pallister–Hall syndrome
* Denys–Drash syndrome
* Duane-radial ray syndrome
* MODY 7
* MRX 89
* Townes–Brocks syndrome
* Acrocallosal syndrome
* Myotonic dystrophy 2
2.5
* Autoimmune polyendocrine syndrome type 1
(3) Helix-turn-helix domains
3.1
* ARX
* Ohtahara syndrome
* Lissencephaly X2
* MNX1
* Currarino syndrome
* HOXD13
* SPD1 synpolydactyly
* PDX1
* MODY 4
* LMX1B
* Nail–patella syndrome
* MSX1
* Tooth and nail syndrome
* OFC5
* PITX2
* Axenfeld syndrome 1
* POU4F3
* DFNA15
* POU3F4
* DFNX2
* ZEB1
* Posterior polymorphous corneal dystrophy
* Fuchs' dystrophy 3
* ZEB2
* Mowat–Wilson syndrome
3.2
* PAX2
* Papillorenal syndrome
* PAX3
* Waardenburg syndrome 1&3
* PAX4
* MODY 9
* PAX6
* Gillespie syndrome
* Coloboma of optic nerve
* PAX8
* Congenital hypothyroidism 2
* PAX9
* STHAG3
3.3
* FOXC1
* Axenfeld syndrome 3
* Iridogoniodysgenesis, dominant type
* FOXC2
* Lymphedema–distichiasis syndrome
* FOXE1
* Bamforth–Lazarus syndrome
* FOXE3
* Anterior segment mesenchymal dysgenesis
* FOXF1
* ACD/MPV
* FOXI1
* Enlarged vestibular aqueduct
* FOXL2
* Premature ovarian failure 3
* FOXP3
* IPEX
3.5
* IRF6
* Van der Woude syndrome
* Popliteal pterygium syndrome
(4) β-Scaffold factors
with minor groove contacts
4.2
* Hyperimmunoglobulin E syndrome
4.3
* Holt–Oram syndrome
* Li–Fraumeni syndrome
* Ulnar–mammary syndrome
4.7
* Campomelic dysplasia
* MODY 3
* MODY 5
* SF1
* SRY XY gonadal dysgenesis
* Premature ovarian failure 7
* SOX10
* Waardenburg syndrome 4c
* Yemenite deaf-blind hypopigmentation syndrome
4.11
* Cleidocranial dysostosis
(0) Other transcription factors
0.6
* Kabuki syndrome
Ungrouped
* TCF4
* Pitt–Hopkins syndrome
* ZFP57
* TNDM1
* TP63
* Rapp–Hodgkin syndrome/Hay–Wells syndrome/Ectrodactyly–ectodermal dysplasia–cleft syndrome 3/Limb–mammary syndrome/OFC8
Transcription coregulators
Coactivator:
* CREBBP
* Rubinstein–Taybi syndrome
Corepressor:
* HR (Atrichia with papular lesions)
This Genodermatoses article is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Tricho–rhino–phalangeal syndrome type 2 | c0265255 | 6,832 | wikipedia | https://en.wikipedia.org/wiki/Tricho%E2%80%93rhino%E2%80%93phalangeal_syndrome_type_2 | 2021-01-18T19:06:35 | {"umls": ["C0265255"], "orphanet": ["324764"], "wikidata": ["Q3508794"]} |
Ectopic kidney
Other namesRenal ectopia
Ectopic crossed fused kidney in a fetus approx. 34 weeks
SpecialtyNephrology
Ectopic kidney describes a kidney that is not located in its usual position. It results from the kidney failing to ascend from its origin in the true pelvis or from a superiorly ascended kidney located in the thorax.[1]
It has an incidence of approximately 1/900.[2]
## See also[edit]
* Crossed dystopia
## References[edit]
1. ^ "Ectopic Kidney - Renal Ectopia - Causes, Symptoms, Diagnosis, Treatment, Complications". Medindia. 18 March 2015. Retrieved 23 December 2016.
2. ^ "Ectopic Kidney". Archived from the original on 2011-06-08. Retrieved 2007-12-01.
## External links[edit]
Classification
D
* ICD-10: Q63.2
* ICD-9-CM: 753.3
* v
* t
* e
Congenital malformations and deformations of urinary system
Abdominal
Kidney
* Renal agenesis/Potter sequence, Papillorenal syndrome
* cystic
* Polycystic kidney disease
* Meckel syndrome
* Multicystic dysplastic kidney
* Medullary sponge kidney
* Horseshoe kidney
* Renal ectopia
* Nephronophthisis
* Supernumerary kidney
* Pelvic kidney
* Dent's disease
* Alport syndrome
Ureter
* Ectopic ureter
* Megaureter
* Duplicated ureter
Pelvic
Bladder
* Bladder exstrophy
Urethra
* Epispadias
* Hypospadias
* Posterior urethral valves
* Penoscrotal transposition
Vestigial
Urachus
* Urachal cyst
* Urachal fistula
* Urachal sinus
This article related to the genitourinary system is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Ectopic kidney | c0238207 | 6,833 | wikipedia | https://en.wikipedia.org/wiki/Ectopic_kidney | 2021-01-18T18:54:52 | {"umls": ["C0238207"], "icd-9": ["753.3"], "icd-10": ["Q63.2"], "wikidata": ["Q3718783"]} |
A sweat allergy is the exacerbation of atopic dermatitis associated with an elevated body temperature and resulting increases in the production of sweat. It appears as small reddish wheals that become visible in response to increased temperature and resulting production of sweat.[1] It can affect all ages. Sweating can trigger intense itching or cholinergic urticaria. The protein MGL_1304 secreted by mycobiota present on the skin such as Malassezia globosa acts as a histamine or antigen. People can be desensitized using their own samples of sweat that have been purified that contains small amounts of the allergen.[2][3] The allergy is not due to the sweat itself but instead to an allergy-producing protein secreted by bacteria found on the skin.[4]
Cholinergic urticaria (CU) is one of the physical urticaria which is provoked during sweating events such as exercise, bathing, staying in a heated environment, or emotional stress. The hives produced are typically smaller than classic hives and are generally shorter-lasting.[5][6]
Multiple subtypes have been elucidated, each of which require distinct treatment.[7][8]
Tannic-acid has been found to suppress the allergic response along with showering.[2]
## See also[edit]
* Miliaria
* Exercise-induced anaphylaxis
* Idiopathic pure sudomotor failure
* Hypohidrosis
* Fabry disease
* Allergy
* Food allergy
* List of allergens
* Tree nut allergy
* Cholinergic urticaria
## References[edit]
1. ^ Kan, Takanobu; Hiragun, Takaaki; Ishii, Kaori; Hiragun, Makiko; Yanase, Yuhki; Tanaka, Akio; Hide, Michihiro (2015). "Evaluation of recombinant MGL_1304 produced by Pichia pastoris for clinical application to sweat allergy". Allergology International. 64 (3): 266–271. doi:10.1016/j.alit.2015.03.003. PMID 26117259.
2. ^ a b Hiragun, Takaaki; Hiragun, Makiko; Ishii, Kaori; Kan, Takanobu; Hide, Michihiro (2017). "Sweat allergy: Extrinsic or intrinsic?". Journal of Dermatological Science. 87 (1): 3–9. doi:10.1016/j.jdermsci.2017.03.002. PMID 28416076.
3. ^ Hiragun, Takaaki; Hide, Michihiro (2016). "Sweat Allergy". Perspiration Research. Current Problems in Dermatology. 51. Karger Publishers. pp. 101–108. doi:10.1159/000446788. ISBN 978-3-318-05904-5. PMID 27584969.
4. ^ Yokozeki, Hiroo (2016). Perspiration research. Basel New York: Karger. p. 52. ISBN 9783318059052.
5. ^ Moore-Robinson, Miriam; Warin, Robert P. (1968). "Some Clikical Aspects of Cholhstergic Urticaria". British Journal of Dermatology. 80 (12): 794–9. doi:10.1111/j.1365-2133.1968.tb11948.x. PMID 5706797.
6. ^ Hirschmann, J. V.; Lawlor, F; English, JS; Louback, JB; Winkelmann, RK; Greaves, MW (1987). "Cholinergic Urticaria - A Clinical and Histologic Study". Archives of Dermatology. 123 (4): 462–7. doi:10.1001/archderm.1987.01660280064024. PMID 3827277.
7. ^ Nakamizo, S.; Egawa, G.; Miyachi, Y.; Kabashima, K. (2012). "Cholinergic urticaria: Pathogenesis-based categorization and its treatment options". Journal of the European Academy of Dermatology and Venereology. 26 (1): 114–6. doi:10.1111/j.1468-3083.2011.04017.x. PMID 21371134.
8. ^ Bito, Toshinori; Sawada, Yu; Tokura, Yoshiki (2012). "Pathogenesis of Cholinergic Urticaria in Relation to Sweating". Allergology International. 61 (4): 539–44. doi:10.2332/allergolint.12-RAI-0485. PMID 23093795.
* v
* t
* e
Allergic conditions
Respiratory system
* Allergic rhinitis (hay fever)
* Asthma
* Hypersensitivity pneumonitis
* Eosinophilic pneumonia
* Eosinophilic granulomatosis with polyangiitis
* Allergic bronchopulmonary aspergillosis
* Farmer's lung
* Laboratory animal allergy
Skin
* Angioedema
* Urticaria
* Atopic dermatitis
* Allergic contact dermatitis
* Hypersensitivity vasculitis
Blood and immune system
* Serum sickness
Circulatory system
* Anaphylaxis
Digestive system
* Coeliac disease
* Eosinophilic gastroenteritis
* Eosinophilic esophagitis
* Food allergy
* Egg allergy
* Milk intolerance
Nervous system
* Eosinophilic meningitis
Genitourinary system
* Acute interstitial nephritis
Other conditions
* Drug allergy
* Allergic conjunctivitis
* Latex allergy
* v
* t
* e
Hypersensitivity and autoimmune diseases
Type I/allergy/atopy
(IgE)
Foreign
* Atopic eczema
* Allergic urticaria
* Allergic rhinitis (Hay fever)
* Allergic asthma
* Anaphylaxis
* Food allergy
* common allergies include: Milk
* Egg
* Peanut
* Tree nut
* Seafood
* Soy
* Wheat
* Penicillin allergy
Autoimmune
* Eosinophilic esophagitis
Type II/ADCC
* * IgM
* IgG
Foreign
* Hemolytic disease of the newborn
Autoimmune
Cytotoxic
* Autoimmune hemolytic anemia
* Immune thrombocytopenic purpura
* Bullous pemphigoid
* Pemphigus vulgaris
* Rheumatic fever
* Goodpasture syndrome
* Guillain–Barré syndrome
"Type V"/receptor
* Graves' disease
* Myasthenia gravis
* Pernicious anemia
Type III
(Immune complex)
Foreign
* Henoch–Schönlein purpura
* Hypersensitivity vasculitis
* Reactive arthritis
* Farmer's lung
* Post-streptococcal glomerulonephritis
* Serum sickness
* Arthus reaction
Autoimmune
* Systemic lupus erythematosus
* Subacute bacterial endocarditis
* Rheumatoid arthritis
Type IV/cell-mediated
(T cells)
Foreign
* Allergic contact dermatitis
* Mantoux test
Autoimmune
* Diabetes mellitus type 1
* Hashimoto's thyroiditis
* Multiple sclerosis
* Coeliac disease
* Giant-cell arteritis
* Postorgasmic illness syndrome
* Reactive arthritis
GVHD
* Transfusion-associated graft versus host disease
Unknown/
multiple
Foreign
* Hypersensitivity pneumonitis
* Allergic bronchopulmonary aspergillosis
* Transplant rejection
* Latex allergy (I+IV)
Autoimmune
* Sjögren syndrome
* Autoimmune hepatitis
* Autoimmune polyendocrine syndrome
* APS1
* APS2
* Autoimmune adrenalitis
* Systemic autoimmune disease
This cutaneous condition article is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Sweat allergy | c1304346 | 6,834 | wikipedia | https://en.wikipedia.org/wiki/Sweat_allergy | 2021-01-18T18:40:35 | {"umls": ["C1304346"], "wikidata": ["Q2256746"]} |
A number sign (#) is used with this entry because of evidence that lethal congenital contracture syndrome-5 (LCCS5) is caused by homozygous mutation in the DNM2 gene (602378) on chromosome 19p13. One such family has been reported.
Heterozygous mutation in the DNM2 gene can also cause a form of autosomal dominant Charcot-Marie-Tooth disease (606482) and autosomal dominant centronuclear myopathy (CNM1; 160150).
For a general phenotypic description and a discussion of genetic heterogeneity of LCCS, see LCCS1 (253310).
Clinical Features
Koutsopoulos et al. (2013) reported 3 sibs, born of consanguineous Pakistani parents, with a lethal congenital neuromuscular syndrome. All exhibited decreased fetal movements, polyhydramnios, and decreased birth weight. At birth, all showed severe hypotonia with respiratory insufficiency, lack of reflexes, joint contractures, and thin ribs and bones. In addition, all had retinal hemorrhages and 2 had evidence of intracranial bleeding (subdural hematoma and blood in the subarachnoid cavity). Muscle biopsy of 1 patient showed small rounded fibers with some centralized nuclei, suggestive of a congenital myopathy component, whereas muscle biopsy of another patient showed showed atrophic fibers without obvious centralization of nuclei. EMG studies of 1 patient suggested a myopathy or lower motor neuron disease, whereas in the other 2 patients, EMG revealed low nerve conduction velocities, suggesting a hypomyelinating neuropathy or anterior horn disease. Death occurred at ages 5 days, 19 days, and 4 months. Both parents showed decreased reflexes on examination, and skeletal muscle biopsy of the mother showed fiber size variation and centralized nuclei, suggestive of a mild form of centronuclear myopathy.
Inheritance
The transmission pattern of a lethal congenital contracture syndrome in the family reported by Koutsopoulos et al. (2013) was consistent with autosomal recessive inheritance.
Molecular Genetics
In 3 sibs, born of consanguineous Pakistani parents, with a lethal congenital contracture syndrome, Koutsopoulos et al. (2013) identified a homozygous missense mutation in the DNM2 gene (F379V; 602378.0013). The mutation, which was found by homozygosity mapping followed by candidate gene sequencing, segregated with the disorder and was not present in controls. Studies on patient cells and in vitro functional analysis indicated that the mutation was hypomorphic. Animal studies in mice and zebrafish suggested a role for Dnm2 in the development of muscle fibers and vasculature.
Animal Model
Koutsopoulos et al. (2013) found that morpholino knockdown of Dnm2 in zebrafish embryos resulted in lethality in 10% and bent tails in 20%. Morphants showed mild misalignment of muscle fibers; muscular innervation appeared normal. There were also defects in the endothelium of the vascular system. The findings suggested that Dnm2 has a pleiotropic role during development.
INHERITANCE \- Autosomal recessive GROWTH Other \- Low birth weight HEAD & NECK Eyes \- Retinal hemorrhage RESPIRATORY \- Respiratory insufficiency CHEST Ribs Sternum Clavicles & Scapulae \- Thin ribs SKELETAL \- Joint contractures \- Thin bones MUSCLE, SOFT TISSUES \- Hypotonia \- Muscle biopsy shows atrophic fibers \- Small rounded fibers \- Centralized nuclei \- EMG may show myopathic features NEUROLOGIC Central Nervous System \- Lack of spontaneous movement \- Intracranial bleeding Peripheral Nervous System \- Areflexia \- Decreased nerve conduction velocities PRENATAL MANIFESTATIONS Movement \- Decreased fetal movements Amniotic Fluid \- Polyhydramnios LABORATORY ABNORMALITIES \- Increased serum creatine kinase MISCELLANEOUS \- Onset in utero \- Death in infancy \- One family has been reported (last curated August 2013) MOLECULAR BASIS \- Caused by mutation in the dynamin-2 gene (DNM2, 602378.0013 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| LETHAL CONGENITAL CONTRACTURE SYNDROME 5 | c3809272 | 6,835 | omim | https://www.omim.org/entry/615368 | 2019-09-22T15:52:26 | {"omim": ["615368"], "orphanet": ["363409"], "synonyms": ["MYOPATHY, CENTRONUCLEAR, LETHAL, AUTOSOMAL RECESSIVE", "Alternative titles", "LCCS5", "Lethal congenital contracture syndrome type 5"]} |
A number sign (#) is used with this entry because chronic lymphocytic leukemia (CLL) is associated with genetic and epigenetic changes in multiple genes.
Description
Chronic lymphocytic leukemia (CLL) is a common neoplasia of B lymphocytes in which these cells progressively accumulate in the bone marrow, blood, and lymphoid tissues. The clinical evolution of the disorder is heterogeneous, with some patients having indolent disease and others having aggressive disease and short survival (summary by Quesada et al., 2012).
### Genetic Heterogeneity of Susceptibility to Chronic Lymphocytic Leukemia
Susceptibility loci have been mapped to chromosomes 11p11 (CLLS1; 609630) and 13q14 (CLLS2; 109543) by genomewide linkage analysis and translocation studies, respectively. Susceptibility mapping to chromosome 9q34 (CLLS3; 612557) is associated with downregulation of the DAPK1 gene (600831). Genomewide association studies have identified susceptibility loci on chromosomes 6p25.3 (CLLS4; 612558) and 11q24.1 (CLLS5; 612559).
Clinical Features
Wiley et al. (2002) noted that CLL is the most frequent type of leukemia in the developed world and results in the progressive accumulation of mature CD5 (153340)-positive B lymphocytes in blood and bone marrow of the affected person. Anemia and thrombocytopenia are features of advanced disease, but recurrent infections and splenomegaly, with or without lymphadenopathy, arise at all stages of CLL. Leukemic CD5-positive B lymphocytes have reduced ability to undergo apoptosis in vivo, a feature generally attributed to the antiapoptotic effects of overexpression of BCL2, although a defect in a proapoptotic pathway might also contribute to the prolonged survival of B lymphocytes in individuals with CLL.
O'Keefe et al. (2002) reported 2 adults, each with a pseudohypopyon (accumulation of tumor cells in the anterior chamber of the eye) due to B-cell lymphoma. In 1 patient, the ocular findings were the presenting signs; the other pseudohypopyon was found in a patient with known abdominal lymphoma. The authors concluded that pseudohypopyons may represent either the initial manifestation or a later complication of systemic lymphoma, similar to what had been reported in acute leukemia.
Inheritance
Chronic lymphocytic leukemia seems especially prone to familial occurrence. Studies of a large number of families (Gunz et al., 1975) indicated that the familial incidence of CLL is nearly 3 times higher than that expected for the general population. The first report of identical twins with CLL was that by Dameshek et al. (1929). Furbetta and Solinas (1963) reported affected grandfather, son, and grandson. Fraumeni et al. (1969) reported familial aggregation of chronic lymphocytic leukemia associated with immune defects in 3 sibs.
Branda et al. (1978) studied lymphocytes in a mother and son with chronic lymphocytic leukemia. Morphologic, functional and surface marker characteristics were very similar, as was the impairment of cellular and humoral immunity. Blattner et al. (1979) reported additional information on the family, including HLA studies and description of nodular, poorly differentiated lymphocytic lymphoma in the daughter of the proband.
Conley et al. (1980) found an increased frequency of chronic lymphocytic leukemia and also of autoimmune disease (hyperthyroidism, pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus) in families of patients with CLL. They concluded that genetic factors in these families disturb the regulation of the immune system.
Lynch et al. (2002) described a family in which the father and all 4 of his children had CLL. All of the children were male, and 2 were identical twins. CLL was diagnosed at the age of 77 in the father, at the ages of 56 and 54 in the identical twins, and at the ages of 47 and 39 in the other brothers. See 612557.
Goldin et al. (2004) used the Swedish Family Cancer Database to test for increased familial risks of CLL and other lymphoproliferative tumors. They found that relatives of cases were at significantly increased risk for CLL (relative risk (RR) = 7.52), for non-Hodgkin lymphoma (605027) (RR = 1.45), and for Hodgkin lymphoma (236000) (RR = 2.35). CLL risks were similar in parents, sibs, and offspring of cases, in male and female relatives, and were not affected by the case's age at diagnosis. Anticipation was not significant when analyzed using life table methods. Goldin et al. (2004) concluded that the familial component of CLL is shared with other lymphoproliferative malignancies, suggesting common genetic pathways; however, because clinically diagnosed CLL is uncommon, absolute excess risk to relatives is small.
### Genetic Anticipation
Horwitz et al. (1996) reported evidence of anticipation in autosomal dominant chronic lymphocytic leukemia (p = 0.008). In 18 affected individuals from 7 pedigrees with autosomal dominant CLL, the mean age of onset in the parental generation was 66 years, versus 51 years in the younger generation. Based on this evidence of anticipation, Horwitz et al. (1996) suggested that dynamic mutations of unstable DNA sequence repeats could be a common mechanism of inherited hematopoietic malignancy. They proposed 3 possible candidate chromosomal regions for familial leukemia with anticipation: 21q22.1-22.2, 11q23.3 in the vicinity of the CBL2 gene (165360), and 16q22 in the vicinity of the CBFB gene (121360).
In a study of 13 families with CLL in 2 successive generations, Goldin et al. (1999) found evidence of anticipation, i.e., earlier disease onset in generation 2. They ruled out various biases that could account for the finding, and stated that they planned to look for expanded trinucleotide repeats in candidate genes in families showing anticipation.
Among 7 CLL families with 2 affected generations showing anticipation (mean presentation parental age of onset 78 years; mean second generation age of onset 50 years), Auer et al. (2006) found no trinucleotide repeat (TNR) expansions in DNA isolated from malignant B cells at 10 CCG- and CAG-repeat loci within the genome that have previously been associated with the phenomenon of anticipation in other disorders. Transmission of repeats followed a mendelian pattern of inheritance in both the control and diseased families. There was also no evidence for TNR expansion among samples from patients with sporadic CLL. There was some evidence for minor differences in the frequency of certain allele lengths present in the patient samples at certain loci.
Cytogenetics
Blattner et al. (1976) reported CLL in 4 of 5 sibs and their father. Follow-up by Neuland et al. (1983) showed spontaneous regression of the disease in 1 sib and shifts in the clinical pattern in the others. The unaffected sib developed lung cancer. Two CLL patients had abnormality of chromosome 12: trisomy in 1 and a mixture of dicentrics and translocations involving chromosome 12 in the other. In this same family, Shen et al. (1987) found that 2 brothers had rearrangement of the same heavy-chain variable region gene. Shen et al. (1987) suggested that the particular V(H) gene, which had an unusual DNA sequence, defined a previously unrecognized V(H) gene family. It was thought to be representative of the genome by, at most, 4 homologous sequences.
### Translocations Involving 11q13 and 14q32
Tsujimoto et al. (1984) cloned the chromosomal breakpoint of CLL cells of the B-cell type carrying t(11;14)(q13;q32). The breakpoint was in the joining segment of the heavy chain locus on chromosome 14. A probe specific for chromosome 11 that mapped immediately 5-prime to the breakpoint on 14q+ detected a rearrangement of the homologous genomic DNA segment in CLL cells; DNA from a diffuse large cell lymphoma with the t(11;14) translocation showed the same rearrangement. This rearranged DNA segment was not present in Burkitt lymphoma cells with the t(8;14) translocation or in nonneoplastic human lymphoblastoid cells. Tsujimoto et al. (1984) concluded that the gene on 11q13, which the authors termed BCL1 (CCND1; 168461), is implicated in the malignant transformation of cells carrying the t(11;14) translocation.
In 2 different cases of B-cell CLL, Tsujimoto et al. (1985) found that the breakpoints on chromosome 11 were within 8 nucleotides of each other and the breakpoints on chromosome 14 involved the J4 DNA segment of the Ig heavy chain segment (see, e.g., IGHV; 147070). Because they detected a 7mer-9mer signal-like sequence with a 12-base-long spacer on the normal chromosome 11 close to the breakpoint, the authors speculated that the t(11;14) chromosome translocation in CLL may be sequence specific and may involve the recombination system for immunoglobulin V-D-J gene segment joining.
Translocation t(14;19)(q32;q13.1) is also a recurring translocation in the neoplastic cells of patients with CLL. In 1 such patient, McKeithan et al. (1987) analyzed the leukemic cells with probes from the immunoglobulin heavy-chain locus. Using a probe for the IGHA1 gene (146900), they detected a rearranged band by Southern blot analysis. After cloning and mapping, a subclone (BCL3; 109560) was shown to be from chromosome 19 by analysis of human-mouse somatic cell hybrids, confirming that the rearranged band contained the translocation breakpoint junction.
### Other Cytogenetic Abnormalities
Espinet et al. (2003) described a sister and brother, 63 and 61 years old at examination, respectively, with B-cell CLL with different abnormal karyotypes detected by conventional cytogenetics: deletion of 7q32 in the sister and an insertion in 1p36 and deletion of 6q21 in the brother. Both sibs had a del(13)(q14) at the D13S319 locus, detected by interphase FISH.
The most frequent deletion of genomic DNA in CLL occurs in chromosome 13q14. This deletion is evident in about 50% of cases and is associated with a long interval between diagnosis and the need for treatment, the so-called treatment-free interval (Dohner et al., 2000). The 13q14 deletion is frequently the sole abnormality in CLL and other types of cancers (Calin et al., 2005).
Ng et al. (2007) identified a deletion at chromosome 13q14 in 11 (85%) of 13 patients with hereditary CLL studied by FISH analysis. Fine mapping of the 13q region found that affected members of 4 families with CLL shared a minimally deleted 3.68-Mb candidate region on chromosome 13q21.33-q22.2 between D13S1324 and D13S162. In 1 family, all affected individuals with CLL had deletions in 13q14 and shared a haplotype at 13q21.33-q22.2, suggesting that inherited factors may predispose to CLL. Two asymptomatic sibs with CD5+ monoclonal B-cell lymphocytosis (MBL) carried the at-risk haplotype at 13q21.33-q22.2, one of whom also had a 13q14 deletion, suggesting a relationship between CLL and MBL. Ng et al. (2007) suggested that 13q24 deletions may represent a very early genomic change in a cascade of genetic events that predispose to developing CLL and/or MBL. Direct sequencing analysis detected no frameshift or nonsense mutations in the coding region of 13 genes in the chromosome 13q21-q22 region.
Pathogenesis
In a review of molecular diagnosis of hematologic cancers, Staudt (2003) noted that studies of immunoglobulin gene mutations in CLL cells suggested that CLL may be 2 distinct diseases. The presence of somatic mutations in the immunoglobulin genes of CLL cells defined a group of patients with stable or slowly progressive disease requiring late or no treatment. By contrast, the absence of immunoglobulin gene mutations in CLL cells defined a group of patients who had a progressive clinical course requiring early treatment. These 2 subtypes of CLL may also differ with respect to oncogenic mechanisms, since deletion of the ATM locus (607585) on chromosome 11q is associated with the absence of immunoglobulin gene mutations in CLL and with shortened survival in some patients (Staudt, 2003). Expression of the single most discriminating gene, ZAP70 (176947), distinguished these 2 subtypes with 93% accuracy (Wiestner et al., 2003). Whereas analysis of the immunoglobulin gene sequence would be a challenging and expensive test to introduce into routine clinical practice, a quantitative RT-PCR assay or protein-based assay for the expression of ZAP70 was feasible, as indicated in the work of Crespo et al. (2003).
In 14 patients with CLL who were concordant for IgV(H) mutation status, CD38 (107270) expression, and clinical behavior, Scielzo et al. (2005) observed that patients with poor prognoses had mostly constitutively phosphorylated HS1 protein (601306), whereas only a fraction of HS1 was phosphorylated in patients with good prognoses. When a larger cohort of 26 unselected patients was investigated, the survival curve of all 40 patients revealed that those with predominantly phosphorylated HS1 had a significantly shorter median survival time. Scielzo et al. (2005) studied the expression pattern of HS1 after B-cell receptor engagement and found that normal mature B cells stimulated by anti-IgM shifted the non- or less-phosphorylated form of HS1 toward the more-phosphorylated form, naive B cells showed both HS1 forms, and memory B cells expressed mainly the phosphorylated fraction. Scielzo et al. (2005) concluded that antigen stimulation plays a central role in CLL.
Molecular Genetics
Puente et al. (2011) performed whole-genome sequencing of 4 cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified 4 genes that are recurrently mutated: NOTCH1 (190198), exportin-1 (XPO1; 602559), myeloid differentiation primary response gene-88 (MYD88; 602170), and kelch-like 6 (KLHL6; 614214). Somatic mutations in the NOTCH1 gene were found in 31 (12.2%) of 255 cases. Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are detected mainly in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicated that the recurrent NOTCH1, MYD88, and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease.
In a follow-up to the study of Puente et al. (2011), Quesada et al. (2012) used whole-exome sequencing of matched tumor and normal samples from 105 individuals with CLL to identify a median of 45 somatic mutations per case, involving 1,100 different genes. The number of protein-altering mutations per case was higher in those with somatic hypermutations in the variable regions of immunoglobulin genes (IGHV) than in those without such mutations. Among the 1,100 genes with somatic mutations, 78 genes were recurrently mutated, and 90% of patients had somatic mutations in at least 1 of the 78 recurrently mutated genes. Functional clustering analysis showed that many of the genes were involved in mRNA splicing pathways and transport and Toll-like receptor (see, e.g., TLR1, 601194) signaling and apoptosis. Specific mutated genes distinct from those reported by Puente et al. (2011) included SF3B1 (605590), POT1 (606478), CHD2 (602119), and LRP1B (608766). All POT1 somatic mutations appeared in tumors without IGHV region mutations, whereas CHD2 somatic mutations exclusively appeared in IGHV-mutated tumors. These findings supported the idea that different mechanisms are involved in disease development in CLL cases with and those without IGHV mutations. Sanger sequencing identified somatic mutations in the NOTCH1 gene in 25 (9.5%) of 260 cases of CLL, and somatic mutations in the SF3B1 gene were found in 27 (9.7%) of 279 cases of CLL. The SF3B1 gene encodes a protein involved in the spliceosomal U2 snRNP (RNU2-1; 180690), indicating an important role in gene expression. All SF3B1 mutations occurred in the nonidentical HEAT domains, and SF3B1-mutant cases showed enhanced expression of truncated mRNAs of various genes. Clinically, patients with SF3B1 mutations had faster disease progression and poorer overall survival compared to those with other mutations. No SF3B1 mutations were found in 156 cases of non-Hodgkin lymphoma (605027).
Wang et al. (2011) performed paired tumor and germline whole-exome and whole-genome sequencing from DNA samples in 91 patients with CLL. Nine genes were mutated at significant frequencies, including TP53 (191170) in 15% of patients, ATM (607585) in 9%, MYD88, in 10%, and NOTCH1 in 4%. Five novel genes were detected: SF3B1, ZMYM3 (300061), MAPK1 (176948), FBXW7 (606278), and DDX3X (300160). SF3B1, which functions at the catalytic core of the spliceosome, was the second most frequently mutated gene, with mutations occurring in 15% of patients. SF3B1 mutations occurred primarily in tumors with deletions in chromosome 11q, which are associated with a poor prognosis in patients with CLL. Wang et al. (2011) discovered that tumor samples with mutations in SF3B1 had alterations in pre-mRNA splicing.
Puente et al. (2015) described a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. Puente et al. (2015) extended the number of CLL driver alterations, including changes in ZNF292 (616213), ZMYM3, ARID1A (603024) and PTPN11 (176876). Puente et al. (2015) also identified novel recurrent mutations in noncoding regions, including the 3-prime region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity, and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5 (167414). The accumulative number of driver alterations (0 to 4 or more) discriminated between patients with differences in clinical behavior.
Landau et al. (2015) identified 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 CLL and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These included previously unrecognized putative cancer drivers (RPS15, 180535; IKZF3, 606221), and collectively identified RNA processing and export, MYC activity, and MAPK signaling as central pathways involved in CLL. Clonality analysis of this large dataset further enabled reconstruction of temporal relationships between driver events. Direct comparison between matched pretreatment and relapse samples from 59 patients demonstrated highly frequent clonal evolution.
For discussion of an association between CLL and somatic mutation in the GNB1 gene, see 139380.
### Associations Pending Confirmation
Wiley et al. (2002) presented evidence that a single-nucleotide polymorphism of the purinergic receptor P2RX7 on chromosome 12q24 resulting in the substitution E496A (see 602566) occurred with increased frequency in patients with CLL, suggesting that it may be a susceptibility factor.
Calin et al. (2005) found that all 5 members with cancer in a kindred with familial CLL harbored a W149X polymorphism in the ARL11 gene (609351) on chromosome 13q14, whereas 2 unaffected members who were analyzed did not. The only member of this kindred who was homozygous for the polymorphism had kidney carcinoma and thyroid adenoma when she was less than 50 years old. In the third generation, 6 members, 1 of whom had received the diagnosis of essential thrombocythemia (a premalignant state), had the polymorphism; the other 5 members were less than 40 years old.
Calin et al. (2002) used positional cloning to identify 2 members of a class of small, noncoding RNAs, or microRNAs, miR15A (609703) and miR16-1 (609704), which are located in the smallest region of the deletion at 13q14 and are frequently deleted or downregulated in CLL cells. The finding that approximately 50% of the known human microRNAs are located at cancer-associated regions of the genome (Calin et al., 2004) suggests that microRNAs play a role in the pathogenesis of various human cancers. Calin et al. (2005) found a unique microRNA expression signature composed of 13 genes that differentiated cases of CLL with low levels of ZAP70 (176947) expression from those with high levels and cases with unmutated immunoglobulin heavy-chain variable-region gene, IgV(H) (see 147070), from those with mutated IgV(H). The same microRNA signature was also associated with the presence or absence of disease progression. They also identified a germline mutation in the primary precursor of miR16-1/miR15A (609704), which caused low levels of microRNA expression in vitro and in vivo and was associated with deletion of the normal allele. Germline or somatic mutations were found in 5 of 42 sequenced microRNAs in 11 of 75 patients with CLL, but no such mutations were found in 160 subjects without cancer (p less than 0.001).
Cimmino et al. (2005) determined that the first 9 nucleotides of miR15A and miR16-1 are complementary to bases in a central region of BCL2 cDNA. By miRNA microarray chip and Western blot analysis of CD5-positive lymphocytes from 4 normal individuals and of samples from 26 CLL patients, they found that low miR15A and miR16-1 levels and high BCL2 protein levels correlated with disease. Overexpression of either miRNA did not affect BCL2 mRNA stability but regulated BCL2 expression at the posttranscriptional level, and overexpression of miR15A or miR16-1 in megakaryocytic leukemia cells induced apoptosis.
To identify novel susceptibility loci for CLL, Slager et al. (2011) performed a genomewide association study in 407 CLL cases, of which 102 had a family history of CLL, and 296 controls. To identify loci specific to these familial CLL cases, they separately analyzed the subset of cases with a family history of CLL. They evaluated their top hits from these analyses in an additional sample of 252 familial CLL cases and 965 controls. In the subset of familial CLL cases, Slager et al. (2011) identified and confirmed a novel locus on chromosome 6p21.3 harboring the HLA-DQA1 (146880) and HLA-DRB5 (604776) genes. The region was tagged by 5 SNPs, the most significant of which was rs674313 in the HLA-DRB5 gene (risk allele T, combined p = 6.92 x 10(-9)). This locus showed no evidence of association among the sporadic CLL cases. The findings of Slager et al. (2011) supported the hypothesis that familial CLL cases have additional genetic variants not seen in sporadic CLL. By linkage analysis, Bevan et al. (2000) had previously reported exclusion of an effect on CLL of genes within the MHC region on chromosome 6.
Berndt et al. (2013) conducted the largest metaanalysis for CLL to that time, including 4 genomewide association studies with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the metaanalysis, Berndt et al. (2013) identified 10 independent associated SNPs in 9 novel loci as well as an independent signal at a previously identified locus at chromosome 2q13.
Population Genetics
Hamblin (2004) pointed out that with sensitive techniques, a monoclonal population of B lymphocytes that is indistinguishable from CLL cells may be found in the blood of 3.5% of persons older than 40 years of age.
History
In the early days of clinical cytogenetics, Gunz et al. (1962) described a chromosome abnormality in CLL affecting a small acrocentric chromosome, probably number 21, and designated it the Ch(1) (Christchurch) chromosome. The abnormality was reported in 6 cases, but was not found in any later cytogenetic studies. Almost a decade would pass before banding methods were described (Caspersson et al., 1970) and almost 2 decades before reliable methods of in situ hybridization were developed.
INHERITANCE \- Autosomal dominant \- Somatic mutation HEMATOLOGY \- Chronic lymphatic leukemia IMMUNOLOGY \- Impaired cellular and humoral immunity LABORATORY ABNORMALITIES \- Recurring t(11,14) and t(14,19)(q32,q13.1) translocations MISCELLANEOUS \- Associated with susceptibility loci on chromosome 11p11 (CLLS1, 609630 ), 13q14 (CLLS2, 109543 ), 9q34.1 (CLLS3, 612557 ), 6p25.3 (CLLS4, 612558 ), and 11q24.1 (CLLS5, 612559 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| LEUKEMIA, CHRONIC LYMPHOCYTIC | c0855095 | 6,836 | omim | https://www.omim.org/entry/151400 | 2019-09-22T16:39:03 | {"doid": ["1040"], "omim": ["151400"], "icd-9": ["204.1"], "icd-10": ["C91.1", "C91.10"], "orphanet": ["67038"], "synonyms": ["Alternative titles", "LEUKEMIA, CHRONIC LYMPHATIC"]} |
Trisomy 18p is an extremely rare chromosomal anomaly with a poorly defined clinical phenotype. Reported manifestations include short stature, mild, moderate or severe developmental delay and intellectual disability, variable but mild facial dysmorphism, and epilepsy.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Trisomy 18p | c2931811 | 6,837 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1715 | 2021-01-23T17:45:40 | {"gard": ["5323"], "mesh": ["C538307"], "umls": ["C2931811"], "icd-10": ["Q92.2"], "synonyms": ["Duplication 18p", "Duplication of the short arm of chromosome 18", "Trisomy of the short arm of chromosome 18"]} |
A number sign (#) is used with this entry because of evidence that spermatogenic failure-38 (SPGF38) is caused by homozygous mutation in the ARMC2 gene (618424) on chromosome 6q21.
For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).
Description
Spermatogenic failure-38 (SPGF38) is characterized by primary infertility and asthenoteratozoospermia due to multiple morphologic abnormalities of the flagella (MMAF). Spermatozoa show total sperm motility below 10% and exhibit morphologic anomalies including short, absent, coiled, bent, or irregular-caliber flagella (Coutton et al., 2019).
Clinical Features
Coutton et al. (2019) studied 5 infertile men with MMAF and severe asthenoteratozoospermia. Semen volumes were normal with low sperm concentrations, and total motility was 6% or less, with some patients showing no motile sperm. Three patients had no normal spermatozoa, and the other 2 patients showed 2% and 3% normal sperm, respectively. The most common flagellar abnormality was irregular-caliber flagella, followed by short, absent, coiled, and bent flagella. Abnormal sperm heads were observed, including tapered, thin, and microcephalic, as well as multiple heads. A high proportion of sperm in some patients also showed an abnormal acrosomal region and abnormal base. Transmission electron microscopy was performed in sperm cells from 1 patient (ARMC2_1), in whom the main defect observed was the absence of the central-pair complex (9 + 0 conformation). Some sections showed severe axonemal disorganization associated with periaxonemal structural defects such as unassembled outer dense fibers. Rare longitudinal sections showed severe abnormalities such as truncated flagella or the presence of cytoplasmic structures encompassing unassembled axonemal components. Immunofluorescence analysis of sperm from patient ARMC2_1 showed total absence of SPAG6 (605730), an axoneme central-pair complex protein.
Molecular Genetics
In a cohort of 167 infertile men with MMAF, Coutton et al. (2019) performed whole-exome sequencing and identified 4 men with homozygous variants in the ARMC2 gene, including a splicing mutation (618424.0001), a missense mutation (I760N; 618424.0002), a 2-bp deletion (618424.0003), and a 5-bp deletion (618424.0004). In addition, a Chinese man with primary infertility and typical MMAF was found to be homozygous for an ARMC2 nonsense mutation (Q141X; 618424.0005), which segregated with disease in his family. All 5 men were negative for pathologic mutations in other MMAF-associated genes, and none of the ARMC2 mutations were found in in-house controls or in public variant databases.
INHERITANCE \- Autosomal recessive GENITOURINARY Internal Genitalia (Male) \- Primary infertility \- Asthenoteratozoospermia \- Low to normal sperm concentrations \- Reduced sperm motility, severe \- Abnormal acrosomal region \- Short flagella \- Irregular-caliber flagella \- Absent flagella \- Coiled flagella \- Angulated flagella \- Tapered head \- Microcephalic sperm \- Thin sperm head \- Multiple sperm heads \- Abnormal acrosomal region \- Abnormal base \- Absent central-pair complex (9 + 0 conformation) \- Severe axonemal disorganization \- Periaxonemal structural defects \- Unassembled outer dense fibers \- Unassembled microtubule doublets MOLECULAR BASIS \- Caused by mutation in the armadillo repeat-containing protein-2 gene (ARMC2, 618424.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| SPERMATOGENIC FAILURE 38 | None | 6,838 | omim | https://www.omim.org/entry/618433 | 2019-09-22T15:41:57 | {"omim": ["618433"]} |
For the common or slang use of imbecile, see Idiot.
The term imbecile was once used by psychiatrists to denote a category of people with moderate to severe intellectual disability, as well as a type of criminal.[1][2] The word arises from the Latin word imbecillus, meaning weak, or weak-minded.[3] It included people with an IQ of 26–50, between "idiot" (IQ of 0–25) and "moron" (IQ of 51–70).[4] In the obsolete medical classification (ICD-9, 1977), these people were said to have "moderate mental retardation" or "moderate mental subnormality" with IQ of 35–49.[5]
The meaning was further refined into mental and moral imbecility.[6][7] The concepts of "moral insanity", "moral idiocy"," and "moral imbecility", led to the emerging field of eugenic criminology, which held that crime can be reduced by preventing "feeble-minded" people from reproducing.[8][9]
"Imbecile" as a concrete classification was popularized by psychologist Henry H. Goddard[10] and was used in 1927 by United States Supreme Court Justice Oliver Wendell Holmes Jr. in his ruling in the forced-sterilization case Buck v. Bell, 274 U.S. 200 (1927).[11]
The concept is closely associated with psychology, psychiatry, criminology, and eugenics. However, the term imbecile quickly passed into vernacular usage as a derogatory term. It fell out of professional use in the 20th century in favor of mental retardation.[12]
Phrases such as "mental retardation", "mentally retarded", and "retarded" are also subject to the euphemism treadmill: initially used in a medical manner, they gradually took on derogatory connotation. This had occurred with the earlier synonyms (for example, moron, imbecile, cretin, and idiot, formerly used as scientific terms in the early 20th century). Professionals searched for connotatively neutral replacements. In the United States, "Rosa's Law" changed references in many federal statutes to "mental retardation" to refer instead to "intellectual disability".[13]
## References
1. ^ Fernald, Walter E. (1912). The imbecile with criminal instincts. Fourth edition. Boston: Ellis. OCLC 543795982.
2. ^ Duncan, P. Martin; Millard, William (1866). A manual for the classification, training, and education of the feeble-minded, imbecile, and idiotic. Longmans, Green, and Co.
3. ^ Chisholm, Hugh, ed. (1911). "Imbecile" . Encyclopædia Britannica. 14 (11th ed.). Cambridge University Press. p. 331.
4. ^ Sternberg, Robert J. (2000). Handbook of Intelligence. Cambridge University Press. ISBN 978-0-521-59648-0.
5. ^ World Health Organization (1977). Manual of the International Statistical Classification of Diseases, Injuries, and Causes of Death (PDF). Vol. 1. Jeneva. p. 212.
6. ^ Kerlin, Isaac N. (1889). "Moral imbecility". Proceedings of the Association of Medical Officers of American Institutions for Idiotic and Feeble-minded Persons, 15–18.
7. ^ Fernald, Walter E. (1 April 1909). "The imbecile with criminal instincts". American Journal of Psychiatry. 65(4):731–749.
8. ^ Rafter, Nicole Hahn (1998). Creating Born Criminals. Urbana, Ill.: University of Illinois Press. ISBN 978-0-252-06741-9.
9. ^ Tredgold, A. F. (1921). "Moral Imbecility". Proc R Soc Med, 1921; 14(Sect Psych): 13–22.
10. ^ Goddard, Henry Herbert (1915). The Criminal Imbecile; an Analysis of Three Remarkable Murder Cases. New York: The Macmillan Company.
11. ^ Lombardo, Paul A. (2008). Three Generations, No Imbeciles: Eugenics, the Supreme Court, and Buck V. Bell. JHU Press, ISBN 978-0-8018-9010-9
12. ^ Kaplan, Robert M.; Saccuzzo, Dennis P. (2008). Psychological Testing: Principles, Applications, and Issues. Cengage Learning, ISBN 978-0-495-09555-2
13. ^ Sweet, Lynn (October 5, 2010). "Obama signs 'Rosa's Law;' 'mental retardation' out, 'intellectual disability' in Archived January 17, 2013, at the Wayback Machine". Chicago Sun-Times.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Imbecile | c0917816 | 6,839 | wikipedia | https://en.wikipedia.org/wiki/Imbecile | 2021-01-18T18:34:00 | {"mesh": ["D008607"], "wikidata": ["Q4200185"]} |
A number sign (#) is used with this entry because Fanconi renotubular syndrome-2 (FRTS2) is caused by homozygous mutation in the SLC34A1 gene (182309) on chromosome 5q35. One such family has been reported.
For a general phenotypic description and a discussion of genetic heterogeneity of Fanconi renotubular syndrome, see FRTS1 (134600).
Clinical Features
Tieder et al. (1988) reported a 14-year-old boy and his 18-year-old sister from a consanguineous Arab family with renal Fanconi syndrome who had severe rickets and osteopenia, marked hypercalciuria without renal tubular acidosis, and, in contrast to previously reported patients with Fanconi renotubular syndrome (see FRTS1, 134600), significantly elevated serum levels of 1,25 dihydroxyvitamin D. Physical examination of the parents and 5 sibs revealed no pathologic findings. Treatment with neutral phosphate resulted in improvement in bone pain, muscle strength, and radiologic signs of rickets, with normalization of urinary calcium excretion and a significant decrease in 1,25(OH)2D. However, the glomerular filtration rate, serum uric acid levels, and rate of urinary excretion of glucose, protein, and amino acids remained unchanged.
Magen et al. (2010) restudied the consanguineous Arab family with renal Fanconi syndrome reported by Tieder et al. (1988) and found that both patients had a generalized proximal tubulopathy, renal phosphate wasting, bone mineral deficiency, and decreased glomerular filtration rates. However, in contrast to the findings 20 years earlier, the patients had normocalciuria and vitamin D deficiency.
Mapping
Magen et al. (2010) performed a genomewide scan in a consanguineous Arab family with renal Fanconi syndrome originally reported by Tieder et al. (1988) and identified a 9.2-Mb segment of shared homozygosity between the affected individuals, flanked by markers rs9313575 and rs6894609 on chromosome 5q35.1-q35.3. A maximum multipoint lod score of 2.4 was obtained, which the authors stated was relatively low due to the low number of affected individuals in the studied pedigree.
Molecular Genetics
In an affected brother and sister from a consanguineous Arab family with renal Fanconi syndrome mapping to chromosome 5q35.1-q35.3, originally reported by Tieder et al. (1988), Magen et al. (2010) analyzed the candidate gene SLC34A1 (182309) and identified homozygosity for an in-frame 21-bp duplication (182309.0003). The unaffected mother and an unaffected brother were heterozygous for the duplication, which was not found in 100 ethnically matched controls.
INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature GENITOURINARY Kidneys \- Proximal tubulopathy, generalized \- Decreased renal tubular reabsorption of phosphate \- Renal failure, mild to moderate SKELETAL \- Osteopenia \- Rickets, severe MUSCLE, SOFT TISSUES \- Muscle weakness LABORATORY ABNORMALITIES \- Hypophosphatemia \- Increased serum alkaline phosphatase activity of skeletal origin \- 1,25-dihydroxyvitamin D was elevated in childhood but deficient in adulthood \- Hypercalciuria (in childhood) \- Glucosuria \- Aminoaciduria, generalized \- Urinary excretion of low-molecular-weight proteins, mild \- Increased fractional excretion of uric acid MOLECULAR BASIS \- Caused by mutation in the solute carrier family 34 (sodium phosphate cotransporter), member 1 gene (SLC34A1, 182309.0003 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| FANCONI RENOTUBULAR SYNDROME 2 | c3150652 | 6,840 | omim | https://www.omim.org/entry/613388 | 2019-09-22T15:58:51 | {"doid": ["1062"], "omim": ["613388", "134600"], "orphanet": ["3337"], "synonyms": ["Primary Fanconi renotubular syndrome"]} |
A number sign (#) is used with this entry because of evidence that primary coenzyme Q10 deficiency-6 (COQ10D6) is caused by homozygous or compound heterozygous mutation in the COQ6 gene (614647) on chromosome 14q24.
For a general phenotypic description and a discussion of genetic heterogeneity of primary coenzyme Q10 deficiency, see COQ10D1 (607426).
Description
Primary coenzyme Q10 deficiency-6 is an autosomal recessive disorder characterized by onset in infancy of severe progressive nephrotic syndrome resulting in end-stage renal failure and sensorineural deafness. Renal biopsy usually shows focal segmental glomerulosclerosis (FSGS). Some patients may show a favorable response to oral coenzyme Q supplementation (summary by Heeringa et al., 2011).
For a general phenotypic description and a discussion of genetic heterogeneity of focal segmental glomerulosclerosis and nephrotic syndrome, see FSGS1 (603278) and NPHS1 (256300).
Clinical Features
Heeringa et al. (2011) reported 11 children from 5 families with autosomal recessive coenzyme Q10 deficiency manifest as nephrotic syndrome. Nine of the 11 patients had sensorineural deafness. The patients presented with proteinuria at a median age of 1.2 years (range, 0.2-6.4 years) and progressed to end-stage renal failure at a median age of 1.7 years (range, 0.4-9.3 years). Five children died in early childhood (median age of 5.0 years). Renal biopsy showed focal segmental glomerulosclerosis in 7 patients and diffuse mesangial sclerosis (DMS) in 1. Other abnormalities included seizures in 1 patient, and white matter abnormalities, seizures, and multiorgan failure in another. Two other patients had ataxia and facial dysmorphism, respectively. Three patients showed variable, but favorable, response to oral coenzyme Q treatment.
Molecular Genetics
By positional cloning, Heeringa et al. (2011) identified homozygous or compound heterozygous pathogenic mutations in the COQ6 gene (614647.0001-614647.0004) in 11 children from 5 families with autosomal recessive coenzyme Q deficiency manifest as nephrotic syndrome. Subsequent analysis of the COQ6 gene in 530 families with nephrotic syndrome identified 2 heterozygous truncating mutations in 2 unrelated patients (614647.0005 and 614647.0006, respectively); a second pathogenic mutation was not found in these 2 patients.
INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Sensorineural deafness GENITOURINARY Kidneys \- Nephrotic syndrome \- Focal segmental glomerulosclerosis \- Diffuse mesangial sclerosis (less common) \- Proteinuria NEUROLOGIC Central Nervous System \- Seizures (uncommon) LABORATORY ABNORMALITIES \- Proteinuria MISCELLANEOUS \- Onset in infancy \- Rapidly progressive \- Death in childhood may occur due to end-stage renal disease \- Treatment with oral coenzyme Q may ameliorate symptoms MOLECULAR BASIS \- Caused by mutation in the homolog of the S. cerevisiae COQ6 gene (COQ6, 614647.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| COENZYME Q10 DEFICIENCY, PRIMARY, 6 | c3553349 | 6,841 | omim | https://www.omim.org/entry/614650 | 2019-09-22T15:54:37 | {"doid": ["0070243"], "omim": ["614650"], "orphanet": ["280406"], "synonyms": [], "genereviews": ["NBK410087"]} |
Non-alcoholic fatty liver disease (NAFLD) is a buildup of excessive fat in the liver that can lead to liver damage resembling the damage caused by alcohol abuse, but that occurs in people who do not drink heavily. The liver is a part of the digestive system that helps break down food, store energy, and remove waste products, including toxins. The liver normally contains some fat; an individual is considered to have a fatty liver (hepatic steatosis) if the liver contains more than 5 to 10 percent fat.
The fat deposits in the liver associated with NAFLD usually cause no symptoms, although they may cause increased levels of liver enzymes that are detected in routine blood tests. Some affected individuals have abdominal pain or fatigue. During a physical examination, the liver may be found to be slightly enlarged.
Between 7 and 30 percent of people with NAFLD develop inflammation of the liver (non-alcoholic steatohepatitis, also known as NASH), leading to liver damage. Minor damage to the liver can be repaired by the body. However, severe or long-term damage can lead to the replacement of normal liver tissue with scar tissue (fibrosis), resulting in irreversible liver disease (cirrhosis) that causes the liver to stop working properly. Signs and symptoms of cirrhosis, which get worse as fibrosis affects more of the liver, include fatigue, weakness, loss of appetite, weight loss, nausea, swelling (edema), and yellowing of the skin and whites of the eyes (jaundice). Scarring in the vein that carries blood into the liver from the other digestive organs (the portal vein) can lead to increased pressure in that blood vessel (portal hypertension), resulting in swollen blood vessels (varices) within the digestive system. Rupture of these varices can cause life-threatening bleeding.
NAFLD and NASH are thought to account for many cases of cirrhosis that have no obvious underlying cause (cryptogenic cirrhosis); at least one-third of people with NASH eventually develop cirrhosis. People with NAFLD, NASH, and cirrhosis are also at increased risk of developing liver cancer (hepatocellular cancer).
NAFLD is most common in middle-aged or older people, although younger people, including children, are also affected. It is often considered as part of a group of conditions known collectively as the metabolic syndrome; in addition to NAFLD, the metabolic syndrome includes obesity, type 2 diabetes or pre-diabetes (insulin resistance), high levels of fats (lipids) such as cholesterol and triglycerides in the blood, and high blood pressure (hypertension). However, a person with NAFLD may not have all or any of the other conditions that make up the metabolic syndrome, and individuals with some or all of those conditions may not have NAFLD.
## Frequency
NAFLD is a very common disorder, occurring in about 25 percent of the global population. Its prevalence is increasing along with the rising prevalence of obesity in industrialized societies, and it is now the most common chronic liver disorder in Western countries, including the United States. NAFLD is more prevalent in individuals of Hispanic, Native American, or Asian ancestry than in individuals of European or African ancestry.
## Causes
The specific causes of NAFLD are unclear. Genetic variations and environmental factors contribute to the development of this complex disorder.
When fat from the diet exceeds the body's requirements and ability to break it down and eliminate it, some of the fat is stored in the liver. Researchers suggest that over-consumption of certain specific nutrients, such as iron, cholesterol, and refined sugars used in processed foods, may increase the likelihood of developing NAFLD.
It is unclear what causes NASH and cirrhosis to develop in some people with NAFLD. Researchers are studying several possible mechanisms. These include inflammation caused by an immune system reaction to the excess fatty tissue in the liver; toxic inflammatory chemicals (cytokines) released by the liver cells or fat cells; self-destruction (apoptosis) of liver cells; and the effect of unstable molecules called free radicals (oxidative stress). The effects of different populations of microorganisms in the intestines (gut microbiota) on the breakdown and absorption of nutrients are also an active area of research.
Studies have identified many genetic changes that may be associated with the development of NAFLD and NASH. Among these is a particular variation in the PNPLA3 gene. This gene provides instructions for making a protein called adiponutrin, which is found in fat cells (adipocytes) and liver cells (hepatocytes). The function of this protein is not well understood, but it is thought to help regulate the production and breakdown of fats (lipogenesis and lipolysis) and the development of adipocytes. Studies indicate that the activity (expression) of the PNPLA3 gene decreases during periods without food (fasting) and increases after eating, suggesting that the amount of adiponutrin protein produced is regulated as needed to help process and store fats in the diet. The PNPLA3 gene variation associated with NAFLD is thought to lead to increased production and decreased breakdown of fats in the liver. Research is ongoing to determine how this and other genetic changes contribute to the development of NAFLD and its complications.
### Learn more about the gene associated with Non-alcoholic fatty liver disease
* PNPLA3
Additional Information from NCBI Gene:
* APOC3
* GCKR
* MBOAT7
* TM6SF2
* TRIB1
## Inheritance Pattern
An increased risk of developing NAFLD can be passed through generations in families, but the inheritance pattern is unknown. Variations in several genes as well as lifestyle and environmental factors contribute to the risk of developing this complex disorder.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Non-alcoholic fatty liver disease | c2750441 | 6,842 | medlineplus | https://medlineplus.gov/genetics/condition/non-alcoholic-fatty-liver-disease/ | 2021-01-27T08:25:21 | {"gard": ["6430"], "omim": ["613282", "613387"], "synonyms": []} |
A number sign (#) is used with this entry because neonatal Bartter syndrome type 4B with sensorineural deafness (BARTS4B) is caused by simultaneous mutation in both the CLCNKA (602024) and CLCNKB (602023) genes.
Description
Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997).
Patients with antenatal (or neonatal) forms of Bartter syndrome (e.g., BARTS1, 601678) typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by Simon et al., 1996 and Fremont and Chan, 2012).
For a discussion of genetic heterogeneity of Bartter syndrome, see 607364.
Molecular Genetics
In a child with renal salt wasting and deafness who had no mutation in the BSND gene (606412), Schlingmann et al. (2004) identified both a homozygous deletion of the CLCNKB gene (602023.0008) and a homozygous trp80-to-cys mutation in the CLCNKA gene (W80C; 602024.0001). The patient was born prematurely to consanguineous parents, and the pregnancy was complicated by severe maternal polyhydramnios during the last 6 weeks of gestation. Because this combined impairment of the CLCNKA and CLCNKB genes resulted in a phenotype mimicking that caused by defects in barttin, Schlingmann et al. (2004) concluded that this case supported the notion that the CLCNK-type channels are regulated by barttin and offered strong evidence of genetic heterogeneity in patients who have both severe renal salt wasting and deafness.
Nozu et al. (2008) reported a 2-year-old Japanese girl with a severe form of Bartter syndrome and sensorineural deafness who was born of nonconsanguineous parents. Genetic analysis showed 2 heterozygous mutations in the CLCNKA (602024.0002) and CLCNKB (602023.0011) genes on the paternal allele, and a 12-kb deletion involving portions of the CLCNKA and CLCNKB genes on the maternal allele. Neither parent was clinically affected. The findings indicated clear digenic inheritance in this patient and confirmed that loss of function of all 4 alleles of the CLCNKA and CLCNKB genes can result in Bartter syndrome type 4B.
