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This article may be too technical for most readers to understand. Please help improve it to make it understandable to non-experts, without removing the technical details. (February 2017) (Learn how and when to remove this template message)
behavioral addiction characterized by compulsory indulgence over foods
A food addiction or eating addiction is a behavioral addiction that is characterized by the compulsive consumption of palatable (e.g., high fat and high sugar) foods which markedly activate the reward system in humans and other animals despite adverse consequences.[1][2]
Psychological dependence has also been observed with the occurrence of withdrawal symptoms when consumption of these foods stops by replacement with foods low in sugar and fat.[1] Because this addictive behavior is not biological, one cannot develop a trait that codes for an eating disorder, so professionals address this by providing behavior therapy[3] and by asking a series of questions called the YFAS questionnaire, a diagnostic criteria of substance dependence.[4]
Sugary and high-fat food have both been shown to increase the expression of ΔFosB, an addiction biomarker, in the D1-type medium spiny neurons of the nucleus accumbens;[1] however, there is very little research on the synaptic plasticity from compulsive food consumption, a phenomenon which is known to be caused by ΔFosB overexpression.[1]
## Contents
* 1 Description
* 2 Signs and symptoms
* 3 Effects
* 4 Management
* 5 Prognosis
* 6 Epidemiology
* 7 Summary of addiction-related plasticity
* 8 See also
* 9 References
* 10 Further reading
* 11 External links
## Description[edit]
"Food addiction" refers to compulsive overeaters who engage in frequent episodes of uncontrolled eating (binge eating). The term binge eating means eating an unhealthy amount of food while feeling that one's sense of control has been lost.[5] At first, the food addiction comes in the form of cravings, so a person is naturally caught unaware when suddenly they find that they cannot cope without the craving.[6] The person’s behavior then begins to shift when the need for more food is not met, in that when the urge is met, binge eating, obesity and bulimia can result as a consequence. To show this, a study done by Sara Parylak and her peers in the physiology and behavior journal reveals that animal models given free access to food became more emotionally withdrawn after the food was taken away from them due to the anxiogenic-like stimuli pestering them for more food.[7] This kind of behavior shows that food addiction is not only a self control problem, but that it goes deeper than that, it is the body controlling a person to the point where the individual has no say on what goes into their bodies despite of all the consequences that can come from overeating. People who engage in binge eating may feel frenzied, and consume a large number of calories before stopping. Food binges may be followed by feelings of guilt and depression;[8] for example, some will cancel their plans for the next day because they "feel fat." Binge eating also has implications on physical health, due to excessive intake of fats and sugars, which can cause numerous health problems.
Unlike individuals with bulimia nervosa, compulsive overeaters do not attempt to compensate for their bingeing with purging behaviors, such as fasting, laxative use, or vomiting. When compulsive overeaters overeat through binge eating and experience feelings of guilt after their binges, they can be said to have binge eating disorder (BED).[5]
In addition to binge eating, compulsive overeaters may also engage in "grazing" behavior, during which they continuously eat throughout the day.[5] These actions result in an excessive overall number of calories consumed, even if the quantities eaten at any one time may be small.
During binges, compulsive overeaters may consume between 5,000 and 15,000 food calories daily (far more than is healthy), resulting in a temporary release from psychological stress through an addictive high not unlike that experienced through drug abuse.[8] Compulsive overeaters tend to show brain changes similar to those of drug addicts, a result of excessive consumption of highly processed food (most likely consisting of high amounts of saturated fat, which is more energy-rich).[9]
## Signs and symptoms[edit]
A food addiction features compulsive overeating, such as binge eating behavior, as its core and only defining feature. There are several potential signs that a person may be suffering from compulsive overeating. Common behaviors of compulsive overeaters include eating alone, consuming food quickly, and gaining weight rapidly, and eating to the point of feeling sick to the stomach. Other signs include significantly decreased mobility and the withdrawal from activities due to weight gain. Emotional indicators can include feelings of guilt, a sense of loss of control, depression and mood swings.[8][10]
Hiding consumption is an emotional indicator of other symptoms that could be a result of having a food addiction. Hiding consumption of food includes eating in secret, late at night, in the car, and hiding certain foods until ready to consume in private. Other signs of hiding consumption are avoiding social interactions to eat the specific foods that are craved. Other emotional indicators are inner guilt; which includes making up excuses to why the palatable food would be beneficial to consume, and then feeling guilty about it shortly after consuming.[11]
Sense of loss of control is indicated in many ways which includes, going out of the way to obtain specific foods, spending unnecessary amounts of money on foods to satisfy cravings. Difficulty concentrating on things such as a job or career can indicate sense of loss of control by not being able to organize thoughts leading to a decrease in efficiency. Other ways to indicate the sense of loss of control, are craving food despite being full. One may set rules to try to eat healthy but the cravings over rule and the rules are failed to be followed. One big indicator of loss of control due to food addiction is even though one knows they have a medical problem caused by the craved foods, they cannot stop consuming the foods, which can be detrimental to their health.[12][11]
Food addiction has some physical signs and symptoms. Decreased energy; not being able to be as active as in the past, not being able to be as active as others around, also a decrease in efficiency due to the lack of energy. Having trouble sleeping; being tired all the time such as fatigue, oversleeping, or the complete opposite and not being able to sleep such as insomnia. Other physical signs and symptoms are restlessness, irritability, digestive disorders, and headaches.[12][11]
In extreme cases food addiction can result in suicidal thoughts.[12]
## Effects[edit]
Obesity has been attributed to eating behavior or fast food, personality issues, depression, addiction and genetics. One proposed explanation of epidemic obesity is food addiction.[13]
## Management[edit]
See also: Jaw wiring
Compulsive overeating is treatable with nutritional assistance and medication. Psychotherapy may also be required, but recent research has proven this to be useful only as a complementary resource, with short-term effectiveness in middle to severe cases.[14][15]
Lisdexamfetamine is an FDA-approved appetite suppressant drug that is indicated (i.e., used clinically) for the treatment of binge eating disorder.[16] The antidepressant fluoxetine is a medication that is approved by the Food and Drug Administration for the treatment of an eating disorder, specifically bulimia nervosa. This medication has been prescribed off-label for the treatment of binge eating disorder. Off-label medications, such as other selective serotonin reuptake inhibitors (SSRIs), have shown some efficacy, as have several atypical[jargon] agents, such as mianserin, trazodone and bupropion.[17][18] Anti-obesity medications[19] have also proven very effective. Studies suggest that anti-obesity drugs, or moderate appetite suppressants, may be key to controlling binge eating.[20]
Many eating disorders are thought to be behavioral patterns that stem from emotional struggles; for the individual to develop lasting improvement and a healthy relationship with food, these affective[jargon] obstacles need to be resolved.[21] Individuals can overcome compulsive overeating through treatment, which should include talk therapy and medical and nutritional counseling. Such counseling has been recently sanctioned by the American Dental Association in their journal article cover-story for the first time in history in 2012: Given "the continued increase in obesity in the United States and the willingness of dentists to assist in prevention and interventional effort, experts in obesity intervention in conjunction with dental educators should develop models of intervention within the scope of dental practice."[22] Moreover, dental appliances such as conventional jaw wiring and orthodontic wiring for controlling compulsive overeating have been shown to be efficient ways in terms of weight control in properly selected obese patients and usually no serious complications could be encountered through the treatment course.[23]
As well, several twelve-step programs exist to help members recover from compulsive overeating and food addiction,[8] such as Overeaters Anonymous.
As of 2018, the Ontario Health Insurance Plan has announced a new program designed to assist individuals struggling with food addiction.[24]
## Prognosis[edit]
Once an eating disorder such as BED is developed there are two potential pathways that can occur for an individual.
Getting help is the first step to getting better but the chances for relapse are high. Those with a food addiction were most likely overweight in childhood[25] which leads to treatment resistance the longer gone untreated. Due to poor mental health and lack of control and environmental factors,[26] overeaters relapse into their old habits even after completing various treatments. BED patients often report and acknowledge using substances daily as a coping mechanism.
However, there is a 50% of recovery at the end of treatment and follow-ups.[27] Overcoming a food addiction isn't easy but those who accomplish it possess enough confidence to change, go through required examinations but most importantly, they receive support and encouragement from their loved ones and environment.
Ultimately, there is no guaranteed prognosis for food addictions. More studies are currently being conducted in order to understand food addictions along with other eating disorders.
A food addiction can lead to chronic conditions and eventually death. Nevertheless, there is a higher chance of recovery when treated in early stages such as teenage years when the symptoms are more noticeable then adulthood where there is more denial on part of the individual.
## Epidemiology[edit]
A review on behavioral addictions listed the estimated the lifetime prevalence (i.e., the proportion of individuals in the population that developed the disorder during their lifetime) for food addiction in the United States as 2.8%.[1]
The problem of obesity is becoming a worldwide problem. A sugar tax is set to be introduced in Ireland to minimise the consumption of harmful foods and drinks.[28]
## Summary of addiction-related plasticity[edit]
Form of neuroplasticity
or behavioral plasticity Type of reinforcer Sources
Opiates Psychostimulants High fat or sugar food Sexual intercourse Physical exercise
(aerobic) Environmental
enrichment
ΔFosB expression in
nucleus accumbens D1-type MSNs ↑ ↑ ↑ ↑ ↑ ↑ [1]
Behavioral plasticity
Escalation of intake Yes Yes Yes [1]
Psychostimulant
cross-sensitization Yes Not applicable Yes Yes Attenuated Attenuated [1]
Psychostimulant
self-administration ↑ ↑ ↓ ↓ ↓ [1]
Psychostimulant
conditioned place preference ↑ ↑ ↓ ↑ ↓ ↑ [1]
Reinstatement of drug-seeking behavior ↑ ↑ ↓ ↓ [1]
Neurochemical plasticity
CREB phosphorylation
in the nucleus accumbens ↓ ↓ ↓ ↓ ↓ [1]
Sensitized dopamine response
in the nucleus accumbens No Yes No Yes [1]
Altered striatal dopamine signaling ↓DRD2, ↑DRD3 ↑DRD1, ↓DRD2, ↑DRD3 ↑DRD1, ↓DRD2, ↑DRD3 ↑DRD2 ↑DRD2 [1]
Altered striatal opioid signaling No change or
↑μ-opioid receptors ↑μ-opioid receptors
↑κ-opioid receptors ↑μ-opioid receptors ↑μ-opioid receptors No change No change [1]
Changes in striatal opioid peptides ↑dynorphin
No change: enkephalin ↑dynorphin ↓enkephalin ↑dynorphin ↑dynorphin [1]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens ↓ ↑ ↑ [1]
Dendritic spine density in
the nucleus accumbens ↓ ↑ ↑ [1]
## See also[edit]
* Binge eating disorder
* Binge eating
* Bulimia nervosa
* Eating disorder
* Eating disorder not otherwise specified
* Food Addicts in Recovery Anonymous
* Food Addicts Anonymous
* Gluttony
* Hyperalimentation – overnutrition
* Overeaters Anonymous
* Overeating
* Polyphagia – excessive hunger
* SMART Recovery
* Sugar industry
## References[edit]
1. ^ a b c d e f g h i j k l m n o p q r Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. "Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. ... In some people, there is a transition from “normal” to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... the transcription factor delta FosB is increased during access to high fat diet (Teegarden and Bale, 2007) or sucrose (Wallace et al, 2008). ...To date, there is very little data directly measuring the effects of food on synaptic plasticity in addiction-related neurocircuitry. ... Following removal of sugar or fat access, withdrawal symptoms including anxiety- and depressive-like behaviors emerge (Colantuoni et al, 2002; Teegarden and Bale, 2007). After this period of “abstinence”, operant testing reveals “craving” and “seeking” behavior for sugar (Avena et al, 2005) or fat (Ward et al, 2007), as well as “incubation of craving” (Grimm et al, 2001; Lu et al, 2004; Grimm et al, 2005), and “relapse” (Nair et al, 2009b) following abstinence from sugar. In fact, when given a re-exposure to sugar after a period of abstinence, animals consume a much greater amount of sugar than during previous sessions (Avena et al., 2005).""Table 1"
2. ^ Hebebrand J, Albayrak Ö, Adan R, Antel J, Dieguez C, de Jong J, Leng G, Menzies J, Mercer JG, Murphy M, van der Plasse G, Dickson SL (November 2014). ""Eating addiction", rather than "food addiction", better captures addictive-like eating behavior" (PDF). Neuroscience and Biobehavioral Reviews. 47: 295–306. doi:10.1016/j.neubiorev.2014.08.016. PMID 25205078. "
• Evidence for addiction to specific macronutrients is lacking in humans.
• 'Eating addiction' describes a behavioral addiction. ...
We concur with Hone-Blanchet and Fecteau (2014) that it is premature to conclude validity of the food addiction phenotype in humans from the current behavioral and neurobiological evidence gained in rodent models. ... To conclude, the society as a whole should be aware of the differences between addiction in the context of substance use versus an addictive behavior. As we pointed out in this review, there is very little evidence to indicate that humans can develop a 'Glucose/Sucrose/Fructose Use Disorder' as a diagnosis within the DSM-5 category Substance Use Disorders. We do, however, view both rodent and human data as consistent with the existence of addictive eating behavior."
3. ^ Ho KS, Nichaman MZ, Taylor WC, Lee ES, Foreyt JP (November 1995). "Binge eating disorder, retention, and dropout in an adult obesity program". The International Journal of Eating Disorders. 18 (3): 291–4. doi:10.1002/1098-108X(199511)18:3<291::AID-EAT2260180312>3.0.CO;2-Y. PMID 8556026.
4. ^ Hebebrand J, Albayrak Ö, Adan R, Antel J, Dieguez C, de Jong J, Leng G, Menzies J, Mercer JG, Murphy M, van der Plasse G, Dickson SL (November 2014). ""Eating addiction", rather than "food addiction", better captures addictive-like eating behavior". Neuroscience and Biobehavioral Reviews. 47: 295–306. doi:10.1016/j.neubiorev.2014.08.016. PMID 25205078.
5. ^ a b c Saunders R (January 2004). ""Grazing": a high-risk behavior". Obesity Surgery. 14 (1): 98–102. doi:10.1381/096089204772787374. PMID 14980042.
6. ^ Corsica JA, Pelchat ML (March 2010). "Food addiction: true or false?". Current Opinion in Gastroenterology. 26 (2): 165–9. doi:10.1097/mog.0b013e328336528d. PMID 20042860.
7. ^ Parylak SL, Koob GF, Zorrilla EP (July 2011). "The dark side of food addiction". Physiology & Behavior. 104 (1): 149–56. doi:10.1016/j.physbeh.2011.04.063. PMC 3304465. PMID 21557958.
8. ^ a b c d Goldberg J (August 21, 2014). "Food Addiction". WebMD. WebMD. Retrieved October 27, 2014.
9. ^ Nolen-Hoeksema S (2014). (ab)normal Psychology. New York, NY: McGraw-Hill Education. p. 348. ISBN 9781308211503.
10. ^ "Food Addiction Signs and Treatments". WebMD. Retrieved 2017-02-28.
11. ^ a b c "What Are The Effects of Food Addiction". Authority Nutrition. 2013-02-18. Retrieved 2017-02-28.
12. ^ a b c "About Food Addiction: Signs, Symptoms, Causes & Articles For Treatment Help". www.eatingdisorderhope.com. Retrieved 2017-02-28.
13. ^ Liu Y, von Deneen KM, Kobeissy FH, Gold MS (June 2010). "Food addiction and obesity: evidence from bench to bedside". Journal of Psychoactive Drugs. 42 (2): 133–45. doi:10.1080/02791072.2010.10400686. PMID 20648909.
14. ^ "Binge-eating disorder Treatment at Mayo Clinic - Diseases and Conditions". Mayo Clinic. 2012-04-03. Retrieved 2014-02-01.
15. ^ Johnson BA, Ait-Daoud N, Wang XQ, Penberthy JK, Javors MA, Seneviratne C, Liu L (December 2013). "Topiramate for the treatment of cocaine addiction: a randomized clinical trial". JAMA Psychiatry. 70 (12): 1338–46. doi:10.1001/jamapsychiatry.2013.2295. PMID 24132249. Lay summary – ScienceDaily (October 25, 2013).
16. ^ "Vyvanse Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. January 2015. Retrieved 24 February 2015.
17. ^ White MA, Grilo CM (April 2013). "Bupropion for overweight women with binge-eating disorder: a randomized, double-blind, placebo-controlled trial". The Journal of Clinical Psychiatry. 74 (4): 400–6. doi:10.4088/JCP.12m08071. PMC 4021866. PMID 23656848.
18. ^ Calandra C, Russo RG, Luca M (June 2012). "Bupropion versus sertraline in the treatment of depressive patients with binge eating disorder: retrospective cohort study". The Psychiatric Quarterly. 83 (2): 177–85. doi:10.1007/s11126-011-9192-0. PMID 21927936.
19. ^ "Obesity Treatment at Mayo Clinic - Diseases and Conditions". Mayo Clinic. 2013-06-07. Retrieved 2014-02-01.
20. ^ McElroy SL, Guerdjikova AI, Mori N, O'Melia AM (2012). "Pharmacological management of binge eating disorder: current and emerging treatment options". Therapeutics and Clinical Risk Management. 8: 219–41. doi:10.2147/TCRM.S25574. PMC 3363296. PMID 22654518.
21. ^ "Factors That May Contribute to Eating Disorders". NEDA. Retrieved October 27, 2014.
22. ^ Curran AE, Caplan DJ, Lee JY, Paynter L, Gizlice Z, Champagne C, Ammerman AS, Agans R (November 2010). "Dentists' attitudes about their role in addressing obesity in patients: a national survey". Journal of the American Dental Association. 141 (11): 1307–16. doi:10.14219/jada.archive.2010.0075. PMID 21037188.
23. ^ Al-Dhubhani MK, Al-Tarawneh AM (July 2015). "The Role of Dentistry in Treatment of Obesity—Review". Saudi Journal of Dental Research. 6 (2): 152–6. doi:10.1016/j.sjdr.2014.11.005.
24. ^ "New program to help people struggling with food addiction". News-Medical-Life Sciences. June 6, 2018. Retrieved June 21, 2018.
25. ^ Halmi, Katherine A (2013-11-07). "Perplexities of treatment resistance in eating disorders". BMC Psychiatry. 13 (1): 292. doi:10.1186/1471-244x-13-292. ISSN 1471-244X. PMC 3829659. PMID 24199597.
26. ^ Lu, Henry; Mannan, Haider; Hay, Phillipa; Lu, Henry Kewen; Mannan, Haider; Hay, Phillipa (2017-07-18). "Exploring Relationships between Recurrent Binge Eating and Illicit Substance Use in a Non-Clinical Sample of Women over Two Years". Behavioral Sciences. 7 (3): 46. doi:10.3390/bs7030046. PMC 5618054. PMID 28718830.
27. ^ Treasure, Janet; Stein, Daniel; Maguire, Sarah (2014-09-29). "Has the time come for a staging model to map the course of eating disorders from high risk to severe enduring illness? An examination of the evidence". Early Intervention in Psychiatry. 9 (3): 173–184. doi:10.1111/eip.12170. ISSN 1751-7885. PMID 25263388.
28. ^ "Sweet taste of success for soft drinks sector". The Irish Times. 14 October 2016.
## Further reading[edit]
* Brownlee, Christen (2009). "Food fix: Neurobiology highlights similarities between obesity and drug addiction". Science News. 168 (10): 155–6. doi:10.1002/scin.5591681012. INIST:17072118.
* "Eating Awareness Training" Molly Gregor, copyright 1983 "...reclaim (your) 'birthright', the right to eat without compulsion, obsession, or suffering. ...what the body wants, as much as it wants, whenever it wants." From the Preface by Thomas Lebherz, M.D.
## External links[edit]
* Media related to Food addiction at Wikimedia Commons
* v
* t
* e
Reinforcement disorders: Addiction and Dependence
Addiction
Drug
* Alcohol
* Amphetamine
* Cocaine
* Methamphetamine
* Methylphenidate
* Nicotine
* Opioid
Behavioral
* Financial
* Gambling
* Shopping
* Palatable food
* Sex-related
* Intercourse
* Pornography
* Internet-related
* Internet addiction disorder
* Internet sex addiction
* Video game addiction
* Digital media addictions
Cellular
mechanisms
* Transcriptional
* ΔFosB
* c-Fos
* Cdk5
* CREB
* GluR2
* NF-κB
* Epigenetic
* G9a
* G9a-like protein
* HDAC1
* HDAC2
* HDAC3
* HDAC4
* HDAC5
* HDAC9
* HDAC10
* SIRT1
* SIRT2
* ...
Dependence
Concepts
* Physical dependence
* Psychological dependence
* Withdrawal
Disorders
* Drugs
* Alcoholism
* Amphetamine
* Barbiturate
* Benzodiazepine
* Caffeine
* Cannabis
* Cocaine
* Nicotine
* Opioid
* Non-drug stimuli
* Tanning dependence
Treatment and management
Detoxification
* Alcohol detoxification
* Drug detoxification
Behavioral therapies
* Cognitive behavioral therapy
* Relapse prevention
* Contingency management
* Community reinforcement approach and family training
* Motivational enhancement therapy
* Motivational interviewing
* Motivational therapy
* Physical exercise
Treatment programs
* Drug rehab
* Residential treatment center
* Heroin-assisted treatment
* Intensive outpatient program
* Methadone maintenance
* Smoking cessation
* Nicotine replacement therapy
* Tobacco cessation clinics in India
* Twelve-step program
Support groups
* Addiction recovery groups
* List of twelve-step groups
Harm reduction
* Category:Harm reduction
* Drug checking
* Reagent testing
* Low-threshold treatment programs
* Managed alcohol program
* Moderation Management
* Needle exchange program
* Responsible drug use
* Stimulant maintenance
* Supervised injection site
* Tobacco harm reduction
See also
* Addiction medicine
* Allen Carr
* Category:Addiction
* Discrimination against drug addicts
* Dopamine dysregulation syndrome
* Cognitive control
* Inhibitory control
* Motivational salience
* Incentive salience
* Sober companion
* Category
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Food addiction | c4505163 | 2,500 | wikipedia | https://en.wikipedia.org/wiki/Food_addiction | 2021-01-18T19:08:59 | {"mesh": ["D000073932"], "wikidata": ["Q2742106"]} |
Tumors that develop within the liver may be either benign (noncancerous) or malignant (cancerous). Tumors can start in the liver, or spread to the liver from another cancer in the body. Malignant liver tumors have been reported to metastasize to other organs such as regional lymph nodes, lungs, kidneys, pancreas, spleen and others.
## Contents
* 1 Signs and symptoms
* 2 Diagnosis
* 3 Treatment
* 4 References
* 5 External links
## Signs and symptoms[edit]
Clinical signs are often vague and include weight loss, loss of appetite, fatigue, and possible jaundice.
## Diagnosis[edit]
Medical imaging techniques such as X-rays, ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) are often used in evaluating animals with suspected liver tumors. Ultrasound-guided fine-needle aspiration or needle-core biopsy of liver masses are useful diagnostic tools that are minimally invasive to obtain samples for histopathological analysis.[1]
## Treatment[edit]
Surgical treatment is recommended for cats and dogs diagnosed with primary liver tumors but not metastasis to the liver. There are not many treatment options for animals who have multiple liver lobes affected.
## References[edit]
1. ^ Withrow SJ, MacEwen EG, eds. (2001). Small Animal Clinical Oncology (3rd ed.). W.B. Saunders Company.
## External links[edit]
* Liver Cancer in Cats and Dogs from Pet Cancer Center
* Liver Tumors in Dogs from Pet Place'
* Hepatic Neoplasia from Merck Veterinary Manual'
* Liver Tumors from Vet Surgery Central
* Liver Cancer in Dogs from Alldoghealth'
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Liver cancer in cats and dogs | None | 2,501 | wikipedia | https://en.wikipedia.org/wiki/Liver_cancer_in_cats_and_dogs | 2021-01-18T18:33:45 | {"wikidata": ["Q6658205"]} |
This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed.
Find sources: "Fibrous dysplasia of bone" – news · newspapers · books · scholar · JSTOR (January 2009) (Learn how and when to remove this template message)
Fibrous dysplasia
Micrograph showing fibrous dysplasia with the characteristic thin, irregular (Chinese character-like) bony trabeculae and fibrotic marrow space. H&E stain.
SpecialtyMedical genetics
SymptomsBone pain, bone deformities, local swelling
ComplicationsBone fractures
Usual onsetAdolescence or early adulthood (monostotic), before age 10 (polyostotic)
TypesMonostotic (75–80% of cases),[1] polyostotic, panostotic
CausesMutations of GNAS locus
Frequency1 in 5,000 to 10,000[1]
Fibrous dysplasia is a disorder where normal bone and marrow is replaced with fibrous tissue, resulting in formation of bone that is weak and prone to expansion. As a result, most complications result from fracture, deformity, functional impairment, and pain.[2] Disease occurs along a broad clinical spectrum ranging from asymptomatic, incidental lesions, to severe disabling disease. Disease can affect one bone (monostotic), multiple (polyostotic), or all bones (panostotic)[3][4] and may occur in isolation or in combination with café au lait skin macules and hyperfunctioning endocrinopathies, termed McCune–Albright syndrome.[2] More rarely, fibrous dysplasia may be associated with intramuscular myxomas, termed Mazabraud's syndrome.[5] Fibrous dysplasia is very rare, and there is no known cure. Fibrous dysplasia is not a form of cancer.
## Contents
* 1 Presentation
* 2 Pathophysiology
* 3 Diagnosis
* 4 Treatment
* 5 See also
* 6 References
* 7 Further reading
* 8 External links
## Presentation[edit]
Fibrous dysplasia of the right zygomatic bone (left). Corresponding T2-weighted MRI (left) and CT (right) of the same patient.
Fibrous dysplasia is a mosaic disease that can involve any part or combination of the craniofacial, axillary, and/or appendicular skeleton.[6] The type and severity of the complications therefore depend on the location and extent of the affected skeleton. The clinical spectrum is very broad, ranging from an isolated, asymptomatic monostotic lesion discovered incidentally, to severe disabling disease involving practically the entire skeleton and leading to loss of vision, hearing, and/or mobility.
Individual bone lesions typically manifest during the first few years of life and expand during childhood. The vast majority of clinically significant bone lesions are detectable by age 10 years, with few new and almost no clinically significant bone lesions appearing after age 15 years.[7] Total body scintigraphy is useful to identify and determine the extent of bone lesions, and should be performed in all patients with suspected fibrous dysplasia.[2]
Children with fibrous dysplasia in the appendicular skeleton typically present with limp, pain, and/or pathologic fractures. Frequent fractures and progressive deformity may lead to difficulties with ambulation and impaired mobility. In the craniofacial skeleton, fibrous dysplasia may present as a painless “lump” or facial asymmetry. Expansion of craniofacial lesions may lead to progressive facial deformity. In rare cases, patients may develop vision and/or hearing loss due to compromise of the optic nerves and/or auditory canals, which is more common in patients with McCune-Albright syndrome associated growth hormone excess.[8] Fibrous dysplasia commonly involves the spine, and may lead to scoliosis, which in rare instances may be severe.[9] Untreated, progressive scoliosis is one of the few features of fibrous dysplasia that can lead to early fatality.
Bone pain is a common complication of fibrous dysplasia. It may present at any age, but most commonly develops during adolescence and progresses into adulthood.[6]
Bone marrow stromal cells in fibrous dysplasia produce excess amounts of the phosphate-regulating hormone fibroblast growth factor-23 (FGF23), leading to loss of phosphate in the urine.[10] Patients with hypophosphatemia may develop rickets/osteomalacia, increased fractures, and bone pain.[11]
Micrograph of fibrous dysplasia (right) juxtaposed with unaffected bone (left). H&E stain.
## Pathophysiology[edit]
Fibrous dysplasia is a mosaic disease resulting from post-zygotic activating mutations of the GNAS locus at 20q13.2-q13.3, which codes for the α subunit of the Gs G-coupled protein receptor.[12] In bone, constitutive Gsα signaling results in impaired differentiation and proliferation of bone marrow stromal cells.[13] Proliferation of these cells causes replacement of normal bone and marrow with fibrous tissue. The bony trabeculae are abnormally thin and irregular, and often likened to Chinese characters (bony spicules on biopsy).
Fibrous dysplasia is not hereditary, and there has never been a case of genetic inheritance from parent to child.
## Diagnosis[edit]
On x-ray, fibrous dysplasia appears as bubbly lytic lesions, or a ground glass appearance. Computerized tomography (CT) or magnetic resonance imaging (MRI) scans may be used to determine how extensively bones are affected. CT can better demonstrate the typical "ground glass" appearance, which is a highly specific radiological finding, while MRI can show cystic areas with fluid contents.[14] A bone scan uses radioactive tracers, which are injected into your bloodstream. The damaged parts of bones take up more of the tracer, which show up more brightly on the scan. A biopsy, which uses a hollow needle to remove a small piece of the affected bone for laboratory analysis, can diagnose fibrous dysplasia definitely.
## Treatment[edit]
Treatment in fibrous dysplasia is mainly palliative, and is focused on managing fractures and preventing deformity. There are no medications capable of altering the disease course. Intravenous bisphosphonates may be helpful for treatment of bone pain, but there is no clear evidence that they strengthen bone lesions or prevent fractures.[15][16] Surgical techniques that are effective in other disorders, such as bone grafting, curettage, and plates and screws, are frequently ineffective in fibrous dysplasia and should be avoided.[17][18] Intramedullary rods are generally preferred for management of fractures and deformity in the lower extremities.[18] Progressive scoliosis can generally be managed with standard instrumentation and fusion techniques.[19] Surgical management in the craniofacial skeleton is complicated by frequent post-operative FD regrowth, and should focus on correction of functional deformities.[20] Prophylactic optic nerve decompression increases the risk of vision loss and is contraindicated.[21]
Managing endocrinopathies is a critical component of management in FD. All patients with fibrous dysplasia should be evaluated and treated for endocrine diseases associated with McCune–Albright syndrome. In particular untreated growth hormone excess may worsen craniofacial fibrous dysplasia and increase the risk of blindness.[22] Untreated hypophosphatemia increases bone pain and risk of fractures.[23]
## See also[edit]
* Cherubism
* Dysplasia
* McCune–Albright syndrome
## References[edit]
1. ^ a b Tafti, Dawood; Cecava, Nathan D. (2018-12-18). "Fibrous Dysplasia". NCBI Bookshelf. PMID 30422542. Retrieved 2019-12-08.
2. ^ a b c Boyce, Alison M.; Collins, Michael T. (1993-01-01). Pagon, Roberta A.; Adam, Margaret P.; Ardinger, Holly H.; Wallace, Stephanie E.; Amemiya, Anne; Bean, Lora J.H.; Bird, Thomas D.; Fong, Chin-To; Mefford, Heather C. (eds.). Fibrous Dysplasia/McCune-Albright Syndrome. Seattle (WA): University of Washington, Seattle. PMID 25719192.
3. ^ Cole DE; Fraser FC; Glorieux FH; Jequier S; Marie PJ; Reade TM; Scriver CR (14 Apr 1983). "Panostotic fibrous dysplasia: a congenital disorder of bone with unusual facial appearance, bone fragility, hyperphosphatasemia, and hypophosphatemia". American Journal of Medical Genetics (4 ed.). 14 (4): 725–35. doi:10.1002/ajmg.1320140414. PMID 6846403.
4. ^ Leslie WD; Reinhold C; Rosenthall L; Tau C; Glorieux FH (July 1992). "Panostotic fibrous dysplasia. A new craniotubular dysplasia". Clinical Nuclear Medicine (7 ed.). 17 (7): 556–60. doi:10.1097/00003072-199207000-00005. PMID 1638836.
5. ^ Cabral, C. E.; Guedes, P.; Fonseca, T.; Rezende, J. F.; Cruz Júnior, L. C.; Smith, J. (1998-05-01). "Polyostotic fibrous dysplasia associated with intramuscular myxomas: Mazabraud's syndrome". Skeletal Radiology. 27 (5): 278–282. doi:10.1007/s002560050381. ISSN 0364-2348. PMID 9638839.
6. ^ a b Kelly, M. H.; Brillante, B.; Collins, M. T. (2008-01-01). "Pain in fibrous dysplasia of bone: age-related changes and the anatomical distribution of skeletal lesions". Osteoporosis International. 19 (1): 57–63. doi:10.1007/s00198-007-0425-x. ISSN 0937-941X. PMID 17622477. S2CID 21276747.
7. ^ Hart, Elizabeth S.; Kelly, Marilyn H.; Brillante, Beth; Chen, Clara C.; Ziran, Navid; Lee, Janice S.; Feuillan, Penelope; Leet, Arabella I.; Kushner, Harvey (2007-09-01). "Onset, progression, and plateau of skeletal lesions in fibrous dysplasia and the relationship to functional outcome". Journal of Bone and Mineral Research. 22 (9): 1468–1474. doi:10.1359/jbmr.070511. ISSN 0884-0431. PMID 17501668.
8. ^ Cutler, Carolee M.; Lee, Janice S.; Butman, John A.; FitzGibbon, Edmond J.; Kelly, Marilyn H.; Brillante, Beth A.; Feuillan, Penelope; Robey, Pamela G.; DuFresne, Craig R. (2006-11-01). "Long-term outcome of optic nerve encasement and optic nerve decompression in patients with fibrous dysplasia: risk factors for blindness and safety of observation". Neurosurgery. 59 (5): 1011–1017, discussion 1017–1018. doi:10.1227/01.NEU.0000254440.02736.E3. ISSN 1524-4040. PMID 17143235. S2CID 19550908.
9. ^ Leet, Arabella I.; Magur, Edward; Lee, Janice S.; Wientroub, Shlomo; Robey, Pamela G.; Collins, Michael T. (2004-03-01). "Fibrous dysplasia in the spine: prevalence of lesions and association with scoliosis". The Journal of Bone and Joint Surgery. American Volume. 86-A (3): 531–537. doi:10.2106/00004623-200403000-00011. ISSN 0021-9355. PMID 14996879.
10. ^ Riminucci, Mara; Collins, Michael T.; Fedarko, Neal S.; Cherman, Natasha; Corsi, Alessandro; White, Kenneth E.; Waguespack, Steven; Gupta, Anurag; Hannon, Tamara (2003-09-01). "FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting". The Journal of Clinical Investigation. 112 (5): 683–692. doi:10.1172/JCI18399. ISSN 0021-9738. PMC 182207. PMID 12952917.
11. ^ Leet, Arabella I.; Chebli, Caroline; Kushner, Harvey; Chen, Clara C.; Kelly, Marilyn H.; Brillante, Beth A.; Robey, Pamela G.; Bianco, Paolo; Wientroub, Shlomo (2004-04-01). "Fracture incidence in polyostotic fibrous dysplasia and the McCune-Albright syndrome". Journal of Bone and Mineral Research. 19 (4): 571–577. doi:10.1359/JBMR.0301262. ISSN 0884-0431. PMID 15005844. S2CID 37760051.
12. ^ Weinstein, L. S.; Shenker, A.; Gejman, P. V.; Merino, M. J.; Friedman, E.; Spiegel, A. M. (1991-12-12). "Activating mutations of the stimulatory G protein in the McCune-Albright syndrome". The New England Journal of Medicine. 325 (24): 1688–1695. doi:10.1056/NEJM199112123252403. ISSN 0028-4793. PMID 1944469.
13. ^ Riminucci, M.; Fisher, L. W.; Shenker, A.; Spiegel, A. M.; Bianco, P.; Gehron Robey, P. (1997-12-01). "Fibrous dysplasia of bone in the McCune-Albright syndrome: abnormalities in bone formation". The American Journal of Pathology. 151 (6): 1587–1600. ISSN 0002-9440. PMC 1858361. PMID 9403710.
