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Trichothiodystrophy, which is commonly called TTD, is a rare inherited condition that affects many parts of the body. The hallmark of this condition is brittle hair that is sparse and easily broken. Tests show that the hair is lacking sulfur, an element that normally gives hair its strength.
The signs and symptoms of trichothiodystrophy vary widely. Mild cases may involve only the hair. More severe cases also cause delayed development, significant intellectual disability, and recurrent infections; severely affected individuals may survive only into infancy or early childhood.
Mothers of children with trichothiodystrophy may experience problems during pregnancy including pregnancy-induced high blood pressure (preeclampsia) and a related condition called HELLP syndrome that can damage the liver. Babies with trichothiodystrophy are at increased risk of premature birth, low birth weight, and slow growth.
Most affected children have short stature compared to others their age. Intellectual disability and delayed development are common, although most affected individuals are highly social with an outgoing and engaging personality. Some have brain abnormalities that can be seen with imaging tests. Trichothiodystrophy is also associated with recurrent infections, particularly respiratory infections, which can be life-threatening. Other features of trichothiodystrophy can include dry, scaly skin (ichthyosis); abnormalities of the fingernails and toenails; clouding of the lens in both eyes from birth (congenital cataracts); poor coordination; and skeletal abnormalities.
About half of all people with trichothiodystrophy have a photosensitive form of the disorder, which causes them to be extremely sensitive to ultraviolet (UV) rays from sunlight. They develop a severe sunburn after spending just a few minutes in the sun. However, for reasons that are unclear, they do not develop other sun-related problems such as excessive freckling of the skin or an increased risk of skin cancer. Many people with trichothiodystrophy report that they do not sweat.
## Frequency
Trichothiodystrophy has an estimated incidence of about 1 in 1 million newborns in the United States and Europe. About 100 affected individuals have been reported worldwide.
## Causes
Most cases of the photosensitive form of trichothiodystrophy result from mutations in one of three genes: ERCC2, ERCC3, or GTF2H5. The proteins produced from these genes work together as part of a group of proteins called the general transcription factor IIH (TFIIH) complex. This complex is involved in the repair of DNA damage, which can be caused by UV radiation from the sun. The TFIIH complex also plays an important role in gene transcription, which is the first step in protein production.
Mutations in the ERCC2, ERCC3, or GTF2H5 genes reduce the amount of TFIIH complex within cells, which impairs both DNA repair and gene transcription. An inability to repair DNA damage probably underlies the sun sensitivity in affected individuals. Studies suggest that many of the other features of trichothiodystrophy may result from problems with the transcription of genes needed for normal development before and after birth.
Mutations in at least one gene, MPLKIP, have been reported to cause a non-photosensitive form of trichothiodystrophy. Mutations in this gene account for fewer than 20 percent of all cases of non-photosensitive trichothiodystrophy. Little is known about the protein produced from the MPLKIP gene, although it does not appear to be involved in DNA repair. It is unclear how mutations in the MPLKIP gene lead to the varied features of trichothiodystrophy.
In some cases, the genetic cause of trichothiodystrophy is unknown.
### Learn more about the genes associated with Trichothiodystrophy
* ERCC2
* ERCC3
* GTF2H5
* MPLKIP
## 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
| Trichothiodystrophy | c1866504 | 1,300 | medlineplus | https://medlineplus.gov/genetics/condition/trichothiodystrophy/ | 2021-01-27T08:25:34 | {"gard": ["12109"], "mesh": ["D054463"], "omim": ["601675", "234050"], "synonyms": []} |
Childhood cancer
Other namesPediatric cancer
A girl trying out hats to wear after chemotherapy against a Wilms' tumor[1]
SpecialtyPediatrics, oncology
Childhood cancer is cancer in a child. In the United States, an arbitrarily adopted standard of the ages used are 0–14 years inclusive, that is, up to 14 years 11.9 months of age.[2][3] However, the definition of childhood cancer sometimes includes adolescents between 15–19 years old.[3] Pediatric oncology is the branch of medicine concerned with the diagnosis and treatment of cancer in children.
Worldwide, it is estimated that childhood cancer has an incidence of more than 175,000 per year, and a mortality rate of approximately 96,000 per year.[4] In developed countries, childhood cancer has a mortality of approximately 20% of cases.[5] In low resource settings, on the other hand, mortality is approximately 80%, or even 90% in the world's poorest countries.[5] In many developed countries the incidence is slowly increasing, as rates of childhood cancer increased by 0.6% per year between 1975 and 2002 in the United States[6] and by 1.1% per year between 1978 and 1997 in Europe.[7] Unlike cancers in adults, which typically arise from years of DNA damage, childhood cancers are caused by a misappropriation of normal developmental processes.[8]
## Contents
* 1 Signs and symptoms
* 1.1 Learning problems
* 2 Risk factors
* 3 Diagnosis
* 3.1 Types
* 4 Adolescent and young adult oncology
* 5 Treatment
* 6 Prognosis
* 7 Epidemiology
* 7.1 US
* 7.2 UK
* 8 Foundations and fundraising
* 9 References
## Signs and symptoms[edit]
### Learning problems[edit]
Main article: Learning problems in childhood cancer
Children with cancer are at risk for developing various cognitive or learning problems.[9] These difficulties may be related to brain injury stemming from the cancer itself, such as a brain tumor or central nervous system metastasis or from side effects of cancer treatments such as chemotherapy and radiation therapy. Studies have shown that chemo and radiation therapies may damage brain white matter and disrupt brain activity.
This cognitive problem is known as post-chemotherapy cognitive impairment (PCCI) or "chemo brain." This term is commonly use by cancer survivors who describe having thinking and memory problems after cancer treatment.[10] Researchers are unsure what exactly causes chemo brain, however, they say it is likely to be linked to either the cancer itself, the cancer treatment, or be an emotional reaction to both.[10]
This cognitive impairment is commonly noticed a few years after a child endures cancer treatment. When a childhood cancer survivor goes back to school, they might experience lower test scores, problems with memory, attention, and behavior, as well as poor hand-eye coordination and slowed development over time.[11] Parents can apply their children for special educational services at school if their cognitive learning disability affects their educational success.[12]
## Risk factors[edit]
Familial and genetic factors are identified in 5-15% of childhood cancer cases. In <5-10% of cases, there are known environmental exposures and exogenous factors, such as prenatal exposure to tobacco, X-rays, or certain medications.[13] For the remaining 75-90% of cases, however, the individual causes remain unknown.[13] In most cases, as in carcinogenesis in general, the cancers are assumed to involve multiple risk factors and variables.[14]
Aspects that make the risk factors of childhood cancer different from those seen in adult cancers include:[15]
* Different, and sometimes unique, exposures to environmental hazards. Children must often rely on adults to protect them from toxic environmental agents.
* Immature physiological systems to clear or metabolize environmental substances
* The growth and development of children in phases known as "developmental windows" result in certain "critical windows of vulnerability".
Also, a longer life expectancy in children avails for a longer time to manifest cancer processes with long latency periods, increasing the risk of developing some cancer types later in life.[15]
Advanced parental age has been associated with increased risk of childhood cancer in the offspring.[16] There are preventable causes of childhood malignancy, such as delivery overuse and misuse of ionizing radiation through computed tomography scans when the test is not indicated or when adult protocols are used.[17][18]
## Diagnosis[edit]
### Types[edit]
Two girls with acute lymphocytic leukemia demonstrating intravenous access for chemotherapy.
The most common cancers in children are (childhood) leukemia (32%), brain tumors (18%), and lymphomas (11%).[7][19] In 2005, 4.1 of every 100,000 young people under 20 years of age in the U.S. were diagnosed with leukemia, and 0.8 per 100,000 died from it.[20] The number of new cases was highest among the 1–4 age group, but the number of deaths was highest among the 10–14 age group.[20]
In 2005, 2.9 of every 100,000 people 0–19 years of age were found to have cancer of the brain or central nervous system, and 0.7 per 100,000 died from it.[20] These cancers were found most often in children between 1 and 4 years of age, but the most deaths occurred among those aged 5–9.[20] The main subtypes of brain and central nervous system tumors in children are: astrocytoma, brain stem glioma, craniopharyngioma, desmoplastic infantile ganglioglioma, ependymoma, high-grade glioma, medulloblastoma and atypical teratoid rhabdoid tumor.[21]
Other, less common childhood cancer types are:[21][19]
* Neuroblastoma (6%, nervous system)
* Wilms tumor (5%, kidney)
* Non-Hodgkin lymphoma (4%, blood)
* Childhood rhabdomyosarcoma (3%, many sites)
* Retinoblastoma (3%, eye)
* Osteosarcoma (3%, bone cancer)
* Ewing sarcoma (1%, many sites)
* Germ cell tumors (5%, many sites)
* Pleuropulmonary blastoma (lung or pleural cavity)
* Hepatoblastoma and hepatocellular carcinoma (liver cancer)
## Adolescent and young adult oncology[edit]
Main article: Adolescent and young adult oncology
Adolescent and young adult oncology (AYA) is a branch of medicine that deals with the prevention, diagnosis, and treatment of cancer in AYA patients aged 13-30. Studies have continuously shown that while pediatric cancer survival rates have gone up, the survival rate for adolescents and young adults has remained stagnant. While many clinical trials exist for adults with cancer and children with cancer, AYAs underutilize clinical trials. Most pediatric clinical trials serve patients up to age 21. Additionally, AYAs face problems that adults and children rarely see including college concerns, fertility, and sense of aloneness. Studies have often shown that treating young adults with the same protocols used in pediatrics is more effective than adult oriented treatments.
## Treatment[edit]
Childhood cancers do not typically consist of tumors with clinically targetable oncogenes. Thus, treatment is frequently limited to chemoradiotherapy, which is a combination of chemotherapy and radiotherapy. The cytotoxicity of chemotherapy can result in immediate and long-term treatment-related comorbidities.[8] For children undergoing treatment for high-risk cancer, more than 80% experience life-threatening or fatal toxicity as a result of their treatment.[22]
## Prognosis[edit]
Main article: Cancer survivor
Adult survivors of childhood cancer have some physical, psychological, and social difficulties.
Premature heart disease is a major long-term complication in adult survivors of childhood cancer.[23] Adult survivors are eight times more likely to die of heart disease than other people, and more than half of children treated for cancer develop some type of cardiac abnormality, although this may be asymptomatic or too mild to qualify for a clinical diagnosis of heart disease.[23]
Childhood cancer survivors are also at risk of developing adverse effects on the kidneys [24] and the liver.[25] The risk of liver late adverse effects in childhood cancer survivors is increased in those who have had radiotherapy to the liver and in people with factors such as higher body mass index and chronic viral hepatitis.[25] Certain treatments and liver surgery may also increase the risk of adverse liver effects in childhood cancer survivors.[25]
## Epidemiology[edit]
Internationally, the greatest variation in childhood cancer incidence occurs when comparing high-income countries to low-income ones.[26] This may result from differences in being able to diagnose cancer, differences in risk among different ethnic or racial population subgroups, as well as differences in risk factors.[26] An example of differing risk factors is in cases of pediatric Burkitt lymphoma, a form of non-Hodgkin lymphoma that sickens 6 to 7 children out of every 100,000 annually in parts of sub-Saharan Africa, where it is associated with a history of infection by both Epstein-Barr virus and malaria.[26][27][28] In industrialized countries, Burkitt lymphoma is not associated with these infectious conditions.[26]
### US[edit]
In the United States, cancer is the second most common cause of death among children between the ages of 1 and 14 years, exceeded only by accidents.[20] More than 16 out of every 100,000 children and teens in the U.S. were diagnosed with cancer, and nearly 3 of every 100,000 died from the disease.[20] In the United States in 2012, it was estimated that there was an incidence of 12,000 new cases, and 1,300 deaths, from cancer among children 0 to 14 years of age.[29] Statistics from the 2014 American Cancer Society report:
Ages birth to 14[30]
Sex Incidence Mortality Observed Survival %
Boys 178.0 23.3 81.3
Girls 160.1 21.1 82.0
Ages 15 to 19[30]
Sex Incidence Mortality Observed Survival %
Boys 237.7 34.5 80.0
Girls 235.5 24.7 85.4
Note: Incidence and mortality rates are per 1,000,000 and age-adjusted to the 2000 US standard population. Observed survival percentage is based on data from 2003-2009.
### UK[edit]
Cancer in children is rare in the UK, with an average of 1,800 diagnoses every year but contributing to less than 1% of all cancer-related deaths.[31] Age is not a confounding factor in mortality from the disease in the UK. From 2014-2016, approximately 230 children died from cancer, with Brain/CNS cancers being the most common culprit.
## Foundations and fundraising[edit]
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Part of the proceeds from the sale of yellow silage wrappings goes to childhood cancer research, Brastad, Sweden
Currently, there are various organizations whose main focus is fighting childhood cancer. Organizations focused on childhood cancer through cancer research and/or support programs include: Childhood Cancer Canada, CLIC Sargent and the Children's Cancer and Leukaemia Group (in United Kingdom), Child Cancer Foundation (in New Zealand), Children's Cancer Recovery Foundation (in United States),[32] American Childhood Cancer Organization (in United States),[33] Childhood Cancer Support (Australia) and the Hayim Association (in Israel).[34] Alex's Lemonade Stand Foundation allows people across the US to raise money for pediatric cancer research by organizing lemonade stands.[35] The National Pediatric Cancer Foundation focuses on finding less toxic and more effective treatments for pediatric cancers. This foundation works with 24 different hospitals across the US in search of treatments effective in practice.[36] Childhood Cancer International is the largest global pediatric cancer foundation. It focuses on early access to care for childhood cancers, focusing on patient support and patient advocacy.[37]
According to estimates by experts in the field of pediatric cancer, by 2020, cancer will cost $158 million annually for both research and treatment which marks a 27% increase since 2010.[38] Ways in which the foundations are helped by people include writing checks, collecting spare coins, bake/lemonade sales, donating portions of purchases from stores or restaurants, or Paid Time Off donations[39] as well as auctions, bike rides, dance-a-thons. Additionally, many of the major foundations have donation buttons.
In addition to advancing research focusing on cancer, the foundations also offer support to families whose children are afflicted by the disease. Support groups are offered both in hospitals and online and are funded by the different foundations.[40] The foundations for pediatric cancers organize in-person and online support groups and direct families toward books that aid in the coping process. The foundations for pediatric cancer all fall under the 501(c)3 designation which means that they are non-profit organizations that are tax-exempt.[41] The "International Childhood Cancer Day" occurs annually on February 15.[5][42]
## References[edit]
1. ^ EBSCO database verified by URAC; accessed from Mount Sinai Hospital, New York
2. ^ Bahadur G, Hindmarsh P (January 2000). "Age definitions, childhood and adolescent cancers in relation to reproductive issues". Human Reproduction. 15 (1): 227. doi:10.1093/humrep/15.1.227. PMID 10611218.
3. ^ a b Childhood Cancers: Basic Facts & Figures from Minnesota Department of Health. Retrieved Dec, 2012
4. ^ About childhood cancer at Childhood Cancer 2012, by Children With Cancer UK
5. ^ a b c International Childhood Cancer Day – 15 February 2013 Archived 20 November 2016 at the Wayback Machine at educationscotland.gov.uk. Retrieved Dec, 2012
6. ^ Ward EM, Thun MJ, Hannan LM, Jemal A (September 2006). "Interpreting cancer trends". Annals of the New York Academy of Sciences. 1076 (1): 29–53. Bibcode:2006NYASA1076...29W. doi:10.1196/annals.1371.048. PMID 17119192.
7. ^ a b Kaatsch P (June 2010). "Epidemiology of childhood cancer". Cancer Treatment Reviews. 36 (4): 277–85. doi:10.1016/j.ctrv.2010.02.003. PMID 20231056.
8. ^ a b Bosse, Kristopher R.; Majzner, Robbie G.; Mackall, Crystal L.; Maris, John M. (2020-03-09). "Immune-Based Approaches for the Treatment of Pediatric Malignancies". Annual Review of Cancer Biology. 4 (1): 353–370. doi:10.1146/annurev-cancerbio-030419-033436. ISSN 2472-3428.
9. ^ Children Diagnosed With Cancer: Returning to School from American Cancer Society. Last Medical Review: 07/02/2012
10. ^ a b "Chemo Brain". Mayo Clinic. Mayo Foundation for Medical Education and Research. Retrieved 2019-03-19.
11. ^ "Late Effects of Childhood Cancer Treatment". American Cancer Society. American Cancer Society Inc. Retrieved 2019-03-19.
12. ^ "Learning Problem After Treatment". Children's Oncology Group. The Children's Oncology Group. Retrieved 2019-03-19.
13. ^ a b Children and Cancer, in Children's Health and the Environment, a WHO Training Package for the Health Sector, World Health Organization. In turn citing:
* Birch JM. Genes & Cancer" Arch Dis Child 1999, 80:1-3.
* Lichtenstein P et al" N Engl J Med 2000, 13;343(2) 78-85
14. ^ Children and Cancer, in Children's Health and the Environment, a WHO Training Package for the Health Sector, World Health Organization. In turn citing: Anderson LM et al. Critical Windows of Exposure for Children’s Health: Cancer in Human Epidemiological Studies and Neoplasms in Experimental Animals Models. Environ Health Perspect, 2000, 108(suppl 3) 573-594.
15. ^ a b Children and Cancer, in Children's Health and the Environment, a WHO Training Package for the Health Sector, World Health Organization.
16. ^ Johnson KJ, Carozza SE, Chow EJ, Fox EE, Horel S, McLaughlin CC, et al. (July 2009). "Parental age and risk of childhood cancer: a pooled analysis". Epidemiology. 20 (4): 475–83. doi:10.1097/EDE.0b013e3181a5a332. PMC 2738598. PMID 19373093.
17. ^ "Radiology Safety - What can I do?". Image Gently. Alliance for Radiation Safety in Pediatric Imaging. Retrieved 8 February 2016.
18. ^ Swensen SJ, Duncan JR, Gibson R, Muething SE, LeBuhn R, Rexford J, et al. (September 2014). "An appeal for safe and appropriate imaging of children". Journal of Patient Safety. 10 (3): 121–4. doi:10.1097/PTS.0000000000000116. PMID 24988212. S2CID 33270800.
19. ^ a b "UpToDate".
20. ^ a b c d e f Cancer in Children from Centers for Disease Control and Prevention. Page last reviewed: July 30, 2009
21. ^ a b Childhood Cancer overview from American Society of Clinical Oncology (ASCO). Retrieved January 2013
22. ^ Adamson PC (2015). "Improving the outcome for children with cancer: Development of targeted new agents". Ca. 65 (3): 212–20. doi:10.3322/caac.21273. PMC 4629487. PMID 25754421.
23. ^ a b Lipshultz SE, Franco VI, Miller TL, Colan SD, Sallan SE (2015-01-01). "Cardiovascular disease in adult survivors of childhood cancer". Annual Review of Medicine. 66 (1): 161–76. doi:10.1146/annurev-med-070213-054849. PMC 5057395. PMID 25587648.
24. ^ Kooijmans EC, Bökenkamp A, Tjahjadi NS, Tettero JM, van Dulmen-den Broeder E, van der Pal HJ, Veening MA (March 2019). "Early and late adverse renal effects after potentially nephrotoxic treatment for childhood cancer". The Cochrane Database of Systematic Reviews. 3: CD008944. doi:10.1002/14651858.cd008944.pub3. PMC 6410614. PMID 30855726.
25. ^ a b c Mulder RL, Bresters D, Van den Hof M, Koot BG, Castellino SM, Loke YK, et al. (April 2019). "Hepatic late adverse effects after antineoplastic treatment for childhood cancer". The Cochrane Database of Systematic Reviews. 4: CD008205. doi:10.1002/14651858.cd008205.pub3. PMC 6463806. PMID 30985922.
26. ^ a b c d Children and Cancer, in Children's Health and the Environment, a WHO Training Package for the Health Sector, World Health Organization. In turn citing: Scott CH. Childhood cancer epidemiology in low-income countries" Cancer 2007, 112;3:461-472
27. ^ "Viral Cancers: Epstein-Barr virus". World Health Organization Initiative for Vaccine Research. Retrieved January 28, 2013.
28. ^ Moormann AM, Snider CJ, Chelimo K (October 2011). "The company malaria keeps: how co-infection with Epstein-Barr virus leads to endemic Burkitt lymphoma". Current Opinion in Infectious Diseases. 24 (5): 435–41. doi:10.1097/QCO.0b013e328349ac4f. PMC 3265160. PMID 21885920.
29. ^ Cancer Facts & Figures 2011 from American Cancer Society.
30. ^ a b Ward E, DeSantis C, Robbins A, Kohler B, Jemal A (Mar–Apr 2014). "Childhood and adolescent cancer statistics, 2014". Ca. 64 (2): 83–103. doi:10.3322/caac.21219. PMID 24488779.
31. ^ "Childhood cancer statistics". Cancer Research UK. Retrieved 27 October 2014.
32. ^ "Children's Cancer Recovery Foundation". Children's Cancer Recovery Foundation. Children's Cancer Recovery Foundation. Retrieved 4 May 2018.
33. ^ American Childhood Cancer Organization homepage
34. ^ "Hayim Association". Retrieved 2016-03-31.
35. ^ "About ALSF". Alex's Lemonade Stand Foundation. Alex's Lemonade Stand Foundation. Retrieved 2 May 2018.
36. ^ "About NPCF". National Pediatric Cancer Foundation. National Pediatric Cancer Foundation. Retrieved 2 May 2018.
37. ^ "Who We Are". Childhood Cancer International. Childhood Cancer International. 2015-09-16. Retrieved 2 May 2018.
38. ^ "Cancer costs projected to reach at least $158 billion in 2020". National Institute of Health. U.S. Department of Health and Human Services. 2015-07-23. Retrieved 2 May 2018.
39. ^ "Fundraising Ideas". Cure Childhood Cancer. Cure Childhood Cancer. Retrieved 2 May 2018.
40. ^ "PSYCHOLOGICAL AND EMOTIONAL SUPPORT". American Childhood Cancer Organization. American Childhood Cancer Organization. 2014-11-18. Retrieved 2 May 2018.
41. ^ "Exemption Requirements - 501(c)(3) Organizations". IRS. Retrieved 2 May 2018.
42. ^ February 15th is International Childhood Cancer Awareness Day!!! at The Foundation for Children with Cancer (FCC). Retrieved Dec, 2012
This article incorporates public domain material from websites or documents of the Centers for Disease Control and Prevention.
*[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
| Childhood cancer | c0278704 | 1,301 | wikipedia | https://en.wikipedia.org/wiki/Childhood_cancer | 2021-01-18T18:59:26 | {"umls": ["C0278704"], "wikidata": ["Q5097977"]} |
Autosomal recessive spastic paraplegia type 45 is a rare, pure or complex form of hereditary spastic paraplegia characterized by onset in infancy of progressive lower limb spasticity, abnormal gait, increased deep tendon reflexes and extensor plantar responses, that may be associated with intellectual disability. Additional signs, such as contractures in the lower limbs, amyotrophy, clubfoot and optic atrophy, have also 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
| Autosomal recessive spastic paraplegia type 45 | c3888209 | 1,302 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=320396 | 2021-01-23T17:01:50 | {"omim": ["613162"], "icd-10": ["G11.4"], "synonyms": ["Autosomal recessive spastic paraplegia type 65", "SPG45", "SPG65"]} |
Melhem-Fahl syndrome was described in two siblings born to consanguineous parents in 1985 and was characterized by the presence of 15 dorsal vertebrae and rib pairs. No other cases have been documented since the initial report.
*[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
| Melhem-Fahl syndrome | c2931453 | 1,303 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2482 | 2021-01-23T17:44:24 | {"gard": ["3462"], "mesh": ["C537238"], "umls": ["C2931453"], "icd-10": ["Q76.4"]} |
Erythema multiforme minor
Other namesEM
SpecialtyDermatology
Erythema multiforme is usually a reaction of the skin and mucous membranes that occurs suddenly. It appears as a symmetrical rash and may include the mucous membrane lesions. This means that the body is sensitive to something that causes the skin and mucous membranes to react. The more common mild form is refer to as EM minor. It consists of a skin rash that involve no more than one mucosal surface. The sudden onset will progress rapidly as symmetrical lesions with circular color changes in some or all of the lesions. Rash will spread towards center or trunk of the body. Evenly distributed bumps on the skin become classic iris or target lesions. They have bright red borders and small white bumps in the center. The cause of EM appears to be a highly sensitive reaction that can be triggered by a variety of causes. The causes can include bacterial, viral or chemical products, such as antibiotics – specifically penicillins or cephalosporins. This reaction is an allergic reaction and is in no way contagious. [1]:140
Erythema multiforme minus is sometimes divided into papular and vesiculobullous forms.[2]
## See also[edit]
* Erythema
* Diascopy
* Erythema multiforme
* List of cutaneous conditions
## References[edit]
1. ^ Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
2. ^ Daniel J. Trozak; Dan J. Tennenhouse (1 October 2005). Dermatology skills for primary care: an illustrated guide. Humana Press. pp. 161–. ISBN 978-1-58829-489-0. Retrieved 5 June 2010.
## External links[edit]
Classification
D
* ICD-9-CM: 695.11
* v
* t
* e
Urticaria and erythema
Urticaria
(acute/chronic)
Allergic urticaria
* Urticarial allergic eruption
Physical urticaria
* Cold urticaria
* Familial
* Primary cold contact urticaria
* Secondary cold contact urticaria
* Reflex cold urticaria
* Heat urticaria
* Localized heat contact urticaria
* Solar urticaria
* Dermatographic urticaria
* Vibratory angioedema
* Pressure urticaria
* Cholinergic urticaria
* Aquagenic urticaria
Other urticaria
* Acquired C1 esterase inhibitor deficiency
* Adrenergic urticaria
* Exercise urticaria
* Galvanic urticaria
* Schnitzler syndrome
* Urticaria-like follicular mucinosis
Angioedema
* Episodic angioedema with eosinophilia
* Hereditary angioedema
Erythema
Erythema multiforme/
drug eruption
* Erythema multiforme minor
* Erythema multiforme major
* Stevens–Johnson syndrome, Toxic epidermal necrolysis
* panniculitis (Erythema nodosum)
* Acute generalized exanthematous pustulosis
Figurate erythema
* Erythema annulare centrifugum
* Erythema marginatum
* Erythema migrans
* Erythema gyratum repens
Other erythema
* Necrolytic migratory erythema
* Erythema toxicum
* Erythroderma
* Palmar erythema
* Generalized erythema
This cutaneous condition article is a stub. You can help Wikipedia by expanding it.
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* e
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Erythema multiforme minor | c0857751 | 1,304 | wikipedia | https://en.wikipedia.org/wiki/Erythema_multiforme_minor | 2021-01-18T18:58:31 | {"umls": ["C0857751"], "icd-9": ["695.11"], "wikidata": ["Q5396393"]} |
Lymphomatoid granulomatosis is a rare disorder characterized by an overproduction of white blood cells known as B lymphocytes. These B cells can build up in the tissues of the body, causing damage to the blood vessels. In many cases of lymphomatoid granulomatosis, the abnormal B cells contain the Epstein-Barr virus. The disease is more common in men, usually after the fifth decade of life. Lymphomatoid granulomatosis most commonly affects the lungs, though other areas of the body may also be affected. Signs and symptoms vary but can include cough, shortness of breath, tightness of the chest, fever, weight loss, and fatigue. Skin lesions and central nervous system changes such as headaches, seizures, and ataxia may also be seen. Rarely, the disorder can affect the kidneys or liver. The cause of the disorder is not well understood, though a combination of genetic and immune factors are thought to play a part. Treatment depends on the extent of the disease but may include interferon alfa-2b and combination chemotherapy with rituximab. Occasionally, the disorder resolves on its own without treatment. There has been some debate as to whether lymphomatoid granulomatosis should be viewed as a as a B-cell lymphoma or a lymphoproliferative disease or whether it should be viewed merely as a condition that can develop into a B-cell lymphoma. The prognosis is variable, though lymphomatoid granulomatosis can progress and become fatal in some cases.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Lymphomatoid granulomatosis | c0024307 | 1,305 | gard | https://rarediseases.info.nih.gov/diseases/6943/lymphomatoid-granulomatosis | 2021-01-18T17:59:17 | {"mesh": ["D008230"], "umls": ["C0024307"], "synonyms": []} |
Porencephaly-microcephaly-bilateral congenital cataract syndrome is a rare, genetic, central nervous system malformation syndrome characterized by bilateral congenital cataracts and severe hemorrhagic destruction of the brain parenchyma with associated massive cystic degeneration, enlarged ventricles and subependymal calcification. Patients typically present generalized spasticity, increased deep tendon reflexes and seizures. Hepatomegaly and renal anomalies have also been reported.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Porencephaly-microcephaly-bilateral congenital cataract syndrome | c3151000 | 1,306 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=306547 | 2021-01-23T17:03:08 | {"omim": ["613730"]} |
Distal monosomy 4q is a partial autosomal monosomy characterized by variable combination of craniofacial, developmental, digital, skeletal, and cardiac features: hypotonia, developmental delay, growth deficiency, cleft palate, cardiovascular malformations, abnormalities of the hands and feet and typical dysmorphic features, such as microcephaly, rounded facies, small eyes, broad nasal bridge, upturned nose, full cheeks, small mouth and chin.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Distal monosomy 4q | None | 1,307 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=96145 | 2021-01-23T18:15:28 | {"icd-10": ["Q93.5"], "synonyms": ["Distal deletion 4q", "Monosomy 4qter", "Telomeric deletion 4q"]} |
Malignant sex cord stromal tumor (SCST) of ovary is a rare ovarian cancer (see this term) arising from granulosa, theca, sertoli and leydig cells or stromal fibroblasts, occurring at any age and presenting with abdominal or pelvic mass, and characterized (with the exception of fibroma) by the production of sex steroids resulting in manifestations of hormone excess, with a relatively favorable prognosis.
## Epidemiology
Age related incidence rate was found to be 1 per 500,000 women. Sex cord stromal tumors constitute about 5% of ovarian malignancies.
## Clinical description
Malignant SCST of ovary may occur at any age but usually occurs in child bearing or post menopausal age groups, presenting with manifestations of mass effect (abdominal pain or distention, gastrointestinal symptoms, or abdominal mass) and/or signs of sex hormone production (isosexual precocity including breast swelling and vaginal bleeding, primary or secondary amenorrhea, and/or virilization). Malignant SCST of ovary comprises the following 4 histological forms: gynandroblastoma; malignant granulosa cell tumor of ovary; malignant Sertoli-Leydig cell tumor of ovary; and malignant steroid cell tumor of ovary, not otherwise specified (see these terms).
## Etiology
Mutations in the DICER1 (14q32.13) gene have been found to be a susceptibility factor for SCST, particularly in malignant Sertoli-Leydig cell tumor of ovary.
## Diagnostic methods
Diagnosis is based on clinical features, particularly hormonal manifestations, and is supported by imaging (ultrasonogram, computed tomography) and tumor markers. Malignant granulosa cell tumor of ovary produces inhibin A and B which is helpful in diagnosis and follow-up. A FOXL2 mutation (3q23) has been found in most malignant granulosa cell tumors of the ovary, in adults. Chromosomal abnormalities have been recently detected among granulosa cell tumors and they include trisomy 12, monosomy 22 and chromosome 6 deletion. Diagnosis is confirmed by histological examination.
## Differential diagnosis
Differential diagnoses include the more common malignant ovarian germ cell tumor of ovary, small cell carcinoma of the ovary (see this term) and ovarian metastasis of non-gonadal tumors. Malignant SCST of ovary is also found in association with enchondromatosis, Peutz Jeghers syndrome (see these terms) and Maffuci syndrome.
## Management and treatment
Surgery is performed for staging, histological confirmation and debulking. Total abdominal hysterectomy and bilateral salphingo-oopherectomy is often the initial management. Fertility sparing surgery is offered to patients with localized disease. In the absence of significant infiltration, preservation of the uterus along with the contralateral tube and ovary is attempted in children. Adjuvant chemotherapy is given to patients with advanced tumors.
## Prognosis
Hormonal symptoms lead to earlier diagnosis and hence a better prognosis in many malignant SCST tumors of ovary. Initial stage at diagnosis is the main prognostic factor. Histological type, presence of atypia and mitotic rate are other important prognostic factors. Stage, tumor size and presence of residual tumor after surgery influence the risk of recurrence
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Malignant sex cord stromal tumor of ovary | c1334609 | 1,308 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=35808 | 2021-01-23T16:53:09 | {"icd-10": ["C56"], "synonyms": ["Malignant ovarian SCST", "Malignant ovarian sex cord-stromal tumor"]} |
Vasoproliferative tumor of the retina is a rare, benign, retinal vascular disease characterized by solitary or multiple, unilateral or bilateral, intra-retinal tumor(s), usually located in the peripheral infero-temporal quadrant, and often associated with sub- and intraretinal exudates, epiretinal membranes, exudative retinal detachment and cystoid macular edema, as well as, occasionally, retinal and vitreous hemorrhage. Patients may present with visual loss, floaters, and/or photopsia. Association with various conditions, such as retinitis pigmentosa, congenital retinal toxoplasmosis, retinopathy of prematurity, or coloboma, has been reported.
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Vasoproliferative tumor of the retina | None | 1,309 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=353356 | 2021-01-23T17:13:33 | {"icd-10": ["D31.2"], "synonyms": ["Retinal vasoproliferative tumor", "VPTR", "Vasoproliferative tumor of the ocular fundus"]} |
## Summary
The goals of this overview on urea cycle disorders are the following:
### Goal 1.
To define the urea cycle and to describe the clinical characteristics of urea cycle disorders
### Goal 2.
To review the causes of urea cycle disorders and their prevalence
### Goal 3.
To provide an evaluation strategy to identify the specific type and genetic cause of a urea cycle defect in a proband
### Goal 4.
To review the differential diagnosis of urea cycle disorders
### Goal 5.
To inform genetic risk assessment in family members of the proband
### Goal 6.
To provide a brief summary of the acute management of a urea cycle disorder
## Diagnosis
## Clinical Characteristics
Severity of the urea cycle defect is influenced by the position of the defective protein in the pathway and the severity of the defect (see Figure 1).
Severe deficiency or total absence of activity of any of the first four enzymes in the pathway (CPS1, OTC, ASS1, and ASL) or the cofactor producer (NAGS) results in the accumulation of ammonia and other precursor metabolites during the first few days of life. Because no effective secondary clearance system for ammonia exists, complete disruption of this pathway results in the rapid accumulation of ammonia and development of related symptoms.
Presentation. Individuals with complete defects normally present in the newborn period, when the immaturity of the neonatal liver accentuates defects in the urea cycle enzymes [Pearson et al 2001, Summar 2001, Summar & Tuchman 2001].
* Infants with a urea cycle disorder appear normal at birth but rapidly develop cerebral edema and the related signs of lethargy, anorexia, hyper- or hypoventilation, hypothermia, seizures, neurologic posturing, and coma.
* Because newborns are usually discharged from the hospital within one to two days after birth, the symptoms of a urea cycle disorder often develop when the child is at home and may not be recognized in a timely manner by the family and primary care physician.
The typical initial symptoms of a child with hyperammonemia are nonspecific [Summar 2001, Kölker et al 2015]:
* Failure to feed
* Loss of thermoregulation with a low core temperature
* Somnolence
Symptoms progress from somnolence to lethargy and coma.
* Abnormal posturing and encephalopathy are often related to the degree of central nervous system swelling and pressure on the brain stem [Summar 2001].
* About 50% of neonates with severe hyperammonemia may have seizures, some without overt clinical manifestations.
* Individuals with closed cranial sutures are at higher risk for rapid neurologic deterioration from the cerebral edema that results from ammonia elevation.
* Hyperventilation secondary to the effect of hyperammonemia on the brain stem, a common early finding in hyperammonemic attacks, results in respiratory alkalosis.
* Hypoventilation and respiratory arrest follow as pressure increases on the brain stem.
In milder (or partial) urea cycle enzyme deficiencies, ammonia accumulation may be triggered at almost any time of life by illness or stress (e.g., surgery, prolonged fasting, holidays, the peripartum period), resulting in multiple mild elevations of plasma ammonia concentration.
* Hyperammonemia in the milder defects is typically less severe and the symptoms more subtle than the neonatal presentation of a UCD.
* In individuals with partial enzyme deficiencies, the first recognized clinical episode may be delayed for months or years.
* Although the clinical abnormalities vary somewhat with the specific urea cycle disorder, in most the hyperammonemic episode is marked by loss of appetite, vomiting, lethargy, and behavioral abnormalities [Gardeitchik et al 2012].
* Sleep disorders, delusions, hallucinations, and psychosis may occur.
* An encephalopathic (slow-wave) EEG pattern may be observed during hyperammonemia and nonspecific brain atrophy seen subsequently on MRI.
Defects in the final enzyme in the pathway (ARG1) cause hyperargininemia, a more subtle disorder involving neurologic symptoms; however, neonatal hyperammonemia has been reported (see Arginase Deficiency).
Defects in the two amino acid transporters (ORNT1 and citrin deficiency) may both cause hyperammonemia. However, ORNT1 deficiency may also present with chronic liver dysfunction. Citrin deficiency typically only presents with hyperammonemia in adolescence or adulthood, but may present in infants with neonatal intrahepatic cholestasis, and in older children with failure to thrive.
Neurologic aspects of UCDs. Ammonia can cause brain damage through a variety of proposed mechanisms, a major component of which is cerebral edema through increased glutamine. The specific roles of ammonia, glutamate, and glutamine in cerebral edema are still under investigation [Gropman et al 2007, Lichter-Konecki 2008, Lichter-Konecki et al 2008, Albrecht et al 2010, Braissant et al 2013].
Damage resulting from acute hyperammonemia in infancy resembles that seen in hypoxic-ischemic events or stroke. The most vulnerable areas are the insular cortex, which represents deep white matter. With prolonged hyperammonemia, the parietal, occipital, and frontal regions are affected. This is best appreciated on T2-weighted MRI sequences or on diffusion tensor imaging.
Neuroimaging may be helpful in identifying affected areas of the brain. However, MRI findings may lag behind clinical changes. In fact, early imaging may be normal as some degree of injury must occur before macroscopic changes are seen on MRI.
Chronic hyperammonemia may disrupt ion-gradients and neurotransmitters, transport of metabolites, mitochondrial function, and the alpha-ketoglutarate/ glutamate/glutamine ratio.
Seizures are common in acute hyperammonemia and may result from cerebral damage. Recent findings suggest that subclinical seizures are common in acute hyperammonemic episodes, especially in neonates, and their effects on cerebral metabolism in an otherwise compromised state should be addressed (see Management, Treatment of Acute Manifestations). These seizures may be seen during the rise of glutamine even before ammonia levels are maximal [Wiwattanadittakul et al, in press].
Survival and intellectual outcome. Historically the outcome of newborns with hyperammonemia was considered poor [Brusilow 1995]. With rapid identification and current treatment strategies, survival of neonates with hyperammonemia has improved dramatically in the last few decades. See Summar [2001], Summar & Tuchman [2001], Enns et al [2007], Summar et al [2008], Tuchman et al [2008], and Krivitzky et al [2009].
More recent data from the NIH-sponsored longitudinal study on patients treated with the more recent protocols show IQ measures within a less severe range as summarized in Table 1.
### Table 1.
Cognitive and Adaptive Outcome in Children with UCD Age 3-16 Years
View in own window
Age GroupAge 3-5 YearsAge 6-16 Years
Age at OnsetNeonatal 1
(n=5)Late 2
(n=7)Neonatal 1
(n=8)Late 2
(n=39)
AssessmentWASI/WPPSI-III 3
composite scores 4 (SD)Verbal IQ81.3 (16.6)101.7 (24.4)72.9 (14.3)94.3 (21.7)
Performance IQ77.7 (15.0)95.6 (17.4)74.4 (11.7)89.5 (20.4)
Full scale IQ77.7 (16.3)99.6 (22.6)71.4 (12.8)94.1 (22.0)
ABAS-II 5 general adaptive composite 4 (SD)73.2 (31.2)91.4 (23.6)66.0 (17.9)84.4 (21.6)
Adapted from Krivitzky et al [2009]
SD = standard deviation
1\.
Clinical presentation in 1st month
2\.
Clinical onset after 1st month or diagnosis based on family history
3\.
Wechsler Abbreviated Scales of Intelligence / Wechsler Preschool and Primary Scale of Intelligence, 3rd Edition
4\.
Clinically significant difference between groups for cognitive and adaptive outcome
5\.
Adaptive Behavior Assessment System, 2nd Edition
While hyperammonemia is thought to be the main contributor to brain damage in UCDs, other factors, such as adverse effects on the nitric oxide production system [Nagamani et al 2012], may also contribute. For instance, neonates with CPS1 deficiency or OTC deficiency have more severe hyperammonemia than those with ASS1 deficiency or ASL deficiency; however, their intellectual outcomes appear similar [Ah Mew et al 2013].
In a recent study, asymptomatic female carriers of OTC deficiency demonstrated no significant differences in cognitive function compared to control participants until they were cognitively challenged with fine motor tasks, measures of executive function, and measures of cognitive flexibility [Sprouse et al 2014].
## Differential Diagnosis
## Management
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Urea Cycle Disorders Overview | None | 1,310 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1217/ | 2021-01-18T20:51:11 | {"synonyms": []} |
Sterile multifocal osteomyelitis with periostitis and pustulosis is a rare, severe, genetic autoinflammatory syndrome characterized by usually neonatal onset of generalized neutrophilic cutaneous pustulosis and severe, recurrent, multifocal, aseptic osteomyelitis with marked periostitis, typically affecting distal ribs, long bones and vertebral bodies. High levels of acute-phase reactants (with no fever associated) and onychosis are frequently observed additional features.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Sterile multifocal osteomyelitis with periostitis and pustulosis | c2748507 | 1,311 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=210115 | 2021-01-23T18:31:23 | {"gard": ["10516"], "mesh": ["C557815"], "omim": ["612852"], "umls": ["C2748507"], "synonyms": ["Autoinflammatory disease due to interleukin-1 receptor antagonist deficiency", "DIRA", "Interleukin-1 receptor antagonist deficiency", "OMPP"]} |
A number sign (#) is used with this entry because mutation in the ABCB1 gene (171050) has been found to cause colchicine resistance.
Chamla et al. (1980) described variants of human cells with altered colchicine sensitivity. These cell lines showed cross-resistance to daunomycin, emetine, vinblastine, and vincristine, and collateral sensitivity to xylocaine. Colchicine-resistant mutants of Chinese hamster ovary (CHO) cells have been found to have a change in the entry of drugs into cells, altered binding of colchicine to its intracellular target, or an altered tubulin. Chamla and Begueret (1982) showed that the 'defect' was one of decreased permeability to the drug.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| COLCHICINE RESISTANCE | c1861502 | 1,312 | omim | https://www.omim.org/entry/120080 | 2019-09-22T16:43:06 | {"omim": ["120080"], "orphanet": ["529825"], "synonyms": ["Alternative titles", "COLCHICINE SENSITIVITY"]} |
Congenital hyperinsulinism is a condition that causes individuals to have abnormally high levels of insulin, which is a hormone that helps control blood sugar levels. People with this condition have frequent episodes of low blood sugar (hypoglycemia). In infants and young children, these episodes are characterized by a lack of energy (lethargy), irritability, or difficulty feeding. Repeated episodes of low blood sugar increase the risk for serious complications such as breathing difficulties, seizures, intellectual disability, vision loss, brain damage, and coma.
The severity of congenital hyperinsulinism varies widely among affected individuals, even among members of the same family. About 60 percent of infants with this condition experience a hypoglycemic episode within the first month of life. Other affected children develop hypoglycemia by early childhood. Unlike typical episodes of hypoglycemia, which occur most often after periods without food (fasting) or after exercising, episodes of hypoglycemia in people with congenital hyperinsulinism can also occur after eating.
## Frequency
Congenital hyperinsulinism affects approximately 1 in 50,000 newborns. This condition is more common in certain populations, affecting up to 1 in 2,500 newborns.
## Causes
Congenital hyperinsulinism is caused by mutations in genes that regulate the release (secretion) of insulin, which is produced by beta cells in the pancreas. Insulin clears excess sugar (in the form of glucose) from the bloodstream by passing glucose into cells to be used as energy.
Gene mutations that cause congenital hyperinsulinism lead to over-secretion of insulin from beta cells. Normally, insulin is secreted in response to the amount of glucose in the bloodstream: when glucose levels rise, so does insulin secretion. However, in people with congenital hyperinsulinism, insulin is secreted from beta cells regardless of the amount of glucose present in the blood. This excessive secretion of insulin results in glucose being rapidly removed from the bloodstream and passed into tissues such as muscle, liver, and fat. A lack of glucose in the blood results in frequent states of hypoglycemia in people with congenital hyperinsulinism. Insufficient blood glucose also deprives the brain of its primary source of fuel.
Mutations in at least nine genes have been found to cause congenital hyperinsulinism. Mutations in the ABCC8 gene are the most common known cause of the disorder. They account for this condition in approximately 40 percent of affected individuals. Less frequently, mutations in the KCNJ11 gene have been found in people with congenital hyperinsulinism. Mutations in each of the other genes associated with this condition account for only a small percentage of cases.
In approximately half of people with congenital hyperinsulinism, the cause is unknown.
### Learn more about the genes associated with Congenital hyperinsulinism
* ABCC8
* GCK
* HADH
* HNF1A
* HNF4A
* KCNJ11
Additional Information from NCBI Gene:
* GLUD1
* SLC16A1
* UCP2
## Inheritance Pattern
Congenital hyperinsulinism can have different inheritance patterns, usually depending on the form of the condition. At least two forms of the condition have been identified. The most common form is the diffuse form, which occurs when all of the beta cells in the pancreas secrete too much insulin. The focal form of congenital hyperinsulinism occurs when only some of the beta cells over-secrete insulin.
Most often, the diffuse form of congenital hyperinsulinism 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.
Less frequently, the diffuse form is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.
The inheritance of the focal form of congenital hyperinsulinism is more complex. For most genes, both copies are turned on (active) in all cells, but for a small subset of genes, one of the two copies is turned off (inactive). Most people with the focal form of this condition inherit one copy of the mutated, inactive gene from their unaffected father. During embryonic development, a mutation occurs in the other, active copy of the gene. This second mutation is found within only some cells in the pancreas. As a result, some pancreatic beta cells have abnormal insulin secretion, while other beta cells function normally.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Congenital hyperinsulinism | c3888018 | 1,313 | medlineplus | https://medlineplus.gov/genetics/condition/congenital-hyperinsulinism/ | 2021-01-27T08:25:08 | {"gard": ["3947"], "mesh": ["D044903"], "omim": ["256450", "601820", "602485", "609975", "609968", "606762", "610021"], "synonyms": []} |
Treacher Collins syndrome
Other namesTreacher Collins–Franceschetti syndrome,[1] mandibulofacial dysostosis,[2] Franceschetti-Zwalen-Klein syndrome[3]
Child with Treacher Collins syndrome[4]
SpecialtyMedical genetics
SymptomsDeformities of the ears, eyes, cheekbones, chin[5]
ComplicationsBreathing problems, problems seeing, hearing loss[5]
CausesGenetic[5]
Diagnostic methodBased on symptoms, X-rays, genetic testing[3]
Differential diagnosisNager syndrome, Miller syndrome, hemifacial microsomia[3]
TreatmentReconstructive surgery, hearing aids, speech therapy[6]
PrognosisGenerally normal life expectancy[6]
Frequency1 in 50,000 people[5]
Treacher Collins syndrome (TCS) is a genetic disorder characterized by deformities of the ears, eyes, cheekbones, and chin.[5] The degree to which a person is affected, however, may vary from mild to severe.[5] Complications may include breathing problems, problems seeing, cleft palate, and hearing loss.[5] Those affected generally have average intelligence.[5]
TCS is usually autosomal dominant.[5] More than half the time it occurs as a result of a new mutation rather than being inherited from a person's parents.[5] The involved genes may include TCOF1, POLR1C, or POLR1D.[5] Diagnosis is generally suspected based on symptoms and X-rays, and potentially confirmation by genetic testing.[3]
Treacher Collins syndrome is not curable.[6] Symptoms may be managed with reconstructive surgery, hearing aids, speech therapy, and other assistive devices.[6] Life expectancy is generally normal.[6] TCS occurs in about one in 50,000 people.[5] The syndrome is named after Edward Treacher Collins, an English surgeon and ophthalmologist, who described its essential traits in 1900.[7][8]
## Contents
* 1 Signs and symptoms
* 2 Genetics
* 2.1 TCOF1
* 2.2 Other mutations
* 3 Diagnosis
* 3.1 Genetic counseling
* 3.2 Prenatal diagnosis
* 3.3 Clinical findings
* 3.4 Radiographs
* 3.5 CT scan
* 3.6 Differential diagnosis
* 4 Treatment
* 4.1 Hearing loss
* 4.2 Psychiatric
* 5 Epidemiology
* 6 History
* 7 Culture
* 8 See also
* 9 References
* 10 External links
## Signs and symptoms[edit]
The same child shown from the front above in infobox, now seen from the side, with small ears and a chin that is far back.[4]
Symptoms in people with Treacher Collins syndrome vary. Some individuals are so mildly affected that they remain undiagnosed, while others have moderate to severe facial involvement and life-threatening airway compromise.[9] Most of the features of TCS are symmetrical and are already recognizable at birth.[citation needed]
The most common symptom of Treacher Collins syndrome is underdevelopment of the lower jaw and underdevelopment of the zygomatic bone. This can be accompanied by the tongue being retracted. The small mandible can result in a poor occlusion of the teeth or in more severe cases, trouble breathing or swallowing. The respiratory system of a child with Treacher Collins syndrome is the primary concern when the child is born and other concerns are addressed after respiratory issues have been addressed.[10] Underdevelopment of the zygomatic bone gives the cheeks a sunken appearance.[11][12]
The external ear is sometimes small, rotated, malformed, or absent entirely in people with TCS. Symmetric, bilateral narrowing or absence of the external ear canal, is also described.[12][13] In most cases, the bones of the middle ear and the middle ear cavity are misshapen. Inner ear malformations are rarely described. As a result of these abnormalities, a majority of the individuals with TCS have conductive hearing loss.[12][14]
Most affected people also experience eye problems, including colobomata (notches) in the lower eyelids, partial or complete absence of eyelashes on the lower lid, downward angled eyelids, drooping of upper and lower eyelids, and narrowing of the tear ducts. Vision loss can occur and is associated with strabismus, refractive errors, and anisometropia. It can also be caused by severely dry eyes, a consequence of lower eyelid abnormalities and frequent eye infections.[12][13][15][16]
Although an abnormally shaped skull is not distinctive for Treacher Collins syndrome, brachycephaly with bitemporal narrowing is sometimes observed.[13] Cleft palate is also common.[12]
Dental anomalies are seen in 60% of affected people, including tooth agenesis (33%), discoloration (enamel opacities) (20%), malplacement of the maxillary first molars (13%), and wide spacing of the teeth. In some cases, dental anomalies in combination with mandible hypoplasia result in a malocclusion. This can lead to problems with food intake and the ability to close the mouth.[12]
Less common features of TCS may add to an affected person's breathing problems, including sleep apnea. Choanal atresia or stenosis is a narrowing or absence of the choanae, the internal opening of the nasal passages, which may also be observed. Underdevelopment of the pharynx can also narrow the airway.[12]
Features related to TCS that are seen less frequently include nasal deformities, high-arched palate, macrostomia, preauricular hair displacement, cleft palate, hypertelorism, notched upper eyelid, and congenital heart defects.[11][12][16]
Although facial deformity is often associated with developmental delay and intellectual disability, more than 95% of people affected with TCS have normal intelligence.[12] The psychological and social problems associated with facial deformity can affect quality of life in individuals with TCS.[citation needed]
## Genetics[edit]
Treacher Collins syndrome is inherited in an autosomal-dominant pattern.
Mutations in TCOF1, POLR1C, or POLR1D genes can cause Treacher Collins syndrome.[17] TCOF1 gene mutations are the most common cause of the disorder, with POLR1C and POLR1D gene mutations causing an additional 2% of cases. In individuals without an identified mutation in one of these genes, the genetic cause of the condition is unknown. The TCOF1, POLR1C, and POLR1D genes code for proteins which play important roles in the early development of bones and other tissues of the face. Mutations in these genes reduce the production of rRNA, which may trigger the self-destruction (apoptosis) of certain cells involved in the development of facial bones and tissues. It is unclear why the effects of a reduction in rRNA are limited to facial development. Mutations in TCOF1 and POLR1D cause the autosomal dominant form of Treacher Collins, and mutations in POLR1C cause the autosomal recessive form.[12]
### TCOF1[edit]
TCOF1 is the primary gene associated with TCS, a mutation in this gene being found in 90–95% of the individuals with TCS.[11][18] However, in some individuals with typical symptoms of TCS, mutations in TCOF1 have not been found.[19] Investigation of the DNA has resulted in the identification of the kind of mutations found in TCOF1. The majority of mutations are small deletions or insertions, though splice site and missense mutations also have been identified.[11][20][21][22]
Mutation analysis has unveiled more than 100 disease-causing mutations in TCOF1, which are mostly family-specific mutations. The only recurrent mutation accounts for about 17% of the cases.[23]
TCOF1 is found on the 5th chromosome in the 5q32 region. It codes for a relatively simple nucleolar protein called treacle, that is thought to be involved in ribosome assembly.[18] Mutations in TCOF1 lead to haploinsufficiency of the treacle protein.[24] Haploinsufficiency occurs when a diploid organism has only one functional copy of a gene, because the other copy is inactivated by a mutation. The one normal copy of the gene does not produce enough protein, causing disease. Haploinsufficiency of the treacle protein leads to a depletion of the neural crest cell precursor, which leads to a reduced number of crest cells migrating to the first and second pharyngeal arches. These cells play an important role in the development of the craniofacial appearance, and loss of one copy of treacle affects the cells' ability to form the bones and tissues of the face.[12][20][25]
### Other mutations[edit]
POLR1C and POLR1D mutations are responsible for a minority of cases of Treacher Collins. POLR1C is found on chromosome 6 at position 6q21.2 and POLR1D is found on chromosome 13 at position 13q12.2. Those genes code for a protein subunits shared between RNA polymerase I and III. Both of these polymerases are important for ribosome biogenesis.[12]
## Diagnosis[edit]
### Genetic counseling[edit]
TCS is inherited in an autosomal dominant manner and the penetrance of the affected gene is almost complete.[26] Some recent investigations, though, described some rare cases in which the penetrance in TCS was not complete. Causes may be a variable expressivity, an incomplete penetrance [27] or germline mosaicism.[28] Only 40% of the mutations are inherited. The remaining 60% are a result of a de novo mutation, where a child has a new mutation in the responsible gene and did not inherit it from either parent.[12][29] In the outcome of the disease, inter- and intrafamilial variability occurs. This suggests that when an affected child is born, it is important to investigate the parents to determine whether the affected gene is present, because the parent could have a mild form of the disease that has not been diagnosed. In this case, the risk of having another affected child is 50%. If the parents do not have the affected gene, the recurrence risk appears to be low.[26] In following generations, the severity of the clinical symptoms increases.[21]
### Prenatal diagnosis[edit]
Mutations in the main genes responsible for TCS can be detected with chorionic villus sampling or amniocentesis. Rare mutations may not be detected by these methods. Ultrasonography can be used to detect craniofacial abnormalities later in pregnancy, but may not detect milder cases.[12]
### Clinical findings[edit]
TCS is often first suspected with characteristic symptoms observed during a physical exam. However, the clinical presentation of TCS can resemble other diseases, making diagnosis difficult.[30] The OMENS classification was developed as a comprehensive and stage-based approach to differentiate the diseases. This acronym describes five distinct dysmorphic manifestations, namely orbital asymmetry, mandibular hypoplasia, auricular deformity, nerve development, and soft-tissue disease.[31]
Orbital symmetry
* O0: normal orbital size, position
* O1: abnormal orbital size
* O2: abnormal orbital position
* O3: abnormal orbital size and position
Mandible
* M0: normal mandible
* M1: small mandible and glenoid fossa with short ramus
* M2: ramus short and abnormally shaped
1. 2A: glenoid fossa in anatomical acceptable position
2. 2B: Temperomandibular joint inferiorly (TMJ), medially, anteriorly displaced, with severely hypoplastic condyle
* M3: Complete absence of ramus, glenoid fossa, and TMJ
Ear
* E0: normal ear
* E1: Minor hypoplasia and cupping with all structures present
* E2: Absence of external auditory canal with variable hypoplasia of the auricle
* E3: Malposition of the lobule with absent auricle, lobular remnant usually inferior anteriorly displaced
Facial nerve
* N0: No facial nerve involvement
* N1: Upper facial nerve involvement (temporal or zygomatic branches)
* N2: Lower facial nerve involvement (buccal, mandibular or cervical)
* N3: All branches affected
Soft tissue
* S0: No soft tissue or muscle deficiency
* S1: Minimal tissue or muscle deficiency
* S2: Moderate tissue or muscle deficiency
* S3: Severe tissue or muscle deficiency
### Radiographs[edit]
A few techniques are used to confirm the diagnosis in TCS.[30][32]
An orthopantomogram (OPG) is a panoramic dental X-ray of the upper and lower jaw. It shows a two-dimensional image from ear to ear. Particularly, OPG facilitates an accurate postoperative follow-up and monitoring of bone growth under a mono- or double-distractor treatment. Thereby, some TCS features could be seen on OPG, but better techniques are used to include the whole spectrum of TCS abnormalities instead of showing only the jaw abnormalities.[30]
Another method of radiographic evaluation is taking an X-ray image of the whole head. The lateral cephalometric radiograph in TCS shows hypoplasia of the facial bones, like the malar bone, mandible, and the mastoid.[30]
Finally, occipitomental radiographs are used to detect hypoplasia or discontinuity of the zygomatic arch.[32]
### CT scan[edit]
A temporal-bone CT using thin slices makes it possible to diagnose the degree of stenosis and atresia of the external auditory canal, the status of the middle ear cavity, the absent or dysplastic and rudimentary ossicles, or inner ear abnormalities such as a deficient cochlea. Two- and three-dimensional CT reconstructions with VRT and bone and skin-surfacing are helpful for more accurate staging and the three-dimensional planning of mandibular and external ear reconstructive surgery.[citation needed]
### Differential diagnosis[edit]
Other diseases have similar characteristics to Treacher Collins syndrome. In the differential diagnosis, one should consider the acrofacial dysostoses. The facial appearance resembles that of Treacher Collins syndrome, but additional limb abnormalities occur in those persons. Examples of these diseases are Nager syndrome and Miller syndrome.[citation needed]
The oculoauriculovertebral spectrum should also be considered in the differential diagnosis. An example is hemifacial microsomia, which primarily affects development of the ear, mouth, and mandible. This anomaly may occur bilaterally. Another disease which belongs to this spectrum is Goldenhar syndrome, which includes vertebral abnormalities, epibulbar dermoids and facial deformities.[33]
## Treatment[edit]
The treatment of individuals with TCS may involve the intervention of professionals from multiple disciplines. The primary concerns are breathing and feeding, as a consequence of the hypoplasia of the mandibula and the obstruction of the hypopharynx by the tongue. Sometimes, they may require a tracheostomy to maintain an adequate airway,[34] and a gastrostomy to assure an adequate caloric intake while protecting the airway. Corrective surgery of the face is performed at defined ages, depending on the developmental state.[35]
An overview of the present guidelines:
* If a cleft palate is present, the repair normally takes place at 9–12 months old. Before surgery, a polysomnography with a palatal plate in place is needed. This may predict the postoperative situation and gives insight on the chance of the presence of sleep apnea (OSAS) after the operation.[11][36][37]
* Hearing loss is treated by bone conduction amplification, speech therapy, and educational intervention to avoid language/speech problems. The bone-anchored hearing aid is an alternative for individuals with ear anomalies.[38]
* Zygomatic and orbital reconstruction is performed when the cranio-orbitozygomatic bone is completely developed, usually at the age of 5–7 years. In children, an autologous bone graft is mostly used. In combination with this transplantation, lipofilling can be used in the periorbital area to get an optimal result of the reconstruction.[citation needed] Reconstruction of the lower eyelid coloboma includes the use of a myocutaneous flap, which is elevated and in this manner closes the eyelid defect.[39]
* External ear reconstruction is usually done when the individual is at least eight years old. Sometimes, the external auditory canal or middle ear can also be treated.
* The optimal age for the maxillomandibular reconstruction is controversial; as of 2004, this classification has been used:[11]
1. Type I (mild) and Type IIa (moderate) 13–16 years
2. Type IIb (moderate to severe malformation) at skeletal maturity
3. Type III (severe) 6–10 years
* When the teeth are cutting, the teeth should be under supervision of an orthodontist to make sure no abnormalities occur. If abnormalities like dislocation or an overgrowth of teeth are seen, appropriate action can be undertaken as soon as possible.[20]
* Orthognatic treatments usually take place after the age of 16 years; at this point, all teeth are in place and the jaw and dentures are mature. Whenever OSAS is detected, the level of obstruction is determined through endoscopy of the upper airways. Mandibular advancement can be an effective way to improve both breathing and æsthetics, while a chinplasty only restores the profile.[11]
* If a nose reconstruction is necessary, it is usually performed after the orthognatic surgery and after the age of 18 years.[11]
* The contour of the facial soft tissues generally requires correction at a later age, because of the facial skeletal maturity. The use of microsurgical methods, like the free flap transfer, has improved the correction of facial soft tissue contours.[40] Another technique to improve the facial soft tissue contours is lipofilling. For instance, lipofilling is used to reconstruct the eyelids.[39]
### Hearing loss[edit]
Hearing loss in Treacher Collins syndrome is caused by deformed structures in the outer and middle ear. The hearing loss is generally bilateral with a conductive loss of about 50-70 dB. Even in cases with normal auricles and open external auditory canals, the ossicular chain is often malformed.[41]
Attempts to surgically reconstruct the external auditory canal and improve hearing in children with TCS have not yielded positive results.[42]
Auditory rehabilitation with bone-anchored hearing aids (BAHAs) or a conventional bone conduction aid has proven preferable to surgical reconstruction.[38]
### Psychiatric[edit]
The disorder can be associated with a number of psychological symptoms, including anxiety, depression, social phobia, and distress about body image. People who have this disorder may also experience discrimination, bullying, and name calling, especially when young. A multi-disciplinary team and parental support should include these issues.
## Epidemiology[edit]
TCS occurs in about one in 50,000 births in Europe.[43] Worldwide, it is estimated to occur in one in 10,000 to one in 50,000 births.[12]
## History[edit]
The syndrome is named with Edward Treacher Collins (1862–1932), the English surgeon and ophthalmologist who described its essential traits in 1900.[7][8][44] In 1949, Adolphe Franceschetti and David Klein described the same condition on their own observations as mandibulofacial dysostosis. The term mandibulofacial dysostosis is used to describe the clinical features.[45]
## Culture[edit]
A July 1977 New York Times article[46] that was reprinted in numerous newspapers nationwide over the ensuing weeks brought this malady to many people's attention for the first time.
The disorder was featured on the show Nip/Tuck, in the episode "Blu Mondae".[47] TLC's Born Without a Face[48] features Juliana Wetmore, who was born with the most severe case in medical history of this syndrome and is missing 30%–40% of the bones in her face.[48]
In 2010, BBC Three documentary Love Me, Love My Face[49] covered the case of a man, Jono Lancaster, with the condition. In 2011, BBC Three returned to Jono to cover his and his partner Laura's quest to start a family,[2] in So What If My Baby Is Born Like Me?,[50] which first aired as part of a BBC Three season of programmes on parenting.[51] The first film was replayed on BBC One shortly ahead of the second film's initial BBC Three broadcast. Lancaster's third BBC Three film, Finding My Family on Facebook, which looked at adoption, aired in 2011.[52]
In Wonder, a children's novel, the main character is a child who has Treacher Collins syndrome.[53] A 2017 film adaptation of Wonder, starring Julia Roberts, Owen Wilson and Jacob Tremblay, was released in November 2017.[54][55]
Alison Midstokke, who appears in the drama film Happy Face (2018),[56] is an actress and activist who has the condition.
## See also[edit]
* First arch syndrome
* Franceschetti-Klein syndrome
* Hearing loss with craniofacial syndromes
## References[edit]
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42. ^ Marres, HA; Cremers, CW; Marres, EH (1995). "Treacher-Collins syndrome. Management of major and minor anomalies of the ear". Revue de Laryngologie – Otologie – Rhinologie. 116 (2): 105–108. PMID 7569369.
43. ^ Conte, Chiara; Maria Rosaria D'Apice; Fabrizio Rinaldi; Stefano Gambardella; Federica Sanguiuolo; Giuseppe Novelli (27 September 2011). "Novel mutations of TCOF1 gene in European patients with treacher Collins syndrome". Medical Genetics. 12: 125. doi:10.1186/1471-2350-12-125. PMC 3199234. PMID 21951868.
44. ^ Treacher Collin E (1900). "Cases with symmetrical congenital notches in the outer part of each lid and defective development of the malar bones". Trans Ophthalmol Soc UK. 20: 190–192.
45. ^ Franceschetti A, Klein D (1949). "Mandibulo-facial dysostosis: new hereditary syndrome". Acta Ophthalmol. 27: 143–224.
46. ^ "Surgical Teamwork Gives Disease Victims a New Life" Archived 2018-07-23 at the Wayback Machine, Donald G. McNeil, Jr., July 26, 1977, page L31.
47. ^ "Nip/Tuck: Blu Mondae - TV.com". Archived from the original on 2008-06-12. Retrieved 2008-05-12.
48. ^ a b "First Coast News: Local Family Has Daughter Born Without a Face".
49. ^ "BBC programme page for Love Me, Love My Face". BBC Three. 17 June 2011. Archived from the original on 21 January 2018. Retrieved 7 November 2017.
50. ^ "BBC programme page for So What If My Baby..." BBC Three. 24 August 2011. Archived from the original on 2 June 2017. Retrieved 7 November 2017.
51. ^ "BBC Three Bringing Up Britain season". BBC One. 12 April 2011. Archived from the original on 12 August 2011. Retrieved 24 August 2011.
52. ^ "Finding My Family on Facebook". bbc.co.uk. BBC Three. 2011. Archived from the original on 2011-10-31..
53. ^ Chilton, Martin (24 February 2012). "Wonder by R. J. Palacio: review". The Telegraph. Archived from the original on 6 October 2017. Retrieved 7 November 2017.
54. ^ "Julia Roberts' Drama 'Wonder' Pushed to November". The Hollywood Reporter. February 13, 2017. Archived from the original on April 22, 2017. Retrieved February 13, 2017.
55. ^ O'Conner, Katie (December 22, 2017). "Real Life Reflected on the Silver Screen". Richmond Times-Dispatch.
56. ^ Wilner, Norman (February 18, 2020). "Canadian Screen Awards 2020: Prepare for a Schitt's show". Now. Archived from the original on 2020-02-18. Retrieved December 28, 2020.
## External links[edit]
Classification
D
* ICD-10: Q75.4
* ICD-9-CM: 756.0
* OMIM: 154500
* MeSH: D008342
* DiseasesDB: 13267
External resources
* MedlinePlus: 001659
* eMedicine: plastic/183
* Orphanet: 861
* v
* t
* e
Congenital malformations and deformations of musculoskeletal system / musculoskeletal abnormality
Appendicular
limb / dysmelia
Arms
clavicle / shoulder
* Cleidocranial dysostosis
* Sprengel's deformity
* Wallis–Zieff–Goldblatt syndrome
hand deformity
* Madelung's deformity
* Clinodactyly
* Oligodactyly
* Polydactyly
Leg
hip
* Hip dislocation / Hip dysplasia
* Upington disease
* Coxa valga
* Coxa vara
knee
* Genu valgum
* Genu varum
* Genu recurvatum
* Discoid meniscus
* Congenital patellar dislocation
* Congenital knee dislocation
foot deformity
* varus
* Club foot
* Pigeon toe
* valgus
* Flat feet
* Pes cavus
* Rocker bottom foot
* Hammer toe
Either / both
fingers and toes
* Polydactyly / Syndactyly
* Webbed toes
* Arachnodactyly
* Cenani–Lenz syndactylism
* Ectrodactyly
* Brachydactyly
* Stub thumb
reduction deficits / limb
* Acheiropodia
* Ectromelia
* Phocomelia
* Amelia
* Hemimelia
multiple joints
* Arthrogryposis
* Larsen syndrome
* RAPADILINO syndrome
Axial
Skull and face
Craniosynostosis
* Scaphocephaly
* Oxycephaly
* Trigonocephaly
Craniofacial dysostosis
* Crouzon syndrome
* Hypertelorism
* Hallermann–Streiff syndrome
* Treacher Collins syndrome
other
* Macrocephaly
* Platybasia
* Craniodiaphyseal dysplasia
* Dolichocephaly
* Greig cephalopolysyndactyly syndrome
* Plagiocephaly
* Saddle nose
Vertebral column
* Spinal curvature
* Scoliosis
* Klippel–Feil syndrome
* Spondylolisthesis
* Spina bifida occulta
* Sacralization
Thoracic skeleton
ribs:
* Cervical
* Bifid
sternum:
* Pectus excavatum
* Pectus carinatum
* v
* t
* e
Nucleus diseases
Telomere
* Revesz syndrome
Nucleolus
* Treacher Collins syndrome
* Spinocerebellar ataxia 7
* Cajal body: Spinal muscular atrophy
Centromere
* CENPJ
* Seckel syndrome 4
Other
* AAAS
* Triple-A syndrome
* Laminopathy
* SMC1A/SMC3
* Cornelia de Lange Syndrome
* SETBP1
* Schinzel–Giedion syndrome
see also nucleus
*[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
| Treacher Collins syndrome | c0265241 | 1,314 | wikipedia | https://en.wikipedia.org/wiki/Treacher_Collins_syndrome | 2021-01-18T19:07:36 | {"gard": ["9124"], "mesh": ["D008342"], "umls": ["C0265241"], "icd-9": ["756.0"], "orphanet": ["861"], "wikidata": ["Q744790"]} |
Jellyfish dermatitis
Jellyfish dermatitis in back abdominal skin. Jellyfish of Mediterranean sea.
SpecialtyDermatology
Jellyfish dermatitis is a cutaneous condition caused by stings from a jellyfish.[1]:430[2]
## See also[edit]
* List of cutaneous conditions
* Skin condition
* Stingray injury
## References[edit]
1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0.
2. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 1318. ISBN 978-1-4160-2999-1.
## External links[edit]
Classification
D
* ICD-10: T63.6
* ICD-9-CM: 989.5
* MeSH: D003064
* DiseasesDB: 32410
* v
* t
* e
Animal bites and stings
Arthropod bites
and stings
Arachnid
* Demodex mite bite
* Scorpion sting
* Spider bite / Arachnidism
* Latrodectism
* Loxoscelism
Insects
* Ant sting
* Bee sting
* Cimicosis
* Mosquito bite
* Pulicosis
* Reduviid bite
Myriapoda
* Centipede bite
* Millipede burn
Vertebrate
* Alligator attack
* Bear attack
* Beaver attack
* Boar attack
* Cougar attack
* Cat bite
* Coyote attack
* Crocodile attack
* Dingo attack
* Dog attack
* Killer whale attack
* Leopard attack
* Lion attack
* Monkey bite
* Piranha fish attack
* Shark attack
* Snakebite
* Stingray attack
* Stonefish attack
* Tiger attack
* Venomous fish
* Walrus attack
* Wolf attack
Other
* Animal attacks
* Bristleworm sting
* Cephalopod attack
* Cone snail sting
* Coral dermatitis
* Dog bite prevention
* Hydroid dermatitis
* Jellyfish dermatitis / Jellyfish sting
* Leech bite
* Man-eater
* Portuguese man-of-war dermatitis
* Sea anemone dermatitis
* Sea urchin injury
* Seabather's eruption
This infection-related 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
| Jellyfish dermatitis | c0413135 | 1,315 | wikipedia | https://en.wikipedia.org/wiki/Jellyfish_dermatitis | 2021-01-18T18:46:33 | {"umls": ["C0413135"], "icd-9": ["989.5"], "icd-10": ["T63.6"], "wikidata": ["Q6176926"]} |
A subtype of autosomal recessive limb girdle muscular dystrophy characterized by a variable age of onset of progressive, typically symmetrical and selective weakness and atrophy of proximal shoulder- and pelvic-girdle muscles (gluteus maximus, thigh adductors, and muscles of the posterior compartment of the limbs are most commonly affected) without cardiac or facial involvement. Clinical manifestations include exercise intolerance, a waddling gait, scapular winging and calf pseudo-hypertrophy.
*[v]: View this template
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*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Calpain-3-related limb-girdle muscular dystrophy R1 | c1869123 | 1,316 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=267 | 2021-01-23T19:00:42 | {"gard": ["1057"], "mesh": ["C535895"], "omim": ["253600", "618129"], "umls": ["C1869123"], "icd-10": ["G71.0"], "synonyms": ["Autosomal recessive limb-girdle muscular dystrophy type 2A", "Calpain-3-related LGMD R1", "LGMD type 2A", "LGMD2A", "Limb-girdle muscular dystrophy due to calpain deficiency", "Limb-girdle muscular dystrophy type 2A", "Primary calpainopathy"]} |
A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome on chromosome 3q29.
Clinical Features
Willatt et al. (2005) reported the identification of 6 patients with 3q29 microdeletion syndrome. The clinical phenotype was variable despite an almost identical deletion size. The phenotype included mild to moderate mental retardation, with only slightly dysmorphic facial features that were similar in most patients: long and narrow face, short philtrum, and high nasal bridge. Autism, gait ataxia, chest wall deformity, and long and tapering fingers were noted in at least 2 of the 6 patients. Additional features, including microcephaly, cleft lip and palate, horseshoe kidney and hypospadias, ligamentous laxity, recurrent middle ear infections, and abnormal pigmentation, were observed, each in a single patient.
Digilio et al. (2009) reported 2 mother-daughter pairs in which the mother and daughter shared a 1.5-Mb deletion at chromosome 3q29. All 4 individuals had delayed psychomotor development with mild to moderate mental retardation and/or learning disabilities with speech delay. All had low birth weight, microcephaly, high nasal bridge, and short philtrum, and 3 had clinodactyly of the toes. Otherwise, dysmorphic features were variable and yielded no discernible phenotype. Digilio et al. (2009) noted the familial transmission of the chromosomal defect and suggested that it may be more common than previously thought.
Li et al. (2009) reported a 6-month-old boy with multiple congenital anomalies who inherited a paternal 1.3- to 1.4-Mb deletion at chromosome 3q29. The boy had primary pulmonary hypertension, patent ductus arteriosus (PDA), subvalvular aortic stenosis, and gastroesophageal reflux, and required neonatal intensive care for 57 days after birth due to complications of meconium aspiration. He had mild dysmorphic features, including posteriorly rotated ears, shallow orbits, frontal bossing, prominent nose, long thin lip, and broad face. He also had bilateral sandal gap toes, single palmar creases, and bilateral inguinal hernia. However, he was developmentally normal at age 6 months. His father had a history of PDA and pulmonic stenosis at birth and mild developmental delay in childhood, with normal cognition as an adult.
Quintero-Rivera et al. (2010) reported 2 unrelated patients, a 10-year-old Caucasian girl and a 15-year-old Hispanic boy, with chromosome 3q29 deletion syndrome. Common clinical features included delayed psychomotor development with delayed waking and poor motor skills, autism with speech delay, mental retardation, and psychiatric disturbances, including aggression, anxiety, hyperactivity, and bipolar disorder with psychosis in 1. Both had dysmorphic features, including high nasal bridge, asymmetric face, and crowded/dysplastic teeth; 1 had micrognathia and epicanthal folds. Both had tapered fingers. The girl had a family history significant for a father and paternal grandfather with bipolar disorder, and a maternal cousin and aunt with attention-deficit hyperactivity disorder and anorexia nervosa, respectively. Chromosomal microarray analysis identified de novo 1.6-Mb and 2.1-Mb deletions at chromosome 3q29 in the girl and boy, respectively. Quintero-Rivera et al. (2010) noted that the dysmorphic features of this disorder are highly variable, but that the psychiatric manifestations often include cognitive defects, autism, and other psychiatric disorders.
Molecular Genetics
The microdeletion in the patients studied by Willatt et al. (2005) was approximately 1.5 Mb, with molecular boundaries mapping within the same or adjacent BAC clones at either end of the deletion in all patients. The deletion encompassed 22 genes, including PAK2 (605022) and DLG1 (601014), which are autosomal homologs of 2 known X-linked mental retardation genes, PAK3 (300142) and DLG3 (300189). The presence of 2 nearly identical low-copy repeat (LCR) sequences in BAC clones on each side of the deletion breakpoint suggested that nonallelic homologous recombination is the likely mechanism of disease causation in this syndrome.
Mulle et al. (2010) identified a region on chromosome 3q29 in which copy number variation (CNV) was significantly associated with schizophrenia (SCZD; 181500). The initial study involved 245 unrelated patients with SCZD and 490 controls, all of Ashkenazi Jewish descent. Combined with prior CNV studies and additional SCZD cohorts, the authors identified chromosome 3q29 deletions in 6 of 7,545 patients compared to 1 of 39,748 controls (odds ratio of 16.98; corrected p value = 0.02). The minimum deletion region overlapped with that observed in the group of children with moderate mental retardation and autism.
Quintero-Rivera et al. (2010) proposed a role for haploinsufficiency of the FBXO45 (609112), DLG1 (601014), and PAK2 (605022) genes in the psychiatric manifestations of 3q29 deletion syndrome, since these genes play putative role in synaptic transmission.
Kaminsky et al. (2011) performed a large CNV case-control study comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 3q29 deletion was identified in 9 cases and no controls for a p value of 0.0147 and a frequency of 1 in 1,750 cases.
INHERITANCE \- Isolated cases GROWTH Weight \- Low birth weight Other \- Failure to thrive HEAD & NECK Face \- Long, narrow face \- Short philtrum Ears \- Large ears \- Low-set ears \- Posteriorly rotated ears Nose \- High nasal bridge Mouth \- Thin upper lip CHEST Ribs Sternum Clavicles & Scapulae \- Pectus excavatum \- Pectus carinatum SKELETAL Hands \- Long, tapered fingers Feet \- Clinodactyly NEUROLOGIC Central Nervous System \- Mental retardation, mild to moderate \- Gait ataxia Behavioral Psychiatric Manifestations \- Autism \- Psychosis \- Anxiety \- Hyperactivity \- Aggression LABORATORY ABNORMALITIES \- Subtelomeric deletion of long arm of chromosome 3 (3q29) MISCELLANEOUS \- Contiguous gene deletion syndrome \- Microdeletion is approximately 1.5Mb in length MOLECULAR BASIS \- Caused by deletion of 1.5Mb on 3q29 encompassing 22 genes ▲ Close
*[v]: View this template
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*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| CHROMOSOME 3q29 DELETION SYNDROME | c2674949 | 1,317 | omim | https://www.omim.org/entry/609425 | 2019-09-22T16:06:05 | {"doid": ["0060419"], "mesh": ["C567184"], "omim": ["609425"], "orphanet": ["65286"], "synonyms": ["Alternative titles", "MICRODELETION 3q29 SYNDROME"], "genereviews": ["NBK385289"]} |
A rare multiple congenital anomalies-intellectual disability syndrome characterized by sensorineural hearing loss (deafness), onychodystrophy, osteodystrophy, mild to profound intellectual disability, and seizures.
## Epidemiology
The prevalence is unknown; about 50 cases have been reported to date.
## Clinical description
Disease onset usually presents shortly after birth, but may present in infancy, with profound sensorineural deafness, small or absent nails, and short distal phalanges of hands and feet. About 1/4 of patients have long, finger-like thumbs. Facial features are highly variable and only a broad nasal bridge is present in 1/2 of all cases. Other facial signs, reported infrequently, include anteverted nares, long philtrum, thin upper vermilion and low set ears. Craniosynostosis has been reported in one patient. Optic atrophy leading to blindness, retinal detachment, strabismus, nystagmus, high myopia and cataracts are sometimes reported. Developmental delay is noted from infancy and can range from mild delays in early motor milestones to generalized and lifelong hypotonia. Seizures (often generalized tonic-clonic) are seen in most cases, usually begin in the first year of life and become more marked with age. Along with learning difficulties, behavioral problems may also be noted. Rare manifestations include dental (hypoplastic enamel, abnormal size of teeth), and internal organ (congenital heart defects, unilateral renal agenesis, cystic kidney, duplicated kidney) malformations. The disease is non-progressive.
## Etiology
DOORS (deafness-onychodystrophy-osteodystrophy-intellectual disability syndrome) syndrome is caused by mutations in the TBC1D24 gene (16p13.3) encoding a protein involved in the regulation of membrane trafficking. It seems likely that DOORS syndrome will prove to be a genetically heterogeneous disease and other causal genes will be identified in the future.
## Diagnostic methods
Patients are checked for each of the 5 major characteristics by conducting X-rays of the hands and feet, a brain stem auditory evoked response test for hearing loss, and an electroencephalogram (EEG). Elevated levels of 2-oxoglutaric acid in the urine and plasma have repeatedly been reported mostly in patients with TBC1D24 mutations. If present, DOORS syndrome is suspected, although elevated levels can also occur in other disorders. Molecular genetic testing identifying a TBC1D24 mutation may confirm the diagnosis but absence of the mutation does not mean a diagnosis of DOORS syndrome is incorrect.
## Differential diagnosis
Differential diagnoses include Coffin-Siris syndrome, intellectual disability-sparse hair-brachydactyly syndrome, Zimmermann-Laband syndrome, fetal alcohol syndrome and Temple-Baraitser syndrome, autosomal dominant deafness-onychodystrophy syndrome, and disorders of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation.
## Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease-causing mutation.
## Genetic counseling
DOORS syndrome is inherited autosomal recessively. If the clinical diagnosis has been established with a high degree of certainty, genetic counseling should be provided accordingly.
## Management and treatment
Treatment is supportive. Long-term management involves regular ophthalmologic and hearing tests as well as neurological exams such as EEGs. A feeding tube may be necessary in infants with feeding difficulties. Antiepileptic medication may be used to prevent or decrease the frequency of seizures but is not always effective.
## Prognosis
Life expectancy is usually normal. Intellectual disability is lifelong but there is no known correlation between clinical manifestations and cognition. The number of known adults with DOORS syndrome is at present too small to predict the long term prognosis. Parkinsonism was reported in an adult.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| DOORS syndrome | c0795927 | 1,318 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79500 | 2021-01-23T18:58:14 | {"gard": ["1685"], "mesh": ["C538204"], "omim": ["220500"], "umls": ["C0795927"], "icd-10": ["Q87.8"], "synonyms": ["Autosomal recessive deafness-onychodystrophy syndrome", "Autosomal recessive hearing loss-onychodystrophy syndrome", "DOOR syndrome", "Deafness-onychodystrophy-osteodystrophy-intellectual disability syndrome", "Deafness-onychodystrophy-osteodystrophy-intellectual disability-seizures syndrome", "Deafness-onychoosteodystrophy-intellectual disability syndrome", "Hearing loss-onychodystrophy-osteodystrophy-intellectual disability syndrome", "Hearing loss-onychodystrophy-osteodystrophy-intellectual disability-seizures syndrome", "Hearing loss-onychoosteodystrophy-intellectual disability syndrome"]} |
A group of rare bone development disorders characterized by an array of abnormalities affecting the eyes, forehead, and nose, and linked to midfacial dysraphia. The clinical picture is highly variable, but the major findings include hypertelorism, a broad nasal root, a large and bifid nasal tip, and widow's peak. Occasionally, abnormalities can include accessory nasal tags, cleft lip, ocular abnormalities (coloboma, cataract, microphthalmia), conductive hearing loss, basal encephalocele and/or agenesis of the corpus callosum. Intellectual deficit is rare and more likely to occur in cases where hypertelorism is severe or where there is extra-cranial involvement.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Frontonasal dysplasia | c1876203 | 1,319 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=250 | 2021-01-23T18:00:44 | {"gard": ["2392"], "mesh": ["C538065"], "umls": ["C0432106", "C1876203"], "icd-10": ["Q75.8"], "synonyms": ["Median cleft face syndrome"]} |
This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (February 2018)
Tracheobronchopathia osteochondroplastica
Other namesTracheopathia osteoplastica
Tracheobronchopathia osteochondroplastica is inherited in an autosomal dominant manner.