INHERITANCE \- Digenic recessive GROWTH Other \- Failure to thrive HEAD & NECK Ears \- Deafness, sensorineural GENITOURINARY Kidneys \- Renal salt wasting \- Inability to concentrate urine \- Polyuria \- Decreased glomerular filtration rate \- Renal failure, chronic MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed motor development \- Hyporeflexia \- Mental retardation \- Motor retardation METABOLIC FEATURES \- Hypokalemic hypochloremic metabolic alkalosis ENDOCRINE FEATURES \- Stimulation of the renin/angiotensin/aldosterone axis \- Hyperaldosteronism PRENATAL MANIFESTATIONS Amniotic Fluid \- Polyhydramnios \- Fetal hydrops \- Fetal polyuria Delivery \- Premature delivery LABORATORY ABNORMALITIES \- Hypokalemia \- Hyponatremia \- Hypochloremia \- Urinary prostaglandin E \- Increased urinary sodium \- Increased urinary potassium \- Increased urinary chloride MISCELLANEOUS \- Onset in utero \- Severe volume depletion \- Genetic heterogeneity \- See also antenatal Bartter syndrome type 1 ( 601678 ) and Bartter syndrome type 2 ( 241200 ) MOLECULAR BASIS \- Caused by simultaneous homozygous mutations in both the chloride channel, kidney, A gene (CLCNKA, 602024.0001 ) and chloride channel, kidney, B gene (CLCNKB, 602023.0008 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| BARTTER SYNDROME, TYPE 4B, NEONATAL, WITH SENSORINEURAL DEAFNESS | c0004775 | 6,843 | omim | https://www.omim.org/entry/613090 | 2019-09-22T15:59:53 | {"doid": ["0110146"], "mesh": ["D001477"], "omim": ["613090"], "orphanet": ["89938", "112"], "synonyms": ["Bartter syndrome type 4", "Bartter syndrome type IV"]} |
Aspartylglucosaminuria
Other namesGlycosylasparaginase deficiency[1]
Autosomal recessive is the inheritance pattern of this condition
SpecialtyMedical genetics, endocrinology
Aspartylglucosaminuria (AGU) is an inherited disease that is characterized by a decline in mental functioning, accompanied by an increase in skin, bone and joint issues.
The disease is caused by a defect in an enzyme known as aspartylglucosaminidase. This enzyme plays a significant role in our bodies because it aids in breaking down certain sugars (for example, oligosaccharides) that are attached to specific proteins (for example, glycoproteins). Aspartylglucosaminuria itself is characterized as a lysosomal disease because it does deal with inadequate activity in an enzyme's function.[2] Aspartylglucosaminidase functions to break down glycoproteins. These proteins are most abundant in the tissues of the body and in the surfaces of major organs, such as the liver, spleen, thyroid and nerves. When glycoproteins are not broken down, aspartylglucosaminidase backs up in the lysosomes along with other substances. This backup causes progressive damage to the tissues and organs.[3]
## Contents
* 1 Signs and symptoms
* 2 Genetics
* 3 Diagnosis
* 3.1 Pre-natal diagnosis
* 4 Treatment
* 4.1 Preventions/interventions to signs and symptoms
* 4.2 Habilitation
* 5 Prognosis
* 6 Epidemiology
* 7 See also
* 8 References
* 9 External links
## Signs and symptoms[edit]
At birth, there is no sign that a child will develop symptoms of aspartylglucosaminuria. Typically, signs and symptoms become apparent between two and four years of age and become progressively worse as the individual ages. The following signs and symptoms may appear:[3]
* Individuals are more prone to respiratory infections
* Development of scoliosis
* Seizures or difficulty with movement
* Skin and joints may become loose
* Facial features change progressively; this may include:
1. thickening of the skin
2. features becoming more prominent
3. large head
4. broad lower jaw
5. short, broad nose
6. rounded cheeks[3]
* Progression of developmental and mental disabilities, including:
1. progressive loss of speech
2. decrease in mental functioning
3. before school age, concentration lowers
4. development continues, but becomes slower than usual[3]
* An intellectual peak occurs in the mid-teens and allows a plateau for the disease. Once an individual hits the age of 25-30 the decrease begins again, including:
1. learned skills become lost which result in severe learning disabilities
2. motor skills deteriorate
3. individuals become less mobile and more dependent
(Children are physically uncoordinated, but remain able to play sports and do everyday activities until they reach adulthood.)
* During the first year of life inguinal and umbilical hernias are common.
* Less severe symptoms include:
1. enlargement of the spleen and liver
2. diarrhea
* People with aspartylglucosaminuria may have lower than average height, because they tend to go through puberty earlier.
* Epilepsy may develop in adulthood.
* Finnish studies have shown that life expectancy is shorter than average.[4]
## Genetics[edit]
Aspartylglucosaminuria is a genetic condition that is inherited from both parents. The AGU patient is born with two copies of the mutated AGA gene. One copy comes from the mother’s egg and the other copy comes from the father’s sperm.[2] In order to develop aspartylglucosaminuria, the individual must inherit changes in both of his AGU genes (autonomic recessive inheritance). When a person receives one changed form of the gene AGU from one of the parents, the individual is then classified as a carrier.[5][6]
## Diagnosis[edit]
In order to be diagnosed with AGU an individual takes a urine test, which will show indication of an increased amount of aspartylglucosamin being secreted. The confirmation of the diagnosis of aspartylglucosaminuria requires a blood test. This helps show if the enzyme aspartylglucosaminidase is present or partially absent. A skin simple will also show the amount of aspartylglucosaminidase present.[4]
### Pre-natal diagnosis[edit]
When families have a child who has already been diagnosed with AGU, they have the option to observe the enzyme's activity that codes for AGU in future pregnancy, to help determine if the next child will also have a positive diagnosis for aspartylglucosaminuria.[2]
## Treatment[edit]
No treatment is available to cure or slow down the progression of aspartylglucosaminuria. Bone marrow transplants have been conducted in hope that the bone marrow will produce the missing enzyme. The results of the tests thus far have shown to be inconclusive.[2]
### Preventions/interventions to signs and symptoms[edit]
Since ear infections and respiratory infections are common for children diagnosed with aspartylglucosaminuria, it is best to have regular checkups for both the ears and the respiratory tract.
Extreme sensitivity to the sun’s rays may develop; the best way to protect an individual diagnosed with aspartylglucosaminuria is to have them wear sunglasses, hats or caps to protect their eyes.
Epilepsy and insomnia can both be treated with medication.
It will be beneficial to children who are diagnosed with AGU to receive an education from a school with special teaching.[4]
### Habilitation[edit]
The process of habilitation for individuals diagnosed with AGU needs to be established in their early stages of life. The team for habilitation should include professionals who are experienced in disabilities and the effects that having a disability can have on everyday life. Habilitation will include assessments, assistance with the choice of aids, and information concerning disabilities and counseling.[4]
## Prognosis[edit]
Individuals with AGU typically have normal development in infancy. Around the age of 2–4 years, they begin showing signs of developmental delay, but development is still progressing. Initial symptoms may present as clumsiness and/or speech delay. Individuals with AGU also show increased upper respiratory infections. Development continues until about puberty; however, an individual at 13–16 years of age typically shows mental and motor development similar to a 5-6 year old. Around puberty, a gradual decline in mental abilities and motor skills occurs. This progressive decline continues until about age 25–28, when rapid impairment of abilities occurs, resulting in severe intellectual disability.[4]
## Epidemiology[edit]
Aspartylglucosaminuria is estimated to affect 1 in 18,500 people in Finland. This condition is less common in other countries, but the incidence is unknown.[5] Even though this disease can occur in various races and ethnicities, another study backed this finding up by stating that 1 in 26,000 people in Finland had the disease and that 1 in 18,000 were carriers.[3]
After trisomy 21 and fragile X syndrome, this is the most frequent multiple congenital anomaly/intellectual disability syndrome in Finland.[7]
## See also[edit]
* Inborn error of metabolism
## References[edit]
1. ^ "Aspartylglycosaminuria | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 11 April 2019.
2. ^ a b c d "Aspartylglucosaminuria".
3. ^ a b c d e "LabCorp". Archived from the original on 2015-01-28. Retrieved 2013-04-02.
4. ^ a b c d e "Aspartylglucosaminuria".
5. ^ a b "Aspartylglucosaminuria".
6. ^ "Archived copy". Archived from the original on 2013-04-28. Retrieved 2013-04-05.CS1 maint: archived copy as title (link)
7. ^ Viitapohja, Kari. "Mental Retardation in Finland". Finnish Information Center on Mental Retardation. Retrieved 2005-01-30.
## External links[edit]
* Aspartylglycosaminuria at NIH's Office of Rare Diseases
Classification
D
* ICD-10: E77.1
* OMIM: 208400
* MeSH: D054880
External resources
* Orphanet: 93
* v
* t
* e
Lysosomal storage diseases: Inborn errors of carbohydrate metabolism (Glycoproteinoses)
Anabolism
* Dolichol kinase deficiency
* Congenital disorder of glycosylation
Post-translational modification
of lysosomal enzymes
* Mucolipidosis: I-cell disease (ML II)
* Pseudo-Hurler polydystrophy (ML III)
Catabolism
* Aspartylglucosaminuria
* Fucosidosis
* mannosidosis
* Alpha-mannosidosis
* Beta-mannosidosis
* Sialidosis
* Schindler disease
Other
* solute carrier family (Salla disease)
* Galactosialidosis
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Aspartylglucosaminuria | c2931840 | 6,844 | wikipedia | https://en.wikipedia.org/wiki/Aspartylglucosaminuria | 2021-01-18T18:38:43 | {"gard": ["5854"], "mesh": ["D054880", "C538402"], "umls": ["C2931840"], "orphanet": ["93"], "wikidata": ["Q4412533"]} |
A rare genetic autoinflammatory syndrome characterized by early-onset of repeated episodes of fever, nodular neutrophil-rich panniculitis, arthralgia, and lipodystrophy. Additional reported features include diarrhea, failure to thrive, lymphadenopathy, and vasculitis. Laboratory examination may reveal elevated serum C-reactive protein and leukocytosis with neutrophilia in the absence of infection.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Infantile-onset periodic fever-panniculitis-dermatosis syndrome | c4310614 | 6,845 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=500062 | 2021-01-23T18:01:32 | {"omim": ["617099"], "icd-10": ["E85.0"], "synonyms": ["ORAS", "OTULIN deficiency", "OTULIN-related autoinflammatory syndrome", "Otulipenia"]} |
A number sign (#) is used with this entry because of evidence that Nestor-Guillermo progeria syndrome is caused by homozygous mutation in the BANF1 gene (603811) on chromosome 11q13.
Clinical Features
Puente et al. (2011) studied a consanguineous Spanish family in which the 31-year-old male proband exhibited an atypical form of progeria. Born to third-cousin healthy parents, the proband showed normal development until 2 years of age, when he experienced failure to thrive and his skin became dry and atrophic with small light-brown spots over the thorax, scalp, and limbs. He also developed generalized lipoatrophy, severe osteoporosis, and marked osteolysis. The atrophic facial subcutaneous fat pad and the marked osteolysis of the maxilla and mandible resulted in a typical pseudosenile facial appearance with micrognathia, prominent subcutaneous venous patterning, convex nasal ridge, and proptosis. Cognitive development was completely normal. Features that differed from other forms of progeria included his age, height of 145 cm (underestimated due to severe scoliosis), presence of eyebrows and eyelashes, persistence of scalp hair to 12 years of age, very severe osteolysis involving the mandible, clavicles, ribs, distal phalanges, and radius, and the absence of coronary dysfunction, atherosclerosis, or metabolic anomalies. A 24-year-old unrelated Spanish man with an almost identical phenotype was also studied. Despite thorough cardiovascular examination, neither patient showed signs of ischemia or atherosclerosis, and neither had insulin resistance, diabetes mellitus, or hypertriglyceridemia.
Cabanillas et al. (2011) described in detail the 2 patients from unrelated Spanish families who were originally studied by Puente et al. (2011), noting that the phenotype was designated 'Nestor-Guillermo' progeria syndrome using the names of these 2 patients. In addition to other progeric features, the 32-year-old index patient had severe progressive scoliosis from 18 years of age and developed secondary pulmonary hypertension by 27 years of age. On examination he had dyspnea upon minor exertion, with a severe restrictive spirometry pattern. Echocardiography showed moderate tricuspid insufficiency, severe mitral regurgitation, and pulmonary hypertension. Electrocardiogram showed sinus tachycardia, with dilation of both atria and right bundle branch block, without signs of ischemia. Doppler ultrasound of the carotid arteries showed no arteriosclerosis, and computed angiography of the coronary arteries showed no coronary calcification or stenosis; his blood pressure was normal. Examination of the second patient revealed a progeria phenotype almost identical to the index case; however, this patient had only mild scoliosis without impact on cardiovascular function. Cardiovascular examination showed no signs of ischemia or atherosclerosis, and blood pressure was normal; electrocardiogram revealed sinus tachycardia and right bundle branch block. Laboratory values in both patients were normal except for low 25-OH-vitamin D and very low leptin; in addition, the index patient had a low fasting glucose. Cabanillas et al. (2011) defined NGPS as a chronic progeria because of the patients' slow clinical course and relatively long survival, despite early onset of disease.
Mapping
In a consanguineous Spanish family in which the proband had an atypical progeroid syndrome and was negative for mutations in the LMNA (150330) and ZMPSTE24 (606480) genes, Puente et al. (2011) performed exon enrichment followed by massively parallel sequencing on DNA samples from the proband and both parents under an assumption of an autosomal recessive mode of inheritance. They identified 4 variants that were heterozygous in the parents and homozygous in the proband, 3 of which were located in a long contiguous stretch of homozygosity on chromosome 11q13.
Molecular Genetics
In a consanguineous Spanish family in which the proband had an atypical progeroid syndrome, Puente et al. (2011) analyzed 4 candidate genes and identified homozygosity for a missense mutation in the BANF1 gene (A12T; 603811.0001) on chromosome 11 that was also found to be present in homozygosity in an unrelated Spanish patient with a nearly identical phenotype. The unaffected parents in both families were heterozygous for the mutation. The presence of a common homozygous haplotype in the 2 patients, who were from geographically distant regions of Spain, suggested that A12T represented a founder mutation.
INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Other \- Failure to thrive HEAD & NECK Face \- Micrognathia \- Mandibular osteolysis \- Midface hypoplasia Eyes \- Proptosis \- Sparse eyebrows \- Sparse eyelashes Nose \- Convex nasal ridge Mouth \- Restricted opening of mouth Teeth \- Dental crowding CARDIOVASCULAR Heart \- Sinus tachycardia \- Right bundle branch block Vascular \- Prominent subcutaneous venous patterning \- Pulmonary hypertension (secondary to scoliosis, in some patients) RESPIRATORY Lung \- Dyspnea on exertion (secondary to scoliosis, in some patients) CHEST Ribs Sternum Clavicles & Scapulae \- Osteolysis of clavicles \- Osteolysis of ribs SKELETAL \- Stiff joints \- Joint contractures \- Osteoporosis, severe \- Osteolysis, severe (of mandible, clavicles, ribs, distal phalanges, and radii) Skull \- Delayed closure of anterior fontanel \- Widely open cranial sutures Spine \- Scoliosis Limbs \- Mobility restriction of elbows and knees \- Osteolysis of radii Hands \- Mobility restriction of hands and fingers \- Osteolysis of distal phalanges SKIN, NAILS, & HAIR Skin \- Patchy hyperpigmentation Hair \- Sparse eyebrows \- Sparse eyelashes \- Scalp hair sparse to absent, beginning in second decade of life MUSCLE, SOFT TISSUES \- Lipoatrophy, generalized LABORATORY ABNORMALITIES \- Very low leptin level \- Low 25-OH-vitamin D level \- Low fasting glucose (in some patients) MISCELLANEOUS \- In contrast to other forms of progeria, these patients do not have atherosclerosis, cardiac ischemia, or metabolic abnormalities \- Two patients from Spain have been reported (as of January 2012) MOLECULAR BASIS \- Caused by mutation in the barrier-to-autointegration factor-1 gene (BANF1, 603811.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| NESTOR-GUILLERMO PROGERIA SYNDROME | c3151446 | 6,846 | omim | https://www.omim.org/entry/614008 | 2019-09-22T15:56:47 | {"omim": ["614008"], "orphanet": ["280576"], "synonyms": ["NGPS", "Alternative titles", "PROGERIA SYNDROME, CHILDHOOD-ONSET, WITH OSTEOLYSIS"]} |
Lassa fever (LF) is a potentially severe viral hemorrhagic disease caused by Lassa virus and characterized by initial fever and malaise followed by gastrointestinal symptoms and, in severe cases, bleeding, shock and multi-organ system failure.
## Epidemiology
LF is endemic in West Africa. Lack of surveillance prohibits accurate estimates of incidence, but estimates range up to 300,000-500,000 infections and 5,000-10,000 cases of LF per year. Up to 80% of infections are thought to be asymptomatic or mild.
## Clinical description
After an incubation period of 1-3 weeks (range 3-21 days), patients typically present with the insidious onset of non-specific signs and symptoms including fever, sore throat, malaise, headache, chest pain and myalgia/arthralgia, followed rapidly by gastrointestinal manifestations (vomiting, diarrhea, abdominal pain) and, in some cases, rash. In the second week, severe cases develop neck and facial swelling, bleeding (usually from the nose and mouth), neurologic involvement, shock and multi-organ system failure. Mild-to-moderate leukopenia and thrombocytopenia are often present. Deafness is a sequelae in up to 30% of survivors.
## Etiology
Over 25 different viruses cause viral hemorrhagic fever. LF is caused by Lassa virus, a member of the virus family Arenaviridae. Lassa virus is maintained in nature in the multimammate rat (Mastomys natalensis) and humans are infected through exposure to this rodent's excreta. Human-to-human transmission occurs through direct contact with blood or bodily fluids of infected persons.
## Diagnostic methods
Common diagnostic modalities include cell culture (restricted to biosafety level-4 laboratories), serologic testing by enzyme linked immunosorbent assay (ELISA) or indirect fluorescent antibody (IFA), and reverse transcription polymerase chain reaction (RT-PCR). Because no commercial assays are presently available, these tests are typically performed only in a few specialized laboratories.
## Differential diagnosis
LF is difficult to distinguish from a host of other febrile illnesses, at least during its onset. Other viral hemorrhagic fevers need to be excluded, as well as malaria, typhoid fever, leptospirosis, rickettsial infection (see these terms), and meningococcemia.
## Management and treatment
Patients should be isolated and viral hemorrhagic fever precautions (face shields, surgical masks, double gloves, surgical gowns, and aprons) should be used to prevent nosocomial transmission. The nucleoside analogue drug ribavirin should be administered intravenously. Oral ribavirin may also be effective but is less so than the IV form. Otherwise, treatment generally follows the guidelines for severe septicemia. Anti-malarials and broad spectrum antibiotics should be considered until the diagnosis of LF can be confirmed. Persons who had unprotected contact with someone with LF should be monitored and post-exposure treatment with oral ribavirin considered.
## Prognosis
The case-fatality rate in hospitalized patients is typically 15-20%. Shock, bleeding, neurological manifestations, high viremia, aspartate aminotransferase (AST > 150 IU/L) and pregnancy confer a poor prognosis.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Lassa fever | c0023092 | 6,847 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99824 | 2021-01-23T18:19:38 | {"mesh": ["D007835"], "umls": ["C0023092"], "icd-10": ["A96.2"], "synonyms": ["LF", "Lassa hemorrhagic fever"]} |
A number sign (#) is used with this entry because of evidence that Antley-Bixler syndrome with disordered steroidogenesis (ABS1) is caused by homozygous or compound heterozygous mutation in the gene encoding cytochrome P450 oxidoreductase (POR; 124015) on chromosome 7q11.
A form of Antley-Bixler syndrome with normal steroidogenesis (ABS2; 207410) is a distinct disorder caused by mutation in the FGFR2 gene (176943). Congenital adrenal hyperplasia without Antley-Bixler skeletal anomalies can also result from POR mutations (613571).
Description
The Antley-Bixler syndrome (ABS) is an exceptionally rare craniosynostosis syndrome characterized by radiohumeral synostosis present from the perinatal period. There is a wide spectrum of anomalies seen in ABS; other features include midface hypoplasia, choanal stenosis or atresia, multiple joint contractures, visceral anomalies (particularly of the genitourinary system), and impaired steroidogenesis (present only in patients with POR mutations). Mortality has been reported to be as high as 80% in the neonatal period, primarily due to airway compromise, and prognosis improves with increasing age (summary by McGlaughlin et al., 2010).
Clinical Features
Miller (2008) considered the phenotypic overlap between ABS caused by POR mutations and ABS caused by FGFR2 mutations (ABS2; 207410) impressive. Aside from genital anomalies and disordered pattern of steroidogenesis present in patients with POR mutations, no dysmorphic feature appears to distinguish the 2 groups.
Reardon et al. (2000) was impressed with the occurrence of genital abnormalities in patients, especially females, who had been diagnosed as having Antley-Bixler syndrome. They reported abnormalities of steroid biogenesis in 7 of 16 patients with an Antley-Bixler phenotype. Reardon et al. (2000) suggested that ABS with disordered steroidogenesis might be a distinct genetic entity.
Diagnosis
McGlaughlin et al. (2010) noted that craniosynostosis and radiohumeral synostosis present from the perinatal period are generally considered to be the minimum criteria for a diagnosis of Antley-Bixler syndrome.
Clinical Management
Huang et al. (2005) noted that it is clinically important to distinguish patients with an ABS phenotype and disordered steroidogenesis from those with ABS and normal steroidogenesis, not only because of differences in inheritance patterns, but also because patients with POR deficiency are vulnerable to different risk factors and require different management and different teams of physicians. Some patients with POR mutations have died unexpectedly without a clear explanation, and Reardon et al. (2000) noted that patients may require steroid hormone supplementation. Patients with POR mutations may be at risk for adrenal insufficiency and Addisonian crisis, especially at times of severe febrile illness or major surgery.
Biochemical Features
In the absence of POR, environmental toxins and drugs that are usually metabolized to benign products by hepatic P450 enzymes may achieve teratogenic concentrations. Fluconazole, which acts on a fungal cytochrome P450 system, has been implicated in this fashion (Aleck and Bartley, 1997). Because fluconazole is a strong inhibitor of lanosterol 14-alpha-demethylase (CYP51A1; 601637), Kelley et al. (2002) evaluated sterol metabolism in lymphoblast cell lines from a patient diagnosed as having Antley-Bixler syndrome with ambiguous genitalia but without an FGFR2 mutation. When grown in the absence of cholesterol to stimulate cholesterol biosynthesis, cells from this patient accumulated markedly increased levels of lanosterol and dihydrolanosterol. Mutation analysis of CYP51A1, however, disclosed no obvious pathogenic mutation.
Shackleton et al. (2004) studied steroid excretion in 8 patients diagnosed with ABS and 1 patient with a milder but related phenotype without skeletal or genital abnormalities. The steroid excretion pattern was consistent and distinctive in all 9 patients, and was significantly different from that measured in controls (p less than 0.01). A high ratio of metabolites of the primary adrenal steroid precursors pregnenolone and progesterone to cortisol metabolites was the most characteristic feature for diagnosis. The authors stated that pregnanediol could be considered a hallmark analyte since it is essentially absent from the urine of normal individuals or those with other defects in steroid biosynthesis. Shackleton et al. (2004) proposed the use of this distinctive steroid metabolic profile as the primary biochemical parameter for the diagnosis of the ABS-like phenotype not associated with FGFR2 mutations.
Molecular Genetics
In individuals with disordered steroidogenesis with bony features of Antley-Bixler syndrome, including the patient reported by Kelley et al. (2002), Fluck et al. (2004) demonstrated mutations in the POR gene (e.g., 124015.0001). Fluck et al. (2004) proposed that severe mutations in POR without associated disorders of FGF receptors are sufficient to cause the ABS-like phenotype. The grossly dysmorphic embryonic lethal phenotype of POR knockout mice, with neural tube, cardiac, eye, and limb anomalies, suggests that severe disorders of POR may be sufficient to account for the skeletal findings in some individuals with an ABS phenotype (Shen et al., 2002; Otto et al., 2003). By contrast, milder mutations in POR may manifest as mild disorders of steroid synthesis.
Huang et al. (2005) sequenced the cytochrome P450 reductase gene and exons 8 and 10 of the FGFR2 gene in 29 individuals diagnosed with Antley-Bixler syndrome with or without hormonal findings suggesting POR deficiency and found that POR and FGFR2 mutations segregated completely. In 15 patients, POR mutations were found on both alleles; in 4, mutations were found on only 1 allele; 6 carried FGFR2 mutations; and 4 patients carried no mutations. One patient, a male infant with an Antley-Bixler syndrome skeletal phenotype and abnormal steroids and genitalia, who had previously been found to carry a missense mutation of unclear significance in the FGFR1 gene (136350.0011) by Hurley et al. (2004), was found to be a compound heterozygote for mutations in the POR gene as well (124015.0015 and 124015.0016). The 34 affected POR alleles included 10 with ala287-to-pro (124015.0002), all from whites, and 7 with arg457-to-his (124015.0005), including 4 Japanese, 1 African, and 2 Caucasians; 17 of the 34 carried 16 'private' mutations, including 9 missense and 7 frameshift mutations. Huang et al. (2005) recreated these 11 missense mutations, plus 10 others found in databases or reported elsewhere, by site-directed mutagenesis and assessed them by 4 assays: assays that were based on cytochrome c, which is not a physiologic substrate for POR, correlated poorly with clinical phenotype, but assays that were based on POR's support of catalysis by P450c17 (the enzyme most closely associated with the hormonal phenotype) provided an excellent genotype/phenotype correlation. Huang et al. (2005) concluded that individuals with an ABS skeletal phenotype and normal steroidogenesis have FGFR mutations, whereas those with ambiguous genitalia and disordered steroidogenesis should be recognized as having a distinct disease: POR deficiency.
INHERITANCE \- Autosomal recessive GROWTH Other \- Small for gestational age HEAD & NECK Head \- Brachycephaly \- Microcephaly Face \- Frontal bossing \- Temporal bossing \- Midface hypoplasia Ears \- Hearing loss, conductive \- Simple ears Eyes \- Proptosis \- Hypertelorism Nose \- Choanal stenosis \- Choanal atresia \- Depressed nasal bridge RESPIRATORY Larynx \- Laryngomalacia Airways \- Bronchomalacia ABDOMEN Gastrointestinal \- Anteriorly places anus GENITOURINARY External Genitalia (Male) \- Micropenis \- Hypospadias \- Chordee \- Hypoplastic scrotum \- Bifid scrotum External Genitalia (Female) \- Hypoplastic labia \- Clitoromegaly \- Fused labia \- Single urogenital orifice Internal Genitalia (Male) \- Cryptorchidism Internal Genitalia (Female) \- Vesicovaginal fistula \- Polycystic ovary Kidneys \- Horseshoe kidney SKELETAL Skull \- Craniosynostosis \- Cloverleaf skull Spine \- Hemivertebrae \- Scoliosis Limbs \- Elbow synostosis \- Ulnar bowing \- Radiohumeral synostosis \- Radioulnar synostosis \- Femoral bowing \- Femoral fractures Hands \- Camptodactyly \- Arachnodactyly \- Carpal synostosis Feet \- Rocker-bottom feet \- Tarsal synostosis NEUROLOGIC Central Nervous System \- Arnold-Chiari malformation ENDOCRINE FEATURES \- Adrenal crisis PRENATAL MANIFESTATIONS Amniotic Fluid \- Oligohydramnios Placenta & Umbilical Cord \- Two vessel cord Maternal \- Maternal virilization (midpregnancy) \- Low maternal serum estriol (E(3)) LABORATORY ABNORMALITIES \- Normal baseline cortisol \- Blunted cortisol response to adrenocorticotropic hormone (ACTH) \- Elevated 17-hydroxyprogesterone \- Mildly elevated ACTH \- Elevated progesterone \- Elevated pregnenolone MISCELLANEOUS \- See also Antley-Bixler syndrome (ABS) with normal steroidogenesis ( 207410 ) \- Majority of POR deficiency patients have an ABS-like phenotype \- Some patients have only ambiguous genitalia or other evidence of disordered steroidogenesis MOLECULAR BASIS \- Caused by mutation in the cytochrome P450 oxidoreductase gene (POR, 124015.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| ANTLEY-BIXLER SYNDROME WITH GENITAL ANOMALIES AND DISORDERED STEROIDOGENESIS | c3150099 | 6,848 | omim | https://www.omim.org/entry/201750 | 2019-09-22T16:31:27 | {"doid": ["0050462"], "omim": ["201750"], "orphanet": ["63269"], "synonyms": ["Ambiguous genitalia-disordered steroidogenesis Antley-Bixler-like syndrome", "Antley-Bixler syndrome type 2", "Antley-Bixler syndrome, POR-related"], "genereviews": ["NBK1419"]} |
A number sign (#) is used with this entry because the phenotype, which is characterized by postnatal progressive microcephaly, seizures, and brain atrophy, is caused by homozygous mutation in the MED17 gene (603810) on chromosome 11.
Clinical Features
Kaufmann et al. (2010) reported 5 infants from 4 Jewish families from the Caucasus region with postnatal progressive microcephaly and severe developmental retardation associated with cerebral and cerebellar atrophy. One of the families was consanguineous. All pregnancies were uneventful, and the infants were born at term with normal head circumference. Ultrasound performed at 22 weeks' gestation in 1 affected infant showed normal brain structure. At 4 to 9 weeks of age, all developed swallowing difficulties leading to failure to thrive, jitteriness, poor visual fixation and lack of tracking, truncal arching, and seizures. Physical examination at that time showed microcephaly, increased muscle tone, clonus, and hyperreflexia. None showed further developmental progression; features included marked spasticity and profound retardation. Progressive microcephaly was evident, with a head circumference of -6 SD at 9 months of age. Dysmorphic features were not noted. At the time of the report, all patients were alive, ranging in age from 5 months to 15 years. EEG abnormalities were progressive, and included dysmature background with multifocal spike and wave activity, hypsarrhythmia, and a diffuse slowing of background with bilateral slow, sharp frontotemporal activity at an older age. Brain MRI revealed severe diffuse cerebral and cerebellar atrophy, small thalami, thin brainstem, and poor myelination. Routine laboratory investigations were normal.
Mapping
By homozygosity mapping of Caucasus Jewish patients with postnatal microcephaly, seizures, and brain atrophy, Kaufmann et al. (2010) identified a 2.28-Mb region of homozygosity on chromosome 11 between rs12363947 and rs333027.
Molecular Genetics
By candidate gene sequencing of 5 patients from 4 families with postnatal progressive microcephaly, seizures, and brain atrophy, Kaufmann et al. (2010) identified a homozygous mutation in the MED17 gene (L371P; 603810.0001). Screening of additional patients with a similar disorder identified the same homozygous mutation in 4 more patients. All affected individuals were of Caucasus Jewish origin, indicating a founder effect. The L371P mutation was found in the heterozygous state in 4 of 76 unaffected individuals in this population. The mutation was not found in 110 individuals of Ashkenazi Jewish origin or in 113 individuals of Arab Moslem origin.
Population Genetics
All patients with infantile postnatal microcephaly, seizures, and brain atrophy, Kaufmann et al. (2010) were of Caucasus Jewish origin and were found to have the same homozygous mutation (L371P; 603810.0001) in the MED17 gene, suggesting a founder effect. The Jewish community in the Caucasus region is believed to have originated from the area of today's (2010) southern Iran. The Caucasus Jews were genetically isolated for more than 2,500 years by their language and religious practice, and most members of this community immigrated to Israel between 1970 and 1990.
INHERITANCE \- Autosomal recessive GROWTH Other \- Failure to thrive HEAD & NECK Head \- Microcephaly, postnatal, progressive Eyes \- Poor visual fixation \- Lack of visual tracking ABDOMEN Gastrointestinal \- Poor feeding \- Swallowing difficulties NEUROLOGIC Central Nervous System \- Developmental retardation, severe \- Spasticity \- Clonus \- Truncal arching \- Seizures \- Hyperreflexia \- EEG abnormalities \- Multifocal spike and wave activity \- Hypsarrhythmia \- Diffuse slowing of background \- Cerebral atrophy, diffuse, severe \- Cerebellar atrophy, diffuse, severe \- Small thalami \- Thin brainstem \- Poor myelination MISCELLANEOUS \- Onset at 4 to 9 weeks of age \- Progressive disorder \- Patients are born with normal head circumference \- Has been described in patients of Caucasus Jewish origin MOLECULAR BASIS \- Caused by mutation in the mediator complex subunit 17 gene (MED17, 603810.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| MICROCEPHALY, POSTNATAL PROGRESSIVE, WITH SEIZURES AND BRAIN ATROPHY | c3150921 | 6,849 | omim | https://www.omim.org/entry/613668 | 2019-09-22T15:58:01 | {"doid": ["0111262"], "omim": ["613668"], "orphanet": ["402364"], "synonyms": []} |
A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with midbrain and hindbrain malformations (NEDMHM) is caused by homozygous mutation in the ARHGEF2 gene (607560) on chromosome 1q22. One such family has been reported.
Clinical Features
Ravindran et al. (2017) reported 2 brothers, born of consanguineous Kurdish-Turkish parents, with intellectual disability and speech delay associated with mild microcephaly and midbrain-hindbrain malformations on brain imaging. At birth, the brothers had mild congenital microcephaly (-1.95 and -2.33 SD, respectively). Motor milestones were not severely delayed, but both had decreased reflexes, stumbled often, and had impaired fine motor movements; 1 brother had hypotonia. Variable dysmorphic features included long philtrum, thin upper lip, downslanting palpebral fissures, long eyelashes, strabismus, astigmatism, and ptosis. One brother had nystagmus, amblyopia, optic disc pallor, abnormalities of the retinal pigment epithelium, and abnormal visual-evoked potentials. The other brother had high-arched palate, widely spaced nipples, broad fingers, and low posterior hairline. Brain imaging showed an elongated midbrain, hypoplasia of the pons, ventral and dorsal longitudinal clefts in the pons and medulla, and hypoplasia of the inferior cerebellar vermis. These findings were not considered to be consistent with pontocerebellar hypoplasia.
Inheritance
The transmission pattern of NEDMHM in the family reported by Ravindran et al. (2017) was consistent with autosomal recessive inheritance.
Molecular Genetics
In 2 brothers, born of consanguineous Kurdish-Turkish parents, with NEDMHM, Ravindran et al. (2017) identified a homozygous frameshift mutation in the ARHGEF2 gene (607560.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed decreased levels of mutant mRNA, consistent with partial nonsense-mediated mRNA decay, and total loss of the ARHGEF2 protein. Knockdown of Arhgef2 in mouse neocortical precursor cells and in mouse embryos resulted in an increase in cycling and eventual apoptosis of cortical precursor cells and a decrease of neurogenesis with decreased proportions of neurons in the cortical plate. Wildtype, but not mutant, ARHGEF2 was able to rescue the phenotype, consistent with the mutation resulting in a loss of function. The abnormalities in mutant mice were associated with a shift in spindle orientation to a more horizontal orientation, which favored more symmetric divisions of neocortical progenitors. Patient lymphoblastoid cells showed abnormal morphology of the mitotic spindle apparatus, decreased spindle pole distance, and decreased cell size, in the absence of a cell cycle defect. Patient cells also showed a decrease in active RhoA (165390) and its downstream signaling pathway, which has been implicated in the regulation of neurogenesis and planar cell divisions.
Animal Model
Ravindran et al. (2017) found that knockdown of Arhgef2 in mice resulted in a reduction in the volume of total brain size, the cerebellum, and the brainstem, as well as absence of the pontine nuclei. There were no major alterations in the distribution of neurons in the neocortical layers or in the development of midbrain and cerebellar structures. However, certain precerebellar nuclei were either absent or severely reduced, and certain precerebellar neurons showed abnormal migration patterns compared to controls. These findings indicated a marked specificity in the molecular control of neuronal migration in the hindbrain.
INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly, mild Face \- Long philtrum Eyes \- Downslanting palpebral fissures \- Long eyelashes \- Ptosis \- Nystagmus \- Strabismus \- Astigmatism \- Amblyopia \- Optic disc pallor \- Abnormalities of the retinal pigment epithelium \- Abnormal visual-evoked potentials Mouth \- Thin upper lip \- High-arched palate CHEST Breasts \- Widely spaced nipples MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Intellectual disability \- Delayed motor development, mild \- Frequent falls \- Poor fine motor skills \- Brain imaging shows elongated midbrain \- Pontine hypoplasia \- Clefts in the pons and medulla \- Hypoplasia of the inferior cerebellar vermis Peripheral Nervous System \- Hyporeflexia MISCELLANEOUS \- Two brothers, born of consanguineous Turkish parents, have been reported (last curated June 2017) \- Variable dysmorphic features MOLECULAR BASIS \- Caused by mutation in the Rho guanine nucleotide exchange factor 2 gene (ARHGEF2, 607560.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| NEURODEVELOPMENTAL DISORDER WITH MIDBRAIN AND HINDBRAIN MALFORMATIONS | c4479613 | 6,850 | omim | https://www.omim.org/entry/617523 | 2019-09-22T15:45:44 | {"omim": ["617523"]} |
A number sign (#) is used with this entry because familial thrombotic thrombocytopenic purpura (TTP) is caused by mutation in the ADAMTS13 gene (604134), which encodes the von Willebrand factor (VWF; 613160)-cleaving protease (VWFCP).
See 235400 for a discussion of the hemolytic-uremic syndrome (HUS), which has signs and symptoms similar to those in thrombotic thrombocytopenic purpura.
Description
The classic pentad of TTP includes hemolytic anemia with fragmentation of erythrocytes, thrombocytopenia, diffuse and nonfocal neurologic findings, decreased renal function, and fever. Congenital TTP, also known as Schulman-Upshaw syndrome, is characterized by neonatal onset, response to fresh plasma infusion, and frequent relapses (Savasan et al., 2003; Kokame et al., 2002).
Acquired TTP, which is usually sporadic, usually occurs in adults and is caused by an IgG inhibitor against the von Willebrand factor-cleaving protease.
Clinical Features
Upshaw (1978) described a female with congenital deficiency of a factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia, indicating a factor important to platelet and red cell survival. The proband, an only child of unrelated parents, was born with rudimentary right radius and ulna and a lobster claw deformity of the right hand. For the first 12 years of life she had 6 to 10 episodes a year of high fever, petechial rash, severe thrombocytopenia, and severe anemia. She would respond dramatically to blood transfusion, whereas adrenocorticosteroids and splenectomy were of no avail. After age 12, the attacks decreased to 3 or 4 yearly.
The same disorder may have been present in the patient of Schulman et al. (1960), an 8-year-old girl who had thrombocytopenia which responded to transfusions of blood or plasma. Deficiency of a stimulating factor that is responsible for megakaryocyte maturation and platelet production was postulated. The family history was negative. The mother's plasma induced normal platelet responses, whereas the father's resulted in submaximal responses. The patient of Schulman et al. (1960) was studied by a number of physicians because she moved from city to city. Splenectomy was of no benefit. In 1965, after a 5-month period of thrombocytopenia during which she did not receive intravenous plasma infusions, she had a complex of symptoms resembling those of glomerulonephritis, which was confirmed by renal biopsy (Abildgaard and Simone, 1967). The symptoms remitted with the reintroduction of plasma therapy. In 1973, the patient had preeclampsia during a pregnancy that resulted in a full-term normal boy. McDonald (1977) also postulated deficiency of a thrombopoietin-like substance in this patient. Plasma saved in 1975 and 1976 from this patient had normal levels of fibronectin (Goodnough et al., 1982). Rennard and Abe (1979) demonstrated deficiency of cold-insoluble globulin (fibronectin) in the patient of Upshaw (1978) but not in 4 other patients with thrombotic thrombocytopenic purpura.
Koizumi et al. (1981) described a patient who had thrombocytopenia and microangiopathic hemolytic anemia that seemed to improve with plasma administration. The plasma concentration of fibronectin was normal and intravenous administration of fibronectin was of no benefit. Shinohara et al. (1982) reported the case of a Japanese girl with similar clinical features responsive to plasma infusions. Hemolytic anemia, thrombocytopenia, distorted and fragmented circulating red cells, and megakaryocytosis of the bone marrow were present from the newborn period. They called the condition 'congenital microangiopathic hemolytic anemia' and suggested it was different from thrombotic thrombocytopenic purpura.
Of 4 affected sibs (2 male, 2 female) described by Wallace et al. (1975), the disease was fatal in 3. Kirchner et al. (1982) described this disorder in mother and daughter. The daughter's illness, characterized primarily by renal insufficiency was most compatible with adult hemolytic uremic syndrome and the mother's illness, which included neurologic findings and fever, was most compatible with thrombotic thrombocytopenic purpura. Merrill et al. (1985) reported 2 certain cases of thrombotic microangiopathy and 3 possible ones in 2 generations of a North Carolina black family. All affected members presented with acute renal failure and accelerated hypertension.
Kinoshita et al. (2001) reported 2 unrelated girls with onset of symptoms of USS at ages 4 years and 11 months, respectively. One of the girls developed a right hemiparesis caused by thrombotic occlusion of the left internal carotid artery at the age of 11 years. Both girls had received fresh frozen plasma infusion every 2 weeks.
Levy et al. (2001) studied 4 pedigrees with TTP. All patients presented at birth, except for 2 who experienced their first episode of TTP at ages 4 and 8 years; however, both of these individuals had sibs with disease onset as neonates. All patients had a chronic relapsing course and responded to plasma infusion. Activity of von Willebrand factor-cleaving protease (VWFCP) (see PATHOGENESIS) was measured in the plasma of 7 affected individuals and was found to be 2 to 7% of normal; none of the patients tested positive for inhibitors. Plasma levels of the protease in the parents of the affected individuals were 0.51 to 0.68 units/ml, consistent with a heterozygous carrier state. Levels for at-risk sibs of the patients and parents fell into a bimodal distribution, with one peak consistent with carriers and the other indistinguishable from the normal distribution.
Moake (2002) reviewed thrombotic microangiopathies. Familial TTP is associated with plasma levels of ADAMTS13 activity less than 5% of normal. The disease usually presents in infancy or childhood but sometimes is not evident until much later (Furlan and Lammle, 2001). Autoantibodies against ADAMTS13 are found in some cases of acquired idiopathic TTP. There is an association with the drug ticlopidine.
Upshaw-Schulman (USS) was originally reported as a disease complex with repeated episodes of thrombocytopenia and hemolytic anemia that quickly responded to infusions of fresh frozen plasma. Clinical signs often develop in the patients during the newborn period or early infancy. Indeed, the earliest and most frequently encountered clinical manifestation is severe hyperbilirubinemia with negative Coombs test soon after birth, which requires exchange blood transfusions. Pediatric hematologists had long been more familiar with this disease than general physicians, and a variety of alternative designations were given to the disease, such as chronic relapsing TTP, congenital microangiopathic hemolytic anemia (MAHA), and familial TTP/HUS, the last because the features of thrombotic thrombocytopenic purpura were almost indistinguishable from those of hemolytic-uremic syndrome (235400) (Matsumoto et al., 2004).
### Pregnancy
Fujimura et al. (2008) reported 9 Japanese women from 6 families with genetically confirmed USS who were diagnosed with the disorder during their first pregnancy. Six of the 9 had episodes of thrombocytopenia during childhood misdiagnosed as autoimmune idiopathic thrombocytopenic purpura (AITP; 188030). Thrombocytopenia occurred during the second to third trimesters in each of their 15 pregnancies, often followed by TTP. Of 15 pregnancies, 8 babies were stillborn or died soon after birth, and the remaining 7 were all premature except 1, who was born naturally following plasma infusions to the mother that had started at 8 weeks' gestation. All women had severely deficient ADAMTS13 activity. Fujimura et al. (2008) emphasized the importance of measuring ADAMTS13 activity in the evaluation of thrombocytopenia during childhood and pregnancy.
Inheritance
Furlan et al. (1997) reported 2 brothers with chronic relapsing TTP who were deficient in the VWF-cleaving protease. In addition to these brothers, Furlan et al. (1998) found complete protease deficiency in 3 sibs: 2 sisters had their first episode of TTP during pregnancy, whereas their protease-deficient brother was asymptomatic for the disorder. Three further unaffected sibs of the family (2 brothers and 1 sister) had normal activity of VWF-cleaving protease. A third family with 2 affected brothers was reported. No consanguinity was established in any of the 3 families Furlan (1999). Autosomal recessive inheritance of the disorder was suggested.
Pathogenesis
Moake et al. (1982) found unusually large multimers of von Willebrand factor (ULVWFMs) in the plasma of 4 patients, including the girl reported by Schulman et al. (1960), with chronic relapsing thrombotic thrombocytopenic purpura and proposed that these are the 'agglutinative' substances. These unusually large multimers are even larger than the largest multimers of VWF in normal plasma and resemble a subgroup of huge VWF forms secreted by human endothelial cells. After retrograde secretion by endothelial cells, these unusually large multimers become entangled in subepithelial fibrous components, thereby maximizing VWF-mediated adhesion of platelets to subendothelium after vascular damage. Normally, a processing activity in plasma prevents the highly adhesive, unusually large multimers from going far or staying long after being secreted into the bloodstream. Moake (1998) proposed that patients with chronic relapsing thrombotic thrombocytopenic purpura have a defect in the processing of these unusually large multimers that makes them susceptible to periodic relapses.
Furlan et al. (1996) and Tsai (1996) independently reported that a metal-containing proteolytic enzyme (metalloprotease) in normal plasma cleaves the peptide bond between tyrosine at position 842 and methionine at position 843 in monomeric subunits of VWF, thereby degrading the large multimers. This von Willebrand factor-cleaving protease was found by Furlan et al. (1997) to be deficient in 4 patients with chronic relapsing thrombotic thrombocytopenic purpura, 2 of whom were brothers. Because no inhibitor of the enzyme was detected in plasma, the deficiency was ascribed to an abnormality in the production, survival, or function of the protease.
Furlan et al. (1998) studied plasma samples from 30 patients with TTP and 23 patients with the hemolytic-uremic syndrome. Of 24 patients with nonfamilial TTP, 20 had severe and 4 had moderate protease deficiency during an acute event. An inhibitor of VWF found in 20 of the 24 patients (in all 5 plasma samples tested) was shown to be an IgG antibody. Furlan et al. (1998) found that 6 patients with familial TTP lacked VWFCP activity but had no inhibitor, whereas all 10 patients with familial hemolytic-uremic syndrome had normal protease activity. In vitro proteolytic degradation of von Willebrand factor by the protease was studied in 5 patients with familial and 7 patients with nonfamilial hemolytic-uremic syndrome and was found to function normally in all 12 patients. Furlan et al. (1998) concluded that nonfamilial TTP is due to an inhibitor of VWFCP, whereas the familial form is caused by a constitutional deficiency of the protease. Patients with the hemolytic-uremic syndrome do not have a deficiency of VWFCP or a defect in von Willebrand factor that leads to its resistance to protease.
Tsai and Lian (1998) found severe deficiency of von Willebrand factor-cleaving protease in 37 patients with acute thrombotic thrombocytopenic purpura. No deficiency was detected in 16 samples of plasma from patients in remission. Inhibitory activity against the protease was detected in 26 of 39 plasma samples obtained during the acute phase of the disease. The inhibitors were IgG antibodies.
Tati et al. (2013) demonstrated deposition of complement C3 (120700) and C5b (120900)-C9 (120940) in renal cortex of 2 TTP patients using immunofluorescence microscopy and immunohistochemical analysis, respectively. Flow cytometric analysis showed that plasma from TTP patients contained significantly higher levels of complement-coated endothelial particles than control plasma. Histamine-stimulated glomerular endothelial cells exposed to patient platelet-rich plasma or patient platelet-poor plasma combined with normal platelets induced C3 deposition, via the alternative pathway, on VWF platelet strings and on endothelial cells in an in vitro perfusion system under shear conditions. No complement was detected when cells were exposed to control plasma or to patient plasma treated with EDTA or that had been heat inactivated. Tati et al. (2013) concluded that the microvascular process induced by ADAMTS13 deficiency triggers complement activation on platelets and endothelium and may contribute to thrombotic microangiopathy.
Clinical Management
In the 2 patients with USS reported by Kinoshita et al. (2001), Yagi et al. (2001) studied the relationship between ULVWFMs and thrombocytopenia by analyzing platelet aggregation using a mixture of the patients' plasma and normal washed platelets under high shear stress. There was a remarkably enhanced high shear stress-induced platelet aggregation by the patients' plasma, which was almost completely normalized by administration of fresh frozen plasma. The results indicated that thrombocytopenia in USS patients is caused by a combination of the presence of ULVWFMs, platelets, and high shear stress generated in the microcirculation.
Vesely et al. (2003) stated that initial management of patients with TTP is difficult because of lack of specific diagnostic criteria, high mortality without plasma exchange treatment, and risks of plasma exchange. They performed a prospective study of ADAMTS13 activity in 142 consecutive patients, making measurements before beginning plasma exchange treatment. Severe ADAMTS13 deficiency, defined in this study as ADAMTS13 activity levels less than 5% of normal, was found in 18 (13%) of the 142 patients; it occurred only among pregnant/postpartum (2 of 10) and idiopathic (16 of 48) patients. Among the 48 patients with idiopathic TTP, the presenting features and clinical outcomes of the 16 who had severe ADAMTS13 deficiency were variable and not distinct from the 32 who did not have severe ADAMTS13 deficiency. Patients at all levels of ADAMTS13 activity apparently responded to plasma exchange treatment.
Mapping
Levy et al. (2001) used the plasma levels of VWF-cleaving protease as a phenotypic trait for linkage analysis. They analyzed DNA from affected individuals and other informative family members using 382 polymorphic microsatellite markers. A lod score of 5.63 at theta of 0.0 was obtained for marker D9S164 on 9q34 using a codominant model. Multipoint analysis for D9S164 and 4 flanking markers yielded a maximum lod score of 7.37 at marker D9S164.
Molecular Genetics
By analysis of genomic DNA from patients with familial TTP, Levy et al. (2001) identified 12 mutations in the ADAMTS13 gene (604134.0001-604134.0012), accounting for 14 of the 15 disease alleles studied. Levy et al. (2001) demonstrated that deficiency of ADAMTS13 is the molecular mechanism responsible for thrombotic thrombocytopenic purpura and suggested that physiologic proteolysis of von Willebrand factor and/or other ADAMTS13 substrates is required for normal vascular homeostasis.
In 2 Japanese families with Upshaw-Schulman syndrome, characterized by congenital TTP with neonatal onset and frequent relapses, Kokame et al. (2002) reported 4 novel mutations in the ADAMTS13 gene (604134.0013-604134.0016). Activity of von Willebrand factor-cleaving protease was less than 3% of normal in all probands; VWFCP activity in heterozygous parents ranged from 30 to 60%.
In a patient with USS and severely reduced levels of VWFCP activity, Savasan et al. (2003) identified a homozygous mutation in the ADAMTS13 gene (604134.0017).
History
Moschcowitz (1924) described the abrupt onset of petechiae and pallor, followed rapidly by paralysis, coma, and death, in a 16-year-old girl. At autopsy, terminal arterioles and capillaries were occluded by hyaline thrombi, later determined to consist mostly of platelet without perivascular inflammation or endothelial desquamation. Moschcowitz (1924) suspected a 'powerful poison which had both agglutinative and hemolytic properties' as the cause of this disorder, now known as thrombotic thrombocytopenic purpura.
INHERITANCE \- Autosomal recessive RESPIRATORY Lung \- Acute respiratory distress syndrome (uncommon) ABDOMEN Liver \- Jaundice, neonatal GENITOURINARY Kidneys \- Renal dysfunction SKIN, NAILS, & HAIR Skin \- Jaundice, neonatal NEUROLOGIC Central Nervous System \- Fluctuating neurologic signs \- Focal neurologic signs \- Disturbances of consciousness \- Confusion \- Tremor METABOLIC FEATURES \- Fever HEMATOLOGY \- Microangiopathic hemolytic anemia (Coomb negative) \- Thrombocytopenia \- Thrombotic microangiopathy (hyaline thrombi of platelets and fibrin in terminal arterioles and capillaries) \- Reticulocytosis \- Schistocytes LABORATORY ABNORMALITIES \- Decreased hemoglobin \- Increased serum lactate dehydrogenase (LDH) \- Decreased serum haptoglobin \- Proteinuria \- Microscopic hematuria \- Increased blood urea nitrogen (BUN) \- Increased creatinine \- Ultra large von Willebrand factor (UL-vWF) in plasma MISCELLANEOUS \- Genetic heterogeneity \- Triggered by pregnancy, drugs, chemotherapy, cancer, bone marrow transplantation, infection \- Familial form - Constitutional deficiency of vWF-cleaving protease \- Acquired form - Presence of inhibiting autoantibody (IgG) to vWF-cleaving protease \- In adults, may be considered part of a spectrum with hemolytic-uremic syndrome (HUS, 235400 ) MOLECULAR BASIS \- Caused by mutation in the von Willebrand-cleaving protease gene (ADAMTS13, 604134.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| THROMBOTIC THROMBOCYTOPENIC PURPURA, CONGENITAL | c0034155 | 6,851 | omim | https://www.omim.org/entry/274150 | 2019-09-22T16:21:44 | {"doid": ["10772"], "mesh": ["D011697"], "omim": ["274150"], "orphanet": ["54057", "93583"], "synonyms": ["Alternative titles", "MICROANGIOPATHIC HEMOLYTIC ANEMIA", "THROMBOTIC MICROANGIOPATHY, FAMILIAL", "UPSHAW-SCHULMAN SYNDROME", "SCHULMAN-UPSHAW SYNDROME", "UPSHAW FACTOR, DEFICIENCY OF", "MICROANGIOPATHIC HEMOLYTIC ANEMIA, CONGENITAL", "THROMBOTIC THROMBOCYTOPENIC PURPURA, FAMILIAL"]} |
A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-59 (EIEE59) is caused by heterozygous mutation in the GABBR2 gene (607340) on chromosome 9q22.
For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).
Clinical Features
The EuroEPINOMICS-RES Consortium et al. (2014) reported 2 unrelated patients, a 3-year-old girl (NLES8) and an 18-year-old man (NLES10), with EIEE59. The patients had onset of seizures within the first 3 months of life. The girl had multiple seizure types, whereas the male had infantile spasms that mostly resolved by age 5 months, although he had a few focal dyscognitive seizures and nonepileptic apneic spells later in life. Both patients had hypsarrhythmia on EEG. The girl had profound intellectual disability with no head control, inability to speak, and severe hypotonia, and she was fed by a G-tube. She reacted to music but not to people. The older patient had severe intellectual disability, autism spectrum disorder, no speech, mild ataxia, sleeping disorder, and automutilation behavior, and he could walk only with support.
Hamdan et al. (2017) reported a 14-year-old boy (HSJ0048), born of unrelated French Canadian parents, who presented with severe developmental delay and onset of brief focal seizures at 11 months of age. The seizures sometimes progressed, and were controlled by medication. EEG showed modified hypsarrhythmia. Refractory seizures of variable types recurred at age 4.5 years. At age 14, he had severe intellectual disability with inability to sit on his own, absent language, poor eye contact, lack of interest in the environment, drooling, hypotonia, scoliosis, and bouts of aggression. Brain imaging showed enlarged ventricles.
Molecular Genetics
In 2 unrelated patients with EIEE59, the EuroEPINOMICS-RES Consortium et al. (2014) identified de novo heterozygous missense mutations in the GABBR2 gene (S695I, 607340.0004 and I705N, 607340.0005). The mutations were found by exome sequencing of a cohort of 356 trios in which the proband had early infantile epileptic encephalopathy. Functional studies of the variants and studies of patient cells were not performed, but the authors noted that GABBR2 is involved in synaptic transmission.
In a 14-year-old boy (HSJ0048) with EIEE59, Hamdan et al. (2017) identified a de novo heterozygous missense mutation in the GABBR2 gene (G693W; 607340.0006). The mutation was found by whole-genome sequencing and confirmed by Sanger sequencing; the patient was part of several cohorts of patients with developmental delay or epilepsy who underwent whole-exome or whole-genome sequencing. Functional studies of the variants and studies of patient cells were not performed, but the authors noted that GABBR2 is involved in synaptic inhibition.
Using in vitro cellular transfection studies and animal models, Yoo et al. (2017) demonstrated that the GABBR2 S695I and I705N mutations, associated with EIEE59, reduced GABA signaling activity. Based on molecular modeling, the S695I and I705N mutations, located in transmembrane 6, were predicted to affect the structural integrity of the receptor.
Animal Model
Yoo et al. (2017) found that tadpoles injected with the EIEE59-associated GABBR2 mutations showed abnormal swimming patterns and increased frequencies of seizure-like behavior compared to wildtype. The variants could not rescue the defect in tadpoles with morpholino knockdown of the Gabbr2 gene, consistent with a loss of function. The addition of baclofen, a GABAB receptor agonist, to the water partially rescued the phenotype of animals, suggesting a potential therapeutic target in patients with GABBR2 mutations.
INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Poor head control Eyes \- Poor visual contact Mouth \- Drooling SKELETAL Spine \- Scoliosis MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Epileptic encephalopathy \- Seizures, multiple types \- Developmental delay, profound \- Intellectual disability \- Absent speech \- Inability to sit or stand \- Inability to walk independently \- Hypsarrhythmia \- Sleep disturbances \- Enlarged ventricles Behavioral Psychiatric Manifestations \- Aggressive outbursts \- Self-injurious behavior MISCELLANEOUS \- Onset in early infancy \- Seizures are usually refractory \- De novo mutation MOLECULAR BASIS \- Caused by mutation in the gamma-aminobutyric acid B receptor 2 gene (GABBR2, 607340.0004 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 59 | c2748910 | 6,852 | omim | https://www.omim.org/entry/617904 | 2019-09-22T15:44:27 | {"doid": ["0080291"], "mesh": ["C567576"], "omim": ["617904"], "orphanet": ["3095"]} |
## Description
The focal dermal dysplasias (FFDDs) are a group of related developmental defects characterized by bitemporal or preauricular skin lesions resembling aplasia cutis congenita. FFFD2 is an autosomal dominant disorder characterized by bitemporal skin lesions with variable facial findings, including thin and puckered periorbital skin, distichiasis and/or absent eyelashes, upslanting palpebral fissures, a flat nasal bridge with a broad nasal tip, large lips, and redundant facial skin. FFDD3 (227260) is characterized by the same facial features as FFDD2, but the inheritance is autosomal recessive (summary by Slavotinek et al., 2013).
For a classification and a discussion of genetic heterogeneity of FFDD, see FFDD1 (136500).
Clinical Features
Ward and Moss (1994) suggested that the Setleis syndrome and type I focal facial dermal dysplasia (Brauer syndrome) 'are a single disorder.' They described a family in which the mother and 3 children had typical lesions on the temples and facial features, which they interpreted as similar to those in Setleis syndrome. The leonine facies described by Setleis et al. (1963) resulted from a combination of frontal bossing, redundant facial skin, periorbital puffiness, and flattened nasal bridge with a bulbous nasal tip.
Kaplan et al. (1995) presented evidence that the Setleis and Brauer forms of focal facial dermal dysplasia may be the same entity inherited in an autosomal dominant manner. They described a proband with bitemporal 'scars,' sparse lateral eyebrows, bulbous nose tip, thick lips, micrognathia, chin crease, imperforate anus and rectocutaneous fistula, bilateral megaureters, hypotonia, growth and developmental delay, and nonconsanguineous parents. His father had only bitemporal 'scarring,' bulbous nose tip, and hypertension.
Masuno et al. (1995) described a Japanese family in which a 9-month-old boy had typical Setleis syndrome; his father who had normal intelligence showed bitemporal focal dermal dysplasia but a normal face; and a paternal second cousin also had Setleis syndrome.
McGaughran and Aftimos (2002) reported Setleis syndrome in 3 patients, a Caucasian boy and a father and son of Pacific Island descent. In addition to bilateral temporal defects, the father and son both had linear markings on their mid-lower foreheads. The other boy had linear indentations parallel and just above the eyebrows. The 2 boys also had unruly hair, 1 with a double whorl. All 3 patients had developmental delay or learning difficulties.