14. ^ Pons Escoda, Albert; Naval Baudin, Pablo; Mora, Paloma; Cos, Mònica; Hernandez Gañan, Javier; Narváez, José A.; Aguilera, Carles; Majós, Carles (2020-02-13). "Imaging of skull vault tumors in adults". Insights into Imaging. 11 (1): 23. doi:10.1186/s13244-019-0820-9. ISSN 1869-4101. PMC 7018895. PMID 32056014.
15. ^ Plotkin, Horacio; Rauch, Frank; Zeitlin, Leonid; Munns, Craig; Travers, Rose; Glorieux, Francis H. (2003-10-01). "Effect of pamidronate treatment in children with polyostotic fibrous dysplasia of bone". The Journal of Clinical Endocrinology and Metabolism. 88 (10): 4569–4575. doi:10.1210/jc.2003-030050. ISSN 0021-972X. PMID 14557424.
16. ^ Boyce, Alison M.; Kelly, Marilyn H.; Brillante, Beth A.; Kushner, Harvey; Wientroub, Shlomo; Riminucci, Mara; Bianco, Paolo; Robey, Pamela G.; Collins, Michael T. (2014-11-01). "A randomized, double blind, placebo-controlled trial of alendronate treatment for fibrous dysplasia of bone". The Journal of Clinical Endocrinology and Metabolism. 99 (11): 4133–4140. doi:10.1210/jc.2014-1371. ISSN 1945-7197. PMC 4223439. PMID 25033066.
17. ^ Leet, Arabella I.; Boyce, Alison M.; Ibrahim, Khalda A.; Wientroub, Shlomo; Kushner, Harvey; Collins, Michael T. (2016-02-03). "Bone-Grafting in Polyostotic Fibrous Dysplasia". The Journal of Bone and Joint Surgery. American Volume. 98 (3): 211–219. doi:10.2106/JBJS.O.00547. ISSN 1535-1386. PMC 4732545. PMID 26842411.
18. ^ a b Stanton, Robert P.; Ippolito, Ernesto; Springfield, Dempsey; Lindaman, Lynn; Wientroub, Shlomo; Leet, Arabella (2012-05-24). "The surgical management of fibrous dysplasia of bone". Orphanet Journal of Rare Diseases. 7 Suppl 1: S1. doi:10.1186/1750-1172-7-S1-S1. ISSN 1750-1172. PMC 3359959. PMID 22640754.
19. ^ Leet, Arabella I.; Magur, Edward; Lee, Janice S.; Wientroub, Shlomo; Robey, Pamela G.; Collins, Michael T. (2004-03-01). "Fibrous dysplasia in the spine: prevalence of lesions and association with scoliosis". The Journal of Bone and Joint Surgery. American Volume. 86-A (3): 531–537. doi:10.2106/00004623-200403000-00011. ISSN 0021-9355. PMID 14996879.
20. ^ Lee, J. S.; FitzGibbon, E. J.; Chen, Y. R.; Kim, H. J.; Lustig, L. R.; Akintoye, S. O.; Collins, M. T.; Kaban, L. B. (2012-05-24). "Clinical guidelines for the management of craniofacial fibrous dysplasia". Orphanet Journal of Rare Diseases. 7 Suppl 1: S2. doi:10.1186/1750-1172-7-S1-S2. ISSN 1750-1172. PMC 3359960. PMID 22640797.
21. ^ Amit, Moran; Collins, Michael T.; FitzGibbon, Edmond J.; Butman, John A.; Fliss, Dan M.; Gil, Ziv (2011-01-01). "Surgery versus watchful waiting in patients with craniofacial fibrous dysplasia--a meta-analysis". PLOS ONE. 6 (9): e25179. Bibcode:2011PLoSO...625179A. doi:10.1371/journal.pone.0025179. ISSN 1932-6203. PMC 3179490. PMID 21966448.
22. ^ Boyce, Alison M.; Glover, McKinley; Kelly, Marilyn H.; Brillante, Beth A.; Butman, John A.; Fitzgibbon, Edmond J.; Brewer, Carmen C.; Zalewski, Christopher K.; Cutler Peck, Carolee M. (2013-01-01). "Optic neuropathy in McCune-Albright syndrome: effects of early diagnosis and treatment of growth hormone excess". The Journal of Clinical Endocrinology and Metabolism. 98 (1): E126–134. doi:10.1210/jc.2012-2111. ISSN 1945-7197. PMC 3537097. PMID 23093488.
23. ^ Leet, Arabella I.; Chebli, Caroline; Kushner, Harvey; Chen, Clara C.; Kelly, Marilyn H.; Brillante, Beth A.; Robey, Pamela G.; Bianco, Paolo; Wientroub, Shlomo (2004-04-01). "Fracture incidence in polyostotic fibrous dysplasia and the McCune-Albright syndrome". Journal of Bone and Mineral Research. 19 (4): 571–577. doi:10.1359/JBMR.0301262. ISSN 0884-0431. PMID 15005844. S2CID 37760051.
## Further reading[edit]
* GeneReviews entry for Fibrous Dysplasia/McCune-Albright Syndrome
## External links[edit]
Classification
D
* ICD-10: K10.8, M85.0, Q78.1
* ICD-9-CM: 526.89, 733.29, 756.54
* MeSH: D005357
External resources
* MedlinePlus: 001234
* eMedicine: radio/284
* Orphanet: 249
* v
* t
* e
Bone and joint disease
Bone
Inflammation
endocrine:
* Osteitis fibrosa cystica
* Brown tumor
infection:
* Osteomyelitis
* Sequestrum
* Involucrum
* Sesamoiditis
* Brodie abscess
* Periostitis
* Vertebral osteomyelitis
Metabolic
* Bone density
* Osteoporosis
* Juvenile
* Osteopenia
* Osteomalacia
* Paget's disease of bone
* Hypophosphatasia
Bone resorption
* Osteolysis
* Hajdu–Cheney syndrome
* Ainhum
* Gorham's disease
Other
* Ischaemia
* Avascular necrosis
* Osteonecrosis of the jaw
* Complex regional pain syndrome
* Hypertrophic pulmonary osteoarthropathy
* Nonossifying fibroma
* Pseudarthrosis
* Stress fracture
* Fibrous dysplasia
* Monostotic
* Polyostotic
* Skeletal fluorosis
* bone cyst
* Aneurysmal bone cyst
* Hyperostosis
* Infantile cortical hyperostosis
* Osteosclerosis
* Melorheostosis
* Pycnodysostosis
Joint
Chondritis
* Relapsing polychondritis
Other
* Tietze's syndrome
Combined
Osteochondritis
* Osteochondritis dissecans
Child
leg:
* hip
* Legg–Calvé–Perthes syndrome
* tibia
* Osgood–Schlatter disease
* Blount's disease
* foot
* Köhler disease
* Sever's disease
spine
* * Scheuermann's_disease
arm:
* wrist
* Kienböck's disease
* elbow
* Panner disease
* v
* t
* e
Osteochondrodysplasia
Osteodysplasia//
osteodystrophy
Diaphysis
* Camurati–Engelmann disease
Metaphysis
* Metaphyseal dysplasia
* Jansen's metaphyseal chondrodysplasia
* Schmid metaphyseal chondrodysplasia
Epiphysis
* Spondyloepiphyseal dysplasia congenita
* Multiple epiphyseal dysplasia
* Otospondylomegaepiphyseal dysplasia
Osteosclerosis
* Raine syndrome
* Osteopoikilosis
* Osteopetrosis
Other/ungrouped
* FLNB
* Boomerang dysplasia
* Opsismodysplasia
* Polyostotic fibrous dysplasia
* McCune–Albright syndrome
Chondrodysplasia/
chondrodystrophy
(including dwarfism)
Osteochondroma
* osteochondromatosis
* Hereditary multiple exostoses
Chondroma/enchondroma
* enchondromatosis
* Ollier disease
* Maffucci syndrome
Growth factor receptor
FGFR2:
* Antley–Bixler syndrome
FGFR3:
* Achondroplasia
* Hypochondroplasia
* Thanatophoric dysplasia
COL2A1 collagen disease
* Achondrogenesis
* type 2
* Hypochondrogenesis
SLC26A2 sulfation defect
* Achondrogenesis
* type 1B
* Autosomal recessive multiple epiphyseal dysplasia
* Atelosteogenesis, type II
* Diastrophic dysplasia
Chondrodysplasia punctata
* Rhizomelic chondrodysplasia punctata
* Conradi–Hünermann syndrome
Other dwarfism
* Fibrochondrogenesis
* Short rib – polydactyly syndrome
* Majewski's polydactyly syndrome
* Léri–Weill dyschondrosteosis
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Fibrous dysplasia of bone | c0259779 | 2,502 | wikipedia | https://en.wikipedia.org/wiki/Fibrous_dysplasia_of_bone | 2021-01-18T19:09:56 | {"gard": ["6444"], "mesh": ["D005357"], "umls": ["C0259779"], "icd-9": ["733.29", "526.89", "756.54"], "icd-10": ["Q78.1", "M85.0", "K10.8"], "orphanet": ["249"], "wikidata": ["Q1410864"]} |
Familial patent arterial duct is a rare, genetic, non-syndromic, congenital anomaly of the great arteries characterized by the presence of an isolated patent arterial duct (PDA) (i.e. failure of closure of ductus arteriosis after birth) in several members of the same family. Clinical presentation is similar to the sporadic form and may range from neonatal-onset tachypnea, diaphoresis and failure to thrive to adult-onset atrial arrhythmia, signs and symptoms of heart failure and cyanosis limited to the lower extremities.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Familial patent arterial duct | c4282128 | 2,503 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=466729 | 2021-01-23T18:45:17 | {"omim": ["607411", "617035", "617039"]} |
Marfan syndrome is a systemic disease of connective tissue characterized by a variable combination of cardiovascular, musculo-skeletal, ophthalmic and pulmonary manifestations.
## Epidemiology
The prevalence is estimated at 1/5,000 and there is no difference between sexes.
## Clinical description
Symptoms can appear at any age and vary greatly between individuals even within the same family. Cardiovascular involvement is characterized by 1) progressive dilation of the aorta accompanied by an increased risk of aortic dissection, which affects prognosis; the aortic dilation can result in a leaky aortic valve; and 2) mitral insufficiency, which can be complicated by arythmias, endocarditis or cardiac insufficiency. Skeletal involvement is often the first sign of the disease and can include dolichostenomelia (excessive length of extremities), large size, arachnodactyly, joint hypermobility, scoliotic deformations, acetabulum protrusion, thoracic deformity (pectus carinatum or pectus excavatum), dolichocephaly of the anteroposterior axis, micrognathism or malar hypoplasia. Ophthalmic involvement results in axile myopia, which can lead to retinal detachment and lens displacement (ectopia or luxation are characteristic signs). Ocular complications, particularly lens ectopia, can lead to blindness. Cutaneous signs (vergetures), a risk of pneumothorax and dural ectasia can also occur.
## Etiology
In the vast majority of cases, Marfan syndrome is caused by mutations of the FBN1 gene (15q21), which codes for fibrilline-1, a protein essential for connective tissues. Frontier forms have been identified that are secondary to mutations in the TGFBR2 gene located on chromosome 3, which codes for a TGF-beta receptor.
## Diagnostic methods
Diagnosis is based on clinical signs and family history. However, as a result of the widely variable clinical picture, the diagnosis can be difficult to establish. International diagnostic criteria (Ghent criteria) based on major and/or minor clinical signs have been established to aid diagnosis.
## Differential diagnosis
Differential diagnoses include MASS syndrome, Shprintzen-Goldberg syndrome, mitral valve prolapse, Ehlers-Danlos syndrome and other diseases that present with aortic aneurysm such as Loeys-Dietz syndrome (see these terms).
## Antenatal diagnosis
Prenatal genetic diagnosis is possible for families in which the causal mutation has been identified.
## Genetic counseling
Transmission is autosomal dominant. An affected individual has a 50% risk of transmitting the mutation responsible for the disease. Some sporadic cases have been reported.
## Management and treatment
Management should be multidisciplinary with consultations from different specialists including cardiologists, geneticists, rheumatologists, ophthalmologists, pediatricians and radiologists. Management should aim to limit aortic dilation (beta-blockers and a reduction in sport activities) and regularly monitor the aorta (annual echocardiograms) in order to allow the aortic root to be replaced before dissection occurs. Surgery can be offered for skeletal anomalies (vertebral column stabilization in the case of scoliosis or reparation of thoracic deformities) and ocular anomalies (laser treatment or replacement of a dislocated lens). Treatment is otherwise symptomatic.
## Prognosis
Prognosis depends on the degree of aortic involvement. With regular follow-up and adequate management, patients now have a life expectancy close to that of the general population. Over the last 30 years that life expectancy has increased by 30 years.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Marfan syndrome | c0024796 | 2,504 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=558 | 2021-01-23T18:08:03 | {"mesh": ["D008382"], "omim": ["154700", "610168"], "umls": ["C0024796"], "icd-10": ["Q87.4"], "synonyms": ["MFS"]} |
Neutrophil immunodeficiency syndrome
SpecialtyImmunology
Frequency<1 / 1 000 000[1]
Neutrophil immunodeficiency syndrome is a condition caused by mutations in the Rac2 gene.[2]
## See also[edit]
* Immunodeficiency with hyper-IgM
* List of cutaneous conditions
* Chronic granulomatous disease
## References[edit]
1. ^ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Neutrophil immunodeficiency syndrome". www.orpha.net. Retrieved 18 March 2019.
2. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1.
## External links[edit]
Classification
D
* ICD-10: D71
* OMIM: 608203
* MeSH: C564275
* SNOMED CT: 723443003
External resources
* Orphanet: 183707
* v
* t
* e
Diseases of monocytes and granulocytes
Monocytes and macrophages
↑
-cytosis:
* Monocytosis
* Histiocytosis
* Chronic granulomatous disease
↓
-penia:
* Monocytopenia
Granulocytes
↑
-cytosis:
* granulocytosis
* Neutrophilia
* Eosinophilia/Hypereosinophilic syndrome
* Basophilia
* Bandemia
↓
-penia:
* Granulocytopenia/agranulocytosis (Neutropenia/Severe congenital neutropenia/Cyclic neutropenia
* Eosinopenia
* Basopenia)
Disorder of phagocytosis
Chemotaxis and degranulation
* Leukocyte adhesion deficiency
* LAD1
* LAD2
* Chédiak–Higashi syndrome
* Neutrophil-specific granule deficiency
Respiratory burst
* Chronic granulomatous disease
* Neutrophil immunodeficiency syndrome
* Myeloperoxidase deficiency
* v
* t
* e
Deficiencies of intracellular signaling peptides and proteins
GTP-binding protein regulators
GTPase-activating protein
* Neurofibromatosis type I
* Watson syndrome
* Tuberous sclerosis
Guanine nucleotide exchange factor
* Marinesco–Sjögren syndrome
* Aarskog–Scott syndrome
* Juvenile primary lateral sclerosis
* X-Linked mental retardation 1
G protein
Heterotrimeic
* cAMP/GNAS1: Pseudopseudohypoparathyroidism
* Progressive osseous heteroplasia
* Pseudohypoparathyroidism
* Albright's hereditary osteodystrophy
* McCune–Albright syndrome
* CGL 2
Monomeric
* RAS: HRAS
* Costello syndrome
* KRAS
* Noonan syndrome 3
* KRAS Cardiofaciocutaneous syndrome
* RAB: RAB7
* Charcot–Marie–Tooth disease
* RAB23
* Carpenter syndrome
* RAB27
* Griscelli syndrome type 2
* RHO: RAC2
* Neutrophil immunodeficiency syndrome
* ARF: SAR1B
* Chylomicron retention disease
* ARL13B
* Joubert syndrome 8
* ARL6
* Bardet–Biedl syndrome 3
MAP kinase
* Cardiofaciocutaneous syndrome
Other kinase/phosphatase
Tyrosine kinase
* BTK
* X-linked agammaglobulinemia
* ZAP70
* ZAP70 deficiency
Serine/threonine kinase
* RPS6KA3
* Coffin-Lowry syndrome
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See also intracellular signaling peptides and proteins
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| Neutrophil immunodeficiency syndrome | c1842398 | 2,505 | wikipedia | https://en.wikipedia.org/wiki/Neutrophil_immunodeficiency_syndrome | 2021-01-18T18:28:59 | {"mesh": ["C564275"], "umls": ["C1842398"], "orphanet": ["183707"], "wikidata": ["Q7003142"]} |
## Summary
### Clinical characteristics.
FH tumor predisposition syndrome is characterized by cutaneous leiomyomata, uterine leiomyomata (fibroids), and/or renal tumors. Pheochromocytoma and paraganglioma have also been described in a small number of families. Cutaneous leiomyomata appear as skin-colored to light brown papules or nodules distributed over the trunk and extremities, and occasionally on the face, and appear at a mean age of 30 years, increasing in size and number with age. Uterine leiomyomata tend to be numerous and large; age at diagnosis ranges from 18 to 53 years, with most women experiencing irregular or heavy menstruation and pelvic pain. Renal tumors are usually unilateral, solitary, and aggressive. They are associated with poor survival due to clinical aggressiveness and propensity to metastasize despite small primary tumor size. The median age of detection is approximately age 40 years.
### Diagnosis/testing.
Diagnosis of FH tumor predisposition syndrome is established by identification of a heterozygous pathogenic variant in FH.
### Management.
Treatment of manifestations: Surgical excision, carbon dioxide laser, cryotherapy, or electrodessication to remove painful cutaneous leiomyomas. Medications are used as an adjunct for pain relief, and may include drugs that lead to vasodilation (e.g., nitroglycerin, nifedipine, phenoxybenzamine, doxazosin) and/or drugs for neuropathic pain (e.g., gabapentin, pregabalin, duloxetine). Treatment of uterine fibroids can include gonadotropin-releasing hormone agonists, antihormonal medications, intrauterine devices releasing progesterone, myomectomy, and hysterectomy. Consultation with a urologic oncology surgeon familiar with this syndrome should be sought for kidney tumors. Total or partial nephrectomy with wide margins may be carefully considered in some settings.
Surveillance: Full skin examination every one to two years to assess for extent of disease and evaluate for changes; annual gynecologic consultation to assess severity of uterine fibroids from age 20 years; annual MRI with 1- to 3-mm slices through kidney from age eight years.
Evaluation of relatives at risk: When the FH pathogenic variant in the family is known, molecular genetic testing of asymptomatic at-risk relatives provides diagnostic certainty, allowing for early surveillance and treatment.
### Genetic counseling.
FH tumor predisposition syndrome is inherited in an autosomal dominant manner. If a parent of a proband has an FH pathogenic variant, the sibs of the proband have a 50% chance of inheriting the pathogenic variant. Each child of an individual with FH tumor predisposition syndrome has a 50% chance of inheriting the pathogenic variant. The degree of clinical severity is not predictable. Preimplantation genetic testing and prenatal testing are possible if the pathogenic variant in the family is known.
## Diagnosis
### Suggestive Findings
FH tumor predisposition syndrome should be suspected in individuals with the following features.
Cutaneous leiomyomata (~50%) [Smit et al 2011, Muller et al 2017, Bhola et al 2018]
* Skin-colored to light brown/reddish papules or nodules distributed over the trunk, extremities, and occasionally on the face and neck
* May be single, grouped/clustered, segmental, or disseminated
* Histopathology shows bundles of smooth muscle fibers with central, long blunt-edged nuclei [Toro et al 2003].
Uterine leiomyomata (uterine fibroids) (~90% of females) [Wei et al 2006, Smit et al 2011, Muller et al 2017]
* Fibroids tend to be numerous and large.
* Fibroids often demonstrate loss of FH staining and positive cytoplasmic staining for S-(2-succino) cysteine [Martínek et al 2015, Andrici et al 2018, Muller et al 2018].
Renal tumors (~15%) [Muller et al 2017]. Usually solitary, highly aggressive renal cell carcinoma (RCC) that metastasizes early
The spectrum of renal tumors includes type 2 papillary, undefined papillary, unclassified, tubulocystic, and collecting-duct carcinoma [Wei et al 2006].
### Establishing the Diagnosis
The diagnosis of FH tumor predisposition syndrome is established in a proband by identification of a heterozygous pathogenic variant in FH on molecular genetic testing (see Table 1).
Molecular genetic testing approaches include gene-targeted testing (multigene panel, single-gene testing) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of FH tumor predisposition 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 FH tumor predisposition 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 FH tumor predisposition syndrome, molecular genetic testing approaches can include use of a multigene panel or single-gene testing:
* A multigene panel that includes FH and other genes of interest (see Differential Diagnosis) may be used as an initial test as it is often the most comprehensive and cost-effective approach. This strategy may yield 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) Almost all multigene panels include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For FH tumor predisposition syndrome, a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
* Single-gene testing. Perform sequence analysis and gene-targeted deletion/duplication analysis of FH to detect small intragenic deletions/insertions, missense, nonsense, splice site variants, and intragenic deletions and duplications.
#### Option 2
When the diagnosis of FH tumor predisposition 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) may be considered. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including FH) that cannot be detected by sequence analysis.
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 FH Tumor Predisposition Syndrome
View in own window
Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
FHSequence analysis 3~90% 4
Gene-targeted deletion/duplication analysis 5~10% 6
1\.
See Table A. Genes and Databases for chromosome locus and protein.
2\.
See Molecular Genetics for information on allelic variants detected in this gene.
3\.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4\.
Toro et al [2003], Alam et al [2005], Wei et al [2006], Gardie et al [2011], Smit et al [2011]
5\.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (as described in Human Gene Mutation Database [Stenson et al 2017]) may not be detected by these methods.
6\.
Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]
## Clinical Characteristics
To date, more than 300 families with characteristic features of FH tumor predisposition syndrome and a pathogenic variant in FH have been reported [Smit et al 2011, Muller et al 2017]. More recent studies have shown wider phenotypic variability in individuals with FH tumor predisposition syndrome than previously described in HLRCC.
### Clinical Description
FH tumor predisposition syndrome is characterized by cutaneous leiomyomas, uterine leiomyomata (fibroids), and/or renal tumors. Pheochromocytoma and paraganglioma have also been described in a small number of families. Affected individuals may have a single, multiple, or no cutaneous leiomyomas, typically one or more uterine fibroids, and/or a single or no renal tumors. Rarely, individuals may develop multifocal renal tumors. Disease severity shows significant intra- and interfamilial variation [Wei et al 2006].
Cutaneous leiomyomas. Clinically, cutaneous leiomyomas present as firm skin-colored to light brown-colored papules and nodules. These cutaneous lesions occur at a mean age of 30 years (range: age 10-77 years) [Muller et al 2017] and tend to increase in size and number with age. Affected individuals often note that the skin lesions are painful or sensitive to light touch and/or cold temperature [Lehtonen 2011].
Histologically, proliferation of bundles of smooth muscle fibers with central blunt-edged nuclei is observed [Toro et al 2003].
Cutaneous leiomyosarcoma. In a series of 182 individuals with FH tumor predisposition syndrome from 114 families, three individuals developed skin leiomyosarcoma [Muller et al 2017]. Due to changes in diagnostic criteria and nomenclature, lesions previously called leiomyosarcoma may have been atypical smooth-muscle neoplasms/leiomyomas [Kraft & Fletcher 2011].
Uterine leiomyomas (uterine fibroids). Women with FH tumor predisposition syndrome have more uterine fibroids and onset at a younger age than women in the general population. The age at identification of fibroids ranges from 18 to 53 years (mean: age ~30 years) [Lehtonen 2011]. Uterine fibroids in women with FH tumor predisposition syndrome are usually large and numerous and associated with irregular menses, menorrhagia, or pain [Lehtonen 2011]. Women with FH tumor predisposition syndrome often undergo hysterectomy or myomectomy for symptomatic uterine fibroids at a younger age. In one series, 59 of 114 women (52%) with FH tumor predisposition syndrome had myomectomy or hysterectomy with median age of 35 (range 25-58) [Muller et al 2017].
Among a cohort of 2,060 women with uterine smooth muscle tumors, a prospective screening program identified a tumor with FH-deficient morphology in 30 individuals (1.4%). Histologic criteria for FH-deficient morphology included alveolar pattern edema and staghorn-shaped blood vessels under low magnification, and smooth muscle cells with a macro-nucleolus surrounded by a halo and eosinophilic globules seen under high magnification [Rabban et al 2019]. Ten women with a tumor with this morphology elected to proceed with germline FH molecular testing; of these, five were found to have a germline FH pathogenic variant, suggesting that uterine tumor histology could be used to identify individuals with FH tumor predisposition syndrome [Rabban et al 2019].
Uterine leiomyosarcoma. Six women with a germline FH pathogenic variant and uterine leiomyosarcoma have been reported in the Finnish population; including three individuals with an additional pathogenic variant identified in tumor tissue, and one individual with isolated leiomyosarcoma, decreased FH activity, but no pathogenic variant identified on tumor tissue testing [Lehtonen et al 2006, Ylisaukko-oja et al 2006b]. However, uterine leiomyosarcoma has not been reported in other cohorts [Muller et al 2017]. Due to changes in diagnostic criteria and nomenclature, lesions previously called leiomyosarcoma may in fact be atypical smooth-muscle neoplasms/leiomyomas [Muller et al 2017].
Renal cancer. Most renal tumors are unilateral and solitary; in a few individuals, they are multifocal. The symptoms of renal cancer may include hematuria, lower back pain, and a palpable mass. However, a large number of individuals with renal cancer are asymptomatic. Furthermore, not all individuals with FH tumor predisposition syndrome present with or develop renal cancer.
Of 182 individuals with FH tumor predisposition syndrome from 114 families, 34 (19%) were diagnosed with RCC(s). The median age at diagnosis was 40 years. Of 31 individuals with follow-up data available, 82% developed metastatic disease: 16 (47%) presented with metastatic RCC (de novo metastatic disease) and another 12 (35%) became metastatic within three years. Among individuals with metastatic RCC, median survival was 18 months [Muller et al 2017].
FH tumor predisposition syndrome is associated with a spectrum of renal tumors including type 2 papillary, undefined papillary, unclassified, tubulocystic, and collecting-duct carcinoma [Wei et al 2006].
FH-related RCC often shows loss of FH staining and positive staining for S-(2-succino) cysteine. Immunohistochemistry cannot distinguish between tumors due to FH tumor predisposition syndrome and those due to biallelic somatic pathogenic variants.
The Cancer Genome Atlas has additionally reported a CpG island methylator phenotype (CIMP) as the signature FH-associated RCC [Cancer Genome Atlas Research Network 2016].
Pheochromocytoma and paraganglioma. In 2014, two studies aimed at identifying new pheochromocytoma and paraganglioma susceptibility genes identified FH germline pathogenic variants in seven of 570 affected individuals [Castro-Vega et al 2014, Clark et al 2014]. Subsequently, two individuals with FH tumor predisposition syndrome from a French cohort (1%) were diagnosed with pheochromocytoma [Muller et al 2017]. The lifetime risks for pheochromocytoma and paraganglioma are unknown.
Other. In a Finnish population-based study of FH tumor predisposition syndrome, four individuals with breast cancer and one individual with bladder cancer were identified. In three of three breast cancers examined, loss of the wild type FH allele was noted [Lehtonen et al 2006].
While other tumors have been described in individuals with germline FH pathogenic variants, further data will be needed to determine whether these are FH-related tumors [Lehtonen et al 2006, Ylisaukko-oja et al 2006a].
### Genotype-Phenotype Correlations
No correlation is observed between specific FH pathogenic variants and the occurrence of cutaneous lesions, uterine fibroids, or renal cancer [Wei et al 2006].
FH pathogenic variants reported in families with paraganglioma include the following missense and splice site variants: p.Ala117Pro, c.268-2A>G, p.Thr381Ile, p.Ala194Thr, p.Asn329Ser, p.Cys43Tyr, p.Glu53Lys [Castro-Vega et al 2014, Clark et al 2014].
Pathogenic variant c.700A>G; p.Thr234Ala has been identified in approximately ten families with paraganglioma/pheochromocytoma with and without renal cell carcinoma [Author, personal communication].
### Penetrance
Penetrance is currently unknown, as most studies have focused on families with clinical manifestations.
### Nomenclature
Historically, the predisposition to the development of cutaneous leiomyomas was referred to as multiple cutaneous leiomyomatosis (MCL/MCUL).
Reed et al [1973] described two kindreds in which multiple members exhibited cutaneous leiomyomas and uterine leiomyomas inherited in an autosomal dominant manner. Subsequently, the association of cutaneous and uterine leiomyomas was referred to as Reed's syndrome.
The association of cutaneous and uterine leiomyomas with renal cancer was described in two Finnish families [Launonen et al 2001]. The name hereditary leiomyomatosis and renal cell cancer (HLRCC) was designated.
Germline FH pathogenic variants are now known to be associated with a predisposition to a variety of tumors. The term "FH tumor predisposition syndrome" acknowledges this emerging understanding.
### Prevalence
The prevalence of FH pathogenic variants is not known. FH tumor predisposition syndrome is likely to be under-recognized.
## Differential Diagnosis
Cutaneous lesions. Cutaneous leiomyomas are rare and highly suggestive of FH tumor predisposition syndrome. Because leiomyomas are clinically similar to various cutaneous lesions, histologic diagnosis is required.
Uterine fibroids. Uterine leiomyoma is the most common benign pelvic tumor in women in the general population. The majority of uterine fibroids are not associated with an increased risk of other tumors. Characteristic histologic features and loss of expression of FH on immunohistochemistry should prompt germline genetic evaluation [Harrison et al 2016].
Renal tumor. Familial renal cancer syndromes are usually associated with specific renal pathology. Selected familial renal cancer syndromes and their specific renal pathology are summarized in Table 2. All are inherited in an autosomal dominant manner. A study of individuals with aggressive renal cell cancer (RCC) (stage 3 and stage 4) found a high proportion of germline pathogenic variants (16%) [Carlo et al 2018], many of which had not been previously associated with RCC. Known monogenic, syndromic, well-delineated causes of RCC are included in the table below.
### Table 2.
Familial Renal Cancer Syndrome Comparisons
View in own window
DisorderGene(s)Renal TumorCutaneous LesionsOther Common Findings
FH tumor predisposition syndromeFHVariable; includes: papillary type 2 RCC, undefined papillary, unclassified, tubulocystic, collecting-duct carcinomaCutaneous leiomyomaUterine fibroids (early onset, multiple lesions)
Von Hippel-Lindau syndromeVHLClear cell RCCNone
* CNS hemangioblastoma
* Retinal angioma
* Renal cysts
* Pancreatic cysts
* Pancreatic tumors
* Pheochromocytoma
Birt-Hogg-Dubé syndromeFLCNVarious:
* Oncocytoma (benign)
* Chromophobe RCC (malignant)
* Hybrid chromophobe/oncocytic tumor
* Cutaneous fibrofolliculoma
* Trichodiscoma
* Acrochordon
* Cutaneous fibrofolliculomas
* Multiple lung cysts
* Spontaneous pneumothorax
Hereditary papillary renal cancer (OMIM 605074)METPapillary type 1 RCCNoneNone
BAP1 tumor predisposition syndromeBAP1Clear cell RCCAtypical cutaneous melanoma (also described as BAPoma, atypical Spitz tumors)
* Mesothelioma (pleural/peritoneal)
* Uveal melanoma
* Cutaneous melanoma
* Rhabdoid meningioma
CNS = central nervous system; RCC = renal cell carcinoma
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with FH tumor predisposition syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
### Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with FH Tumor Predisposition Syndrome
View in own window
System/ConcernEvaluationComment 1
IntegumentDetailed dermatologic examinationAt diagnosis to evaluate extent of disease & presence of atypical lesions
GenitourinaryGynecology consultationBeginning at age 20 yrs or earlier if symptomatic to assess for severity of fibroids if present
Baseline thin-slice (1-3mm) renal MRI
* Beginning at age 8 yrs to evaluate for renal tumors
* Abdominal CT scan w/contrast may also be performed although MRI is preferred.
Pheochromocytoma/
paragangliomaBaseline blood pressure
* At diagnosis; no uniform guidelines currently exist.
* For genotypes assoc w/paraganglioma or persons w/personal/family history of paraganglioma, consider baseline MRI from skull base through pelvis & fractionated plasma metanephrines.
OtherConsultation w/genetic counselor, cancer genetics program, &/or clinical geneticist
1\.
For children diagnosed with FH tumor predisposition syndrome, dermatologic exam, baseline blood pressure, and consultation with a genetic counselor or clinical geneticist may occur at diagnosis. MRI is recommended to begin at age eight, and gynecologic exam at age 20 or earlier if symptomatic [Schultz et al 2017].
### Treatment of Manifestations
Cutaneous lesions. Cutaneous leiomyomas should be examined by a dermatologist. Treatment of cutaneous leiomyomas may involve the following:
* Surgical excision, especially for a solitary or a few symptomatic lesions, is considered standard therapy [Malik et al 2015, Patel et al 2017].
* Lesions may also be treated by carbon dioxide laser, cryotherapy, or electrodessication [Malik et al 2015, Adams et al 2017, Patel et al 2017].
* Lesions have a high rate of recurrence [Malik et al 2015].
* Medications are used as an adjunct for pain relief, and may include drugs that lead to vasodilation (such as nitroglycerin, nifedipine, phenoxybenzamine or doxazosin) and/or drugs for neuropathic pain (such as gabapentin, pregabalin, and duloxetine) [Patel et al 2017].
* In one small randomized controlled trial, intralesional botulinum toxin improved quality of life [Naik et al 2015].
Uterine fibroids should be evaluated by a gynecologist.
* Most women with FH tumor predisposition syndrome require medical and/or surgical intervention earlier than women without an FH germline pathogenic variant.
* Medical therapies include gonadotropin-releasing hormone agonists (GnRHa) and intrauterine devices releasing progesterone [Patel et al 2017].
* Surgical options include myomectomy and hysterectomy.
* If surgery is performed, careful histologic examination is recommended to differentiate between atypical smooth muscle neoplasm and leiomyosarcoma.
Renal tumors. Given the aggressiveness and poor prognosis associated with FH-related RCC, surgical excision of renal malignancies appears to require earlier and possibly more extensive surgery than other hereditary renal cancers.
* Early detection and surgical excision are critical at the first sign of FH-related RCC. Expert opinion should be sought with a urologic oncology surgeon familiar with FH tumor predisposition syndrome. Due to metastatic potential, lymph node dissection may be considered for staging even in the setting of small tumors.
* Given the aggressive nature of these tumors, only total nephrectomy was previously recommended. However, partial nephrectomy with a wide margin may be carefully considered in some settings when small, localized tumors may allow for complete excision (see NCI-PDQ® Genetics of Kidney Cancer).
* Consultation by an expert familiar with this syndrome is indicated.
* Non-surgical approaches such as surveillance, cryoablation, and radiofrequency ablation are not appropriate for the management of FH-related renal malignancies [Adams et al 2017].
### Surveillance
Regular surveillance with an emphasis on early detection of RCC by clinicians familiar with the clinical manifestations of FH tumor predisposition syndrome is recommended. Surveillance may also be considered for individuals with a suspected diagnosis in whom an FH pathogenic variant has not been identified, as well as for at-risk family members who have not undergone molecular genetic testing. Surveillance guidelines still require prospective validation, preferably in the context of international multicenter collaboration [Menko et al 2014, Schultz et al 2017].
