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The leukocyte group-5 antigenic system, first described by van Leeuwen et al. (1964)--leukocyte group-4 was the early designation for HLA-B and LA the designation for HLA-A--has 2 known alleles (a and b) that segregate independently of the HLA system (van Rood et al., 1967). It is expressed in leukocytes, placenta, kidney, spleen, lymph nodes, and platelets but not in red cells (Warren et al., 1981). No involvement in graft rejection or graft-versus-host reactions (see 614395) has been found (Warren et al., 1977). LAG5a is associated with acute lymphoblastic leukemia (Warren et al., 1977). In somatic cell hybrids of Chinese hamster cells with leukocytes from patients with chronic myeloid leukemia, Geurts van Kessel et al. (1983) concluded that the LAG5b allele which was expressed is coded by human chromosome 4. They cautioned that 'it still remains to be established whether this is a structural or a regulatory gene(s).' LAG5 is characteristic of granulocytic leukocytes, not lymphocytes. Granulocyte antigens are important in leukopenia of the newborn. Lalezari (1984) recounted the interesting story of the discovery of alloimmune neonatal neutropenia in the DeR family in which 4 infants had severe neonatal neutropenia with infections that caused the death of 1 infant. The antibody in the mother was strikingly specific for neutrophils; eosinophils, basophils and lymphocytes were unaffected. Luhby and Slobody (1956) and Hitzig and Gitzelmann (1959) made similar observations. NB1 (162860) was the designation Lalezari used for the first anti-neutrophil antibody he demonstrated; see FCGR3A; 146740. NA2 (see 146740.0001) was another neutrophil antigen, found as the cause of chronic autoimmune neutropenia (Lalezari et al., 1975). Yet others were labeled NE1 (162890) (Claas et al., 1979) and ND1 (162880) (Verheugt et al., 1978). [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 inhibitors [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	LEUKOCYTE ANTIGEN GROUP FIVE	None	2,900	omim	https://www.omim.org/entry/151450	2019-09-22T16:38:56	{"omim": ["151450"], "synonyms": ["Alternative titles", "GRANULOCYTE ANTIGEN 5"]}
Type of acute lung injury Ventilator-associated lung injury SpecialtyPulmonology Ventilator-associated lung injury (VALI) is an acute lung injury that develops during mechanical ventilation and is termed ventilator-induced lung injury (VILI) if it can be proven that the mechanical ventilation caused the acute lung injury. In contrast, ventilator-associated lung injury (VALI) exists if the cause cannot be proven. VALI is the appropriate term in most situations because it is virtually impossible to prove what actually caused the lung injury in the hospital.[1] ## Contents * 1 Cause * 2 Pathogenesis * 3 Diagnosis * 4 Prevention * 5 Epidemiology * 6 References * 7 External links ## Cause[edit] It is generally regarded, based on animal models and human studies, that volutrauma is the most harmful aspect of mechanical ventilation.[2][3][4] This may be regarded as the over-stretching of the airways and alveoli.[citation needed] During mechanical ventilation, the flow of gas into the lung will take the path of least resistance. Areas of the lung that are collapsed (atelectasis) or filled with secretions will be underinflated, while those areas that are relatively normal will be overinflated. These areas will become overdistended and injured. This may be reduced by using smaller tidal volumes.[5][6] During positive pressure ventilation, atelectatic regions will inflate, however, the alveoli will be unstable and will collapse during the expiratory phase of the breath (atelectotrauma). This repeated alveolar collapse and expansion (RACE) is thought to cause VALI. By opening the lung and keeping the lung open RACE (and VALI) is reduced.[7] Another possible ventilator-associated lung injury is known as biotrauma. Biotrauma involves the lung suffering injury from any mediators of the inflammatory response or from bacteremia. Finally oxygen toxicity contributes to ventilator-associated lung injury through several mechanisms including oxidative stress. Possible reasons for predisposition to VALI include: * An injured lung may be at risk for further injury * Cyclic atelectasis is particularly common in an injured lung ## Pathogenesis[edit] Overdistension of alveoli and cyclic atelectasis (atelectotrauma) are the primary causes for alveolar injury during positive pressure mechanical ventilation. Severe injury to alveoli causes swelling of the tissues (edema) in the lungs, bleeding of the alveoli, loss of surfactant (decrease in lung compliance) and complete alveoli collapse (biotrauma).[1][8] High flow rates are associated with rheotrauma, high volumes with volutrauma and pressures with barotrauma. Collectively these may be converted into a single unit of mechanical power.[citation needed] ## Diagnosis[edit] VALI does not need to be distinguished from progressive ALI/ARDS because management is the same in both. Additionally, definitive diagnosis of VALI may not be possible because of lack of sign or symptoms.[citation needed] ## Prevention[edit] Preventing alveolar overdistension – Alveolar overdistension is mitigated by using small tidal volumes, maintaining a low plateau pressure, and most effectively by using volume-limited ventilation. A 2018 systematic review by The Cochrane Collaboration provided evidence that low tidal volume ventilation reduced post operative pneumonia and reduced the requirement for both invasive and non invasive ventilation after surgery[9] Preventing cyclic atelectasis (atelectotrauma) – Applied positive end-expiratory pressure (PEEP) is the principal method used to keep the alveoli open and lessen cyclic atelectasis. Open lung ventilationn – Open lung ventilation is a ventilatory strategy that combines small tidal volumes (to lessen alveolar overdistension) and an applied PEEP above the low inflection point on the pressure-volume curve (to lessen cyclic atelectasis). High frequency ventilation is thought to reduce ventilator-associated lung injury, especially in the context of ARDS and acute lung injury.[7] Permissive hypercapnia and hypoxaemia allow the patient to be ventilated at less aggressive settings and can, therefore, mitigate all forms of ventilator-associated lung injury ## Epidemiology[edit] VALI is most common in people receiving mechanical ventilation for acute lung injury or acute respiratory distress syndrome (ALI/ARDS).[1] 24 percent of people mechanically ventilated will develop VALI for reasons other than ALI or ARDS.[1] The incidence is probably higher among people who already have ALI/ARDS, but estimates vary widely.[1] The variable estimates reflect the difficulty in distinguishing VALI from progressive ALI/ARDS.[1] ## References[edit] 1. ^ a b c d e f International (1999). "Ventilator-associated Lung Injury in ARDS. This official conference report was cosponsored by the American Thoracic Society, The European Society of Intensive Care Medicine, and The Societé de Réanimation de Langue Française, and was approved by the ATS Board of Directors, July 1999". Am J Respir Crit Care Med. 160: 2118–24. doi:10.1164/ajrccm.160.6.ats16060. PMID 10588637. 2. ^ Attar MA, Donn SM (Oct 2002). "Mechanisms of ventilator-induced lung injury in premature infants". Semin Neonatol. 7 (5): 353–60. doi:10.1053/siny.2002.0129. PMID 12464497. 3. ^ Rahaman U (Aug 2017). "Mathematics of Ventilator-induced Lung Injury". Indian J Crit Care Med. 21 (8): 521–524. doi:10.4103/ijccm.IJCCM_411_16. PMC 5588487. PMID 28904482. 4. ^ Donn, S M (13 October 2005). "Minimising ventilator induced lung injury in preterm infants". Archives of Disease in Childhood: Fetal and Neonatal Edition. 91 (3): F226–F230. doi:10.1136/adc.2005.082271. PMC 2672704. PMID 16632652. 5. ^ Ng Calvin SH, Arifi Ahmed A, Wan Song, Ho Anthony MH, Wan Innes YP, Wong Eric MC, Yim Anthony PC (2008). "Ventilation during Cardiopulmonary Bypass: Impact on Cytokine Response and Cardiopulmonary Function". Ann Thorac Surg. 85: 154–62. doi:10.1016/j.athoracsur.2007.07.068.CS1 maint: multiple names: authors list (link) 6. ^ Ng Calvin SH, Wan Song, Ho Anthony MH, Underwood Malcolm J (2009). "Gene Expression Changes with "Non-injurious" Ventilation Strategy". Crit Care. 13: 403. doi:10.1186/cc7719.CS1 maint: multiple names: authors list (link) 7. ^ a b Krishnan JA, Brower RG (2000). "High-frequency ventilation for acute lung injury and ARDS". Chest. 118 (3): 795–807. doi:10.1378/chest.118.3.795. PMID 10988205. Free Full Text. 8. ^ Rouby JJ, Brochard L (2007). "Tidal recruitment and overinflation in acute respiratory distress syndrome: yin and yang". Am J Respir Crit Care Med. 175 (2): 104–6. doi:10.1164/rccm.200610-1564ED. PMID 17200505. 9. ^ Guay, Joanne; Ochroch, Edward A; Kopp, Sandra (2018-07-09). "Intraoperative use of low volume ventilation to decrease postoperative mortality, mechanical ventilation, lengths of stay and lung injury in adults without acute lung injury". Cochrane Database of Systematic Reviews. 7: CD011151. doi:10.1002/14651858.cd011151.pub3. ISSN 1465-1858. PMC 6513630. PMID 29985541. ## External links[edit] * Ventilators and COVID-19: What You Need to Know, Yale Medicine Classification D * ICD-9-CM: J95859 * MeSH: D055397 * v * t * e Mechanical ventilation Fundamentals * Modes of mechanical ventilation * Mechanical ventilation in emergencies * Nomenclature of mechanical ventilation Modes * IMV/SIMV * CMV * ACV * CSV * PAP * BPAP/NIV * CPAP * APRV * MMV * PAV * ASV * HFV Related illness * ARDS * Atelectotrauma * Biotrauma * Pulmonary barotrauma * Pulmonary volutrauma * Rheotrauma * Ventilator-associated pneumonia * Oxygen toxicity * Ventilator-associated lung injury Pressure * PEEP * FiO2 * ΔP * PIP * PS * PAW * Pplat Volumes * VT * VE * Vf Other * Cdyn * Cstatic * PAO2 * VD/VT * OI * A-a gradient * Mechanical power [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 inhibitors [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	Ventilator-associated lung injury	c2350350	2,901	wikipedia	https://en.wikipedia.org/wiki/Ventilator-associated_lung_injury	2021-01-18T18:57:28	{"mesh": ["D055397"], "icd-9": ["J95859"], "wikidata": ["Q7920251"]}
12q14 microdeletion syndrome is characterised by mild intellectual deficit, failure to thrive, short stature and osteopoikilosis. It has been described in four unrelated patients. The syndrome appears to be caused by a heterozygous deletion at chromosome region 12q14, which was detected in three of the four patients. The deleted region contains the LEMD3 gene: mutations in this gene have already been implicated in osteopoikilosis. [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 inhibitors [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	12q14 microdeletion syndrome	c4305140	2,902	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=94063	2021-01-23T19:10:46	{"icd-10": ["Q93.5"], "synonyms": ["Del(12)(q14)", "Deletion 12q14", "Monosomy 12q14", "Osteopoikilosis-short stature-intellectual disability syndrome"]}
Gonadoblastoma Micrograph of a gonadoblastoma. H&E stain. SpecialtyUrology, oncology A gonadoblastoma is a complex neoplasm composed of a mixture of gonadal elements,[1] such as large primordial germ cells, immature Sertoli cells or granulosa cells of the sex cord, and gonadal stromal cells. Gonadoblastomas are by definition benign, but more than 50% have a co-existing dysgerminoma which is malignant, and an additional 10% have other more aggressive malignancies, and as such are often treated as malignant.[2] ## Contents * 1 Risk factors * 2 Diagnosis * 2.1 Classification * 3 Treatment * 4 References * 5 External links ## Risk factors[edit] Gonadoblastoma is most often associated with an abnormal chromosomal karyotype, gonadal dysgenesis, or the presence of a Y chromosome in over 90% of cases. Gonadoblastoma has been found in association with androgen insensitivity syndrome, mixed gonadal dysgenesis and Turner syndrome, especially in the presence of Y chromosome-bearing cells.[3][4] Women with Turner syndrome whose karyotype includes a Y chromosome (as in 45,X/46,XY mosaicism) are at increased risk for gonadoblastoma. Because of the risk of gonadoblastoma, individuals with Turner syndrome with detectable Y chromosome material (Mosaic Turner syndrome) should have their gonads prophylactically removed. In a population-based study, the cumulative risk for women with Turner syndrome and Y chromosome material was 7.9 percent by age 25 years.[5] ## Diagnosis[edit] ### Classification[edit] Main article: Germ cell tumor Gonadoblastomas can contain elements of both germ cells and gonadal stroma.[6] Formerly, gonadoblastoma was sometimes regarded as a subset of dysgerminoma. In modern literature, it is sometimes considered to progress to dysgerminoma.[7] ## Treatment[edit] Standard treatment would include surgical exploration via laparotomy. Laparoscopy may be an option if the surgeon is particularly skilled in removing ovarian neoplasms via laparoscopy intact. If the diagnosis of gonadoblastoma is certain, a bilateral salpingo-oophorectomy (BSO) should be performed to remove both the primary tumor and the dysgenic contralateral ovary. If uninvolved, the uterus should be left intact. Modern reproductive endocrinology technology allows patients post BSO to achieve pregnancy via in-vitro fertilization (IVF) with a donor egg. ## References[edit] 1. ^ Cools M, Stoop H, Kersemaekers AM, et al. (June 2006). "Gonadoblastoma arising in undifferentiated gonadal tissue within dysgenetic gonads". J. Clin. Endocrinol. Metab. 91 (6): 2404–13. doi:10.1210/jc.2005-2554. PMID 16608895. 2. ^ Shahrzad Ehdaivand, Nalini Gupta "Gonadoblastoma", PathologyOutlines.com, 2 July 2014 3. ^ Maggio MC, Liotta A, De Grazia E, Cimador M, Di Pace R, Corsello G (2007). "Polycystic ovary and gonadoblastoma in Turner's syndrome". Minerva Pediatr. 59 (4): 397–401. PMID 17947845. 4. ^ Bianco B, Lipay MV, Melaragno MI, Guedes AD, Verreschi IT (2006). "Detection of hidden Y mosaicism in Turner's syndrome: importance in the prevention of gonadoblastoma". J. Pediatr. Endocrinol. Metab. 19 (9): 1113–7. doi:10.1515/JPEM.2006.19.9.1113. PMID 17128558. 5. ^ Lancet Oncol. 2008;9(3):239. Epub 2008 Feb 20 6. ^ Kumar, Vinay; Fausto, Nelso; Abbas, Abul (2009) Robbins & Cotran Pathologic Basis of Disease (8th ed.). Saunders. Chapter 21. ISBN 1-4160-3121-9. 7. ^ Cooper C, Cooper M, Carter J, Russell P (2007). "Gonadoblastoma progressing to dysgerminoma in a 55-year-old woman with normal karyotype". Pathology. 39 (2): 284–5. doi:10.1080/00313020701230708. PMID 17454768. ## External links[edit] Classification D * ICD-O: M9073/1 * MeSH: D018238 * DiseasesDB: 34299 * v * t * e Germ cell tumors Germinomatous * Germinoma * Seminoma * Dysgerminoma Nongerminomatous * Embryonal carcinoma * Endodermal sinus tumor/Yolk sac tumor * Teratoma: Fetus in fetu * Dermoid cyst * Struma ovarii * Strumal carcinoid * Trophoblastic neoplasm: Gestational trophoblastic disease * Hydatidiform mole * Choriocarcinoma * Placental site trophoblastic tumor * Polyembryoma * Gonadoblastoma * v * t * e Tumors of the female urogenital system Adnexa Ovaries Glandular and epithelial/ surface epithelial- stromal tumor CMS: * Ovarian serous cystadenoma * Mucinous cystadenoma * Cystadenocarcinoma * Papillary serous cystadenocarcinoma * Krukenberg tumor * Endometrioid tumor * Clear-cell ovarian carcinoma * Brenner tumour Sex cord–gonadal stromal * Leydig cell tumour * Sertoli cell tumour * Sertoli–Leydig cell tumour * Thecoma * Granulosa cell tumour * Luteoma * Sex cord tumour with annular tubules Germ cell * Dysgerminoma * Nongerminomatous * Embryonal carcinoma * Endodermal sinus tumor * Gonadoblastoma * Teratoma/Struma ovarii * Choriocarcinoma Fibroma * Meigs' syndrome Fallopian tube * Adenomatoid tumor Uterus Myometrium * Uterine fibroids/leiomyoma * Leiomyosarcoma * Adenomyoma Endometrium * Endometrioid tumor * Uterine papillary serous carcinoma * Endometrial intraepithelial neoplasia * Uterine clear-cell carcinoma Cervix * Cervical intraepithelial neoplasia * Clear-cell carcinoma * SCC * Glassy cell carcinoma * Villoglandular adenocarcinoma Placenta * Choriocarcinoma * Gestational trophoblastic disease General * Uterine sarcoma * Mixed Müllerian tumor Vagina * Squamous-cell carcinoma of the vagina * Botryoid rhabdomyosarcoma * Clear-cell adenocarcinoma of the vagina * Vaginal intraepithelial neoplasia * Vaginal cysts Vulva * SCC * Melanoma * Papillary hidradenoma * Extramammary Paget's disease * Vulvar intraepithelial neoplasia * Bartholin gland carcinoma * v * t * e * Tumors of the male urogenital system Testicles Sex cord– gonadal stromal * Sertoli–Leydig cell tumour * Sertoli cell tumour * Leydig cell tumour Germ cell G * Seminoma * Spermatocytic tumor * Germ cell neoplasia in situ NG * Embryonal carcinoma * Endodermal sinus tumor * Gonadoblastoma * Teratoma * Choriocarcinoma * Embryoma Prostate * Adenocarcinoma * High-grade prostatic intraepithelial neoplasia * HGPIN * Small-cell carcinoma * Transitional cell carcinoma Penis * Carcinoma * Extramammary Paget's disease * Bowen's disease * Bowenoid papulosis * Erythroplasia of Queyrat * Hirsuties coronae glandis [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 inhibitors [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	Gonadoblastoma	c0206661	2,903	wikipedia	https://en.wikipedia.org/wiki/Gonadoblastoma	2021-01-18T18:54:44	{"mesh": ["D018238"], "umls": ["C0206661"], "orphanet": ["206484"], "wikidata": ["Q5581320"]}
## Summary ### Clinical characteristics. ELANE-related neutropenia includes congenital neutropenia and cyclic neutropenia, both of which are primary hematologic disorders characterized by recurrent fever, skin and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and pharyngitis), and cervical adenopathy. Infectious complications are generally more severe in congenital neutropenia than in cyclic neutropenia. In congenital neutropenia, omphalitis immediately after birth may be the first sign; in untreated children diarrhea, pneumonia, and deep abscesses in the liver, lungs, and subcutaneous tissues are common in the first year of life. After 15 years with granulocyte colony-stimulating factor treatment, the risk of developing myelodysplasia (MDS) or acute myelogenous leukemia (AML) is approximately 15%-25%. Cyclic neutropenia is usually diagnosed within the first year of life based on approximately three-week intervals of fever and oral ulcerations and regular oscillations of blood cell counts. Cellulitis, especially perianal cellulitis, is common during neutropenic periods. Between neutropenic periods, affected individuals are generally healthy. Symptoms improve in adulthood. Cyclic neutropenia is not associated with risk of malignancy or conversion to leukemia. ### Diagnosis/testing. The diagnosis of ELANE-related neutropenia is established in a proband with suggestive clinical findings and the identification of a heterozygous pathogenic variant in ELANE through molecular genetic testing. ### Management. Treatment of manifestations: All fevers and infections require prompt evaluation and treatment. Abdominal pain requires evaluation for the potentially lethal complications of peritonitis and bacteremia. Immediate treatment with granulocyte colony-stimulating factor (G-CSF) and broad-spectrum antibiotics is important, even lifesaving, when an affected individual has signs of serious infection, which may be caused by both aerobic and anaerobic pathogens. Prevention of primary manifestations: Treatment with G-CSF ameliorates symptoms and reduces infections in almost all affected individuals. Once absolute neutrophil count (ANC) levels normalize, resistance to infection greatly improves, such that affected individuals should be able to attend school, work, and recreational activities without specific concern. For affected individuals with a well-matched donor, hematopoietic stem cell transplantation (HSCT) may be the preferred treatment option. HSCT is the only alternative therapy for individuals with congenital neutropenia who are refractory to high-dose G-CSF or who undergo malignant transformation. Prevention of secondary complications: Good dental hygiene; routine immunizations. Surveillance: Those with congenital neutropenia not undergoing HSCT require surveillance for malignant transformation to MDS/AML. Agents/circumstances to avoid: There is no need to avoid public places, as most infections are due to common organisms that occur on body surfaces. Pregnancy management: Pregnancies in women with severe chronic neutropenia are at substantial risk for miscarriage; treatment with G-CSF may reduce this risk. Evaluation of relatives at risk: Evaluate sibs and other at-risk relatives by molecular genetic testing for the ELANE pathogenic variant found in the proband to identify those with previously unrecognized mild or moderately severe disease who may benefit from treatment. Serial ANCs can also be used for evaluation of family members. ### Genetic counseling. ELANE-related neutropenia is inherited in an autosomal dominant manner. One parent of a proband is usually affected. De novo pathogenic variants have been identified; their frequency is unknown. Each child of an individual with an ELANE pathogenic variant has a 50% chance of inheriting the variant. Prenatal testing for a pregnanciy at increased risk and preimplantation genetic testing are possible if the family-specific pathogenic variant is known. ## Diagnosis ELANE-related neutropenia represents a clinical spectrum that includes congenital neutropenia, cyclic neutropenia, and intermediate findings between these two phenotypes. Identification of the precise clinical phenotype is helpful for diagnosis, prognosis, and management. ### Suggestive Findings ELANE-related neutropenia should be suspected in individuals with the following clinical and supportive laboratory findings. Clinical features * Severe or recurrent infections * Congenital neutropenia. Recurrent fevers, sinusitis, gingivitis, and chronic and severe infections in the lung, liver, and soft tissues occurring at irregular intervals * Cyclic neutropenia * Mouth ulcers, pharyngitis, and fever recurring regularly at three-week intervals * Inflammation and infection of the sinuses, upper- and lower-respiratory tract, and skin including the perianal area * Abdominal pain and signs of an acute abdomen, suggesting sepsis and bacteremia from colonic ulcers Supportive laboratory findings * Congenital neutropenia * At least three absolute neutrophil counts (ANCs) <500/µL obtained ≥3 months after birth supports the diagnosis. Note: The ANC is the white blood cell count (WBC) x % neutrophils. * ANCs are <0.5x109/L in most cases, and usually <0.2x109/L; in one series, the mean ANC was 0.112x109/L. * In some individuals, periods with regular oscillations in blood neutrophil counts can be interspersed with periods in which no oscillations in blood neutrophil counts are apparent. * Other hematopoietic cells * Monocyte counts tend to be increased (i.e., >1.0x109/L). * Platelet counts tend to be increased. * Hematocrit tends to be mildly decreased. * Bone marrow aspirate typically shows "maturation arrest" at the promyelocyte or myelocyte stage of neutrophil formation. Increased bone marrow monocytes and eosinophils may be present. * Cytogenetic analysis of bone marrow is normal. * Cyclic neutropenia * Most affected individuals have an ANC <0.2x109/L for three to five days at approximately three-week intervals. * Oscillations of other cells, including lymphocytes, eosinophils, and platelets may be observed. * Usually, a reciprocal increase in blood monocytes and reticulocytes occurs during the neutrophil nadir. * Bone marrow aspirate shows an abnormality similar to that in congenital neutropenia when neutrophil counts are the lowest; at other times, maturation of cells of the neutrophil lineage is near normal. Note: (1) Cyclic neutropenia is distinguished from congenital neutropenia by the regular oscillations of blood neutrophil counts in cyclic neutropenia. (2) Often, serial blood cell counts are needed to assure that individuals suspected of having congenital neutropenia do not have cyclic neutropenia; however, this approach has limitations because, in some cases of cyclic neutropenia, the amplitude of the oscillations may be very low. ### Establishing the Diagnosis A diagnostic algorithm for cyclic neutropenia has been published [Zeidler et al 2000]. The diagnosis of ELANE-related neutropenia is established in a proband by the identification of a heterozygous pathogenic variant in ELANE by molecular genetic testing (see Table 1). Note: The distinction between cyclic neutropenia and congenital neutropenia is primarily based on clinical findings and only secondarily on genotype (see Genotype-Phenotype Correlations). Molecular genetic testing approaches can include single-gene testing and use of a multigene panel: * Single-gene testing. Sequence analysis of ELANE is performed. Note: Since the presumed mechanism of disease is production of abnormal enzyme that is not inhibited or packaged normally resulting in damage to cells of the neutrophil lineage during their development, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant. * A multigene panel that includes ELANE 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) Pathogenic variants in more than one gene associated with neutropenia have been identified in some individuals [Germeshausen et al 2010], but the clinical significance of finding variants in two or more neutropenia-associated genes is not known. (3) 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. (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 ELANE-Related Neutropenia View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method ELANESequence analysis 3100% 4 Gene-targeted deletion/duplication analysis 5None reported 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\. Aprikyan et al [2002], Ancliff et al [2003b], Bellanné-Chantelot et al [2004] 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\. Makaryan et al [2015] ## Clinical Characteristics ### Clinical Description #### Congenital Neutropenia Infectious complications are generally more severe in congenital neutropenia than in cyclic neutropenia. In both conditions, individuals have fever and recurrent skin and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, pharyngitis, and cervical adenopathy). In congenital neutropenia, diarrhea, pneumonia, and deep abscesses in the liver, lung, and subcutaneous tissues are common. Omphalitis immediately after birth may be the first sign [Dale 2017, Skokowa et al 2017]. Bacteremia occurs infrequently but has severe consequences in affected individuals. Most congenital neutropenia is diagnosed because of fever and severe infection in infants and young children. Treatment with granulocyte colony-stimulating factor (G-CSF) raises blood neutrophil levels and reduces all of these complications in more than 90% of affected individuals [Dale 2017] (see Management). Individuals with ELANE-related neutropenia are at risk of developing myelodysplasia syndrome (MDS) or acute myelogenous leukemia (AML). Myelodysplasia or leukemia typically arises gradually. The affected individual may have a gradual loss in response to G-CSF treatment or what appears to be a minor change in blood cell counts. If there is neutropenia, infections are likely to occur. Anemia may lead to fatigue. Annual bone marrow examinations with cytogenetic analysis are recommended for those treated with G-CSF. Chromosomal deletions, most commonly monosomy 7, are predictors for leukemic evolution; however, there may be a very long lag period, even many years, between the discovery of monosomy 7 and MDS/AML. Similarly, acquired pathogenic variants in CSF3R (the G-CSF receptor) and RUNX1 predict evolution to leukemia, but clinical tests for these findings are not widely available or necessary in clinical practice [Skokowa et al 2017]. In a study conducted by Rosenberg et al [2008] the cumulative incidence of MDS/AML 15 years after starting treatment with G-CSF was 36%. This finding is similar to the cumulative incidence of MDS/AML 15 years after starting treatment with G-CSF in individuals with congenital neutropenia who do not have a pathogenic variant in ELANE (25%; P = 0.96) [Rosenberg et al 2006]. Similarly, a prospective study of 374 persons with severe congenital neutropenia on long-term treatment with G-CSF showed that the overall risk of MDS/AML was 15%-25% at 15 years on treatment [Rosenberg et al 2010], although this study did not distinguish between individuals with ELANE-related neutropenia and those with congenital neutropenia due to other causes. Overall, G-CSF reduced mortality from sepsis but uncovered an underlying disposition to MDS/AML. Individuals requiring higher doses of G-CSF (i.e., those requiring >8 µg/kg/day to achieve a mean neutrophil count equal to the group median [2.188x109/L]) were at greater risk of death from both sepsis and MDS/AML than those responding to lower doses [Rosenberg et al 2010, Makaryan et al 2015, Donadieu et al 2017]. #### Cyclic Neutropenia Cyclic neutropenia is usually diagnosed soon after birth or within the first year of life based on a pattern of recurrent fever and oral ulcerations with serial blood cell counts showing regular oscillations. Peak neutrophil counts are usually <0.2x109/L. Variations in this classic pattern include cycles longer or shorter than three weeks (probably <5% of individuals) and reduced amplitude of oscillations. Counts in children tend to oscillate more obviously than in adults. Untreated individuals have recurrent oropharyngeal inflammation; they are particularly prone to developing oral ulcers at approximately three-week intervals. Cellulitis, especially perianal cellulitis, is common during the neutropenic periods. Bacteremia is rare; the greatest risk appears to be for death from necrotizing enterocolitis, peritonitis, and Clostridium and/or E coli sepsis [Barnes et al 2004]. Symptoms tend to be more severe in children than in adults. Palmer et al [1996] reported that more than 60% of individuals with cyclic neutropenia experience oral ulcerations, gingivitis, lymphadenopathy, fever, pharyngitis/tonsillitis, fatigue, or skin infections five or more times a year. More than 30% of adults report five or more episodes per year of sinusitis and/or otitis media, and more than 20% of children report at least five episodes per year of bone pain or tooth abscesses. More than 10% of individuals report pneumonia, bronchitis, diarrhea, or anal ulcers. Serious neonatal infections and sepsis are rare. Between neutropenic periods, affected individuals are generally healthy. Symptoms improve in adulthood. Skin infections, fever, lymphadenopathy, and pharyngitis occur less frequently. Sinusitis, headache, and bone pain remain the most common symptoms. Oral ulcers, fatigue, and gingivitis also occur frequently. Permanent tooth loss resulting from chronic gingivitis, tooth abscesses, and alveolar bone loss in adolescence or young adulthood is common. There are no associated congenital abnormalities. Cyclic phenomena in other organ systems have not been recognized, probably because ELANE is expressed only in myeloid cells. Cyclic neutropenia is not associated with an increased risk of malignancy or conversion to leukemia. However, confusion may arise when the series of counts is insufficient to clearly determine if an affected individual has congenital or cyclic neutropenia. #### Intermediate Phenotypes Some affected individuals may at times have an obvious cyclic pattern of fluctuations in the neutrophil counts and at other times have counts that do not cycle, so that the diagnosis of congenital neutropenia seems appropriate. In families with multiple affected members in the same generation, one person may appear to have cyclic neutropenia while another has features more consistent with congenital neutropenia [Newburger et al 2010]. Cycling confers a favorable prognosis: better response to G-CSF and a lower risk of MDS/AML [Makaryan et al 2015, Dale et al 2017]. ### Genotype-Phenotype Correlations Genotype-phenotype correlations are only roughly defined for ELANE-related neutropenia. Although the patterns of pathogenic variants in ELANE-associated cyclic neutropenia and congenital neutropenia are distinct on a population basis, the patterns of pathogenic variants do overlap, indicating that the distinction between cyclic neutropenia and congenital neutropenia is primarily based on clinical findings and only secondarily on genotype [Dale 2017, Skokowa et al 2017]. Newburger et al [2010] identified individuals with the same pathogenic variant who had different clinical phenotypes. The risk of developing myelodysplasia or acute myelogenous leukemia varies considerably depending on the specific ELANE variant [Makaryan et al 2015]. The full scope of genotype-phenotype variation is not yet known, but the pathogenic variants p.Cys151Tyr and p.Gly214Arg variants are associated with a poor prognosis and the pathogenic variants p.Ser126Leu and p.Pro139Leu with a good prognosis. Some ELANE pathogenic variants now appear to be exclusively or almost exclusively associated with cyclic neutropenia and no recognized risk of evolution to acute myelogenous leukemia (AML), whereas other pathogenic variants may be associated with severe congenital neutropenia and increased risk of AML [Bellanné-Chantelot et al 2004, Makaryan et al 2015]. At present it is not known how variations in the mutated protein affect the severity of neutropenia or the risk of AML. ### Nomenclature Prior to the discovery of the different genetic causes of severe chronic neutropenia, the term "Kostmann syndrome" was used to refer to individuals with severe chronic neutropenia. The original family reported by Kostmann was found to have bialleic pathogenic variants in HAX1 inherited in an autosomal recessive fashion. However, one individual in a kindred originally described by Kostmann as having Kostmann syndrome was identified to have a pathogenic variant in ELANE [Zeidler & Welte 2002, Carlsson et al 2006] (see Differential Diagnosis). ### Prevalence Congenital neutropenia has an estimated frequency of 2:1,000,000-3:1,000,000 in the general population. Cyclic neutropenia has an estimated frequency of 1:1,000,000 in the general population, including both familial cases and simplex cases (i.e., single occurrences in a family). ELANE-related neutropenia is the most common cause of chronic neutropenia in children, although the precise prevalence of ELANE-related neutropenia is unknown. ## Differential Diagnosis ### Congenital Neutropenia The differential diagnosis of congenital neutropenia includes the following disorders. Isolated neutropenia * Kostmann disease (OMIM 610738), an autosomal recessive form of severe congenital neutropenia caused by biallelic pathogenic variants in HAX1 [Klein et al 2007] Note: De novo heterozygous ELANE pathogenic variants (autosomal dominant severe congenital neutropenia) are much more common than HAX1 pathogenic variants (autosomal recessive congenital neutropenia) as a cause of simplex cases of severe congenital neutropenia (i.e., a single occurrence in a family) [Xia et al 2009]. For this reason, it is usually best to first sequence ELANE in seeking to determine the genetic basis for severe congenital neutropenia. * Nonsyndromic severe congenital neutropenia due to G6PC3 deficiency, an autosomal recessive form of severe congenital neutropenia caused by biallelic pathogenic variants in G6PC3 (see G6PC3 Deficiency) * GFI1-related severe congenital neutropenia. A heterozygous pathogenic variant in GFI1 was reported in one person with severe congenital neutropenia [Person et al 2003]. * Benign familial neutropenia (OMIM 162700), an autosomal dominant form of congenital neutropenia with milder neutropenia and less severe symptoms * Benign ethnic neutropenia associated with the Duffy null genotype (Duffy antigen receptor for chemokines or DARC-null genotype) is a common cause of neutropenia in persons of African heritage [Thobakgale & Ndung'u 2014]. This condition is caused by biallelic pathogenic variants in ACKR1 and is inherited in an autosomal recessive fashion. * Autoimmune neutropenia, usually attributed to anti-neutrophil antibodies * Idiopathic neutropenia (isolated neutropenia of unknown cause) * Cyclic neutropenia Selected syndromes with congenital neutropenia (see Klein [2011]) * Glycogen storage disease type Ib * Shwachman-Diamond syndrome * Reticular dysgenesis (OMIM 267500) * Cartilage-hair hypoplasia * Chediak-Higashi syndrome * Griscelli syndrome (OMIM PS214450) * Barth syndrome * Wiskott-Aldrich syndrome (see WAS-Related Disorders) * Dyskeratosis congenita * Myelokathexis (WHIM syndrome; OMIM 193670) * Classic G6PC3 deficiency (severe congenital neutropenia type 4) (see G6PC3 Deficiency) ### Cyclic Neutropenia Other diagnoses confused with cyclic neutropenia include congenital neutropenia and idiopathic, autoimmune, and benign neutropenia of childhood. ### Fever Other disorders with recurrent fevers are familial Mediterranean fever and PFAPA (periodic fever, adenopathy, pharyngitis, and aphthous ulcers). ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with ELANE-related neutropenia, the following are recommended if they have not already been completed: * Dental examination for gingival and periodontal disease * Evaluation (particularly of those with severe congenital neutropenia) by an otolaryngologist and a pulmonologist for chronic sinopulmonary inflammation and deep abscesses * Evaluation of individuals with severe congenital neutropenia for evidence of myelodysplasia or leukemia with bone marrow aspirate and biopsy * Consultation with a clinical hematologist, geneticist, and/or genetic counselor for specific clinical advice ### Treatment of Manifestations Fevers require prompt evaluation and empiric treatment until the source of the fever can be definitively identified, at which time targeted treatment may be possible: * Initiation of broad-spectrum antibiotics is important, even lifesaving, when an affected individual has signs of serious infection, which may be caused by either aerobic or anaerobic pathogens. Coverage matching local patterns for infections in immunosuppressed individuals should initially be given for both aerobic and anaerobic organisms. * Granulocyte colony-stimulating factor (G-CSF), given subcutaneously, should also be administered daily starting immediately to promote increased neutrophil production and deployment. Fever with abdominal pain is potentially life threatening due to the risk for peritonitis from a perforated colonic ulcer. Surgical evaluation by physical examination and (as needed) imaging studies is indicated. ### Prevention of Primary Manifestations Granulocyte colony-stimulating factor (G-CSF). Treatment with G-CSF is effective in elevating blood neutrophil counts in both congenital neutropenia and cyclic neutropenia. G-CSF treatment ameliorates the symptoms and problems of infections in almost all affected individuals. (Although both G-CSF and granulocyte-macrophage (GM)-CSF have been used to treat ELANE-related neutropenia, G-CSF is much more effective and associated with fewer adverse effects than GM-CSF.) In cyclic neutropenia, G-CSF shortens the periods of neutropenia as well as the length of the neutropenic cycle. Treatment is known to be effective at least as early as age six months to one year. Studies indicate that treatment is effective with no adverse effects on growth, development, or pregnancy outcome with follow up to age 18 years [Dale et al 2017]. Treatment of cyclic neutropenia requires daily or alternate-day injections of G-CSF, normally in a dose of ~2 µg/kg/day. Individuals with congenital neutropenia often require higher doses (e.g., 5-10 µg/kg/day). Common side effects of G-CSF include bone pain, headache, splenomegaly, and osteoporosis. Vasculitis, rashes, arthralgias, and glomerulonephritis have been infrequently reported [Dale et al 2003]. Note: (1) When affected individuals are given G-CSF and their ANC normalizes, their resistance to infection improves greatly. They should be able to attend school, work, and engage in recreational activities without specific concerns; (2) G-CSF treatment is associated with mild increases in the size of the spleen, but this is very rarely, if ever, a cause for specific concern in those with ELANE-related neutropenia. Hematopoietic stem cell transplantation (HSCT) * For affected individuals with a well-matched donor, HSCT may be the preferred treatment option [Choi & Levine 2010, Oshima et al 2010, Connelly et al 2012, Fioredda et al 2015]. * HSCT is the only alternative therapy for individuals with congenital neutropenia who are refractory to high-dose G-CSF or who undergo malignant transformation. ### Prevention of Secondary Complications Good dental hygiene with regular hygiene visits (several times per year) and careful brushing and flossing are recommended. Individuals with ELANE-associated neutropenia are susceptible to common viral infections that may be complicated by bacterial infections, such as pneumonia due to bacteria commonly found in the upper respiratory tract. Such individuals respond well to immunizations to protect them from viral and bacterial infections. They should be given all routine vaccines. ### Surveillance For those individuals with congenital neutropenia not undergoing HSCT, surveillance for evidence of malignant transformation to MDS/AML is critical to allow early therapeutic intervention. Observation should include the following: * General evaluations by parents and medical personnel several times a year * Blood counts several times a year * Annual bone marrow cytogenetic studies because of the frequent association of monosomy 7 and malignant transformation Note: Although sequencing of the receptor for G-CSF (CSF3R) from peripheral blood may also provide evidence of evolution to MDS/AML [Ancliff et al 2003a], its clinical utility is not yet clearly established [Touw 2015, Skokowa et al 2017]. ### Agents/Circumstances to Avoid Most infections are caused by common organisms on body surfaces including Clostridia species and other anaerobes in the intestinal biota. For this reason it is of little or no benefit to avoid public places. ### Evaluation of Relatives at Risk Evaluation of sibs and other at-risk relatives by molecular genetic testing for the ELANE pathogenic variant found in the proband identifies those with previously unrecognized mild or moderately severe disease who may benefit from treatment. Serial ANCs can also be used for evaluation of family members. Note: Relatives of individuals with typical cycles may have neutropenia but lack obvious cycles. Treatment of these individuals with G-CSF or any other modality should be based on medical history and the severity of symptoms. It is not yet clear if there are specific risks (i.e., osteoporosis, myelodysplasia, or leukemia) associated with administering G-CSF to such individuals, but conservative management is recommended. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Pregnancies in women with severe chronic neutropenia are at substantial risk for miscarriage. A review of the records of 88 women (183 pregnancies) with congenital, cyclic, idiopathic, or autoimmune neutropenia compared outcomes in those on G-CSF therapy during pregnancy with those not on G-CSF therapy during pregnancy [Boxer et al 2015]. Of these 88 women, 44 had congenital or cyclic neutropenia – accounting for 95 of the 183 pregnancies. Although genetic testing results were not reported, it is likely that at least half of the 44 women had ELANE-related neutropenia. In general the health of all the infants was equivalent for the two groups. Other findings included the following: * Reduced risk of fetal loss in the women treated during pregnancy * Among 55 women (123 pregnancies) not treated with G-CSF during pregnancy: 11 complications (1 premature rupture of membranes, 2 life-threatening infections, 2 minor infections, and 6 premature labors) * Among 41 women (60 pregnancies) treated with G-CSF during pregnancy: no life-threatening infections, no premature labors, five minor infections, and one woman who developed severe thrombocytopenia See MotherToBaby for further information on medication use during pregnancy. ### Therapies Under Investigation Unrelated cord blood transplantation for neutropenia is being investigated; outcome appears to depend on the closeness of the match [Connelly et al 2012, Fioredda et al 2015]. 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. [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 inhibitors [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	ELANE-Related Neutropenia	None	2,904	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1533/	2021-01-18T21:29:35	{"synonyms": []}
Cogan syndrome is a rare autoimmune disease that affects the eyes and inner ears. Symptoms of the syndrome include irritation and pain in the eyes, decreased vision, hearing loss, and vertigo. Other symptoms may include joint or muscle pain or inflammation of the blood vessels. The exact cause of Cogan syndrome is not well-understood. It is thought that the syndrome is caused by an autoimmune response that causes the immune system to attack the tissues of the eyes and ears. Cogan syndrome is not known to run in families. Diagnosis of Cogan syndrome is based on observing symptoms associated with the syndrome and ruling out other possible causes of the symptoms. Treatment options generally include corticosteroids and immunosuppressive agents. [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 inhibitors [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	Cogan's syndrome	c0271270	2,905	gard	https://rarediseases.info.nih.gov/diseases/1421/cogans-syndrome	2021-01-18T17:56:59	{"mesh": ["D055952"], "synonyms": ["Cogan syndrome"]}
During a large-scale survey of persons with Usher syndrome (retinitis pigmentosa and sensorineural deafness), Beighton et al. (1993) identified 14 children in 9 Afrikaner families in South Africa with a combination of progressive rod-cone dystrophy, sensorineural deafness, and renal dysfunction of the Fanconi type leading to rickets-like skeletal changes and renal failure. Eight of the 11 children had died between the ages of 3 and 20 years; in most patients, the cause of death was reported to be renal failure. Onset of auditory and visual dysfunction was usually before age 5 and invariably before age 10 years. Retinitis pigmentosa or Usher syndrome had initially been diagnosed in every child, and cataracts had been documented as a complicating factor in 4 of the children. Renal dysfunction usually presented with albuminuria during the first 5 years, and the skeletal complications of 'renal rickets' were generally evident during the first decade. A stunted stature and malalignment of the weightbearing bones were the major skeletal manifestations. None of the parents were affected. Although minor changes were found in the eyes of the father of 2 affected sibs, none of the parents were known to be consanguineous. However, the Afrikaner population, which now numbers more than 3 million, is derived from a comparatively small number of founders. [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 inhibitors [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	ROD-CONE DYSTROPHY, SENSORINEURAL DEAFNESS, AND FANCONI-TYPE RENAL DYSFUNCTION	c1849333	2,906	omim	https://www.omim.org/entry/268315	2019-09-22T16:22:32	{"mesh": ["C564829"], "omim": ["268315"]}
Abdominal aura (also known as visceral aura and epigastric aura) is used to denote a type of somatosensory or somaesthetic aura that typically manifests itself as a rising epigastric sensation. The term is indebted to the Latin words abdomen (belly) and aura (wind, smell).[1] Other presentations of the abdominal aura include viscerosensitive sensations such as abdominal discomfort, visceromotor symptoms presenting in the form of tachycardia, borborygmi or vomiting, and vegetative symptoms such as blushing and sweating.[1] Pathophysiologically, the abdominal aura is associated with aberrant neuronal discharges in sensory cortical areas representing the abdominal viscera. Etiologically, it is associated primarily with paroxysmal neurological disorders such as migraine and epilepsy. The abdominal aura can be classified as a somatic or coenesthetic hallucination.[1] The term is used in opposition to various terms denoting other types of somatosensory aura, notably splitting of the body image and paraesthesia.[1] ## Notes[edit] 1. ^ a b c d Jan Dirk Blom: A Dictionary of Hallucinations (2010). ISBN 978-1-4419-1222-0. [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 inhibitors [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	Abdominal aura	c4023506	2,907	wikipedia	https://en.wikipedia.org/wiki/Abdominal_aura	2021-01-18T18:42:33	{"umls": ["C4023506"], "wikidata": ["Q4665116"]}
Thrombotic microangiopathy Micrograph of thrombotic microangiopathy with the characteristic onion-skin layering seen in older lesions. PAS stain. SpecialtyRheumatology Thrombotic microangiopathy (TMA) is a pathology that results in thrombosis in capillaries and arterioles, due to an endothelial injury.[1] It may be seen in association with thrombocytopenia, anemia, purpura and kidney failure. The classic TMAs are hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. Other conditions with TMA include atypical hemolytic uremic syndrome, disseminated intravascular coagulation, scleroderma renal crisis, malignant hypertension, antiphospholipid antibody syndrome, and drug toxicities, e.g. calcineurin inhibitor toxicity.[1] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] The clinical presentation of TMA, although dependent on the type, typically includes: fever, microangiopathic hemolytic anemia (see schistocytes in a blood smear), kidney failure, thrombocytopenia and neurological manifestations. Generally, renal complications are particularly predominant with Shiga-toxin-associated hemolytic uremic syndrome (STx-HUS) and atypical HUS, whereas neurologic complications are more likely with TTP. Individuals with milder forms of TTP may have recurrent symptomatic episodes, including seizures and vision loss.[2] With more threatening cases of TMA, and also as the condition progresses without treatment, multi-organ failure or injury is also possible, as the hyaline thrombi can spread to and affect the brain, kidneys, heart, liver, and other major organs.[3] ## Cause[edit] The specific cause is dependent of the type of TMA that is presented, but the two main pathways that lead to TMA are external triggers of vascular injury, such as viruses, bacterial Shiga toxins or endotoxins, antibodies, and drugs; and congenital predisposing conditions, including decreased levels of tissue factors necessary for the coagulation cascade. Either of these pathways will result in decreased endothelial thromboresistance, leukocyte adhesion to damaged endothelium, complement consumption, enhanced vascular shear stress, and abnormal vWF fragmentation. The central and primary event in this progression is injury to the endothelial cells, which reduces the production of prostaglandin and prostacyclin, ultimately resulting in the loss of physiological thromboresistance, or high thrombus formation rate in blood vessels. Leukocyte adhesion to the damaged endothelial wall and abnormal von Willebrand factor (or vWF) release can also contribute to the increase in thrombus formation.[4] More recently, researchers have attributed both TTP and HUS to targeted agents, such as targeted cancer therapies, immunotoxins, and anti-VEGF therapy.[2] Bacterial toxins are the primary cause of one category of thrombotic microangiopathy known as HUS or hemolytic uremic syndrome. HUS can be divided into two main categories: Shiga-toxin-associated HUS (STx-HUS), which normally presents with diarrhea, and atypical HUS. The Shiga-toxin inhibits the binding of eEF-1-dependent binding of aminoacyl tRNA to the 60S subunit of the ribosome, thus inhibiting protein synthesis. The cytotoxicity from the lack of protein damages glomerular endothelial cells by creating voids in the endothelial wall and detaching the basement membrane of the endothelial layer, activating the coagulation cascade. Atypical HUS may be caused by an infection or diarrheal illness or it may be genetically transmitted. This category of TMA encompasses all forms that do not have obvious etiologies. Mutations in three of the proteins in the complement cascade have been identified in patients with atypical HUS.[3] Several chemotherapeutic drugs have also been shown to cause damage to the epithelial layer by reducing the ability for the cells to produce prostacyclin, ultimately resulting in chemotherapy-associated HUS, or C-HUS.[citation needed] The second category of TMAs is TTP thrombotic thrombocytopenic purpura, which can be divided into 3 categories: congenital, idiopathic, and non-idiopathic.[5] Congenital and idiopathic TTP are generally associated with deficiencies in ADAMTS13, a zinc metalloprotease responsible for cleaving Very Large vWF Multimers in order to prevent inappropriate platelet aggregation and thrombosis in the microvasculature. Natural genetic mutations resulting in the deficiency of ADAMTS13 have been found in homozygous and heterozygous pedigrees in Europe.[3] Researchers have identified common pathways and links between TTP and HUS,[2][6] while other sources express skepticism about their common pathophysiology.[7] The repression of the vascular endothelial growth factor (VEGF) can also cause glomerular TMA (damage to the glomerular microvasculature). It is likely that the absence of VEGF results in the collapse of fenestrations in the glomerular endothelium, thus causing microvascular injury and blockages associated with TMA.[8] Manifestations resembling thrombotic microangiopathy have been reported in clinical trials evaluating high doses of Valacyclovir (8000 mg/day) administered for prolonged periods (months to years) for prophylaxis of cytomegalovirus (CMV) infection and disease, particularly in persons with HIV infection. A number of factors may have contributed to the incidence of thrombotic microangiopathy in those trials including profound immunosuppression, underlying diseases (advanced HIV disease, graft-versus-host disease), and other classes of drug, particularly antifungal agents. There were no reports of thrombotic microangiopathy among the 3050 subjects in the four trials evaluating Valacyclovir for suppression of recurrent genital herpes. Although one of the trials was in HIV-infected subjects, the patients did not have advanced HIV disease. The implication is that the occurrence of thrombotic microangiopathy is restricted to severely immunosuppressed persons receiving higher Valacyclovir dosages than are required to control HSV infection.[9] ## Diagnosis[edit] CBC and blood film: decreased platelets and schistocytes PT, aPTT, fibrinogen: normal markers of hemolysis: increased unconjugated bilirubin, increased LDH, decreased haptoglobin negative Coombs test.Creatinine, urea, to follow renal function ADAMSTS-13 gene, activity or inhibitor testing (TTP).[citation needed] ## Treatment[edit] The course of treatment and the success rate is dependent on the type of TMA. Some patients with atypical HUS and TTP have responded to plasma infusions or exchanges, a procedure which replaces proteins necessary for the complement cascade that the patient does not have; however, this is not a permanent solution or treatment, especially for patients with congenital predispositions.[3] Monoclonal antibodies like Eculizumab and Caplacizumab can assist with aHUS and aTTP respectively whilst Dexamethasone can help with iTTP and low molecular weight Heparin can help with DIC.[citation needed] ## See also[edit] * Microangiopathy * Microangiopathic hemolytic anemia ## References[edit] 1. ^ a b Benz, K.; Amann, K. (May 2010). "Thrombotic microangiopathy: new insights". Current Opinion in Nephrology and Hypertension. 19 (3): 242–7. doi:10.1097/MNH.0b013e3283378f25. PMID 20186056. S2CID 25429151. 2. ^ a b c Blake-Haskins JA, Lechleider RJ, Kreitman RJ (September 2011). "Thrombotic microangiopathy with targeted cancer agents". Clin. Cancer Res. 17 (18): 5858–66. doi:10.1158/1078-0432.CCR-11-0804. PMC 3176977. PMID 21813634. 3. ^ a b c d Tsai HM (July 2006). "The molecular biology of thrombotic microangiopathy". Kidney Int. 70 (1): 16–23. doi:10.1038/sj.ki.5001535. PMC 2497001. PMID 16760911. 4. ^ Ruggenenti P, Noris M, Remuzzi G (September 2001). "Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura". Kidney Int. 60 (3): 831–46. doi:10.1046/j.1523-1755.2001.060003831.x. PMID 11532079. 5. ^ Zheng XL, Sadler JE (2008). "Pathogenesis of thrombotic microangiopathies". Annu Rev Pathol. 3: 249–77. doi:10.1146/annurev.pathmechdis.3.121806.154311. PMC 2582586. PMID 18215115. 6. ^ "Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic-Uremic Syndrome (HUS)". Health Care Professionals: Hematology and Oncology: Thrombocytopenia and Platelet Dysfunction. Merck Manual. 7. ^ Thrombotic Thrombocytopenic Purpura at eMedicine 8. ^ Eremina V, Jefferson JA, Kowalewska J, et al. (March 2008). "VEGF inhibition and renal thrombotic microangiopathy". N. Engl. J. Med. 358 (11): 1129–36. doi:10.1056/NEJMoa0707330. PMC 3030578. PMID 18337603. 9. ^ Bell WR, Chulay JD, Feinberg JE. Manifestations resembling thrombotic microangiopathy in patients with advanced human immunodeficiency virus (HIV) disease in a cytomegalovirus prophylaxis trial (ACTG 204), Medicine, 1997, Vol. 76 (pp. 369-80) ## External links[edit] Classification D * ICD-10: M31.1 * ICD-9-CM: 446.6 * MeSH: D057049 * SNOMED CT: 126729006 External resources * Orphanet: 93573 * v * t * e Diseases of red blood cells ↑ Polycythemia * Polycythemia vera ↓ Anemia Nutritional * Micro-: Iron-deficiency anemia * Plummer–Vinson syndrome * Macro-: Megaloblastic anemia * Pernicious anemia Hemolytic (mostly normo-) Hereditary * enzymopathy: Glucose-6-phosphate dehydrogenase deficiency * glycolysis * pyruvate kinase deficiency * triosephosphate isomerase deficiency * hexokinase deficiency * hemoglobinopathy: Thalassemia * alpha * beta * delta * Sickle cell disease/trait * Hereditary persistence of fetal hemoglobin * membrane: Hereditary spherocytosis * Minkowski–Chauffard syndrome * Hereditary elliptocytosis * Southeast Asian ovalocytosis * Hereditary stomatocytosis Acquired AIHA * Warm antibody autoimmune hemolytic anemia * Cold agglutinin disease * Donath–Landsteiner hemolytic anemia * Paroxysmal cold hemoglobinuria * Mixed autoimmune hemolytic anemia * membrane * paroxysmal nocturnal hemoglobinuria * Microangiopathic hemolytic anemia * Thrombotic microangiopathy * Hemolytic–uremic syndrome * Drug-induced autoimmune * Drug-induced nonautoimmune * Hemolytic disease of the newborn Aplastic (mostly normo-) * Hereditary: Fanconi anemia * Diamond–Blackfan anemia * Acquired: Pure red cell aplasia * Sideroblastic anemia * Myelophthisic Blood tests * Mean corpuscular volume * normocytic * microcytic * macrocytic * Mean corpuscular hemoglobin concentration * normochromic * hypochromic Other * Methemoglobinemia * Sulfhemoglobinemia * Reticulocytopenia * v * t * e Systemic vasculitis Large vessel * Takayasu's arteritis * Giant cell arteritis Medium vessel * Polyarteritis nodosa * Kawasaki disease * Thromboangiitis obliterans Small vessel Pauci-immune * c-ANCA * Granulomatosis with polyangiitis * p-ANCA * Eosinophilic granulomatosis with polyangiitis * Microscopic polyangiitis Type III hypersensitivity * Cutaneous small-vessel vasculitis * IgA vasculitis Ungrouped * Acute hemorrhagic edema of infancy * Cryoglobulinemic vasculitis * Bullous small vessel vasculitis * Cutaneous small-vessel vasculitis Other * Goodpasture syndrome * Sneddon's syndrome [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 inhibitors [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	Thrombotic microangiopathy	c2717961	2,908	wikipedia	https://en.wikipedia.org/wiki/Thrombotic_microangiopathy	2021-01-18T19:07:11	{"gard": ["12465"], "mesh": ["D057049"], "umls": ["C2717961"], "icd-9": ["446.6"], "icd-10": ["M31.1"], "orphanet": ["93573"], "wikidata": ["Q3312044"]}
Osteopetrosis refers to a group of rare, inherited skeletal disorders characterized by increased bone density and abnormal bone growth. Symptoms and severity can vary greatly, ranging from neonatal onset with life-threatening complications (such as bone marrow failure) to the incidental finding of osteopetrosis on X-ray. Depending on severity and age of onset, features may include fractures, short stature, compressive neuropathies (pressure on the nerves), hypocalcemia with attendant tetanic seizures, and life-threatening pancytopenia. In rare cases, there may be neurological impairment or involvement of other body systems. Osteopetrosis may be caused by mutations in at least 10 genes. Inheritance can be autosomal recessive, autosomal dominant, or X-linked recessive with the most severe forms being autosomal recessive. Management depends on the specific symptoms and severity and may include vitamin D supplements, various medications, and/or surgery. Adult osteopetrosis requires no treatment by itself, but complications may require intervention. [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 inhibitors [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	Osteopetrosis	c0029454	2,909	gard	https://rarediseases.info.nih.gov/diseases/4155/osteopetrosis	2021-01-18T17:58:32	{"mesh": ["D010022"], "umls": ["C0029454"], "orphanet": ["2781"], "synonyms": ["Osteopetroses", "Marble bones", "Marble bone disease", "Albers-Schonberg disease", "Osteosclerosis fragilis", "Albers-Schonberg osteopetrosis", "Albers-Schoenberg disease", "Osteopetrosis and related disorders"]}
Extravasation SpecialtyToxicology Extravasation is the leakage of intravenously (IV) infused, and potentially damaging, medications into the extravascular tissue around the site of infusion. The leakage can occur through brittle veins in the elderly, through previous venipuncture access, or through direct leakage from wrongly positioned venous access devices. When the leakage is not of harmful consequence it is known as infiltration. Extravasation of medication during intravenous therapy is an adverse event related to therapy that, depending on the medication, amount of exposure, and location, can potentially cause serious injury and permanent harm, such as tissue necrosis. Milder consequences of extravasation include irritation, characterized by symptoms of pain and inflammation, with the clinical signs of warmth, erythema, or tenderness.[1] ## Contents * 1 Medications * 2 Treatment * 2.1 Pain management and other measures * 3 Prevention * 4 Examples of vesicant medicinal drugs * 4.1 Cytotoxic drugs * 4.2 Non-cytotoxic drugs * 5 References * 6 External links ## Medications[edit] Complications related to extravasation are possible with any medication. Since Vesicants are blistering agents, extravasation may lead to irreversible tissue injury. Extravasation is particularly serious during chemotherapy, since chemotherapy medications are highly toxic. ## Treatment[edit] The best "treatment" of extravasation is prevention. Depending on the medication that has extravasated, there are potential management options and treatments that aim to minimize damage, although the effectiveness of many of these treatments has not been well studied.[2] In cases of tissue necrosis, surgical debridement and reconstruction may be necessary. The following steps are typically involved in managing extravasation: * Stop infusion immediately. Put on sterile gloves. * Replace infusion lead with a disposable syringe. While doing this, do not exert pressure on the extravasation area. * Slowly aspirate back blood back from the arm, preferably with as much of the infusion solution as possible. * Remove the original cannula or other IV access carefully from the arm (removal of the original cannula is not advised by all healthcare institutions, as access to the original cannula by surgeons can be used to help clean extravasated tissue). * Elevate arm and rest in elevated position. If there are blisters on the arm, aspirate content of blisters with a new thin needle. Warm compresses should be placed initially on the site to help diffuse the contrast medium, and cold compresses are used later to help reduce the swelling.[3] * If, for the extravasated medication, substance-specific measures apply, carry them out (e.g. topical cooling, DMSO, hyaluronidase or dexrazoxane may be appropriate).[2][4] * Recent clinical trials have shown that Totect (USA) or Savene (Europe) (dexrazoxane for extravasation) is effective in preventing the progression of anthracycline extravasation into progressive tissue necrosis. In two open-label, single arm, phase II multicenter clinical trials, necrosis was prevented in 98% of the patients. Dexrazoxane for extravasation is the only registered antidote for extravasation of anthracyclines (daunorubicin, doxorubicin, epirubicin, idarubicin, etc.).[5] ### Pain management and other measures[edit] * Pain management and local supportive care is important, as it can help to minimize the additional risk of infection and superinfection. ## Prevention[edit] * Only qualified, chemotherapy-certified nurses who have been trained in venipuncture and administration of medications with vesicant and irritant potential should be allowed to administer vesicants.[6] * Choose a large, intact vein with good blood flow for the venipuncture and placement of the cannula. Do not choose inadvertently "dislodgeable" veins (e.g. dorsum of hand or vicinity of joints) if an alternative vein is available. * The digits, hands, and wrists should be avoided as intravenous sites for vesicant administration because of the close network of tendons and nerves that would be destroyed if an extravasation occurred. * Place the smallest gauge and shortest length catheter to accommodate the infusion. * Monitor the venipuncture site closely for evidence of infiltration and instructing patients to report any pain, discomfort, or tightness at the site. * The IV infusion should be freely flowing. The arm with the infusion should not begin to swell (oedema), "get red" (erythema), "get hot" (local temperature increase), and the patient should not notice any irritation or pain on the arm. If this occurs, extravasation management should be initiated. * The infusion should consist of a suitable carrier solution with an appropriately diluted medicinal/chemotherapy drug inside. * After the IV infusion has finished, flush the cannula with the appropriate fluid. * Finally, depending on clinical circumstances, central line access may be most appropriate for patients who require repeated administrations of vesicants and irritants. ## Examples of vesicant medicinal drugs[edit] List of vesicant and irritant medications:[2] ### Cytotoxic drugs[edit] * Amsacrine * Cisplatin * Dactinomycin * Daunorubicin * Docetaxel * Doxorubicin * Epirubicin * Idarubicin * Mechlorethamine * Mitomycin C * Mitoxantrone * Oxaliplatin * Paclitaxel * Vinblastine * Vincristine * Vindesine * Vinorelbine ### Non-cytotoxic drugs[edit] * Acyclovir[7] * Adrenergic agonists (e.g. dobutamine, adrenaline)[7] * Alcohol * Aminophyllines * Amiodarone[7] * Amphotericin[7] * Arginine[7] * Chlordiazepoxide * Calcium solutions (e.g. calcium gluconate)[7] * Diazepam * Digoxin * Mannitol[7] * Metronidazole[7] * Nafcillin[7] * Nitroglycerine * Oxacillin[7] * Phenytoin[7] * Promethazine[7] * Propylene glycol * Sodium thiopental[7] * Tetracyclines * Total parenteral nutrition[7] * Valproate[7] * Vancomycin[7] * Vasopressin[7] ## References[edit] 1. ^ Rothrock, Jane C. (2015). Alexander's care of the patient in surgery (15th ed.). ISBN 9780323089425. 2. ^ a b c Chemotherapy vesicants, irritants, and treatment for extravasation 3. ^ Shaqdan K; et al. (2014). "Incidence of contrast medium extravasation for CT and MRI in a large academic medical centre: A report on 502, 391 injections". Clinical Radiology. 69: 1264–1272. doi:10.1016/j.crad.2014.08.004. 4. ^ For more information on substance-specific measures, see, for example, the textbook "Extravasation of cytotoxic agents" (Authors: I Mader et al., Springer Publishing House) 5. ^ Mouridsen HT, Langer SW, Buter J, Eidtmann H, Rosti G, de Wit M, Knoblauch P, Rasmussen A, Dahlstrom K, Jensen PB, Giaccone G (Mar 2007). "Treatment of anthracycline extravasation with Savene (dexrazoxane): results from two prospective clinical multicentre studies". Ann Oncol. 18 (3): 546–50. doi:10.1093/annonc/mdl413. 6. ^ Infusion Nurses Society, Infusion Nursing 3rd ed 2010 7. ^ a b c d e f g h i j k l m n o p q Le, A; Patel, S (July 2014). "Extravasation of Noncytotoxic Drugs: A Review of the Literature". The Annals of Pharmacotherapy. 48 (7): 870–886. doi:10.1177/1060028014527820. PMID 24714850. ## External links[edit] Classification D * MeSH: D005119 * Table of chemotherapy vesicants, irritants, and treatments for extravasation * Management of chemotherapy extravasation: ESMO–EONS Clinical Practice Guidelines * UK National Extravasation Information Service * Iv-therapy.net — links to useful websites about extravasation * Savene website [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 inhibitors [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	Extravasation (intravenous)	c0015376	2,910	wikipedia	https://en.wikipedia.org/wiki/Extravasation_(intravenous)	2021-01-18T18:48:34	{"mesh": ["D005119"], "umls": ["C0015376"], "wikidata": ["Q2051919"]}
A number sign (#) is used with this entry because of evidence that fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) is caused by compound heterozygous mutation in the NHLRC2 gene (618277) on chromosome 10q25. Description Fibrosis, neurodegeneration, and cerebral angiomatosis is characterized by severe progressive cerebropulmonary symptoms, resulting in death in infancy from respiratory failure. Features include malabsorption, progressive growth failure, recurrent infections, chronic hemolytic anemia, and transient liver dysfunction. Neuropathology shows increased angiomatosis-like leptomeningeal, cortical, and superficial white matter vascularization and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and granuloma-like lesions are seen in the lungs, and there is hepatomegaly with steatosis and collagen accumulation (Uusimaa et al., 2018). Clinical Features Uusimaa et al. (2018) studied 2 Finnish brothers and an unrelated Finnish boy with a multiorgan syndrome that the authors designated 'FINCA' for the features of fibrosis, neurodegeneration, and cerebral angiomatosis. All 3 children appeared healthy at birth, but presented at age 2 months with irritability, hypotonia, feeding difficulties, diarrhea, and growth failure. During the following months, they exhibited delayed development, reduced vision, recurrent infections, transient hepatic dysfunction, and chronic hemolytic anemia. The 2 brothers developed dystonic tetraplegia, and the other boy was dystonic as well. One patient exhibited cardiomegaly. All had progressive respiratory difficulties that culminated in death from respiratory failure in the second year of life. At autopsy, all 3 brains were atrophic and showed increased angiomatosis-like leptomeningeal, cortical, and superficial white matter vascularization and congestion, as well as white matter degeneration and variable neuronal degeneration. Lung biopsies showed severe interstitial fibrosis, with no normal lung tissue in 2 of the patients. In addition, unusual granuloma-like lesions were observed, which were enriched with myofibroblasts. All 3 patients had hepatomegaly; transmission electron microscopy of a biopsy from 1 of the patients showed steatosis and accumulation of collagen bundles. Molecular Genetics In 3 Finnish male infants from 2 unrelated families with fibrosis, neurodegeneration, and cerebral angiomatosis, Uusimaa et al. (2018) performed whole-exome sequencing and identified compound heterozygosity for a missense mutation (D148Y; 618277.0001) and a 2-bp deletion (618277.0002) in the NHLRC2 gene. Genealogy traced back 7 to 9 generations, to the 1750s, did not show common ancestors for the 2 families, and consanguinity within the families could not be confirmed because their ancestors were born in northern Finland at least 150 miles apart. INHERITANCE \- Autosomal recessive GROWTH Weight \- Poor weight gain Other \- Progressive growth failure HEAD & NECK Eyes \- Strabismus \- Poor visual contact \- Reduced vision \- Increased latencies on visual evoked potentials \- Giant responses on visual evoked potentials CARDIOVASCULAR Heart \- Cardiomegaly RESPIRATORY \- Recurrent infections Lung \- Tachypnea \- Progressive respiratory insufficiency \- Over-inflated lungs seen on chest x-ray \- Interstitial fibrosis \- Atelectasis \- Bullae ABDOMEN Liver \- Hepatomegaly \- Transient hepatic dysfunction (during viral infections) \- Microvesicular steatosis, widespread \- Focal hepatocellular necrosis Gastrointestinal \- Feeding problems \- Diarrhea GENITOURINARY Kidneys \- Atrophic adrenal glands \- Transient renal failure (during viral infections) \- Increased cortical echogenicity \- Hypoechogenic outer zone SKIN, NAILS, & HAIR Skin \- Icterus, intermittent MUSCLE, SOFT TISSUES \- Thin subcutis \- Reduced muscle mass \- Variable muscle tone NEUROLOGIC Central Nervous System \- Irritability \- Axial hypotonia \- Dystonia \- Dystonic tetraplegia \- Developmental delay \- Seizures \- Thin corpus callosum \- Dilated lateral ventricles, mild \- Dilated cortical sulci, mild \- Metabolic encephalopathy determined by electroencephalography \- Brain atrophy on postmortem examination \- Vacuolar degeneration and myelin loss HEMATOLOGY \- Hemolytic anemia, chronic \- Anisocytosis \- Polychromasia \- Macrocytosis \- Microcytosis \- Poikilocytosis \- Reticulocytosis \- Red cell fragments \- Ovalocytes IMMUNOLOGY \- Atrophic thymus MISCELLANEOUS \- Onset of symptoms at 2 months of age \- Death in second year of life due to respiratory failure MOLECULAR BASIS \- Caused by mutation in the NHL repeat-containing protein 2 gene (NHLRC2, 618277.0001 ) ▲ 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 inhibitors [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	FIBROSIS, NEURODEGENERATION, AND CEREBRAL ANGIOMATOSIS	None	2,911	omim	https://www.omim.org/entry/618278	2019-09-22T15:42:43	{"omim": ["618278"]}
A rare, genetic, syndromic intellectual disability disease characterized by global developmental delay, microcephaly, mild to moderate intellectual disability, truncal ataxia, trunk and limb, or generalized, choreiform movements, and elevated serum creatine kinase levels. Variably associated features include mild cerebral atrophy, muscular weakness or hypotonia in early childhood, and/or seizures. Ocular abnormalities (e.g. exophoria, anisometropia, amblyopia) have been reported. [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 inhibitors [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	Intellectual disability-hyperkinetic movement-truncal ataxia syndrome	None	2,912	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=369847	2021-01-23T17:41:30	{"icd-10": ["G25.5"]}
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: "Vesicoureteral reflux" – news · newspapers · books · scholar · JSTOR (July 2017) (Learn how and when to remove this template message) Vesicoureteral reflux Ultrasound image showing abnormal vesicoureteral junction and dilated distal ureter resulting in primary vesicoureteral reflux (VUR). SpecialtyUrology Vesicoureteral reflux (VUR), also known as vesicoureteric reflux, is a condition in which urine flows retrograde, or backward, from the bladder into one or both ureters and then to the renal calyx or kidneys.[1] Urine normally travels in one direction (forward, or anterograde) from the kidneys to the bladder via the ureters, with a 1-way valve at the vesicoureteral (ureteral-bladder) junction preventing backflow. The valve is formed by oblique tunneling of the distal ureter through the wall of the bladder, creating a short length of ureter (1–2 cm) that can be compressed as the bladder fills. Reflux occurs if the ureter enters the bladder without sufficient tunneling, i.e., too "end-on". ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Primary VUR * 2.2 Secondary VUR * 2.2.1 Anatomical * 2.2.2 Functional * 3 Diagnosis * 3.1 Severity * 4 Treatment * 4.1 Endoscopic injection * 4.2 Medical treatment * 4.3 Surgical management * 5 Epidemiology * 6 Surveillance * 7 History * 8 References * 9 External links ## Signs and symptoms[edit] Most children with vesicoureteral reflux are asymptomatic. Vesicoureteral reflux may be diagnosed as a result of further evaluation of dilation of the kidney or ureters draining urine from the kidney while in utero as well as when a sibling has VUR (though routine testing in either circumstance is controversial). Reflux also increases risk of acute bladder and kidney infections, so testing for reflux may be performed after a child has one or more infections. In infants, the signs and symptoms of a urinary tract infection may include only fever and lethargy, with poor appetite and sometimes foul-smelling urine, while older children typically present with discomfort or pain with urination and frequent urination. ## Causes[edit] In healthy individuals the ureters enter the urinary bladder obliquely and run submucosally for some distance. This, in addition to the ureter's muscular attachments, helps secure and support them posteriorly. Together these features produce a valvelike effect that occludes the ureteric opening during storage and voiding of urine. In people with VUR, failure of this mechanism occurs, with resultant backward (retrograde) flow of urine. ### Primary VUR[edit] Insufficient submucosal length of the ureter relative to its diameter causes inadequacy of the valvular mechanism. This is precipitated by a congenital defect or lack of longitudinal muscle of the portion of the ureter within the bladder resulting in an ureterovesicular junction (UVJ) abnormality. ### Secondary VUR[edit] In this category the ureters' valvular mechanism is initially intact and healthy but becomes overwhelmed by increased bladder pressures associated with obstruction, which distorts the ureterovesicular junction. The obstructions may be anatomical or functional. Secondary VUR can be further divided into anatomical and functional groups. #### Anatomical[edit] Posterior urethral valves; urethral or meatal stenosis. These causes are treated surgically when possible. #### Functional[edit] Bladder instability, neurogenic bladder and non-neurogenic bladder. Bladder infections may cause reflux due to the elevated pressures associated with inflammation.[2] Resolution of functional VUR will usually occur if the precipitating cause is treated and resolved. Medical and/or surgical treatment may be indicated. ## Diagnosis[edit] VCUG demonstrating bilateral Grade II (non-dilating) vesicoureteral reflux. The following procedures may be used to diagnose VUR: * Cystography * Fluoroscopic voiding cystourethrogram (VCUG) * Abdominal ultrasound * Technetium-99m Dimercaptosuccunic Acid (DMSA) Scintigraphy An abdominal ultrasound might suggest the presence of VUR if ureteral dilatation is present; however, in many circumstances of VUR of low to moderate, even high severity, the sonogram may be completely normal, thus providing insufficient utility as a single diagnostic test in the evaluation of children suspected of having VUR, such as those presenting with prenatal hydronephrosis or urinary tract infection (UTI).[3] VCUG is the method of choice for grading and initial workup, while RNC is preferred for subsequent evaluations as there is less exposure to radiation. A high index of suspicion should be attached to any case where a child presents with a urinary tract infection, and anatomical causes should be excluded. A VCUG and abdominal ultrasound should be performed in these cases DMSA scintigraphy is used for the evaluation of the paranchymal damage, which is seen as cortical scars. After the first febrile UTI, the diagnostic role of an initial scintigraphy for detecting the damage before the VCUG was investigated and it was suggested that VCUG can be omitted in children who has no cortical scars and urinary tract dilatation.[4][5] Early diagnosis in children is crucial as studies have shown that the children with VUR who present with a UTI and associated acute pyelonephritis are more likely to develop permanent renal cortical scarring than those children without VUR, with an odds ratio of 2.8.[6] Thus VUR not only increases the frequency of UTI's, but also the risk of damage to upper urinary structures and end-stage renal disease.[7] ### Severity[edit] * Grade I – reflux into non-dilated ureter * Grade II – reflux into the renal pelvis and calyces without dilatation * Grade III – mild/moderate dilatation of the ureter, renal pelvis and calyces with minimal blunting of the fornices * Grade IV – dilation of the renal pelvis and calyces with moderate ureteral tortuosity * Grade V – gross dilatation of the ureter, pelvis and calyces; ureteral tortuosity; loss of papillary impressions The younger the patient and the lower the grade at presentation the higher the chance of spontaneous resolution. Approximately 85% of grade I & II VUR cases will resolve spontaneously. Approximately 50% of grade III cases and a lower percentage of higher grades will also resolve spontaneously. ## Treatment[edit] The goal of treatment is to minimize infections, as it is infections that cause renal scarring and not the vesicoureteral reflux.[8] Minimizing infections is primarily done by prophylactic antibiotics in newborns and infants who are not potty trained. However, in children who are older, physicians and parents should focus on bowel and bladder management. Children who hold their bladder or who are constipated have a greater number of infections than children who void on a regular schedule. When medical management fails to prevent recurrent urinary tract infections, or if the kidneys show progressive renal scarring then surgical interventions may be necessary. Medical management is recommended in children with Grade I-III VUR as most cases will resolve spontaneously. A trial of medical treatment is indicated in patients with Grade IV VUR especially in younger patients or those with unilateral disease. Of the patients with Grade V VUR only infants are trialled on a medical approach before surgery is indicated, in older patients surgery is the only option. ### Endoscopic injection[edit] This section does not cite any sources. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. (June 2020) (Learn how and when to remove this template message) Endoscopic injection involves applying a gel around the ureteral opening to create a valve function and stop urine from flowing back up the ureter. The gel consists of two types of sugar-based molecules called dextranomer and hyaluronic acid. Trade names for this combination include Deflux and Zuidex. Both constituents are well-known from previous uses in medicine. They are also biocompatible, which means that they do not cause significant reactions within the body. In fact, hyaluronic acid is produced and found naturally within the body. ### Medical treatment[edit] Medical treatment entails low dose antibiotic prophylaxis until resolution of VUR occurs. Antibiotics are administered nightly at half the normal therapeutic dose. The specific antibiotics used differ with the age of the patient and include: * Amoxicillin or ampicillin – infants younger than 6 weeks * Trimethoprim-sulfamethoxazole (co-trimoxazole) – 6 weeks to 2 months After 2 months the following antibiotics are suitable: * Nitrofurantoin {5–7 mg/kg/24hrs} * Nalidixic acid * Bactrim * Trimethoprim * Cephalosporins Urine cultures are performed 3 monthly to exclude breakthrough infection. Annual radiological investigations are likewise indicated. Good perineal hygiene, and timed and double voiding are also important aspects of medical treatment. Bladder dysfunction is treated with the administration of anticholinergics. ### Surgical management[edit] A surgical approach is necessary in cases where a breakthrough infection results despite prophylaxis, or there is non-compliance with the prophylaxis. Similarly if the VUR is severe (Grade IV & V), there are pyelonephritic changes or congenital abnormalities. Other reasons necessitating surgical intervention are failure of renal growth, formation of new scars, renal deterioration and VUR in girls approaching puberty. There are four types of surgical procedure available for the treatment of VUR: endoscopic (STING/HIT procedures); laparoscopic; robotic-assisted laparoscopic; and open procedures (Cohen procedure, Leadbetter-Politano procedure, Lich-Gregoir technique). Laparoscopic and robotic-assisted laparoscopic procedures are often imitation of classical open procedures in laparoscopic or robotic-assisted laparoscopic environments.[9] ## Epidemiology[edit] It has been estimated that VUR is present in more than 10% of the population. Younger children are more prone to VUR because of the relative shortness of the submucosal ureters. This susceptibility decreases with age as the length of the ureters increases as the children grow. In children under the age of 1 year with a urinary tract infection, 70% will have VUR. This number decreases to 15% by the age of 12. Although VUR is more common in males antenatally, in later life there is a definite female preponderance with 85% of cases being female. ## Surveillance[edit] The American Urological Association recommends ongoing monitoring of children with VUR until the abnormality resolves or is no longer clinically significant. The recommendations are for annual evaluation of blood pressure, height, weight, analysis of the urine, and kidney ultrasound.[6] ## History[edit] As early as the time of Graeco-Roman physician and anatomist Galen described the urinary tract and noted that there were specific mechanisms to prevent the reflux of urine.[10] ## References[edit] 1. ^ Miyakita, Hideshi; Hayashi, Yutaro; Mitsui, Takahiko; Okawada, Manabu; Kinoshita, Yoshiaki; Kimata, Takahisa; Koikawa, Yasuhiro; Sakai, Kiyohide; Satoh, Hiroyuki; Tokunaga, Masatoshi; Naitoh, Yasuyuki (2020-04-01). "Guidelines for the medical management of pediatric vesicoureteral reflux". International Journal of Urology. doi:10.1111/iju.14223. ISSN 1442-2042. PMID 32239562. 2. ^ Institute of Urology & Nephrology, London, UK, The cellular basis of bladder instability UJUS 2009, Retrieved 4-20-2010 3. ^ Wongbencharat, Kunruedi; Tongpenyai, Yothi; Na-rungsri, Kunyalak (2016-03-01). "Renal ultrasound and DMSA screening for high-grade vesicoureteral reflux". Pediatrics International. 58 (3): 214–218. doi:10.1111/ped.12803. ISSN 1442-200X. PMID 26275163. 4. ^ Zhang, Xin; Xu, Hong; Zhou, Lijun; Cao, Qi; Shen, Qian; Sun, Li; Fang, Xiaoyan; Guo, Wei; Zhai, Yihui (2014-01-01). "Accuracy of Early DMSA Scan for VUR in Young Children With Febrile UTI". Pediatrics. 133 (1): e30–e38. doi:10.1542/peds.2012-2650. ISSN 0031-4005. PMID 24366989. 5. ^ Sheu, Ji-Nan; Wu, Kang-Hsi; Chen, Shan-Ming; Tsai, Jeng-Dau; Chao, Yu-Hua; Lue, Ko-Huang (2013). "Acute 99mTc DMSA Scan Predicts Dilating Vesicoureteral Reflux in Young Children With a First Febrile Urinary Tract Infection". Clinical Nuclear Medicine. 38 (3): 163–168. doi:10.1097/rlu.0b013e318279f112. PMID 23354031. 6. ^ a b Peters CA, Skoog SJ, Arant BS, Copp HL, Elder JS, Hudson RG, Khoury AE, Lorenzo AJ, Pohl HG, Shapiro E, Snodgrass WT, Diaz M (September 2010). "Summary of the AUA Guideline on Management of Primary Vesicoureteral Reflux in Children". The Journal of Urology. 184 (3): 1134–44. doi:10.1016/j.juro.2010.05.065. PMID 20650499. 7. ^ Brakeman, Paul (2008-07-21). "Vesicoureteral Reflux, Reflux Nephropathy, and End-Stage Renal Disease". Advances in Urology. 2008: 508949. doi:10.1155/2008/508949. ISSN 1687-6369. PMC 2478704. PMID 18670633. 8. ^ Tekgül, S; Riedmiller, H; Hoebeke, P; Kočvara, R; Nijman, RJ; Radmayr, C; Stein, R; Dogan, HS; European Association of, Urology (September 2012). "EAU guidelines on vesicoureteral reflux in children". European Urology. 62 (3): 534–42. doi:10.1016/j.eururo.2012.05.059. PMID 22698573. 9. ^ Akhavan, Ardavan; Avery, Daniel; Lendvay, Thomas S. (2014). "Robot-assisted extravesical ureteral reimplantation: Outcomes and conclusions from 78 ureters". Journal of Pediatric Urology. 10 (5): 864–868. doi:10.1016/j.jpurol.2014.01.028. PMID 24642080. 10. ^ Nahon, I; Waddington, G; Dorey, G; Adams, R (2011). "The history of urologic surgery: from reeds to robotics". Urologic nursing. 31 (3): 173–80. PMID 21805756. ## External links[edit] Classification D * ICD-10: N13.7 * ICD-9-CM: 593.7 * OMIM: 193000 * MeSH: D014718 * DiseasesDB: 13835 * SNOMED CT: 26836002 External resources * MedlinePlus: 000459 * eMedicine: ped/2750 * v * t * e Diseases of the urinary tract Ureter * Ureteritis * Ureterocele * Megaureter Bladder * Cystitis * Interstitial cystitis * Hunner's ulcer * Trigonitis * Hemorrhagic cystitis * Neurogenic bladder dysfunction * Bladder sphincter dyssynergia * Vesicointestinal fistula * Vesicoureteral reflux Urethra * Urethritis * Non-gonococcal urethritis * Urethral syndrome * Urethral stricture * Meatal stenosis * Urethral caruncle Any/all * Obstructive uropathy * Urinary tract infection * Retroperitoneal fibrosis * Urolithiasis * Bladder stone * Kidney stone * Renal colic * Malakoplakia * Urinary incontinence * Stress * Urge * Overflow [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 inhibitors [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	Vesicoureteral reflux	c0042580	2,913	wikipedia	https://en.wikipedia.org/wiki/Vesicoureteral_reflux	2021-01-18T18:46:57	{"mesh": ["D014718"], "umls": ["C0042580"], "orphanet": ["289365"], "wikidata": ["Q1550521"]}
Birt-Hogg-Dubé syndrome is a rare disorder that affects the skin and lungs and increases the risk of certain types of tumors. Its signs and symptoms vary among affected individuals. Birt-Hogg-Dubé syndrome is characterized by multiple noncancerous (benign) skin tumors, particularly on the face, neck, and upper chest. These growths typically first appear in a person's twenties or thirties and become larger and more numerous over time. Affected individuals also have an increased chance of developing cysts in the lungs and an abnormal accumulation of air in the chest cavity (pneumothorax) that may result in the collapse of a lung. Additionally, Birt-Hogg-Dubé syndrome is associated with an elevated risk of developing cancerous or noncancerous kidney tumors. Other types of cancer have also been reported in affected individuals, but it is unclear whether these tumors are actually a feature of Birt-Hogg-Dubé syndrome. ## Frequency Birt-Hogg-Dubé syndrome is rare; its exact incidence is unknown. This condition has been reported in more than 400 families. ## Causes Mutations in the FLCN gene cause Birt-Hogg-Dubé syndrome. This gene provides instructions for making a protein called folliculin. The normal function of this protein is unknown, but researchers believe that it may act as a tumor suppressor. Tumor suppressors prevent cells from growing and dividing too rapidly or in an uncontrolled way. Mutations in the FLCN gene may interfere with the ability of folliculin to restrain cell growth and division, leading to uncontrolled cell growth and the formation of noncancerous and cancerous tumors. Researchers have not determined how FLCN mutations increase the risk of lung problems, such as pneumothorax. ### Learn more about the gene associated with Birt-Hogg-Dubé syndrome * FLCN ## Inheritance Pattern This condition is inherited in an autosomal dominant pattern, which means one copy of the altered FLCN gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the mutation from one affected parent. Less commonly, the condition results from a new mutation in the gene and occurs in people with no history of the disorder in their family. Having a single mutated copy of the FLCN gene in each cell is enough to cause the skin tumors and lung problems associated with Birt-Hogg-Dubé syndrome. However, both copies of the FLCN gene are often mutated in the kidney tumors that occur with this condition. One of the mutations is inherited from a parent, while the other occurs by chance in a kidney cell during a person's lifetime. These genetic changes disable both copies of the FLCN gene, which allows kidney cells to divide uncontrollably and form tumors. [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 inhibitors [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	Birt-Hogg-Dubé syndrome	c0346010	2,914	medlineplus	https://medlineplus.gov/genetics/condition/birt-hogg-dube-syndrome/	2021-01-27T08:25:34	{"gard": ["2322"], "mesh": ["D058249"], "omim": ["135150"], "synonyms": []}
Wolcott–Rallison syndrome Other namesEarly-onset diabetes mellitus with multiple epiphyseal dysplasia Radiograph of a WRS child presenting with dysplastic bone growth in various regions of the body. Wolcott–Rallison syndrome, WRS, is a rare, autosomal recessive disorder with infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, osteopenia, mental retardation or developmental delay, and hepatic and renal dysfunction as main clinical findings. Patients with WRS have mutations in the EIF2AK3 gene, which encodes the eukaryotic translation initiation factor 2-alpha kinase 3.[1] [2] Other disease names include multiple epiphyseal dysplasia and early-onset diabetes mellitus.[3] Most patients with this disease do not survive to adulthood .[4] The majority of WRS patients die from fulminant hepatitis during childhood.[5] There are few reported cases for this disease. Of the 54 families worldwide with reported WRS cases, 22.2% of them are from the Kingdom of Saudi Arabia.[5] Of the 23 WRS patients in Saudi Arabia, all but one is the result of consanguineous marriages.[5] Another country where WRS cases have been found is Kosovo. Here, the Albanian population is also known for consanguineous marriages, but there were some cases involving patients from non-consanguineous parents that were carriers for the same mutant allele.[4] ## Contents * 1 Genetics * 2 Diagnosis * 3 Treatment * 4 References * 5 External links ## Genetics[edit] The main focus for this autosomal recessive disease is mutations to the EIF2AK3 gene. This gene is located on the short arm of chromosome 2 (2p11.2).[3] In unrelated families, different mutations have been observed in the EIF2AK3 gene, including missense and nonsense mutations.[3] For some cases for unrelated families, identical mutations were rarely observed.[citation needed] The EIKF2AK3 gene codes for PERK (pancreatic endoplasmic reticulum kinase), an explanation for the spectrum of symptoms. PERK is associated with the activity of beta cells in the pancreas. Beta cells are needed for the proper release of insulin into the blood stream after an increase in blood glucose.[4] This kinase is needed for the control of protein levels in the endoplasmic reticulum and is linked to ribosome activity.[6] The endoplasmic reticulum is a major protein sorting and processing center in every body cell. A broad range of bodily systems is affected, including pancreas, kidney, liver, bone, and nervous system, because of deficient stress response to improperly folded proteins inside the endoplasmic reticulum.[4] This is part of the reason why patients suffer from multiple epiphyseal dysplasia and osteopenia.[citation needed] ## Diagnosis[edit] Initially, patients with neonatal or early-childhood onset diabetes are possible candidates for having Wolcott–Rallison syndrome.[1] The other features include multiple epiphyseal dysplasia, osteopenia, intellectual disability, and hepatic and renal dysfunction.[1] Patients having features that suggest Wolcott–Rallison syndrome can be referred for genetics testing. The key way to test for this disease is through genetic testing for EIKF2AK3 mutations.[7] Molecular genetic analysis can be done for the patient and the parents to test for inherited or de novo mutations. It can also show whether the patient's parents are heterozygotes or homozygotes for the normal genotype.[4] X-rays can show bone age in relation to actual age. In typical WRS patients the bone age is a few years less than the chronological age.[4][5][8][9] Hypothyroidism is rare in WRS patients but can occur.[4] ## Treatment[edit] The most common method to manage hyperglycemia and diabetes is with an insulin pump.[9] In infants and very young children long-acting insulins like Glargine and Levemir are preferred to prevent recurrent hypoglycemia.[10] As soon as Walcott-Rallison syndrome is the diagnosis, therapy plans need to be drawn up along with frequent checkups to monitor kidney and liver function and adjust insulin treatment.[4] In the few cases that develop hypothyroidism, treatment with thyroxine is indicated, with the target to maintain normal circulating thyroid stimulating hormone (thyrotropin) concentrations.[4] ## References[edit] 1. ^ a b c Søvik O, Njølstad PR, Jellum E, Molven A (December 2008). "Wolcott-Rallison syndrome with 3-hydroxydicarboxylic aciduria and lethal outcome". Journal of Inherited Metabolic Disease. 31 Suppl 2: S293-7. doi:10.1007/s10545-008-0866-1. PMID 18500571. S2CID 1751676. 2. ^ Durocher F, Faure R, Labrie Y, Pelletier L, Bouchard I, Laframboise R (July 2006). "A novel mutation in the EIF2AK3 gene with variable expressivity in two patients with Wolcott-Rallison syndrome". Clinical Genetics. 70 (1): 34–8. doi:10.1111/j.1399-0004.2006.00632.x. PMID 16813601. 3. ^ a b c McKusick, Victor. "Epiphyseal Dysplasia, Multiple, with Early-Onset Diabetes". Online Mendelian Inheritance in Man. Johns Hopkins University. Retrieved 14 October 2015. 4. ^ a b c d e f g h i Spehar Uroić A, Mulliqi Kotori V, Rojnić Putarek N, Kušec V, Dumić M (April 2014). "Primary hypothyroidism and nipple hypoplasia in a girl with Wolcott-Rallison syndrome". European Journal of Pediatrics. 173 (4): 529–31. doi:10.1007/s00431-013-2189-y. PMID 24194294. S2CID 13336235. 5. ^ a b c d Habeb AM (June 2013). "Frequency and spectrum of Wolcott-Rallison syndrome in Saudi Arabia: a systematic review". The Libyan Journal of Medicine. 8: 21137. doi:10.3402/ljm.v8i0.21137. PMC 3679509. PMID 23759358. 6. ^ Porter JR, Barrett TG (December 2005). "Monogenic syndromes of abnormal glucose homeostasis: clinical review and relevance to the understanding of the pathology of insulin resistance and beta cell failure". Journal of Medical Genetics. 42 (12): 893–902. doi:10.1136/jmg.2005.030791. PMC 1735963. PMID 15772126. 7. ^ Senée V, Vattem KM, Delépine M, Rainbow LA, Haton C, Lecoq A, Shaw NJ, Robert JJ, Rooman R, Diatloff-Zito C, Michaud JL, Bin-Abbas B, Taha D, Zabel B, Franceschini P, Topaloglu AK, Lathrop GM, Barrett TG, Nicolino M, Wek RC, Julier C (July 2004). "Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity". Diabetes. 53 (7): 1876–83. doi:10.2337/diabetes.53.7.1876. PMID 15220213. 8. ^ Hawkes CP, McGlacken-Byrne SM, Murphy NP (September 2013). "Short stature in child with early-onset diabetes". European Journal of Pediatrics. 172 (9): 1255–7. doi:10.1007/s00431-013-2007-6. PMID 23644647. S2CID 12244157. 9. ^ a b Julier C, Nicolino M (November 2010). "Wolcott-Rallison syndrome". Orphanet Journal of Rare Diseases. 5 (1): 29. doi:10.1186/1750-1172-5-29. PMC 2991281. PMID 21050479. 10. ^ Sreeramaneni, Poorna Gopal Azad., & Ambula, S. R. V. (2017). Ketoacidosis in Neonatal Diabetes Mellitus, Part of Wolcott-Rallison Syndrome. The American Journal of Case Reports, 18, 719–722. http://www.amjcaserep.com/abstract/index/idArt/902804 ## External links[edit] * Media related to Wolcott–Rallison syndrome at Wikimedia Commons Classification D * ICD-10: E13 * OMIM: 226980 * MeSH: C536739 External resources * Orphanet: 1667 [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 inhibitors [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	Wolcott–Rallison syndrome	c0432217	2,915	wikipedia	https://en.wikipedia.org/wiki/Wolcott%E2%80%93Rallison_syndrome	2021-01-18T18:30:06	{"gard": ["5589"], "mesh": ["C536739"], "umls": ["C0432217"], "orphanet": ["1667"], "wikidata": ["Q8029730"]}
A number sign (#) is used with this entry because of evidence that short-rib thoracic dysplasia-18 with polydactyly (SRTD18) is caused by homozygous mutation in the IFT43 gene (614068) on chromosome 14q24. Description Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). For a discussion of genetic heterogeneity of short-rib thoracic dysplasia with or without polydactyly, see SRTD1 (208500). Clinical Features Duran et al. (2017) reported a family (R06-303) in which a fetus from a dizygotic twin pregnancy showed features of short-rib polydactyly syndrome. Delivery occurred at 30 weeks' gestation and the affected newborn (R06-303A) died the following day. Significant findings included short long bones with reverse campomelia of the humeri, bending of the bones of the mesomelic segments, long narrow chest with bent ribs, postaxial polydactyly of all extremities, and brain, liver, pancreas, and kidney abnormalities. A second pregnancy (R06-303E) with similar findings was interrupted at 18 weeks' gestation. The authors noted that the features were consistent with SRPS type II, except for the unusual finding of bending of the ribs and mesomelic segments of the appendicular skeleton. Duran et al. (2017) studied another family (R03-121) in which prenatal ultrasound at 18 weeks' gestation showed cystic hygroma, micromelia, poorly calcified calvarium, and postaxial polydactyly of both hands and both feet. The pregnancy was terminated and radiographic and autopsy examination confirmed the SRPS diagnosis, with some unusual radiographic features including short irregularly bent ribs, short campomelic long bones, hypoplastic and bent mesomelic bones, and lack of ossification of the calvarium, hands, and feet. Additional findings included hydrocephalus, malrotation of the intestines, and polycystic kidneys. By history, similar findings had been present in a previous fetus but no postmortem information or material was available. Molecular Genetics In 3 affected individuals with SRTD from 2 unrelated families, Duran et al. (2017) performed exome sequencing and identified homozygosity for missense mutations in the IFT143 gene, M1K (614068.0002) and W179R (614068.0003), respectively. Their unaffected parents were heterozygous for the mutations, which were not found in public variant databases. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Dolichocephaly Face \- Micrognathia Eyes \- Hypertelorism \- Epicanthal folds, bilateral Mouth \- Thin upper lip \- Upper lip attached to maxilla by mucosal fold Neck \- Cystic hygroma CHEST External Features \- Small thorax Ribs Sternum Clavicles & Scapulae \- Short ribs \- Irregularly bent ribs \- Reduced number of ribs ABDOMEN Liver \- Ductal abnormalities of liver Pancreas \- Stellate fibrosis in tail of pancreas Gastrointestinal \- Malrotation of intestine GENITOURINARY Kidneys \- Polycystic kidneys \- Abnormal kidneys \- Poorly formed nephrogenic zone \- Thin cortex \- Thin medulla \- Fibrosis SKELETAL Skull \- Poorly calcified skull Spine \- Platyspondyly, mild \- Vertebral wedging, with round anterior ends Pelvis \- Abnormal ilia \- Decreased height of ilia \- Narrow sciatic notch \- Hypoplastic ischium Limbs \- Curved long bones \- Angulated femur \- Micromelia \- Reverse campomelia of humeri \- Curved radii \- Curved ulnae \- Reduced mineralization of upper extremities \- Hypoplastic tibiae \- Hypoplastic fibulae Hands \- Postaxial polydactyly \- Preaxial polydactyly \- Brachydactyly \- Lack of ossification of hands \- Bilateral simian creases Feet \- Postaxial polydactyly \- Preaxial polydactyly \- Bilateral partial syndactyly of second and third toes \- Lack of ossification of feet NEUROLOGIC Central Nervous System \- Hydrocephalus, mild \- Dilated ventricles, mildly \- Abnormal folding of left hippocampus \- Neuroglial heterotopias in temporal horn roof MISCELLANEOUS \- Based on report of 3 patients (last curated January 2018) MOLECULAR BASIS \- Caused by mutation in the intraflagellar transport 43 gene (IFT43, 614068.0002 ) ▲ 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 inhibitors [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	SHORT-RIB THORACIC DYSPLASIA 18 WITH POLYDACTYLY	c4693420	2,916	omim	https://www.omim.org/entry/617866	2019-09-22T15:44:36	{"omim": ["617866"]}