Graul-Neumann et al. (2009) described the clinical features of 4 of 12 affected members from a large multigenerational German family with what the authors termed 'Brauer-Setleis syndrome.' All 4 had large bitemporal discolored dermal depressions ('forceps marks'), sparse lateral eyebrows, abnormal eyelashes, and dysplastic and low-set ears. Three had congenital horizontal nystagmus, which had hitherto only been reported in a single patient with FFDD.
Inheritance
Di Lernia et al. (1991) and Artlich et al. (1992) each described a family in which one of the parents of a patient with Setleis syndrome showed mild manifestations suggesting autosomal dominant inheritance.
Masuno et al. (1995) suggested that the pattern of inheritance in a Japanese family with Setleis syndrome was consistent with autosomal dominant transmission with variable expressivity and reduced penetrance.
Kaplan et al. (1995) suggested that the disorder they described with features of Brauer and Setleis syndromes was inherited in an autosomal dominant manner with variable expressivity.
Father-to-son transmission of Setleis syndrome in the family reported by McGaughran and Aftimos (2002) was consistent with autosomal dominant inheritance.
The transmission pattern of Brauer-Setleis syndrome in the families reported by Graul-Neumann et al. (2009) was consistent with autosomal dominant inheritance.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| FOCAL FACIAL DERMAL DYSPLASIA 2, BRAUER-SETLEIS TYPE | c1744559 | 6,853 | omim | https://www.omim.org/entry/614973 | 2019-09-22T15:53:34 | {"mesh": ["C536385"], "omim": ["614973"], "orphanet": ["398173", "398166"], "synonyms": ["Alternative titles", "BRAUER-SETLEIS SYNDROME"]} |
For other uses, see Abortion (disambiguation).
Ending of a pregnancy before a fetus can survive outside the uterus
Abortion
Other namesInduced miscarriage, termination of pregnancy
SpecialtyObstetrics and gynecology
ICD-10-PCSO04
ICD-9-CM779.6
MeSHD000028
MedlinePlus007382
[edit on Wikidata]
Abortion is the ending of a pregnancy by removal or expulsion of an embryo or fetus.[note 1] An abortion that occurs without intervention is known as a miscarriage or "spontaneous abortion" and occurs in approximately 30% to 40% of pregnancies.[1][2] When deliberate steps are taken to end a pregnancy, it is called an induced abortion, or less frequently "induced miscarriage". The unmodified word abortion generally refers to an induced abortion.[3][4]
When properly done, abortion is one of the safest procedures in medicine,[5]:1 [6]:1 but unsafe abortion is a major cause of maternal death, especially in the developing world.[7] Making safe abortion legal and accessible reduces maternal deaths.[8][9] It is safer than childbirth, which has a 14 times higher risk of death in the United States.[10] Modern methods use medication or surgery for abortions.[11] The drug mifepristone in combination with prostaglandin appears to be as safe and effective as surgery during the first and second trimester of pregnancy.[11][12] The most common surgical technique involves dilating the cervix and using a suction device.[13] Birth control, such as the pill or intrauterine devices, can be used immediately following abortion.[12] When performed legally and safely on a woman who desires it, induced abortions do not increase the risk of long-term mental or physical problems.[14] In contrast, unsafe abortions (those performed by unskilled individuals, with hazardous equipment, or in unsanitary facilities) cause 47,000 deaths and 5 million hospital admissions each year.[14][15] The World Health Organization recommends safe and legal abortions be available to all women.[16]
Around 56 million abortions are performed each year in the world,[17] with about 45% done unsafely.[18] Abortion rates changed little between 2003 and 2008,[19] before which they decreased for at least two decades as access to family planning and birth control increased.[20] As of 2018[update], 37% of the world's women had access to legal abortions without limits as to reason.[21][22] Countries that permit abortions have different limits on how late in pregnancy abortion is allowed.[22]
Historically, abortions have been attempted using herbal medicines, sharp tools, forceful massage, or through other traditional methods.[23] Abortion laws and cultural or religious views of abortions are different around the world. In some areas abortion is legal only in specific cases such as rape, problems with the fetus, poverty, risk to a woman's health, or incest.[24] There is debate over the moral, ethical, and legal issues of abortion.[25][26] Those who oppose abortion often argue that an embryo or fetus is a human with a right to life, and they may compare abortion to murder.[27][28] Those who support the legality of abortion often hold that it is part of a woman's right to make decisions about her own body.[29] Others favor legal and accessible abortion as a public health measure.[30]
## Contents
* 1 Types
* 1.1 Induced
* 1.2 Spontaneous
* 2 Methods
* 2.1 Medical
* 2.2 Surgical
* 2.3 Labor induction abortion
* 2.4 Other methods
* 3 Safety
* 3.1 Mental health
* 3.2 Unsafe abortion
* 4 Incidence
* 4.1 Gestational age and method
* 5 Motivation
* 5.1 Personal
* 5.2 Societal
* 5.3 Maternal and fetal health
* 5.3.1 Cancer
* 6 History and religion
* 7 Society and culture
* 7.1 Abortion debate
* 7.2 Modern abortion law
* 7.3 Sex-selective abortion
* 7.4 Anti-abortion violence
* 8 Other animals
* 9 Notes
* 10 References
* 11 Bibliography
* 12 External links
## Types
### Induced
Approximately 205 million pregnancies occur each year worldwide. Over a third are unintended and about a fifth end in induced abortion.[19][31] Most abortions result from unintended pregnancies.[32][33] In the United Kingdom, 1 to 2% of abortions are done due to genetic problems in the fetus.[14] A pregnancy can be intentionally aborted in several ways. The manner selected often depends upon the gestational age of the embryo or fetus, which increases in size as the pregnancy progresses.[34][35] Specific procedures may also be selected due to legality, regional availability, and doctor or a woman's personal preference.
Reasons for procuring induced abortions are typically characterized as either therapeutic or elective. An abortion is medically referred to as a therapeutic abortion when it is performed to save the life of the pregnant woman; to prevent harm to the woman's physical or mental health; to terminate a pregnancy where indications are that the child will have a significantly increased chance of mortality or morbidity; or to selectively reduce the number of fetuses to lessen health risks associated with multiple pregnancy.[36][37] An abortion is referred to as an elective or voluntary abortion when it is performed at the request of the woman for non-medical reasons.[37] Confusion sometimes arises over the term "elective" because "elective surgery" generally refers to all scheduled surgery, whether medically necessary or not.[38]
### Spontaneous
Main article: Miscarriage
Miscarriage, also known as spontaneous abortion, is the unintentional expulsion of an embryo or fetus before the 24th week of gestation.[39] A pregnancy that ends before 37 weeks of gestation resulting in a live-born infant is a "premature birth" or a "preterm birth".[40] When a fetus dies in utero after viability, or during delivery, it is usually termed "stillborn".[41] Premature births and stillbirths are generally not considered to be miscarriages although usage of these terms can sometimes overlap.[42]
Only 30% to 50% of conceptions progress past the first trimester.[43] The vast majority of those that do not progress are lost before the woman is aware of the conception,[37] and many pregnancies are lost before medical practitioners can detect an embryo.[44] Between 15% and 30% of known pregnancies end in clinically apparent miscarriage, depending upon the age and health of the pregnant woman.[45] 80% of these spontaneous abortions happen in the first trimester.[46]
The most common cause of spontaneous abortion during the first trimester is chromosomal abnormalities of the embryo or fetus,[37][47] accounting for at least 50% of sampled early pregnancy losses.[48] Other causes include vascular disease (such as lupus), diabetes, other hormonal problems, infection, and abnormalities of the uterus.[47] Advancing maternal age and a woman's history of previous spontaneous abortions are the two leading factors associated with a greater risk of spontaneous abortion.[48] A spontaneous abortion can also be caused by accidental trauma; intentional trauma or stress to cause miscarriage is considered induced abortion or feticide.[49]
## Methods
### Medical
Main article: Medical abortion
Practice of Induced Abortion Methods
MVA
D&E
EVA
Hyst.
D&C
Intact D&X
Mifepr.
Induced Miscarr.
0–12 wks
12–28 weeks
28–40 wks
Gestational age may determine which abortion methods are practiced.
Medical abortions are those induced by abortifacient pharmaceuticals. Medical abortion became an alternative method of abortion with the availability of prostaglandin analogs in the 1970s and the antiprogestogen mifepristone (also known as RU-486) in the 1980s.[11][12][50][51][52]
The most common early first-trimester medical abortion regimens use mifepristone in combination with misoprostol (or sometimes another prostaglandin analog, gemeprost) up to 10 weeks (70 days) gestational age,[53][54] methotrexate in combination with a prostaglandin analog up to 7 weeks gestation, or a prostaglandin analog alone.[50] Mifepristone–misoprostol combination regimens work faster and are more effective at later gestational ages than methotrexate–misoprostol combination regimens, and combination regimens are more effective than misoprostol alone.[51] This regimen is effective in the second trimester.[55] Medical abortion regimens involving mifepristone followed by misoprostol in the cheek between 24 and 48 hours later are effective when performed before 70 days' gestation.[54][56]
In very early abortions, up to 7 weeks gestation, medical abortion using a mifepristone–misoprostol combination regimen is considered to be more effective than surgical abortion (vacuum aspiration), especially when clinical practice does not include detailed inspection of aspirated tissue.[57] Early medical abortion regimens using mifepristone, followed 24–48 hours later by buccal or vaginal misoprostol are 98% effective up to 9 weeks gestational age; from 9 to 10 weeks efficacy decreases modestly to 94%.[56][58] If medical abortion fails, surgical abortion must be used to complete the procedure.[59]
Early medical abortions account for the majority of abortions before 9 weeks gestation in Britain,[60][61] France,[62] Switzerland,[63] and the Nordic countries.[64] In the United States, the percentage of early medical abortions performed in non-hospital facilities is 31% as of 2014[update].[65]
Medical abortion regimens using mifepristone in combination with a prostaglandin analog are the most common methods used for second-trimester abortions in Canada, most of Europe, China and India,[52] in contrast to the United States where 96% of second-trimester abortions are performed surgically by dilation and evacuation.[66]
A 2020 Cochrane Systematic Review concluded that providing women with medications to take home to complete the second stage of the procedure for an early medical abortion results in an effective abortion.[67] Further research is required to determine if self-administered medical abortion is as safe as provider-administered medical abortion, where a health care professional is present to help manage the medical abortion.[67] Safely permitting women to self-administer abortion medication has the potential to improve access to abortion.[67] Other research gaps that were identified include how to best support women who choose to take the medication home for a self-administered abortion.[67]
### Surgical
A vacuum aspiration abortion at eight weeks gestational age (six weeks after fertilization).
1: Amniotic sac
2: Embryo
3: Uterine lining
4: Speculum
5: Vacurette
6: Attached to a suction pump
Up to 15 weeks' gestation, suction-aspiration or vacuum aspiration are the most common surgical methods of induced abortion.[68] Manual vacuum aspiration (MVA) consists of removing the fetus or embryo, placenta, and membranes by suction using a manual syringe, while electric vacuum aspiration (EVA) uses an electric pump. These techniques can both be used very early in pregnancy. MVA can be used up to 14 weeks but is more often used earlier in the U.S. EVA can be used later.[66]
MVA, also known as "mini-suction" and "menstrual extraction" or EVA can be used in very early pregnancy when cervical dilation may not be required. Dilation and curettage (D&C) refers to opening the cervix (dilation) and removing tissue (curettage) via suction or sharp instruments. D&C is a standard gynecological procedure performed for a variety of reasons, including examination of the uterine lining for possible malignancy, investigation of abnormal bleeding, and abortion. The World Health Organization recommends sharp curettage only when suction aspiration is unavailable.[69]
Dilation and evacuation (D&E), used after 12 to 16 weeks, consists of opening the cervix and emptying the uterus using surgical instruments and suction. D&E is performed vaginally and does not require an incision. Intact dilation and extraction(D&X) refers to a variant of D&E sometimes used after 18 to 20 weeks when removal of an intact fetus improves surgical safety or for other reasons.[70]
Abortion may also be performed surgically by hysterotomy or gravid hysterectomy. Hysterotomy abortion is a procedure similar to a caesarean section and is performed under general anesthesia. It requires a smaller incision than a caesarean section and can be used during later stages of pregnancy. Gravid hysterectomy refers to removal of the whole uterus while still containing the pregnancy. Hysterotomy and hysterectomy are associated with much higher rates of maternal morbidity and mortality than D&E or induction abortion.[71]
First-trimester procedures can generally be performed using local anesthesia, while second-trimester methods may require deep sedation or general anesthesia.[72]
### Labor induction abortion
In places lacking the necessary medical skill for dilation and extraction, or where preferred by practitioners, an abortion can be induced by first inducing labor and then inducing fetal demise if necessary.[73] This is sometimes called "induced miscarriage". This procedure may be performed from 13 weeks gestation to the third trimester. Although it is very uncommon in the United States, more than 80% of induced abortions throughout the second trimester are labor-induced abortions in Sweden and other nearby countries.[74]
Only limited data are available comparing this method with dilation and extraction.[74] Unlike D&E, labor-induced abortions after 18 weeks may be complicated by the occurrence of brief fetal survival, which may be legally characterized as live birth. For this reason, labor-induced abortion is legally risky in the United States.[74][75]
### Other methods
Historically, a number of herbs reputed to possess abortifacient properties have been used in folk medicine. Among these are: tansy, pennyroyal, black cohosh, and the now-extinct silphium.[76]:44–47, 62–63, 154–55, 230–31
In 1978 one woman in Colorado died and another developed organ damage when they attempted to terminate their pregnancies by taking pennyroyal oil.[77] Because the indiscriminant use of herbs as abortifacients can cause serious—even lethal—side effects, such as multiple organ failure,[78] such use is not recommended by physicians.
Abortion is sometimes attempted by causing trauma to the abdomen. The degree of force, if severe, can cause serious internal injuries without necessarily succeeding in inducing miscarriage.[79] In Southeast Asia, there is an ancient tradition of attempting abortion through forceful abdominal massage.[80] One of the bas reliefs decorating the temple of Angkor Wat in Cambodia depicts a demon performing such an abortion upon a woman who has been sent to the underworld.[80]
Reported methods of unsafe, self-induced abortion include misuse of misoprostol and insertion of non-surgical implements such as knitting needles and clothes hangers into the uterus. These and other methods to terminate pregnancy may be called "induced miscarriage". Such methods are rarely used in countries where surgical abortion is legal and available.[81]
## Safety
A likely illegal abortion flyer in South Africa
The health risks of abortion depend principally upon whether the procedure is performed safely or unsafely. The World Health Organization (WHO) defines unsafe abortions as those performed by unskilled individuals, with hazardous equipment, or in unsanitary facilities.[82] Legal abortions performed in the developed world are among the safest procedures in medicine.[5][83] In the United States as of 2012, abortion was estimated to be about 14 times safer for women than childbirth.[10] CDC estimated in 2019 that US pregnancy-related mortality was 17.2 maternal deaths per 100,000 live births,[84] while the US abortion mortality rate is 0.7 maternal deaths per 100,000 procedures.[6][85] In the UK, guidelines of the Royal College of Obstetricians and Gynaecologists state that "Women should be advised that abortion is generally safer than continuing a pregnancy to term."[86] Worldwide, on average, abortion is safer than carrying a pregnancy to term. A 2007 study reported that "26% of all pregnancies worldwide are terminated by induced abortion," whereas "deaths from improperly performed [abortion] procedures constitute 13% of maternal mortality globally."[87] In Indonesia in 2000 it was estimated that 2 million pregnancies ended in abortion, 4.5 million pregnancies were carried to term, and 14-16 percent of maternal deaths resulted from abortion.[88]
In the US from 2000 to 2009, abortion had a lower mortality rate than plastic surgery, and a similar or lower mortality rate than running a marathon.[89] Five years after seeking abortion services, women who gave birth after being denied an abortion reported worse health than women who had either first or second trimester abortions.[90] The risk of abortion-related mortality increases with gestational age, but remains lower than that of childbirth.[91] Outpatient abortion is as safe from 64 to 70 days' gestation as it before 63 days.[92]
There is little difference in terms of safety and efficacy between medical abortion using a combined regimen of mifepristone and misoprostol and surgical abortion (vacuum aspiration) in early first trimester abortions up to 10 weeks gestation.[57] Medical abortion using the prostaglandin analog misoprostol alone is less effective and more painful than medical abortion using a combined regimen of mifepristone and misoprostol or surgical abortion.[93][94]
Vacuum aspiration in the first trimester is the safest method of surgical abortion, and can be performed in a primary care office, abortion clinic, or hospital. Complications, which are rare, can include uterine perforation, pelvic infection, and retained products of conception requiring a second procedure to evacuate.[95] Infections account for one-third of abortion-related deaths in the United States.[96] The rate of complications of vacuum aspiration abortion in the first trimester is similar regardless of whether the procedure is performed in a hospital, surgical center, or office.[97] Preventive antibiotics (such as doxycycline or metronidazole) are typically given before abortion procedures,[98] as they are believed to substantially reduce the risk of postoperative uterine infection;[72][99] however, antibiotics are not routinely given with abortion pills.[100] The rate of failed procedures does not appear to vary significantly depending on whether the abortion is performed by a doctor or a mid-level practitioner.[101]
Complications after second-trimester abortion are similar to those after first-trimester abortion, and depend somewhat on the method chosen.[102] The risk of death from abortion approaches roughly half the risk of death from childbirth the farther along a woman is in pregnancy; from one in a million before 9 weeks gestation to nearly one in ten thousand at 21 weeks or more (as measured from the last menstrual period).[103][104] It appears that having had a prior surgical uterine evacuation (whether because of induced abortion or treatment of miscarriage) correlates with a small increase in the risk of preterm birth in future pregnancies. The studies supporting this did not control for factors not related to abortion or miscarriage, and hence the causes of this correlation have not been determined, although multiple possibilities have been suggested.[105][106]
Some purported risks of abortion are promoted primarily by anti-abortion groups,[107][108] but lack scientific support.[107] For example, the question of a link between induced abortion and breast cancer has been investigated extensively. Major medical and scientific bodies (including the WHO, National Cancer Institute, American Cancer Society, Royal College of OBGYN and American Congress of OBGYN) have concluded that abortion does not cause breast cancer.[109]
In the past even illegality has not automatically meant that the abortions were unsafe. Referring to the U.S., historian Linda Gordon states: "In fact, illegal abortions in this country have an impressive safety record."[110]:25 According to Rickie Solinger,
> A related myth, promulgated by a broad spectrum of people concerned about abortion and public policy, is that before legalization abortionists were dirty and dangerous back-alley butchers.... [T]he historical evidence does not support such claims.[111]:4
Authors Jerome Bates and Edward Zawadzki describe the case of an illegal abortionist in the eastern U.S. in the early 20th century who was proud of having successfully completed 13,844 abortions without any fatality.[112]:59 In 1870s New York City the famous abortionist/midwife Madame Restell (Anna Trow Lohman) appears to have lost very few women among her more than 100,000 patients[113]—a lower mortality rate than the childbirth mortality rate at the time. In 1936 the prominent professor of obstetrics and gynecology Frederick J. Taussig wrote that a cause of increasing mortality during the years of illegality in the U.S. was that
> With each decade of the past fifty years the actual and proportionate frequency of this accident [perforation of the uterus] has increased, due, first, to the increase in the number of instrumentally induced abortions; second, to the proportionate increase in abortions handled by doctors as against those handled by midwives; and, third, to the prevailing tendency to use instruments instead of the finger in emptying the uterus. [114]:223
### Mental health
Main article: Abortion and mental health
Current evidence finds no relationship between most induced abortions and mental health problems[14][115] other than those expected for any unwanted pregnancy.[116] A report by the American Psychological Association concluded that a woman's first abortion is not a threat to mental health when carried out in the first trimester, with such women no more likely to have mental-health problems than those carrying an unwanted pregnancy to term; the mental-health outcome of a woman's second or greater abortion is less certain.[116][117] Some older reviews concluded that abortion was associated with an increased risk of psychological problems;[118] however, they did not use an appropriate control group.[115]
Although some studies show negative mental-health outcomes in women who choose abortions after the first trimester because of fetal abnormalities,[119] more rigorous research would be needed to show this conclusively.[120] Some proposed negative psychological effects of abortion have been referred to by anti-abortion advocates as a separate condition called "post-abortion syndrome", but this is not recognized by medical or psychological professionals in the United States.[121]
A long term-study among US women found that about 99% of women felt that they made the right decision five years after they had an abortion. Relief was the primary emotion with few women feeling sadness or guilt. Social stigma was a main factor predicting negative emotions and regret years later.[122]
### Unsafe abortion
Main article: Unsafe abortion
Soviet poster circa 1925, warning against midwives performing abortions. Title translation: "Miscarriages induced by either grandma or self-taught midwives not only maim the woman, they also often lead to death."
Women seeking an abortion may use unsafe methods, especially when abortion is legally restricted. They may attempt self-induced abortion or seek the help of a person without proper medical training or facilities. This can lead to severe complications, such as incomplete abortion, sepsis, hemorrhage, and damage to internal organs.[123]
Unsafe abortions are a major cause of injury and death among women worldwide. Although data are imprecise, it is estimated that approximately 20 million unsafe abortions are performed annually, with 97% taking place in developing countries.[5] Unsafe abortions are believed to result in millions of injuries.[5][124] Estimates of deaths vary according to methodology, and have ranged from 37,000 to 70,000 in the past decade;[5][15][125] deaths from unsafe abortion account for around 13% of all maternal deaths.[126] The World Health Organization believes that mortality has fallen since the 1990s.[127] To reduce the number of unsafe abortions, public health organizations have generally advocated emphasizing the legalization of abortion, training of medical personnel, and ensuring access to reproductive-health services.[128] In response, opponents of abortion point out that abortion bans in no way affect prenatal care for women who choose to carry their fetus to term. The Dublin Declaration on Maternal Health, signed in 2012, notes, "the prohibition of abortion does not affect, in any way, the availability of optimal care to pregnant women."[129]
A major factor in whether abortions are performed safely or not is the legal standing of abortion. Countries with restrictive abortion laws have higher rates of unsafe abortion and similar overall abortion rates compared to those where abortion is legal and available.[15][19][128][130][131][132][133] For example, the 1996 legalization of abortion in South Africa had an immediate positive impact on the frequency of abortion-related complications,[134] with abortion-related deaths dropping by more than 90%.[135] Similar reductions in maternal mortality have been observed after other countries have liberalized their abortion laws, such as Romania and Nepal.[136] A 2011 study concluded that in the United States, some state-level anti-abortion laws are correlated with lower rates of abortion in that state.[137] The analysis, however, did not take into account travel to other states without such laws to obtain an abortion.[138] In addition, a lack of access to effective contraception contributes to unsafe abortion. It has been estimated that the incidence of unsafe abortion could be reduced by up to 75% (from 20 million to 5 million annually) if modern family planning and maternal health services were readily available globally.[139] Rates of such abortions may be difficult to measure because they can be reported variously as miscarriage, "induced miscarriage", "menstrual regulation", "mini-abortion", and "regulation of a delayed/suspended menstruation".[140][141]
Forty percent of the world's women are able to access therapeutic and elective abortions within gestational limits,[22] while an additional 35 percent have access to legal abortion if they meet certain physical, mental, or socioeconomic criteria.[24] While maternal mortality seldom results from safe abortions, unsafe abortions result in 70,000 deaths and 5 million disabilities per year.[15] Complications of unsafe abortion account for approximately an eighth of maternal mortalities worldwide,[142] though this varies by region.[143] Secondary infertility caused by an unsafe abortion affects an estimated 24 million women.[131] The rate of unsafe abortions has increased from 44% to 49% between 1995 and 2008.[19] Health education, access to family planning, and improvements in health care during and after abortion have been proposed to address this phenomenon.[144]
## Incidence
There are two commonly used methods of measuring the incidence of abortion:
* Abortion rate – number of abortions annually per 1000 women between 15 and 44 years of age
* Abortion percentage – number of abortions out of 100 known pregnancies (pregnancies include live births, abortions and miscarriages)
In many places, where abortion is illegal or carries a heavy social stigma, medical reporting of abortion is not reliable.[130] For this reason, estimates of the incidence of abortion must be made without determining certainty related to standard error.[19]
The number of abortions performed worldwide seems to have remained stable in recent years, with 41.6 million having been performed in 2003 and 43.8 million having been performed in 2008.[19] The abortion rate worldwide was 28 per 1000 women per year, though it was 24 per 1000 women per year for developed countries and 29 per 1000 women per year for developing countries.[19] The same 2012 study indicated that in 2008, the estimated abortion percentage of known pregnancies was at 21% worldwide, with 26% in developed countries and 20% in developing countries.[19]
On average, the incidence of abortion is similar in countries with restrictive abortion laws and those with more liberal access to abortion.[145] However, restrictive abortion laws are associated with increases in the percentage of abortions performed unsafely.[22][146][145] The unsafe abortion rate in developing countries is partly attributable to lack of access to modern contraceptives; according to the Guttmacher Institute, providing access to contraceptives would result in about 14.5 million fewer unsafe abortions and 38,000 fewer deaths from unsafe abortion annually worldwide.[147]
The rate of legal, induced abortion varies extensively worldwide. According to the report of employees of Guttmacher Institute it ranged from 7 per 1000 women per year (Germany and Switzerland) to 30 per 1000 women per year (Estonia) in countries with complete statistics in 2008. The proportion of pregnancies that ended in induced abortion ranged from about 10% (Israel, the Netherlands and Switzerland) to 30% (Estonia) in the same group, though it might be as high as 36% in Hungary and Romania, whose statistics were deemed incomplete.[148][149]
An American study in 2002 concluded that about half of women having abortions were using a form of contraception at the time of becoming pregnant. Inconsistent use was reported by half of those using condoms and three-quarters of those using the birth control pill; 42% of those using condoms reported failure through slipping or breakage.[150] The Guttmacher Institute estimated that "most abortions in the United States are obtained by minority women" because minority women "have much higher rates of unintended pregnancy".[151]
The abortion rate may also be expressed as the average number of abortions a woman has during her reproductive years; this is referred to as total abortion rate (TAR).
### Gestational age and method
Histogram of abortions by gestational age in England and Wales during 2019. (left) Abortion in the United States by gestational age, 2016. (right)
Abortion rates also vary depending on the stage of pregnancy and the method practiced. In 2003, the Centers for Disease Control and Prevention (CDC) reported that 26% of reported legal induced abortions in the United States were known to have been obtained at less than 6 weeks' gestation, 18% at 7 weeks, 15% at 8 weeks, 18% at 9 through 10 weeks, 10% at 11 through 12 weeks, 6% at 13 through 15 weeks, 4% at 16 through 20 weeks and 1% at more than 21 weeks. 91% of these were classified as having been done by "curettage" (suction-aspiration, dilation and curettage, dilation and evacuation), 8% by "medical" means (mifepristone), >1% by "intrauterine instillation" (saline or prostaglandin), and 1% by "other" (including hysterotomy and hysterectomy).[152] According to the CDC, due to data collection difficulties the data must be viewed as tentative and some fetal deaths reported beyond 20 weeks may be natural deaths erroneously classified as abortions if the removal of the dead fetus is accomplished by the same procedure as an induced abortion.[153]
The Guttmacher Institute estimated there were 2,200 intact dilation and extraction procedures in the US during 2000; this accounts for <0.2% of the total number of abortions performed that year.[154] Similarly, in England and Wales in 2006, 89% of terminations occurred at or under 12 weeks, 9% between 13 and 19 weeks, and 2% at or over 20 weeks. 64% of those reported were by vacuum aspiration, 6% by D&E, and 30% were medical.[155] There are more second trimester abortions in developing countries such as China, India and Vietnam than in developed countries.[156]
## Motivation
### Personal
A bar chart depicting selected data from a 1998 AGI meta-study on the reasons women stated for having an abortion.
The reasons why women have abortions are diverse and vary across the world.[153][157] Some of the reasons may include an inability to afford a child, domestic violence, lack of support, feeling they are too young, and the wish to complete education or advance a career.[158] Additional reasons include not being willing to raise a child conceived as a result of rape or incest.[157][159]
### Societal
Some abortions are undergone as the result of societal pressures.[160] These might include the preference for children of a specific sex or race, disapproval of single or early motherhood, stigmatization of people with disabilities, insufficient economic support for families, lack of access to or rejection of contraceptive methods, or efforts toward population control (such as China's one-child policy). These factors can sometimes result in compulsory abortion or sex-selective abortion.[161]
### Maternal and fetal health
An additional factor is maternal health which was listed as the main reason by about a third of women in 3 of 27 countries and about 7% of women in a further 7 of these 27 countries.[153][157]
In the U.S., the Supreme Court decisions in Roe v. Wade and Doe v. Bolton: "ruled that the state's interest in the life of the fetus became compelling only at the point of viability, defined as the point at which the fetus can survive independently of its mother. Even after the point of viability, the state cannot favor the life of the fetus over the life or health of the pregnant woman. Under the right of privacy, physicians must be free to use their "medical judgment for the preservation of the life or health of the mother." On the same day that the Court decided Roe, it also decided Doe v. Bolton, in which the Court defined health very broadly: "The medical judgment may be exercised in the light of all factors—physical, emotional, psychological, familial, and the woman's age—relevant to the well-being of the patient. All these factors may relate to health. This allows the attending physician the room he needs to make his best medical judgment."[162]:1200–01
Public opinion shifted in America following television personality Sherri Finkbine's discovery during her fifth month of pregnancy that she had been exposed to thalidomide. Unable to obtain a legal abortion in the United States, she traveled to Sweden. From 1962 to 1965, an outbreak of German measles left 15,000 babies with severe birth defects. In 1967, the American Medical Association publicly supported liberalization of abortion laws. A National Opinion Research Center poll in 1965 showed 73% supported abortion when the mother's life was at risk, 57% when birth defects were present and 59% for pregnancies resulting from rape or incest.[163]
#### Cancer
The rate of cancer during pregnancy is 0.02–1%, and in many cases, cancer of the mother leads to consideration of abortion to protect the life of the mother, or in response to the potential damage that may occur to the fetus during treatment. This is particularly true for cervical cancer, the most common type of which occurs in 1 of every 2,000–13,000 pregnancies, for which initiation of treatment "cannot co-exist with preservation of fetal life (unless neoadjuvant chemotherapy is chosen)". Very early stage cervical cancers (I and IIa) may be treated by radical hysterectomy and pelvic lymph node dissection, radiation therapy, or both, while later stages are treated by radiotherapy. Chemotherapy may be used simultaneously. Treatment of breast cancer during pregnancy also involves fetal considerations, because lumpectomy is discouraged in favor of modified radical mastectomy unless late-term pregnancy allows follow-up radiation therapy to be administered after the birth.[164]
Exposure to a single chemotherapy drug is estimated to cause a 7.5–17% risk of teratogenic effects on the fetus, with higher risks for multiple drug treatments. Treatment with more than 40 Gy of radiation usually causes spontaneous abortion. Exposure to much lower doses during the first trimester, especially 8 to 15 weeks of development, can cause intellectual disability or microcephaly, and exposure at this or subsequent stages can cause reduced intrauterine growth and birth weight. Exposures above 0.005–0.025 Gy cause a dose-dependent reduction in IQ.[164] It is possible to greatly reduce exposure to radiation with abdominal shielding, depending on how far the area to be irradiated is from the fetus.[165][166]
The process of birth itself may also put the mother at risk. "Vaginal delivery may result in dissemination of neoplastic cells into lymphovascular channels, haemorrhage, cervical laceration and implantation of malignant cells in the episiotomy site, while abdominal delivery may delay the initiation of non-surgical treatment."[167]
## History and religion
Main articles: History of abortion and Religion and abortion
Bas-relief at Angkor Wat, Cambodia, c. 1150, depicting a demon inducing an abortion by pounding the abdomen of a pregnant woman with a pestle.[80][168]
"French Periodical Pills". An example of a clandestine advertisement published in a January 1845 edition of the Boston Daily Times.
Since ancient times abortions have been done using a number of methods, including herbal medicines, sharp tools, with force, or through other traditional methods.[23] Induced abortion has long history and can be traced back to civilizations as varied as China under Shennong (c. 2700 BCE), Ancient Egypt with its Ebers Papyrus (c. 1550 BCE), and the Roman Empire in the time of Juvenal (c. 200 CE).[23] One of the earliest known artistic representations of abortion is in a bas relief at Angkor Wat (c. 1150). Found in a series of friezes that represent judgment after death in Hindu and Buddhist culture, it depicts the technique of abdominal abortion.[80]
Some medical scholars and abortion opponents have suggested that the Hippocratic Oath forbade Ancient Greek physicians from performing abortions;[23] other scholars disagree with this interpretation,[23] and state that the medical texts of Hippocratic Corpus contain descriptions of abortive techniques right alongside the Oath.[169] The physician Scribonius Largus wrote in 43 CE that the Hippocratic Oath prohibits abortion, as did Soranus, although apparently not all doctors adhered to it strictly at the time. According to Soranus' 1st or 2nd century CE work Gynaecology, one party of medical practitioners banished all abortives as required by the Hippocratic Oath; the other party—to which he belonged—was willing to prescribe abortions, but only for the sake of the mother's health.[170][171] Aristotle, in his treatise on government Politics (350 BCE), condemns infanticide as a means of population control. He preferred abortion in such cases, with the restriction[172] "[that it] must be practised on it before it has developed sensation and life; for the line between lawful and unlawful abortion will be marked by the fact of having sensation and being alive".[173]
In Christianity, Pope Sixtus V (1585–90) was the first Pope before 1869 to declare that abortion is homicide regardless of the stage of pregnancy;[174] and his pronouncement of 1588 was reversed three years later by his successor. Through most of its history the Catholic Church was divided on whether it believed that early abortion was murder, and it did not begin vigorously opposing abortion until the 19th century.[23] Several historians have written that prior to the 19th century most Catholic authors did not regard termination of pregnancy before "quickening" or "ensoulment" as an abortion.[175][176][177] From 1750, excommunication became the punishment for abortions.[178] Statements made in 1992 in the Catechism of the Catholic Church, the codified summary of the Church's teachings, opposed abortion.[179]
A 1995 survey reported that Catholic women are as likely as the general population to terminate a pregnancy, Protestants are less likely to do so, and Evangelical Christians are the least likely to do so.[153][157] Islamic tradition has traditionally permitted abortion until a point in time when Muslims believe the soul enters the fetus,[23] considered by various theologians to be at conception, 40 days after conception, 120 days after conception, or quickening.[180] However, abortion is largely heavily restricted or forbidden in areas of high Islamic faith such as the Middle East and North Africa.[181]
In Europe and North America, abortion techniques advanced starting in the 17th century. However, conservatism by most physicians with regards to sexual matters prevented the wide expansion of safe abortion techniques.[23] Other medical practitioners in addition to some physicians advertised their services, and they were not widely regulated until the 19th century, when the practice (sometimes called restellism)[182] was banned in both the United States and the United Kingdom.[23] Church groups as well as physicians were highly influential in anti-abortion movements.[23] In the US, according to some sources, abortion was more dangerous than childbirth until about 1930 when incremental improvements in abortion procedures relative to childbirth made abortion safer.[note 2] However, other sources maintain that in the 19th century early abortions under the hygienic conditions in which midwives usually worked were relatively safe.[183][184][185] In addition, some commentators have written that, despite improved medical procedures, the period from the 1930s until legalization also saw more zealous enforcement of anti-abortion laws, and concomitantly an increasing control of abortion providers by organized crime.[186][187][188][189][190]
Soviet Russia (1919), Iceland (1935), and Sweden (1938) were among the first countries to legalize certain or all forms of abortion.[191] In 1935, Nazi Germany, a law was passed permitting abortions for those deemed "hereditarily ill", while women considered of German stock were specifically prohibited from having abortions.[192] Beginning in the second half of the twentieth century, abortion was legalized in a greater number of countries.[23]
## Society and culture
### Abortion debate
Main article: Abortion debate
Induced abortion has long been the source of considerable debate. Ethical, moral, philosophical, biological, religious and legal issues surrounding abortion are related to value systems. Opinions of abortion may be about fetal rights, governmental authority, and women's rights.
In both public and private debate, arguments presented in favor of or against abortion access focus on either the moral permissibility of an induced abortion, or justification of laws permitting or restricting abortion.[193] The World Medical Association Declaration on Therapeutic Abortion notes, "circumstances bringing the interests of a mother into conflict with the interests of her unborn child create a dilemma and raise the question as to whether or not the pregnancy should be deliberately terminated."[194] Abortion debates, especially pertaining to abortion laws, are often spearheaded by groups advocating one of these two positions. Groups who favor greater legal restrictions on abortion, including complete prohibition, most often describe themselves as "pro-life" while groups who are against such legal restrictions describe themselves as "pro-choice".[195] Generally, the former position argues that a human fetus is a human person with a right to live, making abortion morally the same as murder. The latter position argues that a woman has certain reproductive rights, especially the right to decide whether or not to carry a pregnancy to term.
### Modern abortion law
Main article: Abortion law
See also: History of abortion law debate
Legal grounds for abortion by country[196] Legal on woman's request
Legally restricted to cases of:
Risk to woman's life, her health*, rape*, fetal impairment*, or socioeconomic factors
Risk to woman's life, her health*, rape, or fetal impairment
Risk to woman's life, her health*, or fetal impairment
Risk to woman's life*, her health*, or rape
Risk to woman's life or her health
Risk to woman's life
Illegal with no exceptions
No information
* Does not apply to some countries in that category
Current laws pertaining to abortion are diverse. Religious, moral, and cultural factors continue to influence abortion laws throughout the world. The right to life, the right to liberty, the right to security of person, and the right to reproductive health are major issues of human rights that sometimes constitute the basis for the existence or absence of abortion laws.
In jurisdictions where abortion is legal, certain requirements must often be met before a woman may obtain a safe, legal abortion (an abortion performed without the woman's consent is considered feticide). These requirements usually depend on the age of the fetus, often using a trimester-based system to regulate the window of legality, or as in the U.S., on a doctor's evaluation of the fetus' viability. Some jurisdictions require a waiting period before the procedure, prescribe the distribution of information on fetal development, or require that parents be contacted if their minor daughter requests an abortion.[197] Other jurisdictions may require that a woman obtain the consent of the fetus' father before aborting the fetus, that abortion providers inform women of health risks of the procedure—sometimes including "risks" not supported by the medical literature—and that multiple medical authorities certify that the abortion is either medically or socially necessary. Many restrictions are waived in emergency situations. China, which has ended their[198] one-child policy, and now has a two child policy,[199][200] has at times incorporated mandatory abortions as part of their population control strategy.[201]
Other jurisdictions ban abortion almost entirely. Many, but not all, of these allow legal abortions in a variety of circumstances. These circumstances vary based on jurisdiction, but may include whether the pregnancy is a result of rape or incest, the fetus' development is impaired, the woman's physical or mental well-being is endangered, or socioeconomic considerations make childbirth a hardship.[24] In countries where abortion is banned entirely, such as Nicaragua, medical authorities have recorded rises in maternal death directly and indirectly due to pregnancy as well as deaths due to doctors' fears of prosecution if they treat other gynecological emergencies.[202][203] Some countries, such as Bangladesh, that nominally ban abortion, may also support clinics that perform abortions under the guise of menstrual hygiene.[204] This is also a terminology in traditional medicine.[205] In places where abortion is illegal or carries heavy social stigma, pregnant women may engage in medical tourism and travel to countries where they can terminate their pregnancies.[206] Women without the means to travel can resort to providers of illegal abortions or attempt to perform an abortion by themselves.[207]
The organization Women on Waves has been providing education about medical abortions since 1999. The NGO created a mobile medical clinic inside a shipping container, which then travels on rented ships to countries with restrictive abortion laws. Because the ships are registered in the Netherlands, Dutch law prevails when the ship is in international waters. While in port, the organization provides free workshops and education; while in international waters, medical personnel are legally able to prescribe medical abortion drugs and counseling.[208][209][210]
### Sex-selective abortion
Main article: Sex-selective abortion
Sonography and amniocentesis allow parents to determine sex before childbirth. The development of this technology has led to sex-selective abortion, or the termination of a fetus based on sex. The selective termination of a female fetus is most common.
Sex-selective abortion is partially responsible for the noticeable disparities between the birth rates of male and female children in some countries. The preference for male children is reported in many areas of Asia, and abortion used to limit female births has been reported in Taiwan, South Korea, India, and China.[211] This deviation from the standard birth rates of males and females occurs despite the fact that the country in question may have officially banned sex-selective abortion or even sex-screening.[212][213][214][215] In China, a historical preference for a male child has been exacerbated by the one-child policy, which was enacted in 1979.[216]
Many countries have taken legislative steps to reduce the incidence of sex-selective abortion. At the International Conference on Population and Development in 1994 over 180 states agreed to eliminate "all forms of discrimination against the girl child and the root causes of son preference",[217] conditions also condemned by a PACE resolution in 2011.[218] The World Health Organization and UNICEF, along with other United Nations agencies, have found that measures to reduce access to abortion are much less effective at reducing sex-selective abortions than measures to reduce gender inequality.[217]
### Anti-abortion violence
Main article: Anti-abortion violence
In a number of cases, abortion providers and these facilities have been subjected to various forms of violence, including murder, attempted murder, kidnapping, stalking, assault, arson, and bombing. Anti-abortion violence is classified by both governmental and scholarly sources as terrorism.[219][220] In the U.S. and Canada, over 8,000 incidents of violence, trespassing, and death threats have been recorded by providers since 1977, including over 200 bombings/arsons and hundreds of assaults.[221] The majority of abortion opponents have not been involved in violent acts.
In the United States, four physicians who performed abortions have been murdered: David Gunn (1993), John Britton (1994), Barnett Slepian (1998), and George Tiller (2009). Also murdered, in the U.S. and Australia, have been other personnel at abortion clinics, including receptionists and security guards such as James Barrett, Shannon Lowney, Lee Ann Nichols, and Robert Sanderson. Woundings (e.g., Garson Romalis) and attempted murders have also taken place in the United States and Canada. Hundreds of bombings, arsons, acid attacks, invasions, and incidents of vandalism against abortion providers have occurred.[222][223] Notable perpetrators of anti-abortion violence include Eric Robert Rudolph, Scott Roeder, Shelley Shannon, and Paul Jennings Hill, the first person to be executed in the United States for murdering an abortion provider.[224]
Legal protection of access to abortion has been brought into some countries where abortion is legal. These laws typically seek to protect abortion clinics from obstruction, vandalism, picketing, and other actions, or to protect women and employees of such facilities from threats and harassment.
Far more common than physical violence is psychological pressure. In 2003, Chris Danze organized anti-abortion organizations throughout Texas to prevent the construction of a Planned Parenthood facility in Austin. The organizations released the personal information online, of those involved with construction, sending them up to 1200 phone calls a day and contacting their churches.[225] Some protestors record women entering clinics on camera.[225]
## Other animals
Further information: Miscarriage
Spontaneous abortion occurs in various animals. For example, in sheep it may be caused by stress or physical exertion, such as crowding through doors or being chased by dogs.[226] In cows, abortion may be caused by contagious disease, such as brucellosis or Campylobacter, but can often be controlled by vaccination.[227] Eating pine needles can also induce abortions in cows.[228][229] Several plants, including broomweed, skunk cabbage, poison hemlock, and tree tobacco, are known to cause fetal deformities and abortion in cattle[230]:45–46 and in sheep and goats.[230]:77–80 In horses, a fetus may be aborted or resorbed if it has lethal white syndrome (congenital intestinal aganglionosis). Foal embryos that are homozygous for the dominant white gene (WW) are theorized to also be aborted or resorbed before birth.[231] In many species of sharks and rays, stress-induced abortions occur frequently on capture.[232]
Viral infection can cause abortion in dogs.[233] Cats can experience spontaneous abortion for many reasons, including hormonal imbalance. A combined abortion and spaying is performed on pregnant cats, especially in trap–neuter–return programs, to prevent unwanted kittens from being born.[234][235][236] Female rodents may terminate a pregnancy when exposed to the smell of a male not responsible for the pregnancy, known as the Bruce effect.[237]
Abortion may also be induced in animals, in the context of animal husbandry. For example, abortion may be induced in mares that have been mated improperly, or that have been purchased by owners who did not realize the mares were pregnant, or that are pregnant with twin foals.[238] Feticide can occur in horses and zebras due to male harassment of pregnant mares or forced copulation,[239][240][241] although the frequency in the wild has been questioned.[242] Male gray langur monkeys may attack females following male takeover, causing miscarriage.[243]
## Notes
1. ^ Definitions of abortion, as with many words, vary from source to source. Language used to define abortion often reflects societal and political opinions (not only scientific knowledge). For a list of definitions as stated by obstetrics and gynecology (OB/GYN) textbooks, dictionaries, and other sources, please see Definitions of abortion.
2. ^ By 1930, medical procedures in the US had improved for both childbirth and abortion but not equally, and induced abortion in the first trimester had become safer than childbirth. In 1973, Roe v. Wade acknowledged that abortion in the first trimester was safer than childbirth:
* "The 1970s". Time communication 1940–1989: retrospective. Time Inc. 1989. "Blackmun was also swayed by the fact that most abortion prohibitions were enacted in the 19th century when the procedure was more dangerous than now."
* Will, George (1990). Suddenly: the American idea abroad and at home, 1986–1990. Free Press. p. 312. ISBN 0-02-934435-2.
* Lewis, J.; Shimabukuro, Jon O. (28 January 2001). "Abortion Law Development: A Brief Overview". Congressional Research Service. Archived from the original on 14 May 2011. Retrieved 1 May 2011.
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239. ^ Berger, Joel W; Vuletić, L; Boberić, J; Milosavljević, A; Dilparić, S; Tomin, R; Naumović, P (5 May 1983). "Induced abortion and social factors in wild horses". Nature. 303 (5912): 59–61. Bibcode:1983Natur.303...59B. doi:10.1038/303059a0. PMID 6682487. S2CID 4259800.
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243. ^ Agoramoorthy, G.; Mohnot, S.M.; Sommer, V.; Srivastava, A. (1988). "Abortions in free ranging Hanuman langurs (Presbytis entellus) – a male induced strategy?". Human Evolution. 3 (4): 297–308. doi:10.1007/BF02435859. S2CID 84849590.
## Bibliography
Further information: United States anti-abortion movement § Further reading
* Devereux, George (1976). A Study of Abortion in Primitive Societies. International Universities Press. ISBN 978-0-8236-6245-6.
* Doan, Alesha E. (2007). Opposition and Intimidation: The abortion wars and strategies of political harassment. University of Michigan.
* Ganatra, Bela; Tunçalp, Özge; Johnston, Heidi Bart; Johnson Jr, Brooke R; Gülmezoglu, Ahmet Metin; Temmerman, Marleen (1 March 2014). "From concept to measurement: operationalizing WHO's definition of unsafe abortion". Bulletin of the World Health Organization. 92 (3): 155–55. doi:10.2471/BLT.14.136333. PMC 3949603. PMID 24700971.
* Hartmann, Betsy (1995). Reproductive Rights and Wrongs: The Global Politics of Population Control. South End Press. ISBN 978-0-89608-491-9.
* Koblitz, Ann Hibner (2014). Sex and Herbs and Birth Control: Women and Fertility Regulation Through the Ages. Kovalevskaia Fund. ISBN 978-0-9896655-0-6.
* Riddle, John M. (1997). Eve's Herbs: A History of Contraception and Abortion in the West. Harvard University Press.
* Sedgh, Gilda; Bearak, Jonathan; Singh, Susheela; Bankole, Akinrinola; Popinchalk, Anna; Ganatra, Bela; Rossier, Clémentine; Gerdts, Caitlin; Tunçalp, Özge; Johnson, Brooke Ronald; Johnston, Heidi Bart; Alkema, Leontine (July 2016). "Abortion incidence between 1990 and 2014: global, regional, and subregional levels and trends". The Lancet. 388 (10041): 258–67. doi:10.1016/S0140-6736(16)30380-4. PMC 5498988. PMID 27179755.
* UN (2002). Abortion Policies: A Global Review 3 vols. Population Division, Department of Economic and Social Affairs, United Nations.
* WHO (2005). The World Health Report 2005: Make every mother and child count. Geneva: World Health Organization. ISBN 92-4-156290-0.
* WHO (2012). Safe abortion: technical and policy guidance for health systems (PDF) (2nd ed.). Geneva: World Health Organization. ISBN 978-92-4-154843-4.
* WHO (2016). "Health worker roles in providing safe abortion care and post-abortion contraception". Retrieved 8 January 2017.
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*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Abortion | c0000790 | 6,854 | wikipedia | https://en.wikipedia.org/wiki/Abortion | 2021-01-18T18:29:32 | {"mesh": ["D000028"], "icd-9": ["779.6"], "icd-10": ["O04"], "wikidata": ["Q8452"]} |
Beutler et al. (1980) described a woman and all of her 3 children with a small population of markedly distorted red blood cells resembling keratocytes. Red cell life span was normal, and the severely deformed cells appeared to represent the senescent population. The trait appeared to be benign. The mother's ancestors came from England; the father, whose surname was assigned to the trait, was of Ukrainian extraction. The proband was one of the sons, aged 13 years, whose blood had been studied because of his apparent lack of stamina, particularly when playing ice hockey.
Inheritance \- Autosomal dominant Heme \- Distorted red blood cells resembling keratocytes \- Normal red cell life span ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| WORONETS TRAIT | c1860237 | 6,855 | omim | https://www.omim.org/entry/194320 | 2019-09-22T16:31:44 | {"omim": ["194320"]} |
A rare fetal lower urinary tract obstruction (LUTO) characterized by closure or failure to develop an opening in the urethra and resulting in obstructive uropathy presenting in utero as megacystis, oligohydramnios or anhydramnios, and potter sequence.
## Epidemiology
Prevalence is unknown, but is higher in males than females.
## Clinical description
Atresia of urethra often presents on routine antenatal ultrasound with megacystis, oligohydramnios or anhydramnios and sometimes urinary ascites. It may cause fetal death. In cases that survive to birth, additional symptoms include respiratory insufficiency due to pulmonary hypoplasia, megaureter, hydronephrosis and enlarged often cystic and functionally impaired/non-functional dysplastic kidneys as well as abdominal distention. Furthermore, a Potter sequence can be found due to oligo- or anhydramnios. Patients may present with patent urachus or vesicocutaneous fistula.
## Etiology
The etiology of atresia of the urethra is unknown. Common clinical features arise from the inability of urine to pass out of the body of the fetus, resulting in oligohydramnios which in turn affects the development of the lungs and causes features of Potter sequence. Congenital obstruction of the urinary tract at a critical time in organogenesis has a profound and lifelong effect on kidney, ureteral and bladder function. In rare cases, there is an abnormal opening between the bladder and the rectum which may allow the urine to drain.
## Diagnostic methods
Antenatal diagnosis is based on ultrasound. By then it is not possible to clearly distinguish between different forms of LUTO. If megacystis occurs in early pregnancy (around 17 weeks of gestation) atresia of the urethra is more likely to be a possible underlying cause then in later gestation. Postnatally, micturating cysto- urethrography and/or cystoscopy can be used for final diagnosis and differentiation between atresia of the urethra and other forms of LUTO as differential diagnosis.
## Differential diagnosis
Differential diagnoses include other causes of megacystis including posterior urethral valve, anterior urethral valve, urethral stenosis, urethral agenesis, double urethra, cloacal malformation and, in rare and severe cases, different forms of voiding dysfunction or megacystis megaureter syndrome. Atresia of urethra can occur in combination with several other conditions including caudal dysplasia, cloacal extrophy, DiGeorge, prune belly syndrome, Fraser cryptophtalmus, Johnson-Munson, Meckel-Gruber, Sirenomelia, and Townes Brocks.
## Antenatal diagnosis
Antenatal diagnosis is based on ultrasound evidence of megacystis and oligohydramnios. Fetal MRI can be used to attempt confirmation of the diagnosis.
## Genetic counseling
If atresia of the urethra occurs together with other birth defects, genetic counselling should be considered. For isolated atresia of the urethra no genetic causes are known so far.
## Management and treatment
Antenatal treatment involves urinary decompression with a vesico-amniotic shunt. If the antenatal period is survived, postnatal treatment depends on the pulmonary and renal function. All cases with remaining renal function require a suprapubic urine drainage until reconstructive surgery. Successful treatment of severe cases (obstructive uropathy, kidney failure and pulmonary hypoplasia) with extra corporal membrane oxygenation (ECMO) therapy and hemofiltration/peritoneal dialyses has been described.
## Prognosis
The malformation usually results in fetal death without surgical intervention. Prenatal decompression allows survival and may even lead to normal bladder and renal function. Nevertheless, progression into kidney failure is common. Extensive surgical reconstruction is to be expected.
* European Reference Network
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
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*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
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*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Atresia of urethra | c1610065 | 6,856 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=105 | 2021-01-23T17:37:45 | {"umls": ["C0345345", "C1610065"], "icd-10": ["Q64.3"], "synonyms": ["Urethral atresia"]} |
Frontotemporal lobar degeneration
Neuropathologic analysis of brain tissue from FTLD-TDP patients. Ubiquitin immunohistochemistry in cases of familial FTLD-TDP demonstrates staining of (a) neurites and neuronal cytoplasmic inclusions in the superficial cerebral neocortex, (b) neuronal cytoplasmic inclusions in hippocampal dentate granule cells, and (c) neuronal intranuclear inclusions in the cerebral neocortex (arrows). Scale bar; (a) and (b) 40 μm, (c) 25 μm, insert 6 μm.
SpecialtyPsychiatry, neurology
ComplicationsBrain death
Frontotemporal lobar degeneration (FTLD) is a pathological process that occurs in frontotemporal dementia. It is characterized by atrophy in the frontal lobe and temporal lobe of the brain, with sparing of the parietal and occipital lobes.
Common proteinopathies that are found in FTLD include the accumulation of tau proteins and TAR DNA-binding protein 43 (TDP-43). Mutations in the C9orf72 gene have been established as a major genetic contribution of FTLD, although defects in the granulin (GRN) and microtubule-associated proteins (MAPs) are also associated with it.[1]
## Contents
* 1 Classification
* 2 Genetics
* 3 Diagnosis
* 4 Society
* 5 See also
* 6 References
* 7 Bibliography
* 8 Further reading
* 9 External links
## Classification[edit]
There are 3 main histological subtypes found at post-mortem:
* FTLD-tau is characterised by tau positive inclusion bodies often referred to as Pick-bodies.[2] Examples of FTLD-tau include; Pick's disease, corticobasal degeneration, progressive supranuclear palsy.
* FTLD-TDP (or FTLD-U ) is characterised by ubiquitin and TDP-43 positive, tau negative, FUS negative inclusion bodies. The pathological histology of this subtype is so diverse it is subdivided into four subtypes based on the detailed histological findings:
* Type A presents with many small neurites and neuronal cytoplasmic inclusion bodies in the upper (superficial) cortical layers. Bar-like neuronal intranuclear inclusions can also be seen they are fewer in number.
* Type B presents with many neuronal and glial cytoplasmic inclusions in both the upper (superficial) and lower (deep) cortical layers, and lower motor neurons. However neuronal intranuclear inclusions are rare or absent. This is often associated with ALS and C9ORF72 mutations (see next section).
* Type C presents many long neuritic profiles found in the superficial cortical laminae, very few or no neuronal cytoplasmic inclusions, neuronal intranuclear inclusions or glial cytoplasmic inclusions. This is often associated with semantic dementia.
* Type D presents with many neuronal intranuclear inclusions and dystrophic neurites, and an unusual absence of inclusions in the granule cell layer of the hippocampus. Type 4 is associated with VCP mutations.
Two physicians independently categorized the various forms of TDP-43 associated disorders. Both classifications were considered equally valid by the medical community, but the physicians in question have jointly proposed a compromise classification to avoid confusion.[3]
* FTLD-FUS; which is characterised by FUS positive cytoplasmic inclusions, intra nuclear inclusions, and neuritic threads. All of which are present in the cortex, medulla, hippocampus, and motor cells of the spinal cord and XIIth cranial nerve.
## Genetics[edit]
There have been numerous advances in descriptions of genetic causes of FTLD, and the related disease amyotrophic lateral sclerosis.
* Mutations in the Tau gene (known as MAPT or Microtubule Associated Protein Tau) can cause a FTLD presenting with tau pathology (FTLD-tau).[4] There are over 40 known mutations at present.
* Mutations in the Progranulin gene (PGRN) can cause a FTLD presenting with TDP-43 pathology (FTLD-TDP43). Patients with Progranulin mutations have type 3 ubiquitin-positive, TDP-43 positive, tau-negative pathology at post-mortem. Progranulin is associated with tumorgenesis when overproduced, however the mutations seen in FTLD-TDP43 produce a haploinsufficiency, meaning that because one of the two alleles is damaged, only half as much Progranulin is produced.[5]
* Mutations in the CHMP2B gene are associated with a rare behavioural syndrome akin to bvFTLD (mainly in a large Jutland cohort), presenting with a tau negative, TDP-43 negative, FUS negative, Ubiquitin positive pathology.
* Mutations in the VCP gene cause a TDP-43-positive FTLD which is associated with multisystem proteinopathy (MSP), also known as IBMPFD (inclusion body myopathy, Paget's disease and frontotemporal dementia)[6]
* Mutations in the TDP-43 gene (known as TARBP or TAR DNA-binding protein) are an exceptionally rare cause of FTLD, despite this protein being present in the pathological inclusions of many cases (FTLD-TDP43).[7] However, mutations in TARBP are a more common cause of ALS, which can present with frontotemporal dementia. Since these instances are not considered a pure FTLD they are not included here.
Mutations in all of the above genes cause a very small fraction of the FTLD spectrum. Most of the cases are sporadic (no known genetic cause).
* A proportion of FTLD-TDP43 [with ALS] cases had shown genetic linkage to a region on chromosome 9 (FTLD-TDP43/Ch9). This linkage has recently been pinned down to the C9ORF72 gene. Two groups published identical findings back-to-back in the journal Neuron in mid-2011, showing that a hexanucleotide repeat expansion of the GGGGCC genetic sequence within an intron of this gene was responsible. This expansion was found to be present in a large proportion of familial and sporadic cases, particularly in the Finnish population[8]
## Diagnosis[edit]
For diagnostic purposes, magnetic resonance imaging (MRI) and ([18F]fluorodeoxyglucose) positron emission tomography (FDG-PET) are applied. They measure either atrophy or reductions in glucose utilization. The three clinical subtypes of frontotemporal lobar degeneration, frontotemporal dementia, semantic dementia and progressive nonfluent aphasia, are characterized by impairments in specific neural networks.[9] The first subtype with behavioral deficits, frontotemporal dementia, mainly affects a frontomedian network discussed in the context of social cognition. Semantic dementia is mainly related to the inferior temporal poles and amygdalae; brain regions that have been discussed in the context of conceptual knowledge, semantic information processing, and social cognition, whereas progressive nonfluent aphasia affects the whole left frontotemporal network for phonological and syntactical processing.
## Society[edit]
United States Senator Pete Domenici (R-NM) was a known sufferer of FTLD, and the illness was the main reason behind his October 4, 2007 announcement of retirement at the end of his term. American film director, producer, and screenwriter Curtis Hanson died as a result of FTLD on September 20, 2016.
## See also[edit]
* Frontotemporal dementia and parkinsonism linked to chromosome 17
## References[edit]
1. ^ van der Zee, Julie; Van Broeckhoven, Christine (7 January 2014). "Dementia in 2013: Frontotemporal lobar degeneration—building on breakthroughs". Nature Reviews Neurology. 10 (2): 70–72. doi:10.1038/nrneurol.2013.270. PMID 24394289.