Tracheobronchopathia osteochondroplastica (TO) is a rare benign disease of unknown cause, in which multiple cartilaginous or bony submucosal nodules project into the trachea and proximal bronchi. The nodules usually spare the posterior wall of the airway because they are of cartilaginous origin, while the posterior wall of the airway is membranous (does not contain cartilage). This is as opposed to tracheobronchial amyloidosis, which does not spare the posterior wall.
It usually occurs in men around their fifth decade of life, as opposed to tracheobronchial papillomatosis due to HPV infection, which usually occurs in younger patients. TO can cause airway obstruction, bleeding and chronic cough. Treatment involves the use of bronchodilators, and physical dilatation by bronchoscopy. The patients are also more prone to post-obstructive pneumonia and chronic lung infection in severe cases.[1]
## Contents
* 1 Diagnosis
* 1.1 Differential diagnosis
* 2 Treatment
* 3 References
* 4 External links
## Diagnosis[edit]
### Differential diagnosis[edit]
The differential of TO includes amyloidosis, which is typically circumferential, papillomatosis, though this usually occurs in younger patients and can cause lung cavitation when disseminated, granulomatosis with polyangiitis, though this is circumferential as well and often involves distal lung cavitation as well. Relapsing polychondritis can also spare the posterior wall, though it is not typically nodular in appearance.[2]
## Treatment[edit]
This section is empty. You can help by adding to it. (November 2017)
## References[edit]
1. ^ Prakash, UB (April 2002). "Tracheobronchopathia osteochondroplastica". Seminars in respiratory and critical care medicine. 23 (2): 167–75. doi:10.1055/s-2002-25305. PMID 16088609.
2. ^ Prince, JS; Duhamel, DR; Levin, DL; Harrell, JH; Friedman, PJ (October 2002). "Nonneoplastic lesions of the tracheobronchial wall: radiologic findings with bronchoscopic correlation". Radiographics. 22 Spec No: S215–30. doi:10.1148/radiographics.22.suppl_1.g02oc02s215. PMID 12376612.
## External links[edit]
Classification
D
* ICD-10: J98.0
* OMIM: 189961
* MeSH: C536977
This medical treatment–related article is a stub. You can help Wikipedia by expanding it.
* v
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* e
*[v]: View this template
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*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Tracheobronchopathia osteochondroplastica | c0520538 | 1,320 | wikipedia | https://en.wikipedia.org/wiki/Tracheobronchopathia_osteochondroplastica | 2021-01-18T19:06:29 | {"gard": ["5235"], "mesh": ["C536977"], "umls": ["C0520538"], "icd-10": ["J98.0"], "orphanet": ["3348"], "wikidata": ["Q4338645"]} |
Jestico et al. (1985) described 2 brothers and 3 of their maternal uncles who developed neuropathic deformities and ulceration of the feet in the first and second decades of life with slow progression over many years. In this form of hereditary sensory and autonomic neuropathy, there was minimal tendon reflex impairment, cutaneous sensory impairment was restricted to the feet, and there was no autonomic dysfunction. The only neurophysiologic abnormality was reduced or absent sural nerve sensory action potentials. Sural nerve biopsies in 2 affected persons showed loss of myelinated fibers, particularly those of small diameter, with a normal number of unmyelinated fibers.
Misc \- Onset in first and second decades with slow progression Limbs \- Neuropathic deformities \- Foot ulceration Neuro \- Minimal tendon reflex impairment \- Cutaneous sensory loss only in feet Lab \- Reduced or absent sural nerve sensory action potentials \- Loss of myelinated fibers on sural nerve biopsy Inheritance \- X-linked ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| NEUROPATHY, HEREDITARY SENSORY, X-LINKED | c1839602 | 1,321 | omim | https://www.omim.org/entry/310470 | 2019-09-22T16:17:33 | {"mesh": ["C564090"], "omim": ["310470"]} |
Rubeosis iridis
Other namesNeovascularization of the iris
SpecialtyOphthalmology
Rubeosis iridis, is a medical condition of the iris of the eye in which new abnormal blood vessels (formed by neovascularization) are found on the surface of the iris.[1]
## Contents
* 1 Causes
* 2 Pathophysiology
* 3 Treatment
* 4 See also
* 5 References
* 6 External links
## Causes[edit]
This condition is often associated with diabetes in advanced proliferative diabetic retinopathy. Other conditions causing rubeosis iridis include central retinal vein occlusion,[2] ocular ischemic syndrome,[3] and chronic retinal detachment.
## Pathophysiology[edit]
It is usually associated with disease processes in the retina, which involve the retina becoming starved of oxygen (ischaemic). The ischemic retina releases a variety of factors, the most important of which is VEGF. These factors stimulate the formation of new blood vessels (angiogenesis). Unfortunately, these new vessels do not have the same characteristics as the blood vessels originally formed in the eye. In addition, new blood vessels can form in areas that do not have them. Specifically, new blood vessels can be observed on the iris. In addition to the blood vessels in the iris, they can grow into the angle of the eye. These blood vessels eventually go through a process called fibrosis which closes the normal physiologic anatomy of the angle. The closing of the angle prevents fluid from leaving the eye resulting in an increase in intraocular pressure. This is called neovascular glaucoma.
## Treatment[edit]
If caught early, the neovascularization can be reversed with prompt pan retinal photocoagulation (PRP), or injection of anti-VEGF medications with subsequent PRP. The injection blocks the direct effect of VEGF and acts more quickly but will wear off in about 6 weeks.[4] PRP has a slower onset of action but can last permanently. Once the neovascularization has been longstanding, the new vessels recruit fibrous tissue, and as this forms and contracts, the angle can be permanently damaged, and will not respond to treatment. If this occurs, then surgical intervention is required to reduce the pressure (such as a glaucoma drainage implant)
## See also[edit]
* CNV (choroidal neovascularization)
* CNV (corneal neovascularization)
* NVD (neovascularization of the disc)
## References[edit]
1. ^ "rubeosis iridis" at Dorland's Medical Dictionary
2. ^ Laatikainen L, Blach RK. "Behaviour of the iris vasculature in central retinal vein occlusion: a fluorescein angiographic study of the vascular response of the retina and the iris." Br J Ophthalmol. 1977 Apr;61(4):272-7. PMID 857872.
3. ^ Dhooge M, de Laey JJ. "The ocular ischemic syndrome." Bull Soc Belge Ophtalmol. 1989;231:1-13. PMID 2488440.
4. ^ Davidorf FH, Mouser JG, Derick RJ. "Rapid improvement of rubeosis iridis from a single bevacizumab (Avastin) injection." Retina. 2006 Mar;26(3):354-6. PMID 16508439.
## External links[edit]
Classification
D
* ICD-10: H21.1
* ICD-9-CM: 364.42
* DiseasesDB: 11743
* v
* t
* e
* Diseases of the human eye
Adnexa
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Pathways
Optic nerve
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palsies
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Other strabismus
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Other
* Nystagmus
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Infections
* Trachoma
* Onchocerciasis
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Rubeosis iridis | c0154916 | 1,322 | wikipedia | https://en.wikipedia.org/wiki/Rubeosis_iridis | 2021-01-18T18:50:17 | {"umls": ["C0154916"], "icd-10": ["H21.1"], "wikidata": ["Q3297012"]} |
## Description
Distal hereditary motor neuronopathy (dHMN or HMN) is a heterogeneous group of neuromuscular disorders caused by anterior horn cell degeneration and characterized by progressive distal motor weakness and muscular atrophy of the peripheral nervous system without sensory impairment. Distal HMN is also referred to as spinal Charcot-Marie-Tooth disease (spinal CMT). Distal HMN is often referred to as a 'neuronopathy' instead of a 'neuropathy' based on the hypothesis that the primary pathologic process resides in the neuron cell body and not in the axons (Irobi et al., 2006).
### Genetic Heterogeneity of Autosomal Dominant Distal Hereditary Motor Neuronopathy
Harding (1993) proposed a classification of distal HMN into 7 phenotypic subtypes according to age at onset, mode of inheritance, and presence of additional features. Those that show autosomal dominant inheritance include distal HMN type I, and II (HMN2A, 158590 and HMN2B, 608634), characterized by juvenile and adult onset, respectively; HMN type V (HMN5A, 600794 and HMN5B, 614751), characterized by upper limb involvement; HMN VII (HMN7A, 158580 and HMN7B, 607641), with vocal cord paralysis; HMN8 (600175); and HMN9 (617721).
HMN2A is caused by mutation in the HSPB8 gene (608014), HMN2B by mutation in the HSPB1 gene (602195), HMN2C (613376) by mutation in the HSPB3 gene (604624), and HMN2D (615575) by mutation in the FBXO38 gene (608533). HMN5A is caused by mutation in the GARS gene (600287) and HMN5B is caused by mutation in the REEP1 gene (609139). HMN7A is caused by mutation in the SLC5A7 gene (608761). HMN7B is caused by mutation in the DCTN1 gene (601143). HMN8 is caused by mutation in the TRPV4 gene (605427).
See also autosomal dominant ALS4 (602433) and congenital autosomal dominant distal SMA (600175).
### Genetic Heterogeneity of Autosomal Recessive Distal Hereditary Motor Neuronopathy (Distal Spinal Muscular Atrophy)
Harding (1993) classified autosomal recessive distal hereditary motor neuronopathy as dHMN IV (HMN4) and dHMN III (HMN3) (see DSMA3; 607088). HMN has also been referred to as distal spinal muscular atrophy (DSMA). 'Distal' SMA is distinguished from 'proximal' autosomal recessive spinal muscular atrophy (SMA, 253300) by the primary muscles involved. DSMA here refers to the autosomal recessive forms of HMN.
See DSMA1 (SMARD1; 604320), caused by mutation in the IGHMBP2 gene (600502); DSMA2 (605726), caused by mutation in the SIGMAR1 gene (601978) on chromosome 9p13; DSMA3 (607088), encompassing HMN types III and IV, which maps to chromosome 11q13; DSMA4 (611067), caused by mutation in the PLEKHG5 gene (611101); and DSMA5 (614881), caused by mutation in the DNAJB2 gene (604139).
See also X-linked SMAX3 (300489).
Clinical Features
Davis et al. (1978) reported autosomal dominant distal motor neuronopathy without sensory impairment. Motor nerve conduction velocities were normal. Onset was usually in the first decade.
Harding and Thomas (1980) reported 4 families with autosomal dominant inheritance of dHMN. All patients developed symptoms before age 20 years, and most in the first decade. All had distal lower limb weakness and some had pes cavus.
Irobi et al. (2006) noted that descriptions of HMN type I are based on a small series of patients; no large pedigrees had been reported. Patients typically have juvenile onset of classic lower limb muscle weakness and atrophy which progresses throughout adulthood. Life expectancy is normal.
Gopinath et al. (2007) reported a family in which 10 members had autosomal dominant distal HMN type I. The family had previously been reported as having juvenile ALS (602433) as a part of larger studies by De Jonghe et al. (2002) and Chen et al. (2004). Age at onset was usually in the first or second decade (median 10 years), but 1 individual had onset at age 40 years. The presenting features were difficulty with walking and running due to lower limb weakness. All patients had pes cavus and most had hammertoes. Muscle tone was increased in 6 patients, but power was reduced in the ankle extensors and intrinsic feet muscles in all but 1 patient. Plantar responses were extensor in 5 patients. There were no sensory abnormalities except for reduced vibration in the feet of 4 patients. Sural nerve biopsy in 1 patient at age 43 years showed chronic axonal neuropathy.
Mapping
By genomewide linkage analysis of a family with HMN type I, Gopinath et al. (2007) identified a locus on chromosome 7q34-q36 (maximum multipoint lod score of 3.74 at marker D7S661). Recombinant haplotype analysis of affected individuals established that the locus spans a 26.2-cM region between D7S2513 and D7S637. Recombinant haplotype analysis including unaffected individuals over age 25 years suggested a refined 14.3-cM region between D7S2511 and D7S798. Molecular analysis excluded mutations in the CDK5 gene (123831).
Molecular Genetics
### Associations Pending Confirmation
For a discussion of a possible association between autosomal dominant dHMN and variation in the AARS gene, see 601065.0005.
INHERITANCE \- Autosomal dominant SKELETAL Feet \- Pes cavus \- Hammertoes MUSCLE, SOFT TISSUES \- Distal limb muscle weakness and atrophy \- Upper limb involvement may occur later \- Increased muscle tone NEUROLOGIC Central Nervous System \- Increased muscle tone \- Extensor plantar responses Peripheral Nervous System \- Decreased vibration sense in the feet \- Sural nerve biopsy shows chronic axonal neuropathy MISCELLANEOUS \- Onset usually in first or second decade (mean 10 years) \- Adult onset rarely reported \- Progressive disorder ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE I | c1866784 | 1,323 | omim | https://www.omim.org/entry/182960 | 2019-09-22T16:34:34 | {"doid": ["0111200"], "mesh": ["C566675"], "omim": ["182960"], "orphanet": ["139518"], "synonyms": ["Alternative titles", "HMN I", "NEUROPATHY, DISTAL HEREDITARY MOTOR, TYPE I", "SPINAL MUSCULAR ATROPHY, DISTAL, JUVENILE, AUTOSOMAL DOMINANT, I", "CHARCOT-MARIE-TOOTH DISEASE, SPINAL, I"]} |
A number sign (#) is used with this entry because of evidence that neonatal inflammatory skin and bowel disease-2 (NISBD2) is caused by homozygous mutation in the EGFR gene (131550) on chromosome 7p11. One such family has been reported.
For a discussion of genetic heterogeneity of neonatal inflammatory skin and bowel disease, see NISBD1 (614328).
Clinical Features
Campbell et al. (2014) studied a male infant, born to Polish Roma parents, who from birth had widespread erosions affecting his trunk and limbs and later developed papules and pustules, with frequent Staphylococcus aureus infections of the skin. He also had lifelong watery diarrhea and respiratory difficulties, and at 1 year of age exhibited failure to thrive. He had loss of scalp hair but long eyelashes (trichomegaly); no nail abnormalities were seen. He had undergone surgery for probable coarctation of the aorta and was hypertensive. He had recurrent bronchiolitis, and pulmonary infection with Pseudomonas aeruginosa required tracheostomy and oxygen. He had bilateral renal enlargement on ultrasound but no obstruction. Although he had no specific food allergies, he was unable to tolerate solids due to diarrhea and vomiting, and ultimately required total parenteral nutrition. Venous access lines frequently became clotted, and he developed deep vein thromboses. He died at 2.5 years of age due to cutaneous and pulmonary infections and electrolyte imbalance. Light microscopy of nonlesional skin from the patient showed mild acanthosis and slight widening between adjacent keratinocytes compared to controls; electron microscopy revealed intercellular edema from the basal to mid-spinous layer and a slight decrease in the number of gap junctions, but no structural or numerical abnormalities in hemidesmosome or desmosome cell junctions. Skin immunolabeling demonstrated a marked reduction in staining intensity for the desmosomal proteins desmoglein-1 (125670) and plakophilin-1 (601975), as well as altered labeling patterns for markers of terminal differentiation in the epidermis, including profilaggrin (135940), involucrin (147360), and keratin-10 (148080). Immunofluorescence microscopy to assess EGFR in patient skin showed a markedly altered staining pattern with loss of cell peripheral membrane labeling and more cytoplasmic or perinuclear distribution, in contrast to strong cell membrane localization of EGFR in control skin.
Molecular Genetics
By whole-exome sequencing of DNA from a Polish Roma boy who died from neonatal inflammatory skin and bowel disease, Campbell et al. (2014) identified homozygosity for a missense mutation in the EGFR gene (G428D; 131550.0007). His unaffected mother was heterozygous for the mutation, which was not present in an unaffected sib; no DNA from the father was available. The mutation was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 900 unrelated European in-house control exomes.
INHERITANCE \- Autosomal recessive GROWTH Weight \- Failure to thrive HEAD & NECK Eyes \- Long eyelashes (trichomegaly) CARDIOVASCULAR Heart \- Coarcation of the aorta Vascular \- Hypertension \- Deep vein thromoboses RESPIRATORY Airways \- Recurrent bronchiolitis Lung \- Recurrent pulmonary infections ABDOMEN Gastrointestinal \- Vomiting \- Diarrhea, watery \- Severe dehydration GENITOURINARY Kidneys \- Enlarged kidneys without obstruction SKIN, NAILS, & HAIR Skin \- Generalized erosions \- Papules \- Pustules \- Frequent Staphylococcus aureus infections Skin Histology \- Acanthosis, mild \- Widening between adjacent keratinocytes Electron Microscopy \- Intercellular edema from basal layer to mid-spinous layer \- Slight decrease in number of gap junctions Hair \- Loss of scalp hair \- Trichomegaly IMMUNOLOGY \- Elevated IgE levels MISCELLANEOUS \- Based on report of one Polish Roma patient (last curated November 2014) MOLECULAR BASIS \- Caused by mutation in the epidermal growth factor gene (EGFR, 131550.0007 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| INFLAMMATORY SKIN AND BOWEL DISEASE, NEONATAL, 2 | c4015130 | 1,324 | omim | https://www.omim.org/entry/616069 | 2019-09-22T15:50:00 | {"omim": ["616069"], "orphanet": ["294023"], "synonyms": []} |
A rare neurologic disease characterized by visual agnosia, hyperorality (strong tendency to examine objects orally), hypermetamorphosis (described as the irresistible impulse to notice and react to everything within sight), hypersexuality, changes in dietary habits and hyperphagia, placidity, and amnesia, due to bilateral lesions of the temporal lobe including the hippocampus and amygdala.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Klüver-Bucy syndrome | c0270707 | 1,325 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=157823 | 2021-01-23T18:29:18 | {"gard": ["6840"], "mesh": ["D020232"], "umls": ["C0270707"]} |
Windblown hand is a hand deformity that is present from birth. The cause of this deformity is unknown. People with windblown hand have flexion contractures of the joints at the base of each finger that prevents normal mobility of their hand and causes their fingers to bend toward their "little" finger (i.e., ulnar drift). In addition, windblown hand is characterized by a "thumb-in-palm deformity" or "clasped thumb" where the thumb is webbed to the palm by a soft tissue bridge.
Click here to view the anatomy of the hand provided by the American Society for Surgery of the Hand.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Windblown hand | c0431875 | 1,326 | gard | https://rarediseases.info.nih.gov/diseases/10276/windblown-hand | 2021-01-18T17:57:05 | {"umls": ["C0431875"], "synonyms": ["Congenital ulnar drift", "Windswept hand", "Congenital contractures of the digits"]} |
Lissencephaly due to LIS1 mutation is a cerebral malformation with epilepsy characterized predominantly by posterior isolated lissencephaly with developmental delay, intellectual disability and epilepsy that usually evolves from West syndrome to Lennox-Gastaut syndrome. Additional features include muscular hypotonia, acquired microcephaly, failure to thrive and poor control of airways leading to aspiration pneumonia.
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Lissencephaly due to LIS1 mutation | c0431375 | 1,327 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=95232 | 2021-01-23T18:10:17 | {"mesh": ["D054221"], "omim": ["607432"], "icd-10": ["Q04.3"], "synonyms": ["PAFAH1B1-related lissencephaly"]} |
Osteochondritis dissecans is a joint condition that occurs when a piece of cartilage and the thin layer of bone beneath it, separates from the end of the bone. If the piece of cartilage and bone remain close to where they detached, they may not cause any symptoms. However, affected people may experience pain, weakness and/or decreased range of motion in the affected joint if the cartilage and bone travel into the joint space. Although osteochondritis dissecans can affect people of all ages, it is most commonly diagnosed in people between the ages of 10 and 20 years. In most cases, the exact underlying cause is unknown. Rarely, the condition can affect more than one family member (called familial osteochondritis dissecans); in these cases, osteochondritis dissecans is caused by changes (mutations) in the ACAN gene and is inherited in an autosomal dominant manner. Treatment for the condition varies depending on many factors, including the age of the affected person and the severity of the symptoms, but may include rest; casting or splinting; surgery and/or physical therapy.
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Osteochondritis dissecans | c0029421 | 1,328 | gard | https://rarediseases.info.nih.gov/diseases/12703/osteochondritis-dissecans | 2021-01-18T17:58:33 | {"mesh": ["D010008"], "orphanet": ["2764"], "synonyms": ["Kônig disease", "König disease"]} |
A number sign (#) is used with this entry because of evidence that Diamond-Blackfan anemia-20 (DBA20) is caused by heterozygous mutation in the RPS15A gene (603674) on chromosome 16p. One such family has been reported.
For a general phenotypic description and discussion of genetic heterogeneity of Diamond-Blackfan anemia, see DBA1 (105650).
Clinical Features
Ikeda et al. (2017) reported a mother and 2 daughters with DBA20. The proband, who was the youngest daughter, was the most severely affected. She presented at birth with total anomalous pulmonary venous connection and acetabular dysplasia, and was diagnosed with anemia at age 3 months. Bone marrow aspiration showed severe selective erythroid hypoplasia, but otherwise normal cellularity. She developed macrocytosis at age 14. The mother and sister presented with anemia during childhood, but had no additional physical abnormalities. All 3 patients initially responded to corticosteroid treatment and later became steroid-independent.
Inheritance
The transmission pattern of DBA20 in the family reported by Ikeda et al. (2017) was consistent with autosomal dominant inheritance.
Molecular Genetics
In a mother and 2 daughters with DBA20, Ikeda et al. (2017) identified a heterozygous splicing mutation in the RPS15A gene (603674.0001) that was demonstrated to result in a loss of function and haploinsufficiency. The mutation, which was found by whole-exome sequencing and confirmed by direct sequencing, segregated with the disorder in the family. It was not found in the ExAC database. Expression of the mutation in human erythroid K562 cells showed that it suppressed cell proliferation and caused abnormal levels of several pre-rRNA subunits, indicating disturbed RNA processing. The family was 1 of 141 families in the cohort, thus accounting for 0.7%.
Animal Model
Ikeda et al. (2017) found that morpholino knockdown of the rps15a gene in zebrafish embryos resulted in abnormalities, including thin yolk sac, bent tail, and a markedly reduced erythrocyte production. The mutant phenotype could be rescued by expression of wildtype rps15a.
INHERITANCE \- Autosomal dominant HEMATOLOGY \- Anemia, steroid-responsive \- Bone marrow shows erythroid hypoplasia MISCELLANEOUS \- Onset in the first year of life \- One family has been reported (last curated February 2019) MOLECULAR BASIS \- Caused by mutation in the ribosomal protein S15a gene (RPS15A, 603674.0001 ) ▲ 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
| DIAMOND-BLACKFAN ANEMIA 20 | c1260899 | 1,329 | omim | https://www.omim.org/entry/618313 | 2019-09-22T15:42:31 | {"mesh": ["D029503"], "omim": ["618313"], "orphanet": ["124"], "genereviews": ["NBK7047"]} |
A number sign (#) is used with this entry because X-linked dyskeratosis congenita (DKCX) is caused by mutation in the (DKC1; 300126) gene on chromosome Xq28.
Description
Dyskeratosis congenita is classically defined by the triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa. It is characterized by short telomeres. Progressive bone marrow failure occurs in over 80% of cases and is the main cause of early mortality. The phenotype is highly variable, and affected individuals may have multiple additional features, including pulmonary fibrosis, liver cirrhosis, premature hair loss and/or graying, osteoporosis, atresia of the lacrimal ducts, and learning difficulties. Males may have testicular atrophy. Predisposition to malignancy is an important feature. The disorder is caused by defects in the maintenance of telomeres (summary by Kirwan and Dokal, 2008).
Hoyeraal-Hreidarsson syndrome (HHS) refers to a clinically severe variant of DKC that is characterized by multisystem involvement and early onset in utero. Patients with HHS show intrauterine growth retardation, microcephaly, delayed development, and bone marrow failure resulting in immunodeficiency, cerebellar hypoplasia, and sometimes enteropathy. Death often occurs in childhood (summary by Walne et al., 2013).
For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (127550).
Clinical Features
Milgrom et al. (1964) described a black male with dyskeratosis congenita. They pointed out that the 2 serious complications are anemia and cancer, which can develop in the leukoplakia of the anus or mouth or in the skin.
Selmanowitz and van Voolen (1971) pointed out the phenotypic overlap with Fanconi anemia (see 227650) and raised the question whether Fanconi anemia and dyskeratosis congenita might be causally related.
Sirinavin and Trowbridge (1975) reported a large kindred with X-linked DKC. Pancytopenia and malignancy were features, and opportunistic infections were also a major complication. Nail dystrophy, reticulated atrophic telangiectatic hyper- and hypopigmented skin lesions, oral leukoplakia, and mental retardation were described. An extensive review of the literature was provided.
Connor and Teague (1981) reported an affected kindred, and noted 3 previously unreported complications: Hodgkin disease, pancreatic adenocarcinoma, and deafness. Normal chromosomal stability was found in the 3 patients studied. Studies uncovered no early generalized defect of cell-mediated immunity.
Womer et al. (1983) reported 2 brothers who showed reticular hyperpigmentation, dystrophic nails, oral leukoplakia, and aplastic anemia. Less common features included prenatal and postnatal growth retardation, mental retardation, elevated immunoglobulin levels, and gastrointestinal hemorrhage from mucosal ulcerations. 'New' features were intracranial calcifications and nutmeg-like cirrhosis of the liver. No increased chromosomal breakage was noted. Death occurred at ages 18 and 14 years.
Davidson and Connor (1988) provided an extensive review of 104 published cases of which 51 had previously been reviewed by Sirinavin and Trowbridge (1975).
Phillips et al. (1992) described a 5-year-old boy who was treated with bone marrow transplantation for aplastic anemia at the age of 2 years. The diagnosis of dyskeratosis congenita was not made until 18 months after the bone marrow transplant. He had diffuse nonscarring alopecia and problems related to bilateral lacrimal duct blockage. At the age of 5 years, all nails were hypoplastic and irregular, and he had reticulate hyperpigmentation on his neck. He required a hearing aid and had poor vision in one eye. Lacrimal duct stenosis is said to be present in about 80% of cases. In 70%, pancytopenia is the cause of death. Because of a previously widely held view that the outcome of bone marrow transplantation in this disorder is poor, this treatment option was sometimes not considered when pancytopenia developed. Phillips et al. (1992) suggested that the results may be satisfactory if radiation is avoided.
Bone marrow failure has been reported in approximately 50% of cases of dyskeratosis congenita (Dokal, 1996), and in some patients symptoms related to aplastic anemia may precede the diagnosis of DKC (Forni et al., 1993).
Caux et al. (1996) presented a patient and reviewed the pathogenesis of the disorder.
Merchant et al. (1998) described the changes of chronic keratoconjunctivitis in a case of congenital dyskeratosis thought to be autosomal dominant with 'variable penetration.' In general, the disorder is more likely to be X-linked, and the family history suggested that this was the case with partial expression in heterozygous females. The patient was a 58-year-old man from Puerto Rico. In addition to chronic cicatrizing keratoconjunctivitis, which was said to have been a problem since 5 years of age, he had reticulate pigmentation of the skin, dystrophic nails, leukoplakia, alopecia, dental problems resulting in tooth loss, and thrombocytopenia. The patient's mother had a mild form of the disorder with limited skin involvement, and 2 brothers had significant skin pigmentation and nail dystrophy. One of the brothers also had a history of tongue cancer. The patient had 1 son who had no manifestations of the disease but 2 of his 3 daughters had classic skin and nail findings of congenital dyskeratosis, and the third daughter had subtle skin changes. One of the daughter's sons, who was 17 years old, had early pigmentary skin changes and significant thrombocytopenia.
In the Dyskeratosis Congenita Registry at the Hammersmith Hospital in London, 46 families were recruited (Knight et al., 1998). Of 83 patients, 76 were male, suggesting that the major form of DKC is X-linked. In addition to a variety of noncutaneous abnormalities, most of the patients (93%) had bone marrow failure, which was the principal cause (71%) of early mortality. Some patients also developed myelodysplasia and acute myeloid leukemia. Pulmonary abnormalities were present in 19% of patients.
Parry et al. (2011) reported a large family of Irish ancestry with X-linked inheritance of adult-onset pulmonary fibrosis. Clinical history revealed that affected members also had features suggestive of DKC, including nail dystrophy, skin hyperpigmentation, and liver cirrhosis. One patient died of squamous cell carcinoma at age 34 years, but there was no family history of aplastic anemia. Four affected males had telomere lengths at or below the 1st centile compared to controls, as well as low levels of telomerase RNA. Western blot analysis showed low levels of dyskerin in affected males, but sequencing of the DKC1 gene did not identify any pathogenic mutations. However, genomewide linkage analysis identified a 47-cM peak on chromosome Xq28 (lod score of 3.25), and obligate carriers females showed skewed X inactivation. The findings indicated that intact levels of dyskerin, in the absence of coding mutations, are essential for in vito telomere maintenance, and that a defect in dyskerin levels is sufficient to cause telomere-mediated disease. Parry et al. (2011) emphasized the high frequency of pulmonary fibrosis as a manifestation of the disorder in this family. Affected individuals died as adults, suggesting that pulmonary disease may represent an attenuated, adult-onset telomere phenotype.
### Hoyeraal-Hreidarsson Syndrome
Hoyeraal et al. (1970) reported 2 brothers with prenatal growth retardation, microcephaly, mental retardation with spastic paresis and ataxia, pancerebellar hypoplasia, thrombocytopenia, and bone marrow hypoplasia. Hreidarsson et al. (1988) reported a single affected male and proposed that the disorder is autosomal recessive because the parents were consanguineous. The brothers of Hoyeraal et al. (1970) died at 23 and 42 months of age; the patient of Hreidarsson et al. (1988) died at 23 months of age. Aalfs et al. (1995) reported a single case, a male with nonconsanguineous parents who was still alive at the age of 4 years. Like the case of Hreidarsson et al. (1988), the patient had pancytopenia, as well as intrauterine growth retardation, microcephaly, developmental delay, spastic paresis, ataxia, and cerebellar hypoplasia. Berthet et al. (1994) and Berthet et al. (1995) suggested that immunodeficiency is a feature of this syndrome.
Reardon et al. (1994) suggested that this is the same condition as the autosomal recessive congenital intrauterine infection-like syndrome, or pseudo-TORCH syndrome (251290). Aalfs and Hennekam (1995) described several differences between the 2 syndromes. Patients with Hoyeraal-Hreidarsson syndrome show only growth retardation and microcephaly in the first months of life, whereas those with the pseudo-TORCH syndrome have symptoms resembling TORCH infection shortly after birth, including hepatosplenomegaly. Furthermore, in the intrauterine infection-like syndrome, the neonatally present thrombocytopenia resolves within a year if the child survives, whereas in the Hoyeraal-Hreidarsson syndrome the first symptoms of pancytopenia do not occur before the age of 5 months and continue to increase for years. The cerebellum is proportionately small in Hoyeraal-Hreidarsson syndrome, whereas the cerebral abnormalities are more severe in the pseudo-TORCH syndrome.
Ohga et al. (1997) summarized 6 reported cases of Hoyeraal-Hreidarsson syndrome.
Mahmood et al. (1998) described 2 sibs with low birthweight, failure to thrive, chronic persistent tongue ulceration, severe truncal ataxia, and pancytopenia without either telangiectasia or chromosomal instability. One sib died from sepsis and the cerebellum demonstrated reduced cellularity of the molecular and granular layers with relative preservation of Purkinje cells and minimal gliosis. The surviving sib showed hematologic progression to a myelodysplastic disorder. There was no evidence of chromosomal instability following exposure of fibroblasts and lymphocytes to irradiation. Monosomy-7 was not present in the surviving sib. Mahmood et al. (1998) suggested the diagnosis of Hoyeraal-Hreidarsson syndrome.
Yaghmai et al. (2000) reported a 4-year-old boy with pancytopenia and oral ulcers who was born at 32 weeks' gestation with intrauterine growth retardation. He had developed esophageal strictures and gastric ulcers, and also had moderate hypoplasia of the midline cerebellum and Dandy-Walker variant (220200). He had microcephaly, thin, brittle scalp hair, 20-nail dystrophy, and subtle reticulated hyperpigmentation of the shoulder and arms. This child had striking features of both Hoyeraal-Hreidarsson syndrome and X-linked dyskeratosis congenita.
Pearson et al. (2008) reported a 9-month-old Italian boy with HHS. The pregnancy was complicated by decreased fetal movements, intrauterine growth retardation, and oligohydramnios. He had microcephaly, neonatal respiratory distress, and transient thrombocytopenia and leukopenia. At age 4 months, he presented with seizures and axial hypotonia. Brain MRI showed cerebellar hypoplasia, and other radiographs showed distal metaphyseal flaring of the long bones. Although most hematologic indices remained relatively normal, his platelet counts continued to fall below normal, requiring transfusions. He died at age 2 years. Genetic analysis identified a hemizygous mutation in the DKC1 gene (300126.0015).
### Female Carriers
Alder et al. (2013) reported 2 unrelated families with DKCX, confirmed by genetic analysis, in which 5 female mutation carriers showed features of the disorder. In the first family, a man developed pulmonary fibrosis at age 46 years, followed by aplastic anemia and myelodysplastic syndrome resulting in death at age 49. His daughter showed graying of the hair at age 20 and wound dehiscence after surgery at age 23. The father's telomere length was below 1% of controls, and the daughter's telomere length was near 5% of controls. X-inactivation in the daughter was skewed at 93%. In the second family, 2 affected brothers had a total of 3 affected daughters. The daughters showed features of DKC in childhood, including skin hyperpigmentation, nail dystrophy, fragile teeth with caries, and hair graying. One daughter had developmental delay and another had anosmia. X-inactivation studies performed in 2 females showed 100% skewing. The findings indicated that mutations in the DKC1 gene can cause telomere-related phenotypes in heterozygous females, and Alder et al. (2013) suggested that heterozygous females should be followed for telomere-related complications, particularly when exposed to environmental insults.
Other Features
Kalb et al. (1986) described a 33-year-old man with typical features of DKC as well as avascular necrosis of the femoral head. Such had previously been reported in cases of this disorder but only in patients who had received systemic adrenocorticosteroids for pancytopenia or thrombocytopenia.
Reichel et al. (1992) found reports of 15 cases of elevated fetal hemoglobin in association with DKC and added another case, an 11-year-old boy who, in addition to DKC and elevated fetal hemoglobin, had X-linked ocular albinism and juvenile-onset diabetes mellitus.
Biochemical Features
In fibroblasts from a patient with DKC, DeBauche et al. (1990) found increased frequency of chromatid breaks and chromatid gaps after X-radiation during the G-2 phase of the cell cycle.
Ning et al. (1992) found that the mean number of chromosome breaks per cell in bleomycin-treated lymphocytes was higher in patients with dyskeratosis congenita and in obligatory heterozygotes than in normal individuals. Unequivocal heterozygote detection was not possible owing to overlap of values. In vitro clonogenic assays, as well as long-term bone marrow culture studies (Marsh et al., 1992), suggested that symptoms of aplastic anemia in DKC may be due to a defect at the level of the hematopoietic stem cell.
In 4 patients with DKC, 3 from 1 family and 1 from another, Dokal et al. (1992) found that primary skin fibroblast cultures were abnormal both in morphology (polygonal cell shape, ballooning, and dendritic-like projections) and in growth rate (doubling time about twice normal). Fibroblast survival studies using 4 clastogens and gamma radiation showed no significant difference between DKC and normal fibroblasts. Furthermore, cytogenetic studies performed on peripheral blood lymphocytes showed no difference between DKC and normal lymphocytes with or without prior incubation with clastogens. However, bone marrow metaphases from 1 of 3 patients and fibroblasts from 2 of 4 patients showed numerous unbalanced chromosomal rearrangements (dicentrics, tricentrics, and translocations) in the absence of any clastogenic agents. A higher rate of chromosomal rearrangements was found in the older patients and this, together with the cell-specific differences, appeared to correlate with the clinical evolution of the disease.
Clinical Management
In a review, Dokal (1996) noted that late fatal vascular complications had been reported in some cases following bone marrow transplantation (Berthou et al., 1991). This may be related to preexisting endothelial damage in DKC patients, as evidenced by raised von Willebrand factor (613160) levels in the plasma.
Dokal (1996) suggested that DKC may be a good candidate for gene therapy for several reasons: first, it is a single gene disorder; second, the main cause of mortality relates to bone marrow failure and hematopoietic cells are accessible for targeting; and third, hematopoietic stem cells transfected with the normal DKC gene would be expected to have a selective growth advantage in the hypoplastic marrow.
Nobili et al. (2002) summarized the results of hematopoietic stem cell transplantation in 23 DKC patients, only 4 of whom were female, suggesting that most had the X-linked form of the disorder. Allogeneic hematopoietic stem cell transplantation was the only curative approach for the severe bone marrow failure in this disorder. However, results of allograft in these patients had been relatively poor, due to the occurrence of both early and late complications, reflecting the increased sensitivity of endothelial cells to radiotherapy and alkylating agents. Interstitial and obstructive lung disease, as well as liver toxicity, had been observed in DKC patients, leading to the suggestion that radiotherapy and busulfan should be avoided in the conditioning regimens. Nobili et al. (2002) described a 2-year-old boy with DKC who was given cord blood transplantation from an HLA-identical sib, using a fludarabine-based nonmyeloablative conditioning regimen. Improved results were anticipated.
Inheritance
Bryan and Nixon (1965) reported a pedigree with 4 and possibly 5 affected males in a relationship consistent with X-linked recessive inheritance.
Sirinavin and Trowbridge (1975) reported a particularly instructive kindred in which 9 males in 4 sibships and 3 generations were affected.
In the Dyskeratosis Congenita Registry at the Hammersmith Hospital in London, 46 families were recruited (Knight et al., 1998). Of 83 patients, 76 were male, suggesting that the major form of DKC is X-linked.
### X-Chromosome Inactivation
Ferraris et al. (1997) hypothesized that, at least in some DKC families, the selective pressure in the heterozygote might be strong enough to determine negative selection of progenitors bearing the mutant allele, resulting in extreme skewing of X-chromosome inactivation in cells of hematopoietic descent. The pattern of methylation of HpaII and HhaI sites with a highly polymorphic CAG repeat in the coding region of the first exon of the androgen receptor gene (AR; 313700) (Allen et al., 1992) was used in these studies. Ferraris et al. (1997) studied 2 families and found that indeed carrier females showed nonrandom X inactivation in whole blood leukocytes, granulocytes, and mononuclear cells.
Using the methylation-sensitive HpaII site in the androgen receptor gene, Vulliamy et al. (1997) found that in 5 different families in which the inheritance of DKC appeared to be X-linked, all 16 carriers showed skewed X-inactivation patterns. The results indicated that in the hematopoiesis of heterozygous females cells expressing the normal allele had a growth advantage over cells that express the mutant allele. In 7 other families with sporadic cases of DKC or with an uncertain pattern of inheritance, both skewed and normal patterns of X inactivation were observed.
Mapping
In a large kindred with DKC, Sirinavin and Trowbridge (1975) excluded close linkage with the Xg locus. Gutman et al. (1978) observed 2 maternal male cousins. Linkage analysis indicated that dyskeratosis, Xg, and G6PD (305900) are far apart. In an extensively affected kindred, Connor and Teague (1981) excluded close linkage to Xg.
Connor et al. (1986) assigned DKC to chromosome Xq28 by linkage of DNA markers. Its relationships to other loci in this segment were not determined. Arngrimsson et al. (1993) confirmed the linkage with study of 3 further families, which brought the maximum lod score for DKC and DXS52 to 5.33 at zero recombination.
Knight et al. (1996) studied 5 families with additional Xq28 polymorphic markers and concluded that the DKC locus is between GABRA3 (305660) and DXS1108, an interval of approximately 4 Mb.
Devriendt et al. (1997) reported that dyskeratosis congenita was quite clearly X-linked because linkage analysis with markers in the factor VIII gene (F8; 300841) at chromosome Xq28 yielded a lod score of 2.o at a recombination of 0.0, and clinical manifestations of DKC were present in 2 obligate carrier females, e.g., skin lesions following the Blaschko lines. Highly skewed X inactivation was observed in white blood cells, cultured skin fibroblasts, and buccal mucosa from female carriers of DKC in this family. The skewing suggested a critical role for the DKC gene in proliferation of fibroblasts and bone marrow cells. Devriendt et al. (1997) presented photographs of the linear skin lesions of the palmar aspects of the hands.
Molecular Genetics
In patients with X-linked DKC, Heiss et al. (1998) identified 5 different mutations in the DKC1 gene (300126.0001-300126.0005). Three families had previously been reported: Connor et al. (1986) (P40R; 300126.0003); Dokal et al. (1992) (G402Q; 300126.0005); and Devriendt et al. (1997) (F36V; 300126.0001). As a result of large-scale positional cloning and sequencing of the region of Xq28 containing the DKC1 gene, virtually all DKC positional candidates had been identified. By hybridization screening with 28 candidate cDNAs, Heiss et al. (1998) detected a 3-prime deletion in 1 DKC patient with a cDNA probe derived from XAP101. They subsequently identified 5 different missense mutations in 5 unrelated patients in the XAP101 (DKC1) gene. DKC1 is highly conserved across species barriers and is the ortholog of rat NAP57 and S. cerevisiae CBF5. The peptide, referred to as dyskerin, was found to contain 2 TruB pseudouridine synthase motifs, multiple phosphorylation sites, and a carboxy-terminal lysine-rich repeat domain. By analogy to the function of the known dyskerin orthologs, involvement in the cell cycle and nucleolar function was predicted for the protein.
Because of phenotypic similarities between HHS and DKC, Knight et al. (1999) hypothesized that both disorders might be caused by mutation in the same gene. In the family reported by Aalfs et al. (1995) and another family segregating HHS, Knight et al. (1999) identified mutations in the DKC1 gene (300126.0010-300126.0011), demonstrating that HHS is a severe variant of dyskeratosis congenita.
Yaghmai et al. (2000) reported a patient with striking features of both Hoyeraal-Hreidarsson syndrome and DKC who carried an ala353-to-val mutation in the DKC1 gene (300126.0006). Yaghmai et al. (2000) concluded that HHS may be a severe form of DKC in which affected individuals die before characteristic mucocutaneous features develop.
Pathogenesis
Mitchell et al. (1999) demonstrated that dyskerin is associated not only with H/ACA small nucleolar RNAs but also with human telomerase RNA (TERC; 602322), which contains an H/ACA RNA motif. Telomerase adds simple sequence repeats to chromosome ends using an internal region of its RNA as a template and is required for the proliferation of primary human cells. Mitchell et al. (1999) found that primary fibroblasts and lymphoblasts from DKC-affected males were not detectably deficient in conventional H/ACA small nucleolar RNA accumulation or function. However, DKC cells had a lower level of telomerase RNA, produced lower levels of telomerase activity than matched normal cells, and had shorter telomeres. Mitchell et al. (1999) concluded that the pathology of DKC is consistent with compromised telomerase function leading to a defect in telomere maintenance, which may limit the proliferative capacity of human somatic cells in epithelia and blood.
Montanaro et al. (2002) observed that in lymphoblastoid cell lines from patients with dyskeratosis congenita, rRNA transcription and maturation and proliferative capability remained unimpaired. Increasing the number of cell cycles led to a steep rise in the apoptotic fraction of dyskeratosis congenita cells. These findings demonstrated that whereas dyskeratosis congenita cell lines do not display proliferation defects, they do show progressively increasing levels of apoptosis in relation to the number of cell divisions. This observation is consistent with the delayed onset of dyskeratosis congenita proliferating-tissue defects, which do not emerge during embryonal development as would be expected with ribosomal biogenesis alterations, and with the increasing severity of the proliferating-tissue defects over time.
Wong and Collins (2006) found that primary dermal fibroblasts cultured from a DKC patient underwent premature senescence, consistent with the presence of short telomeres, compared with dermal fibroblasts cultured from his asymptomatic maternal grandmother. Expression of exogenous TERT (187270) from a retroviral vector increased telomerase activity in DKC patient cells, resulting in increased steady-state levels of TERC and elimination of premature senescence, but did not confer telomere length maintenance. DKC patient cells expressing both TERT and TERC from a single retroviral vector gained and maintained long telomeres. Following rescue from premature senescence, DKC patient cells from 2 different families had normal levels of rRNA pseudouridine modification and no dramatic delay in rRNA precursor processing, in contrast with phenotypes reported for mouse models of DKC. Wong and Collins (2006) concluded that defects in DKC patient cells arise solely from reduced accumulation of TERC.
Using an unbiased proteomics strategy, Yoon et al. (2006) discovered a specific defect in IRES (internal ribosome entry site)-dependent translation in Dkc1 mutated mice and in cells from X-linked dyskeratosis congenita patients. This defect results in impaired translation of mRNAs containing IRES elements, including those encoding the tumor suppressor p27(Kip1) (CDKN1B; 600778) and the antiapoptotic factors Bcl-xl (BCL2L1; 600039) and XIAP (300079). Moreover, ribosomes from Dkc1 mutant mice were unable to direct translation from IRES elements present in viral mRNAs. Yoon et al. (2006) concluded that their findings revealed a potential mechanism by which defective ribosome activity leads to disease and cancer.
Batista et al. (2011) showed that even in the undifferentiated state, induced pluripotent stem cells (iPSCs) from dyskeratosis congenita patients harbor the precise biochemical defects characteristic of each form of the disease and that the magnitude of the telomere maintenance defect in iPSCs correlates with clinical severity. In iPSCs from patients with heterozygous mutations in TERT, the telomerase reverse transcriptase, a 50% reduction in telomerase levels blunts the natural telomere elongation that accompanies reprogramming. In contrast, mutation of dyskerin (DKC1; 300126) in X-linked dyskeratosis congenita severely impairs telomerase activity by blocking telomerase assembly and disrupts telomere elongation during reprogramming. In iPSCs from a form of dyskeratosis congenita caused by mutations in TCAB1 (also known as WRAP53, 612661), telomerase catalytic activity is unperturbed, yet the ability of telomerase to lengthen telomeres is abrogated, since telomerase mislocalizes from Cajal bodies to nucleoli within the iPSCs. Extended culture of DKC1-mutant iPSCs leads to progressive telomere shortening and eventual loss of self-renewal, indicating that a similar process occurs in tissue stem cells in dyskeratosis congenita patients. Their findings in iPSCs from dyskeratosis congenita patients led Batista et al. (2011) to conclude that undifferentiated iPSCs accurately recapitulate features of a human stem cell disease and may serve as a cell culture-based system for the development of targeted therapeutics.
INHERITANCE \- X-linked recessive GROWTH Height \- Short stature Other \- Intrauterine growth retardation (seen in Hoyeraal-Hreidarsson Syndrome variant, HHS) HEAD & NECK Head \- Microcephaly (seen in HHS variant) Eyes \- Conjunctival leukoplakia \- Epiphora \- Conjunctivitis \- Blepharitis \- Strabismus \- Cataract \- Optic atrophy \- Sparse eyelashes Mouth \- Leukoplakia (71% male patients) Teeth \- Dental caries \- Early tooth loss RESPIRATORY Lung \- Restrictive lung disease \- Reduced diffusion capacity \- Pulmonary fibrosis ABDOMEN Liver \- Cirrhosis Gastrointestinal \- Esophageal stricture \- Anal mucosal leukoplakia GENITOURINARY External Genitalia (Male) \- Hypospadias \- Phimosis Internal Genitalia (Male) \- Testicular hypoplasia \- Cryptorchidism Kidneys \- Horseshoe kidney Bladder \- Urethral stenosis SKELETAL \- Osteoporosis SKIN, NAILS, & HAIR Skin \- Reticulated skin pigmentation, predominantly on face, neck, chest, arms (94% male patients) \- Hyperhidrosis \- Skin atrophy Nails \- Nail dystrophy (92% male patients) \- Longitudinal ridging \- Longitudinal splitting \- Pterygium formation \- Complete nail loss Hair \- Sparse eyelashes \- Hair loss \- Premature greying NEUROLOGIC Central Nervous System \- Delayed development (about 25%) \- Learning difficulties \- Mental retardation (seen in HHS variant) \- Cerebellar ataxia (seen in HHS variant) \- Cerebellar hypoplasia (seen in HHS variant) HEMATOLOGY \- Bone marrow failure \- Myelodysplasia \- Pancytopenia \- Thrombocytopenia \- Leukopenia \- Anemia IMMUNOLOGY \- Immunodeficiency \- Opportunistic infections (CMV, pneumocystis, candida) NEOPLASIA \- Squamous cell carcinoma (skin or mucosa) \- Acute myeloid leukemia \- Hodgkin disease \- Pancreatic carcinoma LABORATORY ABNORMALITIES \- Increased chromosomal rearrangements (bone marrow and fibroblast culture) MISCELLANEOUS \- Classic triad consists of nail dystrophy, skin hyperpigmentation, and mucosal leukoplakia \- Median age of diagnosis - 15 years \- Median age of onset of pigmentation - 8 years (range 1-15 years) \- Median age of onset of nail dystrophy - 7 years (range 1-6 years) \- Median age of onset of leukoplakia - 7 years (range 1-26 years) \- Median age of onset of pancytopenia - 10 years (range 1-32 years) \- HHS is a more severe variant, often resulting in death in childhood MOLECULAR BASIS \- Caused by mutation in the dyskerin gene (DKC1, 300126.0001 ) ▲ 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
| DYSKERATOSIS CONGENITA, X-LINKED | c1846142 | 1,330 | omim | https://www.omim.org/entry/305000 | 2019-09-22T16:18:27 | {"doid": ["0070025"], "mesh": ["C536068"], "omim": ["305000"], "orphanet": ["3322", "1775"], "synonyms": ["Alternative titles", "ZINSSER-COLE-ENGMAN SYNDROME"], "genereviews": ["NBK22301"]} |
A fear of children
Fear of children
Other namesPedophobia, paedophobia, pediaphobia
SpecialtyPsychiatry
Fear of children, hatred of children, or occasionally called pedophobia, is fear triggered by the presence or thinking of children or infants. It is an emotional state of fear, disdain, aversion, or prejudice toward children or youth. Pedophobia is in some usages identical to ephebiphobia.[1][2][3]
The fear of children has been diagnosed and treated by psychiatrists, with studies examining the effects of multiple forms of treatment.[4] Studies have identified the fear of children as a factor affecting biological conception in humans.[5][6]
## Contents
* 1 Causes
* 2 Efforts to decrease
* 3 Terminology
* 4 See also
* 5 References
* 6 Further reading
## Causes[edit]
Letty Cottin Pogrebin, a founding editor of Ms. magazine, diagnosed America as having an "epidemic of paedophobia", saying that, "though most of us make exceptions for our own offspring, we do not seem particularly warm-hearted towards other peoples' children."[7]
One author suggests that the cause of the fear of children in academia specifically extends from adults' distinct awareness of the capacity of children: "Children embarrass us because they point ever too cleverly and clearly to our denial of personal, material, and maternal history."[8]
One report suggests that the source of current trends in the fear of children have a specific source: James Q. Wilson, a professor at UCLA's School of Management, who in 1975 helped inaugurate the current climate of pedophobia when he said "a critical mass of younger persons... creates an explosive increase in the amount of crime."[9]
Sociologists have situated "contemporary fears about children and childhood" as "contributing to the ongoing social construction of childhood", suggesting that "generational power relations, in which children's lives are bounded by adult surveillance" affect many aspects of society.[10]
## Efforts to decrease[edit]
Efforts to decrease inattention to the needs of children or opposition to youths is a focus of several international social justice movements addressing young people, including children's rights and youth participation. Major international organizations addressing discrimination, either outright or by implication, include Save the Children and Children's Defense Fund. However, some organizations, particularly those associated with the youth rights movement, claim that these movements perpetuate discrimination.[11]
The United Nations has created the Convention on the Rights of the Child, which is implicitly designed to foster intergenerational equity between children and adults.[12]
The influence of the fear of youths in American popular culture is examined by critical media analysts who have identified the effects of pedophobia in both Disney[13] and horror films.[14]
Other authors and scholars, including Henry Giroux,[15] Mike Males, and Barbara Kingsolver[16] have suggested that the popular modern fear of youths stems from corporatisation of mass media and its complicity with a range of political and economic interests. Males perhaps goes the furthest, and wrote an entire book exploring the subject.[17]
## Terminology[edit]
Paedophobia is the British English spelling, and pediaphobia is another alternate spelling. The terms come from the Greek roots παιδ- paid- (child) and φόβος -phóbos (fear). Pedophobia is not to be confused with Pediophobia, which is fear of dolls, or Podophobia, which is fear of feet, or Pedophobia as a social phenomenon.
## See also[edit]
* Fear of childbirth
* Adultism
* Ageism
* Adultcentrism
* Ephebiphobia (fear of youths)
* Youth rights
## References[edit]
1. ^ Lewis, Paul (23 October 2006). "Fear of teenagers is growing in Britain, study warns". London: Guardian. Retrieved 2 January 2011. "But it appears that an aversion to young people, or "paedophobia", is becoming a national phenomenon."
2. ^ Kring, A., Davison, G., et al. (2006) Abnormal Psychology Wiley.
3. ^ Djordjevic, S. (2004) Dictionary of Medicine: French-English with English-French Glossary. Schreiber Publishing, Inc.
4. ^ Schwartz, C., Houlihan, D., Krueger, K. F., Simon, D. A. (1997) "The Behavioral Treatment of a Young Adult with Post Traumatic Stress Disorder and a Fear of Children," Child & Family Behavior Therapy, 191, p37-49.
5. ^ Kemeter, P. & Fiegl, J. (1998) "Adjusting to life when assisted conception fails," Human Reproduction. 134 p. 1099–1105.
6. ^ McDonald, R. (1968) "The Role of Emotional Factors in Obstetric Complications: A Review," Psychosomatic Medicine 30 p. 222-237. American Psychosomatic Society.
7. ^ L. Pogrebin, as cited in Zelizer, V. (1994) Pricing the Priceless Child: The Changing Social Value of Children Princeton University Press.
8. ^ Coiner, C. & George, D.H. (1998) The Family Track: Keeping Your Faculties while You Mentor, Nurture, Teach, and Serve University of Illinois Press.
9. ^ Murashige, M. (2001). The Future of Change: Youth Perspectives on Social Justice and Cross-Cultural Collaborative Action in Los Angeles. Los Angeles: MultiCultural Collaborative Archived 2007-12-13 at the Wayback Machine.
10. ^ Scott, S., Jackson, S., & Backett-milburnswings, K. (1998) "Swings and roundabouts: Risk anxiety and the everyday worlds of children," Sociology, 32 p. 689-705. Cambridge University Press.
11. ^ Axon, K. (n.d.) The Anti-Child Bias of Children's Advocacy Groups Archived August 20, 2006, at the Wayback Machine Chicago, IL: Americans for a Society Free of Age Restrictions.
12. ^ Penn, J. (1999), The Rights Of Young Children. London University Institute of Education. "Archived copy" (PDF). Archived from the original on October 11, 2008. Retrieved April 23, 2010.CS1 maint: archived copy as title (link) CS1 maint: bot: original URL status unknown (link)
13. ^ Giroux, H. (1999) The Mouse that Roared: Disney and the End of Innocence. Rowman & Littlefield Publishers
14. ^ Phillips, K. (2005) Projected Fears: Horror Films and American Culture. Praeger Publishers
15. ^ (n.d.) Reading List on Henry Giroux Archived 2007-02-06 at the Wayback Machine. The Freechild Project.
16. ^ Dudley-Marling, C., Jackson, J., & Patel, L. (2006) "Disrespecting Childhood, Phi Delta Kappan 8710 (June 2006).
17. ^ Males, M. (2001) Kids and Guns: How Politicians, Experts, and the Media Fabricate Fear of Youth. Common Courage Press.
## Further reading[edit]
Look up pedophobia in Wiktionary, the free dictionary.
Look up hebephobia in Wiktionary, the free dictionary.
Look up juvenoia in Wiktionary, the free dictionary.
* Raising Cain: Protecting the Emotional Life of Boys by Daniel J. Kindlon, Michael Thompson, et al.
* Prout, R. (2001) Fear and Gendering: Pedophobia, Effeminophobia, and Hyermasculine Desire in the Work of Juan Goytisolo, 'Worlds of Change, 42.
* Scharf, R. (2001) "Pedophobia, the gynarchy, and the androcracy," Journal of Psychohistory 28(3) (Winter 2001) p. 281-302.
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* 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
| Fear of children | None | 1,331 | wikipedia | https://en.wikipedia.org/wiki/Fear_of_children | 2021-01-18T19:00:58 | {"wikidata": ["Q2157065"]} |
A number sign (#) is used with this entry because of evidence that familial candidiasis-9 (CANDF9) is caused by homozygous mutation in the IL17RC gene (610925) on chromosome 3p25.
For a general description and a discussion of genetic heterogeneity of familial candidiasis, see CANDF1 (114580).
Clinical Features
Ling et al. (2015) reported 3 unrelated patients with isolated recurrent chronic mucocutaneous candidiasis infections from early childhood. Symptoms included chronic and recurrent oral thrush and impetigo, sometimes with nail involvement. None of the patients had recurrent viral or bacterial infections, or other fungal infections. Detailed immunologic work-up was normal in all patients, showing normal B-, T-, and NK-cell function and production of normal levels of IL17A (603149).
Inheritance
The transmission pattern of CANDF9 in the families reported by Ling et al. (2015) was consistent with autosomal recessive inheritance.
Molecular Genetics
In 3 unrelated patients with CANDF9, Ling et al. (2015) identified 3 different homozygous truncating mutations in the IL17RC gene (610925.0001-610925.0003). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. Patient fibroblasts showed decreased levels of IL17RC mRNA compared to controls, and HEK293T cells transfected with the mutations showed absence of IL17RC membrane expression. Patient fibroblasts showed no cytokine response to IL17A and IL17F (606496) homo- and heterodimers, but response to IL17E (IL25; 605658) was normal. Whole blood and monocytes derived from the patients showed normal cytokine responses to fungal compounds.
Animal Model
Ho et al. (2010) found that Il17rc-null mice showed a dramatic increase in fungal burden in the oral cavity after infection with Candida albicans compared to wildtype or heterozygous mice. The findings suggested that IL17RC plays an important role in IL17 signaling and in mediating host defense against C. albicans.
INHERITANCE \- Autosomal recessive HEAD & NECK Mouth \- Oral thrush \- Aphthous stomatitis SKIN, NAILS, & HAIR Skin \- Impetigo Nails \- Onychomycosis IMMUNOLOGY \- Candida albicans infections, chronic, recurrent MISCELLANEOUS \- Onset in early childhood \- Three unrelated patients have been reported (last curated July 2015) MOLECULAR BASIS \- Caused by mutation in the interleukin 17 receptor C gene (IR17RC, 610925.0001 ) ▲ 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
| CANDIDIASIS, FAMILIAL, 9 | c0006845 | 1,332 | omim | https://www.omim.org/entry/616445 | 2019-09-22T15:48:53 | {"doid": ["2058"], "mesh": ["D002178"], "omim": ["616445"], "orphanet": ["1334"]} |
A number sign (#) is used with this entry because of evidence that holoprosencephaly-3 (HPE3) is caused by heterozygous mutation in the SHH gene (600725), which encodes the human Sonic hedgehog homolog, on chromosome 7q36.
For a phenotypic description and a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (236100).
Clinical Features
Berry et al. (1984) and Johnson (1989) provided information on a family (family 2 in Johnson, 1989) in which holoprosencephaly occurred in 2 sibs and their first cousin, who were offspring of parents with a single central maxillary incisor. Johnson (1989) reported a second patient (family 1) with full-blown holoprosencephaly whose mother and sister had only a single central maxillary incisor. Johnson (1989) suggested that holoprosencephaly is a developmental field defect of which the mild forms can be single median incisor, hypotelorism, bifid uvula, or pituitary deficiency.
Ardinger and Bartley (1988) reported a family in which 3 individuals in 3 successive generations had severe brain anomalies and 12 individuals had minor manifestations, mainly microcephaly. Other findings in the family included single central incisor and hypotelorism, which have been suggested as mild manifestations of autosomal dominant familial holoprosencephaly.
Nanni et al. (1999) presented a panel of 12 photographs illustrating the range of severity in holoprosencephaly resulting from mutation in the SHH gene.
Marini et al. (2003) studied a family, previously described by Camera et al. (1992), in which the mother presented with a single central maxillary incisor and mild hypotelorism and her daughter and 2 fetuses were diagnosed with HPE. Sequencing of DNA in this family identified a nonsense mutation in the SHH gene (600725.0019).
By detailed ophthalmologic examination of 5 patients with genetically confirmed HPE3, Pineda-Alvarez et al. (2011) found several subtle abnormalities, including refractory errors, small corneal diameter, coloboma, foveal hypoplasia, blepharoptosis, hyperopia, strabismus, and astigmatism. These findings occurred without brain malformations; the patients had single central incisors, microcephaly, hypotelorism, and depressed nasal bridge; 1 had hypoplasia of the left frontal lobe. The patients were part of a larger cohort of 10 patients with genetically confirmed HPE. All had at least 2 ophthalmologic anomalies, including refractive errors, microcornea, microphthalmia, blepharoptosis, exotropia, and coloboma. The findings contributed to the understanding of the phenotypic variability of the HPE spectrum and showed that subtle intraocular abnormalities can occur in HPE.
Cytogenetics
Pfitzer and Muntefering (1968) observed 4 affected children whose mothers were relatives and had the same anomalous karyotype thought to represent balanced translocation between chromosome 3 and a chromosome of the C group. With the introduction of G-banding techniques, Pfitzer et al. (1982) demonstrated that this reciprocal 7/C-translocation was a balanced rearrangement between the short arm of chromosome 3 and the distal part of the long arm of chromosome 7--t(3;7)(p23;q36). Burrig et al. (1989) demonstrated a fifth case of cyclopia in this family, detected prenatally, and showed an unbalanced karyotype attributable to the above-mentioned balanced translocation. They could find no reports of cyclopia associated with similar chromosome abnormalities.
Lurie et al. (1990) pointed out that at least 9 cases of HPE have occurred in patients with confirmed loss of 7q34-q36. They reported balanced rearrangements involving 7q in 2 mothers examined after the birth of their nonkaryotyped infants with HPE and hydronephrosis. They suggested that in both infants del(7q) was the most probable cause of HPE. Cyclopia and cebocephaly were conspicuous features in the cases of del(7q). Sporadic cases of cyclopia have been observed in association with trisomy 13, ring 13, and other chromosomal abnormalities and many have had normal karyotypes. Masuno and Orii (1990) also pointed to reports of holoprosencephaly in association with terminal 7q deletion.
Kleczkowska et al. (1990) described the case of a female fetus with hemilobar holoprosencephaly and 46,XX,der(7)t(7;8)(q36.1;p12)mat karyotype. The holoprosencephaly sequence was considered to be related to the distal 7(q36.1-qter) deficiency. Hatziioannou et al. (1991) reviewed the evidence suggesting that a locus for holoprosencephaly resides at or near 7q36.
Gurrieri et al. (1993) characterized the 7q deletions in 13 HPE patients and constructed a high resolution physical map of 7q32-qter. They defined the HPE minimal critical region in 7q36 between D7S292 and D7S392. They pictured one of the patients with the characteristic facies of the severe form of HPE which included a single fused eye (cyclopia) and a nose-like structure (proboscis) above the eye. Midline structures of the forebrain were absent, consistent with alobar HPE.
Belloni et al. (1996) refined the position of the HPE3 locus by detailed characterization of HPE3 patients with rearrangements involving chromosome 7q36. They also established a contig of genomic clones in this region. Belloni et al. (1996) demonstrated that a cDNA for SHH, the human Sonic hedgehog homolog, showed specific hybridization to the contig which spanned the translocation breakpoint. Further analysis revealed that SHH mapped approximately 250 and 15 kb centromeric of T1 and T2, respectively (T1 and T2 represent the translocation breakpoints in 2 unrelated patients with a mild form of HPE3). Belloni et al. (1996) proposed that the chromosomal rearrangements remove distal cis-acting regulatory elements or exert long-range position effects causing aberrant expression of the gene. They noted that HPE patients exhibiting deletions of the SHH region are generally more severely affected than are the translocation patients. The mild HPE phenotype displayed by the patient with the T2 balanced translocation included premaxillary aplasia with midline cleft lip, hypotelorism, sensorineural hearing loss, lack of tooth eruption, and cervical cord compression due to stenosis.
Benzacken et al. (1997) reported 4 new cases of holoprosencephaly in fetuses with abnormal karyotypes. Three of these had terminal deletions of 7q, confirming the importance of 7q36 in holoprosencephaly. The fourth fetus had an apparently balanced de novo translocation, t(7;13)(q21.2;q33), without any visible loss of the distal part of chromosome 7q. Benzacken et al. (1997) proposed either a long range positional effect or the existence of genes involved in prosencephalon development at 7q21.2 or 13q33 as an explanation for this.
Nowaczyk et al. (2000) reported an infant with holoprosencephaly, sacral anomalies, and situs ambiguus associated with partial monosomy 7q/trisomy 2p, der(7)t(2;7)(p23.2;q36.1), as a result of an adjacent-1 segregation of a t(2;7) in the father. The chromosomal abnormality was diagnosed prenatally after sonographic detection of HPE in the fetus. The baby was born at 37 weeks' gestation and died in the neonatal period; he had dysmorphic features consistent with the HPE sequence. Postmortem examination showed semilobar HPE, abdominal situs ambiguus, multiple segments of bowel atresia, dilatation of the ureters, and bony sacral anomalies. Molecular analysis confirmed hemizygosity for the SHH and HLXB9 (142994) genes, which were thought to be responsible for the HPE and sacral phenotypes, respectively. Immunohistochemical studies showed intact dopaminergic pathways in the mesencephalon, suggesting that midbrain dopamine neuron induction requires only one functioning SHH allele.
Mapping
Muenke et al. (1993) performed linkage studies in 10 families with autosomal dominant HPE. The phenotypic features in affected individuals varied from the most severe forms with single brain ventricle and cyclopia to milder forms with ocular hypotelorism and midface hypoplasia to clinically unaffected carriers. Under the most conservative model-free analysis, linkage between HPE and D7S22 showed a combined lod score of 7.2 at theta = 0.0, with 1 family independently presenting a lod score of 3.0 at theta = 0.0. Muenke et al. (1993) concluded that autosomal dominant HPE is at the locus that has been designated HPE3 and mapped to 7q36.
Muenke et al. (1994) suggested that mutations in the HPE3 gene are responsible for both sporadic HPE and a majority of families with autosomal dominant HPE. Clinical evaluation of the affected individuals in the 9 families in the report of Muenke et al. (1994) confirmed the previously reported phenotypic variability of autosomal dominant HPE. In each family, one or more obligate gene carriers had classic (alobar, semilobar, or lobar) HPE, many of whom died during early infancy. Others had HPE microforms such as microcephaly, mental retardation, microphthalmia, ocular coloboma, ocular hypotelorism, midface hypoplasia, single central upper incisor, cleft lip, and cleft lip and palate. Some obligate gene carriers had normal phenotypes, including normal intellect. In 1 of the 9 families, linkage to D7S22 and other markers on chromosome 7q was excluded, thus indicating genetic heterogeneity. The clinical manifestations, including the HPE microforms, did not differ between individuals in the unlinked kindred and those in the other 8 kindreds linked to 7q36.
Molecular Genetics
Roessler et al. (1996) identified SHH as the gene responsible for HPE3. They analyzed 30 autosomal dominant HPE families and found 5 families that segregated different heterozygous SHH mutations. Two of these mutations predict premature termination of SHH protein (600725.0002 and 600725.0003). The remaining 3 mutations altered highly conserved residues in the vicinity of the alpha helix-1 motif (600725.0004 and 600725.0005) or the signal cleavage site (600725.0001). Roessler et al. (1996) noted that in humans loss of one SHH allele is sufficient to cause HPE, whereas in the mouse both alleles need to be lost to produce a similar CNS phenotype. They observed that haploinsufficiency for SHH in human is sufficient to disturb ventral midline neurogenesis but is insufficient to cause ventralization defects of sclerotome or limb abnormalities.
In 30 unrelated children with holoprosencephaly, Orioli et al. (2001) analyzed for mutations in the SIX3 (603714), SHH, TGIF (602630), and ZIC2 (603073) genes. They identified 3 novel mutations, 2 in the SHH gene and 1 in the ZIC2 gene. Their results explained 8% (2 of 26 newborn samples) of the HPE cases in the South American population studied.
Among 94 fetuses with HPE and a normal karyotype, Bendavid et al. (2006) used quantitative multiplex PCR of short fluorescent fragments (QMPSF) to screen for microdeletions in the 4 major HPE genes, SHH, SIX3, ZIC2, and TGIF. Microdeletions were identified in 8 (8.5%) fetuses: 2 in SHH, 2 in SIX3, 3 in ZIC2, and 1 in TGIF. Further analysis showed that the entire gene was missing in each case. Point mutations in 1 of the 4 genes were identified in 13 of the fetuses. Combining the instances of point mutations and microdeletions for the 94 cases yielded the following percentages: SHH (6.3%), ZIC2 (8.5%), SIX3 (5.3%), and TGIF (2%). Bendavid et al. (2006) reported the use of 2 complementary assays for HPE-associated submicroscopic deletions: a multicolor fluorescence in situ hybridization (FISH) assay using probes for the 4 major HPE genes and 2 candidate genes (DISP1, 607502 and FOXA2, 600288) followed by quantitative PCR to selected samples. Microdeletions for SHH, ZIC2, SIX3, or TGIF were found in 16 of 339 severe HPE cases (i.e., with CNF findings; 4.7%). In contrast, no deletions were found in 85 patients at the mildest end of the HPE spectrum. Based on their data, Bendavid et al. (2006) suggested that microdeletion testing should be considered as part of an evaluation of holoprosencephaly, especially in severe HPE cases.
### Modifier Genes
Martinelli and Fan (2009) demonstrated that a constructed mouse Shh N116K mutant, which corresponds to the HPE3-associated SHH mutation N115K (600725.0020), caused markedly decreased binding to Gas1 (139185), resulting in decreased Shh signaling. These findings indicated that HPE due to the N115K mutation results from an inability of mutant SHH to bind to GAS1 normally, thus interrupting the positive regulatory effect of GAS1. Martinelli and Fan (2009) suggested that mutations in GAS1 may act as possible modifiers of HPE.
In 4 Brazilian patients with HPE or HPE-like phenotype, Ribeiro et al. (2010) identified 4 different heterozygous nonsynonymous variants in the GAS1 gene that were predicted to be damaging. Two of 4 patients also carried heterozygous missense mutations in the SHH gene. The authors suggested that mutations in the GAS1 gene may confer susceptibility to the development of HPE or may act as a modifier locus for HPE in conjunction with mutations in other genes.
Genotype/Phenotype Correlations
Among 34 patients with holoprosencephaly, Dubourg et al. (2004) observed that mutations in the SHH gene were associated with choanal stenosis and ophthalmologic malformations.
Mercier et al. (2011) reported the clinical and molecular features of a large European series of 645 HPE probands (51% fetuses) and 699 relatives in order to examine genotype/phenotype correlations. The facial features were assigned to 4 categories: categories 1 and 2 had severe facial defects, whereas microforms were listed as 3 and 4. SHH mutations were found in 67 (10.4%) probands. The patients had alobar (28%), semilobar (34%), lobar (4%), or microform (34%) HPE, but the 4 categories of facial defects were evenly distributed, although the proportion of coloboma was relatively high (15% for the series as a whole). Extracranial defects were found in 24%, mostly visceral or renal/urinary. The mutations showed high heritability (73%), and 23% of parents with mutations had a microform. Statistical analysis for the whole study showed a positive correlation between the severity of the brain malformation and facial features for those with mutations in the SHH gene, and that microforms were associated with SHH mutations. Based on these results, Mercier et al. (2011) proposed an algorithm for molecular analysis in HPE.
Inheritance
Ardinger and Bartley (1988) reported a family in which the transmission pattern of holoprosencephaly appeared to be autosomal dominant.
Odent et al. (1998) reviewed 258 HPE records involving at least 1 affected child and found 97 cases in 79 families with nonsyndromic, nonchromosomal HPE. A high degree of familial aggregation was found in 29% of families. By segregation analysis, Odent et al. (1998) concluded that autosomal dominant inheritance with incomplete penetrance (82% for major and 88% for major and minor) was the most likely mode of inheritance. Sporadic cases accounted for 68%, and the recurrence risk after an isolated case was predicted to be 13 to 14%.
In familial holoprosencephaly pedigrees, Suthers et al. (1999) reported a skewed sex ratio among transmitting parents with SHH gene mutations, 14 of 16 being mothers (p = 0.002). Suthers et al. (1999) also found that of 16 reported cases of single maxillary central incisor with no other congenital malformation, 13 were female (p = 0.0085). Suthers et al. (1999) concluded that boys with SHH gene mutations may be at greater risk of major malformations outside the central nervous system, thus reducing their reproductive fitness, explaining the observed skewed sex ratio.
Population Genetics
In a targeted screening study of 4 genes in 86 Dutch patients with holoprosencephaly, Paulussen et al. (2010) found that 21 (24%) had heterozygous mutations in 1 of 3 of the genes. Three (3.5%) had mutations in the SHH gene, 9 (10.5%) had mutations in the ZIC2 gene (603073), and 9 (10.5%) had mutations in the SIX3 gene (603714). None had mutations in the TGIF gene (602630). Two deletions were detected, 1 encompassing the ZIC2 gene and another encompassing the SIX3 gene. About half of the mutations were de novo; 1 was germline mosaic. There was marked clinical variability, but those with ZIC2 mutations tended to have less severe facial malformations. Five of 7 parental carriers were asymptomatic, and 2 had minor HPE signs.
INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Microcephaly Face \- Midface hypoplasia Ears \- Hearing deficits Eyes \- Prominent eyes \- Hypotelorism \- Synophthalmia (in some patients) Nose \- Flat nasal bridge \- Short columella \- Single nostril \- Proboscis (in some patients) Mouth \- Cleft lip \- Cleft palate \- Bifid uvula Teeth \- Single central upper incisor NEUROLOGIC Central Nervous System \- Holoprosencephaly (lobar or alobar) \- Dilated ventricles \- Developmental delay \- Mental retardation \- Single anterior ventricle ENDOCRINE FEATURES \- Central diabetes insipidus MISCELLANEOUS \- Severe alobar form may result in death in infancy \- Mild form may include microcephaly, hypotelorism, and single maxillary central incisor \- Variable features may be present MOLECULAR BASIS \- Caused by mutation in the sonic hedgehog signaling molecule (SHH, 600725.0001 ) ▲ Close
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| HOLOPROSENCEPHALY 3 | c0079541 | 1,333 | omim | https://www.omim.org/entry/142945 | 2019-09-22T16:40:10 | {"doid": ["0110875"], "mesh": ["D016142"], "omim": ["142945"], "orphanet": ["2162"], "synonyms": ["Alternative titles", "HLP3"], "genereviews": ["NBK1378", "NBK1530"]} |
Reactive hypoglycemia
Other namesPostprandial hypoglycemia, sugar crash
SymptomsClumsiness, difficulty talking, confusion, loss of consciousness, and other symptoms related to hypoglycemia
Usual onsetWithin 4 hours of a high carbohydrate meal
CausesGastric bypass surgery, over-secretion of insulin
Diagnostic methodWhipple criteria, blood glucose test during spontaneous occurrence of symptoms, HbA1c blood test, 6-hour glucose tolerance test
Differential diagnosisAlimentary hypoglycemia, factitious hypoglycemia, insulin autoimmune hypoglycemia, noninsulinoma pancreatogenous hypoglycemia syndrome, insulinoma, hereditary fructose intolerance
PreventionLow-carbohydrate diet, frequent small meals
Reactive hypoglycemia, postprandial hypoglycemia, or sugar crash is a term describing recurrent episodes of symptomatic hypoglycemia occurring within four hours[1] after a high carbohydrate meal in people with and without diabetes.[2] The term is not necessarily a diagnosis since it requires an evaluation to determine the cause of the hypoglycemia.[3]
The condition is related to homeostatic systems used by the body to control the blood sugar level. It is described as a sense of tiredness, lethargy, irritation, or hangover, although the effects can be lessened if a lot of physical activity is undertaken in the first few hours after food consumption.
The alleged mechanism for the feeling of a crash is correlated with an abnormally rapid rise in blood glucose after eating. This normally leads to insulin secretion (known as an insulin spike), which in turn initiates rapid glucose uptake by tissues, either storing it as glycogen or using it for energy production. The consequent fall in blood glucose is indicated as the reason for the "sugar crash".[4] Another cause might be hysteresis effect of insulin action, i.e., the effect of insulin is still prominent even if both plasma glucose and insulin levels were already low, causing a plasma glucose level eventually much lower than the baseline level.[5]
Sugar crashes are not to be confused with the after-effects of consuming large amounts of protein, which produces fatigue akin to a sugar crash, but are instead the result of the body prioritising the digestion of ingested food.[6]
The prevalence of this condition is difficult to ascertain because a number of stricter or looser definitions have been used. It is recommended that the term reactive hypoglycemia be reserved for the pattern of postprandial hypoglycemia which meets the Whipple criteria (symptoms correspond to measurably low glucose and are relieved by raising the glucose), and that the term idiopathic postprandial syndrome be used for similar patterns of symptoms where abnormally low glucose levels at the time of symptoms cannot be documented.
To assist in diagnosis, a doctor may order an HbA1c test, which measures the blood sugar average over the two or three months before the test. The more specific 6-hour glucose tolerance test can be used to chart changes in the patient's blood sugar levels before ingestion of a special glucose drink and at regular intervals during the six hours following to see if an unusual rise or drop in blood glucose levels occurs.
According to the U.S. National Institutes of Health (NIH), a blood glucose level below 70 mg/dL (3.9 mmol/L) at the time of symptoms followed by relief after eating confirms a diagnosis for reactive hypoglycemia.[1]
## Contents
* 1 Signs and symptoms
* 2 Causes
* 3 Treatment
* 4 Postprandial syndrome
* 5 See also
* 6 References
* 7 Further reading
* 8 External links
## Signs and symptoms[edit]
Symptoms vary according to individuals' hydration level and sensitivity to the rate and/or magnitude of decline of their blood glucose concentration.
A crash is usually felt within four hours of heavy carbohydrate consumption. Along with the symptoms of hypoglycemia, symptoms of reactive hypoglycemia include:[7][8][9]
* double vision or blurry vision
* unclear thinking
* brain fog
* insomnia
* heart palpitation or fibrillation
* fatigue
* dizziness
* light-headedness
* sweating
* headaches
* depression
* nervousness
* muscle twitches
* irritability
* tremors
* flushing
* craving sweets
* increased appetite
* rhinitis
* nausea, vomiting
* panic attack
* numbness/coldness in the extremities
* confusion
* irrationality
* hot flashes
* bad temper
* paleness
* anxiety
* trouble talking
* cold hands
* disorientation
* the need to sleep or 'crash'
The majority of these symptoms, often correlated with feelings of hunger, mimic the effect of inadequate sugar intake as the biology of a crash is similar in itself to the body's response to low blood sugar levels following periods of glucose deficiency.[10]
## Causes[edit]
The NIH states: "The causes of most cases of reactive hypoglycemia are still open to debate. Some researchers suggest that certain people may be more sensitive to the body’s normal release of the hormone epinephrine, which causes many of the symptoms of hypoglycemia. Others believe deficiencies in glucagon secretion might lead to reactive hypoglycemia.[1]
Several other hormones are responsible for modulating the body's response to insulin, including cortisol, growth hormone and sex hormones. Untreated or under-treated hormonal disorders such as adrenal insufficiency (see also Addison's disease[11]) or growth hormone deficiency[12] can therefore sometimes cause insulin hypersensitivity, and reactive hypoglycemia.
Stomach bypass surgery or hereditary fructose intolerance are believed to be causes, albeit uncommon, of reactive hypoglycemia. Myo-inositol or 1D-chiro-inositol withdrawal can cause temporary reactive hypoglycemia.
There are several kinds of reactive hypoglycemia:[13]
1. Alimentary hypoglycemia (consequence of dumping syndrome; it occurs in about 15% of people who have had stomach surgery)
2. Hormonal hypoglycemia (e.g., hypothyroidism)
3. Helicobacter pylori-induced gastritis (some reports suggest this bacteria may contribute to the occurrence of reactive hypoglycemia)[14]
4. Congenital enzyme deficiencies (hereditary fructose intolerance, galactosemia, and leucine sensitivity of childhood)[15]
5. Late hypoglycemia (occult diabetes; characterized by a delay in early insulin release from pancreatic beta-cells, resulting in initial exaggeration of hyperglycemia during a glucose tolerance test)[16]
"Idiopathic reactive hypoglycemia" is a term no longer used because researchers now know the underlying causes of reactive hypoglycemia and have the tools to perform the diagnosis and the pathophysiological data explaining the mechanisms.[13]
To check if there is real hypoglycemia when symptoms occur, neither an oral glucose tolerance test nor a breakfast test is effective; instead, a hyperglucidic breakfast test or ambulatory glucose testing is the current standard.[13][17]
The body requires a relatively constant input of glucose, a sugar produced upon digestion of carbohydrates, for normal functioning. Glucagon and insulin are among the hormones that ensure a normal range of glucose in the human body.[18] Upon consumption of a meal, blood sugar normally rises, which triggers pancreatic cells to produce insulin. This hormone initiates the absorption of the just-digested blood glucose as glycogen into the liver for metabolism or storage, thereby lowering glucose levels in the blood. In contrast, the hormone glucagon is released by the pancreas as a response to lower than normal blood sugar levels. Glucagon initiates uptake of the stored glycogen in the liver into the bloodstream so as to increase glucose levels in the blood.[19] Sporadic, high-carbohydrate snacks and meals are deemed the specific causes of sugar crashes. The “crash” one feels is due to the rapid increase and subsequent decline of blood sugar in the body system as one begins and ceases consumption of high-sugar foods. More insulin than is actually needed is produced in response to the large, rapid ingestion of sugary foods.
## Treatment[edit]
A typical recommendation: Half the plate is filled with high-fiber vegetables, and the rest is divided between tuna fish and a single serving of starchy pasta.