Synucleinopathy Other namesα-Synucleinopathies Positive α-Synuclein staining of a Lewy body in a patient with Parkinson's disease. SpecialtyNeurology Synucleinopathies (also called α-Synucleinopathies) are neurodegenerative diseases characterised by the abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibres or glial cells.[1] There are three main types of synucleinopathy: Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).[1] Other rare disorders, such as various neuroaxonal dystrophies, also have α-synuclein pathologies.[2] ## Contents * 1 Presentation * 2 Diagnosis * 2.1 Differential diagnosis * 3 DNA damage * 4 See also * 5 References ## Presentation[edit] The synucleinopathies have shared features of parkinsonism, impaired cognition, sleep disorders, and visual hallucinations.[3] Synucleinopathies can sometimes overlap with tauopathies, possibly because of interaction between the synuclein and tau proteins.[4] REM sleep behavior disorder (RBD) is a parasomnia in which individuals with RBD lose the paralysis of muscles (atonia) that is normal during rapid eye movement (REM) sleep, and act out their dreams or have other abnormal movements or vocalizations.[5] Abnormal sleep behaviors may appear decades before any other symptoms, often as an early sign of a synucleinopathy.[6] On autopsy, 94 to 98% of individuals with polysomnography-confirmed RBD are found to have a synucleinopathy—most commonly DLB or PD.[5][7][8] Other symptoms of the specific synucleinopathy usually manifest within 15 years of the diagnosis of RBD,[9] but may emerge up to 50 years after RBD diagnosis.[5] Alpha-synuclein deposits can affect the cardiac muscle and blood vessels.[10] Almost all people with synucleinopathies have cardiovascular dysfunction, although most are asymptomatic.[10] From chewing to defecation, alpha-synuclein deposits affect every level of gastrointestinal function. Symptoms include upper gastrointestinal tract dysfunction such as delayed gastric emptying or lower gastrointestinal dysfunction, such as constipation and prolonged stool transit time.[10] Urinary retention, waking at night to urinate, increased urinary frequency and urgency, and over- or underactive bladder are common in people with synucleinopathies.[10] Sexual dysfunction usually appears early in synucleinopathies, and may include erectile dysfunction, and difficulties achieving orgasm or ejaculating.[10] ## Diagnosis[edit] ### Differential diagnosis[edit] Persons with PD are typically less caught up in their visual hallucinations than those with DLB.[11] There is a lower incidence of tremor at rest in DLB than in PD, and signs of parkinsonism in DLB are more symmetrical.[6] In MSA, autonomic dysfunction appears earlier and is more severe, and is accompanied by uncoordinated movements, while visual hallucinations and fluctuating cognition are less common than in DLB.[12] Urinary difficulties are one of the earliest symptoms with MSA, and are often severe.[10] ## DNA damage[edit] Alpha-synuclein modulates DNA repair processes, including the repair of DNA double-strand breaks by the non-homologous end joining pathway.[13] The DNA repair function of alpha-synuclein appears to be compromised in Lewy body inclusion bearing neurons, and this may trigger cell death. Study of synucleinopathy mouse models of Parkinson’s disease indicates that alpha-synuclein pathogenesis is associated with increased DNA damage and activation of the DNA damage response.[14] ## See also[edit] * Proteopathy * Lewy body ## References[edit] 1. ^ a b McCann H, Stevens CH, Cartwright H, Halliday GM (2014). "Α-Synucleinopathy phenotypes". Parkinsonism & Related Disorders. 20 Suppl 1: S62–S67. doi:10.1016/S1353-8020(13)70017-8. PMID 24262191. 2. ^ Goedert M, Jakes R, Spillantini MG (2017). "The Synucleinopathies: Twenty Years On". J Parkinsons Dis. 7 (s1): S53–S71. doi:10.3233/JPD-179005. PMC 5345650. PMID 28282814. 3. ^ Pezzoli S, Cagnin A, Bandmann O, Venneri A (July 2017). "Structural and Functional Neuroimaging of Visual Hallucinations in Lewy Body Disease: A Systematic Literature Review". Brain Sci (Review). 7 (12): 84. doi:10.3390/brainsci7070084. PMC 5532597. PMID 28714891. 4. ^ Moussaud S, Jones DR, Moussaud-Lamodière EL, et al. (October 2014). "Alpha-synuclein and tau: teammates in neurodegeneration?". Mol Neurodegener. 9: 43. doi:10.1186/1750-1326-9-43. PMC 4230508. PMID 25352339. 5. ^ a b c St Louis EK, Boeve BF (November 2017). "REM sleep behavior disorder: Diagnosis, clinical implications, and future directions". Mayo Clin. Proc. (Review). 92 (11): 1723–36. doi:10.1016/j.mayocp.2017.09.007. PMC 6095693. PMID 29101940. 6. ^ a b St Louis EK, Boeve AR, Boeve BF (May 2017). "REM sleep behavior disorder in Parkinson's disease and other synucleinopathies". Mov. Disord. (Review). 32 (5): 645–58. doi:10.1002/mds.27018. PMID 28513079. 7. ^ Boot BP, McDade EM, McGinnis SM, Boeve BF (December 2013). "Treatment of dementia with Lewy bodies". Curr Treat Options Neurol (Review). 15 (6): 738–64. doi:10.1007/s11940-013-0261-6. PMC 3913181. PMID 24222315. 8. ^ Boot BP (2015). "Comprehensive treatment of dementia with Lewy bodies". Alzheimers Res Ther (Review). 7 (1): 45. doi:10.1186/s13195-015-0128-z. PMC 4448151. PMID 26029267. 9. ^ Walker Z, Possin KL, Boeve BF, Aarsland D (October 2015). "Lewy body dementias". Lancet (Review). 386 (10004): 1683–97. doi:10.1016/S0140-6736(15)00462-6. PMC 5792067. PMID 26595642. 10. ^ a b c d e f Palma JA, Kaufmann H (March 2018). "Treatment of autonomic dysfunction in Parkinson disease and other synucleinopathies". Mov. Disord. (Review). 33 (3): 372–90. doi:10.1002/mds.27344. PMC 5844369. PMID 29508455. 11. ^ Burghaus L, Eggers C, Timmermann L, Fink GR, Diederich NJ (February 2012). "Hallucinations in neurodegenerative diseases". CNS Neurosci Ther (Review). 18 (2): 149–59. doi:10.1111/j.1755-5949.2011.00247.x. PMC 6493408. PMID 21592320. 12. ^ Gomperts SN (April 2016). "Lewy body dementias: Dementia with Lewy bodies and Parkinson disease dementia". Continuum (Minneap Minn) (Review). 22 (2 Dementia): 435–63. doi:10.1212/CON.0000000000000309. PMC 5390937. PMID 27042903. 13. ^ Schaser AJ, Osterberg VR, Dent SE, Stackhouse TL, Wakeham CM, Boutros SW, Weston LJ, Owen N, Weissman TA, Luna E, Raber J, Luk KC, McCullough AK, Woltjer RL, Unni VK (Jul 2019). "Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders". Sci. Rep. 9 (1): 10919. doi:10.1038/s41598-019-47227-z. PMC 6662836. PMID 31358782. 14. ^ Milanese C, Cerri S, Ulusoy A, Gornati SV, Plat A, Gabriels S, Blandini F, Di Monte DA, Hoeijmakers JH, Mastroberardino PG (Jul 2018). "Activation of the DNA damage response in vivo in synucleinopathy models of Parkinson's disease". Cell Death Dis. 9 (8): 818. doi:10.1038/s41419-018-0848-7. PMC 6062587. PMID 30050065. [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 inhibitors [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	Synucleinopathy	None	2,917	wikipedia	https://en.wikipedia.org/wiki/Synucleinopathy	2021-01-18T18:56:21	{"wikidata": ["Q2376264"]}
A number sign (#) is used with this entry because immunodeficiency-21 (IMD21) is caused by heterozygous mutation in the GATA2 gene (137295) on chromosome 3q21. Primary lymphedema with myelodysplasia (614038), or Emberger syndrome, is an allelic disorder with overlapping clinical features. Description This primary immunodeficiency, designated IMD21, DCML, or MONOMAC, is characterized by profoundly decreased or absent monocytes, B lymphocytes, natural killer (NK) lymphocytes, and circulating and tissue dendritic cells (DCs), with little or no effect on T-cell numbers. Clinical features of IMD21 are variable and include susceptibility to disseminated nontuberculous mycobacterial infections, papillomavirus infections, opportunistic fungal infections, and pulmonary alveolar proteinosis. Bone marrow hypocellularity and dysplasia of myeloid, erythroid, and megakaryocytic lineages are present in most patients, as are karyotypic abnormalities, including monosomy 7 and trisomy 8. In the absence of cytogenetic abnormalities or overt dysplasia, hypoplastic bone marrow may initially be diagnosed as aplastic anemia. Bone marrow transplantation is the only cure. Some patients may have an increased risk of miscarriage. Both autosomal dominant transmission and sporadic cases occur. Less common manifestations of GATA2 deficiency include lymphedema and sensorineural hearing loss, a phenotype usually termed 'Emberger syndrome' (614038) (summary by Bigley et al. (2011), Hsu et al. (2011), and Spinner et al. (2014)). Clinical Features Biron et al. (1989) reported a 13-year-old girl who presented with disseminated varicella-zoster infection with varicella pneumonia. She had a history of recurrent otitis media from infancy. She later developed recurrent infections, particularly to viruses, including cytomegalovirus and herpes simplex virus. Laboratory studies showed persistent leukopenia, although antibody production and lymphoproliferative responses were normal. Detailed immunologic work-up revealed that she had no NK-cell function and lacked both NK cells and precursor NK cells. There was no family history of a similar disorder. The findings suggested that NK cells play a major defensive role against viral infections. In a follow-up, Mace et al. (2013) noted that the patient reported by Biron et al. (1989) subsequently developed aplastic anemia and died during hematopoietic stem cell transplantation. Vinh et al. (2010) reported 6 male and 12 female patients from 13 white and 3 Hispanic kindreds with a clinical phenotype of susceptibility to disseminated nontuberculous mycobacterial infections, viral infections, especially with human papillomaviruses, and fungal infections, primarily histoplasmosis. The patients ranged in age from 7 to 60 years, with a median age of 32 years. The syndrome typically had its onset in adulthood, and 5 of the patients had died. A literature review identified at least 7 potentially related cases. Five kindreds including 7 of the 18 patients exhibited likely autosomal dominant transmission, and anecdotal evidence suggested autosomal dominant transmission in 3 other kindreds. Immunophenotyping revealed profound monocytopenia, B-cell deficiency without hypogammaglobulinemia, and NK-cell deficiency, but usually normal or near normal T-lymphocyte numbers. Tissue macrophage and plasma cell numbers were normal. Ten patients developed 1 or more malignancies, including myelodysplasia/leukemia in 9 patients. Five patients developed pulmonary alveolar proteinosis. Three patients had abnormal cytogenetics, including trisomy 8, monosomy 7, and dicentric chromosome 6. Bigley et al. (2011) reported 4 additional patients with this immunodeficiency, which they called DCML. In addition to monocyte and B and NK lymphoid cell deficiency, they demonstrated a near absence of DCs in these patients, with preserved numbers of tissue macrophages and epidermal Langerhans cells. Multilymphoid progenitors were absent and granulocyte-macrophage progenitors were depleted in bone marrow. Serum FMS-like tyrosine kinase ligand (FLT3LG; 600007) was elevated, while circulating regulatory T cells were reduced. Bigley et al. (2011) concluded that DC deficiency is an integral part of the syndrome of autosomal and sporadic monocytopenia reported by Vinh et al. (2010). Spinner et al. (2014) retrospectively reviewed the clinical features of 57 patients with GATA2 mutations. Forty patients were identified through clinical presentation and 17 through family screening. The most common manifestations were severe viral or nontuberculous mycobacterial infections and myelodysplasia/acute myeloid leukemia. Less common features included invasive fungal infections (16%), pulmonary alveolar proteinosis (18%), and lymphedema (11%). The age at onset was extremely variable (range, 5 months to 78 years), and 4 (7%) of the mutation carriers were asymptomatic at last follow-up. Hemograms and lymphocyte phenotyping for 55 and 51 patients, respectively, showed B lymphocytopenia (86%), NK lymphocytopenia (82%), monocytopenia (78%), CD4 lymphocytopenia (51%), and neutropenia (47%). Forty-two (84%) of 50 patients who underwent bone marrow biopsy showed myelodysplastic syndrome. Nineteen (76%) of 25 patients who underwent audiograms showed mild to severe sensorineural hearing loss, which may have been complicated by antibiotic use. Dermatologic disease was often an indicator of chronic viral infection or malignancy. Fourteen (33%) of 43 known pregnancies resulted in miscarriage, and 14% of patients developed hypothyroidism. There were no obvious genotype/phenotype correlations, although severe viral infections were more common and showed earlier onset in those with null mutations, and lymphedema was only observed in those with null or regulatory domain mutations. Inheritance The transmission pattern of IMD21 in at least half of the families reported by Vinh et al. (2010) was consistent with autosomal dominant inheritance. Clinical Management Cuellar-Rodriguez et al. (2011) performed nonmyeloablative hematopoietic stem cell transplant in 6 patients with GATA2 deficiency. Two patients received peripheral blood stem cells (PBSCs) from matched related donors; 2 received PBSCs from matched unrelated donors; and 2 received stem cells from umbilical cord blood (UCB) donors. Recipients of matched related and unrelated donors received fludarabine and 200 cGy of total body irradiation (TBI), while UCB recipients received cyclophosphamide in addition to fludarabine and TBI as conditioning. All patients received tacrolimus and sirolimus posttransplantation. Five patients were alive at a median follow-up of 17.4 months (range, 10-25). All patients achieved high levels of donor engraftment in the hematopoietic compartments that were deficient pretransplantation. Adverse events consisted of delayed engraftment in the recipient of a single UCB transplant, graft-versus-host disease in 4 patients, and immune-mediated pancytopenia and nephrotic syndrome in the recipient of a double UCB transplant. Cuellar-Rodriguez et al. (2011) concluded that nonmyeloablative hematopoietic stem cell transplant in GATA2 deficiency results in reconstitution of the severely deficient monocyte, B-cell, and NK-cell populations and in reversal of the clinical phenotype. Molecular Genetics Hsu et al. (2011) identified 12 distinct heterozygous mutations in the GATA2 gene in 20 patients with DCML, which they termed MONOMAC due to monocyte deficiency and susceptibility to mycobacteria, typically M. avium complex (MAC). The mutations were identified in 12 patients from 10 of the 16 kindreds originally reported by Vinh et al. (2010) and in 8 patients from 8 different kindreds not previously reported. In 2 kindreds, the mutation identified in the proband was identified in an affected relative, confirming germline transmission. Of the remaining 6 kindreds reported by Vinh et al. (2010), mutations in GATA2 were not identified in 3, and 3 were not analyzed. Five of the 6 missense mutations, including 2 recurrent mutations, arg398 to trp (R398W; 137295.0001) and thr354 to met (T354M; 137295.0002), affected the zinc finger-2 domain in GATA2, suggesting dominant interference of protein function. The remaining missense mutation, pro254 to leu (P254L; 137295.0003), occurred before the zinc fingers and was predicted to be damaging. Six patients had insertion/deletion mutations, 4 of which (e.g., 137295.0004) led to frameshifts and premature termination and implicated haploinsufficiency. Hsu et al. (2011) concluded that GATA2, like RUNX1 (151385) and CEBPA (116897), is involved in familial leukemia and in a complex congenital immunodeficiency that evolves over decades and leads to predisposition to infection and myeloid malignancy. By exome sequence analysis of 4 unrelated patients with DCML previously reported by Bigley et al. (2011), including 3 with sporadic DCML, Dickinson et al. (2011) found that only mutations in GATA2 were shared by all 4 patients. Each patient harbored a unique mutation, but all were predicted to be deleterious. The mutations included 2 missense mutations within the zinc finger domain, R398W and T354M, a 1-bp insertion in codon 200 (137295.0007) predicted to cause a frameshift and premature termination, and a splice acceptor site mutation (137295.0008) predicted to cause skipping of exon 5 and a 42-amino acid deletion. The frameshift and splice acceptor mutations were expected to result in complete loss of the C-terminal zinc finger domain and to cause DCML through haploinsufficiency of GATA2. Johnson et al. (2012) identified a woman of European descent who developed a constellation of conditions characteristic of MONOMAC by the age of 27 years. The patient lacked mutations in her GATA2 cDNA, and 3 conserved GATA regulatory sites upstream of the GATA2 promoter were identical to wildtype. However, Johnson et al. (2012) identified a 28-bp deletion in intron 5 at +9.5 kb (137295.0015) that affected a conserved composite E-box/GATA element. The deletion excised an imperfect GATA motif (GATAG), the E-box of the conserved composite element (CATCTG), and 5 bp of the 8-bp spacer between the E-box and the GATA motif (AGATAA). Johnson et al. (2012) suggested that heterozygous mutation of the +9.5 site reduces GATA2 expression in vivo. In a girl with primary immunodeficiency originally reported by Biron et al. (1989), Mace et al. (2013) identified a heterozygous mutation in the GATA2 gene (137295.0016). Pathogenesis Mace et al. (2013) found that the NK cells of 5 patients with immunodeficiency due to GATA2 mutations showed a profound defect in NK cell-mediated cytotoxicity, as well as a defect in antibody-mediated cellular toxicity. There was a severe reduction in CD56 (NCAM1; 116930)-bright cells, which represent the precursor NK-cell pool, and the remaining NK cells were CD56-dim, representing the mature pool. Analysis of control NK cells showed that GATA2 was expressed primarily in the CD56-bright pool, suggesting an important role for GATA2 in the differentiation, maturation, and survival of NK cells. INHERITANCE \- Autosomal dominant RESPIRATORY Lung \- Pulmonary alveolar proteinosis (in some patients) HEMATOLOGY \- Aplastic anemia (in some patients) IMMUNOLOGY \- Primary immunodeficiency \- Recurrent infections, particularly to viruses and fungi \- Mycobacterial infections \- Monocytopenia \- Dendritic cell cytopenia \- B-cell lymphopenia \- Neutropenia \- Decreased NK cells, particularly NK cell precursors \- Deficient NK-cell mediated spontaneous and antibody-mediated cytotoxicity NEOPLASIA \- Susceptibility to myelodysplasia \- Susceptibility to myeloid leukemia MISCELLANEOUS \- Variable age at onset \- Variable phenotype \- Increased risk of miscarriage MOLECULAR BASIS \- Caused by mutation in the GATA-binding protein 2 gene (GATA2, 137295.0001 ) ▲ 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 inhibitors [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	IMMUNODEFICIENCY 21	c3280030	2,918	omim	https://www.omim.org/entry/614172	2019-09-22T15:56:14	{"mesh": ["D000077428"], "omim": ["614172"], "orphanet": ["228423"], "synonyms": ["DENDRITIC CELL, MONOCYTE, B LYMPHOCYTE, AND NATURAL KILLER LYMPHOCYTE DEFICIENCY", "MONOCYTOPENIA WITH SUSCEPTIBILITY TO MYCOBACTERIAL, FUNGAL, AND PAPILLOMAVIRUS INFECTIONS AND MYELODYSPLASIA", "Combined immunodeficiency with susceptibility to mycobacterial, viral and fungal infections", "Alternative titles", "Dendritic cell, monocyte, B and NK lymphoid deficiency", "COMBINED IMMUNODEFICIENCY WITH SUSCEPTIBILITY TO MYCOBACTERIAL, VIRAL, AND FUNGAL INFECTIONS", "MONOCYTOPENIA AND MYCOBACTERIAL INFECTION SYNDROME", "MonoMAC", "GATA2 DEFICIENCY", "Monocytopenia and mycobacterial infection syndrome", "Monocyte-B-natural killer-dendritic cell deficiency syndrome"]}
SLC35A3-CDG is a form of congenital disorders of N-linked glycosylation characterized by distal arthrogryposis (mild flexion contractures of the fingers, deviation of the distal phalanges, swan-neck deformity), retromicrognathia, general muscle hypotonia, delayed psychomotor development, autism spectrum disorder (speech delay, abnormal use of speech, difficulties in initiating, understanding and maintaining social interaction, limited non-verbal communication and repetitive behavior), seizures, microcephaly and mild to moderate intellectual disability that becomes apparent with age. The disease is caused by mutations in the gene SLC35A3 (1p21). [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 inhibitors [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	Autism spectrum disorder-epilepsy-arthrogryposis syndrome	c3809910	2,919	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=370943	2021-01-23T17:08:46	{"omim": ["615553"], "icd-10": ["Q87.8"], "synonyms": ["SLC35A3-CDG"]}
A number sign (#) is used with this entry because 3-methylglutaconic aciduria type V (MGCA5), also called dilated cardiomyopathy with ataxia, is caused by homozygous mutation in the DNAJC19 gene (608977) on chromosome 3q26. Description 3-Methylglutaconic aciduria type V is an autosomal recessive disorder characterized by the onset of dilated or noncompaction cardiomyopathy in infancy or early childhood. Many patients die of cardiac failure. Other features include microcytic anemia, growth retardation, mild ataxia, mild muscle weakness, genital anomalies in males, and increased urinary excretion of 3-methylglutaconic acid. Some patients may have optic atrophy or delayed psychomotor development (summary by Davey et al., 2006 and Ojala et al., 2012). For a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (250950). Clinical Features Davey et al. (2006) reported 18 patients with dilated cardiomyopathy and ataxia from 11 consanguineous Canadian Dariusleut Hutterite families. Affected individuals had severe, early-onset dilated cardiomyopathy (sometimes accompanied by long QT syndrome), prenatal or postnatal growth failure, and cerebellar ataxia causing significant motor delays. Genital anomalies secondary to testicular dysgenesis were seen in 9 of 11 male patients, ranging from isolated cryptorchidism to severe perineal hypospadias. Affected patients consistently showed 5- to 10-fold increases in both plasma and urine 3-methylglutaconic acid and 3-methylglutaric acid. Additional features included normochromic microcytic anemia in 12 patients, mild to borderline nonprogressive mental retardation in 10, a mild increase in hepatic enzymes with microvesicular hepatic steatosis in 5, and optic atrophy in 4. The onset of cardiomyopathy was always before the age of 3 years, and over 70% of affected individuals died from either progressive cardiac failure or sudden cardiac death. Sparkes et al. (2007) retrospectively reviewed the clinical course of 17 Hutterite patients reported by Davey et al. (2006). Of the 17, 13 (76%) had an echocardiographic or pathologic diagnosis of dilated cardiomyopathy with a mean age at onset of 12 months (range, 1-36 months). The cardiomyopathy was characterized by increased left ventricular end diastolic dimensions, mural thinning, and poor systolic function, with mild to severe global hypokinesia. Ten children died of congestive heart failure or arrhythmias at a mean age of 22 months (range, 4-48 months). Two males, aged 13 and 23 years, had resolution of the cardiomyopathy with only mild residual mitral regurgitation. Another male patient had persistent but clinically stable mild cardiomyopathy at age 15 years. Four patients did not develop cardiomyopathy. Electrocardiographic findings of 13 patients showed a prolonged QT interval in 8 patients, both in the presence (6) and absence (2) of dilated cardiomyopathy. One of the patients with isolated long QT died suddenly at age 14 months. Ojala et al. (2012) reported 2 Finnish brothers, born of unrelated parents, with MGCA5. Shortly after birth, both showed growth retardation, hypoglycemia, and microcytic anemia. Both patients developed symptomatic noncompaction cardiomyopathy with a prolonged QT interval. The older brother showed mildly delayed psychomotor development, mild ataxia, muscle weakness, and a gradual deterioration of fine motor skills. Laboratory studies showed high urinary excretion of methylglutaconic acid, mild urinary excretion of 3-methylglutarate, mildly increased urinary lactate, and a mild increase in plasma alanine aminotransferase. Muscle biopsy showed mild neutral lipid accumulation and partial deficiency of mitochondrial respiratory chain function. The older brother was doing well at age 49 months. The younger brother had cryptorchidism and chorda penis. Urinary organic acid analysis was normal in this patient at age 10 months. Despite intensive treatment, he died of cardiac failure at age 13 months. Postmortem examination showed a mildly atrophic brainstem with reduction of neuronal density in the cerebellum, as well as a dilated and noncompacted cardiac left ventricle. Inheritance The transmission pattern of MGCA5 in the family reported by Davey et al. (2006) was consistent with autosomal recessive inheritance. Mapping Davey et al. (2006) performed a genome scan using homozygosity mapping in 5 severely affected Canadian Dariusleut Hutterite patients from consanguineous families; fine mapping of candidate regions identified a 23.9-cM disease-associated haplotype on chromosome 3q26.2-q27.3 between markers D3S1282 and D3S1262. Genotyping of an additional 10 affected individuals and their unaffected family members narrowed the critical region to 2.2 Mb between D3S3603 and D3S2314 on 3q26.33. Molecular Genetics Davey et al. (2006) sequenced candidate genes in patients with dilated cardiomyopathy and ataxia from a Canadian Dariusleut Hutterite population and identified homozygosity for a splice site mutation in the DNAJC19 gene (608977.0001) in all 16 patients for whom DNA samples were available. Unaffected parents were heterozygous for the mutation. In 2 Finnish brothers with MGCA5, Ojala et al. (2012) identified a homozygous truncating mutation in the DNAJC19 gene (608977.0002). The unaffected parents were heterozygous for the mutation. Population Genetics In a carrier screening of autosomal recessive mutations involving 1,644 Schmiedeleut (S-leut) Hutterites in the United States, Chong et al. (2012) identified the DNAJC19 dilated cardiomyopathy and ataxia mutation IVS3-1G-C (rs137854888, 608977.0001) in heterozygous state in 42 individuals among 1,504 screened and in homozygous state in none, for a carrier frequency of 0.028 (1 in 36). This is a private mutation in the Hutterite population. INHERITANCE \- Autosomal recessive GROWTH Other \- Prenatal growth failure \- Postnatal growth failure HEAD & NECK Eyes \- Optic atrophy (in some patients) CARDIOVASCULAR Heart \- Dilated cardiomyopathy, early onset \- Long QT syndrome \- Cardiac failure \- Noncompaction cardiomyopathy \- Sudden cardiac death ABDOMEN Liver \- Microvesicular hepatic steatosis GENITOURINARY External Genitalia (Male) \- Hypospadias \- Chorda penis Internal Genitalia (Male) \- Small atrophic testes \- Cryptorchidism MUSCLE, SOFT TISSUES \- Muscle weakness \- Mild decrease in mitochondrial respiratory chain activity NEUROLOGIC Central Nervous System \- Cerebellar ataxia, nonprogressive \- Mental retardation, mild-borderline, nonprogressive HEMATOLOGY \- Microcytic anemia LABORATORY ABNORMALITIES \- 3-methylglutaconic aciduria (3-MGC) \- 3-methylglutaric aciduria (3-MGA) \- Mildly elevated hepatic enzymes MISCELLANEOUS \- Increased frequency in the Dariusleut Hutterites (Canada) \- Onset of dilated cardiomyopathy less than 3 years MOLECULAR BASIS \- Caused by mutation in the homolog of the E. coli DNAJ subfamily C member 19 gene (DNAJC19, 608977.0001 ) ▲ 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 inhibitors [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	3-METHYLGLUTACONIC ACIDURIA, TYPE V	c1857776	2,920	omim	https://www.omim.org/entry/610198	2019-09-22T16:04:58	{"doid": ["0110000"], "mesh": ["C565706"], "omim": ["610198"], "orphanet": ["66634"], "synonyms": ["Alternative titles", "CARDIOMYOPATHY, DILATED, WITH ATAXIA", "MGA, TYPE V"]}
A neuropathy causing itching between the shoulder blades Notalgia paresthetica Other namesNotalgia paraesthetica Notalgia Paresthetica SpecialtyNeurology Notalgia paraesthetica (NP) or notalgia paresthetica (also known as "Hereditary localized pruritus", "Posterior pigmented pruritic patch", and "subscapular pruritus"[1]) is a chronic sensory neuropathy. Notalgia paraesthetica is a common localized itch, affecting mainly the area between the shoulder blades (especially the T2–T6 dermatomes) but occasionally with a more widespread distribution, involving the shoulders, back, and upper chest.[2]:402 The characteristic symptom is pruritus (itch or sensation that makes a person want to scratch) on the back, usually on the left hand side below the shoulder blade (mid to upper back). It is occasionally accompanied by pain, paresthesia (pins and needles), or hyperesthesia (unusual or pathologically increased sensitivity of the skin to sensory stimuli, such as pain, heat, cold, or touch), which results in a well circumscribed hyperpigmentation of a skin patch in the affected area. ## Contents * 1 Causes * 2 Diagnosis * 3 Treatment * 4 See also * 5 References * 6 External links ## Causes[edit] The correlation of notalgia paraesthetica localization with corresponding degenerative changes in the spine suggest that spinal nerve impingement may be a contributing cause. According to Plete and Massey, "The posterior rami of spinal nerves arising in T2 through T6 are unique in that they pursue a right-angle course through the multifidus spinae muscle, and this particular circumstance may predispose them to harm from otherwise innocuous insults of a varied nature." Patients may have other conditions that predispose them to peripheral neuropathies (nerve damage). The causes of this condition have not yet been completely defined.[3] Patients are usually older persons.[4] ## Diagnosis[edit] This section is empty. You can help by adding to it. (October 2017) ## Treatment[edit] Therapy for notalgia paresthetica is directed at controlling symptoms, as no cure exists for the condition. Available treatments include local anesthetics, topical capsaicin,[5][6] topical corticosteroids,[7] hydroxyzine, oxcarbazepine, palmitoylethanolamide and gabapentin. Paravertebral nerve block and botulinum toxin injections may also be helpful. Some patients treated with low concentration topical capsaicin reported pain, burning, or tingling sensations with treatment, and symptoms returned within a month of ceasing treatment.[8] Oxcarbazepine was reported to reduce the severity of symptoms in a few cases.[9] One patient has been treated with "paravertebral nerve blocks, with bupivacaine and methylprednisolone acetate injected into the T3–T4 and T5–T6 intervertebral spaces" [10] Hydroxyzine has also been used with considerable success in some cases as long as the pills are used daily. High concentration topical capsaicin (8%, Qutenza) have been shown to be highly effective in treating neuropathic itch in some patients[11][12] (including notalgia paresthetica) as well as in a recent proof-of-concept study,[13] but this remains to be confirmed in randomised controlled trials. Most recently intradermal injections of botulinum toxin type A (Botox) have been tried with some success. Even though botulinum normally wears off in three to six months, the treatment appears to be long term, and it has been theorised that botulinum type A effects lasting change in pain signaling.[14] Unfortunately, repeated injections have been associated with diminished movement ability of the upper back and arms and its recommendation as a treatment has therefore become less popular. ## See also[edit] * List of cutaneous conditions * Hereditary neuralgic amyotrophy ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0. 3. ^ Savk, E.; Savk, O.; Bolukbasi, O.; Culhaci, N.; Dikicioğlu, E.; Karaman, G.; Sendur, N. (2000-10-01). "ingentaconnect Notalgia paresthetica: a study on pathogenesis". International Journal of Dermatology. Ingentaconnect.com. 39 (10): 754–9. doi:10.1046/j.1365-4362.2000.00080.x. PMID 11095194. 4. ^ "Skinsight - Notalgia Paraesthetica". 5. ^ Andersen, H. H.; Arendt-Nielsen, L.; Elberling, J. (July 2017). "Topical capsaicin 8% for the treatment of neuropathic itch conditions". Clinical and Experimental Dermatology. 42 (5): 596–598. doi:10.1111/ced.13114. ISSN 1365-2230. PMID 28556308. S2CID 3813025. 6. ^ Andersen, Hjalte H.; Sand, Carsten; Elberling, Jesper (February 2016). "Considerable Variability in the Efficacy of 8% Capsaicin Topical Patches in the Treatment of Chronic Pruritus in 3 Patients with Notalgia Paresthetica". Annals of Dermatology. 28 (1): 86–89. doi:10.5021/ad.2016.28.1.86. ISSN 1013-9087. PMC 4737841. PMID 26848223. 7. ^ Journal of the American Academy of Dermatology Volume: 32 Issue: 2 Pages: 287–289 Part: Part Published: FEB 1995 ISSN 0190-9622 8. ^ Weinfeld, Pamela Kirschner (2006-10-16). "JAMA Network \| JAMA Dermatology \| Successful Treatment of Notalgia Paresthetica With Botulinum Toxin Type A". Archives of Dermatology. Archderm.ama-assn.org. 143 (8): 980–982. doi:10.1001/archderm.143.8.980. PMID 17709655. 9. ^ JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Volume: 45 Issue: 4 Pages: 630-632 Published: OCT 2001 ISSN 0190-9622 10. ^ JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Volume: 38 Issue: 1 Pages: 114-116 Published: JAN 1998 ISSN 0190-9622 11. ^ Andersen, Hjalte H.; Sand, Carsten; Elberling, Jesper (February 2016). "Considerable Variability in the Efficacy of 8% Capsaicin Topical Patches in the Treatment of Chronic Pruritus in 3 Patients with Notalgia Paresthetica". Annals of Dermatology. 28 (1): 86–89. doi:10.5021/ad.2016.28.1.86. ISSN 1013-9087. PMC 4737841. PMID 26848223. 12. ^ Andersen, H. H.; Arendt-Nielsen, L.; Elberling, J. (July 2017). "Topical capsaicin 8% for the treatment of neuropathic itch conditions". Clinical and Experimental Dermatology. 42 (5): 596–598. doi:10.1111/ced.13114. ISSN 1365-2230. PMID 28556308. S2CID 3813025. 13. ^ Andersen, H. H.; Marker, J. B.; Hoeck, E. A.; Elberling, J.; Arendt-Nielsen, L. (2017-01-24). "Antipruritic effect of pretreatment with topical capsaicin 8% on histamine- and cowhage-evoked itch in healthy volunteers: a randomized, vehicle-controlled, proof-of-concept trial". The British Journal of Dermatology. 177 (1): 107–116. doi:10.1111/bjd.15335. ISSN 1365-2133. PMID 28117875. S2CID 13377266. 14. ^ NEUROTOXICOLOGY Volume: 26 Issue: 5 Special Issue: Sp. Iss. SI Pages: 785–793 Published: OCT 2005 ISSN 0161-813X * * Pleet, A Bernard and Massey, E Wayne, Notalgia Paresthetica, Neurology, Dec 1978; 28: 1310 * Pleet, A Bernard and Massey, E Wayne, Letter to the Editor: Notalgia Paresthetica, Neurology, Vol. 29, Issue 4, 528 April 1, 1979 ## External links[edit] Classification D * DiseasesDB: 33783 External resources * eMedicine: article/1599159 [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 inhibitors [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	Notalgia paresthetica	c0457010	2,921	wikipedia	https://en.wikipedia.org/wiki/Notalgia_paresthetica	2021-01-18T19:06:03	{"gard": ["7225"], "wikidata": ["Q494925"]}
Belief that symptoms are caused by an unproven infection Not to be confused with Neuroborreliosis or Post-treatment Lyme disease syndrome. Chronic Lyme disease Pseudomedical diagnosis RisksNocebo Treatment risksDangers of long-term antibiotic therapy LegalitySome jurisdictions have legislated to protect doctors offering worthless and potentially dangerous treatments This article is part of a series on Alternative medicine General information * Alternative medicine * Alternative veterinary medicine * Quackery (Health fraud) * History of alternative medicine * Rise of modern medicine * Pseudoscience * Antiscience * Skepticism * Skeptical movement * National Center for Complementary and Integrative Health * Terminology of alternative medicine * Therapeutic nihilism Fringe medicine and science * Acupressure * Acupuncture * Alkaline diet * Anthroposophic medicine * Apitherapy * Applied kinesiology * Aromatherapy * Auriculotherapy * Bates method * Black salve * Bodywork * Bonesetter * Bowen technique * Breathwork * Fake COVID-19 treatments * Cancer treatments * Charcoal cleanse * Chiropractic * Chiropractic treatment techniques * Vertebral subluxation * Christian Science * Chromotherapy * Colon cleansing * Coffee enema * Colorpuncture * Colloidal silver * Craniosacral therapy * Crystal healing * Cupping therapy * Dental amalgam controversy * Detoxification * Foot detox * Ear candling * Energy medicine * Esoteric energy * Therapeutic touch * Fabunan Antiviral Injection * Facilitated communication * Feldenkrais Method * Functional medicine * Hair analysis * Herbal medicine * Holistic dentistry * Hologram bracelet * Homeopathy * Bach flower remedies * Biological terrain assessment * Hypnotherapy * Iridology * Ionized jewelry * Jilly Juice * Lightning Process * Lymphotherapy * Medical intuitive * Mesmerism * Magnet therapy * Manual therapy * Megavitamin therapy * Mind–body interventions * MMS * Myofascial release * NAET * Naturopathy * Oil pulling * Orgone * Orthomolecular medicine * Orthopathy * Osteomyology * Osteopathy * Ozone therapy * Parapsychology * Phrenology * Psychic surgery * Psychodermatology * Radionics * Rapid prompting method * RBOP * Reiki * Reflexology * Rolfing * Scientific racism * ThetaHealing * Thought Field Therapy * Urophagia * Vaginal steaming * Vision therapy * Vitalism * Young blood transfusion * Zero balancing Conspiracy theories (list) * Big Pharma conspiracy theory * HIV/AIDS denialism * OPV AIDS hypothesis * Anti-vaccination * Vaccines and autism * MMR vaccine and autism * Water fluoridation controversy * GMO conspiracy theories * Misinformation related to the COVID-19 pandemic Classifications * Alternative medical systems * Mind–body intervention * Biologically-based therapy * Manipulative methods * Energy therapy Traditional medicine * African * Muti * Southern Africa * Ayurveda * Ayurvedic acupressure * Dosha * Maharishi Vedic Approach to Health * Balneotherapy * Brazilian * Bush medicine * Cambodian * Chinese * Blood stasis * Chinese herbology * Dit Da * Gua sha * Gill plate trade * Meridian * Moxibustion * Pressure point * Qi * San Jiao * Tui na * Zang-fu * Chumash * Curandero * Faith healing * Iranian * Jamu * Kambo * Japanese * Korean * Mien Shiang * Mongolian * Prophetic medicine * Shamanism * Shiatsu * Siddha * Sri Lankan * Thai massage * Tibetan * Unani * Vietnamese Diagnoses * Adrenal fatigue * Aerotoxic syndrome * Candida hypersensitivity * Chronic Lyme disease * Electromagnetic hypersensitivity * Heavy legs * Leaky gut syndrome * Multiple chemical sensitivity * Wilson's temperature syndrome * v * t * e Chronic Lyme disease (CLD) is the name used by some people with "a broad array of illnesses or symptom complexes for which there is no reproducible or convincing scientific evidence of any relationship to Borrelia burgdorferi infection" to describe their condition and their beliefs about its cause.[1] Both the label and the belief that these people's symptoms are caused by this particular infection are generally rejected by medical professionals, and the promotion of chronic lyme disease is an example of health fraud.[1][2] Chronic Lyme disease in this context should not be confused with genuine Lyme disease, a known medical disorder caused by infection with Borrelia burgdorferi, or with post-treatment Lyme disease syndrome, a set of lingering symptoms which may persist after successful treatment of infection with Lyme bacteria. Despite numerous studies, there is no evidence that symptoms associated with CLD are caused by any persistent infection.[3] The symptoms attributed to chronic Lyme are generic and non-specific symptoms, such as fatigue and muscle pain, and in many cases are likely due to fibromyalgia or chronic fatigue syndrome.[4][5] Fibromyalgia can be triggered by an infection, and antibiotics are not a safe or effective treatment for post-infectious fibromyalgia.[6] A number of alternative health products are promoted for chronic Lyme disease,[7] of which possibly the most controversial and harmful is long-term antibiotic therapy, particularly intravenous antibiotics.[8][9] Recognised authorities advise against long-term antibiotic treatment for Lyme disease, even where some symptoms persist post-treatment.[10][11][12] Following disciplinary proceedings by state medical licensing boards in the United States, a subculture of "Lyme literate" physicians has successfully lobbied for specific legal protections, exempting them from the standard of care and Infectious Diseases Society of America treatment guidelines. This political interference in medical care[13][14] has been criticised as an example of "legislative alchemy", the process whereby pseudomedicine is legislated into practice.[15] ## Contents * 1 Description and background * 2 Identity * 3 Political actions * 3.1 IDSA lawsuit * 3.2 Legal mandates to cover unproven treatments * 4 Harassment of researchers * 5 Media * 6 See also * 7 References * 8 External links ## Description and background[edit] There are risks associated with long-term use of antibiotics, such as doxycycline, by people who believe they have chronic Lyme disease. Chronic Lyme disease is distinct from untreated late-stage Lyme disease, which can cause arthritis, peripheral neuropathy and/or encephalomyelitis. Chronic Lyme disease is also distinct from the post-treatment Lyme disease syndrome (PTLDS), when symptoms linger after standard antibiotic treatments.[16][17] PTLDS is estimated to occur in less than 5% of people who had Lyme disease and were treated.[18] In contrast to these recognized medical conditions, the promotion of chronic lyme disease is a quintessential example of health fraud.[2] In many cases there is no objective evidence that people who believe they have chronic Lyme have ever been infected with Lyme disease: standard diagnostic tests for infection are often negative.[1][19] While it is undisputed that people can have severe symptoms of an illness, the cause and appropriate treatment promoted by "chronic Lyme" advocates are controversial. The symptoms are similar to those of fibromyalgia or chronic fatigue syndrome.[4][6] Fibromyalgia can be triggered by an infection, and then persist when the infection is completely removed from the body.[6] A few doctors attribute these symptoms to persistent infection with Borrelia, or co-infections with other tick-borne pathogens, such as Ehrlichia and Babesia.[20][21][22] Some conclude that the initial infection may cause an autoimmune reaction that continues to cause serious symptoms even after the bacteria have been eliminated by antibiotics.[23] A review looked at several animal studies that found persistence of live but disabled spirochetes following treatment of B. burgdorferi infection with antibiotics. The authors noted that none of the lingering spirochetes were associated with inflamed tissues and criticized the studies for not having considered adequately the different pharmacodynamics and pharmacokinetics of the antibiotics used to treat the animals in the trials versus what would be expected to be used to treat humans. The authors concluded, "There is no scientific evidence to support the hypothesis that such spirochetes, should they exist in humans, are the cause of post-Lyme disease syndrome."[24] Major US medical authorities, including the Infectious Diseases Society of America, the American Academy of Neurology, and the National Institutes of Health, have stated there is no convincing evidence that Borrelia is involved in the various symptoms classed as CLD, and particularly advise against long-term antibiotic treatment as it is ineffective and potentially harmful.[1][10][11][12] Prolonged antibiotic therapy presents significant risks and can have dangerous, even deadly, side effects.[25] Randomized placebo-controlled studies have shown that antibiotics offer no sustained benefit in people with chronic Lyme, with evidence of both placebo effects and significant adverse effects from such treatment.[26] Many people who believe that they have chronic Lyme have fibromyalgia.[4][6] Fibromyalgia can be difficult to treat, and antibiotics do not work at all for fibromyalgia.[6] A pressure group called the International Lyme and Associated Diseases Society (ILADS)[27] says that the persistence of B. burgdorferi may be responsible for manifestations of chronic Lyme disease symptoms. ## Identity[edit] Chronic Lyme can generally be explained as a misdiagnosis of fibromyalgia or chronic fatigue syndrome.[4] However, among people who self-identify as having chronic Lyme, the idea of chronic Lyme functions as a type of social identity. In this sense, the goal of the label is not to identify particular objective facts that differentiate one medical condition from another; instead, the main goal is to validate the real suffering experienced by people living with an invisible illness and to provide social support for them as they cope with it.[28] ## Political actions[edit] While there is general agreement on the optimal treatment for Lyme disease, the existence of chronic Lyme is generally rejected because there is no evidence of its existence.[27][29][30] Even among those who believe in it, there is no consensus over its prevalence, symptoms, diagnostic criteria, or treatment.[27][29][30] The evidence-based perspective is exemplified by a 2007 review in The New England Journal of Medicine, which noted the diagnosis of chronic Lyme disease is used by a few physicians despite a lack of "reproducible or convincing scientific evidence", leading the authors to describe this diagnosis as "the latest in a series of syndromes that have been postulated in an attempt to attribute medically unexplained symptoms to particular infections."[1] Medical authorities agree with this viewpoint: the Infectious Diseases Society of America (IDSA), the American Academy of Neurology, the Centers for Disease Control and Prevention (CDC), and the National Institutes of Health (NIH), advise against long-term antibiotic treatment for people who identify as having chronic Lyme disease, given the lack of supporting evidence and the potential for harmful side-effects.[31] including toxicities.[10][11][12] A minority, primarily not medical practitioners, holds that chronic Lyme disease is responsible for a range of unexplained symptoms, sometimes in people without any evidence of past infection.[29] This viewpoint is promoted by many who have been told they have the condition by people who lack experience in science or medicine.[27] Groups, advocates, and the small number of physicians who support the concept of chronic Lyme disease have organized to lobby for recognition of this diagnosis, as well as to argue for insurance coverage of long-term antibiotic therapy, which most insurers deny, as it is at odds with the guidelines of major medical organizations.[29][32] Paul G. Auwaerter, director of infectious disease at Johns Hopkins School of Medicine, cited the political controversy and high emotions as contributing to a "poisonous atmosphere" around Lyme disease, which he believes has led to doctors trying to avoid having Lyme patients in their practices.[33] ### IDSA lawsuit[edit] In 2006, Richard Blumenthal, the Connecticut Attorney General, opened an antitrust investigation against the IDSA, accusing the IDSA Lyme disease panel of undisclosed conflicts of interest and of unduly dismissing alternative therapies and chronic Lyme disease. The investigation was closed on May 1, 2008, without charges when the IDSA agreed to submit to a review of its guidelines by a panel of independent scientists and physicians which would occur on July 30, 2009,[33] citing mounting legal costs and the difficulty of presenting scientific arguments in a legal setting.[34] The medical validity of the IDSA guidelines was not challenged,[35] and a journalist writing in Nature Medicine suggested some IDSA members may not have disclosed potential conflicts of interest,[29] while a Forbes piece described Blumenthal's investigation as "intimidation" of scientists by an elected official with close ties to Lyme advocacy groups.[32] The Journal of the American Medical Association described the decision as an example of the "politicization of health policy" that went against the weight of scientific evidence and may have a chilling effect on future decisions by medical associations.[36] The expert panel's review was published in 2010, with the independent doctors and scientists in the panel unanimously endorsing the guidelines, stating "No changes or revisions to the 2006 Lyme guidelines are necessary at this time", and concluding long-term antibiotic treatments are unproven and potentially dangerous.[37] The IDSA welcomed the final report, stating that "Our number one concern is the patients we treat, and we're glad patients and their physicians now have additional reassurance that the guidelines are medically sound."[38] ### Legal mandates to cover unproven treatments[edit] The state of Connecticut, meanwhile, enacted a law on June 18, 2009, "to allow a licensed physician to prescribe, administer or dispense long-term antibiotics for a therapeutic purpose to a patient clinically diagnosed with Lyme disease."[39] The states of Rhode Island,[40] California,[41] Massachusetts,[41] New Hampshire,[41] Vermont,[41] New York,[42] Maine[43] and Iowa[44] have similar laws. Massachusetts (2016)[45] and Rhode Island (2003)[46] have laws mandating insurance coverage for long-term antibiotic therapy for Lyme disease when deemed medically necessary by a physician.[46] In 1999 Connecticut had passed a similar, though somewhat more restrictive law.[47] ## Harassment of researchers[edit] In 2001, The New York Times Magazine reported that Allen Steere, chief of immunology and rheumatology at Tufts Medical Center and a co-discoverer and leading expert on Lyme disease, had been harassed, stalked, and threatened by patients and patient advocacy groups angry at his refusal to substantiate their diagnoses of "chronic" Lyme disease and endorse long-term antibiotic therapy.[48] Because this intimidation included death threats, Steere was assigned security guards.[49] ## Media[edit] A 2004 study in The Pediatric Infectious Disease Journal stated nine of nineteen Internet websites surveyed contained what were described as major inaccuracies. Websites described as providing inaccurate information included several with the word "lyme" in their domain name (e.g., lymenet.org), as well as the website of the International Lyme and Associated Diseases Society.[50] A 2007 article in The New England Journal of Medicine argued media coverage of chronic Lyme disease ignored scientific evidence in favor of anecdotes and testimonials: > The media frequently disregard complex scientific data in favor of testimonials about patients suffering from purported chronic Lyme disease and may even question the competence of clinicians who are reluctant to diagnose chronic Lyme disease. All these factors have contributed to a great deal of public confusion with little appreciation of the serious harm caused to many patients who have received a misdiagnosis and have been inappropriately treated.[1] The 2008 documentary film Under Our Skin: The Untold Story of Lyme Disease opened June 19, 2009, in New York City.[51] The film, made by a director whose sister self-identified with the condition, is based on the premise that chronic Lyme disease exists.[52] A columnist for Entertainment Weekly wrote of the film: > [Under Our Skin] embraces, with bits and pieces of skimpy evidence and a whole lot more paranoid leftist fervor, the notion that "chronic Lyme disease" is a condition that the medical establishment is locked in a conspiracy to deny the existence of. The filmmakers actually bungle what should have been their real subject (that the belief in chronic Lyme disease has become something of a cult, one that can ruin the lives of the people who think they have it). But the bottom line, to me, is that Under Our Skin is not a very well-made movie.[53] ## See also[edit] * List of questionable diseases ## References[edit] 1. ^ a b c d e f Feder, HM; Johnson, BJB; O'Connell, S; et al. (October 2007). "A Critical Appraisal of "Chronic Lyme Disease"". NEJM. 357 (14): 1422–30. doi:10.1056/NEJMra072023. PMID 17914043. 2. ^ a b Zemel L, Auwaerter PG (13 December 2019). "Treating 'chronic Lyme disease': Is it medical fraud?". Connecticut Mirror. 3. ^ Baker, P. J. (14 July 2010). "Chronic Lyme disease: in defense of the scientific enterprise". The FASEB Journal. 24 (11): 4175–77. doi:10.1096/fj.10-167247. PMID 20631327. S2CID 36141950. 4. ^ a b c d Wolfe F (April 2009). "Fibromyalgia wars". J. Rheumatol. 36 (4): 679–83. doi:10.3899/jrheum.081180. PMID 19342721. S2CID 2091976. 5. ^ Hall, Harriet (2013-09-03). "Does Everybody Have Chronic Lyme Disease? Does Anyone?". Science Based Medicine. 6. ^ a b c d e Ranque-Garnier, S.; Eldin, C.; Sault, C.; Raoult, D.; Donnet, A. (March 2019). "Management of patients presenting with generalized musculoskeletal pain and a suspicion of Lyme disease". Médecine et Maladies Infectieuses. 49 (2): 157–66. doi:10.1016/j.medmal.2019.01.008. ISSN 1769-6690. PMID 30765287. 7. ^ McSweegan, Edward. "Lyme Disease: Questionable Diagnosis and Treatment". Quackwatch. 8. ^ Lantos PM (June 2015). "Chronic Lyme disease". Infect. Dis. Clin. North Am. (Review). 29 (2): 325–40. doi:10.1016/j.idc.2015.02.006. PMC 4477530. PMID 25999227. 9. ^ Salzberg, Steven (2016-04-04). "Long-Term Antibiotic Use For Lyme Disease Doesn't Work, Study Finds". Forbes. 10. ^ a b c Wormser GP; Dattwyler RJ; Shapiro ED; et al. (November 2006). "The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America" (PDF). Clin. Infect. Dis. 43 (9): 1089–1134. doi:10.1086/508667. PMID 17029130. 11. ^ a b c Halperin JJ, Shapiro ED, Logigian E, et al. (July 2007). "Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology". Neurology. 69 (1): 91–102. doi:10.1212/01.wnl.0000265517.66976.28. PMID 17522387. S2CID 959269. 12. ^ a b c "Chronic Lyme Disease". National Institute of Allergy and Infectious Diseases. November 21, 2018. Retrieved 2019-12-05. 13. ^ Mason DJ, Leavitt JK, Chaffee MW (2014). Policy & Politics in Nursing and Health Care. Elsevier Health Sciences. pp. 310–11. ISBN 978-0323316064. 14. ^ Warner, Susan (2007-02-07). "State official subpoenas infectious disease group". The Scientist. 15. ^ Bellamy, Jann (2014-05-15). "Legislative Alchemy 2014 (so far)". Science Based Medicine. 16. ^ "Post Lyme Disease Syndrome". Cdc.gov. February 7, 2013. Retrieved July 5, 2013. 17. ^ Cairns V, Godwin J (December 2005). "Post-Lyme borreliosis syndrome: a meta-analysis of reported symptoms". Int J Epidemiol. 34 (6): 1340–45. doi:10.1093/ije/dyi129. PMID 16040645. 18. ^ Bope, Edward T.; Kellerman, Rick D. (2012). Conn's Current Therapy 2013: Expert Consult: Online. Elsevier Health Sciences. p. 151. ISBN 978-1455733347. 19. ^ "Ten Facts You Should Know About Lyme Disease". Infectious Diseases Society of America. May 10, 2011. Retrieved June 18, 2013. 20. ^ Cameron D; Johnson LB; Maloney EL (2014). "Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease". Expert Review of Anti-infective Therapy. 12 (9): 1103–35. doi:10.1586/14787210.2014.940900. PMC 4196523. PMID 25077519. 21. ^ Phillips, S (2006-07-30). "Lyme Disease Review Panel Hearing". Infectious Diseases Society of America. Retrieved 2010-12-09. 22. ^ Cameron DJ (2006). "Generalizability in two clinical trials of Lyme disease". Epidemiologic Perspectives & Innovations. 3: 12. doi:10.1186/1742-5573-3-12. PMC 1626453. PMID 17044928. 23. ^ Ercolini AM, Miller SD (January 2009). "The role of infections in autoimmune disease". Clin. Exp. Immunol. 155 (1): 1–15. doi:10.1111/j.1365-2249.2008.03834.x. PMC 2665673. PMID 19076824. 24. ^ Wormser GP, Schwartz I (July 2009). "Antibiotic treatment of animals infected with Borrelia burgdorferi". Clin. Microbiol. Rev. 22 (3): 387–95. doi:10.1128/CMR.00004-09. PMC 2708393. PMID 19597005. 25. ^ Dolin, Gerald L Mandell, John E Bennett, Raphael, ed. (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases (7th ed.). Philadelphia, PA: Churchill Livingstone/Elsevier. pp. Chapter 242. ISBN 978-0-443-06839-3. 26. ^ Marques, Adriana (June 2008). "Chronic Lyme Disease: An appraisal". Infect Dis Clin North Am. 22 (2): 341–60. doi:10.1016/j.idc.2007.12.011. PMC 2430045. PMID 18452806. 27. ^ a b c d Tonks A (November 2007). "Lyme wars". BMJ. 335 (7626): 910–12. doi:10.1136/bmj.39363.530961.AD. PMC 2048873. PMID 17974685. 28. ^ Fischer, Molly (2019-07-24). "What Happens When Lyme Disease Becomes an Identity?". The Cut. Retrieved 2019-07-30. "For this community of patients, Lyme has come to function as something more expansive than a diagnosis. While Lyme disease is a specific medical condition—one that may manifest more severely or less, be treated more easily or less—chronic Lyme is something else altogether. (The medical establishment generally avoids using the term chronic Lyme, and because of this establishment wariness, advocates who believe Lyme is a chronic infection now sometimes advise patients to avoid it too.) This version of Lyme has no consistent symptoms, no fixed criteria, and no accurate test. This Lyme is a kind of identity. Lyme is a label for a state of being, a word that conveys your understanding of your lived experience. Lyme provides the language to articulate that experience and join with others who share it. In the world of chronic Lyme, doctors are trustworthy (or not) based on their willingness to treat Lyme. Tests are trustworthy (or not) based on their ability to confirm Lyme. Lyme is the fundamental fact, and you work backward from there. Lyme is a community with a cause: the recognition of its sufferers' suffering—and, with it, the recognition of Lyme." 29. ^ a b c d e Ballantyne C (November 2008). "The chronic debate over Lyme disease". Nat. Med. 14 (11): 1135–39. doi:10.1038/nm1108-1135. PMID 18989271. S2CID 36510820. 30. ^ a b Correspondence, "Reinfection versus Relapse in Lyme Disease", New England Journal of Medicine, March 14, 2013. (This exchange of three letters nicely illustrates the controversy and some of the issues at stake.) 31. ^ "Deceptive Lyme Disease Diagnosis Linked With Serious Infections". JAMA. 318 (4): 324. 2017. doi:10.1001/jama.2017.8897. PMID 28742918. 32. ^ a b Whelan, David (2007-03-12). "Lyme Inc". Forbes. Retrieved 2008-06-24. 33. ^ a b Landers, Susan J (2008-06-09). "Lyme treatment accord ends antitrust probe". American Medical News. Archived from the original on 11 June 2008. Retrieved 2008-06-24. 34. ^ Klein JO (November 2008). "Danger ahead: politics intrude in Infectious Diseases Society of America guideline for Lyme disease". Clin. Infect. Dis. 47 (9): 1197–99. doi:10.1086/592247. PMID 18821849. 35. ^ "Agreement Ends Lyme Disease Investigation By Connecticut Attorney General: Medical Validity of IDSA Guidelines Not Challenged" (Press release). Infectious Diseases Society of America. 2008-05-01. Archived from the original on 2018-01-19. Retrieved 2017-05-19. 36. ^ Kraemer JD, Gostin LO (February 2009). "Science, politics, and values: the politicization of professional practice guidelines". JAMA. 301 (6): 665–67. doi:10.1001/jama.301.6.665. PMID 19211474. 37. ^ Singer, Stephen (2010-04-22). "No changes to Lyme disease treatment". Associated Press. 38. ^ Special Review Panel Unanimously Upholds Lyme Disease Treatment Guidelines: Short-term Antibiotics Proven to be Best Treatment for Patients Infectious Diseases Society of America. April 22, 2010. 39. ^ "An act concerning the use of long-term antibiotics for the treatment of Lyme disease". Connecticut General Assembly. 2009-06-18. Retrieved 2019-12-05. 40. ^ "Lyme Disease and the Law". Rhode Island Department of Health. 2009. Archived from the original on May 2, 2005. Retrieved 2009-07-05. 41. ^ a b c d Rathke, Lisa (July 12, 2014). "New Vt. law aims to aid in treatment of Lyme disease as cases soar". The Providence Journal. Retrieved 28 July 2019. 42. ^ John Ferro (18 December 2014). "Cuomo signs bill safeguarding Lyme treatments". The Poughkeepsie Journal. Retrieved 29 August 2015. 43. ^ "Maine Legislature clears way for long-term Lyme disease treatment". The Portland Press Herald / Maine Sunday Telegram. 2015-06-29. Retrieved 29 August 2015. 44. ^ http://www.tamatoledonews.com/page/content.detail/id/603916/Cornfileds--Common-Sense-and-Community.html?nav=5002 45. ^ Brown, Steve (1 August 2016). "Mad Rush On Beacon Hill Sends 4 Key Bills To Baker's Desk As Legislative Session Ends". wbur.org. Morning Edition – WBUR. Retrieved 24 September 2016. 46. ^ a b "Chapter 113". webserver.rilin.state.ri.us. Retrieved 24 September 2016. 47. ^ "Chapter 700c Health Insurance". ct.gov. Archived from the original on 10 October 2015. Retrieved 29 August 2015. 48. ^ Grann, David (2001-06-17). "Stalking Dr. Steere Over Lyme Disease". The New York Times Magazine. Archived from the original on 2 August 2009. Retrieved 2008-06-25. 49. ^ Abbott A (February 2006). "Lyme disease: uphill struggle". Nature. 439 (7076): 524–25. doi:10.1038/439524a. PMID 16452949. S2CID 4315588. 50. ^ Cooper, JD, Jr.; Feder, HM (December 2004). "Inaccurate information about lyme disease on the internet". Pediatr Infect Dis J. 23 (12): 11050–58. doi:10.1097/01.inf.0000145411.57449.f3 (inactive 2021-01-14). PMID 15626946.CS1 maint: DOI inactive as of January 2021 (link) 51. ^ "Film Focuses on Lyme Patients". The Washington Post. June 17, 2008. Retrieved September 12, 2008. 52. ^ Holden, Stephen (2009-06-19). "Ticked Off". The New York Times. Retrieved 2017-06-28. 53. ^ Gleiberman, Owen (20 November 2009). "Oscar documentary scandal: The real reason that too many good movies got left out". Entertainment Weekly. Retrieved 19 December 2017. ## External links[edit] * Dunning, Brian (March 10, 2020). "Skeptoid #718: Diagnosing Chronic Lyme Disease". Skeptoid. [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 inhibitors [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	Chronic Lyme disease	c3890422	2,922	wikipedia	https://en.wikipedia.org/wiki/Chronic_Lyme_disease	2021-01-18T18:38:19	{"mesh": ["D000077342"], "umls": ["C3890422"], "wikidata": ["Q17103401"]}
A rare, genetic, neuromuscular disease characterized by adult-onset muscle weakness and atrophy in a scapuloperoneal distribution, mild involvement of the facial muscles, dysphagia, and gynecomastia. Elevated serum CK levels and mixed myopathic and neurogenic abnormalities are associated clinical findings. [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 inhibitors [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	Neurogenic scapuloperoneal syndrome, Kaeser type	c1867005	2,923	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=85146	2021-01-23T18:38:13	{"gard": ["10312"], "mesh": ["C566695"], "omim": ["181400"], "umls": ["C1867005"], "icd-10": ["G12.1"], "synonyms": ["Kaeser syndrome", "Stark-Kaeser syndrome"]}
Nephronophthisis Nephronophthisis has an autosomal recessive pattern of inheritance. SpecialtyMedical genetics SymptomsPolyuria[1] TypesInfantile, Juvenile and Adult NPH[2] Diagnostic methodRenal ultrasound[2] TreatmentHypertension and anemia management[2] Nephronophthisis is a genetic disorder of the kidneys which affects children.[3] It is classified as a medullary cystic kidney disease. The disorder is inherited in an autosomal recessive fashion and, although rare, is the most common genetic cause of childhood kidney failure. It is a form of ciliopathy.[4] Its incidence has been estimated to be 0.9 cases per million people in the United States, and 1 in 50,000 births in Canada.[5] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Pathophysiology * 3.1 Related rare genetic disorders * 4 Diagnosis * 4.1 Types * 5 Management * 6 Epidemiology * 7 References * 8 Further reading * 9 External links ## Signs and symptoms[edit] Infantile, juvenile, and adolescent forms of nephronophthisis have been identified. Although the range of characterizations is broad, people affected by nephronophthisis typically present with polyuria (production of a large volume of urine), polydipsia (excessive liquid intake), and after several months to years, end-stage kidney disease, a condition necessitating either dialysis or a kidney transplant in order to survive.[1] Some individuals that suffer from nephronophthisis also have so-called "extra-renal symptoms" which can include tapetoretinal degeneration, liver problems, ocularmotor apraxia, and cone-shaped epiphysis (Saldino-Mainzer syndrome).[6][7] ## Cause[edit] Nephronophthisis is characterized by fibrosis and the formation of cysts at the cortico-medullary junction, it is an autosomal recessive disorder which eventually leads to terminal kidney failure.[8] ## Pathophysiology[edit] Ciliopathy (eukaryotic cilium diagram) Mechanism of nephronophthisis indicates that all proteins mutated in cystic kidney diseases express themselves in primary cilia. NPHP gene mutations cause defects in signaling resulting in flaws of planar cell polarity. The ciliary theory indicates that multiple organs are involved in NPHP (retinal degeneration, cerebellar hypoplasia, liver fibrosis, and intellectual disability).[9] ### Related rare genetic disorders[edit] Nephronophthisis is a ciliopathy. Other known ciliopathies include primary ciliary dyskinesia, Bardet–Biedl syndrome, polycystic kidney and liver disease, Alström syndrome, Meckel–Gruber syndrome and some forms of retinal degeneration.[10] NPHP2 is infantile type of nephropthisis and sometimes associated with situs inversus this can be explained by its relation with inversin gene. NPHP1, NPHP3, NPHP4, NPHP5, and NPHP6 are sometimes seen with retinitis pigmentosa, this particular association has a name, Senior-Loken syndrome.[11] ## Diagnosis[edit] Ultrasound The diagnosis of nephronophthisis can be obtained via a kidney ultrasound, family history and clinical history of the affected individual according to Stockman, et al.[2] ### Types[edit] * Infantile NPH[2] * Juvenile NPH[2] * Adult NPH[2] ## Management[edit] The management of this condition can be done via-improvement of any electrolyte imbalance, as well as, high blood pressure and low red blood cell counts (anemia) treatment as the individual's condition warrants.[2] ## Epidemiology[edit] Nephronophthisis occurs equally in both sexes and has an estimate 9 in about 8 million rate in individuals. Nephronophthisis is the leading monogenic cause of end-stage kidney disease.[12] ## References[edit] 1. ^ a b Hildebrandt, Friedhelm; Zhou, Weibin (2007). "Nephronophthisis-Associated Ciliopathies". Journal of the American Society of Nephrology. 18 (6): 1855–71. doi:10.1681/ASN.2006121344. PMID 17513324. 2. ^ a b c d e f g h Stokman, Marijn; Lilien, Marc; Knoers, Nine (1 January 1993). "Nephronophthisis". GeneReviews. Retrieved 1 August 2016.update 2016 3. ^ "Nephronophthisis". Genetics Home Reference. Retrieved 2015-08-08. 4. ^ Hurd TW, Hildebrandt F (2011). "Mechanisms of nephronophthisis and related ciliopathies". Nephron Exp. Nephrol. 118 (1): e9–e14. doi:10.1159/000320888. PMC 2992643. PMID 21071979. 5. ^ page 831, Chapter 35, in: Avner, Ellis D.; Harmon, William; Niaudet, Patrick; Yoshikawa, Norishige (2009-08-20). Pediatric Nephrology (Avner, Pediatric Nephrology). Springer. ISBN 978-3-540-76327-7. (stating the incidence in the United States as 9 per 8.3 million people. 6. ^ Kanwal, Kher (2007). Clinical Pediatric Nephrology, Second Edition (2nd ed.). McGraw-Hill. p. 205. ISBN 978-1-84184-447-3. Retrieved 9 August 2015. 7. ^ Medullary Cystic Disease~clinical at eMedicine 8. ^ Salomon, Rémi; Saunier, Sophie; Niaudet, Patrick (2009). "Nephronophthisis". Pediatric Nephrology. 24 (12): 2333–44. doi:10.1007/s00467-008-0840-z. PMC 2770134. PMID 18607645. 9. ^ Hildebrandt, Friedhelm; Attanasio, Massimo; Otto, Edgar (2009). "Nephronophthisis: Disease Mechanisms of a Ciliopathy". Journal of the American Society of Nephrology. 20 (1): 23–35. doi:10.1681/ASN.2008050456. PMC 2807379. PMID 19118152. 10. ^ McCormack, Francis X.; Panos, Ralph J.; Trapnell, Bruce C. (2010-03-10). Molecular Basis of Pulmonary Disease: Insights from Rare Lung Disorders. Springer Science & Business Media. ISBN 9781597453844. 11. ^ Badano, Jose L.; Mitsuma, Norimasa; Beales, Phil L.; Katsanis, Nicholas (2006). "The Ciliopathies: An Emerging Class of Human Genetic Disorders". Annual Review of Genomics and Human Genetics. 7: 125–48. doi:10.1146/annurev.genom.7.080505.115610. PMID 16722803. 12. ^ Hildebrandt, Friedhelm (2009). "Nephronophthisis". In Lifton, Richard P.; Somlo, Stefan; Giebisch, Gerhard H.; et al. (eds.). Genetic Diseases of the Kidney. Academic Press. pp. 425–46. ISBN 978-0-08-092427-4. ## Further reading[edit] * Simms, Roslyn J.; Hynes, Ann Marie; Eley, Lorraine; Sayer, John A. (2011). "Nephronophthisis: A Genetically Diverse Ciliopathy". International Journal of Nephrology. 2011: 1–10. doi:10.4061/2011/527137. PMC 3108105. PMID 21660307. * Hildebrandt, Friedhelm; Attanasio, Massimo; Otto, Edgar (2009-01-01). "Nephronophthisis: Disease Mechanisms of a Ciliopathy". Journal of the American Society of Nephrology. 20 (1): 23–35. doi:10.1681/ASN.2008050456. ISSN 1046-6673. PMC 2807379. PMID 19118152. * Murray, Karen F.; Larson, Anne M. (2010-07-23). Fibrocystic Diseases of the Liver. Springer Science & Business Media. ISBN 9781603275248. ## External links[edit] Classification D * ICD-10: Q61.8 * ICD-9-CM: 753.16 * OMIM: 256100 * DiseasesDB: 29224 External resources * Patient UK: Nephronophthisis Scholia has a topic profile for Nephronophthisis. * v * t * e Cystic diseases Respiratory system * Langerhans cell histiocytosis * Lymphangioleiomyomatosis * Cystic bronchiectasis Skin * stratified squamous: follicular infundibulum * Epidermoid cyst and Proliferating epidermoid cyst * Milia * Eruptive vellus hair cyst * outer root sheath * Trichilemmal cyst and Pilar cyst and Proliferating trichilemmal cyst and Malignant trichilemmal cyst * sebaceous duct * Steatocystoma multiplex and Steatocystoma simplex * Keratocyst * nonstratified squamous: Cutaneous ciliated cyst * Hidrocystoma * no epithelium: Pseudocyst of the auricle * Mucocele * other and ungrouped: Cutaneous columnar cyst * Keratin implantation cyst * Verrucous cyst * Adenoid cystic carcinoma * Breast cyst Human musculoskeletal system * Cystic hygroma Human digestive system * oral cavity: Cysts of the jaws * Odontogenic cyst * Periapical cyst * Dentigerous cyst * Odontogenic keratocyst * Nasopalatine duct cyst * liver: Polycystic liver disease * Congenital hepatic fibrosis * Peliosis hepatis * bile duct: Biliary hamartomas * Caroli disease * Choledochal cysts * Bile duct hamartoma Nervous system * Cystic leukoencephalopathy Genitourinary system * Polycystic kidney disease * Autosomal dominant polycystic kidney * Autosomal recessive polycystic kidney * Medullary cystic kidney disease * Nephronophthisis * Congenital cystic dysplasia Other conditions * Hydatid cyst * Von Hippel–Lindau disease * Tuberous sclerosis * 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 * v * t * e Diseases of cilia Structural * receptor: Polycystic kidney disease * cargo: Asphyxiating thoracic dysplasia * basal body: Bardet–Biedl syndrome * mitotic spindle: Meckel syndrome * centrosome: Joubert syndrome Signaling * Nephronophthisis Other/ungrouped * Alström syndrome * Primary ciliary dyskinesia * Senior–Løken syndrome * Orofaciodigital syndrome 1 * McKusick–Kaufman syndrome * Autosomal recessive polycystic kidney See also: ciliary proteins [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 inhibitors [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	Nephronophthisis	c0687120	2,924	wikipedia	https://en.wikipedia.org/wiki/Nephronophthisis	2021-01-18T18:37:21	{"gard": ["206"], "umls": ["C0687120"], "orphanet": ["655"], "wikidata": ["Q1257011"]}
Abandoned child syndrome SpecialtyPsychiatry Abandoned child syndrome is a proposed behavioral or psychological condition that results primarily from the loss of one or both parents, or sexual abuse. Abandonment may be physical (the parent is not present in the child's life) or emotional (the parent withholds affection, nurturing, or stimulation).[1] The abandoned child syndrome is not recognized as a mental disorder in any of the medical manuals, such as the ICD-10[2] or the DSM-IV,[3] neither is it part of the proposed revision of this manual, the DSM-5.[4] Parents who leave their children, or when a parent is alienated from their children by the other parent (after a bitter divorce, DCHS[clarification needed], foster care), can cause psychological damage to the child. This damage is reversible, but only with appropriate assistance.[5][better source needed] Abandoned children may also often suffer physical damage from neglect, malnutrition, starvation, and abuse.[6] ## Contents * 1 Signs and symptoms * 2 Causes * 3 See also * 4 Notes ## Signs and symptoms[edit] Symptoms may be physical or mental, and may extend into adulthood and perhaps throughout a person's life. * Alienation from the environment – withdrawal from social activities and resistance towards others.[citation needed] * Guilt – the child believes that they did something wrong that caused the abandonment (often associated with depression).[citation needed] * Fear and uncertainty – "clinginess" and insecurities.[7][better source needed] * Sleep and eating disorders – malnutrition, starvation, disturbed sleep and nightmares.[7][better source needed] * Physical ailments – fatigue, drug and alcohol abuse, anxiety, depression, lack of energy and creativity, anger, and grief.[7][better source needed] ## Causes[edit] When children are raised without the psychological or physical protection they need, they may internalize incredible fear. This is known as chronic loss. Not receiving the necessary psychological or physical protection results in abandonment. If children live with repeated abandonment, this creates experiences causes toxic shame. Shame arises from the painful message implied in abandonment: "You are not important. You are not of value." This is the pain from which people need to heal.[8][better source needed] ## See also[edit] * Reactive attachment disorder ## Notes[edit] 1. ^ Henley, Arthur. "The abandoned child." Deviancy and the family. Ed. Clifton D. Bryant and J. Gipson Wells. Philadelphia: F. A. Davis, 1973. 199-208. 2. ^ "ICD 10". Priory.com. 2007-02-10. Retrieved 2011-10-27. 3. ^ "BehaveNetŽ Clinical Capsule™: DSM-IV-TR Classification". Behavenet.com. Archived from the original on 2011-10-26. Retrieved 2011-10-27. 4. ^ "Disorders Usually First Diagnosed in Infancy, Childhood, or Adolescence \| APA DSM-5". Dsm5.org. Retrieved 2011-10-27. 5. ^ "Children Deprived of Parental Care". Human Rights Watch. 2006. Archived from the original on 2008-05-13. 6. ^ Golden, M. H.; Samuels, M. P.; Southall, D. P. (2003-02-01). "How to distinguish between neglect and deprivational abuse". Archives of Disease in Childhood. 88 (2): 105–107. doi:10.1136/adc.88.2.105. ISSN 0003-9888. PMC 1719417. PMID 12538306. 7. ^ a b c Myers, Linda Joy (2005). "Connecting the Past and the Present: Healing Abandonment and Abuse through Awareness" Archived 2014-11-01 at the Wayback Machine. 8. ^ "Archived copy". Archived from the original on 2014-01-31. Retrieved 2014-01-31.CS1 maint: archived copy as title (link) [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 inhibitors [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	Abandoned child syndrome	None	2,925	wikipedia	https://en.wikipedia.org/wiki/Abandoned_child_syndrome	2021-01-18T19:05:10	{"wikidata": ["Q4663376"]}
Alpha-methylacyl-CoA racemase (AMACR) deficiency is a disorder that causes a variety of neurological problems that begin in adulthood and slowly get worse. People with AMACR deficiency may have a gradual loss in intellectual functioning (cognitive decline), seizures, and migraines. They may also have acute episodes of brain dysfunction (encephalopathy) similar to stroke, involving altered consciousness and areas of damage (lesions) in the brain. Other features of AMACR deficiency may include weakness and loss of sensation in the limbs due to nerve damage (sensorimotor neuropathy), muscle stiffness (spasticity), and difficulty coordinating movements (ataxia). Vision problems caused by deterioration of the light-sensitive layer at the back of the eye (the retina) can also occur in this disorder. ## Frequency AMACR deficiency is a rare disorder. Its prevalence is unknown. At least 10 cases have been described in the medical literature. ## Causes AMACR deficiency is caused by mutations in the AMACR gene. This gene provides instructions for making an enzyme called alpha-methylacyl-CoA racemase (AMACR). The AMACR enzyme is found in the energy-producing centers in cells (mitochondria) and in cell structures called peroxisomes. Peroxisomes contain a variety of enzymes that break down many different substances, including fatty acids and certain toxic compounds. They are also important for the production (synthesis) of fats (lipids) used in digestion and in the nervous system. In peroxisomes, the AMACR enzyme plays a role in the breakdown of a fatty acid called pristanic acid, which comes from meat and dairy foods in the diet. In mitochondria, AMACR is thought to help further break down the molecules derived from pristanic acid. Most individuals with AMACR deficiency have an AMACR gene mutation that results in a lack (deficiency) of functional enzyme. The enzyme deficiency leads to accumulation of pristanic acid in the blood. However, it is unclear how this accumulation is related to the specific signs and symptoms of AMACR deficiency. ### Learn more about the gene associated with Alpha-methylacyl-CoA racemase deficiency * AMACR ## 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 inhibitors [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	Alpha-methylacyl-CoA racemase deficiency	c3280428	2,926	medlineplus	https://medlineplus.gov/genetics/condition/alpha-methylacyl-coa-racemase-deficiency/	2021-01-27T08:24:36	{"mesh": ["C565768"], "omim": ["614307"], "synonyms": []}
Abortion in Alaska is legal. 63% of adults said in a poll by the Pew Research Center that abortion should be legal in all or most cases. Alaska was one of only four states to make abortion legal between 1967 and 1970, a few years before the US Supreme Court's decision in 1973's Roe v. Wade ruling. Alaska had consent requirements for women seeking abortions by 2007 that required abortion providers to warn patients of a link between abortion and breast cancer, and to issue other scientifically unsupported warnings. A bill was introduced in 2017 that would have banned abortion in Alaska, but it never made it out of committee. The legislation co-sponsor Rep. David Eastman, R-Wasilla tried again in 2019. The number of abortion clinics in Alaska has been declining, going from fourteen in 1982 to thirteen in 1992 to three in 2014. 1,547 abortions took place in Alaska in 2014 and 1,459 took place in 2015. For poor women, there is state funding for abortions. Both abortion rights activists and anti-abortion rights activists are present in the state, and have held protests in 2019. ## Contents * 1 Terminology * 2 Context * 3 History * 3.1 Legislative history * 3.2 Judicial history * 3.3 Clinic history * 4 Statistics * 5 Abortion financing * 6 Women's abortion experiences * 7 Abortion rights views and activities * 7.1 Protests * 8 Anti-abortion views and activism * 8.1 Views * 8.2 Protests * 9 Footnotes * 10 References ## Terminology[edit] Main article: Abortion The abortion debate most commonly relates to the "induced abortion" of an embryo or fetus at some point in a pregnancy, which is also how the term is used in a legal sense.[note 1] Some also use the term "elective abortion", which is used in relation to a claim to an unrestricted right of a woman to an abortion, whether or not she chooses to have one. The term elective abortion or voluntary abortion describes the interruption of pregnancy before viability at the request of the woman, but not for medical reasons.[1] Anti-abortion advocates tend to use terms such as "unborn baby", "unborn child", or "pre-born child",[2][3] and see the medical terms "embryo", "zygote", and "fetus" as dehumanizing.[4][5] Both "pro-choice" and "pro-life" are examples of terms labeled as political framing: they are terms which purposely try to define their philosophies in the best possible light, while by definition attempting to describe their opposition in the worst possible light. "Pro-choice" implies that the alternative viewpoint is "anti-choice", while "pro-life" implies the alternative viewpoint is "pro-death" or "anti-life".[6] The Associated Press encourages journalists to use the terms "abortion rights" and "anti-abortion".[7] ## Context[edit] See also: Abortion in the United States Free birth control correlates to teenage girls having a fewer pregnancies and fewer abortions. A 2014 New England Journal of Medicine study found such a link. At the same time, a 2011 study by Center for Reproductive Rights and Ibis Reproductive Health also found that states with more abortion restrictions have higher rates of maternal death, higher rates of uninsured pregnant women, higher rates of infant and child deaths, higher rates of teen drug and alcohol abuse, and lower rates of cancer screening.[8] According to a 2017 report from the Center for Reproductive Rights and Ibis Reproductive Health, states that tried to pass additional constraints on a women's ability to access legal abortions had fewer policies supporting women's health, maternal health and children's health. These states also tended to resist expanding Medicaid, family leave, medical leave, and sex education in public schools.[9] According to Megan Donovan, a senior policy manager at the Guttmacher Institute, states have legislation seeking to protect a woman's right to access abortion services have the lowest rates of infant mortality in the United States.[9] Poor women in the United States had problems paying for menstrual pads and tampons in 2018 and 2019. Almost two-thirds of American women could not pay for them. These were not available through the federal Women, Infants, and Children Program (WIC).[10] Lack of menstrual supplies has an economic impact on poor women. A study in St. Louis found that 36% had to miss days of work because they lacked adequate menstrual hygiene supplies during their period. This was on top of the fact that many had other menstrual issues including bleeding, cramps and other menstrual induced health issues.[10] As of November 2018, states did not have a state sales tax and so menstrual items were not taxed.[11][12][13][14] ## History[edit] Alaska, California, and New Hampshire did not voluntarily provide the Center for Disease Control with abortion related data in 2000 or 2001.[15][16] In 2014, 63% of adults said in a poll by the Pew Research Center that abortion should be legal in all or most cases.[17] ### Legislative history[edit] Alaska, Hawaii, California and New York were the only four states that made abortion legal between 1967 and 1970 that did not require a reason to request an abortion.[18] In 1970, the state repealed some of its abortion laws along with Hawaii, New York, Alaska and Washington.[19] The following year, Alaska repealed its statute that said inducing an abortion was a criminal offense.[20] State law still required in 1971 that any woman getting a legal abortion in the state needed to be a resident for some specific period between 30 and 90 days.[20] Some states, such as Alaska, Mississippi, West Virginia, Texas, and Kansas, have passed laws requiring abortion providers to warn patients of a link between abortion and breast cancer, and to issue other scientifically unsupported warnings.[21][22] The state was one of 23 states in 2007 to have a detailed abortion-specific informed consent requirement.[23] Alaska and Minnesota both require that women seeking abortions after 20-weeks be informed that, while experts disagree on the issue of whether or not a fetus can feel pain at 20 weeks, it is possible. This expert confusion written into the law is there despite a Journal of the American Medical Association conclusion that pain sensors do not develop in the fetus until between weeks 23 and 30.[24] House Bill 250 was introduced 2017 by Rep. David Eastman, R-Wasilla. The bill was called the Life at Conception Act and it never made it out of committee in Alaska's House.[25] In 2017, Washington State, New Mexico, Illinois, Alaska, Maryland, Massachusetts, Connecticut, and New Jersey allow by state law qualified non-physicians to prescribe drugs for medical abortions only.[26] In May 2019, Rep. David Eastman, R-Wasilla introduced House Bill 178. It defines abortion as "murder of an unborn child." The bill will not be addressed until the Alaska Legislature reconvenes in January 2020.[needs update] House Health and Social Services Committee co-chair Rep. Ivy Spohnholz, D-Anchorage, said she had no interest in having the bill heard before her committee.[25][27] ### Judicial history[edit] The US Supreme Court's decision in 1973's Roe v. Wade ruling meant the state could no longer regulate abortion in the first trimester.[28] ### Clinic history[edit] Number of abortion clinics in Alaska by year. Between 1982 and 1992, the number of abortion clinics in the state decreased by 1, going from 14 in 1982 to 13 in 1992.[29] In 2014, there were 3 abortion clinics in the state.[30] 90% of the counties in the state did not have an abortion clinic. That year, 37% of women in the state aged 15 – 44 lived in a county without an abortion clinic.[31] In March 2016, there were 4 Planned Parenthood clinics in the state.[32] There were still 4 Planned Parenthood clinics the following year, all of which offered abortion services in a state with a population of 167,815 women aged 15 – 49.[33] ## Statistics[edit] In 1990, 69,000 women in the state faced the risk of an unintended pregnancy.[29] In 2013, among white women aged 15–19, there were abortions 130, 10 abortions for black women aged 15–19, 20 abortions for Hispanic women aged 15–19, and 70 abortions for women of all other races.[34] In 2017, the state had an infant mortality rate of 5.6 deaths per 1,000 live births.[9] Number of reported abortions, abortion rate and percentage change in rate by geographic region and state in 1992, 1995 and 1996[35] Census division and state Number Rate % change 1992–1996 1992 1995 1996 1992 1995 1996 US Total 1,528,930 1,363,690 1,365,730 25.9 22.9 22.9 –12 Pacific 368,040 290,520 288,190 38.7 30.5 30.1 –22 Alaska 2,370 1,990 2,040 16.5 14.2 14.6 –11 California 304,230 240,240 237,830 42.1 33.4 33 –22 Hawaii 12,190 7,510 6,930 46 29.3 27.3 –41 Oregon 16,060 15,590 15,050 23.9 22.6 21.6 –10 Washington 33,190 25,190 26,340 27.7 20.2 20.9 –24 Number, rate, and ratio of reported abortions, by reporting area of residence and occurrence and by percentage of abortions obtained by out-of-state residents, US CDC estimates Location Residence Occurrence % obtained by out-of-state residents Year Ref No. Rate^ Ratio^^ No. Rate^ Ratio^^ Alaska 1,990 16.5 1992 [35] Alaska 2,040 14.2 1995 [35] Alaska 16.5 14.6 1996 [35] Alaska 1,647 11.2 145 1,518 10.3 133 1.0 2014 [36] Alaska 1,459 10 129 1,334 9.1 118 0.5 2015 [37] Alaska 1,408 9.6 126 1,260 8.5 112 0.6 2016 [38] ^number of abortions per 1,000 women aged 15–44; ^^number of abortions per 1,000 live births ## Abortion financing[edit] 17 states including this one use their own funds to cover all or most "medically necessary" abortions sought by low-income women under Medicaid, 13 of which are required by State court orders to do so.[39][25] In 2010, the state had 835 publicly funded abortions, of which were zero federally and 835 were state funded.[40] ## Women's abortion experiences[edit] Anchorage's Angela Jenkins, said of her experience, "I got pregnant with my daughter when I was 20 years old. [...] I found myself in an abusive relationship. I faced a difficult decision, but what I decided was best for me and my child was to get an abortion. I couldn't imagine raising two children -- alone, or with this man."[27] ## Abortion rights views and activities[edit] ### Protests[edit] Women from the state participated in marches supporting abortion rights as part of a #StoptheBans movement in May 2019.[41][27] Hundreds of women attended a rally in Anchorage at Town Square Park to protest legislation proposed in Alaska's House to restrict abortion rights. The event was organized by Planned Parenthood Votes and Alaska ACLU.[27] There was another rally at the Alaska Capitol in Juneau in May 2019 in opposition to the bill proposed by Republican Rep. David Eastman of Wasilla.[42] ## Anti-abortion views and activism[edit] ### Views[edit] Rep. David Eastman, R-Wasilla was censored by the Alaska Legislature in 2017 after he said women used Medicaid support for abortion to a "free trip to the city".[25] ### Protests[edit] A small counter protest was organized by anti-abortion rights activists at the Alaska Capitol in Juneau in May 2019 in support of proposed restrictions on women's ability to access legal abortions in the state.[42] ## Footnotes[edit] 1. ^ According to the Supreme Court's decision in Roe v. Wade: > (a) For the stage prior to approximately the end of the first trimester, the abortion decision and its effectuation must be left to the medical judgement of the pregnant woman's attending physician. (b) For the stage subsequent to approximately the end of the first trimester, the State, in promoting its interest in the health of the mother, may, if it chooses, regulate the abortion procedure in ways that are reasonably related to maternal health. (c) For the stage subsequent to viability, the State in promoting its interest in the potentiality of human life may, if it chooses, regulate, and even proscribe, abortion except where it is necessary, in appropriate medical judgement, for the preservation of the life or health of the mother. Likewise, Black's Law Dictionary defines abortion as "knowing destruction" or "intentional expulsion or removal". ## References[edit] 1. ^ Watson, Katie (December 20, 2019). "Why We Should Stop Using the Term "Elective Abortion"". AMA Journal of Ethics. 20 (12): E1175-1180. doi:10.1001/amajethics.2018.1175. PMID 30585581. Retrieved May 17, 2019. 2. ^ Chamberlain, Pam; Hardisty, Jean (2007). "The Importance of the Political 'Framing' of Abortion". The Public Eye Magazine. 14 (1). 3. ^ "The Roberts Court Takes on Abortion". New York Times. November 5, 2006. Retrieved January 18, 2008. 4. ^ Brennan 'Dehumanizing the vulnerable' 2000 5. ^ Getek, Kathryn; Cunningham, Mark (February 1996). "A Sheep in Wolf's Clothing – Language and the Abortion Debate". Princeton Progressive Review. 6. ^ "Example of "anti-life" terminology" (PDF). Archived from the original (PDF) on July 27, 2011. Retrieved November 16, 2011. 7. ^ Goldstein, Norm, ed. The Associated Press Stylebook. Philadelphia: Basic Books, 2007. 8. ^ Castillo, Stephanie (October 3, 2014). "States With More Abortion Restrictions Hurt Women's Health, Increase Risk For Maternal Death". Medical Daily. Retrieved May 27, 2019. 9. ^ a b c "States pushing abortion bans have highest infant mortality rates". NBC News. Retrieved May 25, 2019. 10. ^ a b Mundell, E.J. (January 16, 2019). "Two-Thirds of Poor U.S. Women Can't Afford Menstrual Pads, Tampons: Study". US News & World Report. Retrieved May 26, 2019. 11. ^ Larimer, Sarah (January 8, 2016). "The 'tampon tax,' explained". The Washington Post. Archived from the original on December 11, 2016. Retrieved December 10, 2016. 12. ^ Bowerman, Mary (July 25, 2016). "The 'tampon tax' and what it means for you". USA Today. Archived from the original on December 11, 2016. Retrieved December 10, 2016. 13. ^ Hillin, Taryn. "These are the U.S. states that tax women for having periods". Splinter. Retrieved December 15, 2017. 14. ^ "Election Results 2018: Nevada Ballot Questions 1-6". KNTV. Retrieved November 7, 2018. 15. ^ "Abortion Surveillance --- United States, 2000". www.cdc.gov. Retrieved May 25, 2019. 16. ^ "Abortion Surveillance --- United States, 2001". www.cdc.gov. Retrieved May 25, 2019. 17. ^ "Views about abortion by state - Religion in America: U.S. Religious Data, Demographics and Statistics". Pew Research Center. Retrieved May 23, 2019. 18. ^ Willke, J.C. (September 1992). "Very few illegal abortion deaths". American Journal of Obstetrics and Gynecology. 167 (3): 854–5. doi:10.1016/s0002-9378(11)91601-9. ISSN 0002-9378. PMID 1530050. 19. ^ "Medicine: Abortion on Request". Time. March 9, 1970. Retrieved October 15, 2012. (subscription required) 20. ^ a b Reagan, Leslie J. (September 21, 1998). When Abortion Was a Crime: Women, Medicine, and Law in the United States, 1867–1973. University of California Press. ISBN 9780520216570. 21. ^ "Do abortions cause breast cancer? Kansas State House Abortion Act invokes shaky science for political gain". Slate Magazine. Retrieved June 28, 2015. 22. ^ "Misinformed Consent: The Medical Accuracy of State-Developed Abortion Counseling Materials". October 25, 2006. 23. ^ "State Policy On Informed Consent for Abortion" (PDF). Guttmacher Policy Review. Fall 2007. Retrieved May 22, 2019. 24. ^ "State Abortion Counseling Policies and the Fundamental Principles of Informed Consent". Guttmacher Institute. November 12, 2007. Retrieved May 22, 2019. 25. ^ a b c d McCarthy, Alex (May 17, 2019). "'Dangerous and outrageous': Bill introduced in Alaska House would treat abortion the same as murder". Juneau Empire. Retrieved May 23, 2019. 26. ^ "Study: Abortions Are Safe When Performed By Nurse Practitioners, Physician Assistants, Certified Nurse Midwives". Retrieved January 25, 2017. 27. ^ a b c d Minemyer, Derek. "Hundreds rally against House anti-abortion bill in Anchorage Saturday". www.ktuu.com. Retrieved May 27, 2019. 28. ^ Buell, Samuel (January 1, 1991). "Criminal Abortion Revisited". New York University Law Review. 66 (6): 1774–1831. PMID 11652642. 29. ^ a b Arndorfer, Elizabeth; Michael, Jodi; Moskowitz, Laura; Grant, Juli A.; Siebel, Liza (December 1998). A State-By-State Review of Abortion and Reproductive Rights. DIANE Publishing. ISBN 9780788174810. 30. ^ Gould, Rebecca Harrington, Skye. "The number of abortion clinics in the US has plunged in the last decade — here's how many are in each state". Business Insider. Retrieved May 23, 2019. 31. ^ businessinsider (August 4, 2018). "This is what could happen if Roe v. Wade fell". Business Insider (in Spanish). Retrieved May 24, 2019. 32. ^ Bohatch, Emily. "27 states with the most Planned Parenthood clinics". thestate. Retrieved May 24, 2019. 33. ^ "Here's Where Women Have Less Access to Planned Parenthood". Retrieved May 23, 2019. 34. ^ "No. of abortions among women aged 15–19, by state of residence, 2013 by racial group". Guttmacher Data Center. Retrieved May 24, 2019. 35. ^ a b c d "Abortion Incidence and Services in the United States, 1995-1996". Guttmacher Institute. June 15, 2005. Retrieved June 2, 2019. 36. ^ Jatlaoui, Tara C. (2017). "Abortion Surveillance — United States, 2014". MMWR. Surveillance Summaries. 66 (24): 1–48. doi:10.15585/mmwr.ss6624a1. ISSN 1546-0738. PMID 29166366. 37. ^ Jatlaoui, Tara C. (2018). "Abortion Surveillance — United States, 2015". MMWR. Surveillance Summaries. 67 (13): 1–45. doi:10.15585/mmwr.ss6713a1. ISSN 1546-0738. PMC 6289084. PMID 30462632. 38. ^ Jatlaoui, Tara C. (2019). "Abortion Surveillance — United States, 2016". MMWR. Surveillance Summaries. 68 (11): 1–41. doi:10.15585/mmwr.ss6811a1. ISSN 1546-0738. PMID 31774741. 39. ^ Francis Roberta W. "Frequently Asked Questions". Equal Rights Amendment. Alice Paul Institute. Archived from the original on April 17, 2009. Retrieved September 13, 2009. 40. ^ "Guttmacher Data Center". data.guttmacher.org. Retrieved May 24, 2019. 41. ^ Bacon, John. "Abortion rights supporters' voices thunder at #StopTheBans rallies across the nation". USA TODAY. Retrieved May 25, 2019. 42. ^ a b "Activists rally against abortion ban bill in Alaska". www.citynews1130.com. Retrieved May 27, 2019. Abortion in the United States by state States * Alabama * Alaska * Arizona * Arkansas * California * Colorado * Connecticut * Delaware * Florida * Georgia * Hawaii * Idaho * Illinois * Indiana * Iowa * Kansas * Kentucky * Louisiana * Maine * Maryland * Massachusetts * Michigan * Minnesota * Mississippi * Missouri * Montana * Nebraska * Nevada * New Hampshire * New Jersey * New Mexico * New York * North Carolina * North Dakota * Ohio * Oklahoma * Oregon * Pennsylvania * Rhode Island * South Carolina * South Dakota * Tennessee * Texas * Utah * Vermont * Virginia * Washington * West Virginia * Wisconsin * Wyoming Federal district Washington, D.C. Insular areas * American Samoa * Guam * Northern Mariana Islands * Puerto Rico * U.S. Virgin Islands [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 inhibitors [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	Abortion in Alaska	None	2,927	wikipedia	https://en.wikipedia.org/wiki/Abortion_in_Alaska	2021-01-18T18:30:22	{"wikidata": ["Q64876901"]}
Molar pregnancy is a condition in which the placenta does not develop properly. The symptoms of molar pregnancy, which may include vaginal bleeding, severe morning sickness, stomach cramps, and high blood pressure, typically begin around the 10th week of pregnancy. Because the embryo does not form or is malformed in molar pregnancies, and because there is a small risk of developing a cancer called choriocarcinoma, a D&C is usually performed. [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 inhibitors [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	Hydatidiform mole	c0020217	2,928	gard	https://rarediseases.info.nih.gov/diseases/10263/hydatidiform-mole	2021-01-18T17:59:57	{"mesh": ["D006828"], "orphanet": ["99927"], "synonyms": ["HYDM", "Hydatid mole", "Molar pregnancy"]}
A number sign (#) is used with this entry because autosomal recessive deafness-63 (DFNB63) is caused by homozygous mutation in the LRTOMT gene (612414) on chromosome 11q13. Clinical Features Tlili et al. (2006) reported a consanguineous 6-generation Tunisian family segregating autosomal recessive congenital hearing impairment. Audiometric testing of 7 affected individuals showed bilateral profound hearing impairment involving all frequencies, whereas 11 affected individuals had profound hearing loss affecting mainly mid to high frequencies. Kalay et al. (2007) reported a consanguineous 5-generation Turkish family (TR57) with bilateral prelingual sensorineural hearing loss and use of sign language for communication. There were no signs of vestibular dysfunction. Khan et al. (2007) reported 4 consanguineous Pakistani families in which deafness was linked to 11q13.2-q13.3. All affected individuals displayed congenital bilateral profound hearing loss. Vestibular function appeared to be normal, and clinical evaluation suggested no skin or renal anomalies. Funduscopic examinations revealed no retinitis pigmentosa. Mapping By genomewide linkage analysis of a Tunisian family with congenital hearing impairment, Tlili et al. (2006) identified a locus, termed DFNB63, on chromosome 11q13.3-q13.4 (maximum lod score of 5.33 at markers D11S916 and D11S4207). Haplotype analysis defined a 5.5-Mb critical region between D11S4136 and D11S4081. Screening of the SHANK2 (603290) and KCNE3 (604433) genes failed to reveal any pathogenic mutations. By genomewide linkage analysis of nonsyndromic deafness segregating in a consanguineous Pakistani family, Khan et al. (2007) identified the DFNB63 locus for congenital profound sensorineural hearing loss. Studies indicated linkage to 11q13.2-q13.3. Molecular Genetics In affected members of 4 unrelated families with autosomal recessive deafness-63, Ahmed et al. (2008) identified 4 different homozygous mutations in the LRTOMT gene (612414.0001-612414.0004). The families were of Turkish, Tunisian, and Pakistani origin. Some of the families had been reported by Kalay et al. (2007), Tlili et al. (2006), and Khan et al. (2007). Du et al. (2008) analyzed the LRTOMT gene in 192 unrelated congenitally deaf progeny of consanguineous Iranian parentage and identified homozygosity for a nonsense mutation in 1 family (612414.0005). INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Hearing loss, sensorineural, prelingual, severe to profound (affecting all frequencies) \- Downsloping audiogram \- No vestibular dysfunction Eyes \- Normal electroretinogram MISCELLANEOUS \- Congenital onset \- Hearing loss is nonprogressive MOLECULAR BASIS \- Caused by mutation in the leucine-rich transmembrane O-methyltransferase gene (LRTOMT, 612414.0001 ) ▲ 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 inhibitors [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	DEAFNESS, AUTOSOMAL RECESSIVE 63	c1969621	2,929	omim	https://www.omim.org/entry/611451	2019-09-22T16:03:22	{"doid": ["0110515"], "mesh": ["C566951"], "omim": ["611451"], "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"]}
"Shipping fever" redirects here. For a related family of diseases sometimes referred to as "shipping fever", see Pleuropneumonia. Bovine respiratory disease (BRD) is the most common and costly disease affecting beef cattle in the world.[1] It is a complex, bacterial infection that causes pneumonia in calves which can be fatal. The infection is usually a sum of three codependent factors: stress, an underlying viral infection, and a new bacterial infection.[2] The diagnosis of the disease is complex since there are multiple possible causes.[3] The disease manifests itself most often in calves within four weeks of weaning, when calves are sorted and often sold to different farms; a common nickname for BRD is "shipping fever."[4][a] It is not known whether the stress itself, co-mingling, or travel conditions are at most to blame, and while studies have identified general stressing factors like transport and cold weather conditions, there is still no conclusive evidence on more specific factors (e.g. distance, transport mode, temperature, or temperature volatility).[6] ## Contents * 1 Causes * 2 Clinical signs and diagnosis * 3 Treatment and control * 3.1 Vaccination * 3.2 Antibiotics * 3.3 Stress management * 4 See also * 5 Notes * 6 References ## Causes[edit] BRD is a "multi-factorial syndrome" that is dependent on a number of different causes.[7] The pathologic condition commonly arises where the causative organism becomes established by secondary infection, following a primary bacterial or viral infection, which may occur after stress, e.g. from handling or transport.[8] Usually all three of these factors must be present in order to cause BRD.[9] Viral agents are often present in the herd for an extended time, with almost no symptoms, and only cause severe complications with a bacterial infection.[7] The bacterial agents most commonly linked with BRD are Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis.[7] M. haemolytica serovar A1 is known as a particularly common bacterial cause of the disease.[10] Viral agents include Bovine viral diarrhea (BVD), Infectious Bovine Rhinotracheitis (IBR), Bovine respiratory syncytial virus (BRSV), and Parainfluenza type-3 virus (PI-3).[11] ## Clinical signs and diagnosis[edit] BRD often develops within 4 weeks of cattle transport.[11] The biggest sign of the pneumonia that BRD causes is depression, shown as droopy ears, dull eyes, and social isolation. Additionally, most cows will have a fever above 104 °F (40 °C).[12] Other symptoms include coughing, decreased appetite, and breathing difficulty.[9] ## Treatment and control[edit] Because of the number of possible viral/bacterial precursors to BRD, there are a number of treatment options circling around the three main aggravators of the disease: Viruses, Bacteria, and Stress. ### Vaccination[edit] Vaccinations exist for several biological BRD precursors, but the multitude of possible precursors complicates the process of choosing a vaccine regime.[9] Additionally, vaccines are not completely effective in stopping the disease, but are merely helpful in mitigation.[13] Many of the problems with vaccine effectiveness rest with improper use, such as failing to time vaccine doses appropriately, or not administering them before shipping.[14] Vaccines are available for a number of viral/bacterial agents, including IBR, PI3, BVD, BRSV, Pasteurella, and Haemophilus somnus.[9] Many of these vaccines can be given simultaneously, because of their similar dosing schedule. For example, IBR, PI3, BVD, and BRSV vaccines are often sold in combination with each other.[15] ### Antibiotics[edit] In the absence of vaccination (often because calves are bought unvaccinated), antibiotics can help to stop the bacterial factors of the disease. The Virginia Cooperative Extension recommends Micotil, Nuflor, and Baytril 100 as newer antibiotics that do not need daily dosing, but also notes that Naxcel, Excenel, and Adspec are effective as well.[12] ### Stress management[edit] Stress often serves as the final precursor to BRD. The diseases that make up BRD can persist in a cattle herd for a long period of time before becoming symptomatic, but immune systems weakened by stress can stop controlling the disease. Major sources of stress come from the shipping process[16] and from the co-mingling of cattle.[9] Weather may be another possible factor. Cases are more common in the fall (although this is the traditional time to sell cattle), and while the relationship between weather and BRD is poorly understood,[7] it is often suggested to avoid transporting cattle during extreme weather.[16] ## See also[edit] * Pneumonia (non-human) * Pasteurellosis ## Notes[edit] 1. ^ The name "shipping fever" is also sometimes used for related diseases affecting livestock including sheep, goats, and horses.[5] ## References[edit] 1. ^ Griffin, D (1997). "Economic impact associated with respiratory disease in beef cattle". Vet. Clin. North Am. Food Anim. Pract. 13: 367–77. doi:10.1016/s0749-0720(15)30302-9. PMID 9368983. 2. ^ Lillie, L. E. (1974). "The bovine respiratory disease complex". The Canadian Veterinary Journal. 15 (9): 233–42. PMC 1696627. PMID 4370742. 3. ^ Fulton, R. W.; Confer, A. W. (2012). "Laboratory test descriptions for bovine respiratory disease diagnosis and their strengths and weaknesses: Gold standards for diagnosis, do they exist?". The Canadian Veterinary Journal. 53 (7): 754–61. PMC 3377458. PMID 23277642. 4. ^ "The Latest On Shipping Fever". Beef Magazine. 2000-07-01. Retrieved 2017-12-13. 5. ^ "What is shipping fever?". Archived from the original on 15 June 2018. Retrieved 22 March 2018. 6. ^ Snowder, G. D.; Van Vleck, L. D.; Cundiff, L. V.; Bennett, G. L. (2006). "Bovine respiratory disease in feedlot cattle: Environmental, genetic, and economic factors". Journal of Animal Science. 84 (8): 1999–2008. doi:10.2527/jas.2006-046. PMID 16864858. 7. ^ a b c d Taylor, J. D.; Fulton, R. W.; Lehenbauer, T. W.; Step, D. L.; Confer, A. W. (2010). "The epidemiology of bovine respiratory disease: What is the evidence for predisposing factors?". The Canadian Veterinary Journal. 51 (10): 1095–102. PMC 2942046. PMID 21197200. 8. ^ Brogden KA, Lehmkuhl HD, Cutlip RC (1998). "Pasteurella haemolytica complicated respiratory infections in sheep and goats". Vet. Res. 29 (3–4): 233–54. PMID 9689740. 9. ^ a b c d e Bovine Respiratory Disease, Clell Bagley and the Utah State University Cooperative Extension. 10. ^ Zecchinon L, Fett T, Desmecht D (2005). "How Mannheimia haemolytica defeats host defence through a kiss of death mechanism". Vet. Res. 36 (2): 133–56. doi:10.1051/vetres:2004065. PMID 15720968. 11. ^ a b Bovine Respiratory Disease "Shipping Fever" in Cattle Archived April 4, 2015, at the Wayback Machine, Ram Kasimanickam / Washington State University Veterinary Medicine Extension, 2010 12. ^ a b Recognition and Treatment of Bovine Respiratory Disease Complex, John F. Currin and W. Dee Whittier / Virginia Cooperative Extension 13. ^ Vaccination to Control Bovine Respiratory Disease (Presentation) Archived 2016-03-04 at the Wayback Machine, Amelia R. Woolums 14. ^ Taylor, J. D.; Fulton, R. W.; Lehenbauer, T. W.; Step, D. L.; Confer, A. W. (2010). "The epidemiology of bovine respiratory disease: What is the evidence for preventive measures?". The Canadian Veterinary Journal. 51 (12): 1351–9. PMC 2978987. PMID 21358927. 15. ^ Bowland, S. L.; Shewen, P. E. (2000). "Bovine respiratory disease: Commercial vaccines currently available in Canada". The Canadian Veterinary Journal. 41 (1): 33–48. PMC 1476343. PMID 10642871. 16. ^ a b Management Approaches to Reduce Transportation Stress Risk for BRD, Washington State University Animal Science and Veterinary Medicine Extension [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 inhibitors [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	Bovine respiratory disease	None	2,930	wikipedia	https://en.wikipedia.org/wiki/Bovine_respiratory_disease	2021-01-18T18:34:07	{"wikidata": ["Q17115892"]}