2. ^ Robbins basic pathology (Tenth ed.). Philadelphia, Pennsylvania. 2018. p. 877. ISBN 9780323353175.
3. ^ Ian R. A. Mackenzie; Manuela Neumann; Atik Baborie; Deepak M. Sampathu; Daniel Du Plessis; Evelyn Jaros; Robert H. Perry; John Q. Trojanowski; David M. A. Mann & Virginia M. Y. Lee (July 2011). "A harmonized classification system for FTLD-TDP pathology". Acta Neuropathol. 122 (1): 111–113. doi:10.1007/s00401-011-0845-8. PMC 3285143. PMID 21644037.
4. ^ Goedert, M.; et al. (1989). "Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain". The EMBO Journal. 8 (2): 393–9. doi:10.1002/j.1460-2075.1989.tb03390.x. PMC 400819. PMID 2498079.
5. ^ Cruts, M.; et al. (2006). "Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21". Nature. 442 (7105): 920–4. Bibcode:2006Natur.442..920C. doi:10.1038/nature05017. PMID 16862115.
6. ^ Kimonis, V.E.; et al. (2008). "VCP disease associated with myopathy, Paget disease of bone and frontotemporal dementia: review of a unique disorder" (PDF). Biochim Biophys Acta. 1782 (12): 744–8. doi:10.1016/j.bbadis.2008.09.003. PMID 18845250.
7. ^ Borroni, B.; et al. (2010). "TARDBP mutations in frontotemporal lobar degeneration: frequency, clinical features, and disease course". Rejuvenation Res. 13 (5): 509–17. doi:10.1089/rej.2010.1017. PMID 20645878.
8. ^ Dejesus-Hernandez, M.; et al. (2011). "Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS". Neuron. 72 (2): 245–56. doi:10.1016/j.neuron.2011.09.011. PMC 3202986. PMID 21944778.
9. ^ Schroeter ML, Raczka KK, Neumann J, von Cramon DY (2007). "Towards a nosology for frontotemporal lobar degenerations – A meta-analysis involving 267 subjects". NeuroImage. 36 (3): 497–510. doi:10.1016/j.neuroimage.2007.03.024. PMID 17478101.
## Bibliography[edit]
* Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, et al. (July, 2007). "Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration." Acta Neuropathologica..114 (1): 5-22. doi: 10.1007/s00401-007-0237-2. PMID: 17579875.
* Cairns NJ, Grossman M, Arnold SE, Burn DJ, Jaros E, Perry RH, Duyckaerts C, Stankoff B, Pillon B, Skullerud K, Cruz-Sanchez FF, Bigio EH, Mackenzie IR, Gearing M, Juncos JL, Glass JD, Yokoo H, Nakazato Y, Mosaheb S, Thorpe JR, Uryu K, Lee VM, Trojanowski JQ. (October, 2004).Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease. Neurology. 63 (8):1376-84. doi: 10.1212/01.wnl.0000139809.16817.dd. PMID: 15505152.
* Mackenzie IR, Baborie A, Pickering-Brown S, et al. (November 2006). "Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype". Acta Neuropathologica. 112 (5): 539–49. doi:10.1007/s00401-006-0138-9. PMC 2668618. PMID 17021754.
* Mackenzie IR, Munoz DG, Kusaka H, Yokota O, Ishihara K, Roeber S, Kretzschmar HA, Cairns NJ, Neumann M. (February, 2011). Distinct pathological subtypes of FTLD-FUS. Acta Neuropathologica..121 (2) :207-18. doi: 10.1007/s00401-010-0764-0. PMID: 21052700.
* Davidson Y, Kelley T, Mackenzie IR, et al. (May 2007). "Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43". Acta Neuropathologica. 113 (5): 521–33. doi:10.1007/s00401-006-0189-y. PMID 17219193.
* Neary D, Snowden JS, Gustafson L, et al. (December 1, 1998). "Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria". Neurology. 51 (6): 1546–54. doi:10.1212/wnl.51.6.1546. PMID 9855500. Retrieved 2009-06-20.
* Pickering-Brown SM (July 2007). "The complex aetiology of frontotemporal lobar degeneration". Experimental Neurology. 206 (1): 1–10. doi:10.1016/j.expneurol.2007.03.017. PMID 17509568.
## Further reading[edit]
* Hodges, John R. The Frontotemporal Dementia Syndromes. Cambridge University Press. 2007 ISBN 978-0-521-85477-1
* OMIM entries on FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS as well as C9ORF72
* GeneReviews/NCBI/NIH/UW entry on Amyotrophic Lateral Sclerosis Overview
## External links[edit]
Classification
D
* ICD-10: G31.0
* OMIM: 600274
* MeSH: D003704
* DiseasesDB: 10034
* v
* t
* e
Diseases of the nervous system, primarily CNS
Inflammation
Brain
* Encephalitis
* Viral encephalitis
* Herpesviral encephalitis
* Limbic encephalitis
* Encephalitis lethargica
* Cavernous sinus thrombosis
* Brain abscess
* Amoebic
Brain and spinal cord
* Encephalomyelitis
* Acute disseminated
* Meningitis
* Meningoencephalitis
Brain/
encephalopathy
Degenerative
Extrapyramidal and
movement disorders
* Basal ganglia disease
* Parkinsonism
* PD
* Postencephalitic
* NMS
* PKAN
* Tauopathy
* PSP
* Striatonigral degeneration
* Hemiballismus
* HD
* OA
* Dyskinesia
* Dystonia
* Status dystonicus
* Spasmodic torticollis
* Meige's
* Blepharospasm
* Athetosis
* Chorea
* Choreoathetosis
* Myoclonus
* Myoclonic epilepsy
* Akathisia
* Tremor
* Essential tremor
* Intention tremor
* Restless legs
* Stiff-person
Dementia
* Tauopathy
* Alzheimer's
* Early-onset
* Primary progressive aphasia
* Frontotemporal dementia/Frontotemporal lobar degeneration
* Pick's
* Dementia with Lewy bodies
* Posterior cortical atrophy
* Vascular dementia
Mitochondrial disease
* Leigh syndrome
Demyelinating
* Autoimmune
* Inflammatory
* Multiple sclerosis
* For more detailed coverage, see Template:Demyelinating diseases of CNS
Episodic/
paroxysmal
Seizures and epilepsy
* Focal
* Generalised
* Status epilepticus
* For more detailed coverage, see Template:Epilepsy
Headache
* Migraine
* Cluster
* Tension
* For more detailed coverage, see Template:Headache
Cerebrovascular
* TIA
* Stroke
* For more detailed coverage, see Template:Cerebrovascular diseases
Other
* Sleep disorders
* For more detailed coverage, see Template:Sleep
CSF
* Intracranial hypertension
* Hydrocephalus
* Normal pressure hydrocephalus
* Choroid plexus papilloma
* Idiopathic intracranial hypertension
* Cerebral edema
* Intracranial hypotension
Other
* Brain herniation
* Reye syndrome
* Hepatic encephalopathy
* Toxic encephalopathy
* Hashimoto's encephalopathy
Both/either
Degenerative
SA
* Friedreich's ataxia
* Ataxia–telangiectasia
MND
* UMN only:
* Primary lateral sclerosis
* Pseudobulbar palsy
* Hereditary spastic paraplegia
* LMN only:
* Distal hereditary motor neuronopathies
* Spinal muscular atrophies
* SMA
* SMAX1
* SMAX2
* DSMA1
* Congenital DSMA
* Spinal muscular atrophy with lower extremity predominance (SMALED)
* SMALED1
* SMALED2A
* SMALED2B
* SMA-PCH
* SMA-PME
* Progressive muscular atrophy
* Progressive bulbar palsy
* Fazio–Londe
* Infantile progressive bulbar palsy
* both:
* Amyotrophic lateral sclerosis
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Frontotemporal lobar degeneration | c0751072 | 6,857 | wikipedia | https://en.wikipedia.org/wiki/Frontotemporal_lobar_degeneration | 2021-01-18T19:01:26 | {"mesh": ["D057174"], "wikidata": ["Q18579"]} |
Orthostatic hypertension
Other namesPostural hypertension
Orthostatic hypertension is a medical condition consisting of a sudden and abrupt increase in blood pressure when a person stands up.[1] Orthostatic hypertension is diagnosed by a rise in systolic blood pressure of 20 mmHg or more when standing. Orthostatic diastolic hypertension is a condition in which the diastolic raises to 98 mmHg or over in response to standing;[2][3] however, this definition currently lacks clear medical consensus and is thus subject to change. Orthostatic hypertension involving the systolic is known as systolic orthostatic hypertension.
If affecting an individual's ability to remain upright, orthostatic hypertension is viewed as a form of orthostatic intolerance. The body's inability to regulate the blood pressure can be a type of dysautonomia.
Baroreflex and autonomic pathways normally ensure that blood pressure is maintained despite various stimuli including postural change. The precise mechanism of orthostatic hypertension remains unclear, but it is thought that alpha-adrenergic activity may be the predominant pathophysiologic mechanism of orthostatic hypertension in elderly hypertensive patients.[4] Other mechanisms are proposed for other groups with this disorder.[1]
A prevalence of 1.1% was found in a large population study.[5] The risk of orthostatic hypertension has been found to increase with age, with it being found in 16.3% of older hypertensive patients.[6]
## Contents
* 1 Signs and symptoms
* 1.1 Connections to other disorders
* 2 Risks
* 3 Diagnosis
* 4 Treatments
* 5 References
## Signs and symptoms[edit]
* Mild or moderate orthostatic hypertension may present without any symptoms other than the orthostatic hypertension BP findings. More severe orthostatic hypertension may present with the typical symptoms of hypertension.
* Orthostatic venous pooling is common with orthostatic diastolic hypertension. This occurs in the legs while standing.[7][8]
### Connections to other disorders[edit]
* Essential hypertension
* Other kinds of dysautonomia may coexist, e.g., postural orthostatic tachycardia syndrome is common with this condition, orthostatic hypotension with the BP going both high and low at times due to autonomic dysfunction
* Type 2 diabetes[1]
* Vascular adrenergic hypersensitivity: Orthostatic hypertension can be secondary to this[9]
* Anorexia Nervosa: Many people suffering From anorexia experience orthostatic hypertension[citation needed]
* Hypovolemia can cause orthostatic hypertension
* Renal arterial stenosis (narrowing of the kidney arteries) with nephroptosis (kidney drops on standing) have been known to cause orthostatic hypertension.[10]
* Aortitis (inflammation of the aorta) with nephroptosis: "This orthostatic hypertension largely may be due to an activation of the renin system caused by nephroptosis and partly due to a reduced baroreflex sensitivity caused by aortitis"[11]
* Pheochromocytoma[12]
## Risks[edit]
* Blood pressure variability is associated with progression of target organ damage and cardiovascular risk.[13]
* Orthostatic hypertension was positively associated with peripheral arterial disease.[6]
* Increased occurrence of silent cerebrovascular ischemia[1][4]
* Systolic orthostatic hypertension increases stroke risk.[14]
## Diagnosis[edit]
The condition can be assessed by a tilt table test. If the test is positive the diagnosis is hyperadrenergic postural orthostatic tachycardia syndrome.
## Treatments[edit]
There are no officially recommended treatments currently for orthostatic hypertension as the condition is still little known and can be due to different causes. Hence, treatment for those with this disorder is still a trial and error experimental treatment. Some treatments which have been successfully used for this condition are medications doxazosin,[15] carvedilol,[16] captopril, and propranolol hydrochloride. Treatment of coexisting conditions, e.g., hypovolemia. Some specialists in severe cases give saline IVs for the hypovolemia which, if it is the cause, brings the orthostatic hypertension down to a safe level. Pressure garments over the pelvis and the lower extremeties may be used as part of treatment, due to the blood pooling issue occurring in many with the disorder.[7]
## References[edit]
1. ^ a b c d Fessel, J.; Robertson, D. (2006). "Orthostatic hypertension: When pressor reflexes overcompensate". Nature Clinical Practice Nephrology. 2 (8): 424–431. doi:10.1038/ncpneph0228. PMID 16932477. S2CID 20184856.
2. ^ Bell, David S. (May 2000). "Orthostatic Intolerance (OI) Test Results". Lyndonville News. 2 (3).
3. ^ Streeten, D.H.P. (1987). Orthostatic Disorders of the Circulation. New York: Plenum Medical. p. 116.
4. ^ a b Kario, K.; Eguchi, K.; Hoshide, S.; Hoshide, Y.; Umeda, Y.; Mitsuhashi, T.; Shimada, K. (2002). "U-curve relationship between orthostatic blood pressure change and silent cerebrovascular disease in elderly hypertensives: Orthostatic hypertension as a new cardiovascular risk factor". Journal of the American College of Cardiology. 40 (1): 133–141. doi:10.1016/S0735-1097(02)01923-X. PMID 12103267.
5. ^ Wu, J. S.; Yang, Y. C.; Lu, F. H.; Wu, C. H.; Chang, C. J. (2008). "Population-Based Study on the Prevalence and Correlates of Orthostatic Hypotension/Hypertension and Orthostatic Dizziness". Hypertension Research. 31 (5): 897–904. doi:10.1291/hypres.31.897. PMID 18712045.
6. ^ a b Fan, X. H.; Sun, K.; Zhou, X. L.; Zhang, H. M.; Wu, H. Y.; Hui, R. T. (2011). "Association of orthostatic hypertension and hypotension with target organ damage in middle and old-aged hypertensive patients". Zhonghua Yi Xue Za Zhi. 91 (4): 220–224. PMID 21418863.
7. ^ a b Streeten, D. H.; Auchincloss Jr, J. H.; Anderson Jr, G. H.; Richardson, R. L.; Thomas, F. D.; Miller, J. W. (1985). "Orthostatic hypertension. Pathogenetic studies". Hypertension. 7 (2): 196–203. doi:10.1161/01.hyp.7.2.196. PMID 3980066.
8. ^ Streeten, D. H.; Anderson Jr, G. H.; Richardson, R.; Thomas, F. D. (1988). "Abnormal orthostatic changes in blood pressure and heart rate in subjects with intact sympathetic nervous function: Evidence for excessive venous pooling". The Journal of Laboratory and Clinical Medicine. 111 (3): 326–335. PMID 3343547.
9. ^ Benowitz, N. L.; Zevin, S.; Carlsen, S.; Wright, J.; Schambelan, M.; Cheitlin, M. (1996). "Orthostatic hypertension due to vascular adrenergic hypersensitivity". Hypertension. 28 (1): 42–46. doi:10.1161/01.hyp.28.1.42. PMID 8675262.
10. ^ Tsukamoto, Y.; Komuro, Y.; Akutsu, F.; Fujii, K.; Marumo, F.; Kusano, S.; Kikawada, R. (1988). "Orthostatic hypertension due to coexistence of renal fibromuscular dysplasia and nephroptosis". Japanese Circulation Journal. 52 (12): 1408–1414. doi:10.1253/jcj.52.1408. PMID 2977192.
11. ^ Takada, Y.; Shimizu, H.; Kazatani, Y.; Azechi, H.; Hiwada, K.; Kokubu, T. (1984). "Orthostatic hypertension with nephroptosis and aortitis disease". Archives of Internal Medicine. 144 (1): 152–154. doi:10.1001/archinte.144.1.152. PMID 6362595.
12. ^ Miranda CL, Henderson MC, Wang JL, Nakaue HS, Buhler DR (1986). "Induction of acute renal porphyria in Japanese quail by Aroclor 1254". Biochem. Pharmacol. 35 (20): 3637–9. doi:10.1016/0006-2952(86)90637-4. PMID 3094542.
13. ^ Kario, K. (2009). "Orthostatic hypertension: A measure of blood pressure variation for predicting cardiovascular risk". Circulation Journal. 73 (6): 1002–1007. doi:10.1253/circj.cj-09-0286. PMID 19430163.
14. ^ Yatsuya, H.; Folsom, A. R.; Alonso, A.; Gottesman, R. F.; Rose, K. M.; Aric Study, I. (2011). "Postural changes in blood pressure and incidence of ischemic stroke subtypes: The ARIC study". Hypertension. 57 (2): 167–173. doi:10.1161/HYPERTENSIONAHA.110.161844. PMC 3214760. PMID 21199999.
15. ^ Hoshide, S.; Parati, G.; Matsui, Y.; Shibazaki, S.; Eguchi, K.; Kario, K. (2011). "Orthostatic hypertension: Home blood pressure monitoring for detection and assessment of treatment with doxazosin". Hypertension Research. 35 (1): 100–6. doi:10.1038/hr.2011.156. PMID 21918522.
16. ^ Moriguchi, A.; Nakagami, H.; Kotani, N.; Higaki, J.; Ogihara, T. (2000). "Contribution of cardiovascular hypersensitivity to orthostatic hypertension and the extreme dipper phenomenon". Hypertension Research. 23 (2): 119–123. doi:10.1291/hypres.23.119. PMID 10770258.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Orthostatic hypertension | c0544618 | 6,858 | wikipedia | https://en.wikipedia.org/wiki/Orthostatic_hypertension | 2021-01-18T19:00:47 | {"umls": ["C0544618"], "wikidata": ["Q7104927"]} |
This article includes a list of references, related reading or external links, but its sources remain unclear because it lacks inline citations. Please help to improve this article by introducing more precise citations. (May 2017) (Learn how and when to remove this template message)
Optic pit
Optic disc(# 18)
SpecialtyNeurology
Optic pit, optic nerve pit, or optic disc pit is a congenital excavation (or regional depression) of the optic disc (also optic nerve head), resulting from a malformation during development of the eye. Optic pits are important because they are associated with posterior vitreous detachments (PVD) and even serous retinal detachments.
## Contents
* 1 Signs and symptoms
* 2 Risk factors
* 2.1 Associated retinal changes
* 3 Diagnosis
* 4 Treatment
* 5 Occurrence
* 6 References
* 7 External links
## Signs and symptoms[edit]
Many times, an optic pit is asymptomatic and is just an incidental finding on examination of the eye by a physician. However, some patients may present with the symptoms of a posterior vitreous detachment or serous retinal detachment. This is because optic pits are associated with these disorders and are even speculated to be the actual cause of these disorders when they arise in patients with optic pits (see "Associated Retinal Changes" below for a more in-depth discussion on this theory). The most common visual field defects include an enlarged blind spot and a scotoma. Visual acuity is typically not affected by the pit but may get worse if serous detachment of the macula occurs. Metamorphopsia (distorted vision) may then result.
Optic pits were first described in 1882 as dark gray depressions in the optic disc. They may, however, appear white or yellowish instead. They can also range greatly in size (e.g. some can be minuscule while others may be large enough as to occupy most of optic disc surface). Optic pits are associated with other abnormalities of the optic nerve including large optic nerve size, large inferior colobomas of the optic disc, and colobomas of the retina. The optic disc originates from the optic cup when the optic vesicle invaginates and forms an embryonic fissure (or groove). Optic pits may develop due to failure of the superior end of the embryonic fissure to close completely.
## Risk factors[edit]
No particular risk factors have been conclusively identified; however, there have been a few reports that demonstrate an autosomal dominant pattern of inheritance in some families. Therefore, a family history of optic pits may be a possible risk factor.
### Associated retinal changes[edit]
Large optic pit (fluorescein angiography)
Optic pits have been associated with serous retinal detachments in up to as many as 50% of all cases. These detachments may occur at any age but most frequently present in early adulthood. The most popular theory behind this association is a separation of the layers of the retina, known as retinoschisis, due to fluid (the vitreous humour) entering the optic pit and traveling between the inner and outer layers of the retina. The outer layer may then subsequently detach. Evidence of retinoschisis has been demonstrated using OCT.
Centrally located optic pits are less likely to cause changes in the retina. However, if located more peripherally in the optic disc, then it is more likely to cause a serous retinal detachment. Furthermore, if the optic pit is located temporally (which the majority are), then it is more likely to cause detachment of the macula because of the macula's proximity to the temporal side of the optic disc. If serous macular detachment occurs, a patient's visual acuity may become as poor as 20/200 or worse.
Treatment for optic pit-associated macular detachment involves photocoagulation of the retina by use of an ion laser (either krypton or argon). This procedure works by burning one or more rows in between the optic disc and areas of serous retinal detachment. In most cases, macular reattachment results and visual acuity can be restored to about 20/80. This procedure may also be utilized prior to macular detachment in order to help prevent the future development of macular detachment. Other treatments for optic pit-associated macular detachment include macular buckling, gas tamponade, or vitrectomy. Some experts feel that the best results can be attained when the use of any of the above-mentioned modalities (laser photocoagulation, macular buckling, gas tamponade, and vitrectomy) are used in combination.
## Diagnosis[edit]
Optic pits should be diagnosed by an eye care professional who can perform a thorough exam of the back of the eye using an ophthalmoscope. More recently, the development of a special technology called optical coherence tomography (OCT) has allowed better visualization of the retinal layers. It has been used to demonstrate a marked reduction in the thickness of the retinal nerve fiber layer in the quadrant corresponding to the optic pit. This is not yet in standard use for diagnosis of an optic pit, but may be helpful in supporting a diagnosis.
## Treatment[edit]
Optic pits themselves do not need to be treated. However, patients should follow up with their eye care professional annually or even sooner if the patient notices any visual loss whatsoever. Treatment of PVD or serous retinal detachment will be necessary if either develops in a patient with an optic pit.
## Occurrence[edit]
Optic pits occur equally between men and women. They are seen in roughly 1 in 10,000 eyes, and approximately 85% of optic pits are found to be unilateral (i.e. in only one eye of any affected individual). About 70% are found on the temporal side (or lateral one-half) of the optic disc. Another 20% are found centrally, while the remaining pits are located either superiorly (in the upper one-half), inferiorly (in the lower one-half), or nasally (in the medial one-half towards the nose).
## References[edit]
* Sadun, AA (2005). "Chapter 111: Optic Disc Pits and Associated Serous Macular Detachment". In Ryan, Stephen J. (ed.). Medical Retina. Retina. 2 (4th ed.). St. Louis: Mosby. OCLC 936652565.
* Ferry, Andrew P. (September 1963). "Macular detachment associated with congenital pit of the optic nerve head: pathologic findings in two cases simulating malignant melanoma of the choroid". Archives of Ophthalmology. 70 (3): 346–57. doi:10.1001/archopht.1963.00960050348014. PMID 14048795.
* Brown, Gary C.; Tasman, William S. (1983). Congenital anomalies of the optic disc. New York: Grune & Stratton. p. 31. ISBN 978-0-8089-1515-7. OCLC 8931541.
* Brown, Gary C.; Shields, Jerry A.; Goldberg, Richard E. (January 1980). "Congenital pits of the optic nerve head II: Clinical studies in humans". Ophthalmology. 87 (1): 51–65. doi:10.1016/S0161-6420(80)35278-0. PMID 7375086 – via Elsevier.
* Annesley, W; Brown, G; Bolling, J; Goldberg, R; Fischer, D (1987). "Treatment of retinal detachment with congenital optic pit by krypton laser photocoagulation". Graefe's Archive for Clinical and Experimental Ophthalmology. 225 (5): 311–4. doi:10.1007/BF02153395. PMID 3666472.
* Creel, Donnell J. (November 2012). "The Electroretinogram and the Electro-oculogram: Clinical Applications". In Kolb, Helga; Fernandez, Eduardo; Nelson, Ralph; Jones, Bryan (eds.). Webvision: The Organization of the Retina and Visual System.
* Theodossiadis, George P.; Theodossiadis, Panagiotis G. (April 2005). "The macular buckling procedure in the treatment of retinal detachment in highly myopic eyes with macular hole and posterior staphyloma: mean follow-up of 15 years". Retina. 25 (4): 285–9. doi:10.1097/00006982-200504000-00006. PMID 15805904.
* Theodossiadis, George P.; Theodossiadis, Panagiotis G. (August 2001). "Optical coherence tomography in optic disk pit maculopathy treated by the macular buckling procedure". American Journal of Ophthalmology. 132 (2): 184–90. doi:10.1016/S0002-9394(01)00997-7. PMID 11476677 – via Elsevier.
* Hirakata, A; Okada, AA; Hida, T. (August 2005). "Long-term results of vitrectomy without laser treatment for macular detachment associated with an optic disc pit". Ophthalmology. 112 (8): 1430–5. doi:10.1016/j.ophtha.2005.02.013. PMID 16024082 – via Elsevier.
## External links[edit]
* "Optic Nerve Pit". American Association for Pediatric Ophthalmology and Strabismus. March 2014.
* "Optic Pits". EyeWiki. American Academy of Ophthalmology.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Optic pit | c0155298 | 6,859 | wikipedia | https://en.wikipedia.org/wiki/Optic_pit | 2021-01-18T18:47:03 | {"umls": ["C0155298"], "wikidata": ["Q7098795"]} |
A number sign (#) is used with this entry because BCKDK deficiency is caused by homozygous mutation in the BCKDK (614901) gene on chromosome 16p11.
Clinical Features
Novarino et al. (2012) studied 3 consanguineous families with autism, epilepsy, intellectual disability, and reduced branched-chain amino acids (BCAAs). All patients were born at full term to unaffected parents. The first family (558), of Turkish origin, had 2 affected daughters. The first daughter developed normally until the age of 18 months, when she had her first seizure. She met criteria for autism by 15 years of age. At ages 20 and 21, electroencephalogram (EEG) detected extratemporal and generalized epileptiform abnormalities, and despite treatment with anticonvulsants, she had tonic-clonic seizures every 3 months lasting 3 to 4 minutes each. Her sister was similarly affected. The second family (18) was of Egyptian origin and consisted of an affected brother and sister. The girl had had a febrile seizure at 1 year of age and a generalized nonfebrile seizure at 8 years of age. EEG at age 8 showed frequent focal spike wave complexes over the left temporal region consistent with left temporal epileptogenic dysfunction. Her similarly affected brother had 4 febrile seizures at the age of 12 months; he was started on valproate and had a recurrence of febrile seizures every 4 to 5 months subsequently. At age 2 years 5 months he started on phenobarbital and had not had a seizure since. The family history was notable for a paternal uncle with schizophrenia, a second-degree cousin with intellectual disability, and a distant cousin also with schizophrenia. A third consanguineous family (1435) of Libyan origin consisted of 2 affected brothers. The first boy at 9 years of age was able to follow simple directions but did not speak. EEG was normal at age 11 years. He met criteria for autism on several scales. The similarly affected second brother had abnormal EEG at age 7, with right temporal slowing and rare surface negative frontal sharp waves.
Clinical Management
Novarino et al. (2012) reported that the children in the Turkish (558) and Egyptian (18) families were being treated with supplemental BCAAs. Transient superelevations of BCAAs occurred about 1 hour after ingestion. A trend toward normalization of BCAAs in the fasting state was observed. Urine organic acids showed no evidence of BCAA-related organic acids. Long-term effects were not known at that time; no adverse effects were reported.
Molecular Genetics
In 3 consanguineous families with autism, epilepsy, and intellectual disability, Novarino et al. (2012) detected homozygosity for mutation in the branched-chain keto acid dehydrogenase kinase (BCKDK) gene (614901.0001-614901.0003). Two families carried null mutations (nonsense and frameshift) and 1 family carried a missense mutation of a conserved amino acid. Induced pluripotent stem cells generated from fibroblasts of the healthy brother and the 2 sisters from family 558 all showed normal function and differentiation into neural stem cells. There was no notable difference in the morphology or proliferation of cells from wildtype and mutant genotypes. Cultured neurons also functioned normally, arguing against a major cell-autonomous role for BCKDK in the pathogenesis of disease.
Animal Model
Joshi et al. (2006) showed that Bckdk-null mice showed increased basal activity of the BCKDH complex as well as reduced BCAAs in various tissues. Bckdk-null mice were born at expected mendelian ratios and were healthy at birth but showed growth retardation that could be recovered by feeding a BCAA-rich diet. Adults developed neurologic abnormalities such as tremors, epileptic seizures, and hindlimb clasping phenotypes observed in some other mouse models of autism spectrum disorders. Brain histology was normal.
Novarino et al. (2012) quantified amino acid concentrations in brain homogenates from postnatal day 14 Bckdk wildtype and knockout mice. In addition to expected reduced brain BCAAs in Bckdk-null mice, there were also significantly increased levels of threonine, phenylalanine, tyrosine, histidine, and methionine. These large neutral amino acids are the same as those carried by the SLC7A5 (600182) and SLC3A2 (158070) transporters across the blood-brain barrier, which suggested imbalanced blood-brain barrier transport in these mice.
Novarino et al. (2012) studied the effects of 2 chow diets, one containing 2% BCAAs and the other an enriched diet containing 7% BCAAs, on the neurologic phenotypes of Bckdk-null mice. Mice raised on the BCAA-enriched diet were phenotypically normal. On the 2% BCAA diet, however, Bckdk-null mice had clear neurologic abnormalities not seen in wildtype mice, such as seizures and hindlimb clasping, that appeared within 4 days of instituting the 2% BCAA diet. These neurologic deficits were completely abolished within a week of the Bckdk-null mice starting a BCAA-enriched diet, suggesting that this is an inducible and reversible phenotype.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| BRANCHED-CHAIN KETO ACID DEHYDROGENASE KINASE DEFICIENCY | c3554078 | 6,860 | omim | https://www.omim.org/entry/614923 | 2019-09-22T15:53:47 | {"doid": ["0090126"], "omim": ["614923"], "orphanet": ["308410"], "synonyms": ["BCKDK DEFICIENCY", "Alternative titles"]} |
Abdallat Davis Farrage syndrome
Abdallat–Davis–Farrage syndrome has an autosomal recessive pattern of inheritance.
SpecialtyNeurology
Abdallat–Davis–Farrage syndrome is a form of phakomatosis, a disease of the central nervous system accompanied by skin abnormalities. It is characterized by the out of the ordinary pigment of skin that is abnormal to one's genetics or the color perceived on a basis.
The condition is named after the team of medical professionals who first wrote it up, describing the appearance of the syndrome in a family from Jordan. It was characterized in 1980 by Adnan Abdallat, a Jordanian doctor.[1]
## Contents
* 1 Signs and symptoms
* 2 Genetics
* 3 Diagnosis
* 4 Treatment
* 5 References
* 6 External links
## Signs and symptoms[edit]
* Albinism (hair)
* Irregular decreased skin pigmentation
* Excessive freckling
* Insensitivity to pain
* Paraparesis/quadraparesis
## Genetics[edit]
The syndrome is thought to be inherited as an autosomal recessive genetic trait, meaning that in order to manifest symptoms, a person must inherit a gene for Abdallat–Davis–Farrage syndrome from both parents. As it is also autosomal (not linked to either of the genes that determine gender), it can manifest in both men and women. Those with only one gene are carriers, and they typically manifest no symptoms; in the event that a person inherits both genes, symptoms usually appear before one year of age.[citation needed]
## Diagnosis[edit]
This section is empty. You can help by adding to it. (August 2017)
## Treatment[edit]
This section is empty. You can help by adding to it. (August 2017)
## References[edit]
1. ^ Abdallat, A.; Davis, S. M.; Farrage, J.; McDonald, W. I. (1980). "Disordered pigmentation, spastic paraparesis and peripheral neuropathy in three siblings: A new neurocutaneous syndrome". Journal of Neurology, Neurosurgery, and Psychiatry. 43 (11): 962–966. doi:10.1136/jnnp.43.11.962. PMC 490745. PMID 7441281.
## External links[edit]
Classification
D
* OMIM: 270750
* MeSH: C536859
* v
* t
* e
Phakomatosis
Angiomatosis
* Sturge–Weber syndrome
* Von Hippel–Lindau disease
Hamartoma
* Tuberous sclerosis
* Hypothalamic hamartoma (Pallister–Hall syndrome)
* Multiple hamartoma syndrome
* Proteus syndrome
* Cowden syndrome
* Bannayan–Riley–Ruvalcaba syndrome
* Lhermitte–Duclos disease
Neurofibromatosis
* Type I
* Type II
Other
* Abdallat–Davis–Farrage syndrome
* Ataxia telangiectasia
* Incontinentia pigmenti
* Peutz–Jeghers syndrome
* Encephalocraniocutaneous lipomatosis
This genetic disorder article is a stub. You can help Wikipedia by expanding it.
* v
* t
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*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Abdallat–Davis–Farrage syndrome | c0796019 | 6,861 | wikipedia | https://en.wikipedia.org/wiki/Abdallat%E2%80%93Davis%E2%80%93Farrage_syndrome | 2021-01-18T19:07:12 | {"gard": ["336"], "mesh": ["C536859"], "umls": ["C0796019"], "orphanet": ["101003"], "wikidata": ["Q4664694"]} |
Retinitis pigmentosa is a group of related eye disorders that cause progressive vision loss. These disorders affect the retina, which is the layer of light-sensitive tissue at the back of the eye. In people with retinitis pigmentosa, vision loss occurs as the light-sensing cells of the retina gradually deteriorate.
The first sign of retinitis pigmentosa is usually a loss of night vision, which becomes apparent in childhood. Problems with night vision can make it difficult to navigate in low light. Later, the disease causes blind spots to develop in the side (peripheral) vision. Over time, these blind spots merge to produce tunnel vision. The disease progresses over years or decades to affect central vision, which is needed for detailed tasks such as reading, driving, and recognizing faces. In adulthood, many people with retinitis pigmentosa become legally blind.
The signs and symptoms of retinitis pigmentosa are most often limited to vision loss. When the disorder occurs by itself, it is described as nonsyndromic. Researchers have identified several major types of nonsyndromic retinitis pigmentosa, which are usually distinguished by their pattern of inheritance: autosomal dominant, autosomal recessive, or X-linked.
Less commonly, retinitis pigmentosa occurs as part of syndromes that affect other organs and tissues in the body. These forms of the disease are described as syndromic. The most common form of syndromic retinitis pigmentosa is Usher syndrome, which is characterized by the combination of vision loss and hearing loss beginning early in life. Retinitis pigmentosa is also a feature of several other genetic syndromes, including Bardet-Biedl syndrome; Refsum disease; and neuropathy, ataxia, and retinitis pigmentosa (NARP).
## Frequency
Retinitis pigmentosa is one of the most common inherited diseases of the retina (retinopathies). It is estimated to affect 1 in 3,500 to 1 in 4,000 people in the United States and Europe.
## Causes
Mutations in more than 60 genes are known to cause nonsyndromic retinitis pigmentosa. More than 20 of these genes are associated with the autosomal dominant form of the disorder. Mutations in the RHO gene are the most common cause of autosomal dominant retinitis pigmentosa, accounting for 20 to 30 percent of all cases. At least 35 genes have been associated with the autosomal recessive form of the disorder. The most common of these is USH2A; mutations in this gene are responsible for 10 to 15 percent of all cases of autosomal recessive retinitis pigmentosa. Changes in at least six genes are thought to cause the X-linked form of the disorder. Together, mutations in the RPGR and RP2 genes account for most cases of X-linked retinitis pigmentosa.
The genes associated with retinitis pigmentosa play essential roles in the structure and function of specialized light receptor cells (photoreceptors) in the retina. The retina contains two types of photoreceptors, rods and cones. Rods are responsible for vision in low light, while cones provide vision in bright light, including color vision.
Mutations in any of the genes responsible for retinitis pigmentosa lead to a gradual loss of rods and cones in the retina. The progressive degeneration of these cells causes the characteristic pattern of vision loss that occurs in people with retinitis pigmentosa. Rods typically break down before cones, which is why night vision impairment is usually the first sign of the disorder. Daytime vision is disrupted later, as both rods and cones are lost.
Some of the genes associated with retinitis pigmentosa are also associated with other eye diseases, including a condition called cone-rod dystrophy. Cone-rod dystrophy has signs and symptoms similar to those of retinitis pigmentosa. However, cone-rod dystrophy is characterized by deterioration of the cones first, followed by the rods, so daylight and color vision are affected before night vision.
### Learn more about the genes associated with Retinitis pigmentosa
* ABCA4
* BEST1
* CLRN1
* CRB1
* CRX
* PDE6B
* PRPH2
* RHO
* RP2
* RPE65
* RPGR
* USH2A
* WDR19
Additional Information from NCBI Gene:
* CA4
* CERKL
* CNGA1
* CNGB1
* EYS
* FAM161A
* FSCN2
* GUCA1B
* IDH3B
* IMPDH1
* IMPG2
* KLHL7
* LRAT
* MERTK
* MT-TS2
* NR2E3
* NRL
* PCARE
* PDE6A
* PDE6G
* PRCD
* PROM1
* PRPF3
* PRPF31
* PRPF8
* RBP3
* RDH12
* RGR
* RLBP1
* ROM1
* RP1
* RP9
* SAG
* SEMA4A
* SNRNP200
* SPATA7
* TOPORS
* TTC8
* TULP1
* ZNF513
## Inheritance Pattern
Retinitis pigmentosa often has an autosomal dominant inheritance pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder. Most people with autosomal dominant retinitis pigmentosa have an affected parent and other family members with the disorder.
Retinitis pigmentosa can also have an autosomal recessive pattern of inheritance, which means both copies of a gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
This condition can also be inherited in an X-linked pattern. The genes associated with X-linked retinitis pigmentosa are located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females, (who have two X chromosomes), mutations usually have to occur in both copes of the gene to cause the disorder. However, at least 20 percent of females who carry only one mutated copy of the gene develop retinal degeneration and associated vision loss. In most cases, males experience more severe symptoms of the disorder than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
In 10 to 40 percent of all cases of retinitis pigmentosa, only one person in a family is affected. In these families, the disorder is described as simplex. It can be difficult to determine the inheritance pattern of simplex cases because affected individuals may have no affected relatives or may be unaware of other family members with the disease. Simplex cases can also result from a new gene mutation that is not present in other family members.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Retinitis pigmentosa | c0035334 | 6,862 | medlineplus | https://medlineplus.gov/genetics/condition/retinitis-pigmentosa/ | 2021-01-27T08:24:33 | {"gard": ["10790", "5694"], "mesh": ["D012174"], "omim": ["268000"], "synonyms": []} |
Bruns nystagmus is an unusual type of bilateral nystagmus most commonly occurring in patients with cerebellopontine angle tumours. It is caused by the combination of slow, large amplitude nystagmus (gaze paretic nystagmus) when looking towards the side of the lesion, and rapid, small amplitude nystagmus (vestibular nystagmus) when looking away from the side of the lesion.[1] It occurs in 11% of patients with vestibular schwannoma, and occurs mainly in patients with larger tumours (67% of patients with tumours over 3.5 cm diameter). Bruns nystagmus is also associated with an increased incidence of balance disturbance in patients with vestibular schwannoma.[2] It may be caused by the compression of both flocculi, the vestibular part of the cerebellum, and improvement in both the nystagmus and balance problems occur commonly after removal of the tumour.[3]
Bruns nystagmus is named for Ludwig Bruns (1858 – 1915).
## References[edit]
1. ^ Campbell, William Wesley; Russell N. DeJong; Armin F. Haerer (2005). DeJong's The Neurologic Examination. Lippincott Williams & Wilkins. p. 294. ISBN 978-0-7817-2767-9.
2. ^ Lloyd SK, Baguley DM, Butler K, Donnelly N, Moffat DA (August 2009). "Bruns' nystagmus in patients with vestibular schwannoma". Otol. Neurotol. 30 (5): 625–8. doi:10.1097/MAO.0b013e3181a32bec. PMID 19471169. S2CID 1857869.
3. ^ Nedzelski JM (October 1983). "Cerebellopontine angle tumors: bilateral flocculus compression as cause of associated oculomotor abnormalities". Laryngoscope. 93 (10): 1251–60. doi:10.1002/lary.1983.93.10.1251. PMID 6604857. S2CID 27574873.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Bruns nystagmus | c1321324 | 6,863 | wikipedia | https://en.wikipedia.org/wiki/Bruns_nystagmus | 2021-01-18T18:40:42 | {"wikidata": ["Q4979462"]} |
Potentially fatal complication of pregnancy
Amniotic fluid embolism
SpecialtyObstetrics
Pathophysiology of the amniotic fluid embolism
An amniotic fluid embolism (AFE) is a very uncommon childbirth (obstetric) emergency in which amniotic fluid enters the blood stream of the mother to trigger a serious reaction. This reaction then results in cardiorespiratory (heart and lung) collapse and massive bleeding (coagulopathy).[1][2][3] The rate at which it occurs is 1 instance per 20,000 births and it comprises 10% of all maternal deaths.
## Contents
* 1 Signs and symptoms
* 2 Causes
* 3 Diagnosis
* 4 Treatment
* 5 Epidemiology
* 6 History
* 7 References
* 8 External links
## Signs and symptoms[edit]
Amniotic fluid embolism is suspected when a woman giving birth experiences very sudden insufficient oxygen to body tissues, low blood pressure, and profuse bleeding due to defects in blood coagulation. Though symptoms and signs can be profound, they also can be entirely absent. There is much variation in how each instance progresses.[2]
## Causes[edit]
AFE is very rare and complex. The disorder occurs during the last stages of labor when amniotic fluid enters the circulatory system of the mother via tears in the placental membrane or uterine vein rupture.[4] Upon later analysis, fetal cells are found in the maternal circulation. When the fetal cells and amniotic fluid enter the bloodstream, reactions occur that cause severe changes in the mechanisms that affect blood clotting. Disseminated intravascular coagulation occurs and results in serious bleeding. The condition can also develop after elective abortion, amniocentesis, cesarean delivery or trauma. Small lacerations in the lower reproductive tract are associated with AFE.[2]
According to one study, induction of labor may double the risk of AFE. However, other studies have refuted this claim. A maternal age of 35 years or older is associated with AFE.[5]
## Diagnosis[edit]
AFE is diagnosed when all other causes have been excluded. The presence of fetal squamous cells or other fetal tissues, including meconium, have been found in the maternal circulation after the event. Diagnosis is also based upon the signs and symptoms observed during the birth or procedures.[2]
## Treatment[edit]
A case report on Amniotic Fluid Embolism published in the A & A Practice Journal in 2020 has revealed that when milrinone is administered as an aerosol, selective pulmonary vasodilation occurs without significant changes[6] in mean arterial pressure or systemic vascular resistance; and if used immediately after Amniotic Fluid Embolism, inhaled milrinone may mitigate the pulmonary vasoconstriction.[7][8]
However, since the circumstances that lead to this complication are difficult to influence, treatment to resolve the symptoms and deteriorating vascular conditions can improve outcomes.[2]
## Epidemiology[edit]
Amniotic fluid embolism is very uncommon and the rate at which it occurs is 1 instance per 20,000 births. Though rare, it comprises 10% of all maternal deaths.[2]
## History[edit]
This rare complication has been recorded seventeen times prior to 1950. It was first described in Brazil in the 1920s.[9]
## References[edit]
1. ^ Stafford, Irene; Sheffield, Jeanne (2007). "Amniotic Fluid Embolism". Obstetrics and Gynecology Clinics of North America. 34 (3): 545–553. doi:10.1016/j.ogc.2007.08.002. ISSN 0889-8545. PMID 17921014.[subscription required]
2. ^ a b c d e f Stein, Paul (2016). Pulmonary embolism. Chichester, West Sussex, UK Hoboken, NJ: John Wiley & Sons Inc. ISBN 9781119039099.
3. ^ *Leveno, Kenneth (2016). Williams manual of pregnancy complications. New York: McGraw-Hill Medical. pp. 223–224. ISBN 9780071765626.
4. ^ Vinay Kumar; Abul K. Abbas; Nelson Fausto; Jon C. Aster (2014-08-27). Robbins and Cotran Pathologic Basis of Disease, Professional Edition E-Book. Elsevier Health Sciences. pp. 129–. ISBN 978-0-323-29639-7.
5. ^ Kramer, M.S.; Rouleau, Jocelyn; Baskett, Thomas F; Joseph, KS (2006). "Amniotic-fluid embolism and medical induction of labour: a retrospective, population-based cohort study". The Lancet. 368 (9545): 1444–1448. doi:10.1016/S0140-6736(06)69607-4. PMID 17055946. S2CID 24883108.
6. ^ Baxter, Frederick, MD, CCFP, Whippey, Amanda, MD, FRCPC. Amniotic Fluid Embolism Treated With Inhaled Milrinone: A Case Report. A A Pract. 2020;14(13):e01342. doi:10.1213/XAA.0000000000001342.
7. ^ Gebhard CE, Rochon A, Cogan J, et al. Acute right ventricular failure in cardiac surgery during cardiopulmonary bypass separation: a retrospective case series of 12 years' experience with intratracheal milrinone administration. J Cardiothorac Vasc Anesth. 2019; 33:651-660
8. ^ Sablotzki A, Starzmann W, Scheubel R, Grond S, Czeslick EG. Selective pulmonary vasodilation with inhaled aerosolized milrinone in heart transplant candidates. Can J Anaesth. 2005; 52:1076-1082
9. ^ Amniotic fluid embolus: An update.[permanent dead link] Alfredo Gei, Gary D. V. Hankins: Contemp Ob/Gyn 45 (2000)
## External links[edit]
Classification
D
* ICD-10: O88.1
* ICD-9-CM: 673.1
* MeSH: D004619
* DiseasesDB: 574
External resources
* eMedicine: med/122
* v
* t
* e
Pathology of pregnancy, childbirth and the puerperium
Pregnancy
Pregnancy with
abortive outcome
* Abortion
* Ectopic pregnancy
* Abdominal
* Cervical
* Interstitial
* Ovarian
* Heterotopic
* Embryo loss
* Fetal resorption
* Molar pregnancy
* Miscarriage
* Stillbirth
Oedema, proteinuria and
hypertensive disorders
* Gestational hypertension
* Pre-eclampsia
* HELLP syndrome
* Eclampsia
Other, predominantly
related to pregnancy
Digestive system
* Acute fatty liver of pregnancy
* Gestational diabetes
* Hepatitis E
* Hyperemesis gravidarum
* Intrahepatic cholestasis of pregnancy
Integumentary system /
dermatoses of pregnancy
* Gestational pemphigoid
* Impetigo herpetiformis
* Intrahepatic cholestasis of pregnancy
* Linea nigra
* Prurigo gestationis
* Pruritic folliculitis of pregnancy
* Pruritic urticarial papules and plaques of pregnancy (PUPPP)
* Striae gravidarum
Nervous system
* Chorea gravidarum
Blood
* Gestational thrombocytopenia
* Pregnancy-induced hypercoagulability
Maternal care related to the
fetus and amniotic cavity
* amniotic fluid
* Oligohydramnios
* Polyhydramnios
* Braxton Hicks contractions
* chorion / amnion
* Amniotic band syndrome
* Chorioamnionitis
* Chorionic hematoma
* Monoamniotic twins
* Premature rupture of membranes
* Obstetrical bleeding
* Antepartum
* placenta
* Circumvallate placenta
* Monochorionic twins
* Placenta accreta
* Placenta praevia
* Placental abruption
* Twin-to-twin transfusion syndrome
Labor
* Amniotic fluid embolism
* Cephalopelvic disproportion
* Dystocia
* Shoulder dystocia
* Fetal distress
* Locked twins
* Nuchal cord
* Obstetrical bleeding
* Postpartum
* Pain management during childbirth
* placenta
* Placenta accreta
* Preterm birth
* Postmature birth
* Umbilical cord prolapse
* Uterine inversion
* Uterine rupture
* Vasa praevia
Puerperal
* Breastfeeding difficulties
* Low milk supply
* Cracked nipples
* Breast engorgement
* Childbirth-related posttraumatic stress disorder
* Diastasis symphysis pubis
* Postpartum bleeding
* Peripartum cardiomyopathy
* Postpartum depression
* Postpartum psychosis
* Postpartum thyroiditis
* Puerperal fever
* Puerperal mastitis
Other
* Concomitant conditions
* Diabetes mellitus
* Systemic lupus erythematosus
* Thyroid disorders
* Maternal death
* Sexual activity during pregnancy
* Category
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Amniotic fluid embolism | c0013927 | 6,864 | wikipedia | https://en.wikipedia.org/wiki/Amniotic_fluid_embolism | 2021-01-18T18:28:02 | {"mesh": ["D004619"], "icd-9": ["673.1"], "icd-10": ["O88.1"], "wikidata": ["Q1470833"]} |
Chromosome 1p deletion is a chromosome abnormality that occurs when there is a missing copy of the genetic material located on the short arm (p) of chromosome 1. The severity of the condition and the signs and symptoms depend on the size and location of the deletion and which genes are involved. Features that often occur in people with chromosome 1p deletion include developmental delay, intellectual disability, behavioral problems, and distinctive facial features. Most cases are not inherited, but people can pass the deletion on to their children. Treatment is based on the signs and symptoms present in each person.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Chromosome 1p deletion | c0795796 | 6,865 | gard | https://rarediseases.info.nih.gov/diseases/3730/chromosome-1p-deletion | 2021-01-18T18:01:23 | {"mesh": ["C535591"], "umls": ["C0795796"], "synonyms": ["Deletion 1p", "Monosomy 1p", "1p deletion", "1p monosomy", "Partial monosomy 1p"]} |
## Summary
### Clinical characteristics.
UNC80 deficiency is characterized by hypotonia, strabismus, oral motor dysfunction, postnatal growth deficiency, and developmental delay. The majority of individuals do not learn to walk. All individuals lack expressive language; however, many have expressive body language, and a few have used signs to communicate. Seizures may develop during infancy or childhood. Additional features can include nystagmus, extremity hypertonia, a high-pitched cry, repetitive and self-stimulatory behaviors, constipation, clubfeet, joint contractures, and scoliosis. For most individuals the UNC80 deficiency syndrome is not progressive. Individuals have slow acquisition of skills and do not have a loss of skills suggestive of neurodegeneration.
### Diagnosis/testing.
The diagnosis of UNC80 deficiency is established in a proband with developmental delay and hypotonia by identification of biallelic pathogenic variants in UNC80 on molecular genetic testing.
### Management.
Treatment of manifestations: G-tube feeding as needed for oral feeding difficulties; antiepileptic medications for seizure management; physical and occupational therapy for motor delay and sensory processing difficulties; ophthalmologic management for strabismus; braces and corrective surgeries as needed for orthopedic abnormalities; empiric management of constipation; sign language instruction or use of an alternate communication device for absent speech.
Surveillance: Annual evaluations for growth assessment, back exam for scoliosis, seizure management, evaluation of contractures, and ophthalmology examination.
### Genetic counseling.
UNC80 deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if both pathogenic variants in a family are known.
## Diagnosis
No formal diagnostic criteria have been published.
### Suggestive Findings
UNC80 deficiency should be suspected in individuals with the following clinical features:
* Developmental delay
* Moderate-to-severe intellectual disability
* Absent speech (<5 words)
* Hypotonia
* Joint contractures
* Postnatal growth restriction
### Establishing the Diagnosis
The diagnosis of UNC80 deficiency is established in a proband with developmental delay and hypotonia by identification of biallelic pathogenic variants in UNC80 on molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or a multigene panel) and genomic testing (comprehensive genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotypes of many disorders with hypotonia, developmental delay, and intellectual disability overlap, most children with UNC80 deficiency are diagnosed by the following genomic testing options:
* Comprehensive genomic testing (when clinically available) that includes exome sequencing and genome sequencing is one option.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
* A multigene panel that includes UNC80 and other genes of interest (see Differential Diagnosis) is another option. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Note: Single-gene testing (sequence analysis of UNC80) is rarely useful and typically NOT recommended.
### Table 1.
Molecular Genetic Testing Used in UNC80 Deficiency
View in own window
Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
UNC80Sequence analysis 319/19 4
Gene-targeted deletion/duplication analysis 5Unknown 6
1\.
See Table A. Genes and Databases for chromosome locus and protein.
2\.
See Molecular Genetics for information on allelic variants detected in this gene.
3\.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4\.
Valkanas et al [2016]
5\.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
6\.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Clinical Characteristics
### Clinical Description
UNC80 deficiency is a multisystem disorder. Table 2 indicates the frequency of clinical findings in this condition based on published reports. Clinical features vary and current evidence suggests dependency on the nature of the genetic variations.
Neurodevelopmental features. Individuals have congenital central hypotonia and strabismus. Some also manifest extremity hypertonia and a high-pitched cry. Seizures may develop during infancy or childhood. Focal seizures, generalized tonic-clonic seizures, myotonic seizures, aclonic seizures, and atypical absence seizures have been described. All respond well to anticonvulsive medications.
All individuals have developmental delay as well as severe intellectual disability. Oral motor dysfunction leads to difficulty with oral coordination, chewing, and swallowing. The majority of individuals do not learn to walk. All individuals lack expressive language, although many have expressive body language and a few have used signs to communicate.
For most individuals the UNC80 deficiency syndrome is not progressive. Individuals have slow acquisition of skills and do not have the loss of skills suggestive of neurodegeneration.
Behavioral features. Some individuals have behavioral difficulties including repetitive and self-stimulatory behaviors and difficulties with emotional regulation. The majority of individuals with UNC80 deficiency are social (i.e., they prefer people to objects). Some individuals show tactile aversion and hypersensitivity to stimuli. Some individuals seek significant oral stimulation.
Growth. All individuals have had normal prenatal growth. Postnatally, however, linear growth and weight remained below the 3rd centile. Poor feeding exacerbates the growth restriction; however, tube feedings with a calorie-rich diet generally do not result in weight for age above the 3rd centile. Individuals do not have evidence of endocrine anomalies that would account for the poor weight gain.
Gastrointestinal features. Constipation is common and has been attributed to hypotonia.
Musculoskeletal features. Many individuals have congenital clubfeet. Joint contractures (e.g., hip, elbow, knee) can present from an early age. Later-onset scoliosis can be seen. Ongoing physiotherapy, stretching, and bracing improves some of the limitations encountered with contractures and/or scoliosis. In individuals with more severe clubfeet or scoliosis, surgery may be considered.
Ophthalmologic features. Strabismus has been reported in all affected individuals and nystagmus is seen in half of affected individuals. One individual with structural ocular abnormalities (punctate keratopathy) has been reported. Vision is usually normal.
Facial features. The dysmorphic features reported appear to be nonspecific (see Table 2).
### Table 2.
Frequency of Clinical Features in Individuals with UNC80 Pathogenic Variants
View in own window
Clinical FeatureFrequency in Individuals w/UNC80
Pathogenic Variants 1
# w/feature /
# reported 1% w/feature
Neurodevelopmental
& behavioralSevere ID or DD19/19100%
Hypotonia19/19100%
Global motor delay13/13100%
Feeding difficulties5/683%
Walking achieved3/650%
Absent speech or <5 words19/19100%
Dystonic posture of limbs9/9100%
Seizures10/1953%
Arm flapping2/2100%
Happy disposition2/2100%
Self-injurious behaviors2/2100%
Sensory hypersensitivities5/683%
GrowthNormal birth parameters12/12100%
Postnatal height <3rd centile11/1292%
Postnatal weight <3rd centile11/1292%
Postnatal microcephaly11/1958%
GastrointestinalConstipation5/683%
MusculoskeletalScoliosis10/1377%
Joint contractures10/10100%
Clubfeet6/967%
Long, thin fingers9/9100%
Tapering of distal phalanx9/9100%
Small hands & feet5/683%
OphthalmologicStrabismus11/11100%
Nystagmus2/450%
Nonspecific
facial featuresTriangular face16/1984%
Frontal bossing5/956%
Downslanted palpebral fissures10/1953%
Low-set/posteriorly rotated ears10/1759%
Broad nasal bridge11/1958%
Anteverted nares11/1958%
Enlarged nares7/1937%
Short & smooth philtrum10/1377%
Thin vermilion of upper lip8/1844%
Tented vermilion of upper lip10/1377%
Micrognathia10/1953%
Adapted from Valkanas et al [2016]
DD = developmental delay; ID = intellectual disability
1: Total number of individuals with UNC80 deficiency who were assessed for the feature
Radiographic features. Although most affected individuals have normal brain MRI findings, nonspecific abnormalities such as a thin corpus callosum, mild diffuse brain atrophy, and borderline mild enlargement of the lateral and third ventricles and of the extra-axial space have been reported [Perez et al 2016, Shamseldin et al 2016, Stray-Pedersen et al 2016]. The skeletal features seen in affected individuals to date are primarily identified by physical exam.
Prognosis. Reported individuals span ages from birth to 15 years [Perez et al 2016, Shamseldin et al 2016, Stray-Pedersen et al 2016, Valkanas et al 2016]. To date, only one individual has died, of complications from infection; postmortem studies of the brain, spinal cord, nerve, muscle, liver, skin, and myocardium did not identify evidence of central nervous malformations or findings attributable to the underlying neurologic disorder [Valkanas et al 2016].
### Genotype-Phenotype Correlations
Correlations of genotype to phenotype have shown that genotype does not predict disease severity or outcome either within or among families.
### Nomenclature
UNC80 deficiency is referred to as "infantile hypotonia with psychomotor retardation and characteristic facies 2" (IHPRF2) in OMIM (616801).
### Prevalence
The prevalence is unknown. Nineteen individuals have been reported to date. UNC80 deficiency is presumed pan ethnic.
## Differential Diagnosis
Based on affected individuals described to date [Perez et al 2016, Shamseldin et al 2016, Stray-Pedersen et al 2016, Valkanas et al 2016], UNC80 deficiency does not have pathognomonic features distinguishing it from the many disorders in which central hypotonia, intellectual disability, and developmental delay are observed. Description of additional affected individuals may eventually identify such pathognomonic features; however, until then UNC80 deficiency is best considered as clinically indistinguishable from many other genetic causes of hypotonia, developmental delay, and intellectual disability (some of which are listed in Table 3).
### Table 3.
Disorders to Consider in the Differential Diagnosis of UNC80 Deficiency
View in own window
Disorder 1Gene / Genetic MechanismDistinguishing Clinical Features
Hypotonia, infantile, with psychomotor retardation and characteristic facies 1
(OMIM 615419)NALCNDistinctive facial features incl prominent forehead, short nose, wide mouth, micrognathia, & large, low-set ears; neuroaxonal dystrophy; optic atrophy
Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
(OMIM 616900)TBCKDistinctive facial features incl coarse face, bitemporal narrowing, highly arched eyebrows, deeply set eyes, high nasal bridge w/anteverted nares, macroglossia, gingival hyperplasia, & exaggerated cupid's bow; abnormal brain imaging; optic atrophy
Phelan-McDermid syndromeTerminal or interstitial deletion of chromosome 22q13.3Normal or accelerated growth, dolichocephaly, ptosis, epicanthal folds, large or prominent ears, pointed chin, fleshy hands, dysplastic toenails, tendency to overheat
Ring chromosome 22Mild prenatal growth deficiency; mild dysmorphic features incl hypertelorism, epicanthal folds, depressed nasal bridge, & micrognathia; genitourinary anomalies; coloboma of the iris, choroid, &/or optic nerve; microphthalmia; cleft palate; congenital heart malformations; hernias; internal & external ear anomalies
Prader-Willi syndromeAbnormal parent-specific imprinting w/in PWCRPolyphagia & obesity, thin vermilion of upper lip w/down-turned corners of the mouth, genitourinary anomalies, acquisition of speech & mobility
Angelman syndromeDeficient expression or function of the maternally inherited UBE3A alleleBursts of laughter, macrostomia, tongue protrusion, prognathism, widely spaced teeth, mild cortical atrophy
Glass syndrome
(OMIM 612313)SATB2Cleft palate, arachnodactyly, joint laxity, ectodermal anomalies
Rett syndromeMECP2Postnatal microcephaly, seizures, poor growth, esotropia, scoliosis, repetitive behaviors
PWCR = Prader-Willi critical region
1\.
See hyperlinked GeneReview or OMIM phenotype entry for more information.
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with UNC80 deficiency, the evaluations and referrals summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.