### Table 4.
Recommended Surveillance for Individuals with FH Tumor Predisposition Syndrome
View in own window
System/ConcernEvaluationFrequency
Cutaneous leiomyomaFull skin examination to assess extent of disease & evaluate for changesAnnually to every 2 yrs from time of diagnosis
Uterine leiomyomaGynecologic consultation to assess severity of uterine fibroidsAnnually from age 20 yrs or at time of 1st gynecologic exam (whichever is earlier), or earlier in symptomatic individuals
Renal tumors
* MRI w/contrast w/1- to 3-mm slices through kidney is preferred. 1, 2
* CT w/contrast may be used as an alternative. 3
Annually starting at age 8 yrs 4
Suspicious lesions (indeterminate lesion, questionable or complex cysts) detected at a previous examination should have prompt follow up. 5, 6
* Early detection is important.
* Renal tumors should be evaluated by a urologic oncology surgeon familiar w/FH tumor predisposition syndrome.
Pheochromocytoma/
paragangliomaNo uniform guidelines currently exist.
1\.
Consensus recommendations for surveillance of RCC were developed in the context of an international HLRCC symposium. Renal ultrasound is not recommended for primary surveillance due to low sensitivity to detect small lesions [Menko et al 2014].
2\.
MRI avoids radiation exposure, though gadolinium-based contrast agents – which are incompletely eliminated from the body – are currently used. However, there are currently no known adverse health effects from gadolinium retention in individuals with normal renal function.
3\.
NCI-PDQ® Genetics of Kidney Cancer
4\.
The recommended age at which to begin renal surveillance has ranged significantly, from as early as age five years [Alrashdi et al 2010] to adulthood [Lehtonen 2011, Smit et al 2011]. Consensus guidelines developed at the HLRCC symposium recommended screening beginning at age eight to ten years [Menko et al 2014]. Consensus pediatric cancer predisposition guidelines developed at an AACR workshop similarly recommend starting at age eight years [Schultz et al 2017].
5\.
NCI-PDQ® Genetics of Kidney Cancer
6\.
Surveillance by an expert in this condition is indicated. In the right clinical scenario, renal ultrasound may be used to further characterize a cystic lesion but should never be used to replace MRI or CT as a primary surveillance modality.
### Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual by molecular genetic testing for the FH pathogenic variant in the family in order to identify as early as possible those who would benefit from early surveillance and treatment and reduce costly screening procedures in those who have not inherited the pathogenic variant.
There have been variable recommendations regarding the most appropriate age at which to perform predictive testing for a familial germline FH pathogenic variant. Consensus recommendations from an American Association for Cancer Research (AACR) workshop on cancer predisposition among children and adolescents supports germline testing from age eight years. Surveillance for RCC in heterozygotes is also suggested to begin at age eight years [Schultz et al 2017]. This age was agreed upon as it precedes the youngest reported cases of FH-related RCC. These include an 8.5-cm papillary RCC discovered on first surveillance ultrasound in a child at age 11 years with a palpable renal mass [Alrashdi et al 2010], and an additional child found to have an RCC at age ten years [Menko et al 2014]. Nevertheless, the overall risk of developing RCC before age 20 years remains low (estimated at 1%-2%) [Menko et al 2014].
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Therapies Under Investigation
FH-related RCC
* Many individuals with advanced disease have received vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) or mammalian target of rapamycin (mTOR) inhibitors. Several studies of anti-VEGF and novel tyrosine kinase inhibitor treatment in individuals with FH tumor predisposition syndrome and papillary RCC (including papillary type 2 RCC) have been conducted [Linehan & Rouault 2013]. Improvement of progression-free survival in individuals with papillary type 2 RCC with sunitinib was reported [Choueiri et al 2008, Clinical Trials].
* There is also interest in targeting FH-related RCC using a metabolic approach such as metformin in combination with vandetanib to inhibit DNA hypermethylation related to fumarate accumulation [Clinical Trials].
* Targeting of tumor vasculature and glucose transport has been attempted using bevacizumab and erlotinib. Park et al [2019] reported long-term response to bevacizumab plus erlotinib after failure of temsirolimus followed by axitinib in an adult with FH tumor predisposition syndrome-related RCC [Park et al 2019]. A retrospective analysis of this combination in ten individuals including untreated and previously treated individuals showed an overall response rate of 50% [Choi et al 2019]. A prospective trial of this combination in previously untreated advanced papillary RCC is underway with preliminary results suggesting a 50% (12/20) overall response rate and 100% disease control rate in individuals with FH tumor predisposition syndrome [Srinivasan et al 2014].
Fumarate accumulation in FH-deficient cells may lead to a defect in homologous recombination double-strand break repair. This suggests a vulnerability to PARP (poly ADP-ribose polymerase) inhibition demonstrated in cell lines and in mice with FH-deficient tumors [Sulkowski et al 2018]. Human clinical trials using combination therapy for these tumors are currently in development [Author, personal communication].
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.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| FH Tumor Predisposition Syndrome | c1708350 | 2,506 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1252/ | 2021-01-18T21:27:30 | {"mesh": ["C535516"], "synonyms": ["Hereditary Leiomyomatosis and Renal Cell Cancer", "HLRCC", "Multiple Cutaneous and Uterine Leiomyomatosis (MCL/MCUL)", "Reed's Syndrome"]} |
## Clinical Features
Van Wart (1978) reported a family in which father and 2 daughters had congenital absence of the nasal bones. Two sons and another daughter were normal.
Guerrissi (1993) reported a 20-year-old woman with absence of both nasal bones as an isolated malformation. Absence of the nasal bones was determined by means of internal and external examination, and subsequently confirmed by radiographic scan. The upper cartilaginous vault had a cartilaginous hump that was formed not only by excess cartilage, but also indirectly by lack of the bones. Other esthetic defects included deficient tip projection, small nostrils, and a short columella. Guerrissi (1993) suggested that the absence of both nasal bones was produced by failure of the development of both centers of ossification.
Klinger et al. (2005) reported a 26-year-old woman who had isolated absence of nasal bones, and, in their stead, a hump composed exclusively of septal cartilage and the cranial portion of the upper lateral cartilages. CT scan confirmed that the nose was supported exclusively by cartilaginous structures. Rhinoplasty was performed with good result and without complications during 2-year follow-up. At clinical examination, the patient's father showed the same isolated nasal defect and a deceased maternal uncle was said to have been affected.
Shino et al. (2005) studied a 9-year-old Japanese boy with congenital arhinia, who had absence of the nasal bones, nasal septum, and turbinates. Associated facial anomalies included high-arched palate, maxillary hypoplasia, and absent olfactory bulbs and tracts. The eruptive teeth and nasolacrimal ducts were present in the maxillary bone, but he had epiphora due to obstruction of the ducts medial to the orbits. He did not exhibit hypertelorism, and ophthalmologic examination was normal.
INHERITANCE \- Autosomal dominant HEAD & NECK Nose \- Small nostrils \- Short columella \- Cartilaginous nasal bridge \- Absence of nasal bones SKELETAL Skull \- Absence of nasal bones ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| NASAL BONES, ABSENCE OF | c0339851 | 2,507 | omim | https://www.omim.org/entry/161480 | 2019-09-22T16:37:37 | {"mesh": ["C562753"], "omim": ["161480"]} |
Intermetamorphosis
SpecialtyPsychiatry
Intermetamorphosis is a delusional misidentification syndrome, related to agnosia. The main symptoms consist of patients believing that they can see others change into someone else in both external appearance and internal personality.[1] The disorder is usually comorbid with neurological disorders or mental disorders. The disorder was first described in 1932 by Paul Courbon (1879-1958),a French Psychiatrist.[2] Intermetamorphosis is rare, although issues with diagnostics and comorbidity may lead to under-reporting.[3]
## Contents
* 1 Signs and symptoms
* 1.1 Example
* 1.2 Violence
* 1.3 Comorbidity
* 2 Cause
* 3 Diagnosis
* 4 Treatment
* 5 Reverse Intermetamorphosis
* 6 References
## Signs and symptoms[edit]
Individuals experiencing intermetamorphosis, as well as the other delusional misidentification syndromes (DMS), tend to misidentify those people that are both physically and emotionally close to them; the most commonly misidentified people are parents, siblings and spouses.[4] There are instances of individuals misidentifying people not known to them, however, they still held an affective importance, such as celebrities or politicians.[4] The explanations for the inauthenticity of the misidentified people are associated with the individual experiencing the delusions’ cultural background.[4]
### Example[edit]
An example from medical literature is a man who was diagnosed with Alzheimer's disease. He mistook his wife for his deceased mother and later for his sister. He explained that he had never been married or that his wife had left him. Later he mistook his son for his brother and his daughter for another sister. Visual agnosia or prosopagnosia were not diagnosed, as the misidentification also took place during phone calls. On several occasions he mistook the hospital for the church he used to go to.
### Violence[edit]
There is an association in the literature between misidentification syndromes and violent or aggressive behavior.[3] [5][6][7] In several case studies, individuals with misidentification syndromes acted aggressively towards the object of misidentification, which has the potential for criminal behavior.[3] [5] [7] This may be because the delusions cause individuals to view the misidentified object with suspicion, and they become paranoid about the inauthenticity of the object, leading to an act of presumed preemptive self-defense.[7] [4] Although gender differences in the occurrence of intermetamorphosis are not pronounced, the research demonstrates that a majority (70%) of occurrences with violent behavior involves males.[4] The issue of violent and aggressive behavior within this set of syndromes continues to play an important role in the discussion of criminal responsibility and risk assessment. [7]
### Comorbidity[edit]
Intermetamorphosis and other DMSs often occur together or interchange.[8] [3] [7] [9] DMSs are also often comorbid with psychiatric disorders, such as schizophrenia, schizoaffective disorder, bipolar disorder, and PTSD.[6] [7] [4] Paranoid schizophrenia is most commonly associated with DMSs.[6] [7] [4] They are also associated with neurological conditions or diseases, including dementia, Alzheimer’s disease and alcohol- or drug-induced cognitive impairment.[3] [6] [7] Among comorbid symptoms, paranoid psychotic symptoms, depressive psychotic symptoms and auditory hallucinations are the most often present.[6]
## Cause[edit]
Explanations for the occurrence of intermetamorphosis were first given by psychodynamic theorists.[3] [6] [9] These theories typically involve a psychotic resolution towards an individual’s feelings of intense ambivalence about the misidentified object.[5] These theories may also involve the egos and identity-forming, as well as defense mechanisms involving splitting the negative and positive aspects of the self.[7] Despite their initial popularity, there is not much empirical support for these psychodynamic explanations.
Recent advancements in neuroimaging and structural studies have provided evidence of an organic etiology.[3] [9] Neurological dysfunction and neuropsychiatric abnormalities, in various forms, are now believed to be a central feature in DMSs.[3] [4] Neuropsychological findings suggest that symptoms are produced in some aspect by brain dysfunction or damage, specifically in the right hemisphere.[3] [8][6] Lesions in the right frontal lobe and adjacent areas have been found through neuroimaging in case reports of intermetamorphosis.[7] [9] In studying over 20 patients with misidentification syndromes, Christodoulou[8] found electroencephalographic abnormalities in over 90%. In one case of intermetamorphosis, Joseph[10] reported electroencephalographic abnormalities with right temporo-parietal predominance. Impaired connectivity or dysconnectivity between the right fusiform and right parahippocampal areas and the frontal lobes and the right temporolimbic regions have also been seen in case reports of this syndrome, which are thought to be implicated in deficits in face recognition, visual memory recall, and identification processes.[7] While impairments in facial processing are experienced by most DMSs, it appears to be experienced more consciously in intermetamorphosis than in other DMSs.[4] Cortical atrophy is also sometimes present, although this may be due to co-occurring dementia and other organic mental syndromes.[6] Overactivity in the perirhinal cortex appears to be associated with the loss of familiarity in intermetamorphosis.[3] Depersonalization has also been postulated as a contributing factor to the development of intermetamorphosis; under conditions like the presence of a paranoid element, a charged emotional relationship to the principal misidentified person, and cerebral dysfunction, depersonalization and derealization symptoms may develop into a full delusional misidentification syndrome.[8]
## Diagnosis[edit]
How to define intermetamorphosis and other delusional misidentification syndromes is frequently debated in the literature. Some believe that misidentification is a symptom, and that the overlapping nature of these syndromes suggests that they are “states” associated with other psychiatric or neurological disorders, but that they're not diagnostic in themselves.[5] [6] [7] [4] As their name suggests, many professionals consider them syndromes, because misidentification appears to occur more often in association with certain symptoms, like depersonalization, derealization, and paranoia.[3] [4] Lastly, some believe that they should be discrete diagnoses in the Diagnostic and Statistical Manual of Mental Disorders.[3] [4]
## Treatment[edit]
Results regarding the efficacy of treatments for intermetamorphosis are mixed. Treatment of any co-occurring mental disorder or substance abuse is necessary.[7] There have been no controlled studies about pharmacological treatments of intermetamorphosis.[3] However, both atypical and typical antipsychotics are often used, and have been found to be effective in patients with both organic and functional disorders.[3] [7] Some that have been effective in case studies are clozapine, olanzapine, risperidone, quetiapine, sulpiride, trifluoperazine, pimozide, haloperidol and carbamazepine.[3] [7] [9] Clorazepate, a benzodiazepine used in the treatment of anxiety and seizure disorders, has also been used effectively.[7] [10] Occasionally, antidepressants and lithium have been used, especially in the instance of a co-occurring mood or bipolar disorder.[7]
## Reverse Intermetamorphosis[edit]
A proposed variant of intermetamorphosis is the syndrome of “reverse” intermetamorphosis, in which there is the delusional belief that an individual is undergoing radical changes in both physical and psychological identities.[4]
## References[edit]
1. ^ Semple, David. "Oxford Hand Book Of Psychiatry" Oxford Press. 2005. p238.
2. ^ Illusions d'intermétamorphose et de la charme, Annales Medico-Psychologiques, issue 14, page 401-406.
3. ^ a b c d e f g h i j k l m n o Cipriani, G., Vedovello, M., Ulivi, M., Lucetti, C., Fiorino, A. D., & Nuti, A. (2013). Delusional Misidentification Syndromes and Dementia: A Border Zone Between Neurology and Psychiatry. American Journal of Alzheimer’s Disease & Other Dementias, 28(7), 671–678.
4. ^ a b c d e f g h i j k l m Silva, J. A., Leong, G. B., & Weinstock, R. (1992). The dangerousness of persons with misidentification syndromes. Bulletin of the American Academy of Psychiatry & the Law, 20(1), 77-86.
5. ^ a b c d De Pauw, K. W., & Szulecka, T. K. (1988). Dangerous delusions: Violence and the misidentification syndromes. The British Journal of Psychiatry, 152, 91-96.
6. ^ a b c d e f g h i Förstl, H., Almeida, O., Owen, A., Burns, A., & Howard, R. (1991). Psychiatric, neurological and medical aspects of misidentification syndromes: A review of 260 cases. Psychological Medicine, 21(4), 905-910.
7. ^ a b c d e f g h i j k l m n o p q Klein, C. A., & Hirachan, S. (2014). The masks of identities: Who's who? delusional misidentification syndromes. Journal of the American Academy of Psychiatry and the Law, 42(3), 369-378.
8. ^ a b c d Christodoulou, G.N., Margariti, M., Kontaxakis, V.P. (2009). The delusional misidentification syndromes: Strange, fascinating, and instructive. Current Psychiatry Reports, 11, 185-189.
9. ^ a b c d e Young, A. H., Ellis, H. D., Szulecka, T. K., & de Pauw, K. W. (1990). Face processing impairments and delusional misidentification. Behavioural Neurology, 3(3), 153-168.
10. ^ a b Joseph, A. B. (1987). Delusional misidentification of the Capgras and intermetamorphosis types responding to clorazepate. Acta Psychiatrica Scandinavica, 75, 330-332.
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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
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Intermetamorphosis | c0278086 | 2,508 | wikipedia | https://en.wikipedia.org/wiki/Intermetamorphosis | 2021-01-18T19:08:02 | {"umls": ["C0278086"], "wikidata": ["Q3417919"]} |
Griscelli syndrome (GS) is a rare cutaneous disease characterized by a silvery-gray sheen of the hair and hypopigmentation of the skin, which can be associated to primary neurological impairment (type 1), immunologic impairment (type 2) or be isolated (type 3).
## Epidemiology
To date, approximately 150 cases have been reported, predominantly in Turkish and Mediterranean populations. GS type 2 appears to be the most common of the three known types, while GS type 3 is the least common.
## Clinical description
GS occurs in infancy to childhood. In addition to the silvery-gray sheen of the hair and the light-colored skin, GS type 1 patients present with delayed motor development, intellectual disability and hypotonia. GS type 2 patients have the same hypopigmentation features but in association with immune pathology. Patients exhibit a lymphocyte cytotoxic defect resulting in an uncontrolled T-lymphocyte and macrophage-activation syndrome, also known as hemophagocytic syndrome (HLH), in which activated T cells and macrophages infiltrate the lymph nodes and other organs (including the brain), producing hemophagocytosis. Patients with GS type 2 can present neurological symptoms due to brain infiltration by the activated hematopoietic cells. In GS type 3 patients, hypopigmentation of the skin and hair is the only feature.
## Etiology
GS type 1 is caused by a mutation in the myosin Va (MYO5A) gene located on chromosome 15q21 and likely corresponds to Elejalde disease. GS type 2 is caused by mutations in the RAB27A encoding gene. Myosin-5a and RAB27A genes have been localized to the same chromosomal 15q21 region and encode for proteins which are key effectors of intracellular vesicular transport. Myosin Va regulates organelle transport in both melanocytes and neuronal cells, whereas RAB27A, regulates exocytic pathways, especially the cytotoxic granule exocytosis. The cytotoxic defect caused by RAB27A mutations is responsible for the hemophagocytic syndrome observed. GS type 3 is due to mutations in the MLPH gene, a gene encoding melanophilin, which forms a protein complex with Rab 27a and myosin Va, and participates in melanosome transport in melanocytes.
## Diagnostic methods
The diagnosis of the three types of GS can be established by the clinical signs and light microscopic examination, evidencing large clumps of pigment in hair shafts and the accumulation of mature melanosomes in melanocytes. A decrease in T and NK lymphocyte degranulation and cytotoxicity characterize GS type 2. No immunological or cytotoxic defects have been observed in GS type 1 or 3. Thus, based on the patient's clinical and biological features, sequencing of the corresponding causative gene allows confirmation of the type of GS.
## Differential diagnosis
GS can be distinguished from Chediak-Higashi syndrome by the lack of giant granules in granulocytes of GS patients. The differential diagnosis of GS type 1 also includes Elejalde disease.
## Antenatal diagnosis
Antenatal diagnosis of GS type 1 and 2 can be performed through chorionic villus sampling by the sequencing of the MYO5A or RAB27A gene, respectively.
## Genetic counseling
GS is an autosomal recessive disorder and genetic counseling informing affected couples of a 25% risk of having an affected child is possible.
## Management and treatment
Treatment for GS type 1 is only symptomatic. In GS type 2, the hemophagocytic syndrome is often fatal and the only cure is hematopoietic stem cell transplantation (HSCT). Currently there is no specific management for GS type 3.
## Prognosis
If not treated by HSCT, the prognosis for long-term survival in GS type 2 is relatively poor, with many patients not surviving the first decade. The prognosis of GS type 1 is good. GS type 3 should be better considered as a pigmentation phenotype rather than a pathology with a prognosis similar to the control population.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Griscelli syndrome | c1859194 | 2,509 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=381 | 2021-01-23T18:05:25 | {"gard": ["10913"], "mesh": ["C537301"], "omim": ["214450", "607624", "609227"], "icd-10": ["E70.3"], "synonyms": ["Chédiak-Higashi-like syndrome", "Griscelli-Pruniéras syndrome", "Partial albinism-immunodeficiency syndrome"]} |
A number sign (#) is used with this entry because autosomal dominant oculodentodigital dysplasia (ODDD) is caused by heterozygous mutation in the connexin-43 gene (GJA1; 121014) on chromosome 6q22.
Description
Oculodentodigital syndrome is characterized by a typical facial appearance and variable involvement of the eyes, dentition, and fingers. Characteristic facial features include a narrow, pinched nose with hypoplastic alae nasi, prominent columella and thin anteverted nares together with a narrow nasal bridge, and prominent epicanthic folds giving the impression of hypertelorism. The teeth are usually small and carious. Typical eye findings include microphthalmia and microcornea. The characteristic digital malformation is complete syndactyly of the fourth and fifth fingers (syndactyly type III) but the third finger may be involved and associated camptodactyly is a common finding (summary by Judisch et al., 1979).
Neurologic abnormalities are sometimes associated (Gutmann et al., 1991), and lymphedema has been reported in some patients with ODDD (Brice et al., 2013). See review by De Bock et al. (2013).
### Genetic Heterogeneity of Oculodentodigital Syndrome
An autosomal recessive form of ODDD (257850) is also caused by mutation in the GJA1 gene, but the majority of cases are autosomal dominant.
Clinical Features
Gillespie (1964) described a brother and sister with bilateral microphthalmia, abnormally small nose, hypotrichosis, dental anomalies, fifth finger camptodactyly, syndactyly of the fourth and fifth fingers, and missing toe phalanges. Gillespie (1964) noted that similar features had been reported in 2 unrelated patients by Meyer-Schwickerath et al. (1957), who called the disorder oculodentodigital dysplasia and noted some phenotypic overlap with the Francois dyscephalic syndrome (Hallermann-Streiff syndrome; 234100).
ODDD was probably first described by Lohmann (1920). Lightwood and Lewis (1963) reported affected father and son.
The condition reported as acrocephalosyndactyly by Mohr (1939) and characterized by bilateral syndactyly of the fourth and fifth fingers is probably the same condition. The father and 5 of his children (including 3 sons) presented craniofacial deformity and complete syndactyly of the fourth and fifth fingers.
In 2 unpublished pedigrees, Renwick (1967) found that a constant and characteristic feature of the syndrome is the absence of the middle phalanx of those toes (second through fifth) that normally have 3 phalanges.
Rajic and De Veber (1966) reported a family with many affected members in 3 generations but no male-to-male transmission. Eye features included microphthalmia, microcornea, and glaucoma. The teeth were small with what was termed enamelogenesis imperfecta. The phalanges and metacarpals were widened and syndactyly of fingers 4 and 5 was present. Reisner et al. (1969) reported the syndrome in a mother and 3 of her 4 children.
Jones et al. (1975) found evidence of paternal age effect in new mutations for this disorder.
Fara and Gorlin (1981) found orbital (bony) hypotelorism in about 40% of cases. The distance between the inner canthi was not altered. Thus, the length of the palpebral slit was markedly diminished.
Gorlin (1985) suggested that ODDD was the true diagnosis in the family reported as metaphyseal dysplasia by David and Palmer (1958).
Patton and Laurence (1985) reported 3 new cases. With photographs they traced the development of the facial features. Conductive deafness was present in 1 of the 3 and had been reported in 6 previous cases.
Opjordsmoen and Nyberg-Hansen (1980) described a family from northern Norway with spastic paraplegia and type III syndactyly. The 2 traits were transmitted together through 3 generations and 9 affected persons. The spastic paraplegia was of unusual type: neurogenic bladder was the earliest manifestation. Indeed, the spastic paraplegia easily escaped attention.
Gutmann et al. (1991) pointed out that some previously reported patients manifested spastic quadriparesis and described a sporadic case of ODDD with progressive spastic paraparesis. MRI of the brain demonstrated abnormal white matter, specifically, diffuse, abnormally high signal intensity in the subcortical white matter bilaterally.
Norton et al. (1995) described a 2-generation family with ODDD and progressive paraplegia associated with leukodystrophic changes documented by MRI. The presence of abnormal white matter changes in both sporadic and inherited forms of ODDD suggested that the phenotype of this disorder should be expanded to include spastic paraparesis. Schrander-Stumpel and Franke (1996) highlighted neurologic findings in their previously described 3-generation family (Schrander-Stumpel et al., 1993). They reviewed other reports about neurologic defects in this syndrome and concluded that brain abnormalities may be a manifestation of the syndrome.
Loddenkemper et al. (2002) pointed out that neurologic symptoms are frequent in ODDD and include spasticity, gaze palsy and squinting, bladder and bowel dysfunction, visual and hearing loss, ataxia, and nystagmus. Cognitive impairment was seen in some patients. Subcortical white matter lesions and basal ganglia changes are seen on MRI. Loddenkemper et al. (2002) recommended that a full neurologic evaluation and brain MRI be performed in patients with features suggestive of ODDD.
Ioan et al. (2002) described the full clinical manifestations of ODDD in a 9.5-year-old female whose father had mild manifestations, namely type III syndactyly.
Abnormalities of the skin, hair, and nails have been recognized in ODDD but are often overlooked. Kelly et al. (2006) described an ODDD patient with curly hair, early trichorrhexis nodosa, and discrete keratoderma. Molecular genetic studies revealed a novel GJA1 mutation (121014.0014) affecting the N terminus of the CX43 protein.
Feller et al. (2008) reported a black South African boy with ODDD confirmed by genetic analysis. The patient presented at 11 years of age with a dental abscess. He had multiple dental anomalies, including small, discolored teeth, hypoplastic enamel, multiple caries, and enlarged pulp chambers of the permanent teeth. He also had taurodontism, characterized by lack of normal cervical constriction and elongation of the waist of the tooth, resulting in a rectangular block-like configuration. Characteristic facial features were also noted.
Brice et al. (2013) reported a family segregating autosomal dominant ODDD and lymphedema. The proband was a 40-year-old woman who had the characteristic facial features of ODDD, with a flat face, pinched nose, hypoplastic alae nasi, mild bilateral ptosis, and small, crowded teeth. She was born with bilateral syndactyly of the fourth and fifth fingers, which was surgically corrected. In addition, she had bilateral lower limb edema from age 30 years, which initially fluctuated but then remained constant despite overnight leg elevation. Her upper limbs showed no clinically visible edema. Her father was reported to have syndactyly but no lymphedema; a paternal aunt also had syndactyly and lymphedema, and the affected aunt's daughter had bilateral syndactyly of the fourth and fifth fingers, microphthalmia, microdontia, and poor enamel, as well as bilateral lower limb edema presenting at age 14 years. Lymphoscintigraphy in the proband confirmed primary edema of both lower extremities, with impaired drainage in the left upper extremity as well.
### Clinical Variability
O'Rourk and Bravos (1969) observed the sporadic case of a boy with an oculodentodigital dysplasia probably distinct from that described above and therefore tentatively designated ODD syndrome II. Rather than syndactyly of fingers 4 and 5 the patient showed unilateral preaxial polydactyly of the hand, laterally curved fifth finger on the right, fifth finger camptodactyly on the left, and absent terminal phalanges of right fingers 2 and 5.
Vingolo et al. (1994) described a large kindred with 14 persons in 4 generations affected with bilateral microphthalmia without other ocular or systemic signs. Autosomal dominant inheritance with complete penetrance was suggested. All the patients had microcornea. Vingolo et al. (1994) concluded that the family had a form of nanophthalmos characterized by ultrasonographic reduction of the posterior segment of the eye and a normal anterior segment. On clinical reexamination of the family reported by Vingolo et al. (1994), Vitiello et al. (2005) found extraocular signs that were suggestive of ODDD. In particular, some patients had thin hypoplastic nose, dental color anomalies, inverted palate, fifth finger camptodactyly, and fine, dry hair. None of the patients had hand or foot syndactyly or any neurologic signs. Identification of a mutation in the GJA1 gene (121014.0013) led Vitiello et al. (2005) to conclude that this family had an atypical form of ODDD.
Gabriel et al. (2011) described 2 patients with typical findings of autosomal dominant ODDD and the additional findings of optic nerve and retinal dysplasia in both and ciliary body cysts in one. Gabriel et al. (2011) suggested that retinal and optic nerve dysplasia may be more common than previously appreciated and may be associated with reduced vision and that ciliary body cysts may exacerbate glaucoma or complicate its management.
Mapping
In linkage studies of 6 families with ODDD, Gladwin et al. (1997) mapped the locus to 6q22-q24 (pairwise maximum lod = 9.37 at theta = 0.001). One of the ODDD families was the atypical family reported by Brueton et al. (1990); see type III syndactyly (186100). The family showed type III syndactyly, but none of the ophthalmologic, dental, or skeletal features commonly reported in ODDD. This suggested to Gladwin et al. (1997) that isolated type III syndactyly and ODDD may be caused by mutation in the same gene.
Molecular Genetics
Paznekas et al. (2003) analyzed the connexin-43 gene (GJA1; 121014) as a candidate for ODDD and identified mutations in all 17 families studied (see 121014.0003-121014.0007). Sixteen different missense mutations and 1 codon duplication were detected. These mutations may cause misassembly of channels or alter channel conduction properties. Expression patterns and phenotypic features of Gja1 mutant animals, reported by others, were considered compatible with the pleiotropic clinical presentation of ODDD.
Kjaer et al. (2004) described a 5-generation Danish family with ODDD in which all affected members had a val96-to-met (121014.0009) substitution in GJA1. The authors noted that in available photographs, 7 of 9 affected subjects had curly hair and 8 unaffected relatives did not, suggesting that curly hair is part of the pleiotropic phenotype.
In affected members of the family reported by Vingolo et al. (1994) as having simple microphthalmia without syndactyly, Vitiello et al. (2005) identified a heterozygous mutation in the GJA1 gene (121014.0013). The findings confirmed the highly variable phenotype associated with GJA1 mutations.
Paznekas et al. (2009) reported 18 new GJA1 mutations in 28 ODDD cases, and reviewed the 62 known mutations in GJA1 as well as the phenotypic information available on 177 affected individuals from 54 genotyped families. The characteristic facies was seen in 92% of the families, with ocular, dental, and digital manifestations present in 68%, 70%, and 80% of the families, respectively; 78% of families displayed features from more than 2 of these categories. Neurologic manifestations were seen in 30% of families, conductive hearing loss in 26%, and hair with poor growth in 26%. Secondary features observed more frequently in these ODDD patients than in the general population included cleft palate (3% versus 0.05%), glaucoma (16% versus 1.86%), and conductive hearing loss (10% versus 0.8%). Paznekas et al. (2009) noted that phenotypic variability occurred even among family members with the same mutation, and stated that making genotype/phenotype correlations was difficult, since there were no predominant mutations and mutations were equitably distributed throughout most protein domains.
In 2 patients with typical features of ODDD and the additional features of optic nerve and retinal dysplasia in both and ciliary body cysts in 1, Gabriel et al. (2011) identified heterozygous mutations in the GJA1 gene (121014.0019-121014.0020).
In 4 affected members of a family with ODDD and lymphedema, Brice et al. (2013) identified heterozygosity for a missense mutation in the GJA1 gene (K206R; 121014.0022). The mutation was not found in an unaffected family member or in 600 controls. Brice et al. (2013) noted that mutation in a related gene, GJC2 (608803), had been associated with 4-limb edema (613480) with a similar pattern on lymphoscintigraphy.
Genotype/Phenotype Correlations
In a Dutch kindred with ODDD and palmoplantar keratoderma, van Steensel et al. (2005) identified a 2-bp deletion in the GJA1 gene (121014.0010). The authors stated that this was the first reported mutation affecting the C-terminal loop, and suggested that the mutation might explain the presence of skin symptoms.
Vreeburg et al. (2007) reported another Dutch woman with ODDD and palmar hyperkeratosis with a 2-bp deletion in the GJA1 gene (121014.0015) resulting in truncation of the protein and absence of a significant portion of the C-terminal domain. The findings suggested a genotype/phenotype correlation between pronounced palmoplantar keratoderma and mutations that truncate the C terminus of the GJA1 protein.
Animal Model
Kalcheva et al. (2007) created a mouse model of ODDD by generating mice heterozygous for the human I130T mutation, previously identified by Paznekas et al. (2003) in a family with ODDD and an increased incidence of cardiac arrhythmias. Kalcheva et al. (2007) found that the I130T mutation interfered with posttranslational processing, resulting in diminished cell-cell coupling, slowing of impulse propagation, and a proarrhythmic substrate.
To understand causal links between GJA1 mutations and glaucoma in individuals with ODDD, Tsui et al. (2011) examined the ocular phenotype of Gja1(Jrt/+) mice harboring a Cx43 G60S mutation. Decreased Cx43 protein levels were evident in whole eyes from mutant mice compared with those of wildtype mice at postnatal day 1. Cx43 immunofluorescence in ciliary bodies of mutant mice was diffuse and intracellular, unlike the gap junction plaques prevalent in wildtype mice. Intraocular pressure (IOP) in the mutant mice changed during postnatal development, with significantly lower IOP at 21 weeks of age in comparison to the IOP of wildtype eyes. Microphthalmia, enophthalmia, anterior angle closure, and reduced pupil diameter were observed in the mutant mice of all ages examined. Ocular histology showed prominent separations between the pigmented and nonpigmented ciliary epithelium of mutant mice, split irides, and alterations in the number and distribution of nuclei in the retina. Tsui et al. (2011) concluded that detailed phenotyping of the eyes of Gja1(Jrt/+) mice offered a framework for elucidating human ODDD ocular disease mechanisms and for evaluating new treatments.
INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Microcephaly Ears \- Dysplastic ears (in some patients) \- Hearing loss, conductive Eyes \- Microcornea \- Microphthalmia \- Short palpebral fissures \- Epicanthal folds \- Glaucoma \- Cataract \- Iris anomalies Nose \- Small nares \- Thin hypoplastic alae nasi \- Narrow nasal bridge \- Thin anteverted nares \- Prominent columella Mouth \- Cleft lip \- Cleft palate \- Broad alveolar ridges Teeth \- Enamel hypoplasia \- Selective tooth agenesis \- Microdontia \- Premature loss of teeth \- Dental caries \- Taurodontism (reported in 1 patient) CARDIOVASCULAR Heart \- Endocardial cushion defects (uncommon) \- Atrial septal defect (uncommon) \- Ventral septal defect (uncommon) \- Cardiac conduction defects (uncommon) ABDOMEN Gastrointestinal \- Bowel dysfunction (in some cases) GENITOURINARY Bladder \- Neurogenic bladder (in some patients) SKELETAL Skull \- Skull hyperostosis Spine \- Vertebral hyperostosis Pelvis \- Hip dislocation Limbs \- Broad tubular bones \- Cubitus valgus Hands \- Syndactyly of 4th - 5th fingers \- Short middle phalanx of the 5th finger \- Fifth finger camptodactyly \- Midphalangeal hypoplasia \- Clinodactyly Feet \- Syndactyly of 3rd - 4th toes SKIN, NAILS, & HAIR Skin \- Diffuse yellow-orange non-epidermolytic hyperkeratosis on palms and soles (palmoplantar keratoderma) Nails \- Brittle nails Hair \- Fine, dry hair \- Sparse, slow-growing hair MUSCLE, SOFT TISSUES \- Lymphedema of lower limbs (in some patients) NEUROLOGIC Central Nervous System \- Mental retardation (rare) \- Hyperactive deep tendon reflexes \- Paraparesis \- Quadriparesis \- Ataxia \- Spasticity \- Dysarthria \- Seizures \- Neurogenic bladder \- Basal ganglia calcification \- Cerebral white matter abnormalities MISCELLANEOUS \- Variable phenotype \- Cardiac features are observed in ~3% of cases \- Neurologic features have been diagnosed in ~30% of cases \- 50% of cases represent new mutations associated with advanced paternal age MOLECULAR BASIS \- Caused by mutation in the connexin 43 gene (GJA1, 121014.0003 ) ▲ 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
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| OCULODENTODIGITAL DYSPLASIA | c0812437 | 2,510 | omim | https://www.omim.org/entry/164200 | 2019-09-22T16:37:15 | {"doid": ["0060291"], "mesh": ["C563160"], "omim": ["164200"], "orphanet": ["2710"], "synonyms": ["Alternative titles", "ODD SYNDROME", "OCULODENTOOSSEOUS DYSPLASIA"]} |
Mullerian duct anomalies-limb anomalies syndrome is characterised by the association of mullerian duct and distal limb anomalies. It has been described in five individuals from one family. Females presented with anomalies ranging from a vaginal septum to complete duplication of uterus and vagina, and males presented with micropenis. The limb anomalies varied from postaxial polydactyly to severe upper limb hypoplasia with split hand. The mode of transmission is autosomal dominant.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Müllerian duct anomalies-limb anomalies syndrome | c1840335 | 2,511 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2491 | 2021-01-23T17:03:42 | {"gard": ["2908"], "mesh": ["C537155"], "omim": ["146160"], "umls": ["C1840335"], "icd-10": ["Q87.8"]} |
X-linked myotubular myopathy is a condition that primarily affects muscles used for movement (skeletal muscles) and occurs almost exclusively in males. People with this condition have muscle weakness (myopathy) and decreased muscle tone (hypotonia) that are usually evident at birth.