Endometrioid tumor Histopathology of a well-differentiated endometrioid adenocarcinoma in the ovary SpecialtyOncology, gynecology Endometrioid tumors are a class of tumor characterized by a resemblance to endometrium/[1] endometrial carcinoma, and over a third of cases have focal squamous differentiation. ## Contents * 1 Ovary * 2 Endometrium * 3 Light microscopy * 4 Molecular biology * 4.1 CTNNB1 and PTEN mutations * 5 References * 6 External links ## Ovary[edit] Ovarian cancers in women aged 20+, with area representing relative incidence and color representing 5-year relative survival rate.[2] Endometrioid tumor is labeled at bottom left. They are part of the surface epithelial tumor group of ovarian neoplasms (10–20% of which are the endometrioid type). Benign and borderline variants are rare, as the majority are malignant. There is an association with endometriosis and concurrent primary endometrial carcinoma (endometrial cancer). On gross pathological examination, the tumor is cystic and may be solid and some arise in cystic endometriosis. In 40% of cases, endometrioid tumors are found bilaterally.[3] ## Endometrium[edit] Endometrioid carcinoma can also arise in the endometrium.[4][5] Grades 1 and 2 are considered "type 1" endometrial cancer, while grade 3 is considered "type 2".[6] * Relative incidences of endometrial carcinomas by histopathology, being endometrioid in a majority of cases.[7] ## Light microscopy[edit] Light microscopy shows tubular glands, resembling endometrium.[8] ## Molecular biology[edit] ### CTNNB1 and PTEN mutations[edit] Ovarian and endometrial endometrioid carcinomas have distinct CTNNB1 and PTEN gene mutation profiles. PTEN mutations are more frequent in low-grade endometrial endometrioid carcinomas (67%) compared with low-grade ovarian endometrioid carcinomas (17%). By contrast, CTNNB1 mutations are significantly different in low-grade ovarian endometrioid carcinomas (53%) compared with low-grade endometrial endometrioid carcinomas (28%). This difference in CTNNB1 mutation frequency may be reflective of the distinct tumoral microenvironments; the epithelial cells lining an endometriotic cyst within the ovary are exposed to a highly oxidative environment that promotes tumorigenesis.[9] ## References[edit] 1. ^ "Dorlands Medical Dictionary:endometrioid tumor".[permanent dead link] 2. ^ Kosary, Carol L. (2007). "Chapter 16: Cancers of the Ovary" (PDF). In Baguio, RNL; Young, JL; Keel, GE; Eisner, MP; Lin, YD; Horner, M-J (eds.). SEER Survival Monograph: Cancer Survival Among Adults: US SEER Program, 1988-2001, Patient and Tumor Characteristics. SEER Program. NIH Pub. No. 07-6215. Bethesda, MD: National Cancer Institute. pp. 133–144. 3. ^ Robbins; Cotran, eds. (2005). Pathologic Basis of Disease (7th ed.). Philadelphia: Saunders. ISBN 978-0-7216-0187-8. 4. ^ Mulvany NJ, Allen DG (January 2008). "Combined large cell neuroendocrine and endometrioid carcinoma of the endometrium". Int. J. Gynecol. Pathol. 27 (1): 49–57. doi:10.1097/pgp.0b013e31806219c5. PMID 18156975. 5. ^ Carcinoma,+Endometrioid at the US National Library of Medicine Medical Subject Headings (MeSH) 6. ^ "ACS :: What Is Endometrial Cancer?". Retrieved 2010-03-24. 7. ^ Mendivil, Alberto; Schuler, Kevin M.; Gehrig, Paola A. (2009). "Non-Endometrioid Adenocarcinoma of the Uterine Corpus: A Review of Selected Histological Subtypes". Cancer Control. 16 (1): 46–52. doi:10.1177/107327480901600107. ISSN 1073-2748. 8. ^ Shahrzad Ehdaivand. "Ovary tumor - Endometrioid tumors - General". Pathology Outlines. Topic Completed: 1 December 2012. Revised: 6 March 2020 9. ^ McConechy, M. K.; Ding, J; Senz, J; Yang, W; Melnyk, N; Tone, A. A.; Prentice, L. M.; Wiegand, K. C.; McAlpine, J. N.; Shah, S. P.; Lee, C. H.; Goodfellow, P. J.; Gilks, C. B.; Huntsman, D. G. (2014). "Ovarian and endometrial endometrioid carcinomas have distinct CTNNB1 and PTEN mutation profiles". Modern Pathology. 27 (1): 128–34. doi:10.1038/modpathol.2013.107. PMC 3915240. PMID 23765252. ## External links[edit] Classification D * ICD-O: 8380-8381 * MeSH: D018269 * v * t * e Glandular and epithelial cancer Epithelium Papilloma/carcinoma * Small-cell carcinoma * Combined small-cell carcinoma * Verrucous carcinoma * Squamous cell carcinoma * Basal-cell carcinoma * Transitional cell carcinoma * Inverted papilloma Complex epithelial * Warthin's tumor * Thymoma * Bartholin gland carcinoma Glands Adenomas/ adenocarcinomas Gastrointestinal * tract: Linitis plastica * Familial adenomatous polyposis * pancreas * Insulinoma * Glucagonoma * Gastrinoma * VIPoma * Somatostatinoma * Cholangiocarcinoma * Klatskin tumor * Hepatocellular adenoma/Hepatocellular carcinoma Urogenital * Renal cell carcinoma * Endometrioid tumor * Renal oncocytoma Endocrine * Prolactinoma * Multiple endocrine neoplasia * Adrenocortical adenoma/Adrenocortical carcinoma * Hürthle cell Other/multiple * Neuroendocrine tumor * Carcinoid * Adenoid cystic carcinoma * Oncocytoma * Clear-cell adenocarcinoma * Apudoma * Cylindroma * Papillary hidradenoma Adnexal and skin appendage * sweat gland * Hidrocystoma * Syringoma * Syringocystadenoma papilliferum Cystic, mucinous, and serous Cystic general * Cystadenoma/Cystadenocarcinoma Mucinous * Signet ring cell carcinoma * Krukenberg tumor * Mucinous cystadenoma / Mucinous cystadenocarcinoma * Pseudomyxoma peritonei * Mucoepidermoid carcinoma Serous * Ovarian serous cystadenoma / Pancreatic serous cystadenoma / Serous cystadenocarcinoma / Papillary serous cystadenocarcinoma Ductal, lobular, and medullary Ductal carcinoma * Mammary ductal carcinoma * Pancreatic ductal carcinoma * Comedocarcinoma * Paget's disease of the breast / Extramammary Paget's disease Lobular carcinoma * Lobular carcinoma in situ * Invasive lobular carcinoma Medullary carcinoma * Medullary carcinoma of the breast * Medullary thyroid cancer Acinar cell * Acinic cell carcinoma * v * t * e Tumors of the female urogenital system Adnexa Ovaries Glandular and epithelial/ surface epithelial- stromal tumor CMS: * Ovarian serous cystadenoma * Mucinous cystadenoma * Cystadenocarcinoma * Papillary serous cystadenocarcinoma * Krukenberg tumor * Endometrioid tumor * Clear-cell ovarian carcinoma * Brenner tumour Sex cord–gonadal stromal * Leydig cell tumour * Sertoli cell tumour * Sertoli–Leydig cell tumour * Thecoma * Granulosa cell tumour * Luteoma * Sex cord tumour with annular tubules Germ cell * Dysgerminoma * Nongerminomatous * Embryonal carcinoma * Endodermal sinus tumor * Gonadoblastoma * Teratoma/Struma ovarii * Choriocarcinoma Fibroma * Meigs' syndrome Fallopian tube * Adenomatoid tumor Uterus Myometrium * Uterine fibroids/leiomyoma * Leiomyosarcoma * Adenomyoma Endometrium * Endometrioid tumor * Uterine papillary serous carcinoma * Endometrial intraepithelial neoplasia * Uterine clear-cell carcinoma Cervix * Cervical intraepithelial neoplasia * Clear-cell carcinoma * SCC * Glassy cell carcinoma * Villoglandular adenocarcinoma Placenta * Choriocarcinoma * Gestational trophoblastic disease General * Uterine sarcoma * Mixed Müllerian tumor Vagina * Squamous-cell carcinoma of the vagina * Botryoid rhabdomyosarcoma * Clear-cell adenocarcinoma of the vagina * Vaginal intraepithelial neoplasia * Vaginal cysts Vulva * SCC * Melanoma * Papillary hidradenoma * Extramammary Paget's disease * Vulvar intraepithelial neoplasia * Bartholin gland carcinoma [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 inhibitors [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	Endometrioid tumor	c0474809	2,931	wikipedia	https://en.wikipedia.org/wiki/Endometrioid_tumor	2021-01-18T18:34:27	{"wikidata": ["Q5376366"]}
Moyamoya disease (MMD) is a rare intracranial arteriopathy involving progressive stenosis of the cerebral vasculature located at the base of the brain causing transient ischemic attacks or strokes. ## Epidemiology The incidence of MMD is highest in Asian populations but MMD occurs in many other ethnic groups. The incidence ranges from 1/280,000 to 1/89,000 in Japan and China to1/1,100,000 in the US. The prevalence in Japan is estimated to be 1/30,000-1/9,500. ## Clinical description There are two peak incidence ages: young children (5-9 years) and adults (mid-40s). Involvement is usually bilateral but unilateral cases are reported. Disease manifestations are highly variable. Some affected individuals remain asymptomatic, some develop transient attacks, and others severe neurologic deficits as a result of infarcts or hemorrhage. Hemorrhage occurs less often in children. Other manifestations include headache, dizziness, seizures, and chorea. Some patients present intellectual disability. The course is also highly variable but generally progressive. The term MMD is used when there is no cause and Moyamoya syndrome (MMS) when the disease is associated with other diseases (sickle cell anemia, neurofibromatosis; see these terms). ## Etiology The etiology of MMD is not currently known but is thought to be multifactorial with genetic determinants playing a role. In Japan, about 15% of patients have a family history. Mutations in the RNF213(17q25.3) gene have been found in some patients but their pathogenic role remains unclear. The intracranial vasculopathy associated with smooth muscle actin alpha 2 (ACTA2) (10q23.31) mutations has been referred to as MMS, but it has distinctive angiographic features, including dilatation of proximal ICAs, an abnormally straight course of intracranial arteries, and absence of typical moyamoya collateral vessels. ## Diagnostic methods The diagnosis of MMD may be difficult because it is rare and because of the non-characteristic signs and symptoms. Diagnosis is suspected on the basis of the clinical presentation and imaging findings. Cerebral angiography is the standard confirmatory diagnostic method. Moyamoya disease involves in particular the supraclinoid internal carotid arteries and their proximal branches. The term moyamoya means "puff of smoke" in Japanese, in reference to the appearance of abnormal vascular collateral networks on angiography that develop adjacent to the stenotic vessels. Magnetic resonance angiography (MRA) can also be used. ## Differential diagnosis MMD may develop in an isolated manner but can also be associated with other diseases when it is known as MMS: typical angiographic MMDfeatures associated with other diseases, e.g. sickle cell anemia, Down syndrome, neurofibromatosis type 1 (see these terms) and many others. ## Genetic counseling Autosomal dominant inheritance with incomplete penetrance has been described in affected Japanese families. Other suggested patterns include autosomal-recessive, X-linked-recessive, or multifactorial inheritance. ## Management and treatment No specific treatment to stop progression or reverse the intracranial arteriopathy is available for MMD. Drug therapy is mainly used to counter disease complications such as stroke and transient ischemic attacks, to alleviate symptoms, and to prevent cognitive deterioration. Physical, occupational and speech therapy may be needed after attacks. Surgical revascularization procedures to restore blood flow to the brain involving direct, indirect or combined techniques have also been used and appear to reduce the risk ofischemic stroke and possibly cognitive dysfunction. The indication and timing of surgery remains controversial. ## Prognosis Early detection and appropriate treatment improve the long-term outcome. The prognosis depends on disease severity. Mortality rates are estimated at about 5% for adults and 2% for children. The main cause of death is hemorrhage. [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 inhibitors [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	Moyamoya disease	c0026654	2,932	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2573	2021-01-23T18:16:24	{"gard": ["7064"], "mesh": ["D009072", "C536991"], "omim": ["252350", "607151", "608796", "614042"], "umls": ["C0026654", "C2931384"], "icd-10": ["I67.5"], "synonyms": ["Idiopathic Moyamoya disease"]}
Malonyl-CoA decarboxylase deficiency is a condition that prevents the body from converting certain fats to energy. The signs and symptoms of this disorder typically appear in early childhood. Almost all affected children have delayed development. Additional signs and symptoms can include weak muscle tone (hypotonia), seizures, diarrhea, vomiting, and low blood sugar (hypoglycemia). A heart condition called cardiomyopathy, which weakens and enlarges the heart muscle, is another common feature of malonyl-CoA decarboxylase deficiency. ## Frequency This condition is very rare; fewer than 30 cases have been reported. ## Causes Mutations in the MLYCD gene cause malonyl-CoA decarboxylase deficiency. The MLYCD gene provides instructions for making an enzyme called malonyl-CoA decarboxylase. Within cells, this enzyme helps regulate the formation and breakdown of a group of fats called fatty acids. Many tissues, including the heart muscle, use fatty acids as a major source of energy. Mutations in the MLYCD gene reduce or eliminate the function of malonyl-CoA decarboxylase. A shortage of this enzyme disrupts the normal balance of fatty acid formation and breakdown in the body. As a result, fatty acids cannot be converted to energy, which can lead to characteristic features of this disorder including low blood sugar and cardiomyopathy. Byproducts of fatty acid processing build up in tissues, which also contributes to the signs and symptoms of malonyl-CoA decarboxylase deficiency. ### Learn more about the gene associated with Malonyl-CoA decarboxylase deficiency * MLYCD ## 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 inhibitors [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	Malonyl-CoA decarboxylase deficiency	c0342793	2,933	medlineplus	https://medlineplus.gov/genetics/condition/malonyl-coa-decarboxylase-deficiency/	2021-01-27T08:25:27	{"gard": ["3371"], "mesh": ["C535702"], "omim": ["248360"], "synonyms": []}
Okihiro syndrome is a syndrome of multiple congenital anomalies and is characterized by ocular manifestations (uni- or bilateral Duane anomaly (95% of cases), congenital optic nerve hypoplasia or optic disc coloboma), bilateral deafness and radial ray malformation that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs; hypoplasia or aplasia of the radii; shortening and radial deviation of the forearms; triphalangeal thumbs; and duplication of the thumb (preaxial polydactyly).The phenotype overlaps with other SALL4>/i> related disorders including acro-renal-ocular syndrome and Holt-Oram syndrome (see these terms). Transmission is autosomal dominant. [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 inhibitors [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	Okihiro syndrome	c1623209	2,934	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93293	2021-01-23T18:13:11	{"gard": ["9182"], "mesh": ["D004370"], "omim": ["607323"], "umls": ["C1623209"], "icd-10": ["Q87.8"], "synonyms": ["Duane-radial ray syndrome"]}
A number sign (#) is used with this entry because of evidence that cleft palate, cardiac defects, and mental retardation (CPCMR) is caused by heterozygous mutation in the MEIS2 gene (601740) on chromosome 15q14. Clinical Features Percin et al. (1995) reported a family in which members in 3 generations showed various combinations of malformations: congenital heart defect (primum type atrial septal defect in 1 and Fallot pentalogy in another), cleft lip/palate, short stature, microcephaly, distally-placed thumbs, short second and fifth fingers, long and broad first toes, wide distance between first and second toes, and medial dorsal curvature of the fourth toes with syndactyly of the second and third toes. Whereas some members of the family had full signs of the syndrome, others had fewer and less severe anomalies of the same structures. One of the affected members of the family had an occult right cleft lip. Johansson et al. (2014) studied 5 patients from 4 families with deletions at chromosome 15q14 (see 616898), all involving the MEIS2 gene, as well as a family in which a mother and 3 children had an intragenic duplication in MEIS2. Overall, 7 of 9 patients had clefting, ranging from mild (submucous cleft palate) to severe (cleft lip and palate), and 3 of 9 had ventricular septal defects (VSDs). All patients had delayed motor development, and most had learning difficulties, at worst in the mild intellectual disability range. Affected individuals exhibited overlapping facial features, including broad forehead, finely arched eyebrows, mildly shortened philtrum, and tented upper lip, but individually they were not considered to be dysmorphic. Louw et al. (2015) described a 5-year-old girl with severely delayed motor development, moderate intellectual disability with poor speech, and multiple congenital malformations. She had cleft palate, congenital heart defects, including atrial septal defect (ASD), VSD, and aortic coarctation, and feeding problems due to gastroesophageal reflux, with oral aversion, aerophagia, and achalasia requiring gastrostomy and Botulinum neurotoxin A infiltrations. She also had mild distal skeletal anomalies, including broad first ray of hands and feet, a gap between the first and second toes, and syndactyly of the second and third toes. In addition, she had dysmorphic facial features, including arched and laterally extended eyebrows, mildly upslanting palpebral fissures, deeply set eyes, bitemporal narrowing, tented upper lip, thin upper vermilion, and full lower vermilion. Brain imaging was normal. Fujita et al. (2016) reported a 2.75-year-old French girl who had severe intellectual disability, cleft palate, ASD and VSD, and mild facial dysmorphism, including large forehead, mild trigonocephaly, sparse eyebrows, deeply set eyes, large and low-set ears, full cheeks, and thin upper vermilion. She had serious feeding difficulties with gastroesophageal reflux, requiring gastrostomy at 3 months. She also had moderate delay in motor development and severe hypermetropia. Inheritance Percin et al. (1995) suggested autosomal dominant inheritance for this disorder because of the involvement of 3 generations, variable expressivity, pleiotropism, and lack of consanguinity in the family. Molecular Genetics In a mother and 3 children with cleft palate and mildly delayed motor development and/or mild intellectual disability, Johansson et al. (2014) performed array-based genomic copy number analysis and identified heterozygosity for a 58-kb intragenic duplication in the MEIS2 gene (601740.0002). In a 5-year-old girl with cleft palate, congenital heart defects, severely delayed motor development, and moderate intellectual disability, Louw et al. (2015) identified a de novo heterozygous 3-bp in-frame deletion in the MEIS2 gene (601740.0001). In a 2.75-year-old French girl with cleft palate, atrial and ventricular septal defects, delayed motor development, and severe intellectual disability, Fujita et al. (2016) performed whole-exome sequencing and identified heterozygosity for a de novo nonsense mutation in the MEIS2 gene (S204X; 601740.0003). INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Large forehead \- Bitemporal narrowing \- High anterior hairline Ears \- Large, low-set ears Eyes \- Arched eyebrows \- Laterally extended eyebrows \- Sparse eyebrows \- Upslanting palpebral fissures \- Deep-set eyes \- Severe hypermetropia (in 1 patient) Mouth \- Cleft palate \- Tented upper lip \- Thin upper vermilion \- Full lower vermilion CARDIOVASCULAR Heart \- Atrial septal defect \- Ventricular septal defect \- Small left ventricular outflow tract without obstruction (in 1 patient) Vascular \- Coarctation of the aorta (in 1 patient) RESPIRATORY Lung \- Congenital lobar emphysema (in 1 patient) ABDOMEN Gastrointestinal \- Severe feeding problems \- Gastroesophageal reflux SKELETAL Hands \- Broad thumbs Feet \- Broad great toe \- Sandal gap \- Cutaneous syndactyly between second and third toes NEUROLOGIC Central Nervous System \- Learning disabilities \- Psychomotor retardation \- Intellectual disability, mild to severe Behavioral Psychiatric Manifestations \- Autism spectrum disorder (in 1 patient) MOLECULAR BASIS \- Caused by mutation in the Meis homeobox 2 (MEIS2, 601740.0001 ) ▲ 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 inhibitors [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	CLEFT PALATE, CARDIAC DEFECTS, AND MENTAL RETARDATION	c1832950	2,935	omim	https://www.omim.org/entry/600987	2019-09-22T16:15:32	{"mesh": ["C563414"], "omim": ["600987"], "synonyms": ["Alternative titles", "CARDIAC MALFORMATION, CLEFT LIP/PALATE, MICROCEPHALY, AND DIGITAL ANOMALIES"]}
A number sign (#) is used with this entry because Czech dysplasia is caused by heterozygous mutation in the COL2A1 gene (120140) on chromosome 12q13. Description Czech dysplasia is an autosomal dominant skeletal dysplasia characterized by early-onset, progressive pseudorheumatoid arthritis, platyspondyly, and short third and fourth toes (Marik et al., 2004; Kozlowski et al., 2004). Clinical Features Williams et al. (1993) described a family living in the Chiloe Islands, Chile, in which 7 members in 3 generations had spondyloepiphyseal dysplasia with shortened metacarpals and metatarsals, precocious osteoarthritis, and periarticular apatite-like calcific deposits. The proband was a 40-year-old woman with short fourth and fifth metatarsals and intermittent acute pain and swelling in her knees, ankles, and proximal interphalangeal joints since the age of 12 years. As a result of severe degenerative joint disease, she underwent total hip replacement at age 35; this was complicated by marked heterotopic periarticular calcification. Complete physical examination, anthropometric measurements, and radiographic studies of the spine and peripheral joints in 16 family members revealed that 7 had spondyloepiphyseal dysplasia tarda, brachydactyly, precocious osteoarthritis, and periarticular calcification, while 2 others had the same syndrome without brachydactyly (Reginato et al., 1994). Marik et al. (2004) and Kozlowski et al. (2004) described a dominantly inherited progressive pseudorheumatoid dysplasia that could be distinguished from progressive pseudorheumatoid arthropathy of childhood (PPAC; 208230), the disorder first reported by Spranger et al. (1980), by dominant inheritance and the unique phenotypic feature of hypoplasia/dysplasia of 1 or 2 toes. They reported a total of 7 patients originating from different parts of the Czech Republic. Kozlowski et al. (2004) suggested that the disorder be designated Czech dysplasia, metatarsal type. In the family reported by Marik et al. (2004) in which 4 affected individuals were studied, weather-dependent articular pain was characteristic. This feature was absent in the patients described by Kozlowski et al. (2004). The abnormality of the toes was due to short third and fourth metatarsals. The patients were normal adult height. As outlined by Kozlowski et al. (2004), skeletal abnormalities were located predominantly in the spine, pelvis, hips, and feet. They included mild platyspondyly with irregularity of the vertebral plates, narrowing of the joint and intervertebral disc spaces, rectangular shape of the lumbar spinal canal in the anteroposterior projection, and dysplasia of the pelvis, hips, and proximal femora. Tzschach et al. (2008) described a large German family in which 11 members had Czech dysplasia. In addition to typical features of the disorder, all 11 had hearing loss starting in early adulthood. They noted that hearing deficits had been reported in 2 other families with Czech dysplasia (Bleasel et al., 1995; Lopponen et al., 2004) and suggested that hearing loss be added to the major features of the disorder. Matsui et al. (2009) reported a Japanese family in which a father, daughter, and son had features consistent with Czech dysplasia, including normal height, joint pain in childhood with limited joint mobility, and short toes. The 37-year-old father had already undergone hip replacement. All 3 patients had sensorineural hearing loss. Radiography revealed platyspondyly, irregular vertebral endplates, osteoarthritis, osteochondromatosis, and short metacarpals and metatarsals. In addition, valgus knee, a feature not previously described in Czech dysplasia, was present in all 3 patients. Matsui et al. (2009) stated that this was the first report of a non-European family with Czech dysplasia. Molecular Genetics In affected members of a Chilean family with spondyloepiphyseal dysplasia with shortened metacarpals and metatarsals, precocious osteoarthritis, and periarticular apatite-like calcific deposits, Williams et al. (1993) identified heterozygosity for an arg75-to-cys (R75C) mutation in the COL2A1 gene (120140.0018). (The R75C mutation has also been designated R275C based on a different numbering system.) Hoornaert et al. (2007) noted phenotypic similarities between patients with Czech dysplasia and patients with the COL2A1 R75C mutation. They performed targeted sequencing of exon 13 of the COL2A1 (120140) gene in patients with Czech dysplasia and identified heterozygosity for the R75C mutation in 2 of the 4 original patients described with Czech dysplasia (case I in Marik et al. (2004) and affected mother of case II in Kozlowski et al. (2004)). The R75C mutation was also found in 3 additional patients. All 5 affected individuals had normal height, spondyloarthropathy, and short postaxial toes. Three individuals had osteochondromatosis of the knee. In all affected members of a large German family with Czech dysplasia, Tzschach et al. (2008) identified the R75C mutation resulting from an 823C-T transition in the COL2A1 gene. In 3 affected individuals from a Japanese family with Czech dysplasia, Matsui et al. (2009) identified heterozygosity for the R75C mutation in the COL2A1 gene (120140.0018). INHERITANCE \- Autosomal dominant GROWTH Height \- Normal stature SKELETAL Spine \- Mild platyspondyly \- Irregular vertebral endplates \- Narrow intervertebral disc spaces \- Rectangular lumbar spinal canal \- Accentuated thoracic kyphosis \- Scoliosis \- Elongated vertebrae Pelvis \- Coxa vara \- Irregular, sclerotic acetabulae \- Flattened capital femoral epiphyses \- Narrow iliac wings \- Narrow, short femoral neck \- Prominent trochanter \- Flexion contractures (hip) Limbs \- Arthralgia \- Flexion contractures (knee) \- Osteochondromatosis (knee) Hands \- Short metacarpals (4th-5th) Feet \- Hypoplastic or dysplastic toes (3rd, 4th, and 5th) \- Hypoplastic metatarsals (3rd and 4th) MISCELLANEOUS \- Onset of joint pain in childhood \- Waddling gait \- Hip replacement in early adulthood MOLECULAR BASIS \- Caused by mutation in the collagen II, alpha-1 polypeptide gene (COL2A1, 120140.0018 ) ▲ 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 inhibitors [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	CZECH DYSPLASIA	c1836683	2,936	omim	https://www.omim.org/entry/609162	2019-09-22T16:06:34	{"mesh": ["C535766"], "omim": ["609162"], "orphanet": ["137678"], "synonyms": ["Alternative titles", "CZECH DYSPLASIA, METATARSAL TYPE", "PSEUDORHEUMATOID DYSPLASIA, PROGRESSIVE, WITH HYPOPLASTIC TOES", "SPONDYLOEPIPHYSEAL DYSPLASIA WITH PRECOCIOUS OSTEOARTHRITIS"]}
Contrast-induced nephropathy Other namesCIN SpecialtyNephrology Contrast-induced nephropathy (CIN) is a form of kidney damage in which there has been recent exposure to medical imaging contrast material without another clear cause for the acute kidney injury. CIN is classically defined as a serum creatinine increase of at least 25% and/or an absolute increase in serum creatinine of 0.5 mg/dL[1] after using iodine contrast agent without another clear cause for acute kidney injury,[2] but other definitions have also been used.[3] Despite extensive speculation, the actual occurrence of contrast-induced nephropathy has not been demonstrated in the literature.[4] The mechanism of contrast-induced nephropathy is not entirely understood, but is thought to include direct damage from reactive oxygen species, contrast-induced increase in urine output, increased oxygen consumption, changes in dilation and narrowing of the blood vessels to the kidneys, and changes in urine viscosity.[citation needed] Analysis of observational studies has shown that radiocontrast use in CT scanning is not causally related to changes in kidney function.[3] Given the increasing doubts about the contribution of radiocontrast to acute kidney injury, the American College of Radiology has proposed the name postcontrast acute kidney injury which does not imply a causal role, with CIN reserved for the rare cases where radiocontrast is likely to be causally related.[3][5] ## Contents * 1 Risk factors * 1.1 Decreased kidney function * 1.2 Roxana Mehran score * 1.3 Other factors * 2 Prevention * 2.1 Dose adjustment * 2.2 Treating or mitigating risk factors * 3 Research directions * 4 Clinical relevance * 5 References * 6 External links ## Risk factors[edit] There are multiple risk factors of contrast-induced nephropathy, whereof a review in 2016 emphasized chronic kidney disease, diabetes mellitus, high blood pressure, reduced intravascular volume, and old age.[2] ### Decreased kidney function[edit] European guidelines classify a pre-existing decreased kidney function to be a risk factor of contrast-induced nephropathy in the following cases:[6] * Estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73 m2 of body surface area before intra-arterial administration with first-pass renal exposure (not passing lungs or peripheral circulation before kidneys), or in the intensive care unit * eGFR < 30 ml/min/1.73 m2 before intravenous administration or intra-arterial administration with second-pass renal exposure * Known or suspected acute kidney injury To calculate estimated GFR from creatinine, European guidelines use the CKD-EPI formula in adults ≥ 18 years, and the revised Schwartz formula in children.[6] Swedish guidelines recommends no specific formula in children because of lack of evidence, but on the other hand recommends GFR based on cystatin C rather than creatinine in those with abnormal muscle mass or liver failure or cirrhosis.[6] ### Roxana Mehran score[edit] The Roxana Mehran score is a clinical prediction rule to estimate probability of nephropathy (increase ≥25% and/or ≥0.5 mg/dl in serum creatinine at 48 h):[7][8] Risk Factors: * Systolic blood pressure <80 mm Hg - 5 points (if systolic BP less than 80 mmHg for at least one hour requiring inotropic support) * Intra-arterial balloon pump - 5 points * Congestive heart failure, counting as NYHA class III (marked limitation in activity due to symptoms, even during less-than-ordinary activity) or worse, or history of pulmonary edema \- 5 points * Age >75 y - 4 points * Hematocrit level <39% for men and <35% for women - 3 points * Diabetes mellitus- 3 points * Contrast media volume - 1 point for each 100 mL * Decreased kidney function: * Serum creatinine level >1.5 g/dL - 4 points or * * Estimated Glomerular filtration rate (online calculator) * * 2 for 40–60 mL/min/1.73 m2 * 4 for 20–40 mL/min/1.73 m2 * 6 for < 20 mL/min/1.73 m2 Scoring: 5 or less points * Risk of CIN - 7.5 * Risk of Dialysis - 0.04% 6–10 points * Risk of CIN - 14.0 * Risk of Dialysis - 0.12% 11–16 points * Risk of CIN - 26.1* * Risk of Dialysis - 1.09% >16 points * Risk of CIN - 57.3 * Risk of Dialysis - 12.8% ### Other factors[edit] European guidelines include the following procedure-related risk factors:[6] * Large doses of contrast given intra-arterially with first-pass renal exposure * Use of contrast agents with high osmolality (limited use today) * Multiple contrast injections within 48-72 h. At least Swedish guidelines also include gadolinium MRI contrast agents in this aspect. Swedish guidelines list the following additional risk factors:[6] * Hypoxia * Cirrhosis * NSAID or nephrotoxic medication * Individuals on dialysis with residual renal function of at least 400 ml urine/24h * Individuals having undergone kidney transplantation ## Prevention[edit] In case of low glomerular filtration rate (GFR), the procedure depends on whether the dose that can be given is larger or less than the needed dose. The main alternatives in people with a risk of contrast-induced nephropathy are: * Adjustment of the radiocontrast dose * Treating or mitigating risk factors * Using no intravenous contrast for the investigation. * Switching to another modality such as ultrasonography or MRI. ### Dose adjustment[edit] According to European guidelines, the ratio of the contrast dose (in grams of iodine) divided by the absolute estimated glomerular filtration rate (GFR) should be less than 1.1 g/(ml/min) for intra-arterial contrast medium administration with first-pass renal exposure (not passing lungs or peripheral tissue before reaching the kidneys).[6] Swedish guidelines are more restrictive, recommending a ratio of less than 0.5 g/(ml/min) in patients with risk factors and irrespective of route of administration, and even more caution in first-pass renal exposure.[6] ### Treating or mitigating risk factors[edit] Hydration by drinking or intravenous volume expander, either before or after contrast administration, decreases the risk of contrast-induced nephropathy.[9] Evidence also supports the use of N-acetylcysteine with intravenous saline among those getting low molecular weight contrast.[dubious – discuss] The use of statins with N-acetylcysteine and intravenous saline is also supported.[10] * Oral hydration may be as effective as the intravenous route for volume expansion to prevent contrast-induced nephropathy, according to a review in 2013.[9] * Adenosine antagonists such as the methylxanthines theophylline and aminophylline, may help[11] although studies have conflicting results.[12] * N-acetylcysteine (NAC) by mouth twice a day, on the day before and of the procedure if creatinine clearance is estimated to be less than 60 mL/min [1.00 mL/s]) may reduce risk.[medical citation needed] Some authors believe the benefit is not overwhelming.[13] A systematic review concluded that NAC is "likely to be beneficial" but did not recommend a specific dose.[14][needs update] * Ascorbic acid may be protective against CIN, according to a systematic review of randomized controlled trials.[15] ## Research directions[edit] While there are currently no FDA-approved therapies for contrast-induced nephropathy, two therapies are currently being investigated. CorMedix is currently in the latter part of phase II clinical trials with approved phase III Special Protocol Assessment for CRMD001 (unique formulation Deferiprone) to prevent contrast-induced acute kidney injury and to slow progression of chronic kidney disease. Dosing trials began in June 2010 in the sixty patient trial.[16][17] There is also a phase III clinical trial of RenalGuard Therapy to prevent contrast-induced nephropathy.[18] The therapy utilizes the RenalGuard System, which measures a person's urine output and infuses an equal volume of normal saline in real-time. The therapy involves connecting the person to the RenalGuard System, then injecting a low dose of the loop diuretic furosemide to induce high urine output rates.[19] A number of studies have reported the ability of RenalGuard to protect patients from CIN following catheterization procedures when compared to the standard of care, including: MYTHOS, which found RenalGuard to be superior to overnight hydration;[20] REMEDIAL II, which found RenalGuard to be superior to sodium bicarbonate hydration;[21] Protect-TAVI, which reported a significant reduction in post-procedural acute kidney injury (AKI) following transcatheter aortic valve replacement (TAVR) when using RenalGuard during the procedure, compared to standard therapy;[22] and AKIGUARD, which showed significant improvement in long-term outcomes when using RenalGuard vs. standard therapy.[23] Two meta-analysis of these results (Putzu[24] and Mattathil[25]) found RenalGuard consistently reduced kidney injury, dialysis, adverse events and mortality compared to standard therapy. ## Clinical relevance[edit] Recently, doubts regarding the significance of the phenomenon appeared in the scientific literature. Several studies have shown that Intravenous contrast material administration was not associated with excess risk of acute kidney injury (AKI), dialysis, or death, even among patients with comorbidities reported to predispose them to nephrotoxicity.[4] Moreover, hydration, the most established prevention measure to prevent contrast induced nephropathy was shown to be ineffective in the POSEIDON trial,[26] raising further doubts regarding the significance of this disease state.[27] A meta-analysis of 28 studies of AKI after CT with radiocontrast showed no causal relationship between the use of radiocontrast and AKI.[3] ## References[edit] 1. ^ Barrett BJ, Parfrey PS (2006). "Clinical practice. Preventing nephropathy induced by contrast medium". N. Engl. J. Med. 354 (4): 379–86. doi:10.1056/NEJMcp050801. PMID 16436769. 2. ^ a b Subramaniam, RM; Suarez-Cuervo, C; Wilson, RF; Turban, S; Zhang, A; Sherrod, C; Aboagye, J; Eng, J; Choi, MJ; Hutfless, S; Bass, EB (February 2016). "Effectiveness of Prevention Strategies for Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis". Annals of Internal Medicine. 164 (6): 406–16. doi:10.7326/M15-1456. PMID 26830221. 3. ^ a b c d Aycock, Ryan D.; Westafer, Lauren M.; Boxen, Jennifer L.; Majlesi, Nima; Schoenfeld, Elizabeth M.; Bannuru, Raveendhara R. (August 2017). "Acute Kidney Injury After Computed Tomography: A Meta-analysis". Annals of Emergency Medicine. 71 (1): 44–53.e4. doi:10.1016/j.annemergmed.2017.06.041. PMID 28811122. S2CID 27167779. 4. ^ a b McDonald, Robert; McDonald, Jennifer S.; Carter, Rickey E.; Hartman, Robert P.; Katzberg, Richard W.; Kallmes, David F.; Williamson, Eric E. (December 2014). "Intravenous Contrast Material Exposure Is Not an Independent Risk Factor for Dialysis or Mortality". Radiology. 273 (3): 714–725. doi:10.1148/radiol.14132418. PMID 25203000. 5. ^ Ellis, JH; Davenport, MS; Dillman, JR; Hartman, RP; Herts, BR; Jafri, SZ; Kolbe, AB; Laroia, A; Cohan, RH; MacDonald, RJ; Needleman, L; Newhouse, JH; Pahade, JK; Sirlin, CB; Wang, CL; Wasserman, N; Weinreb, JC (2017). ACR Manual on Contrast Media. American College of Radiology. pp. 35–46. ISBN 978-1-55903-012-0. Retrieved 24 October 2017. 6. ^ a b c d e f g Nyman, Ulf; Ahlkvist, Joanna; Aspelin, Peter; Brismar, Torkel; Frid, Anders; Hellström, Mikael; Liss, Per; Sterner, Gunnar; Leander, Peter (2018). "Preventing contrast medium-induced acute kidney injury". European Radiology. 28 (12): 5384–5395. doi:10.1007/s00330-018-5678-6. ISSN 0938-7994. PMID 30132106. S2CID 52057355. 7. ^ Mehran R, Aymong ED, Nikolsky E, et al. (2004). "A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation". J. Am. Coll. Cardiol. 44 (7): 1393–9. doi:10.1016/j.jacc.2004.06.068. PMID 15464318. 8. ^ Kalgi Modi, Scott C. Dulebohn (2017). Contrast-Induced Nephropathy. StatPearls Publishing. StatPearls Publishing. CC-BY-4.0 9. ^ a b Yang, Xiaoming; Hiremath, Swapnil; Akbari, Ayub; Shabana, Wael; Fergusson, Dean A.; Knoll, Greg A. (2013). "Prevention of Contrast-Induced Acute Kidney Injury: Is Simple Oral Hydration Similar To Intravenous? A Systematic Review of the Evidence". PLOS ONE. 8 (3): e60009. Bibcode:2013PLoSO...860009H. doi:10.1371/journal.pone.0060009. ISSN 1932-6203. PMC 3608617. PMID 23555863. 10. ^ Subramaniam, RM; Suarez-Cuervo, C; Wilson, RF; Turban, S; Zhang, A; Sherrod, C; Aboagye, J; Eng, J; Choi, MJ; Hutfless, S; Bass, EB (15 March 2016). "Effectiveness of Prevention Strategies for Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis". Annals of Internal Medicine. 164 (6): 406–16. doi:10.7326/m15-1456. PMID 26830221. 11. ^ Sinert R, Doty CI (2007). "Evidence-based emergency medicine review. Prevention of contrast-induced nephropathy in the emergency department". Annals of Emergency Medicine. 50 (3): 335–45, 345.e1–2. doi:10.1016/j.annemergmed.2007.01.023. PMID 17512638. 12. ^ Bagshaw SM, Ghali WA (2005). "Theophylline for prevention of contrast-induced nephropathy: a systematic review and meta-analysis". Arch. Intern. Med. 165 (10): 1087–93. doi:10.1001/archinte.165.10.1087. PMID 15911721. 13. ^ Gleeson TG, Bulugahapitiya S (2004). "Contrast-induced nephropathy". AJR Am J Roentgenol. 183 (6): 1673–89. doi:10.2214/ajr.183.6.01831673. PMID 15547209. 14. ^ Kellum J, Leblanc M, Venkataraman R (2006). "Renal failure (acute)". Clinical Evidence (15): 1191–212. PMID 16973048. 15. ^ Sadat U, Usman A, Gillard JH, Boyle JR (2013). "Does ascorbic acid protect against contrast-induced acute kidney injury in patients undergoing coronary angiography: a systematic review with meta-analysis of randomized, controlled trials". J Am Coll Cardiol. 62 (23): 2167–75. doi:10.1016/j.jacc.2013.07.065. PMID 23994417. 16. ^ "Archived copy". Archived from the original on 2010-12-17. Retrieved 2010-12-14.CS1 maint: archived copy as title (link), CorMedix June 25, 2010 Press Release, "CorMedix Doses First Patient in Phase II Clinical Trial of CRMD-001" 17. ^ "Deferiprone for the Prevention of Contrast-Induced Acute Kidney Injury". ClinicalTrials.gov. 18. ^ [1], ClinicalTrials.gov,"Evaluation of RenalGuard® System to Reduce the Incidence of Contrast Induced Nephropathy in At-Risk Patients (CIN-RG)" 19. ^ Marenzi, Giancarlo; Bartorelli, A (2012). "Prevention of Contrast Nephropathy by Furosemide With Matched Hydration". J Am Coll Cardiol Intv. 5 (1): 90–97. doi:10.1016/j.jcin.2011.08.017. PMID 22230154. 20. ^ Marenzi, Giancarlo; Ferrari, Cristina; Marana, Ivana; Assanelli, Emilio; Metrio, Monica De; Teruzzi, Giovanni; Veglia, Fabrizio; Fabbiocchi, Franco; Montorsi, Piero (2012). "Prevention of Contrast Nephropathy by Furosemide With Matched Hydration". JACC: Cardiovascular Interventions. 5 (1): 90–97. doi:10.1016/j.jcin.2011.08.017. PMID 22230154. 21. ^ Briguori, Carlo; Visconti, Gabriella; Focaccio, Amelia; Airoldi, Flavio; Valgimigli, Marco; Sangiorgi, Giuseppe Massimo; Golia, Bruno; Ricciardelli, Bruno; Condorelli, Gerolama (2011-09-13). "Renal Insufficiency After Contrast Media Administration Trial II (REMEDIAL II)Clinical Perspective: RenalGuard System in High-Risk Patients for Contrast-Induced Acute Kidney Injury". Circulation. 124 (11): 1260–1269. doi:10.1161/CIRCULATIONAHA.111.030759. ISSN 0009-7322. PMID 21844075. 22. ^ Barbanti, Marco; Gulino, Simona; Capranzano, Piera; Immè, Sebastiano; Sgroi, Carmelo; Tamburino, Claudia; Ohno, Yohei; Attizzani, Guilherme F.; Patanè, Martina (2015). "Acute Kidney Injury With the RenalGuard System in Patients Undergoing Transcatheter Aortic Valve Replacement". JACC: Cardiovascular Interventions. 8 (12): 1595–1604. doi:10.1016/j.jcin.2015.07.012. PMID 26386766. 23. ^ Usmiani, Tullio; Andreis, Alessandro; Budano, Carlo; Sbarra, Pierluigi; Andriani, Monica; Garrone, Paolo; Fanelli, Anna Laura; Calcagnile, Chiara; Bergamasco, Laura (2016). "AKIGUARD (Acute Kidney Injury GUARding Device) trial". Journal of Cardiovascular Medicine. 17 (7): 530–537. doi:10.2459/jcm.0000000000000348. PMID 26702595. S2CID 23952871. 24. ^ Putzu, Alessandro; Berto, Martina Boscolo; Belletti, Alessandro; Pasotti, Elena; Cassina, Tiziano; Moccetti, Tiziano; Pedrazzini, Giovanni (2017). "Prevention of Contrast-Induced Acute Kidney Injury by Furosemide With Matched Hydration in Patients Undergoing Interventional Procedures". JACC: Cardiovascular Interventions. 10 (4): 355–363. doi:10.1016/j.jcin.2016.11.006. PMID 28231903. 25. ^ Mattathil, Stephanie; Ghumman, Saad; Weinerman, Jonathan; Prasad, Anand (2017-10-01). "Use of the RenalGuard system to prevent contrast-induced AKI: A meta-analysis". Journal of Interventional Cardiology. 30 (5): 480–487. doi:10.1111/joic.12417. ISSN 1540-8183. PMID 28870002. S2CID 27646564. 26. ^ Brar, Somjot S.; Aharonian, Vicken; Mansukhani, Prakash; Moore, Naing; Shen, Albert Y.-J.; Jorgensen, Michael; Dua, Aman; Short, Lindsay; Kane, Kevin (2014-05-24). "Haemodynamic-guided fluid administration for the prevention of contrast-induced acute kidney injury: the POSEIDON randomised controlled trial". Lancet. 383 (9931): 1814–1823. doi:10.1016/S0140-6736(14)60689-9. ISSN 1474-547X. PMID 24856027. S2CID 7882106. 27. ^ "Medscape". www.medscape.com. Retrieved 2017-09-28. ## External links[edit] Classification D * ICD-10: N99.0 * ICD-9-CM: 586 * v * t * e Kidney disease Glomerular disease * See Template:Glomerular disease Tubules * Renal tubular acidosis * proximal * distal * Acute tubular necrosis * Genetic * Fanconi syndrome * Bartter syndrome * Gitelman syndrome * Liddle's syndrome Interstitium * Interstitial nephritis * Pyelonephritis * Balkan endemic nephropathy Vascular * Renal artery stenosis * Renal ischemia * Hypertensive nephropathy * Renovascular hypertension * Renal cortical necrosis General syndromes * Nephritis * Nephrosis * Renal failure * Acute renal failure * Chronic kidney disease * Uremia Other * Analgesic nephropathy * Renal osteodystrophy * Nephroptosis * Abderhalden–Kaufmann–Lignac syndrome * Diabetes insipidus * Nephrogenic * Renal papilla * Renal papillary necrosis * Major calyx/pelvis * Hydronephrosis * Pyonephrosis * Reflux nephropathy [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 inhibitors [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	Contrast-induced nephropathy	c4055183	2,937	wikipedia	https://en.wikipedia.org/wiki/Contrast-induced_nephropathy	2021-01-18T18:58:16	{"umls": ["C4055183"], "icd-9": ["586"], "icd-10": ["N14.1"], "wikidata": ["Q1783300"]}
This article has multiple issues. Please help improve it or discuss these issues on the talk page. (Learn how and when to remove these template messages) This article needs attention from an expert on the subject. Please add a reason or a talk parameter to this template to explain the issue with the article. When placing this tag, consider associating this request with a WikiProject. (April 2014) This article may be too technical for most readers to understand. Please help improve it to make it understandable to non-experts, without removing the technical details. (April 2014) (Learn how and when to remove this template message) This article's tone or style may not reflect the encyclopedic tone used on Wikipedia. See Wikipedia's guide to writing better articles for suggestions. (April 2014) (Learn how and when to remove this template message) (Learn how and when to remove this template message) Langer mesomelic dysplasia SpecialtyMedical genetics Langer mesomelic dysplasia (LMD) is a rare congenital disorder characterized by an altered bone formation that causes a severe short and disproportionate stature. ## Contents * 1 Signs and symptoms * 2 Pathogenesis * 3 Diagnosis * 3.1 Classification * 4 Treatment * 4.1 Prognosis * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] Clinically and radiologically the disease is characterized by severe shortening of long bones (limb's both proximal and median segments are affected), aplasia or severe hypoplasia of ulna and fibula, thickened and curved radius and tibia. These anomalies can cause deformities of the hands and feet. Hypoplasia of the mandible can also be present. ## Pathogenesis[edit] At the core of the disorder there is a homozygous or compound heterozygous mutation or deletion of the SHOX (Short Stature Homeobox), SHOXY (Short Stature Homeobox Y-linked) or PAR1 (where SHOX enhancer elements are located) genes, which is inherited in a pseudosomal recessive manner. ## Diagnosis[edit] Diagnosis may be suspected on the basis of the clinical and radiologic findings, and can supported by molecular analysis of the SHOX, SHOXY and PAR1 genes. May also be suspected by ultrasound during the second trimester of gestation. ### Classification[edit] It's part of the mesomelic and rhizomelic skeletal dysplasias, primary bone diseases in which the short stature is due to a lack of complete bone development of the limb's long bones. It's strictly related to another disease, the Léri–Weill dyschondrosteosis, of which it seems to be the homozygothic variant, clinically more severe (it differs from this disorder for the absence, in some cases, of the Madelung deformity too). ## Treatment[edit] There is no known cure. In selected patients orthopaedic surgery may be helpful to try to gain some functionality of severely impaired joints. ### Prognosis[edit] Life expectancy is normal. ## See also[edit] * Osteochondrodysplasia ## References[edit] ## External links[edit] Classification D * ICD-10: Q87.1 * OMIM: 249700 * MeSH: C537267 [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 inhibitors [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	Langer mesomelic dysplasia	c0432230	2,938	wikipedia	https://en.wikipedia.org/wiki/Langer_mesomelic_dysplasia	2021-01-18T18:35:48	{"gard": ["3553"], "mesh": ["C537267"], "umls": ["C0432230"], "icd-10": ["Q87.1"], "orphanet": ["2632"], "wikidata": ["Q16550087"]}
Vascular tumor A hemangioma, a benign type of vascular tumor SpecialtyOncology A vascular tumor is a tumor of vascular origin; a soft tissue growth that can be either benign or malignant, formed from blood vessels or lymph vessels.[1] Examples of vascular tumors include hemangiomas, lymphangiomas, hemangioendotheliomas, Kaposi's sarcomas, angiosarcomas, and hemangioblastomas. An angioma refers to any type of benign vascular tumor.[2] Some vascular tumors can be associated with serious blood-clotting disorders, making correct diagnosis critical.[3] A vascular tumor may be described in terms of being highly vascularized, or poorly vascularized, referring to the degree of blood supply to the tumor. ## Contents * 1 Classification * 2 Types * 2.1 Benign * 2.1.1 Infantile hemangioma * 2.1.2 Congenital hemangioma * 2.1.3 Hemangioblastoma * 2.1.4 Pyogenic granuloma * 2.1.5 Tufted angioma * 2.2 Borderline * 2.3 Malignant * 3 References ## Classification[edit] Vascular tumors make up one of the classifications of vascular anomalies. The other grouping is vascular malformations. Vascular tumors can be further subclassified as being benign, borderline or aggressive, and malignant. Vascular tumors are described as proliferative, and vascular malformations as nonproliferative.[4] ## Types[edit] A pyogenic granuloma on a thumb. A vascular tumor typically grows quickly by the proliferation of endothelial cells. Most are not birth defects.[4] ### Benign[edit] The most common type of benign vascular tumors are hemangiomas, most commonly infantile hemangiomas, and less commonly congenital hemangiomas. #### Infantile hemangioma[edit] Main article: Infantile hemangioma Infantile hemangiomas are the most common type of vascular tumor to affect babies,[4] accounting for 90% of hemangiomas.[5] They are characterised by the abnormal proliferation of endothelial cells and of deviant blood vessel formation or architecture.[6] Hypoxic stress seems to be a major trigger for this.[7] Infantile hemangiomas are easily diagnosed, and little if any aggressive treatment is needed.[7] They are characterised by rapid growth in the first few months, followed by spontaneous regression in early childhood.[5] #### Congenital hemangioma[edit] Congenital hemangiomas are present and fully formed at birth,[5] and only account for 2% of the hemangiomas. They do not have the postnatal phase of proliferation common to infantile hemangiomas.[6] There are two main variants of congenital hemangioma: non-involuting, and rapidly involuting (beginning in the first year of life).[6] A third variant is also recognised as partially involuting.[8] Congenital hemangiomas can also be distinguished from infantile hemangiomas in that neither variant of congenital hemangioma expresses the glucose transporter GLUT 1.[6][9] Some cases have been associated with a mild form of thrombocytopenia. Rare cases have been associated with heart failure.[6] #### Hemangioblastoma[edit] Main article: Hemangioblastoma Hemangioblastomas are vascular tumors of the central nervous system. #### Pyogenic granuloma[edit] A range of benign vascular tumors are described as reactive proliferative lesions that grow in response to a stimulus, such as trauma, or a local thrombosis. They can also form infrequently during pregnancy as a hormonal reaction affecting the gums.[10] The most common type of reactive proliferative tumors are pyogenic granulomas also known as lobular capillary hemangiomas, that are more often found in children and young adults.[4] These granulomas are well defined growths of less than a centimetre across. They are bright red due to being highly vascularised, and bleed and ulcerate easily.[10] Their colouring fades with age.[4] #### Tufted angioma[edit] Tufted angiomas are hereditary hemangiomas found in infants from birth to five years of age, however they may occur in adults. They are found on the neck, shoulders, and trunk as rounded nodules.[11] Tufted angiomas are usually poorly defined lesions of purple colouration.[12] The tumors are of tufts of capillary-sized vessels in lobules that are scattered in the skin, and that sometimes reach into the subcutaneous tissue, and have lymph vessels on the periphery. Their growth is slow to begin with, and progresses to a stable size. They show a high rate of spontaneous regression, particularly in congenital and early-onset cases.[12] They typically have a deep nodular component sometimes extending into the subcutaneous tissue, fascia, and muscle, and can sometimes be painful.[12] Tufted angiomas are associated with arteriovenous malformations.[12] The origin of tufted angiomas is not clear but markers on the cells suggest a possible derivation from the endothelial cells of lymph vessels.[11] They are also associated with the local secretion of growth factors that affect angiogenesis and promote the development of vascular lobules.[12] ### Borderline[edit] Main article: Hemangioendothelioma Kaposiform hemangioendothelioma Kaposiform hemangioendotheliomas (KHEs) are borderline, locally destructive vascular tumors.[4] They are named after their resemblance to the lesions of Kaposi's sarcoma.[13] KHEs are described as locally destructive because they can infiltrate underlying muscle and fat.[4] They are often seen to overlap with tufted angiomas (TAs) but TAs may be a milder, benign counterpart.[14] KHEs show as a red or purple expanding mass of soft tissue,[14] found mostly in infants. Under the microscope KHE is characterised by nodules of tumor-like spindled endothelial cells.[14] Unlike infantile hemangiomas, KHEs have a high mortality rate.[14] Both KHEs and TAs are unique in that they carry the risk of the development of Kasabach–Merritt syndrome.[15] ### Malignant[edit] Malignant vascular tumors are rare,[7] and include angiosarcomas, and epithelioid hemangioendotheliomas.[4] Other types are hemangiopericytomas,[16] and lymphangiosarcomas. ## References[edit] 1. ^ "NCI Dictionary of Cancer Terms". National Cancer Institute. 2 February 2011. Retrieved 15 November 2019. 2. ^ "Dorlands Medical Dictionary:angioma". 2 February 2009. Archived from the original on 2 February 2009. 3. ^ Johnson, EF; Davis, DM; Tollefson, MM; Fritchie, K; Gibson, LE (April 2018). "Vascular Tumors in Infants: Case Report and Review of Clinical, Histopathologic, and Immunohistochemical Characteristics of Infantile Hemangioma, Pyogenic Granuloma, Noninvoluting Congenital Hemangioma, Tufted Angioma, and Kaposiform Hemangioendothelioma". The American Journal of Dermatopathology. 40 (4): 231–239. doi:10.1097/DAD.0000000000000983. PMID 29561329. 4. ^ a b c d e f g h Steiner, JE; Drolet, BA (September 2017). "Classification of Vascular Anomalies: An Update". Seminars in Interventional Radiology. 34 (3): 225–232. doi:10.1055/s-0037-1604295. PMC 5615389. PMID 28955111. 5. ^ a b c Sadick, M; Müller-Wille, R; Wildgruber, M; Wohlgemuth, WA (September 2018). "Vascular Anomalies (Part I): Classification and Diagnostics of Vascular Anomalies". RoFo : Fortschritte Auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin. 190 (9): 825–835. doi:10.1055/a-0620-8925. PMID 29874693. 6. ^ a b c d e Darrow, DH; Greene, AK; Mancini, AJ; Nopper, AJ; SECTION ON DERMATOLOGY, SECTION ON OTOLARYNGOLOGY–HEAD AND NECK SURGERY, and SECTION ON PLASTIC, SURGERY. (October 2015). "Diagnosis and Management of Infantile Hemangioma". Pediatrics. 136 (4): e1060-104. doi:10.1542/peds.2015-2485. PMID 26416931.CS1 maint: multiple names: authors list (link) 7. ^ a b c Wildgruber, M; Sadick, M; Müller-Wille, R; Wohlgemuth, WA (13 March 2019). "Vascular tumors in infants and adolescents". Insights into Imaging. 10 (1): 30. doi:10.1186/s13244-019-0718-6. PMC 6419671. PMID 30868300. 8. ^ "Congenital haemangioma". www.gosh.nhs.uk. 9. ^ van Vugt, LJ; van der Vleuten, CJM; Flucke, U; Blokx, WAM (June 2017). "The utility of GLUT1 as a diagnostic marker in cutaneous vascular anomalies: A review of literature and recommendations for daily practice". Pathology, Research and Practice. 213 (6): 591–597. doi:10.1016/j.prp.2017.04.023. PMID 28552538. 10. ^ a b Kumar, V; Abbas, A; Aster, J (2018). Robbins basic pathology (Tenth ed.). pp. 392–396. ISBN 9780323353175. 11. ^ a b "MeSH Browser". meshb.nlm.nih.gov. Retrieved 22 November 2019. 12. ^ a b c d e Victoria Martínez, AM; Cubells Sánchez, L; Esteve Martínez, A; Estela Cubells, JR; Febrer Bosch, I; Alegre de Miquel, V; Oliver Martínez, V (September 2015). "[Tufted angiomas in childhood: A series of 9 cases and a literature review]". Anales de Pediatria (Barcelona, Spain : 2003). 83 (3): 201–8. doi:10.1016/j.anpedi.2014.10.018. PMID 25468452. 13. ^ Vivas-Colmenares, GV; Ramirez-Villar, GL; Bernabeu-Wittel, J; Matute de Cardenas, JA; Fernandez-Pineda, I (January 2015). "The importance of early diagnosis and treatment of kaposiform hemangioendothelioma complicated by Kasabach-Merritt phenomenon". Dermatology Practical & Conceptual. 5 (1): 91–3. doi:10.5826/dpc.0501a18. PMC 4325701. PMID 25692091. 14. ^ a b c d Putra, J; Gupta, A (June 2017). "Kaposiform haemangioendothelioma: a review with emphasis on histological differential diagnosis". Pathology. 49 (4): 356–362. doi:10.1016/j.pathol.2017.03.001. PMID 28438388. 15. ^ Croteau, SE; Gupta, D (September 2016). "The clinical spectrum of kaposiform hemangioendothelioma and tufted angioma". Seminars in Cutaneous Medicine and Surgery. 35 (3): 147–52. doi:10.12788/j.sder.2016.048. PMID 27607323. 16. ^ Ghose, A; Guha, G; Kundu, R; Tew, J; Chaudhary, R (June 2017). "CNS Hemangiopericytoma: A Systematic Review of 523 Patients". American Journal of Clinical Oncology. 40 (3): 223–227. doi:10.1097/COC.0000000000000146. PMID 25350465. * v * t * e Tumours of blood vessels Blood vessel * Hemangiosarcoma * Blue rubber bleb nevus syndrome * Hemangioendothelioma * Composite * Endovascular papillary * Epithelioid * Kaposiform * Infantile * Retiform) * Spindle cell * Proliferating angioendotheliomatosis * Hemangiopericytoma * Venous lake * Kaposi's sarcoma * African cutaneous * African lymphadenopathic * AIDS-associated * Classic * Immunosuppression-associated * Hemangioblastoma * Hemangioma * Capillary * Cavernous * Glomeruloid * Microvenular * Targeted hemosiderotic * Angioma * Cherry * Seriginosum * Spider * Tufted * Universal angiomatosis * Angiokeratoma * of Mibelli * Angiolipoma * Pyogenic granuloma Lymphatic * Lymphangioma/lymphangiosarcoma * Lymphangioma circumscriptum * Acquired progressive lymphangioma * PEComa * Lymphangioleiomyomatosis * Cystic hygroma * Multifocal lymphangioendotheliomatosis * Lymphangiomatosis Either * Angioma/angiosarcoma * Angiofibroma [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 inhibitors [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	Vascular tumor	c0282607	2,939	wikipedia	https://en.wikipedia.org/wiki/Vascular_tumor	2021-01-18T19:02:45	{"mesh": ["D019043"], "umls": ["C0282607", "C0027668"], "orphanet": ["211237"], "wikidata": ["Q25422732"]}
Not to be confused with Homothorax. Blood accumulation in the pleural cavity Hemothorax Other namesHaemothorax Haemorrhagic pleural effusion Chest X-ray showing left sided hemothorax (arrowed) SpecialtyPulmonology SymptomsChest pain Difficulty breathing ComplicationsEmpyema Fibrothorax TypesTraumatic Spontaneous CausesTrauma Cancer Endometriosis Diagnostic methodChest X-ray Ultrasound CT scan MRI Thoracentesis TreatmentTube thoracostomy Thoracotomy Fibrinolytic therapy MedicationStreptokinase Urokinase PrognosisFavorable with treatment Frequency300,000 cases in the US per year [1] A hemothorax (derived from hemo- [blood] + thorax [chest], plural hemothoraces) is an accumulation of blood within the pleural cavity. The symptoms of a hemothorax may include chest pain and difficulty breathing, while the clinical signs may include reduced breath sounds on the affected side and a rapid heart rate. Hemothoraces are usually caused by an injury, but they may occur spontaneously due to cancer invading the pleural cavity, as a result of a blood clotting disorder, as an unusual manifestation of endometriosis, in response to a collapsed lung, or rarely in association with other conditions. Hemothoraces are usually diagnosed using a chest X-ray, but they can be identified using other forms of imaging including ultrasound, a CT scan, or an MRI. They can be differentiated from other forms of fluid within the pleural cavity by analysing a sample of the fluid, and are defined as having a hematocrit of greater than 50% that of the person's blood. Hemothoraces may be treated by draining the blood using a chest tube. Surgery may be required if the bleeding continues. If treated, the prognosis is usually good. Complications of a hemothorax include infection within the pleural cavity and the formation of scar tissue. ## Contents * 1 Background * 2 Signs and symptoms * 3 Causes * 3.1 Traumatic * 3.2 Iatrogenic * 3.3 Nontraumatic * 3.3.1 Vascular * 3.3.2 Catamenial * 4 Mechanism * 5 Diagnosis * 5.1 Chest X-ray * 5.2 Other methods * 5.3 Thoracentesis * 6 Treatment * 6.1 Thoracostomy * 6.2 Surgery * 6.3 Other * 7 Prognosis * 7.1 Complications * 8 Epidemology * 9 Other animals * 9.1 Horses * 10 See also * 11 References * 12 External links ## Background[edit] Main article: Pleural cavity The thoracic cavity is a chamber within the chest, containing the lungs, heart, and numerous major blood vessels. Thin sheets of tissue known as the pleural membranes or pleura line the chest and cover the lungs – the chest wall is lined by the parietal pleura, while the visceral pleura covers the outside of the lungs. The visceral and parietal pleura are normally separated by only a thin layer of fluid, forming the pleural cavity.[2] ## Signs and symptoms[edit] The symptoms of a hemothorax depend on the quantity of blood that has been lost into the pleural cavity. A small hemothorax usually causes little in the way of symptoms, while larger hemothoraces commonly cause chest pain, breathlessness, and occasionally lightheadedness. Other symptoms may occur in association with a hemothorax depending on the underlying cause.[3] The clinical signs of a hemothorax include reduced or absent breath sounds and reduced movement of the chest wall on the affected side.[3] When the affected side is tapped or percussed, a dull sound may be heard in contrast to the usual resonant note.[4] Large hemothoraces that interfere with the ability to transfer oxygen may cause a blue tinge to the lips (cyanosis).In these cases the body may try to compensate for the loss of blood, leading to a rapid heart rate (tachycardia), and pale, cool, clammy skin. Massive hemothorax, often defined as over 1.5 liters of blood initially when an intercostal drain is placed, or a bleeding rate greater than .2 liters/hr, can result in shock with two causes: massive bleeding resulting from hypovolemic shock, and venous pressure from the retained blood, impairing blood flow.[5] ## Causes[edit] Hemothoraces are classified in three broad categories according to the cause and in order of frequency: traumatic, iatrogenic, or nontraumatic.[6] ### Traumatic[edit] A hemothorax is most often caused by blunt or penetrating thoracic trauma. These cases are referred to traumatic hemothoraces.[6] Even relatively minor chest injuries can lead to significant hemothoraces, especially when the blood's ability to clot is diminished as result either of anticoagulant medications or when there are bleeding disorders such as hemophilia.[7] Injuries often cause the rupture of small blood vessels such as those found between the ribs. However, if larger blood vessels such as the aorta are damaged, the blood loss can be massive.[8] ### Iatrogenic[edit] Iatrogenic hemothorax can occur as a complication of heart and lung surgery, for example the rupture of lung arteries caused by the placement of catheters,[1] or thoracentesis. It can also be caused by other procedures like pleural, lung, or transbronchial biopsies, CPR, or endoscopic treatment of esophageal varices.[9] ### Nontraumatic[edit] Less frequently, hemothoraces may occur spontaneously. Significant hemothoraces can occur with spontaneous rupture of small vessels when the blood's ability to clot is diminished as result of anticoagulant medications.[7] Nontraumatic hemothoraces most frequently occur as a complication of some forms of cancer[9] if the tumour invades the pleural space.[10] Tumours responsible for hemothoraces include angiosarcomas, schwannomas, mesothelioma, and lung cancer.[7] Those with an abnormal accumulation of air within the pleural space (a pneumothorax) can bleed into the cavity, which occurs in about 5% of cases of spontaneous pneumothorax.[7] The resulting combination of air and blood within the pleural space is known as a hemopneumothorax.[11] Bone growth in exostosis can create sharp edges, which can result in hemothorax by damaging adjacent arteries. It can also occur postpartum due to the change in thoracic pressure during labor.[12] #### Vascular[edit] Vascular causes of hemothorax often include rupture of the descending aorta, in which case it initially involves the left pleural and mediastinal area due to the close vicinity of the pleural cavity. Rarely, a rupture of the thoracic aorta can result in a hemothorax, but the bleeding usually occurs in the pericardial space.[13] Spontaneous tearing of blood vessels is more likely to occur in those with disorders that weaken blood vessels such as some forms of Ehlers-Danlos syndrome, disorders that lead to malformed blood vessels as seen in Rendu-Osler-Weber syndrome, or in bleeding disorders such as hemophilia and Glanzmann thromboastenia. Other rare causes of hemothorax include neurofibromatosis type 1 and extramedullary hematopoiesis. #### Catamenial[edit] Rarely, hemothoraces can arise due to extrapelvic endometriosis, a condition in which tissue similar to the lining that normally covers the inside of the uterus forms in unusual locations outside the pelvis.[14] Endometriotic tissue that implants on the pleural surface can bleed in response to the hormonal changes of the menstrual cycle, causing what is known as a catamenial hemothorax as part of the thoracic endometriosis syndrome along with catamenial pneumothorax, catamenial hemoptysis, and lung nodules of endometriosis.[15] Catamenial hemothorax represents 14% of cases of thoracic endometriosis syndrome[16] while catamenial pneumothorax is seen in 73%, catamenial hemoptysis in 7%, and pulmonary nodules in 6%.[14] ## Mechanism[edit] Autopsy specimen showing a large clotted hemothorax filling the entire pleural cavity When a hemothorax occurs, blood enters the pleural cavity. The blood loss has several effects. Firstly, as blood builds up within the pleural cavity, it begins to interfere with the normal movement of the lungs, preventing one or both lungs from fully expanding and thereby interfering with the normal transfer of oxygen and carbon dioxide to and from the blood.[17] Secondly, blood that has been lost into the pleural cavity can no longer be circulated. Hemothoraces can lead to significant blood loss - each half of the thorax can hold more than 1500 milliliters of blood, representing more than 25% of an average adult's total blood volume.[18] The body may struggle to cope with this blood loss, and tries to compensate by maintaining blood pressure by forcing the heart to pump harder and faster, and by squeezing or constricting small blood vessels in the arms and legs.[19] These compensatory mechanisms can be recognised by a rapid resting heart rate and cool fingers and toes.[20] If the blood within the pleural cavity is not removed, it will eventually clot. This clot tends to stick the parietal and visceral pleura together and has the potential to lead to scarring within the pleura, which if extensive leads to the condition known as a fibrothorax.[1] Following the initial loss of blood, a small hemothorax may irritate the pleura, causing additional fluid to seep out, leading to a bloodstained pleural effusion.[21] Furthermore, as enzymes in the pleural fluid begin to break down the clot, the protein concentration of the pleural fluid increases. As a result, the osmotic pressure of the pleural cavity increases, causing fluid to leak into the pleural cavity from the surrounding tissues.[22] ## Diagnosis[edit] Hemothoraces are most commonly detected using a chest X-ray, although ultrasound is sometimes used in an emergency setting. However, plain X-rays may miss smaller hemothoraces while other imaging modalities such as computed tomography (CT), or magnetic resonance imaging may be more sensitive.[23] In cases where the nature of an effusion is in doubt, a sample of fluid can be aspirated and analysed in a procedure called thoracentesis.[7] Physical examination is used initally. Auscultation has been reported to have an accuracy of nearly 100% in diagnosing hemopneumothorax.[24] ### Chest X-ray[edit] Two chest X-rays: left showing a massive left-sided hemothorax; right showing a massive right hemothorax A chest X-ray is the most common technique used to diagnosis a hemothorax.[25] X-rays should ideally be taken in an upright position (an erect chest X-ray), but may be performed with the person lying on their back (supine) if an erect chest X-ray is not feasible. On an erect chest X-ray, a hemothorax is suggested by blunting of the costophrenic angle or partial or complete opacification of the affected half of the thorax. On a supine film the blood tends to layer in the pleural space, but can be appreciated as a haziness of one half of the thorax relative to the other.[6] A small hemothorax may be missed on a chest X-ray as several hundred milliliters of blood can be hidden by the diaphragm and abdominal viscera on an erect film. Supine X-rays are even less sensitive and as much as one liter of blood can be missed on a supine film.[26] ### Other methods[edit] Ultrasonography may also be used to detect hemothorax and other pleural effusions. This technique is of particular use in the critical care and trauma settings as it provides rapid, reliable results at the bedside.[25] Ultrasound is more sensitive than chest x-ray in detecting hemothorax.[27] Ultrasound can result in issues in people who are morbidly obese or have subcutaneous emphysema. When CT is unavailable in the current setting or the person cannot be moved to the scan, ultrasound is used.[24] Computed tomography (CT or CAT) scans may be useful for diagnosing retained hemothorax as this form of imaging can detect much smaller amounts of fluid than a plain chest X-ray. However, CT is less used as a primary means of diagnosis within the trauma setting, as these scans require a critically ill person to be transported to a scanner, are slower, and require the subject to remain supine.[25][28] Magnetic resonance imaging (MRI) can be used to differentiate between a hemothorax and other forms of pleural effusion, and can suggest how long the hemothorax has been present for. Fresh blood can be seen as a fluid with low T1 but high T2 signals, while blood that has been present for more than a few hours displays both low T1 and T2 signals.[29] MRI is used infrequently in the trauma setting due to the prolonged time required to perform an MRI, and the deterioration in image quality that occurs with motion.[23] * Ultrasound scan of the chest showing a left-sided hemothorax * CT scan of the chest showing a hemothorax caused by warfarin use * Chest MRI showing a hemothorax in a 16-day-old infant ### Thoracentesis[edit] Pleural fluid sample from a hemothorax taken by thoracentesis Although imaging techniques can demonstrate that fluid is present within the pleural space, it may be unclear what this fluid represents. To establish the nature of the fluid, a sample can be removed by inserting a needle into the pleural cavity in a procedure known as a thoracentesis or pleural tap. In this context, the most important assessment of the pleural fluid is the percentage by volume that is taken up by red blood cells (the hematocrit)[10] A hemothorax is defined as having a hematocrit of at least 50% of that found in the affected person's blood, although the hematocrit of a chronic hemothorax may be between 25 and 50% if additional fluid has been secreted by the pleura.[7] Pleural fluid can dilute hemothoraces in as low as 3–4 days.[6] The red blood cells in the effusion spontaneously break down.[12] Distinguishing the pleural fluid from blood by color is impossible when the hematocrit value is over 5%.[24] For these reasons, even if there is a hematocrit value under 50%, further investigations can be done in order to figure out if there is a source of bleeding.[6] Thoracentesis is the test most commonly used to diagnose a hemothorax in animals.[30] Hemothorax can itself be a rare complication of thoracentesis if the intercostal artery is punctured.[31] ## Treatment[edit] The treatment of a hemothorax depends largely on the extent of bleeding. While small hemothoraces may require little in the way of treatment, larger hemothoraces may require fluid resuscitation to replace the blood that has been lost, drainage of the blood within the pleural space using a procedure known as a tube thoracostomy, and potentially surgery in the form of a thoracotomy or video-assisted thoracoscopic surgery (VATS) to prevent further bleeding.[10][25][17][7] Occasionally, transcatheter arterial embolization may be used to stop ongoing arterial bleeding. Additional treatment options include antibiotics to reduce the risk of infection and fibrinolytic therapy to break down clotted blood within the pleural space.[10] ### Thoracostomy[edit] A tube thoracostomy unit Blood in the cavity can be removed by inserting a drain (chest tube) in a procedure called a tube thoracostomy. This procedure is indicated for most causes of hemothorax, but should be avoided in aortic rupture which should be managed with immediate surgery.[8] The thoracostomy tube is usually placed between the ribs in the sixth or seventh intercostal space at the mid-axillary line.[17] It is important to avoid a chest tube becoming obstructed by clotted blood as obstruction prevents adequate drainage of the pleural space. Clotting occurs as the clotting cascade is activated when the blood leaves the blood vessels and comes into contact with the pleural surface, injured lung or chest wall, or the thoracostomy tube. Inadequate drainage may lead to a retained hemothorax, increasing the risk of infection within the pleural space (empyema) or the formation of scar tissue (fibrothorax).[32] Thoracostomy tubes with a diameter of 24–36 F (large-bore tubes) should be used, as these reduce the risk of blood clots obstructing the tube. Manual manipulation of chest tubes (also referred to as milking, stripping, or tapping) is commonly performed to maintain an open tube, but no conclusive evidence has demonstrated that this improves drainage.[7][33] If a chest tube does become obstructed, the tube can be cleared using open or closed techniques.[34] Tubes should be removed as soon as drainage has stopped, as prolonged tube placement increases the risk of empyema.[35][36] ### Surgery[edit] An emergency thoracotomy About 10–20% of traumatic hemothoraces require surgical management.[36] Larger hemothoraces, or those that continue to bleed following drainage, may require surgery. This surgery may take the form of a traditional open-chest procedure (a thoracotomy), but may be performed using video-associated thoracoscopic surgery (VATS). While there is no universally accepted cutoff for the volume of blood loss required before surgery is indicated, generally accepted indications include more than 1500 mL of blood drained from a thoracostomy, bleeding rate of over 500mL/hr in the first hour followed by over 200 mL, hemodynamic instability, or the need for repeat blood transfusions.[7][36] VATS is less invasive and cheaper than an open thoracotomy, and can reduce the length of hospital stay, but a thoracotomy may be preferred when hypovolemic shock is present.[24] The procedure should ideally be performed within 72 hours of the injury as delay may increase the risk of complications.[1] In clotted hemothorax, VATS is the generally preferred procedure to remove the clot, and is indicated if the hemothorax fills 1/3 or more of a hemithorax. The ideal time to remove a clot using VATS is at 48–96 hours, but can be attempted up to nine days after the injury.[36] ### Other[edit] In catamenial hemothorax, the bleeding is typically self-limiting and mild. Most people with the condition are stable and can be treated with hormonal therapies. They are only partially effective. Surgical removal of the endometrial tissue may be necessary in recurrent cases. However, the disease frequently recurs.[12] Resuscitation with intravenous fluids or with blood products may be required. In fulminant cases, transfusions may be administered before admission to the hospital. Clotting abnormalities, such as those caused by anticoagulant medications, should be reversed.[37] Prophylactic antibiotics are given for 24 hours in the case of trauma.[1] Blood clots may be retained within the pleural cavity despite chest tube drainage.[36] They are a risk factor for complications like fibrothorax and empyema.[24] Such retained clots should be removed, preferably with video-assisted thoracoscopic surgery (VATS). If VATS is unavailable, an alternative is fibrinolytic therapy such as streptokinase or urokinase given directly into the pleural space seven to ten days after the injury.[36] Residual clot that does not dissipate in response to fibrinolytics may require surgical removal in the form of decortication.[1] ## Prognosis[edit] The prognosis following a hemothorax depends on its size, the treatment given, and the underlying cause. While small hemothoraces may cause little in the way of problems, in severe cases an untreated hemothorax may be rapidly fatal due to uncontrolled blood loss. If left untreated, the accumulation of blood may put pressure on the mediastinum and the trachea, limiting the heart's ability to fill. However, if treated, the prognosis following a traumatic hemothorax is usually favourable and dependent on other non-thoracic injuries that have been sustained at the same time, the age of the person, and the need for mechanical ventilation.[38] Hemothoraces caused by benign conditions such as endometriosis have a good prognosis, while those caused by neurofibromatosis type 1 has a 36% rate of death, and those caused by aortic rupture are often fatal.[7][8] ### Complications[edit] Complications can occur following a hemothorax, and are more likely to occur if the blood has not been adequately drained from the pleural cavity. Blood that remains within the pleural space can become infected, and is known as an empyema.[24] It occurs in 1–4% of traumatic cases.[9] The retained blood can also irritate the pleura, causing scar tissue (adhesions) to form. If extensive, this scar tissue can encase the lung, restricting movement of the chest wall, and is then referred to as a fibrothorax.[24] It is believed that less than 1 percent of cases go on to develop a fibrothorax. Cases with hemopneumothorax or infection develop fibrothorax more often. After the chest tube is removed, over 10% of cases develop pleural effusions that are mostly self-limited and leave no lasting complications. In such cases, thoracentesis is performed to eliminate the possibility of an infection being present.[9] Other potential complications include atelectasis, lung infection, pneumothorax, sepsis, respiratory distress, hypotension, tachycardia, pneumonia, adhesions, and impaired lung function.[24] ## Epidemology[edit] There are about 300,000 cases of hemothorax in the U.S every year. Polytrauma (injury to multiple body systems) involves chest injuries in 60% of cases and commonly leads to hemothorax.[1] About 37% of people hospitalized for blunt chest trauma have traumatic hemothorax.[36] ## Other animals[edit] ### Horses[edit] Hemothorax in an animal caused by anti-coagulant poisoning In horses, hemothorax is uncommon and usually traumatic.[39][40] It may occur along with pneumothorax.[41] It is mainly diagnosed by ultrasound. Treatment involves supportive care, correction of the underlying cause, and occasionally drainage. The prognosis is variable. Hemothorax is usually caused by trauma to the thorax.[42] It can result from any injury that involves the pleural, intercostal, intervertebreal, cardiac,[39] or thoracic wall muscle.[42] It can rarely be caused by diaphragmatic rupture that results in abdominal herniation. Hemothorax can be caused be cancers involving the thoracic, pulmonary, and mediastinal wall. The most common cancer resulting in hemothorax is a hemangiosarcoma.[39] Clinical signs and symptoms may be variable and cause-dependant. They may include rapid breathing, pain, and shallow breathing in cases with a rib fracture.[41] In the case of extensive bleeding, signs of hypovolemia may occur,[40] and rapid death may result within hours.[43] In less acute cases with slower bleeding, anemia and hypoproteinemia may gradually develop.[41] Ultrasound can detect blood in the pleural cavity. Blood in the thorax is shown by a uniform area without flocculation.[41] Pleural effusions without blood are usually hypoechoic. Echogenicity is indicated by cellular debris and/or fibrin. A swirling, hyperechoic pattern is indicative of bleeding within body cavities. Bloody pleural effusions are shows by a swirling, hyperechoic pattern.[39] When a stethescope is used (auscultation), the heartbeat sounds are faint. When percussion is performed, it produces a dull area. However, especially in traumatic cases, percussion may be painful. Although nonspecific, physical examinations may show reduced lung sounds and muffled, widespread heart sounds. Similar signs and symptoms may occur when other fluids are in the pleural cavity.[41] Treatment includes correction of the underlying cause. Drainage is not always required,[44] but can be performed in case of infection or fluid levels resulting in respiratory compromise. However, drainage in contraindicated in cases caused by clotting disorders.[41] Additionally, broad spectrum antibiotics can be given in the case of open trauma or pulmonary rupture.[43] Supportive care may be required. It may include intranasal oxygen, painkillers, blood transfusions, and fluids. In order to avoid fluid overload, fluids are given slowly.[41] The prognosis significantly depends on the underlying cause of the hemothorax. In cases caused by uncomplicated thoracic trauma, the prognosis may be good, but the prognosis is worse in cases that are complicated by pleuritis. Cases caused by cancer or clotting disorders have a poor prognosis,[41] as do cases with massive bleeding due to injury to the heart or very large blood vessels.[42] ## See also[edit] * Cardiac tamponade * Hemopneumothorax * Pulmonary contusion * Tension pneumothorax ## References[edit] 1. ^ a b c d e f g Boersma WG, Stigt JA, Smit HJ (November 2010). "Treatment of haemothorax". Respir Med. 104 (11): 1583–7. doi:10.1016/j.rmed.2010.08.006. PMID 20817498. 2. ^ Snell, Richard S. (1995). Clinical anatomy for medical students (5th ed.). Boston: Little, Brown. pp. 77–81. ISBN 0316801356. OCLC 31410594. 3. ^ a b "Hemothorax: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 3 Jan 2021. 4. ^ Pumarejo Gomez, Laura; Tran, Vu H. (2020), "Hemothorax", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30855807, retrieved 2021-01-07 5. ^ Kim, Michelle; Moore, James E. (2020). "Chest Trauma: Current Recommendations for Rib Fractures, Pneumothorax, and Other Injuries". Current Anesthesiology Reports. 10 (1): 61–68. doi:10.1007/s40140-020-00374-w. ISSN 1523-3855. PMC 7223697. PMID 32435162. 6. ^ a b c d e Zeiler, Jacob; Idell, Steven; Norwood, Scott; Cook, Alan (27 Jan 2020). "Hemothorax: A Review of the Literature". Clinical Pulmonary Medicine. 27 (1): 1–12. doi:10.1097/CPM.0000000000000343. ISSN 1068-0640. 7. ^ a b c d e f g h i j Patrini D, Panagiotopoulos N, Pararajasingham J, Gvinianidze L, Iqbal Y, Lawrence DR (2015). "Etiology and management of spontaneous haemothorax". J Thorac Dis. 7 (3): 520–526. doi:10.3978/j.issn.2072-1439.2014.12.50. PMC 4387396. PMID 25922734. 8. ^ a b c Seligson, Marc T.; Marx, William H. (2019), "Aortic Rupture", StatPearls, StatPearls Publishing, PMID 29083613 9. ^ a b c d Mason, Robert J.; Slutsky, Arthur; Murray, John F.; Nadel, Jay A.; Gotway, Michael B. (2015-03-17). Murray & Nadel's Textbook of Respiratory Medicine E-Book. Elsevier Health Sciences. p. 1458. ISBN 978-0-323-26193-7. 10. ^ a b c d Light, Richard W. (2007). Pleural Diseases. Lippincott Williams & Wilkins. pp. 340, 341, 342. ISBN 9780781769570. 11. ^ Aragão, Antonio Higor Marques; Fonseca, Letícia Aguiar; Deulefeu, Flávio Clemente; Medeiros, Israel Lopes; de Araújo, Rafael Fernandes Viana; da Cruz Neto, Carlos Alberto; Neto, Antero Gomes (2020-01-23). "Spontaneous Hemopneumothorax: A Rare Cause of Unexplained Hemodynamic Instability in a Young Patient". Case Reports in Pulmonology. 2020. doi:10.1155/2020/5026759. ISSN 2090-6846. PMC 7003253. PMID 32047694. 12. ^ a b c Fishman, Jay A.; Kotloff, Robert; Grippi, Michael A.; Pack, Allan I.; Senior, Robert M.; Elias, Jack A. (2015-04-14). Fishman's Pulmonary Diseases and Disorders, 2-Volume Set, 5th edition. McGraw-Hill Education. p. 1170. ISBN 978-0-07-180728-9. 13. ^ Patrini, Davide; Panagiotopoulos, Nikolaos; Pararajasingham, Jonathan; Gvinianidze, Lasha; Iqbal, Yassir; Lawrence, David R. (7 Mar 2015). "Etiology and management of spontaneous haemothorax". Journal of Thoracic Disease. 7 (3): 520–526. doi:10.3978/j.issn.2072-1439.2014.12.50. ISSN 2072-1439. PMC 4387396. PMID 25922734. 14. ^ a b McCann MR, Schenk WB, Nassar A, Maimone S (September 2020). "Thoracic endometriosis presenting as a catamenial hemothorax with discordant video-assisted thoracoscopic surgery". Radiol Case Rep. 15 (9): 1419–1422. doi:10.1016/j.radcr.2020.05.064. PMC 7334551. PMID 32642009. 15. ^ Rousset P, Rousset-Jablonski C, Alifano M, Mansuet-Lupo A, Buy JN, Revel MP (March 2014). "Thoracic endometriosis syndrome: CT and MRI features". Clin Radiol. 69 (3): 323–30. doi:10.1016/j.crad.2013.10.014. PMID 24331768. 16. ^ Alifano M, Trisolini R, Cancellieri A, Regnard JF (February 2006). "Thoracic endometriosis: current knowledge". Ann Thorac Surg. 81 (2): 761–9. doi:10.1016/j.athoracsur.2005.07.044. PMID 16427904. 17. ^ a b c Broderick SR (February 2013). "Hemothorax: Etiology, diagnosis, and management". Thorac Surg Clin (Review). 23 (1): 89–96, vi–vii. doi:10.1016/j.thorsurg.2012.10.003. PMID 23206720. 18. ^ Advanced Trauma Life Support – student course manual (10th ed.). American College of Surgeons. 2018. p. 68. ISBN 978-0-9968262-3-5. 19. ^ Institute of Medicine Staff; David E Longnecker; Andrew MacPherson Pope; Geoffrey French (1999). Fluid Resuscitation: State of the Science for Treating Combat Casualties and Civilian Injuries. Washington, DC: National Academies Press. ISBN 0-309-06481-3. OCLC 994446545. 20. ^ Hooper, Nicholas; Armstrong, Tyler J. (2019), "Shock, Hemorrhagic", StatPearls, StatPearls Publishing, PMID 29262047 21. ^ Light RW (2010). "Pleural effusion in pulmonary embolism". Semin Respir Crit Care Med. 31 (6): 716–22. doi:10.1055/s-0030-1269832. PMID 21213203. 22. ^ Jones, David; Nelson, Anna; Ma, O. John (2016), Tintinalli, Judith E.; Stapczynski, J. Stephan; Ma, O. John; Yealy, Donald M. (eds.), "Pulmonary Trauma", Tintinalli’s Emergency Medicine: A Comprehensive Study Guide (8th ed.), McGraw-Hill Education 23. ^ a b Hallifax RJ, Talwar A, Wrightson JM, Edey A, Gleeson FV (2017). "State-of-the-art: Radiological investigation of pleural disease". Respiratory Medicine. 124: 88–99. doi:10.1016/j.rmed.2017.02.013. ISSN 1532-3064. PMID 28233652. 24. ^ a b c d e f g h Dogrul, Bekir Nihat; Kiliccalan, Ibrahim; Asci, Ekrem Samet; Peker, Selim Can (June 2020). "Blunt trauma related chest wall and pulmonary injuries: An overview". Chinese Journal of Traumatology. 23 (3): 125–138. doi:10.1016/j.cjtee.2020.04.003. ISSN 1008-1275. PMC 7296362. PMID 32417043. 25. ^ a b c d Weldon E, Williams J (2012). "Pleural disease in the emergency department". Emerg. Med. Clin. North Am. 30 (2): 475–499, ix–x. doi:10.1016/j.emc.2011.10.012. PMID 22487115. 26. ^ "Hemothorax Workup: Approach Considerations, Laboratory Studies, Chest Radiography". emedicine.medscape.com. Retrieved 13 Jul 2020. 27. ^ Gomez, LP; Tran, VH (March 2019). Hemothorax. PMID 30855807. 28. ^ Cannon K, Checchi K, Wisniewski P (2016). "Retained Hemothorax" (PDF). Surgical Critical Care Evidence-Based Medicine Guidelines Committee. 29. ^ Kao S, Yen A, Nakanote K, Brouha S (2016). "Silver lining: Imaging manifestations of pleural pathology". Applied Radiology. 45 (6): 9–23. 30. ^ Slensky K (2009). "Chapter 153: Thoracic Trauma". In Silverstein DC, Hopper K (eds.). Small Animal Critical Care Medicine. pp. 662–667. doi:10.1016/B978-1-4160-2591-7.10153-5. ISBN 978-1-4160-2591-7. 31. ^ Mansour, Wissam; Samaha, Ghassan; El Bitar, Sandy; Esper, Ziad; Maroun, Rabih (2017-08-02). "Intercostal Artery Laceration: Rare Complication of Thoracentesis and Role of Ultrasound in Early Detection". Case Reports in Pulmonology. 32. ^ Kwiatt M, Tarbox A, Seamon MJ, et al. (April 2014). "Thoracostomy tubes: A comprehensive review of complications and related topics". Int J Crit Illn Inj Sci (Review). 4 (2): 143–55. doi:10.4103/2229-5151.134182. PMC 4093965. PMID 25024942. 33. ^ Salmon, Nadine; Lynch, Shelley; Muck, Kelly (2007-08-30). "Chest tube management" (PDF). 34. ^ Miller KS, Sahn SA (1987). "Chest tubes. Indications, technique, management and complications". Chest. 91 (2): 258–264. doi:10.1378/chest.91.2.258. PMID 3542404. 35. ^ Filosso PL, Sandri A, Guerrera F, et al. (July 2016). "When size matters: changing opinion in the management of pleural space-the rise of small-bore pleural catheters". J Thorac Dis (Review). 8 (7): E503–10. doi:10.21037/jtd.2016.06.25. PMC 4958830. PMID 27499983. 36. ^ a b c d e f g Light, RW (2013). "Chapter 25: Hemothorax". Pleural Diseases (6th ed.). Lippincott Williams & Wilkins. pp. 405–411. ISBN 978-1-4511-7599-8. 37. ^ National Clinical Guideline Centre (UK) (2016). Major Trauma: Assessment and Initial Management. National Institute for Health and Care Excellence: Clinical Guidelines. London: National Institute for Health and Care Excellence (UK). PMID 26913320. 38. ^ Mazcuri M, Ahmad T, Abid A, Thapaliya P, Ali M, Ali N (October 2020). "Pattern and outcome of thoracic injuries in a busy tertiary care unit". Cureus. 12 (10): e11181. doi:10.7759/cureus.11181. PMC 7593122. PMID 33133801. 39. ^ a b c d Groover, E. S.; Wooldridge, A. A. (2013). "Equine haemothorax". Equine Veterinary Education. 25 (10): 536–541. doi:10.1111/eve.12072. ISSN 2042-3292. 40. ^ a b Hadden, Will A. (III) (2005-07-01). Rogers, Cheryl; Wilcox, G. Jeanne (eds.). Horseman's Veterinary Encyclopedia, Revised and Updated. Rowman & Littlefield. p. 418. ISBN 978-0-7627-9451-5. 41. ^ a b c d e f g h Weese, Scott; Munroe, Dr Graham; Munroe, Graham (2011-03-15). Equine Clinical Medicine, Surgery and Reproduction. CRC Press. p. 477. ISBN 978-1-84076-608-0. 42. ^ a b c Auer, Jorg A.; Stick, John A. (2018-05-24). Equine Surgery - E-Book. Elsevier Health Sciences. p. 809. ISBN 978-0-323-48419-0. 43. ^ a b Groover, E. S.; Wooldridge, A. A. (2013-08-04). "Equine haemothorax". Equine Veterinary Education. 25 (10): 536–541. doi:10.1111/eve.12072. ISSN 0957-7734. 44. ^ Southwood, Louise; Wilkins, Pamela A. (2014-10-24). Equine Emergency and Critical Care Medicine. CRC Press. p. 296. ISBN 978-1-84076-652-3. ## External links[edit] Wikimedia Commons has media related to Hemothorax. Classification D * ICD-10: J94.2, S27.1 * ICD-9-CM: 511.8, 860 * MeSH: D006491 * DiseasesDB: 19762 External resources * MedlinePlus: 000126 * eMedicine: med/2915 ped/971 * v * t * e Diseases of the respiratory system Upper RT (including URTIs, common cold) Head sinuses Sinusitis nose Rhinitis Vasomotor rhinitis Atrophic rhinitis Hay fever Nasal polyp Rhinorrhea nasal septum Nasal septum deviation Nasal septum perforation Nasal septal hematoma tonsil Tonsillitis Adenoid hypertrophy Peritonsillar abscess Neck pharynx Pharyngitis Strep throat Laryngopharyngeal reflux (LPR) Retropharyngeal abscess larynx Croup Laryngomalacia Laryngeal cyst Laryngitis Laryngopharyngeal reflux (LPR) Laryngospasm vocal cords Laryngopharyngeal reflux (LPR) Vocal fold nodule Vocal fold paresis Vocal cord dysfunction epiglottis Epiglottitis trachea Tracheitis Laryngotracheal stenosis Lower RT/lung disease (including LRTIs) Bronchial/ obstructive acute Acute bronchitis chronic COPD Chronic bronchitis Acute exacerbation of COPD) Asthma (Status asthmaticus Aspirin-induced Exercise-induced Bronchiectasis Cystic fibrosis unspecified Bronchitis Bronchiolitis Bronchiolitis obliterans Diffuse panbronchiolitis Interstitial/ restrictive (fibrosis) External agents/ occupational lung disease Pneumoconiosis Aluminosis Asbestosis Baritosis Bauxite fibrosis Berylliosis Caplan's syndrome Chalicosis Coalworker's pneumoconiosis Siderosis Silicosis Talcosis Byssinosis Hypersensitivity pneumonitis Bagassosis Bird fancier's lung Farmer's lung Lycoperdonosis Other * ARDS * Combined pulmonary fibrosis and emphysema * Pulmonary edema * Löffler's syndrome/Eosinophilic pneumonia * Respiratory hypersensitivity * Allergic bronchopulmonary aspergillosis * Hamman-Rich syndrome * Idiopathic pulmonary fibrosis * Sarcoidosis * Vaping-associated pulmonary injury Obstructive / Restrictive Pneumonia/ pneumonitis By pathogen * Viral * Bacterial * Pneumococcal * Klebsiella * Atypical bacterial * Mycoplasma * Legionnaires' disease * Chlamydiae * Fungal * Pneumocystis * Parasitic * noninfectious * Chemical/Mendelson's syndrome * Aspiration/Lipid By vector/route * Community-acquired * Healthcare-associated * Hospital-acquired By distribution * Broncho- * Lobar IIP * UIP * DIP * BOOP-COP * NSIP * RB Other * Atelectasis * circulatory * Pulmonary hypertension * Pulmonary embolism * Lung abscess Pleural cavity/ mediastinum Pleural disease * Pleuritis/pleurisy * Pneumothorax/Hemopneumothorax Pleural effusion Hemothorax Hydrothorax Chylothorax Empyema/pyothorax Malignant Fibrothorax Mediastinal disease * Mediastinitis * Mediastinal emphysema Other/general * Respiratory failure * Influenza * Common cold * SARS * Coronavirus disease 2019 * Idiopathic pulmonary haemosiderosis * Pulmonary alveolar proteinosis * v * t * e Chest injury, excluding fractures Cardiac and circulatory system injuries * vascular: Traumatic aortic rupture * Thoracic aorta injury * heart: Myocardial contusion/Commotio cordis * Cardiac tamponade * Hemopericardium * Myocardial rupture Lung and lower respiratory tract injuries * Pneumothorax * Hemothorax * Hemopneumothorax * Pulmonary contusion * Pulmonary laceration * Tracheobronchial injury * Diaphragmatic rupture * v * t * e Disorders of bleeding and clotting Coagulation · coagulopathy · Bleeding diathesis Clotting By cause * Clotting factors * Antithrombin III deficiency * Protein C deficiency * Activated protein C resistance * Protein S deficiency * Factor V Leiden * Prothrombin G20210A * Platelets * Sticky platelet syndrome * Thrombocytosis * Essential thrombocythemia * DIC * Purpura fulminans * Antiphospholipid syndrome Clots * Thrombophilia * Thrombus * Thrombosis * Virchow's triad * Trousseau sign of malignancy By site * Deep vein thrombosis * Bancroft's sign * Homans sign * Lisker's sign * Louvel's sign * Lowenberg's sign * Peabody's sign * Pratt's sign * Rose's sign * Pulmonary embolism * Renal vein thrombosis Bleeding By cause Thrombocytopenia * Thrombocytopenic purpura: ITP * Evans syndrome * TM * TTP * Upshaw–Schulman syndrome * Heparin-induced thrombocytopenia * May–Hegglin anomaly Platelet function * adhesion * Bernard–Soulier syndrome * aggregation * Glanzmann's thrombasthenia * platelet storage pool deficiency * Hermansky–Pudlak syndrome * Gray platelet syndrome Clotting factor * Hemophilia * A/VIII * B/IX * C/XI * von Willebrand disease * Hypoprothrombinemia/II * Factor VII deficiency * Factor X deficiency * Factor XII deficiency * Factor XIII deficiency * Dysfibrinogenemia * Congenital afibrinogenemia Signs and symptoms * Bleeding * Bruise * Hematoma * Petechia * Purpura * Nonthrombocytopenic purpura By site * head * Epistaxis * Hemoptysis * Intracranial hemorrhage * Hyphema * Subconjunctival hemorrhage * torso * Hemothorax * Hemopericardium * Pulmonary hematoma * abdomen * Gastrointestinal bleeding * Hemobilia * Hemoperitoneum * Hematocele * Hematosalpinx * joint * Hemarthrosis * 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 inhibitors [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	Hemothorax	c0019123	2,940	wikipedia	https://en.wikipedia.org/wiki/Hemothorax	2021-01-18T19:00:51	{"mesh": ["D006491"], "umls": ["C0019123"], "icd-9": ["860", "511.8"], "icd-10": ["J94.2", "S27.1"], "wikidata": ["Q369073"]}
A number sign (#) is used with this entry because congenital adrenal hyperplasia (CAH) due to 11-beta-hydroxylase deficiency is caused by homozygous or compound heterozygous mutation in the CYP11B1 gene (610613) on chromosome 8q24. Description Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency is an autosomal recessive disorder of corticosteroid biosynthesis resulting in androgen excess, virilization, and hypertension. The defect causes decreased synthesis of cortisol and corticosterone in the zona fasciculata of the adrenal gland, resulting in accumulation of the precursors 11-deoxycortisol and 11-deoxycorticosterone; the latter is a potent salt-retaining mineralocorticoid that leads to arterial hypertension (White et al., 1991). CAH due to 11-beta-hydroxylase deficiency accounts for approximately 5 to 8% of all CAH cases; approximately 90% of cases are caused by 21-hydroxylase deficiency (201910) (White et al., 1991). Clinical Features The nature of the defect in congenital adrenal hyperplasia associated with hypertension was first demonstrated by Eberlein and Bongiovanni (1956) on the basis of the accumulated steroids. Glenthoj et al. (1980) diagnosed 11-beta-hydroxylase deficiency in 3 adult patients who had been thought to have 21-hydroxylase deficiency. Rosler et al. (1982) reported 26 patients with CAH due to 11-beta-hydroxylase deficiency in 18 Jewish families from Morocco, Tunis, Turkey, and Iran. Parental consanguinity was found in 7 families. Patients had severe volume-induced hypertension with low levels of plasma renin activity. Affected females showed a wide range in the clinical expression of androgen excess, ranging from enlarged clitoris to penile urethra with fused labial-scrotal folds. Ten of 14 females were reared as males and diagnosis was often delayed until puberty when breasts developed and menses occurred. Signs of mineralocorticoid excess and degree of virilization were not correlated. Hypertension leading to fatal vascular accidents was observed in only mildly virilized patients, and complete pseudohermaphrodites were sometimes normotensive. Six patients had overt hypokalemia. Hochberg et al. (1985) observed 15 affected girls and 9 affected boys, all Jewish individuals of Moroccan and Iranian extraction. Final height was severely compromised in all, regardless of age at diagnosis and quality of therapeutic control. Onset of puberty was precocious in males and normal in females. Gynecomastia, very unusual in male infants after 1 month, was present in 4 at diagnosis. All were being raised as males, although 2 were karyotypic females. Hydrocortisone acetate was superior to cortisone acetate or prednisone in promotion of growth. Rosler et al. (1992) reviewed the characteristics of 38 persons with 11-beta-hydroxylase deficiency from 25 families over a 39-year period; 19 families came from Morocco, and in another 2 of the families one parent came from Morocco. Helmberg et al. (1992) reported an 8-year-old boy of Turkish origin, born of consanguineous parents, with CAH due to 11-beta-hydroxylase deficiency. The patient had marked hypertension, precocious pseudopuberty, height and weight above the 97th percentile, epiphyseals already completely closed, and completely virilized intersexual genitalia (Prader type IV, penis with hypospadias, scrotum lacking palpable testes) with a 46,XX karyotype. Ultrasound examination disclosed adrenal hyperplasia and the existence of a uterus and vagina ending in the proximal urethra. Four sibs of the patient died shortly after birth or in early childhood. Al-Jurayyan (1995) reported that 78 Saudi children with CAH were seen at a hospital in Riyadh over a 10-year period. Of these, 20 (25.6%) patients from 11 families had 11-beta-hydroxylase deficiency. Pseudoprecocious puberty in males and variable degrees of virilization in females led to wrong sex assignment in 7 (58.3%). Neonatal salt-wasting before treatment occurred in 3. Moderate to severe hypertension associated with hypokalemia was present in another 6. In 4 sibs, hypertension persisted despite adequate hydrocortisone therapy. Al-Jurayyan (1995) observed that the disorder appeared to be relatively frequent in the Saudi Arabian population. Clark (2000) presented 2 patients with what she called 'nonclassic' or 'partial/mild' 11-beta-hydroxylase deficiency that differed by less frequent prenatal virilization and hypertension compared to the classic form. The first child was a 6-year-old boy referred for precocious puberty. He was tall (95th percentile) and had high-normal blood pressure (90th percentile for age) and Tanner III genitalia. Skeletal age was approximately twice chronologic age. The serum level of 11-deoxycortisol was elevated, as was the level of tetrahydro substance S, a metabolite. The second child was a 1-month-old girl with an enlarged clitoris but no labial fusion. She had normal blood pressure for age. Serum 11-deoxycortisol was markedly elevated. Diagnosis ### Prenatal Diagnosis Rosler et al. (1979) and Rosler et al. (1988) found that increased levels of tetrahydro-11-deoxycortisol in the amniotic fluid could be used for prenatal diagnosis of 11-beta-hydroxylase deficiency. The analysis of hormonal parameters was most reliable when sequential maternal urine and amniotic fluid determinations were performed in parallel. ### Misdiagnosis as 21-Hydroxylase Deficiency Tonetto-Fernandes et al. (2006) sought to identify possible misdiagnosed patients with 11-beta-hydroxylase deficiency among those with 21-hydroxylase deficiency. To recognize patients with 21- and/or 11-beta-hydroxylase deficiency, they recommended evaluation of 17-hydroxyprogesterone or 21-deoxycortisol (21DF) and 11-deoxycortisol (S). Also, 21DF may be useful to follow up pubertal patients with 21-hydroxylase deficiency. Their finding that 1% of Brazilian patients with alleged 21-hydroxylase deficiency may have 11-beta-hydroxylase deficiency led Tonetto-Fernandes et al. (2006) to infer that its frequency maybe underestimated. Molecular Genetics In affected individuals of Moroccan Jewish ancestry with CAH due to steroid 11-beta-hydroxylase deficiency, White et al. (1991) identified a homozygous mutation in the CYP11B1 gene (R448H: 610613.0001). Most of the patients had previously been reported by Rosler et al. (1982). Helmberg et al. (1992) identified a homozygous mutation in the CYP11B1 gene (610613.0005) in an 8-year-old boy of Turkish origin with CAH due to 11-beta-hydroxylase deficiency. Geley et al. (1996) identified 7 mutations in the CYP11B1 gene in 9 patients with CAH due to 11-beta-hydroxylase deficiency. A Caucasian patient was homozygous for the R448H mutation previously found in Jews of Moroccan origin. All of the mutations resulted in a complete loss of steroid 11-beta-hydroxylating activity when expressed in cultured cells. History Brautbar et al. (1979) and New et al. (1981) excluded linkage of 11-beta-hydroxylase deficiency to the HLA locus (142800) on chromosome 6. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature CARDIOVASCULAR Vascular \- Hypertension GENITOURINARY External Genitalia (Male) \- Virilization \- Large penis \- Small testes External Genitalia (Female) \- Ambiguous genitalia due to virilization \- Enlarged clitoris \- Penile urethra \- Fused labial-scrotal folds Internal Genitalia (Female) \- Rudimentary uterus and vagina Kidneys \- Adrenal hyperplasia SKELETAL \- Advanced bone age Limbs \- Premature epiphyseal closure SKIN, NAILS, & HAIR Skin \- Hyperpigmentation associated with increased adrenocorticotropic hormone (ACTH) ENDOCRINE FEATURES \- Congenital adrenal hyperplasia \- Precocious puberty in males LABORATORY ABNORMALITIES \- Increased 11-deoxycorticosterone \- Increased 11-deoxycortisol \- Decreased aldosterone \- Decreased renin \- Decreased cortisol \- Increased ACTH \- Increased androgens \- Hypokalemia MISCELLANEOUS \- Onset in neonatal period \- Incidence of 1 in 100,000 births in Caucasians \- Incidence of 1 in 5,000 to 1 in 7,000 in Moroccan Jewish individuals \- Accounts for 5 to 7% of all cases of congenital adrenal hyperplasia MOLECULAR BASIS \- Caused by mutation in the cytochrome P450, subfamily XIB, polypeptide 1 gene (CYP11B1, 610613.0001 ) ▲ 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 inhibitors [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	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO STEROID 11-BETA-HYDROXYLASE DEFICIENCY	c0268292	2,941	omim	https://www.omim.org/entry/202010	2019-09-22T16:31:26	{"doid": ["0050811"], "mesh": ["C535978"], "omim": ["202010"], "orphanet": ["90795", "418"], "synonyms": ["Alternative titles", "ADRENAL HYPERPLASIA IV", "STEROID 11-BETA-HYDROXYLASE DEFICIENCY", "11-BETA-HYDROXYLASE DEFICIENCY", "ADRENAL HYPERPLASIA, HYPERTENSIVE FORM", "P450C11B1 DEFICIENCY"]}
Oral leukoplakia describes a white plaque that does not rub off and cannot be characterized as any other condition. Though it may occur in any part of the mouth, it generally affects the tongue, gums, and inner cheek. Physicians will usually biopsy oral leukoplakia lesions as 20-40% of cases are precancerous or cancerous at the time of biopsy and another 8-15% become cancerous over time. The exact cause of oral leukoplakia is not known. Factors that may increase the risk of developing oral leukoplakia include smoking, alcohol use, vitamin deficiencies, malocclusion, and a weakened immune system.Treatment depends on the biopsy results and the size, appearance, and location of the oral leukoplakia. Removal or ablation of the lesion by surgery, laser, or cryotherapy (use of low temperature) may be recommended. [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 inhibitors [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	Oral leukoplakia	c0023532	2,942	gard	https://rarediseases.info.nih.gov/diseases/7260/oral-leukoplakia	2021-01-18T17:58:34	{"mesh": ["D007972"], "umls": ["C0023532"], "synonyms": []}