Reactive hypoglycemia can usually be relieved by dietary changes:[20]
* Avoiding or limiting sugar intake, including candy, sweet desserts, fruit juice, and drinks with added sugar.[20][21]
* Eating only small amounts of starchy foods, including potatoes, pasta, breakfast cereals, and rice.[20]
* Eating a variety of foods, including:
* eggs, nuts, dairy products, tofu, beans, lentils, meat, poultry, fish, or other sources of protein with every meal or snack,[20]
* whole-grain carbohydrates, such as eating whole wheat bread instead of white bread,[20] and
* more fruits and vegetables (but not fruit juice), with 5 A Day being a recommended goal for most people.[20]
* Eating more high-fiber foods, such as lentils, beans, pulses (legumes), leafy greens, and most fruits and vegetables.[20]
Other tips to prevent sugar crashes include:
* Exercising regularly, as exercise increases cellular sugar uptake, which decreases excessive insulin release.[22][23]
* Avoiding eating meals or snacks composed entirely of carbohydrates;[20] simultaneously ingest fats[dubious – discuss] and proteins, which have slower rates of absorption;[citation needed]
* Consistently choosing longer lasting, complex carbohydrates to prevent rapid blood-sugar dips in the event that one does consume a disproportionately large amount of carbohydrates with a meal;
* Monitoring any effects medication may have on symptoms.[4]
Low-carbohydrate diet and/or frequent small meals is the first treatment of this condition. The first important point is to add small meals at the middle of the morning and of the afternoon, when glycemia would start to decrease. If adequate composition of the meal is found, the fall in blood glucose is thus prevented. Patients should avoid rapidly absorbed sugars and thus avoid popular soft drinks rich in glucose or sucrose. They should also be cautious with drinks associating sugar and alcohol, mainly in the fasting state.[13]
As it is a short-term ailment, a sugar crash that was not caused by injecting too much insulin does not usually require medical intervention in most people. The most important factors to consider when addressing this issue are the composition and timing of foods.[24]
Acute (short-term) low blood sugar symptoms are best treated by consuming small amounts of sweet foods, so as to regain balance in the body's carbohydrate metabolism. Suggestions include sugary foods that are quickly digested, such as:
* Dried fruit
* Soft drinks
* Juice
* Sugar as sweets, tablets or cubes.[25]
The anti-hypertensive class of medication known as calcium channel blockers could be useful for reactive hypoglycemia as inhibition of the calcium channels on beta islet cells can help prevent an overproduction of insulin after a meal is eaten.[26][27]
## Postprandial syndrome[edit]
Main article: Idiopathic postprandial syndrome
If there is no hypoglycemia at the time of the symptoms, this condition is called idiopathic postprandial syndrome. It might be an "adrenergic postprandial syndrome" — blood glucose levels are normal, but the symptoms are caused through autonomic adrenergic counterregulation.[28] Often, this syndrome is associated with emotional distress and anxious behaviour of the patient.[13] This is often seen in dysautonomic disorders as well. Dietary recommendations for reactive hypoglycemia can help to relieve symptoms of postprandial syndrome.
## See also[edit]
* Spontaneous hypoglycemia
* Refeeding syndrome
## References[edit]
1. ^ a b c "Hypoglycemia." It can also be referred to as "sugar crash" or "glucose crash." National Diabetes Information Clearinghouse, October 2008. http://diabetes.niddk.nih.gov/dm/pubs/hypoglycemia/
2. ^ "Hypos After Eating - Reactive Hypoglycemia". Retrieved 2018-09-08.
3. ^ Service, FJ; Vella, A (11 June 2018). "Postprandial (reactive) hypoglycemia". UpToDate. Retrieved 2018-09-08.
4. ^ a b Hendrickson, Kirstin. "Side Effects of a Sugar Overdose". Demand Media, Inc. Retrieved 8 November 2011.
5. ^ Wang, Guanyu (Oct 15, 2014). "Raison d'être of insulin resistance: the adjustable threshold hypothesis". J R Soc Interface. 11 (101): 20140892. doi:10.1098/rsif.2014.0892. PMC 4223910. PMID 25320065.
6. ^ "The Truth about Tryptophan". WebMD.
7. ^ "Hypoglycemia". National Diabetes Information Clearinghouse. U.S. Department of Health and Human Services. Retrieved 8 November 2011.
8. ^ "Hypoglycemia". Mayo Foundation for Medical Education and Research. Mayo Clinic. Retrieved 8 November 2011.
9. ^ Simpson, Jamie. "Causes of Low Blood Sugar". Demand Media. Retrieved 8 November 2011.
10. ^ "Diabetes". American Dietetic Association. Retrieved 11 November 2011.
11. ^ Turner, Edward L. (1 November 1933). "Inverted sugar tolerance curves in a case of Addison's Disease". Endocrinology. 17 (6): 699–702. doi:10.1210/endo-17-6-699.
12. ^ Pia A, Piovesan A, Tassone F, Razzore P, Visconti G, Magro G, Cesario F, Terzolo M, Borretta G (December 2004). "A rare case of adulthood-onset growth hormone deficiency presenting as sporadic, symptomatic hypoglycemia". J. Endocrinol. Invest. 27 (11): 1060–4. doi:10.1007/BF03345310. PMID 15754739.
13. ^ a b c d e Brun JF, Fedou C, Mercier J (November 2000). "Postprandial reactive hypoglycemia". Diabetes Metab. 26 (5): 337–51. PMID 11119013.
14. ^ Açbay O, Celik AF, Kadioğlu P, Göksel S, Gündoğdu S (1999). "Helicobacter pylori-induced gastritis may contribute to occurrence of postprandial symptomatic hypoglycemia". Dig. Dis. Sci. 44 (9): 1837–42. doi:10.1023/A:1018842606388. PMID 10505722.
15. ^ Hamdy O, Srinivasan V, Snow KJ. "Hypoglycemia". Medscape. WebMD LLC. Retrieved 2007-07-06.-Updated March 2018
16. ^ Umesh Masharani (2007). "Postprandial Hypoglycemia (Reactive Hypoglycemia)". The Hypoglycemic states - Hypoglycemia. Armenian Medical Network.
17. ^ Berlin I, Grimaldi A, Landault C, Cesselin F, Puech AJ (November 1994). "Suspected postprandial hypoglycemia is associated with beta-adrenergic hypersensitivity and emotional distress". J. Clin. Endocrinol. Metab. 79 (5): 1428–33. doi:10.1210/jcem.79.5.7962339. PMID 7962339.
18. ^ "How the Body Controls Blood Sugar". Web MD Diabetes. Healthwise Incorporated. Retrieved 8 November 2011.
19. ^ "Hypoglycemia". Hormonal and Metabolic Disorders. Merck Sharp & Dohme Corp. Retrieved 8 November 2011.
20. ^ a b c d e f g h "Healthy Eating for Reactive Hypoglycemia". National Health Service (3rd ed.). UK. 2017. NHS Trust Docs ID: 10513 (Review date: 2020-06-11).
21. ^ Kenrose, S. The Reactive Hypoglycemia Sourcebook, 2009. ISBN 978-0-557-07407-5"
22. ^ Gregory, Justin M.; Muldowney, James A.; Engelhardt, Brian G.; Tyree, Regina; Marks-Shulman, Pam; Silver, Heidi J.; Donahue, E. Patrick; Edgerton, Dale S.; Winnick, Jason J. (2019-09-02). "Aerobic exercise training improves hepatic and muscle insulin sensitivity, but reduces splanchnic glucose uptake in obese humans with type 2 diabetes". Nutrition & Diabetes. 9 (1): 25. doi:10.1038/s41387-019-0090-0. ISSN 2044-4052. PMC 6717736. PMID 31474750.
23. ^ Gibala, Martin J; Little, Jonathan P (2010-09-15). "Just HIT it! A time-efficient exercise strategy to improve muscle insulin sensitivity". The Journal of Physiology. 588 (Pt 18): 3341–3342. doi:10.1113/jphysiol.2010.196303. ISSN 0022-3751. PMC 2988497. PMID 20843832.
24. ^ Collazo-Clavell, Maria. "Reactive Hypoglycemia". Mayo Foundation for Medical Education and Research. Retrieved 11 November 2011.
25. ^ "Hypoglycemia (Low Blood Sugar) in People Without Diabetes". Diabetes Health Center. WebMD, LLC. Retrieved 8 November 2011.
26. ^ Sanke, T; Nanjo, K; Kondo, M; Nishi, M; Moriyama, Y; Miyamura, K (October 1986). "Effect of calcium antagonists on reactive hypoglycemia associated with hyperinsulinemia". Metabolism: Clinical and Experimental. 35 (10): 924–7. doi:10.1016/0026-0495(86)90055-7. PMID 3762399.
27. ^ Guseva, Nina; Phillips, David; Mordes, John (January 2010). "Successful Treatment of Persistent Hyperinsulinemic Hypoglycemia with Nifedipine in an Adult Patient". Endocrine Practice. 16 (1): 107–111. doi:10.4158/EP09110.CRR. PMC 3979460. PMID 19625246.
28. ^ "Postprandial Hypoglycemia". Retrieved 29 November 2011.
## Further reading[edit]
* Açbay O, Celik AF, Kadioğlu P, Göksel S, Gündoğdu S (1999). "Helicobacter pylori-induced gastritis may contribute to occurrence of postprandial symptomatic hypoglycemia". Dig. Dis. Sci. 44 (9): 1837–42. doi:10.1023/A:1018842606388. PMID 10505722.
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| Reactive hypoglycemia | c0271710 | 1,334 | wikipedia | https://en.wikipedia.org/wiki/Reactive_hypoglycemia | 2021-01-18T18:46:33 | {"mesh": ["D007003"], "icd-9": ["251.2"], "wikidata": ["Q1408148"]} |
A number sign (#) is used with this entry because of evidence that pontocerebellar hypoplasia type 1A (PCH1A) is caused by homozygous mutation in the VRK1 gene (602168) on chromosome 14q32.
Description
Pontocerebellar hypoplasia (PCH) refers to a group of severe neurodegenerative disorders affecting growth and function of the brainstem and cerebellum, resulting in little or no development. Different types were classified based on the clinical picture and the spectrum of pathologic changes. PCH type 1 is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration resembling infantile spinal muscular atrophy (SMA; see SMA1, 253300); death usually occurs early.
### Genetic Heterogeneity of Pontocerebellar Hypoplasia
Also see PCH1B (614678), caused by mutation in the EXOSC3 gene (606489); PCH1C (616081), caused by mutation in the EXOSC8 gene (606019); PCH1D (618065), caused by mutation in the EXOSC9 gene (606180); PCH2A (277470), caused by mutation in the TSEN54 gene (608755); PCH2B (612389), caused by mutation in the TSEN2 gene (608753); PCH2C (612390), caused by mutation in the TSEN34 gene (608754); PCH2D (613811), caused by mutation in the SEPSECS gene (613009); PCH3 (608027), caused by mutation in the PCLO gene (604918); PCH4 (225753), caused by mutation in the TSEN54 gene; PCH5 (610204), caused by mutation in the TSEN54 gene; PCH6 (611523), caused by mutation in the RARS2 gene (611524); PCH7 (614969), caused by mutation in the TOE1 gene (613931); PCH8 (614961), caused by mutation in the CHMP1A gene (164010); PCH9 (615809), caused by mutation in the AMPD2 gene (102771); PCH10 (615803), caused by mutation in the CLP1 gene (608757); PCH11 (617695), caused by mutation in the TBC1D23 gene (617687); and PCH12 (618266), caused by mutation in the COASY gene (609855).
Clinical Features
The combination of autosomal recessive PCH and anterior horn cell disease was first described by Norman (1961) and was extensively reviewed by Chou et al. (1990) and Barth (1993).
Rudnik-Schoneborn et al. (2003) reported 5 patients from 2 consanguineous families, one Pakistani and the other Turkish, with pontocerebellar hypoplasia associated with spinal muscular atrophy. The patients presented at birth or in the first months of life with severe hypotonia and delayed psychomotor development. There was muscle wasting; some patients showed spasticity and contractures. The findings suggested an extended phenotype that includes major structural defects of the cerebellum as well as mild cerebellar hypoplasia in combination with anterior horn cell loss. All patients underwent testing for infantile SMA1 (253300), and homozygous absence of the SMN1 gene (600354) was excluded in all.
Renbaum et al. (2009) reported a consanguineous family of Ashkenazi Jewish origin in which 3 children had SMA-PCH. Early features included microcephaly, poor sucking, and developmental delay. In the first 2 years, the proband developed upper limb ataxia, brisk reflexes, and bilateral equinovarus. She was found to have motor and sensory neuropathy due to chronic denervation. Brain MRI showed a small cerebellar vermis and a large cisterna magna, compatible with cerebellar hypoplasia; she had mild mental retardation. Disease progression led to severe weakness, and the child became wheelchair-bound and incontinent, with sleep disturbance, increasing swallowing difficulties, severe ataxia, and progressive intercostal muscle weakness. She died at age 11.5 years. A previously deceased older sister had a similar phenotype, with tongue fasciculations, hypotonia with brisk reflexes, ataxia, and equinovarus deformities. She died at age 9.5 years. Their cousin, also the product of a consanguineous marriage within the extended family, reportedly had a similar phenotype and died at age 8 years. Skeletal muscle studies showed neurogenic atrophy.
Mapping
By homozygosity mapping of 3 consanguineous Iranian families with what was reported to be mild to severe nonsyndromic mental retardation, Kuss et al. (2011) found linkage to a locus on distal chromosome 14q. In 1 family (M017N), the interval spanned 3.0 Mb between SNPs rs763357 and rs1956859 (lod score of 3.4). Lod scores in the other 2 families (M233 and M257) were 2.7 and 2.5, respectively, for SNPs in this region.
Molecular Genetics
By linkage analysis followed by candidate gene sequencing of an affected Ashkenazi Jewish family with SMA-PCH, Renbaum et al. (2009) identified a homozygous mutation in the VRK1 gene (R358X; 602168.0001). The mutation was detected in heterozygosity in 2 of 449 unaffected Ashkenazi Jewish individuals.
Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family M017N, previously mapped to distal chromosome 14q by Kuss et al. (2011), they identified a homozygous missense mutation in the VRK1 gene (602168.0002) in 4 sibs with moderate to severe intellectual disability and a phenotype compatible with pontocerebellar hypoplasia. The parents, who were first cousins once removed, were heterozygous for the mutation and had 3 healthy children.
INHERITANCE \- Autosomal recessive GROWTH Other \- Poor feeding RESPIRATORY \- Respiratory insufficiency SKELETAL \- Congenital contractures Feet \- Foot deformities MUSCLE, SOFT TISSUES \- Muscle weakness \- Fasciculations NEUROLOGIC Central Nervous System \- Psychomotor retardation \- Hypotonia \- Weakness \- Hyperreflexia \- Ataxia \- Mental retardation \- Spinal cord anterior horn cell degeneration \- EMG shows neurogenic changes \- Pontocerebellar hypoplasia \- Hypoplasia of the ventral pons \- Neuronal loss in the brainstem \- Neuronal loss in basal ganglia \- Gliosis in the brainstem \- Gliosis in the basal ganglia MISCELLANEOUS \- Onset prenatally or at birth \- Progressive disorder \- Death often occurs in childhood \- Clinically resembles spinal muscular atrophy-1 (SMA1, 253300 ) MOLECULAR BASIS \- Caused by mutation in the vaccinia-related kinase 1 gene (VRK1, 602168.0001 ) ▲ Close
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*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[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
| PONTOCEREBELLAR HYPOPLASIA, TYPE 1A | c1843504 | 1,335 | omim | https://www.omim.org/entry/607596 | 2019-09-22T16:09:01 | {"doid": ["0060265"], "mesh": ["C548069"], "omim": ["607596"], "orphanet": ["2254"], "synonyms": ["Alternative titles", "PCH1", "PONTOCEREBELLAR HYPOPLASIA WITH INFANTILE SPINAL MUSCULAR ATROPHY", "PONTOCEREBELLAR HYPOPLASIA WITH ANTERIOR HORN CELL DISEASE"]} |
A rare Y chromosome number anomaly that affects only males and is characterized by mild-moderate developmental delay (especially speech), normal to mild intellectual disability, large, irregular teeth with poor enamel, tall stature and acne. Radioulnar synostosis and clinodactyly have also been associated. Boys generally present normal genitalia, while hypogonadism and infertility is frequently reported in adult males.
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*[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
| 48,XYYY syndrome | c4518082 | 1,336 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99329 | 2021-01-23T19:08:06 | {"gard": ["11985"], "icd-10": ["Q98.8"]} |
Pneumocytic hyperplasia is an hyperplasia of pneumocytes lining pulmonary alveoli.
## Types[edit]
* Pulmonary atypical adenomatous hyperplasia
* Multifocal micronodular pneumocyte hyperplasia[1][2][3][4][5]
## References[edit]
1. ^ Behnes, C. L.; Schütze, G; Engelke, C; Bremmer, F; Gunawan, B; Radzun, H. J.; Schweyer, S (2013). "13-year-old tuberous sclerosis patient with renal cell carcinoma associated with multiple renal angiomyolipomas developing multifocal micronodular pneumocyte hyperplasia". BMC Clinical Pathology. 13: 4. doi:10.1186/1472-6890-13-4. PMC 3568416. PMID 23379654.
2. ^ Ishii, M; Asano, K; Kamiishi, N; Hayashi, Y; Arai, D; Haraguchi, M; Sugiura, H; Naoki, K; Tasaka, S; Soejima, K; Sayama, K; Betsuyaku, T (2012). "Tuberous sclerosis diagnosed by incidental computed tomography findings of multifocal micronodular pneumocyte hyperplasia: A case report". Journal of Medical Case Reports. 6 (1): 352. doi:10.1186/1752-1947-6-352. PMC 3512476. PMID 23072249.
3. ^ Miravet Sorribes, L; Mancheño Franch, N; Batalla Bautista, L (2013). "Multifocal micronodular pneumocyte hyperplasia in a patient with tuberous sclerosis". Archivos de Bronconeumología. 49 (1): 36–7. doi:10.1016/j.arbres.2012.06.006. PMID 22884294.
4. ^ Shintani, Y; Ohta, M; Iwasaki, T; Ikeda, N; Tomita, E; Nagano, T; Kawahara, K (2010). "A case of micronodular pneumocyte hyperplasia diagnosed through surgical resection". Annals of Thoracic and Cardiovascular Surgery. 16 (1): 45–7. PMID 20190710.
5. ^ Kobashi, Y; Sugiu, T; Mouri, K; Irei, T; Nakata, M; Oka, M (2008). "Multifocal micronodular pneumocyte hyperplasia associated with tuberous sclerosis: Differentiation from multiple atypical adenomatous hyperplasia". Japanese Journal of Clinical Oncology. 38 (6): 451–4. doi:10.1093/jjco/hyn042. PMID 18535095.
This medical sign article is a stub. You can help Wikipedia by expanding it.
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*[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
| Pneumocytic hyperplasia | None | 1,337 | wikipedia | https://en.wikipedia.org/wiki/Pneumocytic_hyperplasia | 2021-01-18T18:39:45 | {"wikidata": ["Q16886592"]} |
A rare, genetic neuromuscular disease characterized by permanent myotonia, mask-like facies (with blepharospasm, narrow palpebral fissures, small mouth with pursed lips and puckered chin) , and chondrodysplasia (variably manifesting with short stature, pectus carinatum, kyphoscoliosis, bowing of long bones, epiphyseal, metaphyseal, and hip dysplasia).
## Epidemiology
Approximately, 130 cases have been described in the literature to date.
## Clinical description
Presentation is typically by 1 year to 2 years of age, but may occur earlier, with myotonia, maske-like facies, short stature, non-progressive muscle weakness, muscle hypertrophy, progressive restriction of range of motion and paucity of subcutaneous tissue. Facial features consist of blepharospasm, progressive blepharophimosis, pursed lips and a puckered chin. Micrognathia, low-set ears with folded helices and dystopia canthorum have also been reported. The myotonia is characterized by continuous muscle activity recorded on electroneuromyography. Limited joint mobility leads to an unsteady gait. Joint stiffness is progressive, reaching its peak during adolescence The severity of chondrodysplasia is variable and may consist of flattening of the vertebral bodies, hip dysplasia, metaphyseal widening, slender diaphyses, kypho-scoliosis, multiple joint contractures and bowing of long bones. Rarely, myopia, inguinal and umbilical hernias and micro-orchidism have been reported.
## Etiology
Loss of function mutations in HSPG2 (1p36) are causative. HSPG2 encodes perlecan, a major component of the cellular matrix that plays an important role in maintaining cartilaginous tissue integrity and regulating muscle excitability. The exact pathogenesis is unknown.
## Diagnostic methods
Diagnosis is established by demonstration of both myotonia via electromyography and chondrodysplasia via radiographs. Genetic testing may confirm diagnosis.
## Differential diagnosis
Schwartz-Jampel syndrome (SJS) is non-allelic with Stuve-Wiedemann syndrome, a severe skeletal dysplasia that is typically fatal during the neonatal period and was formerly described as SJS type 2. Other differential diagnosis should include Freeman Sheldon and Marden Walker syndrome and, in cases with minimal skeletal abnormalities, myotonic disorders ( including myotonia congenita, myotonia permamens, and myotonic dystrophy).
## Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to affected families, informing them that the risk of disease transmission is 25% where both parents are unaffected carriers.
## Management and treatment
The management of patients with SJS is primarily supportive and best offered by a team comprising a neurologist, a geneticist, a physical therapist, an orthopedic surgeon, an ophthalmologist and a psychologist. Medical treatment with muscle relaxants and antiepileptic drugs, such as carbamazepine, phenytoin, or procainamide, aimed to alleviate myotonia has limited usage, although early initiation of treatment may limit the extent of disability. Physical therapy is important to prevent contracture formation and fixed skeletal deformity. Botulinum toxin A injections for blepharospasm has been reported with limited and variable results Rarely, surgical intervention is considered for blepharospasm including orbicularis oculi myectomy or levator aponeurosis resection improve functional and cosmetic outcome. Malignant hyperthermia is a potentially lethal complication of anesthesia.
## Prognosis
Progressively worsening blepharospasm is an important morbidity that can interfere with vision. The disease appears to stabilize after adolescence and does not affect life span.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Schwartz-Jampel syndrome | c0036391 | 1,338 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=800 | 2021-01-23T19:00:20 | {"gard": ["250"], "mesh": ["D010009"], "omim": ["255800"], "umls": ["C0036391"], "icd-10": ["G71.1", "Q78.8"], "synonyms": ["Aberfeld syndrome", "Burton skeletal dysplasia", "Burton syndrome", "Catel-Hempel syndrome", "Dysostosis enchondralis metaepiphysaria, Catel-Hempel type", "Myotonic chondrodystrophy", "Myotonic myopathy, dwarfism, chondrodystrophy, ocular and facial anomalies", "Osteochondromuscular dystrophy", "SJS", "SJS1", "Schwartz-Jampel syndrome type 1", "Schwartz-Jampel-Aberfeld syndrome"]} |
Desmoplastic trichoepithelioma is a benign neoplasm with follicular differentiation. It was described as a distinctive clinicopathologic entity by Brownstein and Shapiro (1976, 1977) and MacDonald et al. (1977). Brownstein and Shapiro (1976) described desmoplastic trichoepitheliomas as 'a variant of solitary trichoepithelioma with a distinctive annular configuration and sclerotic consistency clinically.' They predicted that a form of multiple desmoplastic trichoepitheliomas inherited in an autosomal dominant fashion would eventually be discovered. Shapiro and Kopf (1991) described such a family. Grandmother, daughter, and son were affected. Dervan et al. (1985) described familial solitary desmoplastic trichoepitheliomas. This disorder is distinct from the inherited syndrome of multiple trichoepitheliomas, also referred to as epithelioma adenoides cysticum of Brooke (601606).
Inheritance \- Autosomal dominant Skin \- Desmoplastic trichoepithelioma ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| TRICHOEPITHELIOMAS, MULTIPLE DESMOPLASTIC | c1860849 | 1,339 | omim | https://www.omim.org/entry/190345 | 2019-09-22T16:32:22 | {"mesh": ["C566034"], "omim": ["190345"]} |
A number sign (#) is used with this entry because of evidence that capillary malformation-arteriovenous malformation-1 (CMAVM1) is caused by heterozygous mutation in the RASA1 gene (139150) on chromosome 5q14.
Description
Capillary malformation-arteriovenous malformation-1 is an autosomal dominant disorder characterized by atypical capillary malformations (CMs), often in association with fast-flow vascular malformations, including arteriovenous malformations (AVMs) and arteriovenous fistulas (AVFs), and Parkes Weber syndrome (PKWS). The CMs are usually multifocal and are surrounded by a pale halo with a central red dot; they increase in number with age. The AVMs generally occur in the brain or on the face or extremities. Intracranial AVMs include vein of Galen aneurysmal malformations (VGAMs). Parkes Weber syndrome is a specific type of CMAVM that presents with limb overgrowth, more commonly affecting one of the lower extremities (Eerola et al., 2003; Revencu et al., 2013; Johnson and Navarro, 2017). Parkes Weber syndrome is characterized by a cutaneous blush with underling multiple micro-AVFs in association with soft-tissue and skeletal hypertrophy of the affected limb (Mulliken and Young, 1988).
### Genetic Heterogeneity of Capillary Malformation-Arteriovenous Malformation
Also see CMAVM2 (618196), caused by mutation in the EPHB2 gene on chromosome 7q22.
Clinical Features
Capillary malformation, or 'port-wine stain,' (see 163000) is a common cutaneous vascular anomaly that appears as a red macular stain that darkens over years. Six families reported by Eerola et al. (2003) manifested atypical capillary malformations that were multiple, small, round to oval in shape, and pinkish red in color. In these 6 families the capillary malformations were associated with arteriovenous malformation, arteriovenous fistula (AVF), or Parkes Weber syndrome. Eerola et al. (2003) named this phenotype caused by RASA1 mutations 'capillary malformation-arteriovenous malformation' (CMAVM).
Boon et al. (2005) provided a review of CMAVM associated with mutations in the RASA1 gene.
In a study of 100 patients with CMAVM, Revencu et al. (2013) observed that several had cutaneous areas of numerous white pale halos of 1-cm diameter with a red punctate spot in the middle.
Mapping
In a study of 13 families with familial capillary malformation, Eerola et al. (2002) identified a susceptibility locus, which they termed CMC1, on 5q14-q21. In a later study, Eerola et al. (2003) used a new family to narrow the locus to 5 cM.
Molecular Genetics
In the 5-cM interval to which Eerola et al. (2003) mapped the CMC1 locus, 8 characterized genes were found, 3 of which were considered to be candidates of functional interest: RASA1 (139150), EDIL3 (606018), and MEF2C (600662). They screened the RASA1 gene, encoding p120-RasGAP, for mutations in 17 families. Heterozygous inactivating RASA1 mutations were detected in 6 families with CMAVM (see, e.g., 139150.0004-139150.0005). Eerola et al. (2003) suggested that the phenotypic variability could be explained by the involvement of p120-RasGAP in signaling for various growth factor receptors that control proliferation, migration, and survival of several cell types, including vascular endothelial cells.
In affected members of 3 Ashkenazi Jewish families with capillary malformations, Hershkovitz et al. (2008) identified heterozygous mutations in the RASA1 gene (139150.0006-139150.0008). An arteriovenous malformation was only identified in 1 of the families, suggesting that the phenotypic spectrum of RASA1-related CMAVM can include patients with only capillary malformations.
In a combined retrospective and prospective study of 261 individuals with CMAVM and related phenotypes, Revencu et al. (2013) screened for mutations in the RASA1 gene and identified 58 in 68 of the 100 individuals with CMAVM and in none in those with related disorders, including 100 with common CMs, 37 with Sturge-Weber syndrome, and 24 with AVMs.
Revencu et al. (2013) analyzed DNA from a neurofibroma that had developed in a congenital Parkes-Weber lesion in a CMAVM patient with a previously confirmed germline mutation in the RASA1 gene. The DHPLC elution profile was indicative of loss of function of the wildtype allele in the tissue. SNP array showed mosaic loss of chromosome 5q, including the RASA1 gene, and part of chromosome 22, including the NF2 gene (607379). Sequencing of the NF2 gene revealed a nonsense mutation in the tissue, but not in the blood. The authors suggested that the 2 hits in the NF2 gene explain the development of the neurofibroma, and they speculated that the somatic loss of 5q, including the RASA1 gene, is involved in the pathogenesis of the Parkes Weber lesion.
Pathogenesis
Another inherited vascular malformation, cerebral capillary malformation (CCM; 116860), has also been related to misregulated Ras signaling. The mutated protein, KRIT1 (604214) was originally identified as a binding partner of Rap1a (179520), an antagonist of Ras transformation. KRIT1 has also been shown to bind ICAP1 (607153), a protein that links integrins and the actin cytoskeleton, which implies a process of integrin-signaling-mediated cellular adhesion in the pathogenesis of CCM. CMAVM and CCM may be due to similar cellular processes, since p120-RasGAP can bind Rap1a, which has an important role in integrin-mediated cellular adhesion. It is noteworthy that in certain families with CCM and mutations in KRIT1, some members also have cutaneous lesions characterized as hyperkeratotic capillary-venous malformations (Labauge et al., 1999; Eerola et al., 2000).
History
Parkes Weber syndrome was described by the same F. Parkes Weber (1863-1962) whose name is also attached to hereditary hemorrhagic telangiectasia (187300), Sturge-Weber syndrome (185300), Weber-Christian disease, and Klippel-Trenaunay-Weber syndrome (149000).
INHERITANCE \- Autosomal dominant CARDIOVASCULAR Vascular \- Arteriovenous malformation \- Arteriovenous fistulas (intracranial, in the spine, or on the face or extremities, but not in liver or lung) SKIN, NAILS, & HAIR Skin \- Capillary malformations, commonly on face or neck, rarely on mucosa \- Maculae can be a few millimeters to several centimeters in diameter and can be surrounded by pale halo with punctate red spot in middle \- Maculae are homogeneous or telangiectatic and may vary in color from pale pink to red, purple or brown MISCELLANEOUS \- In most cases capillary lesions are multifocal at birth and may increase in number with age MOLECULAR BASIS \- Caused by mutation in the RAS p21 protein activator 1 gene (RASA1, 139150.0004 ) ▲ Close
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*[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
| CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 1 | c0022739 | 1,340 | omim | https://www.omim.org/entry/608354 | 2019-09-22T16:07:56 | {"mesh": ["D007715"], "omim": ["608354"], "orphanet": ["2346", "90307", "137667"], "synonyms": ["Alternative titles", "CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION"], "genereviews": ["NBK52764"]} |
Platelet type Von Willebrand disease (PT-VWD) is a bleeding disorder characterized by mild to moderate mucocutaneous bleeding, which becomes more pronounced during pregnancy or following ingestion of drugs that have anti-platelet activity. PT-VWD is due to hyperresponsive platelets, resulting in thrombocytopenia.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Pseudo-von Willebrand disease | c1280798 | 1,341 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=52530 | 2021-01-23T17:06:41 | {"gard": ["8312"], "mesh": ["C536458"], "omim": ["177820"], "umls": ["C1280798"], "icd-10": ["D69.8"], "synonyms": ["PT-VWD", "Platelet type-von Willebrand disease", "Pseudo-von Willebrand disease type 2B"]} |
A number sign (#) is used with this entry because the Duffy blood group system (Fy) is based on variation in the ACKR1 gene (613665) on chromosome 1q23.
Complete resistance to infection by the malarial parasite Plasmodium vivax (see 611162) is associated with the Duffy phenotype Fy(a-b-), which results from a polymorphism in the ACKR1 promoter (613665.0002).
Description
The Duffy blood group system, which consists of 4 alleles, 5 phenotypes, and 5 antigens, is important in clinical medicine because of transfusion incompatibilities and hemolytic disease of the newborn. Duffy antigens are located on ACKR1 (613665), or DARC, an acidic glycoprotein found on erythrocytes and other cells throughout the body. The 2 principal antigens, Fy(a) and Fy(b), are produced by the FYA and FYB codominant alleles (see 613665.0001). Four phenotypes are defined by the corresponding antibodies, anti-Fy(a) and anti-Fy(b): Fy(a+b-), Fy(a-b+), Fy(a+b+), and Fy(a-b-). Fy(a-b-), or Duffy null, is the major phenotype in African and American blacks and is characterized by the presence of Fy(b) on nonerythroid cells, but an absence of Fy(b) on erythrocytes. The Fy(a-b-) phenotype is associated with complete resistance to infection by the malarial parasite Plasmodium vivax (see 611162). Individuals with the Fy(a-b-) phenotype have the FYB-erythroid silent (FYB-ES) allele with a mutation in the DARC promoter (613665.0002). A fifth phenotype, Fy(bwk), or Fy(x), is characterized by weak Fy(b) expression on erythrocytes due to a reduced amount of protein. Individuals with the Fy(bwk) phenotype have the FYB-weak (FYB-WK) allele, also called the FYX allele, with a missense mutation in DARC (613665.0003). Other Duffy antigens include Fy3, Fy4, Fy5, and Fy6 (reviews by Pogo and Chaudhuri (2000), Langhi and Bordin (2006), and Meny (2010)).
Clinical Features
An association between sickle cell trait (603903) and Duffy-null blood group was demonstrated in Saudi Arabs (Gelpi and King, 1976). Neither linkage nor association of the usual type was the basis, but rather a protection against malaria provided by both traits.
Biochemical Features
Nichols et al. (1987) reported a new Duffy specificity, Fy6, defined by a murine monoclonal antibody. Fy6 is related to susceptibility to invasion of red cells by P. vivax.
Diagnosis
Maternal allo-immunization to antigens of the Duffy blood group system can result in hemolytic disease of the newborn (HDN). Hessner et al. (1999) evaluated the use of allele-specific PCR for prenatal genotyping of the Duffy antigen system to identify pregnancies at risk for HDN. Oligonucleotide primers were designed for FYA, FYB, and null-FY alleles. The authors found a perfect match between results of serotyping and detection by molecular methods. They suggested that this assay is particularly useful for rapid genotyping of fetal amniotic cells to identify pregnancies at risk for HDN due to maternal-fetal incompatibilities within the Duffy blood group system.
Mapping
The Duffy system enjoys the distinction of being the first blood group whose genetic locus was assigned to a specific autosome, i.e., chromosome 1 (Donahue et al., 1968). Duffy and the locus for a form of hereditary cataract (116200) are closely linked. From extensive family studies, Robson et al. (1973) arrived at a tentative map of chromosome 1.
Palmer et al. (1977) studied a parent with transposition of segment 1q31-1q32 from the long arm to the short arm of chromosome 1 and a child in whom crossing-over had resulted in duplication of this segment. The Duffy type in the father and a normal son with the same transposition was Fy(ab), while in the mother it was Fy(b). In the proband with the duplication it was Fy(b), suggesting that the Duffy locus is situated at 1q2.
The demonstration of close linkage to alpha-spectrin (SPTA1; 182860) suggests the location of Fy in the q21 band (Raeymaekers et al., 1988). McAlpine et al. (1989) concluded that Fy lies distal to SPTA1.
By fluorescence in situ hybridization, Chaganti (1993) mapped the Fy gene, DARC, to chromosome 1q22-q23.
Molecular Genetics
### FYA/FYB Polymorphism
Tournamille et al. (1995) found that a single amino acid difference (G42D; 613665.0001) in DARC accounts for the difference between the FYA and FYB alleles at the Duffy blood group locus. Mallinson et al. (1995) also reported the basis for the FYA/FYB polymorphism.
For further information on the FYA/FYB polymorphism, see MOLECULAR GENETICS in 613665.
### Fy(a-b-) Phenotype
The Fy(a-b-) phenotype is rare among white and Asian populations, whereas it is the predominant phenotype among populations of black people, especially those originating in West Africa. Tournamille et al. (1995) demonstrated that the molecular basis of the Fy(a-b-) phenotype is a point mutation, -67T-C (613665.0002), in a consensus binding site for GATA1 (305371), a transcription factor active in erythroid cells. The Fy(a-b-) phenotype provides complete protection from Plasmodium vivax infection (see 611162).
Mallinson et al. (1995) presented evidence for 2 different genetic backgrounds giving rise to the Fy(a-b-) phenotype. The Duffy gene from a very rare Caucasian individual (AZ) with the Fy(a-b-) phenotype had a 14-bp deletion (613665.0004) that resulted in a frameshift that introduced a stop codon and produced a putative truncated DARC protein. The only known examples of the Fy(a-b-) phenotype in Caucasians were AZ and Czech gypsies.
For further information on the molecular genetics underlying the Fy(a-b-) phenotype, see MOLECULAR GENETICS in 613665.
### Fy(bwk) Phenotype
Tournamille et al. (1998) and Olsson et al. (1998) described a Duffy allele, FYB-WK, or FYX, in approximately 3.5% of the population that, because of an arg89-to-cys (R89C; 613665.0003) substitution in the first cytoplasmic domain of DARC, results in reduced levels of protein, lower antigen expression, and reduced ability to bind chemokines. The phenotype is called Fy(bwk), Fy(x), or either Fy(a-b+(weak)) or Fy(a+b+(weak))
For further information on the molecular genetics underlying the Fy(bwk) phenotype, see MOLECULAR GENETICS in 613665.
History
On the basis of families studied in Rochester, N.Y., Weitkamp (1972) could demonstrate no linkage of Duffy and the HBB locus (141900), as had been suggested by Nance et al. (1970). An earlier suspicion of localization to chromosome 16 (Crawford et al., 1967) was apparently in error.
From study of a family with a pericentric inversion of chromosome 1, Lee et al. (1974) suggested that the most probable location of the Fy locus is close to the centromere on the short arm (favored) or near the distal end of the centric heterochromatin on the long arm. Assuming that each arm of chromosome 1 is 140 male cM in length, Cook et al. (1974) concluded that, measured from the centromere, map positions are as follows: PGD (172200) 1p124--Rh (see 111700) 1p109--PGM1 (171900) 1p079--Fy 1p010--PEPC (170000) 1q030.
In the course of paternity testing, Herbich et al. (1985) found an apparent maternal exclusion by the PGM1 enzyme system--mother's PGM1 type, 1; child's PGM1 type, 2; and by the Duffy blood group system--mother, Fy(a-b+); child, Fy(a+b-). The father was not available for testing. The karyotype of the child showed a 'new fragile site' at 1p31. The authors concluded that the PGM1 and Duffy loci are located in the 1p31 band, which they stated to be 'a position supposed to carry the PGM1 and the Duffy loci.' The last statement is incorrect and the assignment to 1p31 is inconsistent with previous well-established assignments of PGM1 and Fy to 1p22.1 and 1q12-q21, respectively.
INHERITANCE \- Autosomal dominant \- Autosomal recessive (null phenotype) HEMATOLOGY \- Duffy blood group IMMUNOLOGY \- Duffy null phenotype confers complete resistance to infection by the malarial parasite Plasmodium vivax (see 613665.0002 ) MOLECULAR BASIS \- Caused by mutation in the atypical chemokine receptor 1 gene (ACKR1, 613665.0001 ) ▲ 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
| BLOOD GROUP, DUFFY SYSTEM | c1970105 | 1,342 | omim | https://www.omim.org/entry/110700 | 2019-09-22T16:44:23 | {"omim": ["110700"], "synonyms": ["Alternative titles", "DUFFY BLOOD GROUP SYSTEM"]} |
Not to be confused with Serotonin syndrome.
Antidepressant discontinuation syndrome
Other namesAntidepressant withdrawal syndrome[1]
SpecialtyPsychiatry
SymptomsFlu-like symptoms, trouble sleeping, nausea, poor balance, sensory changes[2]
Usual onsetWithin 3 days[2]
DurationFew weeks to months[3][4]
CausesStopping of an antidepressant medication[2][3]
Diagnostic methodBased on symptoms[2]
Differential diagnosisAnxiety, mania, stroke[2]
PreventionGradual dose reduction[2]
Frequency20-50%(with sudden stopping)[3][4]
Antidepressant discontinuation syndrome, also called antidepressant withdrawal syndrome, is a condition that can occur following the interruption, reduction, or discontinuation of antidepressant medication that was taken continuously for at least one month.[5] The symptoms may include flu-like symptoms, trouble sleeping, nausea, poor balance, sensory changes, and anxiety.[2][3][4] The problem usually begins within three days and may last for several months.[2][4] Rarely psychosis may occur.[2]
A discontinuation syndrome can occur after stopping any antidepressant including selective serotonin re-uptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs).[2][3] The risk is greater among those who have taken the medication for longer and when the medication in question has a short half-life.[2] The underlying reason for its occurrence is unclear.[2] The diagnosis is based on the symptoms.[2]
Methods of prevention include gradually decreasing the dose among those who wish to stop, though it is possible for symptoms to occur with tapering.[2][6][4] Treatment may include restarting the medication and slowly decreasing the dose.[2] People may also be switched to the long acting antidepressant fluoxetine which can then be gradually decreased.[6]
Approximately 20–50% of people who suddenly stop an antidepressant develop an antidepressant discontinuation syndrome.[2][3][4] The condition is generally not serious,[2] though about half of people with symptoms describe them as severe.[4] Some restart antidepressants due to the severity of the symptoms.[4]
## Contents
* 1 Signs and symptoms
* 1.1 Duration
* 2 Mechanism
* 3 Prevention and treatment
* 3.1 Pregnancy and newborns
* 4 Culture and history
* 4.1 2013 class action lawsuit
* 5 Research
* 6 See also
* 7 References
* 8 External links
## Signs and symptoms[edit]
People with antidepressant discontinuation syndrome have been on an antidepressant for at least four weeks and have recently stopped taking the medication, whether abruptly, after a fast taper, or each time the medication is reduced on a slow taper.[2] Commonly reported symptoms include flu-like symptoms (nausea, vomiting, diarrhea, headaches, sweating) and sleep disturbances (insomnia, nightmares, constant sleepiness). Sensory and movement disturbances have also been reported, including imbalance, tremors, vertigo, dizziness, and electric-shock-like experiences in the brain, often described by people who have them as "brain zaps". These "brain zaps" are often described as feeling like an unsettling shiver or shock sensation that starts in the head and moves quickly through the entire body.[citation needed] Mood disturbances such as dysphoria, anxiety, or agitation are also reported, as are cognitive disturbances such as confusion and hyperarousal.
In cases associated with sudden discontinuation of MAO inhibitors, acute psychosis has been observed.[2][7][8] Over fifty symptoms have been reported.[9]
A 2009 Advisory Committee to the FDA found that online anecdotal reports of discontinuation syndrome related to duloxetine included severe symptoms and exceeded prevalence of both paroxetine and venlafaxine reports by over 250% (although acknowledged this may have been influenced by duloxetine being a much newer drug).[10] It also found that the safety information provided by the manufacturer not only neglected important information about managing discontinuation syndrome, but also explicitly advised against opening capsules, a practice required to gradually taper dosage.[10]
### Duration[edit]
Most cases of discontinuation syndrome may last between one and four weeks and resolve on their own.[2] Occasionally symptoms can last up to one year.[3] They typically resolve within a day of restoring the medication.[11] Paroxetine and venlafaxine seem to be particularly difficult to discontinue, and prolonged withdrawal syndrome (post-acute-withdrawal syndrome, or PAWS) lasting over 18 months has been reported with paroxetine.[12][13][14]
## Mechanism[edit]
The underlying reason for its occurrence is unclear,[2] though the syndrome appears similar to withdrawal from other psychotropic drugs such as benzodiazepines.[1]
## Prevention and treatment[edit]
In some cases, withdrawal symptoms may be prevented by taking medication as directed, and when discontinuing, doing so gradually, although symptoms may appear while tapering. When discontinuing an antidepressant with a short half-life, switching to a drug with a longer half-life (e.g. fluoxetine or citalopram) and then tapering, and eventually discontinuing, from that drug can decrease the severity of symptoms in some cases.[7]
Treatment is dependent on the severity of the discontinuation reaction and whether or not further antidepressant treatment is warranted. In cases where further antidepressant treatment is prescribed, then the only option suggested may be restarting the antidepressant. If antidepressants are no longer required, treatment depends on symptom severity. If symptoms of discontinuation are severe, or do not respond to symptom management, the antidepressant can be reinstated and then withdrawn more cautiously, or by switching to a drug with a longer half life, (such as Prozac), and then tapering and discontinuing that drug.[12] In severe cases, hospitalization may be required.[2]
### Pregnancy and newborns[edit]
Antidepressants, including SSRIs, can cross the placenta and have the potential to affect the fetus and newborn, including an increased chance of miscarriage, presenting a dilemma for pregnant women to decide whether to continue to take antidepressants at all, or if they do, considering if tapering and discontinuing during pregnancy could have a protective effect for the newborn.[15]
Postnatal adaptation syndrome (PNAS) (originally called "neonatal behavioral syndrome", "poor neonatal adaptation syndrome", or "neonatal withdrawal syndrome") was first noticed in 1973 in newborns of mothers taking antidepressants; symptoms in the infant include irritability, rapid breathing, hypothermia, and blood sugar problems. The symptoms usually develop from birth to days after delivery and usually resolve within days or weeks of delivery.[15]
## Culture and history[edit]
Antidepressant discontinuation symptoms were first reported with imipramine, the first tricyclic antidepressant (TCA), in the late 1950s, and each new class of antidepressants has brought reports of similar conditions, including monoamine oxidase inhibitors (MAOIs), SSRIs, and SNRIs. As of 2001, at least 21 different antidepressants, covering all the major classes, were known to cause discontinuation syndromes.[12] The problem has been poorly studied, and most of the literature has been case reports or small clinical studies; incidence is hard to determine and controversial.[12]
With the explosion of use and interest in SSRIs in the late 1980s and early 1990s, focused especially on Prozac, interest grew as well in discontinuation syndromes.[16] Some of the symptoms emerged from discussion boards where people with depression discussed their experiences with the disease and their medications; "brain zaps" or "brain shivers" was one symptom that emerged via these websites.[17][18]
Heightened media attention and continuing public concerns led to the formation of an expert group on the safety of selective serotonin reuptake inhibitors in England, to evaluate all the research available prior to 2004.[19]:iv The group determined that the incidence of discontinuation symptoms are between 5% and 49%, depending on the particular SSRI, the length of time on the medicine and abrupt versus gradual cessation.[19]:126–136
With the lack of a definition based on consensus criteria for the syndrome, a panel met in Phoenix, Arizona in 1997 to form a draft definition,[20] which other groups continued to refine.[21][22]
In the late 1990s, some investigators thought that the fact that symptoms emerged when antidepressants were discontinued might mean that antidepressants were causing addiction, and some used the term "withdrawal syndrome" to describe the symptoms. While people taking antidepressants do not commonly exhibit drug-seeking behavior, stopping antidepressants leads to similar symptoms as found in drug withdrawal from benzodiazapines, and other psychotropic drugs.[23][24] As such, some researchers advocate the term withdrawal over discontinuation, to communicate the similar physiological dependence and negative outcomes.[1] Due to pressure from pharmaceutical companies who make anti-depressants, the term "withdrawal syndrome" is no longer used by drug makers, and thus, most doctors, due to concerns that they may be compared to other drugs more commonly associated with withdrawal.[2]
### 2013 class action lawsuit[edit]
In 2013, a proposed class action lawsuit, Jennifer L Saavedra v. Eli Lilly and Company,[25] was brought against Eli Lilly claiming that the Cymbalta label omitted important information about "brain zaps" and other symptoms upon cessation.[26] Eli Lilly moved for dismissal per the "learned intermediary doctrine" as the doctors prescribing the drug were warned of the potential problems and are an intermediary medical judgment between Lilly and patients; in December 2013 Lilly's motion to dismiss was denied.[27]
## Research[edit]
The mechanisms of antidepressant withdrawal syndrome have not yet been conclusively identified.[2][8] The leading hypothesis is that after the antidepressant is discontinued, there is a temporary, but in some cases, long-lasting, deficiency in the brain of one or more essential neurotransmitters that regulate mood, such as serotonin, dopamine, norepinephrine, and gamma-aminobutyric acid, and since neurotransmitters are an interrelated system, dysregulation of one affects the others.[2][28]
## See also[edit]
* Psychiatry portal
* Benzodiazepine withdrawal syndrome
## References[edit]
1. ^ a b c "Antidepressant Withdrawal Syndrome". ubc.ca. Therapeutics Initiative, The University of British Columbia. 23 July 2018. Retrieved 3 August 2018.
2. ^ 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 Warner, CH; Bobo, W; Warner, C; Reid, S; Rachal, J (1 August 2006). "Antidepressant discontinuation syndrome". American Family Physician. 74 (3): 449–56. PMID 16913164.
3. ^ a b c d e f g Gabriel, M; Sharma, V (29 May 2017). "Antidepressant discontinuation syndrome". Canadian Medical Association Journal. 189 (21): E747. doi:10.1503/cmaj.160991. PMC 5449237. PMID 28554948.
4. ^ a b c d e f g h Davies, J; Read, J (4 September 2018). "A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: Are guidelines evidence-based?". Addictive Behaviors. 97: 111–121. doi:10.1016/j.addbeh.2018.08.027. PMID 30292574.
5. ^ Diagnostic and statistical manual of mental disorders : DSM-5 (5th ed.). American Psychiatric Association. 2013. pp. 712–714. ISBN 9780890425541.
6. ^ a b Wilson, E; Lader, M (December 2015). "A review of the management of antidepressant discontinuation symptoms". Therapeutic Advances in Psychopharmacology. 5 (6): 357–68. doi:10.1177/2045125315612334. PMC 4722507. PMID 26834969.
7. ^ a b Haddad, Peter M.; Anderson, Ian M. (October 2007). "Recognising and managing antidepressant discontinuation symptoms". Advances in Psychiatric Treatment. 13 (6): 447–57. doi:10.1192/apt.bp.105.001966.
8. ^ a b Renoir T (2013). "Selective serotonin reuptake inhibitor antidepressant treatment discontinuation syndrome: a review of the clinical evidence and the possible mechanisms involved". Front Pharmacol. 4: 45. doi:10.3389/fphar.2013.00045. PMC 3627130. PMID 23596418.
9. ^ Haddad PM, Dursun SM (2008). "Neurological complications of psychiatric drugs: clinical features and management". Hum Psychopharmacol. 23 (Suppl 1): 15–26. doi:10.1002/hup.918. PMID 18098217.
10. ^ a b "Cymbalta (Duloxetine) Discontinuation Syndrome: Issues of Scope, Severity, Duration & Management" (PDF). U.S. Food and Drug Administration (FDA). 9 June 2009. Retrieved 17 October 2016.
11. ^ Haddad, Peter M.; Anderson, Ian M. (1 November 2007). "Recognising and managing antidepressant discontinuation symptoms". Advances in Psychiatric Treatment. 13 (6): 447–457. doi:10.1192/apt.bp.105.001966. ISSN 2056-4678.
12. ^ a b c d Haddad, Peter M. (March 2001). "Antidepressant discontinuation syndromes". Drug Safety. 24 (3): 183–97. doi:10.2165/00002018-200124030-00003. PMID 11347722.
13. ^ Tamam, L.; Ozpoyraz, N. (January–February 2002). "Selective Serotonin Reuptake Inhibitor Discontinuation Syndrome: A Review". Advances in Therapy. 19 (1): 17–26. doi:10.1007/BF02850015. PMID 12008858.
14. ^ Gartlehner G, Hansen RA, Morgan LC, et al. (December 2011). "Results". Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review (Report). Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality.
15. ^ a b Byatt N, Deligiannidis KM, Freeman MP (Feb 2013). "Antidepressant use in pregnancy: a critical review focused on risks and controversies". Acta Psychiatr Scand. 127 (2): 94–114. doi:10.1111/acps.12042. PMC 4006272. PMID 23240634.
16. ^ Stutz, Bruce (2007-05-06). "Self-Nonmedication". New York Times. Retrieved 2010-05-24.
17. ^ Christmas, M.B. (2005). "'Brain shivers': from chat room to clinic". Psychiatric Bulletin. 29 (6): 219–21. doi:10.1192/pb.29.6.219.
18. ^ Aronson, J. (8 October 2005). "Bottled lightning". BMJ. 331 (7520): 824. doi:10.1136/bmj.331.7520.824. PMC 1246084.
19. ^ a b Expert Group on the Safety of Selective Serotonin Reuptake Inhibitors (SSRIs) (December 2004). Weller, Ian V.D. (ed.). "Report of the CSM Expert Working Group on the Safety of Selective Serotonin Reuptake Inhibitor Antidepressants" (PDF). Medicines and Healthcare Products Regulatory Agency. Retrieved 1 August 2014.
20. ^ Schatzberg, A.F.; Haddad, P.; Kaplan, E.M.; Lejoyeux, M.; Rosenbaum, J.F.; Young, A.H.; Zajecka, J. (1997). "Serotonin reuptake inhibitor discontinuation syndrome: a hypothetical definition. Discontinuation Consensus panel". J Clin Psychiatry. 5u (7): 5–10. PMID 9219487.
21. ^ Black, K.; Shea, C.; Dursun, S.; Kutcher, S. (2000). "Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria". J Psychiatry Neurosci. 25 (3): 255–61. PMC 1407715. PMID 10863885.
22. ^ WHO Expert Committee on Drug Dependence – Thirty-third Report / WHO Technical Report Series 915 (Report). World Health Organization. 2003.
23. ^ Nielsen, M.; Hanse, E.H.; Gøtzsche, P.C. (2012). "What is the difference between dependence and withdrawal reactions? A comparison of benzodiazepines and selective serotonin re-uptake inhibitors". Addiction. 105 (5): 900–8. doi:10.1111/j.1360-0443.2011.03686.x. PMID 21992148.
24. ^ Fava, G.A.; Gatti, A; Belaise, C.; et al. (2015). "Withdrawal Symptoms after Selective Serotonin Reuptake Inhibitor Discontinuation: A Systematic Review". Psychother Psychosom. 84 (2): 72–81. doi:10.1159/000370338. PMID 25721705.
25. ^ Jennifer L Saavedra v. Eli Lilly and Company – via Justia.com
26. ^ Overley, Jeff (January 29, 2013). "Lilly Fights Cymbalta 'Brain Zaps' Suit, Saying It Warned Docs". Law360.com. Retrieved 3 August 2014.
27. ^ Tushnet, Rebecca (December 9, 2013). "Learned intermediary doctrine doesn't bar claim at pleading stage". Rebecca Tushnet's 43(B)log.
28. ^ Damsa, C.; Bumb, A.; Bianchi-Demicheli, F.; et al. (August 2004). "'Dopamine-dependent' side effects of selective serotonin reuptake inhibitors: a clinical review". J Clin Psychiatry. 65 (8): 1064–8. doi:10.4088/JCP.v65n0806. PMID 15323590.
## External links[edit]
Classification
D
* ICD-10: Y49.0 Tricyclic and tetracyclic antidepressants
Y49.1 Monoamine-oxidase-inhibitor antidepressants
Y49.2 Other and unspecified antidepressants
* v
* t
* e
Unnecessary health care
Causes
* Direct-to-consumer advertising
* Overscreening
* Overdiagnosis
* Fee-for-service
* Defensive medicine
* Unwarranted variation
* Overmedication
* Overmedicalization
* Prescription cascade
* Quaternary prevention
* Disease mongering
* Political abuse of psychiatry
Overused health care
* Caesarean delivery on maternal request
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* Effects of long-term benzodiazepine use
* Opioid use disorder
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Tools and Situations
* Deprescribing
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Works about unnecessary health care
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*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Antidepressant discontinuation syndrome | c4509470 | 1,343 | wikipedia | https://en.wikipedia.org/wiki/Antidepressant_discontinuation_syndrome | 2021-01-18T18:57:53 | {"umls": ["CL777146"], "wikidata": ["Q175918"]} |
A number sign (#) is used with this entry because congenital dyserythropoietic anemia type Ib (CDAN1B) is caused by homozygous mutation in the C15ORF41 gene (615626) on chromosome 15q14.
Description
Congenital dyserythropoietic anemia type I is an autosomal recessive hematologic disorder characterized by congenital macrocytic anemia secondary to ineffective erythropoiesis. The bone marrow shows erythroid hyperplasia, with nuclear abnormalities in most erythroblasts. Up to 3% of erythroblasts have interchromatin bridges, and erythroblast nuclei are abnormally electron dense with spongy ('Swiss cheese-like') heterochromatin on electron microscopy. Some reported patients have distal digital abnormalities (summary by Ahmed et al., 2006).
For a general phenotypic description and a discussion of genetic heterogeneity of CDA, see CDAN1A (224120).
Clinical Features
Sabry et al. (1997) reported 3 sibs, born of related Kuwaiti parents, with congenital dyserythropoietic anemia apparent from early childhood. All had a history of jaundice, skin pallor, hepatosplenomegaly, and blood transfusion. Laboratory studies showed increased bilirubin and reticulocytes. Bone marrow biopsies showed erythroid hyperplasia, internuclear chromatin bridges, and multinuclear erythrocyte precursors. The findings were consistent with type I congenital dyserythropoietic anemia. The patients also had skeletal anomalies that varied in severity, including short stature, hypoplastic nails, phalangeal hypoplasia of both the hands and feet, deformed or duplicated metatarsals, and cutaneous syndactyly of the toes. One patient had ptosis and reduced bone age.
Ahmed et al. (2006) reported 2 Pakistani sisters, born of consanguineous parents (family C), with clinical and hematologic findings of type I congenital dyserythropoietic anemia. A substantial proportion of erythroblasts showed 'Swiss-cheese' appearance of heterochromatin on electron microscopy. Linkage and sequence analysis excluded mutations in the CDAN1 gene (607465).
Babbs et al. (2013) restudied the 3 sibs reported by Sabry et al. (1997). Hematologic features included megaloblastic erythropoiesis with severe dyserythropoietic changes, bi- and multinuclear erythroblasts, and internuclear chromatin bridges. All patients were severely affected, requiring transfusion support during childhood.
Inheritance
The transmission pattern of CDAN1B in the families reported by Babbs et al. (2013) was consistent with autosomal recessive inheritance.
Molecular Genetics
In affected members of 3 unrelated consanguineous families with congenital dyserythropoietic anemia type Ib, Babbs et al. (2013) identified 2 different homozygous missense mutations in the C15ORF41 gene (L178Q, 615626.0001 and Y94C, 615626.0002). The mutation in the first family was found by whole-genome sequencing, whereas the mutation in the other 2 families was found by direct sequencing of the C15ORF41 gene in 9 probands with the disorder. Functional studies of the mutations were not performed. Two of the families had previously been reported by Sabry et al. (1997) and Ahmed et al. (2006), respectively.
### Exclusion Studies
By linkage analysis and direct sequencing, Ahmed et al. (2006) excluded mutations in the CDAN1 gene (607465) in the Kuwaiti sibs with CDA type I reported by Sabry et al. (1997). By the same methods, Ahmed et al. (2006) excluded the CDAN1 gene in 2 Pakistani sisters with CDA type I.
INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature (in some patients) Other \- Poor growth ABDOMEN Liver \- Hepatomegaly Spleen \- Splenomegaly SKELETAL Hands \- Phalangeal abnormalities (in some patients) \- Hypoplasia of terminal phalanges (in some patients) Feet \- Phalangeal abnormalities (in some patients) \- Hypoplasia of terminal phalanges (in some patients) \- Metatarsal duplication (in some patients) \- Syndactyly (in some patients) SKIN, NAILS, & HAIR Skin \- Pallor \- Jaundice Nails \- Nail hypoplasia (in some patients) HEMATOLOGY \- Dyserythropoietic anemia \- Peripheral blood smear shows polychromasia \- Poikilocytosis \- Anisocytosis \- Macrocytosis \- Increased reticulocytes \- Erythroid hyperplasia seen on bone marrow biopsy \- Megaloblastic erythropoiesis \- Multinuclear erythroblasts \- Internuclear chromatin bridges \- Heterochromatin clumps with spongy, 'Swiss cheese' appearance LABORATORY ABNORMALITIES \- Decreased hemoglobin \- Increased fetal hemoglobin \- Increased serum bilirubin MISCELLANEOUS \- Onset in childhood \- Anemia is transfusion-dependent \- Anemia does not respond to alpha-interferon treatment MOLECULAR BASIS \- Caused by mutation in the chromosome 15 open reading frame 41 gene (C15ORF41, 615626.0001 ) ▲ 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
| ANEMIA, CONGENITAL DYSERYTHROPOIETIC, TYPE Ib | c0271933 | 1,344 | omim | https://www.omim.org/entry/615631 | 2019-09-22T15:51:23 | {"doid": ["1338"], "mesh": ["D000742"], "omim": ["615631"], "orphanet": ["98869"], "synonyms": ["Alternative titles", "CDA, TYPE Ib"], "genereviews": ["NBK5313"]} |
A number sign (#) is used with this entry because inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD1) is caused by heterozygous mutation in the VCP gene (601023) on chromosome 9p13.
See also amyotrophic lateral sclerosis-14 with or without frontotemporal dementia (ALS14; 613954), which is also caused by heterozygous mutation in the VCP gene and can show overlapping clinical features.
Description
IBMPFD is an autosomal dominant disorder characterized by incomplete penetrance of 3 main features: disabling muscle weakness (in 90%), osteolytic bone lesions consistent with Paget disease (in 51%), and frontotemporal dementia (in 32%). Muscle weakness is an isolated symptom in about 30% of patients and the presenting symptom in greater than half of patients, suggesting that IBMPFD may commonly be seen in a neuromuscular clinic without its other syndromic features (review by Weihl et al., 2009).
### Genetic Heterogeneity of IBMPFD/MSP
IBMPFD2 (MSP2; 615422) is caused by mutation in the HNRNPA2B1 gene (600124) on chromosome 7p15. IBMPFD3 (MSP3; 615424) is caused by mutation in the HNRNPA1 gene (164017) on chromosome 12q13.
Bucelli et al. (2015) suggested use of the designation MSP4 to include disparate phenotypes in muscle, brain, spinal cord, and bone caused by mutation in the SQSTM1 gene (601530); see 617158.
Clinical Features
Tucker et al. (1982) studied a large kindred with a syndrome of lower motor neuron degeneration and polyostotic skeletal disorganization resembling Paget disease of bone (PDB; see 167250). The disorder begins insidiously at about age 35 with weakness and atrophy of the leg and proximal arm muscles. Nerve conductions are normal; EMG shows muscle denervation, as does muscle biopsy. The disorder progresses to wheelchair confinement and later to bed confinement, quadriparesis, dementia, respiratory failure, and death before age 60 years. Even early in the neurologic illness, patients have coarse trabeculation, cortical thickening, and spotty sclerosis on bone x-rays; diffusely increased uptake of radionuclide and elevated heat-labile serum alkaline phosphatase. The disorder affected 6 females and 6 males in 5 sibships of 3 generations with no instance of male-to-male transmission.
Kimonis et al. (2000) described a family in which autosomal dominant limb-girdle muscular dystrophy (LGMD) was associated with early-onset Paget disease of bone PDB and cardiomyopathy. Eight of 11 affected individuals had both disorders. Onset of PDB occurred at a mean age of 35 years, with classic distribution involving the spine, pelvis, and skull. Muscle weakness and atrophy was progressive with mildly elevated to normal CPK levels. Muscle biopsy in the oldest male revealed vacuolated fibers, but in others revealed nonspecific myopathy. Affected individuals die from progressive muscle weakness and respiratory and cardiac failure in their forties to sixties.
Kovach et al. (2001) described the clinical, biochemical, radiologic, and pathologic characteristics of 49 affected individuals from the family described by Kimonis et al. (2000) and 3 other unrelated families with autosomal dominant inclusion body myopathy (IBM), PDB, and frontotemporal dementia. Ninety percent of the patients had myopathy, 43% had PDB, and 37% had premature frontotemporal dementia.
Watts et al. (2004) reported 13 families with IBMPFD, 12 from the U.S. and 1 from Canada. Among those individuals, 82% of affected individuals had myopathy, 49% had PDB, and 30% had early-onset frontotemporal dementia. The mean age at presentation was 42 years for both IBM and PDB, whereas frontotemporal dementia typically presented at age 53 years. In IBMPFD myopathic muscle and PDB osteoclasts, inclusions appear similar, suggestive of disruptions in the same pathologic pathway. Family 11 in the report by Watts et al. (2004) was originally reported by Tucker et al. (1982) (Kimonis, 2005).
Haubenberger et al. (2005) reported an Austrian family in which 4 sibs had autosomal dominant inclusion body myopathy and Paget disease associated with a heterozygous mutation in the VCP gene (R159H; 601023.0007). None of the affected individuals developed frontotemporal dementia even though all were over 60 years of age. Haubenberger et al. (2005) noted that only approximately 30% of patients with VCP mutations develop dementia, illustrating phenotypic variability. In a follow-up of this family, van der Zee et al. (2009) noted that 1 patient had developed dementia at age 64. Van der Zee et al. (2009) also identified the R159H mutation in affected members of 2 unrelated Belgian families. In 1 family, patients presented with frontotemporal lobar degeneration only, whereas in the other family, patients developed frontotemporal lobar degeneration, Paget disease of the bone, or both without signs of inclusion body myopathy for any of the mutation carriers. Haplotype analysis showed that the 2 families and the Austrian family reported by Haubenberger et al. (2005) were unrelated. Autopsy data of 3 patients from the 2 Belgian families showed frontotemporal lobar degeneration with numerous ubiquitin-immunoreactive, intranuclear inclusions and dystrophic neurites staining positive for TDP43 (TARDBP; 605078) protein. Van der Zee et al. (2009) commented on the high degree of clinical heterogeneity and incomplete penetrance of the disorder in different families carrying the same mutation.
Kimonis et al. (2008) reported detailed clinical features of 49 patients from 9 families with IBMPFD confirmed by genetic analysis. One family had been previously reported by Tucker et al. (1982). Forty-two (86%) patients had muscle disease, the majority of whom were initially misdiagnosed as having some other form of muscular dystrophy or spinal muscular atrophy. Weakness was distal and/or proximal, and many patients were confined to wheelchairs. Muscle biopsies showed inclusion bodies and/or rimmed vacuoles (39%) or nonspecific changes. Frontotemporal dementia was diagnosed in 13 (27%) of 49 individuals at a mean age of 57 years, of whom 3 had been originally diagnosed with Alzheimer disease (104300). Paget disease of bone was found in 28 (57%) of 49 patients at a mean age of 40 years and correlated with increased serum alkaline phosphatase. Kimonis et al. (2008) postulated that IBMPFD is underdiagnosed among patients with myopathy and/or dementia.
Viassolo et al. (2008) reported an Italian family in which 2 sibs and their mother had IBMPFD. All 3 had progressive inclusion body myopathy and rapidly progressive severe dementia, but only 1 developed Paget disease. Genetic analysis identified a heterozygous mutation in the VCP gene (R155H; 601023.0001). Several other family members were reportedly affected. Viassolo et al. (2008) discussed the implications of the incomplete penetrance of some of the features for genetic counseling.
Kim et al. (2011) reported 3 Korean sibs with IBMPFD confirmed by genetic analysis (601023.0002). The proband developed progressive dementia presenting as fluent aphasia and language difficulties with onset at age 47. She never developed myopathy, but did develop asymptomatic Paget disease with increased serum alkaline phosphatase and lytic bone lesions on imaging. Her brother developed slowly progressive proximal muscle weakness at age 50, followed by frontotemporal dementia characterized initially by comprehension defects at age 54. He never had Paget disease, although serum alkaline phosphatase was increased. A second brother developed muscle weakness at age 47, followed by Paget disease at age 53, and dementia at age 61. Brain MRI in all patients showed asymmetric atrophy in the anterior inferior and lateral temporal lobes and inferior parietal lobule with ventricular dilatation on the affected side (2 on the left, 1 on the right). Two had glucose hypometabolism in the lateral temporal and inferior parietal areas, with less involvement of the anterior temporal and frontal lobes compared to those with typical semantic dementia.
Sacconi et al. (2012) reported 2 unrelated men in their fifties who presented with a phenotype reminiscent of FSHD1 (158900) but were found to carry a heterozygous VCP mutation (R191Q; 601023.0006). One had scapuloperoneal weakness without facial involvement and increased serum creatine kinase. The second patient had facial weakness, shoulder and pelvic girdle weakness, and anterior foreleg weakness. Creatine kinase was increased 4-fold. Muscle biopsies of both patients showed mild dystrophic changes, but no inclusion bodies. Both had a myopathic pattern on EMG. One was later found to have a mild dysexecutive syndrome, but neither had evidence of Paget disease.
### Neuropathologic Findings
Schroder et al. (2005) reported a patient with frontotemporal dementia (FTD) and inclusion body myopathy caused by mutation in the VCP gene (601023.0002). There was no evidence of Paget disease. Neuropathologic examination showed cortical atrophy and widespread neuronal loss; subcortical neuronal loss was less severe. The cerebral and cerebellar white matter had severe astrogliosis. Surviving cortical pyramidal neurons contained VCP- and ubiquitin (see 191321)-positive intranuclear inclusions and displayed cytoplasmic autofluorescence consistent with lipofuscin. Nuclear inclusions were not seen in astrocytes, oligodendrocytes, or microglial cells. Western blot analysis showed a single 97-kD band corresponding to normal-sized VCP that was similar to control brains. Schroder et al. (2005) concluded that mutant VCP causes a novel form of frontotemporal dementia, distinct from tau (MAPT; 157140)-associated FTD (see 600274), characterized by neuronal nuclear inclusions containing ubiquitin and VCP. The authors suggested that mutant VCP interferes with ubiquitin-dependent pathways, leading to abnormal intracellular and intranuclear protein aggregation.
Mapping
In a family with autosomal dominant LGMD associated with early-onset PDB and cardiomyopathy, Kimonis et al. (2000) excluded autosomal dominant and recessive LGMD, PDB, and cardiomyopathy loci. They argued that their linkage analysis data indicated a unique locus in this family.
By linkage analysis, Kovach et al. (2001) localized autosomal dominant IBM with PDB and frontotemporal dementia to a 1.08- to 6.46-cM critical interval on 9p13.3-p12. The maximum lod score generated from the combined genotype data was 9.29 for marker D91791.
Molecular Genetics
Watts et al. (2004) performed haplotype analysis of 13 families with IBMPFD and identified 2 ancestral disease-associated haplotypes, distinguishing families 1, 3, 7, and 16 (group A) from families 2 and 5 (group B). Both groups were of northern European ancestry. The predominant IBMPFD haplotype of group A includes a core haplotype flanked by D9S1118 and D9S234, probably transmitted from a shared ancestor. Watts et al. (2004) identified 6 missense mutations in the valosin-containing protein (VCP; 601023) in these families. Families 1, 3, 4, 7, 10, 15, and 16 shared the R155H mutation in exon 5 (601023.0001); families 2 and 5 had an R155C mutation (601023.0002); and family 11 had an R155P mutation (601023.0005). Thus, 10 of the 13 families with IBMPFD had an amino acid change at codon 155 in VCP, which therefore seems to be a mutation hotspot. In addition, 1 family had a missense mutation at codon 232 (601023.0003), another at codon 95 (601023.0004), and another at codon 191 (601023.0006).
Genotype/Phenotype Correlations
Mehta et al. (2013) analyzed clinical and biochemical markers from a database of 190 individuals from 27 families harboring 10 missense mutations in the VCP gene. Among these, 145 mutation carriers were symptomatic and 45 were presymptomatic. The most common clinical feature (in 91% of patients) was onset of myopathic weakness at a mean age of 43 years. Paget disease of the bone was found in 52% of patients at a mean age of 41 years. Frontotemporal dementia occurred in 30% of patients at a mean age of 55 years. Significant genotype-phenotype correlations were difficult to establish because of small numbers. However, patients with the R155C mutation had a more severe phenotype with an earlier onset of myopathy and Paget disease, as well as decreased survival, compared to those with the R155H mutation. A diagnosis of ALS was found in at least 13 (8.9%) individuals from the 27 families, including 10 patients with the R155H mutation, and 5 (3%) patients were diagnosed with Parkinson disease.
Nomenclature
IBMPFD may also be referred to as FTLD-TDP (or TDP43), VCP-related, based on neuropathologic findings (MacKenzie et al., 2010).
Animal Model
Weihl et al. (2007) found that transgenic mice overexpressing the R155H mutation became progressively weaker in a dose-dependent manner starting at 6 months of age. There was abnormal muscle pathology, with coarse internal architecture, vacuolation and disorganized membrane morphology with reduced caveolin-3 (CAV3; 601253) expression at the sarcolemma. Even before animals displayed measurable weakness, there was an increase in ubiquitin-containing protein inclusions and high molecular weight ubiquitinated proteins. These findings suggested a dysregulation in protein degradation.
Custer et al. (2010) developed and characterized transgenic mice with ubiquitous expression of wildtype and disease-causing versions of human VCP/p97. Mice expressing VCP/p97 harboring the mutations R155H (601023.0001) or A232E (601023.0003) exhibited progressive muscle weakness, and developed inclusion body myopathy including rimmed vacuoles and TDP43 pathology. The brain showed widespread TDP43 (605078) pathology, and the skeleton exhibited severe osteopenia accompanied by focal lytic and sclerotic lesions in vertebrae and femur. In vitro studies indicated that mutant VCP caused inappropriate activation of the NF-kappa-B (see 164011) signaling cascade, which could contribute to the mechanism of pathogenesis in multiple tissues including muscle, bone, and brain.
INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Facial weakness (less common) CHEST Ribs Sternum Clavicles & Scapulae \- Winged scapulae SKELETAL \- Paget disease (in 50% of patients) Spine \- Back pain \- Lumbar lordosis Pelvis \- Hip pain MUSCLE, SOFT TISSUES \- Muscle weakness (in 90% of patients) \- Proximal muscle weakness \- Shoulder weakness and atrophy \- Limb weakness and atrophy \- Pelvic girdle weakness and atrophy \- Distal muscle atrophy \- Nonspecific myopathic changes seen on biopsy \- Rimmed vacuoles \- Inclusion body myopathy \- Difficulty walking up stairs \- Primary myopathic changes seen on EMG NEUROLOGIC Central Nervous System \- Gait abnormalities \- Frontotemporal dementia (in 30% of patients) \- Dystonia \- Expressive dysphasia \- Dystrophic neurites \- Ubiquitin-positive intranuclear neuronal inclusions \- VCP-positive inclusions \- TDP43-positive inclusions \- MRI shows frontal and temporal cortical atrophy LABORATORY ABNORMALITIES \- Increased serum creatine kinase \- Increased serum bone-specific alkaline phosphatase MISCELLANEOUS \- Mean age at onset of muscle disease is 42 years (range 24-61) \- Mean age at onset of bone disease is 40 years (range 23-65) \- Mean age at onset of dementia is 57 years \- Many patients become wheelchair-bound \- Incomplete penetrance of the 3 main clinical signs, myopathy, dementia, and Paget disease MOLECULAR BASIS \- Caused by mutation in the valosin-containing protein gene (VCP, 601023.0001 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA 1 | c1833662 | 1,345 | omim | https://www.omim.org/entry/167320 | 2019-09-22T16:36:46 | {"doid": ["0050881"], "mesh": ["C563476"], "omim": ["167320"], "orphanet": ["52430"], "synonyms": ["Alternative titles", "MULTISYSTEM PROTEINOPATHY 1", "MUSCULAR DYSTROPHY, LIMB-GIRDLE, WITH PAGET DISEASE OF BONE", "PAGETOID AMYOTROPHIC LATERAL SCLEROSIS", "PAGETOID NEUROSKELETAL SYNDROME", "LOWER MOTOR NEURON DEGENERATION WITH PAGET-LIKE BONE DISEASE"], "genereviews": ["NBK1476"]} |
A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-73 (EIEE73) is caused by heterozygous mutation in the RNF13 gene (609247) on chromosome 3q25.
For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see 308350.
Clinical Features
Edvardson et al. (2019) reported 3 unrelated children with a severe neurodevelopmental and neurodegenerative disorder. Abnormally high alpha-fetoprotein (AFP) in maternal blood was noted in the only pregnancy tested (patient 1). The patients had a small head circumference at birth (-2 to -3) and showed feeding difficulties, restlessness, and abnormally increased muscle tone. They developed refractory tonic, clonic, and myoclonic seizures between 7 weeks and 7 months of age. EEG showed slowing of background activity, with interictal nonsynchronous spikes and sharp waves, as well as focal ictal discharges. All affected individuals had cortical visual impairment with roving eye movements and a pupillary response to light, but failure to fixate or track. A discrepancy in the article regarding hearing loss in the patients was clarified by one of the authors (Moldovan, 2019): 2 patients had profound sensorineural deafness and 1 had mild hearing impairment. None of the patients achieved any developmental milestones; they had no voluntary movements or communication and were tube fed. They had failure to thrive, increased muscle tone, limb contractures, and scoliosis. Head circumference ranged from -5.5 to -2 SD. Dysmorphic features included midface hypoplasia, narrow forehead, short nose, small chin, and narrow nasal bridge. One patient had cataracts, 2 had inguinal hernia, and 1 had hip dysplasia with delayed bone age. Brain imaging performed in 2 patients showed thin corpus callosum; 1 had delayed myelination. One patient died at 33 months, whereas the other 2 were alive at 21 months and 8 years.
Molecular Genetics
In 3 unrelated patients with EIEE73, Edvardson et al. (2019) identified de novo heterozygous missense mutations in the RNF13 gene (L311S, 609247.0001 and L312P, 609247.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not found in the gnomAD database. Both mutations occurred in a highly conserved region important for posttranslational modification. In vitro functional expression studies of cells derived from the patient with the L311S mutation showed enhanced signaling of endoplasmic reticulum (ER) stress and increased ER stress-induced apoptosis compared to controls, consistent with a gain-of-function effect.
INHERITANCE \- Autosomal dominant GROWTH Other \- Failure to thrive HEAD & NECK Head \- Microcephaly (-2 to -5.5 SD) Face \- Narrow forehead \- Midface hypoplasia \- Small chin Ears \- Sensorineural deafness Eyes \- Cortical visual impairment \- No tracking \- No fixation \- Cataract Nose \- Short nose \- Narrow nasal bridge ABDOMEN Gastrointestinal \- Tube feeding SKELETAL \- Contractures \- Delayed bone age Spine \- Scoliosis Limbs \- Hip dysplasia MUSCLE, SOFT TISSUES \- Hypotonia \- Hypertonia \- Inguinal hernia NEUROLOGIC Central Nervous System \- Epileptic encephalopathy \- Lack of development \- Inability to hold head \- Lack of spontaneous movement \- Restlessness \- Background slowing seen on EEG \- Spike wave discharges \- Focal discharges \- Thin corpus callosum \- Delayed myelination LABORATORY ABNORMALITIES \- Increased alpha-fetoprotein in maternal serum (1 patient) MISCELLANEOUS \- Onset at birth \- Three unrelated patients have been reported (last curated April 2019) \- De novo mutation MOLECULAR BASIS \- Caused by mutation in the ring finger protein 13 gene (RNF13, 609247.0001 ) ▲ Close
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*[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
| EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 73 | None | 1,346 | omim | https://www.omim.org/entry/618379 | 2019-09-22T15:42:13 | {"omim": ["618379"]} |
Chorea-acanthocytosis (ChAc) is a form of neuroacanthocytosis (see this term) and is characterized clinically by a Huntington disease-like phenotype with progressive neurological symptoms including movement disorders, psychiatric manifestations and cognitive disturbances.
## Epidemiology
Prevalence and incidence are not known, but it is estimated that there are around 1,000 cases worldwide. ChAc appears to be more prevalent in Japan, possibly due to a founder effect, and clusters have been found elsewhere in geographically isolated communities (e.g. French-Canadian population).
## Clinical description
Onset is in early adulthood and the initial presentation is often subtle cognitive or psychiatric symptoms. However, patients may have developed related psychiatric disorders several years before neurological manifestations. In at least 1/3 of patients, seizures, typically generalized, are the first manifestation. In some cases, seizures may precede the appearance of movement disorders by as much as a decade. During the course, most patients develop a characteristic phenotype including chorea, a very peculiar ''feeding dystonia'' with tongue protrusion, orofacial dyskinesias, limb dystonia, involuntary vocalizations, dysarthria and involuntary tongue- and lip-biting. Gait may have a ''rubber man'' appearance with truncal instability and sudden, violent trunk spasms. Most patients develop generalized chorea and some degree of parkinsonism. Impairment of memory and executive functions is frequent. Psychiatric manifestations are common and may present as schizophrenia-like psychosis or obsessive compulsive disorder (OCD). Myopathy and axonal neuropathy are usually mild. Clinical neuromuscular manifestations include areflexia, sensorimotor neuropathy, and variable weakness and atrophy. ChAc usually progresses slowly over 15-30 years, but sudden death, presumably caused by seizures or autonomic involvement, may occur.
## Etiology
ChAc is caused by various mutations in the VPS13A gene (9q21), coding for chorein. No obvious genotype-phenotype correlations have been observed.
## Diagnostic methods
Diagnosis may be challenging. Presence of self-mutilating lip and tongue biting, or other self-mutilation is strongly suggestive of ChAc. Determination of acanthocytosis in peripheral blood smears may be negative and does not rule out the disorder. Serum CK is mostly elevated. Patients have absent chorein expression in erythrocytes on Western blot. Confirmatory DNA analysis of the VPS13A gene is difficult due to its size and heterogeneity of mutation sites. Electroneurography may demonstrate sensorimotor axonal neuropathy while electromyography shows neurogenic as well as myopathic changes. Electroencephalographic findings are not specific. Neuroradiologically, there is progressive striatal atrophy affecting especially the head of the caudate nucleus as well as impaired striatal glucose metabolism similar to that seen in HD.
## Differential diagnosis
The differential diagnoses depend on the presenting symptoms and include McLeod neuroacanthocytosis syndrome, Huntington's disease, Huntington-like disorders, juvenile Parkinson's disease and Tourette's syndrome (see these terms).
## Antenatal diagnosis
Routine methods for prenatal testing can be applied.
## Genetic counseling
ChAc is an autosomal recessive disorder and genetic counseling is recommended. The risk of a sibling developing ChAc are 1:4. If the causative genetic defect is known, presymptomatic diagnosis in siblings at disease risk may be offered.
## Management and treatment
No curative or disease-modifying treatments are currently available and management is purely symptomatic.
## Prognosis
The course is usually relentlessly progressive and overall prognosis is poor. Sudden death may be due to seizures, or possibly autonomic dysfunction. There may be gradual generalized weakness with fatal aspiration pneumonia or systemic infections.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Choreoacanthocytosis | c0393576 | 1,347 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2388 | 2021-01-23T18:12:28 | {"gard": ["3956"], "mesh": ["D054546"], "omim": ["200150"], "umls": ["C0393576"], "icd-10": ["E78.6"], "synonyms": ["ChAc", "Chorea-acanthocytosis", "Levine-Critchley syndrome"]} |
Muckle-Wells syndrome is an autoinflammatory disease, and the intermediate form of cryopyrin-associated periodic syndrome (CAPS). Signs and symptoms may include recurrent episodes of fever, skin rash, joint pain, abdominal pain, and pinkeye; progressive sensorineural deafness; and amyloidosis. It is caused by mutations in the NLRP3 gene and is inherited in an autosomal dominant manner. Treatment includes medications such as canakinumab and rilonacept.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Muckle-Wells syndrome | c0268390 | 1,348 | gard | https://rarediseases.info.nih.gov/diseases/8472/muckle-wells-syndrome | 2021-01-18T17:58:57 | {"mesh": ["D056587"], "omim": ["191900"], "umls": ["C0268390"], "orphanet": ["575"], "synonyms": ["Urticaria, deafness and amyloidosis", "Urticaria-deafness-amyloidosis syndrome", "UDA syndrome", "Muckle Wells syndrome"]} |
Rectal pain
SpecialtyGeneral surgery
Rectal pain is the symptom of pain in the area of the rectum. A number of different causes (68) have been documented.[1]
## Contents
* 1 Differential diagnosis
* 1.1 Anal fissures
* 1.2 LAS and proctalgia fugax
* 1.3 Anorectal abscess
* 1.4 Infections
* 1.5 Other
* 2 References
* 3 External links
## Differential diagnosis[edit]
### Anal fissures[edit]
One of the most common causes of rectal pain is an anal fissure.[2] It involves a tear in the anal canal probably due to trauma from defecation[3] and are usually treated effectively with sitz baths, stool softeners, and analgesics.[2]
### LAS and proctalgia fugax[edit]
Two more highly common causes of functional anorectal pain are levator ani syndrome (LAS) and proctalgia fugax. Both of these conditions are thought to be caused by muscle spasms of the either the levator ani muscle or the anal sphincter muscle respectively, and may overlap symptomatically with a third less-common condition called coccygodynia which is the result of previous trauma to the coccyx bone. Stress, prolonged sitting, and constipation all seem to be associated with LAS. The majority (90%) of those reporting chronic episodes of such pain are women. Some researchers group these conditions under the medical category of "tension myalgia of the pelvic floor". Less than a third of those experiencing these conditions seek medical treatment for them. Treatment can involve the use of antispasmodic medications as well as the down-training (conscious involvement and relaxation of previously unconscious muscle movements) so that spasms occur less frequently or not at all.[4]
### Anorectal abscess[edit]
An anorectal abscess is an infection that forms a pocket of pus within the tissues around the anus. It is treated surgically by incision and drainage.[2]
### Infections[edit]
Bacterial, viral, and protozoal infections may occur in the area surround the rectum. These may be the result of a sexually transmitted disease.[2]
### Other[edit]
Hemorrhoids or rectal foreign body.[1]
## References[edit]
1. ^ a b "Differential Diagnosis for Rectal pain Rectalgia". Archived from the original on 2009-12-13.