### Table 4.
Recommended Evaluations Following Initial Diagnosis
View in own window
System/ConcernEvaluationComment
ConstitutionalGrowth assessment incl height, weight, & head circumference
EyesOphthalmologic eval
GastrointestinalFeeding eval
MusculoskeletalOrthopedic evalIf clubfeet &/or scoliosis is present
NeurologicEEGIf neurologic history suggests presence of seizures
PsychiatricPsychiatric evalIf behavioral problems are present
Miscellaneous/
OtherPsychoeducational &/or developmental evals (physical therapy, occupational therapy, speech therapy evals) to assess developmental delays & facilitate appropriate interventions
Consultation w/clinical geneticist &/or genetic counselor
### Treatment of Manifestations
### Table 5.
Treatment of Manifestations in Individuals with UNC80 Deficiency
View in own window
Manifestation/ConcernTreatment
Ocular abnormalities (nystagmus/strabismus)Ophthalmologic management
Oral feeding difficultiesG-tube feeding
ConstipationStandard management
Orthopedic abnormalities (clubfeet, scoliosis, joint contractures)Braces &/or corrective surgery
SeizuresAntiepileptic drugs
Self-injurious behaviorBehavior modification therapy
Hypo/hypertonia, gross motor delays, sensory processing difficultiesPhysical therapy, occupational therapy
Absent speechSign language instruction; consider alternate forms of communication
#### Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.
Ages 5-21 years
* In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
* Discussion about transition plans and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
* Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
* Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
#### Motor Dysfunction
Gross motor dysfunction
* Physical therapy is recommended to maximize mobility.
* Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, lifts, bath chairs, orthotics, adaptive strollers).
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.
Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy – typically from an occupational or speech therapist – is recommended for affected individuals who have difficulty feeding due to poor oral motor control.
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication) for individuals who have expressive language difficulties.
### Surveillance
Annual evaluation with the following specialists is appropriate:
* Pediatrician for growth assessment
* Neurologist to identify and manage seizures
* Orthopedist for evaluation of contractures and back examination for scoliosis
* Ophthalmologist for ocular manifestations and corrective therapy if needed
### Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| UNC80 Deficiency | None | 6,866 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK453434/ | 2021-01-18T20:51:53 | {"synonyms": []} |
CLN11 disease is a disorder that primarily affects the nervous system. Individuals with this condition typically show signs and symptoms in adolescence or early adulthood. This condition is characterized by recurrent seizures (epilepsy), vision loss, problems with balance and coordination (cerebellar ataxia), and a decline in intellectual function.
Seizures in CLN11 disease often involve a loss of consciousness, muscle stiffness (rigidity), and generalized convulsions (tonic-clonic seizures).
Vision loss is gradual over time and is due to a condition called retinitis pigmentosa, which is caused by the breakdown of the light-sensitive layer at the back of the eye (retina). People with CLN11 disease can also develop clouding of the lenses of the eyes (cataracts) and rapid, involuntary eye movements (nystagmus).
Affected individuals can also develop muscle twitches (myoclonus), walking problems and falling (gait disturbance), and impaired speech (dysarthria). Over time, people with CLN11 disease develop short-term memory loss and loss of executive function, which is the ability to plan and implement problem-solving strategies and actions. They may also become irritable and impulsive. Some affected individuals experience visual hallucinations involving people or animals.
CLN11 disease is one of a group of disorders known as neuronal ceroid lipofuscinoses (NCLs). All of these disorders affect the nervous system and typically cause progressive problems with vision, movement, and thinking ability. The different NCLs are distinguished by their genetic cause. Each disease type is given the designation "CLN," meaning ceroid lipofuscinosis, neuronal, and then a number to indicate its subtype.
## Frequency
The prevalence of CLN11 disease is unknown; at least 11 cases have been described in the scientific literature.
## Causes
CLN11 disease results from mutations in the GRN gene. This gene provides instructions for making a protein called progranulin. Progranulin is active in many different tissues in the body, where it helps control the growth, division, and survival of cells. Progranulin's function in the brain is not well understood, although it appears to play an important role in the survival of nerve cells (neurons).
GRN gene mutations that cause CLN11 disease result in a complete loss of functional progranulin protein. This lack of progranulin causes the death of nerve cells in the brain, although the exact mechanism is unknown. Widespread loss of neurons in CLN11 disease leads to the development of signs and symptoms in adolescence or early adulthood.
### Learn more about the gene associated with CLN11 disease
* GRN
## Inheritance Pattern
CLN11 disease is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Having a mutation in both copies of the GRN gene eliminates production of any functional progranulin protein.
The parents of individuals with CLN11 disease each carry one copy of the mutated GRN gene in every cell and generally produce about half the normal amount of progranulin protein. Individuals with one GRN gene mutation typically do not show signs and symptoms of CLN11 disease, but they may develop another condition called GRN-related frontotemporal lobar degeneration in which cognitive decline begins between a person's forties and sixties. Some people with two GRN gene mutations that allow the production of some functional progranulin protein develop GRN-related frontotemporal lobar degeneration.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| CLN11 disease | c3539123 | 6,867 | medlineplus | https://medlineplus.gov/genetics/condition/cln11-disease/ | 2021-01-27T08:24:57 | {"omim": ["614706"], "synonyms": []} |
## Summary
### Clinical characteristics.
L1 syndrome involves a phenotypic spectrum ranging from severe to mild and includes three clinical phenotypes:
* X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS)
* MASA (mental retardation [intellectual disability], aphasia [delayed speech], spastic paraplegia [shuffling gait], adducted thumbs) syndrome including X-linked complicated hereditary spastic paraplegia type 1
* X-linked complicated corpus callosum agenesis
Males with HSAS are born with severe hydrocephalus, adducted thumbs, and spasticity; intellectual disability is severe. In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay; intellectual disability ranges from mild (IQ: 50-70) to moderate (IQ: 30-50). It is important to note that all phenotypes can be observed in affected individuals within the same family.
### Diagnosis/testing.
The diagnosis of L1 syndrome is established in a male proband with suggestive findings and a hemizygous pathogenic variant in L1CAM identified by molecular genetic testing. The diagnosis of L1 syndrome in a female is unusual but not impossible (most likely in the setting of general delay and/or hydrocephalus) and is established with the identification of a heterozygous pathogenic variant in L1CAM by molecular genetic testing.
### Management.
Treatment of manifestations: It is best to involve a multidisciplinary team with expertise in pediatrics, child neurology, neurosurgery, rehabilitation, and clinical genetics. Shunting of the cerebrospinal fluid should be performed as needed to reduce intracranial pressure. Individual educational programming is indicated for developmental delay and intellectual disability. Standard treatment guidelines should be followed for spasticity. A splint may help reduce the degree of thumb adduction; surgery is not generally indicated.
Surveillance: Neurologic evaluation at regular intervals to monitor hydrocephalus, developmental progress, and spastic paraplegia.
### Genetic counseling.
L1 syndrome is inherited in an X-linked manner. If the mother of the proband is heterozygous for an L1CAM pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the L1CAM pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and will usually not be affected but may have a range of (typically mild) clinical manifestations. Once the L1CAM pathogenic variant has been identified in an affected family member, heterozygote detection, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
## Diagnosis
### Suggestive Findings
L1 syndrome involves a phenotypic spectrum ranging from severe to mild. L1 syndrome should be suspected in individuals with any of the following clinical phenotypes or neuroimaging findings and supportive family history.
#### Clinical Phenotypes
X-linked hydrocephalus with stenosis of aqueduct of Sylvius (HSAS). Signs present in affected males:
* Severe hydrocephalus, often of prenatal onset. Clinical criteria for hydrocephalus:
* Increased intraventricular fluid volume evidenced by increased occipital-frontal circumference (OFC) and imaging findings including increased ventricular size, loss of cerebral sulci, and transependymal resorption of cerebrospinal fluid
* Increased intraventricular pressure based on: specific clinical signs and symptoms depending on age including progressive increase of OFC, headache, nausea and vomiting, and irritability; and/or ultrasound and/or brain imaging
* Adducted (clasped) thumbs caused by a developmental defect of the extensor pollicus longis and/or brevis muscles (>50% of males) [Schrander-Stumpel & Fryns 1998]
* Spasticity evidenced by brisk tendon reflexes and extensor plantar responses
* Moderate-to-severe intellectual disability
MASA (mental retardation [intellectual disability], aphasia [delayed speech], spastic paraplegia [shuffling gait], adducted thumbs) syndrome including X-linked complicated hereditary spastic paraplegia type 1 (SPG1). Findings in affected males:
* Mild-to-moderate intellectual disability
* Delayed onset of speech
* Hypotonia progressing to spastic paraplegia
* Possible adducted (clasped) thumbs caused by a developmental defect of the extensor pollicis longis and/or brevis muscles
* Variable abnormalities on brain MRI
X-linked complicated corpus callosum agenesis [Yamasaki et al 1995]. Findings in affected males:
* Variable spastic paraplegia
* Mild-to-moderate intellectual disability
* Corpus callosum dysplasia, hypoplasia, or aplasia
#### Neuroimaging Findings
Hydrocephalus with or without stenosis of the aqueduct of Sylvius is found in combination with corpus callosum agenesis/hypogenesis and/or cerebellar hypoplasia, small brain stem, and agenesis of the pyramids (corticospinal tracts) [Yamasaki et al 1995].
Bilateral absence of the pyramids detected by MRI or autopsy is an almost pathognomonic finding [Chow et al 1985].
Aqueductal stenosis is not a constant feature of L1 syndrome [Yamasaki et al 1995].
#### Family History
Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis.
### Establishing the Diagnosis
Male proband. The diagnosis of L1 syndrome is established in a male proband with suggestive findings and a hemizygous pathogenic variant in L1CAM identified by molecular genetic testing (see Table 1).
Female proband. The diagnosis of L1 syndrome in a female is unusual but not impossible (most likely in the setting of general delay and/or hydrocephalus) and is established with the identification of a heterozygous pathogenic variant in L1CAM by molecular genetic testing (see Table 1).
Note: Identification of a hemizygous or heterozygous L1CAM variant of uncertain significance does not establish or rule out a diagnosis of this disorder.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with hydrocephalus, spastic paraplegia, and/or intellectual disability are more likely to be diagnosed using genomic testing (see Option 2).
#### Option 1
Single-gene testing. Sequence analysis of L1CAM is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
A multigene panel that includes L1CAM and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, and deletion/duplication analysis.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
#### Option 2
Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
### Table 1.
Molecular Genetic Testing Used in L1 Syndrome
View in own window
Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
L1CAMSequence analysis 3, 499% 5
Gene-targeted deletion/duplication analysis 61% 7
1\.
See Table A. Genes and Databases for chromosome locus and protein.
2\.
See Molecular Genetics for information on variants detected in this gene.
3\.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4\.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
5\.
Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]
6\.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
7\.
Large deletions or duplications (including one deletion of the entire gene) have been described [Vos & Hofstra 2010, Adle-Biassette et al 2013, Alby et al 2016].
## Clinical Characteristics
### Clinical Description
L1 syndrome is seen almost exclusively in males.
#### Affected Males
L1 syndrome comprises three clinical phenotypes ranging from severe to mild; its major features are hydrocephalus, intellectual disability, spasticity of the legs, and adducted thumbs.
To date, more than 280 individuals have been identified with a pathogenic variant in L1CAM [Vos et al 2010, Vos & Hofstra 2010]. Table 2 compares the features among the various phenotypes associated with L1 syndrome. It is important to note that all phenotypes can be observed within the same family.
### Table 2.
L1 Syndrome: Comparison of Phenotypes in Male Probands by Select Features
View in own window
FeatureL1 Phenotype
HSASMASA syndrome,
incl SPG1X-linked complicated
CC agenesis
Hydrocephalus w/or w/o stenosis
of aqueduct of Sylvius100%Variable dilation of
the 3rd ventricle−
CC agenesis/hypogenesis+
(accompanies
hydrocephalus)\+ in some100%
Intellectual disabilitySevereMild to moderateMild to moderate
Delayed speech+++
Spasticity of legs++Variable
Adducted thumbs50%<50%<50%
CC = corpus callosum; HSAS = X-linked hydrocephalus with stenosis of aqueduct of Sylvius; MASA = mental retardation [intellectual disability], aphasia [delayed speech], spastic paraplegia [shuffling gait], adducted thumbs; SPG1 = X-linked complicated hereditary spastic paraplegia type 1
Hydrocephalus may be present prenatally and result in stillbirth or death in early infancy.
* Males with hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) are born with severe hydrocephalus and adducted thumbs.
Seizures may occur.
* In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay.
Mild-to-moderate ventricular enlargement is compatible with long survival.
Other brain malformations can include corpus callosum agenesis/hypogenesis and/or cerebellar hypoplasia, small brain stem, and agenesis of the pyramids.
Intellectual disability
* The degree of intellectual impairment does not necessarily correlate with head size or severity of hydrocephalus; males with severe intellectual disability and a normal head circumference have been reported.
* In HSAS, intellectual disability is usually severe and is independent of shunting procedures in individuals with severe hydrocephalus.
* In MASA (mental retardation [intellectual disability], aphasia [delayed speech], spastic paraplegia [shuffling gait], adducted thumbs) syndrome, intellectual disability ranges from mild (IQ: 50-70) to moderate (IQ: 30-50).
Behavioral concerns. In general, there are no specific behavior problems in males with the condition. However, childhood-onset psychosis has been reported in two unrelated boys [Sato et al 2020]. Familial factors and interaction with other rare genetic variants may have modulated the presentation.
Spasticity
* Boys initially exhibit hypotonia of the legs, which evolves into spasticity during the first years of life.
* In adult males, the spasticity tends to be somewhat progressive, although this finding has not been documented in a large group.
* Spasticity usually results in atrophy of the muscles of the legs and contractures that together cause the shuffling gait.
Adducted thumbs. Absence of the musculus abductor pollicis longus causes the typical adduction position of the thumb. Surgery with tendon replacement has been used and can be successful in some individuals. Splint therapy may improve the thumb position.
Other findings
* Hirschsprung disease (HSCR). At least 16 individuals with an L1CAM pathogenic variant and a combination of L1 syndrome and HSCR have been reported [Parisi et al 2002, Basel-Vanagaite et al 2006, Tegay et al 2007, Griseri et al 2009, Takenouchi et al 2012, Yang et al 2019]. HSCR is characterized by the absence of ganglion cells and the presence of hypertrophic nerve trunks in the distal bowel. It has been suggested that failure of migration of the neural crest cells underlies aganglionosis. Parisi et al [2002] and Griseri et al [2009] hypothesized that L1CAM may modify the effects of a HSCR-associated gene to cause aganglionosis. An L1CAM pathogenic variant alone does not result in HSCR [Griseri et al 2009].
* Congenital idiopathic intestinal pseudo-obstruction. An association between hydrocephalus and a specific form of congenital idiopathic intestinal pseudo-obstruction was reported in an infant [Bott et al 2004] in whom an L1CAM pathogenic variant had been detected.
#### Heterozygous Females
Females heterozygous for an L1CAM pathogenic variant may manifest minor features such as adducted thumbs and/or mild intellectual disability. Rarely do females manifest the complete L1 syndrome phenotype. Severe hydrocephalus has been reported in a heterozygous female [Kaepernick et al 1994, Vos et al 2010]. A pathogenic variant was detected in a girl with aqueduct stenosis, adducted thumbs, and mild intellectual disability, and without a positive family history [Author, personal observation]. Skewed X inactivation was demonstrated. Otter et al [2017] reported epilepsy in the daughter of a man with very mild L1 syndrome; although the daughter is presumed to be heterozygous for an L1CAM pathogenic variant, this has not been confirmed.
### Genotype-Phenotype Correlations
In their review, Weller & Gärtner [2001] noted that pathogenic missense variants in extracellular domains or pathogenic variants in cytoplasmic regions cause milder phenotypes than those resulting from truncation in extracellular domains or from nondetectable L1 protein.
Pathogenic missense variants that affect "key amino acid residues" are most likely to result in a severe phenotype. Key amino acid residues are those crucial for the structure of the immunoglobulin or fibronectin type III-like domains of the L1 protein [Bateman et al 1996].
A statistical analysis was performed on 33 individuals with L1 syndrome in whom a pathogenic variant was identified to detect any possible genotype-phenotype correlation. Children harboring a pathogenic truncating variant were more likely to die before age three years (52%) than children with a pathogenic missense variant (8%), indicating a relationship between the seriousness of the disease and the type of pathogenic variant. These results are statistically significant (Fisher exact p=0.02) [Vos et al 2010].
The above generalizations about genotype-phenotype correlations notwithstanding, clinical findings in L1 syndrome can range from mild to severe even within a family, indicating that other factors must influence the clinical presentation [Finckh et al 2000].
### Prevalence
HSAS is the most common genetic form of congenital hydrocephalus, with an estimated prevalence of 1:30,000. It accounts for approximately 5%-10% of males with nonsyndromic congenital hydrocephalus [Finckh et al 2000].
In males with complicated spastic paraplegia, the prevalence of L1 syndrome is unknown.
## Differential Diagnosis
The differential diagnosis of males with developmental delay or intellectual disability (ID) and early hypotonia evolving into spastic paraplegia during childhood, with or without adducted thumbs, includes many conditions. See OMIM Phenotypic Series: autosomal dominant ID, autosomal recessive ID, and X-linked nonsyndromic ID.
Nonsyndromic congenital hydrocephalus. Individuals with L1 syndrome and hydrocephalus do not have major additional physical anomalies. Other single-gene causes of nonsyndromic congenital hydrocephalus include biallelic pathogenic variants in CCDC88C, MPDZ, and WDR8 (see OMIM PS236600).
Nonsyndromic congenital hydrocephalus may also occur as part of (or secondary to) the following:
* Neural tube defect
* Congenital aqueductal stenosis (isolated hydrocephalus)
* CNS malformation
* Arnold-Chiari malformation
* Dandy-Walker malformation
* Hydranencephaly
* Vein of Galen malformation
* Midline hyperplasia with malformation of the fornical system
* Congenital cyst
* Other midline abnormalities
* Congenital communicating hydrocephalus secondary to hemorrhage
Spastic paraplegia. To date, approximately 50 genetic types of complicated hereditary spastic paraplegia have been defined (see Hereditary Spastic Paraplegia Overview).
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with L1 syndrome, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
### Table 5.
Recommended Evaluations Following Initial Diagnosis in Individuals with L1 Syndrome
View in own window
System/ConcernEvaluationComment
Hydrocephalus /
Brain malformationBrain imaging studyMRI is preferred.
Intellectual disabilityDevelopmental eval
SpasticityComplete neurologic eval
Adducted thumbsClinical observation
Hirschsprung disease
associationEval for Hirschsprung disease if there is history of constipation
Genetic counselingBy genetics professionals 1To inform patients & families re nature, MOI, & implications of L1 syndrome to facilitate medical & personal decision making
Family support/
resourcesAssess:
* Use of community or online resources, e.g., Parent to Parent;
* Need for social work involvement for parental support;
* Need for home nursing referral.
MOI = mode of inheritance
1\.
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
### Treatment of Manifestations
Optimal management involves a multidisciplinary team with expertise in pediatrics, child neurology, neurosurgery, rehabilitation, and clinical genetics.
### Table 6.
Treatment of Manifestations in Individuals with L1 Syndrome
View in own window
Manifestation/
ConcernTreatmentConsiderations/Other
HydrocephalusSurgical treatment should be performed as needed.
* Shunting of CSF is indicated to ↓ intracranial pressure.
* Prenatal shunting offers no advantage [Pinckert & Golbus 1988].
DD/IDSee DD/ID Management Issues.Developmental outcome is variable & individualized educational program is important.
Spastic
paraplegiaStandard treatment guidelines for spasticity should be followed.Neurologic features should be monitored.
Adducted
thumbsA splint may help ↓ degree of adduction.
* Surgical intervention is not generally indicated.
* In some milder cases, tendon transfer may improve thumb function.
CSF = cerebrospinal fluid; DD = developmental delay; ID = intellectual disability
#### Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:
* IEP services:
* An IEP provides specially designed instruction and related services to children who qualify.
* IEP services will be reviewed annually to determine whether any changes are needed.
* As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
* PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
* As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
* A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
* Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
* Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
#### Motor Dysfunction
Gross motor dysfunction
* Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
* Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
* For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.
Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, and in many cases can improve it.
#### Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
### Surveillance
### Table 7.
Recommended Surveillance for Individuals with L1 Syndrome
View in own window
System/ConcernEvaluationFrequency
HydrocephalusNeurologic evalAt regular intervals as indicated individually
DD/ID
Spastic paraplegia
DD = developmental delay; ID = intellectual disability
### Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| L1 Syndrome | c0795953 | 6,868 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1484/ | 2021-01-18T21:15:37 | {"mesh": ["C536029"], "synonyms": ["L1 Disease"]} |
Couvelaire uterus
SpecialtyObstetrics
Couvelaire uterus (also known as uteroplacental apoplexy)[1] is a life-threatening condition in which loosening of the placenta (abruptio placentae) causes bleeding that penetrates into the uterine myometrium forcing its way into the peritoneal cavity.
## Contents
* 1 Symptoms and signs
* 2 Pathophysiology
* 3 Prevention
* 4 Treatment
* 5 Prognosis
* 6 References
* 7 External links
## Symptoms and signs[edit]
Patients can have pain secondary to uterine contractions, uterine tetany or localized uterine tenderness. Signs can also be due to abruptio placentae including uterine hypertonus, fetal distress, fetal death, and rarely, hypovolemic shock (shock secondary to severe blood loss). The uterus may adopt a bluish/purplish, mottled appearance due to extravasation of blood into uterine muscle.
## Pathophysiology[edit]
Couvelaire uterus is a phenomenon where the retroplacental blood may penetrate through the thickness of the wall of the uterus into the peritoneal cavity. This may occur after abruptio placentae. The hemorrhage that gets into the decidua basalis ultimately splits the decidua, and the haematoma may remain within the decidua or may extravasate into the myometrium (the muscular wall of the uterus). The myometrium becomes weakened and may rupture due to the increase in intrauterine pressure associated with uterine contractions. This may lead to a life-threatening obstetric emergency requiring urgent delivery of the fetus.
## Prevention[edit]
The occurrence of Couvelaire uterus can be prevented by prevention of abruptio placentae. This includes proper management of hypertensive states of pregnancy; treatment of maternal diseases like diabetes mellitus, and other collagen disease complicating pregnancy; prevention of trauma during pregnancy; mothers should also avoid smoking or consumption of alcohol during pregnancy.
## Treatment[edit]
The uterus should be evacuated and contractions should be stimulated using intravenous oxytocin; hysterectomy (the removal of the uterus) may be needed in some cases.
## Prognosis[edit]
The foetus may be compromised if there is prolonged delivery because of the non-contractile uterus; severe bleeding may cause hypovolemic shock in the mother.
## References[edit]
1. ^ Hubbard JL, Hosmer SB (September 1997). "Couvelaire uterus". J Am Osteopath Assoc. 97 (9): 536–7. PMID 9313351.
## External links[edit]
Classification
D
* ICD-10: O45.8
* ICD-9-CM: 641.2
* v
* t
* e
Pathology of pregnancy, childbirth and the puerperium
Pregnancy
Pregnancy with
abortive outcome
* Abortion
* Ectopic pregnancy
* Abdominal
* Cervical
* Interstitial
* Ovarian
* Heterotopic
* Embryo loss
* Fetal resorption
* Molar pregnancy
* Miscarriage
* Stillbirth
Oedema, proteinuria and
hypertensive disorders
* Gestational hypertension
* Pre-eclampsia
* HELLP syndrome
* Eclampsia
Other, predominantly
related to pregnancy
Digestive system
* Acute fatty liver of pregnancy
* Gestational diabetes
* Hepatitis E
* Hyperemesis gravidarum
* Intrahepatic cholestasis of pregnancy
Integumentary system /
dermatoses of pregnancy
* Gestational pemphigoid
* Impetigo herpetiformis
* Intrahepatic cholestasis of pregnancy
* Linea nigra
* Prurigo gestationis
* Pruritic folliculitis of pregnancy
* Pruritic urticarial papules and plaques of pregnancy (PUPPP)
* Striae gravidarum
Nervous system
* Chorea gravidarum
Blood
* Gestational thrombocytopenia
* Pregnancy-induced hypercoagulability
Maternal care related to the
fetus and amniotic cavity
* amniotic fluid
* Oligohydramnios
* Polyhydramnios
* Braxton Hicks contractions
* chorion / amnion
* Amniotic band syndrome
* Chorioamnionitis
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* Antepartum
* placenta
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* Twin-to-twin transfusion syndrome
Labor
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* Dystocia
* Shoulder dystocia
* Fetal distress
* Locked twins
* Nuchal cord
* Obstetrical bleeding
* Postpartum
* Pain management during childbirth
* placenta
* Placenta accreta
* Preterm birth
* Postmature birth
* Umbilical cord prolapse
* Uterine inversion
* Uterine rupture
* Vasa praevia
Puerperal
* Breastfeeding difficulties
* Low milk supply
* Cracked nipples
* Breast engorgement
* Childbirth-related posttraumatic stress disorder
* Diastasis symphysis pubis
* Postpartum bleeding
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* Puerperal fever
* Puerperal mastitis
Other
* Concomitant conditions
* Diabetes mellitus
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* Thyroid disorders
* Maternal death
* Sexual activity during pregnancy
* Category
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Couvelaire uterus | c0221379 | 6,869 | wikipedia | https://en.wikipedia.org/wiki/Couvelaire_uterus | 2021-01-18T18:52:52 | {"umls": ["C0221379"], "icd-9": ["641.2"], "icd-10": ["O45.8"], "wikidata": ["Q5178867"]} |
Glycoproteinosis
SpecialtyEndocrinology
Glycoproteinosis are lysosomal storage diseases[1] affecting glycoproteins, resulting from defects in lysosomal function. The term is sometimes reserved for conditions involving degradation of glycoproteins.[2]
## Types[edit]
* (E77.0) Defects in post-translational modification of lysosomal enzymes
* Mucolipidosis II (I-cell disease)
* Mucolipidosis III (pseudo-Hurler polydystrophy)
* (E77.1) Defects in glycoprotein degradation
* Aspartylglucosaminuria
* Fucosidosis
* Mannosidosis
* Sialidosis (mucolipidosis I)
Another type, recently characterized, is galactosialidosis.[3]
## References[edit]
1. ^ Charles H. Rodeck; Martin J. Whittle (27 October 2008). Fetal medicine: basic science and clinical practice. Elsevier Health Sciences. pp. 362–. ISBN 978-0-443-10408-4. Retrieved 3 November 2010.
2. ^ Robert V. Stick; Spencer J. Williams (2 December 2008). Carbohydrates: the essential molecules of life. Elsevier. pp. 402–. ISBN 978-0-240-52118-3. Retrieved 3 November 2010.
3. ^ Bonten EJ, Wang D, Toy JN, et al. (June 2004). "Targeting macrophages with baculovirus-produced lysosomal enzymes: implications for enzyme replacement therapy of the glycoprotein storage disorder galactosialidosis". FASEB J. 18 (9): 971–3. doi:10.1096/fj.03-0941fje. PMID 15084520.
## External links[edit]
Classification
D
* ICD-10: E77
* ICD-9-CM: 271, 272.7
* NIH
* v
* t
* e
Lysosomal storage diseases: Inborn errors of carbohydrate metabolism (Glycoproteinoses)
Anabolism
* Dolichol kinase deficiency
* Congenital disorder of glycosylation
Post-translational modification
of lysosomal enzymes
* Mucolipidosis: I-cell disease (ML II)
* Pseudo-Hurler polydystrophy (ML III)
Catabolism
* Aspartylglucosaminuria
* Fucosidosis
* mannosidosis
* Alpha-mannosidosis
* Beta-mannosidosis
* Sialidosis
* Schindler disease
Other
* solute carrier family (Salla disease)
* Galactosialidosis
This article about an endocrine, nutritional, or metabolic disease is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Glycoproteinosis | c0026697 | 6,870 | wikipedia | https://en.wikipedia.org/wiki/Glycoproteinosis | 2021-01-18T18:35:25 | {"gard": ["10670"], "mesh": ["D009081"], "umls": ["C0026697"], "icd-9": ["271", "272.7"], "icd-10": ["E77.1"], "orphanet": ["309279"], "wikidata": ["Q2019832"]} |
## Summary
### Clinical characteristics.
SYNGAP1-related intellectual disability (SYNGAP1-ID) is characterized by developmental delay (DD) or intellectual disability (ID) (100% of affected individuals), generalized epilepsy (~84%), and autism spectrum disorder (ASD) and other behavioral abnormalities (≤50%). To date more than 50 individuals with SYNGAP1-ID have been reported. In the majority DD/ID was moderate to severe; in some it was mild. The epilepsy is generalized; a subset of individuals with epilepsy have myoclonic astatic epilepsy (Doose syndrome) or epilepsy with myoclonic absences. Behavioral abnormalities can include stereotypic behaviors (e.g., hand flapping, obsessions with certain objects) as well as poor social development. Feeding difficulties can be significant in some.
### Diagnosis/testing.
The diagnosis of SYNGAP1-ID is established in a proband with developmental delay or intellectual disability in whom molecular genetic testing identifies either a heterozygous pathogenic variant in SYNGAP1 (~89%) or a deletion of 6p21.3 (~11%).
### Management.
Treatment of manifestations: DD/ID are managed as per standard practice. No guidelines are available regarding choice of specific antiepileptic drugs (AEDs). In about 50% of patients, the epilepsy responds to a single antiepileptic drug (AED); in the remainder it is pharmacoresistant. Children may qualify for and benefit from interventions used in treatment of ASD. Consultation with a developmental pediatrician may guide parents through appropriate behavioral management strategies and/or provide prescription medications when necessary. Nasogastric/gastrostomy feeding may be required for individuals with persistent feeding issues.
Surveillance: Monitor seizure manifestations and control; behavioral issues; developmental progress and educational needs.
### Genetic counseling.
SYNGAP1-ID is inherited in an autosomal dominant manner. To date almost all probands with SYNGAP1-ID whose parents have undergone molecular genetic testing have had a de novo germline pathogenic variant; however, vertical transmission (from a mildly affected, mosaic parent to the proband) has been reported in one family. Thus, while the risk to sibs appears to be low, it is presumed to be greater than in the general population because of the possibility of germline mosaicism in a parent. Once the SYNGAP1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
## Diagnosis
No formal diagnostic criteria have been published for SYNGAP1-related intellectual disability.
### Suggestive Findings
SYNGAP1-related intellectual disability (SYNGAP1-ID) should be considered in individuals with developmental delay or intellectual disability with or without:
* Generalized epilepsy;
and/or
* Autism spectrum disorder (ASD).
### Establishing the Diagnosis
The diagnosis of SYNGAP1-ID is established in a proband with developmental delay (DD) or intellectual disability (ID) in whom molecular genetic testing (see Table 1) identifies either:
* A heterozygous pathogenic variant in SYNGAP1 (~89%);
or
* A deletion of 6p21.3 (~11%).
Molecular genetic testing in a child with DD or an older individual with ID typically begins with chromosomal microarray analysis (CMA). If CMA is not diagnostic, the next step is typically either a multigene panel or exome sequencing. Note: Single-gene testing (sequence analysis of SYNGAP1, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.
CMA uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including SYNGAP1) that cannot be detected by sequence analysis. Note: The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 6p21.32 region.
An ID multigene panel that includes SYNGAP1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder, an ID multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Exome sequencing, which does not require the clinician to determine which gene is likely involved, has the advantage over an ID multigene panel of detecting variants in recently identified rare genes not yet included in some ID multigene panels.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
### Table 1.
Molecular Genetic Testing Used in SYNGAP1-Related Intellectual Disability
View in own window
Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method 3
SYNGAP1Sequence analysis 449/55 (89%)
Gene-targeted deletion/duplication analysis 5Unknown, see footnote 6
Chromosomal microarray analysis 76/55 (11%)
1\.
See Table A. Genes and Databases for chromosome locus and protein.
2\.
Based on a review of published series and case reports
3\.
Krepischi et al [2010], Pinto et al [2010], Vissers et al [2010], Hamdan et al [2011a], Hamdan et al [2011b], Klitten et al [2011], Zollino et al [2011], de Ligt et al [2012], Rauch et al [2012], Berryer et al [2013], Carvill et al [2013], Writzl & Knegt [2013], Redin et al [2014], Parker et al [2015], Mignot et al [2016], Prchalova et al [2017]
4\.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
5\.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
6\.
Gene-targeted methods will detect deletions of a single exon up to a whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined. If a whole-gene deletion is detected by a gene-targeted deletion/duplication assay, CMA is needed to determine the size of the deletion.
7\.
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 6p21.3 region; however, some 6p21.3 deletions may not have been detectable by older oligonucleotide or BAC platforms.
## Clinical Characteristics
### Clinical Description
Since the original description of SYNGAP1-related intellectual disability (SYNGAP1-ID) in three individuals [Hamdan et al 2009], more than 50 affected individuals with detailed clinical information have been reported [Krepischi et al 2010, Pinto et al 2010, Vissers et al 2010, Hamdan et al 2011a, Hamdan et al 2011b, Klitten et al 2011, Zollino et al 2011, de Ligt et al 2012, Rauch et al 2012, Berryer et al 2013, Carvill et al 2013, Writzl & Knegt 2013, Redin et al 2014, Parker et al 2015, Mignot et al 2016, Prchalova et al 2017]. The following description of the phenotypic features associated with this condition is based on these reports.
Developmental delay and intellectual disability. The great majority of affected children present with developmental delay or intellectual disability that is typically moderate to severe but can be mild.
Early motor development is characterized by hypotonia. The average age at walking was 26 months (range: 10.5 months to 5 years). A subset of these children had an ataxic gait that remained stable or improved over time.
Language is generally impaired; a third of individuals age five years or more remain nonverbal. In those who are verbal, language development ranges from use of single words only to four-to-five-word sentences.
Epilepsy. Approximately 84% of individuals with SYNGAP1-ID have generalized epilepsy; a subset of these were diagnosed with myoclonic astatic epilepsy (Doose syndrome) or epilepsy with myoclonic absences [Mignot et al 2016].
While the epilepsy responds to a single antiepileptic drug in approximately half of affected individuals, it is pharmacoresistant in the remainder. Children with refractory seizures may be diagnosed with epileptic encephalopathy (i.e., refractory seizures and cognitive slowing or regression associated with frequent ongoing epileptiform activity).
* Age at onset of seizures varies between six months and seven years; mean age of seizure onset was 3.5 years in one study [Mignot et al 2016].
* Seizure types include typical or atypical seizures, myoclonic jerks with or without falls, eyelid myoclonia, tonic-clonic seizures, myoclonic absences, and atonic seizures. In one study, Doose syndrome (myoclonic astatic epilepsy) was diagnosed in three of 17 individuals [Mignot et al 2016].
* Electroencephalography typically shows generalized epileptic activity, frequently with a posterior predominance. Photosensitivity and fixation-off phenomenon have been observed in a number of individuals.
* Brain MRI is typically normal; in rare cases, brain atrophy or delayed myelination has been reported.
Autism spectrum disorder (ASD) and other behavioral abnormalities. The occurrence of ASD could be as high as 50%. This includes stereotypic behaviors such as hand flapping, obsessions with certain objects, and poor social development. In addition, inattention, impulsivity, self-directed and other-directed aggressive behavior, elevated pain threshold, hyperacusis, and sleep disorders have been observed.
Other associated features include the following:
* Acquired microcephaly observed in a minority of affected individuals
* Eye abnormalities including strabismus
* Musculoskeletal disorders including hip rotation or dysplasia, kyphoscoliosis, and pes planus
* Hypertrichosis (predominantly on the limbs and lower spine) occasionally described
* Gastrointestinal dysfunction (including constipation requiring medical intervention) frequently reported; swallowing difficulties rarely reported
* Craniofacial features. Although some authors have suggested a subtle but consistent facial appearance (almond-shaped palpebral fissures, mildly myopathic and open-mouthed appearance) [Parker et al 2015], it is unclear if these changes are distinct enough to allow a clinician to suspect the condition in a child.
Life span. It is unknown if life span in SYNGAP1-ID is abnormal. One reported individual is alive at age 31 years [Prchalova et al 2017], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.
### Genotype-Phenotype Correlations
No definitive phenotype-genotype correlation between the type of SYNGAP1 pathogenic variant (missense, truncating, large intragenic deletion) and cognitive abilities or the occurrence of comorbidities has been observed.
### Penetrance
Penetrance is 100%. All individuals with germline pathogenic variants in SYNGAP1 have developmental delay, cognitive dysfunction, intellectual disability, and/or epilepsy.
### Prevalence
The prevalence of SYNGAP1 pathogenic variants in two studies was:
* 1% in a series of 500 individuals with epileptic encephalopathy [Carvill et al 2013];
* 0.75% in a large series of 931 unrelated children with intellectual disability [Fitzgerald et al 2015].
## Differential Diagnosis
The phenotype associated with SYNGAP1-related intellectual disability (ID) overlaps with that of other disorders of ID and epileptic encephalopathy.
Most genes known to be associated with ID (>50 have been identified; see OMIM Phenotypic Series: Intellectual Disability, Autosomal Dominant) and epileptic encephalopathy (>55 have been identified; see OMIM Phenotypic Series: Epileptic Encephalopathy, Early Infantile) if compatible with walking should be included in the differential diagnosis.
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SYNGAP1-related intellectual disability, the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to diagnosis) are recommended.
### Table 2.
Recommended Evaluations Following Initial Diagnosis in Individuals with SYNGAP1-Related Intellectual Disability
View in own window
System/ConcernEvaluationComment
EyesOphthalmologic evalEvidence of strabismus
Gastrointestinal/
FeedingBaseline eval for reflux &/or constipation; assessment for feeding problemsRefer to gastroenterologist &/or feeding therapist for treatment if indicated.
MusculoskeletalAssessment for hip rotation/dysplasia, kyphoscoliosis, pes planus
NeurologicNeurologic evalIncl EEG & brain MRI if seizures are suspected
Psychiatric/
BehavioralNeuropsychiatric evalScreen persons age >12 mos for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD.
Miscellaneous/
OtherDevelopmental assessmentIncl motor, speech/language eval, general cognitive, & vocational skills.
Consultation w/clinical geneticist &/or genetic counselor
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
### Treatment of Manifestations
### Table 3.
Treatment of Manifestations in Individuals with SYNGAP1-Related Intellectual Disability
View in own window
Manifestation/ConcernTreatmentConsiderations/Other
StrabismusStandard treatment(s) as recommended by ophthalmologist
Swallowing dysfunctionNasogastric/gastrostomy feeding may be required for persistent feeding issues.
ConstipationStandard treatment as recommended by gastroenterologistGastroenterology consultation, if severe
Hip rotation/dysplasia, kyphoscoliosis, & pes planusStandard treatment as recommended by orthopedistOrthopedic consultation may be considered.
EpilepsyStandardized treatment w/AEDs by experienced neurologist
* To date, no guidelines on choice of specific AEDs
* Anecdotal reports of improved seizure control w/ketogenic diet in some persons
AEDs = antiepileptic drugs
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.
#### Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.
Ages 5-21 years
* In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
* Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
* Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
* Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
#### Motor Dysfunction
Gross motor dysfunction
* Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
* Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.
Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy – typically from an occupational or speech therapist – is recommended for affected individuals who have difficulty feeding due to poor oral motor control.
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.
#### Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
### Surveillance
Monitor those with seizures as clinically indicated.
Assess as needed for anxiety, attention, and aggressive or self-injurious behavior.
Monitor developmental progress and educational needs.
### Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| SYNGAP1-Related Intellectual Disability | None | 6,871 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK537721/ | 2021-01-18T20:57:29 | {"synonyms": ["SYNGAP1-Related Developmental and Epileptic Encephalopathy"]} |
Methylmalonic acidemia with homocystinuria is an inherited disorder in which the body is unable to properly process certain nutrients from food including amino acids, lipids and cholesterol. People with this disorder have a combination of features from two separate conditions: methylmalonic acidemia and homocystinuria. When the condition begins early in life, babies have difficulty gaining weight (failure to thrive), feeding difficulties, and a pale appearance. Babies may also have weak muscle tone (hypotonia) and seizures. Most babies and children with this condition have an unusually small head size (microcephaly), intellectual disability and developmental delay. Less common features of the condition include eye problems and a blood disorder called megaloblastic anemia. When the disorder begins in adolescence or adulthood, the signs and symptoms usually include behavior and personality changes and cognitive problems (issues with learning, memory, perception etc). In some cases, abilities are lost, resulting in a decline of performance, memory and speech problems, dementia and lethargy.[12470
Methylmalonic acidemia with homocystinuria can be caused by mutations in one of several genes: MMACHC, MMADHC, LMBRD1, ABCD4, or HCFC1. Mutations in these genes account for the different types of the disorder, cblC, cblD, cblF, cblJ, and cblX, respectively. Although there is no cure for this conditions, treatment may include intramuscular injections of hydroxycobalamin, oral betaine, and folic acid.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Methylmalonic acidemia with homocystinuria | c1848561 | 6,872 | gard | https://rarediseases.info.nih.gov/diseases/3579/methylmalonic-acidemia-with-homocystinuria | 2021-01-18T17:59:07 | {"mesh": ["C537359"], "umls": ["C1848561"], "orphanet": ["26"], "synonyms": ["Methylmalonic acidemia and homocystinemia"]} |
Dacryocystitis - osteopoikilosis is an exceedingly rare autosomal dominant disorder reported in only a few patients to date and is characterized by dacryocystitis due to lacrimal canal stenosis,and osteopoikilosis (demonastratedradiologically as discrete spherical osteosclerotic lesions of 2-10mm in diameter).
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Dacryocystitis-osteopoikilosis syndrome | c1833698 | 6,873 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1562 | 2021-01-23T19:03:41 | {"gard": ["351"], "mesh": ["C536061"], "omim": ["166705"], "umls": ["C1833698"], "synonyms": ["Gunal-Seber-Basaran syndrome"]} |
A number sign (#) is used with this entry because hypogonadotropic hypogonadism-20 with or without anosmia (HH20) can be caused by heterozygous mutation in the FGF17 gene (603725) on chromosome 8p21, sometimes in association with mutations in other genes, e.g., FGFR1 (136350), HS6ST1 (604846), and FLRT3 (604808).
Description
Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).'
For a discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia as well as a discussion of oligogenicity of this disorder, see 147950.
Molecular Genetics
In a cohort of 386 unrelated individuals with congenital hypogonadotropic hypogonadism (CHH), 199 of whom were anosmic and 187 normosmic, many of whom were known to harbor mutations in previously identified HH-associated genes, Miraoui et al. (2013) analyzed 7 genes involved in the FGF8 (600483)-FGFR1 (136350) network and identified 3 HH probands with heterozygous missense mutations in the FGF17 gene (603725.0001-603725.0003). One of the 3 probands belonged to a large consanguineous 10-generation French Canadian family with anosmic HH and cleft palate, previously reported by White et al. (1983) and in which Tornberg et al. (2011) had identified mutations in both the FGFR1 (136350.0025) and HS6ST1 (604846.0002) genes. In that proband, Miraoui et al. (2013) also identified heterozygosity and homozygosity for 2 missense mutations in another FGF-network gene, FLRT3 (604808.0001 and 604808.0002, respectively; see HH21, 615271). Of the 3 probands with FGF17 mutations, 2 were anosmic and 1 was normosmic; additional features included low bone mass in 2 of the patients. Miraoui et al. (2013) concluded that mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.
INHERITANCE \- Autosomal dominant (see MISCELLANEOUS below) HEAD & NECK Nose \- Hyposmia/anosmia (in some patients) Mouth \- Cleft lip and/or palate (in some patients) GENITOURINARY \- Delayed or absent puberty SKELETAL \- Osteopenia (in some patients) \- Osteoporosis (in some patients) \- Fractures (in some patients) NEUROLOGIC Central Nervous System \- Hyposmia/anosmia (in some patients) ENDOCRINE FEATURES \- Delayed or absent puberty MISCELLANEOUS \- Phenotypic variability within families and among patients carrying the same mutation appears to be due to the oligogenic nature of the disorder, with some patients having mutations in more than 1 neuroendocrine-related gene MOLECULAR BASIS \- Caused by mutation in the fibroblast growth factor 17 gene (FGF17, 603725.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| HYPOGONADOTROPIC HYPOGONADISM 20 WITH OR WITHOUT ANOSMIA | c0162809 | 6,874 | omim | https://www.omim.org/entry/615270 | 2019-09-22T15:52:43 | {"doid": ["0090082"], "mesh": ["D017436"], "omim": ["615270"], "orphanet": ["432", "478"], "synonyms": ["Gonadotropic deficiency", "Isolated congenital gonadotropin deficiency", "Normosmic idiopathic hypogonadotropic hypogonadism", "nIHH"], "genereviews": ["NBK1334"]} |
In a brother and sister from one family and a girl from a second, unrelated family, Partington and Anderson (1994) described a seemingly new syndrome comprising pre- and postnatal growth deficiency, developmental delay, a friendly personality, microcephaly, and a distinctive facial appearance marked by thick eyebrows, full cheeks, and a short nose with the columella inserted below the nasal alae. They suggested that the disorder is inherited as an autosomal recessive. The parents were not consanguineous in either family. Thick curly hair of the head in infancy may be a feature.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| PARTINGTON-ANDERSON SYNDROME | c1850075 | 6,875 | omim | https://www.omim.org/entry/260555 | 2019-09-22T16:23:37 | {"mesh": ["C536299"], "omim": ["260555"], "orphanet": ["2829"]} |
## Description
Celiac disease, also known as celiac sprue and gluten-sensitive enteropathy, is a multifactorial disorder of the small intestine that is influenced by both environmental and genetic factors. It is characterized by malabsorption resulting from inflammatory injury to the mucosa of the small intestine after the ingestion of wheat gluten or related rye and barley proteins (summary by Farrell and Kelly, 2002).
For additional information and a discussion of genetic heterogeneity of celiac disease, see 212750.
Mapping
The form of susceptibility to celiac disease here designated CELIAC12 is influenced by genetic variation in the 6q25.3 region, within a linkage disequilibrium (LD) block encompassing the TAGAP (609667) gene.
To identify risk variants contributing to celiac disease susceptibility other than those in the HLA-DQ region (see CELIAC1, 212750) Hunt et al. (2008) genotyped 1,020 of the most strongly associated non-HLA markers identified by van Heel et al. (2007) in an additional 1,643 cases of celiac disease and 3,406 controls. They identified single-nucleotide polymorphism (SNP) rs1738074 (P overall = 6.71 x 10(-8)) on chromosome 6q25.3 within a 200-kb LD block containing the TAGAP (609667) gene, itself within a larger region of weaker LD containing the RSPH3 gene (615876). TAGAP is expressed in activated T cells, has 3 isoforms, and is a Rho GTPase-activating protein important for modulating cytoskeletal changes.
Smyth et al. (2008) evaluated the association between type 1 diabetes (222100) and 8 loci related to the risk of celiac disease in 8,064 patients with type 1 diabetes, 2,828 families providing 3,064 parent-child trios, and 9,339 controls. The authors found significant association between IDDM21 (612521) and rs1738074 in the TAGAP gene, which is associated with CELIAC12.
In an Italian cohort involving 538 patients with celiac disease and 593 healthy controls, Romanos et al. (2009) confirmed moderate association at rs1738074 (p = 0.0495).
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| CELIAC DISEASE, SUSCEPTIBILITY TO, 12 | c2677602 | 6,876 | omim | https://www.omim.org/entry/612010 | 2019-09-22T16:02:33 | {"omim": ["612010"], "synonyms": ["Alternative titles", "GLUTEN-SENSITIVE ENTEROPATHY, SUSCEPTIBILITY TO, 12"]} |
## Clinical Features
Majewski et al. (1982) reported a male infant with a 'new' form of microcephalic primordial dwarfism, then called osteodysplastic bird-headed dwarfism. Features were intrauterine growth retardation (as in the other forms), alopecia, microcephaly, receding forehead and chin, large eyes, and large prominent nose. Radiologic examinations showed platyspondyly, 'dysplasia' of the pelvis, elongated clavicles, and enlarged proximal femora. The 'cause' was not clear.
Majewski (1992) gave a full account of a brother and sister and concluded that the facial appearance in this disorder is quite different from that of Seckel syndrome and very similar to that presented in a portrait reproduced as Figure 7 in Bondeson (1992). The profile was particularly distinctive. Bondeson (1993) provided additional information based on a study of the original autopsy report of Caroline Crachami, a patient with MOPD III (see HISTORY). He commented that although bird-headed dwarfism is 'an imprecise as well as an uncouth denomination,' it is the generally applied descriptive term.
Haan et al. (1989) and Meinecke et al. (1991) raised the possibility that MOPD types I (210710) and III represent the same entity.
History
Bondeson (1992) gave a historical account of Caroline Crachami (1815-1824), the Sicilian Fairy, whose mounted skeleton is preserved in the Hunterian Museum of the Royal College of Surgeons in London. Her skeleton is exhibited next to that of Charles Byrne, 'The Irish Giant' (see 102200).
INHERITANCE \- Autosomal recessive GROWTH Height \- Proportionate dwarfism Other \- Intrauterine growth retardation HEAD & NECK Head \- Microcephaly \- Delayed closure of fontanelles Face \- Steep, narrow forehead \- Micrognathia Eyes \- Prominent eyes \- Strabismus \- Photophobia \- Hyperopia \- Choroid coloboma \- Optic atrophy \- Glaucoma Nose \- Small, pointed nose Mouth \- High palate \- Thin vermilion border of upper lip Teeth \- Oligodontia CHEST Ribs Sternum Clavicles & Scapulae \- Pectus carinatum GENITOURINARY External Genitalia (Male) \- Hypospadias Bladder \- Bladder exstrophy SKELETAL \- Severe osteoporosis \- Dysharmonic delayed bone age Skull \- Hypoplastic mandible \- Enlarged, flat sella turcica Spine \- Kyphoscoliosis Pelvis \- Dislocated femoral heads \- Hip contractures \- Hypoplastic pubic bones \- Hypoplastic ischial bones \- Small proximal femoral epiphyses Limbs \- Slender, gracile long tubular bones \- Knee contractures \- Thin diaphyses of long bones Hands \- Ulnar deviation of fingers \- Fifth finger clinodactyly \- Cone-shaped phalangeal epiphyses Feet \- Talipes MUSCLE, SOFT TISSUES \- Minimal subcutaneous fat NEUROLOGIC Central Nervous System \- Cerebellar atrophy \- Hypotonia \- Mental retardation VOICE \- High-pitched voice ▲ Close
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*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
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*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
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*[FDA]: Food and Drug Administration
| MICROCEPHALIC OSTEODYSPLASTIC PRIMORDIAL DWARFISM, TYPE III | c1859439 | 6,877 | omim | https://www.omim.org/entry/210730 | 2019-09-22T16:30:23 | {"mesh": ["C537320"], "omim": ["210730"], "orphanet": ["2636"], "synonyms": ["Alternative titles", "MOPD, SICILIAN FAIRY TYPE", "MOPD III", "MICROCEPHALIC OSTEODYSPLASTIC PRIMORDIAL DWARFISM, CAROLINE CRACHAMI TYPE", "MOPD types I and III", "Taybi-Linder syndrome", "Primordial microcephalic dwarfism, Crachami type", "MOPD, CAROLINE CRACHAMI TYPE", "MICROCEPHALIC OSTEODYSPLASTIC PRIMORDIAL DWARFISM, SICILIAN FAIRY TYPE", "OSTEODYSPLASTIC PRIMORDIAL DWARFISM, TYPE III", "Microcephalic osteodysplastic primordial dwarfism, Taybi-Linder type"]} |
Nerve damaging injury
Neurotmesis (in Greek tmesis signifies "to cut") is part of Seddon's classification scheme used to classify nerve damage. It is the most serious nerve injury in the scheme. In this type of injury, both the nerve and the nerve sheath are disrupted. While partial recovery may occur, complete recovery is impossible.
## Contents
* 1 Symptoms
* 2 Anatomy
* 3 Mechanisms
* 4 Diagnosis
* 4.1 Classification
* 5 Treatment
* 6 Prognosis
* 7 See also
* 8 References
## Symptoms[edit]
Symptoms of neurotmesis include but are not limited to pain, dysesthesias (uncomfortable sensations), and complete loss of sensory and motor function of the affected nerve.[1]
## Anatomy[edit]
Neurotmesis occurs in the peripheral nervous system and most often in the upper-limb (arms), accounting for 73.5% of all peripheral nerve injury cases.[2] Of these cases, the ulnar nerve was most often injured. Peripheral nerves are structured so that the axons are surrounded by most often a myelinated sheath and then an endoneurium. A perineurium surrounds that and the outermost layer is considered the epineurium.[2] When injury occurs, “local vascular trauma leads to hemorrhage and edema (swelling), which results in vigorous inflammatory response resulting in scarring of the injured segment.[3] In most cases, due to the extreme nature of the injury, there is typically complete loss of function.
## Mechanisms[edit]
Trauma is the most frequent cause of peripheral nerve lesions.[1] There are two classifications of trauma which include civilian trauma and military trauma.[2] Civilian trauma is most commonly caused by motor vehicle accidents but also by lacerations caused by glass, knives, fans, saw blades or fractures and occasionally sports injuries.[2] Of the civilian injuries, stretch injuries are the most common types and are considered to be a closed injury, where the tissue is unexposed.[3] Stretch injures are commonly the result of dislocation, such as a shoulder dislocation that stretches nerves. Opposite of civilian trauma, there is military trauma which most commonly results in open injuries from blasts often by bombs or improvised explosive devices.[2] Other mechanisms of injury are less common but include ischemia, thermal, electric shock, radiation, adverse reactions to certain chemotherapy medications, percussion and vibration.[2]
## Diagnosis[edit]
With Seddon's classification of nerve injuries, it is often tough to identify whether a particular nerve injury is neurotmesis, or axonotmesis, which has damage to the nerve fibres but preservation of the nerve trunk. Due to the damage involved in both of these conditions they will both show paralysis of muscles that are supplied by nerves below the site of the lesion, and will have sensory deficits in accordance with the individual nerves that are damaged.[4] The only way to know for sure if a nerve injury is in fact neurotmesis is to allow for the normal progression of nerve regeneration to take place (nerves regenerate at a rate of approximately 2–4 mm/day proximal to the lesion), and if, after that time, there is still profound muscle paralysis and degeneration in these areas, then it is likely to have been a neurotmesis injury.[4]
Neurotmesis is diagnosed through clinical evaluation of symptoms, physical evaluation, and other diagnostic studies. Patients often undergo a series of muscle strength tests, sensory exam which includes feeling the sensation of light touch, pinprick, vibration, and others.[1] Other tests involved with diagnosis of nerve injury are electromyography (EMG) and nerve conduction studies (NCS). These help to distinguish upper from lower motor neuron disorder as well as diagnose primary muscle disease.[1]
### Classification[edit]
Main article: Peripheral nerve injury classification
Peripheral nerve injuries can be classified in two different ways. Neurotmesis is classified under the Seddon system which is defined by three grades of nerve injury. The mildest grade is referred to as neurapraxia and is characterized by a reduction or complete blockage of conduction across a segment of nerve while axonal continuity is maintained and nerve conduction is preserved.[1] These injuries are almost always reversed and a recovery takes place within days or weeks. The second classification of the Seddon system is referred to as axonotmesis which is a more severe case of peripheral nerve injury. Axonotmesis is classified by an interruption of the axons, but a preservation of the surrounding connective tissues around the axon.[1] These injuries can heal themselves at about 1mm/day, therefore resulting in recovery to be possible but at a slower rate than neurapraxia.[5] The last and most severe case of peripheral nerve injury is known as neurotmesis, which in most cases cannot be completely recovered from even with surgical repair.
The second classification of nerve injury is known as the Sunderland classification which is more complex and specific. This classification uses five different degrees of nerve injury, the first one being the least severe and the equivalent to neurapraxia and the most severe being the fifth degree and having the same classification as neurotmesis. The second through fourth degrees are dependent on the variance of axon discontinuity and are classified under Seddon’s classification of axonotmesis.[2]
## Treatment[edit]
The first line of treatment is often to treat the patient's pain with neuropathic drugs such as tricyclic antidepressants, serotonin reuptake inhibitors, and anticonvulsants. The second lines of drugs to treat pain are non-steroidal anti-inflammatories, tramadol, and opioids. Other techniques used to facilitate healing of the nerve and pain are either static or dynamic splinting that can both help protect the injured part as well as improve function.[2] Sometimes surgery is an option, although the prognosis is still very poor of regaining function of the affected nerve.[2] The goal of surgery is to join healthy nerve to unhealthy nerve. The most common surgical techniques include external neurolysis, end-to-end repair, nerve grafting, and nerve transfer from somewhere else in the body.[2]
## Prognosis[edit]
People who suffer from neurotmesis often face a poor prognosis. They will more than likely never regain full functionality of the affected nerve, but surgical techniques do give people a better chance at regaining some function. Current research is focused on new ways to regenerate nerves and advance surgical techniques.[3]
## See also[edit]
* Nerve injury
* Neuroregeneration
* Wallerian degeneration
## References[edit]
1. ^ a b c d e f Sasser, Karen L. "Medical Student Curriculum in Neurosurgery." Medical Student Curriculum in Neurosurgery. Congress of Neurological Surgeons, n.d. Web. 11 Nov. 2013.
2. ^ a b c d e f g h i j Campbell, W. W. (2008). "Evaluation and management of peripheral nerve injury". Clinical Neurophysiology. 119 (9): 1951–1965. doi:10.1016/j.clinph.2008.03.018. PMID 18482862.
3. ^ a b c Burnett, M. G.; Zager, E. L. (2004). "Pathophysiology of peripheral nerve injury: A brief review". Neurosurgical Focus. 16 (5): E1. doi:10.3171/foc.2004.16.5.2. PMID 15174821.
4. ^ a b Moran, S. L.; Steinmann, S. P.; Shin, A. Y. (2005). "Adult brachial plexus injuries: Mechanism, patterns of injury, and physical diagnosis". Hand Clinics. 21 (1): 13–24. doi:10.1016/j.hcl.2004.09.004. PMID 15668062.
5. ^ Greg. "Nerve Injury (Neuropraxia, Axonotmesis, Neurotmesis) and Healing." Current Health Articles. Health Hype, 4 Dec. 2004. Web. 11 Nov. 2013.
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*[c.]: circa
*[AA]: Adrenergic agonist
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*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
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*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
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*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Neurotmesis | c1142379 | 6,878 | wikipedia | https://en.wikipedia.org/wiki/Neurotmesis | 2021-01-18T18:51:26 | {"mesh": ["D020196"], "umls": ["C1142379"], "wikidata": ["Q1786745"]} |
This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed.
Find sources: "Gingival and periodontal pocket" – news · newspapers · books · scholar · JSTOR (May 2016) (Learn how and when to remove this template message)
Gingival and periodontal pockets are extensions of the gingival sulcus (G). Other letters: A, crown of the tooth, covered by enamel. B, root of the tooth, covered by cementum. C, alveolar bone. D, subepithelial connective tissue. E, oral epithelium. H, principal gingival fibers. I, alveolar crest fibers of the PDL. J, horizontal fibers of the PDL. K, oblique fibers of the PDL.
Gingival and periodontal pockets (also informally referred to as gum pockets[1]) are dental terms indicating the presence of an abnormal depth of the gingival sulcus near the point at which the gingival tissue contacts the tooth.