Bartram et al. (1982) observed subacute sclerosing panencephalitis in a brother and sister of nonconsanguineous parents of 11 children living in rural Turkey. An interval of 4 years separated onset of symptoms in the 2 children. Fibroblast interferon had no beneficial effect. Neuro \- Subacute sclerosing panencephalitis 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 inhibitors [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	PANENCEPHALITIS, SUBACUTE SCLEROSING	c0038522	2,943	omim	https://www.omim.org/entry/260470	2019-09-22T16:23:47	{"doid": ["8970"], "mesh": ["D013344"], "omim": ["260470"], "icd-9": ["046.2"], "icd-10": ["A81.1"], "orphanet": ["2806"], "synonyms": ["Alternative titles", "SUBACUTE SCLEROSING PANENCEPHALITIS"]}
Abortion in Spain is legal upon request up to 14 weeks of pregnancy, and at later stages for serious risk to the health of the woman or fetal defects.[1] Abortion legislation in Spain has a fluctuating history. During the 1930s, abortion law was liberalized in the area controlled by the Republicans, but this was short-lived, as the Franco regime with support of the Catholic Church, outlawed abortion again. The laws were relaxed in 1985, and were further liberalized in 2010. Abortion remains a controversial political issue in Spain, but regular moves to restrict it have lacked majority support.[2] In recent years, abortion rates have been falling, as better access to emergency contraception has been introduced.[3] ## Contents * 1 Overview * 2 Second Spanish Republic * 3 Organic Law 9/1985 * 4 Organic Law 2/2010 * 5 Articles 13 and 14 of Title II of Law 2/2010 * 6 Approval process of the new law * 7 Amendments proposed by the PP government of Mariano Rajoy * 8 Number of abortions in Spain * 9 Surgical and medical abortions in Spain * 10 Other information * 11 References ## Overview[edit] Voluntary interruption of pregnancy (induced abortion) in Spain is regulated under Title II of the Organic Law 2/2010 of sexual and reproductive health and abortion[4] which came into force on 5 July 2010[5] and legalizes abortion during the first 14 weeks of pregnancy. Induced abortion had previously been strictly illegal and punishable[citation needed] except for a period in the 1930s during the Second Republic, until Organic Law 9/1985[6] decriminalized abortion in several circumstances. Under the previous laws, authors such as Ibáñez and García Velasco argued that prohibition and criminalization of abortion failed to prevented about 100,000 abortions a year.[7] Thus, punishment did not save the unborn, but did contribute decisively to the deaths of wome who had obtained illegal, unsanitary abortions (200 to 400 women in 1976, according to a Supreme Court document). Moreover, advocates of legal abortion argue, the problem of hiding mainly affects poor women, as those with more resources would have traveled to other countries to get an abortion, a practice known as "abortion tourism".[8] Oppnents of abortion, including the Catholic Church, counter that it is the taking of innocent human life, an inherently evil and murderous practice which degrades respect for all life and leads society toward a culture of death.[9] The conservative People's Party in June 2010 filed an action against several provisions of law to the Constitutional Court. In the electoral program for the general election held on 20 November 2011, the People's Party included modifying the law on abortion.[10][11] Still, both supporters and opponents of legalization put the bulk of their argument in defense of life, either of the mother or of the unborn child. Virtually all Spanish people interviewed have favored more social awareness of abortion and the need for the government to regulate it.[9] ## Second Spanish Republic[edit] On 25 December 1936, in Catalonia, elective abortion was legalized during the first 12 weeks of pregnancy, with a decree signed by Josep Tarradellas of 9 January 1937 (Diari Oficial de la Generalitat de Catalunya, núm.9).[12][13][14] In 1937, over the area loyal to the Republic during the Spanish Civil War under the socialist Spanish Socialist Workers' Party (PSOE) government of Francisco Largo Caballero, the Minister of Health Catalan Federica Montseny (anarchist CNT) also legalized abortion. The law was repealed by the victorious Franco. ## Organic Law 9/1985[edit] In the Organic Law 9/1985 adopted on 5 July 1985, induced abortion was legalized in three cases: serious risk to the physical or mental health of the pregnant woman (therapeutic justification), rape (criminal justification), and malformations or defects, physical or mental, in the fetus (eugenic justification).[15] According to this law, the mother could terminate the pregnancy in public or private health centres in the first 12 weeks for reasons related to rape, in the first 22 weeks for eugenic reasons, and at any time during pregnancy for therapeutic reasons. In the second and third cases, a medical report was required to certify compliance with the legal conditions; in cases of rape, a police report was required. In these three cases, abortion was not punishable under a doctor's supervision in a medical establishment approved for abortions, with the express consent of the woman. In other cases, the Penal Code provided various terms of imprisonment for both mothers and doctors who performed abortions outside the law. ## Organic Law 2/2010[edit] On 3 March 2010, the Organic Law 2/2010 on sexual and reproductive health and abortion was promulgated. The law is to ensure fundamental rights regarding sexual and reproductive health established by the World Health Organization (WHO), regulating the conditions of abortion and establishing the corresponding obligations of public authorities.[16][17][18] It came into force on 5 July 2010. In Title II, Articles 13 and 14, abortion is legalization during the first 14 weeks of pregnancy. During this time, the woman can take a free and informed decision on the termination of her pregnancy with no third party intervention. Article 15 describes that abortion is allowed up to 22 weeks of pregnancy in cases of "serious risks to life or health of the mother or fetus". From the twenty-second week, pregnancy may be interrupted only if "fetal anomalies incompatible with life are detected" or if "an extremely serious and incurable disease is detected within the fetus at the time of diagnosis and is confirmed by a clinical committee".[5] ## Articles 13 and 14 of Title II of Law 2/2010[edit] Article 13. Common requirements. These are the requirements of the voluntary termination of pregnancy: 1. It is practiced by a physician or under ones supervision. 2. It takes place in an accredited public or private health center. 3. It is done with the express written consent of the pregnant woman or, where appropriate, the legal representative, in accordance with the provisions of Law 41/2002, Basic Regulating Patient Autonomy and Rights and Obligations regarding information and clinical documentation. Express consent may be waived in the case provided for in Article 9.2.b) of that Act 4. For women aged 16 to 17 years, consent to the abortion lies exclusively with them in accordance with the general arrangements for older women. At least one of the legal representatives, parent, people with parental or guardian of women between these ages must be informed of the decision of the women. This information may be dispensed with when the minor reasonably claims that this will cause a serious conflict, manifested in certain danger of family violence, threats, coercion, abuse, or a situation of homelessness. Article 14. Termination of pregnancy at the request of the woman. Pregnancy can be terminated within the first fourteen weeks of gestation at the request of the pregnant woman, provided that these requirements have been followed: a) the pregnant woman has been informed on the rights, benefits and public aid to mothers, on the terms set forth in paragraphs 2 and 4 of Article 17 of this Act b) the pregnant woman has completed a period of at least three days, from the moment the information was given to her mentioned in the previous paragraph to the realization of the intervention.[5] ## Approval process of the new law[edit] In 2009, a reform of the 1985 law that regulated abortion was processed based on three cases delimited by a new law that would permit, under any circumstances, intervention during the first 14 weeks of gestation, and until week 22 if there is serious risk to the life or health of the pregnant woman or risk of serious abnormalities to the fetus. In case of detection of fetal anomalies incompatible with life, there would be no time limit for abortion. The new law would also allow young people between 16 and 17 to have an abortion without requiring parental consent.[19] This reform, supported by the Spanish Socialist Party and endorsed by the Council of State, drew criticism from the conservative People's Party, the Catholic Church and anti-abortion groups.[20][21][22] Law 2/2010 of sexual and reproductive health and abortion was finally passed by 184 votes in favor, 158 against and one abstention. The law was supported by PSOE, the ruling party of Spain led by Jose Luis Rodriguez Zapatero and the Minister for Equality Bibiana Aido. The parties that supported the government were the Basque Nationalist Party (PNV), Republican Left of Catalonia (ERC), United Left (IU), Initiative for Catalonia Greens (ICV), Galician Nationalist Bloc (BNG), Nafarroa Bai, and two members of Convergence and Union (CiU). The People's Party was the only party that opposed the adoption of the new law. It was also opposed by some members of other parties such as the Canarian Coalition, Navarrese People's Union (UPN), Union, Progress and Democracy (UPyD) and seven MPs from CiU. Outside parliament civil society organizations also expressed their rejection: representatives of the Spanish Episcopal Conference of the Catholic Church, Pro Life Associations and the Institute for Family Policies (IPF). In 2009, a survey on Spanish youth conducted by the Sociological Research Center or Centro de Investigaciones Sociológicas indicated that 55% of young people felt that it was only the woman who should decide the issue, one in four believed that society should place certain limits, while 15% objected to abortion in all cases. ## Amendments proposed by the PP government of Mariano Rajoy[edit] In January 2012, Alberto Ruiz-Gallardón, Minister of Justice for the new conservative People's Party (PP) government led by Mariano Rajoy, announced at his first appearance in parliament his intention to reform the Abortion Law of 2010. This act had been passed by the Socialist government of Rodriguez Zapatero, establishing gestation-age-limited model favoured by most European countries, but was contested by the Catholic Church in Spain and the PP, especially on the issue of whether minors between 16 and 18 may abort without parental consent. The new government proposed to return to the model of the 1982 Act, in which women had to argue the grounds for their decision to abort.[23] On 20 December 2013, the Government of Spain published its final draft law on abortion: Women undergoing abortion were to be considered "victims", and the practice would only be lawful in the case of rape or when there was a serious (but as yet undefined) health risk to the mother or the fetus. The likelihood of a child being born with disabilities would not be an acceptable justification for abortion. Under the new law, women under 18 would require parental consent and parental accompaniment during relevant consultations. Those seeking abortion in Spain would need approval from two independent doctors who would not be permitted to participate in the actual procedure. The Spanish Association of Accredited Abortion Clinics estimated that about 100,000 of the 118,000 abortions carried out in 2012 would be illegal under the new legislation. The revision was part of the 2011 PP election manifesto which was strongly influenced by the Roman Catholic church[citation needed] and vigorously opposed by most opposition parties and women's groups, who saw it as an attack on women's rights. In September 2014, Prime Minister Mariano Rajoy announced that the government would abandon the draft law due to lack of consensus, and that the government would seek to reform the 2010 law only by requiring 16 and 17-year-old women to obtain parental consent for an abortion. Minister of Justice Alberto Ruiz-Gallardón announced his resignation.[24] ## Number of abortions in Spain[edit] In 2009, the number of abortions was 112,000, about 4000 less than the previous year (115,812), the first time it had decreased since 1997. According to Trinidad Jimenez, then Minister for Health and Social Policy of Spain, the decline was due to over-the-counter sales in pharmacies for the so-called morning-after pill which was liberalized in late September 2009.[25][26] In Spain, the evolution of the number of abortions, according to statistics from the Ministry of Health,[27] is as follows: Year Notifiable centres of Induced abortion Number of abortions Rate per 1,000 women 1995 49,367[28] 1996 51,002 1997 49,578 1998 117 53,847 6.00 1999 123 58,399 6.52 2000 121 63,756 7.14 2001 121 69,857 7.66 2002 124 77,125 8.46 2003 128 79,788 8.77 2004 133 84,985[29] 8.94 2005 134 91,664[30] 9.60 2006 135 101,592 10.62 2007 137 112,138[31] 11.49[32] 2008 137 115,812 11.78 2009 141 111,482[25][33] 11.41 2010 147 113,031[27][34][35] 11.49 2011 172 118,359[36] 12.44 2012[27] 189 113,419 12.44 2013[27] 198 108,690 12.12 2014[27] 191 94,796 10.46 2015[27] 200 94,188 10.40 2016[27] 201 93,131 10.36 ## Surgical and medical abortions in Spain[edit] Induced abortion or termination of unwanted pregnancy can be performed by two methods: Medical abortion \- Using drugs or medications such as mifepristone and misoprostol. Surgical abortion \- Clinic or hospital intervention : aspiration, dilation and curettage. In Europe the use of medical abortion is generally broad, although its use varies by country. In 2010, medical abortions accounted for: 67% of induced abortions in Portugal, 49% in France, 40% in Great Britain, and 70% in Finland.[37] In Spain this was only 4%, in Italy less than 4% since the beginning of the marketing of mifepristone in December 2009.[37][38] ## Other information[edit] Abortion was available in a restricted form from July 5, 1985.[39] Under the previous law it was only allowed under the following conditions: to preserve the mental health of the mother (in which case two specialists have to approve); if the pregnancy was a byproduct of rape or incest reported to the police (the abortion must be performed in the first twelve weeks); if the fetus would suffer from deformities or mental handicaps upon birth (two specialists had to agree on the findings); or if the mother's physical health was in immediate danger (in which case an abortion could be performed without the consent of the woman's family physician or the woman herself).[39] Under the previous law, the threshold of "endangering the mother's mental health" was reported to be very low, making it a loophole for abortions on-demand.[40] The abortion rate has more than doubled from 54,000 in 1998 to 112,000 in 2007.[41] In 2009, the Socialist government started to liberalize current abortion laws, sending a new law through the lower house of Parliament which would allow abortion on-demand for pregnancies through the fourteenth week.[41] The government almost succeeded in lowering the age of consent for abortions to 16, but in the end the bill states that girls aged 16 and 17 must inform their parents (but do not need parental consent) for an abortion except if the girl comes from an abusive household and such news will cause more strife.[41] An estimated one million protesters turned to the streets of Madrid in protest of the proposed abortion law changes.[40] The law won final approval on February 24, 2010[42] and came into force on July 5, 2010. ## References[edit] 1. ^ https://archive.vn/20120630050651/http://www.boe.es/aeboe/consultas/bases_datos/doc.php?id=BOE-A-2010-3514 2. ^ "Spain abandons plan to introduce tough new abortion laws". The Guardian. 23 September 2014. 3. ^ https://www.thelocal.es/20141230/abortion-numbers-continue-to-fall-in-spain 4. ^ Ley Orgánica 2/2010 de salud sexual y reproductiva y de la interrupción voluntaria del embarazo. 5. ^ a b c Ley Orgánica 2/2010 de salud sexual y reproductiva y de la interrupción voluntaria del embarazo 6. ^ Ley Orgánica 9/1985 7. ^ Ibáñez y García Velasco 8. ^ Francisca García Gallego, La práctica del aborto en España, Página Abierta, 194, julio de 2008, Francisca García Gallego es ginecóloga y miembro de ACAI (Asociación de Clínicas Acreditadas para la Interrupción del Embarazo). 9. ^ a b Gerardo Hernández Rodríguez (1992). El aborto en España: análisis de un proceso socio-político. Universidad Pontificia de Comillas (in Spanish). pp. 73 and ss. ISBN 84-87840-15-9. Retrieved 23 July 2012. "Por lo que se refiere a las razones esgrimidas para rechazar el aborto [...] las expresiones [...] "homicidio", "crimen", "asesinato" son ampliamente utilizadas.; Asimismo, las razones dadas, basándose en la salvaguarda de la vida, son abundantes en ambos sectores. Unos a favor de la vida del nuevo ser y oytros pensando en la vida de la madre. [...] En lo que coinciden prácticamente todos, [...] es en la necesidad de una permanente toma de conciencia frente al problema por parte de la Administración [...]. La II República Española legalizé el aborto siendo ministra de Sanidad Federica Montseny." 10. ^ El PP llevará al Constitucional la futura ley de plazos del aborto, El País, 12 February 2009 11. ^ El Constitucional admite el recurso del PP contra la ley del aborto, El País, 30 June 2010 12. ^ Patricia Campello (15 February 2014). "La Segunda República despenalizó el aborto con la ley más avanzada de Europa". Público. Archived from the original on 22 February 2014. 13. ^ "Decreto de Regulación de la Interrupción Artificial del Embarazo" [Decree on the Regulation of the Artificial Interruption of Pregnancy]. CGT Burgos. Archived from the original on 2019-03-28. Retrieved 2016-02-06. 14. ^ José María Garat (12 May 1937). "En Cataluña existe ya el aborto legal" [In Catalonia there is already legal abortion]. Mundo Gráfico – via National Library of Spain. 15. ^ "Ley Orgánica 9/1985, del 5 de julio, de reforma del Artículo 417 bis del Código Penal" (in Spanish). Boletín Oficial del Estado. Archived from the original on 30 June 2012. Retrieved 23 July 2012. Cite journal requires `\|journal=` (help) 16. ^ ICPD Program of Action ver ChapterVII, Reproductive Rights and Reproductive Health 17. ^ "WHO: Reproductive health". Retrieved 23 July 2012. 18. ^ "Definición de Salud Reproductiva de la OMS, en RHO". Archived from the original on 2009-01-06. Retrieved 2012-07-22. 19. ^ Erika Montañés / EP. "Aprobada la reforma de la ley que permite el aborto libre las primeras 14 semanas". ABC (in Spanish). Retrieved 23 July 2012. 20. ^ P. Rafael y S. García. "El Consejo de Estado avala la ley del aborto". Público (in Spanish). Retrieved 23 July 2012. 21. ^ Jesús Bastante. "La Iglesia quiere excomulgar a quienes voten la Ley del Aborto". Público (in Spanish). Retrieved 23 July 2012. 22. ^ EFE. "El PP enmienda la Ley del Aborto porque "desprotege" a las menores y al nonato". RTVE (in Spanish). Retrieved 23 July 2012. 23. ^ "Rajoy juega a la Contrarreforma". El País (in Spanish). Retrieved 23 July 2012. 24. ^ "Spain abortion: Rajoy scraps tighter law". BBC News. 23 September 2014. 25. ^ a b El número de abortos baja en España por primera vez desde su legalización, en 1985, 20 minutos, 13/9/2010 26. ^ Emily Thigpen, 3 de abril de 2009, Datos concretos sobre las interrupciones voluntarias del embarazo en España 27. ^ a b c d e f g Ministerio de Sanidad, España, Estadísticas IVE 28. ^ El número de abortos en España ha aumentado un 73% en 10 años, El País, 27/12/2005 29. ^ En España se practicaron cerca de 85.000 abortos en 2004, Informativos telecinco 30. ^ Los abortos crecieron casi un 8% en 2005, El País, 29 December 2006 31. ^ El número de abortos practicados en España durante 2007 aumenta, Soitu, 2 December 2008 32. ^ La mitad de los abortos en España se practican a mujeres inmigrantes. Las claves: * La tasa española de abortos sigue siendo de las más bajas de las europeas, y muy por detrás de EEUU. * El uso del preservativo ha disminuido, mientras que ha aumentado la 'píldora del día después', 20 minutos, 27 July 2007 33. ^ El número de abortos baja por primera vez en España desde 1999, Público, 13 December 2010 34. ^ La nueva Ley del aborto no disparó el número de interrupciones. En 2010 se realizaron 113.031 intervenciones, un 1,3% más que en 2009, 13 December 2011, Público (España) 35. ^ Interrupción Voluntaria del Embarazo, Ministerio de Sanidad, Política Social e Igualdad, - Datos completos 2010 36. ^ El aborto sube un 5% en un año de crisis 37. ^ a b Gérvas J. Aborto a domicilio Archived 2011-09-13 at the Wayback Machine, Acta Sanitaria, 13 September 2010 38. ^ España, a la cola europea en aborto farmacológico, Solo un 4% de las interrupciones se realiza por este método, mientras en la UE se acercan a la mitad, 23/11/2010 39. ^ a b "Termination of Pregnancy & Abortion in Spain". Archived from the original on 2009-10-03. Retrieved 2010-01-25. 40. ^ a b Huge crowd protests easing Spain's abortion law 41. ^ a b c Spanish Parliament approves abortion bill, sends to Senate 42. ^ Spain OKs new abortion law * v * t * e Abortion in Europe Sovereign states * Albania * Andorra * Armenia * Austria * Azerbaijan * Belarus * Belgium * Bosnia and Herzegovina * Bulgaria * Croatia * Cyprus * Czech Republic * Denmark * Estonia * Finland * France * Georgia * Germany * Greece * Hungary * Iceland * Ireland * * Italy * Kazakhstan * Latvia * Liechtenstein * Lithuania * Luxembourg * Malta * Moldova * Monaco * Montenegro * Netherlands * North Macedonia * Norway * Poland * Portugal * Romania * Russia * San Marino * Serbia * Slovakia * Slovenia * Spain * Sweden * Switzerland * Turkey * Ukraine * United Kingdom * England * Northern Ireland * Scotland * Wales * Vatican City States with limited recognition * Abkhazia * Artsakh * Kosovo * Northern Cyprus * South Ossetia * Transnistria * 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 * Cambodia * China * Cyprus * East Timor * Georgia * India * Iran * Israel * Japan * Kazakhstan * South Korea * Malaysia * Nepal * Northern Cyprus * Philippines * Qatar * Saudi Arabia * Singapore * Turkey * United Arab Emirates * Vietnam * Yemen Europe * Albania * Andorra * Austria * Belarus * Belgium * Bosnia and Herzegovina * Bulgaria * Croatia * Czech Republic * Denmark * Estonia * Finland * France * Germany * Greece * Hungary * Iceland * Ireland * Italy * Kazakhstan * Latvia * Liechtenstein * Lithuania * Luxembourg * Malta * Moldova * Monaco * Montenegro * Netherlands * North Macedonia * Norway * Poland * Portugal * Romania * Russia * San Marino * Serbia * Slovakia * Slovenia * Spain * Sweden * Switzerland * Ukraine * United Kingdom North America * Belize * Canada * Costa Rica * Cuba * Dominican Republic * El Salvador * Guatemala * Mexico * Nicaragua * Panama * Trinidad and Tobago * United States Oceania * Australia * Micronesia * Fiji * Kiribati * Marshall Islands * New Zealand * Papua New Guinea * Samoa * Solomon Islands * Tonga * Tuvalu * Vanuatu South America * Argentina * Bolivia * Brazil * Chile * Colombia * Ecuador * Guyana * Paraguay * Peru * Suriname * Uruguay * Venezuela 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]: 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 inhibitors [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	Abortion in Spain	None	2,944	wikipedia	https://en.wikipedia.org/wiki/Abortion_in_Spain	2021-01-18T18:29:00	{"wikidata": ["Q2874481"]}
Gaucher disease type 1 (GD1) is the most common form of Gaucher disease. Like other types of Gaucher disease, GD1 is caused when not enough glucocerebrosidase (GBA) is made. GBA is an important enzyme that breaks down a fatty chemical called glucocerebroside. Because the body cannot break down this chemical, fat-filled Gaucher cells build up in areas like the spleen, liver and bone marrow. Unlike type 2 and 3, GD1 does not usually involve the brain and spinal cord (central nervous system). Symptoms of GD1 include enlarged spleen and liver, low blood cell counts, bleeding problems and bone disease. The symptoms can range from mild to severe and may appear anytime from childhood to adulthood. Gaucher disease is caused by changes (mutations) in the GBA gene and is inherited in an autosomal recessive manner. Diagnosis is suspected by clinical symptoms and confirmed by measuring GBA enzyme activity or genetic testing. Treatments may include enzyme replacement therapy or medications that affect the making of fatty molecules (substrate reduction therapy). [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 inhibitors [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	Gaucher disease type 1	c1961835	2,945	gard	https://rarediseases.info.nih.gov/diseases/2441/gaucher-disease-type-1	2021-01-18T18:00:22	{"mesh": ["D005776"], "omim": ["230800"], "orphanet": ["77259"], "synonyms": ["Gaucher disease, noncerebral juvenile", "GD 1", "Glucocerebrosidase deficiency", "Acid beta-glucosidase deficiency", "GBA DEFICIENCY"]}
Relatively benign brain cancer involving ependymal cells Subependymoma Micrograph of a subependymoma showing the characteristic clustering of nuclei. H&E stain. SpecialtyNeoplasms A subependymoma is a type of brain tumor; specifically, it is a rare form of ependymal tumor.[1] They are usually in middle aged people. Earlier, they were called subependymal astrocytomas.[2] The prognosis for a subependymoma is better than for most ependymal tumors,[3] and it is considered a grade I tumor in the World Health Organization (WHO) classification. They are classically found within the fourth ventricle, typically have a well demarcated interface to normal tissue and do not usually extend into the brain parenchyma, like ependymomas often do.[4] ## Contents * 1 Symptoms * 2 Pathology * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 References * 7 External links ## Symptoms[edit] Subependymomas of the fourth ventricle, extending into the cerebellopontine angle via the foramen of Luschka, right side of illustration. Patients are often asymptomatic, and are incidentally diagnosed. Larger tumours are often with increased intracranial pressure.[2] ## Pathology[edit] These tumours are small, no more than two centimeters across, coming from the ependyma. The best way to distinguish it from a subependymal giant cell astrocytoma is the size.[2] ## Diagnosis[edit] The diagnosis is based on tissue, e.g. a biopsy. Histologically subependymomas consistent of microcystic spaces and bland appearing cells without appreciable nuclear atypia or mitoses. The nuclei tend to form clusters. On a CT, it often shows a less dense to equalle dense mass. If it is big, it may have parts that are cystic or calcific.[2]In 50-60% of cases, the tumor is in the fourth ventricle, while the second most common (30-40% of cases) location is the side ventricles. It is rare for it to be in the third ventricle or the central canal of the spinal cord.[2] ## Treatment[edit] Asymptomatic cases may only need watchful waiting. If symptomatic, it can be surgically removed, and partial removal also carries an excellent prognosis.[2] ## Prognosis[edit] The outlook of a cure is extremely favorable.[2] ## References[edit] 1. ^ Orakcioglu B, Schramm P, Kohlhof P, Aschoff A, Unterberg A, Halatsch ME (January 2009). "Characteristics of thoracolumbar intramedullary subependymomas". J Neurosurg Spine. 10 (1): 54–9. doi:10.3171/2008.10.SPI08311. PMID 19119934. 2. ^ a b c d e f g Gaillard, Frank. "Subependymoma \| Radiology Reference Article \| Radiopaedia.org". radiopaedia.org. Retrieved 2018-04-15. 3. ^ Prayson RA, Suh JH (April 1999). "Subependymomas: clinicopathologic study of 14 tumors, including comparative MIB-1 immunohistochemical analysis with other ependymal neoplasms". Arch. Pathol. Lab. Med. 123 (4): 306–9. doi:10.1043/0003-9985(1999)123<0306:S>2.0.CO;2 (inactive 2021-01-11). PMID 10320142.CS1 maint: DOI inactive as of January 2021 (link) 4. ^ Hoeffel, C.; Boukobza, M.; Polivka, M.; Lot, G.; Guichard, JP.; Lafitte, F.; Reizine, D.; Merland, JJ. (1995). "MR manifestations of subependymomas". AJNR Am J Neuroradiol. 16 (10): 2121–9. PMID 8585504. ## External links[edit] Classification D * ICD-O: 9383/1 * DiseasesDB: 34807 External resources * Orphanet: 251639 * 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 inhibitors [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	Subependymoma	c0206725	2,946	wikipedia	https://en.wikipedia.org/wiki/Subependymoma	2021-01-18T18:51:10	{"gard": ["10070"], "mesh": ["D018315"], "wikidata": ["Q7631123"]}
A number sign (#) is used with this entry because autosomal dominant deafness-3A (DFNA3A) is caused by heterozygous mutation in the connexin-26 gene (GJB2; 121011) on chromosome 13q12. See also DFNA3B (612643), which is caused by mutation in the connexin-30 gene (GJB6; 604418) on chromosome 13q12. Clinical Features Morle et al. (2000) reported affected members of a large French family with late childhood onset of autosomal dominant nonsyndromic hearing loss. The hearing loss was detected between 10 and 20 years of age. There was significant intrafamilial variability for the severity of the hearing loss, which was restricted to high frequencies during the first decade and progressed to middle frequencies between 10 and 50 years of age. Mapping By linkage analysis, Chaib et al. (1994) mapped a dominant form of sensorineural nonsyndromic deafness to chromosome 13q11. Molecular Genetics Kelsell et al. (1997) identified a mutation in the GJB2 gene (M34T; 121011.0001) in affected members of a pedigree segregating autosomal dominant deafness. They also identified mutations in the GJB2 gene in 3 autosomal recessive nonsyndromic sensorineural deafness pedigrees (DFNB1A; 220290). Kelley et al. (1998) presented evidence that the M34T missense mutation found by Kelsell et al. (1997) was not sufficient to cause hearing loss. They found this allele in a recessive deafness family where it was segregating independently of the hearing loss phenotype; they also found the allele in 3 of 192 control chromosomes, suggesting that it may be a common polymorphism. In all affected members of a large French family with late childhood onset of autosomal dominant isolated hearing loss, Morle et al. (2000) identified a heterozygous mutation in the GJB2 gene (121011.0018). In affected members of a family with early-onset severe to profound nonsyndromic hearing loss, Tekin et al. (2001) identified a heterozygous mutation in the GJB2 gene (W44C; 121011.0019). The mutation had previously been described in association with prelingual nonsyndromic deafness in 2 families originating from the same geographic region of France (Denoyelle et al., 1998). In 4 individuals over 3 generations of a Turkish family with autosomal dominant nonsyndromic congenital profound hearing loss, Piazza et al. (2005) identified heterozygosity for a missense mutation in the GJB2 gene (R75Q; 121011.0026). Cell transfection and fluorescence imaging, dye transfer experiments, and dual patch-clamp recording showed that the mutant protein completely prevented the formation of functional channels. Iossa et al. (2010) reported an Italian family in which an unaffected mother and 1 of her deaf sons were both heterozygous for an allele carrying 2 GJB2 mutations in cis: the dominant R75Q (121011.0026) and the recessive 35delG (121011.0005), whereas her other deaf son did not carry either of these mutations. The results suggested that the recessive mutation 'canceled out' the effect of the dominant mutation by causing a truncated protein before reaching residue 75. Iossa et al. (2010) suggested that the deafness in the 2 sons was due to another genetic cause and highlighted the importance of the report for genetic counseling. INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Deafness, neurosensory MISCELLANEOUS \- Onset in late childhood MOLECULAR BASIS \- Caused by mutation in the gap junction protein, beta-2 gene (GJB2, 121011.0011 ) ▲ 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 inhibitors [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	DEAFNESS, AUTOSOMAL DOMINANT 3A	c2675750	2,947	omim	https://www.omim.org/entry/601544	2019-09-22T16:14:37	{"doid": ["0110564"], "mesh": ["C567277"], "omim": ["601544"], "orphanet": ["90635"], "synonyms": ["Autosomal dominant isolated neurosensory deafness type DFNA", "Autosomal dominant isolated neurosensory hearing loss type DFNA", "Autosomal dominant isolated sensorineural deafness type DFNA", "Autosomal dominant isolated sensorineural hearing loss type DFNA", "Autosomal dominant non-syndromic neurosensory deafness type DFNA", "Autosomal dominant non-syndromic neurosensory hearing loss type DFNA", "Autosomal dominant non-syndromic sensorineural hearing loss type DFNA"], "genereviews": ["NBK1434", "NBK1536"]}
For a general phenotypic description and a discussion of genetic heterogeneity of neuroblastoma, see NBLST1 (256700). Mapping Maris et al. (2008) provided evidence for 1 or more candidate neuroblastoma susceptibility genes on chromosome 6p22. Among 1,032 neuroblastoma patients and 2,043 controls of European descent, the authors observed an association between disease and 3 SNPs on chromosome 6p22: rs6939340, rs4712653, and rs9295536, yielding p values of 1.71 x 10(-9) to 7.01 x 10(-10) (allelic odds ratio of 1.39 to 1.40). The findings suggested that common genetic variants may predispose to increased risk for neuroblastic malignant transformation. In a genomewide analysis of 397 patients with high-risk aggressive neuroblastoma derived from the 1,032 patients in the study of Maris et al. (2008) and 2,043 controls, Capasso et al. (2009) confirmed the association of the 3 SNPs at 6p22 identified by Maris et al. (2008) as being more significantly associated with a high-risk subtype of neuroblastoma. Molecular Genetics Pandey et al. (2014) noted that rs6939340 is located in intron 2 of the NBAT1 gene (616206), which produces a long noncoding RNA. Cell culture and mouse xenograft models demonstrated that NBAT1 has tumor suppressor properties, such as anticell proliferation and anticell invasion. Among 93 neuroblastoma patients, high NBAT1 expression was associated with a better prognosis and longer survival compared to low NBAT1 expression. These results were validated in an independent cohort of 498 neuroblastomas, suggesting that NBAT1 may act as an independent prognostic marker in predicting event-free survival. Sequencing of genomic DNA for the rs6939340 A-to-G in high-risk tumors showed that tumors with the A/A or A/G genotype had higher expression of NBAT1 than G/G tumors. Fragments carrying the A/A genotype generated more luciferase activity in promoter vectors compared to the G/G genotype, suggesting that the region spanning the SNP may contain a putative enhancer element. High-risk patients showed hypermethylation at 5 CpG sites flanking the NBAT1 promoter, whereas low-risk patients showed hypomethylation at these sites and higher NBAT1 expression. The findings indicated that both genetic and epigenetic changes underlie differential expression of NBAT1 and suggested that these changes may be associated with different subtypes of neuroblastoma. [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 inhibitors [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	NEUROBLASTOMA, SUSCEPTIBILITY TO, 4	c0027819	2,948	omim	https://www.omim.org/entry/613015	2019-09-22T16:00:06	{"mesh": ["D009447"], "omim": ["613015"], "orphanet": ["635"]}
Parkes Weber syndrome is a disorder of the vascular system, which is the body's complex network of blood vessels. The vascular system consists of arteries, which carry oxygen-rich blood from the heart to the body's various organs and tissues; veins, which carry blood back to the heart; and capillaries, which are tiny blood vessels that connect arteries and veins. Parkes Weber syndrome is characterized by vascular abnormalities known as capillary malformations and arteriovenous fistulas (AVFs), which are present from birth. The capillary malformations increase blood flow near the surface of the skin. They usually look like large, flat, pink stains on the skin, and because of their color are sometimes called "port-wine stains." In people with Parkes Weber syndrome, capillary malformations occur together with multiple micro-AVFs, which are tiny abnormal connections between arteries and veins that affect blood circulation. These AVFs can be associated with life-threatening complications including abnormal bleeding and heart failure. Another characteristic feature of Parkes Weber syndrome is overgrowth of one limb, most commonly a leg. Abnormal growth occurs in bones and soft tissues, making one of the limbs longer and larger around than the corresponding one. Some vascular abnormalities seen in Parkes Weber syndrome are similar to those that occur in a condition called capillary malformation-arteriovenous malformation syndrome (CM-AVM). CM-AVM and some cases of Parkes Weber syndrome have the same genetic cause. ## Frequency Parkes Weber syndrome is a rare condition; its exact prevalence is unknown. ## Causes Some cases of Parkes Weber syndrome result from mutations in the RASA1 gene. When the condition is caused by RASA1 gene mutations, affected individuals usually have multiple capillary malformations. People with Parkes Weber syndrome who do not have multiple capillary malformations are unlikely to have mutations in the RASA1 gene; in these cases, the cause of the condition is often unknown. The RASA1 gene provides instructions for making a protein known as p120-RasGAP, which is involved in transmitting chemical signals from outside the cell to the nucleus. These signals help control several important cell functions, including the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), and cell movement. The role of the p120-RasGAP protein is not fully understood, although it appears to be essential for the normal development of the vascular system. Mutations in the RASA1 gene lead to the production of a nonfunctional version of the p120-RasGAP protein. A loss of this protein's activity disrupts tightly regulated chemical signaling during development. However, it is unclear how these changes lead to the specific vascular abnormalities and limb overgrowth seen in people with Parkes Weber syndrome. ### Learn more about the gene associated with Parkes Weber syndrome * RASA1 ## Inheritance Pattern Most cases of Parkes Weber syndrome occur in people with no history of the condition in their family. These cases are described as sporadic. When Parkes Weber syndrome is caused by mutations in the RASA1 gene, it is sometimes inherited from an affected parent. In these cases, the condition has an autosomal dominant pattern of inheritance. Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause 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 inhibitors [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	Parkes Weber syndrome	c1842180	2,949	medlineplus	https://medlineplus.gov/genetics/condition/parkes-weber-syndrome/	2021-01-27T08:24:55	{"gard": ["9787"], "mesh": ["C564254"], "omim": ["608354"], "synonyms": []}
A number sign (#) is used with this entry because several chromosome aberrations, including recurrent translocations and deletions, have been found to be related to the development or progression of multiple myeloma; see CYTOGENETICS section. Description Multiple myeloma is a neoplastic plasma cell disorder characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment, monoclonal protein in the blood or urine, and associated organ dysfunction (Palumbo and Anderson, 2011). Clinical Features Leoncini and Korngold (1964) described multiple myeloma in 2 sisters and reviewed the literature on familial cases. Manson (1961) reported affected sisters, one of whom also had pernicious anemia. Myeloma has also been observed in father and son (Nadeau et al., 1956). Thomas (1964) observed myeloma in a brother and sister. Alexander and Benninghoff (1965) described 3 affected black sibs. Whitehouse (1971) observed affected brother and sister. In a large population survey in Sweden, Axelsson and Hallen (1965) found 2 families, one with 2 and one with 3 sibs, showing high monoclonal (M)-component. In a third family, 2 persons with high M-component were more remotely related. These 7 were from a total group of 59 (out of 7,918) found to have M-component. Their condition was considered to be a variety of essential benign monoclonal hypergammaglobulinemia. Berlin et al. (1968) described familial occurrence of M-components. One possible explanation for familial paraproteinemia is that plasma cell clones with similar structural genes for the paraprotein synthesized by these cells proliferate in related individuals. This hypothesis predicts that paraproteins from 2 members of the same family would be identical. The paraproteins of a mother with multiple myeloma and a son with probably benign monoclonal gammopathy were isolated by Grant et al. (1971). Light chains were of the lambda type, but had differences on peptide map in both the common and variable regions of the proteins. These data showed that the structural genes operative in paraprotein light chain production in these first-degree relatives are different. The presence of a genetic basis was suggested by the occurrence of 2 different monoclonal gammopathies in 1 patient. Humphrey (1973) described a patient who had an intracranial plasmacytoma that was surgically removed. Six years later she developed a plasmacytoma of 1 kidney. The second tumor produced a different gamma globulin from that released into the cerebrospinal fluid by the brain plasmacytoma. Zawadzki et al. (1977) described 19 cases of familial immunopathy, distributed in 9 families. Ten members of 5 families had multiple myeloma, 5 members of 2 families had lanthanic paraproteinemia, and 4 members of 2 families had one or the other of these. 'Lanthanic' is from a Greek word meaning 'to escape.' It is used in place of 'benign' because malignant immunocytic dyscrasia has been known to emerge. The term is intended to convey that the condition was asymptomatic and came to attention only by serendipity. (Actually, in the course of a specific study of relatives of clinically affected probands, this is not serendipity; Walpole's Prince of Serendip set out to find one thing and instead found something else (Cannon, 1945).) Blattner (1980) gave an excellent review, with a classification of monoclonal gammopathies. Multiple myeloma and Waldenstrom macroglobulinemia (153600) are presumably closely related; both are malignant monoclonal gammopathies. Multiple myeloma is about 2 times more frequent in U.S. blacks than in US whites; it is the eleventh and twentieth most frequent malignancy in the 2 races, respectively. Horwitz et al. (1985) reported 3 affected sibs and stated that a review of the literature revealed reports of 38 affected pairs of sibs, 8 families with 3 affected sibs, and 4 families with another affected relative (in addition to the pair of affected sibs). Comotti et al. (1987) and Judson et al. (1985) reported identical twins concordant for multiple myeloma. Jensen et al. (1988) described a brother and sister with progressive mixed axonal and demyelinating polyneuropathy in association with a monoclonal IgM gammopathy of kappa and lambda type, respectively. Sera from both patients contained antibodies directed to bovine peripheral nerve myelin as determined by ELISA technique and to normal human peripheral nerve myelin as demonstrated by indirect immunofluorescence histochemistry. These sibs may have had a genetic predisposition to the formation of autoantibodies with peripheral nerve myelin as the target. Deshpande et al. (1998) described 5 families in which plasma cell dyscrasia occurred in parent and child generations (6 such pairs), and pooled data with those of 16 other families (with 20 parent-child pairs affected) recorded in the literature. In all 6 previously unreported parent-child pairs with plasma cell dyscrasia and in 18 of 20 such pairs found in the literature, the disease occurred at an earlier age in the child generation. The median age of onset of myeloma in parent and child generations of all 26 pairs was 71 years and 50 years, respectively. The ages of onset of malignant plasma cell dyscrasias in the parent and child generations of these families compared with patients in the general population was significantly different for the child generation but not for the parent generation. It thus appears that anticipation occurs in familial myeloma. Grosbois et al. (1999) studied 15 families with 2 or more cases of multiple myeloma. In 10 of the 15, myeloma was observed in sibs, in whom the mean age at diagnosis was similar to that in unrelated multiple myeloma cases. In those families with multiple myeloma in successive generations, the mean age at diagnosis was lower. The monoclonal component was identical (IgG kappa) in 7 families. A family history of monoclonal gammopathy of undetermined significance was observed in 3 families. Five other prospective studies of 1,263 patients identified 4 affected families (3.2 per 1,000 cases of multiple myeloma). Lynch et al. (2008) reported a large African American family in which 5 individuals had multiple myeloma, 3 had monoclonal gammopathy of undetermined significance (MGUS), i.e., without signs of malignant lymphocytic or plasmocytic disease, and 5 had prostate cancer. One additional member had pancreatic cancer. The putative progenitor had died of colon cancer at age 88 years. ### Systemic (AL) Amyloidosis AL amyloidosis, formerly called primary amyloidosis, is a protein conformation disorder associated with a clonal plasma cell dyscrasia (Falk et al., 1997). Multiple organ disease results from the extracellular deposition of monoclonal immunoglobulin light chain fragments in an abnormal insoluble fibrillar form. AL amyloidosis may be associated with myeloma or other B-cell malignancy, but in most cases the underlying plasma cell dyscrasia is subtle and nonproliferating, analogous to MGUS (Guidelines Working Group of UK Myeloma Forum, 2004). Gertz et al. (1986) reported primary immunoglobulin-related amyloidosis in 2 members of each of 3 families: 2 brothers, a brother and a sister, and 2 first cousins. Primary amyloidosis of this type may be closely akin to multiple myeloma and to Waldenstrom macroglobulinemia. Miliani et al. (1996) described 3 Italian sibs (2 brothers and a sister) with immunoglobulin-related amyloidosis. Systemic amyloidosis was associated with monoclonal gammopathy in all 3. One of the sibs had Waldenstrom macroglobulinemia, whereas the other 2 had no evidence of multiple myeloma or related diseases. All 3 sibs showed a common pattern of polyneuropathy to different degrees; 2 presented a sicca syndrome and 1 also suffered from nephropathy. Dispenzieri et al. (2004) concluded that high-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) in AL patients is associated with higher response rates and higher overall survival than standard chemotherapy. Their conclusion was based on a matched case-control study comparing overall survival of 63 AL patients undergoing transplantation with 63 patients not undergoing transplantation. Cytogenetics Dysregulation of oncogenes by translocations to the IgH locus (147100) on 14q32 is a seminal event in the pathogenesis of B-cell tumors, including multiple myeloma. Translocations to the IgH locus occur in 20 to 60% of cases of myeloma; a diverse array of chromosomal partners have been identified, with 11q13 (see cyclin D1; 168461) being frequently involved. Bergsagel et al. (1996) developed a comprehensive Southern blot assay to identify and distinguish different kinds of IgH switch recombination events. Illegitimate switch recombination fragments (defined as containing sequences from only 1 switch region) are potential markers of translocation events into IgH switch regions and were identified in 15 of 21 myeloma cell lines, including 7 of 8 karyotyped lines that had no detectable 14q32 translocation. These translocation breakpoints involved 6 chromosomal loci: 4p16.3; 6; 8q24.13; 11q13.3; 16q23.1; and 21q22.1. Chesi et al. (1997) found the novel, karyotypically silent translocation t(4;14)(p16.3;q32.3) in 5 myeloma cells lines and in at least 3 of 10 primary tumors. The chromosome-4 breakpoints were clustered in a 70-kb region centromeric to FGFR3 (134934), which was thought to be the dysregulated oncogene. This translocation selectively expressed an FGFR3 allele containing activating mutations identified previously in thanatophoric dwarfism: tyr373 to cys (134934.0016), lys650 to glu (134934.0004), and lys650 to met (134934.0015). For K650E, the constitutive activation of FGFR3 in the absence of ligand had been proved by transfection experiments. Chesi et al. (1997) proposed that after the t(4;14) translocation, somatic mutation during tumor progression frequently generates an FGFR3 protein that is active in the absence of ligand. Although they could not exclude the possibility that other genes are dysregulated by the translocation t(4;14), several findings pointed to FGFR3. FGFR3 is located no more than 100 kb from the most centromeric breakpoint at 4p16.3, and is on the derivative(14) chromosome that contains the 3-prime IgH enhancer. This is similar to the situation for cyclin D1, which is located 100 to 400 kb from the breakpoint in the translocation t(11;14) that occurs in mantle-cell lymphoma and multiple myeloma tumors. FGFR3 is another example of a gene that can function both as an oncogene and a 'teratogene.' Palumbo and Anderson (2011) noted that primary early translocations at the Ig switch region at 14q32.33 are commonly juxtaposed to MAF (177075) on chromosome 16q23 and MMSET (602952) on chromosome 4p16.3; the latter results in the deregulation of FGFR3 in 30% of cases. In multiple myeloma cell lines, Iida et al. (1997) identified a t(6;14)(p25;q32) translocation in 2 of 11 cell lines. The translocation juxtaposes the immunoglobulin heavy-chain (IGHG1; 147100) locus to the MUM1 gene (IRF4; 601900), a member of a gene family known to be active in the control of B-cell proliferation and differentiation. As a result of the translocation, the MUM1/IRF4 gene is overexpressed, an event that may contribute to tumorigenesis, as Iida et al. (1997) showed that MUM1/IRF4 has oncogenic activity in vitro. In a study of 32 patients with AL (24 with systemic and 8 with localized disease), Harrison et al. (2002) found translocations involving IGH and in addition found deletions of 13q, using dual-color interface fluorescence in situ hybridization. IGH translocations were observed in 11 patients, of whom 9 had the IGH/CCND1 (168461) fusion from t(11;14)(q13;q32). Mohamed et al. (2007) reviewed the chromosome aberrations in a series of 120 multiple myeloma cases with abnormal karyotypes. Pathogenesis BCLB (BCL2L10; 606910) is an antiapoptotic BCL2 (151430) family protein that is expressed predominantly in B lymphocytes. Using flow cytometric and Western blot analyses, Hamouda et al. (2016) found high expression of BCLB in MM patients compared with low or undetectable expression in MGUS patients and healthy donors. Hamouda et al. (2016) proposed that BCLB may be a robust marker of MM. Molecular Genetics Shaffer et al. (2008) used a loss-of-function, RNA interference-based genetic screen to demonstrate that inhibition of IRF4 (601900) is toxic to myeloma cell lines, regardless of transforming oncogenic mechanism. Gene expression profiling and genomewide chromatin immunoprecipitation analysis uncovered an extensive network of IRF4 target genes and identified MYC (190080) as a direct target of IRF4 in activated B cells and myeloma. Unexpectedly, IRF4 was itself a direct target of MYC transactivation, generating an autoregulatory circuit in myeloma cells. Shaffer et al. (2008) suggested that although IRF4 is not genetically altered in most myelomas, they are nonetheless addicted to an aberrant IRF4 regulatory network that fuses the gene expression programs of normal plasma cells and activated B cells. Roddam et al. (2002) investigated the potential impact of 2 LIG4 polymorphisms--ala3 to val (A3V; 601837.0005) and thr9 to ile (T9I; 601837.0006), both caused by C-to-T transitions--on predisposition to several lymphoproliferative disorders, including leukemia, lymphoma, and multiple myeloma (254500), a tumor characterized by aberrant immunoglobulin class switch recombination. The A3V CT and T9I CT and TT genotypes were significantly associated with reduction in risk of developing multiple myeloma. The polymorphisms were in linkage disequilibrium, and a protective effect associated with them was found to be the result of the inheritance of the A3V-T9I CT and A3V-T9I TT haplotypes. These data suggested that genetic variants of NHEJ LIG4 may modulate predisposition to multiple myeloma. One complication of multiple myeloma patients on bisphosphonate therapy is osteonecrosis of the jaw. In a genomewide association study of 2 series of patients with multiple myeloma, 1 group of 22 with osteonecrosis of the jaw and another group of 65 patients without osteonecrosis of the jaw, Sarasquete et al. (2008) found a significant association between development of the complication and 4 SNPs (rs1934951, rs1934980, rs1341162, and rs17110453) mapping to chromosome 10q23 in the CYP2C8 gene (601129) (p values ranging from 1.07 x 10(-6) to 6.22 x 10(-6)). One SNP, rs1934951, remained significant even after Bonferroni correction (p corrected value = .02). Genotyping revealed an overrepresentation of the T allele of this SNP in cases compared to controls (48% vs 12%). Individuals homozygous for the T allele had a significantly increased likelihood of developing osteonecrosis of the jaw (odds ratio of 12.75). Preuss et al. (2009) screened a human fetal brain-derived macroarray with the IgA or IgG paraprotein-containing sera of 192 consecutive patients with monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma, and found that 29 (15.1%) of the 192 paraproteins reacted with a protein they designated 'paratarg-7,' which was found to be identical to stomatin-like protein-2 (STOML2; 608292). Grass et al. (2009) studied 35 probands with MGUS or multiple myeloma who had an antiparatarg-7 paraprotein and found that all 35 patients expressed hyperphosphorylated paratarg-7 (615121), whereas hyperphosphorylation was not observed in 217 other patients with MGUS or multiple myeloma whose paraprotein did not bind to paratarg-7. Paratarg-7 hyperphosphorylation was also found in 4 (2%) of 200 healthy blood donors, none of whom had monoclonal immunoglobulins in their serum. Thus, hyperphosphorylation of paratarg-7 appeared to be associated with a significantly increased risk of developing MGUS or multiple myeloma (odds ratio, 7.9; p = 0.0001). Analysis of 8 of the 35 families with paratarg-7-specific paraprotein in their serum showed that the hyperphosphorylated state of paratarg-7 was inherited in an autosomal dominant fashion. Grass et al. (2009) noted that there were healthy carriers of hyperphosphorylated paratarg-7 who were older than the respective index patient, indicating that factors other than age determine if and when a carrier of hyperphosphorylated paratarg-7 develops a paratarg-7-specific paraprotein. Chapman et al. (2011) reported the massively parallel sequencing of 38 tumor genomes and their comparison to matched normal DNAs from individuals with multiple myeloma. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These included the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-kappa-B (see 164011) signaling was indicated by mutations in 11 members of the NF-kappa-B pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF (164757) were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. Weinhold et al. (2013) found an association between the 870G allele of a polymorphism in the CCND1 gene (168461.0001) and risk of t(11;14) multiple myeloma. Li et al. (2017) noted that genomewide association studies have suggested that variation at chromosome 5q15 influences risk of MM. They identified a G-C SNP, rs6877329, within a predicted enhancer element that physically interacted with the transcription start site of ELL2 (601874), which is critical for B-cell differentiation. The C risk allele of rs6877329 was associated with reduced enhancer activity and lower ELL2 expression. Li et al. (2017) proposed that reduced ELL2 expression may contribute to arrest of plasma-cell development and facilitate MM clonal expansion. Animal Model Plasma cell tumor induction in mice by pristane is under multigenic control. Backcross and congenic strain analyses indicated that at least 4 genes determine the susceptibility to mouse plasmacytomagenesis. One of these genes, Pctr1, resides in the mid-portion of mouse chromosome 4 near the alpha-interferon locus. Zhang et al. (1998) presented evidence that Cdkn2a (600160) is a strong candidate for the Pctr1 locus. Hamouda et al. (2016) noted that the closest homolog of human BCLB in mouse exhibits different expression and function than the human protein. They generated transgenic mice expressing human BCLB exclusively in B lymphocytes. Mice expressing BCLB developed an MM-like disease. Survival of homozygous (+/+) BCLB-expressing mice was significantly lower than wildtype, and hemizygous (-/+) BCLB-expressing mice had intermediate survival with increased numbers of Cd138 (SDC1; 186355)-positive plasmocytes. Hemizygous Bclb-expressing mice exhibited monoclonal hypergammaglobulinemia. Malignant plasma cells of hemizygous Bclb-expressing mice were both transplantable and treatable with conventional MM therapies. Hamouda et al. (2016) proposed that BCLB-expressing mice recapitulate the pathogenesis of human MM and may be valuable in evaluating novel MM therapies. INHERITANCE \- Somatic mutation NEOPLASIA \- Multiple myeloma LABORATORY ABNORMALITIES \- High M-component \- Monoclonal gammopathy \- Primary immunoglobulin-related amyloidosis (AL) \- Paraproteinemia ▲ 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 inhibitors [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	MYELOMA, MULTIPLE	c0026764	2,950	omim	https://www.omim.org/entry/254500	2019-09-22T16:24:41	{"doid": ["9538"], "mesh": ["D009101"], "omim": ["254500"], "icd-9": ["203.0"], "icd-10": ["C90.0", "C90.00"], "orphanet": ["29073", "314701", "85443"]}
Oodinium, a genus of parasitic dinoflagellates, causes velvet disease in fish Velvet disease (also called gold-dust, rust and coral disease) is a fish disease caused by dinoflagellate parasites of the genus Piscinoodinium, specifically Amyloodinium in marine fish, and Oodinium in freshwater fish. The disease gives infected organisms a dusty, brownish-gold color. The disease occurs most commonly in tropical fish, and to a lesser extent, marine aquaria.[1] ## Contents * 1 Life cycle * 2 Pathology * 3 Symptoms * 4 Treatment * 5 See also * 6 References ## Life cycle[edit] The single-celled parasite's life cycle can be divided into three major phases. First, as a tomont, the parasite rests at the water's floor and divides into as many as 256 tomites. Second, these juvenile, motile tomites swim about in search of a fish host, meanwhile using photosynthesis to grow, and to fuel their search. Finally, the adolescent tomite finds and enters the slime coat of a host fish, dissolving and consuming the host's cells, and needing only three days to reach full maturity before detaching to become a tomont once more.[2] ## Pathology[edit] A 15-day old Siamese fighting fish (Betta splendens) with velvet disease Velvet (in an aquarium environment) is usually spread by contaminated tanks, fish, and tools (such as nets or testing supplies). There are also rare reports of frozen live foods (such as bloodworms) containing dormant forms of the species. Frequently, however, the parasite is endemic to a fish, and only causes a noticeable "outbreak" after the fish's immune system is compromised for some other reason. The disease is highly contagious and can prove fatal to fish. ## Symptoms[edit] Adult Siamese fighting fish (Betta splendens) with velvet disease Initially, infected fish are known to "flash", or sporadically dart from one end of an aquarium to another, scratching against objects in order to relieve their discomfort. They will also "clamp" their fins very close to their body, and exhibit lethargy. If untreated, a 'dusting' of particles (which are in fact the parasites) will be seen all over the infected fish, ranging in color from brown to gold to green. In the most advanced stages, fish will have difficulty respiring, will often refuse food, and will eventually die of hypoxia due to necrosis of their gill tissue.[3] ## Treatment[edit] Sodium chloride (table/sea salt) is believed to mitigate the reproduction of velvet, however this treatment is not itself sufficient for the complete eradication of an outbreak. Additional, common medications added directly to the fish's environment include copper sulfate, methylene blue, formalin, malachite green and acriflavin, all of which can be found in common fish medications designed specifically to combat this disease. Additionally, because velvet parasites derive a portion of their energy from photosynthesis, leaving a tank in total darkness for seven days provides a helpful supplement to chemical curatives. Finally, some enthusiasts recommend raising the water temperature of an infected fish's environment, in order to quicken the life cycle (and subsequent death) of velvet parasites; however this tactic is not practical for all fish, and may induce immunocompromising stress.[4] ## See also[edit] * Pfiesteria piscicida ## References[edit] 1. ^ "Protozoa Infecting Gills and Skin". The Merck Veterinary Manual. Archived from the original on 3 March 2016. Retrieved 14 September 2017. "One of the most serious health problems of captive marine fish is the parasitic dinoflagellate Amyloodinium spp. Its freshwater counterpart, Oodinium spp, is less common but can also result in high mortality. These parasites produce a disease that has been called “velvet,” “rust,” “gold-dust,” and “coral disease” because of the brownish gold color they impart to infected fish. The pathogenic stages of the organism are pigmented, photosynthetic, nonflagellated, nonmotile algae that attach to and invade the skin and gills during their parasitic existence. When mature, these parasites give rise to cysts that contain numerous flagellated, small, free-swimming stages that can initiate new infections" 2. ^ Baker, David G (2007). Phylum Dinoflagellata. Flynn's Parasites of Laboratory Animals. ISBN 9780470344170. Retrieved 2011-05-01. 3. ^ "Shedding Light on Velvet Disease". Federation of British Aquatic Societies. 2005. Retrieved 2011-05-01. 4. ^ "Freshwater Velvet - Piscinoodinium pillulare & Costia". Aquarium and Pond Answers. 2007. Retrieved 2011-05-01. * v * t * e Plankton About plankton * Algal bloom * CLAW hypothesis * High lipid content microalgae * Holoplankton * Marine microorganisms * Meroplankton * Mycoplankton * Milky seas effect * Paradox of the plankton * Planktivore * Planktology * Red tide * Spring bloom * Thin layers * More... By size * Eukaryotic picoplankton * Heterotrophic picoplankton * Marine microplankton * Microphyte (microalgae) * Nanophytoplankton * Photosynthetic picoplankton * Picobiliphyte * Picoeukaryote * Picoplankton Bacterioplankton * Bacteriastrum * Aeromonas salmonicida * Cyanobacteria * Cyanobiont * Cyanotoxin * Enteric redmouth disease * Flavobacterium * Flavobacterium columnare * Pelagibacter ubique * Marine bacteriophage * SAR11 clade * Streptococcus iniae Phytoplankton * Auxospore * Axodine * Chaetoceros * Chaetocerotaceae * Coccolithophore * Emiliania huxleyi * Eustigmatophyte * Frustule * Heterokont * Nannochloropsis * Navicula * Prasinophyceae * Raphidophyte * Thalassiosira pseudonana Diatom orders * Centrales * Pennales * Classes: Coscinodiscophyceae * Fragilariophyceae * Bacillariophyceae Flagellates * Brevetoxin * Choanoflagellates * Dinoflagellates * Flagellum * Pfiesteria piscicida * Saxitoxin * Symbiodinium * Velvet (fish disease) Zooplankton * Chaetognatha * Ciguatera * Ctenophora * Gelatinous zooplankton * Hunting copepods * Ichthyoplankton * Jellyfish * Marine larvae * Crustacean larvae * Salmon louse * Sea louse Copepod orders * Calanoida * Cyclopoida * Harpacticoida * Monstrilloida * Poecilostomatoida * Siphonostomatoida * More... Related topics * Aeroplankton * Algaculture * Algal mat * Algal nutrient solutions * Artificial seawater * Autotrophs * Biological pump * Diel vertical migration * Dimethylsulfoniopropionate * f-ratio * Fish disease and parasites * Heterotroph * HNLC * Macroalgae * Manta trawl * Marine mucilage * Microbial mat * Ocean acidification * Marine microorganisms * Marine primary production * Pseudoplankton * Stromatolite * Tychoplankton * Zoid * C-MORE * CPR * AusCPR * MOCNESS * SCAR * v * t * e Fish diseases and parasites Pathogens * Aeromonas salmonicida * Nervous necrosis virus * Columnaris * Enteric redmouth * Fin rot * Fish dropsy * Flavobacterium * Hematopoietic necrosis * Heterosigma akashiwo * Hole in the head * Hypodermal and hematopoietic necrosis * Infectious pancreatic necrosis * Koi herpes virus * Mycobacterium marinum * Novirhabdovirus * Pfiesteria piscicida * Photobacterium damselae ssp piscicida * Salmon anemia * Streptococcus iniae * Spring viraemia of carp * Taura syndrome * UDN * VHS * White spot * Yellowhead Parasites * Abergasilus * Amoebic gill disease * Anisakis * Carp lice * Ceratomyxa shasta * Clinostomum marginatum * Dactylogyrus vastator * Diphyllobothrium * Cymothoa exigua * Eustrongylidosis * Epizootic ulcerative syndrome * Flukes * Glugea * Gyrodactylus salaris * Henneguya zschokkei * Ich (freshwater) * Ich (marine) * Kudoa thyrsites * Lernaeocera branchialis * Microsporidia * Monogenea * Myxobolus cerebralis * Myxosporea * Nanophyetus salmincola * Pseudorhabdosynochus spp. * Salmon lice * Saprolegnia * Schistocephalus solidus * Sea louse * Sphaerothecum destruens * Swim bladder disease * Tetracapsuloides bryosalmonae * Velvet * Xenoma Fish groups * Diseases and parasites in cod * Diseases and parasites in salmon * Disease in ornamental fish * List of aquarium diseases Related topics * Amnesic shellfish poisoning * Brevetoxin * Ciguatera * Diarrheal shellfish poisoning * Fish kill * Marine viruses * Neurotoxic shellfish poisoning * Paralytic shellfish poisoning * Saxitoxin [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 inhibitors [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	Velvet (fish disease)	None	2,951	wikipedia	https://en.wikipedia.org/wiki/Velvet_(fish_disease)	2021-01-18T18:52:07	{"wikidata": ["Q2217862"]}
A number sign (#) is used with this entry because of evidence that this form of autosomal recessive mental retardation (MRT6) is caused by homozygous mutation in the ionotropic glutamate receptor-6 gene (GRIK2; 138244) on chromosome 6q16. Clinical Features Motazacker et al. (2007) reviewed phenotypic features of the 5-generation family with 6 affected members in 2 sibships described by Najmabadi et al. (2007) as family M097. Mental retardation in affected members ranged from mild to severe. They noted that the patients did not have neurologic problems, congenital malformations, or facial dysmorphism. Body height, weight, and head circumference were normal in all patients. MRI scan, performed in 1 patient, revealed no morphologic abnormalities. Cordoba et al. (2015) reported 2 adult sibs, born of consanguineous parents, with delayed development from birth, cognitive impairment, and well-controlled seizures; one of the patients had movement abnormalities, including dystonia, tremor, and myoclonus. Inheritance The transmission pattern in the family with MRT6 reported by Cordoba et al. (2015) was consistent with autosomal recessive inheritance. Mapping Najmabadi et al. (2007) reported a large consanguineous Iranian family (M097) in which 6 individuals had nonsyndromic mental retardation. Linkage analysis identified a candidate locus on chromosome 6, termed MRT6, with a maximum lod score of 4.3. Haplotype analysis delineated a 10.0-Mb candidate region between rs2246786 and rs720225. Molecular Genetics Motazacker et al. (2007) stated that the MRT6 locus contains 25 annotated genes, of which 8 were considered to be plausible candidate genes for mental retardation and were selected for mutation screening. In DNA from patients from the Iranian family (M097) studied by Najmabadi et al. (2007), Motazacker et al. (2007) detected a complex mutation in the GRIK2 gene (138244.0001). In 2 adult sibs, born of consanguineous parents, with MRT6, Cordoba et al. (2015) identified a homozygous truncating mutation in the GRIK2 gene (R198X; 138244.0002). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. INHERITANCE \- Autosomal recessive NEUROLOGIC Central Nervous System \- Delayed development \- Mental retardation \- Seizures (in some patients) \- Involuntary movements (1 patient) \- Myoclonus (1 patient) \- Dystonia (1 patient) \- Tremor (1 patient) MISCELLANEOUS \- Onset in infancy \- Eight patients from 2 unrelated families have been reported (last curated March 2015) MOLECULAR BASIS \- Caused by mutation in the glutamate receptor, ionotropic, kainate 2 gene (GRIK2, 138244.0001 ) ▲ 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 inhibitors [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	MENTAL RETARDATION, AUTOSOMAL RECESSIVE 6	c1970198	2,952	omim	https://www.omim.org/entry/611092	2019-09-22T16:03:39	{"doid": ["0060308"], "mesh": ["C567017"], "omim": ["611092"], "orphanet": ["88616"], "synonyms": ["AR-NSID", "NS-ARID"]}
A rare ciliopathy characterized by progressive hearing and visual loss in the first decades of life and, in some cases, vestibular dysfunction. Patients have normal hearing at birth. Onset of hearing loss is usually in late childhood or adolescence after development of speech. Profound deafness is mostly reported by middle age. Retinitis pigmentosa related visual loss also develops in late childhood or adolescence. Developmental motor milestones are generally normal but vestibular dysfunction may occur in adulthood. [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 inhibitors [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	Usher syndrome type 3	c1568248	2,953	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=231183	2021-01-23T17:37:50	{"gard": ["5442"], "mesh": ["D052245"], "omim": ["276902", "500004", "614504"], "umls": ["C1568248"], "icd-10": ["H35.5"], "synonyms": ["USH3"]}
Frontotemporal dementia (FTD) comprises a group of neurodegenerative disorders, characterized by progressive changes in behavior, executive dysfunction and language impairment, as a result of degeneration of the medial prefrontal and frontoinsular cortices. Four clinical subtypes have been identified: semantic dementia, progressive non-fluent aphasia, behavioral variant FTD and right temporal lobar atrophy (see these terms). [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 inhibitors [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	Frontotemporal dementia	c0338451	2,954	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=282	2021-01-23T18:00:52	{"gard": ["8436"], "mesh": ["D057180"], "omim": ["172700", "600274", "600795", "607485"], "umls": ["C0338451"], "icd-10": ["G31.0"], "synonyms": ["FTD"]}
Jalili (1989) studied 2 female cousins, both the products of consanguineous marriages, affected with severe retinal dystrophy characterized by visual impairment from birth and profound photophobia in the absence of night blindness. The ophthalmologic characteristics suggested a cone-rod type of congenital amaurosis. Associated in both girls was trichomegaly (190330), bushy eyebrows with synophrys, and excessive facial and body hair (including hypertrophied circumareolar hair on the breasts of the older, postpubertal cousin). The patients were not mentally retarded; see 275400. Hair \- Trichomegaly \- Bushy eyebrows \- Synophrys \- Hirsutism Eye \- Severe retinal dystrophy \- Congenital visual impairment \- Profound photophobia Neuro \- Normal intelligence 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 inhibitors [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	AMAUROSIS CONGENITA, CONE-ROD TYPE, WITH CONGENITAL HYPERTRICHOSIS	c1857588	2,955	omim	https://www.omim.org/entry/204110	2019-09-22T16:31:11	{"mesh": ["C536604"], "omim": ["204110"], "orphanet": ["1021"]}
Spinal enthesopathy SpecialtyRheumatology Spinal enthesopathy is a form of enthesopathy affecting the spine.[1] ## References[edit] 1. ^ Ball, John (1 January 1983). "The Enthesopathy of Ankylosing Spondylitis". Rheumatology. XXII (suppl_2): 25–28. doi:10.1093/rheumatology/XXII.suppl_2.25. ## External links[edit] Classification D * ICD-10: M46.0 * ICD-9-CM: 720.1 * v * t * e Spinal disease Deforming Spinal curvature * Kyphosis * Lordosis * Scoliosis Other * Scheuermann's disease * Torticollis Spondylopathy inflammatory * Spondylitis * Ankylosing spondylitis * Sacroiliitis * Discitis * Spondylodiscitis * Pott disease non inflammatory * Spondylosis * Spondylolysis * Spondylolisthesis * Retrolisthesis * Spinal stenosis * Facet syndrome Back pain * Neck pain * Upper back pain * Low back pain * Coccydynia * Sciatica * Radiculopathy Intervertebral disc disorder * Schmorl's nodes * Degenerative disc disease * Spinal disc herniation * Facet joint arthrosis This article about a disease of musculoskeletal and connective tissue 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 inhibitors [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	Spinal enthesopathy	c0152090	2,956	wikipedia	https://en.wikipedia.org/wiki/Spinal_enthesopathy	2021-01-18T18:48:02	{"icd-9": ["720.1"], "icd-10": ["M46.0"], "wikidata": ["Q7577458"]}
Contact granuloma Other namesContact ulcer, Vocal fold contact ulcer or Vocal process granuloma Healthy vocal folds. Contact granulomas may form in the posterior part of the larynx. SpecialtyOtolaryngologist Contact granuloma is a condition that develops due to persistent tissue irritation in the posterior larynx.[1][2] Benign granulomas, not to be confused with other types of granulomas, occur on the vocal process of the vocal folds, where the vocal ligament attaches. Signs and symptoms may include hoarseness of the voice, or a sensation of having a lump in the throat, but contact granulomas may also be without symptoms.[3] There are two common causes associated with contact granulomas; the first common cause is sustained periods of increased pressure on the vocal folds, and is commonly seen in people who use their voice excessively, such as singers (John Mayer, for example).[4] Treatment typically includes voice therapy and changes to lifestyle factors. The second common cause of granulomas is gastroesophageal reflux and is controlled primarily through the use of anti-reflux medication.[5] Other associated causes are discussed below. ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Mechanical issues * 2.2 Inflammatory issues * 2.3 Intubation * 2.4 Psychosocial factors * 3 Diagnosis * 3.1 Physical characteristics * 3.2 Differential diagnosis * 4 Screening * 5 Prevention * 6 Treatment * 6.1 Steroids * 6.2 Botox injection * 7 Prognosis * 8 Epidemiology * 9 Terminology * 10 Sources * 11 References ## Signs and symptoms[edit] The primary symptoms of contact granuloma include chronic or acute hoarseness of the voice and vocal fatigue.[6][7] More severe granulomas may result in throat ache or soreness, as well as pain that spreads to one or both ears.[1][7] Smaller granulomas may result in a tickling sensation or slight discomfort. Signs of contact granulomas are frequent coughing and throat-clearing.[7][5] Some people may also notice that their pitch range is restricted due to granuloma.[1] ## Causes[edit] The major etiologic factors of contact granulomas have been organized into the following categories: ### Mechanical issues[edit] Mechanical issues resulting in contact granulomas are related to physical trauma at the level of the vocal folds.[1][8] Trauma occurs when adductive forces are excessive, meaning that a person's vocal folds are closing abruptly and forcefully while speaking or engaging in other non-vocal behaviors (such as throat-clearing and coughing).[1][5][8] In addition, the presence of the contact granuloma makes it impossible for the vocal folds to come to a complete closure in adduction. This causes the person to use more force when speaking in an attempt to close the vocal folds completely, which in turn creates more trauma to the vocal folds.[9] Glottal insufficiency (when the vocal folds cannot close completely, often due to vocal fold paralysis) can also be an underlying cause of contact granulomas.[5] Contact trauma can occur when a person frequently speaks at a pitch that is lower than their modal voice, especially in vocally-demanding professions like acting, teaching and singing.[1] Research suggests that men are more commonly affected than women.[5][8] ### Inflammatory issues[edit] Inflammatory issues associated with contact granuloma include gastroesophageal reflux, allergy or infection.[1][5][10] There is some disagreement among researchers as to whether inflammatory issues are a direct cause.[8] Some researchers identify reflux and infection as indirect causes due to aggressive coughing that usually occurs as a result.[citation needed] ### Intubation[edit] Main article: Intubation granuloma For patients in need of tracheal intubation to receive oral drugs, an oversized tube, excessive movement of the tube, or infection can lead to contact granulomas, but this is rare.[1][5][8] ### Psychosocial factors[edit] People with certain personality traits and vocal patterns may be more susceptible to the development of contact granulomas.[8][10][11] Tenseness, high-stress, aggressiveness and impulsiveness are personality traits associated with contact granuloma.[5][8] ## Diagnosis[edit] Diagnosis of contact ulcers normally involves an endoscopy examination, and a biopsy sample is taken so that the ulcer can be examined for cancerous cells. ### Physical characteristics[edit] Contact granulomas can be physically identified and diagnosed by observing the presence of proliferative tissue originating from the vocal process of the arytenoid cartilage.[5] Identification is carried out by laryngoscopy, which produces an image of the lesion in the form of an abnormal growth (nodule or polyp) or ulceration.[8][5] The vocal process is overwhelmingly the most common laryngeal site for these lesions, although they have also been observed on the medial and anterior portions of the vocal folds.[8] In nodule or polyp form, contact granulomas generally have a grey or dark red colouring[8][5] and measure 2 to 15 mm in size.[5] Contact granulomas can occur unilaterally or bilaterally, affecting one or both vocal folds.[8][5] ### Differential diagnosis[edit] Various methods are used to diagnose contact granuloma which aid in differentiating it from other vocal fold pathology.[12][13][3][8] Laryngoscopy can allow visualization of the suspected granuloma while also checking for signs of vocal abuse.[12][8] Laryngoscopy, as well as an acoustic analysis of the voice, can help rule out vocal fold paresis as an underlying cause.[12][8] Microscopic examination of the tissue can help determine that the lesion is benign rather than cancerous, as would be the case in contact granuloma.[8] Other methods such as laryngeal electromyography and reflux testing can also be used to evaluate the function of the vocal folds and determine if laryngopharyngeal reflux is contributing to the pathology.[12] ## Screening[edit] Screening tools for contact granulomas are not currently available. Diagnosis of contact granulomas require visualization using laryngoscopy, and may require further biopsy for differential diagnosis.[8] A combination of symptoms and lifestyle factors may be linked with the development of a contact granuloma, however symptoms vary greatly by individual. Some lifestyle factors that have been linked with elevated risk of development of contact granulomas include frequent use of the voice, especially when in loud environments, and concurrent use of the voice with alcohol consumption (increasing risk of gastroesophageal reflux symptoms). Contact granuloma may also arise after intubation, and so following intubation, patients should be monitored if voice symptoms arise. Symptoms may or may not include hoarse voice, described as "huskiness" by some patients,[5] "aching" in the throat related to increased effort to produce voice,[5] and the feeling of having a lump in one's throat when swallowing.[5] It is also possible to have no such symptoms, especially if the granuloma is small.[5] A patient presenting with such symptoms or risk factors should therefore be referred for further visualization. It is therefore recommended to obtain a diagnosis from a doctor.[citation needed] ## Prevention[edit] The causes of vocal process granulomas are quite varied, and as such prevention must target the individual causes.[8] Education on lifestyle factors such as habitual vocal abuse and habits that may aggravate gastro-esophageal reflux should be implemented to lower risk, and those who use their voice professionally should use vocal hygiene techniques to ensure safe voice use.[8] Vocal hygiene may include increasing water intake, eliminating external irritants such as smoking or airborne chemicals, controlling loudness, and balancing periods of increased vocal use with periods of rest.[14] Since intubation can also cause vocal process granulomas, proper muscle relaxing medications should be used before insertion and removal of tubes, that smaller tubes are used and with proper lubrication, and that patient movement is controlled during intubation.[8] ## Treatment[edit] Specific treatment for contact granuloma depends on the underlying cause of the condition, but often initially includes a combination of speech therapy,[8][12][13][3] vocal rest,[8][12][13] and antireflux medication.[13][3] A more aggressive treatment approach could include steroids (inhalant or injection),[13][3] injections of botulinum toxin,[8][12][13][3] low dose radiotherapy, vocal fold augmentation,[8] or microlaryngeal surgery).[12][13][3] Microlaryngeal surgery can be performed either via cold steel excision or various types of laser.[3] The laser is more accurate and typically results in less damage to the surrounding tissue. These more aggressive approaches might be used in the case of the refractory (i.e. resistant to treatment) contact granuloma where previous interventions have not succeeded or recurrence rates are high.[8] The best outcomes appear to occur when a combination of treatments is used.[3] ### Steroids[edit] The application of corticosteroids to treat contact granulomas is considered a more extreme approach[8] and its utility remains in contention.[8][5] When employed, it is usually used in conjunction with antibiotics for the reduction of pain and inflammation related to the granuloma.[5] This treatment can be administered orally, through inhalation, or through intralesion injection.[5] ### Botox injection[edit] The injection of botulinum neurotoxin A, or Botox, to treat contact granulomas is considered a more extreme approach,[8] and is generally only pursued when the case has been resistant to other treatments.[5][3] In this approach, Botox is injected into the thyroarytenoid muscle (unilaterally or bilaterally), targeting a reduction in the contact forces of the arytenoids.[5] Surgery When all other medical and behavioural treatments have been attempted, surgical removal of the contact granuloma is possible as a last resort option. However, caution needs to be exercised, especially in the cases of contact granuloma resulting from external factors (i.e., when factors are eliminated, the contact granuloma resolves independently), because any irritation can cause the contact granulomas to reappear.[2] ## Prognosis[edit] As the masses of granular tissue are most often benign, prognosis is generally positive.[5] However, due to the variety of treatment options and lifestyle factors, outcomes of individual treatments and form of management vary. A high proportion of contact granulomas are present in patients with concurrent gastroesophageal reflux, and so treatment of the reflux is imperative.[3] Those caused by intubation trauma are less likely to recur.[8] The most common treatment is voice therapy by a speech-language pathologist, and this therapy is enough for many patients.[3] Surgical solutions are sometimes used, however rates of recurrence are higher.[3] Most recent research suggests that surgical options should only be explored once treatment of reflux with or without voice therapy has been introduced.[3] ## Epidemiology[edit] Across all posited etiologies, contact granulomas are more commonly observed in male patients than in female patients, and more commonly in adult patients than in pediatric patients.[8] In cases where gastroesophageal reflux disease is identified as the most likely cause of the granuloma, the patient is most commonly an adult man in his 30s or 40s.[8] When contact granulomas do occur in female and pediatric patients, they usually occur post-intubation.[8] There are no observable age or gender trends within the category of post-intubation patients suffering from contact granulomas, nor within the causation category of vocal abuse history.[8] ## Terminology[edit] Several different terms are used to refer to contact granulomas (contact ulcer, vocal fold granuloma, vocal process granuloma, etc). The term contact ulcer was first used in the early 20th century at which time the single cause of this condition was believed to be excessive force when the vocal folds make contact during phonation or non-phonatory behaviors (i.e. coughing).[5] Later, the same condition was observed in patients recovering from recent intubation[5] and, more recently, came to be associated with inflammation and irritation resulting from gastro-esophageal reflux.[5] Likewise, use of both ulcer and granuloma reflect the fact that this condition can present as an ulcerated lesion or as granulated tissue. [1] In medical literature today, the term vocal process granuloma is preferred over the term contact ulcer or contact granuloma; this reflects the fact that this condition can result from a variety of different causes and not just excessively forceful contact of the vocal folds as was originally believed.[15][5] Nevertheless, the term contact granuloma remains widely used. ## Sources[edit] * Excerpt from Contact Granulomas - eMedicine * Vocal Cord Contact Ulcers - The Merck Manuals Online Medical Library ## References[edit] 1. ^ a b c d e f g h i Stemple, Joseph C.; Roy, Nelson; Klaben, Bernice (2014). Clinical voice pathology : theory and management (Fifth ed.). San Diego, CA: Plural Publishing. ISBN 9781597565561. OCLC 985461970. 2. ^ a b Head & neck surgery--otolaryngology. Bailey, Byron J., 1934-, Johnson, Jonas T., Newlands, Shawn D., 1960- (4th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 2006. ISBN 978-0781755610. OCLC 63176653.CS1 maint: others (link) 3. ^ a b c d e f g h i j k l m n Karkos, Petros D.; George, Michael; Veen, Jan Van Der; Atkinson, Helen; Dwivedi, Raghav C.; Kim, Dae; Repanos, Costa (2014-03-17). "Vocal Process Granulomas". Annals of Otology, Rhinology & Laryngology. 123 (5): 314–320. doi:10.1177/0003489414525921. PMID 24642585. 4. ^ McKINLEY Jr., JAMES (2011-11-18). "Advances in Medicine Lead Stars to Surgery". The New York Times. Retrieved 6 April 2013. 5. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa Hoffman, H. T.; Overholt, E.; Karnell, M.; McCulloch, T. M. (December 2001). "Vocal process granuloma". Head & Neck. 23 (12): 1061–1074. doi:10.1002/hed.10014. ISSN 1043-3074. PMID 11774392. 6. ^ Rubin, John S., Sataloff, Robert T., Korovin, Gwen S. (2014). Diagnosis and Treatment of Voice Disorders, 4th Edition. San Diego: Plural Publishing, Inc. pp. 108–109. ISBN 978-1597565530.CS1 maint: multiple names: authors list (link) 7. ^ a b c The voice and voice therapy. Boone, Daniel R. (8th ed.). Boston: Allyn & Bacon/ Pearson. 2010. ISBN 9780205609536. OCLC 262694323.CS1 maint: others (link) 8. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af Devaney, Kenneth O.; Rinaldo, Alessandra; Ferlito, Alfio (2005). "Vocal process granuloma of the larynx—recognition, differential diagnosis and treatment". Oral Oncology. 41 (7): 666–669. doi:10.1016/j.oraloncology.2004.11.002. PMID 16023983. 9. ^ Sataloff, Robert T.; Hawkshaw, Mary J.; Sataloff, Jonathan B.; Defatta, Rima A.; Eller, Robert (2012-08-01). Atlas of laryngoscopy. Sataloff, Robert Thayer. (Third ed.). San Diego, CA. ISBN 9781597566018. OCLC 865508931. 10. ^ a b Sataloff, Robert T (2015). Sataloff's Comprehensive Textbook of Otolaryngology: Head & Neck Surgery: Six Volume Set. New Delhi, India: Jaypee Brothers, Medical Publishers Pvt. Limited. pp. 705–707. ISBN 978-9351527459. 11. ^ Kleinsasser, O. (1986). Microlaryngoscopic and histologic appearances of polyps, nodules, cysts, Reinke's edema, and granulomas of the vocal cords. San Diego, CA: College-Hill Press. pp. 51–55. 12. ^ a b c d e f g h Zeitels, Steven M.; Casiano, Roy R.; Gardner, Glendon M.; Hogikyan, Norman D.; Koufman, James A.; Rosen, Clark A. (2002). "Management of common voice problems: Committee report". Otolaryngology–Head and Neck Surgery. 126 (4): 333–348. doi:10.1067/mhn.2002.123546. PMID 11997771. 13. ^ a b c d e f g Ulis, Jeffrey M; Yanagisawa, Eiji (2009). "Whatʼs new in differential diagnosis and treatment of hoarseness?". Current Opinion in Otolaryngology & Head and Neck Surgery. 17 (3): 209–215. doi:10.1097/moo.0b013e32832a2230. PMID 19469052. 14. ^ Carding, P.; Bos-Clark, M.; Fu, S.; Gillivan-Murphy, P.; Jones, S.M.; Walton, C. (2017-04-01). "Evaluating the efficacy of voice therapy for functional, organic and neurological voice disorders". Clinical Otolaryngology. 42 (2): 201–217. doi:10.1111/coa.12765. ISSN 1749-4486. PMID 27813336. 15. ^ H., Colton, Raymond (2011). Understanding voice problems : a physiological perspective for diagnosis and treatment. Casper, Janina K.,, Leonard, Rebecca (Fourth ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. ISBN 9781609138745. OCLC 660546194. [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 inhibitors [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	Contact granuloma	c4040427	2,957	wikipedia	https://en.wikipedia.org/wiki/Contact_granuloma	2021-01-18T19:10:03	{"umls": ["C4040427"], "wikidata": ["Q5164829"]}
A number sign (#) is used with this entry because of evidence that hereditary motor and sensory neuropathy type VIB with optic atrophy (HMSN6B) is caused by homozygous or compound heterozygous mutation in the SLC25A46 gene (610826) on chromosome 5q22. Description Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals also have cerebellar or pontocerebellar atrophy on brain imaging, and they may show abnormal movements, such as ataxia, dysmetria, and myoclonus. The most severely affected patients are hypotonic at birth and die in infancy (summary by Abrams et al., 2015 and Wan et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of HMSN6, see HMSN6A (601152). Clinical Features Abrams et al. (2015) reported 8 patients from 4 unrelated families of various ethnic origins with optic atrophy and peripheral neuropathy manifest as axonal Charcot-Marie-Tooth disease. There was extreme phenotypic variability in age at onset, additional features, and severity. Two sibs from the United Kingdom presented with optic atrophy and progressive visual loss at ages 5 and 8 years, but did not develop peripheral neuropathy until their forties. Features included stiffness and distal sensory impairment of the lower limbs associated with hyperreflexia and extensor plantar responses. Nerve conduction studies showed unrecordable sensory nerve action potentials, decreased compound muscle action potentials, and slowed motor nerve conduction velocities, all consistent with an axonal motor and sensory polyneuropathy. Brain imaging and muscle biopsy were unremarkable. A 51-year-old man from Sardinia presented with progressive visual impairment at age 2 years. In his second decade, he developed difficulty walking associated with distal muscle atrophy as well as speech difficulties. Physical examination showed optic atrophy, mild deafness, cerebellar dysfunction with nystagmus and dysmetria, ataxic and steppage gait, hyperreflexia with absent ankle reflexes, and pes cavus. Electromyography showed axonal sensorimotor neuropathy, and brain imaging showed diffuse brain and cerebellar atrophy with cerebellar white matter abnormalities, chiasm atrophy, and calcifications in the basal ganglia. Three sibs from a consanguineous Palestinian family had normal early development in the first 1 to 2 years of life, but then showed developmental delay and visual loss with optic nerve pallor, loss of motor skills, hypertonia, hyperreflexia, and ataxia, and were wheelchair-bound by late childhood. Muscle and nerve biopsy of 1 patient showed autonomic denervation with onion bulb morphology and rare axonal demyelination and degeneration. A deceased sib was similarly affected. In the fourth family, a girl from the United States had hypotonia and contractures at birth, as well as dysmorphic features, including bitemporal narrowing, upturned nose with bulbous tip, tented upper lip, narrow palate, flat midface, inverted nipples, and tapered fingers. She also had optic atrophy. Brain imaging showed progressive cerebellar and brainstem atrophy. She died at age 15 weeks. Charlesworth et al. (2016) reported 2 brothers, born of consanguineous Pakistani parents, with a complicated form of axonal sensorimotor neuropathy. The proband presented with balance problems in infancy. On physical examination at age 15, he had prominent action-induced myoclonus, cerebellar ataxia, nystagmus, dysmetria, tremor, and mild spasticity. He also had profound visual loss with rod-cone dysfunction, exotropia, and difficulties initiating saccades. He had scoliosis and neuropathy-induced trophic changes, and was wheelchair-bound. Brain imaging showed cerebellar atrophy and T2-weighted hyperintensities and cavitations in the cerebellum. Cognition was normal. His 20-year-old brother was similarly, though more mildly, affected. ### Clinical Variability Wan et al. (2016) reported 4 infants from 2 unrelated consanguineous families who died soon after birth with a profound neurodevelopmental disorder associated with congenital pontocerebellar hypoplasia. Three of the 4 pregnancies were noted to be complicated by polyhydramnios. The patients presented at birth with severe hypotonia and respiratory distress necessitating ventilatory support, areflexia, and occasional myoclonic jerks. EEG in 2 patients showed generalized slowing, but no epileptiform activity, whereas 1 patient developed seizures at 3 weeks of age. Additional features included optic atrophy and severe global developmental delay. EMG and nerve conduction studies in 2 patients were consistent with an axonal sensorimotor neuropathy. Brain imaging of all patients showed a small cerebellum and brainstem, consistent with pontocerebellar hypoplasia. Mitochondrial respiratory chain enzyme testing in 2 patients was normal. All patients died between 2 weeks and 3 months of age. Wan et al. (2016) noted the phenotypic similarities to a female infant from the United States with pontocerebellar atrophy who died at age 15 weeks; this infant was previously reported by Abrams et al. (2015). Janer et al. (2016) reported a female infant, born of consanguineous French Canadian parents, with a lethal form of HMSN6B. She developed a convulsion at 4 hours of age, which did not recur. In the first months of life, she showed irritability, feeding and swallowing difficulties, failure to thrive, and delayed psychomotor development. At age 13.5 months, she presented with a febrile seizure and respiratory failure. Brain imaging at that time showed lesions in the cerebellar white matter, cerebellar peduncles, and brainstem, as well as in the globi pallidi, consistent with a clinical diagnosis of Leigh syndrome. Ophthalmologic examination showed optic atrophy. She had mild spasticity and hyperreflexia; EMG and nerve conduction studies were not performed, but muscle biopsy showed neurogenic atrophy. She died soon thereafter. Laboratory studies showed intermittent lactic acidosis, with mildly increased lactate and pyruvate in the CSF. Inheritance The transmission pattern of HMSN6B in the families reported by Abrams et al. (2015) was consistent with autosomal recessive inheritance. Molecular Genetics In affected members of 4 families with HMSN6B, Abrams et al. (2015) identified homozygous or compound heterozygous mutations in the SLC25A46 gene (610826.0001-610826.0006). Mutations in the first 3 families were found by whole-exome sequencing; mutation in the fourth family was found by Sanger sequencing of the SLC25A46 gene in cases with a similar phenotype. Functional studies of the variants were not performed. Fibroblasts from 1 patient showed a hyperfilamentous and interconnected mitochondrial network compared to controls, as well as decreased oxygen consumption rate and a glycolytic shift in metabolism. These findings were consistent with decreased mitochondrial fission. In 4 sibs from 2 unrelated consanguineous families with a severe form of HMSN6B resulting in death in infancy, Wan et al. (2016) identified 2 different homozygous loss-of-function mutations in the SLC25A46 gene (610826.0007 and 610826.0008). Although 1 of the mutations was a missense mutation (L341P; 610826.0007), in vitro studies showed that it resulted in markedly decreased amounts of protein, suggesting that the clinical severity is inversely correlated with relative stability of the mutant protein. In 2 brothers, born of consanguineous Pakistani parents, with HMSN6B, Charlesworth et al. (2016) identified a homozygous missense mutation in the SLC25A46 gene (L138R; 610826.0009). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. In a girl, born of consanguineous French Canadian parents, with infantile lethal HMSN6B, Janer et al. (2016) identified a homozygous missense mutation in the SLC25A46 gene (T142I; 610826.0010). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The mutant protein was virtually undetectable in patient fibroblasts, which showed mitochondrial hyperfusion, alterations in endoplasmic reticulum morphology, impaired cellular respiration, and premature cellular senescence. Genotype/Phenotype Correlations SLC25A46 mutations that result in decreased levels of the mutant protein cause a lethal infantile form of HMSN6B associated with neurodegeneration and pontocerebellar hypoplasia: see 610826.0004-610826.0005 and Abrams et al. (2015); 610826.0007 and 610826.0008 and Wan et al. (2016); and 610826.0010 and Janer et al. (2016). Animal Model In zebrafish, Abrams et al. (2015) found expression of slc25a46 in retinal ganglion cells and their corresponding neuronal projections in axons of the optic nerve and dendrites of the inner plexiform layer. Morpholino knockdown of the gene resulted in fewer retinal ganglion cell axons that reached the tectum, as well as impairment of these dendrites. Morpholino knockouts had a curly tail morphology and impaired swimming, suggesting dysfunction of neural circuits, and spinal motor neurons had shortened axon tracts due to degeneration of neuronal processes. Mitochondria in the degenerating motor neurons showed incomplete fission, abnormal aggregation, and abnormal cell localization compared to wildtype. Wan et al. (2016) found that morpholino knockdown of the slc25a46 gene in zebrafish embryos resulted in a dose-dependent phenotype of brain maldevelopment in the midbrain and hindbrain, as well as loss of spinal motor neurons. Dissociated neurons from mutant animals showed elongated and immotile mitochondria compared to controls, suggesting impaired fission/fusion dynamics. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Bitemporal narrowing (patient A) Ears \- Abnormal ears (patient A) Eyes \- Optic atrophy \- Progressive visual impairment \- Nystagmus \- Rod-cone dysfunction \- Exotropia Nose \- Upturned nose (patient A) \- Bulbous nasal tip (patient A) Mouth \- Tented upper lip (patient A) \- Narrow palate (patient A) RESPIRATORY \- Respiratory failure (in some patients) CHEST Breasts \- Inverted nipples (patient A) SKELETAL \- Contractures (patient A) Spine \- Scoliosis Hands \- Tapered fingers (patient A) Feet \- Pes cavus MUSCLE, SOFT TISSUES \- Distal muscle atrophy, lower legs \- Distal muscle weakness, lower legs \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development (in some patients) \- Loss of motor skills \- Impaired gait \- Steppage gait \- Hyperreflexia Areflexia \- Myoclonus \- Dysmetria \- Tremor \- Extensor plantar responses \- Ataxia \- Cerebellar signs \- Cerebellar atrophy \- T2-weighted hyperintensities and cavitations in the cerebellum \- Pontocerebellar hypoplasia Peripheral Nervous System \- Sensorimotor axonal neuropathy \- Distal sensory impairment \- Hyporeflexia MISCELLANEOUS \- Onset of optic atrophy in first decade \- Onset of peripheral neuropathy ranges from childhood to mid-adulthood \- Highly variable phenotype \- Highly variable severity \- The most severely affected patients may die in infancy MOLECULAR BASIS \- Caused by mutation in the solute carrier family 25, member 46 gene (SLC25A46, 610826.0001 ) ▲ 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 inhibitors [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	NEUROPATHY, HEREDITARY MOTOR AND SENSORY, TYPE VIB, WITH OPTIC ATROPHY	c0393807	2,958	omim	https://www.omim.org/entry/616505	2019-09-22T15:48:39	{"doid": ["0080068"], "mesh": ["C562851"], "omim": ["616505"], "orphanet": ["90120"], "synonyms": ["Alternative titles", "HMSN VIB", "CHARCOT-MARIE-TOOTH DISEASE, TYPE 6B"]}
Late-onset familial Alzheimer disease, is a form of familial Alzheimer disease, that begins after age 65. In general, Alzheimer disease (AD) is a degenerative disease of the brain that causes gradual loss of memory, judgement and the ability to function socially. The exact underlying cause of late-onset familial AD is not completely understood; however, researchers suspect that it is a complex condition, which is likely associated with multiple susceptibility genes in combination with environmental and lifestyle factors. A gene called APOE has been studied extensively as a risk factor for the disease. In particular, a variant of this gene called the "e4 allele" seems to increase an individual's risk for developing late-onset Alzheimer disease (people who have this allele are said to have the late-onset familial AD type 2). It is important to understand that APOE is a susceptibility gene, not a determinative gene, which means that people having two copies of this allele have an increased risk of having AD but not necessarily will have it. There is no cure for AD. Treatment is supportive and 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 inhibitors [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	Late-Onset Familial Alzheimer Disease	None	2,959	gard	https://rarediseases.info.nih.gov/diseases/12799/late-onset-familial-alzheimer-disease	2021-01-18T17:59:30	{"synonyms": []}