2. ^ a b c d Janicke DM, Pundt MR (November 1996). "Anorectal disorders". Emerg. Med. Clin. North Am. 14 (4): 757–88. doi:10.1016/S0733-8627(05)70278-9. PMID 8921768.
3. ^ Metcalf A (November 1995). "Anorectal disorders. Five common causes of pain, itching, and bleeding". Postgrad Med. 98 (5): 81–4, 87–9, 92–4. doi:10.1080/00325481.1995.11946071. PMID 7479460.
4. ^ Giulio Aniello Santoro; Andrzej Paweł Wieczorek; Clive I. Bartram (27 October 2010). Pelvic Floor Disorders: Imaging and Multidisciplinary Approach to Management. Springer. pp. 601–603. ISBN 978-88-470-1542-5.
## External links[edit]
Classification
D
* ICD-9-CM: 569.42
* v
* t
* e
Pain
By region/system
Head and neck
* Headache
* Neck
* Odynophagia (swallowing)
* Toothache
Respiratory system
* Sore throat
* Pleurodynia
Musculoskeletal
* Arthralgia (joint)
* Bone pain
* Myalgia (muscle)
* Acute
* Delayed-onset
Neurologic
* Neuralgia
* Pain asymbolia
* Pain disorder
* Paroxysmal extreme pain disorder
* Allodynia
* Chronic pain
* Hyperalgesia
* Hypoalgesia
* Hyperpathia
* Phantom pain
* Referred pain
* Congenital insensitivity to pain
* congenital insensitivity to pain with anhidrosis
* congenital insensitivity to pain with partial anhidrosis
Other
* Pelvic pain
* Proctalgia
* Back
* Low back pain
Measurement and testing
* Pain scale
* Cold pressor test
* Dolorimeter
* Grimace scale (animals)
* Hot plate test
* Tail flick test
* Visual analogue scale
Pathophysiology
* Nociception
* Anterolateral system
* Posteromarginal nucleus
* Substance P
Management
* Analgesia
* Anesthesia
* Cordotomy
* Pain eradication
Related concepts
* Pain threshold
* Pain tolerance
* Suffering
* SOCRATES
* Philosophy of pain
* Cancer pain
* Drug-seeking behavior
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*[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
| Rectal pain | c0034886 | 1,349 | wikipedia | https://en.wikipedia.org/wiki/Rectal_pain | 2021-01-18T19:00:15 | {"umls": ["C0034886"], "wikidata": ["Q7303135"]} |
Trauma in children
Other namesPediatric trauma
A gunshot wound to the left thigh showing entry and exit wound of a 3 year old girl.
SpecialtyEmergency medicine
Trauma in children, also known as pediatric trauma, refers to a traumatic injury that happens to an infant, child or adolescent. Because of anatomical and physiological differences between children and adults the care and management of this population differs.
## Contents
* 1 Anatomic and physiologic differences
* 2 Diagnosis
* 2.1 Pediatric Trauma Score
* 3 Management
* 4 Epidemiology
* 5 See also
* 6 References
* 7 Further reading
* 8 External links
## Anatomic and physiologic differences[edit]
There are significant anatomical and physiological differences between children and adults. For example, the internal organs are closer in proximity to each other in children than in adults; this places children at higher risk of traumatic injury.[1]
Children present a unique challenge in trauma care because they are so different from adults - anatomically, developmentally, physiologically and emotionally. A 2006 study concluded that the risk of death for injured children is lower when care is provided in pediatric trauma centers rather than in non-pediatric trauma centers. Yet about 10% of injured children are treated at pediatric trauma centers. The highest mortality rates occur in children who are treated in rural areas without access trauma centers.[2]
An important part of managing trauma in children is weight estimation. A number of methods to estimate weight exist, including the Broselow tape, Leffler formula, and Theron formula.[3] Of these three methods, the Broselow tape is the most accurate for weight estimation in children ≤25 kg,[3] while the Theron formula performs better with patients weighing >40 kg.[3]
Due to basic geometry, a child's weight to surface area ratio is lower than an adult's, children more readily lose their body heat through radiation and have a higher risk of becoming hypothermic.[4][5] Smaller body size in children often makes them more prone to poly traumatic injury.[6]
## Diagnosis[edit]
### Pediatric Trauma Score[edit]
Several classification systems have been developed that use some combination of subjective and objective data in an effort to quantify the severity of trauma. Examples include the Injury Severity Score[7][8] and a modified version of the Glasgow Coma Scale.[9] More complex classification systems, such as the Revised Trauma Score, APACHE II,[10] and SAPS II[11] add physiologic data to the equation in an attempt to more precisely define the severity, which can be useful in triaging casualties as well as in determining medical management and predicting prognosis.
Though useful, all of these measures have significant limitations when applied to pediatric patients. For this reason, health care providers often employ classification systems that have been modified or even specifically developed for use in the pediatric population. For example, the Pediatric Glasgow Coma Scale is a modification of the Glasgow Coma Scale that is useful in patients who have not yet developed language skills.[12]
Emphasizing the importance of body weight and airway diameter, the Pediatric Trauma Score (PTS) was developed to specifically reflect the vulnerability of children to traumatic injury. The minimal score is -6 and the maximum score is +12. There is a linear relationship between the decrease in PTS and the mortality risk (i.e. the lower the PTS, the higher the mortality risk).[12] Mortality is estimated at 9% with a PTS > 8, and at 100% with a PTS ≤ 0.[citation needed]
In most cases the severity of a pediatric trauma injury is determined by the pediatric trauma score[4] despite the fact that some research has shown there is no benefit between it and the revised trauma scale.[13]
## Management[edit]
The management of pediatric trauma depends on a knowledge of the physiological, anatomical, and developmental differences in comparison to an adult patient, this requires expertise in this area.[14] In the pre-hospital setting issues may arise with the treatment of pediatric patients due to a lack of knowledge and resources involved in the treatment of these injuries.[15] Despite the fact there is only a slight variation in outcomes in adult trauma centers, definitive care is best reached at a pediatric trauma center.[16][17]
## Epidemiology[edit]
Most common causes of pediatric trauma
Based on the Centers for Disease Control and Prevention's (CDC) WISQARS database for the latest year of data (2010), serious injury kills nearly 10,000 children in America each year.[18]
Pediatric trauma accounted for 59.5% of all mortality for children under 18 in 2004.[1][19] Injury is the leading cause of death in this age group in the United States—greater than all other causes combined.[20] It is also the leading cause of permanent paralysis for children.[21][22] In the US approximately 16,000,000 children go to a hospital emergency room due to some kind of injury every year.[4] Male children are more frequently injured than female children by a ratio of two to one.[4] Some injuries, including chemical eye burns, are more common among young children than among their adult counterparts; these are largely due to cleaning supplies and similar chemicals commonly found around the home.[23] Similarly, penetrating injuries in children is because of writing utensils and other common household objects as many are readily available to children in the course of their day.[24]
## See also[edit]
* Blunt trauma
* Blast injury
* Geriatric trauma
* Penetrating trauma
* Pediatric Advanced Life Support
## References[edit]
1. ^ a b Dickinson E, Limmer D, O'Keefe MF, Grant HD, Murray R (2008). Emergency Care (11th ed.). Englewood Cliffs, New Jersey: Prentice Hall. pp. 848–52. ISBN 978-0-13-500524-8.
2. ^ Petrosyan, Mikael; Guner, Yigit S. MD; Emami, Claudia N. MD; Ford, Henri R. MD (August 2009). "Disparities in the Delivery of Pediatric Trauma Care". The Journal of Trauma. 67 (2 Supplement (Injury, Infection, and Critical Care Issue)): S114–S119. doi:10.1097/TA.0b013e3181ad3251. PMID 19667843.
3. ^ a b c So TY, Farrington E, Absher RK (2009). "Evaluation of the accuracy of different methods used to estimate weights in the pediatric population". Pediatrics. 123 (6): e1045–51. doi:10.1542/peds.2008-1968. PMID 19482737. S2CID 6009482. Retrieved 2010-11-07.
4. ^ a b c d Peitzman AB, Rhodes M, Schwab CW, Yealy DM, Fabian TC, eds. (2008). "Pediatric Trauma". The Trauma Manual (3rd ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 499–514. ISBN 978-0-7817-6275-5.
5. ^ "Pediatric Trauma And Triage: Overview of the Problem and Necessary Care for Positive Outcomes" (powerpoint). Jim Morehead. Retrieved 2010-11-06.
6. ^ Ron Walls MD; John J. Ratey MD; Robert I. Simon MD (2009). Rosen's Emergency Medicine: Expert Consult Premium Edition - Enhanced Online Features and Print (Rosen's Emergency Medicine: Concepts & Clinical Practice (2v.)). St. Louis: Mosby. pp. 262–80. ISBN 978-0-323-05472-0.
7. ^ Baker SP, O'Neill B, Haddon W Jr, Long WB (1974). "The Injury Severity Score: a method for describing patients with multiple injuries and evaluating emergency care". The Journal of Trauma. 14 (3): 187–96. doi:10.1097/00005373-197403000-00001. PMID 4814394.
8. ^ Copes WS, Champion HR, Sacco WJ, Lawnick MM, Keast SL, Bain LW (1988). "The Injury Severity Score revisited". The Journal of Trauma. 28 (1): 69–77. doi:10.1097/00005373-198801000-00010. PMID 3123707.
9. ^ Teasdale G, Jennett B (1974). "Assessment of coma and impaired consciousness. A practical scale". The Lancet. 2 (7872): 81–4. doi:10.1016/S0140-6736(74)91639-0. PMID 4136544.
10. ^ Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985). "APACHE II: a severity of disease classification system". Critical Care Medicine. 13 (10): 818–29. doi:10.1097/00003246-198510000-00009. PMID 3928249.
11. ^ Le Gall JR, Lemeshow S, Saulnier F (1993). "A New Simplified Acute Physiology Score (SAPS II) Based on a European/North American Multicenter Study". Journal of the American Medical Association. 270 (24): 2957–63. doi:10.1001/jama.1993.03510240069035. PMID 8254858.
12. ^ a b Campbell, John Creighton (2000). Basic trauma life support for paramedics and other advanced providers. Upper Saddle River, N.J: Brady/Prentice Hall Health. ISBN 978-0-13-084584-9.
13. ^ Kaufmann CR, Maier RV, Rivara FP, Carrico CJ (January 1990). "Evaluation of the Pediatric Trauma Score". JAMA. 263 (1): 69–72. doi:10.1001/jama.263.1.69. PMID 2293691.
14. ^ Little, Wendalyn K. (1 March 2010). "Golden Hour or Golden Opportunity: Early Management of Pediatric Trauma". Clinical Pediatric Emergency Medicine. 11 (1): 4–9. doi:10.1016/j.cpem.2009.12.005.
15. ^ Lohr, Kathleen N.; Durch, Jane (1993). Emergency medical services for children: Committee on Pediatric Emergency Medical Services. Washington, D.C: National Academy Press. ISBN 978-0-309-04888-0.
16. ^ Densmore JC, Lim HJ, Oldham KT, Guice KS (January 2006). "Outcomes and delivery of care in pediatric injury". J. Pediatr. Surg. 41 (1): 92–8, discussion 92–8. doi:10.1016/j.jpedsurg.2005.10.013. PMID 16410115.
17. ^ Deasy C, Gabbe B, Palmer C, et al. (October 2011). "Paediatric and adolescent trauma care within an integrated trauma system". Injury. 43 (12): 2006–2011. doi:10.1016/j.injury.2011.08.032. PMID 21978766.
18. ^ "CDC statistics".
19. ^ Krug SE, Tuggle DW (2008). "Management of pediatric trauma" (PDF). Pediatrics. 121 (4): 849–54. doi:10.1542/peds.2008-0094. PMID 18381551. S2CID 28319980. Retrieved 2010-11-06.
20. ^ "Childress Institute for Pediatric Trauma". Retrieved 2010-11-06.
21. ^ Aghababian, Richard (2010). Essentials of Emergency Medicine. Jones & Bartlett Learning. pp. 992–1000. ISBN 978-0-7637-6652-8.
22. ^ Moore, Ernest J; Feliciano, David V.; Mattox, Kenneth L. (2008). Trauma. McGraw-Hill Medical. pp. 993–1000. ISBN 978-0-07-146912-8.
23. ^ Haring RS, Sheffield ID, Channa R, Canner JK, Schneider EB (August 2016). "Epidemiologic trends of chemical ocular burns in the United States". JAMA Ophthalmology. 134 (10): 1119–1124. doi:10.1001/jamaophthalmol.2016.2645. PMID 27490908.
24. ^ Fisher, S. B.; Clifton, M. S.; Bhatia, A. M. (September 2011). "Pencils and pens: An under-recognized source of penetrating injuries in children". The American Surgeon. 77 (8): 1076–1080. doi:10.1177/000313481107700831. PMID 21944527. S2CID 24546416.
## Further reading[edit]
* "Full-body Radiographic Imaging of the Injured Child". ajol.info.
* "Pediatric Trauma at an Adult Trauma Center" (PDF). nmanet.org.
* Søreide, Kjetil; Krüger, Andreas J.; Ellingsen, Christian L.; Tjosevik, Kjell E. (2009). "Pediatric trauma deaths are predominated by severe head injuries during spring and summer". Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine. 17: 3. doi:10.1186/1757-7241-17-3. PMC 2637226. PMID 19161621.
* "Considerations in Pediatric Trauma: eMedicine Trauma". 2019-02-02. Cite journal requires `|journal=` (help)
* Mayer T, Walker ML, Johnson DG, Matlak ME (February 1981). "Causes of morbidity and mortality in severe pediatric trauma". JAMA. 245 (7): 719–21. doi:10.1001/jama.245.7.719. PMID 7463661.
* Wesson, David E. (2005). Pediatric Trauma: Pathophysiology, Diagnosis, and Treatment. Informa Healthcare. ISBN 978-0-8247-4117-4.
* Strange, Gary R. (2002). Pediatric emergency medicine: a comprehensive study guide. New York: McGraw-Hill, Medical Publishing Division. ISBN 978-0-07-136979-4.
* Anas, Nick G; Perkin, Ronald M; Swift, James D.; Newton, Dale (2008). Pediatric hospital medicine: textbook of inpatient management. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. ISBN 978-0-7817-7032-3.
## External links[edit]
* American Academy of Pediatrics
Classification
D
External resources
* eMedicine: search/pediatric+trauma
* v
* t
* e
Trauma
Principles
* Polytrauma
* Major trauma
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Clinical prediction rules
* Revised Trauma Score
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Investigations
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Pathophysiology
Injury
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* Blast injury
* Blunt trauma
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Region
* Abdominal trauma
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Demographic
* Geriatric trauma
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Complications
* Posttraumatic stress disorder
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* Rhabdomyolysis
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* 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
| Trauma in children | None | 1,350 | wikipedia | https://en.wikipedia.org/wiki/Trauma_in_children | 2021-01-18T18:55:37 | {"wikidata": ["Q7159235"]} |
This article includes a list of general references, but it remains largely unverified because it lacks sufficient corresponding inline citations. Please help to improve this article by introducing more precise citations. (November 2013) (Learn how and when to remove this template message)
Cuterebriasis is a parasitic disease affecting rodents, lagomorphs (hares, rabbits, pikas), felines, and canines. The etiologic agent is the larval development of botflies within the Cuterebra or Trypoderma genera, which occurs obligatorily in rodents and lagomorphs, respectively. Felines and canines serve as accidental hosts, but research suggests only by Trypoderma spp. Entrance into the body by first-instar larvae occurs via mucous membranes of natural orifices or open wounds as opposed to direct dermic penetration.
## Contents
* 1 Clinical signs
* 2 Diagnosis
* 3 Treatment
* 4 References
* 5 Further reading
## Clinical signs[edit]
In rabbits, hares, and lagomorphs, clinical signs usually do not appear.[1] Subcutaneous cysts, warbles, may present upon larval deposition out of the body at maturation. Three forms in which cuterebriasis may present in canines and felines:[1]
* Myasis involves subcutaneous cyst formation due to third larval-instar maturation, occurring about 30 days after entry into the body.[1] Cysts are often found on the face, neck, and trunk, but location varies with larval migration within the host. Serous discharge may be observed from these cysts, which are typically 3-5 mm in diameter and include a central pore through which the larvae respire. This pore also serves as a means of exit for the larvae, which occurs between 3 and 8 weeks after entry.[2]
* Cerebrospinal cuterebriasis results from larval migration to the brain. This is seen in cats, and is the proposed cause for feline ischemic encephalopathy and a suggestive causative agent of feline idiopathic vestibular disease.[2] Symptoms of this type of presentation include lethargy, seizures, blindness, abnormal vocalization or gait, circling, and abnormal or no reflex responses.[2] When affecting the central nervous system, cats are known to exhibit violent sneezing attacks that can begin weeks prior to manifestation of other clinical signs.[3]
* Respiratory disease results when larval migration occurs through the trachea, pharynx, diaphragm, or lungs. Cuterebriasis has been increasingly noted as a cause for dyspnea in felines.
## Diagnosis[edit]
Definitive diagnosis can only occur with positive identification of the larvae. This involves radiologic imaging (preferably MRI, which can reveal larval migration tracks and in some cases the larvae themselves), as well as surgical exploration during which larvae can be removed and examined for identification.[1] Identification of exact species is often impossible, as the instars of the various Cuterebra and Trychoderma spp. exhibit significant resemblance, but identification as a Cuterebra botfly is sufficient for diagnosis as cuterebriasis. Typically, a third larval-instar is found and identifiable by its dark, thick, heavily spined body.[3]
## Treatment[edit]
Subcutaneous cysts may be surgically opened to remove less-mature bots. If matured, cysts may be opened and Cuterebra may be removed using mosquito forceps. Covering the pore in petroleum jelly may aide in removal.[3] If larvae are discovered within body tissues, rather than subcutaneously, surgical removal is the only means of treatment. Ivermectin may be administered with corticosteroids to halt larval migration in cats presenting with respiratory cuterebriasis,[1] but this is not approved for use in cats.[3] A cure for cerebrospinal cuterebriasis has not been reported.
## References[edit]
1. ^ a b c d e "Cuterebriasis". Companion Animal Parasite Council. June 2012.
2. ^ a b c James, Fiona M. K.; Poma, Roberto (2010). "Neurological Manifestations of Feline Cuterebriasis". The Canadian Veterinary Journal. 51 (2): 213–15. PMC 2808293. PMID 20436872., p. 213.
3. ^ a b c d Moriello, Karen A. (2013). "Cuterebra Infestation in Small Animals". The Merck Veterinary Manual.
## Further reading[edit]
* Bordelon, Jude T.; Newcomb, Brent T.; Rochat, Mark C. (2009). "Surgical Removal of a Cuterebra Larva From the Cervical Trachea of a Cat". Journal of the American Animal Hospital Association. 45 (1): 52–54. doi:10.5326/0450052.
*[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
| Cuterebriasis | None | 1,351 | wikipedia | https://en.wikipedia.org/wiki/Cuterebriasis | 2021-01-18T19:04:44 | {"wikidata": ["Q4249499"]} |
Ectopia lentis
Ectopia Lentis in Marfan syndrome. Zonular fibers are being seen.
SpecialtyMedical genetics
Anterior lens luxation in a dog
Anterior lens luxation with cataract formation in a cat
Ectopia lentis is a displacement or malposition of the eye's crystalline lens from its normal location. A partial dislocation of a lens is termed lens subluxation or subluxated lens; a complete dislocation of a lens is termed lens luxation or luxated lens.
## Contents
* 1 Ectopia lentis in dogs and cats
* 1.1 Anterior lens luxation
* 1.2 Posterior lens luxation
* 1.3 Lens subluxation
* 1.4 Breed predisposition
* 2 Systemic associations in humans
* 3 See also
* 4 References
* 5 External links
## Ectopia lentis in dogs and cats[edit]
Although observed in humans and cats, ectopia lentis is most commonly seen in dogs. Ciliary zonules normally hold the lens in place. Abnormal development of these zonules can lead to primary ectopia lentis, usually a bilateral condition. Luxation can also be a secondary condition, caused by trauma, cataract formation (decrease in lens diameter may stretch and break the zonules), or glaucoma (enlargement of the globe stretches the zonules). Steroid administration weakens the zonules and can lead to luxation, as well. Lens luxation in cats can occur secondary to anterior uveitis (inflammation of the inside of the eye).
### Anterior lens luxation[edit]
With anterior lens luxation, the lens pushes into the iris or actually enters the anterior chamber of the eye. This can cause glaucoma, uveitis, or damage to the cornea. Uveitis (inflammation of the eye) causes the pupil to constrict (miosis) and trap the lens in the anterior chamber, leading to an obstruction of outflow of aqueous humour and subsequent increase in ocular pressure (glaucoma).[1] Better prognosis is valued in lens replacement surgery (retained vision and normal intraocular pressure) when it is performed before the onset of secondary glaucoma.[2] Glaucoma secondary to anterior lens luxation is less common in cats than dogs due to their naturally deeper anterior chamber and the liquification of the vitreous humour secondary to chronic inflammation.[3] Anterior lens luxation is considered to be an ophthalmological emergency.
### Posterior lens luxation[edit]
With posterior lens luxation, the lens falls back into the vitreous humour and lies on the floor of the eye. This type causes fewer problems than anterior lens luxation, although glaucoma or ocular inflammation may occur. Surgery is used to treat dogs with significant symptoms. Removal of the lens before it moves to the anterior chamber may prevent secondary glaucoma.[2]
### Lens subluxation[edit]
Lens subluxation is also seen in dogs and is characterized by a partial displacement of the lens. It can be recognized by trembling of the iris (iridodonesis) or lens (phacodonesis) and the presence of an aphakic crescent (an area of the pupil where the lens is absent).[4] Other signs of lens subluxation include mild conjunctival redness, vitreous humour degeneration, prolapse of the vitreous into the anterior chamber, and an increase or decrease of anterior chamber depth.[5] Removal of the lens before it completely luxates into the anterior chamber may prevent secondary glaucoma.[2] Extreme degree of luxation of lens is called "lenticele" in which lens comes out of the eyeball and becomes trapped under the Tenon's capsule or conjunctiva.[6] A nonsurgical alternative treatment involves the use of a miotic to constrict the pupil and prevent the lens from luxating into the anterior chamber.[7]
### Breed predisposition[edit]
Terrier breeds are predisposed to lens luxation, and it is probably inherited in the Sealyham Terrier, Jack Russell Terrier, Wirehaired Fox Terrier, Rat Terrier, Teddy Roosevelt Terrier, Tibetan Terrier,[8] Miniature Bull Terrier, Shar Pei, and Border Collie.[9] The mode of inheritance in the Tibetan Terrier[5] and Shar Pei[10] is likely autosomal recessive. Labrador Retrievers and Australian Cattle Dogs are also predisposed.[11]
## Systemic associations in humans[edit]
In humans, a number of systemic conditions are associated with ectopia lentis:[12]
More common:
* Marfan syndrome (upward and outward)[13]
* Homocystinuria (downward and inwards)[13]
* Weill–Marchesani syndrome
* Sulfite oxidase deficiency
* Molybdenum cofactor deficiency
* Hyperlysinemia
Less common:
* Ehlers–Danlos syndrome
* Crouzon disease
* Refsum syndrome
* Kniest syndrome
* Mandibulofacial dysostosis
* Sturge–Weber syndrome
* Conradi syndrome
* Pfaundler syndrome
* Pierre Robin syndrome
* Wildervanck syndrome
* Sprengel deformity
## See also[edit]
* List of systemic diseases with ocular manifestations
## References[edit]
1. ^ Ketring, Kerry I. (2006). "Emergency Treatment for Anterior Lens Luxation" (PDF). Proceedings of the North American Veterinary Conference. Archived from the original (PDF) on 2007-09-29. Retrieved 2007-02-22.
2. ^ a b c Glover T, Davidson M, Nasisse M, Olivero D (1995). "The intracapsular extraction of displaced lenses in dogs: a retrospective study of 57 cases (1984-1990)". Journal of the American Animal Hospital Association. 31 (1): 77–81. PMID 7820769.
3. ^ Peiffer, Robert L., Jr. (2004). "Diseases of the Lens in Dogs and Cats". Proceedings of the 29th World Congress of the World Small Animal Veterinary Association. Retrieved 2007-02-22.
4. ^ "Lens". The Merck Veterinary Manual. 2006. Retrieved 2007-02-22.
5. ^ a b Grahn B, Storey E, Cullen C (2003). "Diagnostic ophthalmology. Congenital lens luxation and secondary glaucoma". Canadian Veterinary Journal. 44 (5): 427, 429–30. PMC 340155. PMID 12757137.
6. ^ Shah SIA et al: Concise Ophthalmology Text & Atals. 5th ed. Param B (Pvt.) Ltd. 2018: 60-61
7. ^ Binder DR, Herring IP, Gerhard T (2007). "Outcomes of nonsurgical management and efficacy of demecarium bromide treatment for primary lens instability in dogs: 34 cases (1990-2004)". Journal of the American Veterinary Medical Association. 231 (1): 89–93. doi:10.2460/javma.231.1.89. PMID 17605669.
8. ^ Gelatt, Kirk N., ed. (1999). Veterinary Ophthalmology (3rd ed.). Lippincott, Williams & Wilkins. ISBN 0-683-30076-8.
9. ^ Petersen-Jones, Simon M. (2003). "Conditions of the Lens". Proceedings of the 28th World Congress of the World Small Animal Veterinary Association. Retrieved 2007-02-22.
10. ^ Lazarus J, Pickett J, Champagne E (1998). "Primary lens luxation in the Chinese Shar Pei: clinical and hereditary characteristics". Veterinary Ophthalmology. 1 (2–3): 101–107. doi:10.1046/j.1463-5224.1998.00021.x. PMID 11397217.
11. ^ Johnsen D, Maggs D, Kass P (2006). "Evaluation of risk factors for development of secondary glaucoma in dogs: 156 cases (1999-2004)". Journal of the American Veterinary Medical Association. 229 (8): 1270–4. doi:10.2460/javma.229.8.1270. PMID 17042730.
12. ^ Eifrig CW, Eifrig DE. "Ectopia Lentis". eMedicine.com. November 24, 2004.
13. ^ a b Peter Nicholas Robinson; Maurice Godfrey (2004). Marfan syndrome: a primer for clinicians and scientists. Springer. pp. 5–. ISBN 978-0-306-48238-0. Retrieved 12 April 2010.
## External links[edit]
Classification
D
* ICD-10: H27.1, Q12.1
* ICD-9-CM: 743.37
* OMIM: 225100
* MeSH: D004479
* DiseasesDB: 29374
External resources
* eMedicine: oph/55
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* Uveitis
* Intermediate uveitis
* Hyphema
* Rubeosis iridis
* Persistent pupillary membrane
* Iridodialysis
* Synechia
Choroid
* Choroideremia
* Choroiditis
* Chorioretinitis
Lens
* Cataract
* Congenital cataract
* Childhood cataract
* Aphakia
* Ectopia lentis
Retina
* Retinitis
* Chorioretinitis
* Cytomegalovirus retinitis
* Retinal detachment
* Retinoschisis
* Ocular ischemic syndrome / Central retinal vein occlusion
* Central retinal artery occlusion
* Branch retinal artery occlusion
* Retinopathy
* diabetic
* hypertensive
* Purtscher's
* of prematurity
* Bietti's crystalline dystrophy
* Coats' disease
* Sickle cell
* Macular degeneration
* Retinitis pigmentosa
* Retinal haemorrhage
* Central serous retinopathy
* Macular edema
* Epiretinal membrane (Macular pucker)
* Vitelliform macular dystrophy
* Leber's congenital amaurosis
* Birdshot chorioretinopathy
Other
* Glaucoma / Ocular hypertension / Primary juvenile glaucoma
* Floater
* Leber's hereditary optic neuropathy
* Red eye
* Globe rupture
* Keratomycosis
* Phthisis bulbi
* Persistent fetal vasculature / Persistent hyperplastic primary vitreous
* Persistent tunica vasculosa lentis
* Familial exudative vitreoretinopathy
Pathways
Optic nerve
Optic disc
* Optic neuritis
* optic papillitis
* Papilledema
* Foster Kennedy syndrome
* Optic atrophy
* Optic disc drusen
Optic neuropathy
* Ischemic
* anterior (AION)
* posterior (PION)
* Kjer's
* Leber's hereditary
* Toxic and nutritional
Strabismus
Extraocular muscles
Binocular vision
Accommodation
Paralytic strabismus
* Ophthalmoparesis
* Chronic progressive external ophthalmoplegia
* Kearns–Sayre syndrome
palsies
* Oculomotor (III)
* Fourth-nerve (IV)
* Sixth-nerve (VI)
Other strabismus
* Esotropia / Exotropia
* Hypertropia
* Heterophoria
* Esophoria
* Exophoria
* Cyclotropia
* Brown's syndrome
* Duane syndrome
Other binocular
* Conjugate gaze palsy
* Convergence insufficiency
* Internuclear ophthalmoplegia
* One and a half syndrome
Refraction
* Refractive error
* Hyperopia
* Myopia
* Astigmatism
* Anisometropia / Aniseikonia
* Presbyopia
Vision disorders
Blindness
* Amblyopia
* Leber's congenital amaurosis
* Diplopia
* Scotoma
* Color blindness
* Achromatopsia
* Dichromacy
* Monochromacy
* Nyctalopia
* Oguchi disease
* Blindness / Vision loss / Visual impairment
Anopsia
* Hemianopsia
* binasal
* bitemporal
* homonymous
* Quadrantanopia
subjective
* Asthenopia
* Hemeralopia
* Photophobia
* Scintillating scotoma
Pupil
* Anisocoria
* Argyll Robertson pupil
* Marcus Gunn pupil
* Adie syndrome
* Miosis
* Mydriasis
* Cycloplegia
* Parinaud's syndrome
Other
* Nystagmus
* Childhood blindness
Infections
* Trachoma
* Onchocerciasis
* v
* t
* e
Congenital malformations and deformations of eyes
Adnexa
Eyelid
* Ptosis
* Ectropion
* Entropion
* Distichia
* Blepharophimosis
* Ablepharon
* Marcus Gunn phenomenon
Lacrimal apparatus
* Congenital lacrimal duct obstruction
Globe
Entire eye
* Anophthalmia (Cystic eyeball, Cryptophthalmos)
* Microphthalmia
Lens
* Ectopia lentis
* Aphakia
Iris
* Aniridia
Anterior segment
* Axenfeld–Rieger syndrome
Cornea
* Keratoglobus
* Megalocornea
Other
* Buphthalmos
* Coloboma (Coloboma of optic nerve)
* Hydrophthalmos
* Norrie disease
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Ectopia lentis | c0013581 | 1,352 | wikipedia | https://en.wikipedia.org/wiki/Ectopia_lentis | 2021-01-18T18:52:09 | {"mesh": ["D004479"], "icd-9": ["743.37"], "icd-10": ["H27.1", "Q12.1"], "orphanet": ["1885"], "wikidata": ["Q1827028"]} |
Sternal cleft (SC) is a rare idiopathic congenital thoracic malformation characterized by a sternal fusion defect, that can be complete or partial (either superior or inferior), that is usually asymptomatic in the neonatal period (apart from a paradoxical midline thoracic bulging) but that can lead to dyspnea, cough, frequent respiratory infections and increased risk of trauma-related injury to the heart, lungs and major vessels if left untreated.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Sternal cleft | c2931507 | 1,353 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2017 | 2021-01-23T17:33:08 | {"gard": ["5012"], "mesh": ["C537489"], "umls": ["C0265696", "C2931507"], "icd-10": ["Q76.7"], "synonyms": ["Cleft sternum", "Sternum bifidum"]} |
Dense deposit disease (DDD) is a condition that primarily affects kidney function. Signs and symptoms usually start between the ages of 5 and 15 but may also begin in adulthood. The major features of DDD are due to kidney malfunction, and often include proteinuria; hematuria; reduced amounts of urine; low levels of protein in the blood; and swelling in many areas of the body. About half of affected people develop end-stage renal disease (ESRD) within 10 years after symptoms start. DDD can have genetic or non-genetic causes. It can be caused by mutations in the C3 and CFH genes; it may develop as a result of both genetic risk factors and environmental triggers; or it can result from the presence of autoantibodies that block the activity of proteins needed for the body's immune response. Most cases are sporadic (occurring by chance in people with no history of the disorder in their family).
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Dense deposit disease | c0268743 | 1,354 | gard | https://rarediseases.info.nih.gov/diseases/8555/dense-deposit-disease | 2021-01-18T18:00:56 | {"mesh": ["D015432"], "omim": ["609814"], "orphanet": ["93571"], "synonyms": ["Glomerulonephritis membranoproliferative type 2", "Mesangiocapillary glomerulonephritis type 2", "MPGN 2", "Membranoproliferative glomerulonephritis type II", "DDD", "Membranoproliferative glomerulonephritis type 2"]} |
Hymenolepiasis is a cosmopolitan parasitosis caused by a hymenolepidid tapeworm infection, most commonly Hymenolepis nana, that is reported worldwide but particularly in tropical and subtropical countries and which is usually asymptomatic but in severe cases can also manifest with nausea, abdominal pain, anorexia, diarrhea and overall weakness.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Hymenolepiasis | c0020413 | 1,355 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=401 | 2021-01-23T17:21:24 | {"gard": ["2787"], "mesh": ["D006925"], "umls": ["C0020413"], "icd-10": ["B71.0"]} |
Brachydactyly ('short digits') is a general term that refers to disproportionately short fingers and toes, and forms part of the group of limb malformations characterized by bone dysostosis.
## Epidemiology
The various types of isolated brachydactyly are rare, except for types A3 and D.
## Clinical description
Brachydactyly can occur either as an isolated malformation or as part of a complex malformation syndrome. To date, many different forms of brachydactyly have been identified. Some forms also result in short stature. In isolated brachydactyly, subtle changes elsewhere may be present. Brachydactyly may also be accompanied by other hand malformations, such as syndactyly, polydactyly, reduction defects, or symphalangism.
## Etiology
For the majority of isolated brachydactylies and some syndromic forms of brachydactyly, the causative gene defect has been identified. In isolated brachydactyly, the inheritance is mostly autosomal dominant with variable expressivity and penetrance.
## Diagnostic methods
Diagnosis is clinical, anthropometric and radiological.
## Antenatal diagnosis
Prenatal diagnosis is usually not indicated for isolated forms of brachydactyly, but may be appropriate in syndromic forms. Molecular studies of chorionic villus samples at 11 weeks of gestation and by amniocentesis after the 14th week of gestation can provide antenatal diagnosis if the causative mutation in the family is known.
## Genetic counseling
The nature of genetic counseling depends both on the pattern of inheritance of the type of brachydactyly present in the family and on the presence or absence of accompanying symptoms.
## Management and treatment
There is no specific management or treatment that is applicable to all forms of brachydactyly. Plastic surgery is only indicated if the brachydactyly affects hand function or for cosmetic reasons, but is typically not needed. Physical therapy and ergotherapy may ameliorate hand function.
## Prognosis
Prognosis for the brachydactylies is strongly dependent on the nature of the brachydactyly, and may vary from excellent to severely influencing hand function. If brachydactyly forms part of a syndromic entity, prognosis often depends on the nature of the associated anomalies.
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Dysostosis with brachydactyly | None | 1,356 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=69028 | 2021-01-23T17:41:12 | {"icd-10": ["Q73.8"]} |
Neonatal iodine exposure is a rare endocrine disease characterized by the appearance of transient hypothyroidism, usually in preterm newborns, following long or short-term topical iodine exposure. Parenteral exposure from iodinated contrast agents may similarly alter thyroid funtion in term neonates.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Neonatal iodine exposure | None | 1,357 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=238688 | 2021-01-23T18:18:31 | {"icd-10": ["P72.2"]} |
Mast cell activation syndrome (MCAS), is an immunological condition in which mast cells mistakenly release too many chemical mediators, resulting in several chronic symptoms involving the skin, gastrointestinal tract, heart, respiratory, and neurologic systems. Mast cells are present throughout most of our bodies and secrete different chemicals during allergic reactions. Symptoms include episodes of abdominal pain, cramping, diarrhea, flushing, itching, wheezing, coughing, lightheadedness and potential problems with "brain fog" or other difficulties with memory. The cause of MCAS is unknown. Treatment includes several combinations of medications like anti-histamines and mast cell stabilizers.
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Mast cell activation syndrome | c0024899 | 1,358 | gard | https://rarediseases.info.nih.gov/diseases/12981/mast-cell-activation-syndrome | 2021-01-18T17:59:13 | {"mesh": ["D008415"], "icd-10": ["D89.40 "], "synonyms": ["MCAS"]} |
Heavy metal poisoning refers to when excessive exposure to a heavy metal affects the normal function of the body. Examples of heavy metals that can cause toxicity include lead, mercury, arsenic, cadmium, and chromium. Exposure may occur through the diet, from medications, from the environment, or in the course of work or play. Heavy metals can enter the body through the skin, or by inhalation or ingestion. Toxicity can result from sudden, severe exposure, or from chronic exposure over time. Symptoms can vary depending on the metal involved, the amount absorbed, and the age of the person exposed. For example, young children are more susceptible to the effects of lead exposure because they absorb more compared with adults and their brains are still developing. Nausea, vomiting, diarrhea, and abdominal pain are common symptoms of acute metal ingestion. Chronic exposure may cause various symptoms resulting from damage to body organs, and may increase the risk of cancer. Treatment depends on the circumstances of the exposure.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Heavy metal poisoning | c0274869 | 1,359 | gard | https://rarediseases.info.nih.gov/diseases/6577/heavy-metal-poisoning | 2021-01-18T18:00:08 | {"mesh": ["D000075322"], "umls": ["C0274869"], "synonyms": ["Chronic heavy metal poisoning", "Heavy Metal Toxicity"]} |
A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by the association of short stature and progressive discrete subaortic stenosis. Additional variable manifestations include upturned nose, voice and vocal cord abnormalities, obstructive lung disease, inguinal hernia, kyphoscoliosis and, occasionally, epicanthus, strabismus, microphthalmos and widely spaced teeth. There have been no further descriptions in the literature since 1984.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Subaortic stenosis-short stature syndrome | c0795947 | 1,360 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3191 | 2021-01-23T18:12:40 | {"gard": ["405"], "mesh": ["C537749"], "omim": ["271960"], "umls": ["C0795947"], "synonyms": ["Onat syndrome"]} |
Auricular hypertrichosis
SpecialtyOtology
Auricular hypertrichosis (hypertrichosis lanuginosa acquisita, hypertrichosis pinnae auris) is a genetic condition expressed as long and strong hairs growing from the helix of the pinna.[1][page needed]
## Contents
* 1 Presentation
* 2 Genetics
* 3 See also
* 4 References
## Presentation[edit]
Ear hair generally refers to the terminal hair arising from follicles inside the external auditory meatus in humans.[2] In its broader sense, ear hair may also include the fine vellus hair covering much of the ear, particularly at the prominent parts of the anterior ear, or even the abnormal hair growth as seen in hypertrichosis and hirsutism. Medical research on the function of ear hair is currently very scarce.
Hair growth within the ear canal is often observed to increase in older men,[3] together with increased growth of nose hair.[4] Excessive hair growth within or on the ear is known medically as auricular hypertrichosis.[5] Some men, particularly in the male population of India, have coarse hair growth along the lower portion of the helix, a condition referred to as "having hairy pinnae" (hypertrichosis lanuginosa acquisita).[6]
## Genetics[edit]
There is controversy over whether auricular hypertrichosis is a Y-linked or autosomal trait, or perhaps both (in different families). It was proposed also that this phenotype results from the interaction of two loci, one on the homologous part of the X and Y and one on the nonhomologous sequence of the Y.[7]
Lee et al. (2004), by Y-chromosomal DNA binary-marker haplotyping, suggested that a cohort of southern Indian hairy-eared males carried Y chromosomes from many haplogroups of the Y-phylogeny.[8] According to a hypothesis of Y linkage, it would require multiple independent mutations within a single population. No significant difference between the Y-haplogroup frequencies of hairy-eared males and those of a geographically matched control sample of unaffected males was established. They concluded that the auricular hypertrichosis is not Y-linked in southern India, but it is unlikely to be same in any population.[9]
## See also[edit]
* Ear hair
* Hypertrichosis
## References[edit]
1. ^ Mader, Sylvia S. (2000). Human biology. New York: McGraw-Hill. ISBN 978-0-07-290584-7. OCLC 41049448.
2. ^ W. Steven Pray. "Swimmer's Ear: An Ear Canal Infection". U.S. Pharmacist. Retrieved 31 August 2012.
3. ^ Leyner, Mark; M.D., Billy Goldberg (2005-07-26). Why Do Men Have Nipples?: Hundreds of Questions You'd Only Ask a Doctor After Your Third Martini. Crown Publishing Group. pp. 206–. ISBN 9780307337047. Retrieved 8 September 2014.
4. ^ Nagourney, Eric (December 13, 2012). "Why Is Hair Growing Out of There?". The New York Times. Retrieved 8 September 2014.
5. ^ Scott Jackson; Lee T. Nesbitt (25 April 2012). Differential Diagnosis for the Dermatologist. Springer Science & Business Media. p. 125. ISBN 978-3-642-28006-1. Retrieved 24 October 2014.
6. ^ Hawke Library. "Otoscopy: The Pinna". Retrieved 26 October 2014.
7. ^ Dronamraju, KR (1964). "Y-linkage in Man". Nature. 201 (4917): 424–5. Bibcode:1964Natur.201..424D. doi:10.1038/201424b0. PMID 14110028. S2CID 4275336.
8. ^ Lee, AC; Kamalam, A; Adams, SM; Jobling, MA (2004). "Molecular evidence for absence of Y-linkage of the Hairy Ears trait". Eur J Hum Genet. 12 (12): 1077–9. doi:10.1038/sj.ejhg.5201271. PMID 15367914.
9. ^ Rao, DC (1972). "Hypertrichosis of the ear rims. Two remarks on the two-gene hypothesis". Acta Genet Med Gemellol (Roma). 21 (3): 216–20. doi:10.1017/s1120962300010933. PMID 4669458.
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*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Auricular hypertrichosis | c0263482 | 1,361 | wikipedia | https://en.wikipedia.org/wiki/Auricular_hypertrichosis | 2021-01-18T18:44:51 | {"mesh": ["C562484"], "umls": ["C0263482"], "wikidata": ["Q9003892"]} |
Lymphocytic meningoradiculitis
Other namesBannwarth Syndrome
Lymphocytic meningoradiculitis, also known as Bannwarth syndrome, is a neurological disease characterized as intense nerve pain radiating from the spine.[1] The disease is caused by an infection of Borrelia burgdorferi, a tick-borne spirochete bacterium also responsible for causing Lyme disease.
## Contents
* 1 Signs and symptoms
* 2 History
* 3 See also
* 4 References
* 5 External links
## Signs and symptoms[edit]
Lymphocytic meningoradiculitis is characterized by an intense spinal pain in the lumbar and cervical regions, radiating to the extremities. Symptoms may include facial paralysis, abducens palsy, anorexia, tiredness, headache, double vision, paraesthesia, and erythema migrans.[2]
## History[edit]
The disease was first reported in 1941 by German neurologist, Alfred Bannwarth, who described the main symptoms as intense radicular pain, facial palsy, severe headaches, and vomiting.[3] A common feature he observed in his infected patients was an abnormal increase of lymphocytes in their cerebrospinal fluid (CSF).
## See also[edit]
* Tick-borne disease
## References[edit]
1. ^ Hindfelt, B.; Jeppsson, P. G.; Nilsson, B.; Olsson, J. E.; Ryberg, B.; Sörnäs, R. (1982-10-01). "Clinical and cerebrospinal fluid findings in lymphocytic meningo-radiculitis (Bannwarth's syndrome)". Acta Neurologica Scandinavica. 66 (4): 444–453. ISSN 0001-6314. PMID 7148387.
2. ^ Ryberg, B. (1984-01-01). "Bannwarth's syndrome (lymphocytic meningoradiculitis) in Sweden". The Yale Journal of Biology and Medicine. 57 (4): 499–503. ISSN 0044-0086. PMC 2590032. PMID 6516452.
3. ^ Weber, Klaus; Burgdorfer, Willy (2012-12-06). Aspects of Lyme Borreliosis. Springer Science & Business Media. ISBN 9783642776144.
## External links[edit]
Classification
D
* DiseasesDB: 33278
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Lymphocytic meningoradiculitis | None | 1,362 | wikipedia | https://en.wikipedia.org/wiki/Lymphocytic_meningoradiculitis | 2021-01-18T18:41:54 | {"umls": ["CL512094"], "wikidata": ["Q806910"]} |
Encephalopathy due to sulfite oxidase deficiency is a rare neurometabolic disorder characterized by seizures, progressive encephalopathy and lens dislocation.
## Epidemiology
The prevalence is unknown but is very rare. At least 100 patients with sulfite oxidase deficiency have been reported with approximately 75% of cases being related to molybdenum cofactor (MoCo) deficiency.
## Clinical description
Symptoms usually occur within the first week after birth with feeding difficulties, vomiting and seizures which are difficult to control. The majority of patients exhibit facial dysmorphism (prominent forehead, narrow bifrontal diameter, sunken eyes, elongated palpebral fissures, puffy cheeks, small nose and long philtrum and thick lips). The course is progressive, with spasticity, severe intellectual deficit, and microcephaly seen in survivors. Lens dislocation usually occurs late in infancy but has been observed as early as two months of age. A late onset form with a milder phenotype has also been described.
## Etiology
Isolated sulfite oxidase deficiency is caused by a mutation in the SUOX gene (12q13.13) (see this term). The SUOX gene encodes the enzyme sulfite oxidase which catalyzes sulfite to sulfate, a process essential for the catabolism of sulfur-containing amino acids. MoCo deficiency secondary to mutations in either the MOCS1 (6p21.2) or MOCS2 (5q11) genes also causes sulfite oxidase deficiency (see this term). These genes encode two of the biosynthetic MoCo pathway enzymes. Impaired synthesis of MoCo leads to the combined deficiencies in sulfite oxidase, xanthine dehydrogenase, mitochondrial amidoxime reducing component (mARC) and aldehyde oxidase (the four human molybdoenzymes). The GPHN (14q23.3) gene has also been identified as the cause in one case of MoCo deficiency (see this term).
## Diagnostic methods
A sulfite test strip in a fresh urine sample is a simple screening test but false positive and negative results can occur. Hypouricemia is seen in the MoCo deficiency form of the disease. A third test involves detection of low levels of plasma homocysteine. Diagnosis is confirmed by a skin fibroblast culture showing the absence of sulphite oxidase and/or MoCo activity in cultured fibroblasts. Magnetic resonance imaging shows diffuse cystic lesions within the white matter, basal ganglia and thalamus along with ulegyric changes in the cerebral cortex and cerebellar hypoplasia.
## Differential diagnosis
Isolated sulfite oxidase deficiency is clinically indistinguishable from MoCo deficiency (see these terms). Hypoxic-ischemic encephalopathy (see this term) and neonatal hyperekplexia should be eliminated. Feeding difficulties can mimic amino acid intolerances.
## Antenatal diagnosis
Antenatal diagnosis is possible by measuring the enzyme activity in chorionic villus samples or s-sulfocysteine levels in amniotic fluid, or by DNA analysis.
## Genetic counseling
The disease follows an autosomal recessive pattern of inheritance and genetic counseling is possible.
## Management and treatment
There is no cure for sulfite oxidase deficiency. Antiepileptic drugs in various combinations are used for control of seizures. Administration of diets low in sulfur containing amino acids along with sulfate supplementation have been attempted with positive biochemical responses but with no lasting neurological improvement. MoCo type A defective individuals have benefited from precursor Z (cPMP), a precursor to MoCo. Although it cannot reverse the cerebral injury that has already occurred, seizures are stopped and neurotoxicity and further cerebral damage is prevented. Genetic therapy with a MOCS1 expression cassette being carried by AAV vectors is now being studied as a future treatment.
## Prognosis
The prognosis of the disease is poor. For those who survive infancy, new treatments have led to improvement in some patients.
*[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
| Encephalopathy due to sulfite oxidase deficiency | c1854988 | 1,363 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=833 | 2021-01-23T18:51:04 | {"mesh": ["C565372"], "omim": ["252150", "252160", "272300", "615501"], "icd-10": ["E72.1"]} |
Type of lymphoma
Diffuse large B cell lymphoma
Other namesDLBCL or DLBL
Micrograph (Field stain) of a diffuse large B cell lymphoma.
SpecialtyHematology, oncology, dermatology
Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults,[1] with an annual incidence of 7–8 cases per 100,000 people per year in the US and UK.[2][3] This cancer occurs primarily in older individuals, with a median age of diagnosis at ~70 years,[3] although it can occur in young adults and, in rare cases, children.[4] DLBCL can arise in virtually any part of the body and, depending on various factors, is often a very aggressive malignancy.[5] The first sign of this illness is typically the observation of a rapidly growing mass or tissue infiltration that is sometimes associated with systemic B symptoms, e.g. fever, weight loss, and night sweats.[6]
The causes of diffuse large B-cell lymphoma are not well understood. Usually DLBCL arises from normal B cells, but it can also represent a malignant transformation of other types of lymphoma (particularly marginal zone lymphomas[7]) or, in rare cases termed Richter's transformation, chronic lymphocytic leukemia.[8] An underlying immunodeficiency is a significant risk factor for development of the disease.[9] Infections with the Epstein–Barr virus (EBV),[10][11] Kaposi's sarcoma-associated herpesvirus,[12][13] human immunodeficiency virus (i.e. HIV),[12] and the Helicobacter pylori bacterium [7] are also associated with the development of certain subtypes of diffuse large B-cell lymphoma. However, most cases of this disease are associated with the unexplained step-wise acquisition of increasing numbers of gene mutations and changes in gene expression that occur in, and progressively promote the malignant behavior of, certain B-cell types.[14]
Diagnosis of DLBCL is made by removing a portion of the tumor through a biopsy, and then examining this tissue using a microscope. Usually a hematopathologist makes this diagnosis.[15] Numerous subtypes of DLBCL have been identified which differ in their clinical presentations, biopsy findings, aggressive characteristics, prognoses, and recommended treatments.[16] However, the usual treatment for most subtypes of DLBCL is chemotherapy combined with a monoclonal antibody drug that targets the disease's cancerous B-cells, usually rituximab.[17] Through these treatments, more than half of all patients with DLBCL can be cured;[18] the overall cure rate for older adults is less than this but their five-year survival rate has been around 58%.[19]
## Contents
* 1 Subtypes of diffuse large B-cell lymphoma
* 1.1 Diffuse large B-cell lymphoma, not otherwise specified
* 1.1.1 Presenting signs and symptoms
* 1.1.1.1 Prognostic indicators based on clinical presentation
* 1.1.2 Pathophysiology
* 1.1.3 Diagnosis
* 1.1.4 Variants of DLBCL, NOS
* 1.1.5 Treatments and prognoses
* 1.1.5.1 First-line therapy
* 1.1.5.2 Treatment of recurrent and refractory DLBCL, NOS
* 1.1.5.3 Emerging therapies
* 1.2 Subtypes of diffuse large B-cell lymphoma
* 1.2.1 DLBCL with a distinctive morphology or immunophenotype
* 1.2.1.1 T cell/histiocyte-rich large B-cell lymphoma
* 1.2.1.2 ALK+ large B-cell lymphoma
* 1.2.1.3 Plasmablastic lymphoma
* 1.2.1.4 Intravascular large B-cell lymphoma
* 1.2.1.5 Large B-cell lymphoma with IRF4 rearrangement
* 1.2.2 DLBCL with distinctive clinical issues
* 1.2.2.1 Primary mediastinal large B-cell lymphoma
* 1.2.2.2 Primary cutaneous diffuse large B-cell lymphoma, leg type
* 1.2.2.3 Primary diffuse large B-cell lymphoma of the central nervous system
* 1.2.2.4 Diffuse large B-cell lymphoma associated with chronic inflammation
* 1.2.2.5 Lymphomatoid granulomatosis
* 1.2.2.6 Primary effusion lymphoma
* 1.2.3 DLBCL driven by viruses
* 1.2.3.1 Epstein–Barr virus-positive diffuse large B-cell lymphoma, not otherwise specified
* 1.2.3.2 HHV8-positive diffuse large B-cell lymphoma, NOS
* 2 Related disorders
* 2.1 Helicobactor pylori associated diffuse large B-cell lymphoma
* 2.2 Epstein–Barr virus-positive mucocutaneous ulcer
* 3 See also
* 4 References
* 5 Sources
* 6 External links
## Subtypes of diffuse large B-cell lymphoma[edit]
Diffuse large B-cell lymphoma encompasses a biologically and clinically diverse set of disease subtypes,[20] many of which are difficult to separate from one another based on well-defined and widely accepted criteria. The World Health Organization, 2008, classification system defined more than a dozen subtypes,[21] each of which was identified based on the location of the tumor, the presence of other cell types such as T cells in the tumor, and whether the patient had certain other illnesses related to DLBCL. Based on further research, the World Health Organization, 2016, reclassified DLBCL into its most common subtype, diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). DLBCL, NOS represents 80–85% of all DLBCL.[22] The remaining DLBCL cases consist of relatively rare subtypes that are distinguished by their morphology, (i.e. microscopic appearance), immunophenotype, (i.e. expression of certain marker proteins), clinical findings, and/or association with certain pathogenic viruses.[12] Some cases of DLBCL, NOS, while not included in the 2016 World Health Organization's classification, are clearly associated with, and caused by, chronic infection by the bacterium, Helicobacter pylori.[23]
### Diffuse large B-cell lymphoma, not otherwise specified[edit]
DLBCL cases that do not fit the distinctive clinical presentation, tissue morphology, neoplastic cell phenotype, and/or pathogen-associated criteria of other DLBCL subtypes are termed Diffuse large B-cell lymphoma, not otherwise specified: DLBCL, NOS, while representing 80–85% of all DLBCL cases, is a diagnosis of exclusion. In general, DLBCL, NOS is an aggressive disease with an overall long-term survival rate in patients treated with standard chemotherapy regimens of ~65%. However, this disease has many variants that differ not only in the just cited parameters but also in their aggressiveness and responsiveness to treatment.[24]
#### Presenting signs and symptoms[edit]
About 70% of DLBCL, NOS cases present primarily with lymph node disease. In these cases, the most typical presenting symptom at the time of diagnosis is a mass that is rapidly enlarging and located in a part of the body with multiple lymph nodes such as the groin, arm pits, or neck. In the remaining ~30% of other cases, the disease begins as an extranodal lymphoma, most commonly in the stomach,[12] or, less commonly, in other sites such as the testicles, breasts, uterus, ovaries, kidneys, adrenal glands, thyroid gland, or bone.[25] The presenting signs and symptoms in these cases reflect the presence of a rapidly expanding tumor or infiltrate that produces symptoms specific to the organ of involvement such as increased size, pain, and/or dysfunction.[25] Individuals with nodal or extranodal disease also present with: systemic B symptoms such as weight loss, night sweats, fevers, and/or fatigue in ~33% of cases; unexplained elevations in their blood levels of lactic acid dehydrogenase and beta-2 microglobulin in many cases; malignant cells infiltrating their bone marrow in 10–20% of cases; and/or localized Stage I or II disease in up to 50% of cases and disseminated Stage III or IV disease in the remaining cases.[12] Bone marrow involvement may be due to DLBCL, NOS cells or low grade lymphoma cells; only DLBCL, NOS cell infiltrates indicate a worse prognosis.[22] Uncommonly, DLBCL may arise as a transformation of marginal zone lymphoma (MZL) in individuals who have been diagnosed with this indolent cancer 4–5 years (median times) previously.[26]
##### Prognostic indicators based on clinical presentation[edit]
The International Prognostic Index and more recently, the Index's age-adjusted variant use age >60 years, elevated serum lactate dehydrogenase levels, low performance status, and involvement in more than one extranodal site as contributors to a poor prognosis in patients with DLBCL, NOS.[22] In addition, disease that initially involves the testes, breast, or uterus has a relatively high rate of spreading to the central nervous system while disease initially involving the kidneys, adrenal glands, ovaries, or bone marrow has a high rate of spreading to other organs, including the central nervous system. All of these cases as well as cases initially involving the central nervous system have relatively poor to very poor prognoses. Cases initially involving the stomach, thyroid, or a single bone site have relatively good prognoses.[25]
#### Pathophysiology[edit]
Most cases of DLBCL, NOS appear to result at least in part from the step-wise development of gene changes such as mutations, altered expressions, amplifications (i.e. increases in the number of copies of specific genes), and tranlocations from normal sites to other chromosomal sites. These changes often result in gains or loses in the production or function of the product of these genes and thereby the activity of cell signaling pathways that regulate the maturation, proliferation, survival, spread, evasion of the immune system, and other malignant behaviors of the cells in which they occur. While scores of genes have been reported to be altered in DLBCL, NOS many of these may not contribute to DLBCL, NOS. Changes in the following genes occur frequently in, and are suspected of contributing to, this disease's development and/or progression.[14]
* BCL2: This gene is a protooncogene, i.e. a normal gene that can become cancer-causing when mutated or overexpressed. Its product, Bcl-2 protein, regulates cellular apoptosis (i.e. survival) by inhibiting the apoptosis-causing proteins, Bcl-2-associated X protein and Bcl-2 homologous antagonist killer.[27]
* BCL6: This genes' product, Bcl-6, is a repressor of transcription that regulates the expression of other genes which control cell maturation, proliferation, and survival.[27]
* MYC: This protooncogene's product, Myc, encodes a transcription factor which regulates the expression of other genes whose products stimulate cell proliferation and expansion to extra-nodal tissues.[28]
* EZH2: This gene's product, the EZH2 protein, is a histone-lysine N-methyltransferase. It thereby regulates the expression of other genes which control lymphocyte maturation.[22]
* MYD88: This gene's product is a signal transducing adaptor protein essential for the transduction of interleukin-1 and toll-like receptor signaling pathways. It thereby regulates NF-κB and MAPK/ERK signaling pathways that control cell proliferation and survival.[27]
* CREBBP: This gene's product is a transcriptional coactivator; it activates numerous transcription factors, some of which control cell proliferation.[14]
* CD79A and CD79B: these genes' products are critical components of the B-cell receptor. Mutations in either gene can cause uncontrolled cell activation and proliferation.[14]
* PAX5: this gene's product, Pax-5, is a transcription factor that controls the development, maturation, and survival of B-cells; it also controls expression of the MYC gene in these cells.[29]
As a consequence of these gene changes and possibly other changes that have not yet been identified, the neoplastic cells in DLBCL, NOS exhibit pathologically overactive NF-κB, PI3K/AKT/mTOR, JAK-STAT0, MAPK/ERK, B-cell receptor, toll-like receptor, and NF-κB signaling pathways and thereby uncontrolled pro-malignant behaviors.[27]
#### Diagnosis[edit]
Microscopic examinations of involved tissues reveal large neoplastic cells that are typically classified as B-cells based on their expression of B-cell marker proteins (e.g. CD20, CD19, CD22, CD79, PAX5, BOB1, OCT2, an immunoglobulin [usually IgM but occasionally IgG or IgA)],[12] CD30, and in ~20–25% of cases PD-L1 or PD-L2 (PD-L1 and PD-L2 are transmembrane proteins that normally function to suppress attack by the immune system).[22] These cells arrange in a diffuse pattern, efface the tissues' architecture, and resemble Centroblast cells (80% of cases), Immunoblast cells (8–10% of cases), or anaplastic cells (9% of cases; anaplastic cells have bizarre nuclei and other features that may mimic the Reed–Sternberg cells of Hodgkin disease or the neoplastic cells of anaplastic large cell lymphoma). Rarely, these neoplastic cells are characterized as having signet ring or spindle shaped nuclei, prominent cytoplasmic granules, multiple microvillus projections, or, when viewed by electron microscopy, tight junctions with other cells.[12] These neoplastic tissue infiltrates are often accompanied by small non-malignant T-cell lymphocytes and histiocytes that have a reactive morphology.[22]
#### Variants of DLBCL, NOS[edit]
The World Health Organization, 2016, requires that the neoplastic cells in DLBCL, NOS be further defined based on whether they are derived from germinal center B-cells (i.e. GBC) or activated B-cells (i.e. ABC) as identified by gene expression profiling (GEP) or are GBC or non-GBC as identified by immunohistochemical (IHC) analyses. As identified by GEP, which measures all cellular messenger RNAs, GBC and ABC represent about 50 and ~35% of DLBCL, NOS cases, respectively, with ~15% of cases being unclassifiable.[30] IHC analyses measure the cellular expression of specific proteins using a panel of fluorescent antibodies that bind to and therefore stain a set of key proteins. For example, one commercially available panel uses three antibodies to detect CD10, BCL6, and MUM1 proteins; GBC express whereas ABC and unidentified cells do not express these proteins; accordingly, this as well as other IHC panels classify ABC and undetermined neoplastic cell types together as non-GBC.[27] Individuals with the ABC, unclassifiable, and non-GBC variants have significantly worse prognoses than individuals with the GBC variant:[24] respective 5 year progression-free and overall survival rates have been reported to be 73–80% for GBC variants and 31–56% for ABC variants. Clinically, however, most DLBCL, NOS cases are analyzed by IHC and therefore classified as either GBC or non-GBC variants with non-GBC variants having progression-free and overall survival rates similar to those of the ABC variants.[22]
Gene and protein markers in the neoplastic cells of DLBCL, NOS that have clinical significance include CD5, MYC, BCL2, BCL6,[12] CD20, CD19, CD22, CD30, PD-L1, and PD-L2.[24] The 5–10% of DLBCL, NOS cases in which the neoplastic cells express CD5 have a very poor prognosis that is not improved by even aggressive treatment regimens. Cases in which fluorescence in situ hybridization analysis show that the neoplastic cells' in this disease bear translocations in both the MYC and BCL2 genes or MYC and BCL6 genes (termed double hit lymphomas) or in all three genes (termed triple hit lymphomas)[22] are associated with advanced disease that spreads to the central nervous system.[28] These lymphomas, termed high-grade B-cell lymphoma with MYC, BL2, and/or BL6 rearrangements or, more simply, DH/THL, are regarded as borderline DLBCL,NOS.[22] They represent 6–14% of all DLBCL, NOS and have had long-term survival rates of only 20–25%.[25] Another variant B-cell lymphoma that is also considered to be a borderline DLBCL, NOS is termed high-grade B-cell lymphoma, not otherwise specified (HGBCL, NOS).[22] These two aggressive borderline B-cell lymphomas were previously grouped together as "B-cell lymphoma, unclassifiable with features intermediate between DLBCL and Burkitt lymphoma" (i.e. BCLU) but were separated into DH/THL and HGBC, NOS by the World Health Organization, 2016.[16] The neoplastic cells in a related variant, double expresser lymphoma (i.e. DEL), express the products of MYC and BCL2 genes, i.e. c-Myc and bcl-2 proteins, respectively, but do not have translocations in either of their genes. DEL, which represents about one-third of all DLBCL, NOS cases, has a poorer prognosis than standard DLBCL, NOS but not as poor as DH/THL cases.[22][30] Cases in which the neoplastic cells have alterations in the MYC gene or its expression without changes in BLC2 or BLC6 also have a poor prognosis,[22] particularly in cases where the MYC gene translocates (i.e. rearranges) with one of the immunoglobulin gene loci. DLBCL that begin in the testicles are a variant of DLBCL, NOS that some authors suggest should be classified as a distinct DLBCL subtype.[12] This variant, termed Primary testicular diffuse large B-cell lymphoma (PT-DLBCL), is a DLBCL, NOS that in >75% of cases involves activated B-cells, i.e. ABC.[31] These cells, which typically have a centroblast-like morphology, infiltrate one or, in ~6% of cases, both testicles. PT-DLBCL is an aggressive disease that often spreads to the central nervous system[31] and has median overall survival and progression-free survival times of 96 and 49 months, respectively.[12]
The neoplastic cells in almost all cases of DLBCL, NOS express CD20. Commercially available anti-CD20 antibody agents such as rituximab or Obinutuzumab (which is sometimes used in place of rituximab) kill cells that express high levels of CD20 by binding to this cell-surface protein and thereby targeting them for attack by the hosts adaptive immune system. The addition of one of these immunotherapy agents to chemotherapy protocols has greatly improved the prognosis of most DLBCL, NOS variants.[22] Neoplastic cell expression of CD30, found in 10–15% of DLBCL, NOS cases is a favorable prognostic indicator. As indicated in the following Treatments and prognoses section, expression of the CD20 and CD30 proteins as well as the CD19, CD20 CD22, CD30, CD79A, CD79B, and D-L1 proteins, expression of the MYC, BCL2, MYD88nd, and CREBBP genes, and expression of the PI3K/AKT/mTOR, JAK-STAT, B-cell receptor, toll-like receptor, and NF-κB signaling pathways are being studied as potential therapeutic targets for the individualized treatment of GBC and ABC/non-GBC DLBCL, NOS cases.[14][22]
#### Treatments and prognoses[edit]
##### First-line therapy[edit]
First-line therapy for patients with the GBC variant of DLBCL, NOS is R-CHOP. R-CHOP consists of rituximab, three chemotherapy drugs (cyclophosphamide, hydroxydoxorubicin, and oncovin) and a glucocorticoid (either prednisone or prednisolone).[30] The regimen achieves cure, relapse following remission,[22] and unresponsive rates of 60–70%, 30–40% and <10%, respectively, in GBC variant cases.[32] Relapses generally occur within the first 3 years of diagnosis with few cases doing so after 5 years. Patients who are refractory to, relapse within 1 year of diagnosis before starting, relapse within 6 months after completing, or progress within 2 years of starting R-CHOP have poorer prognoses.[28] R-CHOP is less effective and not recommended for patients who have MYC, BL2, and/or BL6 rearrangements regardless of their GBC, ABC, or non-GBC type. One recommendation for treating these DH/THL cases is the DA-R-EPOCH regimen (dose-adjusted rituximab, etoposide, prednisolone, oncovin, cyclophosphamide, and hydroxydaunorubicin). S-R-EPOCH achieves 2 year survival rates of 40–67% compared to a ~25% survival rate for R-CHOP in these cases.[30] DA-R-EPOCH has also been recommended for patients with double expresser lymphoma[30] although some experts recommend treating this variant more like a typical DLCBL, NOS.[27] First-line therapy for patients with the ABC, undetermined, or non-GBC variants has been the DA-R-EPOCH regimen. Patients with these variants (including those with double expresser lymphoma) have had a ~40% cure rate when treated with it.[30] A randomized clinical trial conducted in France reported that a R-ACVBP chemotherapy regimen (rituximab, adriamycin, cyclophosphamide, vindesine, bleomycin, and cytarabine followed by sequential consolidation therapy with systemic methotrexate, ifosfamide, and etoposide, and then cytarabine) achieved significantly better response rates than R-CHOP in ABC/NGC variant cases lymphoma.[27] In DLBCL, NOS variants which trend to spread or to the central nervous system, methotrexate has been recommended to be added to regimens not containing it for use as prophylaxis to reduce the incidence of this complication.[28] The role of Autologous stem-cell transplantation as an addition to first-line therapy in the treatment of DLBCL, NOS, including cases with a poor prognosis, is unclear.[14]
A phase I clinical research trial found that the addition of lenalidomide to the R-CHOP regimen produce an ~80% complete response rate in GBC as well as non- GBC DLBCL, NOS variants.[14] Two phase III clinical research trials are underway to confirm these results and determine if the R-CHOP + lenalidomide regimen is superior to R-CHOP in the up-front treatment of GBC and/or non-GBC variants.[14]
##### Treatment of recurrent and refractory DLBCL, NOS[edit]
Patients with DLBCL, NOS who relapse or progress following first-line therapy have been treated wit "salvage regimens" consisting of high-dose (also termed high-intensity) chemotherapy conditioning drugs followed by autologous stem cell transplantation. This regimen has attained 3 year progression-free survival rates of 21–37%.[14] Relapse following this treatment carries a very poor prognosis with median overall survival times of ~10 months.[28] Patients who have failed or because of health issues are ineligible for autologous stem cell transplantation have been treated with low-dose (i.e. low-intensity) chemotherapy conditioning regimens followed by allogeneic stem cell transplantation. This regimen has achieved 3 year progression-free and overall survival rates of 41% and 52%, respectively.[32] Further studies are underway to determine the best treatment regimens for these cases.[14][32] Patients refractory to first-line therapy or who relapse within 12 months of receiving salvage therapy (including bone marrow transplant) for recurrent disease have had poor prognoses with median overall survival rates of 3.3 and 6.3 months, respectively.[14] Thee prognosis of these patients appears to be improved by using CAR-T therapy.
Chimeric antigen receptor T cell (i.e. CAR-T) adoptive cellular immunotherapy has emerged as a recent advance in treating refractory and relapsed DLBCL, NOS. Chimeric antigen receptor T cells are genetically engineered to express: 1) an artificial T-cell receptor consisting of antigen-recognition and attached hinge domains expressed on their surface membranes; 2) a surface membrane-spanning domain; 3) an intracellular domain which, when the antigen-recognition domain binds its targeted antigen, activates signaling pathways that cause the T-cell to attack and kill cells that bear the recognized antigen on their surface membranes; and 4), in more recently devised second generation CAR-T strategies, an associated intracellular co-stimulating molecule (e.g. CD28 or 4‐1BB) which augments activation of the cell-killing signaling pathways. CAR-T therapy, as it pertains to DLBCL, NOS, kills a patient's neoplastic B-cells by isolating this patient's T-cells; genetically engineering these cells to express an artificial T-cell receptor designed to bind an antigen expressed on the surface of their neoplastic B-cells; and infusing these cells back into the donor patient. The targeted antigen has usually been CD19, a surface membrane protein expressed on virtually all B-cells including the neoplastic cells in DLBCL, NOS.[28] However, design of CARs[33] as well as the antigens chosen to be their targets [28] are constantly being changed in order to improve the efficacy of this therapeutic strategy.
CAR-T therapy for DLBCL, NOS has been used on patients who are refractory to and/or have progressed on first-line as well as salvage (including autologous stem cell transplantation) treatment regimens. Patients are treated first with a conditioning chemotherapy regimen, usually cyclophosphamide and fludarabine, and then infused with their own T-cells that have been engineered to attack CD19-bearing or, rarely, CD20-bearing cells. A meta-analysis of 17 studies using this or very similar approaches to treat DLBCL, NOS found the treatments gave complete and partial responses rates of 61% and 43%, respectively. While these studies did not have control groups and were too recent for meaningful estimates of remission durations, the remission rates were higher than expected using other treatment approaches. Significant and potentially lethal therapeutic complications of this therapy included development of the cytokine release syndrome (21% of cases), neurotoxicity, i.e. the CAR-T cell-related encephalopathy syndrome (9% of cases),[34] and the hemophagocytic lymphohistiocytosis/macrophage-activation syndrome (i.e. a form of Hemophagocytic lymphohistiocytosis).[35] Individual studies within and outside of this meta-analysis have reported remissions lasting >2 years but also lethal cytokine release syndrome and neurotoxicity responses to this therapy.[32] As a consequence of these studies, the Committee for Advanced Therapies and the Committee for Medicinal Products for Human Use of the European Medicines Agency recommend granting marketing authorization for tisagenlecleucel (i.e. chimeric antigen receptor T cells directed against CD19) in adult patients with DLBCL, NOS who have relapsed after or are refractory to two or more lines of systemic therapy.[36] The Committee for Orphan Medicinal Products of the European Medicines Agency recommends tisagenlecleucel retain its orphan drug designation.[36] The USA Food and Drug Administration (FDA) has also approved the use of this drug for relapsed or refractory DLBCL of the large B-cell lymphoma subtype in patients who have failed after two or more lines of systemic therapy.[37] Monoclonal antibodies directed against CD19, CD22, CD30, and PD-L1 have been developed for use as immunotherapeutic agents in other hematological malignancies and are being or plan to be tested for their usefulness in DLBCL, NOS.[22] In August 2020, the FDA approved the humanized Fc-modified cytolytic CD19 targeting monoclonal antibody tafasitamab in combination with lenalidomide as a treatment for adult patients with relapsed or refractory DLBCL [38]
##### Emerging therapies[edit]
Neoplastic cell expression of CD30 in DLBCL, NOS is a favorable prognostic indicator; in these cases, brentuximab vedotin may be a useful addition to chemotherapy treatment protocols. This agent is a CD30-targeting antibody that delivers a toxin, monomethyl auristatin E, to CD30-expressing cells, has therapeutic efficacy against other CD30-expressing lymphomas, and may prove useful in treating the 10–15% of DLBCL, NOS cases expressing this protein. The neoplastic cells in the GBC variant of DLBCL, NOS often have mutations in the EZH2, BCL2 and CREBBP genes and overactive PI3K/AKT/mTOR and JAK-STAT signaling pathways while neoplastic cells in the ABC variant often have mutations in the MYD88, CD79A and CD79B genes and overactive B-cell receptor, toll-like receptor, and NF-κB signaling pathways.[22] These different gene mutations and dysregulated signaling pathways are also being studied as potential therapeutic targets for the individualized treatment of GBC and ABC/non-GBC cases.[14] CUDC-907, an inhibitor of PI3K and histone deacetylases, is being evaluated in two separate clinical trials[39][40] for the treatment of refractory and/or relapsed DLBCL, NOS including cases with alterations in the MYC gene.[41] GSK525762, an inhibitor of the BET family of proteins, suppresses expression of the MYC gene and is undergoing a phase I clinical trial[42] for the treatment of high-grade B-cell lymphoma with MYC, BL2, and/or BL6 rearrangements (i.e. DH/THL). RO6870810, another BET inhibitor, in combination with Venetoclax, an inhibitor of the Bcl-2 protein, is likewise in a phase I clinical trial[43] for the treatment of DH/THL.[41]
### Subtypes of diffuse large B-cell lymphoma[edit]
DLBCL subtypes have been sorted into groups based on their distinctive morphology or immunophenotype, distinctive clinical issues, and distinctive virus-driven etiology. The prognoses and treatment of these subtypes varies with their severity. Most subtypes are aggressive diseases and consequently treated in a manner similar to DLBCL,NOS. Further details on these subtypes, including their treatments, can be found in their respective main article linkages.
#### DLBCL with a distinctive morphology or immunophenotype[edit]
##### T cell/histiocyte-rich large B-cell lymphoma[edit]
Main article: T cell/histiocyte-rich large B-cell lymphoma
T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a DLBCL in which tumors containing small numbers of usually large neoplastic B-cells embedded in a background of reactive T-cells and histiocytes develop in the liver, spleen, bone marrow and/or, rarely other sites. Patients usually present with advanced disease; their overall 3 year survival rates in different studies range between 46% and 72%.[12]
##### ALK+ large B-cell lymphoma[edit]
Main article: ALK+ large B-cell lymphoma
ALK+ large B-cell lymphoma (ALK+ LBCL) is a DLBCL in which neoplastic lymphocytes that express the ALK tyrosine kinase receptor protein infiltrate lymph nodes as well as extranodal sites, e.g. the mediastinum, bones, bone marrow, nasopharynx, tongue, stomach, liver, spleen, and skin. About 60% of these individuals present with advanced disease. ALK+ LBCL has an overall 5 year survival rate of ~34%.[12]
##### Plasmablastic lymphoma[edit]
Main article: Plasmablastic lymphoma
Plasmablastic lymphoma (PBL) is a DLBCL in which neoplastic immunoblastic or plasmablastic cells embedded in a background of other cell types infiltrate the oral/nasal cavity or much less often the gastrointestinal tract.[12] Some 70% of individuals with PBL are infected with EBV[44] and/or (particularly those with oral/nasal cavity disease) human immunodeficiency virus (HIV).[12] PBL is an aggressive disease with a median survival time of ~15 months.[12]
##### Intravascular large B-cell lymphoma[edit]
Main article: Intravascular large B-cell lymphoma
Intravascular large B-cell lymphoma (IVLBCL) is a DLBCL in which medium- to large-sized neoplastic B-cells infiltrate small- to medium-sized blood vessels and sinusoids in the liver, spleen, and/or bone marrow. IVLBCL may be associated with the hemophagic syndrome (i.e. excessive cytokine secretion and systemic inflammation). Patients afflicted with the latter syndrome have very short survival times.[12] The poor prognosis of this disease has been significantly improved by rituximab or similar immunochemotherapy drugs but significant proportions of these responding cases relapse, often with central nervous system involvement.[45]
##### Large B-cell lymphoma with IRF4 rearrangement[edit]
Main article: IRF4
Large B-cell lymphoma with IRF4 rearrangement (LBCL with IRF4 rearrangement) is a DLBCL in which tissue infiltrates containing intermediate- or large-sized neoplastic B-cells strongly express a chromosomal translocation involving the IRF4 gene on the short arm of chromosome 6. These cells form follicular, follicular and diffuse, or entirely diffuse infiltrates[12] in Waldeyer's tonsillar ring or other regions of the head and neck. The disease, which represents ~0.05% of all DLBCL, occurs primarily in children and young adults and typically has a good prognoses.[24] Cases with a follicular pattern of tissue infiltrates often have indolent disease and an excellent prognosis following excision and may not need chemotherapy. Cases with a purely diffuse tissue infiltrate pattern, in contrast, often do require chemotherapy.[12]
#### DLBCL with distinctive clinical issues[edit]
##### Primary mediastinal large B-cell lymphoma[edit]
Main article: Primary mediastinal large B-cell lymphoma
Primary mediastinal large B-cell lymphoma (PMBL), also termed primary mediastinal (thymic) large B-cell lymphoma, is a DLBCL in which neoplastic B-cells infiltrates are commonly located in sclerotic/fibrous tissues of the thymus and mediastinal lymph nodes. The disease represents 6–10% of all DLBCL cases, presents with early stage disease in ~80% of cases, and has an overall survival rate at 5 years of 75–85%.[12]
##### Primary cutaneous diffuse large B-cell lymphoma, leg type[edit]
Main article: Primary cutaneous diffuse large B-cell lymphoma, leg type
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a DLBCL in which diffuse patterns of immunoblastic and/or centroblastic B-cells infiltrate the dermis and/or subcutaneous tissue principally, but not exclusively, of the legs. This disease's 5-year overall survival rate is 50–60%.[12]
##### Primary diffuse large B-cell lymphoma of the central nervous system[edit]
Main article: Primary central nervous system lymphoma
Primary diffuse large B-cell lymphoma of the central nervous system (DLBCL-CNS, also termed primary central nervous system lymphoma [PCNSL]) is a DLBCL in which diffuse patterns of neoplastic B-cells with centroblastic, immunoblastic, or poorly differentiated features infiltrate the brain, spinal cord, leptomeninges, or eye.[24] The disease usually presents as a single lesion with a predilection for the supratentorial region of the brain but may involve the eye in 15–25% of cases, the cerebrospinal fluid in 7–42% of cases, and the spinal cord in ∼1% of cases. The disease has a 5-year overall survival rate of ~30%.[12]
##### Diffuse large B-cell lymphoma associated with chronic inflammation[edit]
Main article: Diffuse large B-cell lymphoma associated with chronic inflammation
Main article: Fibrin-associated diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) is an Epstein–Barr virus-associated lymphoproliferative disease arising in persons with a long and persistent history of chronic inflammation. The disease's lesions consist of large, mature-appearing B-cells infiltrating the lung's pleura and nearby tissues. Most cases have occurred in patients who were given a pneumothorax (i.e. therapeutic introduction of air into the chest cavity in order to collapse and thereby "rest" the lung) to treat pulmonary tuberculosis that had progressed to a pyothorax (i.e. pus in the pleural cavity). Fibrin-associated large B-cell lymphoma (FA-DLBCL), often considered a sub-type of DLBCL-CI, is an infiltration of large neoplastic B-cells and fibrin affix to a prosthesis (e.g., cardiac valve, orthopaedic device) or accumulate within a hydrocele, pseudocyst, cardiac myxoma, or chronic subdural hematoma. The B-cells in these lesions are often but not always infected with the Epstein–Barr virus.[12] DLBCL-CI occurring in cases of pleural empyema (sometimes termed pyothorax-associated lymphoma, i.e. PAL) is an aggressive lymphoma with a five-year overall survival rate of 20–35%; FA-DLBCL, when involving the heart (e.g. occurring on myxommas or prosthetic valves) or vasculature structures (e.g. on thrombus-laden vascular grafts), may involve life-threatening cardiovascular complications, particularly strokes. Outside of these complications, however, DLBCL-CI usually has a highly favorable outcome.[24]
##### Lymphomatoid granulomatosis[edit]
Main article: Lymphomatoid granulomatosis
Lymphomatoid granulomatosis (LYG) is a DLBCL in which large, atypical B-cells with immunoblastic or Hodgkin disease-like features that are infected by the Epstein-Barr virus center around and destroy the microvasculature. Lymphomatoid granulomatosis almost always involves the lung but may concurrently involve the brain, peripheral nervous system, skin, kidneys, liver, gastrointestinal tract, and/or upper respiratory tract; LYG has an increased incidence in persons with Wiskott–Aldrich syndrome or HIV or who are immunosuppression due to chemotherapy or organ transplantation.[12] The disease's prognosis is highly variable: patients with low grade disease often require no therapy except watchful waiting while patients with high grade disease usually require chemotherapy.[46]
##### Primary effusion lymphoma[edit]
Main article: Primary effusion lymphoma
Primary effusion lymphoma (PEL) is a DLBCL in which neoplastic B cells that resemble immunoblasts, plasmablasts, or Reed–Sternberg cells infiltrate the pleural, pericardial, or peritoneal membranes that surround the lungs, heart, and abdominal organs, respectively. This infiltration leads to the seeping of fluid into the cavities which are encased by these membranes, i.e. it leads to pleural effusions, pericardial effusions, and abdominal ascites. Some cases of PEL also involve the gastrointestinal tract and lymph nodes. The disease occurs primarily in people who are immunosuppressed or test positive for HIV[12] and are also latently infected with Kaposi's sarcoma-associated herpesvirus;[13] PEL is an aggressive disease with an overall 1 year survival rate of ~30%.[13]
#### DLBCL driven by viruses[edit]
##### Epstein–Barr virus-positive diffuse large B-cell lymphoma, not otherwise specified[edit]
Main article: Epstein–Barr virus-associated lymphoproliferative diseases § Epstein–Barr virus-positive diffuse large B cell lymphoma, not otherwise specified
Epstein–Barr virus-positive diffuse large B cell lymphoma, not otherwise specified (EBV+ DLBCL, NOS) is a B-cell lymphoma in which neoplastic B-cells that are infected with the Epstein-Barr virus cause a disease that does not fit into other subtypes of DLBCL. In EBV+ DLBCL, small neoplastic B-cells, other lymphocyte typess, plasma cells, histiocytes and epithelioid cells interspersed with Reed–Sternberg-like cells[24] infiltrate, almost exclusively, lymph nodes.[11] Elderly patients with the disease have median survival times of ~2 years while young patients have long-term treatment-related remissions in >80% of cases.[24]
##### HHV8-positive diffuse large B-cell lymphoma, NOS[edit]
Main article: HHV8-positive diffuse large B-cell lymphoma
Main article: HHV-8-associated MCD
HHV8-positive diffuse large B-cell lymphoma, NOS (HHV8+ DLBCL, NOS; also termed HHV8-positive diffuse large B-cell lymphoma [HHV8+ DLBCL]) is a DLBCL in which Kaposi's sarcoma-associated herpesvirus-infected, medium- to large-size neoplastic B-cells that resemble lymphocytes or immunoblasts infiltrate lymph nodes (~80% of cases) and, when disseminated (20% of cases), the liver and spleen. This infiltration usually disrupts the normal architecture of the involved tissues. HHV8+ DLBCL develops in HIV-infected individuals in ~50% of cases, in individuals with multicentric Castleman disease, plasma cell variant in uncommon cases, and in individuals with Kaposi sarcoma in rare cases. HHV8+ DLBCL commonly takes an aggressive course and has a poor prognosis.[12]
## Related disorders[edit]
### Helicobactor pylori associated diffuse large B-cell lymphoma[edit]
Main article: Helicobacter pylori § Diffuse large B-cell lymphoma
Rare cases of DLBCL are associated with the presence of the bacterium, Helicobacter pylori, in the neoplastic B-cells.[7] While the histology of Helicobactor pylori-associated diffuse large B-cell lymphoma (H. pylori\+ DLBCL) is typical of DLBCL, the disease is sometimes a progression of mantle cell lymphoma, is often restricted to the stomach, is less aggressive that most DLBCL cases, and may respond to a drug regimen consisting of antibiotics and proton pump inhibitors directed at killing the bacterium.[47][23] Perhaps because of these features of the disease, H. pylori\+ DLBCL has not been classified as a DLBCL by the World Health Organization, 2016.[23]
Recent studies suggest that localized, early-stage H. pylori\+ DLBCL, when limited to the stomach, is successfully treated with H. pylori eradication protocols consisting of two or more antibiotics plus a proton pump inhibitor.[48][47][49][23] However, these studies also agree that patients treated with one of these H. pylori eradication regimes need to be carefully followed: those unresponsive to, or worsening on, these regimens should be switched to a chemotherapy regimen (e.g. R-CHOP) and/or, for complicated bulky disease, surgery and/or local radiotherapy.[47][23]
### Epstein–Barr virus-positive mucocutaneous ulcer[edit]
Main article: Mouth ulcer
Main article: Epstein–Barr virus-associated lymphoproliferative diseases § Epstein–Barr virus-positive mucocutaneous ulcer
Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) was first described as a lymphoproliferative disorder in which Epstein–Barr virus-infected B-cells proliferate and cause ulcerations in the mucous membranes and skin of immunosuppressed individuals. Its lesions consist of Epstein–Barr virus-positive, variable-sized, atypical B-cells that by conventional histopathologic criteria indicate the lesions are a form of DLBCL. Since these lesions regress spontaneously without anti-cancer treatment, EBVMCU is now considered a pseudo-malignant disorder.[50] Elderly individuals that evidence the disease but have no other cause for immunosuppression may exhibit a relapsing and remitting course with their ulcers worsening but then regressing spontaneously.[51] Persistent and/or severely symptomatic cases have had excellent responses to rituximab.[52] Individuals developing these ulcers as a consequence of immunosuppressive therapy generally have a remission after the dosage of the drugs used in their immunosuppressive treatments are reduced. Most of these patients do not relapse.[51]
## See also[edit]
Germinal center B-cell like diffuse large B-cell lymphoma
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## Sources[edit]
* Swerdlow, SH; Campo, E; Jaffe, ES; Pileri, SA, eds. (2008). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC. ISBN 978-92-832-2431-0.