## Contents
* 1 Tooth gingival interface
* 2 Gingival pocket
* 3 Periodontal pocket
* 4 Mucogingival defect
* 5 Pocket formation
* 6 External links
* 7 References
## Tooth gingival interface[edit]
The interface between a tooth and the surrounding gingival tissue is a dynamic structure.[2] The gingival tissue forms a crevice surrounding the tooth, similar to a miniature, fluid-filled moat, wherein food debris, endogenous and exogenous cells, and chemicals float. The depth of this crevice, known as a sulcus, is in a constant state of flux due to microbial invasion and subsequent immune response. Located at the depth of the sulcus is the epithelial attachment, consisting of approximately 1 mm of junctional epithelium and another 1 mm of gingival fiber attachment, comprising the 2 mm of biologic width naturally found in the oral cavity. The sulcus is literally the area of separation between the surrounding epithelium and the surface of the encompassed tooth.
## Gingival pocket[edit]
A gingival pocket presents when the marginal gingiva experiences an edematous reaction, whether due to localized irritation and subsequent inflammation, systemic issues, or drug induced gingival hyperplasia. Regardless of the etiology, when gingival hyperplasia occurs, greater than normal (the measurement in a pre-pathological state) periodontal probing measurements can be read, creating the illusion that periodontal pockets have developed. This phenomenon is also referred to as a false pocket or pseudopocket. The epithelial attachment does not migrate, it simply remains at the same attachment level found in pre-pathological health. The only anatomical landmark experiencing migration is the gingival margin in a coronal direction.
In a gingival pocket, no destruction of the connective tissue fibers (gingival fibers) or alveolar bone occurs. This early sign of disease in the mouth is completely reversible when the etiology of the edematous reaction is eliminated and frequently occurs without dental surgical therapy. However, in certain situations, a gingivectomy is necessary to reduce the gingival pocket depths to a healthy 1–3 mm.
## Periodontal pocket[edit]
1: Total loss of attachment (clinical attachment loss, CAL) is the sum of 2: Gingival recession, and 3: Probing depth
As the original sulcular depth increases and the apical migration of the junctional epithelium has simultaneously occurred, the pocket is now lined by pocket epithelium (PE) instead of junctional epithelium (JE).[3] To have a true periodontal pocket, a probing measurement of 4 mm or more must be clinically evidenced. In this state, much of the gingival fibers that initially attached the gingival tissue to the tooth have been irreversibly destroyed. The depth of the periodontal pockets must be recorded in the patient record for proper monitoring of periodontal disease. Unlike in clinically healthy situations, parts of the sulcular epithelium can sometimes be seen in periodontally involved gingival tissue if air is blown into the periodontal pocket, exposing the newly denuded roots of the tooth. A periodontal pocket can become an infected space and may result in an abscess formation with a papule on the gingival surface. Incision and drainage of the abscess may be necessary, as well as systemic antibiotics; placement of local antimicrobial delivery systems within the periodontal pocket to reduce localized infections may also be considered. It is classified as supra bony and infra bony based on its depth in relation to alveolar bone.[4]
## Mucogingival defect[edit]
If the destruction continues unabated apically and reaches the junction of the attached gingiva and alveolar mucosa, the pocket would thus be in violation of the mucogingival junction and would be termed a mucogingival defect.[5]
## Pocket formation[edit]
For the periodontal pocket to form, several elements need to be present. It all starts with the dental plaque [tone]. The invasion of the bacteria from the plaque eventually triggers inflammatory response. This in turn results in the gradual destruction of the tissues surrounding the teeth, known as the periodontium. [6] Plaque that has been present long enough to harden and calcify will welcome additional bacteria to the pocket and make it virtually impossible to clean by means of a traditional toothbrush. [7] Continuous destruction of surrounding tissues due to inflammation will lead to degradation of attachment and bone, eventually causing tooth loss. Certain circumstances can worsen the condition and are known as risk factors. These can either be systemic (like diabetes or smoking) or local (like overhanging dental restorative materials causing food trap). [8] It is, therefore, important to manage plaque levels by appropriate oral hygiene measures. The importance of using interdental brushes along with standard or electric toothbrushing should be stressed on. Early detection of high plaque levels at routine dental visits are found to be beneficial to avoid progression of the pocket formation. [9]
## External links[edit]
* Scapoli, L; Girardi, A; Palmieri, A; Testori, T; Zuffetti, F; Monguzzi, R; Lauritano, D; Carinci, F (2012). "Microflora and periodontal disease". Dental Research Journal. 9 (Suppl 2): S202–6. doi:10.4103/1735-3327.109755 (inactive 2021-01-17). PMC 3692174. PMID 23814584.CS1 maint: DOI inactive as of January 2021 (link)
## References[edit]
1. ^ "What do your Gum Pocket Measurements really mean?" (Staff Blog). Lorne Park Dental Associates. 3 May 2017. Retrieved 4 December 2018.
2. ^ Fermin A. Carranza. CARRANZA'S CLINICAL PERIODONTOLOGY, 9th edition, 2002. page 101
3. ^ Antonio Nanci, Ten Cate's Oral Histology, Elsevier, 2007, page 383
4. ^ Illustrated Dental Embryology, Histology, and Anatomy, Bath-Balogh and Fehrenbach, Elsevier, 2011, page 129
5. ^ Carranza's Clinical Periodontology, Newman, et al, Elsevier, 2011
6. ^ Lamont, Thomas; Worthington, Helen V; Clarkson, Janet E; Beirne, Paul V (2018-12-27). Cochrane Oral Health Group (ed.). "Routine scale and polish for periodontal health in adults". Cochrane Database of Systematic Reviews. 12: CD004625. doi:10.1002/14651858.CD004625.pub5. PMC 6516960. PMID 30590875.
7. ^ Worthington, Helen V; MacDonald, Laura; Poklepovic Pericic, Tina; Sambunjak, Dario; Johnson, Trevor M; Imai, Pauline; Clarkson, Janet E (2019-04-10). Cochrane Oral Health Group (ed.). "Home use of interdental cleaning devices, in addition to toothbrushing, for preventing and controlling periodontal diseases and dental caries". Cochrane Database of Systematic Reviews. 4: CD012018. doi:10.1002/14651858.CD012018.pub2. PMC 6953268. PMID 30968949.
8. ^ Manresa, Carolina; Sanz-Miralles, Elena C.; Twigg, Joshua; Bravo, Manuel (1 January 2018). "Supportive periodontal therapy (SPT) for maintaining the dentition in adults treated for periodontitis". The Cochrane Database of Systematic Reviews. 1: CD009376. doi:10.1002/14651858.CD009376.pub2. ISSN 1469-493X. PMC 6491071. PMID 29291254.
9. ^ "CKS is only available in the UK". NICE. Retrieved 2020-02-19.
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Dentistry involving supporting structures of teeth (Periodontology)
Anatomy
* Periodontium
* Alveolar bone
* Biologic width
* Bundle bone
* Cementum
* Free gingival margin
* Gingiva
* Gingival fibers
* Gingival sulcus
* Junctional epithelium
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* Periodontal ligament
* Sulcular epithelium
* Stippling
Disease
Diagnoses
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* Localized aggressive periodontitis
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* Periodontosis
* Necrotizing periodontal diseases
* Abscesses of the periodontium
* Combined periodontic-endodontic lesions
Infection
* A. actinomycetemcomitans
* Capnocytophaga sp.
* F. nucleatum
* P. gingivalis
* P. intermedia
* T. forsythia
* T. denticola
* Red complex
* Entamoeba gingivalis (amoebic)
* Trichomonas tenax
Other
* Calculus
* Clinical attachment loss
* Edentulism
* Fremitus
* Furcation defect
* Gingival enlargement
* Gingival pocket
* Gingival recession
* Gingivitis
* Horizontal bony defect
* Linear gingival erythema
* Occlusal trauma
* Periodontal pocket
* Periodontal disease
* Periodontitis
* Plaque
* Vertical bony defect
Treatment and prevention
* Periodontal examination
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* Brushing
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*[v]: View this template
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*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
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*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
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*[POR]: Portugal
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*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Gingival and periodontal pocket | None | 6,879 | wikipedia | https://en.wikipedia.org/wiki/Gingival_and_periodontal_pocket | 2021-01-18T19:02:15 | {"wikidata": ["Q1059860"]} |
Carney complex is a disorder characterized by an increased risk of several types of tumors. Affected individuals also usually have changes in skin coloring (pigmentation). Signs and symptoms of this condition commonly begin in the teens or early adulthood.
Individuals with Carney complex are at increased risk of developing noncancerous (benign) tumors called myxomas in the heart (cardiac myxoma) and other parts of the body. Cardiac myxomas may be found in any of the four chambers of the heart and can develop in more than one chamber. These tumors can block the flow of blood through the heart, causing serious complications or sudden death. Myxomas may also develop on the skin and in internal organs. Skin myxomas appear as small bumps on the surface of the skin or as lumps underneath the skin. In Carney complex, myxomas have a tendency to recur after they are removed.
Individuals with Carney complex also develop tumors in hormone-producing (endocrine) glands, such as the adrenal glands located on top of each kidney. People with this condition may develop a specific type of adrenal disease called primary pigmented nodular adrenocortical disease (PPNAD). PPNAD causes the adrenal glands to produce an excess of the hormone cortisol. High levels of cortisol (hypercortisolism) can lead to the development of Cushing syndrome. This syndrome causes weight gain in the face and upper body, slowed growth in children, fragile skin, fatigue, and other health problems.
People with Carney complex may also develop tumors of other endocrine tissues, including the thyroid, testes, and ovaries. A tumor called an adenoma may form in the pituitary gland, which is located at the base of the brain. A pituitary adenoma usually results in the production of too much growth hormone. Excess growth hormone leads to acromegaly, a condition characterized by large hands and feet, arthritis, and "coarse" facial features.
Some people with Carney complex develop a rare tumor called psammomatous melanotic schwannoma. This tumor occurs in specialized cells called Schwann cells, which wrap around and insulate nerves. This tumor is usually benign, but in some cases it can become cancerous (malignant).
Almost all people with Carney complex have areas of unusual skin pigmentation. Brown skin spots called lentigines may appear anywhere on the body but tend to occur around the lips, eyes, or genitalia. In addition, some affected individuals have at least one blue-black mole called a blue nevus.
## Frequency
Carney complex is a rare disorder; fewer than 750 affected individuals have been identified.
## Causes
Mutations in the PRKAR1A gene cause most cases of Carney complex. This gene provides instructions for making one part (subunit) of an enzyme called protein kinase A, which promotes cell growth and division (proliferation). The subunit produced from the PRKAR1A gene, called type 1 alpha, helps control whether protein kinase A is turned on or off.
Most mutations in the PRKAR1A gene that cause Carney complex result in an abnormal type 1 alpha subunit that is quickly broken down (degraded) by the cell. The lack of this subunit causes protein kinase A to be turned on more often than normal, which leads to uncontrolled cell proliferation. The signs and symptoms of Carney complex are related to the unregulated growth of cells in many parts of the body.
Some individuals with Carney complex do not have identified mutations in the PRKAR1A gene. In many of these cases, the disorder is associated with a specific region on the short (p) arm of chromosome 2, designated as 2p16. Researchers have not discovered the gene within this region that is responsible for Carney complex.
### Learn more about the gene associated with Carney complex
* PRKAR1A
## Inheritance Pattern
Carney complex is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In approximately 80 percent of cases, an affected person inherits the mutation from one affected parent. The remaining cases result from new mutations in the gene and occur in people with no history of Carney complex in their family.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Carney complex | c2607929 | 6,880 | medlineplus | https://medlineplus.gov/genetics/condition/carney-complex/ | 2021-01-27T08:25:21 | {"gard": ["1119"], "mesh": ["D056733"], "omim": ["160980"], "synonyms": []} |
A rare superficial pemphigus disease characterized clinically by well-demarcated, localized, erythematous, scaly, hyperkeratotic, crusted plaques, with frequent butterfly distribution over the malar area of the face (but also commonly involving trunk and scalp, and less frequently the extremities, with a photoexposed distribution). Histologically, granular deposits along the dermal-epidermal junction, in addition to intercellular deposition in the upper epidermis, are observed.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Pemphigus erythematosus | c0263312 | 6,881 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79480 | 2021-01-23T17:19:34 | {"umls": ["C0263312"], "icd-10": ["L10.4"], "synonyms": ["Seborrheic pemphigus", "Senear-Usher syndrome"]} |
A number sign (#) is used with this entry because of evidence that ovarian dysgenesis-5 (ODG5) is caused by homozygous mutation in the SOHLH1 gene (610224) on chromosome 9q34.
For a general phenotypic description and a discussion of genetic heterogeneity of ovarian dysgenesis, see ODG1 (233300).
Clinical Features
Bayram et al. (2015) studied 2 pairs of sisters from 2 unrelated consanguineous Turkish families (designated HOU1852 and CF1374) with ovarian dysgenesis, the latter of which (CF1374) had previously been described by Abaci et al. (2007). In both families, the affected sisters presented with primary amenorrhea, lack of secondary sex characteristics, and delayed bone age, and the sisters in family CF1374 also exhibited short stature, with heights in the fifth to tenth percentile. Hormone analysis showed elevated levels of follicle-stimulating hormone (FSH; see 136530) and luteinizing hormone (LH; see 152780), whereas progesterone and estradiol levels were decreased. Pelvic ultrasound imaging revealed prepubertal- or infantile-sized uteri and hypoplastic or absent ovaries. Hormone replacement therapy (HRT) with cyclic estrogen and progesterone resulted in breast development and menstrual cycles, as well as increased height and weight to the twentieth to fiftieth percentile. Ultrasound imaging while on HRT visualized the ovaries, but they were still hypoplastic.
Molecular Genetics
In 4 affected sisters from 2 unrelated consanguineous Turkish families with ovarian dysgenesis, Bayram et al. (2015) performed whole-exome sequencing and identified homozygosity for different truncating mutations in the SOHLH1 gene that segregated with disease in the family: a 1-bp deletion (610224.0001) and a nonsense mutation (Y9X; 610224.0002), respectively. The mutations were not found in more than 3,000 in-house exomes, including more than 700 persons of Turkish ancestry, or in public variant databases. The authors noted that heterozygous carrier parents in each family showed no pathologic findings in sexual or gonadal development. Analysis of SOHLH1 in 21 other Turkish individuals with nonsyndromic hypergonadotropic hypogonadism did not reveal any additional mutations.
INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature (5th to 10th percentile) CHEST Breasts \- Absent thelarche GENITOURINARY Internal Genitalia (Female) \- Primary amenorrhea \- Hypoplastic or absent ovaries \- Small uterus (prepubertal or infantile) SKELETAL \- Delayed bone age ENDOCRINE FEATURES \- Elevated follicle-stimulating hormone (FSH) levels \- Elevated luteinizing hormone (LH) levels \- Reduced estradiol (E2) levels \- Reduced progesterone level MOLECULAR BASIS \- Caused by mutation in the spermatogenesis- and oogenesis-specific basic helix-loop-helix protein 1 gene (SOHLH1, 610224.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| OVARIAN DYSGENESIS 5 | c4540141 | 6,882 | omim | https://www.omim.org/entry/617690 | 2019-09-22T15:45:09 | {"omim": ["617690"]} |
A number sign (#) is used with this entry because of evidence that monilethrix is caused by heterozygous mutation in the hair cortex keratin genes KRTHB1 (KRT81; 602153), KRTHB6 (KRT86; 601928), and KRTHB3 (KRT83; 602765).
Description
Individuals with monilethrix have normal hair at birth, but within the first few months of life develop fragile, brittle hair that tends to fracture and produce varying degrees of dystrophic alopecia. In the mildest forms, only the occipital regions of the scalp are involved; however, in severe forms the eyebrows, eyelashes, and secondary sexual hair may also be involved. Follicular hyperkeratosis with predilection for the scalp, nape of neck, and extensor surfaces of the upper arm and thighs is also a characteristic finding in these patients. Light microscopic examination is diagnostic and reveals elliptical nodes of normal thickness and intermittent constrictions (internodes) at which the hair easily breaks. There may be spontaneous improvement with time, especially during puberty and pregnancy, but the condition never resolves completely (summary by Zlotogorski et al., 2006).
An autosomal recessive form of monilethrix-like congenital hypotrichosis (see 607903) is caused by mutation in the DSG4 gene (607892). The clinical picture of autosomal recessive monilethrix is more severe than the dominant form, with more extensive alopecia of the scalp, body, and limbs, and a papular rash involving the extremities and periumbilical region (Zlotogorski et al., 2006).
The term monilethrix derives from the Latin word for necklace and the Greek for hair (Schweizer, 2006).
Clinical Features
Salamon and Schnyder (1962) reviewed the clinical findings in 4 previously reported Swiss families segregating autosomal dominant monilethrix.
Hypotrichosis may be the presenting manifestation. The degree of hypotrichosis is variable from patient to patient and from time to time in the same individual. Perifollicular hyperkeratosis is a consistent feature. Microscopically, the hair is beaded. The beading is the result of a periodic narrowing of the shaft with nodes separated by about 0.7 mm (Ito et al., 1984).
Expression of monilethrix is variable; in mild cases, dystrophic hair may be confined to the occiput but more severely affected individuals have near total hair loss. In some cases, the hair loss persists throughout life; in others, regrowth of apparently normal hair may occur in adolescence or, temporarily, in pregnancy. Healy et al. (1995) reviewed the phenomenon of beading in this disorder. It had been shown that the periodicity is not diurnal and that it is not synchronous in independent follicles. In mild cases, close inspection is needed to confirm the presence of a few typical beaded hairs. Follicular keratosis and, in some families (Heydt, 1963), nail defects are associated. Electron microscopic studies of affected hair shafts showed defects in the microfibrillar structure of the cortex of the hair shaft and amorphous clumps of cysteine-rich material in both nodal and internodal regions. Hence, the genes for the structural proteins of the hair shaft were considered candidates for causative defects in monilethrix. The major structural proteins of hair are the relatively cysteine-rich 'hard' keratins, also found in nail.
Winter et al. (2000) reported a 3-generation French family with autosomal dominant inheritance of monilethrix. The proband showed diffuse hypotrichosis and onychodystrophy from 2 months of age. Microscopic examination of the hair showed typically beaded or short dystrophic hair. She also had keratosis pilaris. At age 11 years, she still had hypotrichosis with partial regrowth. Her affected father had moderate hypotrichosis with less beaded hair. Most affected family members had hypotrichosis following shedding of initial hair, and then developed individually varying hair growth. Genetic analysis identified a heterozygous mutation in the KRT86 gene (601928.0006).
Van Steensel et al. (2015) reported a Dutch brother and sister (patients 3 and 4) and a Belgian boy (patient 5) who had monilethrix and mutations in the KRT81 gene (see MOLECULAR GENETICS). The 27-year-old brother had fragile hair and alopecia, and complained of 'rough skin' on his upper arms and legs since childhood. Dermoscopic examination showed obvious beading of hair shafts, which was confirmed by light microscopy. He had follicular hyperkeratosis of the neck, upper arms, elbows, and upper thighs. His younger sister had a milder phenotype involving occipital balding with beading of her remaining hair, as well as slight follicular hyperkeratosis on the elbows. Their parents reportedly had normal hair but were not available for examination, and their maternal grandmother was said to have had quite short hair. The 2-year-old Belgian boy, whose mother and her twin sister were also affected, had occipital alopecia with short and brittle remaining hair, and he also exhibited follicular hyperkeratosis. Dermoscopic examination of the boy and his mother revealed beading consistent with the diagnosis of monilethrix.
Mapping
Spence et al. (1979) published a summary of linkage data from 30 tested members of 1 family. Most known cases are of European origin but an Indian pedigree (Bajaj et al., 1978) and an Arab pedigree (Schaap et al., 1982) have been described. The latter pedigree contained a sibship with both parents affected. Of the 8 affected sibs, some might well be homozygotes, but 'discrimination of 2 distinct phenotypic groups...is not obvious.'
Renwick and Izatt (1988) analyzed 2 unrelated Scottish kindreds. The only positive lod score was with the IGHG locus (0.42 at theta = 0.15). Spence et al. (1979) found weakly positive lod scores with PI (107400), which is closely linked to IGHG (147100) on 14q.
Like cytokeratins (see 139350), hair keratins have acidic and basic forms. (Paired keratins form heterodimers, which in turn condense to form intermediate filaments.) At least one acidic human hair keratin (601077) maps to the type I keratin gene cluster at 17q12-q21 and at least one basic hair keratin (148040) maps to the corresponding type II cluster at 12q13 (Rogers et al., 1995).
In 2 families with autosomal dominant monilethrix, Healy et al. (1995) excluded linkage to the type I keratin gene cluster on 17q but showed that the disorder is closely linked to the type II keratin cluster on 12q, where genes for basic trichocyte keratins are found. The combined maximum lod score for linkage to D12S96 was 12.27 at theta = 0.0. The authors noted that this was the first mapping of a primary human hair disorder and the first evidence implicating a defect of the 'hard' keratins of hair and nail in disease. One family studied by Healy et al. (1995) was a Scots family reported several times since 1910 (Cranston Low, 1910; Tomkinson, 1932; Alexander and Grant, 1958). The second family was apparently unrelated and of Irish origin. Follicular keratoses were present on the occiput and, in a few cases, on the limbs. In addition, 5 cases had dystrophic fingernails, including koilonychia, lamellar splitting, and brittleness.
Using microsatellite markers flanking the keratin gene clusters at 17q12-q21 and 12q11-q13, Stevens et al. (1996) demonstrated linkage in a monilethrix pedigree to the chromosome 12 region containing the type II keratin cluster. In 2 new families, Birch-Machin et al. (1997) likewise mapped monilethrix to the type II keratin gene cluster at 12q13. In one of the families, the disease was expressed in 4 of 12 cases only as a follicular keratosis of the neck, elbows, and knees, without clinical or historical evidence of hair anomalies; nonpenetrance in an obligate carrier was also observed in that kindred.
Molecular Genetics
Winter et al. (1997) identified a glu413-to-lys mutation (E413K; 601928.0001) in the type II hair cortex keratin gene they called HB6 in a 4-generation British family with monilethrix previously linked to 12q13, as well as in 3 unrelated isolated monilethrix patients. In a 3-generation French family with monilethrix of a milder and variable phenotype, they detected another heterozygous point mutation in the same glutamic acid codon of HB6 (E413D; 601928.0002). These mutations were the first direct evidence for involvement of hair keratins in hair disease.
Winter et al. (1998) stated that a survey of the 5 monilethrix families and 4 single patients investigated in their laboratory revealed that patients bearing the most prevalent HB6 mutation, E413K (601928.0001), invariably developed dystrophic hypotrichosis and follicular hyperkeratosis in the occipital region and the nape of the neck within the first year after birth. As a rule, these conditions persisted into adulthood, and an essential improvement of hair growth represented a unusual finding. In all cases, moniliform hair could easily be diagnosed by light microscopic examination. In contrast, pronounced intrafamilial phenotypic variation of the disease was observed in those pedigrees in which affected members exhibited the HB6 E413D mutation, the HB1 E413K mutation (602153.0001), or the HB1 E402K mutation (602153.0002) was observed.
Van Steensel et al. (2005) studied 3 patients with monilethrix, identifying a mutation in KRTHB3 in 1 (E407K; 602765.0001), a mutation in KRTHB6 in another (E402K; 601928.0003), and no mutations in KRTHB1, KRTHB3, or KRTHB6 in the third patient. The authors noted that the residue affected in KRTHB3, glu407, is equivalent to glu402 in the KRTHB1 and KRTHB6 genes (see 602153.0002 and 601928.0003, respectively), which is a hotspot for mutations causing monilethrix.
In a consanguineous Turkish family with monilethrix, including 11 affected members over 3 generations, Celep et al. (2009) performed linkage analysis and obtained a maximum lod score of only 1.7 (theta = 0.0) at marker D12S390, compared to the expected maximum calculated for simulated genotypes of 4.6. Screening of exon 7 of the KRTHB6 gene revealed heterozygosity for the E402K mutation (601928.0003) in all affected family members. The authors emphasized the difficulties of mapping a heterozygous disorder in a country with a high rate of consanguinity.
In a Dutch family (patients 3 and 4) and a Belgian family (patient 5) with monilethrix, van Steensel et al. (2015) analyzed the KRT81, KRT83, and KRT86 genes, and identified heterozygosity for the previously reported E407K mutation in KRT83 (602765.0001) in affected members of the Belgian family, as well as a different missense mutation in the KRT83 gene in the affected Dutch sibs (E418K; 602765.0002). Noting that the E418K change in KRT83 is equivalent to previously reported monilethrix-associated mutations in the KRT86 (E413K; 601928.0001) and KRT81 (E413K; 602153.0001) genes, the authors concluded that the E418K variant was likely pathogenic. Van Steensel et al. (2015) also analyzed the 3 genes in a large 4-generation Venezuelan family (patients 1 and 2) with monilethrix, and identified mutations in 2 of the genes: an L409P substitution in the KRT86 gene that segregated fully with disease, as well as an R408C variant of unclear significance in KRT81 that was found in 2 affected individuals as well as in 2 unaffected individuals. In addition, the authors identified a de novo L410P mutation in the KRT86 gene in an affected 5-year-old French boy (patient 6).
INHERITANCE \- Autosomal dominant SKIN, NAILS, & HAIR Skin \- Keratosis pilaris \- Follicular keratosis Nails \- Onychodystrophy Hair \- Hypotrichosis \- Short hair \- Brittle hair \- Beaded hair on microscopy MISCELLANEOUS \- Genetic heterogeneity \- Onset in infancy \- Variable severity \- Hair regrowth may occur later in life MOLECULAR BASIS \- Caused by mutation in the keratin 81 gene (KRT81, 602153.0001 ) \- Caused by mutation in the keratin 83 gene (KRT83, 602765.0001 ) \- Caused by mutation in the keratin 86 gene (KRT86, 601928.0001 ). ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| MONILETHRIX | c0546966 | 6,883 | omim | https://www.omim.org/entry/158000 | 2019-09-22T16:38:01 | {"doid": ["0050472"], "mesh": ["D056734"], "omim": ["158000"], "icd-10": ["Q84.1"], "orphanet": ["573"]} |
A rare mitochondrial oxidative phosphorylation disorder with complex I and IV deficiency characterized by hypertrophic cardiomyopathy, hepatic steatosis with elevated liver transaminases, exercise intolerance and muscle weakness. Neuro-opthalmological features (hemiplegic migraine, Leigh-like lesions on brain MRI, pigmentary retinopathy) have been reported later in life.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Infantile hypertrophic cardiomyopathy due to MRPL44 deficiency | c3809339 | 6,884 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=352563 | 2021-01-23T17:54:23 | {"gard": ["12892"], "omim": ["615395"], "icd-10": ["E88.8"], "synonyms": ["COXPD16", "Combined oxidative phosphorylation defect type 16"]} |
Upset stomach
"Dyspepsia" redirects here. For the Negativland album, see Dispepsi.
Indigestion
Other namesDyspepsia
SpecialtyGastroenterology
SymptomsUpper abdominal pain[1]
FrequencyCommon[1]
Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion.[2] Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain.[3] People may also experience feeling full earlier than expected when eating.[4]
Dyspepsia is a common problem and is frequently caused by gastroesophageal reflux disease (GERD) or gastritis.[5] In a small minority of cases it may be the first symptom of peptic ulcer disease (an ulcer of the stomach or duodenum) and, occasionally, cancer. Hence, unexplained newly onset dyspepsia in people over 55 or the presence of other alarming symptoms may require further investigations.[6]
In those who are older or with worrisome symptoms such as trouble swallowing, weight loss, or blood loss endoscopy is recommended.[1] Otherwise testing for H. pylori followed by treatment of the infection if present is reasonable.[1]
Indigestion is common.[1] Functional indigestion (previously called nonulcer dyspepsia)[7] is indigestion without evidence of underlying disease.[8] Functional indigestion is estimated to affect about 15% of the general population in western countries.[7]
## Contents
* 1 Signs and symptoms
* 2 Cause
* 2.1 Non-ulcer indigestion
* 2.2 Post-infectious
* 2.3 Functional
* 2.4 Liver and pancreas diseases
* 2.5 Food or drug intolerance
* 2.6 Helicobacter pylori infection
* 2.7 Systemic diseases
* 2.8 Duodenal micro-inflammation
* 3 Pathophysiology
* 4 Diagnosis
* 5 Treatment
* 5.1 Acid suppression
* 5.2 Diet
* 5.3 Alternative medicine
* 6 Etymology
* 7 See also
* 8 References
* 9 External links
## Signs and symptoms[edit]
In most cases, the clinical history is of limited use in distinguishing between organic causes and functional dyspepsia. A large systematic review of the literature was recently performed to evaluate the effectiveness of diagnosing organic dyspepsia by clinical opinion versus computer models in patients referred for upper endoscopy. The computer models were based on patient demographics, risk factors, historical items, and symptoms. The study showed that neither clinical impression nor computer models were able to adequately distinguish organic from functional disease.[9]
In a recent study, patients with peptic ulcer disease were compared with patients with functional dyspepsia in an age and sex-matched study. Although the functional dyspepsia group reported more upper abdominal fullness, nausea, and overall greater distress and anxiety, almost all the same symptoms were seen in both groups. Therefore, it is the clinician’s challenging task to separate patients who may have an organic disorder, and thus warrant further diagnostic testing, from patients who have functional dyspepsia, who are given empiric symptomatic treatment. The workup should be targeted to identify or rule out specific causes. Traditionally, people at high-risk have been identified by "alarm" features. However, the utility of these features in identifying the presence of upper cancer of the esophagus or stomach has been debated. A meta analysis looking at the sensitivity and specificity of alarm features found a range of 0–83% and 40–98%, respectively. However, there was high heterogeneity between studies.[10]
The physical examination may elicit abdominal tenderness, but this finding is nonspecific. A positive Carnett sign, or focal tenderness that increases with abdominal wall contraction and palpation, suggests an etiology involving the abdominal wall musculature. Cutaneous dermatomal distribution of pain may suggest a thoracic polyradiculopathy. Thump tenderness over the right upper quadrant may suggest chronic cholecystitis.[11]
## Cause[edit]
When dyspepsia can be attributed to a specific cause, the majority of cases concern gastroesophageal reflux disease (GERD) and gastritis disease. Less common causes include peptic ulcer, gastric cancer, esophageal cancer, coeliac disease, food allergy, inflammatory bowel disease, chronic intestinal ischemia, and gastroparesis.
### Non-ulcer indigestion[edit]
In about 50-70% of people with dyspepsia, no definite organic cause can be determined. In this case, dyspepsia is referred to as non-ulcer dyspepsia and its diagnosis is established by the presence of epigastralgia for at least 6 months, in the absence of any other cause explaining the symptoms.
### Post-infectious[edit]
Gastroenteritis increases the risk of developing chronic dyspepsia. Post infectious dyspepsia is the term given when dyspepsia occurs after an acute gastroenteritis infection. It is believed that the underlying causes of post-infectious IBS and post-infectious dyspepsia may be similar and represent different aspects of the same pathophysiology.[12]
### Functional[edit]
This is the most common cause of chronic dyspepsia. More than 70% of people have no obvious organic cause for their symptoms after evaluation. Symptoms may arise from a complex interaction of increased visceral afferent sensitivity, gastric delayed emptying (gastroparesis) or impaired accommodation to food. Anxiety is also associated with functional dyspepsia. In some people, it appears before the onset of gut symptoms; in other cases, anxiety develops after onset of the disorder, which suggests that a gut-driven brain disorder may be a possible cause. Although benign, these symptoms may be chronic and difficult to treat.[13]
Wheat and dietary fats can lead to dyspepsia and their reduction or withdrawal may improve symptoms.[14]
### Liver and pancreas diseases[edit]
These include cholelithiasis, chronic pancreatitis, and pancreatic cancer.
### Food or drug intolerance[edit]
Acute, self-limited dyspepsia may be caused by overeating, eating too quickly, eating high-fat foods, eating during stressful situations, or drinking too much alcohol or coffee. Many medications cause dyspepsia, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics (metronidazole, macrolides), diabetes drugs (metformin, Alpha-glucosidase inhibitor, amylin analogs, GLP-1 receptor antagonists), antihypertensive medications (angiotensin converting enzyme [ACE] inhibitors, Angiotensin II receptor antagonist), cholesterol-lowering agents (niacin, fibrates), neuropsychiatric medications (cholinesterase inhibitors [donepezil, rivastigmine]), SSRIs (fluoxetine, sertraline), serotonin-norepinephrine-reuptake inhibitors (venlafaxine, duloxetine), Parkinson drugs (Dopamine agonist, monoamine oxidase [MAO]-B inhibitors), corticosteroids, estrogens, digoxin, iron, and opioids.[15]
### Helicobacter pylori infection[edit]
The role of Helicobacter pylori in functional dyspepsia is controversial, and no clear causal relationship has been established. This is true for both the symptom profile and pathophysiology of functional dyspepsia. Although some epidemiologic studies have suggested an association between H. pylori infection and functional dyspepsia, others have not. The discrepancy may stem in part from differences in methodology and lack of adequate consideration of confounding factors such as past history of peptic ulcer disease and socioeconomic status.[16] Controlled trials disagree about whether or not H. pylori eradication is beneficial in functional dyspepsia, with roughly half of the trials showing improvement and the other half no improvement. In a recent multicenter U.S. trial that randomized 240 patients to treatment or placebo, and followed patients for 12 months, 28% of treated patients versus 23% of those receiving placebo reported relief of symptoms at the 12-month follow-up. Similarly, recent European trials have not shown significant differences in symptoms after H. pylori eradication as compared with controls. Systematic reviews of eradication have been conducted, with varying results. A systematic review in the Annals of Internal Medicine suggested no statistically significant effect, with an odds ratio (OR) for treatment success versus control of 1.29 (95% CI, 0.89–1.89; P = 0.18). Still, no effect was seen after adjusting for heterogeneity and for cure of H. pylori. In contrast, a Cochrane review found a small but statistically significant effect in curing symptoms (H. pylori cure vs placebo, 36% vs 30%, respectively).[17][18]
### Systemic diseases[edit]
There are a number of systemic diseases that may involve dyspepsia, including coronary disease, congestive heart failure, diabetes mellitus, hyperparathyroidism, thyroid disease, and chronic kidney disease.
### Duodenal micro-inflammation[edit]
Duodenal micro-inflammation caused by an altered duodenal gut microbiota, reactions to foods (mainly gluten proteins) or infections may induce dyspepsia symptoms in a subset of people.[19]
## Pathophysiology[edit]
Psychosomatic and cognitive factors are important in the evaluation of patients with chronic dyspepsia. The psychiatric hypothesis holds that the symptoms of dyspepsia may be due to depression, increased anxiety, or a somatization disorder. Epidemiological studies suggest there is an association between functional dyspepsia and psychological disorders. Symptoms of neurosis, anxiety, hypochondriasis, and depression are more common in patients being evaluated for unexplained gastrointestinal complaints than in healthy controls. Comparisons of functional and organic dyspepsia have demonstrated that patients with functional dyspepsia are less likely to have decreased stress or anxiety at 1-year follow-up after being reassured of having no serious disease. This suggests that functional dyspepsia symptoms are long-lasting, compared with those of organic dyspepsia, and that the emotional ties are strong.[20]
## Diagnosis[edit]
People under 55 years without alarm symptoms can be treated without investigation. People over 55 years with recent onset dyspepsia or those with alarm symptoms should be urgently investigated by upper gastrointestinal endoscopy. This will rule out peptic ulcer disease, medication-related ulceration, malignancy, and other rarer causes.[6]
People under the age of 55 years with no alarm features do not need endoscopy but are considered for investigation for peptic ulcer disease caused by Helicobacter pylori infection. Investigation for H. pylori infection is usually performed when there is a moderate to high prevalence of this infection in the local community or the person with dyspepsia has other risk factors for H. pylori infection, related for example to ethnicity or immigration from a high-prevalence area. If infection is confirmed, it can usually be eradicated by medication.[citation needed]
Medication-related dyspepsia is usually related to NSAIDs and can be complicated by bleeding or ulceration with perforation of the stomach wall.
## Treatment[edit]
Functional and undifferentiated dyspepsia have similar treatments. Drug therapy decisions are difficult because trials included heartburn in the definition of dyspepsia. This led to the results favoring proton pump inhibitors (PPIs), which are effective for the treatment of heartburn.
Traditional therapies used for this diagnosis include lifestyle modification, antacids, H2-receptor antagonists (H2-RAs), prokinetic agents, and antiflatulents. It has been noted that one of the most frustrating aspects of treating functional dyspepsia is that these traditional agents have been shown to have little or no efficacy.[21]
### Acid suppression[edit]
Antacids and sucralfate were found to be no better than placebo in a literature review.[22] H2-RAs have been shown to have marked benefit in poor quality trials (30% relative risk reduction[22]), but only a marginal benefit in good quality trials.[21] Prokinetic agents would empirically seem to work well since delayed gastric emptying is considered a major pathophysiological mechanism in functional dyspepsia.[21] They have been shown in a meta-analysis to produce a relative risk reduction of up to 50%, but the studies evaluated to come to this conclusion used the drug cisapride which has since been removed from the market (now only available as an investigational agent)[23] due to serious adverse events such as torsades, and publication bias has been cited as a potential partial explanation for such a high benefit.[22] Modern prokinetic agents such as metoclopramide, erythromycin and tegaserod have little or no established efficacy and often result in substantial side effects.[22] Simethicone is of some value, as one trial suggests potential benefit over placebo and another shows equivalence with cisapride.[22] So, with the somewhat recent advent of the proton pump inhibitor (PPI) class of medications, the question of whether these new agents are superior to traditional therapy has arisen.[citation needed]
Currently, PPIs are, depending on the specific drug, FDA indicated for erosive esophagitis, gastroesophageal reflux disease (GERD), Zollinger-Ellison syndrome, eradication of H. pylori, duodenal and gastric ulcers, and NSAID-induced ulcer healing and prevention, but not functional dyspepsia. However, evidence-based guidelines and literature evaluate the use of PPIs for this indication. A helpful chart summarizing the major trials is available from the functional dyspepsia guidelines published in the World Journal of Gastroenterology in 2006.[21]
### Diet[edit]
Due to the association of dyspepsia with non-celiac gluten sensitivity, a gluten-free diet can relieve the symptoms.[19]
### Alternative medicine[edit]
A 2002 systemic review of herbal products found that several herbs, including peppermint and caraway, have anti-dyspeptic effects for non-ulcer dyspepsia with "encouraging safety profiles".[24] A 2004 meta-analysis of the multiple herbal extract Iberogast found it to be more effective than placebo in people with functional dyspepsia.[25]
## Etymology[edit]
The word dyspepsia is from the Greek δυσ- dys-, "bad" or "difficult", and πέψις pepsis "digestion".
## See also[edit]
* Functional bowel disorder
## References[edit]
1. ^ a b c d e Eusebi, Leonardo H; Black, Christopher J; Howden, Colin W; Ford, Alexander C (11 December 2019). "Effectiveness of management strategies for uninvestigated dyspepsia: systematic review and network meta-analysis". BMJ. 367: l6483. doi:10.1136/bmj.l6483. PMC 7190054. PMID 31826881.
2. ^ "dyspepsia" at Dorland's Medical Dictionary
3. ^ Duvnjak, edited by Marko (2011). Dyspepsia in clinical practice (1. Aufl. ed.). New York: Springer. p. 2. ISBN 9781441917300.CS1 maint: extra text: authors list (link)
4. ^ Talley NJ, Vakil N (October 2005). "Guidelines for the management of dyspepsia". Am. J. Gastroenterol. 100 (10): 2324–37. PMID 16181387.
5. ^ Zajac, P; Holbrook, A; Super, ME; Vogt, M (March–April 2013). "An overview: Current clinical guidelines for the evaluation, diagnosis, treatment, and management of dyspepsia". Osteopathic Family Physician. 5 (2): 79–85. doi:10.1016/j.osfp.2012.10.005.
6. ^ a b National Institute for Health and Clinical Excellence. Clinical guideline 17: Dyspepsia. London, 2004.
7. ^ a b Saad RJ, Chey WD (August 2006). "Review article: current and emerging therapies for functional dyspepsia" (PDF). Aliment. Pharmacol. Ther. 24 (3): 475–92. doi:10.1111/j.1365-2036.2006.03005.x. hdl:2027.42/74835. PMID 16886913. Free full-text
8. ^ van Kerkhoven LA, van Rossum LG, van Oijen MG, Tan AC, Laheij RJ, Jansen JB (September 2006). "Upper gastrointestinal endoscopy does not reassure patients with functional dyspepsia". Endoscopy. 38 (9): 879–85. doi:10.1055/s-2006-944661. PMID 16981103. Free full-text Archived 2011-07-27 at the Wayback Machine.
9. ^ Moayyedi P, Talley NJ, Fennerty MB, Vakil N (Apr 5, 2006). "Can the clinical history distinguish between organic and functional dyspepsia?". JAMA (Review). 295 (13): 1566–76. doi:10.1001/jama.295.13.1566. PMID 16595759.
10. ^ Vakil N, Moayyedi P, Fennerty MB, Talley NJ (Aug 2006). "Limited value of alarm features in the diagnosis of upper gastrointestinal malignancy: systematic review and meta-analysis". Gastroenterology (Review). 131 (2): 390–401. doi:10.1053/j.gastro.2006.04.029. PMID 16890592.
11. ^ Flier, SN; S, Rose (2006). "Is functional dyspepsia of particular concern in women? A review of gender differences in epidemiology, pathophysiologic mechanism, clinical presentation and management". Am J Gastroenterol. 101 (12 Suppl): S644–53. PMID 17177870.
12. ^ Futagami S, Itoh T, Sakamoto C (2015). "Systematic review with meta-analysis: post-infectious functional dyspepsia". Aliment. Pharmacol. Ther. 41 (2): 177–88. doi:10.1111/apt.13006. PMID 25348873.
13. ^ Talley NJ, Ford AC (Nov 5, 2015). "Functional Dyspepsia" (PDF). N Engl J Med (Review). 373 (19): 1853–63. doi:10.1056/NEJMra1501505. PMID 26535514.
14. ^ Duncanson KR, Talley NJ, Walker MM, Burrows TL (2017). "Food and functional dyspepsia: a systematic review". J Hum Nutr Diet (Systematic Review). 31 (3): 390–407. doi:10.1111/jhn.12506. PMID 28913843. S2CID 22800900.
15. ^ Ford AC, Moayyedi P (2013). "Dysepsia". BMJ. 347: f5059. doi:10.1136/bmj.f5059. PMID 23990632. S2CID 220190440.
16. ^ Laine L, Schoenfeld P, Fennerty MB (2001). "Therapy for Helicobacter pylori in patients with nonulcer dyspepsia. A meta-analysis of randomized, controlled trials". Ann Intern Med. 134 (5): 361–369. doi:10.7326/0003-4819-134-5-200103060-00008. PMID 11242496. S2CID 12951466.
17. ^ Moayyedi, P; Deeks, J; Talley, NJ (2003). "An update of the Cochrane systematic review of Helicobacter pylori eradication therapy in nonulcer dyspepsia". Am J Gastroenterol. 98 (12): 2621–6. CiteSeerX 10.1.1.663.6840. PMID 14687807.
18. ^ Talley, NJ (2002). "Review article: Helicobacter pylori and nonulcer dyspepsia". Aliment Pharmacol Ther. 16 (1): 58–65. doi:10.1046/j.1365-2036.2002.0160s1058.x. PMID 11849130.
19. ^ a b Jung HK, Talley NJ (2018). "Role of the Duodenum in the Pathogenesis of Functional Dyspepsia: A Paradigm Shift". J Neurogastroenterol Motil (Review). 24 (3): 345–354. doi:10.5056/jnm18060. PMC 6034675. PMID 29791992.
20. ^ Pajala, M; Heikkinen, M (2006). "A prospective 1-year follow-up study in patients with functional or organic dyspepsia: changes in gastrointestinal symptoms, mental distress and fear of serious illness". Aliment Pharmacol Ther. 24 (8): 1241–1246. doi:10.1111/j.1365-2036.2006.03108.x. PMID 17014583.
21. ^ a b c d Mönkemüller K, Malfertheiner P (2006). "Drug treatment of functional dyspepsia". World J. Gastroenterol. 12 (17): 2694–700. doi:10.3748/wjg.v12.i17.2694. PMC 4130977. PMID 16718755.
22. ^ a b c d e Talley NJ, Vakil N (2005). "Guidelines for the management of dyspepsia". Am. J. Gastroenterol. 100 (10): 2324–37. PMID 16181387.
23. ^ Information regarding withdrawal of Propulsid (cisapride) by Janssen Pharmaceutica. From FDA
24. ^ Thompson Coon J, Ernst E (October 2002). "Systematic review: herbal medicinal products for non-ulcer dyspepsia". Aliment. Pharmacol. Ther. 16 (10): 1689–99. doi:10.1046/j.1365-2036.2002.01339.x. PMID 12269960.
25. ^ Melzer J, Rösch W, Reichling J, Brignoli R, Saller R (2004). "Meta-analysis: phytotherapy of functional dyspepsia with the herbal drug preparation STW 5 (Iberogast)". Aliment. Pharmacol. Ther. 20 (11–12): 1279–87. doi:10.1111/j.1365-2036.2004.02275.x. PMID 15606389.
## External links[edit]
Classification
D
* ICD-10: K30
* ICD-9-CM: 536.8
* MeSH: D004415
* DiseasesDB: 30831
External resources
* MedlinePlus: 003260
* Patient UK: Indigestion
Look up indigestion in Wiktionary, the free dictionary.
* v
* t
* e
Diseases of the digestive system
Upper GI tract
Esophagus
* Esophagitis
* Candidal
* Eosinophilic
* Herpetiform
* Rupture
* Boerhaave syndrome
* Mallory–Weiss syndrome
* UES
* Zenker's diverticulum
* LES
* Barrett's esophagus
* Esophageal motility disorder
* Nutcracker esophagus
* Achalasia
* Diffuse esophageal spasm
* Gastroesophageal reflux disease (GERD)
* Laryngopharyngeal reflux (LPR)
* Esophageal stricture
* Megaesophagus
* Esophageal intramural pseudodiverticulosis
Stomach
* Gastritis
* Atrophic
* Ménétrier's disease
* Gastroenteritis
* Peptic (gastric) ulcer
* Cushing ulcer
* Dieulafoy's lesion
* Dyspepsia
* Pyloric stenosis
* Achlorhydria
* Gastroparesis
* Gastroptosis
* Portal hypertensive gastropathy
* Gastric antral vascular ectasia
* Gastric dumping syndrome
* Gastric volvulus
* Buried bumper syndrome
* Gastrinoma
* Zollinger–Ellison syndrome
Lower GI tract
Enteropathy
Small intestine
(Duodenum/Jejunum/Ileum)
* Enteritis
* Duodenitis
* Jejunitis
* Ileitis
* Peptic (duodenal) ulcer
* Curling's ulcer
* Malabsorption: Coeliac
* Tropical sprue
* Blind loop syndrome
* Small bowel bacterial overgrowth syndrome
* Whipple's
* Short bowel syndrome
* Steatorrhea
* Milroy disease
* Bile acid malabsorption
Large intestine
(Appendix/Colon)
* Appendicitis
* Colitis
* Pseudomembranous
* Ulcerative
* Ischemic
* Microscopic
* Collagenous
* Lymphocytic
* Functional colonic disease
* IBS
* Intestinal pseudoobstruction / Ogilvie syndrome
* Megacolon / Toxic megacolon
* Diverticulitis/Diverticulosis/SCAD
Large and/or small
* Enterocolitis
* Necrotizing
* Gastroenterocolitis
* IBD
* Crohn's disease
* Vascular: Abdominal angina
* Mesenteric ischemia
* Angiodysplasia
* Bowel obstruction: Ileus
* Intussusception
* Volvulus
* Fecal impaction
* Constipation
* Diarrhea
* Infectious
* Intestinal adhesions
Rectum
* Proctitis
* Radiation proctitis
* Proctalgia fugax
* Rectal prolapse
* Anismus
Anal canal
* Anal fissure/Anal fistula
* Anal abscess
* Hemorrhoid
* Anal dysplasia
* Pruritus ani
GI bleeding
* Blood in stool
* Upper
* Hematemesis
* Melena
* Lower
* Hematochezia
Accessory
Liver
* Hepatitis
* Viral hepatitis
* Autoimmune hepatitis
* Alcoholic hepatitis
* Cirrhosis
* PBC
* Fatty liver
* NASH
* Vascular
* Budd–Chiari syndrome
* Hepatic veno-occlusive disease
* Portal hypertension
* Nutmeg liver
* Alcoholic liver disease
* Liver failure
* Hepatic encephalopathy
* Acute liver failure
* Liver abscess
* Pyogenic
* Amoebic
* Hepatorenal syndrome
* Peliosis hepatis
* Metabolic disorders
* Wilson's disease
* Hemochromatosis
Gallbladder
* Cholecystitis
* Gallstone / Cholelithiasis
* Cholesterolosis
* Adenomyomatosis
* Postcholecystectomy syndrome
* Porcelain gallbladder
Bile duct/
Other biliary tree
* Cholangitis
* Primary sclerosing cholangitis
* Secondary sclerosing cholangitis
* Ascending
* Cholestasis/Mirizzi's syndrome
* Biliary fistula
* Haemobilia
* Common bile duct
* Choledocholithiasis
* Biliary dyskinesia
* Sphincter of Oddi dysfunction
Pancreatic
* Pancreatitis
* Acute
* Chronic
* Hereditary
* Pancreatic abscess
* Pancreatic pseudocyst
* Exocrine pancreatic insufficiency
* Pancreatic fistula
Other
Hernia
* Diaphragmatic
* Congenital
* Hiatus
* Inguinal
* Indirect
* Direct
* Umbilical
* Femoral
* Obturator
* Spigelian
* Lumbar
* Petit's
* Grynfeltt-Lesshaft
* Undefined location
* Incisional
* Internal hernia
* Richter's
Peritoneal
* Peritonitis
* Spontaneous bacterial peritonitis
* Hemoperitoneum
* Pneumoperitoneum
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*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Indigestion | c0013395 | 6,885 | wikipedia | https://en.wikipedia.org/wiki/Indigestion | 2021-01-18T18:35:35 | {"mesh": ["D004415"], "umls": ["C0013395"], "icd-9": ["536.8"], "wikidata": ["Q653971"]} |
A number sign (#) is used with this entry because this form of congenital cerebellar ataxia with mental retardation (CAMRQ3) is caused by homozygous mutation in the CA8 gene (114815) on chromosome 8q12.
Description
Cerebellar ataxia, mental retardation, and dysequilibrium syndrome (CAMRQ) is a genetically heterogeneous disorder characterized by congenital cerebellar ataxia and mental retardation (summary by Gulsuner et al., 2011).
For a discussion of genetic heterogeneity of CAMRQ, see CAMRQ1 (224050).
Clinical Features
Turkmen et al. (2009) reported a consanguineous Iraqi family in which 4 of 8 sibs had congenital ataxia, mild mental retardation, and dysarthria. All walked with a quadrupedal gait, with straight legs and placing their weight on the palms of their hands. The parents claimed that the affected persons never learned to crawl on their knees as most infants do, but ambulated from infancy on with their legs held straight with a 'bear-like' gait. Attempts to teach the children to walk on 2 legs with crutches or other supports failed. All complained of lack of balance and frequent falls when trying to walk bipedally. There were no other neurologic symptoms. Brain imaging was not performed, but the authors speculated that the ataxia resulted from cerebellar dysfunction based on an animal model.
### Etiology of Quadrupedal Locomotion
Ozcelik et al. (2008) maintained that quadrupedal locomotion in the affected individuals results from abnormal function of brain structures that are critical for gait. Humphrey et al. (2008) concluded that the tendency toward quadrupedal locomotion in affected individuals is an adaptive and effective compensation for problems with balance caused by congenital cerebellar hypoplasia. Thus, the unusual gait could be attributed to the local cultural environment. Herz et al. (2008) also concluded that quadrupedal locomotion is more likely an adaptation to severe truncal ataxia, resulting from a combination of uneven, rough surfaces in rural areas, imitation of affected sibs, and lack of supportive therapy. Ozcelik et al. (2008) defended their position.
Molecular Genetics
By genomewide linkage analysis followed by candidate gene sequencing of a consanguineous Iraqi family with ataxia and mild mental retardation, Turkmen et al. (2009) identified a homozygous mutation in the CA8 gene (S100P; 114815.0001).
By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, Najmabadi et al. (2011) identified a missense mutation in the CA8 gene (114815.0002) as the cause of CAMRQ3 in a family (M107) in which first-cousin parents had 2 healthy and 4 affected children.
Animal Model
The autosomal recessive 'waddles' (wdl) mouse shows ataxia and appendicular dystonia with frequent tail elevation and an abnormally elevated trunk during ambulation. These changes are readily apparent by 2 weeks of age and persist throughout their life span. The appendicular dystonia produces nearly straight limbs with minimal flexion at the knee and elbow joints, elevation of the pelvis, and a waddling motion during ambulation, particularly at higher velocities. Mutant mice also show increased falling compared to wildtype. These abnormalities occur in the absence of associated pathologic changes in the central or peripheral nervous system. Jiao et al. (2005) determined that the wdl phenotype results from a homozygous 19-bp deletion in exon 8 of the Ca8 gene on mouse chromosome 4, resulting in a loss of function.
INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Strabismus NEUROLOGIC Central Nervous System \- Mental retardation, mild \- Cerebellar ataxia \- Quadrupedal gait \- Dysarthria \- Slurred speech \- Tremor MISCELLANEOUS \- One family has been reported \- Congenital onset MOLECULAR BASIS \- Caused by mutation in the carbonic anhydrase VIII gene (CA8, 114815.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| CEREBELLAR ATAXIA, MENTAL RETARDATION, AND DYSEQUILIBRIUM SYNDROME 3 | c0394006 | 6,886 | omim | https://www.omim.org/entry/613227 | 2019-09-22T15:59:18 | {"doid": ["0050997"], "omim": ["613227"], "orphanet": ["1766"], "synonyms": ["Alternative titles", "CEREBELLAR ATAXIA AND MENTAL RETARDATION WITH OR WITHOUT QUADRUPEDAL LOCOMOTION 3"]} |
The Hudson–Stahli line is a line of iron deposition lying roughly on the border between the middle and lower thirds of the cornea.[1]:321 It lies in the corneal epithelium. Usually it has about 0.5 mm in thickness and is 1–2 mm long. It is generally horizontal, with possible mild downward trend in the middle. It is present normally in people over the age of 50, but seems to dissipate to some degree by the age of 70.
The Hudson–Stahli line is not associated with any pathology calling for clinical intervention. Formation of the line may depend upon the rate of tear secretion.[2]
However, the Hudson–Stahli line can be enhanced in hydroxychloroquine toxicity.[3]
## See also[edit]
* Fleischer ring – corneal iron depositions in keratoconus
## References[edit]
1. ^ Ophthalmology Myron Yanoff, Jay S. Duker Edition 3, illustrated Elsevier Health Sciences, 2008 ISBN 0-323-04332-1, ISBN 978-0-323-04332-8
2. ^ Rao, SK; Ananth, VS; Padmanabhan, P (2002-05-01). "Corneal topography and Schirmer testing in eyes with the Hudson|–|Stahli line". Eye. 16 (3): 267–70. doi:10.1038/sj.eye.6700028. PMID 12032715.
3. ^ Denniston, Alastair; Murray, Philip (2014-10-23). Oxford Handbook of Ophthalmology. OUP Oxford. ISBN 9780191057021.
## External links[edit]
* Hudson-Stähli Line – University of Columbia
* Bilateral UV photographs of corneas from four normal subjects[permanent dead link] – HS lines, a figure from a study (Every, SG; Leader, JP; Molteno, AC; Bevin, TH; Sanderson, G (October 2005). "Ultraviolet photography of the in vivo human cornea unmasks the Hudson-Stähli line and physiologic vortex patterns". Invest. Ophthalmol. Vis. Sci. 46: 3616–22. doi:10.1167/iovs.04-1455. PMID 16186341.)
* v
* t
* e
Symptoms and signs relating to the eye
Adnexa
* lacrimal: Schirmer's test
* eyelid: Abadie's sign of exophthalmic goiter
* Boston's sign
* Dalrymple's sign
* Stellwag's sign
Globe
* pupil: Argyll Robertson pupils
* Adie pupil
* Marcus Gunn pupil
* cornea: Fleischer ring
* Kayser–Fleischer ring
* Hudson–Stahli line
* iris: Brushfield spots
* Lisch nodule
* conjunctiva: Bitot's spots
* Arlt's line
* retina: Hollenhorst plaque
* Roth's spot
* Fuchs spot
* others: Alexander's law
* Hirschberg test
* Siegrist streaks
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Hudson–Stahli line | c0271276 | 6,887 | wikipedia | https://en.wikipedia.org/wiki/Hudson%E2%80%93Stahli_line | 2021-01-18T18:47:03 | {"umls": ["C0271276"], "wikidata": ["Q4262207"]} |
A number sign (#) is used with this entry because of evidence that congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (CHDFIDD) is caused by heterozygous mutation in the CDK13 gene (603309) on chromosome 7p14.
Clinical Features
Sifrim et al. (2016) reported 7 unrelated children, ranging in age from infancy to 12 years, with a syndrome associated with atrial and/or ventricular septal congenital heart defects. Two patients had pulmonary valve abnormalities. Each patient had a recognizable facial gestalt characterized by hypertelorism, upslanted palpebral fissures, epicanthal folds, ptosis, strabismus, posteriorly rotated ears, thin upper lip, and small mouth. All had global developmental delay with significantly delayed walking and speech acquisition and intellectual disability. Four patients had seizures. Three patients had mild microcephaly, and 4 had feeding difficulties. Brain imaging showed agenesis of the corpus callosum in 3 patients, aplasia of the inferior half of the cerebellar vermis and small cerebral cortex in 1, and periventricular leukomalacia in another. More variable features included clinodactyly and/or camptodactyly of the fingers, hypotonia, and joint hypermobility. One patient had spasticity.
Hamilton et al. (2018) reported 9 additional patients, ranging in age from 3.5 to 16 years, with CHDFIDD. The patients had global developmental delay and variable intellectual disability, often with learning disabilities and autistic features. All but one had significant feeding difficulties from infancy, although only some had poor growth. All shared a common craniofacial gestalt including short upslanting palpebral fissures, telecanthus or hypertelorism, epicanthal folds, small mouth with thin upper lip, low-set or posteriorly rotated ears, and curly hair. Most had digital anomalies, including clinodactyly and prominent fetal pads, 2 had structural cardiac anomalies, and 1 had seizures.
Molecular Genetics
In 7 unrelated children with CHDFIDD, Sifrim et al. (2016) identified heterozygous missense mutations in the CDK13 gene (603309.0001-603309.0004). Six of the mutations were proven to have occurred de novo; paternal DNA from the seventh patient was not available, but his mother did not carry the variant. Four patients carried the same mutation (N842S; 603309.0001). All mutations occurred in the highly conserved protein kinase domain, and molecular modeling predicted that the mutations would impair ATP binding, binding of the magnesium ion essential for enzyme activity, or interactions with cyclin K (603544). Six of the patients were ascertained from a cohort of 518 trios in which a child with syndromic congenital heart defects underwent exome sequencing; the seventh patient was 1 of 86 singleton cases. Statistical analysis indicated that de novo missense mutations in the CDK13 gene were significantly enriched in patients compared to those expected under a null mutational model (p = 2.26 x 10(-12), Bonferroni-corrected p = 0.05). Functional studies of the variants and studies of patient cells were not performed.