The muscle problems in X-linked myotubular myopathy impair the development of motor skills such as sitting, standing, and walking. Affected infants may also have difficulties with feeding due to muscle weakness. Individuals with this condition often do not have the muscle strength to breathe on their own and must be supported with a machine to help them breathe (mechanical ventilation). Some affected individuals need breathing assistance only periodically, typically during sleep, while others require it continuously. People with X-linked myotubular myopathy may also have weakness in the muscles that control eye movement (ophthalmoplegia), weakness in other muscles of the face, and absent reflexes (areflexia).
In X-linked myotubular myopathy, muscle weakness often disrupts normal bone development and can lead to fragile bones, an abnormal curvature of the spine (scoliosis), and joint deformities (contractures) of the hips and knees. People with X-linked myotubular myopathy may have a large head with a narrow and elongated face and a high, arched roof of the mouth (palate). They may also have liver disease, recurrent ear and respiratory infections, or seizures.
Because of their severe breathing problems, individuals with X-linked myotubular myopathy usually survive only into early childhood; however, some people with this condition have lived into adulthood.
X-linked myotubular myopathy is a member of a group of disorders called centronuclear myopathy. In centronuclear myopathy, the nucleus is found at the center of many rod-shaped muscle cells instead of at either end, where it is normally located.
## Frequency
The incidence of X-linked myotubular myopathy is estimated to be 1 in 50,000 newborn males worldwide.
## Causes
Mutations in the MTM1 gene cause X-linked myotubular myopathy. The MTM1 gene provides instructions for producing an enzyme called myotubularin. Myotubularin is thought to be involved in the development and maintenance of muscle cells.
MTM1 gene mutations probably disrupt myotubularin's role in muscle cell development and maintenance, causing muscle weakness and other signs and symptoms of X-linked myotubular myopathy.
### Learn more about the gene associated with X-linked myotubular myopathy
* MTM1
## Inheritance Pattern
X-linked myotubular myopathy is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation must be present in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
In X-linked myotubular myopathy, the affected male inherits one altered copy from his mother in 80 to 90 percent of cases. In the remaining 10 to 20 percent of cases, the disorder results from a new mutation in the gene that occurs during the formation of a parent's reproductive cells (eggs or sperm) or in early embryonic development. Females with one altered copy of the MTM1 gene generally do not experience signs and symptoms of the disorder. In rare cases, however, females who have one altered copy of the MTM1 gene experience some mild muscle weakness.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| X-linked myotubular myopathy | c0410203 | 2,512 | medlineplus | https://medlineplus.gov/genetics/condition/x-linked-myotubular-myopathy/ | 2021-01-27T08:24:37 | {"gard": ["11925"], "mesh": ["D020914"], "omim": ["310400"], "synonyms": []} |
ZMC complex fracture
Other namesQuadripod fracture
Right zygomaticomaxillary complex fracture with disruption of the lateral orbital wall, orbital floor, zygomatic arch and maxillary sinus.
The zygomaticomaxillary complex fracture, also known as a quadripod fracture, quadramalar fracture, and formerly referred to as a tripod fracture or trimalar fracture, has four components: the lateral orbital wall (at either the zygomaticofrontal suture superiorly along the wall or zygomaticosphenoid suture inferiorly), separation of the maxilla and zygoma along the anterior maxilla (near the zygomaticomaxillary suture), the zygomatic arch, and the orbital floor near the infraorbital canal.
## Contents
* 1 Signs and symptoms
* 2 Cause
* 3 Treatment
* 4 References
* 5 External links
## Signs and symptoms[edit]
On physical exam, the fracture appears as a loss of cheek projection with increased width of the face. In most cases, there is loss of sensation in the cheek and upper lip due to infraorbital nerve injury. Facial bruising, periorbital ecchymosis, soft tissue gas, swelling, trismus, altered mastication, diplopia, and ophthalmoplegia are other indirect features of the injury.[1] The zygomatic arch usually fractures at its weakest point, 1.5 cm behind the zygomaticotemporal suture.[2]
## Cause[edit]
The cause is usually a direct blow to the malar eminence of the cheek during assault. The paired zygomas each have two attachments to the cranium, and two attachments to the maxilla, making up the orbital floors and lateral walls. These complexes are referred to as the zygomaticomaxillary complex. The upper and transverse maxillary bone has the zygomaticomaxillary and zygomaticotemporal sutures, while the lateral and vertical maxillary bone has the zygomaticomaxillary and frontozygomatic sutures.[citation needed]
The formerly used 'tripod fracture' refers to these buttresses, but did not also incorporate the posterior relationship of the zygoma to the sphenoid bone at the zygomaticosphenoid suture.[citation needed]
There is an association of ZMC fractures with naso-orbito-ethmoidal fractures (NOE) on the same side as the injury. Concomitant NOE fractures predict a higher incidence of post operative deformity.[3]
## Treatment[edit]
Non-displaced or minimally displaced fractures may be treated conservatively. Open reduction and internal fixation is reserved for cases that are severely angulated or comminuted. The purpose of fixation is to restore the normal appearance of the face. Specific attention is given to the position of the malar eminence and reduction of orbital volume by realigning the zygoma and sphenoid. Failure to correct can result in rotational deformity and increase the volume of the orbit, causing the eye to sink inwards.[citation needed]
Fractures with displacement require surgery consisting of fracture reduction with miniplates, microplates and screws. Gillie's approach is used for depressed zygomatic fractures.[4] The prognosis of tripod fractures is generally good. In some cases there may be persistent post-surgical facial asymmetry, which can require further treatment.[5]
## References[edit]
1. ^ Fraioli, RE; Branstetter BF, 4th; Deleyiannis, FW (February 2008). "Facial fractures: beyond Le Fort". Otolaryngologic Clinics of North America. 41 (1): 51–76, vi. doi:10.1016/j.otc.2007.10.003. PMID 18261526.
2. ^ Winegar, BA; Murillo, H; Tantiwongkosi, B (2013). "Spectrum of critical imaging findings in complex facial skeletal trauma". Radiographics. 33 (1): 3–19. doi:10.1148/rg.331125080. PMID 23322824.
3. ^ Buchanan, EP; Hopper, RA; Suver, DW; Hayes, AG; Gruss, JS; Birgfeld, CB (December 2012). "Zygomaticomaxillary complex fractures and their association with naso-orbito-ethmoid fractures: a 5-year review". Plastic and Reconstructive Surgery. 130 (6): 1296–304. doi:10.1097/prs.0b013e31826d1643. PMID 23190812.
4. ^ Swanson, E; Vercler, C; Yaremchuk, MJ; Gordon, CR (May 2012). "Modified Gillies approach for zygomatic arch fracture reduction in the setting of bicoronal exposure". The Journal of Craniofacial Surgery. 23 (3): 859–62. doi:10.1097/scs.0b013e31824dd5c3. PMID 22565912.
5. ^ Linnau, KF; Stanley RB, Jr; Hallam, DK; Gross, JA; Mann, FA (October 2003). "Imaging of high-energy midfacial trauma: what the surgeon needs to know". European Journal of Radiology. 48 (1): 17–32. doi:10.1016/s0720-048x(03)00205-5. PMID 14511857.
## External links[edit]
Classification
D
* ICD-10: GroupMajor.minor
* ICD-9-CM: 802.8
External resources
* eMedicine: article/867687
* v
* t
* e
Fractures and cartilage damage
General
* Avulsion fracture
* Chalkstick fracture
* Greenstick fracture
* Open fracture
* Pathologic fracture
* Spiral fracture
Head
* Basilar skull fracture
* Blowout fracture
* Mandibular fracture
* Nasal fracture
* Le Fort fracture of skull
* Zygomaticomaxillary complex fracture
* Zygoma fracture
Spinal fracture
* Cervical fracture
* Jefferson fracture
* Hangman's fracture
* Flexion teardrop fracture
* Clay-shoveler fracture
* Burst fracture
* Compression fracture
* Chance fracture
* Holdsworth fracture
Ribs
* Rib fracture
* Sternal fracture
Shoulder fracture
* Clavicle
* Scapular
Arm fracture
Humerus fracture:
* Proximal
* Supracondylar
* Holstein–Lewis fracture
Forearm fracture:
* Ulna fracture
* Monteggia fracture
* Hume fracture
* Radius fracture/Distal radius
* Galeazzi
* Colles'
* Smith's
* Barton's
* Essex-Lopresti fracture
Hand fracture
* Scaphoid
* Rolando
* Bennett's
* Boxer's
* Busch's
Pelvic fracture
* Duverney fracture
* Pipkin fracture
Leg
Tibia fracture:
* Bumper fracture
* Segond fracture
* Gosselin fracture
* Toddler's fracture
* Pilon fracture
* Plafond fracture
* Tillaux fracture
Fibular fracture:
* Maisonneuve fracture
* Le Fort fracture of ankle
* Bosworth fracture
Combined tibia and fibula fracture:
* Trimalleolar fracture
* Bimalleolar fracture
* Pott's fracture
Crus fracture:
* Patella fracture
Femoral fracture:
* Hip fracture
Foot fracture
* Lisfranc
* Jones
* March
* Calcaneal
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Zygomaticomaxillary complex fracture | c0435331 | 2,513 | wikipedia | https://en.wikipedia.org/wiki/Zygomaticomaxillary_complex_fracture | 2021-01-18T18:58:38 | {"umls": ["C0435331", "CL427957"], "wikidata": ["Q7843657"]} |
## Clinical Features
Daish et al. (1989) described 2 sisters, aged 4 years and 12 months, with hydrocephalus, tall stature, joint laxity, and thoracolumbar kyphosis. They were the only children of a 34-year-old father and a 30-year-old mother who were unrelated. The father was found at the age of 21 to have the murmur of aortic regurgitation. Echocardiogram showed normal aortic root dimensions, mild floppiness of the aortic valve leaflets, and minimal aortic regurgitation. The mother had moderately increased joint mobility. Photographs of the older sister strongly suggested the Marfan syndrome. In both sisters ventriculoatrial or ventriculoperitoneal shunt was required for relief of hydrocephalus.
Inheritance
Daish et al. (1989) suggested that the sibs they reported had a novel autosomal recessive disorder of connective tissue. They also considered the possibility that the sisters represented a genetic compound, having inherited an abnormal connective tissue gene mutation from each parent.
HEENT \- Hydrocephalus Inheritance \- Autosomal recessive \- ? genetic compound Skel \- Tall stature \- Joint laxity \- Thoracolumbar kyphosis ▲ Close
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*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| HYDROCEPHALUS, TALL STATURE, JOINT LAXITY, AND KYPHOSCOLIOSIS | c1856051 | 2,514 | omim | https://www.omim.org/entry/236660 | 2019-09-22T16:26:57 | {"mesh": ["C535770"], "omim": ["236660"], "orphanet": ["2181"]} |
Dens evaginatus involves an outfolding of the enamel organ in such a way that the occlusal surface of the affected posterior tooth has a tuberculated appearance. When these evaginations are fractured off, pulpal exposure may result. Few familial cases have been reported. However, a genetic basis was supported by Bixler (1976) on the following grounds: 1) the anomaly has been found almost only in persons of Mongoloid ancestry, although it has been observed in all parts of the world, and 2) the prevalence in persons of mixed Mongoloid ancestry is lower than in 'pure' groups. Stewart et al. (1978) observed dens evaginatus in several members of a family of Guatemalan Indian descent. Father and 2 daughters were affected.
Inheritance \- Autosomal dominant Teeth \- Tuberculated occlusal tooth surface ▲ 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
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| DENS EVAGINATUS | c0266034 | 2,515 | omim | https://www.omim.org/entry/125280 | 2019-09-22T16:42:31 | {"omim": ["125280"], "icd-10": ["K00.2"]} |
Respiratory bronchiolitis interstitial lung disease
Other namesRB-ILD
SpecialtyPulmonology
Respiratory bronchiolitis interstitial lung disease refers to a form of idiopathic interstitial pneumonia associated with smoking.[1]
It is a histological finding, not a pathological description. When associated with disease, it is known as "Respiratory bronchiolitis-associated interstitial lung disease" or "RB-ILD".[2] Also, this disease is predominately found in the upper lobe with centrilobar ground glass nodules. Importantly, no fibrosis is involved, just bronchial wall thickening. Treatment is to stop smoking.
The appearance is similar to desquamative interstitial pneumonia, and some have suggested that the two conditions are caused by the same processes.[3]
## See also[edit]
* Bronchiolitis
## References[edit]
1. ^ "Idiopathic Interstitial Pneumonias: Interstitial Lung Diseases: Merck Manual Professional". Retrieved 2008-12-09.
2. ^ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease. St. Louis, Mo: Elsevier Saunders. p. 741. ISBN 0-7216-0187-1.
3. ^ Heyneman LE, Ward S, Lynch DA, Remy-Jardin M, Johkoh T, Müller NL (December 1999). "Respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease, and desquamative interstitial pneumonia: different entities or part of the spectrum of the same disease process?". AJR Am J Roentgenol. 173 (6): 1617–22. doi:10.2214/ajr.173.6.10584810. PMID 10584810.
## External links[edit]
Classification
D
* ICD-10: J68.4
External resources
* Orphanet: 79127
* v
* t
* e
Diseases of the respiratory system
Upper RT
(including URTIs,
common cold)
Head
sinuses
Sinusitis
nose
Rhinitis
Vasomotor rhinitis
Atrophic rhinitis
Hay fever
Nasal polyp
Rhinorrhea
nasal septum
Nasal septum deviation
Nasal septum perforation
Nasal septal hematoma
tonsil
Tonsillitis
Adenoid hypertrophy
Peritonsillar abscess
Neck
pharynx
Pharyngitis
Strep throat
Laryngopharyngeal reflux (LPR)
Retropharyngeal abscess
larynx
Croup
Laryngomalacia
Laryngeal cyst
Laryngitis
Laryngopharyngeal reflux (LPR)
Laryngospasm
vocal cords
Laryngopharyngeal reflux (LPR)
Vocal fold nodule
Vocal fold paresis
Vocal cord dysfunction
epiglottis
Epiglottitis
trachea
Tracheitis
Laryngotracheal stenosis
Lower RT/lung disease
(including LRTIs)
Bronchial/
obstructive
acute
Acute bronchitis
chronic
COPD
Chronic bronchitis
Acute exacerbation of COPD)
Asthma (Status asthmaticus
Aspirin-induced
Exercise-induced
Bronchiectasis
Cystic fibrosis
unspecified
Bronchitis
Bronchiolitis
Bronchiolitis obliterans
Diffuse panbronchiolitis
Interstitial/
restrictive
(fibrosis)
External agents/
occupational
lung disease
Pneumoconiosis
Aluminosis
Asbestosis
Baritosis
Bauxite fibrosis
Berylliosis
Caplan's syndrome
Chalicosis
Coalworker's pneumoconiosis
Siderosis
Silicosis
Talcosis
Byssinosis
Hypersensitivity pneumonitis
Bagassosis
Bird fancier's lung
Farmer's lung
Lycoperdonosis
Other
* ARDS
* Combined pulmonary fibrosis and emphysema
* Pulmonary edema
* Löffler's syndrome/Eosinophilic pneumonia
* Respiratory hypersensitivity
* Allergic bronchopulmonary aspergillosis
* Hamman-Rich syndrome
* Idiopathic pulmonary fibrosis
* Sarcoidosis
* Vaping-associated pulmonary injury
Obstructive / Restrictive
Pneumonia/
pneumonitis
By pathogen
* Viral
* Bacterial
* Pneumococcal
* Klebsiella
* Atypical bacterial
* Mycoplasma
* Legionnaires' disease
* Chlamydiae
* Fungal
* Pneumocystis
* Parasitic
* noninfectious
* Chemical/Mendelson's syndrome
* Aspiration/Lipid
By vector/route
* Community-acquired
* Healthcare-associated
* Hospital-acquired
By distribution
* Broncho-
* Lobar
IIP
* UIP
* DIP
* BOOP-COP
* NSIP
* RB
Other
* Atelectasis
* circulatory
* Pulmonary hypertension
* Pulmonary embolism
* Lung abscess
Pleural cavity/
mediastinum
Pleural disease
* Pleuritis/pleurisy
* Pneumothorax/Hemopneumothorax
Pleural effusion
Hemothorax
Hydrothorax
Chylothorax
Empyema/pyothorax
Malignant
Fibrothorax
Mediastinal disease
* Mediastinitis
* Mediastinal emphysema
Other/general
* Respiratory failure
* Influenza
* Common cold
* SARS
* Coronavirus disease 2019
* Idiopathic pulmonary haemosiderosis
* Pulmonary alveolar proteinosis
This article about a medical condition affecting the respiratory system is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Respiratory bronchiolitis interstitial lung disease | c1735355 | 2,516 | wikipedia | https://en.wikipedia.org/wiki/Respiratory_bronchiolitis_interstitial_lung_disease | 2021-01-18T18:50:21 | {"umls": ["C1735355", "C1276236"], "orphanet": ["79127"], "wikidata": ["Q7315909"]} |
Congenital pericardium anomaly comprises a group of rare congenital cardiac malformations characterized by the complete (Congenital complete agenesis of pericardium) or partial absence of the pericardium (Congenital partial agenesis of pericardium), or by the presence of pericardial cysts (Pleuropericardial cyst) (see these terms).
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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
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Congenital pericardium anomaly | c0685699 | 2,517 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2846 | 2021-01-23T17:01:32 | {"umls": ["C0685699"], "icd-10": ["Q24.8"]} |
The intense contact between a musical instrument and skin may exaggerate existing skin conditions or cause new skin conditions. Skin conditions like hyperhidrosis, lichen planus, psoriasis, eczema, and urticaria may be caused in instrumental musicians due to occupational exposure and stress. Allergic contact dermatitis and irritant contact dermatitis are the most common skin conditions seen in string musicians.[1]
## Contents
* 1 Allergic contact dermatitis
* 2 Irritant contact dermatitis
* 3 Skin trauma
* 4 References
## Allergic contact dermatitis[edit]
Rosin, the material commonly used to wax string instruments is known to cause allergic contact dermatitis in musicians. Nickel, a metal found in musical instruments causes allergic contact dermatitis on the fingers and hands of string instrumentalists and in the lip and neck of wind instrumentalists. Wind instrumentalists with lip and neck infection should switch to silver, gold or plastic mouthpieces if allergic dermatitis occurs. (R)-4-methoxydalbergione present in rosewood may cause allergic contact dermatitis in violinists. Cane reed (causing chelitis in saxophone players), propolis (a wax used to close structural gaps in musical instruments), paraphenylenediamine (used to polish musical instruments) and potassium dichromate (tanning agent to the skin of the harp) also cause allergic contact dermatitis in musicians.[1]
## Irritant contact dermatitis[edit]
* Fiddler's neck \- It is seen in violinists due to non-eczematous irritant contact. Lichenification and hyperpigmentation can be seen. It is different from classical irritant contact dermatitis because the etiology is multifactorial : friction (leading to lichenification), local pressure, shearing stress and occlusion. Viola players are more pre-disposed to this condition because of the larger size of the instrument.
* Cellist's chest and cellist's knee \- It is seen in cello players due to the irritant contact of the instrument.
* Flautist's chin \- Irritant contact dermatitis seen in the chin of a wood/brass instrumentalist.
* Clarinetist's cheilitis \- Chelitis in a clarinet player. Caused due to friction, pressure, stress and occlusion.[1]
## Skin trauma[edit]
Frequent, chronic contact of instruments to skin may make it callous by the thickening of stratum corneum. Use of 'thumb position' in cellists may cause callosity of left thumb. Garrod's pads are seen on the dorsal left second and third fingers over the proximal interphalangeal joints in violinists. Drummer's digit is the callosity seen on the lateral phalanx of the left finger. Callosities need treatment only when they are excessive or symptomatic.[1]
## References[edit]
1. ^ a b c d Gambichler, Thilo; Boms, Stefanie; Freitag, Marcus (16 April 2004). "Contact dermatitis and other skin conditions in instrumental musicians". BMC Dermatology. 4 (1): 3. doi:10.1186/1471-5945-4-3. PMC 416484. PMID 15090069.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Skin conditions in instrumental musicians | None | 2,518 | wikipedia | https://en.wikipedia.org/wiki/Skin_conditions_in_instrumental_musicians | 2021-01-18T18:51:45 | {"wikidata": ["Q48999776"]} |
A rare neurometabolic disease characterized by infantile onset of repeated episodes of developmental regression and neurodegeneration, often triggered by febrile illnesses. Patients present with lethargy, hypotonia, irritability, gait ataxia, loss of speech, movement disorder, seizures, ophthalmoplegia, and hearing loss. Brain imaging shows generalized cerebral atrophy and bilateral basal ganglia abnormalities. Extensive skin lesions, cardiomyopathy, and pancytopenia have been reported in association. The condition is fatal in the first years of life.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| NAD(P)HX dehydratase deficiency | None | 2,519 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=555402 | 2021-01-23T18:49:28 | {"omim": ["618321"], "icd-10": ["G31.8"], "synonyms": ["CARKD deficiency"]} |
Examples in traumatic brain injury[1] Primary Secondary
* Intracerebral hemorrhage
* Subdural hemorrhage
* Subarachnoid hemorrhage
* Epidural hemorrhage
* Cerebral contusion
* Cerebral laceration
* Axonal stretch injury
* Cerebral edema
* Impaired metabolism
* Altered cerebral blood flow
* Free radical formation
* Excitotoxicity
Primary and secondary brain injury are ways to classify the injury processes that occur in brain injury. In traumatic brain injury (TBI), primary brain injury occurs during the initial insult, and results from displacement of the physical structures of the brain.[2] Secondary brain injury occurs gradually and may involve an array of cellular processes.[2][3] Secondary injury, which is not caused by mechanical damage, can result from the primary injury or be independent of it.[4] The fact that people sometimes deteriorate after brain injury was originally taken to mean that secondary injury was occurring.[4] It is not well understood how much of a contribution primary and secondary injuries respectively have to the clinical manifestations of TBI.[5]
Primary and secondary injuries occur in instances other than a TBI, such as spinal cord injury and stroke.
## Contents
* 1 Primary
* 2 Secondary
* 3 Prevention
* 4 See also
* 5 References
## Primary[edit]
In TBI, primary injuries result immediately from the initial trauma.[6] Primary injury occurs at the moment of trauma and includes contusion, damage to blood vessels, and axonal shearing, in which the axons of neurons are stretched and torn.[2] The blood brain barrier and meninges may be damaged in the primary injury, and neurons may die.[7] Cells are killed in a nonspecific manner in primary injury.[8] Tissues have a deformation threshold: if they are deformed past this threshold they are injured.[8] Different regions in the brain may be more sensitive to mechanical loading due to differences in their properties that result from differences in their makeup; for example, myelinated tissues may have different properties than other tissues.[8] Thus some tissues may experience more force and be more injured in the primary injury.[8] The primary injury leads to the secondary injury.[8]
## Secondary[edit]
Secondary injury is an indirect result of the injury. It results from processes initiated by the trauma.[6] It occurs in the hours and days following the primary injury[9][10] and plays a large role in the brain damage and death that results from TBI.[10] Unlike in most forms of trauma a large percentage of the people killed by brain trauma do not die right away but rather days to weeks after the event.[11] In addition, rather than improving after being hospitalized as most patients with other types of injuries do, about 40% of people with TBI deteriorate.[12] This is often a result of secondary injury, which can damage neurons that were unharmed in the primary injury. It occurs after a variety of brain injury including subarachnoid hemorrhage, stroke, and traumatic brain injury and involves metabolic cascades.[13]
Secondary injury can result from complications of the injury.[2] These include ischemia (insufficient blood flow); cerebral hypoxia (insufficient oxygen in the brain); hypotension (low blood pressure); cerebral edema (swelling of the brain); changes in the blood flow to the brain; and raised intracranial pressure (the pressure within the skull).[2] If intracranial pressure gets too high, it can lead to deadly brain herniation, in which parts of the brain are squeezed past structures in the skull.
Other secondary injury include hypercapnia (excessive carbon dioxide levels in the blood), acidosis (excessively acidic blood),[14] meningitis, and brain abscess.[4] In addition, alterations in the release of neurotransmitters (the chemicals used by brain cells to communicate) can cause secondary injury. Imbalances in some neurotransmitters can lead to excitotoxicity, damage to brain cells that results from overactivation of biochemical receptors for excitatory neurotransmitters (those that increase the likelihood that a neuron will fire). Excitotoxicity can cause a variety of negative effects, including damage to cells by free radicals, potentially leading to neurodegeneration. Another factor in secondary injury is loss of cerebral autoregulation, the ability of the brain's blood vessels to regulate cerebral blood flow.[1] Other factors in secondary damage are breakdown of the blood–brain barrier, edema, ischemia and hypoxia.[15] Ischemia is one of the leading causes of secondary brain damage after head trauma.[9] Similar mechanisms are involved in secondary injury after ischemia, trauma, and injuries resulting when a person does not get enough oxygen.[1] After stroke, an ischemic cascade, a set of biochemical cascades takes place.
## Prevention[edit]
Since primary injury occurs at the moment of trauma and is over so rapidly, little can be done to interfere with it other than prevention of the trauma itself.[2] However, since secondary injury occurs over time, it can be prevented in part by taking measures to prevent complications such as hypoxia (oxygen deficiency). Furthermore, secondary injury presents opportunities for researchers to find drug therapies to limit or prevent the damage. Since a variety of processes occur in secondary injury, any treatments that are developed to halt or mitigate it will need to address more than one of these mechanisms.[13]
Thus efforts to reduce disability and death from TBI are thought to be best aimed at secondary injury, because the primary injury is thought to be irreversible.[16]
## See also[edit]
* Wallerian degeneration
## References[edit]
1. ^ a b c Hammeke TA, Gennarelli TA (2003). "Traumatic brain injury". In Schiffer RB, Rao SM, Fogel BS (eds.). Neuropsychiatry. Hagerstown, MD: Lippincott Williams & Wilkins. p. 1150. ISBN 0-7817-2655-7. Retrieved 2008-06-16.
2. ^ a b c d e f Scalea TM (2005). "Does it matter how head injured patients are resuscitated?". In Valadka AB, Andrews BT (eds.). Neurotrauma: Evidence-Based Answers To Common Questions. Thieme. pp. 3–4. ISBN 3-13-130781-1.
3. ^ Ortega-Pérez, Stefany; Amaya-Rey, Maria (2018). "Secondary Brain Injury: A Concept Analysis". Journal of Neuroscience Nursing. 50 (4): 220–224. doi:10.1097/JNN.0000000000000384. PMID 29985274. S2CID 51602244.
4. ^ a b c Gennarelli GA, Graham DI (2005). "Neuropathology". In Silver JM, McAllister TW, Yudofsky SC (eds.). Textbook Of Traumatic Brain Injury. Washington, DC: American Psychiatric Association. pp. 27–33. ISBN 1-58562-105-6. Retrieved 2008-06-10.
5. ^ Granacher RP (2007). Traumatic Brain Injury: Methods for Clinical & Forensic Neuropsychiatric Assessment, Second Edition. Boca Raton: CRC. pp. 26–32. ISBN 978-0-8493-8138-6. Retrieved 2008-07-06.
6. ^ a b Porth, Carol (2007). Essentials of Pahtophysiology: Concepts of Altered Health States. Hagerstown, MD: Lippincott Williams & Wilkins. p. 838. ISBN 978-0-7817-7087-3. Retrieved 2008-07-03.
7. ^ Pitkänen A, McIntosh TK (2006). "Animal models of post-traumatic epilepsy". Journal of Neurotrauma. 23 (2): 241–261. doi:10.1089/neu.2006.23.241. PMID 16503807.
8. ^ a b c d e LaPlaca MC, Simon CM, Prado GR, Cullen DR (2007). "CNS injury biomechanics and experimental models". In Weber JT (ed.). Neurotrauma: New Insights Into Pathology and Treatment. Elsevier. pp. 13–19. ISBN 978-0-444-53017-2. Retrieved 2008-06-10.
9. ^ a b Granacher RP (2007). Traumatic Brain Injury: Methods for Clinical & Forensic Neuropsychiatric Assessment, Second Edition. Boca Raton: CRC. pp. 26–32. ISBN 978-0-8493-8138-6. Retrieved 2008-07-06.
10. ^ a b Sullivan PG, Rabchevsky AG, Hicks RR, Gibson TR, Fletcher-Turner A, Scheff SW (2000). "Dose-response curve and optimal dosing regimen of cyclosporin A after traumatic brain injury in rats". Neuroscience. 101 (2): 289–95. doi:10.1016/S0306-4522(00)00380-8. PMID 11074152. S2CID 20457228.
11. ^ Sauaia A, Moore FA, Moore EE, et al. (February 1995). "Epidemiology of trauma deaths: A reassessment". J Trauma. 38 (2): 185–93. doi:10.1097/00005373-199502000-00006. PMID 7869433.
12. ^ Narayan RK, Michel ME, Ansell B, et al. (May 2002). "Clinical trials in head injury". J. Neurotrauma. 19 (5): 503–57. doi:10.1089/089771502753754037. PMC 1462953. PMID 12042091.
13. ^ a b Marion DW (2003). "Pathophysiology and treatment of intracranial hypertention". In Andrews BT (ed.). Intensive Care in Neurosurgery. New York: Thieme Medical Publishers. pp. 52–53. ISBN 1-58890-125-4. Retrieved 2008-06-08.
14. ^ Andrews BT (2003). "Head injury management". In Andrews BT (ed.). Intensive Care in Neurosurgery. New York: Thieme Medical Publishers. p. 125. ISBN 1-58890-125-4. Retrieved 2008-06-08.
15. ^ Garga N, Lowenstein DH (2006). "Posttraumatic epilepsy: A major problem in desperate need of major advances". Epilepsy Curr. 6 (1): 1–5. doi:10.1111/j.1535-7511.2005.00083.x. PMC 1363374. PMID 16477313.
16. ^ Armin SS, Colohan AR, Zhang JH (June 2006). "Traumatic subarachnoid hemorrhage: Our current understanding and its evolution over the past half century". Neurol. Res. 28 (4): 445–52. doi:10.1179/016164106X115053. PMID 16759448. S2CID 23726077.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Primary and secondary brain injury | None | 2,520 | wikipedia | https://en.wikipedia.org/wiki/Primary_and_secondary_brain_injury | 2021-01-18T18:37:54 | {"wikidata": ["Q7243097"]} |
Marfanoid (or Marfanoid habitus) is a constellation of symptoms resembling those of Marfan syndrome, including long limbs, with an arm span that is at least 1.03 of the height of the individual, and a crowded oral maxilla, sometimes with a high arch in the palate, arachnodactyly, and hyperlaxity.
## Contents
* 1 Signs and symptoms
* 1.1 Associated conditions
* 2 Diagnosis
* 3 References
## Signs and symptoms[edit]
Arachnodactyly (long fingers), long limbs, scoliosis (curved spine), a hidden feature of bony lip growth towards vestibular aqueduct (which can be seen in an CT scan reports), and speech characteristic of imprecise articulation due to high-arched palate are all considered Marfanoid. Language and cognitive can be affected in neonatal Marfan syndrome where intellectual disability exists and a hearing impairment of conductive loss due to hypermobility of ossicles or inflamed tympanic membrane and a sensorineural hearing impairment is due to the vestibular aqueduct plus cofactor symptoms of giddiness and imbalance may occur. Crowding of teeth and long or flat feet, often with hammer toes, may also be present.
### Associated conditions[edit]
Marfanoid habitus is a connective tissue disorder which is generally associated with other syndrome such as Ehlers-Danlos syndrome, Perrault syndrome and Stickler syndrome.
Associated conditions include:
* Multiple endocrine neoplasia type 2B[1][2]
* Homocystinuria[3]
* Ehlers-Danlos syndrome:[4] Marfanoid habitus is a connective tissue disorder which is generally associated with Ehlers-Danlos syndrome type 3 (hypermobility type). It is an autosomal dominant inherited or new mutation in chromosome 15.
* Snyder–Robinson syndrome at SMS, where the incidence shows 1 in 5,000-10,000 in all ethnic groups
* Perrault syndrome : Marfanoid habitus is a nonspecific feature of Perrault syndrome.
## Diagnosis[edit]
Medical diagnostic criteria to differentiate Marfanoid habitus from Marfan syndrome :
Marfanoid habitus Marfan syndrome
Arm span to height ratio >1.03 >1.05
Scoliosis >5° >20°
## References[edit]
1. ^ Prabhu M, Khouzam RN, Insel J (November 2004). "Multiple endocrine neoplasia type 2 syndrome presenting with bowel obstruction caused by intestinal neuroma: case report". South. Med. J. 97 (11): 1130–2. doi:10.1097/01.SMJ.0000140873.29381.12. PMID 15586612. S2CID 27428744.
2. ^ Wray CJ, Rich TA, Waguespack SG, Lee JE, Perrier ND, Evans DB (January 2008). "Failure to recognize multiple endocrine neoplasia 2B: more common than we think?". Ann. Surg. Oncol. 15 (1): 293–301. doi:10.1245/s10434-007-9665-4. PMID 17963006. S2CID 2564555.
3. ^ Pagon, RA.; Bird, TC.; Dolan, CR.; Stephens, K.; Picker, JD.; Levy, HL. (1993). "Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency". PMID 20301697. Cite journal requires `|journal=` (help)
4. ^ Yeowell HN, Steinmann B. Ehlers-Danlos Syndrome, Kyphoscoliotic Form. 2000 Feb 2 [Updated 2013 Jan 24]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1462/
This genetic disorder 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
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Marfanoid | c0424617 | 2,521 | wikipedia | https://en.wikipedia.org/wiki/Marfanoid | 2021-01-18T18:56:59 | {"umls": ["C0424617"], "orphanet": ["284993"], "wikidata": ["Q6759035"]} |
Bird fancier's lung
Other namesBird-breeder's lung, pigeon-breeder's lung
Micrograph of hypersensitivity pneumonitis, the histologic correlate of bird fancier's lung. Lung biopsy. Trichrome stain.
SpecialtyPulmonology
Bird fancier's lung (BFL) is a type of hypersensitivity pneumonitis (HP). It is triggered by exposure to avian proteins present in the dry dust of the droppings and sometimes in the feathers of a variety of birds. The lungs become inflamed, with granuloma formation. Birds such as pigeons, parakeets, cockatiels, shell parakeets (budgerigars), parrots, turtle doves, turkeys and chickens have been implicated.
People who work with birds or own many birds are at risk. Bird hobbyists and pet store workers may also be at risk.