Rotor syndrome Other namesRotor type hyperbilirubinemia[1] Bilirubin SpecialtyPediatrics, hepatology Rotor syndrome (also known as Rotor type hyperbilirubinemia)[2] is a rare cause of mixed direct (conjugated) and indirect (unconjugated) hyperbilirubinemia, relatively benign, autosomal recessive[3] bilirubin disorder characterized by non-hemolytic jaundice due to the chronic elevation of predominantly conjugated bilirubin.[2] Rotor type hyperbilirubinemia is a distinct yet similar disorder to Dubin–Johnson syndrome[1] – both diseases cause an increase in conjugated bilirubin. Whereas rotor syndrome differs in that it is a result of impaired hepatocellular storage of conjugated bilirubin that leaks into plasma causing hyperbilirubinemia.[2] ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 2.1 Genetics * 3 Diagnosis * 4 Treatment * 5 Eponym * 6 See also * 7 References * 8 External links ## Signs and symptoms[edit] Rotor syndrome has many features in common with Dubin–Johnson syndrome, an exception being that the liver cells are not pigmented. The main symptom is a non-itching jaundice. There is a rise in bilirubin in the patient's serum, mainly of the conjugated type. It can be differentiated from Dubin–Johnson syndrome in the following ways:[4] Rotor syndrome Dubin–Johnson syndrome appearance of liver normal histology and appearance liver has black pigmentation gallbladder visualization gallbladder can be visualized by oral cholecystogram gallbladder cannot be visualized total urine coproporphyrin content high with <70% being isomer 1 normal with >80% being isomer 1 (normal urine contains more of isomer 3 than isomer 1) It has been suggested that Rotor syndrome may exacerbate toxic side effects of the medication irinotecan.[5] ## Pathophysiology[edit] See also: Coproporphyrinogen I Rotor syndrome is caused by mutations in two proteins responsible for transporting bilirubin and other compounds from the blood to the liver to be metabolized and cleared from the body.[2] Coproporphyrin I, a major coproporphyrin isomer in bile, is transported from the hepatocyte back into the circulation and is excreted in the urine. Thus, urine coproporphyrin is elevated in Rotor syndrome.[2] Cholescintigraphy using sulfobromophthalein (BSP) have shown that the transport capacity of dye into bile is reduced by less than 50%, and the storage capacity in the hepatocytes is decreased more than 5-fold compared with normal values in this disease.[2] ### Genetics[edit] Rotor syndrome has an autosomal recessive pattern of inheritance. Rotor syndrome is inherited in an autosomal recessive manner.[3] The SLCO1B1 and SLCO1B3 genes are involved in Rotor syndrome.[6] Mutations in both genes are required for the condition to occur. The SLCO1B1 and SLCO1B3 genes provide instructions for making similar proteins, called organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3), respectively. Both proteins are found in liver cells; they transport bilirubin and other compounds from the blood into the liver so that they can be cleared from the body. In the liver, bilirubin is dissolved in a digestive fluid called bile and then excreted from the body. The SLCO1B1 and SLCO1B3 gene mutations that cause Rotor syndrome lead to abnormally short, nonfunctional OATP1B1 and OATP1B3 proteins or an absence of these proteins. Without the function of either transport protein, bilirubin is less efficiently taken up by the liver and removed from the body. The buildup of this substance leads to jaundice in people with Rotor syndrome.[7] ## Diagnosis[edit] Increased conjugated hyperbilirubinemia is the hallmark for diagnosing Rotor syndrome. There is no distinct black pigmentation of the liver as seen in a similar, Dubin-Johnson Syndrome. Genes, SLCO1B1 and SLCO1B3 that result in complete functional deficiencies of both protein products (OATP1B1 and OATP1B3, respectively), are also present.[citation needed] Rotor syndrome is largely a diagnosis of exclusion.[2] Serological abnormalities in Rotor syndrome only include elevated total serum bilirubin (typically elevated between 2 to 5 mg/dL but may be as high as 20 mg/dL).[2] Most of the time, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and alkaline phosphatase levels are normal, but mild elevations can be seen.[2] If any of these lab values are markedly elevated, investigation for other, more serious conditions is warranted.[2] Imaging studies cannot diagnose Rotor syndrome but can help rule out other diseases that cause hyperbilirubinemia.[2] For example, ultrasound of the liver and the biliary tree can help investigate the causes of extra-hepatic biliary obstruction.[2] The gallbladder is visualized on oral cholecystography in Rotor syndrome while it is not visualized in Dubin Johnson syndrome.[2] Ultimately, the best method of diagnosing the disease is the analysis of urine coproporphyrin excretion.[2] The total urine coproporphyrin excretion in Rotor syndrome has a 2- to 5-fold elevation, with 65% constituting coproporphyrin I.[2] ## Treatment[edit] To treat the jaundice, phenobarbital is normally used.[citation needed] Rotor syndrome is a benign disease requiring no treatment.[2] Jaundice is a lifelong finding, but the disease is not associated with morbidity or mortality, and life expectancy is not affected.[2] Most individuals with Rotor syndrome are born to consanguineous couples and its diagnosis may coincidently identify consanguinity.[2] Distinguishing Rotor syndrome from other more serious disorders is important to avoid unnecessary workup and interventions.[2] It is also critical to reassure and calm patients or family members of patients with Rotors syndrome that the condition is benign.[2] ## Eponym[edit] Rotor syndrome is named after the Filipino internist Arturo Belleza Rotor (1907–1988).[8] ## See also[edit] * Jaundice * Bilirubin metabolism * Gilbert's syndrome * Crigler–Najjar syndrome ## References[edit] 1. ^ a b Online Mendelian Inheritance in Man (OMIM): 237450 2. ^ a b c d e f g h i j k l m n o p q r s t Kumar, A; Mehta, D (2020), "article-36575", Rotor Syndrome, This book is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, a link is provided to the Creative Commons license, and any changes made are indicated., Treasure Island (FL): StatPearls Publishing, PMID 30335339, retrieved 2020-07-17 3. ^ a b Wolkoff AW, Wolpert E, Pascasio FN, Arias IM (February 1976). "Rotor's syndrome. A distinct inheritable pathophysiologic entity". The American Journal of Medicine. 60 (2): 173–179. doi:10.1016/0002-9343(76)90426-5. PMID 766621. 4. ^ Robert Wyllie; Jeffrey S. Hyams (2010-11-29). Pediatric Gastrointestinal and Liver Disease E-Book. Elsevier Health Sciences. pp. 186–. ISBN 978-1-4377-3566-6. 5. ^ Iusuf, D., Ludwig, M., Elbatsh, A., van Esch, A., van de Steeg, E., & Wagenaar, E. et al. (2013). OATP1A/1B Transporters Affect Irinotecan and SN-38 Pharmacokinetics and Carboxylesterase Expression in Knockout and Humanized Transgenic Mice. Molecular Cancer Therapeutics, 13(2), 492-503. https://dx.doi.org/10.1158/1535-7163.mct-13-0541\ 6. ^ van de Steeg E, Stránecký V, Hartmannová H, Nosková L, Hřebíček M, Wagenaar E, van Esch A, de Waart DR, Oude Elferink RP, Kenworthy KE, Sticová E, al-Edreesi M, Knisely AS, Kmoch S, Jirsa M, Schinkel AH (2012). "Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver". The Journal of Clinical Investigation. 122 (2): 519–28. doi:10.1172/JCI59526. PMC 3266790. PMID 22232210. 7. ^ "Rotor Syndrome". NIH. U.S. Department of Health & Human Services. 8. ^ synd/2296 at Who Named It? ## External links[edit] * Hyperbilirubinemia, Conjugated at eMedicine * Rotor syndrome at NIH's Office of Rare Diseases * Mentioned in MedlinePlus Encyclopedia: Jaundice – yellow skin Classification D * ICD-10: E80.6 * ICD-9-CM: 277.4 * OMIM: 237450 * MeSH: D006933 * DiseasesDB: 11671 External resources * Orphanet: 3111 * v * t * e Heme metabolism disorders Porphyria, hepatic and erythropoietic (porphyrin) early mitochondrial: * ALAD porphyria * Acute intermittent porphyria cytoplasmic: * Gunther disease/congenital erythropoietic porphyria * Porphyria cutanea tarda/Hepatoerythropoietic porphyria late mitochondrial: * Hereditary coproporphyria * Harderoporphyria * Variegate porphyria * Erythropoietic protoporphyria Hereditary hyperbilirubinemia (bilirubin) unconjugated: * Gilbert's syndrome * Crigler–Najjar syndrome * Lucey–Driscoll syndrome conjugated: * Dubin–Johnson syndrome nd sheet * Rotor syndrome [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 inhibitors [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	Rotor syndrome	c0220991	2,960	wikipedia	https://en.wikipedia.org/wiki/Rotor_syndrome	2021-01-18T18:39:30	{"gard": ["218"], "mesh": ["D006933"], "umls": ["C0220991"], "icd-9": ["277.4"], "icd-10": ["E80.6"], "orphanet": ["3111"], "wikidata": ["Q1512812"]}
Cutis laxa is a disorder of connective tissue, which is the tissue that forms the body's supportive framework. Connective tissue provides structure and strength to the muscles, joints, organs, and skin. The term "cutis laxa" is Latin for loose or lax skin, and this condition is characterized by skin that is sagging and not stretchy (inelastic). The skin often hangs in loose folds, causing the face and other parts of the body to have a droopy appearance. Extremely wrinkled skin may be particularly noticeable on the neck and in the armpits and groin. Cutis laxa can also affect connective tissue in other parts of the body, including the heart, blood vessels, joints, intestines, and lungs. The disorder can cause heart problems and abnormal narrowing, bulging, or tearing of critical arteries. Affected individuals may have soft out-pouchings in the lower abdomen (inguinal hernia) or around the belly button (umbilical hernia). Pouches called diverticula can also develop in the walls of certain organs, such as the bladder and intestines. During childhood, some people with cutis laxa develop a lung disease called emphysema, which can make it difficult to breathe. Depending on which organs and tissues are affected, the signs and symptoms of cutis laxa can range from mild to life-threatening. Researchers have described several different forms of cutis laxa. The forms are often distinguished by their pattern of inheritance: autosomal dominant, autosomal recessive, or X-linked. In general, the autosomal recessive forms of cutis laxa tend to be more severe than the autosomal dominant forms. In addition to the features described above, some people with autosomal recessive cutis laxa have delayed development, intellectual disability, seizures, and problems with movement that can worsen over time. The X-linked form of cutis laxa is often called occipital horn syndrome. This form of the disorder is considered a mild type of Menkes syndrome, which is a condition that affects copper levels in the body. In addition to sagging and inelastic skin, occipital horn syndrome is characterized by wedge-shaped calcium deposits in a bone at the base of the skull (the occipital bone), coarse hair, and loose joints. ## Frequency Cutis laxa is a rare disorder. About 200 affected families worldwide have been reported. ## Causes Cutis laxa can be caused by mutations in several genes, including ATP6V0A2, ATP7A, EFEMP2, ELN, and FBLN5. Most of these genes are involved in the formation and function of elastic fibers, which are slender bundles of proteins that provide strength and flexibility to connective tissue throughout the body. Elastic fibers allow the skin to stretch, the lungs to expand and contract, and arteries to handle blood flowing through them at high pressure. The major component of elastic fibers, a protein called elastin, is produced from the ELN gene. Other proteins that appear to have critical roles in the assembly of elastic fibers are produced from the EFEMP2, FBLN5, and ATP6V0A2 genes. Mutations in any of these genes disrupt the formation, assembly, or function of elastic fibers. A shortage of these fibers weakens connective tissue in the skin, arteries, lungs, and other organs. These defects in connective tissue underlie the major features of cutis laxa. Occipital horn syndrome is caused by mutations in the ATP7A gene. This gene provides instructions for making a protein that is important for regulating copper levels in the body. Mutations in the ATP7A gene result in poor distribution of copper to the body's cells. A reduced supply of copper can decrease the activity of numerous copper-containing enzymes that are necessary for the structure and function of bone, skin, hair, blood vessels, and the nervous system. The signs and symptoms of occipital horn syndrome are caused by the reduced activity of these copper-containing enzymes. Mutations in the genes described above account for only a small percentage of all cases of cutis laxa. Mutations in other genes, some of which have not been identified, can also cause the condition. Rare cases of cutis laxa are acquired, which means they do not appear to be caused by inherited gene mutations. Acquired cutis laxa appears later in life and is related to the destruction of normal elastic fibers. The causes of acquired cutis laxa are unclear, although it may occur as a side effect of treatment with medications that remove copper from the body (copper chelating drugs). ### Learn more about the genes associated with Cutis laxa * ATP6V0A2 * ATP7A * EFEMP2 * ELN * FBLN5 Additional Information from NCBI Gene: * ALDH18A1 * LTBP4 * PYCR1 ## Inheritance Pattern Cutis laxa can have an autosomal dominant, autosomal recessive, or X-linked recessive pattern of inheritance. When cutis laxa is caused by ELN mutations, it has an autosomal dominant inheritance pattern. Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder. Rarely, cases of cutis laxa resulting from FBLN5 mutations can also have an autosomal dominant pattern of inheritance. Researchers have described at least three forms of autosomal recessive cutis laxa, which result from mutations in several different genes. Autosomal recessive inheritance 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. Occipital horn syndrome has an X-linked recessive pattern of inheritance. It results from mutations in the ATP7A gene, which is located on the X chromosome. The X chromosome 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), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. [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 inhibitors [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	Cutis laxa	c3276539	2,961	medlineplus	https://medlineplus.gov/genetics/condition/cutis-laxa/	2021-01-27T08:25:11	{"gard": ["6227", "4017"], "omim": ["123700", "614434", "616603", "219100", "614437", "613177", "219200", "612940", "219150", "614438", "614100", "304150"], "synonyms": []}
Bangstad syndrome Other namesAtaxia-diabetes-goiter-gonadal insufficiency syndrome This condition is inherited in an autosomal recessive manner Bangstad syndrome is a severe, inherited congenital disorder associated with abnormalities of the cell membrane. It was characterized in 1989.[1] ## Contents * 1 Presentation * 2 Diagnosis * 3 Treatment * 4 References * 5 External links ## Presentation[edit] Presenting at birth,[2] features of the disorder include moderately severe IUGR, microcephaly, craniosynostosis, moderately severe post uterine growth retardation, deafness, deep set eyes, cryptorchidism, truncal obesity[clarification needed] and acanthosis nigricans, small teeth, prognathism, dislocated radial heads without generalized skeletal dysplasia, however, tall vertebrae, moderate mental retardation, hypothyroidism, insulin resistance, hypoparathyroidism.[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. ^ Bangstad HJ, Beck-Nielsen H, Hother-Nielsen O, et al. (May 1989). "Primordial birdheaded nanism associated with progressive ataxia, early onset insulin resistant diabetes, goiter and primary gonadal insufficiency. A new syndrome". Acta Paediatr Scand. 78 (3): 488–93. doi:10.1111/j.1651-2227.1989.tb11119.x. PMID 2662702. 2. ^ Bruno Bissonnette; Igor Luginbuehl; Bernard J. Dalens (20 July 2006). Syndromes: rapid recognition and perioperative implications. McGraw-Hill Professional. pp. 92–. ISBN 978-0-07-135455-4. Retrieved 29 June 2010. ## External links[edit] Classification D * ICD-10: E31.8 * OMIM: 210740 * MeSH: C537902 External resources * Orphanet: 1227 This article about a congenital malformation 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 inhibitors [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	Bangstad syndrome	c0342284	2,962	wikipedia	https://en.wikipedia.org/wiki/Bangstad_syndrome	2021-01-18T18:47:51	{"gard": ["812"], "mesh": ["C537902"], "umls": ["C0342284"], "orphanet": ["1227"], "wikidata": ["Q4855629"]}
A rare syndromic craniosynostosis with variable phenotypic expression characterized by craniosynostosis, intellectual disability, distinctive facies, abnormalities of the fingers and toes (brachydactyly, polydactyly and syndactyly), short stature, congenital heart disease, skeletal defects, obesity, genital abnormalities and umbilical hernia. ## Epidemiology Over 70 cases have been described in the literature. ## Clinical description Presentation at birth is with macrosomia, umbilical hernia and craniosynostosis which ranges from cloverleaf configuration to predominant involvement of the metopic ridge to craniofacial asymmetry. Cranial anomalies may lead to raised intercranial pressure, difficulty in articulation, frequent otitis media and resultant hearing loss. Typical abnormalities of the digits include brachydactyly, cutaneous syndactyly, preaxial polydactyly in the toes and postaxial polydactlyly in the hands with broad thumbs and absent middle phalanges. Characteristic facial features may include flat nasal bridge with epicanthal folds, down-slanting palpebral fissures, corneal anomalies, low-set, posteriorly rotated malformed ears, and an underdeveloped maxilla and mandible. Congenital cardiac malformations are frequent and may include ventricular septal defect, patent ductus arteriosus, pulmonic stenosis, tetralogy of Fallot, and transposition of great vessels. Intellectual disability is common (affecting 63-75% of cases). Males often have genital abnormalities such as hypogonadism and cryptorchidism. Small primary dentition is usual, teeth are short, undersized and widely spaced, appearing as small buds worn to the gingival margins and often there is prolonged retention of primary teeth. Growth is either slightly delayed or normal and many individuals have short stature. Persistent obesity, particularly truncal obesity, beginning in childhood is common. Additional skeletal abnormalities such as deformed hips, kyphoscoliosis, and genu valgum frequently occur. Situs inversus, dextrocardia, and polysplenia has been observed in a few patients. ## Etiology The syndrome is caused by truncating, misssense and loss of function mutations in two different genes RAB23 gene (6p12.1) and less commonly MEGF8 gene (19q13.2). MEGF8 mutations are associated with defective lateralization and less severe craniosynostosis (usually involving only the metopic suture) in comparison with individuals with RAB23 gene mutations. ## Diagnostic methods Clinical diagnosis is suspected on clinical presentation and confirmed by diagnostic molecular genetic screening firstly of RAB23 and then MEGF8. ## Differential diagnosis Differential diagnosis includes other acrocephalosyndactyly disorders, as well as Gorlin syndrome, Apert syndrome and Greig cephalopolysyndactyly syndrome. Ciliopathy disorders also have overlapping features including the wide clinical variability and features such as obesity and polydactyly. Summitt syndrome and Goodman syndrome falls within the clinical spectrum of Carpenter syndrome. ## Antenatal diagnosis Genetic prenatal diagnosis to screen for the causative familial mutations is possible where the mutation has previously been identified in a family member. Ultrasound may detect abnormal head shape, short and bowed femurs, flattened face, proptosis, heart defect, heterotaxy and digit anomalies. ## Genetic counseling Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy. Phenotypic expression varies considerably, even within the same family. Genetic counseling is recommended to affected families. ## Management and treatment Multidisciplinary management and treatment is required. Most patients with this syndrome will undergo early craniofacial reconstruction to improve appearance and prevent intellectual disability. Surgery may be required for congenital heart defects and shunting may be required if there is raised intercranial pressure. ## Prognosis The prognosis is highly variable depending on the severity of the malformations and the degree of intellectual disability; some children grow up to become independent adults and others require more support due to intellectual disability or physical challenges. Life expectancy is shortened, mainly due to heart defects. * 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 inhibitors [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	Carpenter syndrome	c1275078	2,963	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=65759	2021-01-23T18:52:39	{"gard": ["6003"], "mesh": ["C563187"], "omim": ["201000", "614976"], "umls": ["C1275078"], "icd-10": ["Q87.0"], "synonyms": ["ACPS2", "Acrocephalopolysyndactyly type 2"]}
Common variable immunodeficiency (CVID) is a group of disorders characterized by low levels of a type of protein known as immunoglobulins (Ig). Because of low level of Ig, the immune system cannot make antibodies that fight bacteria, viruses or other toxins in the body. This leads to frequent infections, particularly in the sinuses, lungs, and digestive tract. Symptoms most commonly begin in early adulthood but can occur at any age. While in most cases the cause of CVID is unknown, a genetic change has been found in about one-third of cases. This condition is diagnosed based on the symptoms, specific laboratory testings, and exclusion of other disorders. Treatment for CVID includes Ig replacement therapy, which stops the cycle of recurrent infections. The long term outlook for people with CVID varies depending on the severity of the symptoms and any underlying conditions. [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 inhibitors [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	Common variable immunodeficiency	c0009447	2,964	gard	https://rarediseases.info.nih.gov/diseases/6140/common-variable-immunodeficiency	2021-01-18T18:01:13	{"mesh": ["D017074"], "omim": ["607594"], "orphanet": ["1572"], "synonyms": ["CVID", "Common variable hypogamma-globulinemia", "Hypogamma-globulinemia, acquired", "Immunoglobulin deficiency, late-onset", "Common variable immune deficiency", "Idiopathic immunoglobulin deficiency", "Primary antibody deficiency", "Primary hypogammaglobulinemia"]}
Epithelial basement membrane dystrophy Other namesMap-dot-fingerprint dystrophy and Cogans's microcystic dystrophy SpecialtyOphthalmology Epithelial basement membrane dystrophy (EBMD), is a disorder of the eye that can cause pain and dryness. It is sometimes included in the group of corneal dystrophies.[1] It diverges from the formal definition of corneal dystrophy since it is non-familial in most cases. It also has a fluctuating course, while for a typical corneal dystrophy the course is progressive. When it is considered part of this group, it is the most common type of corneal dystrophy.[2] ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 3 Treatment * 4 See also * 5 References ## Signs and symptoms[edit] Patients may complain of severe problems with dry eyes, or with visual obscurations.[3] It can also be asymptomatic, and only discovered because of subtle lines and marks seen during an eye exam.[2] EBMD is a bilateral anterior corneal dystrophy characterized by grayish epithelial fingerprint lines, geographic map-like lines, and dots (or microcysts) on slit-lamp examination. Findings are variable and can change with time. While the disorder is usually asymptomatic, up to 10% of patients may have recurrent corneal erosions, usually beginning after age 30; conversely, 50% of patients presenting with idiopathic recurrent erosions have evidence of this dystrophy.[4] ## Pathophysiology[edit] In some families autosomal dominant inheritance and point mutations in the TGFBI gene encoding keratoepithelin have been identified,[5] but according to the International Committee for Classification of Corneal Diseases (IC3D)[6] the available data still does not merit a confident inclusion of EBMD in the group of corneal dystrophies. In view of this, the more accurate designation of the disease is possibly not dystrophy but corneal degeneration.[7] The main pathological feature of the disease is thickened, multilaminar and disfigured basement membrane of corneal epithelium. The change in the structure affects the epithelium, some cells of which may become entrapped in the rugged membrane and fail to migrate to the surface where they should undergo desquamation. ## Treatment[edit] Phototherapeutic keratectomy (PTK) done by an ophthalmologist can restore and preserve useful visual function for a significant period of time in patients with anterior corneal dystrophies including EBMD.[4] ## See also[edit] * Corneal dystrophy ## References[edit] 1. ^ Online Mendelian Inheritance in Man, #121820: Corneal dystrophy, epithelial basement membrane; EBMD, archived from the original on 2017-04-30. 2. ^ a b Chan, Colin (2015-02-18). Dry Eye: A Practical Approach. Springer. pp. 111–112. ISBN 9783662441060. 3. ^ John R. Martinelli, O.D. (22 March 2010). "When Should You Treat EBMD with PTK?". Review of Optometry. Retrieved 16 March 2017. 4. ^ a b Online Mendelian Inheritance in Man (OMIM): 121820 5. ^ Boutboul S, Black GC, Moore JE, Sinton J, Menasche M, Munier FL, Laroche L, Abitbol M, Schorderet DF (June 2006). "A subset of patients with epithelial basement membrane corneal dystrophy have mutations in TGFBI/BIGH3". Hum. Mutat. 27 (6): 553–7. doi:10.1002/humu.20331. PMID 16652336. 6. ^ Weiss JS, Møller HU, Lisch W, Kinoshita S, Aldave AJ, Belin MW, Kivelä T, Busin M, Munier FL, Seitz B, Sutphin J, Bredrup C, Mannis MJ, Rapuano CJ, Van Rij G, Kim EK, Klintworth GK (December 2008). "The IC3D classification of the corneal dystrophies". Cornea. 27 (Suppl 2): S1–83. doi:10.1097/ICO.0b013e31817780fb. PMC 2866169. PMID 19337156. 7. ^ David Verdier (2019-02-14). "Map-dot-fingerprint Dystrophy". eMedicine. Cite journal requires `\|journal=` (help) * v * t * e Types of corneal dystrophy Epithelial and subepithelial * Epithelial basement membrane dystrophy * Gelatinous drop-like corneal dystrophy * Lisch epithelial corneal dystrophy * Meesmann corneal dystrophy * Subepithelial mucinous corneal dystrophy Bowman's membrane * Reis–Bucklers corneal dystrophy * Thiel-Behnke dystrophy Stroma * Congenital stromal corneal dystrophy * Fleck corneal dystrophy * Granular corneal dystrophy * Lattice corneal dystrophy * Macular corneal dystrophy * Posterior amorphous corneal dystrophy * Schnyder crystalline corneal dystrophy Descemet's membrane and endothelial * Congenital hereditary endothelial dystrophy * Fuchs' dystrophy * Posterior polymorphous corneal dystrophy * X-linked endothelial corneal dystrophy [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 inhibitors [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	Epithelial basement membrane dystrophy	c0521723	2,965	wikipedia	https://en.wikipedia.org/wiki/Epithelial_basement_membrane_dystrophy	2021-01-18T19:01:02	{"gard": ["9732"], "mesh": ["C535477"], "umls": ["C0521723"], "orphanet": ["98956"], "wikidata": ["Q4162388"]}
Overview of obesity in Germany Obesity in Germany has been increasingly cited as a major health issue in recent years. The federal government has declared this to be a major issue.[1] Data released by the World Health Organisation in 2014 showed that while an issue of growing concern, within the European Union, Germany had incidence of overweight and obese adults as a percentage of the total population at 54.8% as in comparison with France at 60.7%, Spain at 60.9% or the United Kingdom at 63.4%.[2] ## Contents * 1 History * 1.1 Prior to 2007 * 1.2 2007 – 2010 * 1.3 2011 – Present * 1.4 Childhood obesity * 2 Healthy lifestyle * 2.1 State-by-state * 2.1.1 Statistics of people living a "completely healthy" life * 3 Causes * 3.1 Food and drinks * 3.2 Genes * 3.3 Marriage * 4 Effects * 4.1 Employment problems * 4.2 Clothing industry * 4.3 Physical health * 4.4 Costs * 4.5 Intelligence * 5 Programs * 5.1 Fit instead of Fat * 5.2 Bundeswehr's fitness camp * 5.3 Projekt Kugelblitz * 5.4 Anti-obesity clinic * 5.5 School involvement and funding * 6 Forbes 2007 ranking * 7 See also * 8 References ## History[edit] ### Prior to 2007[edit] In 1998, 19 percent of men and 22.5 percent of women met the definition of obesity.[3] Childhood obesity doubled between 1985 and 1999.[4] Childhood obesity is at about 1,9 million children in Germany; of which 800.000 are considered truly obese.[4] ### 2007 – 2010[edit] Chart showing that Germany has the most overweight and obese people in Europe. A 2007 study shows Germany had the highest number of overweight people in Europe.[5][6] However, the United Kingdom, Greece and certain countries in Eastern Europe have a higher rate of "truly obese" people.[7] In 2007, The German obesity rate was considered at the same level as with the American obesity rate.[8] In Germany, 60% of men and 43% of women are considered overweight while in France, 38.5% of men and 26% of women are considered overweight.[9] Germans are considered thinner than people in the United Kingdom.[9] The obesity level in Germany is in the middle compared to other European countries.[10] Out of 44 countries, Germany is ranked 39th for women and 42nd for men for cholesterol levels.[10] The waist of female Germans between the ages of 14 and 70 grew by 4.1 centimetres between 1994 and 2009.[11] The belly girth of men between 16 and 70 grew by 4.4 centimetres between 1980 and 2009.[11] ### 2011 – Present[edit] The number of overweight people in Germany has stagnated between 1998 and December 2011.[12] 67.1% of all men between 18 and 79 are considered overweight with a BMI of 25 or greater.[12] ### Childhood obesity[edit] Italy has surpassed Germany for having the fattest children in Europe.[13] A survey in 2007 had Germany listed as the country with "the highest proportion of overweight children in Europe."[13] However, despite dropping in the rankings, the number of truly obese children have doubled in the past decade.[14] ## Healthy lifestyle[edit] Only 14% live a "completely healthy" life.[15] Almost a quarter of German adults meet the definition of obesity.[3] Both men and women are around 23%[3] ### State-by-state[edit] Mecklenburg-Vorpommern go on foot or by bicycle to get where they need to more often than any other state.[15] Mecklenburg-Vorpommern has the most people living a "completely healthy" life at a rate of 19.8% of the people while Saxony-Anhalt have the fewest people living a "completely healthy" life.[15] Thuringia has the healthiest eating habits while people from North Rhine-Westphalia and Berlin have the worst eating habits.[15] #### Statistics of people living a "completely healthy" life[edit] Ranking State Percentage of people living a "completely healthy" life Source 1 Mecklenburg-Vorpommern 19.8 [15] 2 Lower Saxony & Bremen 19.5 3 Saxony 17.2 4 Bavaria 16.5 5 Hesse 14.7 6 Thuringia 13.9 7 Schleswig-Holstein 13.6 8 Berlin 12.3 9 North Rhine-Westphalia 12.0 Hamburg 12.0 11 Baden-Württemberg 11.3 12 Rhineland-Palatinate & Saarland 9.4 Brandenburg 9.4 14 Saxony-Anhalt 7.9 ## Causes[edit] ### Food and drinks[edit] A high consumption of beer and food, fatty foods and a lack of physical activity are to be blamed for obesity in Germany.[7][10][16] Another issue is the lack of Mediterranean lifestyle and diet.[10] Children's food products do not contribute to a healthy diet.[17] Die Welt reported that a "balanced diet is practically impossible."[17] The profit margin for fruits and vegetables was below five percent while confectionery, soft drinks and snacks was at 15% or more.[17] ### Genes[edit] Genes partly play a role in obesity.[18] Scientists at the German Institute of Human Nutrition and the University Hospital of Leipzig stated that identified two genes that promote fat accumulation in the abdominal cavity.[19] The increased activity of the genes also promotes the release of an enzyme that is responsible for the formation of cortisol.[19] A permanent increase in cortisol levels contribute to obesity.[19] ### Marriage[edit] Marriage has played a factor.[9] Sixty-nine percent of married men are considered overweight while only 43% of single men are considered overweight.[9] Fifty-eight percent of widowed women are considered overweight and 46% of married women are considered overweight, while only 25% of single women are considered overweight.[9] For children, lifestyle choices such as exercise and enough sleep plays a role in weight.[13] ## Effects[edit] ### Employment problems[edit] A study by the German Sport University Cologne revealed that some industries in Germany have a shortage of qualified trainees due to Germany's obesity epidemic.[20] The industries affected are security and emergency services and skilled manual work sectors.[20] ### Clothing industry[edit] A clothing-related study revealed that many clothing companies plan to adjust their sizing partly due to Germany's obesity epidemic.[11] ### Physical health[edit] Several studies have shown that obese men tend to have a lower sperm count, fewer rapidly mobile sperm and fewer progressively motile sperm compared to normal-weight men.[21] Obesity in Germany has created a cholesterol problem.[10] High cholesterol is known to cause premature death, angina, heart disease and strokes.[10] There has been an increase of children with Type 1 diabetes between 1996 and 2011.[22] Diabetics are at higher risk for complications such as heart attack and stroke.[22] In Germany, 600,000 people suffered from diabetes near the end of World War II compared to eight million now.[22] Obesity can increase risk for secondary diseases such as diabetes, cardiovascular disease, certain cancers and Alzheimer's.[14] Children who get diabetes can expect to lose 10 to 15 years off of their lives.[22] Diabetes also affect the eyes, kidneys and nerves in the legs.[22] Obesity is a "very strong promoter of cancer."[23] Obesity causes an increased risk for colon cancer and breast cancer.[23] ### Costs[edit] Health costs because of obesity has increased and accounts for 20% of health costs.[8] A third of patients suffer from a loss of control when eating and how much out of control depends on how thick the patient is.[14] ### Intelligence[edit] Obesity in seniors shows that it makes seniors less intelligent.[24] ## Programs[edit] There are many weight loss children programs for kids.[4] ### Fit instead of Fat[edit] The Fit instead of Fat program is run by the German federal government. The objective of the program is to "sharply" reduce obesity rates by the year 2020.[5][6] The program will try and meet the target by improving the quality of food offered in schools and hospitals along with increasing exercise levels in children.[5][6] ### Bundeswehr's fitness camp[edit] As of 2007, forty percent of the Bundeswehr's 300,000 conscripts doing military service are considered overweight.[25][26] A 2007 report declared "excessive bureaucracy" for limiting the time soldiers have to exercise.[26] As a result, an anti-obesity fitness camp opened in Warendorf, North Rhine-Westphalia.[25] ### Projekt Kugelblitz[edit] A hospital in Leverkusen, North Rhine-Westphalia started Projekt Kugelblitz to help obese children and adolescence.[27] The aim of the program is to "improve the self-perception, so that the participants develop more sensitive to the context of frustration and compulsive eating, and the selection and preparation of foods and of exercise and well-being".[27] ### Anti-obesity clinic[edit] An anti-obesity clinic in Wesseling, North Rhine-Westphalia works with a maximum of eight participants for 27 months.[28] The program is about nutrition counseling, physical exercise and behavior therapy.[28] Each week they are cared for in highly structured and interlinked courses and motivated.[28] Up to 80 appointments are intended per year.[28] ### School involvement and funding[edit] North Rhine-Westphalia introduced fitness test for students in the second grade due to an increase of children and adolescents being overweight.[29] The students will be weighed and be put through a series of eight exercises.[29] The state government also wants to fund sports for children who have a weight problem.[29] ## Forbes 2007 ranking[edit] Source: Forbes.com[30] The following list reflects the percentage of overweight adults aged 15 and over. These are individuals who have individual body mass indexes, which measures weight relative to height, greater than or equal to 25. Ranking Country Percentage 38 Jordan 60.5 39 Bahamas 60.4 40 Iceland 60.4 41 Nicaragua 60.4 42 Cuba 60.1 43 Germany 60.1 44 Brunei Darussalam 59.8 45 Slovenia 59.8 46 Peru 59.6 47 Vanuatu 59.6 48 Finland 58.7 ## See also[edit] * List of countries by Body Mass Index (BMI) ## References[edit] 1. ^ "A Germany worth living in". German Government. Archived from the original on 4 August 2009. Retrieved 1 July 2010. 2. ^ "Health Topics, Obesity". World Health Organisation. Retrieved 25 February 2016. 3. ^ a b c "One in four Germans officially obese". The Local. 15 June 2012. Retrieved 15 June 2012. 4. ^ a b c Löll, Christiane (27 June 2012). "Hilfe, unser Kind wird dicker und dicker". Die Welt (in German). Retrieved 13 September 2012. 5. ^ a b c "Topping the EU Fat Stats, Germany Plans Anti-Obesity Drive". Deutsche Welle. 20 April 2007. Retrieved 25 June 2010. 6. ^ a b c "Germany launches obesity campaign". BBC. 9 May 2007. Retrieved 25 June 2010. 7. ^ a b "Germans Are Fattest People in Europe, Study Shows". Der Spiegel. 19 April 2007. Retrieved 26 June 2010. 8. ^ a b "Deutsche sind die dicksten Europäer" (in German). Süddeutsche Zeitung. April 18, 2007. Retrieved March 8, 2011. 9. ^ a b c d e "Germany is getting fatter". The Local. 2 June 2010. Retrieved 26 June 2010. 10. ^ a b c d e f "New obesity report says world is fatter, rounder, less productive". Deutsche Welle. February 4, 2011. Retrieved February 4, 2011. 11. ^ a b c "Clothing makers mulling bigger sizes to fit tubbier Teutons". The Local. 22 April 2009. Retrieved 26 June 2010. 12. ^ a b Merkel, Wolfgang W (14 June 2012). "So krank sind die Deutschen wirklich". Die Welt (in German). Retrieved 13 September 2012. 13. ^ a b c "Italien hat die dicksten Kinder in Europa". Die Welt. 13 November 2011. Retrieved 14 November 2011. 14. ^ a b c "Die wenigsten Deutschen haben Normalgewicht". Die Welt. 10 June 2011. Retrieved 14 November 2011. 15. ^ a b c d e "Wie gesund lebt Deutschland?". Die Welt. 10 August 2010. Retrieved 14 November 2011. 16. ^ "New Study Shows Extent of Germany's Weight Problem". Deutsche Welle. 30 January 2008. Retrieved 28 June 2010. 17. ^ a b c "Fast jedes Kinder-Produkt ist zu süß und zu fett". Die Welt (in German). 13 March 2012. Retrieved 31 March 2012. 18. ^ Driessen, Barbara (29 July 2012). "800.000 Kinder in Deutschland sind fettleibig". Die Welt (in German). Retrieved 13 September 2012. 19. ^ a b c "Also doch, die Gene sind schuld am Übergewicht!". Die Welt (in German). 14 June 2012. Retrieved 14 June 2012. 20. ^ a b "Germany's young adults are too fat to work". The Local. December 16, 2008. Retrieved June 26, 2010. 21. ^ "Obesity linked to lower sperm count in young men". Reuters. August 11, 2010. Retrieved September 25, 2010. 22. ^ a b c d e "Doppelt so viele Typ-1-Diabetiker wie vor 15 Jahren". Die Welt. 14 November 2011. Retrieved 14 November 2011. 23. ^ a b "Übergewicht ist ein Motor für Krebserkrankungen". Die Welt (in German). 15 March 2012. Retrieved 13 September 2012. 24. ^ "Zu viel Bauchfett bei Senioren: Weniger Intelligenz". Augsburger Allgemeine (in German). 23 March 2012. Retrieved 16 April 2012. 25. ^ a b "German army goes to war against its flabby troops". Telegraph. 9 July 2001. Retrieved 25 June 2010. 26. ^ a b "German soldiers too fat to fight". The Local. 4 March 2008. Retrieved 1 July 2010. 27. ^ a b Sting, Jan (22 April 2005). "Projekt "Kugelblitz" gegen Fettleibigkeit". Kölner Stadt-Anzeiger (in German). Retrieved 11 April 2011. 28. ^ a b c d "Kölner Spezialklinik hilft Übergewichtigen". Die Welt. 2 August 2011. Retrieved 14 November 2011. 29. ^ a b c Preuß, Roland (20 May 2014). "Antreten zum Fitnesstest". Süddeutsche Zeitung (in German). Retrieved 21 May 2014. 30. ^ "World's Fattest Countries". Forbes.com. 8 February 2007. Retrieved 25 June 2010. * v * t * e Obesity in Europe Sovereign states * Albania * Andorra * Armenia * Austria * Azerbaijan * Belarus * Belgium * Bosnia and Herzegovina * Bulgaria * Croatia * Cyprus * Czech Republic * Denmark * Estonia * Finland * France * Georgia * Germany * Greece * Hungary * Iceland * Ireland * * Italy * Kazakhstan * Latvia * Liechtenstein * Lithuania * Luxembourg * Malta * Moldova * Monaco * Montenegro * Netherlands * North Macedonia * Norway * Poland * Portugal * Romania * Russia * San Marino * Serbia * Slovakia * Slovenia * Spain * Sweden * Switzerland * Turkey * Ukraine * United Kingdom States with limited recognition * Abkhazia * Artsakh * Kosovo * Northern Cyprus * South Ossetia * Transnistria Dependencies and other entities * Åland * Faroe Islands * Gibraltar * Guernsey * Isle of Man * Jersey * Svalbard [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 inhibitors [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	Obesity in Germany	None	2,966	wikipedia	https://en.wikipedia.org/wiki/Obesity_in_Germany	2021-01-18T19:02:47	{"wikidata": ["Q7074854"]}
The examples and perspective in this article deal primarily with the United States and do not represent a worldwide view of the subject. You may improve this article, discuss the issue on the talk page, or create a new article, as appropriate. (March 2013) (Learn how and when to remove this template message) Concussions, a type of mild traumatic brain injury, are a frequent concern for those playing sports, from children and teenagers to professional athletes. Repeated concussions are a known cause of various neurological disorders, most notably chronic traumatic encephalopathy (CTE), which in professional athletes has led to premature retirement, erratic behavior and even suicide. In the context of sports-related concussions (SRC), an SRC is currently defined as a "complex pathophysiological process affecting the brain, induced by biomechanical forces".[1] Because concussions cannot be seen on X-rays or CT scans, attempts to prevent concussions have been difficult.[2] The dangers of repeated concussions have long been known for boxers and wrestlers; a form of CTE common in these two sports, dementia pugilistica (DP), was first described in 1928. An awareness of the risks of concussions in other sports began to grow in the 1990s, and especially in the mid-2000s, in both the medical and the professional sports communities, as a result of studies of the brains of prematurely deceased American football players, who showed extremely high incidences of CTE (see concussions in American football). As of 2012, the four major professional sports leagues in the United States and Canada included policies for managing concussion risk.[3] Sports-related concussions are generally analyzed by athletic training or medical staff on the sidelines using an evaluation tool for cognitive function known as the Sport Concussion Assessment Tool (SCAT), a symptom severity checklist, and a balance test.[4] ## Contents * 1 Dangers * 1.1 Post-concussion syndrome * 1.2 Second-impact syndrome * 1.3 Dangers associated with repeated concussions * 1.4 Other risks * 2 Incidence * 2.1 Athlete-Based Concussion Rates Among National Collegiate Athletic Association Student-Athletes in Collegiate Sports[21] * 3 American Football * 3.1 National Football League's concussion policy * 4 Ice Hockey * 4.1 National Hockey League's concussion policy * 5 Association football * 6 Rugby union * 7 Baseball * 7.1 Major League Baseball's concussion policy * 8 Basketball * 8.1 Incidence * 8.2 National Basketball Association's concussion policy * 9 Combat sports * 9.1 Boxing * 10 Cricket * 11 Concussions in other sports * 11.1 Auto racing * 11.2 Gymnastics * 11.3 Bicycling * 12 Female sports * 13 Youth sports * 14 Prevention efforts and technologies * 14.1 Association Football (Soccer) * 14.2 Rugby * 14.3 Running * 14.4 Swimming * 14.5 Play in public playgrounds and sports fields * 14.6 Basketball * 14.7 Baseball * 14.8 Ice hockey * 14.9 Weightlifting * 14.10 Squash/racquetball * 14.11 Alpine skiing * 14.12 Horse riding * 14.13 American football * 14.14 Biycling * 15 Media coverage * 16 Policies summary * 16.1 Policies by major professional sports league * 17 See also * 18 References ## Dangers[edit] Concussion symptoms can last for an undetermined amount of time depending on the player and the severity of the concussion. Concussion symptoms can be described as immediate and delayed.[5] The immediate symptoms experienced immediately after concussions include the following: memory loss, disorientation, and poor balance.[5] Delayed symptoms are experienced in the later stages and include sleeping disorders and behavioral changes. Both immediate and delayed symptoms can continue for long periods of time and have a negative impact on recovery.[5] ### Post-concussion syndrome[edit] There is the potential of post-concussion syndrome, defined as a set of symptoms that may continue after a concussion is sustained.[6] Post-concussion symptoms can be classified into physical, cognitive, emotional, and sleep symptoms.[6] Physical symptoms include a headache, nausea, and vomiting.[6] Athletes may experience cognitive symptoms that include speaking slowly, difficulty remembering and concentrating.[6] Emotional and sleep symptoms include irritability, sadness, drowsiness, and trouble falling asleep.[6] ### Second-impact syndrome[edit] Ignoring concussions makes athletes more vulnerable to incurring further head trauma, stressing the importance of rigorous concussion testing protocols in professional sports. Subsequent impact can cause a rare condition known as second-impact syndrome, which can result in severe injury or death.[7] Second-impact syndrome can as a result of a second head injury before the brain has adequate time to heal in between concussions.[8] It typically give signs and symptoms of a post-concussion syndrome (visual, motor, or sensory abnormalities and difficulties with cognitive processes). Even minor repeated head blow may result in malignant cerebral oedema and even death. Nonetheless, it must be concluded that second-impact syndrome is an infrequent finding, predominately involving young athletes, and only rarely is fatal. [9][10][11] ### Dangers associated with repeated concussions[edit] Repeated concussions have been linked to a variety of neurological disorders among athletes, including chronic traumatic encephalopathy (CTE), Alzheimer's Disease, Parkinsonism and Amyotrophic lateral sclerosis (ALS).[12][13] Repeated concussions or mild-to-moderate traumatic brain injuries (TBI) have also been established to have effects on the motor dysfunction and movement disorders, however a systematic review has concluded that more investigation is needed to fully understand the long term effects of concussions and TBIs.[14] ### Other risks[edit] In addition, returning to sports with impaired sensorimotor function after experiencing a sports-related concussion (SRC) increases the risk of sustaining musculoskeletal (MSK) injuries.[15] In addition, athletes that experienced a concussion are two times more likely to sustain an MSK injury compared to non-concussed athletes.[16] ## Incidence[edit] It is estimated that as many as 1.6–3.8 million concussions occur in the US per year in competitive sports and recreational activities; this is a rough estimate, since as many as 50% of concussions go unreported.[17] Concussions occur in all sports with the highest incidence in American football, ice hockey, rugby, soccer, and basketball.[4] In addition to concussions caused by a single severe impact, multiple minor impacts may also cause brain injury.[18] Less than 10% of cases experience a loss of consciousness, and many typical symptoms appear after the initial concussion evaluation.[19] The overall incidence risk of concussion is higher in adults than in youth, as the injury rate per 1,000 athletic exposures for youth is 0.23, compared to 0.28 in collegiate athletes.[20] ### Athlete-Based Concussion Rates Among National Collegiate Athletic Association Student-Athletes in Collegiate Sports[21][edit] Sport Rates per 1000 Athlete-Exposures (95% Confidence Interval) Overall Competition Practice Men's Baseball 0.09 0.16 0.04 Basketball 0.38 0.53 0.34 Football 0.75 3.25 0.48 Ice hockey 0.74 2.40 0.20 Lacrosse 0.30 0.91 0.19 Soccer 0.26 0.67 0.14 Wrestling 0.89 4.31 0.48 Women's Basketball 0.53 1.00 0.39 Ice hockey 0.78 2.11 0.31 Lacrosse 0.45 1.28 0.25 Soccer 0.54 1.65 0.18 Softball 0.26 0.42 0.18 Volleyball 0.37 0.64 0.27 ## American Football[edit] Main article: Concussions in American football American football causes 250,000 concussions annually, and 20% of high-school football players experience a concussion every year.[22][23] In 2000, researchers from the Sports Medicine Research Laboratory at the University of North Carolina at Chapel Hill analyzed 17,549 players from 242 different schools. 888 (5.1%) of the players analyzed have at least one concussion a season, and 131 (14.7%) of them have had another concussion the year later. Division III and high-school players have a higher tendency to sustain a concussion than Division II and Division I players.[24] In 2001, the National Football League Players Association partnered with the UNC to determine whether professional football players suffer any health effects after any injuries, although the findings were criticized by the NFL for being unreliable due to being based on self-reporting by the players.[25] ### National Football League's concussion policy[edit] Main article: Concussions in American football The National Football League's (NFL) policy was first started in 2007, and injured players are examined on field by the medical team.[26] The league's policy included the "NFL Sidelines Concussion Exam", which requires players who have taken hits to the head to perform tests concerning concentration, thinking and balance.[27] In 2011, the league introduced an assessment test, which combines a symptoms checklist, a limited neurological examination, a cognitive evaluation, and a balance assessment. For a player to be allowed to return, he must be asymptomatic.[28] If a player is cleared by the Unaffiliated Neurotrauma Consultant (UNC), then they will be allowed to play but will be monitored closely throughout the game. If a player is diagnosed with a concussion, then that player is not allowed back in the game. A return to play process is issued, which includes five steps, “1. Rest and recovery 2. Light aerobic exercise 3. Continued aerobic exercise/strength training 4. Football specific activities 5. Full football activity/clearance”[29] Almost every team has experienced a player who will “keep playing, then manage to stumble off the field, unnoticed by the coaches, cameras or press. He might take a breather for a series or two. But he can walk, so he wants to play. He gets back in the game and back to his teammates.”[30] According to Johns Hopkins University, a study took place which “researchers recruited nine former NFL players who retired decades ago and who ranged in age from 57 to 74. The men had played a variety of positions and self-reported a wide range of concussions, varying from none for a running back to 40 for a defensive tackle."[31] ## Ice Hockey[edit] Ice hockey has also been known to have concussions inflict numerous players. Because of this, the NHL made hockey helmets mandatory in the 1979–80 NHL season.[32] According to a data release by the National Academy of Neuropsychology's Sports Concussion Symposium, from 2006 to 2011, 765 NHL players were diagnosed with a concussion.[33] At the Mayo Clinic Sports Medicine Center Ice Hockey Summit: Action on Concussion conference in 2010, a panel made a recommendation that blows to the head are to be prohibited, and to outlaw body checking by 11- and 12-year-olds. For the 2010–11 NHL season, the NHL prohibited blindside hits to the head, but did not ban hits to the face. The conference also urged the NHL and its minor entities to join the International Ice Hockey Federation, the NCAA and the Ontario Hockey League in banning any contact to the head.[34] ### National Hockey League's concussion policy[edit] The National Hockey League's (NHL) concussion policy began in 1997, and players who sustain concussions are evaluated by a team doctor in a quiet room.[26] In March 2011, the NHL adopted guidelines for the league's concussion policy. Before the adoptions, examinations on the bench for concussions was the minimum requirement, but the new guidelines make it mandatory for players showing concussion-like symptoms to be examined by a doctor in the locker room.[35] Dr. Paul Echlin and Dr. Martha Shenton of Brigham and Women's Hospital and other researchers, conducted a study where “Forty-five male and female Canadian university hockey players were observed by independent physicians during the 2011–2012 season. All 45 players were given M.R.I. scans before and after the season. The 11 who received a concussion diagnosis during the season were given additional scans within 72 hours, two weeks and two months of the incident. The scans found microscopic white matter and inflammatory changes in the brains of individuals who had sustained a clinically diagnosed concussion during the period of the study.”[36] > "We celebrate the big hit, we don't like the big head hit. There is an important distinction because we celebrate body-checking."[35] > > — NHL Commissioner Gary Bettman The NHL has been criticized for allowing team doctors to determine whether an injured player can return to the ice, instead of independent doctors.[37] ## Association football[edit] Association football— also known as soccer— is a major source of sports-related concussions around the world. Even though 50–80% of injuries in football are directed to the legs, head injuries have been shown to account for between 4 and 22% of football injuries. There is the possibility that heading the ball could damage the head, as the ball can travel at 100 km/hour; although most professional footballers have reported that they experienced head injuries from colliding with other players and the ground.[38][39] A multi-year study by the University of Colorado published in JAMA Pediatrics confirmed that athlete-to-athlete collisions that occur during heading, not impact with the ball itself, is generally the cause for concussion.[40] A Norwegian study consisting of current and former players of the Norway national football team found out that 3% of the active and 30% of the former players had persistent symptoms of concussions, and that 35% of the active and 32% of that former players had abnormal electroencephalogram (EEG) readings.[41] During the 2006-07 English Premier League season, Czech goalkeeper Petr Čech suffered from a severe concussion in a match between his club Chelsea and Reading. During the match, Reading midfielder Stephen Hunt hit Čech's head with his right knee, knocking the keeper out.[42] Čech underwent surgery for a depressed skull fracture and was told that he would miss a year of playing football. Čech resumed his goalkeeper duties on 20 January 2007 in a match against Liverpool, now wearing a rugby helmet to protect his weakened skull. According to Downs DS and D Abwender in their article Neuropsychological Impairment in Soccer Athletes, “participation in soccer may be associated with poorer neuropsychological performance, although the observed pattern of findings does not specifically implicate heading as the cause”.[43] On 2 November 2013 in a match between Tottenham and Everton, Tottenham goal keeper Hugo Lloris sustained a blow to the head by on -coming player Romelu Lukaku's knee. The blow left Lloris knocked out on the ground. Reluctantly manager Andre Villas Boas decided to leave the player on after regaining consciousness and having passed a medical assessment. This broke the rules of the PFA, which state that any player who has lost consciousness must be substituted.[44] There has been a widespread debate on protective head gear in soccer. Known as a sport associated with intricate footwork, speed, and well-timed passes, soccer also is classified as a high- to moderate-intensity contact/collision sport, with rates of head injury and concussion similar to those seen in football, ice hockey, lacrosse, and rugby. While the benefits of helmets and other head protection are more obvious in the latter sports, the role of headgear in soccer is still unclear.[45] There are clear rules from FIFA regarding what to do when a player gets a concussion. FIFA's guidelines say that a player who has been knocked unconscious should not play again that day. The rules do however allow for "a transient alteration of conscious level" following a head injury, which says that a player can return to play following assessment by medical staff. The rules also state that a player who is injured with head damage is not to be played for five days.[44] ## Rugby union[edit] Main article: Concussions in rugby union Concussions are also a significant factor in rugby union, another full-contact sport. In 2011, the sport's world governing body, World Rugby (then known as the International Rugby Board, or IRB), issued a highly detailed policy for dealing with injured players with suspected concussions. Under the policy, a player suffering from a suspected concussion is not allowed to return to play in that game. Players are not cleared to play after the injury for a minimum of 21 days, unless they are being supervised in their recovery by a medical practitioner. Even when medical advice is present, players must complete a multi-step monitoring process before being cleared to play again; this process requires a minimum of six days.[46] In 2012, the IRB modified the policy, instituting a Pitchside Suspected Concussion Assessment (PSCA), under which players suspected of having suffered concussions are to leave the field for 5 minutes while doctors assess their condition via a series of questions. Players who pass the PSCA are allowed to return to play.[47] However, an incident during the third Test of the 2013 Lions tour of Australia led to criticism of the current protocols. During that match, Australian George Smith clashed heads with the Lions' Richard Hibbard and was sent to pitchside. According to ESPN's UK channel, "despite looking dazed and confused, Smith passed the PSCA and was back on the field minutes later."[47] In 2013, former Scotland international Rory Lamont charged that the current concussion protocols can easily be manipulated. A key part of the current protocols is the "Cogsport" test (also known as COG), a computer-based test of cognitive function. Each player undergoes the test before the start of a new season, and is then tested again on it after a head injury, and the results compared, to determine possible impairment. According to Lamont, some players deliberately do poorly on the pre-season test, so that they will be more likely to match or beat their previous results during play.[48] Lamont was also critical of the PSCA, noting: > The problem with the PSCA is a concussed player can pass the assessment. I know from first hand experience it can be quite ineffective in deciding if a player is concussed. It is argued that allowing the five-minutes assessment is better than zero minutes but it is not as clear cut as one might hope. Concussion symptoms regularly take 10 minutes or longer to actually present. Consequently the five-minute PSCA may be giving concussed players a license to return to the field.[48] The Concussion bin was replaced by the head bin in 2012 with the players assessment taking 10 minutes.[49] If concussed the player must then recover by first returning to general activities in life, then progressing back to playing. Returning to play, the player must follow the Graduated Return to Play (GRTP) protocol, by having clearance from a medical professional, and no symptoms of concussion. ## Baseball[edit] ### Major League Baseball's concussion policy[edit] Major League Baseball's (MLB) policy was first started in 2007, and injured players are examined by a team athletic trainer on the field.[26] On 29 March 2011, MLB and the Major League Baseball Players Association announced that they have created various protocols for the league's concussion policy.[50] The new policy includes the following protocols: * All teams are to run baseline neurocognitive testing for all players and umpires using the ImPACT (Immediate Post-Concussion Assessment and Cognitive Testing) system during spring training or after a player signing.[51] * If a player sustains head impact during a game, the play is stopped and the player's injury is assessed.[51] * A Certified Athletic Trainer (ATC) can evaluate and treat a player during a game.[51] * If the trainer seems that the player has sustained a concussion and seems that it is necessary, he or she can remove the player from the game and move to the clubhouse for further evaluation.[51] * The Team Physician may also evaluate the player in the clubhouse. Player completes the SCAT3(Sport Concussion Assessment Tool, version 3)form in the clubhouse. If the player seems to not have sustained a concussion, he can return the game.The trainer can then evaluate the player throughout the entirety of the game after the injury occurs. If the player is thought to have a concussion, the team, the trainer, and team physician can determine whether to place the player on the 7-day or 10 day injured List (IL).[51] * If a player on a 7-day concussion IL is still unable to return to play after nine days, he is automatically transferred to a 10-day IL.[51] ## Basketball[edit] ### Incidence[edit] In the 2005 high school basketball year, 3.6% of reported injuries were concussions, with 30.5% of concussions occurring during rebounds.[52] Incidence rates for concussions in NCAA men's basketball is lower than NCAA women's basketball, at 0.16 concussion per 1,000 athletes compared to 0.22 per 1,000 athletes respectively. The difference is found mainly in competition activity compared to practice.[53] ### National Basketball Association's concussion policy[edit] On December 12, 2011, the National Basketball Association (NBA) announced that the establishment of a concussions policy for league.[54] The players and staff are required annual education on topics surrounding concussion during play, including mechanisms of injury, signs, symptoms and interventions.[55] The policies surrounding concussion management in NBA are as follows: * If concussion is suspected, the injured player is removed from the game immediately and monitored to ensure safety.[55] At this time, a neurological exam is conducted by the team's physician or athletic trainer.[55] * For the following 24 hours after the primary evaluation, the player is monitored closely by the team's medical staff, so long as they are not diagnosed with a concussion.[55] The player must complete at least one other evaluation before the following game or practice (whichever comes first).[55] * If the player is diagnosed with a concussion, they are prohibited from participating (on the same day or the next day) and must undergo the requried return-to-participation protocol.[55] * The player, under direction of the team's medical staff, must avoid physical exertion and exposure to electronic devices, so as not to aggravate symptoms.[55] Physical activity must be reintroduced gradually according to the medical staff's discretion.[55] * A physician must provide an impression regarding the presence or absence of concussion within 24 hours of the incident.[55] In addition, the Director of the NBA Concussion Program must be informed about the concussion evaluation.[55] ## Combat sports[edit] ### Boxing[edit] Despite boxing's violent nature, a National Safety Council report in 1996 ranked amateur boxing as the safest contact sport in America.[citation needed] However, concussions are one of the most serious injuries that can occur from boxing, and in an 80-year span from 1918 to 1998, there were 659 boxers who died from brain injury.[56] Incidence rates for concussion in boxing may frequently be miscalculated due to the fact that concussions do not always result from a knockout blow.[57] Olympic boxers deliver punches with high impact velocity but lower HIC and translational acceleration than in football impacts because of a lower effective punch mass. They cause proportionately more rotational acceleration than in football. Modeling shows that the greatest strain is in the midbrain late in the exposure, after the primary impact acceleration in boxing and football.[citation needed] Muhammad Ali, possibly the most famous boxer of all time, was “diagnosed with 'a cluster of symptoms that resemble Parkinson's disease,' known as Parkinson's syndrome, which his doctor believed were caused by numerous blows to the head,” which led to his death in 2016.[58] ## Cricket[edit] Main articles: Concussion substitute and Cricket ball § Dangers of cricket balls ## Concussions in other sports[edit] ### Auto racing[edit] The death of Dale Earnhardt at the 2001 Daytona 500, along with those of Kenny Irwin, Adam Petty and Tony Roper in 2000, and serious injuries sustained by Steve Park in a wreck in September 2001 at Darlington, led to NASCAR establishing numerous policies to assist in driver safety, such as the introduction of the Car of Tomorrow. Drivers were eventually instructed to wear both head and neck restraints, and SAFER barriers have been installed on racetrack walls, with foam-padded supports on each side of the helmet that would allow a driver's head to move in the event of a crash. Despite this, 29 identified concussions occurred between 2004 and 2012.[59] In 2012, when Dale Earnhardt, Jr. suffered a concussion after being involved in a crash at the end of the Good Sam Roadside Assistance 500 at Talladega, NASCAR expressed consideration in adding baseline testing to its concussion policies. NASCAR was one of few motorsport organizations that do not have baseline testing,[60] though that ended in 2014, as baseline testing started being performed at the start of the seasons.[61] ### Gymnastics[edit] As many skills in gymnastics involve flipping or a blind landing, incidence of head injury increases. A 15-year study found an incidence of 1.7% for concussion and closed head injury for high school gymnasts.:)[53] ### Bicycling[edit] Bicycling is a sport in which participants are at risk of concussions and head injuries. Each year in the US there are approximately 80,000 bicycling related head injuries that require treatment in an emergency room.[62] Roughly 33% of non-fatal bicyclist injuries are to the head. Many casual and even professional bicyclists don't take safety precautions seriously, and in 2016 more than half of bicyclists involved in fatal crashes were reported not wearing a helmet.[citation needed] ## Female sports[edit] Numerous reports have indicated that female athletes suffer more concussions than male athletes.[63] A December 2008 report states that 29,167 female high school soccer players in the United States suffered from concussions in 2005, compared to 20,929 male players. In high school basketball, 12,923 girls suffered from concussions while only 3,823 boys did. Girls also sustained more concussions in softball, compared to boys in baseball.[64] Female athletes also had longer recovery times than males, and also had lower scores on visual memory tests. Girls also have longer recovery times for concussions, which may be due to a greater rate of blood flow in the brain.[65] Women's ice hockey was reported as one of the most dangerous sports in the NCAA, with a concussion rate of 2.72 per 1,000 player hours. Even though men's ice hockey allows body checking, while women's ice hockey does not, the rate of concussions for men is 46% lower, at 1.47 per 1,000 player hours. College football also has lower concussion rates than women's hockey, with a rate of 2.34 per 1,000.[66] Women's basketball is one of the women's sports with the highest risks of getting a concussion. Women have a greater risk of getting a concussion by dribbling/ball handling rather than defending. Also it was found that female college basketball players typically receive concussions during games rather than practices.[67] ## Youth sports[edit] See also: Concussions in high school sports Many children and teenagers participate in sports and extracurricular activities that create a risk of a head injury or concussion, including basketball, cheerleading, soccer, and football.[68] As a consequence, schools and youth sports groups should implement programs to reduce the risk of concussion, ensure prompt diagnosis[69] and provision of medical care, and that young participants are not endangered by a premature return to sports.[70][71] In 2010, more high school soccer players suffered concussions than basketball, baseball, wrestling, and softball players combined, according to the Center for Injury Research and Policy.[72] According to a study in the JAMA Pediatrics medical journal, many girls do not get necessary care and prevention regarding concussions, and 56 percent of players (or their families) reporting concussion symptoms never sought treatment.[73] A growing topic is concussions in girls' soccer, predominantly among high-school girls. Studies show that girls are reporting nearly twice as many concussions as boys in the sports that they both play. The number of girls suffering concussions in soccer accounts for the second largest amount of all concussions reported by young athletes.[74] Concussion often results in a myriad of symptoms, including difficulty concentrating, focusing, and remembering, that are typically managed with rest from daily activities, namely school for symptomatic youth.[75] The current consensus is that concussions have negligible effect on educational performance and school grades in youth.[75][76] However, a recent study found that male students who sustained a sports-related concussion or sports-related fracture experienced significant drops in school grades post-injury, by approximately 1.73%. In addition, students with a concussion or head trauma missed significantly more days of school.[76] ## Prevention efforts and technologies[edit] There have been numerous attempts at preventing concussions, such as the establishment of the PACE (Protecting Athletes Through Concussion Education) program,[77] which works with the imPACT system, which is currently used by every NFL and some NHL teams.[78] In 2008, the Arena Football League tested an impact monitor created by Schutt Sports called the "Shockometer", which is a triangular device attached to the back of football helmets that has a light on the device that turns red when a concussion occurs.[79] Riddell has also created the Head Impact Telemetry System (HITS) and Sideline Response System (SRS) to record the frequency and severity of player hits during practices and games. On every helmet with the system, MX Encoders are implemented, which can automatically record every hit.[80] Eight NFL teams had originally planned to use the system in the 2010 season, but the NFL Players Association ultimately blocked its use.[81] Other impact-detection devices include CheckLight, by Reebok and MC10.,[82] and the online test providers ImPACT Test, BrainCheck, and XLNTbrain which establish cognitive function baselines against which the athlete is monitored over time. The CCAT online tool developed by Axon Sports is another test to assist doctors in assessing concussion. In addition to force impact sensors used to assess traumatic brain injury, studies have been conducted to assess levels of biological markers for the presence of brain concussion. A variety of concurrently researched biomarkers have been associated with concussions, including S100B, Tau protein and glial fibrillary acid protein (GFAP).[83] In 2018, the FDA approved Banyan Biomarkers Inc. to market devices involving the use of blood samples to evaluate concussions in adults.[84] Banyan BTI (Brain Trauma Indicator) is a blood sample product that the FDA permitted for use before the decision to further assess head injury with CT scanning. Neck collar technology is currently being explored for more widespread use in sports. The Q-Collar (previously known as Bauer Neuroshield) is an example of such a device.[85] Neck collars are designed to gently constrict blood flow through the jugular vein in the neck, increasing fluid pressure in the head.[86] The aim of this technology is to allow greater cushioning for neurological structures in the event head trauma.[87] Despite being unable to prevent serious traumatic brain injury, the device has been associated with a protective effect against microstructural changes in the brain after regular impact.[86] However, further research is necessary to determine if the device's efficacy is substantiated. Since Health Canada's approval of the Q-Collar as a Class 1 Medical Devices, a few players in the Canadian Football League have used it in play.[86][88] Efforts to manage concussion risk in youth and high school sports include online informational resources designed for coaches and parents. For example, the US Centre for Disease Control and Prevention created the HEADS UP program, a free online informational tool. It was first launched in 2007, with aims to improve concussion identification and management.[89] The online tool is available on CDC's website and has been used by 2 million individuals to date.[90] The online resource was updated in 2016 and an interventional study conducted an assessment of the efficacy of the updated version.[89] A systematic review investigated the effects of policies on preventing sports injuries of children at school (ages 4–18) including 26 policies, 14 of which were from the US, and 10 of which were concussion-specific . Of the 10 studies specific to concussion, and 6 studies on guidelines on preventing concussions. The most common recommendation for primary prevention was the 'education of athletes, colleagues and the public ...". Several other guidelines included rule changes, and the adherence of rules during games. Regarding helmets, there was consensus that they may not always protect against concussions. 2 guidelines recommended the development of concussion policies, or the incorporation of concussions into existing head injury policies. Another 2 guidelines recommended supervision of sports injuries. Further research into the effectiveness of guidance for schools on concussion prevention is needed.[91] A systematic review conducted by the Social Science Research Unit in London in 2007 concluded that athletic injuries for young people (ages 12–24) are reduced under supervision by a coach, however strong evidence for interventions to reduce sports-related injuries remains lacking.[92] As such, the authors endorse the establishment of a national sports injury database in order to strengthen the base of evidence for interventions. The review outlined several interventions to prevent injuries specific to certain sports. ### Association Football (Soccer)[edit] Modest evidence was found on the effectiveness of training programs in reducing injuries. Another study within the review, conducted in Sweden, found that implementing a program including a standardised warm-up, ankle taping, shoe design, leg guards, and controlled rehabilitation reduced injuries by 75% when administered by medical personnel, and 50% when done by coaches. However, another systematic review within the London review only found good evidence for ankle supports in preventing ankle sprains for those with a prior ankle strain, limited evidence was found for those ankle training exercises on a sprain reduction, and no conclusions were able to be made on other interventions, including ankle taping and stretches. Possible directions for future research include "further evaluation of shin guards, ankle taping and bracing, protective eye wear and mouth guards, and goal post padding and anchoring ... research into the suitability of safe playing surfaces for younger players".[92] ### Rugby[edit] Custom-fitted mouth guards were found to be effective in 4 of 5 studies done in a review. Having the playing season in the autumn/winter decreases the risk of injury, with the highest risk occurring in the summer. Another study found a change in the rules associated with tackles, scrums and mauls decrease the number of rugby union players suffering permanent quadriplegia.[92] ### Running[edit] A systematic review containing 12 trails found a modification of training schedules, stretching exercises, and use of external supports or footwear modifications to be lacking in strong evidence of their ability to reduce training injuries while maintaining the benefits of exercise. Another study found an association between warm-up techniques and injuries, however, that may be due to a tendency of previously injured athletes to engage more in warm-up exercises. One randomised controlled trial in the Netherlands concluded that there was no reduction in incidence or severity of injuries with standardised warm-up and cool-down exercises in recreational runners. Topics of further research include the effects of knee braces, corrective insoles for misalignment, and the modification of footwear on the prevention of running injuries.[92] ### Swimming[edit] Parent and child education has an effect on swimming injuries. There were also findings of the effectiveness of a community-based program geared towards children 14 years old and under, involving life vest loans and bulk discounts. Pool design modifications may reduce injuries. 2 reviews both found that adult/guard supervision of public swimming spaces reduces injury, and one review found swimming interventions in children may "offer some protection", although no large trials support such claim.[92] ### Play in public playgrounds and sports fields[edit] A UK-based community study found reductions in injury rates after the removal of monkey bars and increases in depth of the bark beneath equipment. A community intervention trial in New Zealand concluded the effectiveness of programs encouraging schools to reduce playground hazards. Another study found a change of environment in sports fields and playgrounds to reduce the incidence of injuries, including 'quick release bases', bases which detach easily from the ground upon contact with a player sliding, often used in recreational softball.[92] ### Basketball[edit] Findings on ankle injury prevention in the 'Football (Soccer)' section also apply. A review found the use of "ankle stabilisers or high-top shoes and ankle taping can reduce the incidence of ankle injuries".[92] ### Baseball[edit] Two reviews independently concluded that modified/'break-away bases' are more effective than standard bases in the prevention of sliding-related injuries.[92] ### Ice hockey[edit] A review found regulatory approaches to be effective in reducing injury rates. E.g. mandatory use of protective equipment, implementation of new rules such as disallowing 'checking' from behind and 'high sticking' (raising the stick above shoulder height). A study found an inverse relationship between ice surface size and injury rate, and the use of correctly fitted helmets in injury reduction. Another review found an association between the use of face protectors and a decrease in facial injuries.[92] ### Weightlifting[edit] A review found evidence of the use of weight lifting belts in the prevention of back injuries.[92] ### Squash/racquetball[edit] A review concluded that the use of eye protectors "meeting certain standards of specification, face protectors, and guards (closed type)" may prevent injury. Additionally, the usage of such protectors increased "when the equipment was available [for borrowing] from the court [with] information about the specific consequences of not wearing eye protection ... displayed".[92] ### Alpine skiing[edit] Ten low-quality studies in a review suggested the beneficial effects of lessons for beginners, mainly composed of children and young adults.[92] Numerous studies have also suggested that while helmets can be of great use in reducing the risk and severity of head injury, they have little effect on the incidence of concussions.[93] Sensation seeking and risk-taking behavior appear to be two domains that need to be addressed in order to optimize prevention efforts for traumatic brain injury in this sport.[93] ### Horse riding[edit] A review found one multi-agency collaboration in publicising the risks of head injury effective in raising awareness and increasing sales of horse-riding helmets.[92] ### American football[edit] A review concluded that the use of face protectors is effective in decreasing facial injuries. Moreover, it was concluded that mouth guards lead to less oral and head injuries. Conflicting evidence was found for the use of knee braces.[92] ### Biycling[edit] One approach to reduction of head injuries in bicycling involves developing and improving helmets in order to protect bicyclists in the event of an accident that results in a blow to the head.[citation needed] ## Media coverage[edit] Recent documentaries and films, such as Concussion, portray the issue to be a common cause of long-term neurological disability and the direct cause of a chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy that is found in individuals with a history of exposure to severe or repeated head trauma.[94] The increasing concern over the potential long-term effects of sport-related concussions has heightened scrutiny of the practice of collision sports, particularly American football, with some individuals advocating for its abolition.[94] Sports concussion has been the subject of much discourse in mainstream media for many years.[95] Media coverage of professional athletes experiencing irreversible damage after repeated brain trauma and of the under-reported rates and risks of paediatric concussion have heightened awareness surrounding head injury in sports and recreation. The frequency of concussion in some of the world's biggest sports such as soccer, football, and rugby has increased the amount of media coverage.[95] Terminology for sports related concussions in media have shown to differ based on the geographical location. Based on media articles evaluated, America used the descriptors “head trauma” (11.7%) and “brain trauma” (6.8%) the most, while articles from the UK and Ireland primarily mentioned the descriptor “blow to head”(22.2%).Australia to have the highest usage of the descriptors “head injury” (57.1%), and “brain injury” (28.6%) while New Zealand was highest for “head knock” (46.7%), “head clash” (13.3%), and “brain damage” (13.3%). The USA used the descriptors “head trauma” (11.7%) and “brain trauma” (6.8%) the most, while articles from the UK and Ireland primarily mentioned the descriptor “blow to head”(22.2%). For the consequences of concussion, the UK and Ireland mentioned “Second Impact Syndrome “(22.2%), “Chronic Traumatic Encephalopathy” (22.2%) and “Parkinson's disease and other neurological conditions” (11.1%) the most. While, America most commonly mentioned “Alzheimer's, dementia and neurocognitive problems” (13.6%) and “Amyotrophic Lateral Sclerosis” (11.7%), while Canada saw the most frequent mention of “depression and suicide” (10.5%).[95] Also, the use of misleading terms such as “mild concussion”, “minor concussion” and “slight concussion” are commonplace in the media.[95] Although media articles are often written by individuals (i.e. journalists) who are not medically trained, these articles have been found to potentially influence perceptions regarding concussion for a wide audience due to the global reach of the internet. In 2012, film producer Steve James created the documentary film Head Games, interviewing former NHL player Keith Primeau, and the parents of Owen Thomas, who hanged himself after sustaining brain damage during his football career at Penn.[96] The documentary also interviewed former athletes Christopher Nowinski, Cindy Parlow, and New York Times reporter Alan Schwarz, among other athletes, journalists, and medical researchers.[97] League of Denial was a 2013 book by sports reporters Mark Fainaru-Wada and Steve Fainaru about concussions within the NFL. The American documentary series Frontline covered the topic in two episodes, one based on the book and also called "League of Denial",[98] and the other called "Football High"[99] Political sports journalist Dave Zirin has also covered the topic in detail.[100] ## Policies summary[edit] ### Policies by major professional sports league[edit] League Year policy first introduced Year baseline testing occurred Year current policy became effective First step after injury Person who approves/denies player to return Person who decides player return NFL 2007 2008 2009 Evaluation by medical team Medical staff Medical staff/Consultant MLB 2007 2011 2007 Evaluation by an athletic trainer using National Association Guidelines Medical staff Head physician/Medical director NBA Never Never Never Depends on team Depends on team Depends on team NHL 1997 1997 2011 Neuropsychological evaluation by team doctor off rink Team doctor Team doctor MLS 2011 2003 2011 Evaluation by medical team Team physician Team physician/Neuropsychologist NASCAR 2003 2003 2003 Ambulance to infield care center NASCAR NASCAR ## See also[edit] * Sports portal * Philosophy portal * Concussions in Australian sport * Concussion grading systems * Head injury criterion * Shock data logger * Impact sensor * Sports-related traumatic brain injury * Concussions in high school sports ## References[edit] 1. ^ McCrory, P.; Feddermann-Demont, P.; Dvořák, J.; al, et (2017). "What is the definition of sports-related concussion: a systematic review". British Journal of Sports Medicine. 51 (11): 877–887. doi:10.1136/bjsports-2016-097393. PMID 29098981. 2. ^ Mayo Clinic Staff. "Concussion Tests and diagnosis". 3. ^ "Concussions in sports – NFL Topics – ESPN". Espn.go.com. Retrieved 30 June 2012. 4. ^ a b Harmon K. G.; Drezner J. A.; Gammons M.; Guskiewicz K. M.; Halstead M.; Herring S. A.; Roberts W. O. (2013). "American Medical Society for Sports Medicine position statement: concussion in sport". British Journal of Sports Medicine. 47 (1): 15–26. doi:10.1136/bjsports-2012-091941. PMID 23243113. 5. ^ a b c Livingston, Scott C (2011). "The Neurophysiology Behind Concussion Signs and Symptoms". International Journal of Athletic Therapy and Training. 16 (5): 5–9. doi:10.1123/ijatt.16.5.5. 6. ^ a b c d e Ganti, Latha; Khalid, Hussain; Patel, Pratik Shashikant; Daneshvar, Yasamin; Bodhit, Aakash N; Peters, Keith R (2014). "Who gets post-concussion syndrome? An emergency department-based prospective analysis". International Journal of Emergency Medicine. 7: 31. doi:10.1186/s12245-014-0031-6. PMC 4306054. PMID 25635191. 7. ^ Bey, T; Ostick, B (2009). "Second impact syndrome". The Western Journal of Emergency Medicine. 10 (1): 6–10. PMC 2672291. PMID 19561758. 8. ^ Edwards, Jonathan C; Bodle, Jeffrey D (2014). "Causes and Consequences of Sports Concussion". The Journal of Law, Medicine & Ethics. 42 (2): 128–32. doi:10.1111/jlme.12126. PMID 25040374. 9. ^ Elgart, E. S.; Gusovsky, T.; Rosenberg, M. D. (20 November 1975). "Preparation and characterization of an enzymatically active immobilized derivative of myosin". Biochimica et Biophysica Acta (BBA) - Enzymology. 410 (1): 178–192. doi:10.1016/0005-2744(75)90219-3. ISSN 0006-3002. PMID 72. 10. ^ Pfister, M.; Schaub, M. C.; Watterson, J. G.; Knecht, M.; Waser, P. G. (20 November 1975). "Radioactive labeling and location of specific thiol groups in myosin from fast, slow and cardiac muscles". Biochimica et Biophysica Acta (BBA) - Enzymology. 410 (1): 193–209. doi:10.1016/0005-2744(75)90220-x. ISSN 0006-3002. PMID 73. 11. ^ Saunders, Richard L. (27 July 1984). "The Second Impact in Catastrophic Contact-Sports Head Trauma". JAMA: The Journal of the American Medical Association. 252 (4): 538. doi:10.1001/jama.1984.03350040068030. ISSN 0098-7484. 12. ^ Cantu RC (2007). "Chronic traumatic encephalopathy in the National Football League". Neurosurgery. 61 (2): 223–5. doi:10.1227/01.NEU.0000255514.73967.90. PMID 17762733. 13. ^ Pellman, E. J; Viano, D. C; Withnall, C; Shewchenko, N; Bir, C. A; Halstead, P. D (2006). "Concussion in professional football: Helmet testing to assess impact performance--part 11". Neurosurgery. 58 (1): 78–96, discussion 78–96. doi:10.1227/01.neu.0000196265.35238.7c. PMID 16385332. 14. ^ Ozolins, Bede; Aimers, Nicole; Parrington, Lucy; Pearce, Alan J. (2016). "Movement disorders and motor impairments following repeated head trauma: A systematic review of the literature 1990–2015". Brain Injury. 30 (8): 937–947. doi:10.3109/02699052.2016.1147080. PMID 27120772. 15. ^ McPherson, April L.; Nagai, Takashi; Webster, Kate E.; Hewett, Timothy E. (2019). "Musculoskeletal Injury Risk After Sport-Related Concussion: A Systematic Review and Meta-analysis". The American Journal of Sports Medicine. 47 (7): 1754–1762. doi:10.1177/0363546518785901. PMID 30074832. 16. ^ McPherson, April L.; Nagai, Takashi; Webster, Kate E.; Hewett, Timothy E. (1 June 2019). "Musculoskeletal Injury Risk After Sport-Related Concussion: A Systematic Review and Meta-analysis". The American Journal of Sports Medicine. 47 (7): 1754–1762. doi:10.1177/0363546518785901. ISSN 0363-5465. PMID 30074832. 17. ^ Harmon, Kimberly G; Drezner, Jonathan A; Gammons, Matthew; Guskiewicz, Kevin M; Halstead, Mark; Herring, Stanley A; Kutcher, Jeffrey S; Pana, Andrea; Putukian, Margot; Roberts, William O (2013). "American Medical Society for Sports Medicine position statement: Concussion in sport". British Journal of Sports Medicine. 47 (1): 15–26. doi:10.1136/bjsports-2012-091941. PMID 23243113. 18. ^ Rivara, G R (2014). Sports-Related Concussions in Youth: Improving the Science, Changing the Culture. Institute of Medicine; National Research Council. Retrieved 12 November 2014. 19. ^ "Sports-Related Concussion". www.reliasmedia.com. Retrieved 3 November 2019. 20. ^ Pfister, Ted; Pfister, Ken; Hagel, Brent; Ghali, William A.; Ronksley, Paul E. (1 March 2016). "The incidence of concussion in youth sports: a systematic review and meta-analysis". British Journal of Sports Medicine. 50 (5): 292–297. doi:10.1136/bjsports-2015-094978. ISSN 0306-3674. PMID 26626271. 21. ^ Kerr, Zachary Y.; Roos, Karen G.; Djoko, Aristarque; Dalton, Sara L.; Broglio, Steven P.; Marshall, Stephen W.; Dompier, Thomas P. (March 2017). "Epidemiologic Measures for Quantifying the Incidence of Concussion in National Collegiate Athletic Association Sports". Journal of Athletic Training. 52 (3): 167–174. doi:10.4085/1062-6050-51.6.05. ISSN 1062-6050. PMC 5384815. PMID 27331336. 22. ^ McKeag, Douglas; Moeller, James L. (1 January 2007). ACSM's Primary Care Sports Medicine. Lippincott Williams & Wilkins. ISBN 978-0-7817-7028-6. 23. ^ SMH. "Sport-Related Concussion". Hughston.com. Archived from the original on 6 February 2013. Retrieved 1 July 2012. 24. ^ "Neuroscience for Kids – Football Concussions". Faculty.washington.edu. Retrieved 1 July 2012. 25. ^ Hadhazy, Adam (2 September 2008). "Concussions Exact Toll on Football Players Long After They Retire". Scientific American. Retrieved 1 July 2012. 26. ^ a b c Brady, Erik; Falgoust, J. Michael (25 October 2011). "Concussions now a hot issue as leagues toughen policies". Usatoday.Com. Retrieved 30 June 2012. 27. ^ "NFL to require sideline test after head blows – – CNN.com Blogs". Thechart.blogs.cnn.com. 25 February 2011. Retrieved 30 June 2012. 28. ^ Mayer, Larry (12 November 2012). "Cutler on mend after suffering concussion". Chicago Bears. Archived from the original on 15 November 2012. Retrieved 12 November 2012. 29. ^ "How does the NFL's concussion protocol work?". SBNation.com. Retrieved 20 March 2018. 30. ^ 1958–, McClafferty, Carla Killough (September 2013). Fourth down and inches : concussions and football's make-or-break moment. Minneapolis. ISBN 978-1-4677-1067-1. OCLC 828775853.CS1 maint: numeric names: authors list (link) 31. ^ "Johns Hopkins study of retired NFL players sheds light on concussion-related brain damage". The Hub. 26 January 2015. Retrieved 19 April 2018. 32. ^ Stubbs, Dave (19 June 2012). "Dave Stubbs: Max Pacioretty richly deserves Masterton trophy". Montrealgazette.com. Retrieved 14 July 2012. 33. ^ "Bigger Hockey Players Causing More Concussions". LiveScience. 10 November 2008. Retrieved 4 July 2012. 34. ^ Klein, Jeff (20 October 2010). "Hockey Urged to Ban All Blows to Head by Concussions Panel". The New York Times. 35. ^ a b "NHL commissioner Gary Bettman pleased with league's concussion protocol – ESPN". Sports.espn.go.com. 23 April 2011. Retrieved 30 June 2012. 36. ^ Klein, Jeff Z. (4 February 2014). "Study Finds Changes in Brains of Hockey Players Who Had Concussions". The New York Times. ISSN 0362-4331. Retrieved 19 April 2018. 37. ^ Proteau, Adam. "NHL Can Do More To Prevent Concussions". The Hockey News. Archived from the original on 1 November 2013. Retrieved 30 October 2013. 38. ^ "Neuroscience for Kids – Soccer". Faculty.washington.edu. Retrieved 4 July 2012. 39. ^ Mozes, Alan. "Banning Soccer 'Headers' Won't Solve Concussion Problem: Study". U.S. News & World Report. Retrieved 13 July 2015. 40. ^ Seaman, Andrew (13 July 2015). "'Heading' bans in soccer may not be enough to stop concussions". Reuters. Retrieved 13 July 2015. 41. ^ Tysvaer, Alf Thorvald (1992). "Head and Neck Injuries in Soccer". Sports Medicine. 14 (3): 200–13. doi:10.2165/00007256-199214030-00006. PMID 1439395. 42. ^ "Mourinho angry as keepers injured". BBC Sport. 14 October 2006. Retrieved 16 October 2006. 43. ^ Downs, DS and D Abwender (2002). "Neuropsychological Impairment in Soccer Athletes". The Journal of Sports Medicine and Physical Fitness. 42 (1): 103–7. PMID 11832883. 44. ^ a b Gibson, Owen (4 November 2013). "Concussion Rules under Spotlight in Wake of Hugo Lloris Row". The Guardian. Retrieved 21 March 2016. 45. ^ Malonie, Jamie, Linda Nield, and Matthew Livley. "Can Headgear Halt Soccer Concussions?" Consultant For Paediatricians, July 2013. Web. 4 March 2014 46. ^ "IRB Concussion Guidelines". International Rugby Board. 24 May 2011. Archived from the original on 14 April 2013. Retrieved 16 February 2013. 47. ^ a b "Lamont: Players are cheating concussion tests". ESPN Scrum. 27 July 2013. Retrieved 26 December 2013. 48. ^ a b Lamont, Rory (19 December 2013). "Players are deliberately cheating concussion tests". ESPN Scrum. Retrieved 26 December 2013. 49. ^ "Rugby is still holding the concussion bomb with tongs in spite of warnings". Irish Independent. Retrieved 13 September 2016. 50. ^ Bhasin, Kim. "MLB Introduces New Concussion Policy To Protect Players". Business Insider. Retrieved 26 November 2019. 51. ^ a b c d e f "2017–2021 Basic Agreement" (PDF). Major League Baseball Players. Major League Baseball Players Association. Archived from the original (PDF) on 28 April 2019. Retrieved 28 April 2019. 52. ^ "Concussions becoming a concern in basketball \| basketball, becoming, concern – Sports – Colorado Springs Gazette, CO". Gazette.com. Retrieved 4 July 2012. 53. ^ a b Daneshvar, Daniel H; Nowinski, Christopher J; McKee, Ann C; Cantu, Robert C (2011). "The Epidemiology of Sport-Related Concussion". Clinics in Sports Medicine. 30 (1): 1–17, vii. doi:10.1016/j.csm.2010.08.006. PMC 2987636. PMID 21074078. 54. ^ "NBA Institutes Concussion Policy". official.nba.com. 12 December 2011. Retrieved 26 November 2019. 55. ^ a b c d e f g h i j "National Basketball Association Concussion Policy Summary – 2019–20 Season" (PDF). NBA Official. 56. ^ Gordon, Serena (29 August 2011). "Pediatricians urge parents to keep kids away from boxing, head injuries". Usatoday.com. Retrieved 4 July 2012. 57. ^ Koh, Jae O; Cassidy, J. David; Watkinson, E. Jane (2009). "Incidence of concussion in contact sports: A systematic review of the evidence". Brain Injury. 17 (10): 901–17. doi:10.1080/0269905031000088869. PMID 12963556. 58. ^ "Boxing Great Muhammad Ali's 'Sad Decline' from Brain Damage Explored in New Biography". PEOPLE.com. Retrieved 19 April 2018. 59. ^ "NASCAR drivers have concussion concerns – Racing – SI.com". Sportsillustrated.cnn.com. 21 February 2012. Retrieved 1 July 2012. 60. ^ Bandoim, Lana. "NASCAR May Be Considering Changes to Its Concussion Policies: Fan View". Yahoo! Sports. Retrieved 21 October 2012. 61. ^ Gluck, Jeff (24 October 2013). "NASCAR will mandate baseline concussion testing in 2014". USA Today. Retrieved 24 October 2013. 62. ^ Gerhardstein, Debby (6 May 2019). "Helmets are key when it comes to injury prevention". National Safety Council. Retrieved 9 May 2020. 63. ^ "Girls, sports and concussions". Retrieved 7 October 2015. 64. ^ "High school headaches: Girls' concussions outnumber boys' in most sports". News.medill.northwestern.edu. Archived from the original on 14 December 2013. Retrieved 4 July 2012. 65. ^ "Concussions: Girls Have Longer Recovery Time". Webmd.com. 11 May 2012. Retrieved 4 July 2012. 66. ^ Klein, Jeff Z. (19 October 2010). "Women's Hockey, a Most Dangerous Game – NYTimes.com". Slapshot.blogs.nytimes.com. Retrieved 4 July 2012. 67. ^ "The Epidemiology of Sport-Related Concussion." Clin Sports Med, 1 January 2012. Web. 8 February 2013. 68. ^ Kerr, Z. Y; Cortes, N; Caswell, A. M; Ambegaonkar, J. P; Hallsmith, K. R; Milbert, A. F; Caswell, S. V (2017). "Concussion Rates in U.S. Middle School Athletes, 2015–2016 School Year". American Journal of Preventive Medicine. 53 (6): 914–918. doi:10.1016/j.amepre.2017.05.017. PMID 28739314. 69. ^ "Sport Concussion Assessment Tool – 3rd edition" (PDF). Sports Concussion Institute. 2013. Retrieved 28 September 2017. 70. ^ Larson, Aaron (24 March 2016). "Liability for Concussions in Youth Sports". ExpertLaw. Retrieved 28 September 2017. 71. ^ "Graduated Return to Play Protocol" (PDF). Sports Concussion Institute. 2008. Retrieved 28 September 2017. 72. ^ Cantu, Robert C., and Mark Hyman. "Soccer." Concussions and Our Kids: America's Leading Expert on How to Protect Young Athletes and Keep Sports Safe. Boston: Houghton Mifflin Harcourt, 2012. 40+. Print. 73. ^ Cook, Bob. "Study Reveals Many Girls Soccer Players Stay On Field Despite Concussions." Forbes. Forbes Magazine, 21 January 2014. Web. 6 May 2014. 74. ^ Snow, Kate, Sarah Koch, Deirdre Cohen, and Jessica Hopper. "Concussion Crisis Growing in Girls' Soccer." NBC News. NBC, 9 May 2012. Web. 16 February 2014. 75. ^ a b Rozbacher, Adrian; Selci, Erin; Leiter, Jeff; Ellis, Michael; Russell, Kelly (15 July 2017). "The Effect of Concussion or Mild Traumatic Brain Injury on School Grades, National Examination Scores, and School Attendance: A Systematic Review". Journal of Neurotrauma. 34 (14): 2195–2203. doi:10.1089/neu.2016.4765. ISSN 1557-9042. PMID 28084891. 76. ^ a b Russell, Kelly; Selci, Erin; Black, Brian; Cochrane, Karis; Ellis, Michael (25 April 2019). "Academic outcomes following adolescent sport-related concussion or fracture injury: A prospective cohort study". PLOS ONE. 14 (4): e0215900. Bibcode:2019PLoSO..1415900R. doi:10.1371/journal.pone.0215900. ISSN 1932-6203. PMC 6483210. PMID 31022262. 77. ^ PACE program website Archived 5 July 2012 at the Wayback Machine 78. ^ "Drew Brees Teams Up Against Concussions in School Sports – ABC News". Abcnews.go.com. 26 June 2012. Retrieved 4 July 2012. 79. ^ "AFL-Test-Drives-Schutt'S-Shockometer / News". NFLPlayers.com. 22 May 2008. Retrieved 4 July 2012. 80. ^ "HITS™ Technology". Riddell. Archived from the original on 23 June 2012. Retrieved 26 June 2012. 81. ^ "Failure to use HIT system exposes league to future concussion liability \| ProFootballTalk". Profootballtalk.nbcsports.com. 24 June 2012. 82. ^ "Mass. Companies team up to prevent head injuries – the Boston Globe". 83. ^ Papa, Linda (2016). "Potential Blood-Based Biomarkers for Concussion". Sports Medicine and Arthroscopy Review. 24 (3): 108–15. doi:10.1097/JSA.0000000000000117. PMC 5055836. PMID 27482776. 84. ^ "FDA authorizes marketing of first blood test to aid in the evaluation of concussion in adults". U.S. Food and Drug Administration. FDA. 10 September 2019. 85. ^ Wyman, Ted. "Bombers star linebacker Adam Bighill trying new device to protect against concussions". The Guardian. Retrieved 19 November 2019. 86. ^ a b c Stefanovic, Deb. "The Science of Jugular Compression: A Potential Solution to Protect Athletes and Youth from Sport-Related Concussion and a Testimonial on the Use of the Q-Collar Medical Device as a Part of a Concussion Protocol Program" (PDF). Parliament of Canada. 87. ^ "Abstracts from The 35th Annual National Neurotrauma Symposium July 7–12, 2017 Snowbird, Utah". Journal of Neurotrauma. 34 (13): A–1. 1 July 2017. doi:10.1089/neu.2017.29011.abstracts. ISSN 0897-7151. PMID 28661788. 88. ^ Myer, G.D.; Yuan, W.; Barber Foss, K.D.; Thomas, S.; Smith, D.; Leach, J.; Kiefer, A.W.; Dicesar, C.; Adams, J.; Gubanich, P.J.; Kitchen, K.; Schneider, D.K.; Braswell, D.; Krueger, D.; Altaye, M. (2016). "Analysis of head impact exposure and brain microstructure response in a season-long application of a jugular vein compression collar: a prospective, neuroimaging investigation in American Football". British Journal of Sports Medicine. 50 (20): 1276–1285. doi:10.1136/bjsports-2016-096134. PMC 5099231. PMID 27307271. 89. ^ a b Daugherty, Jill (6 May 2019). "Effectiveness of the US Centers for Disease Control and Prevention HEADS UP coaches' online training as an educational intervention". Health Education Journal. 78 (7): 784–797. doi:10.1177/0017896919846185. PMC 6747698. PMID 31530957. 90. ^ "HEADS UP to Youth Sports". Centers for Disease Control and Prevention. CDC. 5 March 2019. 91. ^ Göpfert, Anya; Van Hove, Maria; Emond, Alan; Mytton, Julie (8 April 2018). "Prevention of sports injuries in children at school: a systematic review of pol". BMJ Open Sport & Exercise Medicin. 4 (4): e000346. doi:10.1136/bmjsem-2018-000346. PMC 6018845. PMID 29955375. 92. ^ a b c d e f g h i j k l m n J, Thomas; J, Kavanagh; H, Tucker; H, Burchett; J, Tripney; A, Oakley (February 2007). Accidental injury, risk-taking behaviour and the social circumstances in which young people (aged 12-24) live: a systematic review (PDF). London: Institute of Education, University of London. pp. 90–102. ISBN 978-0-9551548-8-1. Retrieved 1 December 2019. 93. ^ a b Masson, Maxime; Lamoureux, Julie; de Guise, Elaine (October 2019). "Self-reported risk-taking and sensation-seeking behavior predict helmet wear amongst Canadian ski and snowboard instructors". Canadian Journal of Behavioural Science. 52 (2): 121–130. doi:10.1037/cbs0000153. 94. ^ a b Mannix, Rebekah; Meehan, William P.; Pascual-Leone, Alvaro (August 2016). "Sports-related concussions — media, science and policy". Nature Reviews. Neurology. 12 (8): 486–490. doi:10.1038/nrneurol.2016.99. ISSN 1759-4758. PMC 5333496. PMID 27364748. 95. ^ a b c d Ahmed, Osman Hassan; Hall, Eric E. (1 January 2017). ""It was only a mild concussion": Exploring the description of sports concussion in online news articles". Physical Therapy in Sport. 23: 7–13. doi:10.1016/j.ptsp.2016.07.003. ISSN 1466-853X. PMID 27639135. 96. ^ "'Head Games' Film Focuses on Concussions, Asks If Enough is Being Done". Athleticbusiness.com. Retrieved 14 July 2012. 97. ^ "Head Games: The People". Headgamesthefilm.com. Archived from the original on 18 June 2012. Retrieved 14 July 2012. 98. ^ League of Denial 99. ^ Football High 100. ^ The Collision of Sports and Politics * v * t * e Occupational safety and health Occupational diseases and injuries * Acrodynia * Asbestosis * Asthma * Barotrauma * Berylliosis * Brucellosis * Byssinosis ("brown lung") * Chalicosis * Chimney sweeps' carcinoma * Chronic solvent-induced encephalopathy * Coalworker's pneumoconiosis ("black lung") * Concussions in sport * Decompression sickness * De Quervain syndrome * Erethism * Exposure to human nail dust * Farmer's lung * Fiddler's neck * Flock worker's lung * Glassblower's cataract * Golfer's elbow * Hearing loss * Hospital-acquired infection * Indium lung * Laboratory animal allergy * Lead poisoning * Mesothelioma * Metal fume fever * Mule spinners' cancer * Noise-induced hearing loss * Phossy jaw * Pneumoconiosis * Radium jaw * Repetitive strain injury * Silicosis * Silo-filler's disease * Sports injury * Surfer's ear * Tennis elbow * Tinnitus * Writer's cramp Occupational hygiene * Occupational hazard * Biological hazard * Chemical hazard * Physical hazard * Psychosocial hazard * Hierarchy of hazard controls * Prevention through design * Exposure assessment * Occupational exposure limit * Occupational epidemiology * Workplace health surveillance Professions * Environmental health * Industrial engineering * Occupational health nursing * Occupational health psychology * Occupational medicine * Occupational therapist * Safety engineering Agencies and organizations * Canadian Centre for Occupational Health and Safety * European Agency for Safety and Health at Work * UK Health and Safety Executive * International Labour Organization * US National Institute for Occupational Safety and Health * US Occupational Safety and Health Administration * National Institute for Safety and Health at Work (Spain) * World Health Organization Standards * Bangladesh Accord * ISO 45001 * Occupational Safety and Health Convention, 1981 * Worker Protection Standard (US) * Working Environment Convention, 1977 Safety * Checklist * Code of practice * Contingency plan * Diving safety * Emergency procedure * Emergency evacuation * Hazard * Hierarchy of hazard controls * Hazard elimination * Administrative controls * Engineering controls * Hazard substitution * Personal protective equipment * Job safety analysis * Lockout-tagout * Permit To Work * Operations manual * Redundancy (engineering) * Risk assessment * Safety culture * Standard operating procedure Legislation * Diving regulations * Occupational Safety and Health Act (United States) See also * Environment, health and safety * Environmental toxicology * Ergonomics * Health physics * Indoor air quality * International Chemical Safety Card * National Day of Mourning (Canadian observance) * Process safety management * Public health * Risk management * Safety data sheet * Toxic tort * Workers' compensation * Category * Occupational diseases * Journals * Organizations * Commons * Glossary [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 inhibitors [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	Concussions in sport	None	2,967	wikipedia	https://en.wikipedia.org/wiki/Concussions_in_sport	2021-01-18T19:05:51	{"wikidata": ["Q5159124"]}
A rare, genetic form of obesity characterized by severe early-onset obesity, hyperphagia, insulin resistance with hyperinsulinemia, reduced adult final height, delayed speech and language development and a tendency for social isolation and aggressive behavior. [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 inhibitors [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	Severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency	None	2,968	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=329249	2021-01-23T17:10:12	{"icd-10": ["E66.8"]}
A number sign (#) is used with this entry because of evidence that multiple fibroadenomas of the breast (MFAB) are caused by heterozygous mutation in the PRLR gene (176761) on chromosome 5p13. Description Fibroadenoma represents a benign breast disease characterized by lobuloalveolar growth with abnormally high proliferation of the epithelium. Patients with more than 3 fibroadenomas in 1 breast are considered to have multiple fibroadenomas (summary by Bogorad et al., 2008). Molecular Genetics In 74 Caucasian women with multiple fibroadenomas of the breast, who were negative for mutation in the prolactin gene (PRL; 176760), Bogorad et al. (2008) analyzed the PRLR gene and identified a missense mutation (I146L; 176761.0001) in 4 unrelated patients. The mutation was not found in 96 control women over 35 years of age who had no history of benign or malignant breast disease, no pituitary disorder, and normal PRL levels, or in a random population of 74 women or the NCBI database. In vitro studies demonstrated that the mutation results in a constitutively active receptor, which was confirmed by increased signaling in patient breast tissue. None of the mutation-positive patients displayed any obvious signs of hyperprolactinemia, although the authors noted that full clinical phenotyping was not performed. Newey et al. (2013) questioned the in vivo significance of the I146L variant, noting that it had been reported as a polymorphism (rs72478580) occurring at 2.39% in a European American population in the Exome Variant Server of the NHLBI GO Exome Sequencing Project. INHERITANCE \- Autosomal dominant CHEST Breasts \- More than 3 fibroadenomas in a single breast MOLECULAR BASIS \- Caused by mutation in the prolactin receptor gene (PRLR, 176761.0001 ) ▲ 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 inhibitors [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	MULTIPLE FIBROADENOMAS OF THE BREAST	c3809918	2,969	omim	https://www.omim.org/entry/615554	2019-09-22T15:51:37	{"omim": ["615554"], "orphanet": ["50920"], "synonyms": ["Mammary polyadenomatosis"]}
Localized lichen myxedematosus with monoclonal gammopathy or systemic symptoms is a form of atypical lichen myxedematosus (see this term), characterized by the appearance of several 2-4 mm erythematous waxy papules confined to a few sites that may be associated with either an immunoglobulin A (IgA) nephropathy in patients with acral persistent papular mucinosis; discrete papular lichen myxedematosus (see these terms); a scleromyxedema-like involvement, with dysphagia, hoarseness, pulmonary involvement, and carpal tunnel syndrome; myositis without skin sclerosis; or paraproteinemia. [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 inhibitors [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	Localized lichen myxedematosus with monoclonal gammopathy or systemic symptoms	None	2,970	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=90399	2021-01-23T17:33:45	{"icd-10": ["L98.5"]}