Hamilton et al. (2018) reported 9 additional unrelated patients with CHDFIDD associated with de novo heterozygous mutations in the CDK13 gene that were identified by whole-exome sequencing (see, e.g., 603309.0001-603309.0002; 603309.0005-603309.0006). Aside from 1 patient with a splice site mutation, all mutations were missense substitutions affecting highly conserved residues. All mutations, including the splice site mutation, occurred within the protein kinase domain, and none were found in the gnomAD database. Molecular modeling and structural analysis indicated that all the missense variants would cause changes to bonding and/or structure that would likely lead to significant loss of catalytic activity. Hamilton et al. (2018) postulated a dominant-negative effect wherein the mutant missense variants would sequester cyclin K into inactive complexes or compete with active complexes for binding to substrates. In vitro functional expression studies of the variants were not performed.
INHERITANCE \- Autosomal dominant GROWTH Other \- Poor overall growth HEAD & NECK Head \- Microcephaly, mild (in some patients) Face \- Short philtrum Ears \- Posteriorly rotated ears \- Low-set ears Eyes \- Hypertelorism \- Short palpebral fissures \- Upslanting palpebral fissures \- Ptosis \- Strabismus \- Epicanthal folds Nose \- Broad nasal bridge Mouth \- Thin upper lip \- Small mouth CARDIOVASCULAR Heart \- Atrial septal defect \- Ventricular septal defect \- Pulmonary valve abnormalities ABDOMEN Gastrointestinal \- Feeding difficulties SKELETAL \- Joint hypermobility Hands \- Clinodactyly \- Camptodactyly \- Prominent fetal pads SKIN, NAILS, & HAIR Hair \- Curly hair MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Global developmental delay \- Delayed walking \- Delayed speech acquisition \- Intellectual disability \- Seizures (in some patients) \- Thin corpus callosum \- Agenesis of the corpus callosum (in some patients) \- Small cerebral cortex (in some patients) MISCELLANEOUS \- De novo mutation MOLECULAR BASIS \- Caused by mutation in the cyclin-dependent kinase 13 gene (CDK13, 603309.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| CONGENITAL HEART DEFECTS, DYSMORPHIC FACIAL FEATURES, AND INTELLECTUAL DEVELOPMENTAL DISORDER | c4479246 | 6,888 | omim | https://www.omim.org/entry/617360 | 2019-09-22T15:46:02 | {"omim": ["617360"], "genereviews": ["NBK536784"]} |
## Summary
### Clinical characteristics.
VPS13D movement disorder is a hyperkinetic movement disorder (dystonia, chorea, and/or ataxia) of variable age of onset that can be associated with developmental delay. Onset ranges from birth to adulthood. Individuals can present in childhood with motor delays and gait instability. Cognitive impairment ranging from mild intellectual disability to developmental delay has been reported, and several individuals have normal cognitive function. Individuals have also presented as young adults with gait difficulties caused by spastic ataxia or ataxia. In addition to gait ataxia, affected individuals had limb ataxia, dysarthria, and eye movement abnormalities (macro-saccadic oscillations, nystagmus, and saccadic pursuit). Additional features reported in some individuals include peripheral neuropathy and/or seizures. The disorder progresses to spastic ataxia or generalized dystonia, which can lead to loss of independent ambulation.
### Diagnosis.
The diagnosis of VPS13D movement disorder is established in a proband by identification of biallelic pathogenic variants in VPS13D on molecular genetic testing.
### Management.
Treatment of manifestations: Standard treatment for seizures; spasticity treatments include baclofen, tizanidine, benzodiazepines, dantrolene sodium, gabapentin, botulinum toxin injections, and intrathecal baclofen; treatment options for dystonia include trihexyphenidyl, botulinum toxin injections, benzodiazepines, baclofen, and levodopa. A multidisciplinary team including occupational and physical therapists and a physiatrist is important; supportive developmental therapies should be provided as needed.
Surveillance: Monitor for urinary urgency, contractures, and seizures; evaluate fall risk and gait stability; monitor developmental progress and educational needs.
### Genetic counseling.
VPS13D movement disorder is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the VPS13D pathogenic variants in the family are known.
## Diagnosis
### Suggestive Findings
VPS13D movement disorder should be suspected in individuals with the following clinical, laboratory, and imaging findings.
Clinical presentation
* Infantile-onset hypotonia and severe developmental delay or motor delay that progresses to severe generalized dystonia or spastic ataxia
* Childhood-onset chorea or dystonia
* Early-adulthood-onset progressive spastic ataxia, dystonia, and myoclonus
Additional clinical features
* Macro-saccadic intrusions; these large abnormal back-and-forth eye movements with stationary inter-saccadic intervals are often triggered by saccades.
* Pyramidal signs (e.g., hyperreflexia, Babinski signs)
* Peripheral axonal neuropathy
* Seizures
Laboratory findings
* Elevated CSF lactate (in 1 individual) [Gauthier et al 2018]
* Enlarged mitochondria with altered morphology on muscle biopsy; identified in the only individual evaluated by muscle biopsy [Gauthier et al 2018, Seong et al 2018]
Brain MRI findings
* Symmetric T2-weighted and FLAIR hyperintensities in the caudate and putamen
* Hyperintense T2-weighted and FLAIR signal abnormalities of periventricular and subcortical regions
* Hypointense basal ganglia (globus pallidus)
* Thin corpus callosum [Gauthier et al 2018]
* Mild cerebellar atrophy, often involving the vermis [Seong et al 2018]
Note: Brain MRI findings can be striking, but imaging results vary among individuals with VPS13D movement disorder. Imaging findings can resemble those seen in Leigh syndrome. Some individuals with VPS13D movement disorder have had normal brain MRI examinations.
### Establishing the Diagnosis
The diagnosis of VPS13D movement disorder is established in a proband by identification of biallelic pathogenic variants in VPS13D on molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of VPS13D movement disorder is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with developmental delay and/or movement disorder are more likely to be diagnosed using genomic testing (see Option 2).
#### Option 1
When the phenotypic and laboratory findings suggest the diagnosis of VPS13D movement disorder, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
* Single-gene testing. Sequence analysis of VPS13D detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
* A multigene panel that includes VPS13D and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the relatively recent description of VPS13D movement disorder, some panels for developmental delay and/or movement disorder may not yet include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
#### Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by developmental delay and/or movement disorder, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
### Table 1.
Molecular Genetic Testing Used in VPS13D Movement Disorder
View in own window
Gene 1Test MethodProportion of Pathogenic Variants 2
Detectable by This Method
VPS13DSequence analysis 323/24 4
Gene-targeted deletion/duplication analysis 51/24 6
1\.
See Table A. Genes and Databases for chromosome locus and protein.
2\.
See Molecular Genetics for information on allelic variants detected in this gene.
3\.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4\.
Gauthier et al [2018], Seong et al [2018]
5\.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
6\.
Partial duplication of VPS13D exons 24 to 30 was reported in one family [Gauthier et al 2018].
## Clinical Characteristics
### Clinical Description
To date, 19 individuals from 12 families have been identified with VPS13D movement disorder. This disorder is characterized by hyperkinetic movement (dystonia, chorea, or ataxia) of variable onset that can be associated with developmental delay. Onset ranging from birth to age 39 years has been reported. Eleven individuals presented in childhood with mainly motor delays and gait instability. Of those, two individuals had arm tremor, one had chorea, and one had torticollis at presentation. Eight individuals presented as young adults with gait difficulties caused by spastic ataxia or ataxia. In addition to gait ataxia, those presenting in young adulthood also had limb ataxia, dysarthria, and eye movement abnormalities (macro-saccadic oscillations, nystagmus, and saccadic pursuit). The disorder progresses to spastic ataxia or generalized dystonia, which can lead to loss of independent ambulation.
Developmental delay. Eleven individuals presented as children with mainly motor delay. However, four individuals have mild intellectual disability and two have developmental delay.
Movement disorder. Dystonia in reported individuals has included generalized dystonia, cervical dystonia, laryngeal dystonia, and bibrachial dystonia with tremor. Other movement disorders reported include chorea and, more rarely, stereotypies and myoclonus.
Pyramidal signs. Most individuals had hyperreflexia, extensor cutaneous plantar signs, and lower-limb (more than upper-limb) spasticity.
Peripheral neuropathy has been reported and is characterized by decreased or absent ankle reflexes (in 2 families) and abnormal deep sensory function. EMG and nerve conduction studies in a few individuals showed sensorimotor axonal neuropathy. Pes cavus is described in one individual. Several adults also had muscle atrophy and lower-limb weakness.
Oculomotor findings have included horizontal macro-saccadic pursuits and square wave jerks. These two entities are often confused and macro-saccadic oscillations are more typical of a cerebellar involvement. In addition, individuals presented with jerky pursuit, hypermetric saccades, and gaze-evoked nystagmus.
Seizures. Three individuals were reported to have childhood-onset seizures. No further details about seizure type or EEG findings were available. One individual was treated with phenobarbital and diazepam.
Brain MRI findings can be striking, but imaging results vary among individuals with VPS13D movement disorder. Reported findings include symmetric T2-weighted and FLAIR hyperintensities in the caudate and putamen, hyperintense T2-weighted and FLAIR signal abnormalities of periventricular and subcortical regions, hypointense basal ganglia (globus pallidus), thin corpus callosum [Gauthier et al 2018], and mild cerebellar atrophy, often involving the vermis [Seong et al 2018]. Imaging findings can resemble those seen in Leigh syndrome. Some individuals with VPS13D movement disorder have had normal brain MRI.
Muscle biopsy in one individual showed abnormal subsarcolemmal mitochondrial accumulation and mild lipidosis suggestive of mitochondrial disease. However, enzymatic analysis for respiratory chain function was normal [Gauthier et al 2018].
Other
* Male infertility associated with azoospermia or oligospermia was reported in two individuals.
* Abnormal head size. Both microcephaly (in 2 individuals) and macrocephaly (1 individual) have been described; no further details were available.
* Hearing loss. One individual was reported to have progressive hearing loss; no further details were available.
### Genotype-Phenotype Correlations
No clear genotype-phenotype correlations are known.
### Nomenclature
VPS13D movement disorder was initially described as spinocerebellar ataxia with saccadic intrusions (SCASI) associated with the spinocerebellar ataxia, recessive type 4 (SCAR4) locus [Swartz et al 2002].
### Prevalence
VPS13D movement disorder is rare and has been described in 19 individuals from 12 families. The families are mainly of European descent (French Canadian, German, Dutch, Slovenian, Italian) [Gauthier et al 2018, Seong et al 2018]. One Indonesian and one Egyptian family have also been described [Gauthier et al 2018, Seong et al 2018].
## Differential Diagnosis
### Table 2.
Disorders to Consider in the Differential Diagnosis of VPS13D Movement Disorder
View in own window
DisorderGene(s)MOIClinical Features of the Differential Diagnosis Disorder
Overlapping w/VPS13D
movement disorderDistinguishing from VPS13D
movement disorder
Spastic ataxia 1 1VAMP1ADSpastic ataxic gait
* Adult onset
* No dystonia
* Normal brain MRI
Spastic ataxia 2 1KIF1CARPediatric-onset spastic ataxic gaitNo extrapyramidal involvement
Spastic ataxia 3 1MARS2AR
* Spastic ataxic gait
* White matter abnormalities
Hearing impairment
Spastic ataxia 4 1MTPAPARSpastic ataxiaNeuropathy w/loss of reflexes
Spastic ataxia 5 1AFG3L2AR
* Pediatric-onset spastic ataxia
* Dystonia
* Myoclonic epilepsy
* Oculomotor apraxia
Leigh syndrome 2ManyAR
XL
mtBilateral basal ganglia lesionsCardiac or skeletal muscle involvement
HSP (incl SPG3A,
SPG4, SPG7,
SPG11) 3ATL1
SPAST
SPG7
SPG11AD
ARPediatric-onset spastic gaitNo cerebellar features
SCAR2 1PMPCAARPediatric-onset ataxic gaitCerebellar atrophy
SCAR7 1TPP1ARPediatric-onset ataxic gaitPosterior column involvement
AD = autosomal dominant; AR = autosomal recessive; HSP = hereditary spastic paraplegia; MOI = mode of inheritance; mt = mitochondrial
SCAR = spinocerebellar ataxia, autosomal recessive; XL = X-linked
1\.
See Hereditary Ataxia Overview.
2\.
See Mitochondrial DNA-Associated Leigh Syndrome and NARP.
3\.
These are the more common subtypes of hereditary spastic paraplegia with onset in childhood.
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with VPS13D movement disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
### Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with VPS13D Movement Disorder
View in own window
System/ConcernEvaluationComment
MusculoskeletalPhysiatry & physiotherapy evaluationTo ensure proper bracing & walking aids
NeurologicNeurologic evaluationEEG, EMG/NCS if clinically indicated
EyesOphthalmologic evaluationEvaluate for macrosaccadic intrusions.
EndocrineFertility evaluation in males of reproductive ageEvaluate for male infertility, oligospermia.
Miscellaneous/
OtherDevelopmental assessmentIncl evaluation of motor, speech/language, general cognitive, & vocational skills
Consultation w/clinical geneticist &/or genetic counselor
EEG = electroencephalogram; EMG = electromyogram; NCS = nerve conduction study
### Treatment of Manifestations
Seizures. Standardized treatment with antiepileptic drugs (AEDs) by an experienced neurologist. Many different AEDs may be effective, and no one AED has been demonstrated to be effective specifically for this disorder. Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.
Spasticity. Recommendations for spasticity treatment include baclofen, tizanidine, benzodiazepines, dantrolene sodium, gabapentin, botulinum toxin injections, and intrathecal baclofen, which are established treatments in a similar condition, Friedreich ataxia [Corben et al 2014].
Dystonia. Treatment options for dystonia include trihexyphenidyl, botulinum toxin injections, benzodiazepines, baclofen, and levodopa [Jinnah & Factor 2015]. Deep brain stimulation has not been reported as a treatment for VPS13D hyperkinetic movement disorder.
Ataxia. No specific pharmacologic treatments for ataxia have been approved. Riluzole is probably effective in reducing ataxia symptoms (European Federation of Neurological Societies [EFNS] – level B rating) and varenicline is probably effective in improving gait and stance in individuals with spinocerebellar ataxia type 3 (SCA3) (EFNS – level B rating ) [van de Warrenburg et al 2014]. Neither of these medications has been tested in individuals with VPS13D spastic ataxia.
A multidisciplinary team including occupational and physical therapists as well as a physiatrist is important in the care of individuals with this complex movement disorder.
#### Developmental Delay / Intellectual Disability Educational Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.
Ages 5-21 years. In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Gross motor dysfunction. Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.
Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy, typically from an occupational or speech therapist, is recommended for affected individuals who have difficulty feeding due to poor oral motor control.
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.
### Surveillance
No specific surveillance guidelines exist. The authors recommend following standard ataxia and spasticity guidelines. Care should include regular visits to a neurologist and physiatrist. A speech therapist and a urologist should be consulted when indicated.
### Table 4.
Recommended Surveillance for Individuals with VPS13D Movement Disorder
View in own window
System/ConcernEvaluation
GenitourinaryAsk about urinary urgency.
MusculoskeletalMonitor contractures.
NeurologicMonitor those w/seizures as clinically indicated; evaluate fall risk & gait stability.
Miscellaneous/OtherMonitor developmental progress & educational needs.
### Agents/Circumstances to Avoid
No specific agents or circumstances are to be avoided aside from excessive alcohol use, which could worsen ataxia.
### Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from developmental services and/or seizure management when appropriate.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Therapies Under Investigation
Studies are currently under way to understand the role of VPS13D in mitochondrial integrity and ultimately develop targeted treatments that can enhance mitochondrial function.
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| VPS13D Movement Disorder | c0087012 | 6,889 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK537720/ | 2021-01-18T20:50:57 | {"mesh": ["D020754"], "synonyms": ["Spinocerebellar Ataxia", "Recessive", "Type 4 (SCAR4); Spinocerebellar Ataxia with Saccadic Intrusion (SCASI); VPS13D Hyperkinetic Movement Disorder"]} |
A rare, epithelial tumor of the pancreas characterized, histologically, by columnar, mucin-producing epithelium associated with ovarian-type subepithelial stroma, which does not communicate with the pancreatic ductal system, most frequently localized to the body or tail of the pancreas. Clinically, small tumors (<3 cm) are usually asymptomatic, while large tumors typically present obstructive jaundice, a palpable abdominal mass, and may associate portal hypertension, hemobilia and diabetes mellitus.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Mucinous cystadenocarcinoma of the pancreas | c2063873 | 6,890 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=424053 | 2021-01-23T18:04:14 | {"umls": ["C2063873"], "icd-10": ["C25.0", "C25.1", "C25.2", "C25.7", "C25.8"], "synonyms": ["Pancreatic mucinous cystadenocarcinoma"]} |
Human disease
Postpartum infections
Other namesPuerperal fever, childbed fever, maternal sepsis, maternal infection, puerperal infections
Streptococcus pyogenes (red-stained spheres) is responsible for many cases of severe puerperal fever. (900× magnification)
SpecialtyObstetrics
SymptomsFever, lower abdominal pain, bad-smelling vaginal discharge[1]
CausesTypically multiple types of bacteria[1]
Risk factorsCesarean section, premature rupture of membranes, prolonged labour, malnutrition, diabetes[1][2]
TreatmentAntibiotics[1]
Frequency11.8 million[3]
Deaths17,900[4]
Postpartum infections, also known as childbed fever and puerperal fever, are any bacterial infections of the female reproductive tract following childbirth or miscarriage.[1] Signs and symptoms usually include a fever greater than 38.0 °C (100.4 °F), chills, lower abdominal pain, and possibly bad-smelling vaginal discharge.[1] It usually occurs after the first 24 hours and within the first ten days following delivery.[5]
The most common infection is that of the uterus and surrounding tissues known as puerperal sepsis, postpartum metritis, or postpartum endometritis.[1][6] Risk factors include Caesarean section (C-section), the presence of certain bacteria such as group B streptococcus in the vagina, premature rupture of membranes, multiple vaginal exams, manual removal of the placenta, and prolonged labour among others.[1][2] Most infections involve a number of types of bacteria.[1] Diagnosis is rarely helped by culturing of the vagina or blood.[1] In those who do not improve, medical imaging may be required.[1] Other causes of fever following delivery include breast engorgement, urinary tract infections, infections of an abdominal incision or an episiotomy, and atelectasis.[1][2]
Due to the risks following Caesarean section, it is recommended that all women receive a preventive dose of antibiotics such as ampicillin around the time of surgery.[1] Treatment of established infections is with antibiotics, with most people improving in two to three days.[1] In those with mild disease, oral antibiotics may be used; otherwise intravenous antibiotics are recommended.[1] Common antibiotics include a combination of ampicillin and gentamicin following vaginal delivery or clindamycin and gentamicin in those who have had a C-section.[1] In those who are not improving with appropriate treatment, other complications such an abscess should be considered.[1]
In 2015, about 11.8 million maternal infections occurred.[3] In the developed world about one to two percent develop uterine infections following vaginal delivery.[1] This increases to five to thirteen percent among those who have more difficult deliveries and 50 percent with C-sections before the use of preventive antibiotics.[1] In 2015, these infections resulted in 17,900 deaths down from 34,000 deaths in 1990.[4][7] They are the cause of about 10% of deaths around the time of pregnancy.[2] The first known descriptions of the condition date back to at least the 5th century BCE in the writings of Hippocrates.[8] These infections were a very common cause of death around the time of childbirth starting in at least the 18th century until the 1930s when antibiotics were introduced.[9] In 1847, Hungarian physician Ignaz Semmelweiss decreased death from the disease in the First Obstetrical Clinic of Vienna from nearly twenty percent to two percent through the use of handwashing with calcium hypochlorite.[10][11]
## Contents
* 1 Signs and symptoms
* 2 Causes
* 2.1 Risk factors
* 3 Diagnosis
* 3.1 Differential diagnosis
* 4 Management
* 5 Epidemiology
* 6 History
* 6.1 "The Doctor's Plague"
* 6.2 Hygienic measures
* 6.3 Notable cases
* 7 See also
* 8 References
* 9 Further reading
* 10 External links
## Signs and symptoms[edit]
Signs and symptoms usually include a fever greater than 38.0 °C (100.4 °F), chills, low abdominal pain, and possibly bad smelling vaginal discharge.[1] It usually occurs after the first 24 hours and within the first ten days following delivery.[5]
## Causes[edit]
After childbirth a woman's genital tract has a large bare surface, which is prone to infection. Infection may be limited to the cavity and wall of her uterus, or it may spread beyond to cause septicaemia (blood poisoning) or other illnesses, especially when her resistance has been lowered by a long labour or severe bleeding. Puerperal infection is most common on the raw surface of the interior of the uterus after separation of the placenta (afterbirth); but pathogenic organisms may also affect lacerations of any part of the genital tract. By whatever portal, they can invade the bloodstream and lymph system to cause sepsis, cellulitis (inflammation of connective tissue), and pelvic or generalized peritonitis (inflammation of the abdominal lining). The severity of the illness depends on the virulence of the infecting organism, the resistance of the invaded tissues, and the general health of the woman. Organisms commonly producing this infection are Streptococcus pyogenes; staphylococci (inhabitants of the skin and of pimples, carbuncles, and many other pustular eruptions); the anaerobic streptococci, which flourish in devitalized tissues such as may be present after long and injurious labour and unskilled instrumental delivery; Escherichia coli and Clostridium perfringens (inhabitants of the lower bowel); and Clostridium tetani.
### Risk factors[edit]
Causes (listed in order of decreasing frequency) include endometritis, urinary tract infection, pneumonia/atelectasis, wound infection, and septic pelvic thrombophlebitis. Septic risk factors for each condition are listed in order of the postpartum day (PPD) on which the condition generally occurs.
* PPD 0: atelectasis risk factors include general anesthesia, cigarette smoking, and obstructive lung disease.
* PPD 1–2: urinary tract infections risk factors include multiple catheterization during labor, multiple vaginal examinations during labor, and untreated bacteriuria.
* PPD 2–3: endometritis ( the most common cause ) risk factors include emergency cesarean section, prolonged membrane rupture, prolonged labor, and multiple vaginal examinations during labor.
* PPD 4–5: wound infection risk factors include emergency cesarean section, prolonged membrane rupture, prolonged labor, and multiple vaginal examination during labor.
* PPD 5–6: septic pelvic thrombophlebitis risk factors include emergency cesarean section, prolonged membrane rupture, prolonged labor, and diffuse difficult vaginal childbirth.
* PPD 7–21: mastitis risk factors include nipple trauma from breastfeeding.
## Diagnosis[edit]
Puerperal fever is diagnosed with:
* A temperature rise above 38 °C (100.4 °F) maintained over 24 hours or recurring during the period from the end of the first to the end of the 10th day after childbirth or abortion. (ICD-10)
* Oral temperature of 38 °C (100.4 °F) or more on any two of the first ten days postpartum. (USJCMW)[12]
Puerperal fever (from the Latin puer, male child (boy)), is no longer favored as a diagnostic category. Instead, contemporary terminology specifies:[13]
1. the specific target of infection: endometritis (inflammation of the inner lining of the uterus), metrophlebitis (inflammation of the veins of the uterus), and peritonitis (inflammation of the membrane lining of the abdomen).
2. the severity of the infection: less serious infection (contained multiplication of microbes) or possibly life-threatening sepsis (uncontrolled and uncontained multiplication of microbes throughout the blood stream).
Endometritis is a polymicrobial infection. It frequently includes organisms such as Ureaplasma, Streptococcus, Mycoplasma, and Bacteroides, and may also include organisms such as Gardnerella, Chlamydia, Lactobacillus, Escherichia, and Staphylococcus.[14]
### Differential diagnosis[edit]
A number of other conditions can cause fevers following delivery including: urinary tract infections, breast engorgement, atelectasis and surgical incisions, among others.[1]
## Management[edit]
Antibiotics have been used to prevent and treat these infections—however, the misuse of antibiotics is a serious problem for global health.[2] It is recommended that guidelines be followed that outline when it is appropriate to give antibiotics and which antibiotics are most effective.[2]
Atelectasis: mild to moderate fever, no changes or mild rales on chest auscultation.
Management: pulmonary exercises, ambulation (deep breathing and walking).
Urinary tract infection: high fever, malaise, costovertebral tenderness, positive urine culture.
Management: antibiotics as per culture sensitivity (cephalosporine).
Endometritis: moderate fever, exquisite uterine tenderness, minimal abdominal findings.
Management: multiple agent IV antibiotics to cover polymicrobial organisms: clindamycin, gentamicin, addition of ampicillin if no response, no cultures are necessary.
Wound infection: persistent spiking fever despite antibiotics, wound erythema or fluctuance, wound drainage.
Management: antibiotics for cellulitis, open and drain wound, saline-soaked packing twice a day, secondary closure.
Septic pelvic thrombophlebitis: persistent wide fever swings despite antibiotics, usually normal abdominal or pelvic exams.
Management: IV heparin for 7–10 days at rates sufficient to prolong the PTT to double the baseline values.
Mastitis: unilateral, localized erythema, edema, tenderness.
Management: antibiotics for cellulitis, open and drain abscess if present.
## Epidemiology[edit]
The number of cases of puerperal sepsis per year shows wide variations among published literature—this may be related to different definitions, recordings etc.[12] Globally, bacterial infections are the cause of 10% of maternal deaths—this is more common in low income countries but is also a direct cause of maternal deaths in high income countries.[2][15]
In the United States, puerperal infections are believed to occur in between one and eight percent of all births. About three die from puerperal sepsis for every 100,000 births. The single most important risk factor is Caesarean section.[16] The number of maternal deaths in the United States is about 13 in 100,000. They make up about 11% of pregnancy related deaths in the United States.[1]
In the United Kingdom from 1985–2005, the number of direct deaths associated with genital tract sepsis per 100,000 pregnancies was 0.40–0.85.[17] In 2003–2005, genital tract sepsis accounted for 14% of direct causes of maternal death.[18]
Puerperal infections in the 18th and 19th centuries affected, on average, 6 to 9 women in every 1,000 births, killing two to three of them with peritonitis or sepsis. It was the single most common cause of maternal mortality, accounting for about half of all deaths related to childbirth, and was second only to tuberculosis in killing women of childbearing age. A rough estimate is that about 250,000–500,000 died from puerperal fever in the 18th and 19th centuries in England and Wales alone.[19]
## History[edit]
Although it had been recognized from as early as the time of the Hippocratic corpus that women in childbed were prone to fevers, the distinct name, "puerperal fever" appears in historical records only from the early 18th century.[20]
The death rate for women giving birth decreased in the 20th century in developed countries. The decline may be partly attributed to improved environmental conditions, better obstetrical care, and the use of antibiotics. Another reason appears to be a lessening of the virulence or invasiveness of Streptococcus pyogenes. This organism is also the cause of scarlet fever, which over the same period has also declined markedly in severity and incidence.[citation needed]
### "The Doctor's Plague"[edit]
In his 1861 book, Ignaz Semmelweis presented evidence to demonstrate that the advent of pathological anatomy in Vienna in 1823 (vertical line) was correlated to the incidence of fatal childbed fever there. Onset of chlorine handwash in 1847 marked by vertical line. Rates for Dublin maternity hospital, which had no pathological anatomy, is shown for comparison (view rates). His efforts were futile, however.
From the 1600s through the mid-to-late 1800s, the majority of childbed fever cases were caused by the doctors themselves. With no knowledge of germs, doctors did not believe hand washing was needed.
Hospitals for childbirth became common in the 17th century in many European cities. These "lying-in" hospitals were established at a time when there was no knowledge of antisepsis or epidemiology, and women were subjected to crowding, frequent vaginal examinations, and the use of contaminated instruments, dressings, and bedding. It was common for a doctor to deliver one baby after another, without washing his hands or changing clothes between patients.
The first recorded epidemic of puerperal fever occurred at the Hôtel-Dieu de Paris in 1646. Hospitals throughout Europe and America consistently reported death rates between 20% to 25% of all women giving birth, punctuated by intermittent epidemics with up to 100% fatalities of women giving birth in childbirth wards.[21]
In the 1800s Ignaz Semmelweis noticed that women giving birth at home had a much lower incidence of childbed fever than those giving birth in the doctor's maternity ward. His investigation discovered that washing hands with an antiseptic, in this case a calcium chloride solution, before a delivery reduced childbed fever fatalities by 90%.[22] Publication of his findings was not well received by the medical profession. The idea conflicted both with the existing medical concepts and with the image doctors had of themselves.[23] The scorn and ridicule of doctors was so extreme that Semmelweis moved from Vienna and, after suffering a breakdown, was eventually committed to a mental asylum where he died.[24]
Semmelweis was not the only doctor ignored after sounding a warning about this issue: in Treatise on the Epidemic of Puerperal Fever (1795), ex-naval surgeon and Aberdonian obstetrician Alexander Gordon (1752–1799) warned that the disease was transmitted from one case to another by midwives and doctors. Gordon wrote, "It is a disagreeable declaration for me to mention, that I myself was the means of carrying the infection to a great number of women."[25][26]
Thomas Watson (1792–1882), Professor of Medicine at King's College Hospital, London, wrote in 1842: "Wherever puerperal fever is rife, or when a practitioner has attended any one instance of it, he should use most diligent ablution." Watson recommended handwashing with chlorine solution and changes of clothing for obstetric attendants "to prevent the practitioner becoming a vehicle of contagion and death between one patient and another."[27][28]
### Hygienic measures[edit]
Ignaz Semmelweis, discoverer of some of the causes of puerperal fever
In 1843, Oliver Wendell Holmes Sr. published The Contagiousness of Puerperal Fever and controversially concluded that puerperal fever was frequently carried from patient to patient by physicians and nurses; he suggested that clean clothing and avoidance of autopsies by those aiding birth would prevent the spread of puerperal fever.[29][30] Holmes quoted Dr. James Blundell as stating, "... in my own family, I had rather that those I esteemed the most should be delivered unaided, in a stable, by the mangerside, than that they should receive the best help, in the fairest apartment, but exposed to the vapors of this pitiless disease."[31]
Holmes' conclusions were ridiculed by many contemporaries, including Charles Delucena Meigs, a well-known obstetrician, who stated, "Doctors are gentlemen, and gentlemen's hands are clean."[32][33] Richard Gordon states that Holmes' exhortations "outraged obstetricians, particularly in Philadelphia".[34] In those days, "surgeons operated in blood-stiffened frock coats—the stiffer the coat, the prouder the busy surgeon", "pus was as inseparable from surgery as blood", and "Cleanliness was next to prudishness". He quotes Sir Frederick Treves on that era: "There was no object in being clean. Indeed, cleanliness was out of place. It was considered to be finicking and affected. An executioner might as well manicure his nails before chopping off a head".[35][36]
In 1844, Ignaz Semmelweis was appointed assistant lecturer in the First Obstetric Division of the Vienna General Hospital (Allgemeines Krankenhaus), where medical students received their training. Working without knowledge of Holmes' essay, Semmelweis noticed his ward's 16% mortality rate from fever was substantially higher than the 2% mortality rate in the Second Division, where midwifery students were trained. Semmelweis also noticed that puerperal fever was rare in women who gave birth before arriving at the hospital. Semmelweis noted that doctors in First Division performed autopsies each morning on women who had died the previous day, but the midwives were not required or allowed to perform such autopsies. He made the connection between the autopsies and puerperal fever after a colleague, Jakob Kolletschka, died of sepsis after accidentally cutting his hand while performing an autopsy.
Semmelweis began experimenting with various cleansing agents and, from May 1847, ordered all doctors and students working in the First Division wash their hands in chlorinated lime solution before starting ward work, and later before each vaginal examination. The mortality rate from puerperal fever in the division fell from 18% in May 1847 to less than 3% in June–November of the same year.[37] While his results were extraordinary, he was treated with skepticism and ridicule (see Response to Semmelweis).
He did the same work in St. Rochus hospital in Pest, Hungary, and published his findings in 1860, but his discovery was again ignored.[38]
In 1935, Leonard Colebrook showed Prontosil was effective against haemolytic streptococcus and hence a cure for puerperal fever.[39][40]
### Notable cases[edit]
See also: List of women who died in childbirth
Elite status was no protection against postpartum infections, as the deaths of several English queens attest. Elizabeth of York, queen consort of Henry VII, died of puerperal fever one week after giving birth to a daughter, who also died. Her son Henry VIII had two wives who died this way, Jane Seymour and Catherine Parr.
Suzanne Barnard, mother of philosopher Jean-Jacques Rousseau, contracted childbed fever after giving birth to him, and died nine days later. Her infant son was also in perilous health following the birth; the adult Rousseau later wrote that "I came into the world with so few signs of life that little hope was entertained of preserving me". He was nursed back to health by an aunt.[41] French natural philosopher Émilie du Châtelet died in 1749. Mary Wollstonecraft, author of Vindication of the Rights of Woman, died ten days after giving birth to her second daughter, who grew up to write Frankenstein. Other notable victims include African-American poet Phillis Wheatley (1784), British housekeeping authority Isabella Beeton, and American author Jean Webster in 1916 died of puerperal fever.
In Charles Dickens' novel A Christmas Carol, it is implied that both Scrooge's mother and younger sister perished from this condition, explaining the character's animosity towards his nephew Fred and also his poor relationship with his own father[citation needed].
## See also[edit]
* Postpartum confinement, a traditional practice after childbirth
## References[edit]
1. ^ a b c d e f g h i j k l m n o p q r s t u v "37". Williams Obstetrics (24th ed.). McGraw-Hill Professional. 2014. pp. Chapter 37. ISBN 978-0-07-179893-8.
2. ^ a b c d e f g WHO recommendations for prevention and treatment of maternal peripartum infections (PDF). World Health Organization. 2015. p. 1. ISBN 978-9241549363. PMID 26598777. Archived (PDF) from the original on 2016-02-07.
3. ^ a b GBD 2015 Disease and Injury Incidence and Prevalence, Collaborators. (8 October 2016). "Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1545–1602. doi:10.1016/S0140-6736(16)31678-6. PMC 5055577. PMID 27733282.
4. ^ a b GBD 2015 Mortality and Causes of Death, Collaborators. (8 October 2016). "Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1459–1544. doi:10.1016/s0140-6736(16)31012-1. PMC 5388903. PMID 27733281.
5. ^ a b Hiralal Konar (2014). DC Dutta's Textbook of Obstetrics. JP Medical Ltd. p. 432. ISBN 978-93-5152-067-2. Archived from the original on 2015-12-08.
6. ^ "Cover of Hacker & Moore's Essentials of Obstetrics and Gynecology". Hacker & Moore's essentials of obstetrics and gynecology (6 ed.). Elsevier Canada. 2015. pp. 276–290. ISBN 978-1455775583.
7. ^ GBD 2013 Mortality and Causes of Death, Collaborators (17 December 2014). "Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013". Lancet. 385 (9963): 117–171. doi:10.1016/S0140-6736(14)61682-2. PMC 4340604. PMID 25530442.
8. ^ Walvekar, Vandana (2005). Manual of perinatal infections. New Delhi: Jaypee Bros. p. 153. ISBN 978-81-8061-472-9. Archived from the original on 2016-03-04.
9. ^ Magner, Lois N. (1992). A history of medicine. New York: Dekker. pp. 257–258. ISBN 978-0-8247-8673-1.
10. ^ Anderson, BL (April 2014). "Puerperal group A streptococcal infection: beyond Semmelweis". Obstetrics and Gynecology. 123 (4): 874–882. doi:10.1097/aog.0000000000000175. PMID 24785617.
11. ^ Ataman, AD; Vatanoğlu-Lutz, EE; Yıldırım, G (2013). "Medicine in stamps-Ignaz Semmelweis and Puerperal Fever". Journal of the Turkish German Gynecological Association. 14 (1): 35–9. doi:10.5152/jtgga.2013.08. PMC 3881728. PMID 24592068.
12. ^ a b The Global Incidence of Puerperal Sepsis Protocol for a Systematic Review Archived 2008-12-17 at the Wayback Machine
13. ^ Carter (2005):98
14. ^ Berenson, AB (April 1990). "Bacteriologic Findings of Post-Cesarian Endometritis in Adolescents". Obstetrics and Gynecology. 75 (4): 627–629. PMID 2314783. Archived from the original on 2013-11-03.
15. ^ "WHO recommendations for prevention and treatment of maternal peripartum infections" (PDF). Archived (PDF) from the original on 2016-03-06.
16. ^ Carter, K. Codell; Carter, Barbara R. (2005). Childbed fever. A scientific biography of Ignaz Semmelweis. Transaction Publishers. p. 100. ISBN 978-1-4128-0467-7.
17. ^ Lewis, Gwyneth, ed. (2007). Saving Mothers' Lives: Reviewing maternal deaths to make motherhood safer – 2003–2005. The Seventh Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. CEMACH. p. 97. ISBN 978-0-9533536-8-2.[permanent dead link]
18. ^ CEMACH: Saving Mothers' Lives 2003–2005 Archived 2008-05-21 at the Wayback Machine
19. ^ Loudon, Irvine (9 March 2000). The Tragedy of Childbed Fever (PDF). Oxford University Press, USA. p. 6. ISBN 978-0-19-820499-2. Archived from the original (PDF) on 11 February 2012.
20. ^ The debate about when this term first emerged is presented by Irvine Loudon, The tragedy of childbed fever, Oxford University Press, 2000, p. 8.
21. ^ Loudon I. "Deaths in childbed from the eighteenth century to 1935". Med History 1986; 30: 1–41
22. ^ Caplan, Caralee E. (1995). "The Childbed Fever Mystery and the Meaning of Medical Journalism". McGill Journal of Medicine. 1 (1). Archived from the original on 2012-07-07.
23. ^ Wyklicky H, Skopec M (1983). "Ignaz Philipp Semmelweis, the prophet of bacteriology". Infect Control. 4 (5): 367–370. doi:10.1017/S0195941700059762. PMID 6354955.
24. ^ De Costa, Caroline M (Nov 2002). ""The contagiousness of childbed fever": a short history of puerperal sepsis and its treatment". The Medical Journal of Australia. 177 (11–12): 668–671. doi:10.5694/j.1326-5377.2002.tb05004.x. PMID 12463995. S2CID 12164328. Archived from the original on 2006-12-03.
25. ^ Gordon, Alexander (1795). A Treatise on the Epidemic Puerperal Fever of Aberdeen. London, England: G.G. and J. Robinson. pp. 63–64. On p. 63, Gordon recognized the puerperal fever as infectious: "But this disease seized such women only, as were visited, or delivered, by a practitioner, or taken care of by a nurse, who had previously attended patients affected with the disease. In short, I had evident proofs of its infectious nature, and that the infection was as readily communicated as that of the smallpox, or measles, and operated more speedily than any other infection, with which I am acquainted." From p. 64: "It is a disagreeable declaration for me to mention, that I myself was the means of carrying the infection to a great number of women."
26. ^ "Treatise on the Epidemic of Puerperal Fever". www.general-anaesthesia.com. Archived from the original on July 20, 2008. Retrieved September 15, 2011.
27. ^ Watson (February 18, 1842). "Lectures on the principles and practice of physic: Diseases of the abdomen". The London Medical Gazette. 29: 801–808. From p. 806: "Whenever puerperal fever is rife, or when a practitioner has attended any one example of it, he should use most diligent ablution; he should even wash his hands with some disinfecting fluid, a weak solution of chlorine for instance: he should avoid going in the same dress to any other of his midwifery patients: in short, he should take all those precautions which, when the danger is understood, common sense will suggest, against his clothes or his body becoming a vehicle of contagion and death between one patient and another."
28. ^ The Medical Journal of Australia."The contagiousness of childbed fever: a short history of puerperal sepsis and its treatment" Archived 2006-12-03 at the Wayback Machine
29. ^ Holmes, Oliver W. (1842–1843). "On the contagiousness of puerperal fever". The New England Quarterly Journal of Medicine. 1: 503–530.
30. ^ Oliver Wendell Holmes: The Contagiousness of Puerperal Fever Archived 2007-02-03 at the Wayback Machine
31. ^ (Holmes, 1842–1843), p. 510.
32. ^ Meigs, Charles Delucena (1854). On the Nature, Signs, and Treatment of Childbed Fevers: In a Series of Letters Addressed to the Students of His Class. Philadelphia, Pennsylvania: Blanchard and Lea. p. 104. From p. 104: Speaking of a physician in Philadelphia, Pennsylvania, Meigs said: "He is a gentlemen who is scrupulously careful of his personal appearance, … But a gentleman's hands are clean."
33. ^ Henderson, David K.; Lee, Laura M.; Palmore, Tara N. (June 1, 2014). "The contemporary Semmelweis reflex: History as an imperfect educator". Infection Control Today.
34. ^ Gordon, Richard (1983). "Disastrous Motherhood: Tales from the Vienna Wards". Great Medical Disasters. London: Hutchinson & Co. pp. 43–46 [43].
35. ^ Treves, Frederick (1923). "Ch. 2: The Old Receiving Room". The Elephant Man and Other Reminiscences. London, England: Cassell and Company, Ltd. pp. 56–57.
36. ^ Gordon, Richard (1983) p. 44
37. ^ Raju, T. N. (1999). "Ignác Semmelweis and the etiology of fetal and neonatal sepsis". Journal of Perinatology. 19 (4): 307–310. doi:10.1038/sj.jp.7200155. PMID 10685244.
38. ^ Christa Colyer."Childbed fever: a nineteenth-century mystery," Archived 2009-04-16 at the Wayback Machine National Center for Case Study Teaching in Science, December 8, 1999 (revised October 27, 2003).
39. ^ Colebrook, L; Kenny, M (June 6, 1936). "Treatment of Human Puerperal Infections, and of Experimental Infections in Mice, with Prontosil".Lancet 227(1): 1279–1286.
40. ^ Sue Bale; Vanessa Jones (2006). Wound care nursing. Elsevier Health Sciences. p. 54. ISBN 978-0-7234-3344-6. Retrieved 2009-08-05.
41. ^ Quoted from Will Durant's "The Age of Rousseau".[full citation needed]
## Further reading[edit]
* Chaim W, Burstein E (August 2003). "Postpartum infection treatments: a review". Expert Opinion on Pharmacotherapy (review). 4 (8): 1297–313. doi:10.1517/14656566.4.8.1297. PMID 12877638. S2CID 26781321.
* French L (August 2003). "Prevention and treatment of postpartum endometritis". Current Women's Health Reports (review). 3 (4): 274–9. PMID 12844449.
* Calhoun BC, Brost B (June 1995). "Emergency management of sudden puerperal fever". Obstetrics and Gynecology Clinics of North America (review). 22 (2): 357–67. PMID 7651676.
## External links[edit]
Classification
D
* ICD-10: O85
* ICD-9-CM: 672
* MeSH: D011645
External resources
* eMedicine: article/796892
* v
* t
* e
Pathology of pregnancy, childbirth and the puerperium
Pregnancy
Pregnancy with
abortive outcome
* Abortion
* Ectopic pregnancy
* Abdominal
* Cervical
* Interstitial
* Ovarian
* Heterotopic
* Embryo loss
* Fetal resorption
* Molar pregnancy
* Miscarriage
* Stillbirth
Oedema, proteinuria and
hypertensive disorders
* Gestational hypertension
* Pre-eclampsia
* HELLP syndrome
* Eclampsia
Other, predominantly
related to pregnancy
Digestive system
* Acute fatty liver of pregnancy
* Gestational diabetes
* Hepatitis E
* Hyperemesis gravidarum
* Intrahepatic cholestasis of pregnancy
Integumentary system /
dermatoses of pregnancy
* Gestational pemphigoid
* Impetigo herpetiformis
* Intrahepatic cholestasis of pregnancy
* Linea nigra
* Prurigo gestationis
* Pruritic folliculitis of pregnancy
* Pruritic urticarial papules and plaques of pregnancy (PUPPP)
* Striae gravidarum
Nervous system
* Chorea gravidarum
Blood
* Gestational thrombocytopenia
* Pregnancy-induced hypercoagulability
Maternal care related to the
fetus and amniotic cavity
* amniotic fluid
* Oligohydramnios
* Polyhydramnios
* Braxton Hicks contractions
* chorion / amnion
* Amniotic band syndrome
* Chorioamnionitis
* Chorionic hematoma
* Monoamniotic twins
* Premature rupture of membranes
* Obstetrical bleeding
* Antepartum
* placenta
* Circumvallate placenta
* Monochorionic twins
* Placenta accreta
* Placenta praevia
* Placental abruption
* Twin-to-twin transfusion syndrome
Labor
* Amniotic fluid embolism
* Cephalopelvic disproportion
* Dystocia
* Shoulder dystocia
* Fetal distress
* Locked twins
* Nuchal cord
* Obstetrical bleeding
* Postpartum
* Pain management during childbirth
* placenta
* Placenta accreta
* Preterm birth
* Postmature birth
* Umbilical cord prolapse
* Uterine inversion
* Uterine rupture
* Vasa praevia
Puerperal
* Breastfeeding difficulties
* Low milk supply
* Cracked nipples
* Breast engorgement
* Childbirth-related posttraumatic stress disorder
* Diastasis symphysis pubis
* Postpartum bleeding
* Peripartum cardiomyopathy
* Postpartum depression
* Postpartum psychosis
* Postpartum thyroiditis
* Puerperal fever
* Puerperal mastitis
Other
* Concomitant conditions
* Diabetes mellitus
* Systemic lupus erythematosus
* Thyroid disorders
* Maternal death
* Sexual activity during pregnancy
* Category
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
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*[RUS]: Russia
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*[IM]: intramuscular injection
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*[GHB]: γ-hydroxybutyric acid
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*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
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*[EPC]: Early Prostate Cancer
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*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
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| Postpartum infections | c0034041 | 6,891 | wikipedia | https://en.wikipedia.org/wiki/Postpartum_infections | 2021-01-18T19:08:53 | {"mesh": ["D011645"], "icd-9": ["672", "672.0"], "icd-10": ["O85"], "wikidata": ["Q1419347"]} |
Corneal opacity
Other namesCorneal scarring
Corneal opacity with neovascularization
SpecialtyOphthalmology
SymptomsLoss of vision
ComplicationsBlindness
Usual onsetCongenital or acquired
TreatmentCorneal transplantation
Frequency4th main cause of blindness globally (5.1%).[1]
The human cornea is a transparent membrane which allows light to pass through it. The word corneal opacification literally means loss of normal transparency of cornea. The term corneal opacity is used particularly for the loss of transparency of cornea due to scarring. Transparency of the cornea is dependent on the uniform diameter and the regular spacing and arrangement of the collagen fibrils within the stroma. Alterations in the spacing of collagen fibrils in a variety of conditions including corneal edema, scars, and macular corneal dystrophy is clinically manifested as corneal opacity.[2] The word 'Corneal blindness' is commonly used to describe blindness due to corneal opacity.
## Contents
* 1 Types
* 1.1 Nebular corneal opacity
* 1.2 Macular corneal opacity
* 1.3 Leucomatous corneal opacity (leucoma simplex)
* 2 Presentation
* 2.1 Complications
* 2.2 Secondary changes in corneal opacity
* 3 Causes
* 4 Genetics
* 4.1 Congenital Corneal Opacities
* 4.2 Acquired Pediatric Corneal Opacities
* 5 Treatment
* 5.1 Keratoplasty
* 5.2 Optical iridectomy
* 5.3 Phototherapeutic keratectomy (PTK)
* 5.4 Tattooing of scar
* 5.4.1 Techniques
* 5.5 Keratoprosthesis
* 6 Epidemiology
* 6.1 Europe
* 6.2 India
* 7 See also
* 8 References
## Types[edit]
Depending on the density, corneal opacity is graded as nebula, macula and leucoma.
### Nebular corneal opacity[edit]
It is a faint opacity which results due to superficial scars involving Bowman's layer and superficial stroma. A nebular corneal opacity allows the details of the iris to be seen through the opacity. A thin, diffuse nebula covering the pupillary area interferes more with vision than a strictly localized dense leucoma, so long as the latter does not block the whole pupillary area. This is because the leucoma stops all the light which falls upon it, whereas the nebula refracts it irregularly, allowing many of the rays to fall upon the retina where they blur the image formed by the regularly refracted rays.[3]
### Macular corneal opacity[edit]
It is a semi-dense opacity produced when scarring involves about half the corneal stroma.[4]
### Leucomatous corneal opacity (leucoma simplex)[edit]
It is a dense white opacity which results due to scarring of more than half of the stroma [4]
* Adherent leucoma: It results when healing occurs after perforation of cornea with incarceration of iris. The iris is adherent to the back of a leucomatous cornea. One of the major complication of adherent leucoma is Secondary glaucoma [5]
* Corneoiridic scar: If iris tissue is incarcerated and incorporated within the scar tissue, as occurs in healing of a large sloughed corneal ulcer, it is called a corneoiridic scar.[3]
* Corneal facet: Sometimes the corneal surface is depressed at the site of healing (due to less fibrous tissue); such a scar is called facet.[4]
* Kerectasia: In this condition, corneal curvature is increased at the site of opacity (bulge due to weak scar).[4]
## Presentation[edit]
Signs and symptoms include the following:
* Loss of vision or Blindness (when dense opacity covers the pupillary area)[6]
* Blurred vision (due to astigmatic effect and light scattering)[7]
* Glare[8]
### Complications[edit]
Congenital corneal opacity that affecting vision will cause amblyopia. That type of amblyopia is known as form-deprivation amblyopia (or amblyopia ex anopsia). [9]
### Secondary changes in corneal opacity[edit]
Secondary changes may be seen in long-standing cases include: hyaline degeneration, calcareous degeneration, pigmentation and atheromatous ulceration.[4]
## Causes[edit]
* Congenital opacities may occur as developmental anomalies or following birth trauma. Causes of congenital corneal opacities include sclerocornea, trauma, ulcer, mucopolysaccharidosis, Peter’s anomaly, congenital hereditary endothelial dystrophy.[3]
* Ocular trauma [10]
* Corneal ulceration [10]
* Xerophthalmia, caused by Vitamin A deficiency [10]
* Trachoma [11]
* Onchocerciasis [12]
* Mucous membrane pemphigoid: Ocular form of mucous membrane pemphigoid may cause corneal opacity and loss of vision.[13]
## Genetics[edit]
Pediatric corneal opacities may be congenital or acquired.
### Congenital Corneal Opacities[edit]
Congenital reasons for this condition include:
* Congenital hereditary endothelial dystrophy (CHED): There are 2 forms of congenital hereditary endothelial dystrophy (CHED). Commonest is an autosomal recessive form, which is present at birth, but nonprogressive. Nystagmus is seen in association with this form. Another is an autosomal dominant form that occurs within the first few years of life. This form is progressive, but nystagmus is not seen. Deafness and CHED are seen in Harboyan syndrome. The histologic findings are very similar to those seen in pseudophakic/ aphakic bullous keratopathy. The appearance of the cornea is similar to that in congenital glaucoma but without increased corneal diameter and elevated intraocular pressure. [14]
* Posterior Polymorphous Corneal Dystrophy (PPMD, PPCD)[15]: PPCD, also known as Schlichting dystrophy, is an autosomal dominant disorder of the corneal endothelium and Descemet’s membrane. It is usually present in the second or third decade of life. It has the same entity as the first form of CHED. Most cases of PPMD are asymptomatic, and these cases generally do not require treatment. PPMD patients with bilateral, corneal opacities that can affect vision, descemet’s membrane endothelial keratoplasty or penetrating keratoplasty are the treatments of choice to improve vision and to avoid amblyopia.
* Congenital hereditary stromal dystrophy (CHSD): CHSD is also known as Congenital stromal corneal dystrophy or Congenital stromal dystrophy of the cornea. It is a rare autosomal dominant disease caused by mutations in the DCN gene.[16] In this bilateral Snowflake, whitish opacities appear throughout the cornea.[17] The stromal lamellae are abnormal and may be separated by amorphous deposits. Moderate to severe vision loss may occur due to corneal opacity. In case of severe vision loss, treatment of choice is penetrating keratoplasty.[17]
* Peters anomaly:[18] Peters anomaly, also known as iridocorneal adhesions or keratolenticular adhesions, is a posterior corneal defect with an overlying stromal opacity, often accompanied by adherent iris strands (Peters anomaly type 1). The size and density of the opacity can range from a mild to dense central leukoma.
* Congenital Anterior Staphyloma:[19] Congenital anterior staphyloma is a rare form of anterior segment dysgenesis that shares similarities with Peters anomaly. It is characterized by an ectatic protrusion of a central opacified cornea lined by uveal tissue. The protrusion extends beyond the plane of the eyelid margins and it can be unilateral or bilateral.
* Lattice Corneal Dystrophy: Lattice corneal dystrophy is an autosomal-dominant characterized by amyloid deposition in the corneal stroma. Due to deposits, lattice-like corneal opacities may occur in stroma. Three types of dystrophies are there, type 1, type 2 and type 3.[17] Type 1 is also known as Biber-Haab-Dimmer corneal dystrophy, TGFBI type Lattice Dystrophy, or Classic Lattice Dystrophy.[20] LCD type II is not included in corneal dystrophies.[20]
* Granular Corneal Dystrophy:[21] Two types, Type 1 and Type 2 are there. Both have autosomal dominant inheritance. In Type 1, Discrete crumb-like opacities are seen in the central anterior stroma. Visual symptoms such as glare and photophobia may occur early in life. In Type 2, deposits begin to appear in early childhood or adolescence as tiny whitish dots in the anterior stroma. Larger stellate, ring, or snowflake opacities may occur in later stages. Decrease in vision starts earlier in type2 than type1.
* Sclerocornea:[22] Sclerocornea is a congenital disorder in which the cornea is opaque and resembles the sclera, making the limbus indistinct. The central cornea is clearer than the periphery.
* Cystinosis: Cystinosis is a rare autosomal recessive metabolic disease characterized by elevated levels of cystine within the cell.[23] Early deposition of cystine crystals in the cornea cause tinsel-like corneal opacities.[24]
* Ichthyosis: X-linked ichthyosis is a genetic skin disorder caused by the hereditary deficiency of the steroid sulfatase enzyme. Ocular manifestations of XLI include superficial or deep corneal opacities.[25][26]
* Trisomy 8 mosaicism (T8M): It is a rare chromosome disorder caused by the presence of an extra chromosome 8 in some cells of the body. Dense corneal opacities may occur in trisomy 8 mosaicism.[25]
* Farber's disease: Nodular corneal opacity may be seen in association with this rare autosomal recessive disease.[25]
### Acquired Pediatric Corneal Opacities[edit]
Acquired reasons for this condition include:
* Traumatic: Traumatic breaks in Descemet membrane may cause corneal opacity. Injuries to Descemet membrane occur during delivery.[22] Opacity is commonly unilateral.[18]
* Congenital or infantile glaucoma:[18] In Congenital glaucoma, the cornea becomes edematous, cloudy, and enlarged. Treatment should be done to reduce Intraocular pressure.
* Congenital corneal ulcers: Unilateral corneal opacity may occur in association with conjunctival injection and other signs of inflammation.[22]
* Mucopolysaccharidoses:[22] The mucopolysaccharidoses are a group of inherited metabolic diseases caused by the absence or malfunctioning of certain enzymes the body needs to break down molecules called glycosaminoglycans.[27] It is an autosomal recessive disorder. Sometimes, Corneal haze may be present in early life. Treatment options for significant opacities include penetrating keratoplasty and DALK.
## Treatment[edit]
### Keratoplasty[edit]
Main article: Keratoplasty
Keratoplasty also known as corneal transplantation is the main treatment option for visual improvement in corneal opacity. In this, the opaque cornea is replaced with donor tissue. Depending on type and density of corneal opacity different types of keratoplasty may be used such as:[28]
* Penetrating keratoplasty: It is the traditional full thickness corneal transplant procedure, in which trephine (a circular cutting device) is used to cut opaque cornea, a similar-sized portion of the donor cornea is removed with a second trephine. The removed part of donor cornea is known as corneal button. The donor tissue is then sutured to the patient eye. Dense corneal opacity which occupies all the corneal layers may be treated with penetrating keratoplasty.[29]
* Superficial lamellar keratoplasty: Superficial lamellar keratoplasty is used to treat superficial corneal opacities, which occupies superficial one third part of stroma. In this technique, the opaque part of the cornea is removed and replaced with donor tissue, leaving healthy part of the cornea including deeper parts of stroma and endothelium.[29]
* Deep anterior lamellar keratoplasty: DALK may be considered in deep opacities with normal endothelium and descemet's membrane. In this procedure, the anterior layers of cornea are removed and replaced with donor tissue, leaving the endothelial layer and the descemet's membrane in place.[29]
### Optical iridectomy[edit]
Optical iridectomy creates a clear entrance pupil, improving vision in patients with segmental corneal opacities. An area of clear peripheral cornea can produce retinal images compatible with good visual acuity.[30]
### Phototherapeutic keratectomy (PTK)[edit]
Excimer laser phototherapeutic keratectomy (PTK) is useful in superficial (nebular) corneal opacities.[31]
### Tattooing of scar[edit]
Keratopigmentation or corneal tattooing is a procedure used for centuries to improve the cosmetic appearance of corneal scars. Tattooing will not improve vision. For tattooing procedure Indian black ink, gold or platinum may be used.[4]
#### Techniques[edit]
* Staining method: In this technique, tattoo ink is directly applied to anterior surface of cornea. Benefits of this procedure include fast procedure with uniform dye application. Risk of fading is a main drawback.[32]
* Femtosecond laser-assisted corneal tattooing: Femtosecond laser-assisted corneal tattooing is a new corneal tattooing technique, with many benefits.[33]
### Keratoprosthesis[edit]
Main article: Keratoprosthesis
Keratoprosthesis is a surgical procedure where damaged or opaque cornea is replaced with an artificial cornea. Artificial corneas currently in commercial use include Boston keratoprosthesis, Osteo-Odonto-Keratoprosthesis (OOKP), AlphaCor, KeraKlear Artificial Cornea etc.[34][35]
## Epidemiology[edit]
Corneal opacity is the 4th main cause of blindness globally (5.1%).[1] Using the World Health Organization's (WHO; Geneva, Switzerland) blindness definition,1 45 million people worldwide are bilaterally blind, of which 6 to 8 million are blind due to corneal disease. In some African areas, nearly 90% of the total blindness is due to corneal pathology.[36]
### Europe[edit]
The prevalence of congenital corneal opacities (CCO) is estimated to be 3 in 100,000 newborns. This number increases to 6 in 100,000 if congenital glaucoma patients are included. A study of live births in Spain reported that corneal opacities accounted for 3.11% of congenital eye malformations (Bermejo et al, 1998). About 4% of keratoplasties done in the pediatric population in Denmark are due to congenital anomalies (Hovlykke et al, 2014).[37]
### India[edit]
In NPCB survey (2001-2002) Corneal opacity was the 6th major cause of blindness in India, which accounts for 0.9% of total blind population. In the RAAB (Rapid Assessment of Avoidable Blindness) survey (2006-2007) Corneal opacity including Trachoma was mentioned as the second major cause of blindness, which accounts for 6.5% of total blindness.[38]
## See also[edit]
* Corneal transplantation
* Corneal ulcer
* Corneal button
## References[edit]
1. ^ a b "WHO -Priority eye diseases". www.who.int.
2. ^ J Alroy , M Haskins, D E Birk (2001). "Altered Corneal Stromal Matrix Organization Is Associated With Mucopolysaccharidosis I, III and VI". Experimental Eye Research. 68 (5): 523–30. doi:10.1006/exer.1998.0622. PMID 10328965.CS1 maint: multiple names: authors list (link)
3. ^ a b c Ramanjit Sihota; Radhika Tandon (15 July 2015). "The posterior segment". Parsons' diseases of the eye (22 ed.). pp. 195, 221. ISBN 978-81-312-3818-9.