## Contents
* 1 Signs and symptoms
* 2 Differential diagnosis
* 3 Treatment
* 4 See also
* 5 References
* 6 External links
## Signs and symptoms[edit]
This disease is an inflammation of the alveoli in the lungs caused by an immune response to inhaled allergens from birds. Initial symptoms include shortness of breath (dyspnea), especially after sudden exertion or when exposed to temperature change, which can resemble asthma, hyperventilation syndrome or pulmonary embolism. Chills, fever, non-productive cough and chest discomfort may also occur. Upon re-exposure to avian proteins, sensitized individuals will typically experience symptoms within 4–6 hours or sooner. In the chronic form there is usually anorexia, weight loss, extreme fatigue and progressive pulmonary fibrosis, which is generally the most serious consequence of the disease because it progressively and irreversibly diminishes the lungs' efficiency over time. As a result, sufferers may have repeated chest infections and ultimately struggle to breathe. This condition can eventually be fatal.[1]
## Differential diagnosis[edit]
A definitive diagnosis can be difficult without invasive testing, but extensive exposure to birds combined with reduced diffusing capacity are strongly suggestive of this disease. X-ray or CT scans will show physical changes to the lung structure (a ground glass appearance) as the disease progresses. Precise distribution and types of tissue damage differ among similar diseases, as does response to treatment with Prednisone. There are two forms of BFL: acute and chronic. Diffuse alveolar damage (DAD) can occur with acute respiratory failure; progressive interstitial fibrosis is typical of the chronic form.[2] In both, the underlying inflammatory response stops upon exclusion of the allergen,[3] but symptoms may persist depending on the degree of damage already sustained. Among invasive procedures, bronchoalveolar lavage typically shows prominent lymphocytosis with an inverted CD4+/CD8+ ratio, and lung biopsy usually reveals non-necrotizing granulomatous inflammation.[4]
## Treatment[edit]
Prednisone often suppresses symptoms temporarily, especially in the early stages of the disease, and by reducing inflammation it might also delay scarring (fibrosis) in the lungs. However, the only recommended long-term treatment is avoidance of the avian proteins that trigger BFL. Unless fibrosis has progressed beyond recovery, symptoms should improve, sometimes dramatically, in the absence of such allergens. Therefore, it is advisable to remove all birds, bedding and pillows containing feathers from the patient's home, as well as any down-filled outerwear and sleeping bags. At a minimum, it is also advisable to wash all soft furnishings, walls, ceilings and furniture, and to avoid future exposure to birds, bird droppings, or any items containing feathers, such as pillows in many hotels. In extreme cases patients may be advised to evacuate their homes permanently and to get rid of all possessions that have been exposed to avian proteins if they cannot be cleaned thoroughly inside and out. (This includes books, beds, and upholstered furniture.) The patient should not attempt to clean any contaminated items; in fact, anyone who comes in contact with items that have been near birds should change clothes and wash their hair before coming in contact with the patient. Depending on the extent of fibrosis at the time of their diagnosis and how well they follow recommended treatment protocols (especially avoidance of allergens), many BFL patients make a full recovery. However, symptoms may recur quickly upon re-exposure to birds or related allergens.
## See also[edit]
* Hypersensitivity pneumonitis
* Farmer's lung
## References[edit]
1. ^ Hashisako, Mikiko; Fukuoka, Junya; Smith, Maxwell L. (2018), "Chronic Diffuse Lung Diseases", Practical Pulmonary Pathology: A Diagnostic Approach, Elsevier, pp. 227–298.e5, doi:10.1016/b978-0-323-44284-8.00008-9, ISBN 9780323442848
2. ^ King, Thomas C. (2007), "Respiratory Tract and Pleura", Elsevier's Integrated Pathology, Elsevier, pp. 197–216, doi:10.1016/b978-0-323-04328-1.50014-0, ISBN 9780323043281
3. ^ King, Thomas C. (2007), "Respiratory Tract and Pleura", Elsevier's Integrated Pathology, Elsevier, pp. 197–216, doi:10.1016/b978-0-323-04328-1.50014-0, ISBN 9780323043281
4. ^ King, Thomas C. (2007), "Respiratory Tract and Pleura", Elsevier's Integrated Pathology, Elsevier, pp. 197–216, doi:10.1016/b978-0-323-04328-1.50014-0, ISBN 9780323043281
Hargreave FE, Pepys J, Longbottom JL, Wraith DG (1966). "Bird breeder's (fancier's) lung". Proc R Soc Med. 59 (10): 1008. PMC 1901065. PMID 6005979.
## External links[edit]
Classification
D
* ICD-10: J67.2
* ICD-9-CM: 495.2
* MeSH: D001716
* DiseasesDB: 29639
* SNOMED CT: 69339004
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Bird fancier's lung | c0005592 | 2,522 | wikipedia | https://en.wikipedia.org/wiki/Bird_fancier%27s_lung | 2021-01-18T18:37:38 | {"mesh": ["D001716"], "umls": ["C0005592"], "wikidata": ["Q2529980"]} |
A number sign (#) is used with this entry because this form of Zellweger syndrome (PBD8A) is caused by homozygous mutation in the PEX16 gene (603360) on chromosome 11p11.
Description
Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by Steinberg et al., 2006).
For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see 214100.
Individuals with PBDs of complementation group 9 (CG9, equivalent to CGD) have mutations in the PEX16 gene. For information on the history of PBD complementation groups, see 214100.
Clinical Features
Honsho et al. (1998) analyzed a cell line (GM06231) from a patient with Zellweger syndrome of complementation group D obtained from the NIGMS Human Genetic Mutant Cell Repository. The catalog of the NIGMS Repository stated that the patient (cell line GM06231) was a 1-month-old white female with consanguineous parents, a similarly affected sib, muscle hypotonia, craniofacial dysmorphia, ventricular septal defect, glossoptosis, cataracts, hepatomegaly with jaundice and elevated SGOT and SGPT, and elevated CSF protein.
Shimozawa et al. (2002) stated that the 2 complementation group D patients analyzed for mutations by them had typical features of Zellweger syndrome.
Molecular Genetics
In a cell line from a patient with Zellweger syndrome, Honsho et al. (1998) identified a homozygous nonsense mutation in the PEX16 gene (603360.0001).
Shimozawa et al. (2002) identified a homozygous splice site mutation in 2 complementation group D Zellweger syndrome patients (603360.0002).
INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Craniofacial dysmorphia Eyes \- Cataracts Mouth \- Glossoptosis CARDIOVASCULAR Heart \- Ventricular septal defect ABDOMEN Liver \- Hepatomegaly \- Jaundice SKIN, NAILS, & HAIR Skin \- Jaundice MUSCLE, SOFT TISSUES \- Hypotonia LABORATORY ABNORMALITIES \- Elevated serum glutamic oxaloacetic transaminase (SGOT) \- Elevated serum glutamic pyruvic transaminase (SGPT) \- Elevated cerebrospinal fluid (CSF) protein MISCELLANEOUS \- Clinical features based on information from NIGMS Human Genetic Mutant Cell Repository, cell line GM06231 MOLECULAR BASIS \- Caused by mutation in the peroxisome biogenesis factor 16 gene (PEX16, 603360.0001 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| PEROXISOME BIOGENESIS DISORDER 8A (ZELLWEGER) | c0043459 | 2,523 | omim | https://www.omim.org/entry/614876 | 2019-09-22T15:53:51 | {"doid": ["0080483"], "mesh": ["D015211"], "omim": ["614876"], "orphanet": ["912"]} |
A rare hereditary renal phosphate-wasting disorder characterized by hypophosphatemia, rickets and/or osteomalacia and slow growth.
## Epidemiology
Prevalence is unknown.
## Clinical description
The disease is clinically similar to X-linked and autosomal dominant hypophosphatemic rickets (see these terms). It manifests during childhood with typical clinical features of rickets such as short stature, bone pain, and skeletal deformities. During adulthood, clinical findings may include bone pain, fatigue, muscle weakness, and repeated bone fractures.
## Etiology
ARHR is caused by inactivating mutations in the gene encoding dentin matrix protein 1 (DMP1) or in the ectonucleotide pyrophosphatase/phosphodiesterase 1 ENPP1 gene. These mutations increase FGF23 production and thus diminish renal tubular phosphate reabsorption and bone demineralization.
## Genetic counseling
Transmission is autosomal recessive.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Autosomal recessive hypophosphatemic rickets | c0342643 | 2,524 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=289176 | 2021-01-23T17:19:00 | {"mesh": ["C562792"], "omim": ["241520", "613312"], "icd-10": ["E83.3"], "synonyms": ["ARHR"]} |
A number sign (#) is used with this entry because of evidence that cone-rod dystrophy and hearing loss-2 (CRDHL2) is caused by homozygous or compound heterozygous mutation in the CEP250 gene (609689) on chromosome 20q11.
Description
Cone-rod dystrophy and hearing loss-2 (CRDHL2) is characterized by retinal dystrophy, with photophobia and progressive reduction in visual acuity, associated with sensorineural hearing loss (Kubota et al., 2018).
For a discussion of genetic heterogeneity of cone-rod dystrophy and hearing loss, see CRDHL1 (617236).
Clinical Features
Khateb et al. (2014) studied a large consanguineous family of Iranian Jewish origin (MOL0028) in which 6 sibs had early-onset severe sensorineural hearing loss, 3 of whom also had relatively mild retinal degeneration and 3 of whom had early-onset severe retinitis pigmentosa (RP). Their father had relatively mild RP with age-related hearing loss, and their mother was unaffected. Funduscopy of affected individuals with milder retinal degeneration showed peripheral retinal atrophy with white scars in the far periphery with a few areas of bone spicule-like pigmentation. There were measurable scotopic and photopic responses on electroretinography (ERG), and optical coherence tomography (OCT) showed preservation of retinal layers in the posterior pole. Goldman visual field testing revealed a constricted visual field with preserved central vision. The 3 sibs with severe RP had visual acuity of light perception only and nondetectable ERG responses, with diffuse retinal atrophy on funduscopy and OCT.
Kubota et al. (2018) reported 2 Japanese sisters with mild cone-rod dystrophy (CRD) and mild high-frequency sensorineural hearing loss. The 24-year-old sister experienced photophobia and a gradual reduction of vision; examination showed best-corrected visual acuities (BCVAs) of about 20/200 and 20/140 in the right and left eyes, with no fundus abnormalities. She had full visual fields by Goldman perimetry, with a relative reduction of central sensitivity by Humphrey Visual Field Analyzer. Her 22-year-old sister also had reduced visual acuity, with BCVAs of about 20/30 and 20/25, and no fundus abnormalities. Spectral domain (SD)-OCT in the affected sisters revealed blurred ellipsoid zones and discontinuous interdigitation zones. Full-field and multifocal ERGs showed slight reduction of b-wave amplitudes bilaterally in the older sister; the younger sister had slightly reduced responses in both eyes to light-adapted 3.0 flicker. High-resolution fundus imaging showed patient cone densities at 2 to 8 degrees horizontally from the foveal center that were lower by more than 1 standard deviation than those of 34 controls.
Fuster-Garcia et al. (2018) described a Spanish woman (RP1973) who had onset of moderate to severe progressive hearing loss at age 13 years, and presented at age 44 years with progressive diminution of vision bilaterally with photophobia. BCVA was about 20/30 and 20/40 in the right and left eyes, and fundus examination showed migration of pigment in a bone-spicule pattern within a midperipheral annular zone bilaterally, with narrowing of the peripheral retinal blood vessels. Humphrey perimetry revealed peripheral field constriction with relative defects in the paracentral region in both eyes. OCT showed normal macular thickness, with loss of retinal pigment epithelium and discontinuity of the outer segment layer around the foveal center bilaterally. Full-field ERG showed only mild alterations in the scotopic flash responses, whereas macular ERG showed an absence of response in both eyes.
Molecular Genetics
By whole-exome sequencing in a large consanguineous family of Iranian Jewish origin (MOL0028) in which 6 sibs had hearing loss and retinal dystrophy, Khateb et al. (2014) identified mutations in 2 genes: all 6 affected sibs were homozygous for a nonsense mutation in the CEP250 gene (R1155X; 609689.0001), and the 3 sibs who had early-onset severe RP were also homozygous for a nonsense mutation (Q1097X) in a known RP gene, C2ORF71 (PCARE, 613425; see RP54, 613428); the 3 sibs with a milder retinal phenotype were heterozygous for the C2ORF71 mutation. Their father, who had relatively mild RP and age-related hearing problems, was homozygous for the C2ORF71 mutation but heterozygous for the CEP250 mutation, whereas their unaffected mother and an unaffected sister were both heterozygous for both mutations. The authors concluded that the severe retinal involvement in the double homozygotes indicated an additive effect caused by nonsense mutations in 2 genes encoding ciliary proteins.
In a cohort of 33 families from Argentina, Saudi Arabia, and Spain diagnosed with 'inherited retinal dystrophy,' de Castro-Miro et al. (2016) performed whole-exome sequencing and identified an affected sister and brother (family A3) who were homozygous for a missense mutation (A609V) in the CEP250 gene that segregated with disease. The patients were tabulated as having autosomal recessive RP; no further clinical information was reported. The authors noted that a known autosomal recessive RP-associated mutation, C948Y in the CRB1 gene (604210.0013), segregated in heterozygosity in this family, and might contribute to the severity of the phenotype.
By whole-exome sequencing in a 24-year-old Japanese woman with mild cone-rod dystrophy and sensorineural hearing loss, Kubota et al. (2018) identified compound heterozygous nonsense mutations in the CEP250 gene, R121X (609689.0002) and R188X (609689.0003). Sanger sequencing showed that her affected 22-year-old sister was also compound heterozygous for the mutations, whereas their unaffected parents were each heterozygous for 1 of the variants and their unaffected sister did not carry either of them. The authors stated that no pathogenic variants in the C2ORF71 gene were found in the proband.
In a cohort of 58 Spanish patients diagnosed with Usher syndrome (see 276900), Fuster-Garcia et al. (2018) performed targeted exome sequencing for variation in 10 known Usher-associated genes and 4 candidate genes, and identified a woman (RP1973) with hearing loss and mild retinal degeneration involving the macula who was compound heterozygous for nonsense mutations in the CEP250 gene: K1113X (609689.0004) and R1336X (609689.0005). Her unaffected parents were each heterozygous for 1 of the mutations, and her unaffected sister did not carry either of them. The authors noted that the proband was also heterozygous for a missense mutation in the USH2A gene (608400; R1521C, rs773526991).
INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Sensorineural hearing loss, mild high-frequency Eyes \- Photophobia \- Progressive loss of visual acuity \- Blurred ellipsoid zones on optical coherence tomography (OCT) \- Discontinuous interdigitation zones on OCT \- Reduction in b-wave amplitudes on electroretinography (ERG) \- Reduced responses to light-adapted 3.0 flicker on ERG \- Reduction in cone densities at 2 to 8 degrees horizontally from foveal center MISCELLANEOUS \- Based on report of 2 Japanese sisters (last curated March 2019) MOLECULAR BASIS \- Caused by mutation in the 250-kD centrosomal protein gene (CEP250, 609689.0001 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| CONE-ROD DYSTROPHY AND HEARING LOSS 2 | None | 2,525 | omim | https://www.omim.org/entry/618358 | 2019-09-22T15:42:24 | {"omim": ["618358"]} |
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Congenital onychodysplasia of the index fingers is defined by the presence of the condition at birth, either unilateral or bilateral index finger involvement, variable distortion of the nail or lunula, and polyonychia, micronychia, anonychia, hemionychogryphosis, or malalignment.[1]
* The original paper was Kikuchi I, Horikawa S, Amano F (November 1974). "Congenital onychodysplasia of the index fingers". Arch Dermatol. 110 (5): 743–6. doi:10.1001/archderm.1974.01630110037008. PMID 4419705.
* This condition is also called Iso-Kikuchi syndrome, since Iso was the first author who published it in a Japanese paper.[2]
## See also[edit]
* List of cutaneous conditions
## References[edit]
1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. p. 783. ISBN 978-0-7216-2921-6.
2. ^ Baran R, Stroud JD (February 1984). "Congenital onychodysplasia of the index fingers. Iso and Kikuchi syndrome". Arch Dermatol. 120 (2): 243–4. doi:10.1001/archderm.1984.01650380103022. PMID 6696480.
## External links[edit]
* Congenital onychodysplasia of the index fingers at eMedicine
This condition of the skin appendages article is a stub. You can help Wikipedia by expanding it.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Congenital onychodysplasia of the index fingers | c1853984 | 2,526 | wikipedia | https://en.wikipedia.org/wiki/Congenital_onychodysplasia_of_the_index_fingers | 2021-01-18T18:57:33 | {"mesh": ["C538333"], "umls": ["C1853984"], "orphanet": ["79144"], "wikidata": ["Q5160446"]} |
A rare, non-syndromic, urogenital tract malformation characterized by complete or partial penile duplication, ranging from only glans duplication to the presence of two penis shafts with either one (i.e. bifid phallus) or two (i.e. true diphallia) corpora cavernosum in each. Additional anomalies, such as urethra duplication, an abnormal voiding pattern, hypo- or epispadias, bifid/ectopic scrotum, bladder exstrophy or duplication, are frequently associated, but it may also present as an isolated anomaly. In severe cases, pubic symphysis diastasis, imperforate or duplicated anus, colon/ rectosigmoidal duplication, inguinal hernia and vertebral anomalies may be observed.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Diphallia | c0345322 | 2,527 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=227 | 2021-01-23T18:31:35 | {"gard": ["1872"], "icd-10": ["Q55.6"]} |
A number sign (#) is used with this entry because of evidence that familial Alzheimer disease-1 (AD1) is caused by mutation in the gene encoding the amyloid precursor protein (APP; 104760) on chromosome 21q.
A homozygous mutation in the APP gene with a dominant-negative effect on amyloidogenesis was found in a patient with an early-onset progressive dementia and his affected younger sister (104760.0022).
A coding single-nucleotide polymorphism (SNP) in the APP gene (104760.0023) has been shown to have a protective effect against Alzheimer disease.
See also APP-related cerebral amyloid angiopathy (CAA; 605714), which shows overlapping clinical and neuropathologic features.
Description
Alzheimer disease is the most common form of progressive dementia in the elderly. It is a neurodegenerative disorder characterized by the neuropathologic findings of intracellular neurofibrillary tangles (NFT) and extracellular amyloid plaques that accumulate in vulnerable brain regions (Sennvik et al., 2000). Terry and Davies (1980) pointed out that the 'presenile' form, with onset before age 65, is identical to the most common form of late-onset or 'senile' dementia, and suggested the term 'senile dementia of the Alzheimer type' (SDAT).
Haines (1991) reviewed the genetics of AD. Selkoe (1996) reviewed the pathophysiology, chromosomal loci, and pathogenetic mechanisms of Alzheimer disease. Theuns and Van Broeckhoven (2000) reviewed the transcriptional regulation of the genes involved in Alzheimer disease.
### Genetic Heterogeneity of Alzheimer Disease
Alzheimer disease is a genetically heterogeneous disorder. See also AD2 (104310), associated with the APOE*4 allele (107741) on chromosome 19; AD3 (607822), caused by mutation in the presenilin-1 gene (PSEN1; 104311) on 14q; and AD4 (606889), caused by mutation in the PSEN2 gene (600759) on 1q31.
There is evidence for additional AD loci on other chromosomes; see AD5 (602096) on 12p11, AD6 (605526) on 10q24, AD7 (606187) on 10p13, AD8 (607116) on 20p, AD9 (608907), associated with variation in the ABCA7 gene (605414) on 19p13, AD10 (609636) on 7q36, AD11 (609790) on 9q22, AD12 (611073) on 8p12-q22, AD13 (611152) on 1q21, AD14 (611154) on 1q25, AD15 (611155) on 3q22-q24, AD16 (300756) on Xq21.3, AD17 (615080) on 6p21.2, and AD18 (615590), associated with variation in the ADAM10 gene (602192) on 15q21.
Evidence also suggests that mitochondrial DNA polymorphisms may be risk factors in Alzheimer disease (502500).
Finally, there have been associations between AD and various polymorphisms in other genes, including alpha-2-macroglobulin (A2M; 103950.0005), low density lipoprotein-related protein-1 (LRP1; 107770), the transferrin gene (TF; 190000), the hemochromatosis gene (HFE; 613609), the NOS3 gene (163729), the vascular endothelial growth factor gene (VEGF; 192240), the ABCA2 gene (600047), and the TNF gene (191160) (see MOLECULAR GENETICS).
Clinical Features
Alzheimer (1907) provided the first report of the disease (see HISTORY).
Schottky (1932) described a familial form of presenile dementia in 4 generations. The diagnosis was confirmed at autopsy in a patient in the fourth generation. Lowenberg and Waggoner (1934) reported a family with unusually early onset of dementia in the father and 4 of 5 children. Postmortem findings in 1 case were consistent with dementia of the Alzheimer type. McMenemey et al. (1939) described 4 affected males in 2 generations with pathologic confirmation in one.
Heston et al. (1966) described a family with 19 affected in 4 generations. Dementia was coupled with conspicuous parkinsonism and long tract signs.
Rice et al. (1980) and Ball (1980) reported a kindred in which members had clinical features of familial AD. Two patients had neuropathologic changes of spongiform encephalopathy of the Creutzfeldt-Jakob type (CJD; 123400) at autopsy, but the long clinical course was unusual for CJD. Corkin et al. (1983) found no difference in parental age of patients with AD compared to controls. Nee et al. (1983) reported an extensively affected kindred, with 51 affected persons in 8 generations. There was no increased incidence of Down syndrome (190685) or hematologic malignancy.
Heyman et al. (1983) found dementia in first-degree relatives of 17 (25%) of 68 probands with AD. These families also demonstrated an increase in the frequency of Down syndrome (3.6 per 1,000 as compared with an expected rate of 1.3 per 1,000). No excess of hematologic malignancy was found in relatives. In a study of the families of 188 Down syndrome children and 185 controls, Berr et al. (1989) found no evidence of an excess of dementia cases suggestive of AD in the families of patients with Down syndrome. In a large multicenter study of first-degree relatives of 118 AD probands and nondemented spouse controls, Silverman et al. (1994) found no association between familial AD and Down syndrome.
Stokin et al. (2005) identified axonal defects in mouse models of Alzheimer disease that preceded known disease-related pathology by more than a year; the authors observed similar axonal defects in the early stages of Alzheimer disease in humans. Axonal defects consisted of swellings that accumulated abnormal amounts of microtubule-associated and molecular motor proteins, organelles, and vesicles. Impairing axonal transport by reducing the dosage of a kinesin molecular motor protein enhanced the frequency of axonal defects and increased amyloid-beta peptide levels and amyloid deposition. Stokin et al. (2005) suggested that reductions in microtubule-dependent transport may stimulate proteolytic processing of beta-amyloid precursor protein (104760), resulting in the development of senile plaques and Alzheimer disease.
Bateman et al. (2012) performed a prospective, longitudinal study analyzing data from 128 subjects at risk for carrying a mutation for autosomal dominant AD. Subjects underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid and blood tests. Bateman et al. (2012) used the participant's age at baseline assessment and the parent's age at the onset of symptoms of AD to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). They then conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiologic changes. Concentrations of amyloid-beta-42 in the CSF appeared to decline 25 years before expected symptom onset. Amyloid-beta deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. Bateman et al. (2012) cautioned that their results required confirmation with use of longitudinal data and may not apply to patients with sporadic Alzheimer disease.
### Familial Alzheimer Disease 1
Karlinsky et al. (1992) reported a family from Toronto with autosomal dominant inheritance of Alzheimer disease. The disorder was characterized by early onset of memory deficits, decreased speed of cognitive processing, and impaired attention to complex cognitive sets. The family immigrated to Canada from the British Isles in the 18th century. Genetic analysis identified a mutation in the APP gene (V717I; 104760.0002).
Farlow et al. (1994) reviewed the clinical characteristics of the disorder in the AD family reported by Murrell et al. (1991) in which affected members had a mutation in the APP gene (V717F; 104760.0003). The mean age of onset of dementia was 43 years. The earliest cognitive functions affected were recent memory, information-processing speed, sequential tracking, and conceptual reasoning. Language and visuoperceptual skills were largely spared early in the course of the disease. Later, there were progressive cognitive deficits and inability to perform the activities of daily living. Death occurred, on average, 6 years after onset. The family was Romanian, many of its members having migrated to Indiana.
Rossi et al. (2004) reported a family in which at least 6 members spanning 3 generations had Alzheimer disease and strokes associated with a heterozygous mutation in the APP gene (A713T; 104760.0009). At age 52 years, the proband developed progressive cognitive decline with memory loss and visuospatial troubles, as well as stroke-like episodes characterized by monoparesis and language disturbances detectable for a few days. MRI showed T2-weighted signal hyperintensities in subcortical and periventricular white matter without bleeding. Neuropathologic examination showed neurofibrillary tangles and A-beta-40- and A-beta-42-immunoreactive deposits in the neuropil. The vessel walls showed only A-beta-40 deposits, consistent with amyloid angiopathy. There were also multiple white matter infarcts along the long penetrating arteries. Other affected family members had a similar clinical picture. Several unaffected family members carried the mutation, and all but 1 were under 65 years of age.
Edwards-Lee et al. (2005) reported an African American family in which multiple members spanning 3 generations had early-onset AD. The distinctive clinical features in this family were a rapidly progressive dementia starting in the fourth decade, seizures, myoclonus, parkinsonism, and spasticity. Variable features included aggressiveness, visual disturbances, and pathologic laughter. Two sibs who were tested were heterozygous for a mutation in the APP gene (T714I; 104760.0015).
### Early-Onset Alzheimer Disease with Cerebral Amyloid Angiopathy
Because Alzheimer disease associated with cerebral amyloid angiopathy (CAA) is also found in Down syndrome, Rovelet-Lecrux et al. (2006) reasoned that the APP locus located on chromosome 21q21 might be affected by gene dosage alterations in a subset of demented individuals. To test this hypothesis, they analyzed APP using quantitative multiplex PCR of short fluorescent fragments, a sensitive method for detecting duplications that is based on the simultaneous amplification of multiple short genomic sequences using dye-labeled primers under quantitative conditions. This analysis was performed in 12 unrelated individuals with autosomal dominant early-onset Alzheimer disease (ADEOAD) in whom a previous mutation screen of PSEN1 (104311), PSEN2 (600759), and APP had been negative; 5 of these individuals belonged to Alzheimer disease-affected families in which the cooccurrence of CAA had been diagnosed according to neuropathologic (Vonsattel et al., 1991) or clinical criteria (intracerebral hemorrhages (ICH) in at least 1 affected individual). In the 5 index cases with the combination of early-onset Alzheimer disease and CAA, they found evidence for a duplication of the APP locus (104760.0020). In the corresponding families, the APP locus duplication was present in affected subjects but not in healthy subjects over the age of 60 years. The phenotypes of the affected subjects in the 5 families were similar. None had mental retardation before the onset of dementia. None had clinical features suggestive of Down syndrome. The most common clinical manifestation was progressive dementia of Alzheimer disease type (mean age of onset 52 +/- 4.4 years) associated, in some cases, with lobar ICH. Neuropathologic examination of the brains of 5 individuals from 3 kindreds showed abundant amyloid deposits, present both as dense-cored plaques and as diffuse deposits, in all regions analyzed. Neurofibrillary tangles were noted in a distribution consistent with the diagnosis of definite Alzheimer disease. However, the most prominent feature was severe CAA. Rovelet-Lecrux et al. (2006) estimated that in their whole cohort of 65 ADEOAD families, the frequency of the APP locus duplication was roughly 8% (5 of 65), which corresponds to half of the contribution of APP missense mutations to ADEOAD.
Other Features
In longitudinal studies using magnetic resonance spectroscopic imaging (MRSI), Adalsteinsson et al. (2000) found that 12 patients with AD had a striking decline in the neuronal marker N-acetyl aspartate, compared to 14 controls. However, there was little decline in underlying gray matter volume in these patients.
In a comparison of 59 unrelated patients with AD and over 1,000 controls, Borenstein Graves et al. (2001) found that a combination of low head circumference and presence of the APOE4 allele strongly predicted earlier onset of AD. The authors suggested that the clinical expression of AD may occur when degeneration in specific brain regions falls below a critical threshold of 'brain reserve,' beyond which normal cognitive function cannot be maintained.
In a study of 461 sibs of 371 probands diagnosed with AD, Sweet et al. (2002) found that AD plus psychosis in probands was associated with a significantly increased risk for AD plus psychosis in family members (odds ratio = 2.4), demonstrating familial aggregation of this phenotype.
In a PET study comparing brain glucose metabolism between 46 patients with sporadic AD and 40 patients with familial AD, Mosconi et al. (2003) found that both groups had reductions in the metabolic rate of glucose in similar regional areas of the brain, particularly the posterior cingulate cortex, the parahippocampal gyrus, and occipital areas, suggesting common neurophysiologic pathways of degeneration. However, patients with familial AD had a more severe reduction in glucose metabolism in all these areas, suggesting that genetic predisposition further strains the degenerative process.
Biochemical Features
Zubenko et al. (1987) described a biophysical alteration of platelet membranes in Alzheimer disease. They concluded that increased platelet membrane fluidity (see 173560) characterized a subgroup of patients with early age of symptomatic onset and rapidly progressive course. Zubenko and Ferrell (1988) described monozygotic twins concordant for probable AD and for increased platelet membrane fluid.
Abraham et al. (1988) identified one of the components of the amyloid deposits seen in AD as the serine protease inhibitor alpha-1-antichymotrypsin (AACT; 107280). Birchall and Chappell (1988) suggested that individual vulnerability of genetic factors influencing intake, transport or excretion of aluminum may be a mechanism for familial AD.
Yan et al. (1996) reported that the RAGE protein (AGER; 600214) is an important receptor for the amyloid beta peptide and that expression of this receptor is increased in AD. They noted that expression of RAGE was particularly increased in neurons close to deposits of amyloid beta peptide and to neurofibrillary tangles.
Cholinergic projection neurons of the basal forebrain nucleus basalis express nerve growth factor (NGF) receptors p75(NTR) (162010) and TrkA (191315), which promote cell survival. These same cells undergo extensive degeneration in AD. Counts et al. (2004) found an approximately 50% average reduction in TrkA levels in 4 cortical brain regions of 15 patients with AD, compared to 18 individuals with no cognitive impairment and 16 with mild/moderate cognitive impairment. By contrast, cortical p75(NTR) levels were stable across the diagnostic groups. Scores on the Mini-Mental State Examination (MMSE) correlated with TrkA levels in the anterior cingulate, superior frontal, and superior temporal cortices. Counts et al. (2004) suggested that reduced TrkA levels may be the cause or result of abnormal cholinergic function in AD.
The Framingham (Massachusetts) Study cohort has been evaluated biennially since 1948. In a sample of 1,092 subjects (mean age, 76 years) from this cohort, Seshadri et al. (2002) analyzed the relation of the plasma total homocysteine level measured at baseline and that measured 8 years earlier to the risk of newly diagnosed dementia on follow-up. They used multivariable proportional-hazards regression to adjust for age, sex, apoE genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6. Over a median follow-up period of 8 years, dementia developed in 111 subjects, including 83 given a diagnosis of Alzheimer disease. The multivariable-adjusted relative risk of dementia was 1.4 for each increase of 1 standard deviation in the log-transformed homocysteine value either at baseline or 8 years earlier. The relative risk of Alzheimer disease was 1.8 per increase of 1 SD at baseline and 1.6 per increase of 1 SD 8 years before baseline. With a plasma homocysteine level greater than 14 micromol per liter, the risk of Alzheimer disease nearly doubled. Seshadri et al. (2002) concluded that an increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer disease.
Among 563 AD patients and 118 controls, Prince et al. (2004) found that presence of the APOE4 allele was strongly associated with reduced CSF levels of beta-amyloid-42 in both patients and controls. In a retrospective study of 443 AD patients, Evans et al. (2004) found that increased serum total cholesterol was associated with more rapid disease progression in patients who did not have the APOE4 allele. The effect was not seen in patients with the APOE4 allele and high cholesterol.
Botella-Lopez et al. (2006) found increased levels of a 180-kD reelin (RELN; 600514) fragment in CSF from 19 patients with AD compared to 11 nondemented controls. Western blot and PCR analysis confirmed increased levels of reelin protein and mRNA in tissue samples from the frontal cortex of AD patients. Reelin was not increased in plasma samples, suggesting distinct cellular origins. The reelin 180-kD fragment was also increased in CSF samples of other neurodegenerative disorders, including frontotemporal dementia (600274), progressive supranuclear palsy (PSP; 601104), and Parkinson disease (PD; 168600).
Tesseur et al. (2006) found significantly decreased levels of TGF-beta receptor type II (TGFBR2; 190182) in human AD brain compared to controls; the decrease was correlated with pathologic hallmarks of the disease. Similar decreases were not seen in brain extracts from patients with other forms of dementia. In a mouse model of AD, reduced neuronal TGFBR2 signaling resulted in accelerated age-dependent neurodegeneration and promoted beta-amyloid accumulation and dendritic loss. Reduced TGFBR2 signaling in neuroblastoma cell cultures resulted in increased levels of secreted beta-amyloid and soluble APP. The findings suggested a role for TGF-beta (TGFB1; 190180) signaling in the pathogenesis of AD.
Counts et al. (2007) found a 60% increase in CHRNA7 (118511) mRNA levels in cholinergic neurons of the nucleus basalis in patients with mild to moderate Alzheimer disease compared to those with mild cognitive impairment or normal controls. Expression levels of CHRNA7 were inversely associated with cognitive test scores. Counts et al. (2007) suggested that upregulation of CHRNA7 receptors may be a compensatory response to maintain basocortical cholinergic activity during disease progression or may act with beta-amyloid in disease pathogenesis.
Pathogenesis
In a study of the families of Alzheimer disease patients, Heston (1977) found an excess of Down syndrome and of myeloproliferative disorders, including lymphoma and leukemia. Neurons of Alzheimer patients show a neurofibrillary tangle that is made up of disordered microtubules. An identical lesion occurs in the neurons of Down syndrome, at an earlier age than in Alzheimer disease. Leukemia and accelerated aging are also features of Down syndrome. Heston (1977) and Heston and Mastri (1977) speculated a disorder of microtubules as a common pathomechanism. Heston and White (1978) further speculated defective organization of microfilaments and microtubules in AD. Using immunoprecipitation techniques, Grundke-Iqbal et al. (1979) showed that neurofibrillary tangles in AD probably originate from neurotubules. Harper et al. (1979) could not confirm a systemic microtubular defect in Alzheimer disease; cultured skin fibroblasts from AD patients showed normal tubulin networks. Nordenson et al. (1980) found an increased frequency of acentric fragments in karyotypes from AD patients, and suggested that this was consistent with defective tubulin protein leading to erratic function of the spindle mechanism.
Gajdusek (1986) suggested that the amyloid in Alzheimer disease and Down syndrome is formed from a precursor synthesized in neurons as well as in microglial cells and brain macrophages. He further suggested that the precursor synthesized in neurons produces intracellular neurofibrillary tangles, and that the precursor synthesized in microglial cells and brain macrophages is exuded from the cell, forming the extracellular amyloid plaques and vascular amyloid deposits. Dying neurons may also contribute to extracellular deposits.
Bergeron et al. (1987) found that cerebral amyloid angiopathy (605714) was present in 86% of AD patients and 40% of age-matched controls. The findings suggested that cerebral amyloid angiopathy is an integral component of AD.
Using immunocytochemistry, Wolozin et al. (1988) identified a 68-kD protein in cerebral cortical neurons from both normal human fetal and neonatal brain and brain tissue from neonates with Down syndrome. The number of reactive neurons decreased sharply after age 2 years, but reappeared in older individuals with Down syndrome and in patients with Alzheimer disease.