A number sign (#) is used with this entry because of evidence that the exclusively skeletal form of Antley-Bixler syndrome can be caused by heterozygous mutation in a fibroblast growth factor receptor gene, FGFR2 (176943), on chromosome 10q26. A form of Antley-Bixler syndrome that includes disordered steroidogenesis (ABS1; 201750) is caused by mutation in the gene encoding cytochrome P450 oxidoreductase (POR; 124015). 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, including midface hypoplasia, choanal stenosis or atresia, and multiple joint contractures. 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 Antley and Bixler (1975) described a child with 'trapezoidocephaly,' midface hypoplasia, humeroradial synostosis, bowing of femora, fractures and other abnormalities. McGlaughlin et al. (2010) noted that Lacheretz et al. (1974) had reported features suggestive of the same disorder in a 10-year-old boy, issue of a consanguineous marriage. DeLozier et al. (1980) described 2 unrelated female children with the same syndrome: craniosynostosis with midface hypoplasia resulting in typical facial appearance and ears; radiohumeral synostosis and bowing of the femora with neonatal femoral fractures. Although the differential diagnosis included campomelic syndrome (see 114290), osteogenesis imperfecta (see 166200), and certain of the acrocephalosyndactyly syndromes (see 101200), the disorder appeared to be unique. DeLozier et al. (1980) proposed the designation multisynostotic osteodysgenesis. DeLozier-Blanchet (1989) provided useful follow-up information on 1 of the patients reported by DeLozier et al. (1980). The patient's primary difficulties during the first decade of life resulted from joint limitations. Radiohumeral synostosis recurred after surgery at 6 months; eating and other everyday tasks were difficult. She had moderate camptodactyly of the hands, particularly at the metacarpal-phalangeal joints, and some restriction of knee movement. A pear-shaped nose was treated by plastic surgery. Intelligence was normal. Schinzel et al. (1983) described 2 affected sisters: a newborn who died at 14 days of respiratory failure, and a fetus from a subsequent pregnancy in which the diagnosis was made in utero by ultrasonography. They described the features as craniosynostosis of coronal and lambdoidal sutures; brachycephaly; frontal bossing; severe midface hypoplasia with proptosis and choanal stenosis or atresia; humeroradial synostosis; medial bowing of ulnas; long, slender fingers with camptodactyly; narrow iliac wings; anterior bowing of femurs; and malformations of the heart and kidneys. Their proband did not have connatal fractures as did the first 2 cases but she did have vaginal atresia. Robinson et al. (1982) reported 3 sporadic cases. Yasui et al. (1983) reported an affected female with consanguineous parents. Suzuki et al. (1987) described this syndrome in a brother and sister with first-cousin parents. Escobar et al. (1988) described a child followed over a period of 3 years. In addition to craniosynostosis, the patient had radiohumeral synostosis, femoral bowing, and multiple joint contractures. Escobar et al. (1988) provided a flow chart for management of patients with ABS. Hassell and Butler (1994) reported a patient and reviewed 13 previously reported cases. The cardinal features included craniosynostosis, severe midface hypoplasia, proptosis, choanal atresia/stenosis, frontal bossing, dysplastic ears, depressed nasal bridge, radiohumeral synostosis, long bone fractures and femoral bowing, and urogenital abnormalities. Early death, usually due to respiratory complications, occurred in 54% of reported cases. The oldest patient was 10 years old at the time of follow-up. Since some patients had normal intelligence, it is likely that brain development is normal if craniectomy is performed to treat sutural synostosis and if secondary factors, such as apnea, are avoided. Choanal stenting during infancy may be important to decrease airway obstruction. Feigin et al. (1995) reported an infant, born to consanguineous parents, with the typical features of Antley-Bixler syndrome in addition to esophageal atresia and trisomy 21 (190685). Crisponi et al. (1997) stated that since the first report by Antley and Bixler (1975) at least 23 cases had been reported. They reported an affected infant who died a few days after birth of respiratory failure. Unlike previously described cases, the elbow joint contracture was due to radioulnar synostosis rather than radiohumeral synostosis. The infant did not have long bone fractures, and the femurs were not markedly bowed. Chabchoub et al. (1998) reported a female infant with bilateral coronal craniosynostosis, craniolacunia, profound midface hypoplasia, arachnodactyly and camptodactyly of fingers and toes, multiple joint contractures, and abnormal bowing of the radius and ulna without radiohumeral synostosis. The child died at 1 year of age after multiple respiratory infections, due to malnutrition and major neurologic deterioration. 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. ### Prenatal Diagnosis LeHeup et al. (1995) reported affected sibs. In the first case, renal agenesis was recognized prenatally when oligohydramnios led to the sonographic diagnosis of absent kidneys during the seventh month. Clinical features were recognized by ultrasonography at 21 weeks in the second case. Molecular Genetics Chun et al. (1998) reported a patient with clinical manifestations that they considered consistent with Antley-Bixler syndrome who carried an ser351-to-cys (S351C; 176943.0024) mutation on one allele of the FGFR2 gene. Chun et al. (1998) suggested that the Antley-Bixler syndrome is an autosomal dominant condition with possible gonadal mosaicism, or that alternatively, an autosomal dominant form and an autosomal recessive form of ABS may exist. They further suggested that FGFR mutations should be sought in other craniosynostosis patients with elbow synostosis. Gorlin (1999) and Gripp et al. (1999) refuted the clinical diagnosis of Antley-Bixler syndrome and suggested that the patient had a nonspecific craniosynostosis syndrome. Chitayat and Chun (1999) in response reiterated the importance of seeking a mutation in the FGFR2 gene, and expressed the wish that authors of previously reported cases of Antley-Bixler syndrome would perform DNA analysis of the FGFR2 gene and publish the results in order to clarify the inheritance of ABS. In 3 patients with ABS, Reardon et al. (2000) identified the S351C substitution in the FGFR2 gene. The patients all had normal-appearing genitalia, and the steroid profile was normal in the 2 patients in whom it was carried out. Huang et al. (2005) sequenced the cytochrome P450 reductase gene (POR; 124015) 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, who had previously been found to have a mutation 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. Huang et al. (2005) concluded that individuals with an ABS-phenotype and normal steroidogenesis have FGFR mutations, whereas those with ambiguous genitalia and disordered steroidogenesis should be recognized as having a distinct new disease: POR deficiency (201750). The existence of 2 distinct disorders was first suggested by Reardon et al. (2000). INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Brachycephaly \- Large anterior fontanel Face \- Frontal bossing \- Midface hypoplasia \- Long philtrum Ears \- Dysplastic ears \- Stenotic external auditory canals Eyes \- Proptosis Nose \- Depressed nasal bridge \- Choanal atresia or choanal stenosis CARDIOVASCULAR Heart \- Atrial septal defect RESPIRATORY Airways \- Upper airway obstruction CHEST Ribs Sternum Clavicles & Scapulae \- Narrow chest SKELETAL Skull \- Craniosynostosis, coronal and lambdoidal Pelvis \- Narrow pelvis Limbs \- Radiohumeral synostosis \- Femoral bowing \- Neonatal femoral fractures \- Ulnar bowing \- Joint contractures Hands \- Arachnodactyly \- Camptodactyly Feet \- Rocker-bottom feet NEUROLOGIC Central Nervous System \- Variable mental retardation \- Hydrocephalus MISCELLANEOUS \- Early death often due to respiratory complications \- For a similar phenotype with genital anomalies and disordered steroidogenesis see POR deficiency ( 201750 ) MOLECULAR BASIS \- Caused by mutation in the fibroblast growth factor receptor 2 gene (FGFR2, 176943.0002 ) ▲ 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 inhibitors [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	ANTLEY-BIXLER SYNDROME WITHOUT GENITAL ANOMALIES OR DISORDERED STEROIDOGENESIS	c2936791	2,971	omim	https://www.omim.org/entry/207410	2019-09-22T16:30:55	{"doid": ["0050462"], "mesh": ["D054882"], "omim": ["207410"], "orphanet": ["83"], "synonyms": ["Alternative titles", "TRAPEZOIDOCEPHALY-SYNOSTOSIS SYNDROME", "MULTISYNOSTOTIC OSTEODYSGENESIS WITH LONG BONE FRACTURES", "OSTEODYSGENESIS, MULTISYNOSTOTIC, WITH FRACTURES"]}
Hidradenoma Other namesAcrospiroma, cystadenoma, hydrocystadenomas Micrograph showing an acrospiroma. H&E stain. SpecialtyDermatology Hidradenoma refers to a benign adnexal tumor of the apical sweat gland.[1][2] These are 1–3 cm translucent blue cystic nodules. It usually presents as a single, small skin-colored lesion, and is considered distinct from the closely related poroma. Hidradenomas are often sub-classified based on subtle histologic differences, for example:[citation needed] * clear-cell hidradenoma or acrospiroma * nodular hidradenoma or acrospiroma * solid-cystic hidradenoma Discussion of sweat gland tumors can be difficult and confusing due to the complex classification and redundant terminology used to describe the same tumors. For example, acrospiroma and hidradenoma are synonymous, and sometimes the term acrospiroma is used to generally describe benign sweat gland tumors. In addition, a single lesion may contain a mixture of cell-types.[2] There has also been a change in understanding about how tumors that were previously believed to strictly derive from specific sweat gland types may, in fact, derive from both eccrine or apocrine glands.[3][4] Hidradenomas are by definition benign, with malignant transformation very rare. When tumors show malignant characteristics, they are known as hidradenocarcinoma.[5] Surgical excision is usually curative and local recurrences are rare, although malignant tumors may metastasize.[3] * Gross pathology of a cystic nodular hidradenoma * Dermal duct tumor * Acrospiroma, solid type * Acrospiroma, clear cell type ## See also[edit] * Spiroma * List of cutaneous conditions * List of cutaneous neoplasms associated with systemic syndromes ## References[edit] 1. ^ Laws RA, English JC, Elston DM (November 1996). "Acrospiroma: a case report and review". Cutis. 58 (5): 349–51. PMID 8934076. 2. ^ a b Obaidat NA, Alsaad KO, Ghazarian D (February 2007). "Skin adnexal neoplasms--part 2: an approach to tumours of cutaneous sweat glands". Journal of Clinical Pathology. 60 (2): 145–59. doi:10.1136/jcp.2006.041608. PMC 1860616. PMID 16882695. 3. ^ a b Griffiths C, Cox N, Breathnach S, et al., eds. (2010). "53. Tumours of the Skin Appendages: Eccrine or aprocrine/follicular tumours". Rook's Textbook of Dermatology (8th ed.). Chichester, West Sussex: John Wiley & Sons Ltd. ISBN 978-1-4051-6169-5. 4. ^ Griffiths C, Cox N, Breathnach S, et al., eds. (2010). "53. Tumours of the Skin Appendages: Eccrine gland tumours". Rook's Textbook of Dermatology (8th ed.). Chichester, West Sussex: John Wiley & Sons Ltd. ISBN 978-1-4051-6169-5. 5. ^ Hernández-Pérez E, Cestoni-Parducci R (1985). "Nodular hidradenoma and hidradenocarcinoma. A 10-year review". Journal of the American Academy of Dermatology. 12 (1 Pt 1): 15–20. doi:10.1016/s0190-9622(85)70002-3. PMID 2984259. ## External links[edit] Classification D * MeSH: D006607 * v * t * e Cancers of skin and associated structures Glands Sweat gland Eccrine * Papillary eccrine adenoma * Eccrine carcinoma * Eccrine nevus * Syringofibroadenoma * Spiradenoma Apocrine * Cylindroma * Dermal cylindroma * Syringocystadenoma papilliferum * Papillary hidradenoma * Hidrocystoma * Apocrine gland carcinoma * Apocrine nevus Eccrine/apocrine * Syringoma * Hidradenoma or Acrospiroma/Hidradenocarcinoma * Ceruminous adenoma Sebaceous gland * Nevus sebaceous * Muir–Torre syndrome * Sebaceous carcinoma * Sebaceous adenoma * Sebaceoma * Sebaceous nevus syndrome * Sebaceous hyperplasia * Mantleoma Hair * Pilomatricoma/Malignant pilomatricoma * Trichoepithelioma * Multiple familial trichoepithelioma * Solitary trichoepithelioma * Desmoplastic trichoepithelioma * Generalized trichoepithelioma * Trichodiscoma * Trichoblastoma * Fibrofolliculoma * Trichilemmoma * Trichilemmal carcinoma * Proliferating trichilemmal cyst * Giant solitary trichoepithelioma * Trichoadenoma * Trichofolliculoma * Dilated pore * Isthmicoma * Fibrofolliculoma * Perifollicular fibroma * Birt–Hogg–Dubé syndrome Hamartoma * Basaloid follicular hamartoma * Folliculosebaceous cystic hamartoma * Folliculosebaceous-apocrine hamartoma Nails * Neoplasms of the nailbed [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 inhibitors [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	Hidradenoma	c0019522	2,972	wikipedia	https://en.wikipedia.org/wiki/Hidradenoma	2021-01-18T19:04:18	{"mesh": ["D006607"], "umls": ["C0019522"], "wikidata": ["Q12822297"]}
## Clinical Features Cantu et al. (1981, 1985) reported a second Guadalajara camptodactyly syndrome; see 211910 for a description of type I. Two sisters, aged 6 and 3 years, presented the same intrauterine growth retardation-malformation syndrome characterized by low birthweight dwarfism and a variety of dysmorphic features including camptodactyly of all fingers, bilateral hallux valgus, short toes 2, 4 and 5, patella hypoplasia, short neck, low-set ears, microcephaly, cuboid vertebral bodies, and others. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Other \- Intrauterine retardation HEAD & NECK Head \- Microcephaly Face \- Micrognathia \- Long philtrum Ears \- Large ears \- Low-set ears Eyes \- Hypotelorism Neck \- Short neck CHEST Ribs Sternum Clavicles & Scapulae \- Pectus excavatum Breasts \- Widely spaced nipples GENITOURINARY External Genitalia (Female) \- Labial hypoplasia SKELETAL \- Osteopenia Spine \- Cuboid vertebral bodies Pelvis \- Pelvis hypoplasia Limbs \- Patellar hypoplasia \- Slender long bones Hands \- Simian creases \- Camptodactyly, all fingers \- Second phalanx hypoplasia Feet \- Hallux valgus \- Brachydactyly, toes 2,4, and 5 \- Talipes equinovarus MUSCLE, SOFT TISSUES \- Gluteal hypoplasia ▲ 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 inhibitors [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	CAMPTODACTYLY SYNDROME, GUADALAJARA, TYPE II	c2673861	2,973	omim	https://www.omim.org/entry/211920	2019-09-22T16:30:13	{"mesh": ["C567138"], "omim": ["211920"], "orphanet": ["1326"]}
"Mucous cyst" redirects here. For swelling of connective oral tissue, see Oral mucocele. Myxoid cyst Other namesDigital mucous cyst,[1] and Mucous cyst[1]) Digital mucous cyst in left index finger with nail depression SpecialtyOncology, rheumatology A Myxoid cyst is a cutaneous condition often characterized by nail plate depression and grooves.[1] ## See also[edit] * Scleroderma * List of cutaneous conditions * List of radiographic findings associated with cutaneous conditions ## References[edit] 1. ^ a b c Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. 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 inhibitors [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	Myxoid cyst	c1258666	2,974	wikipedia	https://en.wikipedia.org/wiki/Myxoid_cyst	2021-01-18T19:01:44	{"mesh": ["D045888"], "wikidata": ["Q6949364"]}
Metatropic dysplasia is a skeletal disorder characterized by short stature, shortened arms and legs, and a long narrow chest. The signs and symptoms of this condition can vary from life threatening to mild. Signs and symptoms may include worsening abnormal curvature of the spine (scoliosis and kyphosis), flattening of the bones of the spine (platyspondyly), and restriction of certain joints in the body. Some individuals are additionally born with an elongated tailbone known as a coccygeal tail. Metatropic dysplasia is caused by mutations in the TRPV4 gene and is inherited in an autosomal dominant manner. Although there is no specific treatment or cure, there can be ways to manage the symptoms. A team of doctors is often needed to figure out the treatment options based on each person’s symptoms. [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 inhibitors [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	Metatropic dysplasia	c0265281	2,975	gard	https://rarediseases.info.nih.gov/diseases/3571/metatropic-dysplasia	2021-01-18T17:59:07	{"mesh": ["C537356"], "omim": ["156530"], "umls": ["C0265281"], "orphanet": ["2635"], "synonyms": ["Metatropic dwarfism", "Metatropic dysplasia, nonlethal dominant"]}
## Clinical Features Duncan et al. (1979) reported 2 female patients and 28 others in the literature with the combination of mullerian duct aplasia, unilateral renal aplasia, and cervicothoracic somite dysplasia (MURCS). The authors postulated an alteration affecting blastemas of the lower cervical-upper thoracic somites, arms buds, and pronephric ducts, all of which have a relationship at the end of the fourth week of fetal life. Patients have also been reported with the association of urogenital and middle ear anomalies (see 267400). Park et al. (1971) described 2 unrelated females with absent vagina, Klippel-Feil deformity of the cervical spine (see 118100), short stature, and conductive deafness from malformation of the temporal bones and ossicles. Secondary sexual characteristics were normal. One of the patients had absent left kidney and ectopic right kidney. Baird and Lowry (1974) described 2 unrelated patients who had absent vagina and Klippel-Feil anomaly, but no deafness. The abnormality in sexual development in this syndrome was similar to that seen in the Rokitansky-Kuster-Hauser syndrome (277000). The patients reported by Park et al. (1971) and Baird and Lowry (1974) are consistent with MURCS (Gorlin et al., 2001). Colavita et al. (1986), Greene et al. (1986), Mendez et al. (1986), and Suri et al. (2000) reported additional cases of MURCS association. Wellesley and Slaney (1995) reported a 28-year-old man with Klippel-Feil deformity, left renal agenesis and right dysplastic kidney, who had thin vasa deferentia; the authors suggested that this represented MURCS in a male patient. Zlotogora (1995) reported a similar patient with Klippel-Feil anomaly and azoospermia in whom bilateral agenesis of the vas deferens was diagnosed; the patient did not return for renal analysis. Zlotogora (1995) suggested that wolffian anomalies in males represent the phenotype corresponding to mullerian anomalies in females. Lin et al. (1996) described the combination of MURCS association and occipital encephalocele in a stillborn girl of 41 weeks' gestation. The malformations in this disorder are compatible with a defect in the organization of the paraxial mesoderm that gives rise to occipital, cervical, and thoracic somites and adjoining intermediate mesoderm. These structures contribute to the occipital bone, cervical spine, upper limbs, and urogenital system. Meschede et al. (1998) described a 34-year-old man with a type 2 Klippel-Feil anomaly and nonobstructive azoospermia, who underwent bilateral surgical repair of cryptorchidism in childhood and had a small unilateral renal cyst but no other anomalies of the kidneys or urinary tract. The patient also reported mild hearing loss in the left ear. The authors suggested the acronym ARCS association, for azoospermia, renal anomalies, and cervicothoracic spine dysplasia, to designate this association when found in males. McGaughran (1999) reported a 57-year-old man with a type 2 Klippel-Feil anomaly and azoospermia, who underwent perineal hypospadias repair in childhood; upon examination he had a small, soft right testis with an apparently detached epididymis on palpation, and a nearly nonpalpable left testis with intact spermatic cord and vas deferens. Renal ultrasound was normal; the patient also had sensorineural hearing loss. Lopez et al. (2002) described the MURCS association with duplicated right thumb in a 29-year-old female. Differentiation should be made between the MURCS association and the VACTERL association (192350), in which genital anomalies are not a feature. Both associations appear to be sporadic. Pittock et al. (2005) found that 4 (16%) of 25 patients with Mayer-Rokitansky-Kuster-Hauser anomaly had all the features of MURCS, suggesting an association between the 2 conditions. Guerrier et al. (2006) reviewed the clinical features of the MRKH syndrome and MURCS association phenotypes and discussed genetic hypotheses. Noting that combinations of wolffian duct agenesis or severe hypoplasia with or without renal and/or skeletal anomalies have been described, the authors suggested that the term GRES syndrome (for genital, renal, ear, and skeletal) might be more appropriate when applied to both sexes. Tan et al. (2007) reported a 15-year-old girl with features of MURCS, including bicornuate uterus, unilateral ovarian agenesis, multicystic dysplastic kidney, and cervical block vertebrae, who also had seizures, mental retardation, cortical brain heterotopia, bilateral subclinical cataracts, submucous cleft palate, and patent ductus arteriosus. Tan et al. (2007) suggested that this patient represents a more severe form of MURCS, which they designated 'MURCS-plus.' Gardner et al. (2007) reported a 32-year-old woman with fusion of 2 cervical vertebrae and a unicornuate uterus, who also had radial ray anomalies, with bilateral thenar muscle hypoplasia and absent radial pulses. The authors suggested that this patient had incomplete MURCS. They noted previously reported MURCS patients with thenar anomalies, including 2 patients with features of MURCS and unilateral hypoplastic thumb (Michels and Caskey, 1979), and the patient with MURCS described by Lopez et al. (2002), who also had a duplicated thumb. Al Kaissi et al. (2009) described a 17-year-old girl who had been followed since childhood due to congenital thoracolumbar kyphoscoliosis. At age 17 years, menstruation had not started, and pelvic ultrasound revealed vaginal atresia, fallopian tube aplasia, bicornuate uterus, and ovarian dysplasia. Endocrine investigation showed normal hormone levels. Her neck was short and curved, with obvious torticollis; 3-dimensional (3D) reconstruction CT scan revealed assimilation of the entire anterior arch of the atlas with the foramen magnum, as well as congenital block vertebrae superimposed by progressive ossification of the anterior longitudinal spine ligaments along T4 to T9. Abdominal 3D reconstruction CT scan showed hypertrophied congenital left solitary kidney. Al Kaissi et al. (2009) stated that this appeared to be the first report of a MURCS patient with occipitoatlantoaxial junction malformation and ankylosing vertebral hyperostosis, and suggested that MURCS patients should be evaluated with 3D CT scan, especially if they experience symptoms of myelopathy. INHERITANCE \- Isolated cases GROWTH Height \- Short stature (adult height <152cm) HEAD & NECK Face \- Facial asymmetry \- Micrognathia Ears \- Conductive hearing loss \- External ear defects Mouth \- Cleft lip \- Cleft palate CHEST Ribs Sternum Clavicles & Scapulae \- Rib anomalies \- Sprengel deformity GENITOURINARY Internal Genitalia (Male) \- Azoospermia Internal Genitalia (Female) \- Bicornuate uterus \- Absent-hypoplastic uterus \- Absent proximal 2/3 of vagina Kidneys \- Renal agenesis \- Ectopic kidneys SKELETAL Spine \- Cervicothoracic vertebral defects (especially C5-T1) \- Klippel-Feil anomaly Limbs \- Upper limb defects NEUROLOGIC Central Nervous System \- Cerebellar cysts MISCELLANEOUS \- MURCS - MUllerian duct aplasia, Renal agenesis/ectopia, Cervical Somite dysplasia ▲ 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 inhibitors [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	MULLERIAN DUCT APLASIA, UNILATERAL RENAL AGENESIS, AND CERVICOTHORACIC SOMITE ANOMALIES	c1698581	2,976	omim	https://www.omim.org/entry/601076	2019-09-22T16:15:27	{"mesh": ["C537371"], "omim": ["601076"], "orphanet": ["3109", "2578"], "synonyms": ["Alternative titles", "MAYER-ROKITANSKY-KUSTER-HAUSER SYNDROME, TYPE II", "MRKH, TYPE II", "KLIPPEL-FEIL DEFORMITY, CONDUCTIVE DEAFNESS, AND ABSENT VAGINA"]}
Palilalia (from the Greek πάλιν (pálin) meaning "again" and λαλιά (laliá) meaning "speech" or "to talk"),[1] a complex tic, is a language disorder characterized by the involuntary repetition of syllables, words, or phrases. It has features resembling other complex tics such as echolalia or coprolalia, but, unlike other aphasias, palilalia is based upon contextually correct speech.[2] It was originally described by Alexandre-Achille Souques in a patient with stroke that resulted in left-side hemiplegia,[3] although a condition described as auto-echolalia in 1899 by Édouard Brissaud may have been the same condition.[1] ## Contents * 1 Classification * 2 Characteristics * 3 Causes * 4 Diagnosis * 5 References ## Classification[edit] Palilalia is considered an aphasia, a disorder of language, and is not to be confused with speech disorders, as there is no difficulty in the formation of internal speech.[1] Palilalia is similar to speech disorders such as stuttering or cluttering, as it tends to only express itself in spontaneous speech, such as answering basic questions, and not in automatic speech such as reading or singing; however, it distinctively affects words and phrases rather than syllables and sounds.[1] Palilalia may occur in conditions affecting the pre-frontal cortex or basal ganglia regions, either from physical trauma, neurodegenerative disorders, genetic disorders, or a loss of dopamine in these brain regions.[4] Palilalia occurs most commonly in Tourette syndrome and may be present in neurodegenerative disorders like Alzheimer's disease and progressive supranuclear palsy.[4][5] ## Characteristics[edit] Palilalia is defined as the repetition of the speaker's words or phrases, often for a varying number of repeats. Repeated units are generally whole sections of words and are larger than a syllable, with words being repeated the most often, followed by phrases, and then syllables or sounds.[2][3] Palilalic repetitions are often spoken with decreasing volume and speed up over time.[6] A 2007 case study by Van Borsel et al. examined the acoustic features in palilalia.[5] AB, a 60-year-old male was diagnosed with idiopathic Parkinson's disease and had noticed changes in gait, posture, writing, and speech.[5] Observation of his perceptual speech characteristics and Frenchay Dysarthria Assessment results suggested AB suffered from hypokinetic dysarthria with a marked palilalia. It was determined to start speech therapy with passive (metronome) and active (pacing boards) pacing techniques to reduce the number of palilalic repetitions. Unfortunately AB was not able to enunciate despite extensive training.[5] Analysis of AB's speech therapy showed that his repetitions lasted from 1 minute 33 seconds to 2 minutes 28 seconds, ranging from 1 to 32 repetitions on some words, and differed from trial to trial. Pauses were present between each repetition, ranging from 0.1 to 0.7 seconds. Van Borsel et al. concluded that AB's palilalic repetitions followed no pattern: the duration of each repetition train did not decrease over time, the number of repetitions per train did not increase, and the duration of each individual word did not decrease in duration. Such results indicated not all palilalic repetitions show an increasing rate with decreasing volume, and defied the two distinct subtypes of palilalia as suggested by Sterling.[7] Sterling's Type A, sometimes called palilalie spasmodique, is characterized by fast repetitions and decreasing volume, while Sterling's Type B, sometimes called palilalie atonique, is characterized by repetitions at a constant rate with interspersed periods of silence.[8] AB showed neither a systematic increase (Sterling's Type A) or a constant duration (Sterling's Type B) and instead fell between the two. Palilalia has been theorized to occur in writing and sign language.[5][9] A case study by Tyrone and Moll examined a 79-year-old right-handed deaf man named PSP who showed anomalies in his signing.[9] PSP had learned British sign language (BSL) at the age of seven and had developed left-sided weakness and dysphagia at age 77. PSP showed involuntary movements and repetitions in his signing.[9] Tyrone and Moll reported his movements were palilalic in nature, as entire signs were repeated and the repetitional movements became smaller and smaller in amplitude.[9] ## Causes[edit] Palilalia also occurs in a variety of neurological disorders, occurring most commonly in Tourette syndrome, Alzheimer's disease, and progressive supranuclear palsy.[5] Such degradation can occur in the substantia nigra where decreased dopamine production results in a loss of function.[4] It can also occur in a variety of genetic disorders including Fragile X syndrome, Prader-Willi syndrome, Asperger syndrome and autism.[4] ## Diagnosis[edit] Palilalia must be differentiated from other complex tic disorders (such as echolalia), stuttering,[10] and logoclonia. In contrast to stuttering or logoclonia, palilalic repetitions tend to consist of complete sections of words or phrases,[5] are often repeated many times,[11] and the speaker has no difficulty initiating speech.[1] ## References[edit] 1. ^ a b c d e Critchley M (July 1927). "On palilalia". J Neurol Psychopathol. 8 (29): 23–32. doi:10.1136/jnnp.s1-8.29.23. PMC 1068500. PMID 21611242. 2. ^ a b Maassen B, Kent R, Peters H, et al. Speech motor control: In normal and disordered speech. Oxford University Press. pp. 342–345. ISBN 978-0-19-852627-8. 3. ^ a b Mantie-Kozlowski A (2008). Repetitive verbal behaviors in free conversation with a person with progressive multifocal leukoencephalopathy. ProQuest. pp. 5, 8. ISBN 978-0-549-62729-6. 4. ^ a b c d Van Borsel J, Tetnowski JA (2007). "Fluency disorders in genetic syndromes". J Fluency Disord. 32 (4): 279–96. doi:10.1016/j.jfludis.2007.07.002. PMID 17963937. 5. ^ a b c d e f g Van Borsel J, Bontinck C, Coryn M, Paemeleire F, Vandemaele P (April 2007). "Acoustic features of palilalia: a case study". Brain and Language. 101 (1): 90–6. doi:10.1016/j.bandl.2006.06.118. PMID 16890278. 6. ^ Benson DF, Ardila A (1996). Aphasia: a clinical perspective. Oxford University Press. pp. 291. ISBN 978-0-19-508934-9. Retrieved 19 November 2012. 7. ^ Sterling W (1924). "Palilalie et le symptome 'linguosalivaire' dans le Parkinsonisme encéphalitique". Revue Neurologique (in French). 32: 205–20. 8. ^ Benke T, Butterworth B (July 2001). "Palilalia and repetitive speech: two case studies". Brain and Language. 78 (1): 62–81. doi:10.1006/brln.2000.2445. PMID 11412016. 9. ^ a b c d Tyrone ME, Woll B (January 2008). "Palilalia in sign language". Neurology. 70 (2): 155–6. doi:10.1212/01.wnl.0000279378.09844.89. PMID 18180445. 10. ^ Lundgren K, Helm-Estabrooks N, Klein R (September 2010). "Stuttering Following Acquired Brain Damage: A Review of the Literature". J Neurolinguistics. 23 (5): 447–454. doi:10.1016/j.jneuroling.2009.08.008. PMC 2901556. PMID 20628582. 11. ^ Blanken G, Dittman J, Grimm H, Marshall J, Wallesh C.-W. (Eds.), "Repetitive phenomena in aphasia" in Linguistic disorders and pathologies. An international handbook, Waltger de Gruyter, Berlin/New York (1993), pp. 225–238 * v * t * e Tourette syndrome Main * Causes and origins * History * Societal and cultural aspects * Management Terms * Coprolalia * Copropraxia * Echolalia * Echophenomenon * Echopraxia * Palilalia * Palipraxia * PANDAS * Premonitory urge * Sensory phenomena * Tic * Tic disorder * Tourettism People * Jean-Martin Charcot * Donald J. Cohen * Georges Gilles de la Tourette * Tim Howard * Jean Marc Gaspard Itard * Samuel Johnson * James F. Leckman * Arthur K. Shapiro Organizations * Tourette Association of America * Tourette Canada * Tourettes Action * Yale Child Study Center Media * Front of the Class * Hichki * I Have Tourette's but Tourette's Doesn't Have Me * John's Not Mad * "Le Petit Tourette" * Maze * Motherless Brooklyn * Quit It * The Secret Life of Lele Pons * The Tic Code * Tic Talk: Living with Tourette Syndrome [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 inhibitors [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	Palilalia	c0392185	2,977	wikipedia	https://en.wikipedia.org/wiki/Palilalia	2021-01-18T18:53:29	{"wikidata": ["Q1757666"]}
Patients with acute lymphoblastic leukemia (ALL) who present with bulky disease of the lymph nodes, spleen, and mediastinum, so-called lymphomatous ALL (LALL), appear clinically to represent a distinct category of ALL of T-cell lineage. The biologic basis of this distinction was pointed out by Chilcote et al. (1985) who found that 6 of 8 patients with clinical features of LALL had karyotypic abnormalities leading to loss of bands 9p22-p21. The mechanisms varied and included deletions, unbalanced translocations, and loss of the entire chromosome. Only 1 of 57 patients without LALL had an abnormality of chromosome 9 at diagnosis. Loss of a 'suppressor' gene (RB1; 614041) comparable to that in retinoblastoma (180200) was postulated. A relationship to methylthioadenosine phosphorylase (156540) was postulated because the structural gene for this enzyme maps to the same region and patients with LALL may lack this enzyme in malignant cells during relapse. Lymphoblasts lacking this enzyme are unable to salvage adenine and methionine and are therefore especially sensitive to inhibitors of de novo purine synthesis (Kamatani et al., 1981). Kowalczyk and Sandberg (1981) had earlier found changes in 9p in a subgroup of ALL cases. Chilcote et al. (1985) pointed out that there is a fragile site at 9p21 and raised the question of familial predisposition on this basis. (This fragile site is the breakpoint in the translocation t(9;11)(p21-22;q23), which is associated with acute nonlymphocytic leukemia with monocytic features, ANLL-AMoL-M5a.) The aunt of one of the patients of Chilcote et al. (1985) had died as a child from ALL with lymphomatous features. If the analogy to RB1 holds, there is the same dilemma as to whether this should be called dominant or recessive; by the Chilcote hypothesis, it is presumably recessive. In a large series, Murphy et al. (1985) confirmed an abnormality of 9p in 10 to 11% of cases (33 out of more than 300) of acute lymphoblastic leukemia. The breakpoints in 9p clustered in the p22-p21 region. They could not, however, corroborate the specific association with T-cell origin or so-called lymphomatous clinical features. (Although to our knowledge not the determinant of an inherited phenotype, dominant or recessive, LALL appears to be a specific DNA coding segment that is involved in causation of a specific neoplasm through somatic cell mutation.) Inheritance \- Acquired specific neoplasm by autosomal recessive mechanism through somatic cell mutation Misc \- Bulky disease of lymph nodes, spleen, and mediastinum Lab \- Chromosome loss of bands 9p22-p21 by deletion, unbalanced translocation, or loss of entire chromosome \- Loss of methylthioadenosine phosphorylase in malignant cells during relapse Heme \- Acute lymphoblastic leukemia (ALL) \- Lymphomatous ALL (LALL) \- T-cell ALL ▲ 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 inhibitors [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	LYMPHOBLASTIC LEUKEMIA, ACUTE, WITH LYMPHOMATOUS FEATURES	c0023449	2,978	omim	https://www.omim.org/entry/247640	2019-09-22T16:25:45	{"doid": ["9952"], "omim": ["247640"], "orphanet": ["513"], "synonyms": ["Alternative titles", "LYMPHOMATOUS ALL"]}
A number sign (#) is used with this entry because heme oxygenase-1 deficiency can be caused by compound heterozygous mutation in the HMOX1 gene (141250) on chromosome 22q13. Clinical Features Yachie et al. (1999) reported the first human case of heme oxygenase-1 deficiency. The patient was 26 months old when he was first brought for medical care because of recurrent fever and generalized erythematous rash. Growth retardation was apparent and marked hepatomegaly was noted, but the spleen was not palpable. Asplenia was confirmed by abdominal ultrasonography and isotope image scanning. Hematuria and proteinuria were consistently present. At 6 years of age, the boy had severe growth retardation. Persistent hemolytic anemia was characterized by marked erythrocyte fragmentation and intravascular hemolysis, with paradoxical increase of serum haptoglobin and low bilirubin. An abnormal coagulation/fibrinolysis system, associated with elevated thrombomodulin and von Willebrand factor, indicated the presence of severe, persistent endothelial damage. Electron microscopy of renal glomeruli revealed detachment of endothelium, with subendothelial deposition of an unidentified material. Iron deposition was noted in renal and hepatic tissue. Immunohistochemistry of hepatic tissue and immunoblotting of a lymphoblastoid cell line revealed complete absence of heme oxygenase-1 production. A lymphoblastoid cell line derived from the patient was extremely sensitive to hemin-induced cell injury. Molecular Genetics By sequence analysis of the HMOX1 gene in a patient with heme oxygenase-1 deficiency, Yachie et al. (1999) identified complete loss of exon 2 on the maternal allele (141250.0001) and a 2-nucleotide deletion in exon 3 on the paternal allele (141250.0002). Animal Model Growth retardation, anemia, iron deposition, and vulnerability to stressful injury are all characteristics observed in mice in whom the heme oxygenase-1 gene has been knocked out (Poss and Tonegawa, 1997). [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 inhibitors [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	HEME OXYGENASE 1 DEFICIENCY	c1841651	2,979	omim	https://www.omim.org/entry/614034	2019-09-22T15:56:44	{"mesh": ["C564200"], "omim": ["614034"]}
A rare genetic disease associated with mild to severe intellectual deficit that may be associated with behavioral disorders and characteristic physical features including a high forehead, prominent and large ears, hyperextensible finger joints, flat feet with pronation and, in adolescent and adult males, macroorchidism. ## Epidemiology Prevalence is estimated at approximately 1/2400-1/6000 although the prevalence may vary, depending on where the screening is carried out in the world. ## Clinical description Fragile X syndrome (FXS) presents with a variable clinical phenotype. In males, the disease presents during childhood with delayed developmental milestones. Intellectual deficit can be of variable severity and may include problems with working and short-term memory, executive function, language, mathematics and visuospatial abilities. Behavioral anomalies can be mild (e.g. anxiety, mood instability) to severe (e.g. aggressive behavior, autism). Autistic-like behavior can include hand flapping, poor eye contact, hand biting, gaze avoidance, social phobia, social and communication deficits and tactile defensiveness. In females, intellectual and behavioral disorders are typically mild and usually consist of shyness, social anxiety, and mild learning problems with a normal IQ, although 25% of girls have an IQ less than 70. Attention deficit hyperactivity disorder (ADHD) is present in over 89% of males and 30% of females and behavioral disinhibition is very common. Recurrent otitis (60%) and seizures (16 to 20%) can also be observed. ## Etiology FXS is caused by the transcriptional silencing of the FMR1 gene (Xq27.3) due to the progressive expansion and subsequent methylation of (CGG)n trinuleotide repeats in the 5'-untranslated region of the gene. These full mutations originate from unstable alleles called premutations (55-200 CGG repeats). In some rare cases, FXS was shown to result from intragenic FMR1 point mutations or deletions. FMR1 codes for the FMRP, an RNA-binding protein that regulates protein synthesis and other signaling pathways in neuronal dendrites. FMR1 silencing is thought to reduce synaptic plasticity and modulation throughout the brain including the hippocampus. ## Diagnostic methods Diagnosis cannot be based on the clinical picture as physical features may be mild or absent and is therefore based on FMR1 DNA testing, that should be performed for all patients with an intellectual deficiency or autism. ## Differential diagnosis The differential diagnosis includes other X-linked intellectual deficiencies, Sotos syndrome, microdeletion syndromes (e.g. 22q11.2 deletion syndrome), fetal alcohol syndrome or idiopathic autism. ## Antenatal diagnosis Prenatal diagnosis is based on Southern blot hybridization and PCR on samples of chorionic villi or amniotic fluid. ## Genetic counseling FXS is an X-linked dominant disorder with reduced penetrance in females. Genetic counseling should be offered to families of an affected individual or carriers of the premutation. ## Management and treatment Management is symptom-based and requires a multidisciplinary approach. Speech, physical and sensory integration therapy as well as individualized educational plans and behavioral interventions may be combined with medication, such as stimulants for attention deficit-hyperactivity disorder; selective serotonin reuptake inhibitors (SSRIs) for anxiety, depression, obsessive-compulsive disorder; and atypical antipsychotic agents for self-injury and aggressive behaviors. New targeted treatments for FXS are being studied. ## Prognosis Life expectancy is assumed to be normal. The general outlook is variable and depends on the severity of the symptoms; independent living with limited support is possible although severely affected individuals will need more significant, life-long care due to intellectual disabilities and behavioral difficulties. [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 inhibitors [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	Fragile X syndrome	c0016667	2,980	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=908	2021-01-23T16:52:56	{"gard": ["6464"], "mesh": ["D005600"], "omim": ["300624", "311360"], "umls": ["C0016667", "C0751156"], "icd-10": ["Q99.2"], "synonyms": ["FRAXA syndrome", "FXS", "FraX syndrome", "Martin-Bell syndrome"]}
A number sign (#) is used with this entry because of evidence that pyruvate dehydrogenase E2 deficiency is caused by homozygous mutation in the DLAT gene (608770) on chromosome 11q23. For a general phenotypic description and a discussion of genetic heterogeneity of pyruvate dehydrogenase deficiency, see 312170. Clinical Features Robinson et al. (1990) described a black infant who presented at 2 weeks of age with hyperammonemia and profound lactic acidosis. Control of blood lactates was achieved by carbohydrate restriction and bicarbonate supplementation, but at age 3.5 years she had profound psychomotor retardation and was microcephalic. Deficiency in the E2 dihydrolipoyl transacetylase activity of the pyruvate dehydrogenase complex was demonstrated enzymatically, and a very low E2 protein component was found on Western blotting of fibroblast proteins. The inheritance pattern was unclear. Head et al. (2005) reported 2 unrelated patients with pyruvate dehydrogenase E2 deficiency. Both patients were born of first-cousin parents, indicating autosomal recessive inheritance. The first patient developed nystagmus, jerky head movements, and episodic clenching of his hands at age 5 months. Other features included general hypotonia and delayed psychomotor development. By age 4 years, he had ataxia with gross and fine motor delay, oculomotor apraxia, dystonic movements of the face, hands, and feet, and hyperreflexia. Treatment with lipoic acid, thiamine, and a ketogenic diet resulted in marked clinical improvement. The second patient developed dystonic episodes at age 11 months, consisting of arching of the back with stiffening of the limbs and eye rolling. By age 8 years, he had developmental delay, borderline mental retardation, and generalized dystonia. Biochemical analysis showed reduced activity of the pyruvate dehydrogenase complex in both patients, with an intermediate reduction in the unaffected parents. MRI of both patients showed abnormal signals in the globus pallidus bilaterally, although only the first patient showed increased serum and CSF lactate. Friedman et al. (2017) reported a patient with pyruvate dehydrogenase E2 deficiency who also had paroxysmal exercise-induced dyskinesia. The patient was born to consanguineous Iraqi parents. He had developmental delay with a cognitive assessment at age 8 years showing an IQ of 44. At age 3, he developed paroxysmal episodes after 5 to 15 minutes of ambulation, characterized by dystonic arm and leg posturing, sometimes with leg shaking and with progressive inability to stand. The episodes would resolve with rest, but would recur multiple times daily with repeated exertion. The patient also had microcephaly, disconjugate gaze with limitation of upward right eye excursion, mildly increased tone, brisk lower extremity reflexes without clonus, and left Babinski sign. EMG showed probable myopathic features. Brain MRI showed abnormal symmetric hypointensity in the bilateral globus pallidus bilaterally. Pyruvate dehydrogenase complex (PDC) enzyme activity in blood lymphocytes was reduced. Treatment with thiamine reversed the patient's deterioration, but not his exercise-induced paroxysmal symptoms. Ketogenic diet was initiated, but was not tolerated. Molecular Genetics In 2 unrelated patients with pyruvate dehydrogenase E2 deficiency, Head et al. (2005) identified 2 different homozygous mutations in the DLAT gene (c.361del3, 608770.0001 and F576L, 608770.0002). In a patient with PDHDD and paroxysmal exercise-induced dyskinesia, who was born to consanguineous Iraqi parents, Friedman et al. (2017) identified a homozygous mutation in the DLAT gene (V157G; 608770.0003). INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly Eyes \- Nystagmus \- Ptosis \- Saccade initiation failure \- Oculomotor apraxia NEUROLOGIC Central Nervous System \- Psychomotor retardation \- Hypotonia, neonatal \- Mental retardation, mild \- Ataxia \- Gross motor delay \- Fine motor delay \- Drooling \- Poor speech \- Dystonia, episodic \- Jerky head movements \- Hyperreflexia \- Choreoathetoid movements \- MRI shows globus pallidus signal abnormalities METABOLIC FEATURES \- Lactic acidosis, may be mild LABORATORY ABNORMALITIES \- Serum and CSF lactate may be increased \- Decreased activity of the pyruvate dehydrogenase complex (PDH) \- Decreased activity of the E2 subunit (lipoyl transacetylase, 608770 ) of the PDH \- Decreased levels of the E2 subunit protein MISCELLANEOUS \- Onset in infancy \- Very rare MOLECULAR BASIS \- Caused by mutation in the dihydrolipoamide acetyltransferase gene (DLAT, 608770.0001 ) ▲ 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 inhibitors [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	PYRUVATE DEHYDROGENASE E2 DEFICIENCY	c0034345	2,981	omim	https://www.omim.org/entry/245348	2019-09-22T16:26:03	{"doid": ["3649"], "mesh": ["D015325"], "omim": ["245348"], "orphanet": ["765", "79244"], "synonyms": ["Alternative titles", "LACTIC ACIDEMIA DUE TO DEFECT OF E2 LIPOYL TRANSACETYLASE OF THE PYRUVATE DEHYDROGENASE COMPLEX"]}
Isobutyryl-CoA dehydrogenase deficiency is an inborn error of valine metabolism. The prevalence is unknown. Only one symptomatic patient (with anaemia, failure to thrive, dilated cardiomyopathy and plasma carnitine deficiency) has been described so far, but several series of patients have been identified through newborn screening programs relying on detection of increased C(4)-carnitine levels by tandem mass spectrometry. The disorder is caused by mutations in the ACAD8 gene (11q25). [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 inhibitors [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	Isobutyryl-CoA dehydrogenase deficiency	c1969809	2,982	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79159	2021-01-23T17:31:09	{"gard": ["10223"], "mesh": ["C535541"], "omim": ["611283"], "umls": ["C1969809"], "icd-10": ["E71.1"], "synonyms": ["Isobutyric aciduria"]}
Oxygen shortage of the brain For other uses, see hypoxia (disambiguation). Cerebral hypoxia Circle of Willis Arteries beneath brain SpecialtyCritical care medicine Cerebral hypoxia is a form of hypoxia (reduced supply of oxygen), specifically involving the brain; when the brain is completely deprived of oxygen, it is called cerebral anoxia. There are four categories of cerebral hypoxia; they are, in order of severity: diffuse cerebral hypoxia (DCH), focal cerebral ischemia, cerebral infarction, and global cerebral ischemia. Prolonged hypoxia induces neuronal cell death via apoptosis, resulting in a hypoxic brain injury.[1][2] Cases of total oxygen deprivation are termed "anoxia", which can be hypoxic in origin (reduced oxygen availability) or ischemic in origin (oxygen deprivation due to a disruption in blood flow). Brain injury as a result of oxygen deprivation either due to hypoxic or anoxic mechanisms are generally termed hypoxic/anoxic injuries (HAI). Hypoxic ischemic encephalopathy (HIE) is a condition that occurs when the entire brain is deprived of an adequate oxygen supply, but the deprivation is not total. While HIE is associated in most cases with oxygen deprivation in the neonate due to birth asphyxia, it can occur in all age groups, and is often a complication of cardiac arrest.[3][4][5] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Pre- and postnatal * 3 Mechanism * 4 Diagnosis * 4.1 Classification * 5 Treatment * 6 Prognosis * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] CT in a person after generalized hypoxia. The brain requires approximately 3.3 ml of oxygen per 100 g of brain tissue per minute. Initially the body responds to lowered blood oxygen by redirecting blood to the brain and increasing cerebral blood flow. Blood flow may increase up to twice the normal flow but no more. If the increased blood flow is sufficient to supply the brain's oxygen needs then no symptoms will result.[6] However, if blood flow cannot be increased or if doubled blood flow does not correct the problem, symptoms of cerebral hypoxia will begin to appear. Mild symptoms include difficulties with complex learning tasks and reductions in short-term memory. If oxygen deprivation continues, cognitive disturbances, and decreased motor control will result.[6] The skin may also appear bluish (cyanosis) and heart rate increases. Continued oxygen deprivation results in fainting, long-term loss of consciousness, coma, seizures, cessation of brain stem reflexes, and brain death.[7] Objective measurements of the severity of cerebral hypoxia depend on the cause. Blood oxygen saturation may be used for hypoxic hypoxia, but is generally meaningless in other forms of hypoxia. In hypoxic hypoxia 95–100% saturation is considered normal; 91–94% is considered mild and 86–90% moderate. Anything below 86% is considered severe.[8] Cerebral hypoxia refers to oxygen levels in brain tissue, not blood. Blood oxygenation will usually appear normal in cases of hypemic, ischemic, and hystoxic cerebral hypoxia. Even in hypoxic hypoxia blood measures are only an approximate guide; the oxygen level in the brain tissue will depend on how the body deals with the reduced oxygen content of the blood. ## Causes[edit] Cerebral hypoxia can be caused by any event that severely interferes with the brain's ability to receive or process oxygen. This event may be internal or external to the body. Mild and moderate forms of cerebral hypoxia may be caused by various diseases that interfere with breathing and blood oxygenation. Severe asthma and various sorts of anemia can cause some degree of diffuse cerebral hypoxia. Other causes include status epilepticus, work in nitrogen-rich environments, ascent from a deep-water dive, flying at high altitudes in an unpressurized cabin without supplemental oxygen, and intense exercise at high altitudes prior to acclimatization. Severe cerebral hypoxia and anoxia is usually caused by traumatic events such as choking, drowning, strangulation, smoke inhalation, drug overdoses, crushing of the trachea, status asthmaticus, and shock.[9] It is also recreationally self-induced in the fainting game and in erotic asphyxiation. * Transient ischemic attack (TIA), is often referred to as a "mini-stroke". The American Heart Association and American Stroke Association (AHA/ASA) refined the definition of transient ischemic attack. TIA is now defined as a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. The symptoms of a TIA can resolve within a few minutes, unlike a stroke. TIAs share the same underlying etiology as strokes; a disruption of cerebral blood flow. TIAs and strokes present with the same symptoms such as contralateral paralysis (opposite side of body from affected brain hemisphere), or sudden weakness or numbness. A TIA may cause sudden dimming or loss of vision, aphasia, slurred speech, and mental confusion. The symptoms of a TIA typically resolve within 24 hours, unlike a stroke. Brain injury may still occur in a TIA lasting only a few minutes. Having a TIA is a risk factor for eventually having a stroke.[10][11] * Silent stroke is a stroke which does not have any outward symptoms, and the patient is typically unaware they have suffered a stroke. Despite its lack of identifiable symptoms, a silent stroke still causes brain damage and places the patient at increased risk for a major stroke in the future. In a broad study in 1998, more than 11 million people were estimated to have experienced a stroke in the United States. Approximately 770,000 of these strokes were symptomatic and 11 million were first-ever silent MRI infarcts or hemorrhages. Silent strokes typically cause lesions which are detected via the use of neuroimaging such as fMRI.[12][13] The risk of silent stroke increases with age but may also affect younger adults. Women appear to be at increased risk for silent stroke, with hypertension and current cigarette smoking being predisposing factors.[14][15] ### Pre- and postnatal[edit] Further information: Neonatal encephalopathy Hypoxic-anoxic events may affect the fetus at various stages of fetal development, during labor and delivery and in the postnatal period. Problems during pregnancy may include preeclampsia, maternal diabetes with vascular disease, congenital fetal infections, drug/alcohol abuse, severe fetal anemia, cardiac disease, lung malformations, or problems with blood flow to the placenta. Problems during labor and delivery can include umbilical cord occlusion, torsion or prolapse, rupture of the placenta or uterus, excessive bleeding from the placenta, abnormal fetal position such as the breech position, prolonged late stages of labor, or very low blood pressure in the mother. Problems after delivery can include severe prematurity, severe lung or heart disease, serious infections, trauma to the brain or skull, congenital malformations of the brain or very low blood pressure in the baby[16] and due to suffocation in cases of Münchausen syndrome by proxy.[17] The severity of a neonatal hypoxic-ischaemic brain injury may be assessed using Sarnat staging, which is based on clinical presentation and EEG findings, and also using MRI.[18] ## Mechanism[edit] Main article: Mechanism of anoxic depolarization in the brain Details of the mechanism of damage from cerebral hypoxia, along with anoxic depolarization, can be found here: Mechanism of anoxic depolarization in the brain ## Diagnosis[edit] ### Classification[edit] Cerebral hypoxia is typically grouped into four categories depending on the severity and location of the brain's oxygen deprivation:[19] Aneurysm in a cerebral artery, one cause of hypoxic anoxic injury (HAI). 1. Diffuse cerebral hypoxia – A mild to moderate impairment of brain function due to low oxygen levels in the blood. 2. Focal cerebral ischemia – A stroke occurring in a localized area that can either be acute or transient. This may be due to a variety of medical conditions such as an aneurysm that causes a hemorrhagic stroke, or an occlusion occurring in the affected blood vessels due to a thrombus (thrombotic stroke) or embolus (embolic stroke).[20] Focal cerebral ischemia constitutes a large majority of the clinical cases in stroke pathology with the infarct usually occurring in the middle cerebral artery (MCA).[21] 3. Global cerebral ischemia – A complete stoppage of blood flow to the brain. 4. Cerebral infarction – A "stroke", caused by complete oxygen deprivation due to an interference in cerebral blood flow which affects multiple areas of the brain. Cerebral hypoxia can also be classified by the cause of the reduced brain oxygen:[22] * Hypoxic hypoxia – Limited oxygen in the environment causes reduced brain function. Divers, aviators,[23] mountain climbers, and fire fighters are all at risk for this kind of cerebral hypoxia. The term also includes oxygen deprivation due to obstructions in the lungs. Choking, strangulation, the crushing of the windpipe all cause this sort of hypoxia. Severe asthmatics may also experience symptoms of hypoxic hypoxia. * Hypemic hypoxia – Reduced brain function is caused by inadequate oxygen in the blood despite adequate environmental oxygen. Anemia and carbon monoxide poisoning are common causes of hypemic hypoxia. * Ischemic hypoxia ( or "stagnant hypoxia") – Reduced brain oxygen is caused by inadequate blood flow to the brain. Stroke, shock, cardiac arrest and heart attack may cause stagnant hypoxia. Ischemic hypoxia can also be created by pressure on the brain. Cerebral edema, brain hemorrhages and hydrocephalus exert pressure on brain tissue and impede their absorption of oxygen. * Histotoxic hypoxia – Oxygen is present in brain tissue but cannot be metabolized by the brain tissue. Cyanide poisoning is a well-known example. ## Treatment[edit] For newborn infants starved of oxygen during birth there is now evidence that hypothermia therapy for neonatal encephalopathy applied within 6 hours of cerebral hypoxia effectively improves survival and neurological outcome.[24] In adults, however, the evidence is less convincing and the first goal of treatment is to restore oxygen to the brain. The method of restoration depends on the cause of the hypoxia. For mild-to-moderate cases of hypoxia, removal of the cause of hypoxia may be sufficient. Inhaled oxygen may also be provided. In severe cases treatment may also involve life support and damage control measures. A deep coma will interfere with the body's breathing reflexes even after the initial cause of hypoxia has been dealt with; mechanical ventilation may be required. Additionally, severe cerebral hypoxia causes an elevated heart rate, and in extreme cases the heart may tire and stop pumping. CPR, defibrilation, epinephrine, and atropine may all be tried in an effort to get the heart to resume pumping.[8] Severe cerebral hypoxia can also cause seizures, which put the patient at risk of self-injury, and various anti-convulsant drugs may need to be administered before treatment. There has long been a debate over whether newborn infants with cerebral hypoxia should be resuscitated with 100% oxygen or normal air.[25] It has been demonstrated that high concentrations of oxygen lead to generation of oxygen free radicals, which have a role in reperfusion injury after asphyxia.[26] Research by Ola Didrik Saugstad and others led to new international guidelines on newborn resuscitation in 2010, recommending the use of normal air instead of 100% oxygen.[27][28] Brain damage can occur both during and after oxygen deprivation. During oxygen deprivation, cells die due to an increasing acidity in the brain tissue (acidosis). Additionally, during the period of oxygen deprivation, materials that can easily create free radicals build up. When oxygen enters the tissue these materials interact with oxygen to create high levels of oxidants. Oxidants interfere with the normal brain chemistry and cause further damage (this is known as "reperfusion injury"). Techniques for preventing damage to brain cells are an area of ongoing research. Hypothermia therapy for neonatal encephalopathy is the only evidence-supported therapy, but antioxidant drugs, control of blood glucose levels, and hemodilution (thinning of the blood) coupled with drug-induced hypertension are some treatment techniques currently under investigation.[29] Hyperbaric oxygen therapy is being evaluated with the reduction in total and myocardial creatine phosphokinase levels showing a possible reduction in the overall systemic inflammatory process.[30] In severe cases it is extremely important to act quickly. Brain cells are very sensitive to reduced oxygen levels. Once deprived of oxygen they will begin to die off within five minutes.[29] ## Prognosis[edit] Mild and moderate cerebral hypoxia generally has no impact beyond the episode of hypoxia; on the other hand, the outcome of severe cerebral hypoxia will depend on the success of damage control, amount of brain tissue deprived of oxygen, and the speed with which oxygen was restored. If cerebral hypoxia was localized to a specific part of the brain, brain damage will be localized to that region. A general consequence may be epilepsy. The long-term effects will depend on the purpose of that portion of the brain. Damage to the Broca's area and the Wernicke's area of the brain (left side) typically causes problems with speech and language. Damage to the right side of the brain may interfere with the ability to express emotions or interpret what one sees. Damage on either side can cause paralysis of the opposite side of the body. The effects of certain kinds of severe generalized hypoxias may take time to develop. For example, the long-term effects of serious carbon monoxide poisoning usually may take several weeks to appear. Recent research suggests this may be due to an autoimmune response caused by carbon monoxide-induced changes in the myelin sheath surrounding neurons.[31] If hypoxia results in coma, the length of unconsciousness is often indicative of long-term damage. In some cases coma can give the brain an opportunity to heal and regenerate,[32] but, in general, the longer a coma, the greater the likelihood that the person will remain in a vegetative state until death.[9] Even if the patient wakes up, brain damage is likely to be significant enough to prevent a return to normal functioning. Long-term comas can have a significant impact on a patient's families.[33] Families of coma victims often have idealized images of the outcome based on Hollywood movie depictions of coma.[34] Adjusting to the realities of ventilators, feeding tubes, bedsores, and muscle wasting may be difficult.[35] Treatment decision often involve complex ethical choices and can strain family dynamics.[36] ## See also[edit] * Altitude sickness * Choking game * Hypothermia cap * Space exposure * Ulegyria ## References[edit] 1. ^ Malhotra R, et al. (Nov 2001). "Hypoxia induces apoptosis via two independent pathways in Jurkat cells: differential regulation by glucose". American Journal of Physiology. Cell Physiology. 281 (5): C1596–603. doi:10.1152/ajpcell.2001.281.5.c1596. PMID 11600423. 2. ^ Mattiesen W. R.; et al. (May 2009). "Increased neurogenesis after hypoxic-ischemic encephalopathy in humans is age related". Acta Neuropathol. 117 (5): 525–34. doi:10.1007/s00401-009-0509-0. PMID 19277687. 3. ^ Robinson, LR; Micklesen, PJ; Tirschwell, DL; Lew, HL (Mar 2003). "Predictive value of somatosensory evoked potentials for awakening from coma". Critical Care Medicine. 31 (3): 960–7. doi:10.1097/01.ccm.0000053643.21751.3b. PMID 12627012. 4. ^ Geraghty M. C.; Torbey M. T. (2006). "Neuroimaging and serologic markers of neurologic injury after cardiac arrest". Neurol Clin. 24 (1): 107–21. doi:10.1016/j.ncl.2005.10.006. PMID 16443133. 5. ^ Busl K. M.; Greer D. M. (Jan 2010). "Hypoxic-ischemic brain injury: pathophysiology, neuropathology and mechanisms". NeuroRehabilitation. 26 (1): 5–13. doi:10.3233/NRE-2010-0531. PMID 20130351. 6. ^ a b Butterworth, Roger F. (1999). "Hypoxic Encephalopathy". In: Siegel, George J. et al. (eds.) Basic Neurochemistry: Molecular, Cellular and Medical Aspects, 6th edition, Philadelphia: Lippincott Williams & Wilkins. ISBN 0-397-51820-X. Freely available at NCBI Bookshelf. Retrieved on 2007-04-13. 7. ^ "Cerebral hypoxia". MedlinePlus Medical Encyclopedia. U.S. National Library of Medicine. 2007-04-05. Retrieved 2007-04-13. 8. ^ a b "The Maryland Medical Protocols for Emergency Medical Services Providers" (PDF). (1.00 MiB). Maryland Institute for Emergency Medical Services Systems (2004). Retrieved on 2007-04-13. 9. ^ a b National Institute of Neurological Disorders and Stroke (2018-03-08). "Cerebral Hypoxia Information Page". U.S. National Institutes of Health. Retrieved 2007-04-13. 10. ^ Ferro J. M.; et al. (Dec 1996). "Diagnosis of transient ischemic attack by the nonneurologist: A validation study". Stroke. 27 (12): 2225–9. doi:10.1161/01.STR.27.12.2225. PMID 8969785. 11. ^ Easton JD, et al. (Jun 2009). "Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council". Stroke. 40 (6): 2276–93. doi:10.1161/STROKEAHA.108.192218. PMID 19423857. 12. ^ Herderscheê D, et al. (Sep 1992). "Silent stroke in patients with transient ischemic attack or minor ischemic stroke. The Dutch TIA Trial Study Group". Stroke. 23 (9): 1220–4. doi:10.1161/01.str.23.9.1220. PMID 1519274. 13. ^ Leary M. C.; Saver J. L. (2003). "Annual incidence of first silent stroke in the United States: a preliminary estimate". Cerebrovasc Dis. 16 (3): 280–5. doi:10.1159/000071128. PMID 12865617. 14. ^ Vermeer S. E.; et al. (Jan 2002). "Prevalence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study". Stroke. 33 (1): 21–5. doi:10.1161/hs0102.101629. PMID 11779883. 15. ^ Herderscheê D, et al. (Sep 1992). ""Silent stroke in patients with transient ischemic attack or minor ischemic stroke". The Dutch TIA Trial Study Group". Stroke. 23 (9): 1220–4. doi:10.1161/01.str.23.9.1220. PMID 1519274. 16. ^ "Parent Info". Florida Neonatal Neurologic Network. Retrieved 28 January 2012. 17. ^ Bellemare S (2006). "Child abuse by suffocation: A cause of apparent life-threatening events Info". Paediatr Child Health. 11 (8): 493–5. PMC 2528639. PMID 19030315. 18. ^ Gardiner M, Eisen S, Murphy C. Training in paediatrics: the essential curriculum. Oxford University Press, Oxford 2009. 19. ^ "Hypoxia". The Gale Encyclopedia of Neurological Disorders. The Gale Group, Inc. 2005. Retrieved on 2007-04-13 from Answers.com. 20. ^ Pressman B. D.; Tourje E. J.; Thompson J. R. (Sep 1987). "An early CT sign of ischemic infarction: increased density in a cerebral artery". AJR Am J Roentgenol. 149 (3): 583–6. doi:10.2214/ajr.149.3.583. PMID 3497548. 21. ^ Jun Chen, Zao C. Xu, Xiao-Ming Xu, Animal Models of Acute Neurological Injuries, Humana Press; 1 edition, ISBN 978-1-60327-184-4 22. ^ "What is Hypoxia?". Gray Laboratory Cancer Research Trust. 1999-08-01. Archived from the original on 2003-09-21. Retrieved on 2007-04-13 from Archive.org. 23. ^ Brooks, Kevin E. (May–June 2005). "Are you a hypoxia expert?". Approach. United States Navy Naval Safety Center. Archived from the original on 2007-02-08. Retrieved 2007-04-13. This website provides hypoxia related safety tips for aviators working for the United States Navy aviators. 24. ^ Laurance, Jeremy (October 1, 2009). "Cooling 'cure' averts infant brain damage", The Independent. 25. ^ Davis, PG; Tan, A; O'Donnell, CPF; Schulze, A (2004). "Resuscitation of newborn infants with 100% oxygen or air: a systematic review and meta-analysis". The Lancet. 364 (9442): 1329–1333. doi:10.1016/S0140-6736(04)17189-4. PMID 15474135. 26. ^ Kutzsche, S; Ilves, P; Kirkeby, OJ; Saugstad, OD (2001). "Hydrogen peroxide production in leukocytes during cerebral hypoxia and reoxygenation with 100% or 21% oxygen in newborn piglets". Pediatric Research. 49 (6): 834–842. doi:10.1203/00006450-200106000-00020. PMID 11385146. 27. ^ ILCOR Neonatal Resuscitation Guidelines 2010 28. ^ Norwegian paediatrician honoured by University of Athens, Norway.gr 29. ^ a b Richmond, T. S. (May 1997). "Cerebral Resuscitation after Global Brain Ischemia", AACN Clinical Issues 8 (2). Retrieved on 2007-04-13. Free full text Archived September 27, 2007, at the Wayback Machine at the American Association of Critical-Care Nurses website. 30. ^ Orozco-Gutierrez A, Rojas-Cerda L, Estrada RM, Gil-Rosales C (December 2010). "Hyperbaric oxygen in the treatment of asphyxia in two newborn infants". Diving and Hyperbaric Medicine. 40 (4): 218–20. PMID 23111939. Retrieved 2013-06-06. 31. ^ University Of Pennsylvania Medical Center (2004-09-06). "Long-Term Effects of Carbon Monoxide Poisoning Are an Autoimmune Reaction". ScienceDaily. Retrieved 2007-04-13. 32. ^ Phillips, Helen (2006-07-03). "'Rewired brain' revives patient after 19 years". New Scientist. Retrieved 2007-04-13. 33. ^ Mayo Clinic staff (2006-05-17). "Coma: Coping skills". Mayo Clinic. Retrieved 2007-04-13. 34. ^ Wijdicks E. F. M.; Wijdicks C. A. (2006). "The portrayal of coma in contemporary motion pictures". Neurology. 66 (9): 1300–1303. doi:10.1212/01.wnl.0000210497.62202.e9. PMID 16682658. 35. ^ Konig P, et al. (1992). "Psychological counseling of the family of patients with craniocerebral injuries (psychological family counseling of severely ill patients)"". Zentralbl Neurochir. 53 (2): 78–84. PMID 1636327. 36. ^ Montgomery V, et al. (2002). "The effect of severe traumatic brain injury on the family". Journal of Trauma. 52 (6): 1121–4. doi:10.1097/00005373-200206000-00016. PMID 12045640. ## External links[edit] Classification D * ICD-9-CM: 437.9 * MeSH: D002534 * SNOMED CT: 389088001 External resources * MedlinePlus: 001435 * Hypoxia experiment * 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 * t * e Cardiovascular disease (vessels) Arteries, arterioles and capillaries Inflammation * Arteritis * Aortitis * Buerger's disease Peripheral artery disease Arteriosclerosis * Atherosclerosis * Foam cell * Fatty streak * Atheroma * Intermittent claudication * Critical limb ischemia * Monckeberg's arteriosclerosis * Arteriolosclerosis * Hyaline * Hyperplastic * Cholesterol * LDL * Oxycholesterol * Trans fat Stenosis * Carotid artery stenosis * Renal artery stenosis Other * Aortoiliac occlusive disease * Degos disease * Erythromelalgia * Fibromuscular dysplasia * Raynaud's phenomenon Aneurysm / dissection / pseudoaneurysm * torso: Aortic aneurysm * Abdominal aortic aneurysm * Thoracic aortic aneurysm * Aneurysm of sinus of Valsalva * Aortic dissection * Aortic rupture * Coronary artery aneurysm * head / neck * Intracranial aneurysm * Intracranial berry aneurysm * Carotid artery dissection * Vertebral artery dissection * Familial aortic dissection Vascular malformation * Arteriovenous fistula * Arteriovenous malformation * Telangiectasia * Hereditary hemorrhagic telangiectasia Vascular nevus * Cherry hemangioma * Halo nevus * Spider angioma Veins Inflammation * Phlebitis Venous thrombosis / Thrombophlebitis * primarily lower limb * Deep vein thrombosis * abdomen * Hepatic veno-occlusive disease * Budd–Chiari syndrome * May–Thurner syndrome * Portal vein thrombosis * Renal vein thrombosis * upper limb / torso * Mondor's disease * Paget–Schroetter disease * head * Cerebral venous sinus thrombosis * Post-thrombotic syndrome Varicose veins * Gastric varices * Portacaval anastomosis * Caput medusae * Esophageal varices * Hemorrhoid * Varicocele Other * Chronic venous insufficiency * Chronic cerebrospinal venous insufficiency * Superior vena cava syndrome * Inferior vena cava syndrome * Venous ulcer Arteries or veins * Angiopathy * Macroangiopathy * Microangiopathy * Embolism * Pulmonary embolism * Cholesterol embolism * Paradoxical embolism * Thrombosis * Vasculitis Blood pressure Hypertension * Hypertensive heart disease * Hypertensive emergency * Hypertensive nephropathy * Essential hypertension * Secondary hypertension * Renovascular hypertension * Benign hypertension * Pulmonary hypertension * Systolic hypertension * White coat hypertension Hypotension * Orthostatic hypotension [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 inhibitors [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	Cerebral hypoxia	c1140716	2,983	wikipedia	https://en.wikipedia.org/wiki/Cerebral_hypoxia	2021-01-18T18:46:58	{"mesh": ["D002534"], "icd-9": ["437.9"], "wikidata": ["Q2249526"]}
A number sign (#) is used with this entry because of evidence that mutations in the NOD2/CARD15 gene (605956) are associated with susceptibility to Crohn disease in families linked to chromosome 16. A promoter polymorphism in the IL6 gene (147620) is associated with susceptibility to Crohn disease-associated growth failure. For information on genetic heterogeneity of IBD, see MAPPING and MOLECULAR GENETICS sections. Clinical Features Inflammatory bowel disease is characterized by a chronic relapsing intestinal inflammation. IBD is subdivided into Crohn disease and ulcerative colitis phenotypes. Crohn disease and ulcerative colitis have a combined prevalence of 200 to 300 per 100,000 in the United States. Crohn disease may involve any part of the gastrointestinal tract, but most frequently the terminal ileum and colon. Bowel inflammation is transmural and discontinuous; it may contain granulomas or be associated with intestinal or perianal fistulas. In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal layers; fistulas and granulomas are not observed. In approximately 10% of cases confined to the rectum and colon, definitive classification of Crohn disease or ulcerative colitis cannot be made and are designated 'indeterminate colitis.' Both diseases include extraintestinal inflammation of the skin, eyes, or joints. Crohn disease and ulcerative colitis are commonly classified as autoimmune diseases. The prevalence of inflammatory bowel disease is increased in individuals with other autoimmune diseases, particularly ankylosing spondylitis, psoriasis, sclerosing cholangitis, and multiple sclerosis. There is strong evidence from twin studies, familial risk data, and segregation analysis that inflammatory bowel disease, especially Crohn disease, is genetic (Yang and Rotter, 1994; Duerr, 1996). Crohn disease and ulcerative colitis are considered complex genetic traits as inheritance does not follow any simple mendelian models. Both genetic and environmental factors seem to be important in its etiology. Monsen et al. (1989) performed segregation analysis in 124 families with ulcerative colitis in 2 or more members. They concluded that a rare additive major gene causes the disease, with about 20% affected among those heterozygous for the gene. They found no evidence for multifactorial inheritance. They raised the possibility that the major gene may be associated with a separate type of ulcerative colitis with more extensive involvement, younger age of onset, and more immunologic side effects such as extraintestinal manifestation. Prevalence in first-degree relatives has been estimated to be between 4 and 16% (Lewkonia and McConnell, 1976; Farmer et al., 1980). Orholm et al. (1991) found that first-degree relatives of patients with either ulcerative colitis or Crohn disease had a 10-fold increase in the risk of having the same disease as the patients. The risk of having the other of the 2 diseases was also increased, but less so, and the increase in the risk of having Crohn disease was not significant in the relatives of patients with ulcerative colitis. Yang et al. (1993) found evidence of higher frequency of inflammatory bowel disease among first-degree relatives of Jewish patients than among the relatives of non-Jewish patients. The first-degree relatives of Jewish patients had a lifetime risk for inflammatory bowel disease of 7.8% and 4.5% when probands had Crohn disease and ulcerative colitis, respectively. The values for first-degree relatives of non-Jewish probands were 5.2% and 1.6%. Satsangi et al. (1996) studied the clinical characteristics (disease type, extent, age of onset, need for surgery, and presence of extraintestinal manifestations) in affected subjects in multiply-affected families with inflammatory bowel disease. They identified 54 families in which 1 parent and at least 1 child were affected (a total of 77 parent-child pairs) and 155 families in which 2 sibs were affected (a total of 190 affected sib pairs). In affected parent-child pairs, parent and child were concordant for 'disease type' (Crohn disease or ulcerative colitis) in 58 of 77 pairs (75.3%), for extent in 63.6%, for extraintestinal manifestations in 70.1%, and for smoking history in 85%. The median age of onset in parents was significantly higher than in offspring (p = less than 0.0001). In 40 pairs (60.6%) the parent was at least 10 years older than the child at age of onset. Sibs were concordant for disease type in 81.6% of the affected sib pairs, extent in 76.0%, extraintestinal manifestations in 83.8%, and smoking history in 81.3%. In contrast with the parent-child pairs, 68.1% of sibs (111 sib pairs) were diagnosed within 10 years of each other. Median age of onset was 24.0 years. Satsangi et al. (1996) felt that the differences in age of onset between parents and children was not readily explained by a simple cohort effect or ascertainment bias, and may it reflect effects of genetic factors, producing anticipation between generations. ### Crohn Disease About 10% of persons with regional enteritis have 1 or more close relatives with granulomatous disease of the bowel. In 5 persons of Ashkenazi Jewish origin (ancestors from area of Russia-Poland around Vilna), Sheehan et al. (1967) found red cell glucose-6-phosphate dehydrogenase deficiency associated with regional enteritis or granulomatous colitis. The affected persons were 2 males and 3 females. Regional enteritis and sarcoidosis have been observed in the same family (see 181000); Gronhagen-Riska et al. (1983) commented on the association. Schwartz et al. (1980) found no HLA association in sporadic cases or in familial cases. However, in 5 affected sib pairs, 4 shared both haplotypes (i.e., were HLA-identical) and the 5th shared one haplotype. Only 1 unaffected sib shared both haplotypes with an affected sib. Kuster et al. (1989) suggested that a recessive gene with incomplete penetrance is responsible for susceptibility to Crohn disease. McConnell (1988) suggested polygenic inheritance; an individual inheriting few susceptibility genes would develop ulcerative colitis, while someone inheriting a larger number of these genes would develop regional enteritis. Although controversial, epidemiologic evidence (Greenstein et al., 1988) suggests that there may be 2 distinct clinical forms of Crohn disease: perforating and nonperforating. Patients with perforating Crohn disease have abscesses and/or free perforations. Perforating Crohn disease is the more aggressive form with a higher reoperation rate. By contrast, nonperforating Crohn disease has a more indolent clinical course and is associated with obstruction and bleeding as the main features. Gilberts et al. (1994) reasoned that the host immune response may determine which clinical presentation the disease assumes. Leprosy is an incontrovertible example of 2 clinical forms of disease, tuberculous and lepromatous, with the same etiologic factor. Resected intestinal tissue from control patients, as well as perforating and nonperforating Crohn disease patients, was evaluated for mRNA levels of a housekeeping gene (beta-actin; 102630), a human T-cell marker, CD3-delta (186790), and 6 cytokines. Differences were observed with interleukin-1-beta (IL1B; 147720) and with interleukin-1 receptor alpha (IL1RA; 147810). Nonperforating Crohn disease, the more benign form, was associated with increased IL1B and IL1RA mRNA expression. Pathogenesis Cattan et al. (2000) studied the incidence of IBD in non-Ashkenazi Jewish patients with familial Mediterranean fever (FMF; 249100). The association was 8 to 14 times greater than expected. The prevalence of IBD in non-Ashkenazi Jews is 120 per 100,000, whereas Cattan et al. (2000) estimated a prevalence of at least 3 per 300 (or 3 per 173 if the calculation is done through probands) in non-Ashkenazi Jews with FMF. They postulated that the inflammatory processes of FMF and IBD are additive, resulting in increased severity of disease in the new patients. Lawrance et al. (2001) examined global gene expression profiles of inflamed colonic tissue using DNA microarrays. They identified several genes with altered expression not previously linked to IBD. In addition to the expected upregulation of various cytokine and chemokine genes, novel immune function-related genes such as IGHG3 (147120), IGLL2, and CD74 (142790), inflammation-related lipocalins HNL and NGAL (600181), and proliferation-related GRO genes (see, e.g., 139110) were overexpressed in ulcerative colitis. Certain cancer-related genes such as DD96, DRAL (602633), and MXI1 (600020) were differentially expressed only in ulcerative colitis. Other genes overexpressed in both ulcerative colitis and Crohn disease included the REG gene family (see 167770) and the calcium-binding S100 protein genes S100A9 (123886) and S100P (600614). The natural antimicrobial defensin DEFA5 (600472) and DEFA6 (600471) genes were particularly overexpressed in Crohn disease. Overall, significant differences in the expression profiles of 170 genes identified ulcerative colitis and Crohn disease as distinct molecular entities. By yeast 2-hybrid analysis and reciprocal immunoprecipitations, Barnich et al. (2005) found that NOD2 interacts directly with GRIM19 (NDUFA13; 609435). The authors also found that expression of GRIM19 was significantly reduced in affected mucosa from Crohn disease and ulcerative colitis patients, whereas uninvolved patient mucosa showed GRIM19 mRNA expression comparable with that in control patients. By microarray analysis, Moehle et al. (2006) found coordinated downregulation of mucins, including MUC1 (158340), MUC2 (158370), MUC4 (158372), MUC5AC (158373), MUC5B (600770), MUC12 (604609), MUC13 (612181), MUC17 (608424), and MUC20 (610360), in ileum and colon of Crohn disease and ulcerative colitis patients compared with controls. They identified NF-kappa-B (see 164011)-binding sites in all mucin promoters and showed that activation of the NF-kappa-B signaling pathway by inflammatory cytokines TNF-alpha (TNF; 191160) and TGF-beta (TGFB1; 190180) upregulated mRNA expression of all the mucin genes under study. Baumgart and Carding (2007) reviewed the pathogenesis of Crohn disease and ulcerative colitis, including environmental factors and immunobiologic mechanisms. Abraham and Cho (2009) reviewed normal function of the intestinal immune system and discussed mechanisms of disease in inflammatory bowel disease, including genetic associations with Crohn disease and ulcerative colitis. Khor et al. (2011) gave an excellent review of the genetics and pathogenesis of inflammatory bowel disease. ### Crohn Disease Targan and Murphy (1995) reviewed briefly the current literature on both potential animal models for Crohn disease and human research on the mechanisms of its pathogenesis and molecular genetics. They stated that an updated hypothesis of Crohn disease pathogenicity 'holds that the foundation for its heterogeneity is at the primary genetic level, and expression of genetic susceptibility requires environmental triggers.' Because of the parallel to the tuberculoid and lepromatous forms of leprosy, Mishina et al. (1996) investigated the possibility of a Mycobacterium, namely M. paratuberculosis, as a cause of Crohn disease. They used RT-PCR with M. paratuberculosis subspecies-specific primers on total RNA from 12 ileal mucosal specimens of which 8 were from patients with Crohn disease, 2 represented cases of ulcerative colitis, and 2 represented cases of colonic cancer. As a negative control, they used M. avium DNA, originally cultured from the drinking water of a major city in the United States. Their cDNA sequence analysis showed that all 8 cases of Crohn disease and both samples from the patients with ulcerative colitis contained M. paratuberculosis RNA. Additionally, the M. avium control had the DNA sequence of M. paratuberculosis. They then demonstrated the DNA sequence of M. paratuberculosis from mucosal specimens in humans with Crohn disease. They concluded that the potable water supply may be a reservoir of infection. They suggested that clinical trials with therapy directed against M. paratuberculosis is indicated in patients with Crohn disease. Pizarro et al. (1999) detected increased IL18 (600953) mRNA and protein expression in intestinal epithelial cells and lamina propria mononuclear cells in Crohn disease tissue compared with ulcerative colitis and normal tissue. By immunohistochemical analysis, Corbaz et al. (2002) showed that IL18-binding protein (IL18BP; 604113) expression in intestinal tissue is increased in endothelial cells as well as cells of the submucosa and overlying lymphoid aggregates in Crohn disease patients compared with controls. Immunofluorescent microscopy demonstrated colocalization with macrophage and endothelial cell markers, but not with those of lymphocytes or epithelial cells. Real-time PCR and ELISA analysis detected increased levels of both IL18 and IL18BP in the Crohn disease intestinal tissue. Unbound neutralizing isoforms a and c of IL18BP were in excess compared with IL18 in the Crohn disease patients, indicating that IL18BP upregulation correlates with increased IL18 expression in Crohn disease. Corbaz et al. (2002) suggested that despite the presence of IL18BP, which has been shown to ameliorate colitis in a mouse model (ten Hove et al., 2001), some IL18 activity may be available for perpetuating the pathogenesis of Crohn disease. Lovato et al. (2003) found that intestinal T cells from Crohn disease patients, but not healthy volunteers, showed constitutive activation of STAT3 (102582) and STAT4 (600558). SOCS3 (604176), a STAT3-regulated protein, was also constitutively expressed in Crohn disease T cells. Lovato et al. (2003) concluded that there is abnormal STAT/SOCS signaling in Crohn disease. Van Heel et al. (2005) analyzed the cytokine response of peripheral blood mononuclear cells to muramyl dipeptide (MDP), the ligand for NOD2. MDP induced strong IL8 (146930) secretion and substantially upregulated the secretion of TNF-alpha (191160) and IL1B (147720) induced by Toll-like receptor (see 601194) ligands. At low nanomolar MDP concentrations, these effects were abolished by the most common Crohn disease NOD2 double-mutant genotypes (702W (605956.0003)/1007fs (605956.0001), 702W/702W, 1007fs/1007fs, and 908R (605956.0002)/1007fs). Van Heel et al. (2005) suggested that NOD2 activation provides a priming signal to condition a broad early immune response to pathogens, and that the absence of this priming signal in NOD2-associated Crohn disease causes failure of early immune pathogen clearance and explains the abnormal adaptive immune responses to microbial antigens in Crohn disease patients. In 15 patients with CD and 9 controls, Barnich et al. (2007) found that adherent-invasive E. coli (AIEC) adhesion was dependent on type 1 pili expression on the bacterial surface and on CEACAM6 (163980) expression on the apical surface of ileal epithelial cells. CEACAM6 acted as a receptor for AIEC adhesion and was upregulated in the ileal mucosa of CD patients compared to colonic mucosa or to controls. In vitro studies showed increased CEACAM6 expression in cultured intestinal epithelial cells after IFN-gamma (147570) or TNF-alpha (191160) stimulation and after infection with AIEC. Adolph et al. (2013) showed that impairment of either the unfolded protein response (UPR) or autophagy function in intestinal epithelial cells results in each other's compensatory engagement, and severe spontaneous Crohn disease-like transmural ileitis if both mechanisms are compromised. Xbp1 (194355)-deficient mouse intestinal epithelial cells showed autophagosome formation in hypomorphic Paneth cells, which is linked to endoplasmic reticulum (ER) stress via protein kinase RNA-like ER kinase (PERK; 604032), elongation initiation factor 2-alpha (eIF2-alpha; 609234), and activating transcription factor-4 (ATF4; 604064). Ileitis is dependent on commensal microbiota and derives from increased intestinal epithelial cell death, inositol-requiring enzyme 1-alpha (IRE1-alpha; 604033)-regulated NF-kappa-B (see 164011) activation, and TNF signaling, which are synergistically increased when autophagy is deficient. ATG16L1 (610767) restrains IRE1-alpha activity, and augmentation of autophagy in intestinal epithelial cells ameliorates ER stress-induced intestinal inflammation and eases NF-kappa-B overactivation and intestinal epithelial cell death. ER stress, autophagy induction, and spontaneous ileitis emerge from Paneth cell-specific deletion of Xbp1. Adolph et al. (2013) concluded that genetically and environmentally controlled UPR function within Paneth cells may therefore set the threshold for the development of intestinal inflammation upon hypomorphic ATG16L1 function and implicate ileal Crohn disease as a specific disorder of Paneth cells. Yoneno et al. (2013) examined TGR5 (GPBAR1; 610147) expression in peripheral blood monocytes and in vitro-differentiated macrophages and dendritic cells. They found that macrophages differentiated with MCSF (CSF1; 120420) and IFNG, which are similar to intestinal lamina propria CD14 (158120)-positive macrophages that contribute to Crohn disease pathogenesis by producing proinflammatory cytokines (e.g., TNF), highly expressed TGR5 compared with other types of differentiated macrophages and dendritic cells. TNF production was inhibited in these cells by 2 types of bile acid, deoxycholic acid and lithocholic acid, as well as by a TGR5 agonist. The inhibitory effect was mediated through the TGR5-cAMP pathway to induce phosphorylation of FOS (164810), which regulates NFKB p65 (RELA; 164014) activation. Analysis of lamina propria mononuclear cells from Crohn disease patients and controls showed increased TGR5 expression in Crohn disease patients compared with controls. A TGR5 agonist inhibited TNF production by isolated intestinal CD14-positive differentiated macrophages from Crohn disease patients. Yoneno et al. (2013) proposed that control of TGR5 signaling may modulate immune responses in inflammatory bowel disease. ### Ulcerative Colitis A role for PLA2G2A (172411) in the pathogenesis of ulcerative colitis was postulated by Haapamaki et al. (1997), who demonstrated expression of the PLA2G2A gene in metaplastic Paneth cells and columnar epithelial cells in inflamed colonic mucosa from patients with ulcerative colitis. No expression was detected in other tissues from the same patients or, by Northern blot analysis, in colonic biopsies from disease-free controls. Haapamaki et al. (1997) hypothesized that intraluminal secretion of PLA2G2A during the active phase of ulcerative colitis is a host defense mechanism. Hofseth et al. (2003) studied the relationship between the chronic inflammation of ulcerative colitis and the development of colon cancer. They examined tissues from noncancerous colons of ulcerative colitis patients to determine the activity of 2 base excision repair enzymes, 3-methyladenine DNA glycosylase (AAG; 156565) and apurinic/apyrimidinic endonuclease (APE1; 107748), and the prevalence of microsatellite instability (MSI). AAG and APE1 were significantly increased in ulcerative colitis colon epithelium undergoing elevated inflammation and MSI was positively correlated with their imbalanced enzymatic activities. These latter results were supported by mechanistic studies using yeast and human cell models in which overexpression of AAG and/or APE1 was associated with frameshift mutations and MSI. The results were consistent with the hypothesis that the adaptive and imbalanced increase in AAG and APE1 is a novel mechanism contributing to MSI in patients with ulcerative colitis. Fuss et al. (2004) examined lamina propria T cells from patients with ulcerative colitis and found that they produced significantly greater amounts of IL13 (147683) and IL5 (147850) than control or Crohn disease cells and little IFN-gamma (147570). The authors stimulated ulcerative colitis lamina propria T cells bearing the NK marker CD161 with anti-CD2 (186990)/anti-CD28 (186760) or with B cells expressing transfected CD1d (188410) and observed substantial IL13 production. Fuss et al. (2004) noted that these ulcerative colitis NKT cells did not express the invariant cell receptors characteristic of most NKT cells. The authors demonstrated that human NKT cell lines and the ulcerative colitis CD161+ lamina propria cells were cytotoxic for HT-29 epithelial cells and that this cytotoxicity was augmented by IL13. Fuss et al. (2004) concluded that ulcerative colitis is associated with an atypical Th2 response mediated by nonclassic NKT cells that produce IL13 and have cytotoxic potential for epithelial cells. Pang et al. (2007) investigated the expression of IL12B (161561), IFNG (147570), and the activational state of STAT4 (600558) signaling in mucosal tissues at the site of disease in 30 Chinese patients with active ulcerative colitis compared with 30 healthy controls. They found increased mRNA expression of IL12B, but not IFNG, in the UC patients, and Western blot analysis demonstrated increased levels of STAT4 in the cytoplasm and phosphorylated STAT4 in the nucleus of mucosal cells from UC patients. The authors concluded that a heightened, perhaps persistent, activational state of IL12/STAT4 and/or IL23/STAT4 signaling may be present in active Chinese UC patients and may be involved in the chronic inflammation of UC. Clinical Management ### Crohn Disease Miller et al. (2003) and Ghosh et al. (2003) reported clinical trials of natalizumab, a recombinant anticlonal antibody against alpha-4-integrins (192975), for the treatment of multiple sclerosis (126200) and Crohn disease, respectively. Miller et al. (2003) reported that a group of patients with multiple sclerosis who received monthly injections of natalizumab had significantly fewer new inflammatory central nervous system lesions than the placebo group (a reduction of approximately 90%) and had approximately half as many clinical relapses. Ghosh et al. (2003) reported that patients with Crohn disease also had a favorable response to natalizumab, with remission rates that were approximately twice as high in patients who received 2 injections of the antibody as in patients from the placebo group. The rate of adverse events did not differ significantly between the natalizumab and placebo groups in either trial. Von Andrian and Engelhardt (2003) stated that natalizumab probably has therapeutic effects because it blocks the ability of alpha-4/beta-1 and alpha-4/beta-7 to bind to their respective endothelial counter-receptors, VCAM1 (192225) and MADCAM1 (102670). In both disorders, lesions result from autoimmune responses involving activated lymphocytes and monocytes. Alpha-4-integrin is expressed on the surface of these cells and plays an integral part in their adhesion to the vascular endothelium and migration into the parenchyma. Using immunohistochemistry, immunofluorescence microscopy, and RT-PCR, Ricciardelli et al. (2008) showed that children with Crohn disease treated with infliximab, an anti-TNF antibody, had increased FOXP3 (300292)-positive T regulatory cells (Tregs) in their mucosa after treatment. Before treatment, FOXP3-positive T cells were reduced compared with controls. Ricciardelli et al. (2008) concluded that infliximab not only neutralizes soluble TNF, but also affects the activation and possibly the expansion of mucosal Tregs. They suggested that anti-TNF immunotherapy may restore mucosal homeostasis in Crohn disease. Monteleone et al. (2015) conducted a double-blind, placebo-controlled, phase 2 trial to evaluate the efficacy of mongersen, an oral SMAD7 (602932) antisense oligonucleotide, for the treatment of individuals with active Crohn disease. Mongersen targets ileal and colonic SMAD7. Patients were randomly assigned to receive 10, 40, or 160 mg of mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohn Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of mongersen treatment. A secondary outcome was clinical response (defined as a reduction of 100 points or more in the CDAI score) at day 28. The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg mongersen groups, respectively, as compared with 10% for the placebo group (p less than 0.001). There was no significant difference in the percentage of participants reaching clinical remission between the 10-mg group (12%) and the placebo group. The rate of clinical response was significantly greater among patients receiving 10 mg (37%), 40 mg (58%), or 160 mg (72%) of mongersen than among those receiving placebo (17%) (p = 0.04, p less than 0.001, and p less than 0.001, respectively). Most adverse events were related to complications and symptoms of Crohn disease. Mapping ### IBD1 on Chromosome 16q12 Hugot et al. (1996) performed a genomewide linkage study of 2 consecutive and independent panels of Crohn disease families with multiple affected members using a nonparametric 2-point sib pair linkage method. They identified a putative Crohn disease locus on chromosome 16 (P less than 0.01 for each panel) centered near loci D16S409 and D16S419 by using multipoint sib pair analysis. The authors stated that the locus on chromosome 16 probably accounts for only a small fraction of the 10-fold increased risk for first-degree relatives of Crohn disease patients. The most conspicuous examples of Crohn disease candidate genes that map to the pericentromeric region of chromosome 16 are CD19 (107265), which is involved in B-lymphocyte function; sialophorin (182160), which is involved in leukocyte adhesion; the CD11 integrin cluster (153370), which is involved in mycobacterial cell adhesion; and the interleukin-4 receptor (IL4R; 147781) because IL4-mediated regulation of mononuclear phagocyte effector functions is altered in inflammatory bowel diseases. The authors noted that some of the genetic factors involved in Crohn disease may also contribute to ulcerative colitis susceptibility. Indeed, Crohn disease and ulcerative colitis share the same ethnic predisposition, and mixed families in which some members are affected with Crohn disease and others with ulcerative colitis are commonly found. The studies of Hugot et al. (1996) also suggested the possible involvement of a locus on 1p. In an accompanying editorial comment, Ott (1996) pointed to the study by Hugot et al. (1996) in the analysis of complex traits. The parametric approach determines the recombination fraction between disease and marker loci on the basis of family data and the mode of inheritance and penetrance assumed for the trait. A misspecification of mode of inheritance generally results in an overestimation of the recombination fraction. In sib pair analysis, pairs of affected sibs are studied and all linkage information is gained from the inheritance of marker alleles by the 2 sibs, with no assumptions as to mode of inheritance. One determines the number of alleles inherited by sib 2 that are copies of the same parental alleles as those inherited by sib 1, i.e., the number of alleles shared identical by descent. Hugot et al. (1996) used multipoint sib pair analysis, implemented in the MAPMAKER/SIBS computer program, for their genomic screen for complex-trait loci. Although the number of families was relatively small (78 in the final analysis), this new approach allowed them to localize the gene for Crohn disease with greater confidence than had been possible using conventional methods. Ohmen et al. (1996) and Parkes et al. (1996) concluded that the localization to chromosome 16 is important for susceptibility to Crohn disease rather than ulcerative colitis. Cavanaugh et al. (1998) investigated the contribution of this localization to the inheritance of inflammatory bowel disease in 54 multiplex Australian families and confirmed its importance in a significant proportion of Crohn disease families. They refined the localization to a region near D16S409, obtaining a maximum lod score of 6.3 between D16S409 and D16S753. Annese et al. (1999) conducted a linkage study in a series of 58 Italian families with inflammatory bowel disease: 16 with Crohn disease, 23 with ulcerative colitis, and 19 with coexistent Crohn disease and ulcerative colitis. The findings of their study supported the 16p localization; no significant linkage was found for markers on chromosomes 3, 6, 7, and 12. In an extended sample of 82 Italian families with inflammatory bowel disease, Forabosco et al. (2000) performed combined linkage and segregation analysis in the identified IBD1 region, which allowed them to estimate the mode of inheritance. A 2-loci model gave a significantly better fit than a single-locus model when information on severity was included in the analysis. A model with a major dominant gene in linkage with D16S408 (theta = 0.0) and a modifier recessive gene, with a major effect on severity of the trait, provided the best fit. The possibility that both putative major genes in the IBD1 region represent the same gene could not be ruled out. The authors suggested the presence of a major gene in the IBD1 region involved in both ulcerative colitis and Crohn disease, with a single mutation in the gene leading more frequently to ulcerative colitis and 2 mutant alleles resulting in the more severe Crohn disease. Zouali et al. (2001) genotyped 26 microsatellite markers from the pericentromeric region of chromosome 16 in 77 multiplex Crohn disease families that included 179 patients, or 100 independent affected pairs. Nonparametric linkage analyses gave a maximum NPL score of 3.49 around the marker D16S3117. A BAC contig map of 2.5 Mb spanning the genetic region from D16S541 to D16S2623 in chromosome 16q12 was built, consisting of 99 BAC clones and 102 STSs. The results provided a crucial step toward linkage disequilibrium mapping for the identification of the IBD1 gene. The IBD International Genetics Consortium (2001) investigated the proposed linkage to the pericentric region of chromosome 16 (IBD1) and 12p (IBD2; 601458) of Crohn disease susceptibility loci. They found unequivocal evidence of a Crohn disease susceptibility locus on chromosome 16 (maximum lod score 5.79). In this study of 12 microsatellite markers from the 2 chromosomal regions in 613 families they could not replicate the previous evidence for linkage on chromosome 12; however, the results of their study indicated the need to investigate further the potential role of the chromosome 12 locus in susceptibility to ulcerative colitis. Van Heel et al. (2004) obtained genome scan data (markers, significance scores) from 10 separate IBD studies and performed metaanalysis using the genome scan metaanalysis (GSMA) method. The studies comprised 1,952 inflammatory bowel disease, 1,068 Crohn disease, and 457 ulcerative colitis affected relative pairs. Study results were divided into 34-cM chromosomal bins, ranked, weighted by study size, summed across studies and bin-by-bin significance obtained by simulation. The authors identified the chromosome 16 locus (NOD2/CARD15 region) as one meeting suggestive significance for both inflammatory bowel disease and Crohn disease; they also obtained suggestive evidence for linkage to chromosome 2q for ulcerative colitis, inflammatory bowel disease, and Crohn disease. Shugart et al. (2008) performed a high-density SNP genomewide linkage study of 993 multiply affected IBD pedigrees, 25% of which were of Jewish ancestry, and observed the strongest linkage evidence at the IBD1 locus on chromosome 16q12.1, for all CD pedigrees (peak lod score, 4.86). Elding et al. (2011) reanalyzed Crohn disease GWAS data from the Wellcome Trust Case-Control Consortium and National Institute of Diabetes and Digestive and Kidney Diseases and found genetic heterogeneity within the NOD2 locus, as well as independent involvement of a neighboring gene, CYLD (605018). They also found associations on chromosome 16q with the IRF8 (601565) region and the region containing CDH1 (192090) and CDH3 (114021), as well as substantial phenotypic and genetic heterogeneity for CD itself. ### IBD2 on Chromosome 12p13.2-q24.1 See IBD2 (601458) for an ulcerative colitis/Crohn disease susceptibility locus on chromosome 12p13.2-q24.1. ### IBD3 on Chromosome 6p21.3 See IBD3 (604519) for an ulcerative colitis/Crohn disease susceptibility locus on chromosome 6p21.3. ### IBD4 on Chromosome 14q11-q12 See IBD4 (606675) for a Crohn disease susceptibility locus on chromosome 14q11-q12. ### IBD5 on Chromosome 5q31 See IBD5 (606348) for a Crohn disease susceptibility locus on chromosome 5q31. ### IBD6 on Chromosome 19p13 See IBD6 (606674) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 19p13. ### IBD7 on Chromosome 1p36 See IBD7 (605225) for an ulcerative colitis/Crohn disease susceptibility locus on chromosome 1p36. ### IBD8 on Chromosome 16p See IBD8 (606668) for an ulcerative colitis susceptibility locus on chromosome 16p. ### IBD9 on Chromosome 3p26 See IBD9 (608448) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 3p26. ### IBD10 on Chromosome 2q37.1 See IBD10 (611081) for a Crohn disease susceptibility locus on chromosome 2q37.1. This locus is associated with variation in the ATG16L1 gene (610767). ### IBD11 on Chromosome 7q22 See IBD11 (191390) for an ulcerative colitis/Crohn disease susceptibility locus on chromosome 7q22. This locus may be associated with variation in the MUC3A gene (158371). ### IBD12 on Chromosome 3p21 See IBD12 (612241) for an ulcerative colitis/Crohn disease susceptibility locus on chromosome 3p21. This locus may be associated with variation in the MST1 gene (142408) or in the BSN gene (604020). ### IBD13 on Chromosome 7q21.1 See IBD13 (612244) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 7q21.1. This locus is associated with variation in the ABCB1 gene (171050). ### IBD14 on Chromosome 7q32 See IBD14 (612245) for an ulcerative colitis/Crohn disease susceptibility locus on chromosome 7q32. This locus is associated with variation in the IRF5 gene (607218). ### IBD15 on Chromosome 10q21 See IBD15 (612255) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 10q21. ### IBD16 on Chromosome 9q32 See IBD16 (612259) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 9q32. This locus may be associated with variation in the TNFSF15 gene (604052). ### IBD17 on Chromosome 1p31.1 See IBD17 (612261) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 1p31.1. This locus is associated with variation in the IL23R gene (607562). ### IBD18 on Chromosome 5p13.1 See IBD18 (612262) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 5p13.1. ### IBD19 on