* Goldman, L; Schafer, AI (2012). Goldman's Cecil Medicine (24th ed.). ISBN 978-1-4377-1604-7.
* Turgeon, ML (2005). Clinical hematology: theory and procedures. Hagerstown, MD: Lippincott Williams & Wilkins. ISBN 978-0-7817-5007-3.
## External links[edit]
Classification
D
* ICD-10: C83.3
* ICD-O: M9680/3
* MeSH: D016403
External resources
* eMedicine: article/202969
* v
* t
* e
Leukaemias, lymphomas and related disease
B cell
(lymphoma,
leukemia)
(most CD19
* CD20)
By
development/
marker
TdT+
* ALL (Precursor B acute lymphoblastic leukemia/lymphoma)
CD5+
* naive B cell (CLL/SLL)
* mantle zone (Mantle cell)
CD22+
* Prolymphocytic
* CD11c+ (Hairy cell leukemia)
CD79a+
* germinal center/follicular B cell (Follicular
* Burkitt's
* GCB DLBCL
* Primary cutaneous follicle center lymphoma)
* marginal zone/marginal zone B-cell (Splenic marginal zone
* MALT
* Nodal marginal zone
* Primary cutaneous marginal zone lymphoma)
RS (CD15+, CD30+)
* Classic Hodgkin lymphoma (Nodular sclerosis)
* CD20+ (Nodular lymphocyte predominant Hodgkin lymphoma)
PCDs/PP
(CD38+/CD138+)
* see immunoproliferative immunoglobulin disorders
By infection
* KSHV (Primary effusion)
* EBV
* Lymphomatoid granulomatosis
* Post-transplant lymphoproliferative disorder
* Classic Hodgkin lymphoma
* Burkitt's lymphoma
* HCV
* Splenic marginal zone lymphoma
* HIV (AIDS-related lymphoma)
* Helicobacter pylori (MALT lymphoma)
Cutaneous
* Diffuse large B-cell lymphoma
* Intravascular large B-cell lymphoma
* Primary cutaneous marginal zone lymphoma
* Primary cutaneous immunocytoma
* Plasmacytoma
* Plasmacytosis
* Primary cutaneous follicle center lymphoma
T/NK
T cell
(lymphoma,
leukemia)
(most CD3
* CD4
* CD8)
By
development/
marker
* TdT+: ALL (Precursor T acute lymphoblastic leukemia/lymphoma)
* prolymphocyte (Prolymphocytic)
* CD30+ (Anaplastic large-cell lymphoma
* Lymphomatoid papulosis type A)
Cutaneous
MF+variants
* indolent: Mycosis fungoides
* Pagetoid reticulosis
* Granulomatous slack skin
aggressive: Sézary disease
* Adult T-cell leukemia/lymphoma
Non-MF
* CD30-: Non-mycosis fungoides CD30− cutaneous large T-cell lymphoma
* Pleomorphic T-cell lymphoma
* Lymphomatoid papulosis type B
* CD30+: CD30+ cutaneous T-cell lymphoma
* Secondary cutaneous CD30+ large-cell lymphoma
* Lymphomatoid papulosis type A
Other
peripheral
* Hepatosplenic
* Angioimmunoblastic
* Enteropathy-associated T-cell lymphoma
* Peripheral T-cell lymphoma not otherwise specified (Lennert lymphoma)
* Subcutaneous T-cell lymphoma
By infection
* HTLV-1 (Adult T-cell leukemia/lymphoma)
NK cell/
(most CD56)
* Aggressive NK-cell leukemia
* Blastic NK cell lymphoma
T or NK
* EBV (Extranodal NK-T-cell lymphoma/Angiocentric lymphoma)
* Large granular lymphocytic leukemia
Lymphoid+
myeloid
* Acute biphenotypic leukaemia
Lymphocytosis
* Lymphoproliferative disorders (X-linked lymphoproliferative disease
* Autoimmune lymphoproliferative syndrome)
* Leukemoid reaction
* Diffuse infiltrative lymphocytosis syndrome
Cutaneous lymphoid hyperplasia
* Cutaneous lymphoid hyperplasia
* with bandlike and perivascular patterns
* with nodular pattern
* Jessner lymphocytic infiltrate of the skin
General
* Hematological malignancy
* leukemia
* Lymphoproliferative disorders
* Lymphoid leukemias
* v
* t
* e
Chromosome abnormalities
Autosomal
Trisomies/Tetrasomies
* Down syndrome
* 21
* Edwards syndrome
* 18
* Patau syndrome
* 13
* Trisomy 9
* Tetrasomy 9p
* Warkany syndrome 2
* 8
* Cat eye syndrome/Trisomy 22
* 22
* Trisomy 16
Monosomies/deletions
* (1q21.1 copy number variations/1q21.1 deletion syndrome/1q21.1 duplication syndrome/TAR syndrome/1p36 deletion syndrome)
* 1
* Wolf–Hirschhorn syndrome
* 4
* Cri du chat syndrome/Chromosome 5q deletion syndrome
* 5
* Williams syndrome
* 7
* Jacobsen syndrome
* 11
* Miller–Dieker syndrome/Smith–Magenis syndrome
* 17
* DiGeorge syndrome
* 22
* 22q11.2 distal deletion syndrome
* 22
* 22q13 deletion syndrome
* 22
* genomic imprinting
* Angelman syndrome/Prader–Willi syndrome (15)
* Distal 18q-/Proximal 18q-
X/Y linked
Monosomy
* Turner syndrome (45,X)
Trisomy/tetrasomy,
other karyotypes/mosaics
* Klinefelter syndrome (47,XXY)
* XXYY syndrome (48,XXYY)
* XXXY syndrome (48,XXXY)
* 49,XXXYY
* 49,XXXXY
* Triple X syndrome (47,XXX)
* Tetrasomy X (48,XXXX)
* 49,XXXXX
* Jacobs syndrome (47,XYY)
* 48,XYYY
* 49,XYYYY
* 45,X/46,XY
* 46,XX/46,XY
Translocations
Leukemia/lymphoma
Lymphoid
* Burkitt's lymphoma t(8 MYC;14 IGH)
* Follicular lymphoma t(14 IGH;18 BCL2)
* Mantle cell lymphoma/Multiple myeloma t(11 CCND1:14 IGH)
* Anaplastic large-cell lymphoma t(2 ALK;5 NPM1)
* Acute lymphoblastic leukemia
Myeloid
* Philadelphia chromosome t(9 ABL; 22 BCR)
* Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1)
* Acute promyelocytic leukemia t(15 PML,17 RARA)
* Acute megakaryoblastic leukemia t(1 RBM15;22 MKL1)
Other
* Ewing's sarcoma t(11 FLI1; 22 EWS)
* Synovial sarcoma t(x SYT;18 SSX)
* Dermatofibrosarcoma protuberans t(17 COL1A1;22 PDGFB)
* Myxoid liposarcoma t(12 DDIT3; 16 FUS)
* Desmoplastic small-round-cell tumor t(11 WT1; 22 EWS)
* Alveolar rhabdomyosarcoma t(2 PAX3; 13 FOXO1) t (1 PAX7; 13 FOXO1)
Other
* Fragile X syndrome
* Uniparental disomy
* XX male syndrome/46,XX testicular disorders of sex development
* Marker chromosome
* Ring chromosome
* 6; 9; 14; 15; 18; 20; 21, 22
*[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
| Diffuse large B-cell lymphoma | c0079744 | 1,364 | wikipedia | https://en.wikipedia.org/wiki/Diffuse_large_B-cell_lymphoma | 2021-01-18T18:46:55 | {"gard": ["3178"], "mesh": ["D016403"], "umls": ["C0079744"], "icd-10": ["C83.3"], "orphanet": ["544"], "wikidata": ["Q2626074"]} |
Disease caused by Rinderpest morbillivirus
Rinderpest morbillivirus
Virus classification
(unranked): Virus
Realm: Riboviria
Kingdom: Orthornavirae
Phylum: Negarnaviricota
Class: Monjiviricetes
Order: Mononegavirales
Family: Paramyxoviridae
Genus: Morbillivirus
Species:
Rinderpest morbillivirus
Synonyms[1]
Rinderpest virus
Rinderpest (also cattle plague or steppe murrain) was an infectious viral disease of cattle, domestic buffalo, and many other species of even-toed ungulates, including buffaloes, large antelope, deer, giraffes, wildebeests, and warthogs.[2] The disease was characterized by fever, oral erosions, diarrhea, lymphoid necrosis, and high mortality. Death rates during outbreaks were usually extremely high, approaching 100% in immunologically naïve populations.[3] Rinderpest was mainly transmitted by direct contact and by drinking contaminated water, although it could also be transmitted by air.[4] After a global eradication campaign since the mid-20th century, the last confirmed case of rinderpest was diagnosed in 2001.[5]
On 14 October 2010, the United Nations Food and Agriculture Organization (FAO) announced that field activities in the decades-long, worldwide campaign to eradicate the disease were ending, paving the way for a formal declaration in June 2011 of the global eradication of rinderpest.[6] On 25 May 2011, the World Organisation for Animal Health announced the free status of the last eight countries not yet recognized (a total of 198 countries were now free of the disease), officially declaring the eradication of the disease.[7] In June 2011, the United Nations FAO confirmed the disease was eradicated, making rinderpest only the second disease in history to be fully wiped out (outside laboratory stocks), following smallpox.[8] In June 2019 the UK destroyed its stocks of rinderpest virus, held at the Pirbright Institute in Surrey, which were most of the world's retained samples. This followed the compilation of a digital record of the virus's genetic code, thereby obviating the need to store samples as a protective resource in case the virus re-emerges. Researchers at Pirbright and the United Nations expressed a hope that the other samples in laboratories around the world will also be destroyed, totally eradicating the virus from the Earth.[9]
Rinderpest is believed to have originated in Asia, later spreading through the transport of cattle.[10] The term Rinderpest is a German word meaning "cattle-plague".[2][10] The rinderpest virus (RPV) was closely related to the measles and canine distemper viruses.[11] The measles virus possibly emerged from rinderpest as a zoonotic disease around 600 BC, a period that coincides with the rise of large human settlements.[12][13]
## Contents
* 1 Virus
* 2 Disease and symptoms
* 3 History and epizootics
* 3.1 Early history
* 3.2 18th century
* 3.2.1 Inoculation
* 3.2.2 Early English experimentation
* 3.2.3 Further trials in the Netherlands
* 3.2.4 In other countries
* 3.3 19th century
* 3.4 20th century
* 3.5 Vaccination
* 4 Eradication
* 5 Use as a biological weapon
* 6 See also
* 7 Footnotes
* 8 General references
* 9 External links
## Virus[edit]
Rinderpest virus (RPV), a member of the genus Morbillivirus, is closely related to the measles and canine distemper viruses.[11] Like other members of the Paramyxoviridae family, it produces enveloped virions, and is a negative-sense single-stranded RNA virus. The virus was particularly fragile and is quickly inactivated by heat, desiccation and sunlight.[14]
Measles virus evolved from the then-widespread rinderpest virus most probably between the 11th and 12th centuries.[13] The earliest likely origin is during the seventh century; some linguistic evidence exists for this earlier origin.[15][16]
## Disease and symptoms[edit]
A cow with rinderpest in the "milk fever" position, 1982
Death rates during outbreaks were usually extremely high, approaching 100% in immunologically naïve populations.[3] The disease was mainly spread by direct contact and by drinking contaminated water, although it could also be transmitted by air.[4]
Initial symptoms include fever, loss of appetite, and nasal and eye discharges. Subsequently, irregular erosions appear in the mouth, the lining of the nose, and the genital tract.[3] Acute diarrhea, preceded by constipation, is also a common feature.[4] Most animals die six to twelve days after the onset of these clinical signs.[3]
## History and epizootics[edit]
See also: Epizootic
Rinderpest outbreak in 18th-century Netherlands
### Early history[edit]
The disease is believed to have originated in Asia, later spreading through the transport of cattle.[10] Other cattle epizootics are noted in ancient times: a cattle plague is thought to be one of the 10 plagues of Egypt described in the Hebrew Bible. By around 3,000 BC, a cattle plague had reached Egypt, and rinderpest later spread throughout the remainder of Africa, following European colonization.[10]
In the 4th century, Roman writer Severus Sanctus Endelechius described rinderpest in his book, On the Deaths of Cattle.[17]
### 18th century[edit]
Cattle plagues recurred throughout history, often accompanying wars and military campaigns. They hit Europe especially hard in the 18th century, with three long panzootics, which although varying in intensity and duration from region to region, took place in the periods of 1709–1720, 1742–1760, and 1768–1786.[18]
#### Inoculation[edit]
In the early 18th century, the disease was seen as similar to smallpox, due to its analogous symptoms. The personal physician of the pope, Giovanni Maria Lancisi, recommended the destruction of all infected and exposed animals. This policy was not very popular and used only sparingly in the first part of the century. Later, it was used successfully in several countries, although it was sometimes seen as too costly or drastic, and depended on a strong central authority to be effective (which was notably lacking in the Dutch Republic). Because of these downsides, numerous attempts were made to inoculate animals against the disease. These attempts met with varying success, but the procedure was not widely used and was no longer practiced at all in 19th-century Western or Central Europe. Rinderpest was an immense problem, but inoculation was not a valid solution. In many cases, it caused too many losses. Even more importantly, it perpetuated the circulation of the virus in the cattle population. The pioneers of inoculation did contribute significantly to knowledge about infectious diseases. Their experiments confirmed the concepts of those who saw infectious diseases as caused by specific agents, and were the first to recognize maternally derived immunity.[11]
#### Early English experimentation[edit]
The first written report of rinderpest inoculation was published in a letter signed "T.S." in the November 1754 issue of The Gentleman's Magazine,[11] a widely read journal which also supported the progress of smallpox inoculation. This letter reported that a Mr Dobsen had inoculated his cattle and had thus preserved 9 out of 10 of them, although this was retracted in the next issue, as it was apparently a Sir William St. Quintin who had done the inoculating (this was done by placing bits of material previously dipped in morbid discharge into an incision made in the dewlap of the animal). These letters encouraged further application of inoculation in the fight against diseases. The first inoculation against measles was made three years after their publication.[11]
From early 1755 onwards, experiments were taking place in the Netherlands, as well, results of which were also published in The Gentleman's Magazine. As in England, the disease was seen as analogous with smallpox. While these experiments were reasonably successful, they did not have a significant impact: The total number of inoculations in England appears to have been very limited, and after 1780, the English interest in inoculation disappeared almost entirely.[11] Almost all further experimentation was done in the Netherlands, northern Germany and Denmark.
#### Further trials in the Netherlands[edit]
Due to a very severe outbreak at the end of the 1760s, some of the best-known names in Dutch medicine became involved in the struggle against the disease. Several independent trials were begun, most notably by Pieter Camper in Groningen and Friesland. The results of his experiment in Friesland were encouraging, but they proved to be the exception; testing by others in the provinces of Utrecht and Friesland obtained disastrous results. As a result, the Frisian authorities concluded in 1769 that the cause of rinderpest was God's displeasure with the sinful behavior of the Frisian people, and proclaimed 15 November a day of fasting and prayer. Interest in inoculation declined sharply across the country.[11]
In this climate of discouragement and scepticism, Geert Reinders, a farmer in the province of Groningen and a self-taught man, decided to continue the experiments. He collaborated with Wijnold Munniks, who had supervised earlier trials. They tried different inoculation procedures and a variety of treatments to lighten the symptoms, all of them without significant effect. Although they were not able to perfect the inoculation procedure, they did make some useful observations.[11]
Reinders resumed his experiments in 1774, concentrating on the inoculation of calves from cows that had recovered from rinderpest. He was probably the first to make practical use of maternally derived immunity.[11] The detailed results of his trials were published in 1776 and reprinted in 1777. His inoculation procedure did not differ much from what had been used previously, except for the use of three separate inoculations at an early age. This produced far better results, and the publication of his work renewed interest in inoculation. For the period of 1777 to 1781, 89% of inoculated animals survived, compared to a 29% survival rate after natural infection.[11]
In the Netherlands, too, interest in rinderpest inoculation declined in the 1780s because the disease itself decreased in intensity.
#### In other countries[edit]
Apart from the Dutch Republic, the only other regions where inoculation was used to any significant level were northern Germany and Denmark. Experiments started in Mecklenburg during the epizootic of the late 1770s. "Insurance companies" were created which provided inoculation in special "institutes". Although these were private initiatives, they were created with full encouragement from the authorities. Though neighboring states followed this practice with interest, the practice never caught on outside Mecklenburg; many were still opposed to inoculation.[11]
While some experimentation occurred in other countries (most extensively in Denmark), in the majority of European countries, the struggle against the disease was based on stamping it out. Sometimes this could be done with minimal sacrifices; at other times, it required slaughter at a massive scale.[11]
### 19th century[edit]
Cows dead from rinderpest in South Africa, 1896
A major outbreak affected the whole of the British Isles for three years after 1865.[19]
Around the turn of the century, a plague struck in Southern Africa.[19] The outbreak in the 1890s killed an estimated 80 to 90% of all cattle in eastern and southern Africa, as well as in the Horn of Africa. Sir Arnold Theiler was instrumental in developing a vaccine that curbed the epizootic. The loss of animals caused famine which depopulated sub-Saharan Africa, allowing thornbush to colonise. This formed ideal habitat for tsetse fly, which carries sleeping sickness, and is unsuitable for livestock.[20]
### 20th century[edit]
In his classic study of the Nuer of southern Sudan, E. E. Evans-Pritchard suggested rinderpest might have affected the Nuer's social organization before and during the 1930s. Since the Nuer were pastoralists, much of their livelihood was based on cattle husbandry, and bride-prices were paid in cattle; prices may have changed as a result of cattle depletion. Rinderpest might also have increased dependence on horticulture among the Nuer.[21]
A more recent rinderpest outbreak in Africa in 1982–1984 resulted in an estimated US$2 billion in stock losses.[22]
### Vaccination[edit]
In 1917–18, William Hutchins Boynton (1881–1959), the chief veterinary pathologist with the Philippine Bureau of Agriculture, developed an early vaccine for rinderpest, based on treated animal organ extracts.[23][24]
Walter Plowright worked on a vaccine for the RBOK strain of the rinderpest virus for about a decade, from 1956 to 1962.[25] Plowright was awarded the World Food Prize in 1999 for developing a vaccine against a strain of rinderpest. In 1999, the FAO predicted that with vaccination, rinderpest would be eradicated by 2010.[26]
## Eradication[edit]
Year of the last reported Rinderpest case.[27]
Widespread eradication efforts began in the early 20th century although, until the 1950s, they mostly took place on an individual country basis, using vaccination campaigns. In 1924, the World Organisation for Animal Health (OIE) was formed in response to rinderpest.[28] In 1950, the Inter-African Bureau of Epizootic Diseases was formed, with the stated goal of eliminating rinderpest from Africa.[28] During the 1960s, a program called JP 15 attempted to vaccinate all cattle in participating countries and, by 1979, only one of the countries involved, Sudan, reported cases of rinderpest.[28]
In 1969, an outbreak of the disease originated in Afghanistan, travelling westwards and promoting a mass vaccination plan, which by 1972, had eliminated rinderpest in all areas of Asia except for Lebanon and India; both countries were the site of further occurrences of the disease in the 1980s.[28]
During the 1980s, however, an outbreak of rinderpest from Sudan spread throughout Africa, killing millions of cattle, as well as wildlife.[28] In response, the Pan-African Rinderpest Campaign was initiated in 1987, using vaccination and surveillance to combat the disease.[28] By the 1990s, nearly all of Africa, with the exception of parts of Sudan and Somalia, was declared free of rinderpest.[28]
Worldwide, the Global Rinderpest Eradication Programme was initiated in 1994, supported by the Food and Agriculture Organization, the OIE, and the International Atomic Energy Agency.[28] This program was successful in reducing rinderpest outbreaks to few and far between by the late 1990s.[28] The program is estimated to have saved affected farmers 58 million net euros.[29]
The last confirmed case of rinderpest was reported in Kenya in 2001.[30] Since then, while no cases have been confirmed, the disease is believed to have been present in parts of Somalia past that date.[30] The final vaccinations were administered in 2006, and the last surveillance operations took place in 2009, failing to find any evidence of the disease.[30]
In 2008, scientists involved in rinderpest eradication efforts believed a good chance existed that rinderpest would join smallpox as officially "wiped off the face of the planet".[5] The FAO, which had been co-ordinating the global eradication program for the disease, announced in November 2009 that it expected the disease to be eradicated within 18 months.[31]
In October 2010, the FAO announced it was confident the disease has been eradicated.[6] The agency said that "[a]s of mid 2010, FAO is confident that the rinderpest virus has been eliminated from Europe, Asia, Middle East, Arabian Peninsula, and Africa," which were the locations where the virus had been last reported.[6] Eradication was confirmed by the World Organization for Animal Health on 25 May 2011.[7]
On 28 June 2011, FAO and its members countries officially recognized global freedom from the deadly cattle virus. On this day, the FAO Conference, the highest body of the UN agency, adopted a resolution declaring the eradication of rinderpest. The resolution also called on the world community to follow up by ensuring that samples of rinderpest viruses and vaccines be kept under safe laboratory conditions and that rigorous standards for disease surveillance and reporting be applied. "While we are celebrating one of the greatest successes for FAO and its partners, I wish to remind you that this extraordinary achievement would not have been possible without the joint efforts and strong commitments of governments, the main organizations in Africa, Asia and Europe, and without the continuous support of donors and international institutions", FAO Director-General Jacques Diouf commented.[32]
The rinderpest eradication effort is estimated to have cost $5 billion.[33]
Stocks of the rinderpest virus are still maintained by highly specialized laboratories.[30] In 2015, FAO launched a campaign calling for the destruction or sequestering of the remaining stocks of rinderpest virus in laboratories in 24 different countries, citing risks of inadvertent or malicious release.[34]
On 14 June 2019 the largest stock of the rinderpest virus was destroyed at the Pirbright Institute.[35]
## Use as a biological weapon[edit]
Rinderpest was one of more than a dozen agents the United States researched as potential biological weapons before terminating its biological weapons program.[36]
Rinderpest is of concern as a biological weapon for the following reasons:
* The disease has high rates of morbidity and mortality.
* The disease is highly communicable and spreads rapidly once introduced into nonimmune herds.
* Cattle herds are no longer immunized against RPV, so are susceptible to infection.[37]
Rinderpest was also considered as a biological weapon in the United Kingdom's program during World War II.[38]
## See also[edit]
* Viruses portal
* Murrain
* Ovine rinderpest
* Rift Valley fever
* Smallpox
## Footnotes[edit]
1. ^ "ICTV Taxonomy history: Rinderpest morbillivirus". International Committee on Taxonomy of Viruses (ICTV). Retrieved 15 January 2019.
2. ^ a b Donald G. McNeil Jr. (27 June 2011). "Rinderpest, Scourge of Cattle, Is Vanquished". The New York Times. Retrieved 28 June 2011.
3. ^ a b c d "Exotic animal diseases - Rinderpest". .dpi.qld.gov.au. Archived from the original on March 30, 2010. Retrieved 2010-10-15.
4. ^ a b c "Rinderpest - the toll and treatment of a plague". Food and Agriculture Organization (FAO). 1996. Archived from the original on 1997-06-09.
5. ^ a b Dennis Normile (2008). "Driven to Extinction". Science. 319 (5870): 1606–1609. doi:10.1126/science.319.5870.1606. PMID 18356500. S2CID 46157093.
6. ^ a b c "UN 'confident' disease has been wiped out". BBC News. 14 October 2010. Retrieved 14 October 2010.
7. ^ a b "No More Deaths From Rinderpest" (Press release). World Organisation for Animal Health. Retrieved 25 May 2011.
8. ^ McNeil Jr, Donald G. (27 June 2011). "Rinderpest, a Centuries-Old Animal Disease, Is Eradicated". The New York Times.
9. ^ "Largest world stock of animal-killing virus destroyed by UK lab". BBC News. 15 June 2019.
10. ^ a b c d Donald G. McNeil Jr. (15 October 2010). "Virus Deadly in Livestock Is No More, U.N. Declares". The New York Times. Retrieved 15 October 2010.
11. ^ a b c d e f g h i j k l Huygelen, C. (1997). "The immunization of cattle against rinderpest in eighteenth-century Europe". Medical History. 41 (2): 182–196. doi:10.1017/s0025727300062372. PMC 1043905. PMID 9156464.
12. ^ Düx, Ariane; Lequime, Sebastian; Patrono, Livia Victoria; Vrancken, Bram; Boral, Sengül; Gogarten, Jan F.; Hilbig, Antonia; Horst, David; Merkel, Kevin; Prepoint, Baptiste; Santibanez, Sabine (2020-06-19). "Measles virus and rinderpest virus divergence dated to the sixth century BCE". Science. 368 (6497): 1367–1370. doi:10.1126/science.aba9411. ISSN 0036-8075. PMC 7713999. PMID 32554594. S2CID 219843735.
13. ^ a b Furuse, Yuki; Akira Suzuki; Hitoshi Oshitani (2010-03-04). "Origin of measles virus: divergence from rinderpest virus between the 11th and 12th centuries". Virology Journal. 7: 52. doi:10.1186/1743-422X-7-52. ISSN 1743-422X. PMC 2838858. PMID 20202190.
14. ^ "Rinderpest". Disease Facts. Institute for Animal Health. Archived from the original on June 26, 2009. Retrieved 2010-10-15.
15. ^ Griffin DE. In: Fields VIROLOGY. 5. Knipe DM, Howley PM, editor. Lippincott Williams & Wilkins; 2007. Measles Virus
16. ^ McNeil W. Plagues and Peoples. New York: Anchor Press/Doubleday. 1976
17. ^ Pastoret, Paul-Pierre; Yamanouchi, Kazuya; Mueller-Doblies*, Uwe; Rweyemamu, Mark M.; Horzinek, Marian; Barrett, Thomas (17 December 2005). "Rinderpest — an old and worldwide story: history to c. 1902". Rinderpest and peste des petits ruminants : virus plagues of large and small ruminants. Academic Press. pp. 86–104. doi:10.1016/B978-012088385-1/50035-6. ISBN 978-0120883851.
18. ^ Broad, J. (1983). "Cattle Plague in Eighteenth-Century England" (PDF). Agricultural History Review. 31 (2): 104–115. PMID 11620313. Retrieved 2013-09-17.
19. ^ a b Fisher, John R. (1998). "Cattle Plagues Past and Present: The Mystery of Mad Cow Disease". Journal of Contemporary History. 33 (2): 215–228. doi:10.1177/002200949803300202. JSTOR 260973. S2CID 161148001.
20. ^ Pearce, Fred (12 August 2000). "Inventing Africa" (PDF). New Scientist. 167 (2251): 30.
21. ^ Evans-Pritchard, E. E. (1940). The Nuer: A description of the modes of livelihood and political institutions of a Nilotic people. Oxford University Press.
22. ^ "Progress against rinderpest — livestock disease — threatened as a re-emergence of virus noted in Kenya, Somalia". United Nations. 20 November 2002. AFR/520-SAG/112. Retrieved 2018-01-10.
23. ^ Boynton, W.H. (1917). "Preliminary report on the virulence of certain body organs in riderpest". Philippine Agricultural Review. 10 (4): 410–433.
24. ^ Boynton, W.H. (1918). "Use of organ extracts instead of virulent blood in immunization and hyperimmunization against rinderpest". Philippine Journal of Science. 13 (3): 151–158.
25. ^ Plowright, W.; Ferris, R. D. (1962). "Studies with rinderpest virus in tissue culture. The use of attenuated culture virus as a vaccine for cattle". Res Vet Sci. 3: 172–182. doi:10.1016/S0034-5288(18)34916-6.
26. ^ "EMPRES Transboundary Animal Diseases Bulletin No. 11 - Rinderpest". Food and Agriculture Organization (FAO). 1923-07-20. Retrieved 2010-10-15.
27. ^ "Year of the last reported Rinderpest case". Our World in Data. Retrieved 5 March 2020.
28. ^ a b c d e f g h i "History of battle against rinderpest". International Atomic Energy Association. Retrieved 15 October 2010.
29. ^ Tambi, EN; Maina, OW; Mukhebi, AW; Randolph, TF (1999). "Economic impact assessment of rinderpest control in Africa" (PDF). Rev Sci Tech. 18 (2): 458–77. doi:10.20506/rst.18.2.1164. hdl:10568/35032. PMID 10472679.
30. ^ a b c d Sample, Ian (14 October 2010). "Scientists eradicate deadly rinderpest virus". The Guardian. London. Retrieved 15 October 2010.
31. ^ Platt, John (30 November 2009). "Cattle plague: An extinction worth celebrating". Scientific American. Retrieved 30 November 2009.
32. ^ "Rinderpest eradicated, what's next?" (Press release). Food and Agriculture Organization (FAO). 28 June 2011. Retrieved 30 June 2011.
33. ^ McNeil Jr, Donald G. (27 June 2011). "Rinderpest". New York Times.
34. ^ "Maintaining global freedom from Rinderpest" (Press release). Food and Agriculture Organization (FAO). 1 November 2015. Retrieved 23 November 2016.
35. ^ "Killer virus destroyed by UK lab". 2019-06-14. Retrieved 2019-06-14.
36. ^ "Chemical and Biological Weapons: Possession and Programs Past and Present" (PDF). James Martin Center for Nonproliferation Studies, Middlebury College. April 9, 2002. Retrieved November 14, 2008.
37. ^ "Rinderpest". CIDRAP. Archived from the original on 24 June 2013. Retrieved 15 April 2018.
38. ^ Bowcott, Owen; Evans, Rob (16 May 2010). "British secret biological warfare testing". The Guardian. London.
## General references[edit]
* Spinage, Clive A. (2003). Cattle Plague: A History. New York: Springer. ISBN 978-0-306-47789-8. OCLC 52178719. Retrieved February 25, 2017.
## External links[edit]
Wikimedia Commons has media related to Rinderpest.
* The IAEA's activities with rinderpest
* Rinderpest reviewed and published by WikiVet
* FAO Maintaining Global Freedom from Rinderpest
* OIE Rinderpest disease card
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* Vaccination
* Zoonosis
Taxon identifiers
Rinderpest morbillivirus
* Wikidata: Q29004635
* Wikispecies: Rinderpest morbillivirus
* NCBI: 11241
Rinderpest virus
* Wikidata: Q2153407
* IRMNG: 11460688
Authority control
* NDL: 00562736
*[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
| Rinderpest | c0035637 | 1,365 | wikipedia | https://en.wikipedia.org/wiki/Rinderpest | 2021-01-18T18:35:58 | {"mesh": ["D012301"], "wikidata": ["Q157008"]} |
An AV fistula.
A Cimino fistula, also Cimino-Brescia fistula, surgically created arteriovenous fistula and (less precisely) arteriovenous fistula (often abbreviated AV fistula or AVF), is a type of vascular access for hemodialysis. It is typically a surgically created connection between an artery and a vein in the arm, although there have been acquired arteriovenous fistulas which do not in fact demonstrate connection to an artery.[1]
Surgically created AV fistula
## Contents
* 1 Theoretical basis
* 2 History
* 3 Anatomy
* 4 See also
* 5 References
* 6 External links
## Theoretical basis[edit]
Surgically created AV fistulas work effectively because they:
* Have high volume flow rates (as blood takes the path of least resistance; it prefers the (low resistance) AV fistula over traversing (high resistance) capillary beds).
* Use native blood vessels, which, when compared to synthetic grafts,[2] are less likely to develop stenoses and fail.
## History[edit]
The procedure was invented by doctors James Cimino and M. J. Brescia in 1966.[3] Before the Cimino fistula was invented, access was through a Scribner shunt, which consisted of a Teflon tube with a needle at each end. Between treatments, the needles were left in place and the tube allowed blood flow to reduce clotting. But Scribner shunts lasted only a few days to weeks. Frustrated by this limitation, James E. Cimino recalled his days as a phlebotomist (blood drawer) at New York City's Bellevue Hospital in the 1950s when Korean War veterans showed up with fistulas caused by trauma. Cimino recognized that these fistulas did not cause the patients harm and were easy places to get repeated blood samples. He convinced surgeon Kenneth Appell to create some in patients with chronic kidney failure and the result was a complete success. Scribner shunts were quickly replaced with Cimino fistulas, and they remain the most effective, longest-lasting method for long-term access to patients' blood for hemodialysis today.
## Anatomy[edit]
The radiocephalic arteriovenous fistula (RC-AVF) is a shortcut between cephalic vein and radial artery at the wrist. It is the recommended first choice for hemodialysis access. Possible underlying causes for failure are stenosis and thrombosis especially in diabetics and those with low blood flow such as due to narrow vessels, arteriosclerosis and advanced age. Reported patency of fistulae after 1 year is about 62.5%.[4]
## See also[edit]
* Arteriovenous fistula
## References[edit]
1. ^ "Case Report : Acquired Arteriovenous Fistula of the Right Forearm Caused by Repeated Blunt Trauma: a Report of a Rare Case" (PDF). Atcs.jp. Retrieved 2013-09-08.
2. ^ Konner K (2002). "Vascular access in the 21st century". J. Nephrol. 15 Suppl 6: S28–32. PMID 12515371.
3. ^ Brescia MJ, Cimino JE, Appel K, Hurwich BJ (1966). "Chronic hemodialysis using venipuncture and a surgically created arteriovenous fistula". N. Engl. J. Med. 275 (20): 1089–92. doi:10.1056/NEJM196611172752002. PMID 5923023.
4. ^ 1A. A. Al-Jaishi; M. J. Oliver; S. M. Thomas; C. E. Lok (2014). "Patency Rates of the Arteriovenous Fistula for Hemodialysis: A Systematic Review and Meta-analysis". Cite journal requires `|journal=` (help)
## External links[edit]
* A Milestone in Hemodialysis: James E. Cimino, MD, and the Development of the AV Fistula
*[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
| Cimino fistula | None | 1,366 | wikipedia | https://en.wikipedia.org/wiki/Cimino_fistula | 2021-01-18T18:28:01 | {"mesh": ["D001166"], "wikidata": ["Q1092122"]} |
Human disease caused by West Nile virus infection
This article is about the disease. For the virus, see West Nile virus.
West Nile fever
West Nile virus
SpecialtyInfectious disease
SymptomsNone, fever, headache, vomiting or diarrhea and muscle aches rash[1]
ComplicationsEncephalitis, meningitis[1]
Usual onset2 to 14 days after exposure[1]
DurationWeeks to months[1]
CausesWest Nile virus spread by mosquito[1]
Diagnostic methodBased on symptoms and blood tests[1]
PreventionReducing mosquitoes, preventing mosquito bites[1]
TreatmentSupportive care (pain medication)[1]
Prognosis10% risk of death among those seriously affected[1]
West Nile fever is an infection by the West Nile virus, which is typically spread by mosquitoes.[1] In about 80% of infections people have few or no symptoms.[2] About 20% of people develop a fever, headache, vomiting, or a rash.[1] In less than 1% of people, encephalitis or meningitis occurs, with associated neck stiffness, confusion, or seizures.[1] Recovery may take weeks to months.[1] The risk of death among those in whom the nervous system is affected is about 10%.[1]
West Nile virus (WNV) is usually spread by mosquitoes that become infected when they feed on infected birds, which often carry the disease.[1] Rarely the virus is spread through blood transfusions, organ transplants, or from mother to baby during pregnancy, delivery, or breastfeeding,[1] but it otherwise does not spread directly between people.[3] Risks for severe disease include being over 60 years old and having other health problems.[1] Diagnosis is typically based on symptoms and blood tests.[1]
There is no human vaccine.[1] The best way to reduce the risk of infection is to avoid mosquito bites.[1] Mosquito populations may be reduced by eliminating standing pools of water, such as in old tires, buckets, gutters, and swimming pools.[1] When mosquitoes cannot be avoided, mosquito repellent, window screens, and mosquito nets reduce the likelihood of being bitten.[1][3] There is no specific treatment for the disease; pain medications may reduce symptoms.[1]
The virus was discovered in Uganda in 1937, and was first detected in North America in 1999.[1][3] WNV has occurred in Europe, Africa, Asia, Australia, and North America.[1] In the United States thousands of cases are reported a year, with most occurring in August and September.[4] It can occur in outbreaks of disease.[3] Severe disease may also occur in horses, for which a vaccine is available.[3] A surveillance system in birds is useful for early detection of a potential human outbreak.[3]
## Contents
* 1 Signs and symptoms
* 2 Cause
* 2.1 Virology
* 2.2 Transmission
* 2.2.1 Vertical transmission
* 2.3 Risk factors
* 3 Diagnosis
* 3.1 Differential diagnosis
* 4 Prevention
* 4.1 Monitoring and control
* 5 Treatment
* 6 Prognosis
* 7 Epidemiology
* 7.1 Weather
* 8 Research
* 9 References
* 10 External links
## Signs and symptoms[edit]
About 80% of those infected with West Nile virus (WNV) show no symptoms and go unreported.[5] About 20% of infected people develop symptoms. These vary in severity, and begin 3 to 14 days after being bitten. Most people with mild symptoms of WNV recover completely, though fatigue and weakness may last for weeks or months. Symptoms may range from mild, such as fever, to severe, such as paralysis and meningitis. A severe infection can last weeks and can, rarely, cause permanent brain damage. Death may ensue if the central nervous system is affected. Medical conditions such as cancer and diabetes, and age over 60 years, increase the risk of developing severe symptoms.[6][7]
Headache can be a prominent symptom of WNV fever, meningitis, encephalitis, meningoencephalitis, and it may or may not be present in poliomyelitis-like syndrome. Thus, headache is not a useful indicator of neuroinvasive disease.
* West Nile fever (WNF), which occurs in 20 percent of cases, is a febrile syndrome that causes flu-like symptoms.[8] Most characterizations of WNF describe it as a mild, acute syndrome lasting 3 to 6 days after symptom onset. Systematic follow-up studies of patients with WNF have not been done, so this information is largely anecdotal. Possible symptoms include high fever, headache, chills, excessive sweating, weakness, fatigue, swollen lymph nodes, drowsiness, pain in the joints and flu-like symptoms. There may be gastrointestinal symptoms including nausea, vomiting, loss of appetite, and diarrhea. Fewer than one-third of patients develop a rash.
* West Nile neuroinvasive disease (WNND), which occurs in less than 1 percent of cases, is when the virus infects the central nervous system resulting in meningitis, encephalitis, meningoencephalitis or a poliomyelitis-like syndrome.[9] Many patients with WNND have normal neuroimaging studies, although abnormalities may be present in various cerebral areas including the basal ganglia, thalamus, cerebellum, and brainstem.[9]
* West Nile virus encephalitis (WNE) is the most common neuroinvasive manifestation of WNND. WNE presents with similar symptoms to other viral encephalitis with fever, headaches, and altered mental status. A prominent finding in WNE is muscular weakness (30 to 50 percent of patients with encephalitis), often with lower motor neuron symptoms, flaccid paralysis, and hyporeflexia with no sensory abnormalities.[10][11]
* West Nile meningitis (WNM) usually involves fever, headache, stiff neck and pleocytosis, an increase of white blood cells in cerebrospinal fluid. Changes in consciousness are not usually seen and are mild when present.
* West Nile meningoencephalitis is inflammation of both the brain (encephalitis) and meninges (meningitis).
* West Nile poliomyelitis (WNP), an acute flaccid paralysis syndrome associated with WNV infection, is less common than WNM or WNE. This syndrome is generally characterized by the acute onset of asymmetric limb weakness or paralysis in the absence of sensory loss. Pain sometimes precedes the paralysis. The paralysis can occur in the absence of fever, headache, or other common symptoms associated with WNV infection. Involvement of respiratory muscles, leading to acute respiratory failure, sometimes occurs.
* West-Nile reversible paralysis, Like WNP, the weakness or paralysis is asymmetric.[12] Reported cases have been noted to have an initial preservation of deep tendon reflexes, which is not expected for a pure anterior horn involvement.[12] Disconnect of upper motor neuron influences on the anterior horn cells possibly by myelitis or glutamate excitotoxicity have been suggested as mechanisms.[12] The prognosis for recovery is excellent.
* Nonneurologic complications of WNV infection that may rarely occur include fulminant hepatitis, pancreatitis,[13] myocarditis, rhabdomyolysis,[14] orchitis,[15] nephritis, optic neuritis[16] and cardiac dysrhythmias and hemorrhagic fever with coagulopathy.[17] Chorioretinitis may also be more common than previously thought.[18]
* Skin manifestations, specifically rashes, are common; however, there are few detailed descriptions in case reports, and few images are available. Punctate erythematous, macular, and papular eruptions, most pronounced on the extremities have been observed in WNV cases and in some cases histopathologic findings have shown a sparse superficial perivascular lymphocytic infiltrate, a manifestation commonly seen in viral exanthems. A literature review provides support that this punctate rash is a common cutaneous presentation of WNV infection.[19]
## Cause[edit]
### Virology[edit]
Main article: West Nile virus
West Nile virus life cycle. After binding and uptake, the virion envelope fuses with cellular membranes, followed by uncoating of the nucleocapsid and release of the RNA genome into the cytoplasm. The viral genome serves as messenger RNA (mRNA) for translation of all viral proteins and as template during RNA replication. Copies are subsequently packaged within new virus particles that are transported in vesicles to the cell membrane.
WNV is one of the Japanese encephalitis antigenic serocomplex of viruses.[20] Image reconstructions and cryoelectron microscopy reveal a 45–50 nm virion covered with a relatively smooth protein surface. This structure is similar to the dengue fever virus; both belong to the genus Flavivirus within the family Flaviviridae. The genetic material of WNV is a positive-sense, single strand of RNA, which is between 11,000 and 12,000 nucleotides long; these genes encode seven nonstructural proteins and three structural proteins. The RNA strand is held within a nucleocapsid formed from 12-kDa protein blocks; the capsid is contained within a host-derived membrane altered by two viral membrane proteins.[citation needed]
West Nile virus has been seen to replicate faster and spread more easily to birds at higher temperatures; one of several ways climate change could impact the epidemiology of this disease.[21]
### Transmission[edit]
West Nile virus maintains itself in nature by cycling between mosquitoes in the genus Culex and certain species of birds. A mosquito (the vector) bites an uninfected bird (the host), the virus amplifies within the bird, an uninfected mosquito bites the bird and is in turn infected. Other species such as humans and horses are incidental infections, because the virus does not amplify well within these species and they are considered dead-end hosts.
The prime method of spread of the West Nile virus (WNV) is the female mosquito. In Europe, cats were identified as being hosts for West Nile virus.[22] The important mosquito vectors vary according to area; in the United States, Culex pipiens (Eastern United States, and urban and residential areas of the United States north of 36–39°N), Culex tarsalis (Midwest and West), and Culex quinquefasciatus (Southeast) are the main vector species.[23]
The mosquito species that are most frequently infected with WNV feed primarily on birds.[24] Different species of mosquitos take a blood meal from different types of vertebrate hosts, Mosquitoes show further selectivity, exhibiting preference for different species of birds. In the United States, WNV mosquito vectors feed preferentially on members of the Corvidae and thrush family. Among the preferred species within these families are the American crow, a corvid, and the American robin (Turdus migratorius).[25]
Some species of birds develop sufficient viral levels (>~104.2 log PFU/ml;[26]) after being infected to transmit the infection to biting mosquitoes that in turn go on to infect other birds. In birds that die from WNV, death usually occurs after 4 to 6 days.[27] In mammals and several species of birds, the virus does not multiply as readily and so does not develop high viremia during infection. Mosquitoes biting such hosts are not believed to ingest sufficient virus to become infected, making them so-called dead-end hosts.[26] As a result of the differential infectiousness of hosts, the feeding patterns of mosquitoes play an important role in WNV transmission,[24][25] and they are partly genetically controlled, even within a species.
Direct human-to-human transmission initially was believed to be caused only by occupational exposure, such as in a laboratory setting,[28] or conjunctival exposure to infected blood.[29] The US outbreak identified additional transmission methods through blood transfusion,[30] organ transplant,[31] intrauterine exposure,[32] and breast feeding.[33] Since 2003, blood banks in the United States routinely screen for the virus among their donors.[34] As a precautionary measure, the UK's National Blood Service initially ran a test for this disease in donors who donate within 28 days of a visit to the United States, Canada, or the northeastern provinces of Italy, and the Scottish National Blood Transfusion Service[35] asks prospective donors to wait 28 days after returning from North America or the northeastern provinces of Italy before donating. There also have been reports of possible transmission of the virus from mother to child during pregnancy or breastfeeding or exposure to the virus in a lab, but these are rare cases and not conclusively confirmed.[36]
Recently, the potential for mosquito saliva to affect the course of WNV disease was demonstrated.[37][38][39] Mosquitoes inoculate their saliva into the skin while obtaining blood. Mosquito saliva is a pharmacological cocktail of secreted molecules, principally proteins, that can affect vascular constriction, blood coagulation, platelet aggregation, inflammation, and immunity. It clearly alters the immune response in a manner that may be advantageous to a virus.[40][41][42][43] Studies have shown it can specifically modulate the immune response during early virus infection,[44] and mosquito feeding can exacerbate WNV infection, leading to higher viremia and more severe forms of disease.[37][38][39]
#### Vertical transmission[edit]
Vertical transmission, the transmission of a viral or bacterial disease from the female of the species to her offspring, has been observed in various West Nile virus studies, amongst different species of mosquitoes in both the laboratory and in nature.[45] Mosquito progeny infected vertically in autumn may potentially serve as a mechanism for WNV to overwinter and initiate enzootic horizontal transmission the following spring, although it likely plays little role in transmission in the summer and fall.[46]
### Risk factors[edit]
Risk factors independently associated with developing a clinical infection with WNV include a suppressed immune system and a patient history of organ transplantation.[47] For neuroinvasive disease the additional risk factors include older age (>50+), male sex, hypertension, and diabetes mellitus.[48][49]
A genetic factor also appears to increase susceptibility to West Nile disease. A mutation of the gene CCR5 gives some protection against HIV but leads to more serious complications of WNV infection. Carriers of two mutated copies of CCR5 made up 4.0 to 4.5% of a sample of West Nile disease sufferers, while the incidence of the gene in the general population is only 1.0%.[50][51]
The most at risk occupations in the U.S. are outdoor workers, for example farmers, loggers, landscapers/groundskeepers, construction workers, painters, summer camp workers and pavers.[52] Two reports of accidental exposure by laboratory personnel working with infected fluids or tissues have been received. While this appears to be a rare occurrence, it highlights the need for proper handling of infected materials. The World Health Organization states that there are no known cases of health care workers acquiring the virus from infected patients when the appropriate infection control precautions are observed.[53]
## Diagnosis[edit]
An immunoglobulin M antibody molecule: Definitive diagnosis of WNV is obtained through detection of virus-specific IgM and neutralizing antibodies.
Preliminary diagnosis is often based on the patient's clinical symptoms, places and dates of travel (if patient is from a nonendemic country or area), activities, and epidemiologic history of the location where infection occurred. A recent history of mosquito bites and an acute febrile illness associated with neurologic signs and symptoms should cause clinical suspicion of WNV.
Diagnosis of West Nile virus infections is generally accomplished by serologic testing of blood serum or cerebrospinal fluid (CSF), which is obtained via a lumbar puncture. Initial screening could be done using the ELISA technique detecting immunoglobulins in the sera of the tested individuals.
Typical findings of WNV infection include lymphocytic pleocytosis, elevated protein level, reference glucose and lactic acid levels, and no erythrocytes.
Definitive diagnosis of WNV is obtained through detection of virus-specific antibody IgM and neutralizing antibodies. Cases of West Nile virus meningitis and encephalitis that have been serologically confirmed produce similar degrees of CSF pleocytosis and are often associated with substantial CSF neutrophilia.[54] Specimens collected within eight days following onset of illness may not test positive for West Nile IgM, and testing should be repeated. A positive test for West Nile IgG in the absence of a positive West Nile IgM is indicative of a previous flavivirus infection and is not by itself evidence of an acute West Nile virus infection.[55]
If cases of suspected West Nile virus infection, sera should be collected on both the acute and convalescent phases of the illness. Convalescent specimens should be collected 2–3 weeks after acute specimens.
It is common in serologic testing for cross-reactions to occur among flaviviruses such as dengue virus (DENV) and tick-borne encephalitis virus; this necessitates caution when evaluating serologic results of flaviviral infections.[56]
Four FDA-cleared WNV IgM ELISA kits are commercially available from different manufacturers in the U.S., each of these kits is indicated for use on serum to aid in the presumptive laboratory diagnosis of WNV infection in patients with clinical symptoms of meningitis or encephalitis. Positive WNV test results obtained via use of these kits should be confirmed by additional testing at a state health department laboratory or CDC.
In fatal cases, nucleic acid amplification, histopathology with immunohistochemistry, and virus culture of autopsy tissues can also be useful. Only a few state laboratories or other specialized laboratories, including those at CDC, are capable of doing this specialized testing.
### Differential diagnosis[edit]
A number of various diseases may present with symptoms similar to those caused by a clinical West Nile virus infection. Those causing neuroinvasive disease symptoms include the enterovirus infection and bacterial meningitis. Accounting for differential diagnoses is a crucial step in the definitive diagnosis of WNV infection. Consideration of a differential diagnosis is required when a patient presents with unexplained febrile illness, extreme headache, encephalitis or meningitis. Diagnostic and serologic laboratory testing using polymerase chain reaction (PCR) testing and viral culture of CSF to identify the specific pathogen causing the symptoms, is the only currently available means of differentiating between causes of encephalitis and meningitis.
## Prevention[edit]
Low-cost, ceiling hung mosquito netting for a bed
Many of the guidelines for preventing occupational West Nile virus exposure are common to all mosquito-borne diseases.[57]
Public health measures include taking steps to reduce mosquito populations. Personal recommendations are to reduce the likelihood of being bitten. General measures to avoid bites include:
* Using insect repellent on exposed skin to repel mosquitoes. Repellents include products containing DEET and picaridin. DEET concentrations of 30% to 50% are effective for several hours. Picaridin, available at 7% and 15% concentrations, needs more frequent application. DEET formulations as high as 30% are recommended for children over two months of age.[58] The CDC also recommends the use of: IR3535, oil of lemon eucalyptus, para-menthane-diol, or 2-undecanone.[59] Protect infants less than two months of age by using a carrier draped with mosquito netting with an elastic edge for a tight fit.
* When using sunscreen, apply sunscreen first and then repellent. Repellent should be washed off at the end of the day before going to bed.
* Wear long-sleeve shirts, which should be tucked in, long trousers, socks, and hats to cover exposed skin (although most fabrics do not totally protect against bites). Insect repellents should be applied over top of protective clothing for greater protection. Do not apply insect repellents underneath clothing.
* Repellents containing permethrin (e.g., Permanone) or other insect repellents may be applied to clothing, shoes, tents, mosquito nets, and other gear. (Permethrin is not suitable for use directly on skin.) Most repellent is generally removed from clothing and gear by a single washing, but permethrin-treated clothing is effective for up to five washings.
* Most mosquitoes that transmit disease are most active at dawn and in the evening dusk. A notable exception is the Asian tiger mosquito, which is a daytime feeder and is more apt to be found in, or on the periphery of, shaded areas with heavy vegetation. They are now widespread in the United States, and in Florida they have been found in all 67 counties.[60]
* In an at-risk area, staying in air-conditioned or well-screened room, or sleeping under an insecticide-treated bed net is recommended. Bed nets should be tucked under mattresses, and can be sprayed with a repellent if not already treated with an insecticide.[57]
### Monitoring and control[edit]
West Nile virus can be sampled from the environment by the pooling of trapped mosquitoes via ovitraps, carbon dioxide-baited light traps, and gravid traps, testing blood samples drawn from wild birds, dogs, and sentinel monkeys, and testing brains of dead birds found by various animal control agencies and the public.
Testing of the mosquito samples requires the use of reverse-transcriptase PCR (RT-PCR) to directly amplify and show the presence of virus in the submitted samples. When using the blood sera of wild birds and sentinel chickens, samples must be tested for the presence of WNV antibodies by use of immunohistochemistry (IHC)[61] or enzyme-linked immunosorbent assay (ELISA).[62]
Dead birds, after necropsy, or their oral swab samples collected on specific RNA-preserving filter paper card,[63][64] can have their virus presence tested by either RT-PCR or IHC, where virus shows up as brown-stained tissue because of a substrate-enzyme reaction.
West Nile control is achieved through mosquito control, by elimination of mosquito breeding sites such as abandoned pools, applying larvacide to active breeding areas, and targeting the adult population via lethal ovitraps and aerial spraying of pesticides.
Environmentalists have condemned attempts to control the transmitting mosquitoes by spraying pesticide, saying the detrimental health effects of spraying outweigh the relatively few lives that may be saved, and more environmentally friendly ways of controlling mosquitoes are available. They also question the effectiveness of insecticide spraying, as they believe mosquitoes that are resting or flying above the level of spraying will not be killed; the most common vector in the northeastern United States, Culex pipiens, is a canopy feeder.
* A carbon dioxide-baited CDC light trap at NPSmonitoring site: The highest individual light trap total for 2010 was from a trap located in a salt marsh in the Fire Island National Seashore: around 25,142 mosquitoes were collected during a 16-hour period on August 31.[65]
* Eggs of permanent water mosquitoes can hatch, and the larvae survive, in only a few ounces of water. Less than half the amount that may collect in a discarded coffee cup. Floodwater species lay their eggs on wet soil or other moist surfaces. Hatch time is variable for both types; under favorable circumstances (such as warm weather), the eggs of some species may hatch in as few as 1–3 days after being laid.[66]
* Used tires often hold stagnant water and are a breeding ground for many species of mosquitoes. Some species such as the Asian tiger mosquito prefer manmade containers, such as tires, in which to lay their eggs. The rapid spread of this aggressive daytime feeding species beyond their native range has been attributed to the used tire trade.[60][67]
## Treatment[edit]
No specific treatment is available for WNV infection. Most people recover without treatment. In mild cases, over-the-counter pain relievers can help ease mild headaches and muscle aches in adults. In severe cases supportive care is provided, often in hospital, with intravenous fluids, pain medication, respiratory support, and prevention of secondary infections.[citation needed]
## Prognosis[edit]
While the general prognosis is favorable, current studies indicate that West Nile Fever can often be more severe than previously recognized, with studies of various recent outbreaks indicating that it may take as long as 60 to 90 days to recover.[11][68] Patients with milder WNF are just as likely as those with more severe manifestations of neuroinvasive disease to experience multiple somatic complaints such as tremor, and dysfunction in motor skills and executive functions for over a year. People with milder symptoms are just as likely as people with more severe symptoms to experience adverse outcomes.[69] Recovery is marked by a long convalescence with fatigue. One study found that neuroinvasive WNV infection was associated with an increased risk for subsequent kidney disease.[70][71]
## Epidemiology[edit]
Global distribution of West Nile virus (2006)
See also: List of West Nile virus outbreaks and West Nile virus in the United States
WNV was first isolated from a feverish 37-year-old woman at Omogo in the West Nile District of Uganda in 1937 during research on yellow fever virus.[72] A series of serosurveys in 1939 in central Africa found anti-WNV positive results ranging from 1.4% (Congo) to 46.4% (White Nile region, Sudan). It was subsequently identified in Egypt (1942) and India (1953), a 1950 serosurvey in Egypt found 90% of those over 40 years in age had WNV antibodies. The ecology was characterized in 1953 with studies in Egypt[73] and Israel.[74] The virus became recognized as a cause of severe human meningoencephalitis in elderly patients during an outbreak in Israel in 1957. The disease was first noted in horses in Egypt and France in the early 1960s and found to be widespread in southern Europe, southwest Asia and Australia.
The first appearance of WNV in the Western Hemisphere was in 1999[75] with encephalitis reported in humans, dogs, cats, and horses, and the subsequent spread in the United States may be an important milestone in the evolving history of this virus. The American outbreak began in College Point, Queens in New York City and was later spread to the neighboring states of New Jersey and Connecticut. The virus is believed to have entered in an infected bird or mosquito, although there is no clear evidence.[76] West Nile virus is now endemic in Africa, Europe, the Middle East, west and central Asia, Oceania (subtype Kunjin), and most recently, North America and is spreading into Central and South America.
Outbreaks of West Nile virus encephalitis in humans have occurred in Algeria (1994), Romania (1996 to 1997), the Czech Republic (1997), Congo (1998), Russia (1999), the United States (1999 to 2009), Canada (1999–2007), Israel (2000) and Greece (2010).
Epizootics of disease in horses occurred in Morocco (1996), Italy (1998), the United States (1999 to 2001), and France (2000), Mexico (2003) and Sardinia (2011).
Outdoor workers (including biological fieldworkers, construction workers, farmers, landscapers, and painters), healthcare personnel, and laboratory personnel who perform necropsies on animals are at risk of contracting WNV.[77]
In 2012, the US experienced one of its worst epidemics in which 286 people died, with the state of Texas being hard hit by this virus.[78][79]
### Weather[edit]
Drought has been associated with a higher number of West Nile virus cases in the following year.[80] As drought can decrease fish and other populations that eat mosquito eggs, higher numbers of mosquitoes can result.[80] Higher temperatures are linked to decreased time for replication and increased viral load in birds and mosquitoes.[21]
## Research[edit]
A vaccine for horses (ATCvet code: QI05AA10 (WHO)) based on killed viruses exists; some zoos have given this vaccine to their birds, although its effectiveness is unknown. Dogs and cats show few if any signs of infection. There have been no known cases of direct canine-human or feline-human transmission; although these pets can become infected, it is unlikely they are, in turn, capable of infecting native mosquitoes and thus continuing the disease cycle.[81] AMD3100, which had been proposed as an antiretroviral drug for HIV, has shown promise against West Nile encephalitis. Morpholino antisense oligos conjugated to cell penetrating peptides have been shown to partially protect mice from WNV disease.[82] There have also been attempts to treat infections using ribavirin, intravenous immunoglobulin, or alpha interferon.[83] GenoMed, a U.S. biotech company, has found that blocking angiotensin II can treat the "cytokine storm" of West Nile virus encephalitis as well as other viruses.[84]
As of 2019, six vaccines had progressed to human trials but none had been licensed in the United States. Only the two live attenuated vaccines produced strong immunity after a single dose.
## References[edit]
1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y "General Questions About West Nile Virus". www.cdc.gov. 19 October 2017. Archived from the original on 26 October 2017. Retrieved 26 October 2017.
2. ^ "Symptoms, Diagnosis, & Treatment". www.cdc.gov. 15 January 2019. Archived from the original on 26 October 2017. Retrieved 15 January 2019.
3. ^ a b c d e f "West Nile virus". World Health Organization. July 2011. Archived from the original on 18 October 2017. Retrieved 28 October 2017.
4. ^ "Final Cumulative Maps and Data | West Nile Virus | CDC". www.cdc.gov. 24 October 2017. Archived from the original on 27 October 2017. Retrieved 28 October 2017.
5. ^ Gompf, Sandra. "West Nile Virus". Medicine Net. MedicineNet Inc. Retrieved 15 January 2019.
6. ^ "Symptoms, Diagnosis, & Treatment". Centers for Disease Control and Prevention. USA.gov. 2018-12-10. Retrieved 15 January 2019.
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## External links[edit]
* Medicine portal
* Viruses portal
Wikimedia Commons has media related to West Nile virus.
* De Filette M, Ulbert S, Diamond M, Sanders NN (2012). "Recent progress in West Nile virus diagnosis and vaccination". Vet. Res. 43 (1): 16. doi:10.1186/1297-9716-43-16. PMC 3311072. PMID 22380523.
* "West Nile Virus". Division of Vector-Borne Diseases, U.S. Centers for Disease Control and Prevention (CDC). 2018-10-30.
* CDC—West Nile Virus—NIOSH Workplace Safety and Health Topic
* West Nile Virus Resource Guide—National Pesticide Information Center
* Virus Pathogen Database and Analysis Resource (ViPR): Flaviviridae
* Species Profile – West Nile Virus (Flavivirus), National Invasive Species Information Center, United States National Agricultural Library. Lists general information and resources for West Nile Virus.
Classification
D
* ICD-10: A92.3
* ICD-9-CM: 066.4
* MeSH: D014901
* DiseasesDB: 30025
External resources
* MedlinePlus: 007186
* v
* t
* e
Zoonotic viral diseases (A80–B34, 042–079)
Arthropod
-borne
Mosquito
-borne
Bunyavirales
* Arbovirus encephalitides: La Crosse encephalitis
* LACV
* Batai virus
* BATV
* Bwamba Fever
* BWAV
* California encephalitis
* CEV
* Jamestown Canyon encephalitis
* Tete virus
* Tahyna virus
* TAHV
* Viral hemorrhagic fevers: Rift Valley fever
* RVFV
* Bunyamwera fever
* BUNV
* Ngari virus
* NRIV
Flaviviridae
* Arbovirus encephalitides: Japanese encephalitis
* JEV
* Australian encephalitis
* MVEV
* KUNV
* Saint Louis encephalitis
* SLEV
* Usutu virus
* West Nile fever
* WNV
* Viral hemorrhagic fevers: Dengue fever
* DENV-1-4
* Yellow fever
* YFV
* Zika fever
* Zika virus
Togaviridae
* Arbovirus encephalitides: Eastern equine encephalomyelitis
* EEEV
* Western equine encephalomyelitis
* WEEV
* Venezuelan equine encephalomyelitis
* VEEV
* Chikungunya
* CHIKV
* O'nyong'nyong fever
* ONNV
* Pogosta disease
* Sindbis virus
* Ross River fever
* RRV
* Semliki Forest virus
Reoviridae
* Banna virus encephalitis
Tick
-borne
Bunyavirales
* Viral hemorrhagic fevers: Bhanja virus
* Crimean–Congo hemorrhagic fever (CCHFV)
* Heartland virus
* Severe fever with thrombocytopenia syndrome (Huaiyangshan banyangvirus)
* Tete virus
Flaviviridae
* Arbovirus encephalitides: Tick-borne encephalitis
* TBEV
* Powassan encephalitis
* POWV
* Viral hemorrhagic fevers: Omsk hemorrhagic fever
* OHFV
* Kyasanur Forest disease
* KFDV
* AHFV
* Langat virus
* LGTV
Orthomyxoviridae
* Bourbon virus
Reoviridae
* Colorado tick fever
* CTFV
* Kemerovo tickborne viral fever
Sandfly
-borne
Bunyavirales
* Adria virus (ADRV)
* Oropouche fever
* Oropouche virus
* Pappataci fever
* Toscana virus
* Sandfly fever Naples virus
Rhabdoviridae
* Chandipura virus
Mammal
-borne
Rodent
-borne
Arenaviridae
* Viral hemorrhagic fevers: Lassa fever
* LASV
* Venezuelan hemorrhagic fever
* GTOV
* Argentine hemorrhagic fever
* JUNV
* Brazilian hemorrhagic fever
* SABV
* Bolivian hemorrhagic fever
* MACV
* LUJV
* CHPV
Bunyavirales
* Hemorrhagic fever with renal syndrome
* DOBV
* HTNV
* PUUV
* SEOV
* AMRV
* THAIV
* Hantavirus pulmonary syndrome
* ANDV
* SNV
Herpesviridae
* Murid gammaherpesvirus 4
Bat
-borne
Filoviridae
* BDBV
* SUDV
* TAFV
* Marburg virus disease
* MARV
* RAVV
Rhabdoviridae
* Rabies
* ABLV
* MOKV
* DUVV
* LBV
* CHPV
Paramyxoviridae
* Henipavirus encephalitis
* HeV
* NiV
Coronaviridae
* SARS-related coronavirus
* SARS-CoV
* MERS-CoV
* SARS-CoV-2
Primate
-borne
Herpesviridae
* Macacine alphaherpesvirus 1
Retroviridae
* Simian foamy virus
* HTLV-1
* HTLV-2
Poxviridae
* Tanapox
* Yaba monkey tumor virus
Multiple
vectors
Rhabdoviridae
* Rabies
* RABV
* Mokola virus
Poxviridae
* Monkeypox
*[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
| West Nile fever | c0043124 | 1,367 | wikipedia | https://en.wikipedia.org/wiki/West_Nile_fever | 2021-01-18T18:36:23 | {"mesh": ["D014901"], "umls": ["C0043124"], "icd-9": ["066.3"], "icd-10": ["A92.3"], "wikidata": ["Q11627066"]} |
A rare infectious disease caused by inhalation of the opportunistic fungus aspergillus that can lead to the following manifestations: allergic bronchopulmonary aspergillosis (ABPA), aspergilloma, chronic necrotizing pulmonary aspergillosis (CNPA), and invasive aspergillosis (IA). Aspergilloma occurs in patients with cavitary lung disease and results in a fungal mass with variable clinical presentations from asymptomatic to life-threatening (massive hemoptysis). CNPA manifests as subacute pneumonia in patients with underlying disease. IA is disseminated aspergillosis that eventually invades other organs. Cutaneous aspergillosis is usually the dermatological manifestation of IA that manifests as erythematous-to-violaceous plaques or papules, often characterized by a central necrotic ulcer or eschar.
*[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
| Aspergillosis | c0004030 | 1,368 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1163 | 2021-01-23T17:14:08 | {"gard": ["5856"], "mesh": ["D001228"], "omim": ["614079"], "umls": ["C0004030"], "icd-10": ["B44.0", "B44.1", "B44.2", "B44.7", "B44.8", "B44.9"]} |
A number sign (#) is used with this entry because of evidence that B-cell expansion with NFKB and T-cell anergy (BENTA) is caused by heterozygous mutation in the CARD11 gene (607210) on chromosome 7p22.
Description
B-cell expansion with NFKB and T-cell anergy is an autosomal dominant disorder characterized by onset in infancy of splenomegaly and polyclonal expansion of B cells, resulting in peripheral lymphocytosis. Affected individuals also show mild immune dysfunction, including some defective antibody responses and T-cell anergy. There may be a predisposition to the development of B-cell malignancy (summary by Snow et al., 2012).
Clinical Features
Snow et al. (2012) reported a man and his 2 daughters with B-cell expansion with NFKB and T-cell anergy. The father, who was originally reported by Darte et al. (1971), had presented at age 7 months with splenomegaly and lymphocytosis but did not have anemia or thrombocytopenia. He showed normal growth and development through childhood, but continued to have generalized lymphadenopathy, hepatomegaly, and splenomegaly necessitating splenectomy. Bone marrow biopsy showed lymphoid hyperplasia with normal cellular elements. Laboratory studies showed decreased serum IgM and defective T-cell response to mitogens. Overall, the features at that time did not justify a diagnosis of chronic lymphocytic leukemia (CLL). However, the patient presented 30 years later with a monoclonal expansion of B cells consistent with CLL and underwent successful hematopoietic stem cell transplantation. FISH analysis showed that the leukemic cells had a monoallelic deletion of chromosome 13q14.3, which is associated with about 50% of B-cell CLL (CLLS2; 109543). Both of his daughters had splenomegaly and B-cell lymphocytosis apparent in the first year of life. Both had recurrent upper respiratory infections, low IgM, and normal titers to T cell-dependent vaccine antigens, but protective antibody titers to polysaccharide-based vaccines were decreased. T-cell proliferative responses were also decreased. Snow et al. (2012) also reported a 6-year-old adopted Chinese girl with splenomegaly, lymphadenopathy, and lymphocytosis. She had recurrent infections and deficient antibodies to several vaccines. She also showed some evidence of autoimmunity. B-cell phenotyping in these patients showed expansion of the immature/transitional cell compartment, consistent with increased output of immature B cells from the bone marrow. In addition, these B cells showed decreased peripheral survival compared to control cells.
Brohl et al. (2015) reported a 12-year-old boy who presented at 3 months of age with lymphocytosis, splenomegaly, and anemia. Flow cytometric analysis of peripheral blood showed an excess of polyclonal mature B cells and normal T cells. Bone marrow biopsy showed polyclonal naive B-cell lymphocytosis. At age 4 years, he developed an acute Epstein-Barr virus (EBV) infection with massive adenopathy, splenomegaly, and immune thrombocytopenic purpura; he recovered and subsequently became EBV negative. He underwent splenectomy, and the spleen showed follicular hyperplasia but was architecturally normal. Brohl et al. (2015) noted that the striking B-cell lymphocytosis in this patient (greater than 100-fold above normal) was even higher than in other patients with BENTA. Autoimmunity workup was normal at age 3 years, but the patient later developed antinuclear antibodies without clinical evidence of autoimmune disease. He also showed poor antibody response to vaccination. Detailed studies of patient B cells showed slightly enhanced proliferation in response to stimulation by some stimuli, although the cells were not actively proliferating, as well as a defect in differentiation. T cells showed poor proliferation in response to stimulation and hyporesponsiveness of cytokine secretion.
Buchbinder et al. (2015) reported 3 patients, including a mother and son, with a relatively mild form of BENTA. An 18-year-old woman presented at age 13 months with splenomegaly, leukocytosis, and recurrent upper respiratory tract infections. An unrelated 18-year-old man was diagnosed at age 2 years with a humoral immunodeficiency and recurrent upper respiratory tract infections. The man's 51-year-old mother was clinically asymptomatic but had a history of sinusitis. T-cell responses to phytohemagglutinin were close to normal or normal in all patients, but responses to Candida albicans and tetanus toxoid were absent or strongly impaired. None of the patients underwent splenectomy, and the circulating B-cell levels were normal in all 3 at the time of the report.
Inheritance
The transmission pattern of BENTA in the family reported by Snow et al. (2012) was consistent with autosomal dominant inheritance.
Molecular Genetics
In a man and his 2 daughters with BENTA, Snow et al. (2012) identified a germline heterozygous mutation in the CARD11 gene (E127G; 607210.0001). The mutation was found by massively parallel mRNA sequencing and by searching for shared mutations in the B-cell transcriptome. An unrelated child with a similar condition was found to have a different heterozygous mutation in CARD11 (G116S; 607210.0002); this mutation was previously found by Lenz et al. (2008) as a somatic mutation in a B-cell lymphoma. In vitro functional expression studies showed that both mutations resulted in constitutive NFKB (see 164011) activation, consistent with a gain of function. The mutant proteins spontaneously localized into large protein aggregates that stained with coactivating signaling molecules. The increase in numbers of B cells appeared to result from increased B-cell output from the bone marrow, rather than from increased survival or proliferation in the periphery.
In a patient with BENTA, Brohl et al. (2015) identified a de novo heterozygous missense mutation in the CARD11 gene (G123D; 607210.0005). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that the mutation resulted in a gain of function and increased IKBKB (603258) activation. Gene expression profiling of patient B cells showed elevation of a signature associated with cell cycle progression and downregulation of tumor suppressor genes. Patient B cells showed both increased proliferation and decreased sensitivity to cell death, which reflected the severe B-cell lymphocytosis observed clinically.
In 3 patients, including a mother and son, with a mild form of BENTA, Buchbinder et al. (2015) identified a heterozygous missense mutation in the CARD domain of the CARD11 gene (C49Y; 607210.0006).
INHERITANCE \- Autosomal dominant ABDOMEN Spleen \- Splenomegaly IMMUNOLOGY \- Enlarged lymph nodes \- Lymphocytosis, polyclonal B-cell \- Bone marrow shows lymphoid hyperplasia \- Defective antibody production against polysaccharide-based vaccines \- Normal titers to T cell-dependent vaccines \- Relative T-cell anergy \- Decreased IgM \- Recurrent infections NEOPLASIA \- Chronic lymphocytic leukemia, B-cell, susceptibility to MISCELLANEOUS \- Onset in childhood MOLECULAR BASIS \- Caused by mutation in the caspase recruitment domain-containing protein 11 gene (CARD11, 607210.0001 ) ▲ 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
| B-CELL EXPANSION WITH NFKB AND T-CELL ANERGY | c4551967 | 1,369 | omim | https://www.omim.org/entry/616452 | 2019-09-22T15:48:51 | {"omim": ["616452"], "orphanet": ["464336"], "synonyms": ["B-cell expansion with NF-kB and T-cell anergy disease"]} |
Absence of a menstrual period in a woman of reproductive age
Amenorrhea
Other namesAmenorrhea, amenorrhœa
SpecialtyGynecology
Amenorrhea is the absence of a menstrual period in a woman of reproductive age.[1] Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding), the latter also forming the basis of a form of contraception known as the lactational amenorrhoea method. Outside the reproductive years, there is absence of menses during childhood and after menopause.
Amenorrhoea is a symptom with many potential causes.[2] Primary amenorrhoea is defined as an absence of secondary sexual characteristics by age 14 with no menarche or normal secondary sexual characteristics but no menarche by 16 years of age. It may be caused by developmental problems, such as the congenital absence of the uterus, failure of the ovary to receive or maintain egg cells, or delay in pubertal development.[3] Secondary amenorrhoea (menstrual cycles ceasing) is often caused by hormonal disturbances from the hypothalamus and the pituitary gland, from premature menopause or intrauterine scar formation. It is defined as the absence of menses for three months in a woman with previously normal menstruation, or six months for women with a history of oligomenorrhoea.[4]
## Contents
* 1 Classification
* 2 Cause
* 2.1 Low body weight
* 2.2 Drug-induced
* 2.3 Breastfeeding
* 2.4 Celiac disease
* 2.5 Physical
* 2.6 Stress
* 3 Diagnosis
* 3.1 Primary amenorrhoea
* 3.2 Secondary amenorrhea
* 4 Treatments
* 5 History
* 6 Etymology
* 7 References
* 8 External links
## Classification[edit]
There are two primary ways to classify amenorrhoea. Types of amenorrhoea are classified as primary or secondary, or based on functional "compartments".[5] The latter classification relates to the hormonal state of the patient that hypo-, eu-, or hypergonadotropic (whereby interruption to the communication between gonads and follicle stimulating hormone (FSH) causes FSH levels to be either low, normal or high).
* By primary vs. secondary: Primary amenorrhoea is the absence of menstruation in a woman by the age of 16.[6] As pubertal changes precede the first period, or menarche, female children by the age of 14 who still have not reached menarche, plus having no sign of secondary sexual characteristics, such as thelarche or pubarche—thus are without evidence of initiation of puberty—are also considered as having primary amenorrhoea.[7] Secondary amenorrhoea is where an established menstruation has ceased—for three months in a woman with a history of regular cyclic bleeding, or six months in a woman with a history of irregular periods. This usually happens to women aged 40–55. However, adolescent athletes are more likely to experience disturbances to the menstrual cycle than athletes of any other age.[8] Amenorrhoea may cause serious pain in the back near the pelvis and spine. This pain has no cure, but can be relieved by a short course of progesterone to trigger menstrual bleeding.
* By compartment: The reproductive axis can be viewed as having four compartments: 1. outflow tract (uterus, cervix, vagina), 2. ovaries, 3. pituitary gland, and 4. hypothalamus. Pituitary and hypothalamic causes are often grouped together.
Primary/secondary Outflow tract anomalies/obstruction Gonadal/end-organ disorders Pituitary and hypothalamic/central regulatory disorders
Overview The hypothalamic-pituitary-ovarian axis is functional. The ovary or gonad does not respond to pituitary stimulation. Gonadal dysgenesis or premature menopause are possible causes. Chromosome testing is usually indicated in younger individuals with hypergonadotropic amenorrhoea. Low oestrogen levels are seen in these patients and the hypo-oestrogenism may require treatment. Generally, inadequate levels of FSH lead to inadequately stimulated ovaries which then fail to produce enough oestrogen to stimulate the endometrium (uterine lining), hence amenorrhoea. In general, women with hypogonadotropic amenorrhoea are potentially fertile.
FSH Outflow tract abnormalities tend to be normogonadotropic and FSH levels are in the normal range. Gonadal, usually ovarian, abnormalities tend to be linked to elevated FSH levels or hypergonadotropic amenorrhoea. FSH levels are typically in the menopausal range. Both hypothalamic and pituitary disorders are linked to low FSH levels leading to hypogonadotropic amenorrhoea.
Primary
* Uterine: Müllerian agenesis (Second most common cause, 15% of primary amenorrhoea)[9]
* Vaginal: Vaginal atresia, cryptomenorrhoea, imperforate hymen.
* Gonadal dysgenesis, including Turner syndrome, is the most common cause.
* Androgen insensitivity syndrome (Testicular feminization syndrome)
* Receptor abnormalities for hormones FSH and LH
* Specific forms of congenital adrenal hyperplasia
* Swyer syndrome
* Galactosaemia
* Aromatase deficiency
* Prader-Willi syndrome
* Male pseudo-hermaphroditism (about 1 in every 150,000 births)
* Müllerian agenesis/MRKH Syndrome
* Other intersexed conditions
* Hypothalamic: Kallmann syndrome
Secondary
* Intrauterine adhesions (Asherman's syndrome)
* Pregnancy (most common cause)
* Anovulation
* Menopause
* Premature menopause
* Polycystic ovary syndrome (PCO-S)
* Drug-induced
* Breastfeeding
* Celiac disease
* Functional Hypothalamic: Exercise amenorrhoea, related to physical exercise, stress amenorrhoea, eating disorders and weight loss (obesity, anorexia nervosa, or bulimia)
* Pituitary: Sheehan syndrome, hyperprolactinaemia, haemochromatosis
* Other central regulatory: hypothyroidism, hyperthyroidism, arrhenoblastoma
## Cause[edit]
### Low body weight[edit]
Women who perform considerable amounts of exercise on a regular basis or lose a significant amount of weight are at risk of developing hypothalamic (or 'athletic') amenorrhoea. Functional Hypothalamic Amenorrhoea (FHA) can be caused by stress, weight loss, and/or excessive exercise. Many women who diet or who exercise at a high level do not take in enough calories to expend on their exercise as well as to maintain their normal menstrual cycles.[10] The threshold of developing amenorrhoea appears to be dependent on low energy availability rather than absolute weight because a critical minimum amount of stored, easily mobilized energy is necessary to maintain regular menstrual cycles.[11]
Energy imbalance and weight loss can disrupt menstrual cycles through several hormonal mechanisms. Weight loss can cause elevations in the hormone ghrelin which inhibits the hypothalamic-pituitary-ovarial axis.[12] Elevated concentrations of ghrelin alter the amplitude of GnRH pulses, which causes diminished pituitary release of LH and follicle-stimulating hormone (FSH).[13]
Secondary amenorrhea is caused by low levels of the hormone leptin in females with low body weight.[14] Like ghrelin, leptin signals energy balance and fat stores to the reproductive axis.[15] Decreased levels of leptin are closely related to low levels of body fat, and correlate with a slowing of GnRH pulsing. When a woman is experiencing amenorrhoea, an eating disorder, and osteoporosis together, this is called female athlete triad syndrome.[16] A lack of eating causes amenorrhoea and bone loss leading to osteopenia and sometimes progressing to osteoporosis.[17]
The social effects of amenorrhoea on a person vary significantly. Amenorrhoea is often associated with anorexia nervosa and other eating disorders, which have their own effects. If secondary amenorrhoea is triggered early in life, for example through excessive exercise or weight loss, menarche may not return later in life. A woman in this situation may be unable to become pregnant, even with the help of drugs. Long-term amenorrhoea leads to an estrogen deficiency which can bring about menopause at an early age. The hormone estrogen plays a significant role in regulating calcium loss after ages 25–30. When her ovaries no longer produce estrogen because of amenorrhoea, a woman is more likely to suffer rapid calcium loss, which in turn can lead to osteoporosis.[18] Increased testosterone levels cause by amenorrhoea may lead to body hair growth and decreased breast size.[19] Increased levels of androgens, especially testosterone, can also lead to ovarian cysts. Some research among amenorrhoeic runners indicates that the loss of menses may be accompanied by a loss of self-esteem.[20]
### Drug-induced[edit]
Certain medications, particularly contraceptive medications, can induce amenorrhoea in a healthy woman. The lack of menstruation usually begins shortly after beginning the medication and can take up to a year to resume after stopping a medication. Hormonal contraceptives that contain only progestogen like the oral contraceptive Micronor, and especially higher-dose formulations like the injectable Depo Provera commonly induce this side effect. Extended cycle use of combined hormonal contraceptives also allow suppression of menstruation. Patients who use and then cease using contraceptives like the combined oral contraceptive pill (COCP) may experience secondary amenorrhoea as a withdrawal symptom.[21] The link is not well understood, as studies have found no difference in hormone levels between women who develop amenorrhoea as a withdrawal symptom following the cessation of COCP use and women who experience secondary amenorrhoea because of other reasons.[22] New contraceptive pills, like continuous oral contraceptive pills (OCPs) which do not have the normal 7 days of placebo pills in each cycle, have been shown to increase rates of amenorrhoea in women. Studies show that women are most likely to experience amenorrhoea after 1 year of treatment with continuous OCP use.[23]
The use of opiates (such as heroin) on a regular basis has also been known to cause amenorrhoea in longer term users.[24][25]
Anti-psychotic drugs used to treat schizophrenia have been known to cause amenorrhoea as well. New research suggests that adding a dosage of Metformin to an anti-psychotic drug regimen can restore menstruation.[26] Metformin decreases resistance to the hormone insulin, as well as levels of prolactin, testosterone, and lutenizing hormone (LH). Metformin also decreases the LH/FSH ratio. Results of the study on Metformin further implicate the regulation of these hormones as a main cause of secondary amenorrhoea.