Carrell (1988) speculated that plaque formation in AD was a consequence of proteolysis of a precursor protein; self-aggregation of the cleaved A4 peptides explained the precipitated amyloid, while release of a trophic inhibitory domain explained the interwoven neuritic development. Using computer-enhanced imaging of immunocytochemical stains of Alzheimer disease prefrontal cortex, Majocha et al. (1988) described the distribution of amyloid protein deposits exclusive of other senile plaque components. Joachim et al. (1989) presented evidence suggesting that Alzheimer disease is not restricted to the brain but is a widespread systemic disorder with accumulation of amyloid beta protein (104760) in nonneuronal tissues.
Ellis et al. (1996) found that 83% of 117 patients with autopsy-confirmed AD had at least a mild degree of cerebral amyloid angiopathy. Thirty (25.6%) of 117 brains showed moderate to severe CAA affecting the cerebral vessels in one or more cortical regions. These brains also showed a significantly higher frequency of hemorrhages or ischemic lesions compared to those with little or no amyloid angiopathy (43.3% versus 23.0%; odds ratio = 2.6). High CAA scores also correlated with the presence of cerebral arteriosclerosis and with older age at onset of dementia.
In light of the findings of Tomita et al. (1997) concerning PSEN2 mutation and altered metabolism of APP (summarized in 600759.0001), Hardy (1997) reviewed the evidence that Alzheimer disease has many etiologies, but one pathogenesis. Mutations in all known pathogenic genes have in common the fact that they alter processing of APP, thus lending strong support to the amyloid cascade hypothesis. Heintz and Zoghbi (1997) suggested that alpha-synuclein (163890) may provide a link between Parkinson disease (see 168600) and Alzheimer disease and possibly other neurodegenerative diseases.
The neurofibrillary tangle, one of the neuropathologic hallmarks of AD, contains paired helical filaments (PHFs) composed of the microtubule-associated protein tau (MAPT; 157140). Tau is hyperphosphorylated in PHFs, and phosphorylation of tau abolishes its ability to bind microtubules and promote microtubule assembly. Lu et al. (1999) demonstrated that PIN1 (601052) binds hyperphosphorylated tau and copurifies with PHFs, resulting in depletion of soluble PIN1 in the brains of patients with AD. PIN1 can restore the ability of phosphorylated tau to bind microtubules and promote microtubule assembly in vitro. Since depletion of PIN1 induces mitotic arrest and apoptotic cell death, sequestration of PIN1 into PHFs may contribute to neuronal death.
From detailed analysis of pathologic load and spatiotemporal distribution of beta-amyloid deposits and tau pathology in sporadic AD, Delacourte et al. (2002) concluded that there is a synergistic effect of amyloid aggregation in the propagation of tau pathology.
Kayed et al. (2003) produced an antibody that specifically recognized micellar amyloid beta but not soluble, low molecular weight amyloid beta or amyloid beta fibrils. The antibody also specifically recognized soluble oligomers among all other types of amyloidogenic proteins and peptides examined, indicating that they have a common structure and may share a common pathogenic mechanism. Kayed et al. (2003) showed that all of the soluble oligomers tested displayed a common conformation-dependent structure that was unique to soluble oligomers regardless of sequence. The in vitro toxicity of soluble oligomers was inhibited by oligomer-specific antibody. Soluble oligomers have a unique distribution in human Alzheimer disease brain that is distinct from that of fibrillar amyloid. Kayed et al. (2003) concluded that different types of soluble amyloid oligomers have a common structure and suggested that they share a common mechanism of toxicity.
Revesz et al. (2003) reviewed the pathology and genetics of APP-related CAA and discussed the different neuropathologic consequences of different APP mutations. Those that result in increased beta-amyloid-40 tend to result in increased deposition of amyloid in the vessels, consistent with CAA, whereas those that result in increased beta-amyloid-42 tend to result in parenchymal deposition of amyloid and the formation of amyloid plaques. These latter changes are common in classic Alzheimer disease.
To determine whether decreased neprilysin (MME; 120520) levels contribute to the accumulation of amyloid deposits in AD or normal aging, Russo et al. (2005) analyzed MME mRNA and protein levels in cerebral cortex from 10 cognitively normal elderly individuals with amyloid plaques (NA), 10 individuals with AD, and 10 controls who were free of amyloid plaques. They found a significant decrease in MME mRNA levels in both AD and NA individuals compared to controls. Russo et al. (2005) concluded that decreased MME expression correlates with amyloid-beta deposition but not with degeneration and dementia.
Using Western blotting, immunoprecipitation assays, and surface plasmon resonance analysis, Guo et al. (2006) showed that beta-amyloid-40 and -42 formed stable complexes with soluble tau and that prior phosphorylation of MAPT inhibited complex formation. Immunostaining of brain extracts from patients with AD and controls showed that phosphorylated tau and beta-amyloid were present within the same neuron. Guo et al. (2006) postulated that an initial step in AD pathogenesis may be the intracellular binding of soluble beta-amyloid to soluble nonphosphorylated tau.
By neuropathologic examination, Wilkins et al. (2006) found no difference in the presence or degree of neurofibrillary tangles, senile plaques, Lewy bodies, or amyloid angiopathy between 10 African American and 10 white individuals with AD. The findings suggested that race is not a major influence on AD pathology.
In HEK293 cells in vitro, Ni et al. (2006) found that activation of beta-2-adrenergic receptors (ADRB2; 109690) stimulated gamma-secretase activity and beta-amyloid production. Stimulation involved the association of ADRB2 with PSEN1 and required agonist-induced endocytosis of ADRB2. Similar effects were observed after activation of the opioid receptor OPRD1 (165195). In mouse models of AD, chronic treatment with ADRB2 agonists increased cerebral amyloid plaques, and treatment with ADRB2 antagonists reduced cerebral amyloid plaques. Ni et al. (2006) postulated that abnormal activation of ADRB2 receptors may contribute to beta-amyloid accumulation in AD.
Sun et al. (2006) found that hypoxia increased BACE1 (604252) beta-secretase activity and resulted in significantly increased beta-amyloid production in both wildtype human cells and human cells that stably overexpressed an AD-related APP mutation. Studies in transgenic mice with APP mutations showed that hypoxia upregulated Bace1 mRNA and increased deposition of brain beta-A40 and A42 compared to transgenic mice not exposed to hypoxic conditions. The findings suggested that hypoxia can facilitate AD pathogenesis and provided a molecular mechanism that linked vascular factors to AD.
In studies of rodent and human cells, Li et al. (2007) found that overexpression of hyperphosphorylated tau antagonized apoptosis of neuronal cells by stabilizing beta-catenin (CTNNB1; 116806). The findings explained why NFT-bearing neurons survive proapoptotic insults and instead die chronically of degeneration.
Schilling et al. (2008) found that the N-terminal pyroglutamate (pE) formation of amyloid beta (104760) is catalyzed by glutaminyl cyclase (607065) in vivo. Glutaminyl cyclase expression was upregulated in the cortices of individuals with Alzheimer disease and correlated with the appearance of pE-modified amyloid beta. Oral application of a glutaminyl cyclase inhibitor resulted in reduced amyloid beta(3(pE)-42) burden in 2 different transgenic mouse models of Alzheimer disease and in a new Drosophila model. Treatment of mice was accompanied by reductions in amyloid beta(X-40/42), diminished plaque formation and gliosis, and improved performance in context memory and spatial learning tests. Schilling et al. (2008) suggested that their observations were consistent with the hypothesis that amyloid beta(3(pE)-42) acts as a seed for amyloid beta aggregation by self-aggregation and coaggregation with amyloid beta(1-40/42). Therefore, amyloid beta(3(pE)-40/42) peptides seem to represent amyloid beta forms with exceptional potency for disturbing neuronal function. The authors suggested that the reduction of brain pE-modified amyloid beta by inhibition of glutaminyl cyclase offers a new therapeutic option for the treatment of Alzheimer disease and provides implications for other amyloidoses.
In vascular smooth muscle cells isolated from AD patients with CAA, Bell et al. (2009) found an association between beta-amyloid deposition and increased expression of serum response factor (SRF; 600589) and myocardin (MYOCD; 606127) compared to controls. Further studies indicated the MYOCD upregulated SRF and generated a beta-amyloid nonclearing phenotype through transactivation of SREBP2 (600481), which downregulates LRP1, a key beta-amyloid clearance receptor. SRF silencing led to increased beta-amyloid clearance. Hypoxia stimulated SRF/MYOCD expression in human cerebral vascular smooth muscle cells and in animal models of AD. Bell et al. (2009) suggested that SRF and MYOCD function as a transcriptional switch, controlling beta-amyloid cerebrovascular clearance and progression of AD.
Using microarray analysis, followed by RT-PCR of human postmortem hippocampus, Qin et al. (2009) found that decreased expression of the PPARGC1A gene (604517), a regulator of gluconeogenesis, correlated with progression of moderate to severe clinical dementia in patients with AD, as well as increased density of neuritic plaques and beta-amyloid-42. Hyperglycemia was found to attenuate PPARGC1A expression and increase beta-amyloid in the medium of Tg2576 AD neurons; this phenomenon was decreased by exogenous expression of PPARGC1A. Further studies indicated that suppression of PPARGC1A in hyperglycemia resulted in activation of the FOXO3A (602681) transcription factor, which inhibits nonamyloidogenic secretase processing of APP and promotes amyloidogenic processing of APP. The findings provided a molecular mechanism for a link between glucose metabolism and AD.
Mawuenyega et al. (2010) measured amyloid-beta kinetics in the CNS of 12 AD participants and 12 cognitively intact controls. Mawuenyega et al. (2010) found no differences in the rate of production of amyloid-beta-42 or amyloid-beta-40 in AD patients versus controls. However, there was a significant difference in the rate of amyloid-beta-40 and amyloid-beta-42 clearance in the AD subjects versus controls. There was roughly 30% impairment in the clearance of both amyloid-beta-42 and amyloid-beta-40, with a P value of 0.03 and 0.01, respectively. Estimates based on a 30% decrease in amyloid-beta clearance rate suggested that brain amyloid-beta accumulates over about 10 years in AD. The authors pointed out that the limitations of this study included the relatively small number of participants and the inability to prove causality of impaired amyloid-beta clearance for AD.
Israel et al. (2012) reprogrammed primary fibroblasts from 2 patients with familial Alzheimer disease, in both caused by a duplication of the amyloid-beta precursor protein gene (APP; 104760), 2 with sporadic Alzheimer disease, and 2 nondemented control individuals into induced pluripotent stem cell (iPSC) lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain mRNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiologic activity. Relative to controls, iPSC-derived, purified neurons from the 2 patients with the duplication and 1 sporadic patient exhibited significantly higher levels of the pathologic markers of amyloid-beta(1-40), phospho-tau(thr231), and active glycogen synthase kinase-3-beta (aGSK-3-beta). Neurons from the duplication and the same sporadic patient also accumulated large RAB5 (179512)-positive early endosomes compared to controls. Treatment of purified neurons with beta-secretase inhibitors, but not gamma-secretase inhibitors, caused significant reductions in phospho-tau(thr231) and aGSK-3-beta levels. Israel et al. (2012) concluded that their results suggested a direct relationship between APP proteolytic processing, but not amyloid-beta, in GSK-3-beta activation and tau phosphorylation in human neurons. Additionally, Israel et al. (2012) observed that neurons with the genome of 1 of the sporadic patients exhibited the phenotypes seen in familial Alzheimer disease samples.
Laganowsky et al. (2012) identified a segment of the amyloid-forming protein alpha-B crystallin (123590) that forms an oligomeric complex exhibiting properties of other amyloid oligomers: beta-sheet-rich structure, cytotoxicity, and recognition by an oligomer-specific antibody. The x-ray-derived atomic structure of the oligomer revealed a cylindrical barrel formed from 6 antiparallel protein strands that Laganowsky et al. (2012) termed a cylindrin. The cylindrin structure is compatible with a sequence segment from the beta-amyloid protein of Alzheimer disease. Laganowsky et al. (2012) concluded that cylindrins offer models for the hitherto elusive structures of amyloid oligomers.
Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-beta are strongly associated with Alzheimer disease, are more toxic than amyloid-beta(1-42) and amyloid-beta(1-40), and have been proposed as initiators of Alzheimer disease pathogenesis. Nussbaum et al. (2012) reported a mechanism by which pE-amyloid-beta may trigger Alzheimer disease. Amyloid-beta-3(pE)-42 co-oligomerizes with excess amyloid-beta(1-42) to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from amyloid-beta(1-42) alone. Tau (157140) is required for cytotoxicity, and LNOs comprising 5% amyloid-beta-3(pE)-42 plus 95% amyloid-beta(1-42) (5% pE-amyloid-beta) seed new cytotoxic LNOs through multiple serial dilutions into amyloid-beta(1-42) monomers in the absence of additional amyloid-beta-3(pE)-42. LNOs isolated from human Alzheimer disease brain contained amyloid-beta-3(pE)-42, and enhanced amyloid-beta-3(pE)-42 formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau-null background. Nussbaum et al. (2012) concluded that amyloid-beta-3(pE)-42 confers tau-dependent neuronal death and causes template-induced misfolding of amyloid-beta(1-42) into structurally distinct LNOs that propagate by a prion-like mechanism. Nussbaum et al. (2012) concluded that their results raised the possibility that amyloid-beta-3(pE)-42 acts similarly at a primary step in Alzheimer disease pathogenesis.
Raj et al. (2014) performed an expression quantitative trait locus (eQTL) study of purified CD4 (186940)+ T cells and monocytes, representing adaptive and innate immunity, in a multiethnic cohort of 461 healthy individuals. Context-specific cis- and trans-eQTLs were identified, and cross-population mapping allowed, in some cases, putative functional assignment of candidate causal regulatory variants for disease-associated loci. Raj et al. (2014) noted an overrepresentation of monocyte-specific eQTLs among Alzheimer disease and Parkinson disease (168600) variants, and of T cell-specific eQTLs among susceptibility alleles for autoimmune diseases, including rheumatoid arthritis (180300) and multiple sclerosis (126200). Raj et al. (2014) concluded that this polarization implicates specific immune cell types in these diseases and points to the need to identify the cell-autonomous effects of disease susceptibility variants.
Using solid-state nuclear magnetic resonance (ssNMR) measurements on amyloid beta-40 and amyloid beta-42 fibrils prepared by seeded growth from extracts of Alzheimer disease brain cortex, Qiang et al. (2017) investigated correlations between structural variation and Alzheimer disease phenotype. The authors compared 2 atypical Alzheimer disease clinical subtypes, the rapidly progressive form (r-AD) and the posterior cortical atrophy variant (PCA-AD), with a typical prolonged-duration form (t-AD). On the basis of ssNMR data from 37 cortical tissue samples from 18 individuals, Qiang et al. (2017) found that a single amyloid beta-40 fibril structure is most abundant in samples from patients with t-AD and PCA-AD, whereas amyloid beta-40 fibrils from r-AD samples exhibit a significantly greater proportion of additional structures. Data for amyloid beta-42 fibrils indicated structural heterogeneity in most samples from all patient categories, with at least 2 prevalent structures. Qiang et al. (2017) concluded that these results demonstrated the existence of a specific predominant amyloid beta-40 fibril structure in t-AD and PCA-AD, suggested that r-AD may relate to additional fibril structures, and indicated that there is a qualitative difference between amyloid beta-40 and amyloid beta-42 aggregates in the brain tissue of patients with Alzheimer disease.
In patients with Alzheimer disease, deposition of amyloid-beta is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC (606838) specks in microglia. ASC specks released by microglia bind rapidly to amyloid-beta and increase the formation of amyloid-beta oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-beta pathology. Venegas et al. (2017) showed that intrahippocampal injection of ASC specks resulted in spreading of amyloid-beta pathology in transgenic double-mutant APP(Swe)PSEN1(dE9) mice. By contrast, homogenates from brains of APP(Swe)PSEN1(dE9) mice failed to induce seeding and spreading of amyloid-beta pathology in ASC-deficient double-mutant mice. Moreover, coapplication of an anti-ASC antibody blocked the increase in amyloid-beta pathology in the double-mutant mice. Venegas et al. (2017) concluded that these findings supported the concept that inflammasome activation is connected to seeding and spreading of amyloid-beta pathology in patients with Alzheimer disease.
In mice, Da Mesquita et al. (2018) demonstrated that meningeal lymphatic vessels drain macromolecules from the CNS (cerebrospinal and interstitial fluids) into the cervical lymph nodes. Impairment of meningeal lymphatic function slowed paravascular influx of macromolecules into the brain and efflux of macromolecules from the interstitial fluid, and induced cognitive impairment in mice. Treatment of aged mice with vascular endothelial growth factor C (VEGFC; 601528) enhanced meningeal lymphatic drainage of macromolecules from the cerebrospinal fluid, improving brain perfusion and learning and memory performance. Disruption of meningeal lymphatic vessels in transgenic mouse models of Alzheimer disease promoted amyloid-beta deposition in the meninges, which resembles human meningeal pathology, and aggravated parenchymal amyloid-beta accumulation. Da Mesquita et al. (2018) suggested that meningeal lymphatic dysfunction may be an aggravating factor in Alzheimer disease pathology and in age-associated cognitive decline.
Inheritance
From an extensive study in Sweden, Sjogren et al. (1952) suggested that Alzheimer disease shows multifactorial inheritance. In a study of 52 families with AD, Masters et al. (1981) concluded that the disorder showed autosomal dominant inheritance without maternal effect.
In 7 of 21 families with AD, Powell and Folstein (1984) found evidence of 3-generation transmission. Breitner and Folstein (1984) suggested that most cases of Alzheimer disease are familial. Fitch et al. (1988) found a familial incidence of 43%, and detected no clinical differences between the familial and sporadic cases. In one-third of the familial cases, the disorder developed after age 70. Breitner et al. (1988) found that the cumulative incidence of AD among relatives was 49% by age 87. The risk was similar among parents and sibs, and did not differ significantly between relatives of those with early or late onset.
In a study of 70 kindreds containing 541 affected and 1,066 unaffected offspring of parents with AD parents, Farrer et al. (1990) identified 2 distinct clinical groups: early onset (less than 58 years) and late onset (greater than 58 years). At-risk offspring in early-onset families had an estimated lifetime risk for dementia of 53%, suggesting autosomal dominant inheritance. The lifetime risk in late-onset families was 86%. Farrer et al. (1990) concluded that late-onset AD may be autosomal dominant in some families.
In a complex segregation analysis on 232 nuclear families ascertained through a single proband who was referred for diagnostic evaluation of memory disorder, Farrer et al. (1991) concluded that susceptibility to AD is determined, in part, by a major autosomal dominant allele with an additional multifactorial component. The frequency of the AD susceptibility allele was estimated to be 0.038, but the major locus was thought to account for only 24% of the 'transmission variance,' indicating a substantial role for other genetic and nongenetic mechanisms.
Silverman et al. (1994) used a standardized family history assessment to study first-degree relatives of Alzheimer disease probands and nondemented spouse controls. First-degree relatives of AD probands had a significantly greater cumulative risk of AD (24.8%) than did the relatives of spouse controls (15.2%). The cumulative risk for the disorder among female relatives of probands was significantly greater than that among male relatives.
Rao et al. (1996) carried out a complex segregation analysis in 636 nuclear families of consecutively ascertained and rigorously diagnosed probands in the Multi-Institutional Research in Alzheimer Genetic Epidemiology study in order to derive models of disease transmission that account for the influences of the APOE genotype of the proband and gender. In the total group of families, models postulating sporadic occurrence, no major gene effect, random environmental transmission, and mendelian inheritance were rejected. Transmission of AD in families of probands with at least 1 APOE4 allele best fitted a dominant model. Moreover, single gene inheritance best explained clustering of the disorder in families of probands lacking APOE4, but a more complex genetic model or multiple genetic models may ultimately account for risk in this group of families. The results suggested to Rao et al. (1996) that susceptibility to AD differs between men and women regardless of the proband's APOE status. Assuming a dominant model, AD appeared to be completely penetrant in women, whereas only 62 to 65% of men with predisposing genotypes developed AD. However, parameter estimates from the arbitrary major gene model suggested that AD is expressed dominantly in women and additively in men. These observations, taken together with epidemiologic data, were considered consistent with the hypothesis of an interaction between genes and other biologic factors affecting disease susceptibility.
In a study of 290 patients with Alzheimer disease in the French Collaborative Group and 1,176 of their first-degree relatives, Martinez et al. (1998) found that familial clustering of Alzheimer disease was largely due to factors other than APOE status.
Silverman et al. (1999) hypothesized that elderly individuals who lived beyond the age of 90 years without dementia had a concentration of genetic protective factors against Alzheimer disease. Although they recognized that testing this hypothesis was complicated, probands carrying genetic protective factors should have relatives with lower illness rates not only for early-onset disease, in which genetic risk factors are a strong contributing factor to the incidence of AD, but also for later-onset disease, when the role of these factors appears to be markedly diminished. AD dementia was assessed through family informants in 6,660 first-degree relatives of 1,049 nondemented probands aged 60 to 102 years. Cumulative survival without AD was significantly greater in the relatives of the oldest proband group (aged 90 to 102 years) than it was in the 2 younger groups. In addition, the reduction in the rate of illness for this group was relatively constant across the entire late life span. The results suggested that genetic factors conferring a lifelong reduced liability to AD may be more highly concentrated among nondemented probands aged 90 or more years and their relatives.
Gatz et al. (2006) evaluated genetic and environmental influences on Alzheimer disease in a population of like- and unlike-sex twin pairs (11,884 twin pairs, 392 with one or both members diagnosed with AD from the Swedish Twin Registry; participants were 65 years of age or older). Participants were divided into 5 quantitative genetic groups; male/female monozygotic twins, male/female dizygotic twins, and unlike-sex twins. On the basis of screening for cognitive dysfunction and environmental variables, estimates on heritability, shared environmental influences, and nonshared environmental influences, adjusted for age, were derived from the twin data. Heritability for AD was estimated to be 58% in the full model and 79% in the best-fitting model with the balance of variation explained by nonshared environmental influences. There were no significant differences between men and women in prevalence or heritability after controlling for age. In pairs concordant for AD, intrapair difference in age at onset was significantly greater in dizygotic than in monozygotic pairs, suggesting genetic influences on timing of the disease.
### Autosomal Recessive Inheritance
Bowirrat et al. (2000) presented data they interpreted as suggesting an autosomal recessive form of AD. They screened all 821 elderly residents of an Arab community located in Wadi Ara, northern Israel. An unusually high prevalence of AD was observed (20% of those 65 years old or older; 60.5% of those 85 years old or older). Data on the APOE4 allele suggested that it could not explain the AD prevalence in this population. The APOE4 allele was relatively uncommon in Arabs in Wadi Ara; in fact, Bowirrat et al. (2000) stated that it was the lowest frequency of the allele ever recorded. Because of the high consanguinity rate of Arab marriages in Israel, Bowirrat et al. (2000) speculated that recessive genes for AD exist and are responsible for the high AD prevalence in Wadi Ara. Further information was provided by Bowirrat et al. (2001) and Bowirrat et al. (2002). Bowirrat et al. (2002) reported on vascular dementia among elderly Arabs in the same area.
A form of AD mapped to chromosome 10q24, AD6 (605526), showed some evidence of autosomal recessive inheritance.
Di Fede et al. (2009) identified a homozygous mutation in the APP gene (A673V; 104760.0022) in a patient with early-onset progressive AD beginning at age 36 years. He was noncommunicative and could not walk by age 44. Serial MRI showed progressive cortico-subcortical atrophy, and cerebrospinal fluid analysis showed decreased A-beta-1-42 and increased total and 181T-phosphorylated tau compared to controls and similar to subjects with Alzheimer disease. The mutation was also found in homozygosity in the proband's younger sister, who had multiple domain mild cognitive impairment (MCI), believed to a high risk condition for the development of clinically probable Alzheimer disease (Petersen et al., 2001). In the plasma of both the patient and his homozygous sister, amyloid-beta-1-40 and amyloid-beta-1-42 were higher than in nondemented controls, whereas the A673V heterozygous carriers from the family that were tested had intermediate amounts. None of 6 heterozygous individuals in the family had any evidence of dementia when tested at ages ranging from 21 to 88. The A673V mutation, which corresponds to position 2 of amyloid beta, affected APP processing, resulting in enhanced beta-amyloid production and formation of amyloid fibrils in vitro. Coincubation of mutated and wildtype peptides conferred instability on amyloid beta aggregates and inhibited amyloidogenesis and neurotoxicity. Di Fede et al. (2009) concluded that the interaction between mutant and wildtype amyloid beta, favored by the A-to-V substitution at position 2, interferes with nucleation or nucleation-dependent polymerization or both, hindering amyloidogenesis and neurotoxicity and thus protecting the heterozygous carriers.
Diagnosis
Croes et al. (2000) argued against using genetic testing for Alzheimer disease as a diagnostic tool. They suggested that the contribution of genetic testing to clinical diagnosis is small and does not counterbalance the problems associated either with interpretation or with secondary effects on family members.
Itoh et al. (2001) proposed a CSF analysis of hyperphosphorylated tau protein (phosphorylation at serine 199; tau-199) for the antemortem diagnosis of AD. In over 500 patients with dementia, including 236 believed to have AD, there was a significant increase in the tau-199 levels in the AD group compared to the non-AD group. Itoh et al. (2001) noted that the tau-199 test exceeds both sensitivity and specificity over 85% as a sole biomarker of AD; however, they also noted that many of the non-AD tauopathy and degenerative dementias also showed increased tau-199 levels.
Among 131 patients with AD and 72 healthy controls, Sunderland et al. (2003) found significantly lower levels of beta-amyloid(1-42) and significantly higher levels of tau in the CSF of AD patients than in the CSF of controls. However, the data showed considerable variance, with significant overlap between the groups. Metaanalysis of previous studies comparing these markers demonstrated similar findings. The authors suggested that CSF beta-amyloid and tau are biologic markers of AD pathophysiology and that the measures may have potential clinical utility in the future diagnosis of AD.
Among 78 patients with mild cognitive impairment, 23 of whom developed dementia, Herukka et al. (2005) found that a combination of low CSF beta-amyloid-42 and high CSF tau and phosphorylated tau was associated with the development of dementia. The high positive likelihood ratio indicated that combined biomarker tests were useful in confirming the diagnosis of AD, but the low negative likelihood ratio indicated that a negative test result could not rule out the disease. The sensitivity of beta-amyloid-42 and phosphorylated tau ranged from 60.0 to 66.7%, and specificity ranged from 84.6 to 89.7%. Herukka et al. (2005) concluded that changes in CSF biomarkers occur early in the course of AD in most patients.
In a study of 22 patients with AD, Hampel et al. (2005) found a correlation between levels of CSF phosphorylated tau and hippocampal atrophy, independent of disease duration and severity. The authors suggested that CSF phosphorylated tau levels may reflect neuronal damage in AD.
Iqbal et al. (2005) classified 353 AD patients into at least 5 subgroups based on CSF levels of beta-amyloid-42, tau, and ubiquitin. Each subgroup presented a different clinical profile, and the authors suggested that the subgroups may benefit from different therapeutic drugs.
Among 184 healthy individual with normal cognition aged 21 to 88 years, Peskind et al. (2006) found that the concentration of CSF beta-amyloid-42, but not beta-amyloid-40, decreased with age. Those with an APOE4 allele showed a sharp and significant decline in CSF beta-A-42 beginning in the sixth decade compared to those without the APOE4 allele. The findings were consistent with APOE4-modulated acceleration of pathogenic beta-A-42 deposition starting in late middle age in persons with normal cognition, and suggested that early treatment for AD in susceptible individuals may be necessary in midlife or earlier.
In a study of 211 cognitively normal controls, 98 patients with early symptomatic AD, and 19 individuals with other forms of dementia, Tarawneh et al. (2011) found a significant difference in CSF VILIP1 (600817) levels, with higher levels in AD compared to the other 2 groups. CSF VILIP1 levels correlated with CSF tau and phosphorylated-tau181, and negatively correlated with brain volumes in AD. VILIP1 and VILIP1/beta-amyloid-42 predicted future cognitive impairment in the normal controls over the follow-up period. Importantly, this CSF ratio (VILIP1/beta-amyloid-42) predicted future cognitive impairment at least as well as tau/beta-amyloid-42 and p-tau181/beta-amyloid-42. VILIP1 is abundantly expressed in neurons and has been shown to be a marker of neuronal injury in brain injury models (Laterza et al., 2006). The findings of Tarawneh et al. (2011) suggested that CSF VILIP1 and VILIP1/beta-amyloid-42 may offer diagnostic utility for early AD and can predict future cognitive impairment in cognitively normal individuals.
Clinical Management
Donepezil is a specific piperidine-based inhibitor of acetylcholinesterase (AChE) used for the treatment of mild to moderate Alzheimer disease with variable efficacy. Pilotto et al. (2009) examined a group of 115 white AD patients taking the medication, including 69 (60%) responders and 46 patients (40%) nonresponders. Nonresponders had a significantly higher frequency of the -1584G allele (rs1080985) in the CYP2D6 gene (124030) compared to responders (58.7% vs 34.8%, p = 0.013), with an odds ratio of 3.43 for poor response. The -1584G allele is associated with higher enzymatic activity and more rapid drug metabolism. The findings suggested that the rs1080985 SNP in the CYP2D6 gene may influence the clinical efficacy of donepezil in AD patients.
Salloway et al. (2009) found insufficient evidence to support or refute the benefit of the use of bapineuzumab, an anti-beta-amyloid monoclonal antibody, in a randomized control trial of 234 AD patients. However, there was some evidence to suggest improved cognitive and functional endpoints in APOE E4 noncarriers, which supported further investigation. Vasogenic edema in the brain, which occurred in 9.7% of treated patients and none of untreated patients, was identified as a potential side effect, particularly in APOE E4 carriers.
Mapping
### Early Linkage Studies
Wheelan and Race (1959) studied a family in which the mother and 5 of 10 children were affected. Possible linkage with the MNS locus was found.
In the large AD kindred reported by Nee et al. (1983), Weitkamp et al. (1983) concluded that genes in the HLA region of chromosome 6 and perhaps also in the Gm region of chromosome 14 are determinants of susceptibility. The association between immunoglobulins and the amyloid in the senile plaque of AD was thought to be significant in this connection. The peak lod score with Gm was 1.37 (at theta = 0.05). Nerl et al. (1984) reported an increase in the frequency of a complement component-4B allele (C4B; 120820) on chromosome 6p21 in patients with AD, but Eikelenboom et al. (1988) failed to find a significant association between C4*B2 allelic frequency and AD.
### Linkage to Chromosome 21q
Delabar et al. (1986) analyzed DNA from 4 patients with a phenotype of trisomy 21 and dementia of the Alzheimer type, but who had normal karyotypes. In all 4 cases, duplication of the ETS2 locus (164740) was found, whereas SOD1 (147450) was normal. Chemical investigations and DNA analyses indicated partial trisomy due to duplication of a short segment of chromosome 21, located at the interface between 21q21 and 21q22.1 and carrying the SOD1 and ETS2 genes.
In 4 extensive kindreds with early-onset AD, St. George-Hyslop et al. (1987) found linkage to DNA markers on the centromeric side of chromosome 21q11.2-21q21. The markers in band 21q22, critical to the development of Down syndrome, showed negative lod scores. There was not tight linkage to the SOD1 gene. Using a RFLP of SOD1 in the study of a large AD family David et al. (1988) also concluded that AD and SOD1 are not closely linked.
By somatic cell hybridization and linkage studies, Tanzi et al. (1987) localized the gene responsible for beta-amyloid deposition in Down syndrome to the same vicinity on chromosome 21 as that responsible for AD.
Haines et al. (1987), who studied 4 large families with FAD, found linkage with 2 DNA markers on chromosome 21 that had previously been shown to be linked to each other at a distance of 8 cM. Pair-wise linkage analysis showed a lod score of 2.37 at theta = 0.08 for one and 2.32 at theta = 0.00 for the other. The use of multipoint analysis provided stronger evidence for linkage with a peak score of 4.25.
Blanquet et al. (1987) found that the APP gene and the ETS2 oncogene are distally located. Surprisingly, 2 hybridization peaks were observed for ETS2 in patients with AD, 1 at the normal site of the oncogene and 1 at the site of the amyloid protein. Blanquet et al. (1987) interpreted these results as indicating that AD is associated with a complex rearrangement within chromosome 21, by which 2 distantly related genes come to lie in the vicinity of each other.
Pulst et al. (1989) used a panel of aneuploid cell lines containing various regions of human chromosome 21 to map the physical order of DNA probes linked to the FAD locus. Van Camp et al. (1989) described the isolation of 35 chromosome 21-specific DNA probes for analysis in Alzheimer disease and Down syndrome. Ross et al. (1989) described the isolation of cDNAs from brain and spinal cord, mapping to chromosome 21, for investigation in Alzheimer disease. Using pulsed field gel electrophoresis to construct a physical map of the region of chromosome 21 around the FAD locus, Owen et al. (1989) suggested the following order: cen--D21S16--D21S48--D21S13--D21S46--(D21S52, D21S4)--(D21S1, D21S11).
Van Broeckhoven et al. (1988) concluded that the gene for early-onset familial AD was located close to the centromere of chromosome 21. In 2 AD families, Van Broeckhoven et al. (1989) found linkage to chromosome 21. Results of 1 family yielded a lod score of 1.52 at marker D21S13. Further studies yielded a peak lod score of 6.24 at D21S16. Using genetic linkage analysis, Goate et al. (1989) found a peak lod score of 3.3 between the familial AD locus and locus D21S16.
St. George-Hyslop et al. (1990), including many members of the FAD collaborative study group, undertook a study of 5 polymorphic chromosome 21 markers in a large unselected series of pedigrees with FAD. The results seemed to indicate that, in many families at least, early-onset AD is due to a mutation on chromosome 21, whereas late-onset AD has other causes.
Lawrence et al. (1992) reviewed the reported data on multiplex Alzheimer pedigrees for which lod scores had been reported; the AD1 locus that mapped to the site of the APP locus on 21q accounted for 63 +/- 11% of these pedigrees. The AD1/APP locus was placed at approximately 27.7 Mb from pter, corresponding to genetic intervals of 10.9 cM in males and 33.9 cM in females, flanked proximally by D21S8 and distally by D21S111. There was no evidence in this analysis for a second locus on chromosome 21.
Olson et al. (2001) reported convincing evidence of a major role for the APP locus in late-onset AD. They used a covariate-based affected-sib-pair linkage method to analyze the chromosome 21 clinical and genetic data obtained on affected sibships by the Alzheimer Disease Genetics Initiative of the National Institute of Mental Health. A lod score of 5.54 (P = 0.000002) was obtained when age at last examination/death was included in the linkage model, and a lod score of 5.63 (P = 0.000006) was obtained when age at onset and disease duration were included. Olson et al. (2001) concluded that the APP locus may predispose to AD in the very elderly.
In further use of a covariate-based linkage method to reanalyze genome scan data, Olson et al. (2002) determined that a region on chromosome 20p (AD8; 607116) showed the same linkage pattern to very-late-onset AD as APP. Two-locus analysis provided evidence of strong epistasis between 20p and the APP region, limited to the oldest age group and to those lacking E4 alleles at the APOE locus. Olson et al. (2002) speculated that high-risk polymorphisms in both regions produce a biologic interaction between these 2 proteins that increases susceptibility to a very-late-onset form of AD.
### Genetic Heterogeneity
In several families with AD, Van Broeckhoven et al. (1987), Tanzi et al. (1987), and Pulst et al. (1991) excluded linkage to chromosome 21q, indicating genetic heterogeneity.
Percy et al. (1991) described 2 sisters thought to have late-onset AD who also had an unusual chromosome 22-derived marker with a greatly elongated short arm containing 2 well-separated nucleolus organizer regions. Eleven of 24 of their biologic relatives were also found to have the marker; individuals with the marker were 4 times more likely to develop AD.