Chromosome 5q33.1 See IBD19 (612278) for a Crohn disease susceptibility locus on chromosome 5q33.1. ### IBD20 on Chromosome 10q24 See IBD20 (612288) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 10q23-q24. ### IBD21 on Chromosome 18p11 See IBD21 (612354) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 18p11. ### IBD22 on Chromosome 17q21 See IBD22 (612380) for a Crohn disease susceptibility locus on chromosome 17q21. ### IBD23 on Chromosome 1q32 See IBD23 (612381) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 1q32. This locus may be associated with variation in the IL10 gene (124092). ### IBD24 on Chromosome 20q13 See IBD24 (612566) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 20q13. ### IBD25 on Chromosome 21q22 See IBD25 (612567) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 21q22. This locus is associated with mutation in the IL10RB gene (123889). ### IBD26 on Chromosome 12q15 See IBD26 (612639) for an ulcerative colitis susceptibility locus on chromosome 12q15. ### IBD27 on Chromosome 13q13.3 See IBD27 (612796) for a Crohn disease susceptibility locus on chromosome 13q13.3. ### IBD28 on Chromosome 11q23.3 See IBD28 (613148) for a Crohn disease/ulcerative colitis susceptibility locus on chromosome 11q23.3. This locus is associated with mutation in the IL10RA gene (146933). ### IBD29 on Chromosome 1q32 See IBD29 (618077) for a Crohn disease/ulcertative colitis susceptibility locus on chromosome 1q32. IBD29 is associated with variation in the INAVA gene (618051). ### Genomewide Association Studies Satsangi et al. (1996) undertook a systematic screening of the entire genome for identification of susceptibility genes for inflammatory bowel disease involving 186 affected sib pairs from 160 nuclear families. They provided strong evidence for the presence of susceptibility loci for both Crohn disease and ulcerative colitis on chromosomes 3, 7, and 12. The highest lod score (5.47) was obtained with marker D12S83 and lod scores of 3.08 and 2.69 were obtained for markers D7S669 and D3S573, respectively. The data suggested that Crohn disease and ulcerative colitis are closely related but distinct polygenic disorders that share some, but not all, susceptibility genes. Cho et al. (1998) used 377 autosomal markers in a genomewide linkage screen on 297 Crohn disease, ulcerative colitis, or mixed relative pairs from 174 families, of which 37% were Ashkenazi Jewish. They observed evidence for linkage at 3q for all families (multipoint lod score = 2.29), with greatest significance for non-Ashkenazi Caucasians (multipoint lod = 3.39), and at chromosome 1p (multipoint lod = 2.65) for all families. In a limited subset of mixed families, containing 1 member with Crohn disease and another with ulcerative colitis, evidence for linkage was observed on 4q (multipoint lod = 2.76), especially among Ashkenazim. There was confirmatory evidence for a Crohn disease locus, overlapping IBD1, in the pericentromeric region of chromosome 16 (multipoint lod = 1.69), particularly among Ashkenazim; however, positive multipoint lod scores were observed over a very broad region of chromosome 16. Furthermore, evidence for epistasis between IBD1 and chromosome 1p was observed. Thirteen additional loci demonstrated nominal (multipoint lod less than 1.0) evidence for linkage. This screen provided strong evidence that there are several major susceptibility loci contributing to the genetic risk for Crohn disease and ulcerative colitis. In a large European cohort, Hampe et al. (1999) confirmed previously described linkages on chromosomes 16 and 12. Evidence for a previous chromosome 4 linkage was extended. New suggestive evidence for autosomal linkage was observed on chromosomes 1, 6, 10, and 22. A maximum lod score of 1.76 was observed on the X chromosome, for ulcerative colitis, which is consistent with the clinical association of IBD with Turner syndrome. The finding of linkage to 6p was of interest because of the possible contribution of HLA and tumor necrosis factor genes in IBD. In a genomewide search of 158 Canadian sib-pair families, Rioux et al. (2000) identified 3 regions of suggestive linkage (3p, 5q31-q33, and 6p) and 1 region of significant linkage to 19p13 (lod score 4.6). Higher-density mapping in the 5q31-q33 region revealed a locus of genomewide significance (lod score 3.9) that contributed to Crohn disease susceptibility in families with early-onset disease. Both the chromosome 19 and chromosome 5 regions contain numerous genes that are important to the immune and inflammatory systems and that provided good targets for candidate gene studies. Lo and Zheng (2004) applied a novel approach to the analysis of the genome-scan data of Rioux et al. (2000): the backward haplotype transmission association (BHTA) algorithm. They showed that the method has increased efficiency in the use of available data and can lead to novel and surprising results. Dechairo et al. (2001) conducted a replication study on the chromosome 6p region (IBD3) and extension studies on 2 other regions on chromosomes 3p and 7q. Microsatellite markers across each region were genotyped in 284 IBD-affected sib pairs from 234 UK Caucasian families. A nonparametric peak multipoint lod score of 3.04 was detected near D6S291, thus replicating the previous linkage to chromosome 6p. There was almost equal contribution from Crohn disease and ulcerative colitis sib pairs to the linkage. Nominal evidence of linkage was observed at both the 3p and 7q regions, and the largest LOD score for each region was 1.25 and 1.26, respectively, for Crohn disease patients. Van Heel et al. (2003) performed a genomewide scan of 137 Crohn disease affected relative pairs from 112 families. The authors verified linkage of Crohn disease to regions on chromosome 3 (p = 0.0009) and X (p = 0.001) in their cohort. Linkage to chromosome 16 was observed in Crohn disease pairs not possessing common CARD15 mutations (p = 0.0007), approximately 25 cM telomeric of CARD15. Evidence for linkage to chromosome 19 was observed in Crohn disease pairs not possessing CARD15 mutations (p = 0.0001), and in pairs possessing 1 or 2 copies of the IBD5 risk haplotype (p = 0.0005), with significant evidence for genetic heterogeneity and epistasis, respectively. These analyses demonstrated the complex genetic basis to Crohn disease, and that the discovery of disease-causing variants may be used to aid identification of further susceptibility loci in complex diseases. Gaya et al. (2006) reviewed advances in genetics of IBD since the discovery of the CARD15 gene and discussed plausible candidate genes for analysis. The Wellcome Trust Case Control Consortium (2007) described a joint genomewide association study using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals and a shared set of approximately 3,000 controls for each of 7 major diseases. They replicated associations of Crohn disease with CARD15, IL23R (607562), and ATG16L1 (610767), and the association of the risk haplotype represented by IBD5 (606348). They also identified several new associations. Rioux et al. (2007) reported a genomewide association study of ileal Crohn disease and 2 independent replication studies that identified several new regions of association to Crohn disease: in addition to the previously established CARD15 (605956) and IL23R (607562) associations, they identified strong and significantly replicated associations with an intergenic region on 10q21.1 and the rs2241880-coding variant in ATG16L1 (610767). Rioux et al. (2007) also reported strong associations with independent replication to variation in the genomic regions encoding PHOX2B (603851), NCF4 (601488), and a predicted gene on 16q24.1. Cho and Weaver (2007) reviewed the genetics of inflammatory bowel disease, including murine genetic models relevant to IBD. Mathew (2008) reviewed new links to the pathogenesis of CD provided by genomewide association scans; they noted that because most of the SNPs that were genotyped in these scans were selected to tag the genome efficiently rather than for their possible effect on gene function, most CD-associated SNPs are unlikely to be the causal variants that actually confer disease susceptibility. In a metaanalysis of data from 3 studies of Crohn disease involving a total of 3,230 cases and 4,829 controls (Rioux et al., 2007, the Wellcome Trust Case Control Consortium, 2007, and Libioulle et al., 2007) with replication in 3,664 independent cases, Barrett et al. (2008) strongly confirmed 11 previously reported loci, including the NOD2 locus (combined p = 5.10 x 10(-24); case-control odds ratio, 3.99), and identified 21 additional CD susceptibility loci on chromosomes 1, 5, 6, 7, 8, 9, 10, 11, 12, 13, 17, and 21. Glas et al. (2009) attempted to replicate the findings of Rioux et al. (2007) in a European cohort involving 854 German patients with CD, 476 with UC, and 1,503 healthy controls. Of the 7 strongest associations in the earlier study, Glas et al. (2009) confirmed the 3 strongest, e.g., NOD2/CARD15, IL23R, and ATG16L1; however, they found no association between CD and PHOX2B (rs16853571), NCF4 (rs4821544), FAM92B (rs8050910), or rs224136, a SNP in the intergenic region on chromosome 10q21.1, even after subanalysis of 529 German patients with an ileal CD phenotype. Noting that other European studies had shown similar results (e.g., Wellcome Trust Case Control Consortium, 2007, Libioulle et al., 2007, and Barrett et al., 2008), Glas et al. (2009) concluded that these findings were likely due to ethnic differences between the North American and European IBD populations. Franke et al. (2008) conducted a genomewide association study involving 440,794 SNPs genotyped in 1,167 ulcerative colitis patients and 777 healthy controls, followed by testing for replication of the 20 most significantly associated SNPs in 3 independent European case-control panels comprising a total of 1,855 ulcerative colitis patients and 3,091 controls, and confirmed association at chromosomes 6p21, 1p31, and 1q32. They also found a new association at rs12612347 near the ARPC2 locus (604224) on chromosome 2q35 (p = 8.42 x 10(-6) in the initial panel, odds ratio = 1.60; combined p = 2.00 x 10(-4), combined odds ratio 1.18), and noted that Van Heel et al. (2004) had previously obtained suggestive linkage to chromosome 2q for ulcerative colitis, CD, and IBD. Wang et al. (2009) applied pathway analysis using Affymetrix SNP genotype data from the Wellcome Trust Case Control Consortium and uncovered significant association between Crohn disease and the IL12/IL23 pathway (see 161561), harboring 20 genes (p = 8 x 10(-5)). Interestingly, the pathway contains multiple genes (IL12B and JAK2, 147796) or homologs of genes (STAT3, 102582 and CCR6, 601835) that had been identified as genuine susceptibility genes only through metaanalysis of several genomewide association studies. In addition, the pathway contains other susceptibility genes for Crohn disease, including IL18R1 (604494), JUN (165160), IL12RB1 (601604), and TYK2 (176941), which do not reach genomewide significance by single marker association tests. The observed pathway-specific association signal was subsequently replicated in 3 additional genomewide association studies of European and African American ancestry generated on the Illumina HumanHap550 platform. Wang et al. (2009) concluded that examination beyond individual SNP hits, by focusing on genetic networks and pathways, is important to realizing the true power of genomewide association studies. It was notable, however, that examination of the IL12/IL23 pathway failed to detect the well-known association between Crohn disease and NOD2 (605956). In a study involving 2,731 Dutch and Belgian IBD patients, including 1,656 CD patients and 1,075 UC patients, Weersma et al. (2009) found association at rs916977 in the HERC2 gene (605837) on chromosome 15q13.1 for CD (corrected p = 4.48 x 10(-3); odds ratio, 1.39); there was no significant association with UC. In a genomewide association study involving 1,897,764 SNPs in 1,043 German UC cases and 1,703 controls, Franke et al. (2010) found significant association at a nonsynonymous SNP (L333P; rs5771069) in the IL17REL gene (613414) on chromosome 22q13 (p = 4.37 x 10(-5)). Combined analysis, including 6 replication panels involving a total of 2,539 UC cases and 5,428 controls, yielded a Cochran-Mantel-Haenzsel p = 8.81 x 10(-8) (odds ratio, 1.17; 95% CI 1.11-1.25). Gene ontology analyses for the rs5771069 G allele revealed downregulated transcripts including IL17RE (614995), CSF3 (138970), and CD276 (605715). McGovern et al. (2010) combined new data from 2 genomewide association studies of ulcerative colitis involving 266,047 SNPs and performed a metaanalysis with previously published data (Silverberg et al., 2009), thus bringing together a discovery set of 2,693 European UC patients and 6,791 controls; the top results from the metaanalysis were then independently replicated with 2,009 additional European UC cases and 1,580 controls. McGovern et al. (2010) identified 13 loci that were significantly associated with UC (p less than 5 x 10(-8)), including SNPs on chromosome 2p16 and 5p15.3, and confirmed association with 14 previously identified UC susceptibility loci. An analysis of known Crohn disease loci showed that roughly half were shared with UC. Overall, these data implicated approximately 30 loci in ulcerative colitis. Momozawa et al. (2011) used high-throughput sequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn disease in 63 GWAS-identified positional candidate genes, but detected significantly associated low-frequency coding variants only in the IL23R gene (see 607562 and IBD17, 612261). Momozawa et al. (2011) concluded that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn disease. Jostins et al. (2012) expanded on the knowledge of relevant pathways of inflammatory bowel disease by undertaking a metaanalysis of Crohn disease and ulcerative colitis genomewide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. They identified 71 new associations, for a total of 163 IBD loci, that meet genomewide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favoring one allele over the course of human history) and balancing (favoring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. Jostins et al. (2012) also observed considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene coexpression network analysis emphasized this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD. McGovern et al. (2010) performed a GWAS in 896 CD cases and 3,204 healthy Caucasian controls. An association was identified with FUT2 (182100) on chromosome 19q13 (rs602662, p = 3.4 x 10(-5)). Replication was demonstrated in an independent cohort of 1,174 CD cases and 357 controls between the 4 primary FUT2 SNPs and CD (rs602662, combined p = 4.90 x 10(-8)) and also association with FUT2 W143X (182100.0001) (p = 2.6 x 10(-5)). ### Association on 10p11 Franke et al. (2008) investigated 50 previously reported susceptibility loci in a German sample of 1,850 CD patients, 1,103 UC patients, and 1,817 controls, and replicated the association between rs3936503 in the CCNY gene (612786) on chromosome 10p11.2 for both CD and UC (corrected p = 5.76 x 10(-5) and 8.90 x 10(-5), respectively). In a metaanalysis of data from 3 studies of Crohn disease involving a total of 3,230 cases and 4,829 controls (Rioux et al., 2007, the Wellcome Trust Case Control Consortium, 2007, and Libioulle et al., 2007) with replication in 3,664 independent cases, Barrett et al. (2008) identified a new locus at rs17582416 on chromosome 10p11 (combined p = 1.79 x 10(-9)) in a region containing 3 genes. In a study involving 2,731 Dutch and Belgian IBD patients, including 1,656 CD patients and 1,075 UC patients, Weersma et al. (2009) replicated association at rs3936503 for CD (corrected p = 8.36 x 10(-3); odds ratio, 1.31) but did not find significant association with UC. Combined analysis with data from the Wellcome Trust Case Control Consortium (2007) yielded a p of 1.46 x 10(-8). Anderson et al. (2009) analyzed 45 SNPs tagging 29 CD-associated loci in 2,527 UC cases and 4,070 controls and found association at chromosome 10p11 with rs17582416 (p = 4.27 x 10(-4)). Molecular Genetics ### Association with NOD2/CARD15 on Chromosome 16q12 Using a positional cloning strategy based on linkage analysis followed by linkage disequilibrium mapping, Hugot et al. (2001) identified 3 independent mutations in the NOD2 gene that were associated with Crohn disease. They determined that the relative risk of Crohn disease for individuals who were heterozygous, homozygous, or compound heterozygous for the identified NOD2 mutations was 3-fold, 38-fold, and 44-fold higher than for normal controls, respectively. Raelson et al. (2007) performed a genomewide association study in 477 parent-proband trios with Crohn disease from the Quebec Founder Population and tested for replication in 2 independent German samples. They confirmed 3 of the most replicated loci, NOD2, IBD5, and IL23R, and replicated a previously reported region on chromosome 3p21.3. Rivas et al. (2011) used pooled next-generation sequencing to study 56 genes from regions associated with Crohn disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in 9 independent case-control series (16,054 Crohn disease cases, 12,153 ulcerative colitis cases, and 17,575 healthy controls), they identified 4 additional independent risk factors in NOD2. ### Crohn Disease-Associated Growth Failure Crohn disease inhibits growth in up to one-third of affected children. Sawczenko et al. (2005) hypothesized that IL6 (147620) on chromosome 7p21, induced by intestinal inflammation, retards growth and suppresses IGF1 (147440). They treated rats with trinitrobenzenesulfonic acid-induced colitis with anti-IL6 and found that nutrient intake and inflammation did not decrease, but linear growth was restored and plasma and hepatic Igf1 levels increased. Sawczenko et al. (2005) suggested that, in humans, Crohn disease-associated growth failure would vary with the genotype at the IL6 -174 G/C promoter polymorphism (147620.0001). They found that English and Swedish children with Crohn disease and the -174 GG genotype were more growth retarded at diagnosis and had higher levels of the IL6-induced inflammatory marker C-reactive protein (CRP; 123260) than children with GC or CC genotypes. After corticosteroid or enteral feeding treatment, CRP levels decreased significantly and became comparable to those in children with GC or CC genotypes. Sawczenko et al. (2005) concluded that IL6 -174 genotype mediates growth failure in Crohn disease. ### Associations Pending Confirmation Polymorphism in the AGT gene (106150.0002) on chromosome 1q42-q43 has been associated with Crohn disease. In 1,174 Crohn disease cases and 357 controls, McGovern et al. (2010) found association of the FUT2 W143X polymorphism (182100.0001) and CD (p = 2.6 x 10(-5)). McGovern et al. (2010) noted that Barrett et al. (2008) had identified genomewide significant association with CD for SNPs on chromosome 19p13 (combined p = 2.12 x 10(-9)). The FUT2 gene product, alpha-(1,2)fucosyltransferase, regulates the expression of the H antigen, a precursor of the blood group A and B antigens, on the gastrointestinal mucosa. About 20% of Caucasians are nonsecretors who do not express ABO antigens in saliva as a result of homozygosity for the FUT2 W143X allele. McGovern et al. (2010) concluded that FUT2 may play a role in CD susceptibility and highlighted the role of the mucus layer in the development of CD. Mwantembe et al. (2001) noted that IBD is more prevalent in South African whites than in blacks, a pattern observed elsewhere as well. By restriction enzyme and linkage disequilibrium analysis of IL1B (147720) on chromosome 2q14, IL1RA (147810), and IL1RN (147679) polymorphisms, Mwantembe et al. (2001) determined that a mutant IL1B allele (Taq-) was significantly more common in white patients than in white controls, whose frequency was similar to black patients and controls. On the other hand, a mutant IL1RA allele (Pst-) was significantly more frequent in blacks than in whites, regardless of disease status. Although other population differences were observed, no other alleles were significantly associated with disease in either group. Plasma IL1RN levels were significantly higher in black patients than in black controls or white patients and controls. Plasma concentrations of the alpha-1 protease inhibitor (PI; 107400), an indicator of inflammation, were significantly higher in both black and white patients than in black and white controls. Mwantembe et al. (2001) concluded that the inflammatory processes leading to IBD may be distinct in the different population groups. Karban et al. (2004) identified 6 nucleotide variants in the NFKB1 gene on chromosome 4q, including a common insertion/deletion promoter polymorphism (-94ins/delATTG). Using the family-based association test and the pedigree disequilibrium test, they observed modest evidence for linkage disequilibrium between the -94delATTG allele and ulcerative colitis in 131 IBD pedigrees with ulcerative colitis offspring (p = 0.047 and p = 0.052, respectively). The -94delATTG association with ulcerative colitis was replicated in a second set of 258 unrelated, non-Jewish ulcerative colitis patients and 653 non-Jewish controls (p = 0.021). Nuclear proteins from normal human colon tissue and colonic cell lines showed significant binding to -94insATTG-containing but not to -94delATTG-containing oligonucleotides. Cells transfected with reporter plasmid constructs containing the -94delATTG allele showed less promoter activity than comparable constructs containing the -94insATTG allele. Borm et al. (2005) confirmed the association in Dutch patients with ulcerative colitis; however, Oliver et al. (2005) and Mirza et al. (2005) found no association between the -94delATTG allele and ulcerative colitis in Spanish and British ulcerative colitis patients, respectively. The NOD1 gene (605980), on chromosome 7p15-p14, encodes an intracellular bacterial pathogen-associated molecular pattern receptor that is closely related to NOD2 (605956). McGovern et al. (2005) identified strong association between haplotypes in the terminal exons of NOD1 and IBD (multiallelic p = 0.0000003) in a panel of 556 IBD trios. The deletion allele of a complex functional NOD1 indel polymorphism (ND1+326561; partially identified as rs6958571) was significantly associated with early-onset IBD (p = 0.0003) in unrelated cases and controls of 2 independent populations. Defensins are endogenous antimicrobial peptides that protect the intestinal mucosa against bacterial invasion. DNA copy number of the beta-defensin gene cluster on 8p23.1 is highly polymorphic, and evidence has been presented suggesting that low copy number of the beta-defensin-2 gene (602215) predisposes to Crohn disease of the colon (Fellermann et al., 2006). In a panel of 1,182 individuals with Crohn disease and 2,024 controls, Parkes et al. (2007) analyzed 37 SNPs from 31 distinct loci that were associated at p values of less than 10(-5) in the Wellcome Trust Case Control Consortium (2007) dataset and obtained replication for multiple loci, including the NKX2C (606727), PTPN2 (176887), and IL12B (161561) genes and the 'gene desert' on chromosome 1q. In a 3-stage study involving a total of 1,851 patients with IBD and 1,936 controls, Zhernakova et al. (2008) analyzed 85 genes located in 74 genomic regions and found strong association for both Crohn disease and ulcerative colitis with rs917997 (uncorrected combined p = 1.9 x 10(-8)), a SNP located in an extended haplotype block on chromosome 2q11-2q12 that includes 4 genes: IL1RL1 (601203), IL18R1 (604494), IL18RAP (604509), and SLC9A4 (600531). In addition, the authors found an association for Crohn disease and ulcerative colitis with rs10870077 (uncorrected combined p = 3.25 x 10(-5)), located in an extended haplotype block on chromosome 9q34.3 that encompasses multiple genes, including the functional candidates CARD9 (607212), GPSM1 (609491), and SDCCAG3. Martinez et al. (2008) genotyped 700 Spanish patients with inflammatory bowel disease and 723 ethnically matched controls for a SNP in the STAT4 gene (rs7574865) and found an association with IBD (p = 0.006; odds ratio, 1.29). In a 2-stage genomewide association and replication study involving a total of 1,384 Japanese patients with ulcerative colitis (UC) and 3,057 controls, Asano et al. (2009) found significant association (heterogeneity-corrected p = 1.56 x 10(-12)) between UC and a nonsynonymous SNP (rs1801274) in the FCGR2A gene (H121R; 146790.0001). The authors noted that the H131 variant was the susceptibility allele for UC, a reversal of previous associations observed between R131 and other autoimmune diseases. Villani et al. (2009) used a candidate gene approach to identify a set of SNPs located in a predicted regulatory region on chromosome 1q44 downstream of NLRP3 (606416) that are associated with Crohn disease. The associations were consistently replicated in 4 sample sets from individuals of European descent. In the combined analysis of all samples (710 father-mother-child trios, 239 cases, and 107 controls), these SNPs were strongly associated with risk of Crohn disease (P combined = 3.49 x 10(-9), odds ratio = 1.78, confidence interval = 1.47-2.16 for rs10733113). In addition, Villani et al. (2009) observed significant associations between SNPs in the associated regions and NLRP3 expression and IL1-beta (IL1B; 147720) production. Since mutations in NLRP3 are responsible for 3 rare autoinflammatory disorders, these results suggested that the NLRP3 region is also implicated in the susceptibility of more common inflammatory diseases such as Crohn disease. In 2 independent samples of healthy donors, Villani et al. (2009) also found that the risk allele of rs6672995 (G) was associated with a decrease in LPS-induced IL1-beta production, and the risk allele of rs4353135 (T) was associated with a decrease in baseline NLRP3 expression. All 3 SNPs in the associated 5.3-kb region influence NLRP3 at both the gene expression and functional levels. Iliev et al. (2012) compared a group with medically refractory ulcerative colitis who required colectomy with a group of ulcerative colitis patients who did not, and found an association of CLEC7A rs2078178 in patients with medically refractory ulcerative colitis (logistic regression, p = 0.007). Notably, a 2-marker haplotype, rs2078178 to rs16910631, was more strongly associated with medically refractory ulcerative colitis (AG haplotype: logistic regression, p = 0.00013, and Fisher's test, p = 0.0005), a shorter time to surgery, and thus with a more severe ulcerative colitis. Compared with healthy controls, the haplotype was strongly associated with medically refractory ulcerative colitis and not with nonmedically refractory ulcerative colitis, further consistent with the idea that the haplotype is associated with severe disease. Rivas et al. (2011) used pooled next-generation sequencing to study 56 genes from regions associated with Crohn disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in 9 independent case-control series (16,054 Crohn disease cases, 12,153 ulcerative colitis cases, and 17,575 healthy controls), they identified a significant association with a protective splice variant in CARD9. CARD9 is associated with both Crohn disease and ulcerative colitis risk, with a common coding variant, rs4077515, creating protein substitution S12N with both alleles of roughly equal frequency, that represents a typical GWAS hit (odds ratio approximately 1.2 in both disorders) (Franke et al., 2010; McGovern et al., 2010). In the pooled sequencing, Rivas et al. (2011) identified a splice site variant in CARD9 that altered the first base after exon 11 in 6 controls and zero cases, suggesting a potentially strong protective effect. Follow-up analyses confirmed a significant association (p less than 10(-16)), with the allele appearing in approximately 0.20% of cases and 0.64% of controls (odds ratio approximately 0.3). Although skipping exon 11 places translation out of frame, Rivas et al. (2011) predicted that the resulting transcript would escape nonsense-mediated decay as premature termination occurs close to the final splice junction in exon 12. Indeed, this hypothetical transcript has been observed in cDNA libraries from spleen, lymph node, and peripheral blood mononuclear cells. Notably, Rivas et al. (2011) pointed out that this rare protective variant occurs on a haplotype carrying the risk allele at rs4077515, indicating not only that the 2 associations are independent but also that the splice variant completely eliminates the risk normally associated with the common haplotype. Because the Crohn disease risk allele at rs4077515 has been associated with higher expression of CARD9, a consistent allelic series may exist if the splice variant is substantially lower or nonfunctional and therefore highly protective. Cao et al. (2015) analyzed immunochip datasets from 33,311 IBD-affected individuals and 33,938 healthy controls from the International Inflammatory Bowel Disease Genetics Consortium and found that 166 cases and 441 controls carried at least 1 copy of the CARD9 IVS11+1G-C splice variant. Conditioning the proportion of cases on the combination of the splice and the S12N variants, Cao et al. (2015) found that individuals with the splice variant were less likely to develop IBD regardless of the presence of the S12N alteration. Rivas et al. (2011) found association of Crohn disease and inflammatory bowel disease with coding variants in IL18RAP (604509), CUL2 (603135), C1ORF106, PTPN22 (600716), and MUC19 (612170). Inflammatory bowel disease, including Crohn disease (CD) and ulcerative colitis (UC), and type 1 diabetes (T1D; see IDDM; 222100) are autoimmune diseases that may share common susceptibility pathways. Wang et al. (2010) examined known susceptibility loci for these diseases in a cohort of 1,689 CD cases, 777 UC cases, 989 T1D cases, and 6,197 shared control subjects of European ancestry. Multiple previously unreported or unconfirmed disease-loci associations were identified, including CD loci (ICOSLG, 605717; TNFSF15, 604052) and T1D loci (TNFAIP3; 191163) that conferred UC risk; UC loci (HERC2, 605837; IL26, 605679) that conferred T1D risk; and UC loci (IL10, 124092; CCNY, 612786) that conferred CD risk. T1D risk alleles residing at the PTPN22, IL27 (608273), IL18RAP, and IL10 loci protected against CD. The strongest risk alleles for T1D within the major histocompatibility complex (MHC) conferred strong protection against CD and UC. The authors suggested that many loci involved in autoimmunity may be under a balancing selection due to antagonistic pleiotropic effects, and variants with opposite effects on different diseases may facilitate the maintenance of common susceptibility alleles in human populations. Fransen et al. (2010) selected SNPs from CD GWAS that showed a correlation to gene expression (cis-expression quantitative trait loci, or eQTLs). Ten such cis-eQTL SNPs were tested for association with CD in 2 independent cohorts of Dutch CD patients (1,539) and healthy controls (2,648). Two cis-eQTL SNPs were associated with CD, rs2298428 in UBE2L3 (603721) (p = 5.22 x 10(-5)) and rs2927488 in BCL3 (109560) (p = 2.94 x 10(-4)). The authors concluded that UBE2L3 and BCL3 are likely novel risk genes for CD, and that eQTL-based selection is a useful approach for identifying risk loci from a moderately sized GWAS. ### Fine Mapping of Associations Huang et al. (2017) reported fine mapping of inflammatory bowel disease-associated loci using high density genotyping in 67,852 individuals. They pinpointed 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. Among the 45 variants, there were 13 protein-coding changes, 3 causing direct disruption of transcription factor binding sites, and 10 resulting in tissue-specific epigenetic marks, with the last category showing enrichment in specific immune cells among associations stronger in Crohn disease, and in gut mucosa among associations stronger in ulcerative colitis. Huang et al. (2017) concluded that high resolution fine mapping in large samples can convert many discoveries from genomewide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms. Animal Model Mouse models of colitis offer an avenue for identifying IBD genes or pathways that may lead to identification of the human orthologs. Targeted mutations in a variety of mouse genes produce colitis. Mice homozygous for a disrupted interleukin-10 gene (Kuhn et al., 1993) supported the hypothesis that a dysregulated immune response to enteric flora can trigger IBD. The severity of the colitis depends on the inbred strain background in which the disrupted gene is placed. The C3H strain is highly susceptible to several experimentally induced forms of IBD, whereas the B6 background is resistant. Hermiston and Gordon (1995) transfected embryonic stem cells with a dominant-negative N-cadherin (CDH2; 114020) mutant under the control of promoters active in small intestinal epithelial cells and introduced them into C57BL/6 blastocysts. Analysis of adult chimeric mice revealed that expression of the mutant along the entire crypt-villus axis, but not in the villus epithelium alone, produced an inflammatory bowel disease resembling Crohn disease. The mutation perturbed proliferation, migration, and death patterns in crypts, leading to adenomas. The model provided insights into cadherin function in an adult organ and the factors underlying inflammatory bowel disease and intestinal neoplasia. Neurath et al. (1996) reported that chronic intestinal inflammation induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) is characterized by a transmural granulomatous colitis that mimics some characteristics of human Crohn disease. They demonstrated that the p65 subunit of transcription factor NF-kappa-B (164014) was strongly activated in TNBS-induced colitis and in colitis of interleukin-10 (IL10; 124092)-deficient mice. They administered a p65 antisense phosphorothioate oligonucleotide to mice intravenously and intrarectally. The p65 antisense treatment abrogated clinical and histologic signs of colitis. The investigators noted that the p65 antisense treatment was more effective in treating TNBS-induced colitis than single or daily administration of glucocorticoids. Neurath et al. (1996) stated that their data provided direct evidence for the involvement of p65 in chronic intestinal inflammation and suggested a potential therapeutic role for p65 antisense oligonucleotides for the treatment of patients with Crohn disease. Farmer et al. (2001) used quantitative trait locus (QTL) analysis to identify modifiers of cytokine deficiency-induced colitis susceptibility. They found a colitogenic susceptibility QTL on mouse chromosome 3 that exacerbated colitis in combination with modifiers contributed from both parental genomes. The complex nature of interactions among loci in this mouse model, coupled with separate deleterious contributions from both parental strains, illustrated why detection of human inflammatory bowel disease linkages has proven to be so difficult. A human ortholog of the mouse chromosome 3 QTL, if one exists, would map to chromosome 4q or 1p in the human. Using semiquantitative RT-PCR analysis, Singh et al. (2003) detected increased expression of Ip10 (CXCL10; 147310) and its receptor, Cxcr3 (300574), in mesenteric lymph nodes and inflamed colons of Il10 -/- mice. The Crohn disease-like colitis in Il10 -/- mice was associated with increased serum amyloid A (SAA; 104750), Il6, and Th1 cytokine levels and weight loss, all of which could be abrogated by anti-Ip10 treatment. Singh et al. (2003) concluded that anti-IP10 treatment can successfully impede development of inflammatory bowel disease, and that SAA levels can reveal the intensity of colitis. Maeda et al. (2005) generated mice with a Nod2 locus harboring the homolog of the most common Crohn disease susceptibility allele, 3020insC (605956.0001), which encodes a truncated protein lacking the last 33 amino acids. Homozygous Nod2 mutant mice were obtained at the expected mendelian ratio, were healthy, and showed no abnormalities of the gastrointestinal tract or other organs. The mutation had no effect on Nod2 mRNA or protein amounts in bone marrow-derived macrophages. Mutant mice exhibited elevated NFKB (164011) activation in response to bacteria-derived muramyl dipeptide and more efficient processing and secretion of the cytokine IL1B. These effects were linked to increased susceptibility to bacteria-induced intestinal inflammation and identified NOD2 as a positive regulator of NFKB activation and IL1B secretion. Mice deficient in Il10 develop spontaneous IBD. Yen et al. (2006) found that mice deficient in both Il10 and Il12 p35 (IL12A; 161560), but not mice deficient in both Il10 and Il23 p19 (IL23A; 605580), developed spontaneous IBD, indicating that IL23, but not IL12, is necessary for chronic intestinal inflammation. Adding recombinant IL23 to T cells from Il10 -/- mice adoptively transferred to T cell-deficient mice accelerated IBD development, which was accompanied by enhanced production of Il6 and Il17 (603149). Blockade of Il6 and Il17 ameliorated IBD. Yen et al. (2006) concluded that IL23 promotes development and expansion of a pathogenic IL6- and IL17-producing memory-activated T-cell population that triggers the inflammatory cascade leading to intestinal inflammation. In a murine model of Crohn disease, Gonzalez-Rey et al. (2006) demonstrated that cortistatin (602784) treatment significantly ameliorated the clinical and histopathologic severity of inflammatory colitis, abrogating weight loss, diarrhea, and inflammation and increasing the survival rate of colitic mice. The therapeutic effect was associated with downregulation of inflammatory and Th1-driven autoimmune responses, including regulation of a wide spectrum of inflammatory mediators. Cortistatin was effective in the treatment of established colitis and in avoiding the recurrence of disease. Gonzalez-Rey et al. (2006) concluded that cortistatin is an antiinflammatory factor capable of deactivating intestinal inflammatory response and restoring mucosal immune tolerance at multiple levels. Using 2 mouse models of Helicobacter hepaticus-induced T-cell-dependent colitis, Kullberg et al. (2006) showed that Il23, but not Il12, was essential for development of maximal intestinal disease. They proposed that IL23 drives both gamma-interferon (IFNG; 147570) and IL17 responses that synergize to trigger severe intestinal inflammation. Nenci et al. (2007) demonstrated that the transcription factor NFKB, a master regulator of proinflammatory responses, functions in gut epithelial cells to control epithelial integrity and the interaction between the mucosal immune system and gut microflora. Intestinal epithelial-specific inhibition of NFKB through conditional ablation of NEMO (300248) or both IKK1 (600664) and IKK2 (603258), IKK subunits essential for NFKB activation, spontaneously caused severe chronic intestinal inflammation in mice. NFKB deficiency led to apoptosis of colonic epithelial cells, impaired expression of antimicrobial peptides, and translocation of bacteria into the mucosa. Concurrently, this epithelial defect triggered a chronic inflammatory response in the colon, initially dominated by innate immune cells but later also involving T lymphocytes. Deficiency of the gene encoding the adaptor protein MyD88 (602170) prevented the development of intestinal inflammation, demonstrating that Toll-like receptor activation by intestinal bacteria is essential for disease pathogenesis in this mouse model. Furthermore, NEMO deficiency sensitized epithelial cells to TNF-induced apoptosis, whereas TNF receptor-1 (TNFR1; 191190) inactivation inhibited intestinal inflammation, demonstrating that TNFR1 signaling is crucial for disease induction. Nenci et al. (2007) concluded that a primary NFKB signaling defect in intestinal epithelial cells disrupts immune homeostasis in the gastrointestinal tract, causing an inflammatory bowel disease-like phenotype. Their results further identified NFKB signaling in the gut epithelium as a critical regulator of epithelial integrity and intestinal immune homeostasis and have important implications for understanding the mechanisms controlling the pathogenesis of human inflammatory bowel disease. History In 25 families with multiple cases of Crohn disease, Hugot et al. (1994) excluded the Crohn disease predisposing locus from the entire chromosome 6 with lod scores less than -2. The locus was excluded from the major histocompatibility complex and from 91% of the chromosome 6 genetic map with lod scores of less than -4. INHERITANCE \- Multifactorial GROWTH Weight \- Weight loss HEAD & NECK Mouth \- Aphthous ulcers (lips, gingiva, buccal mucosa) ABDOMEN Gastrointestinal \- Abdominal pain \- Diarrhea \- Bowel obstruction \- Aphthous ulcers \- Strictures \- Fistulas \- Transmural granulomatous inflammation with 'skip lesions' MISCELLANEOUS \- Genetic heterogeneity \- 5-10% of patients have a first degree relative with IBD (Crohn or ulcerative colitis) \- 35% of cases involve ileum only (ileitis), 45% of cases involve ileum and colon (ileocolitis), 20% of cases involve colon alone - rectum spared (granulomatous colitis) MOLECULAR BASIS \- Susceptibility conferred by mutation in the nucleotide-binding oligomerization domain protein 2 gene (NOD2, 605956.0001 ) ▲ 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 inhibitors [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	INFLAMMATORY BOWEL DISEASE (CROHN DISEASE) 1	c0010346	2,984	omim	https://www.omim.org/entry/266600	2019-09-22T16:22:49	{"doid": ["0110892"], "mesh": ["D003424"], "omim": ["266600"], "icd-9": ["556.9", "556"], "icd-10": ["K50.90", "K51", "K50", "K50.9", "K51.9"]}
Erdheim-Chester disease (ECD), a non-Langerhans form of histiocytosis, is a multisystemic disease characterized by various manifestations such as skeletal involvement with bone pain, exophthalmos, diabetes insipidus, renal impairment and central nervous system (CNS) and/or cardiovascular involvement. ## Epidemiology Prevalence is unknown. More than 500 cases (<15 pediatric) have been reported since 1930. ## Clinical description ECD usually presents in adults aged 40-60 with a 3:1 male to female ratio. Clinical course varies from asymptomatic to multisystemic, life-threatening forms. The pathognomonic feature of ECD is osteosclerosis of the long bones manifesting as bone pain, mainly affecting the distal lowerlimbs (50% of cases). Pituitary gland infiltration leads to diabetes insipidus and rarely hyperprolactinemia and gonadotropin insufficiency. Constitutional symptoms include fever, weakness and weight loss. Infiltrations in other organs can lead to intracranial hypertension, exophthalmos, papilledema, adrenal insufficiency, xanthelasmas and papulonodular skin lesions. CNS involvement can cause cerebellar and pyramidal syndromes, headaches, seizures, cognitive impairment, cranial nerve palsies and sensory disturbances. A frequent cardiovascular involvement is the ''coated aorta''. Renal arteries can also be involved, leading to reno-vascular hypertension. Pericardial involvement may be complicated by a tamponade. Pseudo-tumoral infiltration of the right atrium is also seen. Dyspnea, due to lung infiltration, has been reported. Pseudo retroperitoneal fibrosis is sometimes complicated by bilateral hydronephrosis. ## Etiology Etiology is unknown but it is thought to be either a reactive or neoplastic disorder. Elevated levels of interferon-alpha (IFN-alpha), interleukin (IL)-7, IL-12, monocyte chemoattractant protein-1 and decreased levels of IL-4 found in ECD patients support an associated systemic immune Th-1 oriented perturbation. Recent findings of mutations in the BRAF proto-oncogene in > 50% of ECD cases clearly add further complexity to the pathophysiology of ECD. ## Diagnostic methods The hallmark histological finding is the xanthogranulomatous or xanthomatous infiltration of tissues with spumous histiocytes. Immunohistochemical staining of a biopsy sample is CD68-positive and CD1a-negative. Bone x-rays usually display bilateral and symmetric cortical osteosclerosis of the long bones, while technetium 99m bone scintigraphy shows almost constantly evidence of symmetric and abnormally strong labeling of the distal ends of the long bones of the lower limbs (and sometimes the upper limbs). Abdominal CT scan may show a ''hairy kidney'' appearance (in 50%) which can be biopsied. ## Differential diagnosis Differential diagnosis includes Langerhans' cell histiocytosis, Rosai-Dorfman disease, Takayasu arteritis, Wegener's granulomatosis, primary hypophysitis, chronic recurrent multifocal osteomyelitis (see these terms), malignancies, neurosarcoidosis, mycobacterial infections and metabolic disorders. ## Management and treatment First line treatment is the administration of standard or pegylated IFN-alpha for all forms of ECD with higher doses (9 million units, 3 times per week) required on a long-term basis for those with CNS and cardiac localizations (if well tolerated). Bisphosphonates may be given to alleviate bone pain. Cladribine can be given to those with orbital involvement that have been resistant to other forms of treatment. Anakinra can improve symptoms of mild forms of ECD in patients where IFN-alpha was ineffective. Recently, infliximab and vemurafenib have been used with some success, this latter drug seeming very promising for patients with a BRAFV600 mutation. PET scans are recommended for the assessment of disease activity. ## Prognosis ECD has a variable prognosis but is overall poorer in those with CNS involvement. Before IFN-alpha, the mean survival after diagnosis was 19.2 months. Nowadays, with IFN-alpha treatments, the mortality rate is only 26%, and 5-year survival is 68%. [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 inhibitors [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	Erdheim-Chester disease	c0878675	2,985	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=35687	2021-01-23T18:38:16	{"gard": ["6369"], "mesh": ["D031249"], "umls": ["C0878675"], "icd-10": ["D76.3"]}
Myxopapillary ependymoma (MEPN) describes a slow growing ependymoma located almost exclusively in the conus medullaris-cauda equina-filum terminale region of the spinal cord, presenting in all age groups, and manifesting with variable symptoms such as neck pain, vomiting and unsteady gait and metastasis. It has a more aggressive disease course and is seen in the pediatric population. [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 inhibitors [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	Myxopapillary ependymoma	c0205769	2,986	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=251643	2021-01-23T16:59:13	{"gard": ["10633"], "mesh": ["D004806"], "umls": ["C0205769"], "icd-10": ["D43.2"]}
Hypochondroplasia is a form of skeletal disease characterized by very short stature. Hypochondroplasia is similar to achondroplasia, but the features tend to be milder. People with hypochondroplasia usually have very short stature, large head, accentuated lordosis, short arms and legs, and broad, short hands and feet. Other features include a limited range of motion in the elbows, lordosis, and bowed legs. Uncommon symptoms may include learning difficulties and convulsions. Hypochondroplasia is caused by mutations in the FGFR3 gene and is inherited in an autosomal dominant fashion. Treatment is symptomatic and may include surgery (laminectomy and decompression) to treat lumbar (low back) spinal stenosis (nerve compression caused by the the spine defects), physical therapy, and medication. Trials of growth hormone treatment in hypochondroplasia have shown good results in a few cases. [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 inhibitors [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	Hypochondroplasia	c0410529	2,987	gard	https://rarediseases.info.nih.gov/diseases/6724/hypochondroplasia	2021-01-18T17:59:53	{"mesh": ["C562937"], "omim": ["146000"], "umls": ["C0410529"], "orphanet": ["429"], "synonyms": ["HCH"]}
Carcinoma in situ Other namesin situ neoplasm SpecialtyOncology Carcinoma in situ (CIS) is a group of abnormal cells.[1][2] While they are a form of neoplasm,[3] there is disagreement over whether CIS should be classified as cancer. This controversy also depends on the exact CIS in question (i.e. cervical, skin, breast). Some authors do not classify them as cancer, however, recognizing that they can potentially become cancer.[1] Others classify certain types as a non-invasive form of cancer.[4][5] The term "pre-cancer" has also been used. These abnormal cells grow in their normal place, thus "in situ" (from Latin for "in its place"). For example, carcinoma in situ of the skin, also called Bowen's disease, is the accumulation of dysplastic epidermal cells within the epidermis only, that has failed to penetrate into the deeper dermis. For this reason, CIS will usually not form a tumor. Rather, the lesion is flat (in the skin, cervix, etc.) or follows the existing architecture of the organ (in the breast, lung, etc.). Exceptions include CIS of the colon (polyps), the bladder (preinvasive papillary cancer), or the breast (ductal carcinoma in situ or lobular carcinoma in situ). Many forms of CIS have a high probability of progression into cancer,[6] and therefore removal may be recommended; however, progression of CIS is known to be highly variable and not all CIS becomes invasive cancer. In the TNM classification, carcinoma in situ is reported as TisN0M0 (stage 0).[7] ## Contents * 1 Terminology * 2 Examples * 3 Treatment * 4 References * 5 External links ## Terminology[edit] These terms are related since they represent the steps of the progression toward cancer: * Dysplasia is the earliest form of precancerous lesion recognizable in a biopsy. Dysplasia can be low-grade or high-grade. High-grade dysplasia may also be referred to as carcinoma in situ. * Invasive carcinoma, usually simply called cancer, has the potential to invade and spread to surrounding tissues and structures, and may eventually be lethal. ## Examples[edit] High-grade dysplasia (carcinoma in situ) in the uterine cervix: The abnormal epithelium is extending into a mucous gland to the left of center. This disease can progress to invasive cancer (squamous cell carcinoma) of the cervix. * Cervical squamous intraepithelial lesion (SIL), previously called cervical intraepithelial neoplasia (CIN), is a form of dysplasia that can progress to cervical cancer. The term carcinoma in situ may be used interchangeably with high-grade SIL.[8] * Ductal carcinoma in situ of the breast is the most common precancer in women. * Bowen's disease is a squamous carcinoma in situ of the skin. * Colon polyps often contain areas of CIS that will almost always transform into colon cancer if left untreated. * High-grade prostatic intraepithelial neoplasia is equivalent to CIS of the prostate. * Bronchioloalveolar carcinoma (BAC) of the lung is the only form of CIS that can kill directly because, in rare cases (the "pneumonic form"), it expands greatly and fills the lungs, preventing breathing and causing other dire effects on the host. Thus, the pneumonic form of BAC is a true malignant entity, but is not "invasive" in the classical sense. For this reason, it is considered a form of CIS by pathologists, but not by oncologists or surgeons, and inclusion of this form of cancer among the types of CIS is controversial. ## Treatment[edit] Carcinoma in situ is, by definition, a localized phenomenon, with no potential for metastasis unless it progresses into cancer. Therefore, its removal eliminates the risk of subsequent progression into a life-threatening condition. Some forms of CIS (e.g., colon polyps and polypoid tumours of the bladder) can be removed using an endoscope, without conventional surgical resection. Dysplasia of the uterine cervix is removed by excision (cutting it out) or by burning with a laser. Bowen's disease of the skin is removed by excision. Other forms require major surgery, the best known being intraductal carcinoma of the breast (also treated with radiotherapy). ## References[edit] 1. ^ a b Chang, Alfred (2007). Oncology: An Evidence-Based Approach. Springer. p. 162. ISBN 9780387310565. 2. ^ "II Neoplams". World Health Organization. Retrieved 19 June 2014. 3. ^ Organization, World Health (2004). International statistical classification of diseases and related health problems (10. rev., 2. ed.). Geneva: World Health Organization. p. 38. ISBN 9789241546492. 4. ^ J.@Saclarides, ed. by Jonathan A.@Myers, Keith W.@Millikan, Theodore (2008). Common surgical diseases an algorithmic approach to problem solving (2nd rev. ed.). New York: Springer. ISBN 9780387752464.CS1 maint: extra text: authors list (link) 5. ^ Allred, DC (2010). "Ductal carcinoma in situ: terminology, classification, and natural history". Journal of the National Cancer Institute. Monographs. 2010 (41): 134–8. doi:10.1093/jncimonographs/lgq035. PMC 5161057. PMID 20956817. 6. ^ Ridge JA, Glisson BS, Lango MN, et al. "Head and Neck Tumors" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008. 7. ^ "Cancer Staging Fact Sheet". National Cancer Institute. Retrieved June 24, 2014. 8. ^ "Understanding Cervical Changes" (PDF). National Cancer Institute. National Institute of Health. Retrieved 17 June 2014.[permanent dead link] ## External links[edit] Classification D * ICD-O: M8010/2 * MeSH: D002278 * SNOMED CT: 68956006 * v * t * e Overview of tumors, cancer and oncology Conditions Benign tumors * Hyperplasia * Cyst * Pseudocyst * Hamartoma Malignant progression * Dysplasia * Carcinoma in situ * Cancer * Metastasis * Primary tumor * Sentinel lymph node Topography * Head and neck (oral, nasopharyngeal) * Digestive system * Respiratory system * Bone * Skin * Blood * Urogenital * Nervous system * Endocrine system Histology * Carcinoma * Sarcoma * Blastoma * Papilloma * Adenoma Other * Precancerous condition * Paraneoplastic syndrome Staging/grading * TNM * Ann Arbor * Prostate cancer staging * Gleason grading system * Dukes classification Carcinogenesis * Cancer cell * Carcinogen * Tumor suppressor genes/oncogenes * Clonally transmissible cancer * Oncovirus * Carcinogenic bacteria Misc. * Research * Index of oncology articles * History * Cancer pain * Cancer and nausea [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 inhibitors [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	Carcinoma in situ	c0007099	2,988	wikipedia	https://en.wikipedia.org/wiki/Carcinoma_in_situ	2021-01-18T19:09:20	{"mesh": ["D002278"], "umls": ["C0007099"], "wikidata": ["Q1035645"]}
Dermatologic terminology Atrophoderma refers to conditions involving skin atrophy.[1] Types include: * Follicular atrophoderma * Linear atrophoderma of Moulin * Atrophoderma of Pasini and Pierini ## References[edit] 1. ^ "Atrophoderma" at Dorland's Medical Dictionary * v * t * e Cutaneous keratosis, ulcer, atrophy, and necrobiosis Epidermal thickening * keratoderma: Keratoderma climactericum * Paraneoplastic keratoderma * Acrokeratosis paraneoplastica of Bazex * Aquagenic keratoderma * Drug-induced keratoderma * psoriasis * Keratoderma blennorrhagicum * keratosis: Seborrheic keratosis * Clonal seborrheic keratosis * Common seborrheic keratosis * Irritated seborrheic keratosis * Seborrheic keratosis with squamous atypia * Reticulated seborrheic keratosis * Dermatosis papulosa nigra * Keratosis punctata of the palmar creases * other hyperkeratosis: Acanthosis nigricans * Confluent and reticulated papillomatosis * Callus * Ichthyosis acquisita * Arsenical keratosis * Chronic scar keratosis * Hyperkeratosis lenticularis perstans * Hydrocarbon keratosis * Hyperkeratosis of the nipple and areola * Inverted follicular keratosis * Lichenoid keratosis * Multiple minute digitate hyperkeratosis * PUVA keratosis * Reactional keratosis * Stucco keratosis * Thermal keratosis * Viral keratosis * Warty dyskeratoma * Waxy keratosis of childhood * other hypertrophy: Keloid * Hypertrophic scar * Cutis verticis gyrata Necrobiosis/granuloma Necrobiotic/palisading * Granuloma annulare * Perforating * Generalized * Subcutaneous * Granuloma annulare in HIV disease * Localized granuloma annulare * Patch-type granuloma annulare * Necrobiosis lipoidica * Annular elastolytic giant-cell granuloma * Granuloma multiforme * Necrobiotic xanthogranuloma * Palisaded neutrophilic and granulomatous dermatitis * Rheumatoid nodulosis * Interstitial granulomatous dermatitis/Interstitial granulomatous drug reaction Foreign body granuloma * Beryllium granuloma * Mercury granuloma * Silica granuloma * Silicone granuloma * Zirconium granuloma * Soot tattoo * Tattoo * Carbon stain Other/ungrouped * eosinophilic dermatosis * Granuloma faciale Dermis/ localized CTD Cutaneous lupus erythematosus * chronic: Discoid * Panniculitis * subacute: Neonatal * ungrouped: Chilblain * Lupus erythematosus–lichen planus overlap syndrome * Tumid * Verrucous * Rowell's syndrome Scleroderma/ Morphea * Localized scleroderma * Localized morphea * Morphea–lichen sclerosus et atrophicus overlap * Generalized morphea * Atrophoderma of Pasini and Pierini * Pansclerotic morphea * Morphea profunda * Linear scleroderma Atrophic/ atrophoderma * Lichen sclerosus * Anetoderma * Schweninger–Buzzi anetoderma * Jadassohn–Pellizzari anetoderma * Atrophoderma of Pasini and Pierini * Acrodermatitis chronica atrophicans * Semicircular lipoatrophy * Follicular atrophoderma * Linear atrophoderma of Moulin Perforating * Kyrle disease * Reactive perforating collagenosis * Elastosis perforans serpiginosa * Perforating folliculitis * Acquired perforating dermatosis Skin ulcer * Pyoderma gangrenosum Other * Calcinosis cutis * Sclerodactyly * Poikiloderma vasculare atrophicans * Ainhum/Pseudo-ainhum 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 inhibitors [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	Atrophoderma	c0151514	2,989	wikipedia	https://en.wikipedia.org/wiki/Atrophoderma	2021-01-18T18:58:34	{"wikidata": ["Q4072263"]}
Inherited isolated adrenal insufficiency due to partial CYP11A1 deficiency is a rare, genetic, chronic, primary adrenal insufficiency disorder, due to partial loss-of-function CYP11A1 mutations, characterized by early-onset adrenal insufficiency without associated abnormal external male genitalia. Patients present with signs of adrenal crisis, including electrolite abnormalities, severe weakness, recurrent vomiting and seizures. Ultrasound reveals absent (or very small) adrenal glands. [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 inhibitors [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	Inherited isolated adrenal insufficiency due to partial CYP11A1 deficiency	c4707238	2,990	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=289548	2021-01-23T17:42:04	{"icd-10": ["E27.1"]}
In psychiatry, complicated grief disorder (CGD) is a proposed disorder for those who are significantly and functionally impaired by prolonged grief symptoms for at least twelve months after the bereavement.[1] It is distinguished from non-impairing grief[2] and other disorders (such as major depressive disorder[3][4][5][6][7][8] and posttraumatic stress disorder).[4][5][6][9][10] This disorder has been reviewed by the DSM-5 work groups, who have decided that it be called Persistent complex bereavement disorder and placed it in the chapter on Conditions for Further Study in the new DSM-5.[11] ## Contents * 1 Description * 1.1 Symptoms * 1.2 Causes and predictors * 1.3 Consequences * 2 Incidence * 3 Treatment * 3.1 Complicated grief therapy (CGT) * 4 CGD and bereavement-related adjustment disorder * 5 Ethical considerations * 5.1 Medicalizing (or misdiagnosing) normal grief * 5.2 Cultural norms for grief * 6 See also * 7 References * 8 Further reading * 9 External links ## Description[edit] Complicated grief is considered when an individual’s ability to resume normal activities and responsibilities is continually disrupted beyond six months of bereavement. Six months is considered to be the appropriate point of CGD consideration, since studies show that most people are able to integrate bereavement into their lives by this time.[12][13][14][15][16] ### Symptoms[edit] The symptoms of complicated grief are mentioned in the most-recently proposed diagnostic criteria; they include maladaptive thoughts and behaviors related to the death or the deceased, continuous emotional dysregulation about the death, social isolation and suicidal ideation.[17] Central to complicated grief is the presence of yearning.[1] ### Causes and predictors[edit] Although more research is needed to determine the multiple pathways to complicated grief disorder, preexisting conditions (such as major depression, PTSD, and sleep disorders) are thought to exacerbate the interruption of the natural healing process.[17] There are some known predictive characteristics for CGD.[17] An individual is at increased risk for CGD if they are: * Female[5][18] and Age of 61 or older [19] * Pessimistic[20][21] * Previously diagnosed with a mood disorder[4][6] * Low self-reported social support[22] * An insecure attachment[23][24][25][26][27] * High stress[22] * A positive caregiving experience and dependency on the deceased[28][29][30] * Have had an early pregnancy loss (miscarriage)[31][32] * Monthly income below €1250[19] ### Consequences[edit] Untreated CGD has clinically significant consequences. A high level of impairment can be pervasive,[3][4][6][10][18][33][34][35][36][37][38][39][40] including destructive thoughts and behaviors (such as substance abuse).[16][41] CGD may worsen the course of preexisting disorders and contribute to the development of new ones.[42][43] ## Incidence[edit] CGD is an atypical grief response, occurring only in a minority of the bereaved population.[16][24] It is considered more common in those experiencing disasters,[5][18][44][45] violence,[46][47][48][49] the loss of a child,[50][51][52] and the loss of a spouse.[19][53] It has also been found in family members (or friends) of: * Patients with life-threatening illnesses[28][54][55][56] * Suicides and homicides[48][57] CGD is found to be prevalent cross-culturally in Europe,[20][23][58][59][60][61][62][63][64] the Middle East,[44][65] Africa,[66] and Asia.[28][67][68][69][70][71] ## Treatment[edit] CGD is relatively unresponsive to antidepressants[72] or interpersonal psychotherapy;[73] however, recent studies support the use of CG-targeted psychotherapy[54][74][75] (similar to PTSD-targeted psychotherapy). Other methods of psycho-pharmacological treatment are under investigation. ### Complicated grief therapy (CGT)[edit] CGT was developed in 2001 by Shear et al. (2001)[76] and has been researched extensively by its creators and other researchers. CGT identifies the areas of CGD that is impeding the individual to grieve naturally. This is completed through a 16-weekly therapy session. These sessions are based on seven principles that help the individual understand and accept their grief, manage and monitor symptoms, think about the future, reconnect with others, tell the death story, learn to live with reminders, and connect with memories. [77] This treatment has been found to show greater response rates and faster response times compared to interpersonal psychotherapy for CGD. [78] ## CGD and bereavement-related adjustment disorder[edit] Although the DSM-5 work groups have suggested using "adjustment disorder, specified as bereavement-related" to diagnose complicated grief, opposing opinions contend that this does not fit the nature of CGD and is an inappropriate diagnosis for those suffering from CGD.[17][79] The DSM-5 has now included Persistent complex bereavement disorder as a diagnosis under conditions for further study. [1] ## Ethical considerations[edit] ### Medicalizing (or misdiagnosing) normal grief[edit] Following the DSM-5 work groups’ recommendation to remove the bereavement-exclusionary criteria,[80] there is some concern that the addition of CGD may increase the possibility of medicalizing the grieving process. However, proponents of CGD claim that with proper clinical assessment only those with abnormally incapacitating levels of grief will receive this diagnosis and benefit from treatment. Furthermore, despite the possibility of diagnosis-related stigma the clinical necessity for treatment is a priority for those suffering from CGD.[17] ### Cultural norms for grief[edit] An individual’s culture plays a large role in determining an inappropriate pattern of grief, and it is necessary to consider cultural norms before reaching a CGD diagnosis.[17] There are cultural differences in expected emotional levels, their expression and duration; the external symptoms of grief differ in non-Western cultures, presenting increased somatization.[81] ## See also[edit] * Ghost sickness ## References[edit] 1. ^ a b c "Diagnostic and Statistical Manual of Mental Disorders: DSM-5 (5th edition)2014 102 Diagnostic and Statistical Manual of Mental Disorders: DSM-5 (5th edition) Washington, DC American Psychiatric Association 2013 xliv+947 pp. 9780890425541(hbck);9780890425558(pbck) £175 $199 (hbck); £45 $69 (pbck)". Reference Reviews. 28 (3): 36–37. 2014-03-11. doi:10.1108/rr-10-2013-0256. ISSN 0950-4125. 2. ^ O'Connor MF, Wellisch DK, Stanton AL, Eisenberger NI, Irwin MR, Lieberman MD (August 2008). "Craving love? Enduring grief activates brain's reward center". NeuroImage. 42 (2): 969–72. doi:10.1016/j.neuroimage.2008.04.256. PMC 2553561. PMID 18559294. 3. ^ a b Silverman GK, Jacobs SC, Kasl SV, Shear MK, Maciejewski PK, Noaghiul FS, Prigerson HG (July 2000). "Quality of life impairments associated with diagnostic criteria for traumatic grief". Psychological Medicine. 30 (4): 857–62. doi:10.1017/s0033291799002524. PMID 11037094. 4. ^ a b c d Simon NM, Shear KM, Thompson EH, Zalta AK, Perlman C, Reynolds CF, Frank E, Melhem NM, Silowash R (2007). "The prevalence and correlates of psychiatric comorbidity in individuals with complicated grief". Comprehensive Psychiatry. 48 (5): 395–9. doi:10.1016/j.comppsych.2007.05.002. PMID 17707245. 5. ^ a b c d Neria Y, Gross R, Litz B, Maguen S, Insel B, Seirmarco G, Rosenfeld H, Suh EJ, Kishon R, Cook J, Marshall RD (June 2007). "Prevalence and psychological correlates of complicated grief among bereaved adults 2.5-3.5 years after September 11th attacks". Journal of Traumatic Stress. 20 (3): 251–62. doi:10.1002/jts.20223. PMID 17597124. 6. ^ a b c d Melhem NM, Rosales C, Karageorge J, Reynolds CF, Frank E, Shear MK (November 2001). "Comorbidity of axis I disorders in patients with traumatic grief". The Journal of Clinical Psychiatry. 62 (11): 884–7. doi:10.4088/jcp.v62n1108. PMID 11775048. 7. ^ Kersting A, Kroker K, Horstmann J, Baune BT, Hohoff C, Mortensen LS, Neumann LC, Arolt V, Domschke K (2007). "Association of MAO-A variant with complicated grief in major depression". Neuropsychobiology. 56 (4): 191–6. doi:10.1159/000120624. PMID 18337637. S2CID 9857681. 8. ^ Viederman M (January 1995). "Grief: normal and pathological variants". The American Journal of Psychiatry. 152 (1): 1–4. doi:10.1176/ajp.152.1.1. PMID 7802098. 9. ^ Melhem NM, Moritz G, Walker M, Shear MK, Brent D (April 2007). "Phenomenology and correlates of complicated grief in children and adolescents". Journal of the American Academy of Child and Adolescent Psychiatry. 46 (4): 493–499. doi:10.1097/chi.0b013e31803062a9. PMID 17420684. 10. ^ a b Bonanno GA, Neria Y, Mancini A, Coifman KG, Litz B, Insel B (May 2007). "Is there more to complicated grief than depression and posttraumatic stress disorder? A test of incremental validity". Journal of Abnormal Psychology. 116 (2): 342–51. doi:10.1037/0021-843X.116.2.342. PMID 17516766. 11. ^ Conditions Proposed by Outside Sources \| APA DSM-5 12. ^ Bonanno GA, Wortman CB, Lehman DR, Tweed RG, Haring M, Sonnega J, Carr D, Nesse RM (November 2002). "Resilience to loss and chronic grief: a prospective study from preloss to 18-months postloss". Journal of Personality and Social Psychology. 83 (5): 1150–64. doi:10.1037//0022-3514.83.5.1150. PMID 12416919. 13. ^ DeVaul RA, Zisook S (May 1976). "Psychiatry: unresolved grief. Clinical considerations". Postgraduate Medicine. 59 (5): 267–71. doi:10.1080/00325481.1976.11714374. PMID 1264920. 14. ^ DeVaul RA, Zisook S, Faschingbauer TR (June 1979). "Clinical aspects of grief and bereavement". Primary Care. 6 (2): 391–402. PMID 258819. 15. ^ Zisook S, Shuchter S, Schuckit M (June 1985). "Factors in the persistence of unresolved grief among psychiatric outpatients". Psychosomatics. 26 (6): 497–9, 503. doi:10.1016/S0033-3182(85)72830-7. PMID 4011815. 16. ^ a b c Dopson CC, Harper MB (January 1983). "Unresolved grief in the family". American Family Physician. 27 (1): 207–11. PMID 6823793. 17. ^ a b c d e f Shear MK, Simon N, Wall M, Zisook S, Neimeyer R, Duan N, et al. (February 2011). "Complicated grief and related bereavement issues for DSM-5". Depression and Anxiety. 28 (2): 103–17. doi:10.1002/da.20780. PMC 3075805. PMID 21284063. 18. ^ a b c Shear MK, Jackson CT, Essock SM, et al. Screening for complicated grief among project liberty service recipients 18 months after september 11, 2001. Psychiatr Serv 2006;57: 1291–1297. 19. ^ a b c Kersting A, Brähler E, Glaesmer H, Wagner B (June 2011). "Prevalence of complicated grief in a representative population-based sample". Journal of Affective Disorders. 131 (1–3): 339–43. doi:10.1016/j.jad.2010.11.032. PMID 21216470. 20. ^ a b Piper WE, McCallum M, Joyce AS, Rosie JS, Ogrodniczuk JS (October 2001). "Patient personality and time-limited group psychotherapy for complicated grief". International Journal of Group Psychotherapy. 51 (4): 525–52. doi:10.1521/ijgp.51.4.525.51307. PMID 11582899. S2CID 27390606. 21. ^ Robinson T, Marwit SJ (September 2006). "An investigation of the relationship of personality, coping, and grief intensity among bereaved mothers". Death Studies. 30 (7): 677–96. doi:10.1080/07481180600776093. PMID 16869060. S2CID 35066443. 22. ^ a b Ott CH (April 2003). "The impact of complicated grief on mental and physical health at various points in the bereavement process". Death Studies. 27 (3): 249–72. doi:10.1080/07481180302887. PMID 12703505. S2CID 22920006. 23. ^ a b Johnson JG, Zhang B, Greer JA, Prigerson HG (January 2007). "Parental control, partner dependency, and complicated grief among widowed adults in the community". The Journal of Nervous and Mental Disease. 195 (1): 26–30. doi:10.1097/01.nmd.0000252009.45915.b2. PMID 17220736. S2CID 45358849. 24. ^ a b Vanderwerker LC, Jacobs SC, Parkes CM, Prigerson HG (February 2006). "An exploration of associations between separation anxiety in childhood and complicated grief in later life". The Journal of Nervous and Mental Disease. 194 (2): 121–3. doi:10.1097/01.nmd.0000198146.28182.d5. PMID 16477190. S2CID 8995920. 25. ^ Prigerson HG, Shear MK, Bierhals AJ, Pilkonis PA, Wolfson L, Hall M, Zonarich DL, Reynolds III CF (1997). "Case histories of traumatic grief". Omega: Journal of Death and Dying. 35 (1): 9–24. doi:10.2190/TDYG-MRB4-H5H8-HHR7. S2CID 144991438. 26. ^ Prigerson HG, Shear MK, Frank E, Beery LC, Silberman R, Prigerson J, Reynolds CF (July 1997). "Traumatic grief: a case of loss-induced trauma". The American Journal of Psychiatry. 154 (7): 1003–9. doi:10.1176/ajp.154.7.1003. PMID 9210753. 27. ^ van Doorn C, Kasl SV, Beery LC, Jacobs SC, Prigerson HG (September 1998). "The influence of marital quality and attachment styles on traumatic grief and depressive symptoms". The Journal of Nervous and Mental Disease. 186 (9): 566–73. doi:10.1097/00005053-199809000-00008. PMID 9741563. 28. ^ a b c Chiu YW, Huang CT, Yin SM, Huang YC, Chien CH, Chuang HY (October 2010). "Determinants of complicated grief in caregivers who cared for terminal cancer patients". Supportive Care in Cancer : Official Journal of the Multinational Association of Supportive Care in Cancer. 18 (10): 1321–7. doi:10.1007/s00520-009-0756-6. PMID 19816716. S2CID 25628986. 29. ^ Schulz R, Boerner K, Shear K, Zhang S, Gitlin LN (August 2006). "Predictors of complicated grief among dementia caregivers: a prospective study of bereavement". The American Journal of Geriatric Psychiatry : Official Journal of the American Association for Geriatric Psychiatry. 14 (8): 650–8. doi:10.1097/01.JGP.0000203178.44894.db. PMID 16861369. 30. ^ Boerner K, Schulz R, Horowitz A (December 2004). "Positive aspects of caregiving and adaptation to bereavement". Psychology and Aging. 19 (4): 668–75. doi:10.1037/0882-7974.19.4.668. PMID 15584791. 31. ^ Kersting A, Wagner B (June 2012). "Complicated grief after perinatal loss". Dialogues in Clinical Neuroscience. 14 (2): 187–94. doi:10.31887/DCNS.2012.14.2/akersting. PMC 3384447. PMID 22754291. 32. ^ "Miscarriage and loss". American Psychological Association. 2017. Retrieved 2017-09-23. 33. ^ Prigerson HG, Bierhals AJ, Kasl SV, Reynolds CF, Shear MK, Day N, Beery LC, Newsom JT, Jacobs S (May 1997). "Traumatic grief as a risk factor for mental and physical morbidity". The American Journal of Psychiatry. 154 (5): 616–23. doi:10.1176/ajp.154.5.616. PMID 9137115. 34. ^ Chen JH, Bierhals AJ, Prigerson HG, Kasl SV, Mazure CM, Jacobs S (March 1999). "Gender differences in the effects of bereavement-related psychological distress in health outcomes". Psychological Medicine. 29 (2): 367–80. doi:10.1017/s0033291798008137. PMID 10218927. 35. ^ Boelen PA, Prigerson HG (December 2007). "The influence of symptoms of prolonged grief disorder, depression, and anxiety on quality of life among bereaved adults: a prospective study". European Archives of Psychiatry and Clinical Neuroscience. 257 (8): 444–52. doi:10.1007/s00406-007-0744-0. PMID 17629728. S2CID 9410388. 36. ^ Ott CH, Lueger RJ, Kelber ST, Prigerson HG (April 2007). "Spousal bereavement in older adults: common, resilient, and chronic grief with defining characteristics". The Journal of Nervous and Mental Disease. 195 (4): 332–41. doi:10.1097/01.nmd.0000243890.93992.1e. PMID 17435484. S2CID 23836831. 37. ^ Lannen PK, Wolfe J, Prigerson HG, Onelov E, Kreicbergs UC (December 2008). "Unresolved grief in a national sample of bereaved parents: impaired mental and physical health 4 to 9 years later". Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 26 (36): 5870–6. doi:10.1200/JCO.2007.14.6738. PMC 2645112. PMID 19029425. 38. ^ Shear K, Monk T, Houck P, Melhem N, Frank E, Reynolds C, Sillowash R (December 2007). "An attachment-based model of complicated grief including the role of avoidance". European Archives of Psychiatry and Clinical Neuroscience. 257 (8): 453–61. doi:10.1007/s00406-007-0745-z. PMC 2806638. PMID 17629727. 39. ^ Cruz M, Scott J, Houck P, Reynolds CF, Frank E, Shear MK (May 2007). "Clinical presentation and treatment outcome of African Americans with complicated grief". Psychiatric Services (Washington, D.C.). 58 (5): 700–2. doi:10.1176/ps.2007.58.5.700. PMC 3579573. PMID 17463353. 40. ^ Zuckoff A, Shear K, Frank E, Daley DC, Seligman K, Silowash R (April 2006). "Treating complicated grief and substance use disorders: a pilot study". Journal of Substance Abuse Treatment. 30 (3): 205–11. doi:10.1016/j.jsat.2005.12.001. PMID 16616164. 41. ^ Hardison HG, Neimeyer RA, Lichstein KL (2005). "Insomnia and complicated grief symptoms in bereaved college students". Behavioral Sleep Medicine. 3 (2): 99–111. doi:10.1207/s15402010bsm0302_4. PMID 15802260. S2CID 23826266. 42. ^ Simon NM, Pollack MH, Fischmann D, Perlman CA, Muriel AC, Moore CW, Nierenberg AA, Shear MK (September 2005). "Complicated grief and its correlates in patients with bipolar disorder". The Journal of Clinical Psychiatry. 66 (9): 1105–10. doi:10.4088/jcp.v66n0903. PMID 16187766. 43. ^ Maytal G, Zalta AK, Thompson E, Chow CW, Perlman C, Ostacher MJ, Pollack MH, Shear K, Simon NM (December 2007). "Complicated grief and impaired sleep in patients with bipolar disorder". Bipolar Disorders. 9 (8): 913–7. doi:10.1111/j.1399-5618.2007.00446.x. PMID 18076543. 44. ^ a b Ghaffari-Nejad A, Ahmadi-Mousavi M, Gandomkar M, Reihani-Kermani H. The prevalence of complicated grief among bam earthquake survivors in iran. Arch Iran Med 2007;10:525–528. 45. ^ Shear, M. K., McLaughlin, K. A., Ghesquiere, A., Gruber, M. J., Sampson, N. A., & Kessler, R. C. (2011). COMPLICATED GRIEF ASSOCIATED WITH HURRICANE KATRINA. Depression and Anxiety, 28(8), 648-657. doi:10.1002/da.20865 46. ^ Mancini A, Prati G, Black S. Self-worth mediates the effects of violent loss on ptsd symptoms. J Trauma Stress 2010, in press. 47. ^ Mitchell AM, Kim Y, Prigerson HG, Mortimer-Stephens M. Complicated grief in survivors of suicide. Crisis 2004;25:12–18. 48. ^ a b Vessier-Batchen M, Douglas D. Coping and complicated grief in survivors of homicide and suicide decedents. J Forensic Nurs 2006;2:25–32. 49. ^ Melhem NM, Day N, Shear MK, et al. Traumatic grief among adolescents exposed to a peer’s suicide. Am J Psychiatry 2004; 161:1411–1416. 50. ^ Keesee NJ, Currier JM, Neimeyer RA. Predictors of grief following the death of one’s child: the contribution of finding meaning. J Clin Psychol 2008;64:1145–1163. 51. ^ Meert KL, Thurston CS, Thomas R. Parental coping and bereavement outcome after the death of a child in the pediatric intensive care unit. Pediatric Critical Care Medicine 2001;2:324–328. 52. ^ Murphy SA. The loss of a child: sudden death and extended illness perspectives. In: Stroebe M, Hansson RO, Schut H, Stroebe W, editors. Handbook of Bereavement Research and Practice: Advances in Theory and Intervention. Washington, DC: American Psychological Association; 2008. 53. ^ Fujisawa D, Miyashita M, Nakajima S, Ito M, Kato M, Kim Y (December 2010). "Prevalence and determinants of complicated grief in general population". Journal of Affective Disorders. 127 (1–3): 352–8. doi:10.1016/j.jad.2010.06.008. PMID 20580096. 54. ^ a b Tomarken A, Holland J, Schachter S, et al. Factors of complicated grief pre-death in caregivers of cancer patients. Psychooncology 2008;17:105–111. 55. ^ Anderson WG, Arnold RM, Angus DC, Bryce CL. Posttraumatic stress and complicated grief in family members of patients in the intensive care unit. J Gen Intern Med 2008;23: 1871–1876. 56. ^ Siegel MD, Hayes E, Vanderwerker LC, et al. Psychiatric illness in the next of kin of patients who die in the intensive care unit. Crit Care Med 2008;36:1722–1728. 57. ^ Currier JM, Holland JM, Neimeyer RA. Sense-making, grief, and the experience of violent loss: toward a mediational model. Death Stud 2006;30:403–428. 58. ^ Forstmeier S, Maercker A. Comparison of two diagnostic systems for complicated grief. J Affect Disord 2007;99:203–211. 59. ^ Kersting A, Kroker K, Horstmann J, et al. Complicated grief in patients with unipolar depression. J Affect Disord 2009;118:201–204. 60. ^ Kersting A, Kroker K, Steinhard J, et al. Complicated grief after traumatic loss: a 14-month follow up study. Eur Arch Psychiatry Clin Neurosci 2007;257:437–443. 61. ^ Langner R, Maercker A. Complicated grief as a stress response disorder: evaluating diagnostic criteria in a german sample. J Psychosom Res 2005;58:235–242. 62. ^ Parkes CM. Symposium on complicated grief. OMEGA 2005–2006;52:1–7. 63. ^ Stroebe M, Schut H. Complicated grief: a conceptual analysis of the field. OMEGA 2005–2006;52:53–70. 64. ^ Morina N, Rudari V, Bleichhardt G, Prigerson HG. Prolonged grief disorder, depression, and posttraumatic stress disorder among bereaved kosovar civilian war survivors: a preliminary investigation. International Journal of Social Psychiatry 2010;56:288–297. 65. ^ Prigerson H, Ahmed I, Silverman GK, et al. Rates and risks of complicated grief among psychiatric clinic patients in karachi, pakistan. Death Stud 2002;26:781–792. 66. ^ Schaal S, Elbert T, Neuner F. Prolonged grief disorder and depression in widows due to the rwandan genocide. Omega (Westport) 2009;59:203–219. 67. ^ Laor N, Wolmer L, Kora M, et al. Posttraumatic, dissociative and grief symptoms in Turkish children exposed to the 1999 earthquakes. J Nerv Ment Dis 2002;190:824–832. 68. ^ Bonanno GA, Papa A, Lalande K, et al. Grief processing and deliberate grief avoidance: a prospective comparison of bereaved spouses and parents in the united states and the People’s Republic of China. J Consult Clin Psychol 2005;73:86–98. 69. ^ Ito M. Complicated grief among general Japanese population: validity and reliability of Brief Grief Questionnaire. Presentation World Congress of Behavioral and Cognitive Therapies, Boston, MA; 2010. 70. ^ Nakajima S, Shirai A, Maki S, et al. Mental health of the families of crime victims and factors related to their recovery. Seishin Shinkeigaku Zasshi 2009;111:423–429. 71. ^ Fujisawa D, Miyashita M, Nakajima S, Ito M, Kato M, Kim Y. Prevalence and determinants of complicated grief in general population. J Affect Disord 2010;127:352–358. 72. ^ Pasternak RE, Reynolds III CF, Schlernitzauer M, et al. Acute open-trial nortriptyline therapy of bereavement-related depression in late life. J Clin Psychiatry 1991;52:307–310. 73. ^ Reynolds 3rd CF, Miller MD, Pasternak RE, et al. Treatment of bereavement-related major depressive episodes in later life: a controlled study of acute and continuation treatment with nortriptyline and interpersonal psychotherapy. Am J Psychiatry 1999;156:202–208. 74. ^ Shear MK, Frank E, Foa E, et al. Traumatic grief treatment: a pilot study. Am J Psychiatry 2001;158:1506–1508. 75. ^ Shear K, Frank E, Houck PR, Reynolds 3rd CF. Treatment of complicated grief: a randomized controlled trial. J Am Med Assoc 2005;293:2601–2608. 76. ^ Shear MK, Frank E, Foa E, Cherry C, Reynolds CF, Vander Bilt J, Masters S (September 2001). "Traumatic grief treatment: a pilot study". The American Journal of Psychiatry. 158 (9): 1506–8. doi:10.1176/appi.ajp.158.9.1506. PMID 11532739. 77. ^ Iglewicz A, Shear MK, Reynolds CF, Simon N, Lebowitz B, Zisook S (January 2020). "Complicated grief therapy for clinicians: An evidence-based protocol for mental health practice". Depression and Anxiety. 37 (1): 90–98. doi:10.1002/da.22965. PMID 31622522. S2CID 204774193. 78. ^ Shear K, Frank E, Houck PR, Reynolds CF (June 2005). "Treatment of complicated grief: a randomized controlled trial". JAMA. 293 (21): 2601–8. doi:10.1001/jama.293.21.2601. PMC 5953417. PMID 15928281. 79. ^ Shear, M. K. (2011). BEREAVEMENT AND THE DSM5. Omega-Journal of Death and Dying, 64(2), 101-118. doi:10.2190 80. ^ Wakefield and First, 2012 Wakefield JC, First MB. Validity of the bereavement exclusion to major depression: does the empirical evidence support the proposal to eliminate the exclusion in DSM-5?. World Psychiatry 2012; 11: 3-10. 81. ^ Horwitz, A. V., & Wakefield, J. C. (2007). The Loss of Sadness: How Psychiatry Transformed Normal Sorrow Into Depressive Disorder. Oxford University Press. ## Further reading[edit] * Tafà M, Cerniglia L, Cimino S, Ballarotto G, Marzilli E, Tambelli R (2018). "Predictive Values of Early Parental Loss and Psychopathological Risk for Physical Problems in Early Adolescents". Frontiers in Psychology. 9: 922. doi:10.3389/fpsyg.2018.00922. PMC 5998644. PMID 29928249. ## External links[edit] * Complicated Grief Program * Is mourning madness? * After a Death, an Extreme Form of Grieving * APA’s Ethical Principles of Psychologists and Code of Conduct [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 inhibitors [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	Complicated grief disorder	None	2,991	wikipedia	https://en.wikipedia.org/wiki/Complicated_grief_disorder	2021-01-18T18:53:56	{"wikidata": ["Q5156653"]}
A number sign (#) is used with this entry because susceptibility to thrombophilia (THPH1) can be conferred by heterozygous mutation in the thrombin gene (F2; 176930) on chromosome 11p11. Description Thrombophilia is a multifactorial disorder of inappropriate clot formation resulting from an interaction of genetic, acquired, and circumstantial predisposing factors. Venous thromboembolism most commonly manifests as deep vein thrombosis, which may progress to pulmonary embolism if the clot dislodges and travels to the lung. Other manifestations include thromboses of the cerebral or visceral veins and recurrent pregnancy loss (summary by Seligsohn and Lubetsky, 2001 and Varga and Kujovich, 2012). ### Genetic Heterogeneity of Thrombophilia THPH2 (188055) is caused by mutation in the F5 gene (612309) on chromosome 1q23; THPH3 (176860) and THPH4 (612304) are both caused by mutation in the PROC gene (612283) on 2q; THPH5 (612336) and THPH6 (614514) are caused by mutation in the PROS1 gene (176880) on 3q11; THPH7 (613118) is caused by mutation in the AT3 gene (107300) on 1q25; THPH8 (300807) is caused by mutation in the F9 gene (300746) on Xq27; THPH9 (612348) is associated with decreased release of tissue plasminogen activator (PLAT; 173370); THPH10 (612356) is caused by mutation in the HCF2 gene (142360) on 22q11; THPH11 (613116) is caused by mutation in the HRG gene (142640) on 3q27; and THPH12 (614486) is associated with variation in the THBD gene (188040) on 20p11. Susceptibility to thrombosis has also been associated with variation in additional genes, including MTHFR (607093.0003); F13B (134580.0003); plasminogen activator inhibitor (SERPINE1; 173360); and several genes encoding fibrinogen (FGA, 134820; FGB, 134830; FGG, 134850). Variation in the SERPINA10 (see 605271.0001), KNG1 (612358) and HABP2 (603924) genes has also been reported. Protection against venous thrombosis is associated with variation in the F13A1 gene (134570) on 6p25. Clinical Features Miyawaki et al. (2012) reported a Japanese family, originating from Yukuhashi in the northern part of the Kyushu islands, with recurrent thrombophilia. The family had originally been reported by Sakai et al. (2001). There were at least 9 affected individuals spanning 3 generations. The proband had onset of recurrent deep vein thrombosis at age 11 years, and many affected family members had onset of deep vein thrombosis or pulmonary embolism before age 50 years. Mapping ### Associations Pending Confirmation In a multistage study using a collection of 5,862 cases with venous thrombosis and 7,112 healthy controls, Morange et al. (2010) identified a locus on chromosome 6p24.1 as a susceptibility locus for venous thrombosis. The C allele of the single-nucleotide polymorphism (SNP) rs169713, which resides 92 kb 5-prime of the HIVEP1 gene (194540), was associated with an increased risk for venous thrombosis, with an odds ratio of 1.2 (95% confidence interval 1.13-1.27, P = 2.86 x 10(-9)). HIVEP1 codes for a protein that participates in the transcriptional regulation of inflammatory target genes by binding specific DNA sequences in their promoter and enhancer regions. Morange et al. (2010) concluded that these results identified a locus involved in venous thrombosis susceptibility that lies outside the traditional coagulation/fibrinolysis pathway. Inheritance In general, thrombophilia is a complex (multifactorial) trait. The genes involved in complex traits are, for the most part, susceptibility genes, not genes that represent the primary cause of the disorder, as in the case of mendelian disorders. Mendelian disorders fit the model which might be referred to as mendelian/garrodian; complex, or multifactorial, traits follow the galtonian/fisherian model. Archibald Garrod's conception of metabolic blocks in a biochemical pathway caused by a mendelizing mutation obtains for the inborn errors of metabolism which he first described and named. Francis Galton (1822-1911) conceived the notion of multiple genetic factors involved in quantitative traits such as intelligence and stature. His disciples argued against the relevance of mendelism in relation to quantitative traits, indeed in relation to most inherited traits. Fisher (1918) showed that the behavior of quantitative traits is consistent with collaboration of multiple genetic factors, each behaving in a mendelian manner. Schafer (1999) discussed venous thrombosis as a chronic and polygenic disease. The transmission pattern of recurrent thrombophilia due to an F2 mutation in the Japanese family reported by Sakai et al. (2001) and Miyawaki et al. (2012) was consistent with autosomal dominant inheritance. Clinical Management Kearon et al. (1999) presented evidence suggesting that patients with a first episode of idiopathic venous embolism should be treated with anticoagulant agents for longer than 3 months. Molecular Genetics Poort et al. (1996) found that a common 20210G-A transition in the 3-prime untranslated region of the prothrombin gene (176930.0009) was associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis. The SNP was found in 18% of probands of families with thrombosis, 6% of unselected consecutive patients with deep vein thrombosis, and 2% of healthy controls. Chamouard et al. (1999) studied the frequency of the factor II 20210G-A mutation in 10 white European patients with idiopathic portal vein thrombosis. They studied 5 women and 5 men; mean age was 50.4 years. The frequency of the 20210G-A mutation was found to be 40% in idiopathic portal vein thrombosis compared with 4.8% in controls or patients with nonidiopathic portal vein thrombosis or deep vein thrombosis. De Stefano et al. (1999) found that patients who were heterozygous for both factor V Leiden (1691G-A; 612309.0001) and prothrombin 20210G-A had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. Patients who were heterozygous for factor V Leiden had a risk of recurrent deep venous thrombosis that was similar to that among patients who had no known mutations in either factor II or factor V. In a Spanish family, Corral et al. (1999) identified 3 subjects homozygous for the 20210A prothrombin mutation who were also heterozygous for factor V Leiden. The combination of the 2 mutations increased the risk of developing venous thrombotic episodes at an earlier age. However, even in association with factor V Leiden, the homozygous condition of the 20210A prothrombin mutation required additional risk factors to induce a thrombotic event. In affected members of a Japanese family with recurrent thrombophilia, Miyawaki et al. (2012) identified a heterozygous mutation in the F2 gene (R596L; 176930.0015). The family had originally been reported by Sakai et al. (2001). In vitro ELISA studies showed that the mutant prothrombin did not form a complex with antithrombin (SERPINC1; 107300) even when heparin was added. A thrombin generation assay showed that the mutant prothrombin activity was lower than wildtype, but its inactivation in reconstituted plasma was exceedingly slow. Miyawaki et al. (2012) concluded that although the procoagulant activity of the R596L mutant prothrombin was somewhat impaired, the antithrombin:thrombin complex was considerably impaired, causing continued facilitation of coagulation. The findings indicated that R596L was a gain-of-function mutation resulting in the resistance to antithrombin, and conferring susceptibility to thrombosis. The mutant variant was termed 'prothrombin Yukuhashi.' INHERITANCE \- Autosomal dominant CARDIOVASCULAR Vascular \- Thrombosis, recurrent \- Deep vein thrombosis RESPIRATORY Lung \- Pulmonary embolism NEUROLOGIC Central Nervous System \- Cerebral thrombosis MISCELLANEOUS \- Onset in childhood MOLECULAR BASIS \- Caused by mutation in the coagulation factor 2 gene (F2, 176930.0009 ) ▲ 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 inhibitors [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	THROMBOPHILIA DUE TO THROMBIN DEFECT	c3160733	2,992	omim	https://www.omim.org/entry/188050	2019-09-22T16:32:38	{"omim": ["188050"], "synonyms": ["Alternative titles", "THROMBOPHILIA DUE TO FACTOR 2 DEFECT", "VENOUS THROMBOSIS", "VENOUS THROMBOEMBOLISM"], "genereviews": ["NBK1148"]}
Pelz et al. (1972) described cholesterol pneumonia in brother and sister, who died at 9.5 and 4 months, respectively. Tachypnea, cough and cyanosis were symptoms. Pulmonary \- Cholesterol pneumonia \- Tachypnea \- Cough Inheritance \- Autosomal recessive Misc \- Death in infancy Skin \- Cyanosis ▲ 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 inhibitors [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	CHOLESTEROL PNEUMONIA	c0549472	2,993	omim	https://www.omim.org/entry/215030	2019-09-22T16:29:44	{"mesh": ["C535937"], "omim": ["215030"]}
Fructose malabsorption Other namesDietary fructose intolerance Chemical structure of fructose SpecialtyEndocrinology Fructose malabsorption, formerly named dietary fructose intolerance (DFI), is a digestive disorder[1] in which absorption of fructose is impaired by deficient fructose carriers in the small intestine's enterocytes. This results in an increased concentration of fructose in the entire intestine. Intolerance to fructose was first identified and reported in 1956.[2] Occurrence in patients identified to be suffering symptoms of irritable bowel syndrome is not higher than occurrence in the normal population. However, due to the similarity in symptoms, patients with fructose malabsorption often fit the profile of those with irritable bowel syndrome.[3] In some cases, fructose malabsorption may be caused by several diseases which cause intestinal damage, such as celiac disease.[4] Fructose malabsorption is not to be confused with hereditary fructose intolerance, a potentially fatal condition in which the liver enzymes that break up fructose are deficient. ## Contents * 1 Symptoms and signs * 2 Pathophysiology * 3 Diagnosis * 4 Treatment * 4.1 Xylose isomerase * 4.2 Diet * 4.2.1 Foods with high fructose content * 4.3 Dietary guidelines for management * 4.3.1 Unfavorable foods (i.e. more fructose than glucose) * 4.3.2 Favorable foods (i.e. fructose equal to or less than glucose) * 5 Food-labeling * 6 Research * 7 See also * 8 References * 9 External links ## Symptoms and signs[edit] Fructose malabsorption may cause gastrointestinal symptoms such as abdominal pain, bloating, flatulence or diarrhea.[5][6] ## Pathophysiology[edit] Fructose is absorbed in the small intestine without help of digestive enzymes. Even in healthy persons, however, only about 25–50 g of fructose per sitting can be properly absorbed. People with fructose malabsorption absorb less than 25 g per sitting.[7] Simultaneous ingestion of fructose and sorbitol seems to increase malabsorption of fructose.[4] Fructose that has not been adequately absorbed is fermented by intestinal bacteria producing hydrogen, carbon dioxide, methane and short-chain fatty acids.[5][8] This abnormal increase in hydrogen may be detectable with the hydrogen breath test.[4] The physiological consequences of fructose malabsorption include increased osmotic load, rapid bacterial fermentation, altered gastrointestinal motility, the formation of mucosal biofilm and altered profile of bacteria. These effects are additive with other short-chain poorly absorbed carbohydrates such as sorbitol. The clinical significance of these events depends upon the response of the bowel to such changes. Some effects of fructose malabsorption are decreased tryptophan,[9] folic acid[10] and zinc in the blood.[10] Restricting dietary intake of free fructose and/or fructans may provide symptom relief in a high proportion of patients with functional gut disorders.[11] ## Diagnosis[edit] The diagnostic test, when used, is similar to that used to diagnose lactose intolerance. It is called a hydrogen breath test and is the method currently used for a clinical diagnosis. Nevertheless, some authors argue this test is not an appropriate diagnostic tool, because a negative result does not exclude a positive response to fructose restriction, implying a lack of sensitivity.[4] ## Treatment[edit] There is no known cure, but an appropriate diet and the enzyme xylose isomerase can help.[4] The ingestion of glucose simultaneously with fructose improves fructose absorption and may prevent the development of symptoms. For example, people may tolerate fruits such as grapefruits or bananas, which contain similar amounts of fructose and glucose, but apples are not tolerated because they contain high levels of fructose and lower levels of glucose.[5] ### Xylose isomerase[edit] Xylose isomerase acts to convert fructose sugars into glucose. Dietary supplements of xylose isomerase may improve some symptoms of fructose malabsorption, although there is currently only a single scientific study available.[12] ### Diet[edit] Foods that should be avoided by people with fructose malabsorption include: * Foods and beverages containing greater than 0.5 g fructose in excess of glucose per 100 g and greater than 0.2 g of fructans per serving should be avoided. Foods with >3 g of fructose per serving are termed a 'high fructose load' and possibly present a risk of inducing symptoms. However, the concept of a 'high fructose load' has not been evaluated in terms of its importance in the success of the diet.[13] * Foods with high fructose-to-glucose ratio. Glucose enhances absorption of fructose, so fructose from foods with fructose-to-glucose ratio <1, like white potatoes, are readily absorbed, whereas foods with fructose-to-glucose ratio >1, like apples and pears, are often problematic regardless of the total amount of fructose in the food.[14] * Foods rich in fructans and other fermentable oligo-, di- and mono-saccharides and polyols (FODMAPs), including artichokes, asparagus, leeks, onions, and wheat-containing products, including breads, cakes, biscuits, breakfast cereals, pies, pastas, pizzas, and wheat noodles. * Foods containing sorbitol, present in some diet drinks and foods, and occurring naturally in some stone fruits, or xylitol, present in some berries, and other polyols (sugar alcohols), such as erythritol, mannitol, and other ingredients that end with -tol, commonly added as artificial sweeteners in commercial foods. * Foods containing high fructose corn syrup. Foods with a high glucose content ingested with foods containing excess fructose may help sufferers absorb the excess fructose.[15] The role that fructans play in fructose malabsorption is still under investigation. However, it is recommended that fructan intake for fructose malabsorbers should be kept to less than 0.5 grams/serving,[16] and supplements with inulin and fructooligosaccharide (FOS), both fructans, should be avoided.[16] #### Foods with high fructose content[edit] According to the USDA database,[17] foods with more fructose than glucose include: Food Fructose (grams / 100 grams) Glucose (grams / 100 grams) Sucrose (for reference) 50 50 Apples 5.9 2.4 Pears 6.2 2.8 Fruit juice e.g. Apples, Pears 5–7 2–3 Watermelon 3.4 1.6 Raisins 29.8 27.8 Honey 40.9 35.7 High fructose corn syrup 42–55 42–53 Mango 4.68 2.01 Agave nectar 55.6 12.43 Ginger 1.78 1.22 The USDA food database reveals that many common fruits contain nearly equal amounts of the fructose and glucose, and they do not present problems for those individuals with fructose malabsorption.[18] Some fruits with a greater ratio of fructose than glucose are apples, pears and watermelon, which contain more than twice as much fructose as glucose. Fructose levels in grapes varies depending on ripeness and variety, where unripe grapes contain more glucose. ### Dietary guidelines for management[edit] Researchers at Monash University in Australia developed dietary guidelines[16] for managing fructose malabsorption, particularly for individuals with IBS. #### Unfavorable foods (i.e. more fructose than glucose)[edit] * Fruit – apple, pear, honeydew melon, nashi pear, pawpaw, papaya, quince, star fruit, watermelon; * Dried fruit – apple, currant, date, fig, pear, raisin, sultana; * Fortified wines * Foods containing added sugars, such as agave nectar, some corn syrups, and fruit juice concentrates. #### Favorable foods (i.e. fructose equal to or less than glucose)[edit] The following list of favorable foods was cited in the paper: "Fructose malabsorption and symptoms of Irritable Bowel Syndrome Guidelines for effective dietary management".[16] The fructose and glucose contents of foods listed on the Australian food standards[19] would appear to indicate that most of the listed foods have higher fructose levels. * Stone fruit: apricot, nectarine, peach, plum (caution – these fruits contain sorbitol); * Berry fruit: blackberry, boysenberry, cranberry, raspberry, strawberry, loganberry; * Citrus fruit: kumquat, grapefruit, lemon, lime, mandarin, orange, tangelo; * Other fruits: ripe banana, jackfruit, passion fruit, pineapple, rhubarb, tamarillo. ## Food-labeling[edit] Producers of processed food in most or all countries, including the USA, are not currently required by law to mark foods containing "fructose in excess of glucose". This can cause some surprises and pitfalls for fructose malabsorbers. Foods (such as bread) marked "gluten-free" are usually suitable for fructose malabsorbers, though sufferers need to be careful of gluten-free foods that contain dried fruit or high fructose corn syrup or fructose itself in sugar form. However, fructose malabsorbers do not need to avoid gluten, as those with celiac disease must. Many fructose malabsorbers can eat breads made from rye and corn flour. However, these may contain wheat unless marked "wheat-free" (or "gluten-free") (Note: Rye bread is not gluten-free.) Although often assumed to be an acceptable alternative to wheat, spelt flour is not suitable for sufferers of fructose malabsorption[citation needed], just as it is not appropriate for those with wheat allergies or celiac disease. However, some fructose malabsorbers do not have difficulty with fructans from wheat products while they may have problems with foods that contain excess free fructose.[citation needed] There are many breads on the market that boast having no high fructose corn syrup. In lieu of high fructose corn syrup, however, one may find the production of special breads with a high inulin content, where inulin is a replacement in the baking process for the following: high fructose corn syrup, flour and fat. Because of the caloric reduction, lower fat content, dramatic fiber increase and prebiotic tendencies of the replacement inulin, these breads are considered a healthier alternative to traditionally prepared leavening breads. Though the touted health benefits may exist, sufferers of fructose malabsorption will likely find no difference between these new breads and traditionally prepared breads in alleviating their symptoms because inulin is a fructan, and, again, consumption of fructans should be reduced dramatically in those with fructose malabsorption in an effort to appease symptoms. ## Research[edit] Fructose and fructans are FODMAPs (fermentable oligo-, di- and mono-saccharides and polyols) known to cause gastrointestinal discomfort in susceptible individuals. FODMAPs are not the cause of these disorders,[20] but FODMAPs restriction (a low-FODMAP diet) might help to improve short-term digestive symptoms in adults with irritable bowel syndrome (IBS) and other functional gastrointestinal disorders (FGID).[20][21][22][23] Nevertheless, its long-term follow-up can have negative effects because it causes a detrimental impact on the gut microbiota and metabolome.[22][23][24][25] ## See also[edit] * Hereditary fructose intolerance * Food intolerance * Gastroenterology * Invisible disability ## References[edit] 1. ^ MayoClinic.com 2. ^ Chambers, R.A; Pratt, R.T.C (1956). "Idiosyncrasy to Fructose". The Lancet. 268 (6938): 340. doi:10.1016/S0140-6736(56)92196-1. PMID 13358219. 3. ^ Ledochowski M, et al. (2001). "Fruktosemalabsorption" (PDF). Journal für Ernährungsmedizin (in German). 3 (1): 15–19. 4. ^ a b c d e Berni Canani, Roberto; Pezzella, Vincenza; Amoroso, Antonio; Cozzolino, Tommaso; Di Scala, Carmen; Passariello, Annalisa (2016). "Diagnosing and Treating Intolerance to Carbohydrates in Children". Nutrients. 8 (3): 157. doi:10.3390/nu8030157. PMC 4808885. PMID 26978392. 5. ^ a b c Ebert, Karolin; Witt, Heiko (2016). "Fructose malabsorption". Molecular and Cellular Pediatrics. 3 (1): 10. doi:10.1186/s40348-016-0035-9. PMC 4755956. PMID 26883354. 6. ^ Putkonen L, Yao CK, Gibson PR (July 2013). "Fructose malabsorption syndrome". Curr Opin Clin Nutr Metab Care (Review). 16 (4): 473–7. doi:10.1097/MCO.0b013e328361c556. PMID 23739630. 7. ^ "University of Iowa Hospitals & Clinics". 8. ^ Montalto M, Gallo A, Ojetti V, Gasbarrini A (2013). "Fructose, trehalose and sorbitol malabsorption" (PDF). Eur Rev Med Pharmacol Sci (Review). 17 (Suppl 2): 26–9. PMID 24443064. 9. ^ Ledochowski M, Widner B, Murr C, Sperner-Unterweger B, Fuchs D (2001). "Fructose malabsorption is associated with decreased plasma tryptophan". Scand. J. Gastroenterol. 36 (4): 367–71. CiteSeerX 10.1.1.627.6642. doi:10.1080/003655201300051135. PMID 11336160. 10. ^ a b Ledochowski M, Uberall F, Propst T, Fuchs D (1999). "Fructose malabsorption is associated with lower plasma folic acid concentrations in middle-aged subjects". Clin. Chem. 45 (11): 2013–4. doi:10.1093/clinchem/45.11.2013. PMID 10545075. 11. ^ Gibson, P. R; Newnham, E; Barrett, J. S; Shepherd, S. J; Muir, J. G (2006). "Review article: Fructose malabsorption and the bigger picture". Alimentary Pharmacology & Therapeutics. 25 (4): 349–63. doi:10.1111/j.1365-2036.2006.03186.x. PMID 17217453. 12. ^ Komericki, P.; Akkilic-Materna, M.; Strimitzer, T.; Weyermair, K.; Hammer, H.F.; Aberer, W. (2012). "Oral xylose isomerase decreases breath hydrogen excretion and improves gastrointestinal symptoms in fructose malabsorption — a double-blind, placebo-controlled study". Alimentary Pharmacology & Therapeutics. 36 (10): 980. doi:10.1111/apt.12057. 13. ^ Gibson, Peter R; Shepherd, Susan J (2010). "Evidence-based dietary management of functional gastrointestinal symptoms: The FODMAP approach". Journal of Gastroenterology and Hepatology. 25 (2): 252–8. doi:10.1111/j.1440-1746.2009.06149.x. PMID 20136989. 14. ^ http://www.healthsystem.virginia.edu/internet/digestive-health/nutrition/BarrettArticle.pdf 15. ^ Skoog SM, Bharucha AE (2004). "Dietary fructose and gastrointestinal symptoms: a review" (PDF). Am. J. Gastroenterol. 99 (10): 2046–50. PMID 15447771. 16. ^ a b c d Shepherd SJ, Gibson PR (2006). "Fructose malabsorption and symptoms of irritable bowel syndrome: guidelines for effective dietary management" (PDF). Journal of the American Dietetic Association. 106 (10): 1631–9. doi:10.1016/j.jada.2006.07.010. PMID 17000196. 17. ^ USDA National Nutrient Database Archived 3 March 2015 at the Wayback Machine Release 20, September 2007 18. ^ Sugar Content of Selected Foods: Individual and Total Sugars Archived 7 September 2006 at the Wayback Machine Ruth H. Matthews, Pamela R. Pehrsson, and Mojgan Farhat-Sabet, (1987) U.S.D.A. 19. ^ "NUTTAB 2010 Online Searchable Database". Food Standards Australia New Zealand. Archived from the original on 24 March 2012. Retrieved 7 July 2013. 20. ^ a b Peter R Gibson & Susan J Shepherd (2010). "Evidence-based dietary management of functional gastrointestinal symptoms: The FODMAP approach". Journal of Gastroenterology and Hepatology. 25 (2): 252–258. doi:10.1111/j.1440-1746.2009.06149.x. PMID 20136989. 21. ^ Turco R, Salvatore S, Miele E, Romano C, Marseglia GL, Staiano A (2018). "Does a low FODMAPs diet reduce symptoms of functional abdominal pain disorders? A systematic review in adult and paediatric population, on behalf of Italian Society of Pediatrics". Ital J Pediatr (Systematic Review). 44 (1): 53. doi:10.1186/s13052-018-0495-8. PMC 5952847. PMID 29764491. 22. ^ a b Staudacher HM, Irving PM, Lomer MC, Whelan K (April 2014). "Mechanisms and efficacy of dietary FODMAP restriction in IBS". Nat Rev Gastroenterol Hepatol (Review). 11 (4): 256–66. doi:10.1038/nrgastro.2013.259. PMID 24445613. "An emerging body of research now demonstrates the efficacy of fermentable carbohydrate restriction in IBS. [...] However, further work is urgently needed both to confirm clinical efficacy of fermentable carbohydrate restriction in a variety of clinical subgroups and to fully characterize the effect on the gut microbiota and the colonic environ¬ment. Whether the effect on luminal bifidobacteria is clinically relevant, preventable, or long lasting, needs to be investigated. The influence on nutrient intake, dietary diversity, which might also affect the gut microbiota,137 and quality of life also requires further exploration as does the possible economic effects due to reduced physician contact and need for medication. Although further work is required to confirm its place in IBS and functional bowel disorder clinical pathways, fermentable carbohydrate restriction is an important consideration for future national and international IBS guidelines." 23. ^ a b Rao SS, Yu S, Fedewa A (2015). "Systematic review: dietary fibre and FODMAP-restricted diet in the management of constipation and irritable bowel syndrome". Aliment. Pharmacol. Ther. 41 (12): 1256–70. doi:10.1111/apt.13167. PMID 25903636. 24. ^ Tuck, CJ; Muir, JG; Barrett, JS; Gibson, PR (2014). "Fermentable oligosaccharides, disaccharides, monosaccharides and polyols: role in irritable bowel syndrome". Expert Rev Gastroenterol Hepatol. 8 (7): 819–834. doi:10.1586/17474124.2014.917956. PMID 24830318. 25. ^ Heiman ML, Greenway FL (2016). "A healthy gastrointestinal microbiome is dependent on dietary diversity". Mol Metab (Review). 5 (5): 317–320. doi:10.1016/j.molmet.2016.02.005. PMC 4837298. PMID 27110483. ## External links[edit] Classification D * ICD-10: E74.3 * ICD-9-CM: 271 * OMIM: 138230 * 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 * v * t * e Genetic disorder, membrane: Solute carrier disorders 1-10 * SLC1A3 * Episodic ataxia 6 * SLC2A1 * De Vivo disease * SLC2A5 * Fructose malabsorption * SLC2A10 * Arterial tortuosity syndrome * SLC3A1 * Cystinuria * SLC4A1 * Hereditary spherocytosis 4/Hereditary elliptocytosis 4 * SLC4A11 * Congenital endothelial dystrophy type 2 * Fuchs' dystrophy 4 * SLC5A1 * Glucose-galactose malabsorption * SLC5A2 * Renal glycosuria * SLC5A5 * Thyroid dyshormonogenesis type 1 * SLC6A19 * Hartnup disease * SLC7A7 * Lysinuric protein intolerance * SLC7A9 * Cystinuria 11-20 * SLC11A1 * Crohn's disease * SLC12A3 * Gitelman syndrome * SLC16A1 * HHF7 * SLC16A2 * Allan–Herndon–Dudley syndrome * SLC17A5 * Salla disease * SLC17A8 * DFNA25 21-40 * SLC26A2 * Multiple epiphyseal dysplasia 4 * Achondrogenesis type 1B * Recessive multiple epiphyseal dysplasia * Atelosteogenesis, type II * Diastrophic dysplasia * SLC26A4 * Pendred syndrome * SLC35C1 * CDOG 2C * SLC39A4 * Acrodermatitis enteropathica * SLC40A1 * African iron overload see also solute carrier family * v * t * e Inborn error of carbohydrate metabolism: monosaccharide metabolism disorders Including glycogen storage diseases (GSD) Sucrose, transport (extracellular) Disaccharide catabolism * Congenital alactasia * Sucrose intolerance Monosaccharide transport * Glucose-galactose malabsorption * Inborn errors of renal tubular transport (Renal glycosuria) * Fructose malabsorption Hexose → glucose Monosaccharide catabolism Fructose: * Essential fructosuria * Fructose intolerance Galactose / galactosemia: * GALK deficiency * GALT deficiency/GALE deficiency Glucose ⇄ glycogen Glycogenesis * GSD type 0 (glycogen synthase deficiency) * GSD type IV (Andersen's disease, branching enzyme deficiency) * Adult polyglucosan body disease (APBD) Glycogenolysis Extralysosomal: * GSD type III (Cori's disease, debranching enzyme deficiency) * GSD type VI (Hers' disease, liver glycogen phosphorylase deficiency) * GSD type V (McArdle's disease, myophosphorylase deficiency) * GSD type IX (phosphorylase kinase deficiency) Lysosomal (LSD): * GSD type II (Pompe's disease, glucosidase deficiency) Glucose ⇄ CAC Glycolysis * MODY 2/HHF3 * GSD type VII (Tarui's disease, phosphofructokinase deficiency) * Triosephosphate isomerase deficiency * Pyruvate kinase deficiency Gluconeogenesis * PCD * Fructose bisphosphatase deficiency * GSD type I (von Gierke's disease, glucose 6-phosphatase deficiency) Pentose phosphate pathway * Glucose-6-phosphate dehydrogenase deficiency * Transaldolase deficiency * 6-phosphogluconate dehydrogenase deficiency Other * Hyperoxaluria * Primary hyperoxaluria * Pentosuria * Aldolase A deficiency [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 inhibitors [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	Fructose malabsorption	c1531694	2,994	wikipedia	https://en.wikipedia.org/wiki/Fructose_malabsorption	2021-01-18T19:02:14	{"umls": ["C1531694"], "icd-9": ["271"], "icd-10": ["E74.3"], "wikidata": ["Q1671489"]}