### Breastfeeding[edit]
Breastfeeding is a common cause of secondary amenorrhoea, and often the condition lasts for over six months.[27] Breastfeeding typically lasts longer than lactational amenorrhoea, and the duration of amenorrhoea varies depending on how often a woman breastfeeds.[28] Lactational amenorrhoea has been advocated as a method of family planning, especially in developing countries where access to other methods of contraception may be limited. Breastfeeding is said to prevent more births in the developing world than any other method of birth control or contraception. Lactational amenorrhoea is 98% percent effective as a method of preventing pregnancy in the first six months postpartum.[29]
### Celiac disease[edit]
Untreated celiac disease can cause amenorrhea. Reproductive disorders may be the only manifestation of undiagnosed celiac disease and most cases are not recognized. For people with celiac, a gluten-free diet avoids or reduces the risk of developing reproductive disorders.[30][31]
### Physical[edit]
Amenorrhoea can also be caused by physical deformities. One example of this is MRKH (Mayer–Rokitansky–Küster–Hauser) syndrome, the second-most common cause of primary amenorrhoea.[32] The syndrome is characterized by Müllerian agenesis. In MRKH Syndrome, the Müllerian ducts develop abnormally and can result in vaginal obstructions preventing menstruation. The syndrome develops prenatally early in the development of the female reproductive system.
### Stress[edit]
Secondary amenorrhea is also caused by stress, extreme weight loss, or excessive exercise. Young athletes are particularly vulnerable, although normal menses usually return with healthy body weight. Causes of secondary amenorrhea can also result in primary amenorrhea, especially if present before onset of menarche.[33][34]
## Diagnosis[edit]
### Primary amenorrhoea[edit]
Primary amenorrhoea can be diagnosed in female children by age 14 if no secondary sex characteristics, such as enlarged breasts and body hair, are present.[35] In the absence of secondary sex characteristics, the most common cause of amenorrhoea is low levels of FSH and LH caused by a delay in puberty. Gonadal dysgenesis, often associated with Turner's Syndrome, or premature ovarian failure may also be to blame. If secondary sex characteristics are present, but menstruation is not, primary amenorrhoea can be diagnosed by age 16. A reason for this occurrence may be that a person phenotypically female but genetically male, a situation known as androgen insensitivity syndrome. If undescended testes are present, they are often removed after puberty (~21 years of age) due to the increased risk of testicular cancer. In the absence of undescended testes, an MRI can be used to determine whether or not a uterus is present. Müllerian agenesis causes around 15% of primary amenorrhoea cases. If a uterus is present, outflow track obstruction may be to blame for primary amenorrhoea.
### Secondary amenorrhea[edit]
See also: Functional hypothalamic amenorrhea
Secondary amenorrhea's most common and most easily diagnosable causes are pregnancy, thyroid disease, and hyperprolactinemia. A pregnancy test is a common first step for diagnosis.[36] Hyperprolactinemia, characterized by high levels of the hormone prolactin, is often associated with a pituitary tumor. A dopamine agonist can often help relieve symptoms. The subsiding of the causal syndrome is usually enough to restore menses after a few months. Secondary amenorrhea may also be caused by outflow tract obstruction, often related to Asherman's Syndrome. Polycystic ovary syndrome can cause secondary amenorrhea, although the link between the two is not well understood. Ovarian failure related to early onset menopause can cause secondary amenorrhea, and although the condition can usually be treated, it is not always reversible. Secondary amenorrhea is also caused by stress, extreme weight loss, or excessive exercise. Young athletes are particularly vulnerable, although normal menses usually return with healthy body weight. Causes of secondary amenorrhea can also result in primary amenorrhea, especially if present before onset of menarche.[33][34]
## Treatments[edit]
Treatments vary based on the underlying condition.[37] Key issues are problems of surgical correction if appropriate and oestrogen therapy if oestrogen levels are low. For those who do not plan to have biological children, treatment may be unnecessary if the underlying cause of the amenorrhoea is not threatening to their health. However, in the case of athletic amenorrhoea, deficiencies in estrogen and leptin often simultaneously result in bone loss, potentially leading to osteoporosis.
"Athletic" amenorrhoea which is part of the female athlete triad is treated by eating more and decreasing the amount and intensity of exercise.[38] If the underlying cause is the athlete triad then a multidisciplinary treatment including monitoring from a physician, dietitian, and mental health counselor is recommended, along with support from family, friends, and coaches. Although oral contraceptives can causes menses to return, oral contraceptives should not be the initial treatment as they can mask the underlying problem and allow other effects of the eating disorder, like osteoporosis, continue to develop.[38] Weight recovery, or increased rest does not always catalyze the return of a menses. Recommencement of ovulation suggests a dependency on a whole network of neurotransmitters and hormones, altered in response to the initial triggers of secondary amenorrhoea. To treat drug-induced amenorrhoea, stopping the medication on the advice of a doctor is a usual course of action.
Looking at Hypothalamic amenorrhoea, studies have provided that the administration of a selective serotonin reuptake inhibitor (SSRI) might correct abnormalities of Functional Hypothalamic Amenorrhoea (FHA) related to the condition of stress-related amenorrhoea.[39] This involves the repair of the PI3K signaling pathway, which facilitates the integration of metabolic and neural signals regulating gonadotropin releasing hormone (GnRH)/luteinizing hormone (LH). In other words, it regulates the neuronal activity and expression of neuropeptide systems that promote GnRH release. However, SSRI therapy represents a possible hormonal solution to just one hormonal condition of hypothalamic amenorrhoea. Furthermore, because the condition involves the inter workings of many different neurotransmitters, much research is still to be done on presenting hormonal treatment that would counteract the hormonal affects.
As for physiological treatments to hypothalamic amenorrhoea, injections of metreleptin (r-metHuLeptin) have been tested as treatment to oestrogen deficiency resulting from low gonadotropins and other neuroendocrine defects such as low concentrations of thyroid and IGF-1. R-metHuLeptin has appeared effective in restoring defects in the hypothalamic-pituitary-gonadal axis and improving reproductive, thyroid, and IGF hormones, as well as bone formation, thus curing the amenorrhoea and infertility. However, it has not proved effective in restoring of cortisol and adrenocorticotropin levels, or bone resorption.[40]
## History[edit]
In preindustrial societies, menarche typically occurred later than in current industrial societies. After menarche, menstruation was suppressed during much of a woman's reproductive life by either pregnancy or nursing. Reductions in age of menarche and lower fertility rates mean that modern women menstruate far more often than they did under the conditions prevalent for most of human evolutionary history.[41]
## Etymology[edit]
The term is derived from Greek: a = negative, men = month, rhoia = flow. Derived adjectives are amenorrhoeal and amenorrhoeic. The opposite is the normal menstrual period (eumenorrhoea).
## References[edit]
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16. ^ "Bones, Muscles, and Joints". kidshealth.org. Retrieved 2018-11-07.
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18. ^ Konstantinovsky M. "Amenorrhea: Dieting to the extreme". Archived from the original on 2013-12-03.
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20. ^ Comenitz L (1983). "The psychological effects of secondary amenorrhea in women runners". Clinical Social Work Journal. 11 (1): 87–96. doi:10.1007/BF00755658. S2CID 143591523.
21. ^ Willacy H. "Combined Oral Contraceptive (Follow-up and Common Problems)".
22. ^ Weisberg E (December 1982). "Fertility after discontinuation of oral contraceptives". Clinical Reproduction and Fertility. 1 (4): 261–72. PMID 6764883.
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24. ^ Santen FJ, Sofsky J, Bilic N, Lippert R (June 1975). "Mechanism of action of narcotics in the production of menstrual dysfunction in women". Fertility and Sterility. 26 (6): 538–48. doi:10.1016/S0015-0282(16)41173-8. PMID 236938.
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26. ^ Wu RR, Jin H, Gao K, Twamley EW, Ou JJ, Shao P, Wang J, Guo XF, Davis JM, Chan PK, Zhao JP (August 2012). "Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: a double-blind, randomized, placebo-controlled study". The American Journal of Psychiatry. 169 (8): 813–21. doi:10.1176/appi.ajp.2012.11091432. PMID 22711171.
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28. ^ Labbok M. "Physiology of lactational amenorrhea and its implications for spacing of pregnancies". Archived from the original on 2013-11-11.
29. ^ Kennedy K (April–May 1990). "Lactation and contraception" (PDF). Ginecologia y Obstetricia de Mexico. 58 (1): 25–34. PMID 2276655. Archived (PDF) from the original on 2013-11-11.
30. ^ Tersigni C, Castellani R, de Waure C, Fattorossi A, De Spirito M, Gasbarrini A, Scambia G, Di Simone N (2014). "Celiac disease and reproductive disorders: meta-analysis of epidemiologic associations and potential pathogenic mechanisms". Human Reproduction Update. 20 (4): 582–93. doi:10.1093/humupd/dmu007. PMID 24619876.
31. ^ Saccone G, Berghella V, Sarno L, Maruotti GM, Cetin I, Greco L, Khashan AS, McCarthy F, Martinelli D, Fortunato F, Martinelli P (February 2016). "Celiac disease and obstetric complications: a systematic review and metaanalysis". American Journal of Obstetrics and Gynecology. 214 (2): 225–234. doi:10.1016/j.ajog.2015.09.080. PMID 26432464.
32. ^ Rousset P, Raudrant D, Peyron N, Buy JN, Valette PJ, Hoeffel C (September 2013). "Ultrasonography and MRI features of the Mayer-Rokitansky-Küster-Hauser syndrome". Clinical Radiology. 68 (9): 945–52. doi:10.1016/j.crad.2013.04.005. PMID 23725784.
33. ^ a b Newson L. "Amenorrhea".
34. ^ a b Welt CK. "Etiology, diagnosis, and treatment of primary amenorrhea". Archived from the original on 2013-11-11.
35. ^ Master-Hunter T, Heiman DL (April 2006). "Amenorrhea: evaluation and treatment". American Family Physician. 8. 73 (8): 1374–82. PMID 16669559. Archived from the original on 2013-11-11.
36. ^ Welt C. "Etiology, diagnosis, and treatment of secondary amenorrhea". Archived from the original on 2013-11-11.
37. ^ "What are the treatments for amenorrhea?". nichd.nih.gov/. Retrieved 2018-11-08.
38. ^ a b American Medical Society for Sports Medicine (24 April 2014), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation, American Association of Blood Banks, archived from the original on 29 July 2014, retrieved 29 July 2014, which cites
* De Souza MJ, Nattiv A, Joy E, Misra M, Williams NI, Mallinson RJ, Gibbs JC, Olmsted M, Goolsby M, Matheson G (February 2014). "2014 Female Athlete Triad Coalition Consensus Statement on Treatment and Return to Play of the Female Athlete Triad: 1st International Conference held in San Francisco, California, May 2012 and 2nd International Conference held in Indianapolis, Indiana, May 2013". British Journal of Sports Medicine. 48 (4): 289. doi:10.1136/bjsports-2013-093218. PMID 24463911.
* Javed A, Tebben PJ, Fischer PR, Lteif AN (September 2013). "Female athlete triad and its components: toward improved screening and management". Mayo Clinic Proceedings. 88 (9): 996–1009. doi:10.1016/j.mayocp.2013.07.001. PMID 24001492.
* Nazem TG, Ackerman KE (July 2012). "The female athlete triad". Sports Health. 4 (4): 302–11. doi:10.1177/1941738112439685. PMC 3435916. PMID 23016101.
39. ^ Acosta-Martínez M (24 January 2012). "PI3K: An Attractive Candidate for the Central Integration of Metabolism and Reproduction". Frontiers in Endocrinology. 2: 110. doi:10.3389/fendo.2011.00110. PMC 3356143. PMID 22654843.
40. ^ Chan JL, Mantzoros CS (8 July 2005). "Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa". Lancet. 366 (9479): 74–85. doi:10.1016/S0140-6736(05)66830-4. PMID 15993236. S2CID 37180870.
41. ^ Gladwell, Malcolm (2000-03-10). "John Rock's Error". The New Yorker. Archived from the original on 2013-12-03. Retrieved 2013-11-30.
## External links[edit]
Classification
D
* ICD-10: N91.0-N91.2
* ICD-9-CM: 626.0
* MeSH: D000568
* DiseasesDB: 14843
External resources
* MedlinePlus: 001218
* eMedicine: article/953850
* Patient UK: Amenorrhea
Look up amenorrhea in Wiktionary, the free dictionary.
* Disability Online's amenorrhoea page
* Disability Online's athletic amenorrhoea page
* Amenorrhea
* v
* t
* e
Female diseases of the pelvis and genitals
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* Endometriosis of ovary
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* Folliculogenesis
* Menstrual synchrony
* Premenstrual syndrome / Premenstrual dysphoric disorder / Menstrual psychosis
* Sexual activity
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* Chhaupadi
* Feminine hygiene
* Sanitary napkin
* Tampon
* Menstrual cup
* Menstrual Hygiene Day
* Menstrual taboo
* Menstruation hut
* Niddah
*[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
| Amenorrhea | c0002453 | 1,370 | wikipedia | https://en.wikipedia.org/wiki/Amenorrhea | 2021-01-18T18:41:00 | {"mesh": ["D000568"], "umls": ["C0002453", "C2219717"], "wikidata": ["Q334655"]} |
A number sign (#) is used with this entry because the genetic defect in leukocyte adhesion deficiency (also known as LFA-1 immunodeficiency and by several other designations) has been shown to reside in the gene encoding the beta-2 integrin chain (ITGB2; 600065), a subunit that is common to 3 cell adhesion molecules with gene designations ITGAL (153370), ITGAM (120980), and ITGAX (151510). The leukocyte antigen of the beta-2 integrin chain gene has been designated CD18.
Description
Leukocyte adhesion deficiency (LAD) is an autosomal recessive disorder of neutrophil function resulting from a deficiency of the beta-2 integrin subunit of the leukocyte cell adhesion molecule. The leukocyte cell adhesion molecule is present on the surface of peripheral blood mononuclear leukocytes and granulocytes and mediates cell-cell and cell-extracellular matrix adhesion. LAD is characterized by recurrent bacterial infections; impaired pus formation and wound healing; abnormalities of a wide variety of adhesion-dependent functions of granulocytes, monocytes, and lymphocytes; and a lack of beta-2/alpha-L, beta-2/alpha-M, and beta-2/alpha-X expression.
Nomenclature
The 3 alpha-integrin chains that each heterodimerize with the beta-2 chain (ITGAL, ITGAM, and ITGAX) have leukocyte antigen designations of (1) CD18/CD11A: also referred to as LFA-1, Leu CAMa, and integrin beta-2/alpha-L; (2) CD18/CD11B: also referred to as CR3, Leu CAMb, Mac-1, Mo1, OKM-1 and integrin beta-2/alpha-M; (3) CD18/CD11C: also referred to as p150 (p150, 95) Leu CAMc, and integrin beta-2/alpha-X (Barclay et al., 1993).
Clinical Features
Beginning in the 1970s, patients were recognized who had recurrent bacterial infections, defective neutrophil mobility, and delayed separation of the umbilical cord (e.g., Hayward et al., 1979). Before the elucidation by Springer et al. (1984, 1986) and Barclay et al. (1993), extraordinary confusion surrounded the group of patients with leukocyte dysfunction and deficiency of cell surface antigens (see, for example, Arnaout et al., 1982; Bowen et al., 1982; Dana et al., 1984). In the seventh edition of these catalogs (1986), one entry related to the ITGB2 locus (which is mutant in these patients), but 3 others described neutrophil dysfunction syndromes now known to be leukocyte adhesion deficiency. Confusion was created by different investigators looking at the different alpha subunits which share a common beta subunit.
Van der Meer et al. (1975) described a 'new' defect in the intracellular killing of ingested microorganisms. A sister and probably 2 brothers were affected. During infections, the white blood count was as high as 55,000 per cu mm, mostly neutrophils, with a slight shift to the left. Other patients with recurring bacterial infections were reported who had defects in initiation of the neutrophil respiratory burst to particulate but not soluble stimuli (e.g., Weening et al., 1976; Harvath and Andersen, 1979), defects in neutrophil chemotaxis and phagocytosis (e.g., Niethammer et al., 1975), or both (Harvath and Andersen, 1979). Crowley et al. (1980) were the first to propose that the defects in neutrophil chemotaxis and phagocytosis were secondary to an abnormality in cell adhesion.
Using specific monoclonal antibodies, Dana et al. (1984), Beatty et al. (1984), and others demonstrated deficiency of both the alpha and the beta subunits of Mac-1 (also designated Mo1, and as beta-2/alpha M in integrin terminology) in the neutrophils of patients of this type. Arnaout et al. (1984) and others demonstrated that the LFA-1 alpha-beta complex (beta-2/alpha-X) is also deficient on patients' neutrophils and lymphocytes. Springer et al. (1984, 1986) found that a third type of alpha-beta complex is also deficient on patients' neutrophils and lymphocytes. Springer et al. (1984, 1986) proposed that the primary defect in these patients resides in the beta subunit (which is shared by all 3 deficient proteins) and that the beta subunit is necessary for cell surface expression on the alpha subunit. Such neutrophils have a reduced phagocytic and respiratory burst response to bacteria and yeast as well as a reduced ability to adhere to various substances and migrate into sites of infection. Most of the clinical features are probably the result of neutrophil and monocyte deficiency of CR3 (beta-2/alpha-M).
There have been reports of about 30 patients with recurrent bacterial infections due to deficiency of this family of cell membrane glycoproteins. Ross (1986) tabulated the findings in reported cases. Often the first manifestation is infection of the umbilical cord stump, occasionally progressing to omphalitis (Abramson et al., 1981; Bissenden et al., 1981). Gingivitis (periodontitis) may be noted with eruption of the primary teeth. Systemic bacterial infections such as pneumonia, peritonitis, and deep abscesses are more frequent during infancy and with complete deficiency.
See review by Todd and Freyer (1988), who found reports of 41 patients in whom the clinical picture fitted that of CD18/CD11 (beta-2/alpha) glycoprotein deficiency. At least 4 patients suspected or documented to have a moderately severe variant (10% expression of CD18/CD11 glycoprotein) have survived to adulthood (Anderson et al., 1985; van der Meer et al., 1975; Weening et al., 1976) and 3 homozygous persons are known to have parented affected or presumably heterozygous offspring.
Kobayashi et al. (1984) described a 3-month-old Japanese female infant with persistent navel infection due to Pseudomonas aeruginosa since birth and recurrent bacterial skin infections. They found a severe abnormality of neutrophil adhesion on a surface, leading to a lack of chemotaxis and mild impairment of phagocytosis. Neutrophil bactericidal activity and nitroblue tetrazolium reduction were unimpaired. By sodium dodecyl sulfate polyacrylamide gel electrophoresis of neutrophil membrane proteins, 2 glycoproteins were shown to be lacking. In both parents, both glycoproteins were reduced. Fujita et al. (1985) reported the subsequent birth of a male sib with the same defect. Fujita et al. (1988) described juvenile rheumatoid arthritis of systemic onset in these sibs, then aged 5 and 3 years, respectively, who had a severe form of congenital leukocyte adhesion deficiency.
Etzioni and Harlan (1999) provided a comprehensive review of both type I (LAD1) and type II LAD (LAD2; 266265). While the functional neutrophil studies are similar in the 2 LADs, the clinical course is milder in LAD2. Furthermore, patients with LAD2 present other abnormal features, such as growth and mental retardation, which are related to the primary defect in fucose metabolism. Delayed separation of the umbilical cord occurs in LAD1.
Biochemical Features
Kishimoto et al. (1987) identified 5 distinct beta-subunit phenotypes among LAD patients: an undetectable beta-subunit mRNA and protein precursor; low levels of beta-subunit mRNA and precursor; an aberrantly large beta-subunit precursor, probably due to an extra glycosylation site; an aberrantly small precursor; and a grossly normal precursor. Mutant beta-subunit precursors from LAD patients failed to associate with the LFA-1 alpha subunit (alpha-L). Family studies with aberrant precursors correlated with recessive inheritance of leukocyte adhesion deficiency.
Marlin et al. (1986) showed that the genetic defect in leukocyte adhesion deficiency (also known as LFA-1 immunodeficiency and by several other designations) resides in the beta subunit that is common to 3 cell adhesion molecules. Boucheix (1987) indicated that a tentative designation for the beta chain of these 3 proteins is CD18. The 3, each with a unique alpha chain, are CD11A (153370), CD11B (120980), and CD11C (151510).
Inheritance
The neutrophils from parents and sibs of patients often show half-normal amounts of CR3/LFA1/p150,95 antigens (CD18/CD11B, CD18/CD11A and CD18/CD11C, respectively) (Arnaout et al., 1984; Springer et al., 1984). In other cases, both parents have normal amounts of antigen or only 1 parent has half-normal amounts (Ross et al., 1985; Arnaout et al., 1984). The only suggestion of a mode of inheritance other than autosomal recessive came from Crowley et al. (1980), who first proposed that an adhesion defect exists in this condition. X-linked recessive inheritance was suggested because only the mother and sister of the affected male showed evidence of the carrier state; the cells of the father and brother were functionally normal and had a normal content of the relevant glycoprotein.
Mapping
Suomalainen et al. (1985, 1986) showed that the integrin beta-2 gene is located on chromosome 21.
Molecular Genetics
Dana et al. (1987) studied 4 unrelated patients with the family of 3 leukocyte adhesion molecules, which they called Leu-CAM. They called the 3 antigens Mo1, LFA-1, and Leu M5. In all 4 patients, they found that B cells synthesized a normal-sized, beta-subunit precursor that either failed to 'mature' or matured only partially to the membrane-expressed form. Furthermore, B cells from all 4 patients had a single normal-sized, beta-subunit mRNA of about 3.4 kb. Thus, leukocyte adhesion deficiency in these 4 patients was not due to the absence of the beta chain gene or to aberrant splicing of its mRNA. The findings were consistent with a defective beta-subunit gene (ITGB2) resulting in abnormal posttranslational processing of the synthesized beta molecule.
### Somatic Revertant Mosaicism
Tone et al. (2007) reported an unusual case of somatic revertant mosaicism in a Japanese infant with LAD1 caused by compound heterozygosity for 2 truncating mutations in the ITGB2 gene, predicting complete loss of the CD18 antigen. However, flow cytometric analysis showed that a small proportion of the patient's memory/effector CD8+ T cells were CD18+. Sequencing of these CD18+ T cells indicated that they resulted from spontaneous site-specific single nucleotide reversion of the inherited paternal mutation. Although these T cells were functional in vitro, the patient did not show clinical improvement, likely because no reversion events had occurred in myeloid cells. Tone et al. (2007) concluded that somatic genetic reversion in a primary immunodeficiency can occur, but may be undetected in some cases if the changes do not result in modification of the clinical phenotype.
Diagnosis
Diagnosis of hereditary deficiency of CR3 is facilitated by commercial availability of monoclonal antibodies specific for the alpha-integrin chains of CR3 and p150,95.
Clinical Management
In a retrospective survey of 162 patients in whom bone marrow transplantation was performed in 14 European centers between 1969 and 1985, Fischer et al. (1986) found 4 patients with leukocyte adhesion deficiency. Bone marrow transplantation was successful; engraftment of donor cells resulted in complete restoration of leukocyte function and the absence of need for any further treatment in some of these patients.
Wilson et al. (1990) corrected the genetic and functional abnormalities in a lymphocyte cell line from a patient with LAD by retrovirus-mediated transduction of a functional ITGB2 (CD18) gene. Yorifuji et al. (1993) extended this work by reporting the introduction of human CD18 cDNA into the bone marrow progenitor cells of patients with LAD.
Evolution
This glycoprotein family is conserved in mouse and human.
Animal Model
Vedder et al. (1988) showed that use of a monoclonal antibody against CD18 reduced organ injury and improved survival from hemorrhagic shock in rabbits. Krauss et al. (1991) developed an in vivo model for gene therapy of LAD. Recombinant retroviruses were used to transduce a functional human ITGB2 (CD18) gene into murine bone marrow cells which were then transplanted into lethally irradiated syngeneic recipients. Since they had human-specific CD18 monoclonal antibodies and since human CD18 can form chimeric heterodimers with murine CD11A on the cell surface, Krauss et al. (1991) were able to do a reliable flow cytometric assay for human CD18 in transplant recipients. Human CD18 was detected in leukocytes in a substantial number of transplant recipients for at least 6 months, suggesting that the gene had been transduced into stem cells. There were no apparent untoward effects. Expression was consistently highest and most frequent in granulocytes. Murine granulocytes demonstrated appropriate posttranscriptional regulation of human CD18 in response to activation of protein kinase C with PMA.
Kehrli et al. (1992) described beta-2 integrin deficiency in Holstein cattle. The disorder was characterized by recurrent pneumonia, ulcerative and granulomatous stomatitis, enteritis with bacterial overgrowth, periodontitis, delayed wound healing, persistent neutrophilia, and death at an early age. The underlying genetic defect was identified as a D128G (asp128-to-gly) amino acid substitution in the 26-amino acid sequence that is completely homologous with human and murine CD18 protein sequences. In a Holstein calf afflicted with leukocyte adhesion deficiency, Shuster et al. (1992) found 2 point mutations: one caused a D128G substitution in a highly conserved extracellular region where several mutations have been found to cause human LAD, and the other mutation was silent. All 20 calves tested were homozygous for the D128G allele. The carrier frequency among Holstein cattle in the United States was approximately 15% among bulls and 6% among cows. All cattle with a mutant allele are related to 1 bull, who through the use of artificial insemination sired many calves in the 1950s and 1960s. It was suggested that the organization of the dairy industry and the diagnostic test described by Shuster et al. (1992) would enable nearly complete eradication of bovine LAD within 1 year.
Using homologous recombination, Scharffetter-Kochanek et al. (1998) created and characterized mice with a CD18 null mutation. These mice have a phenotype closely resembling type I LAD in humans and cattle, including leukocytosis, chronic dermatitis, alopecia, and mucocutaneous infections. Intravital microscopy in these mice revealed a lack of firm neutrophil attachment to venules in the cremaster muscle in response to FMLP (see 136537). Scharffetter-Kochanek et al. (1998) also observed defective T-cell proliferation after stimulation with alloantigen or staphylococcal enterotoxin A.
INHERITANCE \- Autosomal recessive HEAD & NECK Mouth \- Gingivitis Teeth \- Periodontitis HEMATOLOGY \- Leukocytosis with predominant granulocytosis (20,000-100,000 /mm3) common IMMUNOLOGY \- Perirectal abscesses \- Recurrent staphylococcal and gram-negative infections \- Poor adhesion related functions, such as adhesion to endothelial cells, chemotaxis, and antibody-dependent cellular cytotoxicity LABORATORY ABNORMALITIES \- Low levels of CD11/CD18 (LFA-1 or leukocyte function antigen-1) glycoprotein MISCELLANEOUS \- Corrected by bone marrow transplantation \- Delayed separation of umbilical cord MOLECULAR BASIS \- Caused by mutations in the beta-2 integrin gene (ITGB2, 600065.0001 ) ▲ 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
| LEUKOCYTE ADHESION DEFICIENCY, TYPE I | c0242597 | 1,371 | omim | https://www.omim.org/entry/116920 | 2019-09-22T16:43:36 | {"doid": ["0110910"], "mesh": ["D018370"], "omim": ["116920"], "orphanet": ["2968", "99842"], "synonyms": ["Alternative titles", "LAD1", "LYMPHOCYTE FUNCTION-ASSOCIATED ANTIGEN 1 IMMUNODEFICIENCY", "LFA1 IMMUNODEFICIENCY"]} |
## Summary
### Clinical characteristics.
Dent disease, an X-linked disorder of proximal renal tubular dysfunction, is characterized by low molecular weight (LMW) proteinuria, hypercalciuria, and at least one additional finding including nephrocalcinosis, nephrolithiasis, hematuria, hypophosphatemia, chronic kidney disease (CKD), and evidence of X-linked inheritance. Males younger than age ten years may manifest only LMW proteinuria and/or hypercalciuria, which are usually asymptomatic. Thirty to 80% of affected males develop end-stage renal disease (ESRD) between ages 30 and 50 years; in some instances ESRD does not develop until the sixth decade of life or later. The disease may also be accompanied by rickets or osteomalacia, growth restriction, and short stature. Disease severity can vary within the same family. Males with Dent disease 2 (caused by pathogenic variants in OCRL) may also have mild intellectual disability, cataracts, and/or elevated muscle enzymes. Due to random X-chromosome inactivation, some female carriers may manifest hypercalciuria and, rarely, renal calculi and moderate LMW proteinuria. Females rarely develop CKD.
### Diagnosis/testing.
The diagnosis is established in a male proband with the typical clinical findings and a family history consistent with X-linked inheritance who has a pathogenic variant in either CLCN5 (known as Dent disease 1) or in OCRL (known as Dent disease 2). Heterozygous females are usually asymptomatic, but some exhibit LMW proteinuria and hypercalciuria, and others with kidney stones have also been described. Heterozygous females are most likely to be identified by familial molecular genetic testing related to a male proband.
### Management.
Treatment of manifestations: The primary goals of treatment are to decrease hypercalciuria, prevent kidney stones and nephrocalcinosis, and delay the progression of CKD. Interventions aimed at decreasing hypercalciuria and preventing kidney stones and nephrocalcinosis have not been tested in randomized controlled trials. Although thiazide diuretics can decrease urinary calcium excretion in boys with Dent disease, side effects limit their use. The effectiveness of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in preventing or delaying further loss of kidney function in children with proteinuria is unclear. Renal replacement therapy is necessary in those with ESRD.
Prevention of secondary complications: Bone disease, when present, responds to vitamin D supplementation and phosphorus repletion. Growth failure may be treated with human growth hormone without adversely affecting kidney function.
Surveillance: Monitor at least annually urinary calcium excretion, renal function (glomerular filtration rate), and the parameters used to stage CKD (i.e., blood pressure, hematocrit/hemoglobin, and serum calcium and phosphorous concentrations). Monitor more frequently when CKD is evident.
Agents/circumstances to avoid: Exposure to potential renal toxins (nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, and intravenous contrast agents).
Evaluation of relatives at risk: Clarify the genetic status of at-risk male relatives either by molecular genetic testing (if the pathogenic variant in the family is known) or by measurement of urinary excretion of low molecular weight proteins (LMWPs).
### Genetic counseling.
Dent disease is inherited in an X-linked manner. The father of an affected male will not have the disease nor will he be hemizygous for the pathogenic variant. If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be significantly affected. Affected males pass the pathogenic variant to all of their daughters (who become carriers) and none of their sons. Carrier testing for at-risk female relatives and prenatal and preimplantation genetic testing are possible if the pathogenic variant in the family has been identified.
## Diagnosis
### Suggestive Findings
Dent disease should be suspected in an individual with the three criteria below in the absence of other known causes of proximal tubule dysfunction [Hoopes et al 2004, Edvardsson et al 2013]. Note: A possible diagnosis of Dent disease is considered if LMW proteinuria and at least one other criterion are present.
1.
LMW proteinuria (the pathognomonic finding of Dent disease) at least five times (and often 10x) above the upper limit of normal. Commonly screened LMW proteins are retinol binding protein and α1 microglobulin.
Note: β2 microglobulin is also often measured to screen for LMW proteinuria. To the authors' knowledge, no known cases of Dent disease have been missed using this screening method; however, its use is cautioned since it is not stable in even minimally acidic urine [Davey & Gosling 1982] and thus could theoretically yield a false negative result.
2.
Hypercalciuria
* Adults (age >18 years). >4.0 mg calcium (0.1 mmol) /kg in 24 hours or >0.25 calcium/creatinine mg/mg (0.57 mmol/mmol) in spot urine
* Children. See Table 1 for 95th percentile calcium/creatinine mg/mg reference values in random urine collections.
3.
At least one of the following:
* Nephrocalcinosis (diffuse renal calcification)
* Nephrolithiasis (kidney stones; composed of calcium oxalate and/or calcium phosphate)
* Hematuria (microscopic or macroscopic blood in the urine)
* Hypophosphatemia (low blood phosphorous concentration)
* Chronic kidney disease (CKD); measured or estimated glomerular filtration rate (GFR) that is below the normal limits for age
* Family history consistent with X-linked inheritance
### Table 1.
Calcium/Creatinine (mg/mg) Reference Values in Children (age <18 yrs)
View in own window
Age (yrs)95th percentile
0-1<0.81
1-2<0.56
2-3<0.50
3-5<0.41
5-7<0.30
7-10<0.25
10-14<0.24
14-17<0.24
In random urine collections
Matos et al [1997]
### Establishing the Diagnosis
Male proband. The diagnosis of Dent disease is established in a male proband with the identification of a hemizygous pathogenic variant in either CLCN5 (Dent disease 1) or OCRL (Dent disease 2) by molecular genetic testing (see Table 2).
Female proband. Female carriers, who are heterozygous for a pathogenic variant in either CLCN5 (Dent disease 1) or OCRL (Dent disease 2), are usually asymptomatic. However, some exhibit LMW proteinuria and hypercalciuria, and others with kidney stones have also been described [Hoopes et al 1998]. Rare females with CKD have been reported. Although biallelic pathogenic variants could occur, it has been assumed that any manifestations are due to skewed X-chromosome inactivation, and many of these symptomatic carriers have other unaffected male children [Dinour et al 2009].
Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.
Single-gene testing can be considered:
* For males or females. Sequence analysis of CLCN5 is usually performed first; if a pathogenic variant is not identified, sequence analysis of OCRL is performed next.
Note: Sequence analysis of affected males provides putative identification of (multi)exon and whole-gene deletions due to lack of amplification; confirmation may require gene-targeted deletion/duplication analysis.
* In a female. If a pathogenic variant is not detected in either gene by sequence analysis, consider gene-targeted deletion/duplication analysis of CLCN5, followed by OCRL.
A multigene panel that includes CLCN5, OCRL, and other genes of interest (see Differential Diagnosis) can also be considered as a first step. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
### Table 2.
Molecular Genetic Testing Used in Dent Disease
View in own window
Gene 1Proportion of Dent Disease Attributed to Pathogenic Variants in Gene 2Proportion of Pathogenic Variants 3 Detectable by Method
Sequence analysis 4, 5Gene-targeted deletion/duplication analysis 6
CLCN560%~92%~8% 7
OCRL15%~95%~5% 8
Unknown 9NA
1\.
See Table A. Genes and Databases for chromosome locus and protein.
2\.
Claverie-Martín et al [2011]
3\.
See Molecular Genetics for information on allelic variants detected in this gene.
4\.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
5\.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
6\.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
7\.
Of the 245 different CLCN5 pathogenic variants known to cause Dent disease 1 identified to date, 7.8% are complex rearrangements (large deletions, insertions, or indels) (HGMD 2016).
8\.
Of the 42 different OCRL pathogenic variants known to cause Dent disease 2 identified to date, 4.7% are multiexon deletions (HGMD 2016).
9\.
In a cohort of affected individuals, approximately 18% (20/110) of males with a Dent disease phenotype did not have a pathogenic variant identified in CLCN5 and OCRL1 [Authors, unpublished observation].
## Clinical Characteristics
### Clinical Description
Presentation. In the early stages of Dent disease, children (typically <~10 years) may manifest only low molecular weight (LMW) proteinuria and/or hypercalciuria, both of which are usually asymptomatic [Claverie-Martín et al 2011]. In the asymptomatic individual, detection of proteinuria may occur on a urinalysis done for screening or other purposes.
LMW proteinuria and/or hypercalciuria can be accompanied by stone disease or nephrocalcinosis, and less frequently by other manifestations of proximal tubular dysfunction including aminoaciduria, phosphaturia, and glycosuria [Hodgin et al 2008].
* Hypercalciuria is typically accompanied by elevated or high-normal levels of 1,25-dihydroxyvitamin D, and depressed or low-normal levels of intact parathyroid hormone (PTH) [Scheinman 1998].
* Hypercalciuria largely or completely resolves with dietary calcium restriction, suggesting that the major component of hypercalciuria is intestinal hyperabsorption.
Renal biopsy. Since patients often present with CKD and proteinuria, a renal biopsy is often obtained. Findings consistent with Dent disease include nephrocalcinosis, interstitial fibrosis, and focal segmental glomerulosclerosis and/or focal global glomerulosclerosis [Copelovitch et al 2007, Frishberg et al 2009]. However, a kidney biopsy alone cannot definitively diagnose Dent disease, and is not required to make the diagnosis.
Other features. The disease may also be accompanied by rickets or osteomalacia, growth restriction, and short stature [Bökenkamp et al 2009].
Short stature is common, although not usually profound in Dent disease 1. In one series height was -0.58 SD of the age-appropriate mean value for Dent disease 1, but more significantly reduced at -2.10 SD for Dent disease 2 [Bökenkamp et al 2009].
Disease progression. An estimated 30%-80% of affected males develop end-stage renal disease (ESRD) between ages 30 and 50 years; in some instances ESRD does not develop until the sixth decade or later [Wrong et al 1994, Lloyd et al 1997]. Of note, deterioration of renal function can occur even in the absence of nephrocalcinosis. Disease severity can vary even within the same family.
#### Dent Disease 1 (caused by pathogenic variants in CLCN5)
The renal phenotypic findings in Dent 1 vary considerably.
Scheinman et al [2000] reported a family in which all affected individuals had the same CLCN5 missense variant (c.1517G>A; p.Gly506Glu) and the Dent disease phenotype ranged from severe in several members to isolated hypercalciuria without proteinuria, nephrocalcinosis, or chronic kidney disease (CKD) in one individual. It is not currently known how often an individual with a CLCN5 pathogenic variant manifests only asymptomatic hypercalciuria and/or proteinuria without developing CKD.
Some individuals with a pathogenic variant in CLCN5 and a family history of Dent disease developed ESRD with proteinuria, but without other typical features of Dent disease (i.e., kidney stones, nephrocalcinosis, and bone disease) [Copelovitch et al 2007, Frishberg et al 2009]. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS) and focal global glomerulosclerosis. The findings in these individuals illustrate that the spectrum of Dent disease includes persons with proteinuria and a biopsy consistent with FSGS and that the diagnosis is only considered when evaluations for LMW proteinuria and/or hypercalciuria are performed.
It is currently unclear whether Dent disease will be diagnosed among a larger number of individuals with clinical FSGS, although it is now known that focal global sclerosis is very common in Dent disease [Wang et al 2016] and instances of Dent disease being misdiagnosed as FSGS continue to be reported [Fervenza 2013].
#### Dent Disease 2 (caused by pathogenic variants in OCRL)
To date, 42 pathogenic variants have been identified in males with a Dent disease 2 phenotype and have been reported in the literature.
In addition to the Dent disease-related renal findings, individuals with Dent disease 2 may also have:
* Mild intellectual disability
* Cataracts (rare)
* Elevated muscle enzymes (LDH, CK)
#### Symptomatic Females
There have been occasional reports of renal calculi and moderate LMW proteinuria when carrier females have been studied in large kindreds. Rarely, heterozygous females manifest clinically significant kidney disease resulting from skewed X-chromosome inactivation. One female from a family with Dent disease developed renal insufficiency and nephrocalcinosis; however, she did not have molecular genetic testing [Wrong et al 1994]. Another carrier female with a known pathogenic variant, developed symptomatic nephrolithiasis and stage 3B CKD by age 65 [Hoopes et al 1998].
Although not reported in the literature, a symptomatic female could have an X-chromosome abnormality (e.g., absence of one X chromosome [45,X] and a CLCN5 or OCRL pathogenic variant on the remaining X chromosome).
Although not reported in the literature, a female with biallelic pathogenic variants in CLCN5 or OCRL (inherited from a carrier mother and an affected father) would be predicted to manifest clinically significant kidney disease.
### Genotype-Phenotype Correlations
CLCN5. Genotype-phenotype correlations have yet to be established.
OCRL. It has been suggested that pathogenic variants in OCRL are associated with a phenotypic spectrum ranging from Lowe syndrome at the severe end (see Genetically Related Disorders) to Dent disease 2 at the mild end.
Note: Although the renal tubulopathy in Lowe syndrome (which is mainly characterized by altered protein reabsorption) and Dent disease is similar, it is generally milder in Dent disease. Of note, this milder Dent disease phenotype could not be attributed to lesser protein expression or enzyme activity.
Frameshift and nonsense OCRL variants associated with Dent disease 2 have been mapped to exons different from those causing Lowe syndrome [Hichri et al 2011]; however, OCRL missense and splicing variants and in-frame deletions that cause these two disorders do not map exclusively to specific gene regions.
* Frameshift and nonsense variants associated with Dent disease 2 are in the first seven exons. Missense variants associated with Dent disease 2 are most often, but not exclusively, located in exons 9-15, which encode the catalytic phosphatase domain.
* Frameshift and nonsense variants associated with Lowe syndrome are located in the middle and later regions of the gene, exons 8-23, which encode the catalytic phosphatase and the Rho-GAP-like domain [Tosetto et al 2009, Hichri et al 2011].
### Prevalence
To date about 250 affected families have been reported [Devuyst & Thakker 2010]. However, the wide variability of clinical presentation in Dent disease and (in some cases) absence of family history make diagnosis difficult; thus, the disorder is likely underdiagnosed.
## Differential Diagnosis
The differential diagnosis of Dent disease includes other causes of proximal tubular dysfunction.
Renal Fanconi syndrome. The presence of more generalized proximal tubular dysfunction (glucosuria, amino aciduria, renal tubular acidosis) would suggest the possibility of a renal Fanconi syndrome. Causes of renal Fanconi syndromes can be hereditary (e.g., Wilson disease, glycogen storage disease) or acquired (e.g., exposure to heavy metal, toluene, or cisplatin).
Glomerular disease. Some individuals with Dent disease 1 with more severe proteinuria were found to have focal segmental glomerulosclerosis (FSGS) or global sclerosis on kidney biopsy [Copelovitch et al 2007, Frishberg et al 2009]. Most cases of FSGS are idiopathic, but FSGS can be seen in association with obesity or progressive chronic kidney disease of any cause. FSGS associated with Dent disease can be identified by the prominent low molecular weight (LMW) proteinuria and confirmed by genetic testing.
Donnai-Barrow syndrome, caused by biallelic pathogenic variants in LRP2, which encodes a 600-kd megalin protein, bears some similarities to Dent disease [Kantarci et al 2007]. Clinical manifestations of this rare disorder include hypertelorism, large anterior fontanelle, agenesis of the corpus callosum, and congenital diaphragmatic hernia [Pober et al 2009]. LMW proteinuria and high myopia have been consistently observed in these patients [Pober et al 2009]. However, other typical findings of Dent disease, including nephrolithiasis, nephrocalcinosis, hypercalciuria, chronic kidney disease, or bone disease, have not been reported to date.
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with Dent disease, the following evaluations are recommended if they have not already been completed:
* Assessment of renal function (measured or estimated GFR; urine protein excretion)
* Assessment for nephrocalcinosis and kidney stones by imaging studies, typically low-dose noncontrast CT scan or ultrasound
For those with evidence of renal stones or nephrocalcinosis, urine studies for kidney stone risk factors (including calcium and citrate excretion)
* Assessment of risk for bone disease (serum calcium, phosphorus, and alkaline phosphatase)
Note: Elevated alkaline phosphatase has been reported in all individuals with clinical rickets [Wrong et al 1994].
For those with evidence of bone disease and/or growth delay, more complete assessment of bone health (i.e., serum vitamin D concentration and PTH level; x-ray of long bones for evidence of osteomalacia)
* In children, evaluation of stature using standard growth charts. If short stature is present, evaluation by an endocrinologist for the possibility of growth hormone therapy can be considered.
* Evaluation for intellectual disability
* Careful eye exam for cataracts, especially if there is any concern for visual impairment
* Consultation with a clinical geneticist and/or genetic counselor
* Although it is not necessary to specifically screen for the possibility, elevated serum muscle enzyme levels are often seen in patients with Dent disease.
### Treatment of Manifestations
No guidelines have been established for treatment of Dent disease. The primary goals of treatment are to decrease hypercalciuria, prevent kidney stones and nephrocalcinosis, and delay the progression of chronic kidney disease (CKD).
Interventions aimed at decreasing hypercalciuria and preventing kidney stones and nephrocalcinosis have not been tested in randomized controlled trials. Thiazide diuretics in doses greater than 0.4 mg/kg/day have decreased urinary calcium excretion by more than 40% in boys with Dent disease [Raja et al 2002, Blanchard et al 2008]. However, frequent side effects included hypokalemia, volume depletion, and cramping. Careful dosing and close monitoring for these side effects are necessary.
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have been used in children with proteinuria to prevent or delay further loss of kidney function; however, their effectiveness has not been clear. Although treatment with ACE inhibitors or ARB may be somewhat beneficial for individuals with focal segmental glomerulosclerosis (FSGS), they are not known to be helpful for the focal global glomerulosclerosis that is associated with Dent disease, and angiotensin blockade is not thought to significantly affect LMW proteinuria or any potential ill effects of it. A kidney biopsy to exclude other causes of proteinuria and CKD is reasonable.
While a high-citrate diet has been shown to slow progression of CKD in Clcn5 knockout mice [Cebotaru et al 2005] and has been used in the treatment of Dent disease, no human trials have proven its effectiveness. Note: Citrate is commonly used in Lowe syndrome to treat the metabolic acidosis resulting from renal tubular acidosis.
If males with Dent disease progress to ESRD, renal replacement therapy becomes necessary. Hemodialysis, peritoneal dialysis, and renal transplantation are appropriate options. Because Dent disease manifestations are largely localized in the kidney, the disease will not recur.
School-aged individuals with mild intellectual disability will benefit from individual educational plans and special educational services.
Cataracts, if present, are treated in a standard manner.
### Prevention of Secondary Complications
Bone disease has not been a prominent component of Dent disease in a recent case series based in France [Blanchard et al 2016] but was more prominent in a Chinese population [Li et al 2016]; whether this reflects environmental or genetic effects is not known. When present it has been reported to respond to vitamin D supplementation and phosphorus repletion in those with elevated serum alkaline phosphatase levels [Wrong et al 1994].
Limited reports suggest that growth failure can be successfully treated with human growth hormone without adversely affecting kidney function [Sheffer-Babila et al 2008].
### Surveillance
Renal function measured as glomerular filtration rate (GFR) should be monitored at least annually together with the parameters used to stage chronic kidney disease (i.e., blood pressure, hematocrit/hemoglobin, urinary calcium excretion, and serum calcium and phosphorus concentrations).
More frequent visits and monitoring for complications of chronic kidney disease (i.e., hypertension, anemia, and secondary hyperparathyroidism) as well as consideration of intensified treatment of cardiovascular risk factors may be indicated if GFR falls below 45 mL/min/1.73 m2 (CKD Stage 3B).
### Agents/Circumstances to Avoid
Exposure to potential renal toxins (nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, and intravenous contrast agents) should be avoided, especially if renal function is below 45 mL/min/1.73 m2 (CKD stage 3B).
### Evaluation of Relatives at Risk
It is appropriate to evaluate male relatives at risk for Dent disease 1 (caused by mutation of CLCN5) or Dent disease 2 (caused by mutation of OCRL) in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.
* If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
* If the pathogenic variant in the family is not known, measurement of urinary excretion of low molecular weight proteins (e.g., alpha 1 microglobulin, retinol binding protein) is a sensitive and specific test.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
*[v]: View this template
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*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Dent Disease | c0878681 | 1,372 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99494/ | 2021-01-18T21:31:03 | {"mesh": ["D057973"], "synonyms": []} |
Factor XII deficiency
Other namesHageman factor deficiency
SpecialtyHematology, medical genetics
Factor XII deficiency is a deficiency in the production of factor XII (FXII), a plasma glycoprotein and clotting factor that participates in the coagulation cascade and activates factor XI. FXII appears to be not essential for blood clotting, as individuals with this condition are usually asymptomatic and form blood clots in vivo. FXII deficiency tends to be identified during presurgical laboratory screening for bleeding disorders.[1]
The condition can be inherited or acquired.
## Contents
* 1 Symptoms and signs
* 2 Causes
* 3 Diagnosis
* 4 Treatment
* 5 History
* 6 References
* 7 External links
## Symptoms and signs[edit]
While it is indicated that people with FXII deficiency are generally asymptomatic,[2] studies in women with recurrent miscarriages suggest an association with FXII deficiency.[3] The condition is of importance in the differential diagnosis to other bleeding disorders, specifically the hemophilias: hemophilia A with a deficiency in factor VIII or antihemophilic globulin, hemophilia B with a deficiency in factor IX (Christmas disease), and hemophilia C with a deficiency in factor XI. Other rare forms of bleeding disorders are also in the differential diagnosis.[citation needed]
There is concern that individuals with FXII deficiency are more prone to thrombophilic disease,[1] however, this is at variance with a long term study from Switzerland.[4]
## Causes[edit]
Inherited or congenital FXII deficiency is usually passed on by autosomal recessive inheritance.[2] A person needs to inherit a defective gene from both parents. People who have only one defective gene are asymptomatic, but may have lower FXII levels and can pass the gene on to half their offspring.[citation needed]
In persons with congenital FXII deficiency the condition is lifelong. People affected may want to alert other family members as they may also carry the gene. A 1994 study of 300 healthy blood donors found that 7 persons (2.3%) had FXII deficiencies with one subject having no detectable FXII (0.3%).[5] This study is at variance with estimates that only 1 in 1,000,000 people has the condition.[2]
The acquired form of FXII deficiency is seen in patients with the nephrotic syndrome, liver disease, sepsis and shock, disseminated intravascular coagulation, and other diseases.[1]
## Diagnosis[edit]
The condition is diagnosed by blood tests in the laboratory when it is noted that special blood clotting test are abnormal. Specifically prothrombin time (PT) or activated partial thromboplastin time (aPTT) are prolonged.[2] The diagnosis is confirmed by an assay detecting very low or absent FXII levels.
The FXII (F12) gene is found on chromosome 5q33-qter.[2]In hereditary angioedema type III an increased activity of factor XII has been described.[6]
## Treatment[edit]
In congenital FXII deficiency treatment is not necessary. In acquired FXII deficiency the underlying problem needs to be addressed.[citation needed]
## History[edit]
The condition was first described in 1955 based by blood testing of a patient named John Hageman.[7]
## References[edit]
1. ^ a b c Riley RS (April 2005). "Factor XII Deficiency" (PDF). Pathology, Virginia Commonwealth University. Retrieved February 20, 2017.
2. ^ a b c d e "Factor XII Deficiency". National Organization for Rare Disorders(NORD). Retrieved February 20, 2017.
3. ^ Pauer HU, Burfeind P, Köstering H, Emons G, Hinney B (2003). "Factor XII deficiency is strongly associated with primary recurrent abortions". Fertility and Sterility. 80 (3): 590–594. doi:10.1016/S0015-0282(03)00788-X. PMID 12969703.
4. ^ Zeerleder S, Schloesser M, Redondo M, Wuillemin WA, Engel W, Furlan M, Laemmle B (1999). "Reevaluation of the Incidence of Thromboembolic Complications in Congenital Factor XII Deficiency A Study on 73 Subjects from 14 Swiss Families". Thrombosis and Haemostasis. 82 (4): 1240–1246. doi:10.1055/s-0037-1614368. PMID 10544906. Retrieved February 20, 2017.
5. ^ Halbmayer WM, Haushofer A, Schoen R, Mannhalter C, Strohmer E, Baumgarten K, Fischer M (1994). "The prevalence of moderate and severe FXII (Hageman factor) deficiency among the normal population: evaluation of the incidence of FXII deficiency among 300 healthy blood donors". Thromb Haemost. 71 (1): 68–72. doi:10.1055/s-0038-1642386. PMID 8165648.
6. ^ Cichon S, Martin L, Hennies HC, Müller F, Van Driessche K, Karpushova A, Stevens W, Colombo R, Renné T, Drouet C, Bork K, Nöthen MM (2006). "Increased Activity of Coagulation Factor XII (Hageman Factor) Causes Hereditary Angioedema Type III". Am J Hum Genet. 79 (6): 1098–1104. doi:10.1086/509899. PMC 1698720. PMID 17186468.
7. ^ Ratnoff OD, Margolius A (1955). "Hageman trait: an asymptomatic disorder of blood coagulation". Transactions of the Association of American Physicians. 68: 149–54. PMID 13299324.
## External links[edit]
Classification
D
* ICD-10: D68.2
* OMIM: 234000
* MeSH: D005175
External resources
* MedlinePlus: 000545
* Orphanet: 330
* 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 thrombocythaemia
* 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
* Haemophilia
* 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
* Haematoma
* Petechia
* Purpura
* Nonthrombocytopenic purpura
By site
* head
* Epistaxis
* Haemoptysis
* Intracranial haemorrhage
* Hyphaema
* Subconjunctival haemorrhage
* torso
* Haemothorax
* Haemopericardium
* Pulmonary haematoma
* abdomen
* Gastrointestinal bleeding
* Haemobilia
* Haemoperitoneum
* Haematocele
* Haematosalpinx
* joint
* Haemarthrosis
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*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Factor XII deficiency | c0015526 | 1,373 | wikipedia | https://en.wikipedia.org/wiki/Factor_XII_deficiency | 2021-01-18T18:31:28 | {"gard": ["6558"], "mesh": ["D005175"], "umls": ["C0015526"], "orphanet": ["330"], "wikidata": ["Q2841213"]} |
Frontonasal dysplasia-severe microphthalmia-severe facial clefting syndrome is a rare, genetic, orofacial clefting malformation syndrome characterized by severe frontonasal dysplasia with complete cleft palate, facial cleft, extreme microphtalmia and hypertelorism, frequently associated with eyelid colobomata, sparse or absent eyelashes/eyebrows, wide nasal bridge with hypoplastic alae nasi, low-set, posteriorly rotated ears and caudal appendage in the sacral region.
*[v]: View this template
*[t]: Discuss this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Frontonasal dysplasia-severe microphthalmia-severe facial clefting syndrome | c3150706 | 1,374 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=306542 | 2021-01-23T18:00:44 | {"gard": ["12640"], "omim": ["613456"], "synonyms": ["ALX1-related frontonasal dysplasia", "Frontonasal dysplasia type 3"]} |
A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-78 (SPG78) is caused by homozygous or compound heterozygous mutation in the ATP13A2 gene (610513) on chromosome 1p36.
Description
Autosomal recessive spastic paraplegia-78 is an adult-onset neurodegenerative disorder characterized predominantly by spasticity and muscle weakness of the lower limbs, resulting in gait difficulties and loss of ambulation in some patients. Affected individuals also have cerebellar signs, such as dysarthria, oculomotor disturbances, and limb and gait ataxia; brain imaging shows cerebellar atrophy. Some patients may have mild cognitive impairment or frank dementia. The phenotype is highly variable (summary by Estrada-Cuzcano et al., 2017).
Biallelic mutation in the ATP13A2 gene also causes Kufor-Rakeb syndrome (KRS; 606693), a neurodegenerative disorder with overlapping features. Patients with KRS have earlier onset and prominent parkinsonism. Loss of ATP13A2 function results in a multidimensional spectrum of neurologic features reflecting various regions of the brain and nervous system, including cortical, pyramidal, extrapyramidal, brainstem, cerebellar, and peripheral (summary by Estrada-Cuzcano et al., 2017).
Clinical Features
Kara et al. (2016) reported a 46-year-old man, born of consanguineous Pakistani parents, with onset of spastic quadriplegia and cognitive decline at age 18 years. He also showed bilateral pes cavus, ataxia, and oculomotor abnormalities, including nystagmus, squint, and reduced upgaze. Brain imaging showed cerebral atrophy and subtle abnormalities in the basal ganglia. The patient had no features of parkinsonism. Treatment with L-DOPA did not result in lasting clinical improvement.
Estrada-Cuzcano et al. (2017) reported 5 patients from 3 unrelated families with complicated spastic paraplegia. The mean age at onset was 32 years, and the patients presented with abnormal gait, spastic paraplegia, weakness of the lower limbs, and dysarthria; 1 patient had neurogenic bladder dysfunction. Physical examination showed hyperreflexia in the upper and lower limbs, and 4 patients had extensor plantar responses. Three patients lost ambulation 8 to 18 years after disease onset. Additional features included oculomotor disturbance and limb and gait ataxia, indicating cerebellar involvement, as well as axonal motor and sensory polyneuropathy. Only 1 patient had mild resting tremor and bradykinesia; the others did not have clinical evidence of involvement of the extrapyramidal motor system. Of 3 affected brothers in a family of Belgian origin, 2 had mild verbal memory deficits, whereas the third had no cognitive impairment. The 2 other unrelated patients, both female, had severe dementia with supranuclear gaze palsy, and 1 also had acoustic hallucinations. Brain imaging showed cerebellar and cortical atrophy in all patients, thin corpus callosum and periventricular white matter changes in 1 patient, and abnormalities of the anterior fornix of the corpus callosum in 2 patients. Dopamine transporter scintigraphy performed in 1 patient who had no clinical signs or symptoms of extrapyramidal involvement showed a drastic decrease in dopamine transporter density that was most pronounced in the putamen. Estrada-Cuzcano et al. (2017) also reported the clinical features of a Lebanese man with a similar phenotype. He presented with rapidly progressive parkinsonism, supranuclear gaze palsy, perioral myokymia, and cognitive decline at age 44 years. He had pyramidal involvement with marked spasticity and hyperreflexia, most pronounced in the lower limbs. He did not have ataxia.
Inheritance
The transmission pattern of SPG78 in the families reported by Estrada-Cuzcano et al. (2017) was consistent with autosomal recessive inheritance.
Molecular Genetics
In a 46-year-old man, born of consanguineous Pakistani parents, with SPG78, Kara et al. (2016) identified a homozygous mutation in the ATP13A2 gene (610513.0009). Functional studies of the variant and studies of patient cells were not performed. The patient was 1 of 97 probands with complicated spastic paraplegia who underwent molecular analysis.
In 5 patients from 3 unrelated families with SPG78, Estrada-Cuzcano et al. (2017) identified homozygous or compound heterozygous mutations in the ATP13A2 gene (610513.0010-610513.0013). The mutation in the first family was found by whole-exome sequencing; the mutations in the 2 subsequent patients were found by direct sequencing of the ATP13A2 gene in a cohort of 795 probands with spastic paraplegia. Studies of selected patient cells and in vitro studies of some of the mutations showed abnormal intracellular localization of the mutant proteins, transcript or protein instability in some cases, and impaired lysosomal and mitochondrial function, all consistent with a loss of function.
INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Supranuclear gaze palsy \- Nystagmus GENITOURINARY Bladder \- Urge incontinence SKELETAL Feet \- Pes cavus (in some patients) NEUROLOGIC Central Nervous System \- Spastic paraplegia \- Spastic quadriplegia \- Hyperreflexia \- Extensor plantar responses \- Pyramidal signs \- Impaired gait \- Loss of ambulation \- Dysarthria \- Ataxia \- Cognitive decline \- Dementia (in some patients) \- Perioral myokymia (1 patient) \- Parkinsonism (1 patient) \- Cerebellar atrophy \- Cortical atrophy Peripheral Nervous System \- Axonal sensorimotor peripheral neuropathy \- Distal sensory impairment Behavioral Psychiatric Manifestations \- Hallucinations \- Aggression MISCELLANEOUS \- Mean age at onset 32 years \- Earlier onset has been reported in 1 patient \- Variable neurologic phenotype MOLECULAR BASIS \- Caused by mutation in the ATPase type 13A2 gene (ATP13A2, 610513.0009 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| SPASTIC PARAPLEGIA 78, AUTOSOMAL RECESSIVE | c4310662 | 1,375 | omim | https://www.omim.org/entry/617225 | 2019-09-22T15:46:25 | {"omim": ["617225"], "orphanet": ["513436"], "synonyms": ["SPG78"]} |
Post-LASIK ectasia is a condition similar to keratoconus where the cornea starts to bulge forwards at a variable time after LASIK, PRK, or SMILE corneal laser eye surgery.[1]
## Risk factors[edit]
Before corneal refractive surgery such as LASIK, SMILE, and PRK, people must be examined for possible risk factors such as keratoconus.[2]
Abnormal corneal topography compromises of keratoconus, pellucid marginal degeneration, or forme fruste keratoconus with an I-S value of 1.4 or more[3] is the most significant risk factor. Low age, low residual stromal bed (RSB) thickness, low preoperative corneal thickness, and high myopia are other important risk factors.[4][5]
## Treatments[edit]
Treatment options include contact lenses,[6][7] intrastromal corneal ring segments, custom topography-guided transepithelial PRK combined with corneal collagen cross-linking,[8] or corneal transplant.
When cross-linking is performed only after the cornea becomes distorted, vision remains blurry even though the disease is stabilised. As a result, combining corneal collagen cross-linking with LASIK ('LASIK Xtra') aims to strengthen the cornea at the point of surgery and may be useful in cases where a very thin cornea is expected after the LASIK procedure.[9] This would include cases of high spectacle power and people with thin corneas before surgery. Definitive evidence that the procedure can reduce the risk of corneal ectasia will only become available a number of years later as corneal ectasia, if it happens, usually occurs in the late post-operative period. Some study show that combining LASIK with cross-linking adds refractive stability to hyperopic treatments and may also do the same for very high myopic treatments.[9][10][11]
In 2016, the FDA approved the KXL system and two photoenhancers for the treatment of corneal ectasia following refractive surgery.[12]
## References[edit]
1. ^ "Ectasia After LASIK". American Academy of Ophthalmology.
2. ^ Finn, Peter (20 December 2012). "Medical Mystery: Preparation for surgery revealed cause of deteriorating eyesight". The Washington Post.
3. ^ Rabinowitz, YS; McDonnell, PJ (1989). "Computer-assisted corneal topography in keratoconus". Refractive & Corneal Surgery. 5 (6): 400–8. PMID 2488838.
4. ^ Kohlhaas, M; Spoerl, E; Schilde, T; Unger, G; Wittig, C; Pillunat, LE (February 2006). "Biomechanical evidence of the distribution of cross-links in corneas treated with riboflavin and ultraviolet A light". Journal of Cataract and Refractive Surgery. 32 (2): 279–83. doi:10.1016/j.jcrs.2005.12.092. PMID 16565005.
5. ^ Randleman, JB; Banning, CS; Stulting, RD (January 2007). "Corneal ectasia after hyperopic LASIK". Journal of Refractive Surgery. 23 (1): 98–102. doi:10.3928/1081-597X-20070101-17. PMID 17269252.
6. ^ Marsack, Jason D.; Parker, Katrina E.; Applegate, Raymond A. (December 2008). "Performance of Wavefront-Guided Soft Lenses in Three Keratoconus Subjects". Optometry and Vision Science. 85 (12): E1172–E1178. doi:10.1097/OPX.0b013e31818e8eaa. PMC 2614306. PMID 19050464.
7. ^ Marsack, JD; Parker, KE; Niu, Y; Pesudovs, K; Applegate, RA (November 2007). "On-eye performance of custom wavefront-guided soft contact lenses in a habitual soft lens-wearing keratoconic patient". Journal of Refractive Surgery. 23 (9): 960–4. doi:10.3928/1081-597X-20071101-18. PMID 18041254.
8. ^ Lam, Kay; Rootman, Dan B.; Lichtinger, Alejandro; Rootman, David S. (6 January 2013). "Post-LASIK ectasia treated with intrastromal corneal ring segments and corneal crosslinking". Digital Journal of Ophthalmology. 19 (1): 1–8. doi:10.5693/djo.02.2012.10.001. ISSN 1542-8958. PMC 3689440. PMID 23794955.
9. ^ a b Stephenson, Michelle (2014). "LASIK Xtra: Is It for Everyone?". Review of Ophthalmology. Jobson Medical Information LLC.
10. ^ Kanellopoulos, AnastasiosJohn; Pamel, GregoryJ (2013). "Review of current indications for combined very high fluence collagen cross-linking and laser in situ keratomileusis surgery". Indian Journal of Ophthalmology. 61 (8): 430–2. doi:10.4103/0301-4738.116074. PMC 3775081. PMID 23925331.
11. ^ "How To Treat Keratoconus". Wednesday, 13 January 2021
12. ^ "Highlights of Prescribing Information: PHOTREXA VISCOUS (riboflavin 5'-phosphate in 20% dextran ophthalmic solution) 0.146% for topical ophthalmic use PHOTREXA (riboflavin 5'-phosphate ophthalmic solution) 0.146% for topical ophthalmic use For use with the KXL® System" (PDF). U.S. Food and Drug Administration. pp. 5–14.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Post-LASIK ectasia | c1531855 | 1,376 | wikipedia | https://en.wikipedia.org/wiki/Post-LASIK_ectasia | 2021-01-18T18:45:44 | {"umls": ["C1531855"], "wikidata": ["Q25312769"]} |
## Clinical Features
Cranial and facial hyperostosis results in a characteristic clinical and radiographic appearance. The diaphyses of the bones are generally expanded. Halliday (1949) and Stransky et al. (1962) reported isolated cases with similar findings. Facial and cranial thickening and distortion are particularly striking in this form. Most cases have been mentally retarded. Unlike the situation in the craniometaphyseal dysplasias (e.g., 218400), the long bones do not show metaphyseal flaring but show diaphyseal endostosis and are shaped like a policeman's nightstick.
Joseph et al. (1958), who first suggested the designation of progressive craniodiaphyseal dysplasia, described a patient with a picture they considered identical to that described by Halliday (1949). Brueton and Winter (1990) indicated the unsatisfactory state of the genetic understanding of this disorder. On review of the report by de Souza (1927), they concluded that the sibs most likely had Van Buchem disease (239100).
Inheritance
Affected male and female sibs reported by de Souza (1927) and consanguineous parents in the patient discussed by Halliday (1949) suggest autosomal recessive inheritance.
There is also evidence for an autosomal dominant form of CDD; see 122860.
Limbs \- Diaphyseal dysplasia \- Diaphyseal sclerosis \- No metaphyseal flaring in distinction to craniometaphyseal dysplasia Radiology \- Diaphyses generally expanded Neuro \- Mental retardation Skull \- Cranial hyperostosis Inheritance \- Autosomal recessive HEENT \- Facial hyperostosis ▲ Close
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*[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
| CRANIODIAPHYSEAL DYSPLASIA | c0410539 | 1,377 | omim | https://www.omim.org/entry/218300 | 2019-09-22T16:29:17 | {"doid": ["0080032"], "mesh": ["C562940"], "omim": ["218300"], "orphanet": ["1513"]} |
Not to be confused with Potter sequence.
Doege–Potter syndrome
The structure of IGF-2, responsible for the hypoglycemia associated with Doege–Potter syndrome
SpecialtyOncology
Doege–Potter syndrome (DPS) is a paraneoplastic syndrome[1] in which hypoglycemia is associated with solitary fibrous tumors. The hypoglycemia is the result of the tumors producing insulin-like growth factor 2.[2] The syndrome was first described in 1930, by Karl Walter Doege (1867–1932), a German-American physician[3] and by Roy Pilling Potter (1879–1968), an American radiologist, working independently;[4] the full term Doege–Potter syndrome was infrequently used until the publication of a 2000 article[5] using the eponym.[6]
DPS is rare (as of 1976, less than one hundred cases were described[7]), with a malignancy rate of 12–15%. Actual rates of hypoglycemia associated with a fibrous tumor are quite rare (a 1981 study of 360 solitary fibrous tumors of the lungs found that only 4% caused hypoglycemia[8]), and are linked to large tumors with high rates of mitosis.[9] Removal of the tumor will normally resolve the symptoms.[1][9]
Tumors causing DPS tend to be quite large;[10] in one case a 3 kg (6.6 lb), 23×21×12 cm (9.1×8.3×4.7 in) mass was removed, sufficiently large to cause a collapsed lung.[5] In X-rays, they appear as a single mass with visible, defined borders, appearing at the edges of the lungs or a fissure dividing the lobes of the lungs.[10] Similar hypoglycemic effects have been related to mesenchymal tumors.[6]
## References[edit]
1. ^ a b Balduyck B, Lauwers P, Govaert K, Hendriks J, De Maeseneer M, Van Schil P (July 2006). "Solitary fibrous tumor of the pleura with associated hypoglycemia: Doege–Potter syndrome: a case report". J Thorac Oncol. 1 (6): 588–90. doi:10.1097/01243894-200607000-00016. PMID 17409923.
2. ^ Herrmann BL, Saller B, Kiess W, et al. (2000). "Primary malignant fibrous histiocytoma of the lung: IGF-II producing tumor induces fasting hypoglycemia". Exp. Clin. Endocrinol. Diabetes. 108 (8): 515–18. doi:10.1055/s-2000-11007. PMID 11149628.
3. ^ Doege, KW (1930). "Fibrosarcoma of the mediastinum". Ann Surg. 92 (5): 955–960. PMC 1398259. PMID 17866430.
4. ^ Roy M, Burns MV, Overly DJ, Curd BT (November 1992). "Solitary fibrous tumor of the pleura with hypoglycemia: the Doege–Potter syndrome". J Ky Med Assoc. 90 (11): 557–60. PMID 1474302.
5. ^ a b Chamberlain MH, Taggart DP (January 2000). "Solitary fibrous tumor associated with hypoglycemia: an example of the Doege–Potter syndrome". J. Thorac. Cardiovasc. Surg. 119 (1): 185–7. doi:10.1016/S0022-5223(00)70242-X. PMID 10612786. Archived from the original on 2013-01-12.
6. ^ a b Shields, TW; LoCicero J; Ponn RB; Rusch VW (2005). General thoracic surgery. Hagerstwon, MD: Lippincott Williams & Wilkins. pp. 893. ISBN 0-7817-3889-X.
7. ^ Ellorhaoui M, Graf B (February 1976). "[Intrathoracal tumor with accompanying hypoglycemia]". Z Gesamte Inn Med (in German). 31 (3): 77–81. PMID 785836.
8. ^ Briselli M, Mark EJ, Dickersin GR (June 1981). "Solitary fibrous tumors of the pleura: eight new cases and review of 360 cases in the literature". Cancer. 47 (11): 2678–89. doi:10.1002/1097-0142(19810601)47:11<2678::AID-CNCR2820471126>3.0.CO;2-9. PMID 7260861.
9. ^ a b Zafar H, Takimoto CH, Weiss G (2003). "Doege–Potter syndrome: hypoglycemia associated with malignant solitary fibrous tumor". Med. Oncol. 20 (4): 403–08. doi:10.1385/MO:20:4:403. PMID 14716039.
10. ^ a b Light, Richard J. (2007). Pleural diseases. Hagerstwon, MD: Lippincott Williams & Wilkins. pp. 172–3. ISBN 978-0-7817-6957-0.
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*[AA]: Adrenergic agonist
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*[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
| Doege–Potter syndrome | None | 1,378 | wikipedia | https://en.wikipedia.org/wiki/Doege%E2%80%93Potter_syndrome | 2021-01-18T18:42:05 | {"wikidata": ["Q1234529"]} |
A number sign (#) is used with this entry because Dyggve-Melchior-Clausen disease (DMC) is caused by homozygous or compound heterozygous mutation in the DYM gene (607461) on chromosome 18q21. Mutations in the same gene cause Smith-McCort dysplasia-1 (607326).
Clinical Features
Among the children from an uncle-niece marriage in Greenland, Dyggve et al. (1962) found 3 with a condition resembling Hurler syndrome (607014) and Morquio syndrome (253000) in some respects. The fingers were clawed with limitation in extension. The patients were mentally retarded, and the urine showed mucopolysaccharide. The spine showed generalized platyspondyly. Irregularities of the iliac crest gave an appearance of a lace border around it. The patient shown in family 12 (plate XII) of the Norwegian study by Hobaek (1961) is probably identical. Naffah and Taleb (1974) described spinal compression from odontoid hypoplasia, as in the Morquio syndrome.
The DMC gene may have a relatively high frequency in Lebanese (Naffah, 1976; Bonafede and Beighton, 1978). Schorr et al. (1977) described the DMC syndrome in 6 Moroccan Jews and 2 Arabs from Gaza, distributed in 2 families and ranging in age from 4 to 25 years. They drew attention to a characteristic double hump with central constriction of the vertebral bodies which is present at age 4 years and becomes more distinct in late childhood. In adult patients, the vertebral bodies become more rectangular as the appositional bone which appears during adolescence becomes fused. In a review of DMC disease, Beighton (1990) gave information on the 3 authors whose names are attached to the disorder. He emphasized prominence of the jaw and relative microcephaly. Subluxation of the hips is frequent. In South Africa, Winship and Rubin (1992) described an affected brother and sister whose parents were first cousins and whose ancestors migrated to South Africa from India in the 19th century.
Spranger et al. (1976) suggested that there is a distinct entity similar to DMC dwarfism except that the patients are not mentally retarded; they recommended the designation Smith-McCort dwarfism (607326). Spinal cord compression due to atlantoaxial instability occurs in both.
Nakamura et al. (1997) examined iliac crest biopsies from 2 patients with Smith-McCort dysplasia. The lace-like appearance of the iliac crests, which is a characteristic radiologic sign, was found to be caused by bone tissue deposited in a wavy pattern at the osteochondral junction. The growth plate showed abnormal enchondral ossification with no columnarization of chondrocytes. Electron microscopy demonstrated chondrocytes with dilated cisternae of rough endoplasmic reticulum (RER) containing fine granular or amorphous material similar to what had been reported in cases of DMC syndrome. Thus, Nakamura et al. (1997) concluded that Smith-McCort dysplasia has pathologic changes in common with DMC disease as an RER storage disorder, even though the mental condition is different.
Mapping
In a consanguineous family from Guam affected by Smith-McCort dysplasia, Ehtesham et al. (2002) performed a genomewide scan and found evidence of linkage to loci on chromosome 18q12. Analysis of a second, smaller family was also consistent with linkage to this region, producing a maximum combined 2-point lod score of 3.04 at a recombination fraction of zero for marker D18S450. A 10.7-cM region containing the disease gene was defined by recombination events in 2 affected individuals in the larger family. Furthermore, all affected children in the larger family were homozygous for a subset of marker loci within this region, defining a 1.5-cM interval likely to contain the mutated gene. Analysis of 3 small, unrelated families with DMC syndrome provided evidence of linkage to the same region, a result consistent with the hypothesis that the 2 disorders are allelic. By homozygosity mapping, Thauvin-Robinet et al. (2002) mapped the DMC syndrome to 18q12.
Molecular Genetics
Cohn et al. (2003) sequenced the coding exons of the DYM gene, a highly evolutionarily conserved gene located within the 18q12 region defined by linkage study, and identified mutations in both DMC (607461.0001-607461.0004) and SMC (607461.0005-607461.0006) families. The data corroborated the impression that these 2 disorders are allelic and identified a gene necessary for normal skeletal development and brain function.
Independently, using a positional cloning strategy, El Ghouzzi et al. (2003) identified the DMC gene as mutant in the DMC syndrome. They detected 7 deleterious mutations, 4 of which were nonsense, 2 splice site, and 1 frameshift, among 10 affected families (see, e.g., 607461.0007-607461.0008).
Neumann et al. (2006) reported 2 consanguineous families from Lebanon and Georgia (Caucasus), respectively, with 2 patients each with DMC confirmed by genetic analysis.
INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature, disproportionate \- Adult height 98-127 cm Other \- Postnatal growth retardation HEAD & NECK Head \- Microcephaly Face \- Coarse facies \- Prognathism Neck \- Short neck CHEST External Features \- Short trunk \- Broad chest Ribs Sternum Clavicles & Scapulae \- Sternal protrusion \- Wide costochondral junctions \- Small scapula \- Flat glenoid fossa \- Flared acromion SKELETAL Skull \- Calvarial thickening (parietal and occipital regions) \- Hyperpneumatization of paranasal sinuses \- Deformed sella turcica \- Hypoplastic facial bones Spine \- Platyspondyly \- Scoliosis \- Thoracic kyphosis \- Anterior beaking of vertebral bodies \- Increased lumbar lordosis \- Hypoplastic odontoid process \- C1-C2 dislocation Pelvis \- Small iliac wings \- Irregular, lacy iliac crests \- Wide sacroiliac joint \- Small sacrosciatic notch \- Wide pubic ramus \- Ischiopubic synchondrosis \- Flat acetabular roof \- Wide pubic symphysis Limbs \- Rhizomelia \- Genu valgum \- Multicentric ossification of proximal humeral epiphyses \- Multicentric ossification of proximal femoral epiphyses Hands \- Broad hands \- Camptodactyly \- Small carpals \- Short metacarpals \- Cone-shaped epiphyses Feet \- Broad feet \- Short metatarsals NEUROLOGIC Central Nervous System \- Severe psychomotor retardation (IQ 35-65) MISCELLANEOUS \- Allelic with Smith-McCort dysplasia ( 607326 ) \- Waddling gait MOLECULAR BASIS \- Caused by mutations in the FLJ90130 gene (FLJ90130, 607461.0001 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| DYGGVE-MELCHIOR-CLAUSEN DISEASE | c0265286 | 1,379 | omim | https://www.omim.org/entry/223800 | 2019-09-22T16:28:35 | {"doid": ["0111167"], "mesh": ["C535726"], "omim": ["223800"], "orphanet": ["239"]} |
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
| Osteopetrosis autosomal recessive 1 | c1850127 | 1,380 | gard | https://rarediseases.info.nih.gov/diseases/2579/osteopetrosis-autosomal-recessive-1 | 2021-01-18T17:58:31 | {"mesh": ["C564915"], "omim": ["259700"], "umls": ["C1850127"], "synonyms": ["OPTB1", "Autosomal recessive osteopetrosis type 1", "Osteopetrosis infantile malignant 1", "Marble bones autosomal recessive"]} |
## Summary
### Clinical characteristics.
Troyer syndrome is characterized by progressive spastic paraparesis, dysarthria, pseudobulbar palsy, distal amyotrophy, short stature, and subtle skeletal abnormalities. Most affected children exhibit delays in walking and speech and difficulty in managing oral secretions, followed by increased lower-limb spasticity and slow deterioration in both gait and speech. Mild cerebellar signs are common. The most severely affected individuals have choreoathetosis. Emotional lability / difficulty in controlling emotions and affective disorders, such as inappropriate euphoria and/or crying, are frequently described. Life expectancy is normal.
### Diagnosis/testing.
The diagnosis of Troyer syndrome is established in an individual with characteristic clinical findings. Identification of biallelic pathogenic variants in SPART confirms the diagnosis if clinical features are inconclusive.
### Management.
Treatment of manifestations: Antispasticity drugs; daily physical therapy; occupational therapy, assistive walking devices, and ankle-foot orthotics as needed; antidepressant or mood stabilizer medication for individuals with emotional lability.
Surveillance: Neurologic and developmental/cognitive assessments; monitoring for dysphagia to reduce the risk of aspiration.
Agents/circumstances to avoid: Dantrolene should be avoided in persons who are ambulatory as it may induce irreversible weakness, which can adversely interfere with overall mobility.
### Genetic counseling.
Troyer syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if both pathogenic variants have been identified in an affected family member.
## Diagnosis
### Suggestive Findings
Troyer syndrome should be suspected in individuals with the following findings:
Clinical features
* Childhood-onset spastic paraplegia
* Dysarthria
* Persistent drooling
* Symmetric amyotrophy of the small muscles of hands and feet
* Short stature
* Emotional lability
Additional clinical features
* At birth: low/low-normal birth weight, relative macrocephaly, triangular face shape, poor feeding
* Early infancy / childhood: delayed walking, delayed speech, swallowing difficulties
* Pyramidal signs: hyperreflexia, extensor plantar responses
* Extrapyramidal signs: mild choreoathetoid movements
* Cerebellar signs: dysdiadochokinesia, mild intention tremor
* Skeletal abnormalities: pes cavus, mild talipes equinovarus, kyphoscoliosis
* Mild to moderate intellectual disability
Imaging features on brain MRI. White matter abnormalities, particularly in the temporoparietal periventricular area (3/3 affected individuals)
### Establishing the Diagnosis
The diagnosis of Troyer syndrome is established in a proband with childhood-onset spastic paraplegia, distal amyotrophy, short stature, and/or biallelic pathogenic variants in SPART identified by molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Troyer syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Troyer syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
#### Option 1
When the phenotypic and laboratory findings suggest the diagnosis of Troyer syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
* Single-gene testing. Sequence analysis of SPART detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
Note: Targeted analysis for pathogenic variant c.1110delA can be performed first in individuals of Amish ancestry [Patel et al 2002].
* A hereditary spastic paraplegia multigene panel that includes SPART and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of Troyer syndrome, some panels for hereditary spastic paraplegia may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
#### Option 2
When the diagnosis of Troyer syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
### Table 1.
Molecular Genetic Testing Used in Troyer Syndrome
View in own window
Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
SPARTSequence analysis 3100%
Gene-targeted deletion/duplication analysis 4Unknown, none reported
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\.
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.
## Clinical Characteristics
### Clinical Description
Troyer syndrome is characterized by both developmental and neurodegenerative processes. Symptoms are usually apparent in early childhood and progress slowly. The cardinal features of Troyer syndrome include developmental delay, spastic paraparesis, dysarthria, distal amyotrophy, and short stature. To date, 36 individuals with Troyer syndrome have been reported, including 21 individuals from an Old Order Amish population in Ohio, USA [Patel et al 2002, Proukakis et al 2004, Manzini et al 2010, Tawamie et al 2015, Butler et al 2016, Dardour et al 2017, Spiegel et al 2017].
Onset. Clinical features that may be recognized from birth in the Amish, where the condition occurs at an increased frequency, include low birth weight, relative macrocephaly, triangular face shape, and poor feeding. Neurologic features become more apparent in early childhood and progress slowly.
Early developmental milestones. In the Old Order Amish, Proukakis et al [2004] reported that the presenting feature in most individuals was a delay in reaching early gross motor and speech and language milestones (walking and talking) compared to unaffected sibs. Twenty of the 21 individuals were delayed in walking (age range 12-22 months; mean age 16.1 months). The age at which they started talking ranged from seven to 36 months, with a mean age of 17.5 months. In those whose milestones were not noticeably delayed, the character of the gait and/or speech was the first abnormality reported.
Neurologic features. Troyer syndrome leads to gait ataxia and progressive spastic paraparesis that typically develops during childhood. Lower-limb distal tendon reflexes are increased. Distal weakness, when present, is mild and disproportionate to the observed spasticity. Distal amyotrophy was found in all individuals older than age 13 years and also in one child age seven years reported by Proukakis et al [2004]. In the more severely affected, generally older, individuals, weakness of the small hand muscles was observed. Most individuals had mild weakness of the abductor pollicis brevis, abductor digiti minimi, and palmar and dorsal interossei. More proximal upper-limb strength is preserved. The most severely affected individuals had choreoathetoid movements (i.e., an irregular, constant succession of slow, spasmodic writhing with involuntary flexion, extension, pronation, and supination) of the fingers and hands, and sometimes the toes and feet. Difficulty with walking increased with age; affected individuals generally became wheelchair bound during the sixth to seventh decade of life.