Zubenko et al. (1998) performed an association study with 391 simple sequence tandem repeat polymorphisms, comparing DNA from 100 autopsied brains with AD, 50 control brains, and 50 nondemented nonagenarians. The strongest association was seen with marker D19S178, presumably reflecting association with APOE. In addition, weaker associations were seen with 5 other markers, D1S518 (1q31-q32.1), D1S547 (1q44), D10S1423 (10p12-p14), D12S1045 (12q24.3), and DXS1047 (Xq25), suggesting the possibility of other susceptibility genes.
In a study in eastern Finland, Hiltunen et al. (1999) found an association between AD and 2 markers on chromosome 13q12 (D13S787 and D13S292.) The 13q12 locus was associated with female familial AD patients regardless of APOE genotype. The 2 markers were estimated to reside in an 810-kb YAC clone together with 2 ESTs derived from infant brain and the ATP1AL1 (182360) gene.
Blacker et al. (2003) performed a 9-cM genome screen of 437 families with AD, comprising the full National Institute of Mental Health sample. In standard parametric and nonparametric linkage analyses, they observed a 'highly significant' linkage peak by the criteria of Lander and Kruglyak (1995) on chromosome 19q13, which probably represented APOE. Twelve additional locations, 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26, and 21q22, met criteria for 'suggestive' linkage.
Scott et al. (2003) considered age of onset as a covariant in the analysis of data from 336 markers in 437 multiplex white AD families. A statistically significant increase in the nonparametric multipoint lod score was observed on 2q34, with a peak lod score of 3.2 at D2S2944 in 31 families with a minimum age at onset between 50 and 60 years. Lod scores were also significantly increased on 15q22. The results indicated that linkage to regions on 2q34 and 15q22 were linked to early-onset AD and very-late-onset AD, respectively.
Holmans et al. (2005) performed linkage analyses on 28 sib pairs with late-onset AD. Linkage was observed with chromosome 21 for age-at-onset effects (lod = 2.57). This association was strongest in pairs with mean age at onset greater than 80 years. A similar effect was observed on chromosome 2q (maximum lod = 2.73). Suggestive evidence was observed for age at onset on chromosome 19q (maximum lod = 2.33) and in the vicinity of APOE at 12p (maximum lod = 2.22). Mean rate of decline showed suggestive evidence of linkage to chromosome 9q (maximum lod = 2.29). Holmans et al. (2005) observed suggestive evidence of increased identical by descent in APOE4 homozygotes on chromosome 1 (maximum lod = 3.08) and chromosome 9 (maximum lod = 3.34).
Sillen et al. (2006) conducted a genomewide linkage study on 188 individuals with AD from 71 Swedish families, using 365 markers (average intermarker distance 8.97 cM). They performed nonparametric linkage analyses in the total family material as well as stratified the families with respect to the presence or absence of APOE4. The results suggested that the disorder in these families was tightly linked to the APOE region (19q13). The next highest lod score was to chromosome 5q35, and no linkage was found to chromosomes 9, 10, and 12.
Katzov et al. (2004) presented evidence that both single marker alleles and haplotypes of the ABCA1 gene (600046) may contribute to variable cerebrospinal fluid MAPT and APP levels, and brain beta-amyloid load. The results indicated that variants of ABCA1 may affect the risk of AD, providing support for a genetic link between AD and cholesterol metabolism. In 42 individuals with AD, Katzov et al. (2006) found an association between increased CSF cholesterol and beta-amyloid protein levels. In a study of 1,567 Swedish dementia cases, including 1,275 with Alzheimer disease, and 2,203 controls, Reynolds et al. (2009) found an association between rs2230805 in the ABCA1 gene on chromosome 9q22 and dementia risk (odds ratio of 1.39; p = 7.7 x 10 (-8)). The putative risk allele of rs2230805 was also found to be associated with reduced cerebrospinal fluid levels of beta-amyloid.
Rogaeva et al. (2007) reported that inherited variants of the SORL1 (602005) neuronal sorting receptor on chromosome 11q23 are associated with late-onset Alzheimer disease. These variants, which occur in at least 2 different clusters of intronic sequences within the SORL1 gene, may regulate tissue-specific expression of SORL1. Lee et al. (2007) reported associations between various SNPs and haplotypes in the SORL1 gene and AD among a total of 296 AD patients comprising 3 cohorts of African American, Caribbean Hispanic, and non-Hispanic white individuals. The findings suggested extensive allelic heterogeneity in SORL1, with specific SNPs associated with specific groups. Cellini et al. (2009) also reported an association between SNPs in the SORL1 gene (rs661057, rs12364988, and rs641120) and LOAD among 251 Italian patients with LOAD and 358 healthy controls (p = 0.002 to 0.03; odds ratio, 1.27 to 1.47). There was a more significant association in women, suggesting that SORL1 may possibly affect LOAD through a female-specific mechanism. By metaanalysis of previous studies including 12,464 cases and 17,929 controls of white or Asian descent, Reitz et al. (2011) showed that multiple SORL1 alleles in distinct linkage disequilibrium blocks are associated with risk for AD in white and Asian populations, demonstrating intralocus heterogeneity in the associations with this gene. Reitz et al. (2011) concluded that their findings provided confirmatory evidence of the association of multiple SORL1 variants with AD risk.
Harold et al. (2009) undertook a 2-stage genomewide association study of Alzheimer disease involving 16,000 individuals, which they stated was the most powerful AD GWAS to date. They observed genomewide association with a SNP in the intron of the CLU gene (APOJ; 185430) not previously associated with the disease: rs11136000, P = 1.4 x 10(-9). This association was replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer disease in the combined dataset (P = 8.5 and 10(-10), odds ratio = 0.86).
Lambert et al. (2009) conducted a large genomewide association study of 2,032 individuals from France with Alzheimer disease and 5,328 controls. Markers outside APOE with suggestive evidence of association (P less than 10(-5)) were examined in collections from Belgium, Finland, Italy, and Spain totaling 3,978 Alzheimer disease cases and 3,297 controls. Two loci gave replicated evidence of association: one with CLU, encoding clusterin or apolipoprotein J, on chromosome 8 (rs11136000, odds ratio = 0.86, 95% confidence interval 0.81-0.90, P = 7.5 x 10(-9) for combined data) and the other within CR1 (120620), encoding the complement component (3b/4b) receptor 1, on chromosome 1 (rs6656401, odds ratio = 1.21, 95% confidence interval 1.14-1.29, P = 3.7 x 10(-9) for combined data). Lambert et al. (2009) stated that previous biologic studies supported roles of CLU and CR1 in the clearance of beta-amyloid.
Carrasquillo et al. (2010) replicated the findings of Harold et al. (2009) and Lambert et al. (2009). Among 1,829 Caucasian LOAD cases and 2,576 controls, Carrasquillo et al. (2010) found significant associations with CLU (rs11136000; OR of 0.82, p = 8.6 x 10(-5)), CR1 (rs3818361; OR of 1.15, p = 0.014), and PICALM (rs3851179; OR of 0.80; 1.3 x 10(-5)). All associations remained significant even after Bonferroni correction.
By metaanalysis, Jun et al. (2010) also replicated the findings of Harold et al. (2009) and Lambert et al. (2009). Among 7,070 AD cases and 8,169 controls from 12 different studies of different populations, Jun et al. (2010) found significant associations, after adjusting for age, sex, and APOE status, between LOAD and rs11136000 in CLU (OR of 0.92; p = 0.0096), rs3818361 in CR1 (OR of 1.15; p = 0.0002), and rs3851179 in PICALM (OR of 0.93; p = 0.026), but only in whites. No SNP was significantly associated with AD in the other ethnic groups. The association with CLU was only evident among those without the APOE E4 allele, and the association with PICALM was only evident among those with the APOE E4 allele.
In a genomewide association study of 549 Caribbean Hispanic patients with LOAD and 544 controls, Lee et al. (2011) found that none of the SNPs studied showed a significant association of p = 7.97 x 10(-8) or lower. The strongest evidence for association was with rs9945493 (p = 1.7 x 10(-7); OR of 0.33) on chromosome 18q23. Candidate genes implicated included CUGBP2 (602538) on chromosome 10p13 in APOE E4 carriers and DGKB (604070) on chromosome 7p21. Among Caribbean Hispanics, there was an association between rs881146 in CLU and LOAD (p = 0.002) in APOE E4 carriers, but not with rs11136000. There was a marginal association with rs17159904 in PICALM (p = 0.04) in APOE E4 noncarriers, and with rs7561528 in BIN1 (p = 0.0054) in APOE E4 carriers.
Hollingworth et al. (2011) undertook a combined analysis of 4 genomewide association datasets (stage 1) and identified 10 newly associated variants with p = 1 x 10(-5) or less. They tested these variants for association in an independent sample (stage 2). Three SNPs at 2 loci replicated and showed evidence for association in a further sample (stage 3). Metaanalyses of all data provided compelling evidence that ABCA7 (rs3764650, meta p = 4.5 x 10(-17); including the Alzheimer's Disease Genetic Consortium (ADGC) data, meta p = 5.0 x 10(-21)) and the MS4A gene cluster (rs610932, meta p = 1.8 x 10(-14); including ADGC data, meta p = 1.2 x 10(-16)) were novel Alzheimer disease susceptibility loci.
In a longitudinal study of 1,666 individuals, including 404 (24%) who developed AD at some point, Chibnik et al. (2011) found a significant association between each additional risk allele (A) of rs6656401 in the CR1 gene and faster rate of global cognitive decline (p = 0.011). There was also an association between this risk allele and AD-related amyloid plaques on neuropathology (p = 0.025) in those with postmortem brain material available. For the PICALM locus, there was a trend for faster rate of cognitive decline associated with 2 copies of the risk allele (G) of rs7110631 (p = 0.03). No association was observed between rate of cognitive decline and rs11136000 in the CLU gene.
Reynolds et al. (2010) conducted dense linkage disequilibrium (LD) mapping of a series of 25 genes putatively involved in lipid metabolism in 1,567 Swedish dementia cases (including 1,275 with possible or probable Alzheimer disease (AD)) and 2,203 Swedish controls. Two markers near SREBF1 (184756) in a 400-kb linkage disequilibrium (LD) block on chromosome 17p had significant association after multiple testing correction. Secondary analyses of gene expression levels of candidates within the LD region together with an investigation of gene network context highlighted 2 possible susceptibility genes, ATPAF2 (608918) and TOM1L2. Reynolds et al. (2010) identified several markers in strong LD with rs3183702 that were significantly associated with AD risk in other genomewide association studies with similar effect sizes.
Molecular Genetics
### Familial Alzheimer Disease 1
In affected members of 2 families with AD1, Goate et al. (1991) identified a mutation in the APP gene (V717I; 104760.0002). The average age of onset in 1 family was 57 +/- 5 years. The same mutation was found by Naruse et al. (1991) in 2 unrelated Japanese cases of familial early-onset AD, and Yoshioka et al. (1991) found it in a third Japanese family with AD.
In affected members of 2 large Swedish families with early-onset familial Alzheimer disease, Mullan et al. (1992) identified a double mutation in exon 16 of the APP gene (104760.0008). The 2 families were found to be linked by genealogy.
### Protection Against Alzheimer Disease
Jonsson et al. (2012) searched for low-frequency variants in the amyloid-beta precursor protein gene with a significant effect on the risk of Alzheimer disease by studying coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. Jonsson et al. (2012) found a coding mutation (A673T; 104760.0023) in the APP gene that protects against Alzheimer disease and cognitive decline in the elderly without Alzheimer disease. This substitution is adjacent to the aspartyl protease beta-site in APP, and resulted in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer disease provided proof of principle for the hypothesis that reducing the beta-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer disease, Jonsson et al. (2012) hypothesized that the 2 may be mediated through the same or similar mechanisms.
### Modifier Genes
It is clear that apoE plays an important role in the genetics of late-onset Alzheimer disease (see AD2; 104310); however, estimates of the total contribution of apoE to the variance in onset of AD vary widely. In an oligogenic segregation analysis of 75 families ascertained through members with late-onset AD, Daw et al. (2000) estimated the number of additional quantitative trait loci (QTLs) and their contribution to the variance in age at onset of AD, as well as the contribution of apoE and sex. They found evidence that 4 additional loci make a contribution to the variance in age at onset of late-onset AD similar to or greater in magnitude than that made by apoE, with 1 locus making a contribution several times greater than that of apoE. They confirmed the previous findings of a dosage effect for the apoE epsilon-4 allele, a protective effect for the epsilon-2 allele, evidence for allelic interactions at the apoE locus, and a small protective effect for males. Although Daw et al. (2000) estimated that the apoE genotype can make a difference of as many as 17 years in age at onset of AD, their estimate of the contribution of apoE (7 to 9%) to total variance in onset of AD was somewhat smaller than that previously reported. Their results suggested that several genes not yet localized to that time may play a larger role than does apoE in late-onset AD.
Li et al. (2002) performed a genome screen to identify genes influencing age at onset in 449 families with Alzheimer disease and 174 families with Parkinson disease. Heritabilities between 40% and 60% for age at onset were found in both the AD and the PD data sets. For PD, significant evidence for linkage to age at onset was found on 1p (lod = 3.41); see 606852. For AD, the age at onset effect of APOE (lod = 3.28) was confirmed. In addition, evidence for age at onset linkage on chromosomes 6 and 10 was identified independently in both the AD and PD data sets. Subsequent unified analyses of these regions identified a single peak on 10q between D10S1239 and D10S1237, with a maximum lod score of 2.62. These data suggested that a common gene affects age at onset in these 2 common complex neurodegenerative diseases.
Li et al. (2003) combined gene expression studies on hippocampus obtained from AD patients and controls with their previously reported linkage data to identify 4 candidate genes on chromosome 10q. Allelic association studies for age-at-onset effects in 1,773 AD patients and 1,041 relatives and 635 PD patients and 727 relatives further limited association to GSTO1 (605482) (p = 0.007) and a second transcribed member of the GST omega class, GSTO2 (612314) (p = 0.005), located next to GSTO1. The authors suggested that GSTO1 may be involved in the posttranslational modification of IL1B (147720).
Zareparsi et al. (2002) noted that several studies had found an increased frequency of the HLA-A2 (142800) allele in patients with early-onset AD and that others had found an association between the A2 allele and an earlier age of onset of AD. Among 458 unrelated patients with AD, Zareparsi et al. (2002) found that HLA-A2 homozygotes had onset of AD 5 years earlier, on average, than either A2 heterozygotes or those without A2, reflecting a gene dosage effect. The risk associated with the A2 homozygous genotype was 2.6 times greater in patients with early-onset AD (less than age 60 years) than in those with late-onset AD. These effects were present regardless of gender, familial or sporadic nature of the disease, or presence or absence of the APOE4 allele. The authors suggested that the A2 allele may have a role in regulating an immune response in the pathogenesis of AD or that there may be a responsible gene in close linkage to A2.
The APBB2 gene (602710) encodes a protein that is capable of binding to APP. In a genetic association study of 3 independently collected case-control series totaling approximately 2,000 samples, Li et al. (2005) found that a SNP in the APBB2 gene, located in a region conserved between the human and mouse genomes, showed a significant interaction with age of disease onset. For this marker, Li et al. (2005) reported that the association of late-onset Alzheimer disease was most pronounced in subjects with disease onset before 75 years of age; odds ratio for homozygotes = 2.43 and for heterozygotes = 2.15.
Go et al. (2005) performed linkage analysis on an NIMH Alzheimer disease sample and demonstrated a specific linkage peak for AD with psychosis on chromosome 8p12, which encompasses the NRG1 gene (142445). The authors also demonstrated a significant association between an NRG1 SNP (rs3924999) and AD with psychosis (chi-square = 7.0; P = 0.008). This SNP is part of a 3-SNP haplotype preferentially transmitted to individuals with the phenotype. Go et al. (2005) suggested that NRG1 plays a role in increasing the genetic risk for positive symptoms of psychosis in a proportion of late-onset AD families.
Sweet et al. (2005) conducted a study to determine if genetic variation in the COMT gene (116790) was associated with a risk of psychosis in Alzheimer disease. The study included a case-control sample of 373 individuals diagnosed with AD with or without psychosis. Subjects were characterized for alleles at 3 COMT loci previously associated with schizophrenia (rs737865, rs4680, and rs165599), and for a C/T transition adjacent to an estrogen response element (ERE6) in the COMT P2 promoter region. Single-locus and haplotype tests of association were conducted. Logit models were used to examine independent and interacting effects of alleles at the associated loci and all analyses were stratified by sex. In female subjects, rs4680 demonstrated a modest association with AD plus psychosis; rs737865 demonstrated a trend towards an association. There was a highly significant association of AD plus psychosis with a 4-locus haplotype, which resulted from additive effects of alleles at and ERE6/rs737865 (the latter were in linkage disequilibrium). In male subjects, no single-locus test was significant, although a strong association between AD with psychosis and the 4-locus haplotype was observed. That association appeared to result from interaction of the ERE6/rs737865, rs4680, rs165599 loci. Genetic variation in COMT was associated with AD plus psychosis and thus appears to contribute to psychosis risk across disorders.
### Associations with Susceptibility to Alzheimer Disease
McIlroy et al. (2000) reported a case-control study of 175 individuals with late-onset Alzheimer disease and 187 age- and sex-matched controls from Northern Ireland. The presence of the butyrylcholinesterase K variant (BCHE; 177400.0005) was found to be associated with an increased risk of Alzheimer disease (odds ratio = 3.50, 95% CI 2.20-6.07). This risk increased in subjects 75 years or older (odds ratio = 5.50, 95% CI 2.56-11.87). No evidence of synergy between BCHE K and APOE epsilon-4 was found in this population.
In a series of 239 necropsy-confirmed late-onset AD cases and 342 elderly nondemented controls older than 73 years, Narain et al. (2000) found an association between homozygosity for both the ACE I and D allele polymorphisms (106180.0001) and AD. Whereas the APOE epsilon-4 allele was strongly associated with AD risk in their series, Narain et al. (2000) found no evidence for an interaction between the APOE and ACE loci. In addition, no interactions were observed between ACE and gender or age at death of the AD cases. A metaanalysis of all published reports (12 case-control series in total) suggested that both the I/I and I/D ACE genotypes are associated with increased AD risk (odds ratio for I/I vs D/D, 1.36, 95% CI = 1.13-1.63; OR for D/I vs D/D, 1.33, 95% CI = 1.14-1.53, p = 0.0002). In a metaanalysis of 23 independent published studies, Elkins et al. (2004) found that the OR for AD in individuals with the I allele (I/I or I/D genotype) was 1.27 compared to those with the D/D genotype. The risk of AD was higher among Asians (OR, 2.44) and in patients younger than 75 years of age (OR, 1.54). Elkins et al. (2004) concluded that the ACE I allele is associated with an increased risk of late-onset AD, but noted that the risk is very small compared to the effects of other alleles, especially APOE4.
Prince et al. (2001) genotyped 204 Swedish patients with sporadic late-onset Alzheimer disease and 186 Swedish control subjects for polymorphisms within 15 candidate genes previously reported to show significant association in Alzheimer disease. The genes chosen for analysis were LRP1, ACE, A2M, BLMH (602403), DLST (126063), TNFRSF6 (134637), NOS3 (163729), PSEN1, PSEN2, BCHE, APBB1 (602709), ESR1 (133430), CTSD (116840), MTHFR (607093), and IL1A (147760). No strong evidence was found for genetic association among the 15 tested variants, and the authors concluded that with the exception of possession of the APOE4 allele, none of the other investigated single-nucleotide polymorphisms contributed substantially to the development of AD in the studied sample.
In 2 groups of patients with AD, comprising a total of 201 patients, Papassotiropoulos et al. (2003) found that the frequency of a 24-cholesterol hydroxylase (CYP46; 604087) T-C polymorphism, CYP46*TT, was associated with increased risk of AD (OR = 2.16). The OR for the APOE4 allele carriers was 4.38. The OR for the presence of both CYP46*TT and APOE4 was 9.63, suggesting a synergistic effect of the 2 genotypes. Neuropathologic examination of AD patients and controls showed that brain beta-amyloid load, CSF levels of soluble beta-amyloid-42, and CSF levels of phosphorylated tau were significantly higher in subjects with the CYP46*TT genotype. Papassotiropoulos et al. (2003) suggested that functional alterations of cholesterol 24-hydroxylase may modulate cholesterol concentrations in vulnerable neurons, thereby affecting changes in amyloid precursor protein processing and beta-amyloid production leading to the development of AD. See also Wolozin (2003).
Because glucocorticoid excess increases neuronal vulnerability, genetic variations in the glucocorticoid system may be related to the risk for AD. De Quervain et al. (2004) analyzed SNPs in 10 glucocorticoid-related genes in 351 AD patients and 463 unrelated control subjects. A rare haplotype in the 5-prime regulatory region of the HSD11B1 gene (600713) was associated with a 6-fold increased risk for sporadic AD. The HSD11B1 enzyme controls tissue levels of biologically active glucocorticoids and thereby may influence neuronal vulnerability. In human embryonic kidney cells, the risk-associated haplotype reduced HSD11B1 transcription by 20% compared to the common haplotype.
Robson et al. (2004) examined the interaction between the C2 variant of the TF gene (190000.0004) and the cys282-to-tyr allele of the HFE gene (C282Y; 613609.0001), the most common basis of hemochromatosis, as risk factors for developing AD. The results showed that each of the 2 variants was associated with an increased risk of AD only in the presence of the other. Neither allele alone had any effect. Carriers of both variants were at 5 times greater risk of AD compared with all others. Furthermore, carriers of these 2 alleles plus APOE4 were at still higher risk of AD: of the 14 carriers of the 3 variants identified in this study, 12 had AD and 2 had mild cognitive impairment. Robson et al. (2004) concluded that the combination of TF*C2 and HFE C282Y may lead to an excess of redoxactive iron and the induction of oxidative stress in neurons, which is exacerbated in carriers of APOE4. They noted that 4% of northern Europeans carry the 2 iron-related variants and that iron overload is a treatable condition.
In a study of 148 patients from southern Italy with sporadic AD, Zappia et al. (2004) found that having a myeloperoxidase (MPO) polymorphism genotype, -463G/G (606989.0008), conferred an odds ratio of 1.65 for development of the disease. When combined with an alpha-2-macroglobulin polymorphism genotype, 1000val/val (103950.0001), the odds ratio increased to 23.19. The authors suggested that the synergistic effect of the 2 genotypes may represent a facilitation of beta-amyloid deposition or a decrease in amyloid clearance, and noted that MPO produces oxidizing conditions. The findings were independent of APOE4 status.
Bian et al. (2005) found no association of 6 A2M gene (103950) polymorphisms with Alzheimer disease in a study of 216 late-onset AD patients and 200 control subjects from the Han Chinese population. Comparison of allele, genotype, and haplotype frequencies for polymorphisms in A2M revealed no significant differences between patients and control subjects.
Mace et al. (2005) found a significant association between a C-T SNP (rs908832) in exon 14 of the ABCA2 gene (600047) and Alzheimer disease in a large case-control study involving 440 AD patients. Additional analysis showed the strongest association between the SNP and early-onset AD (odds ratio of 3.82 for disease development in carriers of the T allele compared to controls).
In a survey of 138 published studies on genetic association for AD, Blomqvist et al. (2006) found evidence for publication bias for positive associations. The authors analyzed 62 genetic markers for AD risk in 940 Scottish and Swedish individuals with AD and 405 Scottish and Swedish controls and found no significant associations except for APOE. In particular, no association was found with variants in the PLAU gene (191840).
Kamboh et al. (2006) studied the association of polymorphisms in the UBQLN1 gene (605046) on chromosome 9q21 with AD. They examined the association of 3 SNPs in the gene (intron 6 A/C, intron 8 T/C, and intron 9 A/G), all of which are in significant linkage disequilibrium (p less than 0.0001), in up to 978 late-onset Alzheimer disease patients and 808 controls. Modestly significant associations were observed in the single-site regression analysis, but 3-site haplotype analysis revealed significant associations (p less than 0.0001). One common haplotype, called H4, was associated with AD risk, whereas a less common haplotype, called H5, was associated with protection, Kamboh et al. (2006) suggested that genetic variation in the UBQLN1 gene has a modest effect on risk, age at onset, and disease duration of Alzheimer disease and that the presence of additional putative functional variants either in UBQLN1 or nearby genes exist.
In a study of 265 AD patients and 347 controls, Ramos et al. (2006) reported a possible protective effect against AD development associated with a polymorphism in the TNF gene (-863C-A; 191160.0006). The -863A allele was present in 16.9% of controls and 12.6% of patients. Comparison of the 3 genotypes (C/C, C/A, and A/A) suggested a dose-response effect with the A/A genotype conferring an odds ratio of 0.58. The findings supported a role for inflammation in AD.
Reiman et al. (2007) used a genomewide SNP survey to examine 1,411 individuals with late-onset AD and controls, including 644 carriers of the APOE4 allele and 767 noncarriers. The authors found a significant association between AD and 6 SNPs in the GAB2 gene (606203) that are part of a common haplotype block. Maximal significance of the association was at rs2373115 with an odds ratio of 4.06 (uncorrected p value of 9 x 10(-11)). Carriers of the APOE4 alleles had an even higher disease risk when the SNP risk allele was present (odds ratio of 24.64) compared to noncarriers. Neuropathologic studies found that GAB2 was overexpressed in neurons from AD patients and the protein was detected in neurons, tangle-bearing neurons, and dystrophic neurites. In contrast, both Chapuis et al. (2008) and Miyashita et al. (2009) failed to detect an association between the GAB2 SNP rs2373115 and risk of developing AD in Caucasian and Japanese individuals, respectively. Chapuis et al. (2008) studied 3 European Caucasian populations totaling 1,749 AD cases and 1,406 controls, and Miyashita et al. (2009) studied 1,656 Japanese cases and 1,656 Japanese controls; they suggested that GAB2 is, at best, a minor disease susceptibility gene for AD.
See GSK3B (605004) for a discussion of a possible association between risk of AD and epistatic interaction between variants in the GSK3B and MAPT genes (157140).
Lambert et al. (2013) conducted a large, 2-stage metaanalysis of genomewide association studies in individuals of European ancestry for risk of late-onset Alzheimer disease. In stage 1, Lambert et al. (2013) used genotyped and imputed data (7 million SNPs) to perform metaanalysis on 4 previously published genomewide association studies datasets containing 17,008 Alzheimer disease cases and 37,154 controls. In stage 2, Lambert et al. (2013) genotyped 11,632 SNPs and tested them for association in an independent set of 8,572 Alzheimer disease cases and 11,312 controls. In addition to the APOE locus, 19 loci reached genomewide significance (p less than 5 x 10(-8)) in the combined stage 1 and stage 2 analyses, of which 11 are newly associated with Alzheimer disease.
Population Genetics
In a population-based study in the city of Rouen, France (426,710 residents), Campion et al. (1999) estimated the prevalence of early-onset AD and autosomal dominant early-onset AD to be 41.2 and 5.3 per 100,000 persons, respectively. Early-onset AD was defined as onset of disease at age less than 61 years, and autosomal dominant early-onset AD was defined as the occurrence of at least 3 cases in 3 generations. They identified PSEN1 gene mutations in 19 (56%) of 34 families, and APP gene mutations in 5 (15%) families. In the 10 remaining families and in 9 additional autosomal dominant AD families, no PSEN1, PSEN2, or APP mutations were found. These results showed that PSEN1 and APP mutations account for 71% of autosomal dominant early-onset AD, and that nonpenetrance at age less than 61 years is probably infrequent for PSEN1 or APP mutations.
Finckh et al. (2000) investigated the proportion of early-onset dementia attributable to known genes. They screened for mutations in 4 genes, PSEN1, PSEN2, APP, and the prion protein gene PRNP (176640), in patients with early-onset dementia before age 60 years. In 16 patients the family history was positive for dementia, in 17 patients it was negative, and in 3 patients it was unknown. In 12 patients, they found 5 novel mutations and 5 previously reported mutations that were all considered to be disease-causing. Nine of these 12 patients had a positive family history, indicating a detection rate of 56% (9/16) in patients with a positive family history.
Animal Model
For a detailed discussion of animal models of Alzheimer disease, see 104760.
McGowan et al. (2006) provided a detailed review of mouse models of Alzheimer disease.
Cheng et al. (1988) described the comparative mapping of DNA markers in the region of familial Alzheimer disease on human chromosome 21 and mouse chromosome 16. The linkage group shared by mouse chromosome 16 and human chromosome 21 included both APP and markers linked to familial Alzheimer disease. The linkage group of 6 loci extends from anonymous DNA marker D21S52 to ETS2, and spans 39% recombination in man but only 6.4% recombination in the mouse. A break in synteny occurs distal to ETS2, and the homolog of human marker D21S56 maps to mouse chromosome 17.
Alzheimer disease has a substantial inflammatory component, and activated microglia may play a central role in neuronal degeneration. Tan et al. (1999) demonstrated that the CD40 (109535) expression was increased on cultured microglia treated with freshly solubilized amyloid-beta and on microglia from a transgenic murine model of Alzheimer disease (Tg APPsw). Increased TNF-alpha (191160) production and induction of neuronal injury occurred when amyloid-beta-stimulated microglia were treated with CD40 ligand (300386). Microglia from Tg APPsw mice deficient for CD40 ligand had less activation, suggesting that the CD40-CD40 ligand interaction is necessary for amyloid-beta-induced microglial activation. In addition, abnormal tau phosphorylation was reduced in Tg APPsw animals deficient for CD40 ligand, suggesting that the CD40-CD40 ligand interaction is an early event in Alzheimer disease pathogenesis.
Phosphorylation of tau and other proteins on serine or threonine residues preceding a proline seems to precede formation of neurofibrillary tangles and neurodegeneration in AD. These phospho(ser/thr)-pro motifs exist in 2 distinct conformations, whose conversion in some proteins is catalyzed by the Pin1 prolyl isomerase (PIN1; 601052). Pin1 activity can directly restore the conformation and function of phosphorylated tau or it can do so indirectly by promoting its dephosphorylation. Liou et al. (2003) found that mice with targeted deletion of the Pin1 gene developed several age-dependent phenotypes including retinal atrophy. In addition, Pin1-null mice showed progressive age-dependent motor and behavioral deficits which included abnormal limb clasping reflexes, hunched postures, and reduced mobility in eye irritation. Neuropathologic changes included tau hyperphosphorylation, tau filament formation, and neuronal degeneration in brain and spinal cord.
Lesne et al. (2006) found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kD soluble amyloid-beta assembly, which they termed A-beta-*56. A-beta-*56 purified from the brains of impaired Tg2576 mice disrupted memory when administered to young rats. Lesne et al. (2006) proposed that A-beta-*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer disease.
The neurodegeneration observed in Alzheimer disease has been associated with synaptic dismantling and progressive decrease in neuronal activity. Busche et al. (2008) tested this hypothesis in vivo by using 2-photon calcium ion imaging in a mouse model of Alzheimer disease. The mouse model consists of double transgenic mice overexpressing both beta-amyloid precursor protein (APP; 104760) and mutant presenilin-1 (104311). Although a decrease in neuronal activity was seen in 29% of layer 2/3 cortical neurons, 21% of neurons displayed an unexpected increase in the frequency of spontaneous calcium ion transients. These 'hyperactive' neurons were found exclusively near the plaques of amyloid beta-depositing mice. The hyperactivity appeared to be due to a relative decrease in synaptic inhibition. Thus, Busche et al. (2008) suggested that a redistribution of synaptic drive between silent and hyperactive neurons, rather than an overall decrease in synaptic activity, provides a mechanism for the disturbed cortical function in Alzheimer disease.
Nagahara et al. (2009) reported beneficial effects of entorhinal administration of brain-derived neurotrophic factor (BDNF; 113505) in 3 models of AD-related cognitive decline in mouse and nonhuman primates: an App-mutant mouse strain, aged rats, and aged monkeys. BDNF is widely expressed in the entorhinal cortex and undergoes anterograde transport into the hippocampus, where it is implicated in plasticity mechanisms. In App-transgenic mice, lentiviral BDNF gene delivery administered after disease onset reversed synapse loss, partially normalized aberrant gene expression, improved cell signaling, and restored learning and memory. These changes occurred independently of amyloid plaque load. In aged rats, BDNF protein and lentiviral gene infusion, respectively, reversed cognitive decline and improved age-related perturbations in gene expression. In adult rats and primates, lentiviral BDNF gene delivery prevented lesion-induced death of entorhinal cortical neurons. Finally, lentiviral BDNF gene delivery and expression in aged primates reversed neuronal atrophy and ameliorated age-related cognitive impairment. Nagahara et al. (2009) suggested that BDNF exerts substantial protective effects on crucial neuronal circuitry involved in AD, acting through amyloid-independent mechanisms.
Treusch et al. (2011) modeled amyloid-beta toxicity in yeast by directing the peptide to the secretory pathway. A genomewide screen for toxicity modifiers identified the yeast homolog of phosphatidylinositol-binding clathrin assembly protein (PICALM; 603025) and other endocytic factors connected to Alzheimer disease whose relationship to amyloid-beta had been unknown. The factors identified in yeast modified amyloid-beta toxicity in glutamatergic neurons of C. elegans and in primary rat cortical neurons. In yeast, amyloid-beta impaired the endocytic trafficking of a plasma membrane receptor, which was ameliorated by endocytic pathway factors identified in the yeast screen. Treusch et al. (2011) concluded that links between amyloid-beta, endocytosis, and human Alzheimer disease risk factors can be ascertained with yeast as a model system.
By screening a library of about 80,000 chemical compounds, Kounnas et al. (2010) identified a class of gamma-secretase modulators (GSMs), diarylaminothiazoles, or series A GSMs, that could target production of A-beta-42 and A-beta-40 in cell lines and in Tg 2576 transgenic AD mice. Immobilized series A GSMs bound to Pen2 (PSENEN; 607632) and, to a lesser degree, Ps1. Series A GSMs reduced gamma-secretase activity without interfering with related off-target reactions, lowered A-beta-42 levels in both plasma and brain of Tg 2576 mice, and reduced plaque density and amyloid in Tg 2576 hippocampus and cortex. Daily dosing was well tolerated over the 7-month study.
Metabolites in the kynurenine pathway of tryptophan degradation in mammals are thought to play an important role in neurodegenerative disorders, including Alzheimer disease. Kynurenic acid (KYNA) had been shown to reduce neuronal vulnerability in animal models by inhibiting ionotropic excitatory amino acid receptors, and is neuroprotective in animal models of brain ischemia. Zwilling et al. (2011) synthesized a small-molecule prodrug inhibitor of kynurenine 3-monooxygenase (KMO; 603538), termed JM6, and found that oral administration of JM6 to rats increased KYNA levels and reduced extracellular glutamate in the brain. In a transgenic mouse model of Alzheimer disease, JM6 prevented spatial memory deficits, anxiety-related behavior, and synaptic loss. These findings supported a critical link between tryptophan metabolism in the blood and neurodegeneration.
Cramer et al. (2012) found that oral administration of the RXR (see 180245) agonist bexarotene to a mouse model of Alzheimer disease resulted in enhanced clearance of soluble amyloid-beta within hours in an ApoE-dependent manner. Amyloid-beta plaque area was reduced more than 50% within just 72 hours. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function. Thus, Cramer et al. (2012) concluded that RXR activation stimulates physiologic amyloid-beta clearance mechanisms, resulting in the rapid reversal of a broad range of amyloid-beta-induced deficits.