Yokkaichi asthma (四日市ぜんそく, Yokkaichi zensoku) refers to cases of chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema, and bronchial asthma in humans and various environmental changes usually attributed to sulfur dioxide (SO2) emissions which appeared as smog over the city of Yokkaichi in Mie Prefecture, Japan between 1960 and 1972, though other SOx compounds have been proposed. The generally accepted source of the sulfur oxide pollution was the Yokkaichi Kombinato petrochemical processing facilities and refineries built in Yokkaichi between 1959 and 1972 which did not properly desulfurize the high sulfur content in its crude oil. Yokkaichi asthma is considered one of the Four Big Pollution Diseases of Japan and was the subject of Japan's first court case related to pollution.[1][2][3] ## Contents * 1 Industry background * 1.1 Petrochemical Complex No.1 * 1.2 Petrochemical Complex No.2 * 2 Symptoms * 3 Environmental effects * 3.1 Marine life * 3.2 Air quality * 3.3 Soil quality * 4 Cause * 5 Legal action * 6 Other cases * 7 References * 8 External links ## Industry background[edit] In 1899, wealthy Yokkaichi landowner Inaba San'emon transformed Yokkaichi's wetlands into a port for textile exports. Ishihara Industries built an oil refinery in Yokkaichi's remaining marshes in 1937. In 1938, the imperial navy built another oil refinery in Yokkaichi that would later become a target for American air raid bombing during the Pacific War. The oil refineries and a majority of the city were destroyed in 1945.[4] In 1955, the Ministry of International Trade and Industry began its policy to transition Japan's primary fossil fuel source from coal to petroleum, and oil refineries were once again opened in Yokkaichi. The oil used in Yokkaichi was primarily imported from the Middle East, which contained 2% sulfur in sulfur containing compounds, resulting in a white-colored smog developing over the city.[5] ### Petrochemical Complex No.1[edit] To accomplish the goal of the government-issued Petrochem Industry Program - Phase I from 1955, the Daichi Petrochemical Complex, a joint project of Showa Oil and Shell Oil Company, began construction in 1956 around the remnants of World War II naval fuel factories in south Yokkaichi Harbor which were destroyed by bombing before their operation began. The location was convenient because waste could easily be dumped into the ocean and Yokkaichi's port provided a means for easily shipping products.[4][6] Daichi Petrochemical Complex, the first of its kind in Japan, contained an oil refinery, a petrochemical plant, ethylene plant, and a power station when it began operation in 1959.[3] As demand increased, the operation expanded its workday so that production could continue twenty four hours a day.[4] ### Petrochemical Complex No.2[edit] In 1960, the government of Prime Minister Hayato Ikeda accelerated the growth of petrochemical production as part of its goal to double individual incomes of Japanese citizens over a 10-year period. The Petrochemical Industry Program - Phase II began as MITI announced that a second complex was to be constructed on reclaimed land in northern Yokkaichi. During its trial run, the complex broke down and expelled odorous runoff that spurred many complaints by citizens. The second complex went online officially in 1963.[3] ## Symptoms[edit] Beginning shortly after the opening of the first complex in 1959, severe cases of chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema, and bronchial asthma rose quickly among the local inhabitants, particularly in the Isozu and Shiohama districts which were closest to the factories, and among males over 50.[3][7] Other chronic symptoms included sore throat.[2] Symptoms showed some relief when sufferers left areas of high air pollution. By 1964, Isozu Village, which was most affected, had 2.5% of the population exhibiting symptoms.[6][8] A 2008 study by researchers from the Mie University Graduate School of Medicine and the Hiroshima University Natural Science Center for Basic Research and Development indicated a 10- to 20-fold higher mortality rate as a result of COPD and asthma in the affected populations of Yokkaichi versus the general population of Mie Prefecture.[9] Several asthma victims committed suicide, such as Kihira Usaburou, with some writing suicide notes attributing their deaths to the disease.[4] For one 40-year-old Yokkaichi asthma sufferer reported in Respiratory Medicine Case Reports journal, Symptoms showed relief when treated using a vibrating mesh nebulizer.[10] ## Environmental effects[edit] ### Marine life[edit] The fishing industry is considered the first victim of Yokkaichi pollution. Fish caught in Ise Bay as far as five miles from the mouth of Suzuka River developed a bad taste and greasy smell in 1959. Fish sent to Tsukiji, Tokyo were returned to Ise due to complaints, causing local fishermen to petition the government for compensation for their unsaleable fish in 1960.[1] Special Committee of Promotion Council for Ise Bay Industrial Waste Water Pollution Countermeasures was organized by the Mie Prefectural Government in response to the incident and attributed the foul smelling fish and oily water texture to mineral oil in waste water expelled into the bay by nearby petrochemical plants and oil refineries.[3] In 1962 during a factory tour, factory officials interviewed by Research Committee on Pollution founding member Miyamato Ken'ichi maintained despite these findings that the foul smelling fish was due to a sunken ship in Ise bay.[2] ### Air quality[edit] Soot and white smog from the petrochemical plants filled the skies of Yokkaichi, and were the main concern of complaints before Petrochemical Complex No. 2 was constructed in 1963. The air was said to have an offensive odor.[3] Researchers in the Journal of Environmental Health found in 1985 that as air quality decreased, mortality rate for bronchial asthma and chronic bronchitis cases increased.[11] ### Soil quality[edit] A study in 1975 from Mie University in Japan found a significant correlation between the number of Yokkaichi asthma patients and decrease in expected grain yield for May to September summer crops.[12] ## Cause[edit] Sulfur dioxide, a toxic gas found in high concentrations in the air of Yokkaichi and initially believed to be the cause of the asthma cases. All clinical cases of Yokkaichi asthma began after the establishment of the oil refinery and petroleum chemical plants in 1959.[7] Complaints from citizens of offensive odors spurred investigation. Initially, the suspected sources of the odors included SO2, hydrogen sulfide (H2S), methylmercaptan, aldehydes, and other substances found to be leaking from the factories.[3] However, sulfur dioxide emitted from the combustion of high sulfur content oil has typically been attributed as the cause of the disease since the beginning. Despite common belief that SO2 was the main source of the asthma, by investigating sulfur dioxide and sulfur trioxide levels in Yokkaichi and analyzing compound toxicity levels, a study conducted in 1984 from Yokohama National University concluded that respiratory diseases were not a result of sulfur dioxide, but rather due to a titanium oxide manufacturing plant venting concentrated sulfuric acid mists downwind onto populated urban areas. The high concentration of Yokkaichi asthma patients in Isozu Village can be farther accounted for under this conclusion, as the source of sulfur trioxide emissions is 2 kilometers south of the most effected population.[8] A 2001 study by several researchers in the Environmental Management journal confirmed by analyzing the effects of SO2 and SO3 on humans that SO3 was likely the real cause of the asthma. They farther propose that one of the reasons flue-gas desulfurization implementation did not lead to the disappearance of all cases was due to differences in SO2 and SO3 cleanup.[13] ## Legal action[edit] In 1960, those living in Isozu complained to Yokkaichi officials about noise from the factories and sickness caused by the chemicals, but they were ignored. Children were advised by teachers in Mihana Primary School to avoid breathing as much as possible. When the fishing industries in Yokkaichi began to collapse in spring 1960, the government finally issued a 100 million yen settlement that was to be divided up and distributed by Yokkaichi fishing unions. This settlement did nothing about the source of pollution.[4] In August 1960, The Yokkaichi City Environmental Pollution Control Measures Committee was organized by the city of Yokkaichi prompted by farther citizen complaints. The committee found that the Isozu district had six times the SO2 content in air of the rest of Yokkaichi and concluded that the asthma would likely cause an increase in mortality rate.[3] They found that children suffered the most, and that about half of the children in Isozu district suffered from the disease.[4] When the pollution did not stop, angry fishermen from Isozu upset with the government's lack of action attempted to plug an industrial drainpipe belonging to Mie electric company with sandbags. To prevent the fishermen from doing so, the company increased emissions and a fight broke out between those working for the company and the fishermen that had to be defused by local officials. This incident led to investigations in Yokkaichi by the national government.[4] The national government sent out investigators with the issue of the Special Survey Council on Yokkaichi Area Air Pollution in 1963, and they concluded their report in March 1964.[3] Meanwhile, the government offered more compensation to fishermen following findings in 1965. Through the survey council's investigation Yokkaichi became an official target area of the 1968 Soot and Smoke Regulation Law. However, SO2 air pollution did not decrease, most notable through the suicide of confection shop owner Outani Kazuhiko, who wrote a note blaming the bad air for his death.[4] Through this law, taller smokestacks were built, but they simply spread the pollution over a wider area and did not help alleviate the health issues.[3] In 1965, the local government offered more compensation to fishermen following Special Survey Council on Yokkaichi Area Air Pollution findings in what would become the world's first public-relief system for pollution victims.[4] For the first year, this was financed by the local government, but was financed by the national government's treasury in its second year.[9] Isozu district Yokkaichi Asthma sufferers filed a civil suit against companies with ties to Showa Yokkaichi Oil's Petrochemical Complex No. 1 in 1967 which would go on to become Japan's first court trial related to pollution. The trial ended in 1972 in favor of the plaintiffs, ruling that the company had committed negligence.[3] After the trial, the local Yokkaichi government requested that the city be considered a target area for the 1968 Soot and Smoke Regulation Law. The 1968 Air Pollution Control Law led to the implementation of a flue-gas desulfurization processes for all emissions, which gradually led to health improvement in the local populace.[3] ## Other cases[edit] Yokkaichi asthma has been identified in other rapidly industrializing areas in parts of the world, including Mexico City, Singapore, and cities in mainland China like Guangzhou where air pollution caused by smog can lead to chronic asthma.[14][15] Sulfur oxides have also been attributed to causing other Japanese city asthma outbreaks, such as in the Nishiyodogawa industrial district of Osaka, Japan.[16] ## References[edit] 1. ^ a b Yokkaichi Asthma. Environmental Encyclopedia. Retrieved 15 July 2009. 2. ^ a b c Avenell, Simon (2017). Transnational Japan in the Global Environmental Movement. University of Hawaii Press. 3. ^ a b c d e f g h i j k l "Approaches to Air pollution Control (Case Study-1) Yokkaichi City, Mie prefecture". International Center for Environmental Technology Transfer. Retrieved 31 March 2020. 4. ^ a b c d e f g h i Walker, Brett L. (2010). Toxic Archipelago: A history of industrial disease in Japan. University of Washington Press. 5. ^ "Japan's Post-Second World War environmental problems". United Nations University. Retrieved 1 April 2010. 6. ^ a b "Yokkaichi asthma, Japan". Environmental Justice Atlas. Retrieved 29 March 2020. 7. ^ a b Yoshida, Katsumi; Oshima, Hidehiko; Imai, Masayuki (1964). "Air Pollution in Yokkaichi Area with Special Regards to the Problem of 'Yokkaichi-Asthma'". Industrial Health. 2:2 (2): 87–94. doi:10.2486/indhealth.2.87. 8. ^ a b Kitagawa, Tetsuzo (1984). "Cause Analysis of the Yokkaichi Asthma Episode in Japan". Journal of the Air Pollution Control Association. 34:7 (7): 743–746. doi:10.1080/00022470.1984.10465807. PMID 6481002. 9. ^ a b Guo, Peng; Yokoyama, Kazuhito; Suenaga, Masami; Kida, Hirotaka (2008). "Mortality and life expectancy of Yokkaichi Asthma patients, Japan: Late effects of air pollution in 1960–70s". Environmental Health. 7. 8. doi:10.1186/1476-069X-7-8. PMC 2311286. PMID 18302742. 10. ^ Yano, Takeshi; Yonaha, Tetsu; Hidaka, Koutaro; Nagahama, Masumi; Koshida, Tomohiro; Matsuoka, Hiroshi; Taniguchi, Masahiko; Tsuneyoshi, Isao (2016). "A case of severe acute exacerbation of Yokkaichi asthma treated with a vibrating mesh nebulizer". Respiratory Medicine Case Reports. 19: 83–85. doi:10.1016/j.rmcr.2016.08.002. PMC 4982920. PMID 27547723. 11. ^ Masayuki, Imai; Yoshida, Katsumi; Kitabatake, Masayoshi (1986). "Mortality from Asthma and Chronic Bronchitis Associated with Changes in Sulfur Oxides Air Pollution". Archives of Environmental Health. 41 (1): 29–35. doi:10.1080/00039896.1986.9935762. 12. ^ Taniyama, T. (1975). "Characteristics in the growth and grain production of rice plant in air pollution area (Yokkaichi City), and the significance as the indicator plant for monitoring of air pollution". International Congress of Scientists on the Human Environment. 13. ^ Kikuchi, Ryunosuke (2001). "Environmental Management of Sulfur Trioxide Emission: Impact of SO3 on Human Health". Environmental Management. 27 (6): 837–844. doi:10.1007/s002670010192. PMID 11393318. 14. ^ "Asthma on the rise in Asia due to mounting urbanisation, pollution". TerraDaily.com. Retrieved 1 April 2010. 15. ^ "Mexico City's dirty truth". BBC. 11 February 2002. Retrieved 1 April 2010. 16. ^ "Nishiyodogawa in Osaka, air pollution court cases, Japan". Environmental Justice Atlas. Retrieved 31 March 2020. ## External links[edit] * Yoshiro Hoshino, 1992, "Japan's Post-Second World War environmental problems" Ui ed. Industrial pollution in Japan. * Atmospheric Pollution Due to Mobile Sources and Effects on Human Health in Japan * Yoshida et al., 2007, "Epidemiology and Environmental Pollution: A Lesson from Yokkaichi Asthma, Japan" in Willis ed. Progress in Environmental Research. * v * t * e Four Big Pollution Diseases of Japan * Itai-itai disease * Minamata disease * Niigata Minamata disease * Yokkaichi asthma [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 inhibitors [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	Yokkaichi asthma	None	2,995	wikipedia	https://en.wikipedia.org/wiki/Yokkaichi_asthma	2021-01-18T19:10:43	{"wikidata": ["Q8054567"]}
## Description The type of diabetes mellitus called IDDM is a disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. It is a genetically heterogeneous autoimmune disease affecting about 0.3% of Caucasian populations (Todd, 1990). Genetic studies of IDDM have focused on the identification of loci associated with increased susceptibility to this multifactorial phenotype. The classical phenotype of diabetes mellitus is polydipsia, polyphagia, and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. Clinical Features The term diabetes mellitus is not precisely defined and the lack of a consensus on diagnostic criteria has made its genetic analysis difficult. Diabetes mellitus is classified clinically into 2 major forms of the primary illness, insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM; 125853), and secondary forms related to gestation or medical disorders. Appearance of the IDDM phenotype is thought to require a predisposing genetic background and interaction with other environmental factors. Rotter and Rimoin (1978) hypothesized that there are at least 2 forms of IDDM: a B8 (DR3)-associated form characterized by pancreatic autoimmunity, and a B15-associated form characterized by antibody response to exogenous insulin. Interestingly, the DR3 and DR4 alleles seem to have a synergistic effect on the predisposition to IDDM based on the greatly increased risk observed in persons having both the B8 and B15 antigens (Svejgaard and Ryder, 1977). Rotter and Rimoin (1979) hypothesized a combined form. Tolins and Raij (1988) cited clinical and experimental evidence to support the idea that those IDDM patients in whom diabetic nephropathy (see 603933) eventually develops may have a genetic predisposition to essential hypertension. Gambelunghe et al. (2001) noted heterogeneity of the clinical and immunologic features of IDDM in relation to age at clinical onset. Childhood IDDM is characterized by an abrupt onset and ketosis and is associated with HLA-DRB104-DQA10301-DQB10302 and a high frequency of insulin and IA-2 autoantibodies. On the other hand, the so-called latent autoimmune diabetes of the adult (LADA) is a slowly progressive form of adult-onset autoimmune diabetes that is noninsulin-dependent at the time of clinical diagnosis and is characterized by the presence of glutamic acid decarboxylase-65 (GAD65: 138275) autoantibodies and/or islet cell antibodies. Biochemical Features Nepom et al. (1987) studied the mechanism of the exaggerated susceptibility to IDDM in DR3/DR4 heterozygotes, and concluded that its basis is the formation of hybrid molecules of the closely linked DQ-alpha (HLA-DQA1; 146880) and -beta (HLA-DQB1; 604305) chains. The DR-alpha molecules are not polymorphic, and mixed DR alpha-beta dimers would not result in novel HLA molecules. On the other hand, both the alpha and beta chains of DQ are polymorphic, and a DQ alpha-beta dimer composed of transcomplementing chains would be unique to a heterozygous individual and not expressed in either parent. In the mouse, such transcomplementation has been demonstrated structurally, and epitopes newly formed in the resulting hybrid molecules allow for an altered functional immune response different from that of either parent. The human MHC class II molecule encoded by DQA10102/DQB10602 (termed DQ0602) confers strong susceptibility to narcolepsy (161400) but dominant protection against type I diabetes. To elucidate the molecular features underlying these contrasting genetic properties, Siebold et al. (2004) determined the crystal structure of the DQ0602 molecule at 1.8-angstrom resolution. Structural comparisons to homologous DQ molecules with differential disease associations highlighted a previously unrecognized interplay between the volume of the P6 pocket and the specificity of the P9 pocket, which implies that presentation of the expanded peptide repertoire is critical for dominant protection against type I diabetes. In narcolepsy, the volume of the P4 pocket appears central to the susceptibility, suggesting that the presentation of a specific peptide population plays a major role. Other Features Hyperglycemia, the basic metabolic abnormality in IDDM, is caused by abnormally increased gluconeogenesis and insufficient glucose disposal. Ketosis results from the accumulation of free fatty acids and their oxidation. McCorry et al. (2006) found an association between IDDM and idiopathic generalized epilepsy (EIG; 600669) in a population-based survey in the U.K. Among 518 EIG patients aged 15 to 30 years, 7 also had IDDM. In contrast, there were 465 IDDM patients among an age-matched cohort of 150,000 individuals. The findings suggested that the prevalence of IDDM is increased in patients with EIG (odds ratio of 4.4). Pathogenesis Type 1 diabetic patients have diminished responses following T-cell activation. By immunoblot analysis, Nervi et al. (2000) found reduced levels of phosphorylated CD3Z (186780) in IDDM1 patients after T-cell stimulation. Immunoblot, immunoprecipitation, and densitometric analyses revealed significantly reduced LCK expression in unstimulated peripheral blood cells of IDDM1 patients compared to controls. The reduced LCK expression correlated with a lower proliferative response. Very low LCK expression may also correlate with the HLA-DQB10201/0302 (see 604305) genotype. Confocal microscopy demonstrated normal plasma membrane expression of LCK in patients and controls. Downstream signal transducing molecules were not affected in these patients. Kent et al. (2005) examined T cells from pancreatic draining lymph nodes, the site of islet cell-specific self-antigen presentation. They cloned single T cells in a nonbiased manner from pancreatic draining lymph nodes of patients with type I diabetes and from nondiabetic controls. A high degree of T-cell clonal expansion was observed in pancreatic lymph nodes from long-term diabetic patients but not from controls. The oligoclonally expanded T cells from diabetic patients with DR4, a susceptibility allele for type I diabetes, recognized the insulin A 1-15 epitope restricted by DR4. Kent et al. (2005) concluded that their results identified insulin-reactive, clonally expanded T cells from the site of autoinflammatory drainage in long-term type I diabetics, indicating that insulin may indeed be the target antigen causing autoimmune diabetes. Porter and Barrett (2005) reviewed monogenic syndromes of abnormal glucose homeostasis, focusing on 3 mechanisms: insulin resistance, insulin secretion defects, and beta-cell apoptosis. Stechova et al. (2012) reported a family with naturally conceived monozygotic female quadruplets, in which type 1 diabetes was diagnosed in 2 of the quadruplets simultaneously and a third quadruplet was diagnosed as pre-diabetic. All 4 quadruplets were positive for anti-islet cell autoantibodies to GAD65 (138275) and to IA-2 (601773), indicating an ongoing anti-islet autoimmunity in the nondiabetic quadruplets. Serologic examination confirmed that all the quadruplets and their father had recently undergone an enteroviral infection of the EV68-81 serotype. Immunocompetent cells from all family members were characterized by gene expression arrays, immune-cell enumerations, and cytokine-production assays. The microarray data provided evidence that the viral infection and IL27 (608273) and IL9 (146931) cytokine signaling contributed to the onset of T1D in 2 of the quadruplets. Stechova et al. (2012) stated that the propensity of stimulated immunocompetent cells from nondiabetic members of the family to secrete high levels of IFN-alpha (IFNA1; 147660) further corroborated their conclusion. They observed that the number of T-regulatory cells as well as plasmacytoid and/or myeloid dendritic cells was diminished in all family members. Stechova et al. (2012) concluded that this family supported the so-called 'fertile-field' hypothesis proposing that genetic predisposition to anti-islet autoimmunity, if 'fertilized' and precipitated by a viral infection, results in full-blown type 1 diabetes. Inheritance IDDM exhibits 30 to 50% concordance in monozygotic twins, suggesting that the disorder is dependent on environmental factors as well as genes. The average risk to sibs is 6% (Todd, 1990). Recessive, dominant, and multifactorial hypotheses have been advanced, as well as 'susceptibility' hypotheses (Rotter, 1981). Genetic and environmental influences in IDDM were reviewed by Craighead (1978). Usually in genetic disease the most severe form of a disorder shows the clearest genetic basis. It is therefore surprising to find that the genetics of IDDM is less clear than that of NIDDM. Concordance in NIDDM was 100% for identical twins in which the index case had onset of diabetes after age 45 years, and nearly half had a diabetic parent, while discordance was found in half the pairs with earlier onset, few of whom had a family history of diabetes (Tattersall and Pyke, 1972). Nilsson (1964) commented on the difficulties of distinguishing dominant and recessive inheritance when gene frequency is high. He considered autosomal recessive inheritance to be most likely, with a gene frequency of about 0.30 and a lifetime penetrance of about 70% for males and 90% for females. A gene frequency of about 0.05 and a penetrance of 25 to 30% would be required to account for the findings on a dominant hypothesis. Hodge et al. (1980) proposed a 3-allele model based on a susceptibility locus (S) tightly linked to the HLA complex. Thomson (1980) espoused a 2-locus model. See 125850 for a clear example of an autosomal dominant type of diabetes mellitus: maturity-onset diabetes of the young (MODY). Cudworth and Woodrow (1975) found that the relative risk of IDDM was 2.12 for HLA-A 8 and 2.60 for W15. Rubinstein et al. (1977) found that diabetic sibs shared their HLA genes with a significantly increased frequency, leading them to postulate a recessive gene linked to HLA (and specifically to HLA-D as indicated by 3 informative cases with recombination within the HLA). They estimated the penetrance at 50% because half the HLA-identical sibs of index cases were diabetic. This conclusion fits with published observations of 6-10% risk to sibs of patients when both parents are normal. As an appendix to their paper, they presented a table of risk to relatives on the basis of the above hypotheses. Barbosa et al. (1978) also concluded that IDDM is a recessive with 50% penetrance and with linkage to HLA (theta = 0.13, lod = 3.98) on the basis of the study of 21 families with 2 or more affected sibs and normal parents. Vadheim et al. (1986) pointed out that several studies suggested a higher incidence of IDDM among the offspring of affected males than among those of affected females. To test the hypothesis that differential transmission by the father of genes predisposed to diabetes may explain this phenomenon, Vadheim et al. (1986) examined parent-to-offspring transmission of HLA haplotypes and DR alleles in 107 nuclear families in which a child had IDDM. They found that fathers with a DR4 allele were significantly more likely to transmit this allele to their diabetic or nondiabetic children than were mothers with a DR4 allele. No difference between parents was observed for HLA-DR3; however, DR3 was transmitted significantly more than 50% of the time from either parent. Field et al. (1986) reconfirmed the fact that sharing of 2 HLA haplotypes by sibs with diabetes mellitus was increased in comparison to mendelian expectations. Whereas sharing of GM-region genes was not different from mendelian expectations in the total sampled, affected pairs who shared 2 HLA haplotypes did show significantly increased sharing of GM-region genes. MacDonald et al. (1986) studied families with IDDM in parent and child. The proportion of diabetic parents who transmitted DR4 to diabetic offspring (78%) was significantly higher (P less than 0.001) than the gene frequency of DR4 in the overall diabetic population (43%). The proportion of nondiabetic parents who transmitted DR4 to diabetic offspring (22%) was not significantly different from the gene frequency in the nondiabetic population but significantly lower (P less than 0.05) than the gene frequency in the overall IDDM population. This was taken to indicate a strong dominant effect of DR4. The proportion of nondiabetic parents who transmitted DR3 was similar to the gene frequency of DR3 in the overall diabetic population, but it was significantly higher than the gene frequency of DR 3 in the nondiabetic population (15%; P less than 0.005). The percentage of diabetic offspring who were DR3/DR4 (35%) was identical to that in the overall IDDM population (35%). MacDonald et al. (1986) interpreted this to mean that DR3 plays an enhancing role, with DR4 playing the main role. Thomson et al. (1988) analyzed the results from 11 studies involving 1,792 Caucasian probands with IDDM. Antigen genotype frequencies in patients, transmission from affected parents to affected children, and the relative frequencies of HLA-DR3 and -DR4 homozygous patients all indicated that DR3 predisposes in a 'recessive'-like and DR4 in a 'dominant'-like or 'intermediate' fashion, after allowing for the synergistic effect of the 2 HLA types. DR2 showed a protective effect, DR1 and DRw8 showed predisposing effects, and DR5 showed a slight protective effect. They found evidence that only subsets of DR3 and DR4 are predisposing. The presence or absence of asp at position 57 of the DQ-beta gene was shown to be insufficient of itself in explaining the inheritance of IDDM. They suggested that the distinguishing features of the DR3-associated and DR4-associated predisposition remain to be identified at the molecular level. Using an overall sib risk of 6%, Thomson et al. (1988) estimated that the risks for those sharing 2, 1, or 0 haplotypes are 12.9%, 4.5%, and 1.8%, respectively. The highest sib risk was 19.2% for sibs sharing 2 haplotypes with a DR3/DR4 proband. Field (1988) put this study in perspective with a discussion of other factors, including nongenetic factors. Sheehy et al. (1989) likewise concluded that susceptibility to diabetes is best defined by a combination of HLA-DR and HLA-DQ alleles. In a study of 266 unrelated white patients with IDDM, Baisch et al. (1990) extended the assessment of the role of HLA-DQ alleles in susceptibility to the disease. They used allele-specific oligonucleotide probes and PCR to study HLA-DQ beta-chain alleles. Two major findings emerged. First, HLA-DQw1.2 was protective; it was found in only 2.3% of IDDM patients and in 36.4% of controls. This was 'dominant protection,' i.e., it did not matter what other allele was present. Second, HLA-DQw8 increased the risk of IDDM and the effect was one of 'dominant susceptibility' except that persons who were HLA-DQw1.2/DQw8 had a relative risk of 0.37, demonstrating that the protective effect of HLA-DQw1.2 predominated over the effect of HLA-DQw8. Segall and Bach (1990) reviewed the significance of these findings. See also review by Todd (1990). The Eurodiab Ace Study Group and the Eurodiab Ace Substudy 2 Study Group (1998) studied the characteristics of familial type I diabetes mellitus, i.e., cases in which more than one affected first-degree relative was diagnosed before the age of 15 years. They used data from an international network of population-based registries and from a case-control study conducted in 8 of the network's centers. They found a positive association between the population incidence rate of type I diabetes and the prevalence of type I diabetes in fathers of affected children. A similar association was observed with the prevalence in sibs, but the association with prevalence in mothers was weaker and not significant. Pooling results from all centers showed that a greater proportion of fathers (3.4%) of affected children had type I diabetes than mothers (1.8%) giving a risk ratio of 1.8. Affected girls were more likely to have a father with type I diabetes than affected boys, but there was no evidence of a similar finding for mothers or sibs. Familial type I diabetes patients had a younger age at onset than nonfamilial patients. Krischer et al. (2003) determined the extent to which different screening strategies could identify a population of nondiabetic relatives of a proband with type 1 diabetes who had 2 or more immunologic markers from the group consisting of islet cell antibodies (ICA), microinsulin autoantibodies (MIAA), GAD65 (138275) autoantibodies (GAA), and ICA512 (601773) autoantibodies (ICA512AA). Screening for any 3 antibodies guaranteed that all multiple antibody-positive subjects were detected. Screening for 2 antibodies at once and testing for the remaining antibodies among those who were positive for 1 resulted in a sensitivity of 99% for GAA and ICA, 97% for GAA and MIAA or GAA and ICA512AA, 93% for ICA512AA and ICA, 92% for MIAA and ICA, and 73% for ICA512AA and MIAA. From a laboratory perspective, screenings for GAA, ICA512AA, and MIAA are semiautomated tests with high throughput that, if used as initial screen, would identify at first testing 67% of the 2.3% of multiple antibody-positive relatives (100% if antibody-positive subjects are subsequently tested for ICA) as well as 4.7% of relatives with a single biochemical autoantibody, some of whom may convert to multiple autoantibody positivity on follow-up. Testing for ICA among relatives with 1 biochemical antibody would identify the remaining 33% of multiple antibody-positive relatives. They concluded that further follow-up and analysis of actual progression to diabetes will be essential to define actual diabetes risk in this large cohort. Mapping ### General Clerget-Darpoux et al. (1981) concluded that the data in 30 multiplex families best fitted a model with a susceptibility gene which was not linked to but interacted with the HLA system. Under 3 different genetic models for IDDM, Hodge et al. (1981) found evidence for linkage with 2 different sets of marker loci: HLA, properdin factor B, and glyoxalase-1 on chromosome 6, and Kidd blood group (then thought to be on chromosome 2, but later shown to be on chromosome 18). Thus, 2 distinct disease-susceptibility loci may be involved in IDDM, a situation also postulated for Graves disease (275000). Bell et al. (1984) described an association between IDDM and a polymorphic region in the 5-prime flanking region of the insulin gene (INS; 176730). This polymorphism (Bell et al., 1981) arises from a variable number of tandemly repeated (VNTR) 14-bp oligonucleotides. When divided into 3 size classes, a significant association was seen between the short-length (class I) alleles and IDDM. Several studies were unable to demonstrate linkage of these VNTR alleles to IDDM in families, but this may in part be attributable to the fact that the disease-associated allele is present at high frequency in the general population. Several disease-associated polymorphisms were identified and the boundaries of association were mapped to a region of 19 kb on 11p15.5. Ferns et al. (1986) studied 14 families in which 13 had 2 cases of IDDM and found no linkage to polymorphic loci 5-prime to the insulin gene or to those 3-prime to the HRAS gene. Association with HLA was again found; persons who were HLA identical to the diabetic proband were more likely to be diabetic than those who were nonidentical. From studies of allele sharing in affected sib pairs, Cox et al. (1988) found evidence of HLA-linked susceptibility to IDDM but no evidence of a contribution of similar magnitude by the insulin-gene region. This failure of family studies to demonstrate linkage is difficult to reconcile with the association demonstrated between alleles at the VNTR locus in the 5-prime region of the insulin gene on 11p (Bell et al., 1984; Bell et al., 1985). Donald et al. (1989) used DR and DQ RFLPs for linkage analysis and demonstrated very close linkage of an IDDM-susceptibility locus. No evidence was found of any effect of the insulin gene. Raum et al. (1979) found a rare genetic type of properdin factor B (F1) in 22.6% of patients with IDDM but in only 1.9% of the general population. If, as the authors suggested, this is an indication of linkage disequilibrium, not association, some populations should not show the relationship. Based on a study in mice (Prochazka et al., 1987) it may be that corresponding recessive genes are located on chromosomes 6 and 11 in man; the THY1 (188230) and the APOA1 (107680) genes are on human 11q. By use of an affected sib pair method, Hyer et al. (1991) excluded the possibility of an IDDM susceptibility gene on 11q. Lucassen et al. (1993) presented a detailed sequence comparison of the predominant haplotypes found in the region of 19 kb on 11p15.5 in a population of French-Canadian IDDM patients and controls. Identification of polymorphisms, both associated and unassociated with IDDM, permitted a further definition of the region of association to 4.1 kb. Ten polymorphisms within this region were found to be in strong linkage disequilibrium with each other and extended across the insulin gene locus and the VNTR situated immediately 5-prime to the insulin gene. These represent a set of candidate disease polymorphisms, one or more of which may account for the susceptibility to IDDM. Using 96 affected sib pairs and a fluorescence-based linkage map of 290 marker loci (average spacing 11 cM), Davies et al. (1994) searched the human genome for genes that predispose to type I (insulin-dependent) diabetes mellitus. A total of 18 different chromosomal regions showed some positive evidence of linkage to the disease, strongly suggesting that IDDM is inherited in a polygenic fashion. Although the authors determined that no genes are likely to have as large effects as IDDM1 (in the major histocompatibility complex on 6p21), significant linkage was confirmed in the insulin gene region on 11p15 (IDDM2; 125852) and established to 11q (IDDM4; 600319), 6q (600320), and possibly to chromosome 18. Possible candidate genes within regions of linkage include GAD1 (605363) and GAD2 (138275), which encode the enzyme glutamic acid decarboxylase; SOD2 (147460), which encodes superoxide dismutase; and the Kidd blood group locus. Linkage of IDDM susceptibility to the region of the FGF gene on chromosome 11q13 was also reported by Hashimoto et al. (1994). Genetic analysis of a mouse model of major histocompatibility complex-associated autoimmune type I (insulin-dependent) diabetes mellitus showed that the disease is caused by a combination of a major effect at the MHC and at least 10 other susceptibility loci elsewhere in the genome (Risch et al., 1993). In a genomewide scan of 93 affected sib pair families from the UK, Davies et al. (1994) found a similar genetic basis for human type I diabetes, with a major component at the MHC locus (IDDM1) explaining 34% of the familial clustering of the disease. Mein et al. (1998) analyzed a further 263 multiplex families from the same population to provide a total UK dataset of 356 affected sib pair families. Only 4 regions of the genome outside IDDM1/MHC, which was still the only major locus detected, were not excluded, and 2 of these showed evidence of linkage: 10p13-p11 (maximum lod score = 4.7) and 16q22-q24 (maximum lod score = 3.4). They stated that these and other novel regions, including 14q12-q21 and 19p13-q13, could potentially harbor disease loci. Concannon et al. (1998) reported the results of a genome screen for linkage with IDDM and analyzed the data by multipoint linkage methods. An initial panel of 212 affected sib pairs were genotyped for 438 markers spanning all autosomes, and an additional 467 affected sib pairs were used for follow-up genotyping. Other than the well-established linkage with the HLA region at 6p21.3, they found only 1 region, located on 1q and not previously reported, where the lod score exceeded 3.0. Lods between 1.0 and 1.8 were found in 6 other regions, 3 of which had been reported in other studies. Cox et al. (2001) reported a genome scan using a new collection of 225 multiplex families with type I diabetes and combining the data with those from previous genome scans (Davies et al., 1994; Concannon et al., 1998; Mein et al., 1998). The combined sample of 831 affected sib pairs, all with both parents genotyped, provided 90% power to detect linkage. Three chromosome regions were identified that showed significant evidence of linkage with lod scores greater than 4: 6p21 (IDDM1); 11p15 (IDDM2); and 16q22-q24; 4 other regions showed suggestive evidence of linkage with lod scores of 2.2 or greater: 10p11 (IDDM10, 601942); 2q31 (IDDM7, 600321; IDDM12, 601388; IDDM13, 601318); 6q21 (IDDM15, 601666); and 1q42. Exploratory analyses, taking into account the presence of specific high-risk HLA genotypes or affected sibs' ages at disease onset, provided evidence of linkage at several additional sites, including the putative IDDM8 (600883) locus on 6q27. The results indicated that much of the difficulty in mapping type I diabetes susceptibility genes results from inadequate sample sizes, and pointed to the value of international collaborations to assemble and analyze much larger datasets for linkage in complex diseases. Paterson and Petronis (2000) used data from a genomewide linkage study of 356 affected sib pairs with type I diabetes to perform linkage analyses using parental origin of shared alleles in subgroups based on sex of affected sibs and age of diagnosis. They found that evidence for linkage to IDDM4 occurred predominantly from opposite sex sib pairs and that for linkage to a locus on chromosome 4q occurred in sibs where one was diagnosed before age 10 years and one after age 10. Paterson and Petronis (2000) concluded that these methods might help reduce locus heterogeneity in type I diabetes. Using DNA from 253 Danish IDDM families, Bergholdt et al. (2005) analyzed the chromosomal region 21q21.3-qter, which had been previously linked to IDDM by the European Consortium for IDDM Genome Studies (2001). Multipoint nonparametric linkage analysis showed a peak score of 3.61 at marker D21S1920 (p = 0.0002), and a '1-lod drop' interval of 6.3 Mb was identified between markers D21S261 and D21S270. No association was found with 74 coding SNPs from 32 candidate genes within the '1-lod drop' interval. Using 2,360 SNP markers in the 4.4-Mb human major histocompatibility complex (MHC) locus and the adjacent 493 kb centromeric to the MHC, Roach et al. (2006) mapped the genetic influences for type 1 diabetes in 2 Swedish samples. They confirmed previous studies showing association with T1D in the MHC, most significantly near HLA-DR/DQ. In the region centromeric to the MHC, they identified a peak of association within the inositol 1,4,5-triphosphate receptor 3 gene (ITPR3; 147267). The most significant single SNP in this region was at the center of the ITPR3 peak of association. The estimated population-attributable risk of 21.6% suggested that variation within ITPR3 reflects an important contribution to T1D in Sweden. Two-locus regression analysis supported an influence of ITPR3 variation on T1D that is distinct from that of any MHC class II gene. The Wellcome Trust Case Control Consortium (2007) described a joint genomewide association study using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals and a shared set of approximately 3,000 controls for each of 7 major diseases. Case-control comparisons identified 7 independent association signals in type 1 diabetes at p values of less than 5.0 x 10(-7). In a study of 4,000 individuals with type 1 diabetes, 5,000 controls, and 2,997 family trios independent of the Wellcome Trust Case Control Consortium (2007) study, Todd et al. (2007) confirmed the previously reported associations of rs2542151 in the PTPN2 gene (176887) on chromosome 18p11, rs17696736 in the C12ORF30 gene on chromosome 12q24, rs2292239 in the ERBB3 gene (190151) on chromosome 12q13, and rs12708716 in the KIAA0350 gene (CLEC16A; 611303) on chromosome 16p13 (p less than or equal to 10(-9); combined with WTCCC p less than or equal to 1.15 x 10(-14)), leaving 8 regions with small effects or false-positive associations. The association with rs17696736 led to the identification of a nonsynonymous SNP (rs3184504) in the SH2B3 gene (605093) that was sufficient to model the association of the entire region (p = 1.73 x 10(-21); see IDDM20, 612520). To identify genetic factors that increase the risk of type 1 diabetes, Hakonarson et al. (2007) performed a genomewide association study in a large pediatric cohort of European descent. In addition to confirming previously identified loci, they found that type 1 diabetes was significantly associated with variation within a 233-kb linkage disequilibrium block on chromosome 16p13 that contains the KIAA0350 gene, which is predicted to encode a sugar-binding, C-type lectin. Three common noncoding variants of this gene (rs2903692, rs725613, and rs17673553) in strong linkage disequilibrium reached genomewide significance for association with type 1 diabetes. A subsequent transmission disequilibrium test replication study in an independent cohort confirmed the association. The combined P values for these SNPs ranged from 2.74 x 10(-5) to 6.7 x 10(-7). Hakonarson et al. (2007) noted that the Wellcome Trust Case Control Consortium (2007) had identified the KIAA0350 gene as a type 1 diabetes locus in a genomewide association study. Smyth et al. (2008) evaluated the association between type 1 diabetes 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 type 1 diabetes and rs1738074 in the TAGAP gene on chromosome 6q25 (see IDDM21, 612521) and confirmed association with rs3184504 in the SH2B3 gene (605093) on chromosome 12q24 (see IDDM20, 612520). Cooper et al. (2008) performed a metaanalysis of 3 genomewide association studies, combining British type 1 diabetes (T1D) case-control data (Wellcome Trust Case Control Consortium, 2007) with T1D cases from the Genetics of Kidneys in Diabetes study (Mueller et al., 2006) for a total of 3,561 cases and 4,646 controls. Cooper et al. (2008) found support for a previously detected locus on chromosome 4q27 at rs17388568 (p = 1.87 x 10(-8); see IDDM23, 612622). After genotyping an additional 6,225 cases, 6,946 controls, and 2,828 families, they also found evidence for 4 previously unknown and distinct risk loci: at rs11755527 in intron 3 of the BACH2 gene (605394) on chromosome 6q15 (p = 4.7 x 10(-12)); at rs947474, near the PRKCQ gene (600448) on chromosome 10p15 (p = 3.7 x 10(-9)); at rs3825932 in intron 1 of the CTSH gene (116820) on chromosome 15q24 (p = 3.2 x 10(-15)); and at rs229541, located between the C1QTNF6 and SSTR3 (182453) genes on chromosome 22q13 (p = 2.0 x 10(-8)). Barrett et al. (2009) reported the findings of a genomewide association study of type 1 diabetes, combined in a metaanalysis with 2 previously published studies (Wellcome Trust Case Control Consortium, 2007; Cooper et al., 2008). The total sample set included 7,514 cases and 9,045 reference samples. Forty-one distinct genomic locations provided evidence for association with type 1 diabetes in the metaanalysis (P less than 10(-6)). Using an analysis that combined comparisons over the 3 studies, they confirmed several previously reported associations, including rs2476601 at chromosome 1p13.2 (P = 8.5 x 10(-85)), rs7111341 at 11p15.5 (P = 4.4 x 10(-48)), rs2292239 at 12q13.2 (P = 2.2 x 10(-25)), and rs3184504 at 12q24.12 (P = 2.8 x 10(-27)). Barrett et al. (2009) further tested 27 novel regions in an independent set of 4,267 cases and 4,463 controls, and 2,319 affected sib pair families. Of these, 18 regions were replicated (P less than 0.01; overall P less than 5 x 10(-8)) and 4 additional regions provided nominal evidence of replication. A region on 1q32.1 represented by SNP rs3024505 (combined P = 1.9 x 10(-9)) contains the immunoregulatory cytokine genes IL10 (124092), IL19 (605687), and IL20 (605619). The strongest evidence of association among these 27 novel regions was achieved at rs10509540 on chromosome 10q23.31; see IDDM24, 613006. Wallace et al. (2010) used imputation to assess association with T1D across 2.6 million SNPs in a total of 7,514 cases and 9,405 controls from 3 existing GWA studies (Wellcome Trust Case Control Consortium, 2007; Cooper et al., 2008; Barrett et al., 2009). They obtained evidence of an association at rs941576, a marker in the imprinted region of chromosome 14q32.2, for paternally inherited risk of T1D (p = 1.62 x 10(-10); ratio of allelic affects for paternal versus maternal transmissions = 0.75). Wallace et al. (2010) suggested that rs941576, which is located within intron 6 of the maternally expressed noncoding RNA gene MEG3 (605636), or another nearby variant alters the regulation of the neighboring functional candidate gene DLK1 (176290). Inflammatory bowel disease (see 266600), including Crohn disease (CD) and ulcerative colitis (UC), and T1D are autoimmune diseases that may share common susceptibility pathways. Wang et al. (2010) examined known susceptibility loci for these diseases in a cohort of 1,689 CD cases, 777 UC cases, 989 T1D cases, and 6,197 shared control subjects of European ancestry. Multiple previously unreported or unconfirmed disease-loci associations were identified, including CD loci (ICOSLG, 605717; TNFSF15, 604052) and T1D loci (TNFAIP3; 191163) that conferred UC risk; UC loci (HERC2, 605837; IL26, 605679) that conferred T1D risk; and UC loci (IL10, 124092; CCNY, 612786) that conferred CD risk. T1D risk alleles residing at the PTPN22 (600716), IL27 (608273), IL18RAP (604509), and IL10 loci protected against CD. The strongest risk alleles for T1D within the major histocompatibility complex (MHC) conferred strong protection against CD and UC. The authors suggested that many loci involved in autoimmunity may be under a balancing selection due to antagonistic pleiotropic effects, and variants with opposite effects on different diseases may facilitate the maintenance of common susceptibility alleles in human populations. ### HLA Associations IDDM, although called the juvenile-onset type of diabetes, has its onset after the age of 20 years in 50% of cases. Caillat-Zucman et al. (1992) investigated whether the association of IDDM with certain HLA alleles, well documented in pediatric patients, also holds for adults. Interestingly, they found quite different HLA class II gene profiles, with a significantly higher percentage of non-DR3/non-DR4 genotypes and a lower percentage of DR3/4 genotypes in older patients. Although the non-DR3/non-DR4 patients presented clinically as IDDM, they showed a lower frequency of islet cell antibodies (ICA) at diagnosis and a significantly milder insulin deficiency. These data (1) suggest these subjects probably represent a particular subset of IDDM patients in whom frequency increases with age; (2) confirm the genetic heterogeneity of IDDM; and (3) prompt caution in extrapolating the genetic concepts derived from childhood IDDM to adult patients. Nerup et al. (1974) found that IDDM (but not NIDDM) is associated with 2 particular HLA-A types (142800)--HLA-A8 and W15. Woodrow and Cudworth (1975) interpreted the association of HLA-A8 and W15 with IDDM as resulting from linkage disequilibrium between genes for these antigens and a gene determining susceptibility of diabetes. To test for linkage between HLA and a locus for susceptibility to this disease, Clerget-Darpoux et al. (1980) studied 28 informative families with at least 1 child suffering from juvenile-onset IDDM. The 28 families were pooled with 21 from the literature and autosomal recessive inheritance was assumed. Maximum lod scores (6.00 to 7.36) were obtained for recombination fractions from 4% to 16%, according to the level of assumed penetrance (from 90% down to 10%). These high estimates of the recombination fraction are not consistent with the hypothesis that the association between IDDM and specific HLA haplotypes is a consequence of simple linkage disequilibrium between HLA and a susceptibility locus. Spielman et al. (1980) did HLA-typing on all members of 33 families in which 2 or more sibs had IDDM. They interpreted the results as supporting the hypothesis that, closely linked to the HLA region, there is a locus (symbolized S by them) for susceptibility to insulin-dependent diabetes. (S(d) was their symbol for the susceptibility allele and S(a) for all other alleles.) They estimated penetrance for the homozygote for S(d) to be 71% and for the heterozygote 6.5%. The recombination fraction between S and HLA was estimated to be under 3%. Rubinstein et al. (1981) analyzed 3 sets of published data on HLA-typed families with IDDM in which no significant heterogeneity was detected. Autosomal recessive inheritance and incomplete penetrance were assumed. A maximum lod score of 7.40 at theta = 0.05 was found. The segregation of HLA and GLO in 5 affected sib pairs (4 of the 5 pairs were HLA-identical and GLO-different), in which one of the sibs carried an HLA-GLO recombinant, placed the IDDM locus closer to HLA than to GLO. Dunsworth et al. (1982) performed complex segregation and linkage analysis in 182 families with at least 1 IDDM proband. All families were typed for HLA-B antigens and 118 for HLA-DR. The recessive model best fitted the data, with the maximum likelihood estimate of recombination between HLA-DR and the diabetes susceptibility factor being 0.019. Substantial heterogeneity was suggested; the smallest recombination was for families whose probands had 2 high-risk D alleles. Using RFLPs of the HLA-DR-alpha gene, Stetler et al. (1985) could show a higher association than is found with serologic markers. Rich et al. (1987) studied linkage of IDDM with HLA and factor B (138470) in combination with segregation analysis. They found evidence of strong linkage disequilibrium with the B-BF-D haplotype, with IDDM probably tightly linked to HLA-DR. The recombination fraction between the postulated major locus for IDDM and HLA was 0 in all models. They concluded that the best fitting genetic model of diabetic susceptibility is that of a single major locus with 'near recessivity' on a scale of standardized genetic liability, with a gene frequency of the IDDM susceptibility allele of approximately 14%. Julier et al. (1991) studied polymorphisms of INS and neighboring loci in random diabetics, IDDM multiplex families, and controls. They found that HLA-DR4-positive diabetics showed an increased risk associated with common variants at polymorphic sites in a 19-kb segment spanned by the 5-prime INS VNTR and the third intron of the gene for insulin-like growth factor II (147470). In multiplex families the IDDM-associated alleles for polymorphisms in this region were transmitted preferentially to HLA-DR4-positive diabetic offspring from heterozygous parents. The effect was strongest in paternal meioses, suggesting a possible role for maternal imprinting. Julier et al. (1991) suggested that the results strongly support the existence of a gene or genes affecting HLA-DR4 IDDM susceptibility in a 19-kb region of INS-IGF2. Their approach may be useful in mapping susceptibility loci in other common diseases. The fact that the association between IDDM and certain HLA-DQ alleles is even stronger than that with certain DR alleles and that there is little association with HLA-DP provides a boundary of disease association to the 430 kb between DQ and DP. In further studies of disease association with TAP (transporter associated with antigen processing) genes (170260), which map approximately midway between DP and DQ, Jackson and Capra (1993) found a higher association of a TAP allele with IDDM than with any single HLA-DP allele but the risk was lower than with HLA-DQB10302. These data provided new limits for IDDM susceptibility to the 190-kb interval between TAP1 and HLA-DQB1. In a 2-stage approach to fine mapping, Herr et al. (2000) evaluated linkage in 385 affected sib-pair families using 13 evenly spaced polymorphic microsatellite markers spanning 14 Mb. Evidence of disease association was found for D6S2444, located within the 95% confidence interval of 1.7 cM obtained by linkage. Analysis of an additional 12 flanking markers revealed a highly specific region of 570 kb associated with disease that included the HLA class II genes. The peak of association was as close as 85 kb centromeric of HLA-DQB1. Recombination within the major histocompatibility complex was rare and nearly absent in the class III region. The authors concluded that the majority of disease association in the region can be explained by linkage disequilibrium with the class II susceptibility genes. Greenbaum et al. (2000) noted that the presence of HLA haplotype DQA10102-DQB10602 is associated with protection from type I diabetes. The Diabetes Prevention Trial-type I has identified 100 islet cell antibody (ICA)-positive relatives with this protective haplotype, far exceeding the number of such subjects reported in other studies worldwide. Comparisons between ICA+ relatives with and without DQB10602 demonstrated no differences in gender or age; however, among racial groups, African American ICA+ relatives were more likely to carry this haplotype than others. The ICA+ DQB10602 individuals were less likely to have additional risk factors for diabetes (insulin autoantibody (IAA) positive or low first phase insulin release (FPIR)) than ICA+ relatives without DQB10602. However, 29% of the ICA+ DQB10602 relatives did have IAA or low FPIR. Hispanic ICA+ individuals with DQB10602 were more likely to be IAA positive or to have low FPIR than other racial groups. The authors conclude that the presence of ICA found in relatives suggests that whatever the mechanism that protects DQB10602 individuals from diabetes, it is likely to occur after the diabetes disease process has begun. In addition, they suggest that there may be different effects of DQB10602 between ethnic groups. Redondo et al. (2000) used the transmission disequilibrium test to analyze haplotypes for association and linkage to diabetes within families from the Human Biological Data Interchange type I diabetes repository (1,371 subjects) and from the Norwegian Type 1 Diabetes Simplex Families study (2,441 subjects). DQA10102-DQB10602 was transmitted to 2 of 313 (0.6%) affected offspring (P less than 0.001, vs the expected 50% transmission). Protection was associated with the DQ alleles rather than DRB11501 in linkage disequilibrium with DQA10102-DQB10602: rare DRB11501 haplotypes without DQA10102-DQB10602 were transmitted to 5 of 11 affected offspring, whereas DQA10102-DQB10602 was transmitted to 2 of 313 affected offspring (P less than 0.0001). The authors concluded that both DR and DQ molecules (the DRB11401 and DQA10102-DQB10602 alleles) can provide protection from type IA diabetes. Li et al. (2001) assessed the prevalence of families with both type I and type II diabetes in Finland and studied, in patients with type II diabetes, the association between a family history of type I diabetes, GAD antibodies (GADab), and type I diabetes-associated HLA-DQB1 genotypes. Further, in mixed type I/type II diabetes families, they investigated whether sharing an HLA haplotype with a family member with type I diabetes influenced the manifestation of type II diabetes. Among 695 families with more than 1 patient with type II diabetes, 100 (14%) also had members with type I diabetes. Type II diabetic patients from the mixed families more often had GADab (18% vs 8%) and DQB10302/X genotype (25% vs 12%) than patients from families with only type II diabetes; however, they had a lower frequency of DQB102/0302 genotype compared with adult-onset type I patients (4% vs 27%). In the mixed families, the insulin response to oral glucose load was impaired in patients who had HLA class II risk haplotypes, either DR3(17)-DQA10501-DQB102 or DR40401/4-DQA10301-DQB10302, compared with patients without such haplotypes. This finding was independent of the presence of GADab. The authors concluded that type I and type II diabetes cluster in the same families. A shared genetic background with a patient with type I diabetes predisposes type II diabetic patients both to autoantibody positivity and, irrespective of antibody positivity, to impaired insulin secretion. Their findings also supported a possible genetic interaction between type I and type II diabetes mediated by the HLA locus. Linkage data implicating other disease susceptibility loci for type I diabetes are conflicting. This is likely due to (1) the limited power for detection of contributions of additional susceptibility loci, given the limited number of informative families available for study, (2) factors such as genetic heterogeneity between populations, and (3) potential gene-gene and gene-environment interactions. To circumvent some of these problems, the European Consortium for IDDM Genome Studies (2001) conducted a genomewide linkage analysis for type I diabetes mellitus-susceptibility loci in 408 multiplex families from Scandinavia, a population expected to be homogeneous for genetic and environmental factors. In addition to verifying the HLA and INS susceptibility loci, the study confirmed the locus of IDDM15 (601666) on chromosome 6q21. Suggestive evidence of additional susceptibility loci was found on 2p, 5q, and 16p. For some loci, the support for linkage increased substantially when families were stratified on the basis of HLA or INS genotypes, with statistically significant heterogeneity between the stratified subgroups. These data support both the existence of non-HLA genes of significance for type I diabetes mellitus and the interaction between HLA and non-HLA loci in the determination of the type I diabetes mellitus phenotype. Gambelunghe et al. (2001) estimated the frequency of major histocompatibility complex class I chain-related A gene (MICA; 600169) alleles and HLA-DRB103-DQA10501-DQB10201 and HLA-DRB104-DQA10301-DQB10302 in 195 type I diabetes mellitus subjects, in 80 latent autoimmune diabetes of the adult subjects, and in 158 healthy subjects from central Italy. The MICA5 allele was significantly associated with type I diabetes mellitus only in the group diagnosed before 25 years of age, and the odds ratio of the simultaneous presence of both the MICA5 allele and HLA-DRB103-DQA10501-DQB10201 and/or HLA-DRB104-DQA10301-DQB10302 was as high as 54 and higher than 388 when compared with double-negative individuals. Adult-onset type I diabetes mellitus (age at diagnosis greater than 25 years) and latent autoimmune diabetes of the adult were significantly associated with the MICA5.1 allele, which was not significantly increased among diabetic children. Only the combination of MICA5.1 and HLA-DRB103-DQA10501-DQB10201 and/or HLA-DRB104-DQA10301-DQB10302 conferred increased risk for adult-onset type I diabetes mellitus or for latent autoimmune diabetes of the adult. The authors concluded the existence of distinct genetic markers for childhood/young-onset IDDM and for adult-onset IDDM, namely the MICA5 and MICA5.1 alleles, respectively. Qu and Polychronakos (2009) analyzed anti-IA-2 and anti-GAD65 autoantibody data from 2,282 type 1 diabetes patients from 1,117 multiplex families and found no association between anti-GAD65 (138275) autoantibodies and HLA. However, significant positive association was detected between anti-IA-2 (601773) autoantibodies and HLA-DRB10401, whereas negative association was detected with the DRB103-DQA10501-DQB10201 haplotype as well as with HLA-A24, independent of the DRB103-DQA10501-DQB10201 haplotype. The Wellcome Trust Case Control Consortium (2010) undertook a large direct genomewide study of association between copy number variants (CNVs) and 8 common human diseases. Using a purpose-designed array, they typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs greater than 500 basepairs. The Wellcome Trust Case Control Consortium (2010) identified several biologic artifacts that led to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed 3 loci where CNVs were associated with disease: HLA for Crohn disease (266600), rheumatoid arthritis (RA; 180300), and IDDM; IRGM (608282) for Crohn disease; and TSPAN8 (600769) for type 2 diabetes (125853). In each case the locus had previously been identified in SNP-based studies, reflecting the observation of The Wellcome Trust Case Control Consortium (2010) that most common CNVs that are well-typed on their array are well-tagged by SNPs and so have been indirectly explored through SNP studies. The Wellcome Trust Case Control Consortium (2010) concluded that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. Molecular Genetics Todd et al. (1987) estimated that more than half of the inherited predisposition to IDDM maps to the region of the HLA class II genes on chromosome 6. Analysis of the DNA sequences from diabetics indicated that alleles of HLA-DQ(beta) determined both disease susceptibility and resistance. A non-asp at residue 57 of the beta-chain in particular confers susceptibility to IDDM and the autoimmune response against the insulin-producing islet cells. Morel et al. (1988) found that HLA haplotypes carrying an asp in position 57 of the DQ-beta chain (146880) were significantly increased in frequency among nondiabetics, while non-asp57 haplotypes were significantly increased in frequency among diabetics. Ninety-six percent of the diabetic probands were homozygous non-asp/non-asp as compared to 19.5% of healthy, unrelated controls. This represented a relative risk of 107 for non-asp57 homozygous individuals. See critique by Klitz (1988). Khalil et al. (1990) presented evidence suggesting that asp57-negative DQ-beta as well as arg52-positive DQ-alpha chains are important to susceptibility to IDDM. Presumably, the modulation of susceptibility operates via the presentation of viral-antigenic peptide and/or autoantigen. I-Ag7, the only class II allele expressed by the nonobese diabetic mouse, lacks asp57. Corper et al. (2000) determined the crystal structure of the I-Ag7 molecule at 2.6-angstrom resolution as a complex with a high-affinity peptide from the autoantigen glutamic acid decarboxylase (GAD) 65 (138275). I-Ag7 has a substantially wider peptide-binding groove around beta-57, which accounts for distinct peptide preferences compared with other MHC class II alleles. Loss of asp-beta-57 leads to an oxyanion hole in I-Ag7 that can be filled by peptide carboxyl residues or, perhaps, through interaction with the T-cell receptor (see 186830). Nakanishi et al. (1999) sought to identify IDDM-susceptible HLA antigens in IDDM patients who did not have the HLA-DQA10301 allele and to correlate the relationship of these HLA antigens to the degree of beta-cell destruction. In 139 Japanese IDDM patients and 158 normal controls, they typed HLA-A, -C, -B, -DR, and -DQ antigens. Serum C-peptide immunoreactivity response (delta-CPR) to a 100-g oral glucose load of 0.033 nmol/L or less was regarded as complete beta-cell destruction. All 14 patients without HLA-DQA10301 had HLA-A24, whereas only 35 of 58 (60.3%) normal controls without HLA-DQA10301 and only 72 of 125 (57.6%) IDDM patients with HLA-DQA10301 had this antigen (Pc of 0.0256 and 0.0080, respectively). Delta-CPR in IDDM patients with both HLA-DQA10301 and HLA-A24 was lower than in IDDM patients with HLA-DQA10301 only and in IDDM patients with HLA-A24 only. The authors concluded that both HLA-DQA10301 and HLA-A24 contribute susceptibility to IDDM independently and accelerate beta-cell destruction in an additive manner. Donner et al. (1999) analyzed the presence of a solitary human endogenous retrovirus-K (HERV-K) long terminal repeat (LTR) in the HLA-DQ region (DQ-LTR3) and its linkage to DRB1, DQA1, and DQB1 haplotypes derived from 246 German and Belgian families with a patient suffering from IDDM. Segregation analysis of 984 HLA-DQA1/B1 haplotypes showed that DQ-LTR3 is linked to distinct DQA1 and DQB1 haplotypes but is absent in others. The presence of DQ-LTR3 on HLA-DQB10302 haplotypes was preferentially transmitted to patients from heterozygous parents (82%; P less than 10-6), in contrast to only 2 of 7 DQB10302 haplotypes without DQ-LTR3. Also, the extended HLA-DRB10401, DQB10302 DQ-LTR3-positive haplotypes were preferentially transmitted (84%; P less than 10-6) compared with 1 of 6 DR-DQ-matched DQ-LTR3-negative haplotypes. DQ-LTR3 is missing on most DQB10201 haplotypes, and those LTR3-negative haplotypes were also preferentially transmitted to patients (80%; P less than 10-6), whereas DQB10201 DQ-LTR3-positive haplotypes were less often transmitted to patients (36%). The authors concluded that the presence of DQ-LTR3 on HLA-DQB10302 and its absence on DQB10201 haplotypes are independent genetic risk markers for IDDM. Pugliese et al. (1999) sequenced the DQB10602 and DQA10102 alleles in 8 ICA/DQB10602-positive relatives and in 6 rare patients with type I diabetes and DQB10602. They found that all relatives and patients carry the known DQB10602 and DQA10102 sequences, and none of them had the mtDNA 3243A-G mutation (590050.0001) associated with late-onset diabetes in ICA-positive individuals. Because they did not find diabetes in ICA/DQB10602-positive relatives, the authors concluded that the development of diabetes in individuals with DQB10602 remains very unlikely, even in the presence of ICA. Cordell et al. (1995) applied to insulin-dependent diabetes mellitus an extension of the maximum lod score method of Risch (1990), which allowed the simultaneous detection and modeling of 2 unlinked disease loci. The method was applied to affected sib pair data, and the joint effects of IDDM1 (HLA) and IDDM2, the INS VNTR, and IDDM1 and IDDM4 (FGF3-linked) were assessed. In the presence of genetic heterogeneity, there seemed to be a significant advantage in analyzing more than 1 locus simultaneously. Cordell et al. (1995) stated that the effects at IDDM1 and IDDM2 were well described by a multiplicative genetic model, while those at IDDM1 and IDDM4 followed a heterogeneity model. Cucca et al. (2001) predicted the protein structure of HLA-DQ by using the published crystal structures of different allotypes of the murine ortholog of DQ, IA. There were marked similarities both within and across species between type 1 diabetes protective class II molecules. Likewise, the type 1 diabetes predisposing molecules DR and murine IE showed conserved similarities that contrasted with the shared patterns observed between the protective molecules. There was also inter-isotypic conservation between protective DQ, IA allotypes, and protective DR4 subtypes. The authors proposed a model for a joint action of the class II peptide-binding pockets P1, P4, and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. They suggested shared epitope(s) in the target autoantigen(s) and common pathways in human and murine type 1 diabetes. Kristiansen et al. (2003) demonstrated that the -174C variant of the -174G/C SNP in the IL6 gene (147620.0001) was significantly associated with IDDM in Danish females, but not in males, and that the association was not caused by preferential transmission distortion in females. Using reporter assay studies, they also demonstrated evidence suggesting that the repressed PMA-stimulated activity of the -174G variant was reverted by 17-beta-estradiol (E2), whereas the stimulated activity of the -174C variant was E2 insensitive and higher than the stimulated activity of the -174G variant in the absence of E2. Kristiansen et al. (2003) concluded that higher IL6 promoter activity may confer risk to IDDM in very young females and that this risk may be negated with increasing age, possibly by the increasing E2 levels in puberty. Bottini et al. (2004) demonstrated association of a missense SNP in the PTPN22 gene (R620W; 600716.0001) with type I diabetes. Kawasaki et al. (2006) identified a promoter SNP in the PTPN22 gene (600716.0002) that associated with type 1 diabetes in Japanese and Korean IDDM patients. Tessier et al. (2006) confirmed association of type 1 diabetes with 2 SNPs in the OAS1 gene (164350.0001, 164350.0002). Smyth et al. (2008) identified a significant association between an insertion-deletion variant in the CCR5 gene on chromosome 3p21 (601373.0001) and a reduced risk for type 1 diabetes (IDDM22; 612522). Concannon et al. (2009) reviewed the genetics of type 1A (immune-mediated) diabetes, noting that genes within the HLA region, predominantly those that encode antigen-presenting molecules, confer the greatest part of the genetic risk for type 1A diabetes. The authors concluded that the existence of other loci with individual effects on risk of a similar magnitude is very unlikely, and suggested that the remaining non-HLA loci will make only modest individual contributions to risk, with odds ratios of 1.3 or less. Concannon et al. (2009) noted that a majority of the other loci appear to exert their effects in the immune system, particularly on T cells. Zalloua et al. (2008) identified homozygous or compound heterozygous mutations in the WFS1 gene (see, e.g., 606201.0024) in 22 (5.5%) of 399 Lebanese probands ascertained with juvenile-onset insulin-dependent diabetes, of whom 17 had Wolfram syndrome (WFS1; 222300) and 5 had nonsyndromic nonautoimmune diabetes mellitus. There were 2 additional probands who were given an initial diagnosis of nonsyndromic DM that was revised to WFS when they developed optic atrophy during the course of the study, and Zalloua et al. (2008) noted that longer follow-up of the nonsyndromic DM patients or a specific study of WFS adult patient populations would be needed to determine whether a subset of the WFS1-mutated nonsyndromic DM patients are exempted from extrapancreatic manifestations during their lifetime. Diagnosis The diagnosis is made on the basis of hyperglycemia with relative insulin deficiency with or, in the early stages, without ketosis in the absence of medications or conditions known to promote hyperglycemia. In a study of an unselected population of 755 sibs of children with IDDM, Kulmala et al. (1998) evaluated the predictive value of islet cell antibodies, antibodies to the IA-2 protein, antibodies to the 65-kD isoform of GADA, insulin autoantibodies, and combinations of these markers. Within 7.7 years of the initial sample taken at or close to the diagnosis in the index case, 32 sibs progressed to IDDM. The positive predictive values of the 4 antibodies mentioned were 43%, 55%, 42%, and 29%, and their sensitivities 81%, 69%, 69%, and 25%, respectively. The final conclusion made by Kulmala et al. (1998) was that accurate assessment of the risk for IDDM in sibs is complicated, as not even all those with 4 antibody specificities contract the disease, and some with only 1 or no antibodies initially will progress to IDDM. Kimpimaki et al. (2000) evaluated the emergence of diabetes-associated autoantibodies in young children and assessed whether such antibodies could be used as surrogate markers of type I diabetes in young subjects at increased genetic risk. They studied 180 initially unaffected sibs (92 boys and 88 girls) of children with newly diagnosed type I diabetes. All sibs were younger than 6 years of age at the initial sampling, and they were monitored for the emergence of islet cell antibodies (ICA), insulin autoantibodies (IAA), glutamate decarboxylase antibodies (GADA), and IA-2 antibodies (IA-2A) up to the age of 6 years and for progression to clinical type I diabetes up to the age of 10 years. Twenty-two sibs (12.2%) tested positive for ICA in their first antibody-positive sample before the age of 6 years, 13 (7.2%) tested positive for IAA, 15 (8.3%) tested positive for GADA, and 14 (7.8%) tested positive for IA-2A. There were 16 sibs (8.9%) who had 1 detectable autoantibody, 5 (2.8%) who had 2, and 12 (6.7%) who had 3 or more. These observations suggested to Kimpimaki et al. (2000) that disease-associated autoantibodies could be used as surrogate markers of clinical type I diabetes in primary prevention trials targeting young subjects with increased genetic disease susceptibility. Wenzlau et al. (2007) identified type 1 diabetes autoantigen candidates from microarray expression profiling of human and rodent pancreas and islet cells, then screened the candidates with radioimmunoprecipitation assays using new-onset type 1 diabetes and prediabetic sera. The zinc transporter SLC30A8 (611145) was targeted by autoantibodies in 60 to 80% of new-onset type 1 diabetes compared with less than 2% of controls, less than 3% of type 2 diabetics, and up to 30% of patients with other autoimmune disorders with a type 1 diabetes association. SLC30A8 antibodies were found in 26% of type 1 diabetics classified as autoantibody-negative on the basis of existing markers; the combined measurement of antibodies to SLC30A8, GADA, IA2, and insulin raised autoimmunity detection rates to 98% at disease onset. Wenzlau et al. (2007) concluded that SLC30A8 is a major autoantigen in type 1 diabetes. Clinical Management Clinical management requires use of dietary alterations and insulin therapy to maintain blood glucose levels within accepted range. Lee et al. (2000) reported that a single-chain insulin analog (SIA) produced from the gene construct recombinant adeno-associated virus (AAV)-L-type pyruvate kinase (LPK)-SIA caused remission of diabetes in streptozotocin-induced diabetic rats and autoimmune diabetic mice for up to 8 months without any apparent side effects. Three of the authors retracted the paper in 2009 on the grounds that they had not been able to reproduce the results. Cheung et al. (2000) found that gut K cells could be induced to produce human insulin by providing the cells with the human insulin gene linked to the 5-prime regulatory region of the gene encoding glucose-dependent insulinotropic polypeptide (GIP; 137240). Mice expressing this transgene produced human insulin specifically in gut K cells. This insulin protected the mice from developing diabetes and maintained glucose tolerance after destruction of the native insulin-producing beta cells. Population Genetics IDDM occurs about 20 times more frequently among children in the United States than among those in China. Bao et al. (1989) examined the question of whether this was due to a difference in the frequency of the allele leading to aspartic acid in position 57 of the HLA-DQ-beta chain. The presence of asp57 (or A) seems to protect against IDDM, while a noncharged amino acid in the same position (NA) is associated with increased susceptibility. Among probands in the IDDM registries in Allegheny County, Pa., 96% were homozygous NA, 4% were heterozygous, and none was homozygous A. In studies of 18 Chinese IDDM patients and 25 unrelated healthy Chinese controls, Bao et al. (1989) found that only 1 patient was homozygous NA and 13 were heterozygous, while among the 25 Chinese controls, 23 were homozygous A. The large proportion of homozygous A persons in the Chinese population is consistent with the low incidence of IDDM in China. The association between NA and IDDM may be strong in both populations. Dorman et al. (1990) hypothesized that the 30-fold difference in IDDM incidence across racial groups and countries is related to variability in the frequency of NA alleles. To test the hypothesis, they evaluated diabetic and nondiabetic persons in 5 populations, with risks that were low, moderate, and high. NA alleles were significantly associated with IDDM in all areas, with population-specific odds ratios for NA homozygotes relative to A homozygotes ranging from 14 to 111. Dorman et al. (1990) used estimated genotype-specific incidence rates for Allegheny County, Pa., Caucasians to predict the overall incidence rates in the remaining populations. These predictions fell within the 95% confidence limits of the actual rates established from incidence registries. Results were considered consistent with the hypothesis that population variation in the distribution of NA alleles explains much of the geographic variation in IDDM incidence. Concannon et al. (1990) excluded close linkage of a gene making a major contribution to susceptibility to IDDM and the genes for 2 T-cell receptors, TCRA (see 186880) and TCRB (see 186930). In a Japanese study, Imagawa et al. (2000) described what appeared to be a novel subtype of type I diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Lernmark (2000) argued that, despite the unusual features, these patients had autoimmune type I diabetes. Since the patients described by Imagawa et al. (2000) had features of genetic susceptibility to autoimmune type I diabetes, Lernmark (2000) found it tempting to speculate that diabetes resulted from accelerated beta-cell destruction due to some environmental factor that had such a rapid effect that the autoimmune response characteristic of autoimmune type I diabetes was precluded. Along the same lines, Honeyman et al. (2000) suggested that rotavirus, which is not infectious until it is activated by trypsin (a product of the exocrine pancreas that can infect islets in tissue culture), may have been a cause of clinically silent pancreatic infection in the patients reported by Imagawa et al. (2000) and may have led to T cell-mediated loss of beta cells before islet-cell antibodies could develop. The incidence of IDDM in Korea is less than one-tenth of that in the United States, and it has been suggested that HLA alleles of Asian patients associated with diabetes differ from those of Caucasians. Park et al. (2000) analyzed the common susceptibility and transmission pattern of a series of HLA DRB1-DQB1 haplotypes to Korean and Caucasian patients with IDDM. They performed HLA DR and DQ typing of 158 IDDM patients in a case control study, 140 nondiabetic subjects from the same geographic area, 49 simplex families from Seoul, and 283 families from the Human Biological Data Interchange. Although the haplotype frequencies in the 2 populations are quite different, when identical haplotypes are compared, their odds ratios are nearly the same. For all parental haplotypes, the transmission to diabetic offspring was similar for Korean and Caucasian families. The authors concluded that, not only by case-control comparison but also by transmission analyses of the haplotypes, that the susceptibility effects of DRB1-DQB1 haplotypes are consistent in Koreans and Caucasians. Thus, the influence of class II susceptibility and resistance alleles appears to transcend ethnic and geographic diversity of IDDM. Animal Model Onodera et al. (1978) presented evidence that a single locus controls susceptibility to virus-induced diabetes mellitus in mice. They speculated that the gene might modulate expression of viral receptors on the beta cells of islets. DRw3 and DRw4 appear to be associated with JOD. The disease may be somewhat different depending on which is associated. The disease is more severe in homozygotes or genetic compounds (Bodmer, 1978). Prochazka et al. (1987) established a polygenic basis for susceptibility to IDDM in nonobese diabetic mice (NOD) by outcross to a related inbred strain, nonobese normal. Analysis of first and second backcross progeny showed that at least 3 recessive genes are required for development of overt diabetes. One of them was tightly linked to the major histocompatibility complex on chromosome 17 of the mouse; a second was localized proximal to the Thy-1/Alp-1 cluster on mouse chromosome 9. (In an erratum, the authors stated that the original recombinant designation was erroneous.) It may be that corresponding recessive genes are located on chromosomes 6 and 11 in man; the THY1 (188230) and APOA1 (107680) genes are on human 11q. By use of an affected sib pair method, however, Hyer et al. (1991) appeared to have excluded the possibility of an IDDM susceptibility gene on 11q (see 125852). Several features of the genetics and immunopathology of diabetes in the NOD mouse are closely similar to those of the human disease. Three murine diabetes susceptibility genes, Idd-1, Idd-3, and Idd-4, had been mapped, but only in the case of Idd-1 was there evidence concerning the identity of the gene product. Allelic variation within the murine immune response I-A(beta) gene and its human homolog, HLA-DQB1, correlated with susceptibility. Cornall et al. (1991) mapped Idd-5 to the proximal region of mouse chromosome 1. This region contains at least 2 candidate susceptibility genes: the interleukin-1 receptor gene (see 147810) and the Lsh/Ity/Bcg gene which encodes resistance to bacterial and parasitic infections and affects the function of macrophages (see 209950). Garchon et al. (1991) demonstrated close association of periinsulitis in the NOD mouse with a locus on chromosome 1. In the NOD mouse, furthermore, insulitis and early-onset diabetes had been linked to chromosomes 3 and 11, respectively (Todd et al., 1991). Garchon et al. (1991) suggested that the existence of conserved syntenies between the human and murine genomes point to possible IDDM genes on human chromosomes 1, 2, or 18. Overt type I diabetes is often preceded by the appearance of insulin autoantibodies. Furthermore, prophylactic administration of insulin to diabetes-prone rats, NOD mice, and human subjects results in protection from diabetes. These 2 observations suggest that an immune response to insulin is involved in the process of beta cell destruction in the pancreas. Daniel and Wegmann (1996) noted that islet-infiltrating cells isolated from NOD mice are enriched for insulin-specific T cells, insulin-specific T cell clones are capable of adoptive transfer of diabetes, and epitopes present on residues 9-23 of the B chain appear to be dominant in this spontaneous response. Against this background, Daniel and Wegmann (1996) tested the effect of either subcutaneous or intranasal administration of B-(9-23) on the incidence of diabetes in NOD mice. The results indicated to them that both modes of administration resulted in a marked delay in the onset and a decrease in the incidence of diabetes relative to mice given the control peptide, a tetanus toxin. The protective effect was associated with reduced T-cell proliferative response to B-(9-23) in B-(9-23)-treated mice. Amrani et al. (2000) demonstrated that progression of pancreatic islet inflammation to overt diabetes in NOD mice is driven by the 'avidity maturation' of a prevailing, pancreatic beta-cell-specific T lymphocyte population carrying the CD8 antigen (186910). This T lymphocyte population recognizes 2 related peptides, NRP and NRP-A7, in the context of H-2K(d) class I molecules of the major histocompatibility complex. As prediabetic NOD mice age, their islet-associated CD8+ T lymphocytes contain increasing numbers of NRP-A7-reactive cells, and these cells bind NRP-A7/H-2K(d) tetramers with increased specificity, increased avidity, and longer half-lives. Repeated treatment of prediabetic NOD mice with soluble NRP-A7 peptide blunts the avidity maturation of the NRP-A7-reactive-CD8+ T cell population. This inhibits the local production of T cells that are cytotoxic to beta cells, and halts the progression from severe insulitis to diabetes. Amrani et al. (2000) concluded that avidity maturation of pathogenic T-cell populations may be the key event in the progression of benign inflammation to overt disease in autoimmunity. Given the presence of islet beta-cell-reactive autoantibodies in prediabetic nonobese diabetic mice, Greeley et al. (2002) abrogated the maternal transmission of such antibodies in order to assess their influence on susceptibility of progeny to diabetes. First, they used B cell-deficient NOD mothers to eliminate the transmission of maternal immunoglobulins. In a complementary approach, they used immunoglobulin transgenic NOD mothers to exclude autoreactive specificities from the maternal B-cell repertoire. Finally, the authors implanted NOD embryos in pseudopregnant mothers of a nonautoimmune strain. In a commentary on the publication of Greeley et al. (2002), von Herrath and Bach (2002) noted that in the first experiment the incidence of diabetes was reduced to 25%, compared with 65% in offspring of B cell-competent mothers. The second experiment resulted in a more significant reduction: 20% of offspring developed diabetes versus 70% of offspring of nontransgenic mothers. In the third experiment, diabetes incidence was only 15% of offspring versus 73% of offspring of NOD mothers. Greeley et al. (2002) concluded that the maternal transmission of antibodies is a critical environmental parameter influencing the ontogeny of T cell-mediated destruction of islet beta cells in NOD mice. Lang et al. (2005) investigated the circumstances under which CD8+ T cells specific for pancreatic beta islet antigens induce disease in mice expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) as a transgene under the control of the rat insulin promoter. In contrast to infection with LCMV, immunization with LCMV-GP-derived peptide did not induce autoimmune diabetes despite large numbers of autoreactive cytotoxic T cells; only subsequent treatment with Toll-like receptor (see 601194) ligands elicited overt diabetes. This difference was critically regulated by the pancreas itself, which upregulated class I major histocompatibility complex (MHC) in response to systemic Toll-like receptor-triggered interferon-alpha (147660) production. Lang et al. (2005) concluded that the 'inflammatory status' of the target organ is a separate and limiting factor determining the development of autoimmune disease. The NOD mouse is not only the best model for spontaneous type 1 diabetes, but also for Sjogren syndrome (270150). In NOD mice, in which loss of salivary secretory function develops spontaneously (as in human Sjogren syndrome), Winer et al. (2002) found that disruption of the Ica69 gene (147625), which is expressed in salivary and lacrimal glands, prevented lacrimal gland disease and greatly reduced salivary gland disease. These animals developed type 1 diabetes with slight delay but at much the same incidence as wildtype animals, assigning a facultative rather than obligate role to ICA69 in the development of diabetes. Nakayama et al. (2005) showed that the proinsulin/insulin molecules have a sequence that is a primary target of the autoimmunity that causes diabetes of the NOD mouse. They created insulin-1 and insulin-2 gene knockouts combined with a mutated proinsulin transgene, in which residue 16 on the B chain was changed to alanine, in NOD mice. This mutation abrogated the T-cell stimulation of a series of the major insulin autoreactive NOD T-cell clones. Female mice with only the altered insulin did not develop insulin autoantibodies, insulitis, or autoimmune diabetes, in contrast with mice containing at least 1 copy of the native insulin gene. Nakayama et al. (2005) suggested that proinsulin is a primary autoantigen of the NOD mouse and speculated that organ-restricted autoimmune disorders with marked major histocompatibility complex restriction of disease are likely to have specific primary autoantigens. Treatment of NOD mice with end-stage disease by injection of donor splenocytes and complete Freund adjuvant eliminates autoimmunity and permanently restores normoglycemia. The return of endogenous insulin secretion is accompanied by the reappearance of pancreatic beta cells. Kodama et al. (2003) showed that live donor male or labeled splenocytes administered to diabetic NOD females contain cells that rapidly differentiate into islet or ductal epithelial cells within the pancreas. Treatment with irradiated splenocytes is also followed by islet regeneration, but at a slower rate. The islets generated in both instances are persistent, functional, and apparent in all NOD hosts with permanent disease reversal. Chong et al. (2006), Nishio et al. (2006), and Suri et al. (2006) replicated the studies of Kodama et al. (2003). Chong et al. (2006) cured 32% of NOD mice of established diabetes (greater than 340 milligrams per deciliter blood glucose), although beta cells in these mice were not derived from donor splenocytes. Nishio et al. (2006) provided data indicating that the recovered islets were all of host origin, reflecting that the diabetic NOD mice actually retained substantial beta cell mass, which can be rejuvenated/regenerated to reverse disease upon adjuvant-dependent dampening of autoimmunity. Their study reported a 70% reversion rate to spontaneous diabetes among the treated animals compared to an 8% reversion rate in the study by Kodama et al. (2003). Suri et al. (2006) found that islet transplantation and immunization with Freund complete adjuvant along with multiple injections of allogeneic male splenocytes allowed for survival of transplanted islets and recovery of endogenous beta-cell function in a proportion of mice, but with no evidence for allogeneic splenocyte-derived differentiation of new islet beta cells. Suri et al. (2006) concluded that control of autoimmune disease at a crucial time in diabetogenesis can result in recovery of beta-cell function. In a commentary on the papers of Chong et al. (2006), Nishio et al. (2006), and Suri and Unanue (2006), Faustman et al. (2006) stated that while these groups did not find that donor spleen cells contribute to the regeneration of the pancreas, Faustman et al. (2006) confirmed the results of Kodama et al. (2003) of a direct splenocyte contribution to insulin-expressing cells of the islets. In response to the comments by Faustman et al. (2006), Chong et al. (2006), Nishio et al. (2006), Suri and Unanue (2006) stated that they could not detect spleen cell transdifferentiation of spleen cells into beta cells in NOD mice. Faustman (2007) refuted comments made by Nishio et al. (2006) that they did not use the appropriate controls. Wen et al. (2008) showed that specific pathogen-free NOD mice lacking Myd88 (602170), an adaptor for multiple innate immune receptors that recognize microbial stimuli, do not develop type 1 diabetes. The effect is dependent on commensal microbes because germ-free Myd88-negative NOD mice develop robust diabetes, whereas colonization of these germ-free Myd88-negative NOD mice with a defined microbial consortium (representing bacterial phyla normally present in human gut) attenuates type 1 diabetes. Wen et al. (2008) also found that Myd88 deficiency changes the composition of the distal gut microbiota, and that exposure to the microbiota of specific pathogen-free Myd88-negative NOD donors attenuates type 1 diabetes in germ-free NOD recipients. Wen et al. (2008) concluded that, taken together, their findings indicated that interaction of the intestinal microbes with the innate immune system is a critical epigenetic factor modifying type 1 diabetes predisposition. ### Reviews Tisch and McDevitt (1996) reviewed the molecular understanding of the pathogenesis of this autoimmune disease. Complete molecular understanding may permit the design of rational and effective means of prevention. Prevention could then replace insulin therapy, which is effective but associated with long-term renal, vascular, and retinal complications. They pointed to the concordance rate of only 50% in monozygotic twins, indicating as yet unidentified environmental factors. There is a north-south gradient in incidence of the disease, with the highest incidence in northern Europe (1% to 1.5% in Finland) and decreasing incidence in more southerly and tropical locations. Although this suggests the effect of infectious agents in the nonobese diabetic (NOD) mouse, germ-free NOD mice have the highest incidence (nearly 100%) that has been seen in any NOD colony. Tisch and McDevitt (1996) reviewed the role of the major histocompatibility complex, the autoantigens targeted in IDDM, the T-cell response in IDDM, and experience to date with immunotherapy. Even if safe, effective, and long-lasting immunotherapies are developed, their application presents a formidable challenge. Only 15% of new cases of IDDM occur in families with a previous case. Overt diabetes develops only when beta cell destruction is nearly complete, and the patient is asymptomatic for months or years until that point is reached. Thus, immunotherapy must be preventive, which requires inexpensive and accurate genetic, autoantibody, and T cell screening techniques. As indicated, linkage studies have shown that type I diabetes in NOD mice is a polygenic disease involving more than 15 chromosome susceptibility regions. Despite extensive investigation, the identification of individual susceptibility genes either within or outside the major histocompatibility complex region has proved problematic because of the limitations of linkage analysis. Hamilton-Williams et al. (2001) provided evidence implicating a single diabetes susceptibility gene that lies outside the MHC region, namely, beta-2-microglobulin (B2M; 109700). Using allelic reconstitution by transgenic rescue, they showed that NOD mice expressing the B2ma allele developed diabetes, whereas NOD mice expressing a murine B2mb or human allele of B2M were protected. The murine B2ma allele differs from the B2mb allele at only a single amino acid. Mechanistic studies indicated that the absence of the NOD B2ma isoform on nonhematopoietic cells inhibited the development or activation of diabetogenic T cells. Hamilton-Williams et al. (2001) stated that it was not yet possible to determine whether subtle variations in B2M may also contribute to autoimmune diabetes in humans because the extent of polymorphism in this gene had not been extensively investigated. However, they noted that the B2ma allele implicated as a dominant diabetes susceptibility gene in NOD mice is not a biologically aberrant variant but rather a common physiologically normal allele, which may exert its pathogenic functions only in certain combinatorial contexts. This supports the hypothesis of combinatorial context of 'normal' alleles (Nerup et al., 1994). They also noted that further support for this concept is strong linkage disequilibrium implicating a number of other physiologically normal cytokine variants as candidate susceptibility genes for diabetes (Lyons et al., 2000; Morahan et al., 2001); see 605998. Vyse and Todd (1996) gave a general review of genetic analyses of autoimmune diseases, including this one. History Using synalbumin insulin antagonism as a test, Vallance-Owen (1966) studied 9 families containing 16 overt cases of diabetes mellitus and concluded that the state of synalbumin positivity is a dominant. GU \- Polyuria \- Hyperglycemia-induced osmotic diuresis Immunology \- Pancreatic autoimmunity Metabolic \- Ketoacidosis \- Abnormally increased gluconeogenesis \- Insufficient glucose disposal Endocrine \- Diabetes mellitus Inheritance \- Autosomal recessive susceptibility \- heterogeneous Lab \- Hyperglycemia \- Relative insulin deficiency GI \- Polydipsia \- Polyphagia ▲ 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 inhibitors [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	DIABETES MELLITUS, INSULIN-DEPENDENT	c0011854	2,996	omim	https://www.omim.org/entry/222100	2019-09-22T16:28:46	{"doid": ["9744"], "mesh": ["D003922"], "omim": ["222100"], "icd-10": ["E10"], "synonyms": ["Alternative titles", "DIABETES MELLITUS, TYPE I", "JUVENILE-ONSET DIABETES"]}
This article needs attention from an expert in medicine or Psychology. Please add a reason or a talk parameter to this template to explain the issue with the article. WikiProject Medicine or WikiProject Psychology may be able to help recruit an expert. (February 2009) Semantic dyslexia is, as the name suggests, a subtype of the group of cognitive disorders known as alexia (acquired dyslexia). Those who suffer from semantic dyslexia are unable to properly attach words to their meanings in reading and/or speech. When confronted with the word "diamond", they may understand it as "sapphire", "shiny" or "diamonds"; when asking for a bus ticket, they may ask for some paper or simply "a thing". Semantic dementia (SD) is a degenerative disease characterized by atrophy of anterior temporal regions (the primary auditory cortex; process auditory information) and progressive loss of semantic memory. SD patients often present with surface dyslexia, a relatively selective impairment in reading low-frequency words with exceptional or atypical spelling-to-sound correspondences.[1] ## References[edit] 1. ^ Wilson, SM; Brambati, SM; Henry, RG; Handwerker, DA; Agosta, F; Miller, BL; Wilkins, DP; Ogar, JM; Gorno-Tempini, ML (Jan 2009). "The neural basis of surface dyslexia in semantic dementia". Brain : A Journal of Neurology. 132 (Pt 1): 71–86. doi:10.1093/brain/awn300. PMC 2638692. PMID 19022856. ## Further reading[edit] * Marshall JC.; Newcombe, F. (Jul 1973). "Patterns of paralexia: a psycholinguistic approach". J Psycholinguist Res. 2 (3): 175–99. doi:10.1007/BF01067101. PMID 4795473. S2CID 145387879. [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 inhibitors [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	Semantic dyslexia	None	2,997	wikipedia	https://en.wikipedia.org/wiki/Semantic_dyslexia	2021-01-18T18:59:50	{"wikidata": ["Q7449060"]}
A rare, genetic, neurological disorder characterized by horizontal gaze palsy, sensorineural deafness, central hypoventilation, developmental delay, and intellectual disability, described in persons of Athabascan American Indian heritage. Swallowing dysfunction, vocal cord paralysis, facial paresis, seizures, internal carotid artery, and cardiac outflow tract anomalies may be additionally observed. No dysmorphic facial features are associated. [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 inhibitors [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	Athabaskan brainstem dysgenesis syndrome	c1832215	2,998	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=69739	2021-01-23T18:59:54	{"gard": ["8333"], "mesh": ["C535397"], "omim": ["601536"], "umls": ["C1832215"], "synonyms": ["ABSD", "Athabascan brainstem dysgenesis syndrome", "Navajo brainstem syndrome"]}
Klebe et al. (1970), using mouse-human hybrid somatic cells in culture, found that Es-2 esterase activity was depressed. Human chromosomes are selectively lost from the hybrid cells. Depression of esterase activity was present when human chromosome 10 was present and the activity returned to normal when chromosome 10 was lost. Thus, they concluded that the regulator 'element' is probably linked to chromosome 10. This assignment must be considered 'in limbo' (Ruddle, 1977). [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 inhibitors [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	ESTERASE ES-2, REGULATOR FOR	c1851475	2,999	omim	https://www.omim.org/entry/133300	2019-09-22T16:41:28	{"omim": ["133300"]}

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