Progressive spastic dysarthria is reported with brisk jaw jerk, often accompanied by slow, spastic tongue movements. Excessive drooling is commonly observed in childhood and persists into adulthood in the most severely affected individuals.
Microcephaly and macrocephaly have both been reported [Patel et al 2002, Proukakis et al 2004, Manzini et al 2010, Tawamie et al 2015, Butler et al 2016, Dardour et al 2017, Spiegel et al 2017].
Learning difficulties were reported in all but one affected individual of Amish descent. Most were able to complete eighth grade, the traditional end point of Amish education. In all but one individual, school performance was significantly worse than that of unaffected sibs. Most affected individuals had persistent cognitive deficits. Two individuals completed high school and worked for several years [Proukakis et al 2004].
Emotional lability and affective disorders including inappropriate euphoria and/or crying are common [Proukakis et al 2004, Tawamie et al 2015].
Skeletal abnormalities described in individuals with Troyer syndrome include the following:
* Short stature when compared to parents and/or sibs [Proukakis et al 2004]
* Overgrowth of the maxilla leading to overbite (5/6 individuals) [Manzini et al 2010]
* Small feet with pes cavus (17/21 individuals) [Proukakis et al 2004]
* "Hammer toes" in the most severely affected individuals [Proukakis et al 2004]
* Hyperextensible proximal interphalangeal joints of the fingers (8/21) [Proukakis et al 2004]
* Brachydactyly (5/6 individuals), clinodactyly, camptodactyly, and hypoplastic fifth middle phalanges [Manzini et al 2010]
* Mild knee valgus (4/21) [Proukakis et al 2004]
* Mild kyphoscoliosis has been reported but radiographic correlation was not available [Proukakis et al 2004]
Life expectancy is normal.
Neuroimaging. White-matter hyperintensities described include periventricular white-matter hyperintensity on T2-weighted images reported in eight individuals [Proukakis et al 2004, Manzini et al 2010, Dardour et al 2017] and increased T2/FLAIR signal within the ventrolateral thalami and posterior limb of the internal capsule reported in one individual [Butler et al 2016]. The white-matter abnormalities described are not specific to Troyer syndrome and can be present in other forms of hereditary spastic paraplegia.
Nerve conduction studies performed in two individuals who were not severely affected were normal in the right upper and lower limb. In one of these individuals, electromyography (EMG) was normal bilaterally except for a polyphasic potential in the medial head of the gastrocnemius on one side. In the other individual, EMG of the right upper and lower limb was normal [Proukakis et al 2004].
### Genotype-Phenotype Correlations
No genotype-phenotype correlations have been observed.
### Prevalence
The prevalence is unknown. A previous study documented 21 individuals with Troyer syndrome in a population of approximately 50,000 Amish [Patel et al 2002]. To date the c.1110delA variant has not been observed outside of the Old Order Amish population.
Troyer syndrome has now been reported in several additional individuals worldwide.
## Differential Diagnosis
See Hereditary Spastic Paraplegia Overview for a review.
Troyer syndrome shares some features with ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay); however, nystagmus, abnormalities of ocular movement, and mitral valve prolapse are not features of Troyer syndrome.
Some Amish children/infants have been diagnosed with Silver-Russell syndrome due to low birth weight, relatively preserved head circumference, triangular face shape, and short stature; however, spastic paraplegia, a consistent feature of Troyer syndrome, is not seen in individuals with Silver-Russell syndrome.
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with Troyer syndrome, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
* Growth assessment including height, weight, and head circumference
* Consultation with a neurologist and examination to identify features of Troyer syndrome with attention to evidence of pyramidal and/or extrapyramidal movement disorders, distal amyotrophy, hyperreflexia, swallowing difficulties
* Developmental assessment with attention to gross motor and fine motor skills, as well as speech and language development, looking for possible dysarthria and tongue dyspraxia
* Psychological assessment, with attention to presence or absence of emotional lability
* Physical examination for skeletal abnormalities and x-ray examination for kyphoscoliosis as needed
* Consultation with a clinical geneticist and/or genetic counselor
### Treatment of Manifestations
No specific treatment to prevent or reverse the neurologic degeneration in Troyer syndrome currently exists. Treatments are directed at reducing symptoms, maintaining mobility, and improving balance, strength, and agility. Individuals should be evaluated periodically (annually or as needed) by a neurologist, physiatrist, occupational therapist, and speech and language therapist to assess progression and develop treatment strategies to maximize walking ability and reduce symptoms.
* Daily physical therapy regimen directed toward maintaining and improving cardiovascular health, muscle strength, and gait and reducing spasticity. These recommendations are based on the experience of approximately 200 persons with hereditary spastic paraplegia, who nearly unanimously reported benefit from daily physical exercise [Fink 2003].
* Occupational therapy, assistive walking devices, and ankle-foot orthotics as required
* Speech and language therapy to improve/maintain speech and swallowing, and communication devices as required
* Medication to reduce drooling may be helpful.
* Medications to reduce muscle spasticity (e.g., Lioresal® [oral or intrathecal]). Dosages need to be individualized as some individuals have weakness with less spasticity (and thus do not benefit from large doses), while others have significant spasticity and require high doses. Tizanidine, dantrolene (see Agents/Circumstances to Avoid), and botulinum A and B toxin injections (Botox®, Dysport®, Xeomin®, or Myobloc®) have also been useful in reducing muscle spasticity.
* Medications to reduce urinary urgency (e.g., oxybutynin, solifenacin, mirabegron, intrabladder injections with Botox®)
* Antidepressants or mood stabilizers to manage emotional lability
See also Hereditary Spastic Paraplegia Overview.
### Surveillance
The following are appropriate:
* Evaluation with a neurologist every six to 12 months (or as required depending on age and severity) to review symptoms, assess need for multidisciplinary input, and update medications
* Monitor for dysphagia to reduce risk of aspiration
* Psychiatric/psychological assessment as indicated
* Developmental assessment / cognitive testing as indicated depending on age and severity
* Annual assessment of orthopedic manifestations
### Agents/Circumstances to Avoid
Dantrolene should be avoided in persons who are ambulatory as it may induce irreversible weakness, which can adversely interfere with overall mobility.
### Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Troyer Syndrome | c0393559 | 1,381 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1382/ | 2021-01-18T20:52:07 | {"mesh": ["C536858"], "synonyms": ["SPG20"]} |
Vibratory angioedema
SpecialtyDermatology
Vibratory angioedema is a form of physical urticaria that may be an inherited autosomal dominant trait,[1] or may be acquired after prolonged exposure to occupational vibration.[2]:155[3]
## See also[edit]
* Urticaria
* Skin lesion
* List of cutaneous conditions
## References[edit]
1. ^ Boyden SE, Desai A, Cruse G, Young ML, Bolan HC, Scott LM, et al. (February 2016). "Vibratory Urticaria Associated with a Missense Variant in ADGRE2". N. Engl. J. Med. 374 (7): 656–63. doi:10.1056/NEJMoa1500611. PMC 4782791. PMID 26841242.
2. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
3. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 267. ISBN 978-1-4160-2999-1.
* v
* t
* e
Urticaria and erythema
Urticaria
(acute/chronic)
Allergic urticaria
* Urticarial allergic eruption
Physical urticaria
* Cold urticaria
* Familial
* Primary cold contact urticaria
* Secondary cold contact urticaria
* Reflex cold urticaria
* Heat urticaria
* Localized heat contact urticaria
* Solar urticaria
* Dermatographic urticaria
* Vibratory angioedema
* Pressure urticaria
* Cholinergic urticaria
* Aquagenic urticaria
Other urticaria
* Acquired C1 esterase inhibitor deficiency
* Adrenergic urticaria
* Exercise urticaria
* Galvanic urticaria
* Schnitzler syndrome
* Urticaria-like follicular mucinosis
Angioedema
* Episodic angioedema with eosinophilia
* Hereditary angioedema
Erythema
Erythema multiforme/
drug eruption
* Erythema multiforme minor
* Erythema multiforme major
* Stevens–Johnson syndrome, Toxic epidermal necrolysis
* panniculitis (Erythema nodosum)
* Acute generalized exanthematous pustulosis
Figurate erythema
* Erythema annulare centrifugum
* Erythema marginatum
* Erythema migrans
* Erythema gyratum repens
Other erythema
* Necrolytic migratory erythema
* Erythema toxicum
* Erythroderma
* Palmar erythema
* Generalized erythema
This cutaneous condition article is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Vibratory angioedema | c0473546 | 1,382 | wikipedia | https://en.wikipedia.org/wiki/Vibratory_angioedema | 2021-01-18T19:06:10 | {"mesh": ["C536347"], "umls": ["C0473546"], "orphanet": ["493348"], "wikidata": ["Q7924673"]} |
A ganglioglioma is a rare type of brain tumor, accounting for approximately 1% of all brain tumors. Gangliogliomas occur when a single cell in the brain starts to divide into more cells, forming a tumor. This can occur when the cell randomly acquires changes (mutations) in genes that regulate how a cell divides. Most gangliogliomas grow slowly and are considered benign. However, up to 10% of gangliogliomas may grow more rapidly and become malignant, meaning the tumor affects the surrounding brain tissue. The main treatment for ganglioglioma is removal of the entire tumor during surgery. If the entire tumor is not removed, it has the potential to recur and may require additional surgery or treatments, such as radiation therapy or chemotherapy. Unfortunately, because gangliogliomas are quite rare, there is limited information to show that radiation therapy or chemotherapy are effective treatments for this condition.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Ganglioglioma | c0206716 | 1,383 | gard | https://rarediseases.info.nih.gov/diseases/2430/ganglioglioma | 2021-01-18T18:00:22 | {"mesh": ["D018303"], "umls": ["C0206716"], "synonyms": ["Mixed cell tumors containing both neural ganglionic cells and neural glial cell components"]} |
Leukocyte adhesion deficiency type II (LAD-II) is a form of LAD (see this term) characterized by recurrent bacterial infections, severe growth delay and severe intellectual deficit.
## Epidemiology
LAD-II is extremely rare: less than 10 cases have been reported so far.
## Clinical description
The first signs usually occur in infancy or early childhood. Patients present recurrent bacterial infections, severe growth delay resulting in short stature, and severe intellectual deficit. Patients have the Bombay phenotype (they do not express the H antigen). Facial dysmorphism is common, characterized mainly by a depressed nasal bridge. Severe periodontitis is often present later in life and leads to early tooth loss. In adulthood, intellectual deficit and growth retardation, rather than infections, dominate the clinical picture.
## Etiology
LAD-II is a carbohydrate-deficient glycoprotein syndrome (CDG syndrome; see this term) and is therefore also referred to as CDG IIc. It results from mutations in the SLC35C1 gene (11p11.2), encoding the guanosine 5'-diphosphate (GDP)-fucose transporter localized in the Golgi apparatus. This is a specific fucose transporter that translocates GDP-fucose from the cytosol to the Golgi where it is used as a substrate for fucosylation.
## Diagnostic methods
Diagnosis is based on clinical findings and complete blood counts revealing leukocytosis with neutrophilia. Blood typing is essential to look for the Bombay blood group, which is present in all patients with LAD-II and is extremely rare in the general population. Final diagnosis is based on genetic analysis.
## Differential diagnosis
There is no differential diagnosis as the clinical symptoms of recurrent infections, leukocytosis, the Bombay blood group, and severe growth and intellectual deficit are unique to LAD-II.
## Antenatal diagnosis
Antenatal diagnosis through biochemical or molecular analysis of chorionic villus cells or amniocytes is possible in families for which the mutation has been identified.
## Genetic counseling
Transmission is autosomal recessive.
## Management and treatment
Management should focus on controlling infections and includes antibiotics. Fucose replacement may improve phagocytic function in some cases.
## Prognosis
Infections in LAD-II are rarely life-threatening and thus patients may live to adulthood.
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Leukocyte adhesion deficiency type II | c0398739 | 1,384 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99843 | 2021-01-23T18:37:04 | {"gard": ["4634"], "mesh": ["C535755"], "omim": ["266265"], "umls": ["C0398739"], "icd-10": ["D84.8"], "synonyms": ["CDG syndrome type IIc", "CDG-IIc", "CDG2C", "LAD-II", "Rambam-Hasharon syndrome", "SLC35C1-CDG"]} |
Fibromatosis colli (also known as sternomastoid tumor of infancy) is a benign proliferation of fibrous tissue infiltrating the lower third of the sternocleidomastoid, (SCM) and is the most common cause of neonatal torticollis.[1]
The mass, also known as a hematoma of the sternocleidomastoid, is firm and hard on palpation, but is neither tender nor inflamed.
The mass is easily diagnosed using ultrasound, where it is found within the SCM and enlarges the muscle. The lesion is self-limiting and benign, usually resolving with time and physical therapy. Rarely does it need to be removed surgically. Surgery is performed on patients in whom torticollis persists for 1 year.
## See also[edit]
* Skin lesion
## References[edit]
1. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). Page 989. McGraw-Hill. ISBN 0-07-138076-0.
This Dermal and subcutaneous growths article is a stub. You can help Wikipedia by expanding it.
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*[AA]: Adrenergic agonist
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*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
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| Fibromatosis colli | c0549175 | 1,385 | wikipedia | https://en.wikipedia.org/wiki/Fibromatosis_colli | 2021-01-18T18:53:02 | {"umls": ["C0549175"], "wikidata": ["Q5446471"]} |
## Clinical Features
Tranebjaerg et al. (1988) described 4 males, the sons of 2 sisters, with a syndrome of mental retardation, seizures, and psoriasis. Normal levels of steroid sulfatase excluded X-linked ichthyosis, which the lesions resembled somewhat at certain stages of their evolution.
Inheritance \- X-linked Neuro \- Mental retardation \- Seizures Lab \- Normal steroid sulfatase Skin \- Psoriasis ▲ Close
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*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
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| MENTAL RETARDATION AND PSORIASIS | c2931381 | 1,386 | omim | https://www.omim.org/entry/309480 | 2019-09-22T16:17:52 | {"mesh": ["C536978"], "omim": ["309480"], "orphanet": ["3052"]} |
A number sign (#) is used with this entry because of evidence that osteogenesis imperfecta type V (OI5) is caused by heterozygous mutation in the IFITM5 gene (614757), encoding interferon-induced transmembrane protein-5, on chromosome 11p15.
Description
Osteogenesis imperfecta is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most forms of OI are autosomal dominant with mutations in one of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Glorieux et al. (2000) described a novel autosomal dominant form of OI, which they designated OI type V, in 7 patients. The disorder was similar to OI type IV but had distinctive clinical, histologic, and molecular characteristics. OI type V is characterized by calcification of the forearm interosseous membrane, radial head dislocation, a subphyseal metaphyseal radiodense line, and hyperplastic callus formation (summary by Cho et al., 2012).
Clinical Features
Type V OI is moderately deforming and patients exhibit moderate to severe bone fragility of long bones and vertebral bodies. All type V patients (4 males and 3 females) described by Glorieux et al. (2000) had experienced fractures in the first year of life and had a history of frequent fractures (3.2 +/- 2.3 fractures/year). None of the patients had blue sclerae or dentinogenesis imperfecta. Radiographically, the patients were characterized by 3 distinctive features: hyperplastic callus formation at fracture sites, calcification of the interosseous membrane between the radius and ulna, and the presence of a radioopaque metaphyseal band adjacent to the growth plates. Hyperplastic callus presents as a hard painful swelling over affected bone and was present in 4 patients. All 7 patients had limitation of pronation/supination in one or both forearms, which was associated with a radiologically apparent calcification of the interosseous membrane. Three patients had anterior dislocation of the radial head. One patient had an additional calcified interosseous membrane in the left lower leg. A radiodense metaphyseal band immediately adjacent to the growth plates was a constant feature in growing patients. The band was most clearly visible in the metaphyses of the distal femora, proximal tibias, and the distal radii. Other radiologic findings included flattened, wedge-shaped, or biconcave vertebrae and wormian bones of the skull. Lumbar spine bone mineral density was low and similar to age-matched patients with OI type IV. Histology of iliac biopsy specimens revealed that lamellae were arranged in an irregular mesh-like pattern distinct from normal lamellar organization. Levels of biochemical bone markers were generally within the reference range, but serum alkaline phosphatase (171760) and urinary collagen type I N-telopeptide excretion (NTx) increased during periods of active hyperplastic callus formation.
Shapiro et al. (2013) studied 17 patients from 12 families with OI type V, all of whom were heterozygous for a c.-14C-T mutation in the IFITM5 gene (see MOLECULAR GENETICS). Typical features of OI type V in these patients included limited range of supination or pronation of the forearm in 15, radial head dislocation in 14, calcification of interosseous membranes in 13, and hyperplastic callus formation in 10; however, none of the patients exhibited a metaphyseal banding pattern. Other features included hyperextensible joints in 11 patients, triangular facies in 10, long bone bowing in 9, pes planus in 3, blue sclerae in 2, and mild unilateral mixed hearing loss in 1. Eleven affected individuals could ambulate without assistance. Ultrasound scans of the first child of an affected man revealed bowing of the femur at 22 weeks' gestation and a thin calvarium and angulated ribs suggesting intrauterine fracture at 33 weeks' gestation; at birth, the infant had 2 healing rib fractures, bowing of the femurs, and a thin calvarium but no other anomalies. Shapiro et al. (2013) noted that bone mineral density varied greatly among these patients, even within families. Three patients had chronically elevated levels of alkaline phosphatase, including 2 brothers in whom levels remained elevated even during bisphosphonate therapy.
Grover et al. (2013) reported a 5.5-year-old Hispanic girl with OI, originally classified as type III or severe type IV, who was found to carry the IFITM5 c.-14C-T mutation. She was small at birth, with weight and length at and below the 5th percentile, respectively. Forearm deformities and fussiness on handling prompted a skeletal survey, which showed multiple bilateral posterior rib fractures, bowing deformities of both forearms, and nondisplaced fractures of the left ulna and proximal right humeral shaft. Examination at 5.5 years revealed the characteristic triangular facies of OI with gray sclerae, midface hypoplasia, and hypotonia of the limbs. The patient had a history of multiple fractures of long bones after minimal or no trauma. Despite multiple fractures, there was no evidence of hyperplastic callus formation, interosseous membrane calcification, or radial head dislocation; in addition, she did not exhibit rhizomelia, limitation of forearm supination/pronation, vertebral compression fractures, or dentinogenesis imperfecta.
Balasubramanian et al. (2013) studied 4 patients from 3 families with OI type V and the c.-14C-T mutation. All had a similar facial gestalt with a broad forehead, a short up-turned nose, a small mouth with a thin upper lip, a prominent chin, and grayish blue sclerae.
Lazarus et al. (2014) described 9 patients from 8 families with OI type V and the c.-14C-T mutation. All displayed the characteristic radial head dislocation and calcification of the forearm interosseous membrane, and 5 developed hyperplastic callus. In contrast, bone fragility was quite variable, as shown by an 8-year-old patient who had experienced approximately 35 fractures and a 32-year-old patient who had never had a clinical fracture. Heterogeneity was also observed regarding height and physical activity level. None of the patients had blue sclerae or opalescent dentine.
Guillen-Navarro et al. (2014) reported a 5.75-year-old Spanish girl with OI diagnosed prenatally due to limb shortening, who was heterozygous for an S40L missense mutation in the IFITM5 gene (see MOLECULAR GENETICS). The authors stated that this was, to their knowledge, the first patient with an IFITM5 mutation who was prenatally diagnosed with bone shortening, a clinical feature characteristic of OI types II and III. The patient did not exhibit the typical signs of OI type V, although limited pronation/supination of the forearms was observed, in addition to characteristic radiodense lines on long bone x-rays. Despite the lack of hyperplastic callus formation, she had had elevated urinary excretion of the bone marker collagen type I N-telopeptide from the first months of life. Guillen-Navarro et al. (2014) also described a 30-year-old woman of Lithuanian origin with OI due to the c.-14C-T mutation who had a history of multiple fractures in childhood and short stature due to progressively severe skeletal deformities and loss of mobility. At age 13 years, her height was 160 cm (50th to 75th percentile), but by age 30 it had decreased to 125 cm (below the 3rd percentile). Radiologic examination revealed some of the typical clinical features of OI type V, including fracture-related hyperplastic callus formation and calcification of the interosseous membrane of the forearm; however, dislocation of the radial head and radiodense metaphysical banding were not detected.
Farber et al. (2014) studied a 25-year-old Caucasian woman with severe progressive OI without the typical features of OI type V who was heterozygous for the S40L missense mutation in the IFITM5 gene. Examination at age 25 revealed extreme short stature, with length of 87 cm (50th percentile for a 2-year-old girl) and weight of 33.3 kg (50th percentile for a 10-year-old girl), as well as relative macrocephaly, with a head circumference of 53.5 cm (25th percentile for an adult). She had a round face with a high bossed forehead and bluish sclerae. She also exhibited dentinogenesis imperfecta, as well as prominent and irregular ridges on the cutting surface of the teeth. She had a barrel chest with pectus excavatum, extreme bowing of all extremities, and S-curve scoliosis as well as prominent lordosis. She did not display radial head dislocation, hypertrophic callus formation, ossification of the interosseous membrane, or dense metaphyseal bands; rather, transiliac biopsy at 7 years of age revealed broad bands of unmineralized osteoid and a fish-scale pattern of lamellation, as seen in OI type VI (OI6; 613982).
Inheritance
In 3 patients with OI type V studied by Glorieux et al. (2000), the family history was positive for OI with documented father-to-son transmission in 2 families, consistent with an autosomal dominant pattern of inheritance.
Clinical Management
Zeitlin et al. (2006) described the results of 2 years of pamidronate treatment in 11 children and adolescents (5 boys, 6 girls) with OI type V (age at start of therapy, 1.8 to 15.0 years). Pamidronate was given in intravenous cycles at a cumulative yearly dose of 9 mg/kg. After 2 years, pamidronate treatment led to a decrease in the urinary excretion of N-terminal telopeptide of type I collagen to 50% of baseline levels. Both the size and volumetric bone mineral density of lumbar vertebrae increased compared to age- and sex-matched reference data (P less than 0.05 in both cases). Histomorphometry of transiliac bone samples in 7 patients showed an average increase of 86% in cortical thickness (p = 0.005). Fracture incidence decreased from 1.5 fractures per year before treatment to 0.5 fractures per year during the first 2 years of treatment. Ambulation status improved in 4 patients and remained unchanged in the others. Zeitlin et al. (2006) concluded that intravenous pamidronate therapy has a similar effect in OI type V as it has in other OI types.
Mapping
Cho et al. (2012) performed genomewide linkage analysis on a 4-generation family (family 1) with OI type V. Using 407 microsatellite markers with an average interval of 10 cM, they genotyped 14 family members (9 affected and 5 unaffected). A maximum lod score of 2.52 was obtained at marker D11S4046. Additional markers defined the locus at the 11pter-p15.4 region spanning 9.1 Mb from D11S4149.
Molecular Genetics
Cho et al. (2012) studied 19 Korean individuals with OI type V, including 13 affected individuals from 3 families and 6 simplex individuals. Cho et al. (2012) performed whole-exome sequencing in an affected simplex individual and 3 unaffected members of her family, and manually selected sequence variations (including those of the 5-prime and 3-prime UTRs and intron regions) unique to the proband. Among the variations located in the linked region of family 1, Cho et al. (2012) focused on a heterozygous change in the IFITM5 gene (c.-14C-T; 614757.0001). Sanger sequencing confirmed that this variation completely cosegregated with the disease in family 1. Furthermore, it was not found in 200 unrelated normal chromosomes from individuals with the same ethnic background. Cosegregation in the other 2 families (families 2 and 3) and de novo occurrence in the 5 other simplex individuals confirmed that this variation is a disease-causing mutation of OI type V.
Semler et al. (2012) independently performed whole-exome sequencing in a female with OI type V and her unaffected parents and identified a heterozygous de novo mutation in the 5-prime UTR of IFITM5 (c.-14C-T). They subsequently identified the identical heterozygous de novo mutation in a second individual with OI type V by Sanger sequencing.
Rauch et al. (2013) sequenced exon 1 of the IFITM5 gene in 42 patients with OI type V (ages, 2-67 years; 18 females) from 23 different families and identified the c.-14C-T mutation in all. Despite the presence of the same mutation, there was marked interindividual phenotypic variability. Indicators of disease severity varied widely: height z-scores in 38 patients ranged from -8.7 to -0.1, median -3.5; median final height was 147 cm in 15 men and 145 cm in 10 women; lumbar spine areal bone mineral density z-score in the absence of bisphosphonate treatment was between -7.7 and -0.7 in 29 men, median -5.3; scoliosis was present in 57% and vertebral compression fractures in 90% of all patients. Rauch et al. (2013) suggested that the IFITM5 mutation leads to a dysregulation of periosteal bone formation in addition to the bone formation deficit in trabecular bone.
In 17 affected individuals from 12 families with OI type V, 13 of whom were known to be negative for mutation in the COL1A1 (120150) and COL1A2 (120160) genes, Shapiro et al. (2013) identified heterozygosity for the c.-14C-T mutation in the IFITM5 gene. The authors noted strikingly variable phenotypic expressivity, both within and between affected OI type V families.
In a 5.5-year-old Hispanic girl with OI, originally classified as type III or severe type IV, who was negative for mutation in 10 known OI-associated genes, Grover et al. (2013) performed exome sequencing and identified heterozygosity for a de novo c.-14C-T mutation in IFITM5 that was not present in her unaffected parents. The patient did not exhibit any of the classic features of OI type V described in previous patients with this mutation, including hyperplastic callus formation, calcification of interosseous membranes, and radial head dislocation. Noting the marked phenotypic variability of OI type V, Grover et al. (2013) suggested that all unsolved OI patients should be screened for this recurrent IFITM5 mutation.
In 9 patients from 8 families with OI type V, Lazarus et al. (2014) sequenced the IFITM5 gene and identified heterozygosity for the c.-14C-T mutation in all. The mutation segregated with disease in the 3 families for which unaffected members were available.
In a 5.75-year-old Spanish girl with OI diagnosed prenatally on the basis of limb shortening, who was negative for mutation in 11 known OI-associated genes, Guillen-Navarro et al. (2014) identified heterozygosity for a de novo missense mutation in the IFITM5 gene (S40L; 614757.0002). Despite the lack of hyperplastic callus, the patient had had elevated urinary excretion of the bone marker collagen type I N-telopeptide from the first months of life; the authors recommended screening of IFITM5 in OI patients who lack the classic signs of OI type V but in whom urinary excretion of collagen type I N-telopeptide is above normal. Guillen-Navarro et al. (2014) also identified heterozygosity for the c.-14C-T mutation in IFITM5 in a 30-year-old woman of Lithuanian origin with OI. The patient had a history of multiple fractures in childhood, with progressively severe skeletal deformities; she exhibited fracture-related hyperplastic callus formation and calcification of the interosseous membrane of the forearm.
In a 25-year-old Caucasian woman who had extremely severe progressive OI without the typical features of OI type V and who was negative for mutation in 8 known OI-associated genes, including PEDF (SERPINF1; 172860), Farber et al. (2014) performed exome sequencing and identified a de novo missense mutation (S40L) in the IFITM5 gene. IFITM5 expression was normal in proband fibroblasts and osteoblasts, and BRIL protein level was similar to control. Farber et al. (2014) noted, however, that the patient's iliac biopsy had shown an OI6-associated fish-scale pattern of lamellation and that secretion of PEDF by patient fibroblasts was barely detectable; they thus hypothesized that the mutant gene was in a pathway with and/or interacted with PEDF. Analysis of patient osteoblasts confirmed minimal secretion of PEDF; in addition, COL1A1 (120150) expression and protein secretion was about one-fifth of control, and expression of alkaline phosphatase (171760) and osteocalcin (OC; 112260) were significantly reduced, whereas osteopontin (OPN; 166490) and bone sialoprotein (BSP; 147563) expression was 7- and 24-fold increased, respectively. Conversely, during a differentiation assay using osteoblasts from a patient with the c.-14C-T mutation and a typical OI type V phenotype, expression of PEDF increased 2-fold compared to control osteoblasts, with a consequent increase in secreted PEDF. Farber et al. (2014) concluded that BRIL and PEDF have a relationship that connects the genes for OI types V and VI and their roles in bone mineralization.
### Exclusion Studies
Glorieux et al. (2000) screened the coding regions and exon/intron boundaries of both type I collagen genes (COL1A1 and COL1A2) in their patients and detected no mutations affecting glycine residues or splice sites.
Animal Model
Lietman et al. (2015) generated transgenic mice with the Ifitm5 variant corresponding to the recurrent human mutation, c.-14C-T, and observed perinatal lethality. Skeletal preparations and radiographs of embryonic day (E) 15.5 and E18.5 transgenic embryos revealed delayed/abnormal mineralization and skeletal defects, including abnormal rib cage formation, long bone deformities, and fractures. Primary osteoblast cultures derived from mutant calvaria at E18.5 showed decreased mineralization and reduced expression of osteoblast differentiation markers, such as osteocalcin, compared to wildtype. Overexpression of wildtype Ifitm5 did not, however, manifest a significant bone phenotype. Noting that previous studies had shown that knockout of Ifitm5 also did not result in significant bone abnormalities, Lietman et al. (2015) concluded that the c.-14C-T mutation acts in a neomorphic fashion.
INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature (childhood) \- Birth length normal Weight \- Birth weight normal HEAD & NECK Face \- Triangular facies Eyes \- Bluish sclerae (in some patients) Teeth \- Dentinogenesis imperfecta (rare) \- Prominent, irregular ridges on cutting surface of teeth (rare) SKELETAL \- Moderate to severe bone fragility \- Moderately deforming osteogenesis imperfecta \- Varying degree of multiple fractures \- Decreased bone mineral density \- Broad bands of unmineralized osteoid on transiliac biopsy (rare) \- Fish-scale pattern of lamellae on transiliac biopsy (rare) Skull \- Wormian bones Spine \- Biconcave vertebrae \- Wedge-shaped vertebrae \- Flattened vertebrae Pelvis \- Irregular, meshlike matrix lamellae in the histology of the iliac crest Limbs \- Limited pronation/supination of forearm \- Anterior dislocation of radial head \- Calcified interosseous membrane (forearms) \- Hyperplastic callus \- Metaphyseal bands adjacent to growth plate (distal femora, proximal tibiae, distal radii) \- Hyperextensible joints (in some patients) LABORATORY ABNORMALITIES \- Elevated serum alkaline phosphatase during hyperplastic callus formation \- Increased urinary collagen type I N-telopeptide excretion (NTx) during hyperplastic callus formation MISCELLANEOUS \- Variable phenotype within and between OI5 families \- Highly variable degree of bone fragility, even among patients carrying the same mutation \- Bone anomalies may be seen on prenatal ultrasound (in some patients) MOLECULAR BASIS \- Caused by mutation in the interferon-induced transmembrane protein 5 gene (IFITM5, 614757.0001 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| OSTEOGENESIS IMPERFECTA, TYPE V | c2931093 | 1,387 | omim | https://www.omim.org/entry/610967 | 2019-09-22T16:03:52 | {"doid": ["0110344"], "mesh": ["C567042", "C536046"], "omim": ["610967"], "orphanet": ["216828", "666"], "synonyms": ["Alternative titles", "OI, TYPE V"]} |
A number sign (#) is used with this entry because combined oxidative phosphorylation deficiency-15 (COXPD15) is caused by homozygous or compound heterozygous mutation in the MTFMT gene (611766) on chromosome 15q22.
For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Clinical Features
Tucker et al. (2011) reported 2 unrelated probands with combined oxidative phosphorylation deficiency. The first patient presented at age 9 years with acquired strabismus and mildly decreased visual acuity. She had a history of mild developmental delay affecting speech and coordination, and also had reading difficulties. Brain MRI showed T2-weighted hyperintense lesions in several brain regions, including the lentiform nuclei, caudate, midbrain tectum, red nuclei, corpus callosum, and subcortical white matter. CSF lactate was increased, although blood lactate levels were normal. Echocardiography showed short PR waves and delta waves consistent with Wolff-Parkinson-White syndrome. At age 21 years, she worked a menial job. Family history revealed a maternal first cousin with a similar but more severe disorder. That patient had global developmental delay, optic atrophy, impaired vision, pyramidal tract signs, incoordination, and Wolff-Parkinson-White syndrome. In a second family, a girl was first evaluated for obesity at age 5 years and was found to have a pituitary adenoma. Brain MRI also showed bilateral signal abnormalities in the putamen, globus pallidus, and brainstem. There was progression of these lesions to include white matter changes. Serum and CSF lactate were elevated. She developed seizures, acute neurologic decompensation, and died several months later. Tissue samples and cell lines from all the patients showed deficiencies of complexes I and IV, with deficient complex III in some samples. There was no evidence of mtDNA depletion. Patient fibroblasts showed reduced levels of most mtDNA-encoded proteins, suggesting a defect in mitochondrial translation.
Neeve et al. (2013) reported 2 German sisters, born of unrelated parents, with COXPD15. Both patients had developmental delay, affecting speech more than motor skills, and hypotonia. The older sister, aged 16 years, had short stature, slight dysarthria, mild ataxia, and clumsy fine finger movements. Brain MRI showed mild signal abnormalities in the dorsal periventricular white matter and increased T2-weighted signal intensities in the caudate and putamen, consistent with Leigh syndrome (256000). The younger sister, aged 6 years, had short stature and mild intention tremor, but no ataxia. Brain MRI was normal. Both girls had mild cognitive dysfunction and poor speech. Skeletal muscle analysis of the older sister showed mild lipid accumulation in type 1 fibers, but no ragged-red fibers. Activities of mitochondrial complexes I and IV were decreased compared to normal; complexes II and III were normal.
Haack et al. (2014) reported 9 patients from 8 unrelated families with COXPD15. The phenotype was variable in severity, but all had an encephalomyopathic phenotype with onset in infancy or early childhood of delayed psychomotor development and subsequent retardation, gait ataxia, and hypotonia. Seven patients had microcephaly. Other features observed in some patients included nystagmus and spasticity. Laboratory studies showed increased serum and CSF lactate, often with increased alanine. Muscle biopsies showed mitochondrial complex I deficiency (range, 7 to 89% of normal), with some also showing complex IV deficiency (range, 45% to normal). Seven patients had abnormal increased T2-weighted signal abnormalities in the basal ganglia and/or midbrain, consistent with classic Leigh syndrome, and some had additional subcortical white matter lesions. None of the patients had severe involvement of other organs, although several had ventricular septal defect or thickening of the ventricular septum. Two patients died in early childhood, some showed episodic decompensation, and others were able to attend special school or do supervised shelter work. One patient was wheelchair-bound with spastic quadriplegia in his twenties.
Inheritance
The transmission pattern of COXPD15 in the families reported by Tucker et al. (2011) was consistent with autosomal recessive inheritance.
Molecular Genetics
In 2 unrelated patients with COXPD15, Tucker et al. (2011) identified compound heterozygosity for 2 mutations in the MTFMT gene (611766.0001-611766.0003). The mutations were identified by next-generation sequencing of coding exons from nuclear-encoded mitochondrial-associated genes. MTFMT activity was 9% in 1 patient and 56% in the other patient. Patient fibroblasts also lacked detectable formylmethionine tRNA-met. In patients cells, the biochemical defects were rescued by exogenous expression of wildtype MTFMT. Both patients had some residual MTFMT activity, as evidenced by the presence of decreased levels of formylated MTCO1 (516030) in patient cells.
In 2 German sisters with COXPD15, Neeve et al. (2013) identified compound heterozygous mutations in the MTFMT gene (611766.0004 and 611766.0005). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Myoblasts from 1 of the patients showed a severe decrease in MTFMT protein, as well as decreases in mitochondrial complexes I and IV. Complex V appeared to be unstable.
Haack et al. (2014) identified compound heterozygous MTFMT mutations in 9 patients from 8 families with COXPD15. Eight of the 9 patients carried a c.626C-T transition (611766.0001) on 1 allele, making it the most common variant. Some of the other mutations had previously been reported (see, e.g., 611766.0004) and some were novel (see, e.g., 611766.0007 and 611766.0008). Patient cells showed a severe decrease in MTFMT protein, and all of the mutations were predicted to result in a loss of function. The mutations were identified using several techniques, including exome sequencing, high resolution melting curve analysis, and Sanger sequencing. Exome sequencing initially failed to detect the mutations in several patients.
INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature (in some patients) Weight \- Obesity (in some patients) HEAD & NECK Head \- Microcephaly (in some patients) Eyes \- Decreased visual acuity (in some patients) \- Strabismus (in some patients) \- Optic atrophy (in some patients) \- Nystagmus (in some patients) CARDIOVASCULAR Heart \- Wolff-Parkinson-White syndrome (in some patients) \- Ventricular septal hypertrophy (in some patients) \- Ventricular septal defect (in some patients) MUSCLE, SOFT TISSUES \- Hypotonia (in some patients) NEUROLOGIC Central Nervous System \- Global developmental delay \- Reading difficulties \- Speech difficulties \- Incoordination \- Cognitive impairment \- Ataxia \- Gait instability \- Pyramidal tract signs (in some patients) \- Tremor (in some patients) \- Seizures (rare) \- T2-weighted hyperintensities in the basal ganglia, corpus callosum, and brainstem seen on MRI \- Leigh syndrome \- Subcortical white matter abnormalities LABORATORY ABNORMALITIES \- Increased CSF lactate \- Increased serum lactate (in some patients) \- Patient fibroblasts and muscle show decreased activities of mitochondrial complexes I, III, and IV \- Impaired mitochondrial translation MISCELLANEOUS \- Highly variable phenotype \- Onset in childhood MOLECULAR BASIS \- Caused by mutation in the mitochondrial methionyl-tRNA formyltransferase gene (MTFMT, 611766.0001 ) ▲ Close
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*[t]: Discuss this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 15 | c3554182 | 1,388 | omim | https://www.omim.org/entry/614947 | 2019-09-22T15:53:34 | {"doid": ["0060286"], "omim": ["614947"], "orphanet": ["319524"], "synonyms": ["COXPD15"]} |
In Chinese alchemy, elixir poisoning refers to the toxic effects from elixirs of immortality that contained metals and minerals such as mercury and arsenic. The official Twenty-Four Histories record numerous Chinese emperors, nobles, and officials who died from taking elixirs in order to prolong their lifespans. The first emperor to die from elixir poisoning was likely Qin Shi Huang (d. 210 BCE) and the last was Yongzheng (d. 1735 AD). Despite common knowledge that immortality potions could be deadly, fangshi and Daoist alchemists continued the elixir-making practice for two millennia.
Chinese woodblock illustration of a waidan alchemical refining furnace, 1856 Waike tushuo 外科圖説 (Illustrated Manual of External Medicine)
## Contents
* 1 Terminology
* 2 List of Emperors who tried to create an Elixir of Immortality
* 3 History
* 3.1 Warring States period
* 3.2 Qin dynasty
* 3.3 Han dynasty
* 3.4 Six dynasties
* 3.5 Tang dynasty
* 3.6 Five dynasties
* 3.7 Song dynasty
* 3.8 Ming dynasty
* 3.9 Qing dynasty
* 3.10 Historical interpretations
* 4 Hypothetical explanations
* 4.1 Initial exhilaration
* 4.2 Incorruptibility
* 4.3 Temporary death
* 4.4 Ritual suicide
* 5 References
* 6 External links
## Terminology[edit]
The etymology of English elixir derives from Medieval Latin elixir, from Arabic إكسير (al-ʾiksīr), probably from Ancient Greek ξήριον (xḗrion "a desiccative powder for wounds"). Elixir originated in medieval European alchemy meaning "A preparation by the use of which it was sought to change metals into gold" (elixir stone or philosopher's stone) or "A supposed drug or essence with the property of indefinitely prolonging life" (elixir of life). The word was figuratively extended to mean "A sovereign remedy for disease. Hence adopted as a name for quack medicines" (e.g., Daffy's Elixir) and "The quintessence or soul of a thing; its kernel or secret principle". In modern usage, elixir is a pharmaceutical term for "A sweetened aromatic solution of alcohol and water, serving as a vehicle for medicine" (Oxford English Dictionary, 2nd ed., 2009). Outside of Chinese cultural contexts, English elixir poisoning usually refers to accidental contamination, such as the 1937 elixir sulfanilamide mass poisoning in the United States.
Dān 丹 "cinnabar; vermillion; elixir; alchemy" is the keyword for Chinese immortality elixirs. The red mineral cinnabar (dānshā 丹砂 lit. "cinnabar sand") was anciently used to produce the pigment vermilion (zhūhóng 朱紅) and the element mercury (shuǐyín 水銀 "watery silver" or gǒng 汞).
According to the ABC Etymological Dictionary of Old Chinese, the etymology of Modern Standard Chinese dān from Old Chinese *tān (< *tlan ?) 丹 "red; vermillion; cinnabar", gān 矸 in dāngān 丹矸 from *tân-kân (< *tlan-klan ?) "cinnabar; vermillion ore", and zhān from *tan 旃 "a red flag" derive from Proto-Kam-Sui *h-lan "red" or Proto-Sino-Tibetan *tja-n or *tya-n "red". The *t- initial and *t- or *k- doublets indicate that Old Chinese borrowed this item. (Schuessler 2007: 204).
Oracle script for 丹 "cinnabar"
Although the word dan 丹 "cinnabar; red" frequently occurs in oracle script from the late Shang Dynasty (c. 1600–1046 BCE) and bronzeware script and seal script from the Zhou Dynasty (1045–256 BCE), paleographers disagree about the graphic origins of the logograph 丹 and its ancient variants 𠁿 and 𠕑. Early scripts combine a 丶 dot or ⼀ stroke (depicting a piece of cinnabar) in the middle of a surrounding frame, which is said to represent:
* jǐng 井 "well" represents the mine from which the cinnabar is taken" (Shuowen Jiezi)
* "the crucible of the Taoist alchemists" (Léon Wieger)
* "the contents of a square receptacle" (Bernhard Karlgren)
* "placed in a tray or palette to be used as red pigment" (Wang Hongyuan 王宏源)
* "mineral powder on a stretched filter-cloth" (Needham and Lu).
Many Chinese elixir names are compounds of dan, such as jīndān 金丹 (with "gold") meaning "golden elixir; elixir of immortality; potable gold" and xiāndān 仙丹 (with "Daoist immortal") "elixir of immortality; panacea", and shéndān 神丹 (with "spirit; god") "divine elixir". Bùsǐ zhī yào 不死之藥 "drug of deathlessness" was another early name for the elixir of immortality. Chinese alchemists would liàndān 煉丹 (with "smelt; refine") "concoct pills of immortality" using a dāndǐng 丹鼎 (with "tripod cooking vessel; cauldron") "furnace for concocting pills of immortality". In addition, the ancient Chinese believed that other substances provided longevity and immortality, notably the língzhī 靈芝 "Ganoderma mushroom".
The transformation from chemistry-based waidan 外丹 "external elixir/alchemy" to physiology-based neidan 內丹 "internal elixir/alchemy" gave new analogous meanings to old terms. The human body metaphorically becomes a ding "cauldron" in which the adept forges the Three Treasures (essence, life-force, and spirit) within the jindan Golden Elixir within the dāntián 丹田 (with "field") "lower part of the abdomen".
In early China, alchemists and pharmacists were one and the same. Traditional Chinese medicine also used less concentrated cinnabar and mercury preparations, and dan means "pill; medicine" in general, for example, dānfāng 丹方 semantically changed from "prescription for elixir of immortality" to "medical prescription". Dan was lexicalized into medical terms such as dānjì 丹劑 "pill preparation" and dānyào 丹藥 "pill medicine".
The Chinese names for immortality elixirs have parallels in other cultures and languages, for example, Indo-Iranian soma or haoma, Sanskrit amrita, and Greek ambrosia.
## List of Emperors who tried to create an Elixir of Immortality[edit]
Image Emperor Description Result Date
King Qingxiang of Chu According to legend King Qingxiang of Chu (a state during the Warring States period)
was presented with an elixir of immortality. Luckily for him, it was quickly snatched
away by a guard who drank it.
N/A some time during his reign (298–263 BC)
Qin Shi Huang During his later years Qin Shi Huang would become obsessed with his own mortality,
reportedly sending out multiple expeditions to find an elixir of immortality most notably
Xu Fu who according to legend became the first emperor of Japan after getting lost
on his voyage. Never the less, a few alchemists would present Huang with mercury
pills, which would proceed to kill him.
death 210 BC
Emperor Wu of Han During his reign Wu would employ many alchemists to try and help him find an elixir
of immortality. Notably Li Shaojun gave him a guide to making one involving
summoning spirit. Oddly Wu would never actually create and consume an elixir.
N/A some time during his reign (141 BC–87 BC)
Emperor Ai of Jin At the young age of 25 Ai began to fear aging, he was soon presented pills by his
team of alchemists which would result in his death.
death 365 AD
Emperor Daowu Emperor Daowu was distantly interested in the art of alchemy. He would begin testing
elixirs on prisoners sentenced to death, after none of them worked he gave up on the
project.
N/A some time during his reign (371–409 AD)
Emperor Wu of Liang Wu was originally cautious about elixirs of immortality, but was eventually convinced
and took one during his reign , it was reported to have no effect, and he would die
many years later of illness.
no effect some time during his reign (502–549 AD)
Emperor Wenxuan Wenxuan was skeptical of these elixirs, but just in case he had one made and preserved
in a jade box, vowing to drink it when he grew old. It is unknown if he ever drank it.
N/A some time during his reign (550--559 AD)
Emperor Xianzong Emperor Xianzong was very enthusiastic about immortality took an elixir early in his reign
After taking the elixir he started acting strangely and went insane. After ignoring the
advice of an official telling him to make the alchemists test the elixirs on themselves
before he had one, he was promptly assassinated by the Eunuchs.
insanity some time during his reign (805--820 AD)
Emperor Muzong After the death of his father instead of thinking that maybe he shouldn't drink these elixirs
he thought that the ones his father had were just defective, so he kept on taking them
until he himself died of mercury poisoning.
death all throughout his reign (820--824 AD)
Wuzong Wuzong after taking an elixir would go insane,he would not be able to speak for ten days
at a time and lost control of his emotions. He proceededly would die in 846.
insanity 846 AD
Emperor Xuānzong Carrying with the tradition of emperors and their sons both dying of immortality
poisoning, Xuanzong would die of elixir poisoning in 849.
death 849 AD
Zhu Wen After taking an elixir at the advice of his alchemists, Zhu Wen would become incapacitated
and shortly die.
incapacitated 912 AD
Li Bian After taking an elixir at the advice of his alchemists, Li Bian would become deathly ill and
die.
death 943 AD
Jiajing Emperor Despite elixirs being incredibly unpopular during his time in the Ming dynasty, the Jiajing
emperor continued to invest in and consume elixirs. When he inevitably died, his head
alchemist fled, but was caught and exiled.
death 1567 AD
Yongzheng Emperor The last emperor to die of elixir poisoning would be the Yongzheng emperor during the
Qing dynasty. He was a superstitious man who suddenly died after drinking an elixir in
1735
death 1735 AD
## History[edit]
In Chinese history, the alchemical practice of concocting elixirs of immortality from metallic and mineral substances began circa the 4th century BCE in the late Warring states period, reached a peak in the 9th century CE Tang dynasty when five emperors died, and, despite common knowledge of the dangers, elixir poisoning continued until the 18th century Qing dynasty.
### Warring States period[edit]
The earliest mention of alchemy in China occurs in connection with fangshi ("masters of the methods") specialists in cosmological and esoteric arts employed by rulers from the 4th century BCE (De Woskin 1981: 19).
The 3rd-century BCE Zhanguo Ce and Han Feizi both record a story about King Qingxiang of Chu (r. 298–263 BCE) being presented a busi zhi yao 不死之藥 "immortality medicine". As the chamberlain was taking the elixir into the palace, a guard asked if it was edible and when he answered yes, the guard grabbed and ate it. The king was angered and condemned the guard to death. A friend of the guard tried to persuade the king, saying, "After all the guard did ask the chamberlain whether it could be eaten before he ate it. Hence the blame attaches to the chamberlain and not to him. Besides what the guest presented was an elixir of life, but if you now execute your servant after eating it, it will be an elixir of death (and the guest will be a liar). Now rather than killing an innocent officer in order to demonstrate a guest's false claim, it would be better to release the guard." This logic convinced the king to let the guard live (Needham and Ho 1970: 316).
### Qin dynasty[edit]
Qin Shi Huang, the founder of the Qin dynasty (221–206 BCE), feared death and spent the last part of his life seeking the elixir of life. He reportedly died from elixir poisoning (Wright 2001: 49). The first emperor also sent Xu Fu to sail an expeditionary fleet into the Pacific seeking the legendary Mount Penglai where the busi zhi shu 不死之樹 "tree of deathlessness" grew, but they never returned.
### Han dynasty[edit]
Interest in elixirs of immortality increased during the Han dynasty (206 BC–220 AD). Emperor Wu (156–87 BCE) employed many fangshi alchemists who claimed they could produce the legendary substance. The Book of Han says that around 133 BCE the fangshi Li Shaojun said to Emperor Wu, "Sacrifice to the stove [zao 竈] and you will be able to summon ' things ' [i.e. spirits]. Summon spirits and you will be able to change cinnabar powder into yellow gold. With this yellow gold you may make vessels to eat and drink out of. You will then increase your span of life. Having increased your span of life, you will be able to see the [xian 仙] of [Penglai] that is in the midst of the sea. Then you may perform the sacrifices feng [封] and shan [禅], and escape death." (tr. Waley 1930: 2).
Wei Boyang's c. 142 Cantong qi, which is regarded as the oldest complete alchemical book extant in any culture, influenced developments in elixir alchemy. It listed mercury and lead as the prime ingredients for elixirs, which limited later potential experiments and resulted in numerous cases of poisoning. It is quite possible that "many of the most brilliant and creative alchemists fell victim to their own experiments by taking dangerous elixirs" (Needham et al. 1976: 74). There is a famous story about animal testing of elixirs by Wei Boyang. Wei entered the mountains to prepare the elixir of immortality, accompanied by three disciples, two of whom were skeptical. When the alchemy was completed he said, "Although the gold elixir is now accomplished we ought first to test it by feeding it to a white dog. If the dog can fly after taking it then it is edible for man; if the dog dies then it is not." The dog fell over and died, but Wei and his disciple Yu took the medicine and immediately died, after which the two cautious disciples fled. Wei and Yu later revived, rejoiced in their faith, took more of the elixir and became immortals (Needham and Ho 1970: 322).
Elixir ingestion is first mentioned in the c. 81 BCE Discourses on Salt and Iron (Pregadio 2000: 166).
### Six dynasties[edit]
During the turbulent Six dynasties period (220–589), self-experimentation with drugs became commonplace, and many people tried taking poisonous elixirs of immortality as well as the psychoactive drug Cold-Food Powder. At this time, Daoist alchemists began to record the often fatal side effects of elixirs. In an unusual case of involuntary elixir poisoning, Empress Jia Nanfeng (257–300) was forced to commit suicide by drinking "jinxiaojiu" 金屑酒 "wine with gold fragments" (Needham and Ho 1970: 326).
The Daoist scholar Ge Hong's c. 320 Baopuzi lists 56 chemical preparations and elixirs, 8 of which were poisonous, with visions from mercury poisoning the most commonly reported symptom (Needham et al. 1976: 89–96).
The individuals who experimented with Six Dynasties alchemy often had different understandings and intentions. A single alchemical formula could be interpreted as being "suicidal, therapeutic, or symbolic and contemplative", and its implementation might be "a unique, decisive event or a repeated, ritual phantasmagoria" (Strickmann 1979: 192).
Emperor Ai of Jin (r. 361–365) died at the age of twenty-five, as the result of his desire to avoid growing old. The Book of Jin says the emperor practiced bigu "grain avoidance" and consumed alchemical elixirs, but was poisoned from an overdose and "no longer knew what was going on around him" (Needham and Ho 1970: 317). In a sardonic sense, the emperor fulfilled his desire since the elixir "did actually prevent him from growing any older" (Ho 2000: 184).
Emperor Daowu (r. 371–409), founder of the Northern Wei dynasty, was cautiously interested in alchemy and used condemned criminals for clinical trials of immortality elixirs (like Mithridates VI of Pontus r. 120–63 BCE) . The Book of Wei records that in 400, he instituted the office of the Royal Alchemist, built an imperial laboratory for the preparation of drugs and elixirs, and reserved the Western mountains for the supply of firewood (used in the alchemical furnaces). "Furthermore, he ordered criminals who had been sentenced to death to test (the products) against their will. Many of them died and (the experiments gave) no decisive result." (tr. Needham and Ho 1970: 321).
Many texts from the Six dynasties period specifically warned about the toxicity of elixirs. For instance, the Shangqing School Daoist pharmacologist Tao Hongjing's 499 Zhen'gao (真誥, Declarations of the Perfected) describes taking a White Powder elixir.
> When you have taken a spatulaful of it, you will feel an intense pain in your heart, as if you had been stabbed there with a knife. After three days you will want to drink, and when you have drunk a full hu 斛 [about 50 liters] your breath will be cut off. When that happens, it will mean that you are dead. When your body has been laid out, it will suddenly disappear, and only your clothing will remain. Thus you will be an immortal released in broad daylight by means of his waistband. If one knows the name of the drug [or, perhaps, the secret names of its ingredients] he will not feel the pain in his heart, but after he has drunk a full hu he will still die. When he is dead, he will become aware that he has left his corpse below him on the ground. At the proper time, jade youths and maidens will come with an azure carriage to take it away. If one wishes to linger on in the world, he should strictly regulate his drinking during the three days when he feels the pain in his heart. This formula may be used by the whole family. (tr. Strickmann 1979: 137–138)
Within this context, Strickmann says a prospective Daoist alchemist must have been strongly motivated by faith and a firm confidence in his posthumous destiny, in effect, "he would be committing suicide by consecrated means." Tao Hongjing's disciple Zhou Ziliang 周子良 (497–516) had repeated visions of Maoshan divinities who said his destiny was to become an immortal, and instructed him to commit ritual suicide with a poisonous elixir composed of mushrooms and cinnabar (Strickmann 1994: 40). In 517, Tao edited the Zhoushi mingtong ji 周氏冥通記 (Records of Mr. Zhou's Communications with the Unseen) detailing his disciples visions.
The Liang dynasty founder Emperor Wu (r. 502–549) was cautious about taking elixirs of immortality. He and Tao Hongjing were old friends, and the History of the Southern Dynasties says the emperor requested him to study elixir alchemy. After Tao had learned the secret art of making elixirs, he was worried about the shortage of materials. "So the emperor supplied him with gold, cinnabar, copper sulphate, realgar, and so forth. When the process was accomplished the elixirs had the appearance of frost and snow and really did make the body feel lighter. The emperor took an elixir and found it effective." (tr. Needham et al. 1976: 120). Tao spent his last years working on different elixirs and presented three to the emperor, who had refused immortality elixirs from Deng Yu 鄧郁 (who claimed to have lived 30 years without food, only consuming pieces of mica in stream water).
Emperor Wenxuan (r. 550–559) of the Northern Qi dynasty was an early skeptic about immortality elixirs. He ordered alchemists to make the jiuhuan jindan 九還金丹 (Ninefold Cyclically Transformed Elixir), which he kept in a jade box, and explained, "I am still too fond of the pleasures of the world to take flight to the heavens immediately—I intend to consume the elixir only when I am about to die." (tr. Needham and Ho 1970: 320).
### Tang dynasty[edit]
At least five Tang dynasty (618–907) emperors were incapacitated and killed by immortality elixirs. In the 9th century Tang imperial order of succession, two father-son emperor pairs died from elixirs: first Xianzong (r. 805–820) and Muzong (r. 820–824), then Wuzong (r. 840–846) and Xuanzong (r. 847–859). In historic recurrences, the newly enthroned emperor understandably executed the Daoist alchemists whose elixirs had killed his father, and then subsequently came to believe in other charlatans enough to consume their poisonous elixirs (Ho 2000: 184).
Emperor Xianzong (r. 805–820) indirectly lost his life due to elixir poisoning. The Xu Tongzhi (Supplement to the Historical Collections) says, "Deluded by the sayings of the alchemists, [Xianzong] ingested gold elixirs and his behaviour became very abnormal. He was easily offended by those officials whom he daily met, and thus the prisons were left with little vacant space." (tr. Needham and Ho 1970: 317). In response, an official wrote an 819 memorial to the throne that said:
> Of late years, however, (the capital) has been overrun by a host of pharmacists and alchemists ... recommending one another right and left with ever wilder and more extravagant claims. Now if there really were immortals, and scholars possessing the Tao, would they not conceal their names and hide themselves in mountain recesses far from the ken of man? ... The medicines of the sages of old were meant to cure bodily illnesses, and were not meant to be taken constantly like food. How much less so these metallic and mineral substances which are full of burning poison! ... Of old, as the Li Chi says, when the prince took physic, his minister tasted it first, and when a parent was sick, his son did likewise. Ministers and sons are in the same position. I humbly pray that all those persons who have elixirs made from transformed metals and minerals, and also those who recommend them, may be compelled to consume (their own elixirs) first for the space of one year. Such an investigation will distinguish truth from falsehood, and automatically clarify the matter by experiment. (abridged, tr. Needham and Ho 1970: 318)
After the emperor rejected this appeal, the palace eunuchs Wang Shoucheng and Chen Hongzhi 陳弘志 assassinated him in 820.
When Xianzong's son and successor Emperor Muzong (r. 820–824) came to the throne, he executed the alchemists who had poisoned his father, but later began to take immortality elixirs himself. An official wrote Muzong an 823 memorial that warned:
> Medicines are for use against illnesses, and should not be taken as food. ... Even when one is ill medicines must be used with great circumspection; how much more so when one is not ill. If this is true for the common people how much more so will it be for the emperor! Your imperial predecessor believed the nonsense of the alchemists and thus became ill; this your majesty already knows only too well. How could your majesty still repeat the same mistake? (tr. Needham and Ho 1970: 319)
The emperor appreciated this reasoning but soon afterwards fell ill and died from poisoning. Palace eunuchs supposedly used poisonous elixirs to assassinate Muzong's young successor Emperor Jingzong (r. 824–827) (Needham et al. 1976: 151, 182).
The next Tang emperor to die from elixir poisoning was Wuzong (r. 840–846). According to the Old Book of Tang, "The emperor [Wuzong] favoured alchemists, took some of their elixirs, cultivated the arts of longevity and personally accepted (Taoist) talismans. The medicines made him very irritable, losing all normal self-control in joy or anger; finally when his illness took a turn for the worse he could not speak for ten days at a time." Chancellor Li Deyu and others requested audiences with the emperor, but he refused and subsequently died in 846 (Needham and Ho 1970: 319).
Wuzong's successor Emperor Xuānzong (r. 846–849) astonishingly also died of elixir poisoning. Xuānzong made himself the patron of some Daoists who concocted immortality elixirs of vegetable origin, possibly because his father Wuzong had died from metallic and mineral elixir poisoning (Needham et al. 1976: 146). The New Book of Tang records that the emperor received a wine tincture of ivy (常春藤, Hedera helix) that the Daoist adept Jiang Lu 姜攎 claimed would turn white hair black and provide longevity. However, when the emperor heard that many people died a violent death after drinking ivy tincture, he stopped taking it. Jiang was publicly shamed and the emperor granted his request to search in the mountains for the right plant, but he never appeared again (Needham et al. 1976: 147). According to the 890 Dongguan zuoji (Record of Memorials from the Eastern Library), "A medical official, Li [Xuanbo], presented to the emperor [Xuanzong] cinnabar which had been heated and subdued by fire, in order to gain favour from him. Thus the ulcerous disease of the emperor was all attributable to his crime." (tr. Needham and Ho 1970: 319).
Besides emperors, many Tang literati were interested in alchemy. Both Li Bai (Waley 1950: 55–56) and Bai Juyi (Ho, Goh, and Parker 1974) wrote poems about the Cantong qi and alchemical elixirs. Other poets, including Meng Haoran, Liu Yuxi, and Liu Zongyuan also referred to elixir compounding in their works (Pregadio 2000: 171).
The influential Tang physician and alchemist Sun Simiao's c. 640 alchemical Taiqing zhenren dadan 太清真人大丹 (Great Purity Essentials of Elixir Manuals for Oral Transmission) recommends 14 elixir formulas he found successful, most of which seem poisonous, containing mercury and lead, if not arsenic, as ingredients (Needham et al. 1976: 133). Sun's medical c. 659 Qianjin yifang 千金要方 (Supplement to the Thousand Golden Remedies) categorically states that mercury, realgar, orpiment, sulphur, gold, silver, and vitriol are poisonous, but prescribed them in much larger amounts for elixirs than for medicines. In contrast to drinking soluble arsenic (as in groundwater), when powdered arsenic is eaten "astonishing degrees of tolerance can be achieved", and Sun Simiao might have thought that when human beings reached to a level "approaching that of the immortals their bodies would no longer be susceptible to poison" (Needham et al. 1976: 135).
Tang alchemists were well aware of elixir poisoning. The c. 8th–9th century Zhenyuan miaodao yaolüe 真元妙道要略 (Synopsis of the Essentials of the Mysterious Dao of the True Origin) lists 35 common mistakes in elixir preparation: cases where people died from eating elixirs made from cinnabar, mercury, lead, and silver; cases where people suffered from boils on the head and sores on the back by ingesting cinnabar prepared by roasting together mercury and sulphur, and cases where people became seriously ill through drinking melted "liquid lead" (Needham and Ho 1970: 330). The c. 850 Xuanjie lu 玄解錄 (Record of Mysterious Antidotes)—which is notable as the world's oldest printed book on a scientific subject—recommends a potent herbal composition that serves both as an elixir and as an antidote for common elixir poisoning (Needham and Ho 1970: 335). The procedure to make Shouxian wuzi wan 守仙五子丸 (Five-herbs Immortality-safeguarding Pills) is to take 5 ounces each of Indian gooseberry, wild raspberry, dodder, five-flavor berry, and broadleaf plantain and pound them into flour. Mix it with boxthorn juice and false daisy juice and dry. Heat almonds and good wine in a silver vessel, and add foxglove, tofu, and "deer glue". Combine this with the five herbs, and dry into small pills. The usual dosage is 30 pills a day taken with wine, but one should avoid eating pork, garlic, mustard, and turnips when taking the medicine (Needham and Ho 1970: 335).
During the Tang period, Chinese alchemists divided into two schools of thought about elixir poisoning. The first altogether ignored the poison danger and considered the unpleasant symptoms after taking an elixir as signs of its efficacy. The c. 6th century Taiqing shibi ji 太清石壁記 (Records of the Rock Chamber) described away the side effects and recommended methods of bringing relief.
> After taking an elixir, if your face and body itch as though insects were crawling over them, if your hands and feet swell dropsically, if you cannot stand the smell of food and bring it up after you have eaten it, if you feel as though you were going to be sick most of the time, if you experience weakness in the four limbs, if you have to go often to the latrine, or if your head or stomach violently ache—do not be alarmed or disturbed. All these effects are merely proofs that the elixir you are taking is successfully dispelling your latent disorders. (tr. Needham and Lu 1974: 283)
Many of these symptoms are characteristic of metallic poisoning: formication, edema, and weakness of the extremities, later leading to infected boils and ulcers, nausea, vomiting, gastric and abdominal pain, diarrhea, and headaches (Needham and Lu 1974: 283). For relieving the side-effects when the elixir takes effect, the Taiqing shibi ji recommends that one should take hot and cold baths, and drink a mixture of scallion, soy sauce, and wine. If that does not bring relief, then one should combine and boil a hornets' nest, spurge, Solomon's seal, and ephedra into a medicine and take one dose (Needham and Ho 1970: 331).
The second school of alchemists, admitted that some metal and mineral elixir constituents were poisonous and tried either to neutralize them or to replace them with less dangerous herbal substances (Needham et al. 1976: 182). For instance, the 8th-century Zhang zhenren jinshi lingsha lun 張真人金石靈沙論 (The Adept Zhang's Discourse on Metals, Minerals, and Cinnabar) emphasized the poisonous nature of gold, silver, lead, mercury, and arsenic, and described witnessing many cases of premature death brought about by consuming cinnabar. Zhang believed however that the poisons could be rendered harmless by properly choosing and combining adjuvant and complimentary ingredients; for example gold should always be used together with mercury, while silver can only be used when combined with gold, copper carbonate, and realgar for the preparation of the jindan Golden Elixir (tr. Needham and Ho 1970: 331). Many Tang alchemical writers returned to the fashion of using obscure synonyms for ingredients, perhaps because of the alarming number of elixir poisonings, and the desire to dissuade amateur alchemists from experimenting on themselves (Needham et al. 1976: 138). By the end of the Yuan dynasty (1271–1368), the more cautious alchemists had generally changed the elixirs ingredients from minerals and metals to plants and animals (Ho and Lisowski 1997: 39).
The late Tang or early Song Huangdi jiuding shendan jingjue 黄帝九鼎神丹經訣 (Explanation of the Yellow Emperor's Manual of the Nine-Vessel Magical Elixir) says, "The ancient masters (lit. sages) all attained longevity and preserved their lives (lit. bones) by consuming elixirs. But later disciples (lit. scholars) have suffered loss of life and decay of their bones as the result of taking them." The treatise explains the secret ancient methods for rendering elixir ingredients harmless by treating them with wine made from chastetree leaves and roots, or with saltpeter and vinegar. Another method of supposedly removing the poison from mercury was to put it in three-year-old wine, add sal ammoniac and boil it for 100 days (Needham and Ho 1970: 332–3).
### Five dynasties[edit]
Two rulers died from elixir poisoning during the Five Dynasties period (907–979) of political turmoil after the overthrow of the Tang dynasty. Zhu Wen or Emperor Taizu (r. 907–912), the founder of the Later Liang dynasty, became seriously incapacitated as a result of elixir poisoning, and fell victim to an assassination plot. Li Bian or Emperor Liezu (r. 937–943), the founder of the Southern Tang kingdom, took immortality elixirs that made him irritable and deathly ill (Needham et al. 1976: 180).
The Daoist adept Chen Tuan (d. 989) advised two emperors that they should not worry about elixirs but direct their minds to improving the state administration, Chai Rong or Emperor Shizong of Later Zhou in 956, and then Emperor Taizu of Song in 976 (Needham et al. 1976: 194).
### Song dynasty[edit]
After its heyday in the Tang dynasty Daoist alchemy continued to flourish during the Song dynasty (960–1279) period. However, since six Tang emperors and many court officials died from elixir poisoning, Song alchemists exercised more caution, not only in the composition of the elixirs themselves, but also in attempts to find pharmaceutical methods of counteracting the toxic effects. The number of ingredients used in elixir formulas was reduced and there was a tendency to return to the ancient and difficult terminology of the Cantongqi, perhaps to conceal the processes from rash and ignorant operators. Psycho-physiological neidan alchemy became steadily more popular than laboratory waidan alchemy (Needham et al. 1976: 208).
During the Song dynasty, the practice of consuming metallic elixirs was not confined to the imperial court and expanded to anyone wealthy enough to pay. The author and official Ye Mengde (1077–1148) described how two of his friends had died from elixirs of immortality in one decade. First, Lin Yanzhen, who boasted about his health and muscular strength, took an elixir for three years, "Whereupon ulcers developed in his chest, first near the hairs as large as rice-grains, then after a couple of days his neck swelled up so that chin and chest seemed continuous." Lin died after ten months of suffering, and his doctors discovered cinnabar powder had accumulated in his pus and blood. Second, whenever Xie Renbo "heard of anyone who had some cinnabar subdued by fire he went after it, caring nothing about the distance, and his only fear was that he would not have enough." He also developed ulcers on the chest. Although his friends noticed changes in his appearance and behavior, Xie did not recognize that he had been poisoned, "till suddenly it came upon him like a storm of wind and rain, and he died in a single night." (tr. Needham and Ho 1970: 320)
The scientist and statesman Shen Kuo's 1088 Dream Pool Essays suggested that mercury compounds might be medicinally valuable and needed further study—foreshadowing the use of metallic compounds in modern medicine, such as mercury in salvarsan for syphilis or antimony for visceral leishmaniasis. Shen says his cousin once transformed cinnabar into an elixir, but one of his students mistakenly ate a leftover piece, became delirious, and died the next day.
> Now cinnabar is an extremely good drug and can be taken even by a newborn baby, but once it has been changed by heat it can kill an (adult) person. If we consider the change and transformation of opposites into one another, since (cinnabar) can be changed into a deadly poison why should it not also be changed into something of extreme benefit? Since it can change into something which kills, there is good reason to believe that it may have the pattern-principle [li] of saving life; it is simply that we have not yet found out the art (of doing this). Thus we cannot deny the possibility of the existence of methods for transforming people into feathered immortals, but we have to be very careful about what we do. (tr. Needham and Ho 1970: 327).
Su Shi (1037–1101), the Song dynasty scholar and pharmacologist, was familiar with the life-prolonging claims of alchemists, but wrote in a letter that, "I have recently received some cinnabar (elixir) which shows a most remarkable colour, but I cannot summon up enough courage to try it." (tr. Needham and Ho 1970: 320).
The forensic medical expert Song Ci was familiar with the effects of metal poisoning, and his c. 1235 Collected Cases of Injustice Rectified handbook for coroners gives a test for mercury poisoning: plunge a piece of gold into the intestine or tissues and see if a superficial amalgam forms. He also describes the colic, cramps, and discharge of blood from arsenic poisoning, and gives several antidotes including emetics.
### Ming dynasty[edit]
Chinese woodblock illustration of a neidan practice "Putting the miraculous elixir into the ding tripod", 1615 Xingming guizhi 性命圭旨 (Pointers on Spiritual Nature and Bodily Life)
Ming dynasty (1368–1644) authorities strongly disapproved of immortality elixirs, but the Jiajing Emperor (r. 1521–1567) supposedly died from consuming them. The emperor was interested in the art of immortality and put great confidence in Daoist physicians, magicians, and alchemists. One named Wang Jin 王金, who was appointed a Physician-in-Attendance in the Imperial Academy of Medicine, convinced the emperor that eating and drinking from vessels made of alchemical gold and silver would bring about immortality, but it only resulted in his death. Wang fled but was caught and exiled to the frontiers in 1570 (Needham et al. 1976: 212).
Li Shizhen's classic 1578 Compendium of Materia Medica discusses the historical tradition of producing gold and cinnabar elixirs, and concludes, "(the alchemists) will never realise that the human body, which thrives on water and the cereals, is unable to sustain such heavy substances as gold and other minerals within the stomach and intestines for any length of time. How blind it is, in the pursuit of longevity, to lose one's life instead!" (tr. Needham and Ho 1970: 325–326). In another section, Li criticizes alchemists and pharmacologists for perpetuating the belief in mercury elixirs.
> I am not able to tell the number of people who since the Six Dynasties period (3rd to 6th centuries) so coveted life that they took (mercury), but all that happened was that they impaired their health permanently or lost their lives. I need not bother to mention the alchemists, but I cannot bear to see these false statements made in pharmacopoeias. However, while mercury is not to be taken orally, its use as a medicine must not be ignored. (tr. Needham and Ho 1970: 325–326)
### Qing dynasty[edit]
The Qing dynasty Yongzheng Emperor (r. 1722–1735) was the last Chinese ruler known to die from elixir poisoning. He was a superstitious man, affected by portents and omens, and a firm believer in Daoist longevity techniques. Taking immortality elixirs is thought to have caused his sudden death in 1735 (Zelin 2002: 229).
### Historical interpretations[edit]
The Chinese tradition of using toxic heavy metals in elixirs of immortality has historical parallels in Ayurvedic medicine. Rasa shastra is the practice of adding metals and minerals to herbal medicines, rasayana is an alchemical tradition that used mercury and cinnabar for lengthening lifespan, raseśvara is a tradition that advocated the use of mercury to make the body immortal, and samskara is a process said to detoxify heavy metals and toxic herbs.
The historians of Chinese science Joseph Needham and Ho Peng-Yoke wrote a seminal article about poisonous alchemical elixirs (1959, 1970). Based upon early Chinese descriptions of elixir poisoning, they decisively demonstrated a close correspondence with the known medical symptoms of mercury poisoning, lead poisoning, and arsenic poisoning. Compare the historical descriptions of Jin Emperor Ai (d. 365) who "no longer knew what was going on around him" and Tang Emperor Wuzong (d. 846) who was "very irritable, losing all normal self-control in joy or anger ... he could not speak for ten days at a time" with the distinctive psychological effects of mercury poisoning: progressing from "abnormal irritability to idiotic, melancholic, or manic conditions" (1970: 327). Needham and his collaborators further discussed elixir poisoning in the Science and Civilisation in China series, particularly Needham and Lu Gwei-djen (1974), and Needham, Ho, and Lu (1976).
Although Chinese elixir poisoning may lead some to dismiss Chinese alchemy as another example of human follies in history, Ho Peng-Yoke and F. Peter Lisowski note its positive aspect upon Chinese medicine. The caution given to elixir poisoning later led Chinese alchemy to "shade imperceptibly" into iatrochemistry, the preparation of medicine by chemical methods, "in other words chemotherapy" (1997: 39).
A recent study found that Chinese emperors lived comparatively short lives, with a mean age at death of emperors at 41.3, which was significantly lower than that of Buddhist monks at 66.9 and traditional Chinese doctors at 75.1. Causes of imperial death were natural disease (66.4%), homicide (28.2%), drug toxicity (3.3%), and suicide (2.1%). Homicide resulted in a significantly lower age of death (mean age 31.1) than disease (45.6), suicide (38.8), or drug toxicity (43.1, mentioning Qin Shi Huang taking mercury pills of immortality). Lifestyles seem to have been a determining factor, and 93.2% of the emperors studied were overindulgent in drinking alcohol, sexual activity, or both (Zhao et al. 2006: 1295). The study does not refer to the Chinese belief that the arsenic sulphides realgar and orpiment, frequently used in immortality elixirs, had aphrodisiac properties (Needham and Lu 1974: 285).
## Hypothetical explanations[edit]
A significant question remains unanswered. If the insidious dangers of alchemical elixir poisoning were common knowledge, why did people continue to consume them for centuries? Joseph Needham and his collaborators suggested three hypothetical explanations, and Michel Strickmann proposed another.
### Initial exhilaration[edit]
Needham and Lu's first explanation is that many alchemical mineral preparations were capable of giving an "initial exhilaration" or transient sense of well-being, usually involving weight loss and increased libido. These preliminary tonic effects could have acted as a kind of "bait" inveigling an elixir-taker deeper into substance intoxication, even to the point of death (1974: 282). Chinese medical texts recorded that realgar (arsenic disulphide) and orpiment (arsenic trisulphide) were aphrodisiacs and stimulated fertility, while cinnabar and sulphur elixirs increased longevity, averted hunger, and "lightened the body" (namely, qīngshēn 輕身, which is a common description of elixir effects) (1974: 285).
Wine, as mentioned above, was both prescribed to be drunk when taking elixir pills and to relieve the unpleasant side-effects of elixir poisoning. Needham and Lu further suggest the possibility that elixir alchemy included hallucinogenic drugs, tentatively identifying the busi zhi yao 不死之藥 "drug of deathlessness" as fly-agaric and busi zhi shu 不死之樹 "tree of deathlessness" as birch (1974: 117). The elixir that Tao Hongjing's disciple Zhou Ziliang took to commit suicide "probably had hallucinogenic and toxic mushrooms" (1974: 296). In the present day, realgar wine is traditionally consumed as part of the Dragon Boat Festival.
### Incorruptibility[edit]
Jade burial suit of Nanyue King Zhao Mo (d. 122 BCE)
The preserved body of Xin Zhui (d. 163 BCE)
The apparent incorruptibility of an elixir-taker's corpse is Needham and Lu's second explanation for the persistent belief in immortality elixirs. They suggest that in some cases a body did not decompose because the deceased had died from mercury or arsenic poisoning, which is forensically known to often preserve a corpse from decay. For a believer in Daoist immortality drugs, even when an elixir-taker had unmistakably died, if the corpse was comparatively undecomposed, that could be interpreted as proof that the adept had become a xian immortal, as well as evidence for the alchemical elixir's efficacy. (1974: 298).
Terminal incorruptibility was an ancient Chinese belief associated with jade, gold, and cinnabar. The Baopuzi says, "When gold and jade are inserted into the nine orifices, corpses do not decay. When salt and brine are absorbed into flesh and marrow, dried meats do not spoil. So when men ingest substances which are able to benefit their bodies and lengthen their days, why should it be strange that (some of these) should confer life perpetual?" The abolition of decay was believed to demonstrate the power of elixirs, "the corruptible had put on incorruptibility" (Needham and Lu 1974: 284). Chinese jade burial suits are a better known example of using a mineral to preserve corpses.
There is a possibility that Sun Simiao (above) died from taking mercury elixirs (Needham and Ho 1970: 330). According to Sun's hagiography in the 10th-century Xuxian zhuan 續仙傳 (Further Biographies of the Immortals), after his death in 682 there was no visible sign of putrefaction, "After more than a month had passed there was no change in his appearance, and when the corpse was raised to be placed in the coffin it was as light as (a bundle of) empty clothes." (tr. Needham and Lu 1974:298).
The incorruptibility stories about elixir users were not all myth, and recent archeological evidence showed that the ancient Chinese knew how "to achieve an almost perpetual conservation". The 1972 excavation of a tomb at Mawangdui discovered the extremely well-preserved body of Xin Zhui or Lady Dai, which resembled that of "a person who had died only a week or two before" (Needham and Lu 1974: 303–304). A subsequent autopsy on her corpse found "abnormally high levels" of mercury and lead in her internal organs (Brown 2002: 213).
### Temporary death[edit]
Needham and Lu's third justification for taking poisonous elixirs is a drug-induced "temporary death", possibly a trance or coma. In the classic legend (above) about Wei Boyang drinking an elixir of immortality, he appears to die, subsequently revives, and takes more elixir to achieve immortality.
The Baopuzi describes a Five Mineral-based multicolored Ninefold Radiance Elixir that can bring a corpse back to life: "If you wish to raise a body that has not been dead for fully three days, bathe the corpse with a solution of one spatula of the blue elixir, open its mouth, and insert another spatula full; it will revive immediately." (tr. Ware 1966:82).
A Tang Daoist text prescribes taking an elixir in doses half the size of a millet grain, but adds, "If one is sincerely determined, and dares to take a whole spatula-full all at once, one will temporarily die [zànsǐ 暫死] for half a day or so, and then be restored to life like someone waking from sleep. This however is perilous in the extreme." (tr. Needham and Lu 1974: 295).
### Ritual suicide[edit]
Michel Strickmann, a scholar of Daoist and Buddhist studies, analyzed the well-documented Shangqing School's alchemy in the Maoshan revelations and in the life of Tao Hongjing, and concluded that scholars need to reexamine the Western stereotype of "accidental elixir poisoning" that supposedly applied to "misguided alchemists and their unwitting imperial patrons". Since Six Dynasties and Tang period Daoist literature thoroughly, "even rapturously", described the deadly toxic qualities of many elixirs, and Strickmann proposed that some of the recorded alchemical deaths were intentional ritual suicide (1979: 191). Two reviewers disagreed about Strickmann's conclusions. The first questions why he defends the logic of alchemical suicide rather than simply accepting the idea of accidental elixir poisoning, and says Tao Hongjing never experimented with alchemy seriously enough to achieve suicide himself—but fails to mention Strickmann's prime example: Tao's disciple Zhou Ziliang whom Shangqing deities reportedly instructed to prepare a poisonous elixir and commit suicide in order to achieve immortality (Chen 1981: 547). The second describes Strickmann's chapter as "one of the most thorough and useful" in the volume, and says he proves that it is "almost ludicrous to assume that a Taoist (commoner or emperor) could have died from accidental elixir poisoning" (Cass 1982: 92–93).
## References[edit]
* Bokenkamp, Stephen R. (2009), "Daoist Pantheons", in Early Chinese Religion, Part Two: The Period of Division (220–589 AD), ed. by John Lagerwey and Pengzhi Lü, Brill, 1179–1214.
* Brown, Miranda (2002), "Did the Early Chinese Preserve Corpses? A Reconsideration of Elite Conceptions of Death", Journal of East Asian Archaeology 4.1, 201–223.
* Cass, Victoria B. (1982), "[Review of] Facets of Taoism: Essays in Chinese Religion by Holmes Welch and Anna K. Seidel", Chinese Literature: Essays, Articles, Reviews (CLEAR) 4.1: 91–93.
* Chen, Ellen (1981), "[Review of] Facets of Taoism: Essays in Chinese Religion by Holmes Welch and Anna K. Seidel", Philosophy East and West 31.4: 545–549.
* DeWoskin, Kenneth (1981), Doctors, Diviners and Magicians of Ancient China: Biographies of Fang-shih, Columbia University Press.
* Ho Peng Yoke, Goh Thean Chye, and David Parker (1974), "Po Chu-i's Poems on Immortality," Harvard Journal of Asiatic Studies 34: 163–86.
* Ho Peng-Yoke [Ho Ping-Yü] and F. Peter Lisowski (1997), A Brief History of Chinese Medicine, World Scientific.
* Ho Peng-Yoke (2000), Li, Qi and Shu: An Introduction to Science and Civilization in China, Courier.
* Needham, Joseph and Ho Ping-Yü (1959, 1970), "Elixir poisoning in medieval China", Janus 48: 221–251, reprinted in Clerks and Craftsmen in China and the West: lectures and addresses on the history of science and technology, Cambridge University Press, 316–339.
* Needham, Joseph and Lu Gwei-djen (1974), Science and Civilization in China. Volume 5, Chemistry and Chemical Technology, Part 2, Spagyrical Discovery and Invention: Magisteries of Gold and Immortality, Cambridge University Press.
* Needham, Joseph, Ho Ping-Yü, and Lu Gwei-djen (1976), Science and Civilisation in China, Volume 5, Chemistry and Chemical Technology, Part 3, Spagyrical Discovery and Invention: Historical Survey, from Cinnabar Elixirs to Synthetic Insulin, Cambridge University Press.
* Pregadio, Fabrizio (2000), "Elixirs and Alchemy", in Daoism Handbook, ed. by Livia Kohn, Brill, 165–195.
* Pregadio, Fabrizio (2012), The Way of the Golden Elixir: An Introduction to Taoist Alchemy, Golden Elixir Press.
* Schuessler, Axel. 2007. ABC Etymological Dictionary of Old Chinese. University of Hawaii Press.
* Strickmann, Michel (1979), "On the Alchemy of T'ao Hung-ching", in Holmes Welch and Anna Seidel, eds., Facets of Taoism: Essays in Chinese Religion, 123–192, Yale University Press.
* Strickmann, Michel (1994), "Saintly Fools and Chinese Masters (Holy Fools)", Asia Major 7.1: 35–57.
* Turner, Bryan S. (2009), " Piety, Prolongevity and Perpetuity: The Consequences of Living Forever", Medicine, Religion, and the Body, ed. by Elizabeth Burns Coleman and Kevin White, Brill, 79–104.
* Waley, Arthur (1930), "Notes on Chinese Alchemy ("Supplementary to Johnson's" A Study of Chinese Alchemy)", Bulletin of the School of Oriental Studies, 6.1: 1–24.
* Waley, Arthur (1950), The Poetry and Career of Li Po, MacMillan.
* Wright, David Curtis (2001), The History of China, Greenwood Publishing Group.
* Zelin Madeleine (2002), "The Yung-cheng Reign", in The Cambridge History of China, Volume 9, Part One: The Ch’ing Empire to 1800, ed. by Willard J. Peterson, 183–229, Cambridge.
* Zhao Hai-Lu, Zhu Xun, and Sui Yi (2006), "The short-lived Chinese emperors", Journal of the American Geriatrics Society, 54.8: 1295–1296.
## External links[edit]
* An Introduction to Taoist Alchemy, The Golden Elixir.
* 丹 Seal, Bronze, and Oracle Characters, Chinese Etymology.