4. ^ a b c d e f AK Khurana. "Diseases of the Cornea". Comprehensive Ophthalmology (6 ed.). Jaypee. pp. 121–122.
5. ^ J Das, S Bhomaj, Z Chaudhuri, P Sharma, A Negi, A Dasgupta (2001). "Profile of Glaucoma in a Major Eye Hospital in North India". Indian Journal of Ophthalmology. 49 (1): 25–30. PMID 15887712.CS1 maint: multiple names: authors list (link)
6. ^ Khurana, AK (31 August 2015). Comprehensive ophthalmology (6th ed.). Jaypee, The Health Sciences Publisher. pp. 133–139. ISBN 978-93-5152-657-5.
7. ^ Shachar Tauber. "Help for Patients With Corneal Scarring". CRSToday.
8. ^ Spadea, Leopoldo; Maraone, Giorgia; Verboschi, Francesca; Vingolo, Enzo Maria; Tognetto, Daniele (18 March 2016). "Effect of corneal light scatter on vision: a review of the literature". International Journal of Ophthalmology. 9 (3): 459–464. doi:10.18240/ijo.2016.03.24. ISSN 2222-3959. PMC 4844042. PMID 27158621.
9. ^ "Amblyopia".
10. ^ a b c John P. Whitcher; M. Srinivasan; Madan P. Upadhyay. "Corneal blindness: a global perspective" (PDF). www.who.int.
11. ^ "What is trachoma".
12. ^ JHubert H Fam (2019-11-21). "Onchocerciasis (African River Blindness)". American Academy of Ophthalmology.
13. ^ Schonberg, Stacy; Stokkermans, Thomas J. (2020). "Ocular Pemphigoid". StatPearls. StatPearls Publishing. PMID 30252356.
14. ^ "Congenital Hereditary Endothelial Dystrophy - EyeWiki". eyewiki.aao.org.
15. ^ "Posterior Polymorphous Corneal Dystrophy - EyeWiki". eyewiki.aao.org.
16. ^ Reference, Genetics Home. "Congenital stromal corneal dystrophy". Genetics Home Reference.
17. ^ a b c "Cornea". Oxford handbook of ophthalmology (4th ed.). Oxford university press. 2018. ISBN 978-0-19-881675-1.
18. ^ a b c Myra Vita F Ocubillo (2018-10-10). "Congenital Clouding of the Cornea: Background, Pathophysiology, Epidemiology".
19. ^ Salour, Hossein; Owji, Nasser; Sadeghipour, Alireza (2009). "Congenital Corneal Staphyloma". Journal of Ophthalmic & Vision Research. 4 (3): 182–184. ISSN 2008-2010. PMC 3498567. PMID 23198071.
20. ^ a b Moshirfar, Majid; West, William; Ronquillo, Yasmyne (2020). "Lattice Corneal Dystrophy". StatPearls. StatPearls Publishing. PMID 32310559.
21. ^ "Granular Corneal Dystrophy: Background, Pathophysiology, Epidemiology". 10 June 2020.
22. ^ a b c d Themes, U. F. O.; Frenkel, Shahar (9 November 2016). "Congenital Corneal Opacity". Ento Key.
23. ^ "Cystinosis | Hereditary Ocular Diseases". disorders.eyes.arizona.edu.
24. ^ Cogan, David G.; Kuwabara, Toichiro (1 January 1960). "Ocular Pathology of Cystinosis: With Particular Reference to the Elusiveness of the Corneal Crystals". Archives of Ophthalmology (Chicago, Ill. : 1960). 63: 51–57. doi:10.1001/archopht.1960.00950020053008. PMID 13810884.
25. ^ a b c Creig S, Hoyt; David, Taylor (January 2012). Pediatric ophthalmology and strabismus (4th ed.). Saunders/Elsevier. ISBN 9780702046919.
26. ^ Barre, Jay; R K, Blach; R S, Wells. "Ocular manifestations of ichthyosis" (PDF). Britisn Journalof Ophthalmology.
27. ^ "Mucopolysaccharidoses Fact Sheet".
28. ^ Radhika Tandon; M Vanathi; Noopur Gupta; Rashmi Singh. "Corneal transplantation in the modern era". Indian Journal of Medical Research.
29. ^ a b c Salmon, John F. (31 October 2019). Kanski's clinical ophthalmology : a systematic approach (Ninth ed.). [Edinburgh]. ISBN 978-0-7020-7713-5. OCLC 1131846767.
30. ^ Kannan Sundaresh, Jitendra Jethani, Perumalsamy Vijayalakshmi (2008). "Optical Iridectomy in Children With Corneal Opacities". Journal of AAPOS. 12 (2): 163–5. doi:10.1016/j.jaapos.2007.10.008. PMID 18155942.CS1 maint: multiple names: authors list (link)
31. ^ Antonio Jaime Villarreal Gonzalez, Alejandro Rodríguez-García. (2020-03-01). "Phototherapeutic keratectomy". American Academy of Ophthalmology.
32. ^ Isdin Oke (2020-03-01). "Corneal tattooing". American Academy of Ophthalmology.
33. ^ Jin-Hyoung Kim, Doh Lee, Tae-Won Hahn, Suk-Kyue Choi (2009). "New Surgical Strategy for Corneal Tattooing Using a Femtosecond Laser". Cornea. 28 (1): 80–4. doi:10.1097/ICO.0b013e318181a83c. PMID 19092411. S2CID 42110930.CS1 maint: multiple names: authors list (link)
34. ^ Zarei-Ghanavati, Mehran; Liu, Christopher (2 December 2019). "Keratoprosthesis: Current Choices and Future Development". Asia-Pacific Journal of Ophthalmology (Philadelphia, Pa.). 8 (6): 429–431. doi:10.1097/APO.0000000000000268. ISSN 2162-0989. PMC 6903338. PMID 31789643.
35. ^ "Foldable artificial cornea may provide another option for corneal transplantation". www.healio.com.
36. ^ "Corneal Blindness".
37. ^ "Congenital Corneal Opacities - Europe".
38. ^ Khurana, AK (31 August 2015). "Systemic and community ophthalmology". Comprehensive ophthalmology (6th ed.). Jaypee, The Health Sciences Publisher. p. 478. ISBN 978-93-5152-657-5.
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*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
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*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Corneal opacity | c0010038 | 6,892 | wikipedia | https://en.wikipedia.org/wiki/Corneal_opacity | 2021-01-18T18:45:25 | {"mesh": ["D003318"], "umls": ["C0010038"], "wikidata": ["Q21110038"]} |
A number sign (#) is used with this entry because autosomal recessive deafness-23 (DFNB23) is caused by homozygous mutation in the gene encoding protocadherin-15 (PCDH15; 605514) on chromosome 10q21.
Mutation in the PCDH15 gene can also cause Usher syndrome type IF (602083).
Clinical Features
Ahmed et al. (2003) reported 3 families with isolated deafness. Two of the families had no history of nyctalopia, and the funduscopy and electroretinograms were normal in 2 older affected individuals from each family (age range, 13-44 years). Vestibular responses were intact in affected individuals.
Doucette et al. (2009) reported a consanguineous family from Newfoundland, Canada, with isolated hearing loss that was neurosensory, prelingual, and severe to profound. Ancestors of the family had emigrated from England in the early 1800s to settle a fishing 'outport' on Newfoundland's southern coast. Detailed examination of 2 homozygous carriers in middle age showed no evidence of Usher syndrome and no vestibular abnormalities.
Molecular Genetics
In affected members of 2 unrelated families with isolated deafness, Ahmed et al. (2003) identified 2 different homozygous mutations in the PCDH15 gene (605514.0006 and 605514.0007, respectively).
In affected members of a consanguineous family from Newfoundland with isolated deafness, Doucette et al. (2009) identified a homozygous mutation in the PCDH15 gene (V528D; 605514.0010).
INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Deafness, neurosensory \- Severe to profound deafness Eyes \- Normal vision MISCELLANEOUS \- Prelingual onset \- Allelic disorder to Usher syndrome type 1F ( 602083 ) MOLECULAR BASIS \- Caused by mutation in the protocadherin-15 gene (PCDH15, 605514.0006 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| DEAFNESS, AUTOSOMAL RECESSIVE 23 | c1836027 | 6,893 | omim | https://www.omim.org/entry/609533 | 2019-09-22T16:05:57 | {"doid": ["0110481"], "mesh": ["C563705"], "omim": ["609533"], "orphanet": ["90636"], "synonyms": ["Autosomal recessive isolated neurosensory deafness type DFNB", "Autosomal recessive isolated sensorineural deafness type DFNB", "Autosomal recessive non-syndromic neurosensory deafness type DFNB"], "genereviews": ["NBK1434"]} |
Univentricular heart (UVH) is a severe congenital cardiac malformation characterized by both atria related entirely or almost entirely to one functionally single ventricular chamber. The clinical manifestations include congestive heart failure, failure to thrive, cyanosis, hypoxemia and neurodevelopmental disabilities.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Univentricular heart | c0152424 | 6,894 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1464 | 2021-01-23T17:54:00 | {"icd-10": ["Q20.4"], "synonyms": ["Double inlet left ventricle"]} |
## Summary
### Clinical characteristics.
The classic phenotype of megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterized by early-onset macrocephaly, often in combination with mild gross motor developmental delay and seizures; gradual onset of ataxia, spasticity, and sometimes extrapyramidal findings; and usually late onset of mild mental deterioration. Macrocephaly, observed in virtually all individuals, may be present at birth but more frequently develops during the first year of life. The degree of macrocephaly is variable and can be as great as 4 to 6 SD above the mean in some individuals. After the first year of life, head growth rate normalizes and growth follows a line parallel to and usually several centimeters above the 98th centile. Initial mental and motor development is normal in most individuals. Walking is often unstable, followed by ataxia of the trunk and extremities, then minor signs of pyramidal dysfunction and brisk deep-tendon stretch reflexes. Almost all individuals have epilepsy from an early age. The epilepsy is typically well controlled with medication, but status epilepticus occurs relatively frequently. Mental deterioration is late and mild. Disease severity ranges from independent walking for a few years only to independent walking in the fifth decade. Some individuals have died in their teens or twenties; others are alive in their fifties.
An improving phenotype has a similar initial presentation with delayed mental or motor development, followed by an improving clinical course: macrocephaly usually persists, but some children become normocephalic; motor function improves or normalizes; hypotonia and clumsiness may persist in some or neurologic examination may become normal. Some have intellectual disability that is stable, with or without autism. Epilepsy and status epilepticus may occur.
### Diagnosis/testing.
The diagnosis of MLC is established in individuals with typical clinical findings and characteristic abnormalities identified on brain MRI examination, including abnormal and swollen cerebral hemispheric white matter and presence of subcortical cysts in the anterior temporal region and often in the frontoparietal region. Identification of biallelic pathogenic variants in MLC1 or HEPACAM by molecular genetic testing can confirm the diagnosis of classic MLC (MLC1 or MLC2A, respectively) – particularly important if clinical features are inconclusive – and allow for family studies. Identification of a heterozygous HEPACAM pathogenic variant can confirm the diagnosis of MLC with improving phenotype (MLC2B) if clinical features are inconclusive, and/or allow for family studies.
### Management.
Treatment of manifestations: Physical therapy to improve motor function; speech therapy as needed; special education; antiepileptic drugs to control epileptic seizures.
Prevention of secondary complications: A helmet should be considered for situations involving increased risk of head trauma.
Agents/circumstances to avoid: Contact sports and other activities with a high risk of head trauma should be avoided.
### Genetic counseling.
MLC1 and MLC2A are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if both pathogenic alleles have been identified in the family.
MLC2B is inherited in an autosomal dominant manner. De novo pathogenic variants are common. Each child of an individual with MLC2B has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant has been identified in an affected family member.
## Diagnosis
### Suggestive Findings
Two phenotypes are observed in megalencephalic leukoencephalopathy with subcortical cysts (MLC).
* Classic phenotype (includes MLC1 and MLC2A)
* MLC1, associated with MLC1 biallelic pathogenic variants
* MLC2A, associated with HEPACAM biallelic pathogenic variants
* Improving phenotype (includes MLC2B)
* MLC2B, associated with a HEPACAM heterozygous pathogenic variant
MLC classic phenotype should be suspected in individuals with the following clinical and radiographic features:
* Macrocephaly (onset in the first year of life or congenital)
* Early development normal or mildly delayed
* Slow deterioration of motor functions with cerebellar ataxia and mild spasticity
* Dysarthria
* Mental decline (occurs later and is much milder than motor decline)
* Seizures
* Behavioral problems in some individuals
* Temporary exacerbation of signs and symptoms after minor head trauma
* On brain MRI (see Figure 1):
* Cerebral hemispheric white matter is diffusely abnormal and mildly swollen.
* Central white matter structures, including the corpus callosum, internal capsule, and brain stem, are better preserved than other structures, although they are not usually entirely normal.
* Cerebellar white matter usually has a mildly abnormal signal and is not swollen.
* Subcortical cysts are almost invariably present in the anterior temporal region and often in the frontoparietal region.
* Over time, the white matter swelling decreases and cerebral atrophy ensues. The subcortical cysts may increase in size and number. In some individuals, the cysts become huge, occupying a large part of the frontoparietal white matter. In others, the cerebral white matter abnormalities decrease over time, and the signal intensity of the cerebral white matter becomes less abnormal.
* Diffusion-weighted imaging reveals increased diffusivity of abnormal white matter [Itoh et al 2006, van der Voorn et al 2006].
#### Figure 1.
Brain images of an individual with MLC (A, C) and an unaffected individual (B, D) A. Transverse T2-weighted image of a child age nine years with MLC, showing diffusely abnormal and mildly swollen white matter
MLC improving phenotype should be suspected in individuals with the following clinical features:
* Macrocephaly (onset in the first year of life or congenital macrocephaly)
* Early development normal or mildly delayed
* Motor function improves after the first year of life (clumsiness and hypotonia may persist)
* Seizures in some individuals
* Intellectual disability (with or without autism) or normal cognitive function
* No regression of mental or motor functions
* Macrocephaly that may persist or may turn into normocephaly
* On brain MRI:
* Findings within the first year of life are similar to those seen in the classic phenotype, but cerebellar white matter is usually normal in signal.
* Striking improvement occurs over time. The MRI may appear normal within a few years, or minor frontal and temporal subcortical white matter abnormalities and anterior temporal cysts may remain.
### Establishing the Diagnosis
The diagnosis of MLC is established in a proband with the above Suggestive Findings. The characteristic abnormalities on brain MRI examination described in Suggestive Findings are diagnostic.
Identification of biallelic pathogenic variants in MLC1 or HEPACAM by molecular genetic testing (see Table 1) can confirm the diagnosis of classic MLC (MLC1 or MLC2A, respectively) if clinical features are inconclusive, and/or allow for family studies if the diagnosis has been established based on clinical and characteristic radiographic features.
Identification of a heterozygous HEPACAM pathogenic variant can confirm the diagnosis of MLC with improving phenotype (MLC2B) if clinical features are inconclusive, and/or allow for family studies if the diagnosis has been established based on clinical and characteristic radiographic features.
Molecular genetic testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.
Serial single-gene testing
* Sequence analysis of MLC1 can be performed first in individuals with the classic phenotype, followed by sequence analysis of HEPACAM. Gene-targeted deletion/duplication analysis of MLC1 and HEPACAM can be considered next if no pathogenic variant is found.
* Sequence analysis of HEPACAM can be performed first in individuals with the improving phenotype. Gene-targeted deletion/duplication analysis of HEPACAM can be considered next if no pathogenic variant is found.
A multigene panel that includes HEPACAM, MLC1, and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
### Table 1.
Molecular Genetic Testing Used in Megalencephalic Leukoencephalopathy with Subcortical Cysts
View in own window
Gene 1, 2Proportion of MLC Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 3 Detectable by Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
HEPACAM22% 6100%Unknown 7
MLC176%97%3% 8
Unknown 9~2%NA
1\.
Genes are listed alphabetically.
2\.
See Table A. Genes and Databases for chromosome locus and protein.
3\.
See Molecular Genetics for information on allelic variants detected in this gene.
4\.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
5\.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
6\.
López-Hernández et al [2011]
7\.
No data on detection rate of gene-targeted deletion/duplication analysis are available. See Molecular Genetics, MLC1.
8\.
Leegwater et al [2002], Ilja Boor et al [2006]
9\.
In some individuals with clinical features of MLC, pathogenic variants in HEPACAM or MLC1 have not been identified [Author, personal observation].
Neuropathologic examination. Brain biopsy shows the presence of numerous vacuoles between the outer lamellae of myelin sheaths, suggesting splitting of these lamellae along the intraperiod line or incomplete compaction [van der Knaap et al 1996]. In addition, small vacuoles are observed in astrocytic endfeet [Duarri et al 2011].
## Clinical Characteristics
### Clinical Description
The two phenotypes observed in individuals with megalencephalic leukoencephalopathy with subcortical cysts (MLC) include the classic phenotype and the improving phenotype. When associated with biallelic MLC1 pathogenic variants, the classic phenotype is known as MLC1; when caused by biallelic HEPACAM pathogenic variants, MLC is known as MLC2A. The improving phenotype associated with heterozygous HEPACAM pathogenic variants is known as MLC2B.
#### Classic Phenotype (MLC1 and MLC2A)
Macrocephaly. To date, macrocephaly has been observed in almost all individuals with MLC. Macrocephaly can be present at birth but more frequently develops during the first year of life. The degree of macrocephaly is variable; it may be as great as 4 to 6 SD above the mean in some affected individuals. After the first year of life, head growth rate normalizes and growth follows a line above and parallel to the 98th centile.
Motor development. Prior to age one year motor development is normal in most infants and mildly delayed in some. Apart from progressive macrocephaly, the first clinical sign is usually a delay in walking. Walking is often unstable, and the child falls frequently. However, most children achieve independent walking. Muscle tone tends to be low, apart from some ankle hypertonia.
After an interval of several years, slow deterioration of motor function occurs over years with development of ataxia of the trunk and extremities. Signs of pyramidal dysfunction are late and minor and are dominated by the signs of cerebellar ataxia. Speech becomes increasingly dysarthric and dysphagia may develop. Deep-tendon stretch reflexes become brisk and Babinski signs become apparent. Some individuals display extrapyramidal movement abnormalities with dystonia and athetosis. Some individuals develop tics [Sugiura et al 2006].
Gradually, the ability to walk independently is lost; many children become completely wheelchair dependent at the end of the first decade or in the second decade of life. Some children have a more severe clinical course and maintain their ability to walk independently for only a few years, or never achieve independent walking. Others maintain the ability to walk independently into the fifth decade.
Cognitive development. Initial cognitive development is normal in most children and mildly delayed in some. Intellectual deterioration is late and mild. Decreasing school performance becomes evident during the later years of primary school. In a minority of children, intellectual capacities are mildly decreased in the early years. Some children develop behavior problems [Sugiura et al 2006].
Seizures. Approximately 75% of individuals with classic MLC experience at least one seizure before age 20 years [Dubey et al 2018; EMC Hamilton, personal communication]. Seizure onset is typically early, within a few years after birth [EMC Hamilton, personal communication]. Although the epilepsy is most often easily controlled with medication, 15%-20% of individuals experience one or more episodes of status epilepticus, the first of which typically occurs within a few years after seizure onset [Dubey et al 2018]. Seizures and status epilepticus are frequently precipitated by minor head trauma.
Minor head trauma may induce temporary deterioration in some individuals, most often observed as seizures or status epilepticus, prolonged unconsciousness, or acute motor deterioration with gradual improvement [Bugiani et al 2003, Dubey et al 2018].
Prognosis. Some children have a more benign clinical course and, even as teenagers, have macrocephaly only. Individuals who are ambulatory with or without support at age 15 years are most likely to remain ambulatory [EMC Hamilton, personal communication]. Because the disease has been known for a relatively short time, information regarding average life span is very limited. Some individuals have died in their teens or twenties; others are alive in their fifties.
#### Improving Phenotype (MLC2B)
In children diagnosed with MLC2B the initial disease course is the same as that in children with the classic phenotype: mental and motor development is normal in most and mildly delayed in some.
Macrocephaly is present at birth or (more commonly) develops within the first year of life in 90% of individuals. In individuals with the improving phenotype, head circumference is initially equally large. After the first year of life, growth of the head usually either decreases or follows a line above and parallel to the 98th centile. In 40%-50% of affected children, the head circumference normalizes [EMC Hamilton, personal communication].
Motor development. Apart from progressive macrocephaly, the first clinical sign is usually delay in walking. Walking is often unstable, and the child falls frequently. All children achieve independent walking. After the second or third year of life, motor function improves or normalizes in most. Neurologic examination may become normal, but some children have persistent hypotonia and clumsiness. Regression does not occur.
Cognitive function is normal in approximately 75% of individuals; 25% have mild intellectual disability [EMC Hamilton, personal communication]. Autism is observed in 25% of individuals. Regression has not been observed.
Seizures. Epilepsy and status epilepticus may occur, but 90% of individuals have no history of seizures [EMC Hamilton, personal communication].
Prognosis. Because the disease has been known for a relatively short time, information regarding average life span is very limited. Considering the normal health of parents heterozygous for a dominant HEPACAM pathogenic variant, it does not appear that MLC2B-related HEPACAM pathogenic variants shorten life span; however, no formal study has addressed this issue. One child died in status epilepticus at age three years [EMC Hamilton, personal communication].
In families with affected individuals from more than one generation, the proband is usually a child and the affected parent is subsequently diagnosed. Parents with the pathogenic variant often have macrocephaly but normal motor and cognitive function. Some parents have cognitive or behavioral problems or motor clumsiness.
### Phenotype Correlations by Gene
Classic MLC. A review of 17 individuals with MLC2A (biallelic HEPACAM pathogenic variants) revealed no phenotypic differences from individuals with MLC1 who have identifiable biallelic pathogenic variants in MLC1 [Hamilton et al, unpublished].
### Genotype-Phenotype Correlations
MLC1. A review of 187 individuals with biallelic MLC1 pathogenic variants revealed that in individuals from the same family, disease severity and clinical course can vary significantly [EMC Hamilton, personal communication]. There is no known genotype-phenotype correlation.
HEPACAM. All known MLC-related HEPACAM pathogenic variants affect the extracellular part of the protein and not its transmembrane and intracellular part, independent of whether they have dominant or recessive effects [López-Hernández et al 2011]. Recessive HEPACAM pathogenic variants are spread over the entire extracellular region of the protein; dominant pathogenic variants are clustered in the first immunoglobulin domain [López-Hernández et al 2011]. Dominant and recessive pathogenic variants do not overlap, although they may affect the same residue [López-Hernández et al 2011]. At present, it is unclear why some HEPACAM pathogenic variants have recessive inheritance and others dominant inheritance.
### Penetrance
MLC2B. The penetrance of dominant HEPACAM pathogenic variants is reduced. The proportion of individuals with a pathogenic HEPACAM variant who exhibit or have exhibited clinical manifestations of MLC2B is not known. There is no evidence of a difference in penetrance based on sex.
### Nomenclature
Names previously used for MLC:
* Leukoencephalopathy with swelling and a discrepantly mild course
* Leukoencephalopathy with swelling and cysts
* Infantile leukoencephalopathy and megalencephaly
* Vacuolating leukoencephalopathy
### Prevalence
Megalencephalic leukoencephalopathy with subcortical cysts is a rare disorder with a low carrier rate in the general population. Consequently, the disease is rarer in communities with a low rate of consanguinity and higher in communities with a high rate of consanguinity (e.g., see Topçu et al [1998]). The parents of many individuals with classic megalencephalic leukoencephalopathy with subcortical cysts are consanguineous.
* Almost all East Indian individuals with MLC1 belong to the Agrawal community; and all individuals within this community are biallelic for the same pathogenic variant (c.135dupC), providing evidence for a founder effect [Leegwater et al 2002, Singhal et al 2003, Gorospe et al 2004].
* MLC1 is also relatively common among Libyan Jews [Ben-Zeev et al 2001]. One common pathogenic variant (c.176G>A) was found in five unrelated Libyan Jewish families [Ben-Zeev et al 2002]. The same variant was identified in several affected individuals from a single Turkish Jewish family descended from the same ancestors. Screening of 200 normal Libyan Jewish individuals for this particular pathogenic variant revealed a carrier rate of one in 40, as compared with an expected carrier rate of one in 81. Non-Jewish Turkish individuals do not share a common pathogenic variant.
* The MLC1 pathogenic variant c.278C>T appears to be common in Japanese individuals [Shimada et al 2014] but has also been observed in Finland, Turkey [Leegwater et al 2001], and Italy [Montagna et al 2006].
* Among Egyptians with MLC, the MLC1 pathogenic variant c.908_918delinsGCA is common and affected individuals share a haplotype, indicating a founder effect [Abdel-Salam et al 2016].
* In Korea, c.824C>A accounted for 70% of alleles in affected individuals were [Choi et al 2017].
## Differential Diagnosis
The differential diagnosis of macrocephaly and a diffuse leukoencephalopathy is limited; it includes Canavan disease, Alexander disease, infantile-onset GM2 gangliosidosis, and, on occasion, infantile-onset GM1 gangliosidosis and L-2-hydroxyglutaric aciduria. Some children with congenital muscular dystrophy caused by laminin alpha-2 (merosin) deficiency (also known as MDC1A) have macrocephaly. The clinical features and course of these disorders are usually different from those of MLC. If the head circumference is well within the normal limits at age one year, it is highly unlikely that the infant has MLC. None of these disorders shares all the MRI characteristics of megalencephalic leukoencephalopathy with subcortical cysts (MLC).
### Table 2.
Disorders to Consider in the Differential Diagnosis of MLC
View in own window
DisorderGeneMOIClinical Features of This Disorder
Overlapping w/MLCDistinguishing from MLC
Laminin alpha 2 deficiencyLAMA2ARSimilar cerebral WM disease w/swelling of the abnormal WM
* Usually lacking the typical subcortical cysts seen in MLC
* Prominent weakness & hypotonia (not seen in MLC)
Canavan diseaseASPAARSimilar cerebral WM disease w/swelling of the abnormal WM
* In some cases: WM abnormalities limited to the directly subcortical WM
* Typically on MRI: involvement of the thalamus & globus pallidus w/relative sparing of a bilateral crescent formed by the putamen & caudate nucleus (The globus pallidus & thalamus are not involved in MLC.)
* Lacking the typical subcortical cysts seen in MLC
Alexander diseaseGFAPADSimilar WM disease w/swelling of the abnormal WM
* Frontal predominance of MRI abnormalities (Predilection for the anterior parts of the brain is less clear in MLC.)
* Mild signal abnormalities of basal ganglia & thalami (not seen in MLC)
* Contrast enhancement of particular brain structures almost invariably seen (not seen in MLC)
* Cysts usually located in deep frontal WM (different from MLC)
* Typical involvement of brain stem structures (signal abnormalities, tumor-like structures, atrophy) (not seen in MLC)
L-2-hydroxyglutaric aciduria (OMIM 236792)L2HGDHARSimilar WM disease w/swelling of the abnormal WM
* Cerebral WM abnormalities in some cases limited to the directly subcortical WM
* Cerebral WM abnormalities multifocal in some cases (invariably diffuse in MLC)
* Typicially on MRI: involvement of the basal nuclei (not seen in MLC)
* Dentate nucleus typically prominently affected (not in MLC)
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; WM = white matter
See OMIM Phenotypic Series: Leukoencephalopathy, megalencephalic to view genes associated with this phenotype in OMIM.
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with megalencephalic leukoencephalopathy with subcortical cysts (MLC) the following evaluations are recommended if they have not already been completed:
* Neurologic examination
* Brain MRI examination
* Physical therapy / occupational therapy assessment
* Assessment of cognitive function (neuropsychological testing)
* Consultation with a clinical geneticist and/or genetic counselor
### Treatment of Manifestations
Supportive therapy includes the following:
* Physical therapy to improve motor function
* Speech therapy as needed
* Special education
* Antiepileptic drugs if epileptic seizures are present
### Prevention of Secondary Complications
If patients have epilepsy, treatment with antiepileptic drugs should be considered.
Minor head trauma may lead to temporary motor deterioration, seizures, or (rarely) coma. Wearing of a helmet should be considered for situations involving increased risk of head trauma.
### Surveillance
There are no published guidelines for surveillance. Most affected individuals are reevaluated in neurology clinics annually to document disease progression and determine if other interventions are necessary. For some patients more frequent visits are needed to treat the epilepsy.
Initially, annual MRI may be considered to monitor disease development, while eventually one MRI every five years should suffice because of the slow disease course.
### Agents/Circumstances to Avoid
Minor head trauma may lead to temporary motor deterioration, seizures, or (rarely) to coma. For this reason, contact sports and other activities with a high risk of head trauma should be avoided.
### Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Pregnancy Management
Potential teratogenic effects of antiepileptic drugs should be discussed with affected women of childbearing age, ideally prior to conception.
See MotherToBaby for more information on medication use during pregnancy.
### Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
### Other
Unsuccessful therapies have included diuretics, acetazolamide, and creatine monohydrate.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Megalencephalic Leukoencephalopathy with Subcortical Cysts | c1858854 | 6,895 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1535/ | 2021-01-18T21:11:49 | {"mesh": ["C536141"], "synonyms": ["Van der Knaap Disease"]} |
A large, or giant, congenital melanocytic nevus (LCMN or GCMN) is a pigmented skin lesion of more than 20 cm - or 40 cm- respectively, projected adult diameter, composed of melanocytes, and presenting with an elevated risk of malignant transformation.
## Epidemiology
LCMN has a prevalence of about 1/20,000, while GCMN is estimated to occur in 1/50,000 to 1/500,000 births, becoming increasingly rare as more body surface is implicated. While present in all ethnic groups examined to date and in both genders, there is a slight female predominance.
## Clinical description
CMN develop during the first trimester of pregnancy. An LCMN is a darkly colored, circumscribed area of the skin sometimes covered with dense hair or proliferative nodules, and/or accompanied by multiple small satellite nevi that develop at birth or during early childhood (tardive satellites). Certain forms of LCMN entail only congenital "satellites" (also known as "multiple medium CMN") with a total surface, when summed, similar to that of other LCMN; these forms seem to be associated more frequently with complications. Neurological involvement, such as leptomeningeal melanocytosis (see this term), epilepsy, hydrocephalus and tethered spinal cord has been observed. Patients with LCMN also present an elevated risk of malignant pediatric melanoma, particularly intracranial, and other neuroectodermal tumors of varying severity (rhabdomyosarcoma, schwannoma (see these terms), lipoma, neurofibroma).
## Etiology
LCMN is a neurocristopathy (a disorder of the development of the embryonic neural crest) but its etiology is unknown.
## Diagnostic methods
The diagnosis is clinical. Magnetic resonance imaging (MRI) and neurological evaluations are also performed in order to screen for complications. Skin biopsy shows an abnormal histological accumulation of melanocytes at the epidermal/dermal junction and below, even to the subfascia, as well as disorganization of the dermis. When malignant transformation is suspected, biopsy is necessary.
## Differential diagnosis
Differential diagnoses include atypical mole, Becker's nevus syndrome, malignant melanoma, nevus of Ota, nevus of Ito, Spitz nevus, blue nevus, and congenital smooth muscle hamartome (see these terms).
## Genetic counseling
Familial cases have been observed, but the vast majority of LCMN cases are sporadic. A paradominant mode of transmission (postzygotic mutation occurring at an early developmental stage and resulting in somatic loss of heterozygosity) has been proposed to explain this observation.
## Management and treatment
Because of possible malignant transformation, dermatological follow-up of the nevus should be regular. In some cases excision may be advisable by an experienced plastic surgeon. Dermabrasion, curettage and laser treatments are performed but are currently considered inferior options to full-thickness removal, sometimes in stages, or simple surveillance.
## Prognosis
The majority of patients have normal adult lives without any complications.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Large congenital melanocytic nevus | c1318558 | 6,896 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=626 | 2021-01-23T18:39:10 | {"gard": ["2469"], "omim": ["137550"], "umls": ["C1318558", "C1842036"], "icd-10": ["Q82.5"], "synonyms": ["Congenital pigmented nevus", "GMN", "Giant congenital melanocytic nevus", "Giant pigmented hairy nevus", "LCMN"]} |
Hyperphenylalaninemia (HPA) due to tetrahydrobiopterin (BH4) deficiency, also known as malignant HPA is an amino acid disorder with neonatal onset that is clinically characterized by the classic manifestations of phenylketonuria (PKA; see this term) and that later on is clinically differentiated by neurologic symptoms such as microcephaly, intellectual disability, central hypotonia, delayed motor development, peripheral spasticity and seizures, that develop and persist despite an established metabolic control of plasma phenylalanine.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Hyperphenylalaninemia due to tetrahydrobiopterin deficiency | c0751435 | 6,897 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=238583 | 2021-01-23T17:44:57 | {"gard": ["7751"], "mesh": ["D010661"], "omim": ["233910", "261630", "261640", "264070"], "umls": ["C0751435", "C0751436"], "icd-10": ["E70.1"], "synonyms": ["Hyperphenylalaninemia due to BH4 deficiency", "Non-phenylketonuric hyperphenylalaninemia"]} |
Diastasis symphysis pubis
Post traumatic diastasis of symphysis pubis
SpecialtyOrthopaedic
Diastasis symphysis pubis is the separation of normally joined pubic bones, as in the dislocation of the bones, without a fracture. Separation of the symphysis pubis can occur spontaneously in at least 1 in 800 vaginal deliveries. It is usually noticed after delivery and has been associated with forceps delivery, rapid second stage of labour or severe abduction of the thighs during delivery. Common signs and symptoms include symphyseal pain aggravated by weight bearing and walking, a waddling gait, pubic tenderness, and a palpable interpubic gap
## Contents
* 1 Cause
* 2 Diagnosis
* 2.1 Differential diagnosis
* 2.2 X-ray
* 2.3 CT scan and MRI
* 2.4 Bone scan
* 3 Management
* 4 References
* 5 External links
## Cause[edit]
External forces such as falling from a horse or a car accident can result in this type of injury to the symphysis pubis.
## Diagnosis[edit]
This abnormally wide gap can be diagnosed by radiologic studies such as X-ray, MRI, CT scan or bone scan. Manual testing by a healthcare professional can also be used. The patient is placed in various positions and pressure is applied in such a way that it provokes pain and maybe movement in the pubis.
### Differential diagnosis[edit]
* In bladder extrophy[1] there is a gap between the pubis, which are joined by a strong interpubic ligament.
### X-ray[edit]
Separation of symphysis pubis (diastasis)
An X-ray film will show a marked gap between the pubic bones, normally there is a 4–5 mm gap but in pregnancy, hormonal influences cause relaxation of the connecting ligaments and the bones separate up to 9 mm. To demonstrate instability of the joint the patient is required to stand in the "flamingo" position, (standing with weight on one leg and the other bent).[2] A vertical displacement of more than 1 cm is an indicator of symphysis pubis instability.[3] A displacement of more than 2 cm usually indicates involvement of the sacroiliac joints.
### CT scan and MRI[edit]
Both diagnostic machines can produce detailed cross sections of the pelvic area. Images will show degrees soft tissue injury, inflammation of the subchondral region and the bone marrow [4] and any abnormal posturing of the pelvic joints.
### Bone scan[edit]
A bone scan is able to determine areas of bone inflammation.
## Management[edit]
Treatment include bed rest, anti inflammatory agents, physiotherapy and a pelvic corset to provide support and stability
## References[edit]
1. ^ http://www.bartleby.com/107/255.html (end of page)
2. ^ An Analysis of Pubis Symphysis Misalignment Using Plain Film Radiography Ruch WJ, Ruch BM. J Manipulative Physiol Ther. 2005;28(5):330-335
3. ^ Vertically Unstable Pelvic Fractures Fixed with Percutaneous Iliosacral Screws: Does Posterior Injury Predict Fixation Failure? Damian R. Griffin, MA, FRCS (Orth); Adam J. Starr, MD; Charles M. Reinert, MD; Alan L. Jones, MD; Shelly Whitlock, CCRA; University of Texas Southwestern Medical Center, Dallas, TX
4. ^ Magnetic resonance imaging changes of sacroiliac joints in patients with recent-onset inflammatory back pain: inter-reader reliability and prevalence of abnormalities. Arthritis Research & Therapy 2006, 8:R11 doi:10.1186/ar1859. Liesbeth Heuft-Dorenbosch1, René Weijers, Robert Landewé1, Sjef van der Linden1, Désirée van der Heijde1
## External links[edit]
Classification
D
* MeSH: D046548
* v
* t
* e
Pathology of pregnancy, childbirth and the puerperium
Pregnancy
Pregnancy with
abortive outcome
* Abortion
* Ectopic pregnancy
* Abdominal
* Cervical
* Interstitial
* Ovarian
* Heterotopic
* Embryo loss
* Fetal resorption
* Molar pregnancy
* Miscarriage
* Stillbirth
Oedema, proteinuria and
hypertensive disorders
* Gestational hypertension
* Pre-eclampsia
* HELLP syndrome
* Eclampsia
Other, predominantly
related to pregnancy
Digestive system
* Acute fatty liver of pregnancy
* Gestational diabetes
* Hepatitis E
* Hyperemesis gravidarum
* Intrahepatic cholestasis of pregnancy
Integumentary system /
dermatoses of pregnancy
* Gestational pemphigoid
* Impetigo herpetiformis
* Intrahepatic cholestasis of pregnancy
* Linea nigra
* Prurigo gestationis
* Pruritic folliculitis of pregnancy
* Pruritic urticarial papules and plaques of pregnancy (PUPPP)
* Striae gravidarum
Nervous system
* Chorea gravidarum
Blood
* Gestational thrombocytopenia
* Pregnancy-induced hypercoagulability
Maternal care related to the
fetus and amniotic cavity
* amniotic fluid
* Oligohydramnios
* Polyhydramnios
* Braxton Hicks contractions
* chorion / amnion
* Amniotic band syndrome
* Chorioamnionitis
* Chorionic hematoma
* Monoamniotic twins
* Premature rupture of membranes
* Obstetrical bleeding
* Antepartum
* placenta
* Circumvallate placenta
* Monochorionic twins
* Placenta accreta
* Placenta praevia
* Placental abruption
* Twin-to-twin transfusion syndrome
Labor
* Amniotic fluid embolism
* Cephalopelvic disproportion
* Dystocia
* Shoulder dystocia
* Fetal distress
* Locked twins
* Nuchal cord
* Obstetrical bleeding
* Postpartum
* Pain management during childbirth
* placenta
* Placenta accreta
* Preterm birth
* Postmature birth
* Umbilical cord prolapse
* Uterine inversion
* Uterine rupture
* Vasa praevia
Puerperal
* Breastfeeding difficulties
* Low milk supply
* Cracked nipples
* Breast engorgement
* Childbirth-related posttraumatic stress disorder
* Diastasis symphysis pubis
* Postpartum bleeding
* Peripartum cardiomyopathy
* Postpartum depression
* Postpartum psychosis
* Postpartum thyroiditis
* Puerperal fever
* Puerperal mastitis
Other
* Concomitant conditions
* Diabetes mellitus
* Systemic lupus erythematosus
* Thyroid disorders
* Maternal death
* Sexual activity during pregnancy
* Category
* v
* t
* e
Dislocations/subluxations, sprains and strains
Joints and
ligaments
Head and neck
* Dislocation of jaw
* Whiplash
Shoulder and upper arm
* GH (Dislocated shoulder)
* AC (Separated shoulder)
* ALPSA lesion
* SLAP tear
* Bankart lesion
Elbow and forearm
* Pulled elbow
* Gamekeeper's thumb
Hip and thigh
* Hip dislocation
Knee and leg
* Tear of meniscus
* Anterior cruciate ligament injury
* Unhappy triad
* Patellar dislocation
* Knee dislocation
Ankle and foot
* Sprained ankle (High ankle sprain)
* Turf toe
Muscles and
tendons
Shoulder and upper arm
* Rotator cuff tear
Hip and thigh
* Pulled hamstring
Knee and leg
* Patellar tendon rupture
* Achilles tendon rupture
* Shin splints
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
*[DHT]: dihydrotestosterone
*[IM]: intramuscular injection
*[SC]: subcutaneous injection
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[pop.]: population
*[et al.]: et alia (and others)
*[a.k.a.]: also known as
*[mRNA]: messenger RNA
*[kDa]: kilodalton
*[EPC]: Early Prostate Cancer
*[LAPC]: locally advanced prostate cancer
*[NSAAs]: nonsteroidal antiandrogens
*[NSAA]: nonsteroidal antiandrogen
*[GnRH]: gonadotropin-releasing hormone
*[ADT]: androgen deprivation therapy
*[LH]: luteinizing hormone
*[AR]: androgen receptor
*[CAB]: combined androgen blockade
*[LPC]: localized prostate cancer
*[CPA]: cyproterone acetate
*[U.S.]: United States
*[FDA]: Food and Drug Administration
| Diastasis symphysis pubis | c0238442 | 6,898 | wikipedia | https://en.wikipedia.org/wiki/Diastasis_symphysis_pubis | 2021-01-18T18:37:04 | {"mesh": ["D046548"], "wikidata": ["Q5272095"]} |
Neonatal meningitis
The meninges
SpecialtyNeonatology
Neonatal meningitis is a serious medical condition in infants that is rapidly fatal if untreated. Meningitis is an inflammation of the meninges, the protective membranes of the central nervous system, is more common in the neonatal period (infants less than 44 days old) than any other time in life, and is an important cause of morbidity and mortality globally.[1][2] Mortality is roughly half in developing countries and ranges from 8%-12.5% in developed countries.[2][3]
Symptoms seen with neonatal meningitis are often unspecific and may point to several conditions, such as sepsis (whole body inflammation). These can include fever, irritability, and dyspnea. The only method to determine if meningitis is the cause of these symptoms is lumbar puncture (an examination of the cerebrospinal fluid).[1][4]
The most common cause of neonatal meningitis is bacterial infection of blood, known as bacteremia. Organisms responsible are different; most commonly group B streptococci (i.e. Streptococcus agalactiae), Escherichia coli, and Listeria monocytogenes.[1] Although there is a low mortality rate in developed countries, there is a 50% prevalence rate of neurodevelopmental disabilities after meningitis caused by E. coli and Streptococcus agalactiae, and a 79% prevalence after meningitis caused by Gram-negative rods other than E. coli.[1] Delayed treatment of neonatal meningitis may cause cerebral palsy, blindness, deafness, seizure disorders, and learning deficiencies.[5]
## Contents
* 1 Signs and symptoms
* 1.1 Complications
* 1.2 Hearing Loss
* 1.3 Laboratory features
* 2 Causes
* 2.1 Early-onset
* 2.2 Late-onset
* 2.3 Herpes Simplex Virus
* 3 Pathogenesis
* 3.1 Group B Streptococcus
* 3.2 Neonatal meningitis-causing E. coli
* 4 Diagnosis
* 4.1 Bacterial Infection
* 4.2 Viral Infection
* 5 Prevention
* 5.1 Bacterial
* 5.2 Viral
* 6 Treatment
* 6.1 Group B Streptococci
* 6.2 Gram-negative Enterics
* 6.3 Listeria monocytogenes
* 6.4 Streptococcus pneumoniae
* 6.5 Herpes Simplex Virus
* 7 Epidemiology
* 8 References
## Signs and symptoms[edit]
The following is a list of common signs and symptoms of neonatal meningitis.
* Fever
* poor appetite
* anterior fontanelle bulging
* seizures
* jitteriness
* dyspnea
* irritability
* anorexia
* vomiting
* diarrhea
* abdominal distention (increase in abdominal size)
* neck rigidity
* cyanosis
* jaundice
* sunset eyes (downward gaze of the eyes)
* abnormal body temperature (hypo-or hyperthermia)
* change of activity (lethargy or irritability)
These symptoms are unspecific and may point to many different conditions.[4]
### Complications[edit]
Neuroimaging (X-ray imaging of the brain) is recommended to detect the complications of meningitis. Complications should be suspected when the clinical course is characterized by shock, respiratory failure, focal neurological deficits, a positive cerebrospinal fluid culture after 48 to 72 hours of appropriate antibiotic therapy, or infection with certain organisms, such as Citrobacter koseri and Cronobacter sakazakii for example. Ultrasounds are useful for early imaging to determine ventricular size and hemorrhaging. CT scans later in the therapy should be used to dictate prolonged treatment.[1][6]
If intracranial abscesses (collection of pus in the brain) are found, treatment consisting of a combination of surgical drainage of the abscess and antimicrobial therapy for 4 to 6 weeks is recommended. More imaging should be completed after the end of antibiotic treatment because abscesses have been found after weeks from start of treatment.[6]
Relapses have also occurred after appropriate treatment when infected by Gram-negative enteric bacilli.[6]
### Hearing Loss[edit]
Meningitis is one of the leading causes of acquired deafness. Nearly 8% of those with Meningitis will have a permanent sensorineural hearing loss.[7] The longer meningitis is left untreated, the greater the risk of seizures and permanent neurological damage such as hearing loss, memory difficulty, learning disabilities, brain damage, gait problems, kidney failure, shock, and even death.[8] Hearing loss in those with Meningitis can occur when the body is fighting off the infection and the cells reach the inner ear where the hair cells and nerve fibers become damaged.[9] Hearing loss can also occur after Meningitis is resolved due to an increased risk for ossification of the cochlea. Ossification of the cochlea can make it difficult to place a Cochlear Implant for hearing losses that are treated unsuccessfully with hearing aids.[10] Bacterial Meningitis is likely to lead to hearing loss.[11] It is important to have a hearing test as soon as possible. It would be best to complete a hearing test before leaving the hospital or within four weeks of improvement of symptoms.[12] Fluctuating hearing loss has been observed in a large number of patients, so it is best to have routine hearing tests to monitor the hearing loss.[13] Viral Meningitis is less likely to cause hearing loss and it is recommended to perform a hearing test if the patient is experiencing any hearing difficulties.[14] All hearing losses are different so there is no predictive loss for Meningitis. Children are assessed through behavioral testing (if old enough), Otoacoustic Emissions (OAEs), and Auditory Brainstem Response (ABR).
Impact in Children for Communication
If hearing loss is left undetected and/or untreated, this can lead to later acquisition of language and delayed reading skills. Since untreated Meningitis can cause brain damage and learning disabilities, children with a history of Meningitis may be developmentally delayed when compared to their typically developing peers.
### Laboratory features[edit]
Laboratory features that are characteristic of neonatal bacterial meningitis include:[15]
* Isolation of a bacterial pathogen from the cerebrospinal fluid by culture and/or visualization by Gram stain
* Increased cerebrospinal fluid white blood cell count (typically >1000 white blood cells/μL, but may be lower, especially with Gram-positive bacteria), usually with a predominance of neutrophils
* Elevated cerebrospinal fluid]] protein concentration (>150 mg/dL in preterm (premature birth) and >100 mg/dL in term infants)
* Decreased cerebrospinal fluid glucose concentration (<20 mg/dL [1.1 mmol/L] in preterm (premature birth) and <30 mg/dL [1.7 mmol/L] in term (on time) infants)
## Causes[edit]
Streptococci
Escherichia coli
Electron micrograph of a flagellated Listeria monocytogenes, Magnified 41,250X.
Streptococcus pneumoniae in cerebrospinal fluid
Scanning electron micrograph shows Staphylococcus aureus.
Transmission electron micrograph of Herpes simplex virus.
Neonatal meningitis is caused by group B streptococci Streptococcus agalactiae (39%-48% of cases), Escherichia coli (30%-35%), other Gram-negative rods (8%-12%), Streptococcus pneumoniae (about 6%), and Listeria monocytogenes (5%-7%).[1] Meningitis is typically caused from either a bacterial or viral infection, however, it can be caused by fungal, parasitic, or amebic infections as well.[16] [17] Even more rare, Meningitis can be caused by some cancers, Lupus, specific drugs, head injuries, and brain surgeries.[18] Most neonatal meningitis results from bacteremia (bacterial infection of the blood).[4][5]
### Early-onset[edit]
In early-onset neonatal meningitis, acquisition of the bacteria is from the mother either before the baby is born or during birth. The most common bacteria found in early-onset are Streptococcus agalactiae, Escherichia coli, and Listeria monocytogenes. In developing countries, Gram-negative enteric (gut) bacteria are responsible for the majority of early onset meningitis.[1]
### Late-onset[edit]
Late-onset meningitis may be caused by other Gram-negative bacteria and staphylococcal species. In developing countries, Streptococcus pneumoniae accounts for most cases of late onset.[1]
### Herpes Simplex Virus[edit]
Herpes simplex virus is a rare cause of meningitis, occurring only 0.165 in 10,000 live births in the UK and 0.2-5 in 10,000 live births in the US[2][4][19] Both HSV-1 and HSV-2 can cause neonatal meningitis, however, HSV-2 accounts for 70% of the cases.
Herpes simplex virus is transmitted to neonates mainly during delivery (when infected maternal secretions come into contact with the baby and accounting for 85% of cases), but also occur in utero (while the fetus is still in the womb, 5% of cases) or even post-delivery, receiving the infection from the community (10% of cases).[19] The most important factors impacting the transmission of the virus is the stage of the mother's infection (symptomatic or non-symptomatic) and the damage of any maternal membranes during birth (the longer the tissue is damaged, the higher the chance of neonatal infection).[19]
## Pathogenesis[edit]
Generally, the progression of neonatal meningitis starts with bacteria colonizing the gastrointestinal tract. The bacteria then invades through the intestinal mucosa layer into the blood, causing bacteremia followed by invasion of the cerebrospinal fluid. The neonate's less efficient immune system (especially the alternative complement system) lessens their defense against invading bacteria. Colonization of the mother plays an important role in transmission to the neonate, causing early-onset meningitis.[5]
### Group B Streptococcus[edit]
Neonatal Streptococcus agalactiae infection is acquired in utero or during passage through the vagina. Evidence suggests that vaginal colonization by Streptococcus agalactiae during pregnancy increases the risk of vertical transmission and early-onset disease in neonates.[20]
### Neonatal meningitis-causing E. coli[edit]
Some strains of E. coli have a capsule, called K1, which protects the bacteria from the innate immune system and allows it to penetrate the central nervous system. The capsule contains sialic acid, which is found widely in humans and so does not set off the defenses of the body. Sialic acid also plays a role in the bacteria's ability to invade through the blood-brain barrier. The capsule can be variably O-acetylated.[5]
## Diagnosis[edit]
### Bacterial Infection[edit]
A lumbar puncture (spinal tap) is necessary to diagnose meningitis. Cerebrospinal fluid culture is the most important study for the diagnosis of neonatal bacterial meningitis because clinical signs are non-specific and unreliable. Blood cultures may be negative in 15-55% of cases, making them unreliable as well.[1] However, a cerebrospinal fluid to blood glucose ratio below two-thirds has a strong relationship to bacterial meningitis.[6] A spinal tap should be done in all neonates with suspected meningitis, with suspected or proven sepsis (whole body inflammation) and should be considered in all neonates in whom sepsis is a possibility. The role of the spinal tap in neonates who are healthy appearing but have maternal risk factors for sepsis is more controversial; its diagnostic yield in these patients may be low.[1][6]
Early-onset is deemed when infection is within one week of birth. Late-onset is deemed after the first week.[3]
### Viral Infection[edit]
Babies born from mothers with symptoms of Herpes simplex virus should be tested for viral infection. Liver tests, complete blood count, cerebrospinal fluid analysis, and a chest X-ray should all be completed to diagnose meningitis.[19] Samples should be taken from skin, conjunctiva (eye), mouth and throat, rectum, urine, and the cerebrospinal fluid for viral culture and polymerase chain reaction.
## Prevention[edit]
### Bacterial[edit]
Prevention of neonatal meningitis is primarily intrapartum (during labor) antibiotic prophylaxis (prevention) of pregnant mothers to decrease chance of early-onset meningitis by Streptococcus agalactiae. For late-onset meningitis, prevention is passed onto the caretakers to stop the spread of infectious microorganisms. Proper hygiene habits are first and foremost, while stopping improper antibiotic use; such as over-prescriptions, use of broad spectrum antibiotics, and extended dosing times will aid prevention of late-onset neonatal meningitis. A possible prevention may be vaccination of mothers against Streptococcus agalactiae and E. coli, however, this is still under development.[1][6]
### Viral[edit]
The only form of prevention from viral infection of the neonate is a Caesarean section form of delivery if the mother is showing symptoms of infection.[19]
## Treatment[edit]
cal structure of penicillin
cal structure of gentamicin
Chemical structure of cefotaxime
Chemical structure of Ceftazidime
Chemical structure of ampicillin
Chemical structure of aciclovir
Treatment for meningitis is antibiotics. The particular drugs used are based on culture results that identify the infecting bacteria, but a mix of ampicillin, gentamicin, and cefotaxime is used for early-onset meningitis before their identification. A regimen of antistaphylococcal antibiotic, such as nafcillin or vancomycin, plus cefotaxime or ceftazidime with or without an aminoglycoside is recommended for late-onset neonatal meningitis. The aim for these treatments is to sterilize the cerebrospinal fluid of all pathogens. A repeat spinal tap 24 to 48 hours after treatment has been started should be done to confirm sterilization.[1][6]
Limited evidence suggests that adjuvant corticosteroids may reduce the short-term risk of hearing loss in newborn infants with meningitis, but it is uncertain whether corticosteroids help to reduce the risk of death or longer-term hearing loss.[21]
### Group B Streptococci[edit]
For meningitis suspected to be caused by Streptococcus agalactiae, the following treatment is recommended by the American Academy of Pediatrics: doses of penicillin up to 450 000 U/kg daily (270 mg/kg/day) divided 8 hourly if <7 days of age and divided 6 hourly if >7 days of age. For penicillin [the recommended dose is up to 300 mg/kg/daily divided 8 hourly if <7 days of age or 4–6 hourly if >7 days of age. After confirmation of Streptococcus agalactiae by culture, penicillin alone should be used for the rest of the course of treatment, including the 14-day post-sterilization therapy.[1][6]
### Gram-negative Enterics[edit]
For suspected Gram-negative enteric (including E. coli) meningitis a combination of cefotaxime and aminoglycoside, usually gentamicin, is recommended. This treatment should last for 14 days after sterilization and then only cefotaxime for another 7 days creating a minimum of 21 days of therapy after sterilization.[1][6]
### Listeria monocytogenes[edit]
Meningitis caused by Listeria monocytogenes should be treated with a combination of ampicillin and gentamicin because it is synergistic in vitro and provides more rapid bacterial clearance in animal models of infection.
### Streptococcus pneumoniae[edit]
Streptococcus pneumoniae can be treated with either penicillin or ampicillin.[1][6]
### Herpes Simplex Virus[edit]
In cases of meningitis caused by Herpes simplex virus, antiviral therapy with (acyclovir or vidarabine) must be started immediately for a favorable outcome.[1][6] Acyclovir is a better antiviral because it shows a similar effect on the infection as vidarabine and is safer to use in neonates. The recommended dosage is 20 mg/kg every six hours for 21 days.[19]
## Epidemiology[edit]
In industrialized countries, the incidence of bacterial meningitis is approximately 3 in 10,000 live births. The incidence of Herpes simplex virus meningitis is estimated to be 0.2-5.0 cases per 10,000 live births. Neonatal meningitis is much more common in developing countries. Neonatal meningitis ranges from 4.8 per 10,000 live births in Hong Kong to 24 per 10,000 live births in Kuwait. In Africa and South Asia, figures ranging from 8.0 to 61 per 10,000 live births are found. It is expected that these numbers are lower than reality due to the difficulty of diagnosing and the healthcare available to underdeveloped countries in Asia and Africa.[2][3]
## References[edit]
1. ^ a b c d e f g h i j k l m n o p Heath, P T (2003). "Neonatal meningitis". Archives of Disease in Childhood: Fetal and Neonatal Edition. 88 (3): F173–8. doi:10.1136/fn.88.3.F173. PMC 1721548. PMID 12719388.
2. ^ a b c d Neonatal Meningitis at eMedicine
3. ^ a b c Furyk, J. S.; Swann, O.; Molyneux, E. (2011). "Systematic review: neonatal meningitis in the developing world". Tropical Medicine & International Health. 16 (6): 672–9. doi:10.1111/j.1365-3156.2011.02750.x. PMID 21395927.
4. ^ a b c d Lin, Mu-Chun; Chi, Hsin; Chiu, Nan-Chang; Huang, Fu-Yuan; Ho, Che-Sheng (2012). "Factors for poor prognosis of neonatal bacterial meningitis in a medical center in Northern Taiwan". Journal of Microbiology, Immunology and Infection. 45 (6): 442–7. doi:10.1016/j.jmii.2011.12.034. PMID 22571998.
5. ^ a b c d Wilson, Brenda A.; Salyers, Abigail A.; Whitt, Dixie D.; et al., eds. (2011). Bacterial Pathogenesis: A Molecular Approach (3rd ed.). ASM. pp. 212–3, 441. ISBN 978-1-55581-418-2.
6. ^ a b c d e f g h i j k Sivanandan, S., Soraisham, A. S., & Swarnam, K. (2011). Choice and duration of antimicrobial therapy for neonatal sepsis and meningitis. International Journal of Pediatrics, 2011
7. ^ "Hearing loss following meningitis | Meningitis Now". www.meningitisnow.org. Retrieved 2020-04-07.
8. ^ "Meningitis - Symptoms and causes". Mayo Clinic. Retrieved 2020-04-07.
9. ^ "Hearing loss following meningitis | Meningitis Now". www.meningitisnow.org. Retrieved 2020-04-07.
10. ^ "Hearing loss following meningitis | Meningitis Now". www.meningitisnow.org. Retrieved 2020-04-07.
11. ^ "Hearing loss following meningitis | Meningitis Now". www.meningitisnow.org. Retrieved 2020-04-07.
12. ^ "Hearing loss following meningitis | Meningitis Now". www.meningitisnow.org. Retrieved 2020-04-07.
13. ^ "Hearing loss following meningitis | Meningitis Now". www.meningitisnow.org. Retrieved 2020-04-07.
14. ^ "Hearing loss following meningitis | Meningitis Now". www.meningitisnow.org. Retrieved 2020-04-07.
15. ^ Edwards, Morven S; Baker, Carol J (August 23, 2013). "Bacterial meningitis in the neonate: Clinical features and diagnosis". UpToDate.
16. ^ "Meningitis | Home | CDC". www.cdc.gov. 2020-02-19. Retrieved 2020-04-07.
17. ^ "Meningitis - Symptoms and causes". Mayo Clinic. Retrieved 2020-04-07.
18. ^ "Meningitis - Symptoms and causes". Mayo Clinic. Retrieved 2020-04-07.
19. ^ a b c d e f Kimberlin, D. (2004). Herpes simplex virus, meningitis and encephalitis in neonates. breast, 20, 22.
20. ^ Puopolo, Karen M; Baker, Carol J (August 10, 2015). "Group B streptococcal infection in neonates and young infants". UpToDate.
21. ^ Ogunlesi, TA; Odigwe, CC; Oladapo, OT (11 November 2015). "Adjuvant corticosteroids for reducing death in neonatal bacterial meningitis". The Cochrane Database of Systematic Reviews (11): CD010435. doi:10.1002/14651858.CD010435.pub2. PMID 26560739.
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| Neonatal meningitis | c0456107 | 6,899 | wikipedia | https://en.wikipedia.org/wiki/Neonatal_meningitis | 2021-01-18T18:49:46 | {"gard": ["10440"], "wikidata": ["Q6993489"]} |
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