*[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
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Hori's nevus
SpecialtyDermatology
Hori's nevus (also known as "Acquired bilateral nevus of Ota-like macules"[1]) is a cutaneous condition characterized by multiple brown–gray to brown–blue macules, primarily in the malar region of the face.[1]
## See also[edit]
* Nevus of Ota
* List of cutaneous conditions
## References[edit]
1. ^ a b 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
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## Summary
### Clinical characteristics.
The MPPH syndrome is a developmental brain disorder characterized by megalencephaly (brain overgrowth) with the cortical malformation bilateral perisylvian polymicrogyria (BPP). At birth the occipital frontal circumference (OFC) ranges from normal to 6 standard deviations (SD) above the mean for age, sex, and gestational age; in older individuals the range is from 3 to 10 SD above the mean. A variable degree of ventriculomegaly is seen in almost all children with MPPH syndrome; nearly 50% of those have frank hydrocephalus. Neurologic problems associated with BPP include oromotor dysfunction (100%), epilepsy (50%), and mild to severe intellectual disability (100%). Postaxial hexadactyly occurs in 50% of individuals with MPPH syndrome.
### Diagnosis/testing.
The clinical diagnosis of MPPH syndrome can be established in individuals with the two core features: megalencephaly and BPP. The molecular diagnosis of MPPH syndrome is established in a proband with some of the suggestive clinical and imaging features and the identification of a heterozygous pathogenic variant in one of three genes: AKT3, CCND2, or PIK3R2. While most individuals with MPPH syndrome have a germline pathogenic variant in one of these three genes, some have a somatic mosaic pathogenic variant (most commonly reported in PIK3R2).
### Management.
Treatment of manifestations: Hydrocephalus warrants early neurosurgical intervention. Oromotor difficulties, developmental delays, and epilepsy are treated as per usual clinical care standards.
Surveillance: Follow up with a pediatric neurologist, at least every six months until age six years, and yearly thereafter. Brain MRI to detect hydrocephalus and/or cerebellar tonsillar ectopia is provisionally recommended every six months from birth to age two years, and yearly from age two to six years. In older individuals, the frequency should be determined within the context of prior brain imaging findings and clinical findings. Long-term neurologic follow up is warranted for epilepsy. Routine follow up with a developmental pediatrician given the high risk of developmental delays and/or intellectual disability.
### Genetic counseling.
MPPH syndrome is inherited in an autosomal dominant manner. Most individuals with MPPH syndrome have the disorder as the result of a de novo AKT3, CCND2, or PIK3R2 pathogenic variant. In one family, vertical transmission of a PIK3R2 pathogenic variant was observed; in two families, parental germline mosaicism for a PIK3R2 pathogenic variant seemed likely (given recurrence of MPPH syndrome in sibs and failure to detect the pathogenic variant in DNA isolated from parental blood samples). Each child of an individual with a germline pathogenic variant has a 50% chance of inheriting the pathogenic variant. Once the AKT3, CCND2, or PIK3R2 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for MPPH syndrome and preimplantation genetic testing are possible.
## Diagnosis
### Suggestive Findings
MPPH syndrome should be suspected in individuals with the following clinical and imaging findings [Mirzaa et al 2004, Mirzaa et al 2012]. Note: Findings shown in bold are core features.
Clinical findings
* Macrocephaly or megalencephaly (occipito-frontal circumference ≥2 SD above the mean); onset either prenatally or postnatally
* Postaxial polydactyly of one or more extremities
* Hypotonia
* Early-onset epilepsy
* Intellectual disability
* Oromotor dysfunction
Imaging findings
* Cortical brain malformations, particularly bilateral perisylvian polymicrogyria (BPP)
* Progressive ventriculomegaly leading to hydrocephalus
* Cerebellar tonsillar ectopia or Chiari malformations
* Thick corpus callosum (or mega corpus callosum)
### Establishing the Diagnosis
The clinical diagnosis of MPPH syndrome can be established in individuals with the two core features: megalencephaly and polymicrogyria).
The molecular diagnosis of MPPH syndrome is established in a proband with some of the suggestive clinical and imaging features and the identification of a heterozygous pathogenic variant in one of three genes: AKT3, CCND2, or PIK3R2 (Table 1). While most individuals with MPPH syndrome have a germline (i.e., constitutional) pathogenic variant in one of these three genes, some individuals have been reported with a somatic mosaic pathogenic variant in one of these genes (most commonly PIK3R2).
Note that failure to detect either a germline or somatic mosaic pathogenic variant in one of these three genes in a proband does not exclude a clinical diagnosis of MPPH syndrome in individuals with the two core clinical and imaging features.
Molecular genetic testing approaches used to identify germline and somatic pathogenic variants can include a combination of serial single-gene testing, chromosomal microarray analysis (CMA), and use of a multigene panel.
#### First-Tier Testing
Serial single-gene testing can be considered in order of the likelihood of identifying a germline pathogenic variant (Table 1). Sequence analysis of the gene of interest is performed first.
#### Second-Tier Testing
For somatic mosaicism. If no germline pathogenic variant is found in any of the three genes, sequence analysis for AKT3 or PIK3R2 with methods to detect somatic mosaicism may be warranted and/or testing for a large duplication of 1q43-q44 that includes AKT3.
* Sequence analysis of DNA derived from saliva or skin (whether visibly affected or not) may detect a pathogenic variant not detected in DNA isolated from blood.
* Sensitivity to detect low-level mosaicism of a somatic pathogenic variant is theoretically greatest using massively parallel sequencing (also known as next-generation sequencing) in tissues other than blood, and in particular will be of high yield when analyzing affected tissues
For duplication of 1q43-q44 that includes AKT3. Because not all gene-targeted deletion/duplication methods are designed to size large CNVs, CMA is the most appropriate for detection of this duplication.
#### Testing to Consider
A multigene panel that includes AKT3, CCND2, PIK3R2, and other genes of interest (see Differential Diagnosis) may also be considered to detect germline and somatic variants in the MPPH-related genes. Note: (1) The genes included and the sensitivity of multigene panels vary by laboratory and are likely to change over time. (2) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests. (3) Somatic mosaicism for variants in the three MPPH-related genes may not be detected by all commercially available multigene panels due primarily to the inability to test tissues other than blood (e.g., skin or buccal cells) and/or technical limitations in detecting low-level mosaicism; thus, clinicians considering use of a multigene panel need to select a panel specifically optimized to detect mosaicism for the three MPPH-related genes.
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 MPPH Syndrome
View in own window
Gene 1Number of Persons w/Molecularly Confirmed MPPH Syndrome Attributed to a Pathogenic Variant in Gene 2Number of Pathogenic Variants 3 Detectable by Method
Sequence analysis 4CMA 5
AKT312/416/126/12 6
CCND212/4112/12NA
PIK3R217/4117/17 7, 8NA
1\.
See Table A. Genes and Databases for chromosome locus and protein.
2\.
References for the 41 patients with a molecularly confirmed diagnosis: Mirzaa et al [2012], Poduri et al [2012], Rivière et al [2012], Wang et al [2013], Chung et al [2014], Jamuar et al [2014], Mirzaa et al [2014], Nakamura et al [2014], Tapper et al [2014], Conti et al [2015], Harada et al [2015], Nellist et al [2015], Hemming et al [2016], Terrone et al [2016]. Note that the other 23 individuals with a clinical diagnosis of MPPH syndrome did not undergo the complete molecular and cytogenetic testing required to detect the range of causative germline and somatic pathogenic variants.
3\.
See Molecular Genetics for information on allelic variants detected in this gene.
4\.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
5\.
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 1q44 region.
6\.
Duplications of 1q43-q44, which include AKT3, are detectable by CMA and cause macrocephaly and intellectual disability [Chung et al 2014, Wang et al 2013, Hemming et al 2016]. Somatic duplication of this locus has been identified in individuals with hemimegalencephaly and focal cortical dysplasia [Poduri et al 2012, Jamuar et al 2014, Conti et al 2015]. Although these large duplications would be detected by gene-targeted deletion/duplication assays, some methods would be unable to size the duplication.
7\.
Mosaicism for a PIK3R2 pathogenic variant has been reported in individuals with MPPH syndrome [Mirzaa et al 2015].
8\.
Most individuals with a PIK3R2 pathogenic variant have the same recurrent p.Gly373Arg variant. Only three other PIK3R2 pathogenic variants have been reported to date [Nakamura et al 2014, Mirzaa et al 2015, Terrone et al 2016].
## Clinical Characteristics
### Clinical Description
The MPPH syndrome is a developmental brain disorder characterized by megalencephaly (brain overgrowth) with the cortical malformation bilateral perisylvian polymicrogyria. Males and females are affected similarly.
To date 62 individuals with features of MPPH syndrome have been reported with either a clinical diagnosis (presence of the two core clinical and imaging findings: megalencephaly and polymicrogyria) , and/or a molecularly confirmed diagnosis (Table 1) [Mirzaa et al 2004, Colombani et al 2006, Garavelli et al 2007, Tohyama et al 2007, Pisano et al 2008, Tore et al 2009, Verkerk et al 2010, Osterling et al 2011, Mirzaa et al 2012, Rivière et al 2012, Kariminejad et al 2013, Zamora & Roberts 2013, Mirzaa et al 2014, Nakamura et al 2014, Tapper et al 2014, Demir et al 2015, Mirzaa et al 2015, Nellist et al 2015, Terrone et al 2016].
#### Neurologic Findings
Megalencephaly (brain overgrowth). Most individuals with MPPH syndrome reported to date have congenital or early postnatal megalencephaly (i.e., rapidly progressive megalencephaly within the first year of life).
Occipital frontal circumference (OFC) at birth ranges from normal to 6 SD above the mean for age, sex, and gestational age.
Later OFCs range from 3 to 10 SD above the mean.
In individuals with MPPH syndrome who develop hydrocephalus, brain overgrowth persists after surgical intervention (e.g., neurosurgical shunting), an observation consistent with true brain overgrowth [Mirzaa et al 2012].
Cortical malformations. To date, all individuals with MPPH syndrome have cortical brain malformations, particularly polymicrogyria (PMG). In almost all instances, the PMG is bilateral perisylvian polymicrogyria (BPP) and is largely symmetric. BPP is associated with neurologic problems that can include oromotor dysfunction, epilepsy, and intellectual disability.
Ventriculomegaly and hydrocephalus. Variable degrees of ventriculomegaly are seen in almost all children with MPPH syndrome. Nearly 50% of reported individuals with MPPH syndrome have frank hydrocephalus requiring neurosurgical placement of a shunt. Based on limited retrospective data, the risk for hydrocephalus and/or cerebellar tonsillar ectopia with low brain stem or high spinal cord compression appears to be highest in the first two years of life [Mirzaa et al 2012].
Oromotor dysfunction, including expressive language or speech delay, difficulties handing oral secretions (with profuse drooling), and dysphagia is seen in most individuals with MPPH syndrome. These features are largely attributed to (and well-known to occur with) bilateral perisylvian polymicrogyria [Mirzaa et al 2015].
Epilepsy. Approximately 50% of individuals with MPPH syndrome have early-onset epilepsy. Epilepsy types range from focal to generalized. Eight children with infantile spasms have been reported. Epilepsy may be refractory to several antiepileptic drugs. One individual with an AKT3 pathogenic variant had severe refractory infantile spasms that responded to a ketogenic diet [Nellist et al 2015].
Tone abnormalities, particularly hypotonia, are present at birth in most infants. Although tone may improve with age, several older individuals have remained severely hypotonic.
Intellectual disability. Almost all reported individuals with MPPH syndrome have intellectual disability that ranges from mild to severe. The degree of intellectual disability is largely determined by the following:
* Extent and severity of the cortical malformations (i.e., severity and distribution of PMG) (see Phenotype Correlations by Gene)
* Age of onset and severity of epilepsy. Early-onset epilepsy (particularly in the newborn period), and generalized epilepsy are typically associated with more severe developmental and cognitive issues.
#### Other Findings
Postaxial polydactyly involving from one to all four extremities has been reported in 50% of children with MPPH syndrome.
Additional clinical features
* Common
* Feeding difficulties (occasionally requiring gastrostomy tube placement)
* Visual problems (including cortical visual impairment and blindness)
* Seen in <5 individuals each
* Congenital cardiovascular defects (including ventricular septal defect, atrial septal defect)
* Thyroid problems (including hypothyroidism, Hashimoto thyroiditis)
* Renal anomalies (e.g., duplicated renal collecting system)
* Seen in one individual only
* Medulloblastoma [Osterling et al 2011]
* Encephalocele, cleft palate, and multiple polyps of the tongue [Demir et al 2015]
### Phenotype Correlations by Gene
AKT3. Features including connective tissue laxity and cutaneous capillary malformations can overlap with the megalencephaly-capillary malformation (MCAP) syndrome (see Differential Diagnosis) [Mirzaa et al 2012, Rivière et al 2012, Nakamura et al 2014, Nellist et al 2015].
CCND2. Polymicrogyria (PMG) appears to be more severe and widespread, typically extending to the frontal and/or occipital lobes. These extensive cortical malformations correlate with increased severity of epilepsy and intellectual disability [Mirzaa et al 2014].
Postaxial polydactyly is more commonly observed than with mutation of either PIK3R2 or AKT3 [Mirzaa et al 2014].
### Genotype-Phenotype Correlations
In general no differences in phenotype have been observed between individuals with a molecularly confirmed diagnosis and those with a clinical diagnosis only. The exceptions are several individuals with a molecularly confirmed diagnosis of MPPH syndrome who had bilateral perisylvian polymicrogyria but lacked the core clinical feature of megalencephaly [Mirzaa et al 2015].
### Penetrance
Although penetrance for MPPH syndrome is expected to be high, to date it cannot be definitively determined to be 100% due to the identification of low-level mosaic somatic PIK3R2 pathogenic variants in individuals who have only one of the core features (i.e., bilateral perisylvian polymicrogyria) [Mirzaa et al 2015].
### Prevalence
MPPH syndrome has been reported to date in 62 individuals from various ethnic backgrounds. Therefore, data regarding prevalence are limited.
## Differential Diagnosis
### Table 3.
Disorders to Consider in the Differential Diagnosis of MPPH Syndrome
View in own window
DisorderGeneMOIClinical Features of the Disorder
Also in MPPH syndromeNot in MPPH syndrome
MCAP syndrome (See PIK3CA-Related Segmental Overgrowth.)PIK3CADe novo / mosaic 1
* MEG (congenital or postnatal)
* BPP
* Postaxial polydactyly
* Ventriculomegaly or hydrocephalus
* Somatic vascular malformations (capillary malformations, often multiple)
* Somatic overgrowth (focal segmental)
PTEN hamartoma tumor syndromePTENDe novo / AD
* MEG (congenital or postnatal)
* Focal segmental cortical malformations (rare)
* Papillomatous papules
* Trichilemmomas
* Vascular malformations (hemangiomas, arteriovenous malformations)
* ↑ cancer predisposition (thyroid, breast, endometrium)
MTOR-related disorders 2MTORDe novo / mosaic
* MEG (congenital or postnatal)
* FCD
* Pigmentary mosaicism 2
STRADA-related disorders (OMIM 611087)STRADA (LYK5)AR
* MEG (congenital or postnatal)
* Early-onset epilepsy
* Early lethality
* Uniformly poor neurodevelopmental outcome
AD = autosomal dominant; AR = autosomal recessive; BPP = bilateral perisylvian polymicrogyria; FCD = focal cortical dysplasia; MCAP = megalencephaly-capillary malformation; MEG = megalencephaly; MOI = mode(s) of inheritance
1\.
MCAP is not typically inherited; to date most affected individuals (21/24) had somatic mosaicism for a PIK3CA pathogenic variant, suggesting that the variant occurred post-fertilization in one cell of the multicellular embryo.
2\.
Mirzaa et al [2016]
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with megalencephaly-postaxial polydactyly-polymicrogyria-hydrocephalus (MPPH) syndrome, the following evaluations are recommended:
* Physical examination with particular attention to head size (OFC)
* In the presence of hydrocephalus and/or cerebellar tonsillar ectopia, full spinal MRI to evaluate for syringomyelia or syrinx formation
* Assessment by a pediatric neurologist with evaluation of suspected seizures as indicated
* Assessment of feeding by a feeding specialist, nutritionist, and gastroenterologist for evidence of chewing and swallowing difficulties and dysphagia
* Developmental assessment
* Echocardiogram (to evaluate for structural cardiac defects)
* Renal ultrasound examination (to evaluate for structural renal defects)
* Consultation with a clinical geneticist and/or genetic counselor
### Treatment of Manifestations
Neurosurgical complications (hydrocephalus and cerebellar tonsillar ectopia). Findings warranting neurosurgical referral include rapidly enlarging OFC, obstructive hydrocephalus, symptoms of increased intracranial pressure, and progressive or symptomatic cerebellar tonsillar ectopia (CBTE) or Chiari malformation. Early treatment of hydrocephalus may reduce the risk for progressive CBTE, but data to determine the most appropriate neurosurgical management are lacking.
Feeding difficulties such as chewing and swallowing difficulties and dysphagia require evaluation by a feeding specialist and/or gastroenterologist to promote early identification and prompt intervention which may include dietary modification and/or placement of a gastrostomy (G) tube.
Speech therapy is indicated for difficulties with speech, swallowing, and feeding.
Epilepsy may require long-term antiepileptic treatment.
Developmental delays. Initiation of physical, occupational, and speech therapy is recommended within the first year of life.
### Surveillance
Given the limited number of individuals reported with MPPH syndrome, no formal surveillance guidelines exist; however, recommended surveillance includes the following:
* Follow-up with a pediatric neurologist, at least every six months until age six years, and annually thereafter.
* Brain MRI to detect hydrocephalus and/or cerebellar tonsillar ectopia; provisionally recommended every six months from birth to age two years, and annually from age two to six years. In older individuals, the frequency should be based on prior results and clinical findings, with particular attention to apnea or other abnormal patterns of respiration, headaches, changes in gait, or other neurologic problems.
* Long-term neurologic follow up is recommended for management of epilepsy.
* Routine follow up with a developmental pediatrician is appropriate, given the high risk for developmental delays and/or intellectual disability.
### Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| MPPH Syndrome | c4302893 | 1,391 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK396098/ | 2021-01-18T21:13:03 | {"synonyms": ["Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome", "Megalencephaly-Postaxial Polydactyly-Polymicrogyria-Hydrocephalus Syndrome"]} |
This article is about the disease. For the parasite, see Loa loa.
"Eye worm" redirects here. For another parasitic nematode known as "eye worm", see Thelazia.
Loa loa
Other namesloiasis, loaiasis, Calabar swellings, fugitive swelling, tropical swelling,[1]:439 African eyeworm
Loa loa microfilaria in thin blood smear (Giemsa stain)
SpecialtyInfectious disease
Loa loa filariasis is a skin and eye disease caused by the nematode worm Loa loa. Humans contract this disease through the bite of a deer fly or mango fly (Chrysops spp), the vectors for Loa loa. The adult Loa loa filarial worm migrates throughout the subcutaneous tissues of humans, occasionally crossing into subconjunctival tissues of the eye where it can be easily observed. Loa loa does not normally affect one's vision but can be painful when moving about the eyeball or across the bridge of the nose.[2][3] The disease can cause red itchy swellings below the skin called "Calabar swellings". The disease is treated with the drug diethylcarbamazine (DEC), and when appropriate, surgical methods may be employed to remove adult worms from the conjunctiva. Loiasis belongs to the so-called neglected diseases.[4]
## Contents
* 1 Signs and symptoms
* 2 Cause
* 2.1 Transmission
* 2.2 Reservoir
* 2.3 Vector
* 2.4 Morphology
* 2.5 Lifecycle
* 3 Diagnosis
* 4 Prevention
* 5 Treatment
* 6 Epidemiology
* 7 History
* 8 Synonyms
* 9 References
* 10 External links
## Signs and symptoms[edit]
A filariasis such as loiasis most often consists of asymptomatic microfilaremia. Some patients can develop lymphatic dysfunction causing lymphedema. Episodic angioedema (Calabar swellings) in the arms and legs, caused by immune reactions, are common. Calabar swellings are 3–10 cm in surface area, sometimes erythematous, and not pitting. When chronic, they can form cyst-like enlargements of the connective tissue around the sheaths of muscle tendons, becoming very painful when moved. The swellings may last for one to three days and may be accompanied by localized urticaria (skin eruptions) and pruritus (itching). They reappear at referent locations at irregular time intervals. Subconjunctival migration of an adult worm to the eyes can also occur frequently, and this is the reason Loa loa is also called the "African eye worm." The passage over the eyeball can be sensed, but it usually takes less than 15 minutes. Eyeworms affect men and women equally, but advanced age is a risk factor. Eosinophilia is often prominent in filarial infections. Dead worms may cause chronic abscesses, which may lead to the formation of granulomatous reactions and fibrosis.[citation needed]
In the human host, Loa loa larvae migrate to the subcutaneous tissue, where they mature to adult worms in approximately one year, but sometimes up to four years. Adult worms migrate in the subcutaneous tissues at a speed less than 1 cm/min, mating and producing more microfilariae. The adult worms can live up to 17 years in the human host.[5]
## Cause[edit]
### Transmission[edit]
Loa loa infective larvae (L3) are transmitted to humans by the deer fly vectors Chrysops silica and C. dimidiata. These carriers are blood-sucking and day-biting, and they are found in rainforest-like environments in western and central Africa. Infective larvae (L3) mature to adults (L5) in the subcutaneous tissues of the human host, after which the adult worms—assuming presence of a male and female worm—mate and produce microfilariae. The cycle of infection continues when a non-infected mango or deer fly takes a blood meal from a microfilaremic human host, and this stage of the transmission is possible because of the combination of the diurnal periodicity of microfilariae and the day-biting tendencies of the Chrysops spp.[5]
### Reservoir[edit]
Humans are the primary reservoir for Loa loa. Other minor potential reservoirs have been indicated in various fly-biting habit studies, such as hippopotamus, wild ruminants (e.g. buffalo), rodents and lizards. A simian type of loiasis exists in monkeys and apes but it is transmitted by Chrysops langi. There is no crossover between the human and simian types of the disease.[6] A related fly, Chrysops langi, has been isolated as a vector of simian loiasis, but this variant hunts within the forest and has not as yet been associated with human infection.[6]
### Vector[edit]
Loa loa is transmitted by several species of tabanid flies (Order: Diptera; Family: Tabanidae). Although horseflies of the genus Tabanus are often mentioned as vectors, the two most prominent vectors are from the tabanid genus Chrysops—C. silacea and C. dimidiata. These species exist only in Africa and are popularly known as deer flies and mango, or mangrove, flies.[7]
Chrysops spp are small (5–20 mm long) with a large head and downward-pointing mouthparts.[5][7] Their wings are clear or speckled brown. They are hematophagous and typically live in forested and muddy habitats like swamps, streams and reservoirs, and in rotting vegetation. Female mango and deer flies require a blood meal for production of a second batch of eggs. This batch is deposited near water, where the eggs hatch in 5–7 days. The larvae mature in water or soil,[5] where they feed on organic material such as decaying animal and vegetable products. Fly larvae are 1–6 cm long and take 1–3 years to mature from egg to adult.[7] When fully mature, C. silacea and C. dimidiata assume the day-biting tendencies of all tabanids.[5]
The bite of the mango fly can be very painful, possibly because of the laceration style employed; rather than puncturing the skin as a mosquito does, the mango fly (and deer fly) makes a laceration in the skin and subsequently laps up the blood. Female flies require a fair amount of blood for their aforementioned reproductive purposes and thus may take multiple blood meals from the same host if disturbed during the first one.[5]
Although Chrysops silacea and C. dimidiata are attracted to canopied rainforests, they do not do their biting there. Instead, they leave the forest and take most blood meals in open areas. The flies are attracted to smoke from wood fires and they use visual cues and sensation of carbon dioxide plumes to find their preferred host, humans.[6]
A study of Chrysops spp biting habits showed that C. silacea and C. dimidiata take human blood meals approximately 90% of the time, with hippopotamus, wild ruminant, rodent and lizard blood meals making up the other 10%.[6]
### Morphology[edit]
Adult Loa worms are sexually dimorphic, with males considerably smaller than females at 30–34 mm long and 0.35–0.42 mm wide compared to 40–70 mm long and 0.5 mm wide. Adults live in the subcutaneous tissues of humans, where they mate and produce wormlike eggs called microfilariae. These microfilariae are 250–300 μm long, 6–8 μm wide and can be distinguished morphologically from other filariae, as they are sheathed and contain body nuclei that extend to the tip of the tail.[3]
### Lifecycle[edit]
Loa loa life cycle. Source: CDC
The vector for Loa loa filariasis originates with flies from two hematophagous species of the genus Chrysops (deer flies), C. silacea and C. dimidiata. During a blood meal, an infected fly (genus Chrysops, day-biting flies) introduces third-stage filarial larvae onto the skin of the human host, where they penetrate into the bite wound. The larvae develop into adults that commonly reside in subcutaneous tissue. The female worms measure 40 to 70 mm in length and 0.5 mm in diameter, while the males measure 30 to 34 mm in length and 0.35 to 0.43 mm in diameter. Adults produce microfilariae measuring 250 to 300 μm by 6 to 8 μm, which are sheathed and have diurnal periodicity. Microfilariae have been recovered from spinal fluids, urine and sputum. During the day, they are found in peripheral blood, but during the noncirculation phase, they are found in the lungs. The fly ingests microfilariae during a blood meal. After ingestion, the microfilariae lose their sheaths and migrate from the fly's midgut through the hemocoel to the thoracic muscles of the arthropod. There the microfilariae develop into first-stage larvae and subsequently into third-stage infective larvae. The third-stage infective larvae migrate to the fly's proboscis and can infect another human when the fly takes a blood meal.[citation needed]
## Diagnosis[edit]
Microscopic examination of microfilariae is a practical diagnostic procedure to find Loa loa. It is important to time the blood collection with the known periodicity of the microfilariae (between 10:00 a.m. and 2:00 p.m.).[8] The blood sample can be a thick smear, stained with Giemsa or haematoxylin and eosin (see staining). For increased sensitivity, concentration techniques can be used. These include centrifugation of the blood sample lyzed in 2% formalin (Knott's technique), or filtration through a nucleopore membrane.
Antigen detection using an immunoassay for circulating filarial antigens constitutes a useful diagnostic approach, because microfilaremia can be low and variable. Though the Institute for Tropical Medicine reports that no serologic diagnostics are available,[9] tests that are highly specific to Loa loa have been developed in recent years. This is despite the fact that many recently developed methods of antibody detection are of limited value because substantial antigenic cross-reactivity exists between filaria and other parasitic worms (helminths), and that a positive serologic test does not necessarily distinguish among infections. The new tests have not reached the point-of-care level yet, but show promise for highlighting high-risk areas and individuals with co-endemic loiasis and onchocerciasis. Specifically, Dr. Thomas Nutman and colleagues at the National Institutes of Health have described the a luciferase immunoprecipitation assay (LIPS) and the related QLIPS (quick version). Whereas a previously described LISXP-1 ELISA test had a poor sensitivity (55%), the QLIPS test is practical, as it requires only a 15 minutes incubation, while delivering high sensitivity (97%) and specificity (100%).[10] No report on the distribution status of LIPS or QLIPS testing is available, but these tests would help to limit complications derived from mass ivermectin treatment for onchocerciasis or dangerous strong doses of diethylcarbamazine for loiasis alone (as pertains to individual with high Loa loa microfilarial loads).
Calabar swellings are the primary tool for visual diagnosis. Identification of adult worms is possible from tissue samples collected during subcutaneous biopsies. Adult worms migrating across the eye are another potential diagnostic, but the short timeframe for the worm's passage through the conjunctiva makes this observation less common.
In the past, healthcare providers used a provocative injection of Dirofilaria immitis as a skin-test antigen for filariasis diagnosis. If the patient was infected, the extract would cause an artificial allergic reaction and associated Calabar swelling similar to that caused, in theory, by metabolic products of the worm or dead worms.
Blood tests to reveal microfilaremia are useful in many, but not all cases, as one-third of loiasis patients are amicrofilaremic. By contrast, eosinophilia is almost guaranteed in cases of loiasis, and blood testing for eosinophil fraction may be useful.[3]
## Prevention[edit]
Diethylcarbamazine has been shown as an effective prophylaxis for Loa loa infection. A study of Peace Corps volunteers in the highly Loa—endemic Gabon, for example, had the following results: 6 of 20 individuals in a placebo group contracted the disease, compared to 0 of 16 in the DEC-treated group. Seropositivity for antifilarial IgG antibody was also much higher in the placebo group. The recommended prophylactic dose is 300 mg DEC given orally once weekly. The only associated symptom in the Peace Corps study was nausea.[11][12]
Researchers believe that geo-mapping of appropriate habitat and human settlement patterns may, with the use of predictor variables such as forest, land cover, rainfall, temperature, and soil type, allow for estimation of Loa loa transmission in the absence of point-of-care diagnostic tests.[13] In addition to geo-mapping and chemoprophylaxis, the same preventative strategies used for malaria should be undertaken to avoid contraction of loiasis. Specifically, DEET-containing insect repellent, permethrin-soaked clothing, and thick, long-sleeved and long-legged clothing ought to be worn to decrease susceptibility to the bite of the mango or deer fly vector. Because the vector is day-biting, mosquito (bed) nets do not increase protection against loiasis.[citation needed]
Vector elimination strategies are an interesting consideration. It has been shown that the Chrysops vector has a limited flying range,[14] but vector elimination efforts are not common, likely because the insects bite outdoors and have a diverse, if not long, range, living in the forest and biting in the open, as mentioned in the vector section.No vaccine has been developed for loiasis and there is little report on this possibility.[citation needed]
## Treatment[edit]
Treatment of loiasis involves chemotherapy or, in some cases, surgical removal of adult worms followed by systemic treatment. The current drug of choice for therapy is diethylcarbamazine (DEC), though ivermectin use while not curative (i.e., it will not kill the adult worms) can substantially reduce the microfilarial load. The recommended dosage of DEC is 8–10 mg/kg/d taken three times daily for 21 days per CDC. The pediatric dose is the same. DEC is effective against microfilariae and somewhat effective against macrofilariae (adult worms).[15] The recommended dosage of ivermectin is 150 µg/kg in patients with a low microfilaria load (with densities less than 8000 mf/mL).
In patients with high microfilaria load and/or the possibility of an onchocerciasis coinfection, treatment with DEC and/or ivermectin may be contraindicated or require a substantially lower initial dose, as the rapid microfilaricidal actions of the drugs can provoke encephalopathy. In these cases, initial albendazole administration has proved helpful (and is superior to ivermectin, which can also be risky despite its slower-acting microfilaricidal effects over DEC).[15] The CDC recommended dosage for albendazole is 200 mg taken twice a day for 21 days. Also, in cases where two or more DEC treatments have failed to provide a cure, subsequent albendazole treatment can be administered.
Management of Loa loa infection in some instances can involve surgery, though the timeframe during which surgical removal of the worm must be carried out is very short. A detailed surgical strategy to remove an adult worm is as follows (from a real case in New York City). The 2007 procedure to remove an adult worm from a male Gabonian immigrant employed proparacaine and povidone-iodine drops, a wire eyelid speculum, and 0.5 ml 2% lidocaine with epinephrine 1:100,000, injected superiorly. A 2-mm incision was made and the immobile worm was removed with forceps. Gatifloxacin drops and an eye-patch over ointment were utilized post surgery and there were no complications (unfortunately, the patient did not return for DEC therapy to manage the additional worm—and microfilariae—present in his body).[16]
## Epidemiology[edit]
As of 2009, loiasis is endemic to 11 countries, all in western or central Africa, and an estimated 12–13 million people have the disease. The highest incidence is seen in Cameroon, Republic of the Congo, Democratic Republic of Congo, Central African Republic, Nigeria, Gabon, and Equatorial Guinea. The rates of Loa loa infection are lower but it is still present in and Angola, Benin, Chad and Uganda. The disease was once endemic to the western African countries of Ghana, Guinea, Guinea Bissau, Ivory Coast and Mali but has since disappeared.[11]
Throughout Loa loa-endemic regions, infection rates vary from 9 to 70 percent of the population.[3] Areas at high risk of severe adverse reactions to mass treatment (with Ivermectin) are at present determined by the prevalence in a population of >20% microfilaremia, which has been recently shown in eastern Cameroon (2007 study), for example, among other locales in the region.[11]
Endemicity is closely linked to the habitats of the two known human loiasis vectors, Chrysops dimidiata and C. silicea.
Cases have been reported on occasion in the United States but are restricted to travelers who have returned from endemic regions.[16][17]
In the 1990s, the only method of determining Loa loa intensity was with microscopic examination of standardized blood smears, which is not practical in endemic regions. Because mass diagnostic methods were not available, complications started to surface once mass ivermectin treatment programs started being carried out for onchocerciasis, another filariasis. Ivermectin, a microfilaricidal drug, may be contraindicated in patients who are co-infected with loiasis and have associated high microfilarial loads. The theory is that the killing of massive numbers of microfilaria, some of which may be near the ocular and brain region, can lead to encephalopathy. Indeed, cases of this have been documented so frequently over the last decade that a term has been given for this set of complication: neurologic serious adverse events (SAEs).[18]
Advanced diagnostic methods have been developed since the appearance the SAEs, but more specific diagnostic tests that have been or are currently being development (see: Diagnostics) must to be supported and distributed if adequate loiasis surveillance is to be achieved.
There is much overlap between the endemicity of the two distinct filariases, which complicates mass treatment programs for onchocerciasis and necessitates the development of greater diagnostics for loiasis.
In Central and West Africa, initiatives to control onchocerciasis involve mass treatment with Ivermectin. However, these regions typically have high rates of co-infection with both L. loa and O. volvulus, and mass treatment with Ivermectin can have severe adverse effects (SAE). These include hemorrhage of the conjunctiva and retina, heamaturia, and other encephalopathies that are all attributed to the initial L. loa microfilarial load in the patient prior to treatment. Studies have sought to delineate the sequence of events following Ivermectin treatment that lead to neurologic SAE and sometimes death, while also trying to understand the mechanisms of adverse reactions to develop more appropriate treatments.
In a study looking at mass Ivermectin treatment in Cameroon, one of the greatest endemic regions for both onchocerciasis and loiasis, a sequence of events in the clinical manifestation of adverse effects was outlined.
It was noted that the patients used in this study had a L. loa microfilarial load of greater than 3,000 per ml of blood.
Within 12–24 hours post-Ivermectin treatment (D1), individuals complained of fatigue, anorexia, and headache, joint and lumbar pain—a bent forward walk was characteristic during this initial stage accompanied by fever. Stomach pain and diarrhea were also reported in several individuals.
By day 2 (D2), many patients experienced confusion, agitation, dysarthria, mutism and incontinence. Some cases of coma were reported as early as D2. The severity of adverse effects increased with higher microfilarial loads. Hemorrhaging of the eye, particularly the retinal and conjunctiva regions, is another common sign associated with SAE of Ivermectin treatment in patients with L. loa infections and is observed between D2 and D5 post-treatment. This can be visible for up to 5 weeks following treatment and has increased severity with higher microfilarial loads.
Haematuria and proteinuria have also been observed following Ivermectin treatment, but this is common when using Ivermectin to treat onchocerciasis. The effect is exacerbated when there are high L. loa microfilarial loads however, and microfilariae can be observed in the urine occasionally. Generally, patients recovered from SAE within 6–7 months post-Ivermectin treatment; however, when their complications were unmanaged and patients were left bed-ridden, death resulted due to gastrointestinal bleeding, septic shock, and large abscesses.[19]
Mechanisms for SAE have been proposed. Though microfilarial load is a major risk factor to post-Ivermectin SAE, three main hypotheses have been proposed for the mechanisms.
The first mechanism suggests that Ivermectin causes immobility in microfilariae, which then obstructs microcirculation in cerebral regions. This is supported by the retinal hemorrhaging seen in some patients, and is possibly responsible for the neurologic SAE reported.
The second hypothesis suggests that microfilariae may try to escape drug treatment by migrating to brain capillaries and further into brain tissue; this is supported by pathology reports demonstrating a microfilarial presence in brain tissue post-Ivermectin treatment.
Lastly, the third hypothesis attributes hypersensitivity and inflammation at the cerebral level to post-Ivermectin treatment complications, and perhaps the release of bacteria from L. loa after treatment to SAE. This has been observed with the bacteria Wolbachia that live with O. volvulus.
More research into the mechanisms of post-Ivermectin treatment SAE is needed to develop drugs that are appropriate for individuals suffering from multiple parasitic infections.[19]
One drug that has been proposed for the treatment of onchocerciasis is doxycycline. This drug has been shown to be effective in killing both the adult worm of O. volvulus and Wolbachia, the bacteria believed to play a major role in the onset of onchocerciasis, while having no effect on the microfilariae of L. loa. In a study done at 5 different co-endemic regions for onchocerciasis and loiasis, doxycycline was shown to be effective in treating over 12,000 individuals infected with both parasites with minimal complications. Drawbacks to using Doxycycline include bacterial resistance and patient compliance because of a longer treatment regimen and emergence of doxycycline-resistant Wolbachia. However, in the study over 97% of the patients complied with treatment, so it does pose as a promising treatment for onchocerciasis, while avoiding complications associated with L. loa co-infections.[20]
Human loiasis geographical distribution is restricted to the rain forest and swamp forest areas of West Africa, being especially common in Cameroon and on the Ogooué River. Humans are the only known natural reservoir. It is estimated that over 10 million humans are infected with Loa loa larvae.[21]
An area of tremendous concern regarding loiasis is its co-endemicity with onchocerciasis in certain areas of west and central Africa, as mass ivermectin treatment of onchocerciasis can lead to serious adverse events (SAEs) in patients who have high Loa loa microfilarial densities, or loads. This fact necessitates the development of more specific diagnostics tests for Loa loa so that areas and individuals at a higher risk for neurologic consequences can be identified prior to microfilaricidal treatment. Additionally, the treatment of choice for loiasis, diethylcarbamazine, can lead to serious complications in and of itself when administered in standard doses to patients with high Loa loa microfilarial loads.[3]
## History[edit]
The first case of Loa loa infection was noted in the Caribbean (Santo Domingo) in 1770. A French surgeon named Mongin tried but failed to remove a worm passing across a woman's eye. A few years later, in 1778, the surgeon François Guyot noted worms in the eyes of West African slaves on a French ship to America; he successfully removed a worm from one man's eye.
The identification of microfilariae was made in 1890 by the ophthalmologist Stephen McKenzie. Localized angioedema, a common clinical presentation of loiasis, was observed in 1895 in the coastal Nigerian town of Calabar—hence the name "Calabar" swellings. This observation was made by a Scottish ophthalmologist named Douglas Argyll-Robertson, but the association between Loa loa and Calabar swellings was not realized until 1910 (by Dr. Patrick Manson). The determination of vector—Chrysops spp.—was made in 1912 by the British parasitologist Robert Thomson Leiper.[22]
## Synonyms[edit]
Synonyms for the disease include African eye worm, loaiasis, loaina, Loa loa filariasis, filaria loa, filaria lacrimalis, filaria subconjunctivalis, Calabar swellings, Fugitive swellings, and microfilaria diurnal.[11] Loa loa, the scientific name for the infectious agent, is an indigenous term itself and it is likely that there are many other terms used from region to region.
## References[edit]
1. ^ James, William D.; Berger, Timothy G. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6.
2. ^ Osuntokun O, Olurin O (March 1975). "Filarial worm (Loa loa) in the anterior chamber. Report of two cases". Br J Ophthalmol. 59 (3): 166–67. doi:10.1136/bjo.59.3.166. PMC 1017374. PMID 1131358.
3. ^ a b c d e John, David T. and William A. Petri, Jr. Markell and Voge's Medical Parasitology. 9th ed. 2006.
4. ^ Metzger, Wolfram Gottfried; Mordmüller, Benjamin (April 2014). "Loa loa—does it deserve to be neglected?". The Lancet Infectious Diseases. 14 (4): 353–357. doi:10.1016/S1473-3099(13)70263-9. PMID 24332895.
5. ^ a b c d e f Padgett JJ, Jacobsen KH (October 2008). "Loiasis: African eye worm". Trans. R. Soc. Trop. Med. Hyg. 102 (10): 983–89. doi:10.1016/j.trstmh.2008.03.022. PMID 18466939.
6. ^ a b c d Gouteux JP, Noireau F, Staak C (April 1989). "The host preferences of Chrysops silacea and C. dimidiata (Diptera: Tabanidae) in an endemic area of Loa loa in the Congo". Ann Trop Med Parasitol. 83 (2): 167–72. doi:10.1080/00034983.1989.11812326. PMID 2604456.
7. ^ a b c World Health Organization (WHO). Vector Control – Horseflies and deerflies (tabanids). 1997.
8. ^ Parasites – Loiasis, https://www.cdc.gov/parasites/loiasis/diagnosis.html
9. ^ "Loiasis." 2009. The Institute of Tropical Medicine. Available online at: http://www.itg.be/itg/distancelearning/lecturenotesvandenendene/41_Filariasisp5.htm Archived 2008-12-02 at the Wayback Machine.
10. ^ Burbelo PD, Ramanathan R, Klion AD, Iadarola MJ, Nutman TB (July 2008). "Rapid, Novel, Specific, High-Throughput Assay for Diagnosis of Loa loa Infection". J. Clin. Microbiol. 46 (7): 2298–304. doi:10.1128/JCM.00490-08. PMC 2446928. PMID 18508942.
11. ^ a b c d The Gideon Online.
12. ^ Nutman, TB, KD Miller, M Mulligan, GN Reinhardt, BJ currie, C Steel, and EA Ottesen. "Diethylcarbamazine prophylaxis for human loiasis. Results of a double-blind study."New Eng J Med. (1988), 319: 752–56.
13. ^ Thomson MC, Obsomer V, Dunne M, Connor SJ, Molyneux DH (September 2000). "Satellite mapping of Loa loa prevalence in relation to ivermectin use in west and central Africa". Lancet. 356 (9235): 1077–78. doi:10.1016/S0140-6736(00)02733-1. PMID 11009145. S2CID 11743223.
14. ^ Chippaux JP, Bouchité B, Demanou M, Morlais I, Le Goff G (September 2000). "Density and dispersal of the loaiasis vector Chrysops dimidiata in southern Cameroon". Med. Vet. Entomol. 14 (3): 339–44. doi:10.1046/j.1365-2915.2000.00249.x. PMID 11016443.
15. ^ a b The Medical Letter – Filariasis. Available online at: "Archived copy" (PDF). Archived from the original (PDF) on 2009-01-15. Retrieved 2009-02-27.CS1 maint: archived copy as title (link).
16. ^ a b Nam, Julie N., Shanian Reddy, and Norman C. Charles. "Surgical Management of Conjunctival Loiasis." Ophthal Plastic Reconstr Surg. (2008). Vol 24(4): 316–17.
17. ^ Grigsby, Margaret E. and Donald H. Keller. "Loa-loa in the District of Columbia." J Narl Med Assoc. (1971), Vol 63(3): 198–201.
18. ^ Kamgno J, Boussinesq M, Labrousse F, Nkegoum B, Thylefors BI, Mackenzie CD (April 2008). "Encephalopathy after ivermectin treatment in a patient infected with Loa loa and Plasmodium spp". Am. J. Trop. Med. Hyg. 78 (4): 546–51. doi:10.4269/ajtmh.2008.78.546. PMID 18385346.
19. ^ a b 1.Boussinesq, M., Gardon, J., Gardon-Wendel, N., and J. Chippaux. 2003. Clinical picture, epidemiology and outcome of Loa-associated serious adverse events related to mass ivermectin treatment of onchocerciasis in Cameroon. Filaria Journal 2: 1–13.
20. ^ 2\. Wanji, S., Tendongfor, N., Nji, T., Esum, M., Che, J. N., Nkwescheu, A., Alassa, F., Kamnang, G., Enyong, P. A., Taylor, M. J., Hoerauf, A., and D. W. Taylor. 2009. Community-directed delivery of doxycycline for the treatment of onchocerciasis in areas of co-endemicity with loiasis in Cameroon. Parasites & Vectors. 2(39): 1–10.
21. ^ Metzger, Wolfram Gottfried; Benjamin Mordmüller (2013). "Loa loa – does it deserve to be neglected?". The Lancet Infectious Diseases. 14 (4): 353–357. doi:10.1016/S1473-3099(13)70263-9. ISSN 1473-3099. PMID 24332895.
22. ^ Cox FE (October 2002). "History of Human Parasitology". Clin. Microbiol. Rev. 15 (4): 595–612. doi:10.1128/CMR.15.4.595-612.2002. PMC 126866. PMID 12364371.
## External links[edit]
Classification
D
* ICD-10: B74.3
* ICD-9-CM: 125.2
* MeSH: D008118
* DiseasesDB: 7576
External resources
* eMedicine: derm/888 med/794
* v
* t
* e
Parasitic disease caused by helminthiases
Flatworm/
platyhelminth
infection
Fluke/trematode
(Trematode infection)
Blood fluke
* Schistosoma mansoni / S. japonicum / S. mekongi / S. haematobium / S. intercalatum
* Schistosomiasis
* Trichobilharzia regenti
* Swimmer's itch
Liver fluke
* Clonorchis sinensis
* Clonorchiasis
* Dicrocoelium dendriticum / D. hospes
* Dicrocoeliasis
* Fasciola hepatica / F. gigantica
* Fasciolosis
* Opisthorchis viverrini / O. felineus
* Opisthorchiasis
Lung fluke
* Paragonimus westermani / P. kellicotti
* Paragonimiasis
Intestinal fluke
* Fasciolopsis buski
* Fasciolopsiasis
* Metagonimus yokogawai
* Metagonimiasis
* Heterophyes heterophyes
* Heterophyiasis
Cestoda
(Tapeworm infection)
Cyclophyllidea
* Echinococcus granulosus / E. multilocularis
* Echinococcosis
* Taenia saginata / T. asiatica / T. solium (pork)
* Taeniasis / Cysticercosis
* Hymenolepis nana / H. diminuta
* Hymenolepiasis
Pseudophyllidea
* Diphyllobothrium latum
* Diphyllobothriasis
* Spirometra erinaceieuropaei
* Sparganosis
* Diphyllobothrium mansonoides
* Sparganosis
Roundworm/
Nematode
infection
Secernentea
Spiruria
Camallanida
* Dracunculus medinensis
* Dracunculiasis
Spirurida
Filarioidea
(Filariasis)
* Onchocerca volvulus
* Onchocerciasis
* Loa loa
* Loa loa filariasis
* Mansonella
* Mansonelliasis
* Dirofilaria repens
* D. immitis
* Dirofilariasis
* Wuchereria bancrofti / Brugia malayi / |B. timori
* Lymphatic filariasis
Thelazioidea
* Gnathostoma spinigerum / G. hispidum
* Gnathostomiasis
* Thelazia
* Thelaziasis
Spiruroidea
* Gongylonema
Strongylida
(hookworm)
* Hookworm infection
* Ancylostoma duodenale / A. braziliense
* Ancylostomiasis / Cutaneous larva migrans
* Necator americanus
* Necatoriasis
* Angiostrongylus cantonensis
* Angiostrongyliasis
* Metastrongylus
* Metastrongylosis
Ascaridida
* Ascaris lumbricoides
* Ascariasis
* Anisakis
* Anisakiasis
* Toxocara canis / T. cati
* Visceral larva migrans / Toxocariasis
* Baylisascaris
* Dioctophyme renale
* Dioctophymosis
* Parascaris equorum
Rhabditida
* Strongyloides stercoralis
* Strongyloidiasis
* Trichostrongylus spp.
* Trichostrongyliasis
* Halicephalobus gingivalis
Oxyurida
* Enterobius vermicularis
* Enterobiasis
Adenophorea
* Trichinella spiralis
* Trichinosis
* Trichuris trichiura (Trichuriasis / Whipworm)
* Capillaria philippinensis
* Intestinal capillariasis
* C. hepatica
*[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
| Loa loa filariasis | c0023968 | 1,392 | wikipedia | https://en.wikipedia.org/wiki/Loa_loa_filariasis | 2021-01-18T18:30:33 | {"gard": ["3283"], "mesh": ["D008118"], "umls": ["C0023968"], "orphanet": ["2404"], "wikidata": ["Q1760607"]} |
A number sign (#) is used with this entry because of evidence that familial MTC occurs from mutation in the RET gene (164761) on chromosome 10. Familial MTC can also be caused by mutations in the NTRK1 gene (191315) located on 1q21-q22.
Description
Medullary thyroid carcinoma (MTC) is a malignant tumor of the calcitonin (114130)-secreting parafollicular C cells of the thyroid, and occurs sporadically or as a component of the multiple endocrine neoplasia (MEN) type 2 (see 171400)/familial medullary thyroid carcinoma (FMTC) syndromes (summary by Abu-Amero et al., 2006). Thyroid cancer derived from follicular epithelial cells is referred to as nonmedullary thyroid cancer and comprises several subtypes; see 188550.
Clinical Features
About 75% of medullary thyroid carcinoma is sporadic; these cases are unilateral. Bilateral multifocal medullary carcinoma is a cardinal feature of autosomal dominant multiple endocrine neoplasia type II (MEN2A; 171400). In addition, there are cases of familial medullary thyroid carcinoma in which there are no extrathyroid manifestations of multiple endocrine neoplasia; otherwise the behavior of the tumor is the same as that in the hereditary disease. Such families were observed by Farndon et al. (1986).
Primary localized cutaneous amyloidosis (PLCA), which has been observed with MEN2A, was reported also in a family in which multiple affected members had an association only with medullary thyroid carcinoma (Ferrer et al., 1991).
Rakover et al. (1994) described 2 sibs in whom isolated familial medullary carcinoma of the thyroid was diagnosed at the ages of 16 and 19 years. Hirschsprung disease was identified at the age of 1 year in both of them. Twelve other members of the family had medullary carcinoma of the thyroid. The authors stated that, although this was the first report of an association between Hirschsprung disease and isolated familial medullary carcinoma of the thyroid, the association should not be surprising because of the known association of both with mutations in the RET gene (164761).
Other Features
Lore et al. (2000, 2001) described a 4-generation family with medullary thyroid carcinoma associated with a heterozygous RET mutation (C620S; 164761.0041). One of these individuals was found to have absence of the left kidney. Her son was found to have Hirschsprung disease (142623) at a few months of age and had undergone surgical resection of the involved intestinal segment. Subsequently, he was found to have the RET mutation and at the age of 15 years underwent total thyroidectomy, which revealed medullary thyroid carcinoma. Abnormal ultrasonography revealed the absence of the left kidney in the son also. No renal abnormalities were found on abdominal ultrasonography of the other living members. Lore et al. (2001) concluded that MEN2 syndromes may be associated with renal malformations.
Biochemical Features
By RT-PCR, Maio et al. (2003) examined the expression of a number of genes encoding cancer/testis antigens (CTAs) in 23 surgical samples of sporadic MTC. Of 11 cDNA antigens examined, NYESO1 (300156) cDNA was the most frequent, being detected in 15 of 23 examined samples (65.2%). NYESO1 expression in primary MTC tissues significantly correlated with tumor recurrence. The presence of specific anti-NYESO1 antibodies was searched in the sera of MTC-affected patients examined by ELISA using recombinant NYESO1 protein. A humoral response against this CTA was detected in 6 of 11 NYESO1-expressing patients (54.5%), and in 1 of 6 patients with an NYESO1-negative tumor. Anti-NYESO1 antibodies were present in 15 of 42 sera (35.7%), demonstrating that MTC is a neoplasm frequently associated with humoral immune response to NYESO1.
Clinical Management
Machens et al. (2003) conducted a European multicenter study in which patients who had a RET point mutation in the germline were 20 years of age or younger, were asymptomatic, and had undergone total thyroidectomy after confirmation of the RET mutation. Altogether, 207 patients from 145 families were identified. There was a significant age-related progression from C cell hyperplasia to medullary thyroid carcinoma and, ultimately, lymph node metastasis in patients whose RET mutations were grouped according to the extracellular- and intracellular-domain codons affected and in those with mutations at codon 634 (e.g., 164761.0003). No lymph node metastases were noted in patients younger than 14 years. The age-related penetrance was unaffected by the type of amino acid substitution encoded by the various codon 634 mutations. The codon-specific differences in the age at presentation of cancer and the familial rates of concomitant adrenal and parathyroid involvement suggested that the risk of progression was based on the transforming potential of the individual RET mutations. These data provided initial guidelines for the timing of prophylactic thyroidectomy in asymptomatic carriers of RET gene mutations.
Cote and Gagel (2003) provided an optimistic review of the management of familial medullary thyroid carcinoma. They diagrammed the extracellular, transmembrane, and intracellular portions of the RET gene and presented a graph of the earliest reported age at onset of MTC according to the specific mutated RET codon.
Mapping
The linkage studies of Narod et al. (1989) appear to indicate conclusively that familial medullary carcinoma of the thyroid (without pheochromocytoma) is caused by an allele in the same gene that is the site of the mutation in MEN2. They studied 18 families, 9 with MEN2 and 9 with medullary carcinoma of the thyroid without pheochromocytoma, with probes specific for the pericentromeric region of chromosome 10 and found close linkage in both cases. Genetic heterogeneity of the susceptibility locus was not observed. The genetic mutation for medullary carcinoma was in disequilibrium with alleles of 2 closely linked marker loci.
In 2 large families with medullary thyroid carcinoma (MTC1), Lairmore et al. (1991) showed that the maximum lod score between the neoplasia and marker D10Z1 was 5.88 with 0% recombination. They found no evidence for genetic heterogeneity among families with medullary thyroid carcinoma, MEN2B (162300), or MEN2A. The mutations causing these disorders thus appear to be related to each other as alleles. On the other hand, Carson et al. (1991) reported 2 families in which the MTC mutation appeared not to be linked to the pericentromeric markers on chromosome 10.
Molecular Genetics
Gimm et al. (1999) used SSCP analysis of 16 exons of NTRK1 (191315) from 31 sporadic MTCs and observed variants in 5 exons (exons 4 and 14-17). Sequence analysis demonstrated 1 sequence variant each in exons 4, 14, 16, and 17, and 4 different variants in exon 15. Differential restriction enzyme digestion specific for each variant confirmed the sequencing results. All variants were also present in the corresponding germline DNA. Interestingly, the sequence variants at codon 604 (C1810T; 191315.0008) and codon 613 (G1838T; 191315.0009) of exon 15 always occurred together, possibly representing linkage disequilibrium. The frequencies of the sequence variants in germline DNA from patients with sporadic MTC did not differ significantly from those in a race-matched control group.
Marsh et al. (2003) identified chromosomal imbalances that occur in MTC including deletions of chromosomes 1p, 3q26.3-q27, 4, 9q13-q22, 13q, and 22q and amplifications of chromosome 19. These regions house known tumor suppressor genes as well as genes encoding subunits of the multicomponent complex of glycosylphosphatidylinositol-linked proteins (glial cell line-derived neurotrophic factor family receptors alpha-2-4; see 601496) and their ligands glial cell line-derived neurotrophic factor (600837), neurturin (602018), persephin (602921), and artemin (603886) that facilitate RET dimerization and downstream signaling. Chromosomal imbalances in the MTC cell line TT were largely identical to those identified in primary MTC tumors, consolidating its use as a model for studying MTC.
Abu-Amero et al. (2006) identified nonsynonymous germline mitochondrial DNA (mtDNA) mutations in both normal and tumor tissue from 20 (76.9%) of 26 cases of medullary thyroid carcinoma, including 9 (69.2%) of 13 sporadic cases and 11 (84.6%) of 13 familial cases; 10 of 13 familial cases were patients with MEN2. The familial cases tended to have transversion mtDNA mutations rather than transition mutations. All 13 familial cases also had germline RET mutations. Abu-Amero et al. (2006) suggested that mtDNA mutations may be involved in medullary thyroid carcinoma tumorigenesis and/or progression.
Nomenclature
Simpson (1991) proposed a branching classification of the forms of medullary thyroid carcinoma (MTC). MTC has 2 forms: MTC1 (with no other primary tumors) and MEN2. MEN2 has 2 forms: MEN2A and MEN2B. MEN2A has 3 forms: MEN2A-1 (MTC with pheochromocytoma and parathyroid tumor), MEN2A-2 (MTC with pheochromocytoma), and MEN2A-3 (MTC with parathyroid tumor).
Oncology \- Medullary thyroid carcinoma \- No other primary tumors Inheritance \- Autosomal dominant ▲ 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
| THYROID CARCINOMA, FAMILIAL MEDULLARY | c1833921 | 1,393 | omim | https://www.omim.org/entry/155240 | 2019-09-22T16:38:30 | {"doid": ["0050547"], "mesh": ["C536911"], "omim": ["155240"], "orphanet": ["99361", "653"], "synonyms": ["Alternative titles", "FMTC", "MTC1"], "genereviews": ["NBK1257"]} |
Berdon syndrome
Other namesMegacystis-microcolon-intestinal hypoperistalsis syndrome, MMIH syndrome, MMIHS
Berdon syndrome has an autosomal recessive pattern of inheritance.
SpecialtyMedical genetics
Berdon syndrome, also called Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIH syndrome),[1] is an autosomal recessive[2] fatal[3] genetic disorder affecting newborns. In a 2011 study of 227 children with the syndrome, "the oldest survivor [was] 24 years old."[3] The Ann Arbor News reported a five year old survivor at the end of 2015.[4]
It is more prevalent in females (7 females to 3 males)[3] and is characterized by constipation and urinary retention, microcolon, giant bladder (megacystis), intestinal hypoperistalsis, hydronephrosis and dilated small bowel. The pathological findings consist of an abundance of ganglion cells in both dilated and narrow areas of the intestine. It is a familial disturbance of unknown cause.
Walter Berdon et al. in 1976 first described[5] the condition in five female infants, two of whom were sisters. All had marked dilatation of the bladder and some had hydronephrosis and the external appearance of prune belly. The infants also had microcolon and dilated small intestines.
## Contents
* 1 Genetics
* 2 Diagnosis
* 3 Treatment
* 4 References
* 5 External links
## Genetics[edit]
Berdon syndrome is autosomal recessive, which means the defective gene is located on an autosome, and two copies of the gene – one inherited from each parent – are required to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene but are usually not affected by the disorder.[citation needed]
Several genes are known to be implicated in this syndrome: these include ACTG2, LMOD1, MYH11 and MYLK.[6]
## Diagnosis[edit]
Berdon syndrome is generally diagnosed after birth by the signs and symptoms as well as radiological and surgical findings. It can be diagnosed in the womb by ultrasound, revealing the enlarged bladder and hydronephrosis.[7]
## Treatment[edit]
Long-term survival with Berdon syndrome usually requires parenteral nutrition and urinary catheterisation or diversion. Most long-term survivors also have ileostomies.[8] A multivisceral transplant (stomach, pancreas, small bowel, liver and large intestine) has also been successful.[9]
## References[edit]
1. ^ Online Mendelian Inheritance in Man (OMIM): 249210
2. ^ Annerén, Göran; Meurling, Staffan; Olsen, Leif (1991). "Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), an autosomal recessive disorder: Clinical reports and review of the literature". American Journal of Medical Genetics. 41 (2): 251–4. doi:10.1002/ajmg.1320410224. PMID 1785644.
3. ^ a b c Gosemann, Jan-Hendrik; Puri, Prem (2011). "Megacystis microcolon intestinal hypoperistalsis syndrome: Systematic review of outcome". Pediatric Surgery International. 27 (10): 1041–6. doi:10.1007/s00383-011-2954-9. PMID 21792650. S2CID 27499683.
4. ^ "Ann Arbor boy, 5, overcomes rare diseases: 'He's a fighter'". 2015-12-24.
5. ^ Berdon, WE; Baker, DH; Blanc, WA; Gay, B; Santulli, TV; Donovan, C (1976). "Megacystis-microcolon-intestinal hypoperistalsis syndrome: A new cause of intestinal obstruction in the newborn. Report of radiologic findings in five newborn girls". American Journal of Roentgenology. 126 (5): 957–64. doi:10.2214/ajr.126.5.957. PMID 178239.
6. ^ Halim, Danny; Brosens, Erwin; Muller, Françoise; Wangler, Michael F; Beaudet, Arthur L; Lupski, James R; Akdemir, Zeynep H Coban; Doukas, Michael; Stoop, Hans J; De Graaf, Bianca M; Brouwer, Rutger WW; Van Ijcken, Wilfred FJ; Oury, Jean-François; Rosenblatt, Jonathan; Burns, Alan J; Tibboel, Dick; Hofstra, Robert MW; Alves, Maria M (2017). "Loss-of-Function Variants in MYLK Cause Recessive Megacystis Microcolon Intestinal Hypoperistalsis Syndrome". The American Journal of Human Genetics. 101 (1): 123–129. doi:10.1016/j.ajhg.2017.05.011. PMC 5501771. PMID 28602422.
7. ^ RESERVED, INSERM US14 -- ALL RIGHTS. "Orphanet: Megacystis microcolon intestinal hypoperistalsis hydronephrosis Berdon syndrome". www.orpha.net. Retrieved 2018-03-18.
8. ^ "Megacystis microcolon intestinal hypoperistalsis syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2018-03-17.
9. ^ America, Good Morning. "This teen is living her best life after surviving a rare 18-hour transplant surgery". Good Morning America. Retrieved 2019-08-26.
## External links[edit]
* Megacystis microcolon intestinal hypoperistalsis syndrome at NIH's Office of Rare Diseases
* Online Mendelian Inheritance in Man (OMIM): Megacystis microcolon intestinal hypoperistalsis syndrome; MMIH syndrome; Berdon syndrome - 249210
Classification
D
* OMIM: 249210
* MeSH: C536138
* DiseasesDB: 32131
*[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
| Berdon syndrome | c1608393 | 1,394 | wikipedia | https://en.wikipedia.org/wiki/Berdon_syndrome | 2021-01-18T19:10:57 | {"gard": ["3442"], "mesh": ["C536138"], "umls": ["C1608393"], "orphanet": ["2241"], "wikidata": ["Q4891136"]} |
Hippocampal sclerosis
Mesial Temporal Sclerosis
SpecialtyNeurology
Hippocampal sclerosis (HS) is a neuropathological condition with severe neuronal cell loss and gliosis in the hippocampus, specifically in the CA-1 (Cornu Ammonis area 1) and subiculum of the hippocampus. It was first described in 1880 by Wilhelm Sommer.[1] Hippocampal sclerosis is a frequent pathologic finding in community-based dementia. Hippocampal sclerosis can be detected with autopsy or MRI. Individuals with hippocampal sclerosis have similar initial symptoms and rates of dementia progression to those with Alzheimer's disease (AD) and therefore are frequently misclassified as having Alzheimer's Disease. But clinical and pathologic findings suggest that hippocampal sclerosis has characteristics of a progressive disorder although the underlying cause remains elusive.[2] A diagnosis of hippocampal sclerosis has a significant effect on the life of patients because of the notable mortality, morbidity and social impact related to epilepsy, as well as side effects associated with antiepileptic treatments.[3]
## Contents
* 1 Symptoms
* 1.1 Temporal lobe epilepsy
* 2 Causes
* 2.1 Aging
* 2.2 Vascular risk factors
* 2.3 Socioeconomic status
* 3 Diagnosis
* 3.1 Classification
* 4 Treatment
* 5 References
* 6 External links
## Symptoms[edit]
This section may be confusing or unclear to readers. In particular, incomplete and confusing sentences. Please help us clarify the section. There might be a discussion about this on the talk page. (February 2016) (Learn how and when to remove this template message)
Histopathological hallmarks of hippocampal sclerosis include segmental loss of pyramidal neurons, granule cell dispersion and reactive gliosis. This means that pyramidal neuronal cells are lost, granule cells are spread widely or driven off, and glial cells are changed in response to damage to the central nervous system (CNS). Generally, hippocampal sclerosis may be seen in some cases of epilepsy, particularly temporal lobe epilepsy. It is important to clarify the nature of insults that most likely have caused the hippocampal sclerosis and have initiated the epileptogenic process.[clarification needed][4] Presence of hippocampal sclerosis and duration of epilepsy longer than 10 years were found to cause parasympathetic autonomic dysfunction, whereas seizure refractoriness was found to cause sympathetic autonomic dysfunction. Apart from its association with the chronic nature of epilepsy, hippocampal sclerosis was shown to have an important role in internal cardiac autonomic dysfunction. Patients with left hippocampal sclerosis had more severe parasympathetic dysfunction as compared with those with right hippocampal sclerosis.[5] In young individuals, mesial temporal sclerosis is commonly recognized with temporal lobe epilepsy (TLE). On the other hand, it is an often unrecognized cause of cognitive decline, typically presenting with severe memory loss.[6]
### Temporal lobe epilepsy[edit]
Ammon's horn (or hippocampal) sclerosis (AHS) is the most common type of neuropathological damage seen in individuals with temporal lobe epilepsy.[7] This type of neuron cell loss, primarily in the hippocampus, can be observed in approximately 65% of people suffering from this form of epilepsy. Sclerotic hippocampus is pointed to as the most likely origin of chronic seizures in temporal lobe epilepsy patients, rather than the amygdala or other temporal lobe regions.[8] Although hippocampal sclerosis has been identified as a distinctive feature of the pathology associated with temporal lobe epilepsy, this disorder is not merely a consequence of prolonged seizures as argued.[8] A long and ongoing debate addresses the issue of whether hippocampal sclerosis is the cause or the consequence of chronic and pharmaceutically resistant seizure activity. Temporal lobectomy is a common treatment for TLE, surgically removing the seizure focal area, though complications can be severe.[9]
Other variants of temporal lobe epilepsy include mesial temporal lobe epilepsy (MTLE),[10] MTLE due to hippocampal sclerosis,[11] thalamic changes in temporal lobe epilepsy with and without hippocampal sclerosis,[12] and hippocampal sclerosis with and without mesial temporal lobe epilepsy.[10]
## Causes[edit]
### Aging[edit]
Although hippocampal sclerosis is relatively commonly found among elderly people (≈10% of individuals over the age of 85 years), association between this disease and ageing remains unknown.[13]
### Vascular risk factors[edit]
There were also observations that hippocampal sclerosis was associated with vascular risk factors. Hippocampal sclerosis cases were more likely than Alzheimer's disease to have had a history of stroke (56% vs. 25%) or hypertension (56% vs. 40%), evidence of small vessel disease (25% vs. 6%), but less likely to have had diabetes mellitus (0% vs. 22%).[6]
### Socioeconomic status[edit]
Socioeconomic correlates of health have been well established in the study of heart disease, lung cancer, and diabetes. Many of the explanations for the increased incidence of these conditions in people with lower socioeconomic status (SES) suggest they are the result of poor diet, low levels of exercise, dangerous jobs (exposure to toxins etc.) and increased levels of smoking and alcohol intake in socially deprived populations. Hesdorffer et al. found that low SES, indexed by poor education and lack of home ownership, was a risk factor for epilepsy in adults, but not in children in a population study.[14] Low socioeconomic status may have a cumulative effect for the risk of developing epilepsy over a lifetime.[15]
## Diagnosis[edit]
### Classification[edit]
Mesial temporal sclerosis is a specific pattern of hippocampal neuron cell loss.[16][17] There are 3 specific patterns of cell loss. Cell loss might involve sectors CA1 and CA4, CA4 alone, or CA1 to CA4.[17] Associated hippocampal atrophy and gliosis is common.[16] MRI scan commonly displays increased T2 signal and hippocampal atrophy.[16] Mesial temporal sclerosis might occur with other temporal lobe abnormalities (dual pathology).[16] Mesial temporal sclerosis is the most common pathological abnormality in temporal lobe epilepsy.[16][17] It has been linked to abnormalities in TDP-43.[18]
## Treatment[edit]
This section is empty. You can help by adding to it. (October 2017)
## References[edit]
1. ^ Sommer, W (1880). "Erkrankung des Ammon's horn als aetiologis ches moment der epilepsien". Arch Psychiatr Nurs. 10 (3): 631–675. doi:10.1007/BF02224538.
2. ^ Leverenz, JB; Agustin, CM; Tsuang, D; Peskind, ER; Edland, SD; Nochlin, D; DiGiacomo, L; Bowen, JD; McCormick, WC; Teri, L; Raskind, MA; Kukull, WA; Larson, EB (2002). "Clinical and neuropathological characteristics of hippocampal sclerosis: a community-based study". Arch. Neurol. 59 (7): 1099–1106. doi:10.1001/archneur.59.7.1099. PMID 12117357.
3. ^ Kadom, N; Tsuchida, T; Gaillard, WD (2011). "Hippocampal sclerosis in children younger than 2 years". Pediatr Radiol. 41 (10): 1239–1245. doi:10.1007/s00247-011-2166-4. PMID 21735179.
4. ^ Norwood, BA; Burmanglag, AV; Osculati, F; Sbarbati, A; Marzola, P; Nicolato, E; Fabene, PF; Sloviter, RS (2010). "Classic hippocampal sclerosis and hippocampal-onset epilepsy produced by a single "cryptic" episode of focal hippocampal excitation in awake rats". The Journal of Comparative Neurology. 518 (16): 3381–3407. doi:10.1002/cne.22406. PMC 2894278. PMID 20575073.
5. ^ Koseoglu, E; Kucuk, S; Arman, F; Erosoy, AO (2009). "Factors that affect interictal cardiovascular autonomic dysfunction in temporal lobe epilepsy: Role of hippocampal sclerosis". Epilepsy Behav. 16 (4): 617–621. doi:10.1016/j.yebeh.2009.09.021. PMID 19854109.
6. ^ a b Zarow, C; Weiner, MW; Ellis, WG; Chui, HC (2012). "Prevalence, laterality, and comorbidity of hippocampal sclerosis in an autopsy sample". Brain Behav. 2 (4): 435–442. doi:10.1002/brb3.66. PMC 3432966. PMID 22950047.
7. ^ Blümcke, I; Thom, M; Wiestler, OD (2002). "Ammon's Horn Sclerosis: A Maldevelopmental Disorder Associated with Temporal Lobe Epilepsy". Brain Pathology. 12: 199–211.
8. ^ a b De Lanerolle, NC; Lee, TS (2005). "New facets of the neuropathology and molecular profile of human temporal lobe epilepsy". Epilepsy Behav. 7 (2): 190–203. doi:10.1016/j.yebeh.2005.06.003. PMID 16098816.
9. ^ Borelli, P; Shorvon, SD; Stevens, JM; Smith, SJ; Scott, CA; Walker, MC (2008). "Extratemporal ictal clinical features in hippocampal sclerosis: their relationship to the degree of hippocampal volume loss and to the outcome of temporal lobectomy". Epilepsia. 49 (8): 1333–1339. doi:10.1111/j.1528-1167.2008.01694.x. PMID 18557777.
10. ^ a b Blumcke, I; Coras, R; Miyata, H; Ozkara, C (2012). "Defining Clinico-Neuropathological Subtypes of Mesial Temporal Lobe Epilepsy with hippocampal Sclerosis". Brain Pathology. 22 (3): 402–411. doi:10.1111/j.1750-3639.2012.00583.x. PMID 22497612.
11. ^ Asuman, OV; Serap, S; Hamit, A; Abdurrahman, C (2009). "Prognosis of patients with mesial temporal lobe epilepsy due to hippocampal sclerosis". Epilepsy Research. 85 (2): 206–211. doi:10.1016/j.eplepsyres.2009.03.001. PMID 19345070.
12. ^ Kim, CH; Koo, BB; Chung, CK; Lee, JM; Kim, JS; Lee, SK (2010). "Thalamic changes in temporal lobe epilepsy with and without hippocampal sclerosis: A diffusion tensor imaging study". Epilepsy Res. 90 (1): 21–27. doi:10.1016/j.eplepsyres.2010.03.002. PMID 20307957.
13. ^ Nelson, PT; Schmitt, FA; Lin, YS; Abner, EL; Jicha, GA; Patel, E; Thomason, PC; Neltner, JH; Smith, CD; Santacruz, KS; Sonnen, JA; Poon, LW; Gearing, M; Green, RC; Woodard, JL; Van Eldik, LJ; Rj, Kryscio (2011). "Hippocampal sclerosis in advanced age: clinical and pathological features". Brain. 134 (5): 1506–1518. doi:10.1093/brain/awr053. PMC 3097889. PMID 21596774.
14. ^ Hesdorffer, DC; Tian, H; Anand, K; et al. (2005). "Socioeconomic status is a risk factor for epilepsy in Icelandic adults but not in children". Epilepsia. 46 (8): 1297–303. doi:10.1111/j.1528-1167.2005.10705.x. PMID 16060943.
15. ^ Bazendale S, Heaney D (2010). "Socioeconomic status, cognition, and hippocampal sclerosis". Epilepsy Behav. 20 (1): 64–67. doi:10.1016/j.yebeh.2010.10.019. PMID 21130698.
16. ^ a b c d e Bronen RA, Fulbright RK, Spencer DD, et al. 1997
17. ^ a b c [1] Trepeta, Scott 2007
18. ^ Aoki N, Murray ME, Ogaki K, Fujioka S, Rutherford NJ, Rademakers R, Ross OA, Dickson DW (Jan 2015). "Hippocampal sclerosis in Lewy body disease is a TDP-43 proteinopathy similar to FTLD-TDP Type A". Acta Neuropathol. 129 (1): 53–64. doi:10.1007/s00401-014-1358-z. PMC 4282950. PMID 25367383.
## External links[edit]
Classification
D
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Rostral basal ganglia of the human brain and associated structures
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| Hippocampal sclerosis | c1504404 | 1,395 | wikipedia | https://en.wikipedia.org/wiki/Hippocampal_sclerosis | 2021-01-18T19:00:22 | {"wikidata": ["Q4421929"]} |
Congenital hereditary facial paralysis-variable hearing loss syndrome is an extremely rare autosomal recessive disorder characterized by bilateral facial palsy with masked facies, sensorineural hearing loss, dysmorphic features (midfacial retrusion, low-set ears), and strabismus.
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| Congenital hereditary facial paralysis-variable hearing loss syndrome | c1858717 | 1,396 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=306530 | 2021-01-23T17:05:20 | {"mesh": ["C536386"], "omim": ["604185", "614744"], "icd-10": ["Q87.0"], "synonyms": ["Congenital hereditary facial palsy with variable deafness", "Congenital hereditary facial palsy with variable hearing loss", "Congenital hereditary facial paralysis with variable deafness", "Congenital hereditary facial paralysis-variable deafness syndrome"]} |
C3 glomerulopathy is a group of related conditions that cause the kidneys to malfunction. The major features of C3 glomerulopathy include high levels of protein in the urine (proteinuria), blood in the urine (hematuria), reduced amounts of urine, low levels of protein in the blood, and swelling in many areas of the body. Affected individuals may have particularly low levels of a protein called complement component 3 (or C3) in the blood.
The kidney problems associated with C3 glomerulopathy tend to worsen over time. About half of affected individuals develop end-stage renal disease (ESRD) within 10 years after their diagnosis. ESRD is a life-threatening condition that prevents the kidneys from filtering fluids and waste products from the body effectively.
Researchers have identified two major forms of C3 glomerulopathy: dense deposit disease and C3 glomerulonephritis. Although the two disorders cause similar kidney problems, the features of dense deposit disease tend to appear earlier than those of C3 glomerulonephritis, usually in adolescence. However, the signs and symptoms of either disease may not begin until adulthood.
One of the two forms of C3 glomerulopathy, dense deposit disease, can also be associated with other conditions unrelated to kidney function. For example, people with dense deposit disease may have acquired partial lipodystrophy, a condition characterized by a lack of fatty (adipose) tissue under the skin in the upper part of the body. Additionally, some people with dense deposit disease develop a buildup of yellowish deposits called drusen in the light-sensitive tissue at the back of the eye (the retina). These deposits usually appear in childhood or adolescence and can cause vision problems later in life.
## Frequency
C3 glomerulopathy is very rare, affecting 1 to 2 per million people worldwide. It is equally common in men and women.
## Causes
C3 glomerulopathy is associated with changes in many genes. Most of these genes provide instructions for making proteins that help regulate a part of the body's immune response known as the complement system. This system is a group of proteins that work together to destroy foreign invaders (such as bacteria and viruses), trigger inflammation, and remove debris from cells and tissues. The complement system must be carefully regulated so it targets only unwanted materials and does not damage the body's healthy cells.
A specific mutation in one of the complement system-related genes, CFHR5, has been found to cause C3 glomerulopathy in people from the Mediterranean island of Cyprus. Mutation in the C3 and CFH genes, as well as other complement system-related genes, have been found to cause the condition in other populations. The known mutations account for only a small percentage of all cases of C3 glomerulopathy. In most cases, the cause of the condition is unknown.
Several normal variants (polymorphisms) in complement system-related genes are associated with an increased likelihood of developing C3 glomerulopathy. In some cases, the increased risk is related to a group of specific variants in several genes, a combination known as a C3 glomerulopathy at-risk haplotype. While these polymorphisms increase the risk of C3 glomerulopathy, many people who inherit these genetic changes will never develop the condition.
The genetic changes related to C3 glomerulopathy "turn up," or increase the activation of, the complement system. The overactive system damages structures called glomeruli in the kidneys. These structures are clusters of tiny blood vessels that help filter waste products from the blood. Damage to glomeruli prevents the kidneys from filtering waste products normally and can lead to ESRD. Studies suggest that uncontrolled activation of the complement system also causes the other health problems that can occur with dense deposit disease, including acquired partial lipodystrophy and a buildup of drusen in the retina. Researchers are working to determine how these associated health problems are related to overactivity of the complement system.
Studies suggest that C3 glomerulopathy can also result from the presence of specialized proteins called autoantibodies. Autoantibodies cause the condition by altering the activity of proteins involved in regulating the complement system.
### Learn more about the genes associated with C3 glomerulopathy
* C3
* C8A
* CFH
* CFHR5
* CFI
Additional Information from NCBI Gene:
* ADAM19
* C3AR1
* CD46
* CFB
* CFD
* CFHR1
* CFHR2
* CFHR3
* CR1
## Inheritance Pattern
Most cases of C3 glomerulopathy are sporadic, which means they occur in people with no history of the disorder in their family. Only a few reported families have had more than one family member with C3 glomerulopathy. However, many affected people have had close relatives with autoimmune diseases, which occur when the immune system malfunctions and attacks the body's tissues and organs. The connection between C3 glomerulopathy and autoimmune diseases is not fully understood.
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*[DOR]: δ-opioid receptor
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*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
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*[ND]: No data
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*[BMI]: body mass index
| C3 glomerulopathy | c3553720 | 1,397 | medlineplus | https://medlineplus.gov/genetics/condition/c3-glomerulopathy/ | 2021-01-27T08:25:38 | {"gard": ["8555", "6516"], "omim": ["614809", "609814"], "synonyms": []} |
## Description
Electrocardiographic (ECG) early repolarization, defined as an elevation of the QRS-ST junction (J-point) of at least 1.0 mm (0.1 mV) from baseline in the inferior or lateral lead, manifest as QRS slurring or notching, is a common ECG finding that is generally considered to be benign but may be associated with ventricular fibrillation in some patients (summary by Haissaguerre et al., 2008).
Clinical Features
Haissaguerre et al. (2008) reviewed data from 206 patients who were resuscitated after cardiac arrest due to idiopathic ventricular fibrillation, compared to 412 age-, sex-, race-, and physical activity-matched controls without heart disease. Patients with short or long QT intervals (see 609620 and 192500, respectively) or Brugada syndrome (see 601144) were excluded from the study. Early repolarization occurred in 64 (31%) of 206 patients compared to 21 (5%) of 412 controls (p less than 0.001). The magnitude of early repolarization was also greater in patients than in controls, with a J-point elevation of approximately 2.0 mm versus 1.2 mm, respectively (p less than 0.001). After adjustment for age, sex, race, and level of physical activity, the odds ratio for the presence of early repolarization in patients compared to controls was 10.9 (95% confidence interval, 6.3 to 18.9). Patients with early repolarization were more likely to be male (p = 0.007), to have experienced symptoms during sleep (p = 0.03), and to have a shorter QTc interval (p = 0.01) than those without early repolarization. All patients received an implantable cardioverter-defibrillator (ICD) device. Arrhythmic recurrences were more frequent in patients with early repolarization than in those without such repolarization (41% vs. 23%, respectively), with a hazard ratio for recurrence of 2.1 (p = 0.008). The 3 patients with the highest J-point elevations (greater than 5.0 mm) had more than 50 episodes of ventricular fibrillation, leading to death in 1 of the patients. Of the 64 patients with early repolarization, 10 had a family history of sudden cardiac arrest. Haissaguerre et al. (2008) concluded that among patients with a history of idiopathic ventricular fibrillation, there is an increased prevalence of early repolarization.
Commenting on the study by Haissaguerre et al. (2008), Myerburg and Castellanos (2008) noted that case-control associations do not prove causality, and stated that until prospective population data were available, physicians should continue to view this common ECG variant as generally benign. They suggested, however, that careful attention be paid to patients with early repolarization and J-point elevations greater than 2.0 mm, particularly in patients with otherwise unexplained arrhythmias or a family history of unexplained sudden death.
Molecular Genetics
### Associations Pending Confirmation
For discussion of a possible association between ventricular fibrillation with early repolarization and variation in the KCNJ8 gene, see 600935.0001.
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*[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
| EARLY REPOLARIZATION ASSOCIATED WITH VENTRICULAR FIBRILLATION | c3150852 | 1,398 | omim | https://www.omim.org/entry/613601 | 2019-09-22T15:58:10 | {"omim": ["613601"], "synonyms": ["Alternative titles", "EARLY REPOLARIZATION SYNDROME"]} |
Green nails may be (1) due to a Pseudomonas aeruginosa infection causing a green nail syndrome or (2) the result of copper in tap water.[1]:791
## Pseudomonas aeruginosa[edit]
Main article: Pseudomonas aeruginosa
Pseudomonas aeruginosa is a common bacterium that can cause disease in animals, including humans. It is found in soil, water, skin flora, and most man-made environments throughout the world. It thrives not only in normal atmospheres, but also in hypoxic atmospheres, and has, thus, colonized many natural and artificial environments. It uses a wide range of organic material for food; in animals, the versatility enables the organism to infect damaged tissues or those with reduced immunity. The symptoms of such infections are generalized inflammation and sepsis. If such colonizations occur in critical body organs, such as the lungs, the urinary tract, and kidneys, the results can be fatal.[2] Because it thrives on most surfaces, this bacterium is also found on and in medical equipment, including catheters, causing cross-infections in hospitals and clinics. It is implicated in hot-tub rash. It is also able to decompose hydrocarbons and has been used to break down tarballs and oil from oil spills.[3][4]
## See also[edit]
* Nail anatomy
* List of cutaneous conditions
## References[edit]
1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
2. ^ Balcht, Aldona; Smith, Raymond (1994). Pseudomonas Aeruginosa: Infections and Treatment. Informa Health Care. pp. 83–84. ISBN 978-0-8247-9210-7.
3. ^ A. Y. Itah; J. P. Essien (2005). "Growth Profile and Hydrocarbonoclastic Potential of Microorganisms Isolated from Tarballs in the Bight of Bonny, Nigeria". World Journal of Microbiology and Biotechnology. 21 (6–7): 1317–1322. doi:10.1007/s11274-004-6694-z.
4. ^ AVI Biopharma (2007-01-18). "Antisense antibacterial method and compound". World Intellectual Property Organization. Retrieved 2008-10-18.[permanent dead link]
This condition of the skin appendages article is a stub. You can help Wikipedia by expanding it.
* v
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*[v]: View this template
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*[AA]: Adrenergic agonist
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*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
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| Green nails | None | 1,399 | wikipedia | https://en.wikipedia.org/wiki/Green_nails | 2021-01-18T18:32:32 | {"wikidata": ["Q5603561"]} |
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