Several groups provided technical comments on the report of Cramer et al. (2012). While Fitz et al. (2013) confirmed that administration of bexarotene reversed memory deficits in APP/PS1-delta-E9 mice expressing human APOE3 or APOE4 to the levels of their nontransgenic controls and significantly decreased interstitial fluid amyloid-beta, they could not confirm the effects on amyloid deposition. Using a nearly identical treatment regimen, Price et al. (2013) were unable to detect any evidence of drug efficacy despite evidence of target engagement. Tesseur et al. (2013) were not able to reproduce the described effects in several animal models. They remarked that drug formulation appeared to be very critical and that their data called for 'extreme caution' when considering this compound for use in AD patients. Veeraraghavalu et al. (2013) found that although bexarotene reduced soluble beta-amyloid-40 levels in 1 of the mouse models, the drug had no impact on plaque burden in 3 strains that exhibit amyloid beta amyloidosis. Landreth et al. (2013) replied that the data of Fitz et al. (2013), Price et al. (2013), Tesseur et al. (2013), and Veeraraghavalu et al. (2013) replicated and validated their central conclusion that bexarotene stimulates the clearance of soluble beta-amyloid peptides and results in the reversal of behavioral deficits in mouse models of AD. They considered the basis of the inability to reproduce the drug-stimulated microglial-mediated reduction in plaque burden to be unexplained. However, they concluded that plaque burden is functionally unrelated to improved cognition and memory elicited by bexarotene.
Ahn et al. (2014) noted that fibrinogen (see 134820) is a cerebrovascular risk factor in AD that specifically binds beta-amyloid, thereby altering fibrin clot structure and delaying clot degradation. Using a high-throughput screen, they identified RU-505 as an inhibitor of the interaction between beta-amyloid and fibrinogen. RU-505 restored beta-amyloid-induced altered fibrin clot formation and degradation in vitro and inhibited vessel occlusion in AD transgenic mice. Long-term treatment with RU-505 significantly reduced vascular amyloid deposition and microgliosis in cortex and improved cognitive impairment in mouse models of AD. Ahn et al. (2014) proposed that inhibitors of the interaction between beta-amyloid and fibrinogen may be useful in AD therapy.
Using mouse models, Hong et al. (2016) showed that complement and microglia mediate synaptic loss early in AD. C1q (see 120550), the initiating protein of the classical complement cascade, was increased and associated with synapses before overt plaque deposition. Inhibition of C1q, C3 (120700), or the microglial complement receptor CR3 (CD11b/CD18; see 600065) reduced the number of phagocytic microglia, as well as the extent of early synapse loss. C1q was necessary for the toxic effects of soluble beta-amyloid (A-beta) oligomers on synapses and hippocampal long-term potentiation. Finally, microglia in adult brains engulfed synaptic material in a CR3-dependent process when exposed to soluble A-beta oligomers. Together, these findings suggested that the complement-dependent pathway and microglia that prune excess synapses in development are inappropriately activated and mediate synapse loss in AD.
BECN1 (604378) is an essential autophagy protein. Rocchi et al. (2017) found that mice with knockin of a Becn1 gene containing a phe121-to-ala (F121A) mutation had significantly reduced interaction of Becn1 with its inhibitor, Bcl2 (151430), leading to constitutive autophagy in multiple tissues, including brain. The Becn1 F121A-mediated hyperactivation of autophagy significantly decreased amyloid accumulation, prevented cognitive decline, and restored survival in AD mouse models. The authors found that amyloid-beta oligomers were autophagic substrates sequestered in autophagosomes in brains of autophagy-hyperactive AD mice. Chemical inducers and exercise induced autophagy through Becn1-dependent protective effects on amyloid-beta removal and memory in AD mice. Rocchi et al. (2017) concluded that genetic mutations, chemical agents, or exercise can hyperactivate autophagy in vivo by disrupting BECN1-BCL2 binding, sequestering amyloid oligomers and preventing AD progression.
History
Bogerts (1993) provided a biographical sketch and photograph of Alois Alzheimer (1864-1915). Alzheimer was a neuropathologist, clinical psychiatrist, and chairman of psychiatry. He always considered himself a psychiatrist. He worked with Nissl in the application of the Nissl staining techniques for the study of the cerebral cortex in psychosis. Alzheimer discovered the disorder that bears his name when he reported on 'a strange disease of the cerebral cortex' in a 51-year-old woman (Auguste D.) with presenile dementia who displayed diffuse cortical atrophy, nerve cell loss, plaques, and tangles (Alzheimer, 1907). He was then working in Munich in the department of Emil Kraepelin, director of the Munich psychiatric clinic, who coined the term 'Alzheimer's disease.'
O'Brien (1996) reported that the file on the case of Auguste D., who at the age of 51 came under the care of Alois Alzheimer, had come to light; it had been missing since 1910. Auguste D. came under the care of Alzheimer at a Frankfurt hospital in 1901. On the basis of the record, some questions of whether Auguste D. had the disorder now called Alzheimer disease were raised; namely, that autopsy findings included arteriosclerosis noted in the smaller cerebral blood vessels. O'Brien (1996) noted that today this is a criterion for exclusion from a diagnosis of AD.
Maurer et al. (1997) announced that the long-sought clinical record of Auguste D. was discovered in Frankfurt only 2 days after the eightieth anniversary of the death of Professor Alzheimer, who died December 19, 1915. A photograph of the patient, dated November 1902, was provided by Maurer et al. (1997), as well as a copy of her handwriting which led Alzheimer to refer to the condition as 'amnestic writing disorder.'
Graeber et al. (1997) did a retrospective analysis on the case of Johann F., the second patient reported by Alois Alzheimer (1911). Johann F. was a 56-year-old male who suffered from presenile dementia and was hospitalized in Kraepelin's clinic for more than 3 years. Postmortem examination of the patient's brain revealed numerous amyloid plaques but no neurofibrillary tangles in the cerebral cortex, corresponding to a less common form of Alzheimer disease which may be referred to as 'plaque only.' Graeber et al. (1997) recovered well-preserved histologic sections of this case and performed mutation screening of exon 17 of the APP gene and genotyping for APOE alleles. The patient was shown to be homozygous for APOE3 and lacked APP mutations at codons 692, 693, 713, and 717. The investigators speculated that the patient may have had mutations in the PS1 or PS2 gene.
Graeber et al. (1998) described the histopathology and APOE genotype of Alois Alzheimer's first patient, Auguste D. As in the case of Johann F., a large number of tissue sections belonging to Alzheimer's laboratory, which was later headed by Spielmeyer (Spielmeyer, 1916), were later found among material kept at the Institute of Neuropathology of the University of Munich. As described by Alzheimer (1907) in his original report, there were numerous neurofibrillary tangles and many amyloid plaques, especially in the upper cortical layers of this patient. However, there was no microscopic evidence for vascular, i.e., arteriosclerotic, lesions. The histologic preparations did not include the hippocampus or entorhinal region. The APOE genotype of this patient was shown to be E3/E3 by PCR-based restriction enzyme analysis.
Yu et al. (2010) demonstrated that a family from Fulda (Hesse), Germany with Alzheimer disease-4 (AD4; 606889) caused by the N141I mutation in the PSEN2 gene (600759.0001) shared the same haplotype as affected Volga German families reported earlier. This finding indicated that the N141I mutation must have occurred prior to the emigration of the Volga Germans from the Hesse region of Germany to Russia in the 1760s during the reign of Catherine the Great. In addition, the original patient with AD reported by Alzheimer (1907) also lived in same Hesse region as the modern family, which raised the possibility that the original patient may have had the N141I mutation.
INHERITANCE \- Autosomal dominant NEUROLOGIC Central Nervous System \- Presenile and senile dementia \- Parkinsonism \- Long tract signs \- Neurofibrillary tangles composed of disordered microtubules MISCELLANEOUS \- Genetic heterogeneity MOLECULAR BASIS \- Caused by mutation in the amyloid beta (A4) precursor protein gene (APP, 104760.0002 ) \- Susceptibility conferred by mutation in the alpha-2-macroglobulin gene (A2M, 103950.0005 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| ALZHEIMER DISEASE | c0276496 | 2,528 | omim | https://www.omim.org/entry/104300 | 2019-09-22T16:45:17 | {"doid": ["0080348"], "mesh": ["D000544"], "omim": ["104300"], "icd-9": ["331.0"], "icd-10": ["G30", "G30.9"], "orphanet": ["1020"], "synonyms": ["Alternative titles", "PRESENILE AND SENILE DEMENTIA"], "genereviews": ["NBK1161"]} |
McElfresh (1962) described a form of neonatal hyperbilirubinemia in 6 males of 2 generations in a pattern consistent with X-linked recessive inheritance. One affected member of the earlier generation was jaundiced with light stools for the first 5 months of life. He was 31 years of age and well, with 2 normal children, at the time of report.
Inheritance \- X-linked recessive Lab \- Neonatal hyperbilirubinemia Skin \- Neonatal obstructive jaundice ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| JAUNDICE, FAMILIAL OBSTRUCTIVE, OF INFANCY | c1839927 | 2,529 | omim | https://www.omim.org/entry/308600 | 2019-09-22T16:18:06 | {"mesh": ["C564118"], "omim": ["308600"]} |
A number sign (#) is used with this entry because of evidence that susceptibility to atopic dermatitis (ATOD2) linked to chromosome 1q21 is conferred by variation in the FLG gene (135940).
For a clinical description of atopic dermatitis and an overview of linkage studies, see 603165.
Mapping
Cookson et al. (2001) identified linkage of atopic dermatitis to chromosome 1q21 at markers D1S252 and D1S498. The marker D1S498 is linked to psoriasis (PSORS4; 603935).
Molecular Genetics
In genotype and haplotype analysis of 2 independent cohorts of 128 psoriasis triads and 120 atopic dermatitis triads, Giardina et al. (2006) detected a significant association between haplotypes defined by MIDDLE and ENDAL16 markers and psoriasis (p = 0.0000036) and atopic dermatitis (p = 0.0276), colocalizing within a 42-kb interval on chromosome 1q21 containing a single gene, LOR (152445). Analysis of LOR SNPs from regulatory and coding regions did not show evidence of association for either of the 2 diseases, but expression profiles of LOR in skin biopsies showed reduced levels in psoriasis and increased levels in atopic dermatitis, suggesting a specific misregulation of LOR mRNA production.
The FLG gene encodes a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Palmer et al. (2006) showed that 2 independent loss-of-function genetic variants in the FLG gene, R501X (135940.0001) and 2282del4 (135940.0002), are very strong predisposing factors for atopic dermatitis. These mutations had been shown to be the cause of ichthyosis vulgaris (146700) in 15 families and isolated cases by Smith et al. (2006). The R501X and 2282del4 variants, carried by approximately 9% of people of European origin, also showed highly significant association with asthma (see 600807) occurring in the context of atopic dermatitis.
Using the transmission-disequilibrium test in 476 German parent-offspring trios with atopic dermatitis, Weidinger et al. (2006) found a significant association between the loss-of-function mutations R501X and 2282del4 in the FLG gene and extrinsic atopic dermatitis, allergic sensitization, total IgE level, asthma, and palmar hyperlinearity; there was no significant association with intrinsic atopic dermatitis.
Marenholz et al. (2006) genotyped 1,092 children with eczema (atopic dermatitis) from 2 large European populations for the R501X and 2282del4 mutations in the FLG gene and confirmed a highly significant association between the null mutations and eczema and concomitant asthma. Moreover, the authors found that these mutations predisposed to asthma, allergic rhinitis, and allergic sensitization only in the presence of eczema, and that the mutations predisposed equally to atopic (intrinsic) and nonatopic (extrinsic) forms of eczema. They demonstrated that the presence of 2 null alleles was an independent risk factor for asthma in children with eczema (OR, 11.76, p = 0.0085). Together, the 2 mutations accounted for an estimated 11% of eczema cases in the German population. Noting that previous expression of eczema was a prerequisite for the manifestation of allergic airways disease and specific sensitization, Marenholz et al. (2006) emphasized the importance of the epidermal barrier in the pathogenesis of these disorders (the so-called 'atopic march').
Nomura et al. (2007) studied 143 Japanese patients with atopic dermatitis from 140 unrelated families who were negative for known mutations in the FLG gene, screening them for 2 novel FLG mutations that the authors had identified in Japanese ichthyosis vulgaris patients, S2554X (135940.0003) and 3321delA (135940.0004). The S2554X mutation was identified in 6 patients and 3321delA in 2 patients; neither was found in 156 unrelated Japanese nonatopic and nonichthyotic controls, yielding a chi-square p value of 0.0015. Noting that the R501X and 2282del4 mutations were absent from a total of 253 Japanese individuals, including their patients with ichthyosis vulgaris and atopic dermatitis, Nomura et al. (2007) concluded that FLG mutations in Japan are different from those found in European-origin populations.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| DERMATITIS, ATOPIC, 2 | c1853965 | 2,530 | omim | https://www.omim.org/entry/605803 | 2019-09-22T16:11:04 | {"mesh": ["C565293"], "omim": ["605803"]} |
Paramedian nasal cleft is a rare developmental defect during embryogenesis characterized by a unilateral or bilateral coloboma of the nose, ranging in severity from a small notch, resulting in minor deviation of the nasal septum, to variable-sized clefts of the nasal ala which may be associated with small cysts or sinuses in the nasal midline. Defect may be isolated or may occur in association with cleft lip and/or other craniofacial anomalies (e.g. hypertelorism, broadening of nasal root, midline cleft). Dorsum and apex of nose are usually well preserved.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Paramedian nasal cleft | c0221363 | 2,531 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=141242 | 2021-01-23T18:00:52 | {"mesh": ["C535441"], "omim": ["614687"], "umls": ["C0221363"], "icd-10": ["Q18.8"], "synonyms": ["Alar cleft", "Alar rim cleft", "Cleft nose", "Isolated cleft of the ala nasi", "Isolated coloboma of the nose", "Tessier number 1 cleft"]} |
Androgen insensitivity syndrome
AIS results when the function of the androgen receptor (AR) is impaired. The AR protein (pictured) mediates the effects of androgens in the human body.
SpecialtyEndocrinology
Androgen insensitivity syndrome (AIS) is an intersex condition occurring in 1:20,000 individuals to 1:64,000, resulting in the partial or complete inability of the cell to respond to androgens.[1] The unresponsiveness of the cell to the presence of androgenic hormones can impair or prevent the masculinization of male genitalia in the developing fetus, as well as impairing or preventing the development of male secondary sexual characteristics at puberty, but does not significantly impair female genital or sexual development.[2][3] As such, the insensitivity to androgens is clinically significant only when it occurs in genetic males (i.e. individuals with a Y-chromosome, or more specifically, an SRY gene).[4] Clinical phenotypes in these individuals range from a typical male habitus with mild spermatogenic defect or reduced secondary terminal hair, to a full female habitus, despite the presence of a Y-chromosome.[5]
AIS is divided into three categories that are differentiated by the degree of genital masculinization: complete androgen insensitivity syndrome (CAIS) is indicated when the external genitalia are those of a typical female; mild androgen insensitivity syndrome (MAIS) is indicated when the external genitalia are those of a typical male, and partial androgen insensitivity syndrome (PAIS) is indicated when the external genitalia are partially, but not fully, masculinized.[6][7] Androgen insensitivity syndrome is the largest single entity that leads to 46,XY undermasculinized genitalia.[8]
Management of AIS is currently limited to symptomatic management; no method is currently available to correct the malfunctioning androgen receptor proteins produced by AR gene mutations. Areas of management include sex assignment, genitoplasty, gonadectomy to reduce tumor risk, hormone replacement therapy, genetic counseling, and psychological counseling.
## Contents
* 1 Genetics
* 1.1 Trinucleotide satellite lengths and AR transcriptional activity
* 1.2 AR mutations
* 1.3 Other causes
* 1.4 XY karyotype
* 1.5 XX karyotype
* 1.6 Correlation of genotype and phenotype
* 2 Pathophysiology
* 2.1 Androgens and the androgen receptor
* 2.2 Androgens in fetal development
* 2.3 Pathogenesis of AIS
* 3 Diagnosis
* 3.1 Classification
* 3.1.1 Complete AIS
* 3.1.2 Partial AIS
* 3.1.3 Mild AIS
* 4 Management
* 4.1 CAIS
* 4.2 PAIS
* 4.3 MAIS
* 5 Epidemiology
* 6 Controversy
* 6.1 Preimplantation genetic diagnosis
* 7 History
* 7.1 Timeline of major milestones
* 7.2 Early terminology
* 7.3 Pseudohermaphroditism
* 7.4 Testicular feminization
* 7.5 Other names
* 8 Society and culture
* 8.1 People with AIS
* 8.1.1 People with Complete androgen insensitivity syndrome
* 8.1.2 People with Partial androgen insensitivity syndrome
* 9 See also
* 10 References
* 11 External links
* 11.1 Information
## Genetics[edit]
Location and structure of the human androgen receptor: Top, the AR gene is located on the proximal long arm of the X chromosome. Middle, the eight exons are separated by introns of various lengths. Bottom, illustration of the AR protein, with primary functional domains labeled (not representative of actual 3-D structure).[2]
The human androgen receptor (AR) is a protein encoded by a gene located on the proximal long arm of the X chromosome (locus Xq11-Xq12).[9] The protein coding region consists of approximately 2,757 nucleotides (919 codons) spanning eight exons, designated 1-8 or A-H.[4][2] Introns vary in size between 0.7 and 26 kb.[2] Like other nuclear receptors, the AR protein consists of several functional domains: the transactivation domain (also called the transcription-regulation domain or the amino / NH2-terminal domain), the DNA-binding domain, the hinge region, and the steroid-binding domain (also called the carboxyl-terminal ligand-binding domain).[4][10][2][11] The transactivation domain is encoded by exon 1, and makes up more than half of the AR protein.[2] Exons 2 and 3 encode the DNA-binding domain, while the 5' portion of exon 4 encodes the hinge region.[2] The remainder of exons 4 through 8 encodes the ligand binding domain.[2]
### Trinucleotide satellite lengths and AR transcriptional activity[edit]
The AR gene contains two polymorphic trinucleotide microsatellites in exon 1.[10] The first microsatellite (nearest the 5' end) contains 8 [12] to 60 [13][14] repetitions of the glutamine codon "CAG" and is thus known as the polyglutamine tract.[2] The second microsatellite contains 4 [15] to 31 [16] repetitions of the glycine codon "GGC" and is known as the polyglycine tract.[17] The average number of repetitions varies by ethnicity, with Caucasians exhibiting an average of 21 CAG repeats, and Blacks 18.[18] In men, disease states are associated with extremes in polyglutamine tract length; prostate cancer,[19] hepatocellular carcinoma,[20] and intellectual disability [12] are associated with too few repetitions, while spinal and bulbar muscular atrophy (SBMA) is associated with a CAG repetition length of 40 or more.[21] Some studies indicate that the length of the polyglutamine tract is inversely correlated with transcriptional activity in the AR protein, and that longer polyglutamine tracts may be associated with male infertility [22][23][24] and undermasculinized genitalia in men.[25] However, other studies have indicated no such correlation exists.[26][27][28][29][30][31] A comprehensive meta-analysis of the subject published in 2007 supports the existence of the correlation, and concluded these discrepancies could be resolved when sample size and study design are taken into account.[32] Some studies suggest longer polyglycine tract lengths are also associated with genital masculinization defects in men.[33][34] Other studies find no such association.[35]
### AR mutations[edit]
As of 2010, over 400 AR mutations have been reported in the AR mutation database, and the number continues to grow.[10] Inheritance is typically maternal and follows an X-linked recessive pattern;[4][36] individuals with a 46,XY karyotype always express the mutant gene since they have only one X chromosome, whereas 46,XX carriers are minimally affected. About 30% of the time, the AR mutation is a spontaneous result, and is not inherited.[37] Such de novo mutations are the result of a germ cell mutation or germ cell mosaicism in the gonads of one of the parents, or a mutation in the fertilized egg itself.[38] In one study,[39] three of eight de novo mutations occurred in the postzygotic stage, leading to the estimate that up to one-third of de novo mutations result in somatic mosaicism.[4] Not every mutation of the AR gene results in androgen insensitivity; one particular mutation occurs in 8 to 14% of genetic males,[40][41][42][43] and is thought to adversely affect only a small number of individuals when other genetic factors are present.[44]
### Other causes[edit]
Some individuals with CAIS or PAIS do not have any AR mutations despite clinical, hormonal, and histological features sufficient to warrant an AIS diagnosis; up to 5% of women with CAIS do not have an AR mutation,[10] as well as between 27[45][46] and 72%[47] of individuals with PAIS.
In one patient, the underlying cause for presumptive PAIS was a mutant steroidogenic factor-1 (SF-1) protein.[48] In another patient, CAIS was the result of a deficit in the transmission of a transactivating signal from the N-terminal region of the androgen receptor to the basal transcription machinery of the cell.[49] A coactivator protein interacting with the activation function 1 (AF-1) transactivation domain of the androgen receptor may have been deficient in this patient.[49] The signal disruption could not be corrected by supplementation with any coactivators known at the time, nor was the absent coactivator protein characterized, which left some in the field unconvinced that a mutant coactivator would explain the mechanism of androgen resistance in CAIS or PAIS patients with a typical AR gene.[4]
### XY karyotype[edit]
Depending on the mutation, a person with a 46,XY karyotype and AIS can have either a male (MAIS) or female (CAIS) phenotype,[50] or may have genitalia that are only partially masculinized (PAIS).[51] The gonads are testes regardless of phenotype due to the influence of the Y chromosome.[52][53] A 46,XY female, thus, does not have ovaries or a uterus,[54] and can neither contribute an egg towards conception nor gestate a child.
Several case studies of fertile 46,XY males with AIS have been published,[3][55][56][57][58] although this group is thought to be a minority.[11] Additionally, some infertile males with MAIS have been able to conceive children after increasing their sperm count through the use of supplementary testosterone.[4][59] A genetic male conceived by a man with AIS would not receive his father's X chromosome, thus would neither inherit nor carry the gene for the syndrome. A genetic female conceived in such a way would receive her father's X chromosome, thus would become a carrier.
### XX karyotype[edit]
Genetic females (46,XX karyotype) have two X chromosomes, thus have two AR genes. A mutation in one (but not both) results in a minimally affected, fertile, female carrier. Some carriers have been noted to have slightly reduced body hair, delayed puberty, and/or tall stature, presumably due to skewed X-inactivation.[2][3] A female carrier will pass the affected AR gene to her children 50% of the time. If the affected child is a genetic female, she, too, will be a carrier. An affected 46,XY child will have AIS.
A genetic female with mutations in both AR genes could theoretically result from the union of a fertile man with AIS and a female carrier of the gene, or from de novo mutation. However, given the scarcity of fertile AIS men and low incidence of AR mutation, the chances of this occurrence are small. The phenotype of such an individual is a matter of speculation; as of 2010, no such documented case has been published.
### Correlation of genotype and phenotype[edit]
Individuals with partial AIS, unlike those with the complete or mild forms, present at birth with ambiguous genitalia, and the decision to raise the child as male or female is often not obvious.[4][38][60] Unfortunately, little information regarding phenotype can be gleaned from precise knowledge of the AR mutation itself; the same AR mutation may cause significant variation in the degree of masculinization in different individuals, even among members of the same family.[4][36][51][61][62][63][64][65][66][67] Exactly what causes this variation is not entirely understood, although factors contributing to it could include the lengths of the polyglutamine and polyglycine tracts,[68] sensitivity to and variations in the intrauterine endocrine milieu,[51] the effect of coregulatory proteins active in Sertoli cells,[17][69] somatic mosaicism,[4] expression of the 5RD2 gene in genital skin fibroblasts,[61] reduced AR transcription and translation from factors other than mutations in the AR coding region,[70] an unidentified coactivator protein,[49] enzyme deficiencies such as 21-hydroxylase deficiency,[3] or other genetic variations such as a mutant steroidogenic factor-1 protein.[48] The degree of variation, however, does not appear to be constant across all AR mutations, and is much more extreme in some.[4][3][44][51] Missense mutations that result in a single amino acid substitution are known to produce the most phenotypic diversity.[10]
## Pathophysiology[edit]
Normal function of the androgen receptor: Testosterone (T) enters the cell and, if 5-alpha-reductase is present, is converted into dihydrotestone (DHT). Upon steroid binding, the androgen receptor (AR) undergoes a conformational change and releases heat shock proteins (hsps). Phosphorylation (P) occurs before or after steroid binding. The AR translocates to the nucleus where dimerization, DNA binding, and the recruitment of coactivators occur. Target genes are transcribed (mRNA) and translated into proteins.[2][11][14][71]
### Androgens and the androgen receptor[edit]
Main article: Androgen receptor
The effects that androgens have on the human body (virilization, masculinization, anabolism, etc.) are not brought about by androgens themselves, but rather are the result of androgens bound to androgen receptors; the androgen receptor mediates the effects of androgens in the human body.[72] Likewise, the androgen receptor itself is generally inactive in the cell until androgen binding occurs.[2]
The following series of steps illustrates how androgens and the androgen receptor work together to produce androgenic effects:[4][10][2][11][14][73][74]
1. Androgen enters the cell.
1. Only certain organs in the body, such as the gonads and the adrenal glands, produce the androgen testosterone.
2. Testosterone is converted into dihydrotestosterone, a chemically similar androgen, in cells containing the enzyme 5-alpha reductase.
3. Both androgens exert their influence through binding with the androgen receptor.
2. Androgen binds with the androgen receptor.
1. The androgen receptor is expressed ubiquitously throughout the tissues of the human body.
2. Before it binds with an androgen, the androgen receptor is bound to heat shock proteins.
3. These heat shock proteins are released upon androgen binding.
4. Androgen binding induces a stabilizing, conformational change in the androgen receptor.
5. The two zinc fingers of the DNA-binding domain are exposed as a result of this new conformation.
6. AR stability is thought to be aided by type II coregulators, which modulate protein folding and androgen binding, or facilitate NH2/carboxyl-terminal interaction.
3. The hormone-activated androgen receptor is phosphorylated.
1. Receptor phosphorylation can occur before androgen binding, although the presence of androgen promotes hyperphosphorylation.
2. The biological ramifications of receptor phosphorylation are unknown.
4. The hormone-activated androgen receptor translocates to the nucleus.
1. Nucleocytoplasmic transport is in part facilitated by an amino acid sequence on the AR called the nuclear localization signal.
2. The AR's nuclear localization signal is primarily encoded in the hinge region of the AR gene.
5. Homodimerization occurs.
1. Dimerization is mediated by the second (nearest the 3' end) zinc finger.
6. DNA binding to regulatory androgen response elements occurs.
1. Target genes contain (or are flanked by) transcriptional enhancer nucleotide sequences that interact with the first zinc finger.
2. These areas are called androgen response elements.
7. Coactivators are recruited by the AR.
1. Type I coactivators (i.e., coregulators) are thought to influence AR transcriptional activity by facilitating DNA occupancy, chromatin remodeling, or the recruitment of general transcription factors associated with RNA polymerase II holocomplex.
8. Target gene transcription ensues.
In this way, androgens bound to androgen receptors regulate the expression of target genes, thus produce androgenic effects.
Theoretically, certain mutant androgen receptors can function without androgens; in vitro studies have demonstrated that a mutant androgen receptor protein can induce transcription in the absence of androgen if its steroid binding domain is deleted.[75][76] Conversely, the steroid-binding domain may act to repress the AR transactivation domain, perhaps due to the AR's unliganded conformation.[2]
Sexual differentiation: The human embryo has indifferent sex accessory ducts until the seventh week of development.[77]
### Androgens in fetal development[edit]
Human embryos develop similarly for the first six weeks, regardless of genetic sex (46,XX or 46,XY karyotype); the only way to tell the difference between 46,XX or 46,XY embryos during this time period is to look for Barr bodies or a Y chromosome.[78] The gonads begin as bulges of tissue called the genital ridges at the back of the abdominal cavity, near the midline. By the fifth week, the genital ridges differentiate into an outer cortex and an inner medulla, and are called indifferent gonads.[78] By the sixth week, the indifferent gonads begin to differentiate according to genetic sex. If the karyotype is 46,XY, testes develop due to the influence of the Y chromosome’s SRY gene.[52][53] This process does not require the presence of androgen, nor a functional androgen receptor.[52][53]
Until around the seventh week of development, the embryo has indifferent sex accessory ducts, which consist of two pairs of ducts: the Müllerian ducts and the Wolffian ducts.[78] Sertoli cells within the testes secrete anti-Müllerian hormone around this time to suppress the development of the Müllerian ducts, and cause their degeneration.[78] Without this anti-Müllerian hormone, the Müllerian ducts develop into the female internal genitalia (uterus, cervix, fallopian tubes, and upper vaginal barrel).[78] Unlike the Müllerian ducts, the Wolffian ducts will not continue to develop by default.[79] In the presence of testosterone and functional androgen receptors, the Wolffian ducts develop into the epididymides, vasa deferentia, and seminal vesicles.[78] If the testes fail to secrete testosterone, or the androgen receptors do not function properly, the Wolffian ducts degenerate.[80]
Masculinization of the male genitalia is dependent on both testosterone and dihydrotestosterone.[77]
Masculinization of the male external genitalia (the penis, penile urethra, and scrotum), as well as the prostate, are dependent on the androgen dihydrotestosterone.[81][82][83][84] Testosterone is converted into dihydrotestosterone by the 5-alpha reductase enzyme.[85] If this enzyme is absent or deficient, then dihydrotestosterone is not created, and the external male genitalia do not develop properly.[81][82][83][84][85] As is the case with the internal male genitalia, a functional androgen receptor is needed for dihydrotestosterone to regulate the transcription of target genes involved in development.[72]
### Pathogenesis of AIS[edit]
Mutations in the androgen receptor gene can cause problems with any of the steps involved in androgenization, from the synthesis of the androgen receptor protein itself, through the transcriptional ability of the dimerized, androgen-AR complex.[2] AIS can result if even one of these steps is significantly disrupted, as each step is required for androgens to activate the AR successfully and regulate gene expression.[2] Exactly which steps a particular mutation will impair can be predicted, to some extent, by identifying the area of the AR in which the mutation resides. This predictive ability is primarily retrospective in origin; the different functional domains of the AR gene have been elucidated by analyzing the effects of specific mutations in different regions of the AR.[2] For example, mutations in the steroid binding domain have been known to affect androgen binding affinity or retention, mutations in the hinge region have been known to affect nuclear translocation, mutations in the DNA-binding domain have been known to affect dimerization and binding to target DNA, and mutations in the transactivation domain have been known to affect target gene transcription regulation.[2][79] Unfortunately, even when the affected functional domain is known, predicting the phenotypical consequences of a particular mutation (see Correlation of genotype and phenotype) is difficult.
Some mutations can adversely impact more than one functional domain. For example, a mutation in one functional domain can have deleterious effects on another by altering the way in which the domains interact.[79] A single mutation can affect all downstream functional domains if a premature stop codon or framing error results; such a mutation can result in a completely unusable (or unsynthesizable) androgen receptor protein.[2] The steroid binding domain is particularly vulnerable to the effects of a premature stop codon or framing error, since it occurs at the end of the gene, and its information is thus more likely to be truncated or misinterpreted than other functional domains.[2]
Other, more complex relationships have been observed as a consequence of mutated AR; some mutations associated with male phenotypes have been linked to male breast cancer, prostate cancer, or in the case of spinal and bulbar muscular atrophy, disease of the central nervous system.[86][19][87][88][89] The form of breast cancer seen in some men with PAIS is caused by a mutation in the AR's DNA-binding domain.[87][89] This mutation is thought to cause a disturbance of the AR's target gene interaction that allows it to act at certain additional targets, possibly in conjunction with the estrogen receptor protein, to cause cancerous growth.[2] The pathogenesis of spinal and bulbar muscular atrophy (SBMA) demonstrates that even the mutant AR protein itself can result in pathology. The trinucleotide repeat expansion of the polyglutamine tract of the AR gene that is associated with SBMA results in the synthesis of a misfolded AR protein that the cell fails to proteolyze and disperse properly.[90] These misfolded AR proteins form aggregates in the cell cytoplasm and nucleus.[90] Over the course of 30 to 50 years, these aggregates accumulate and have a cytotoxic effect, eventually resulting in the neurodegenerative symptoms associated with SBMA.[90]
## Diagnosis[edit]
The phenotypes that result from the insensitivity to androgens are not unique to AIS, thus the diagnosis of AIS requires thorough exclusion of other causes.[8][63] Clinical findings indicative of AIS include the presence of a short vagina [91] or undermasculinized genitalia,[4][62][81] partial or complete regression of Müllerian structures,[92] bilateral nondysplastic testes,[93] and impaired spermatogenesis and/or virilization.[4][94][45][86] Laboratory findings include a 46,XY karyotype[10] and typical or elevated postpubertal testosterone, luteinizing hormone, and estradiol levels.[10][8] The androgen binding activity of genital skin fibroblasts is typically diminished,[2][95] although exceptions have been reported.[96] Conversion of testosterone to dihydrotestosterone may be impaired.[2] The diagnosis of AIS is confirmed if androgen receptor gene sequencing reveals a mutation, although not all individuals with AIS (particularly PAIS) will have an AR mutation (see Other Causes).[10][45][46][47]
Each of the three types of AIS (complete, partial, and mild) has a different list of differential diagnoses to consider.[4] Depending on the form of AIS suspected, the list of differentials can include:[52][53][97][98][99]
* Chromosomal anomalies:
* Klinefelter syndrome (47,XXY karyotype)
* Turner syndrome (45,XO karyotype)
* Mixed gonadal dysgenesis (45,XO/46,XY karyotype)
* Tetragametic chimerism (46,XX/46,XY karyotype)
* Androgen biosynthetic dysfunction in 46,XY individuals:
* Luteinizing hormone (LH) receptor mutations
* Smith–Lemli–Opitz syndrome (associated with intellectual disability)
* Lipoid congenital adrenal hyperplasia
* 3β-hydroxysteroid dehydrogenase 2 deficiency
* 17α-hydroxylase deficiency
* 17,20 lyase deficiency
* 17β-hydroxysteroid dehydrogenase deficiency
* 5α-reductase deficiency
* Androgen excess in 46,XX individuals:
* 21-hydroxylase deficiency
* 3β-hydroxysteroid dehydrogenase 2 deficiency
* Cytochrome P450 oxidoreductase deficiency (disorder in mother causes 46,XX fetal virilization)
* 11β-hydroxylase deficiency
* Aromatase deficiency
* Glucocorticoid receptor mutations
* Maternal virilizing tumor (e.g. luteoma)
* Increased androgen exposure in utero, not otherwise specified (e.g. androgenic drugs)
* Developmental
* Mayer–Rokitansky–Küster–Hauser syndrome (46,XX karyotype)
* Swyer syndrome (46,XY karyotype)
* XX gonadal dysgenesis (46,XX karyotype)
* Leydig cell agenesis or hypoplasia, not otherwise specified (46,XY karyotype)
* Absent (vanishing) testes syndrome
* Ovotesticular DSD
* Testicular DSD (i.e. 46,XX sex reversal)
* Teratogenic causes (e.g. estrogens, antiestrogens)
* Other causes:
* Frasier syndrome (associated with progressive glomerulopathy)
* Denys–Drash syndrome (associated with nephropathy and Wilms tumor)
* WAGR syndrome (associated with Wilms tumor and aniridia)
* McKusick–Kaufman syndrome (associated with postaxial polydactyly)
* Robinow syndrome (associated with dwarfism)
* Aarskog–Scott syndrome (associated with facial anomalies)
* Hand-foot-genital syndrome (associated with limb malformations)
* Popliteal pterygium syndrome (associated with extensive webbing behind knees)
* Kallmann syndrome (often associated with anosmia)
* Hypospadias not otherwise specified
* Cryptorchidism not otherwise specified
* vaginal atresia not otherwise specified
### Classification[edit]
Women with AIS and related DSD/intersex conditions
AIS is broken down into three classes based on phenotype: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), and mild androgen insensitivity syndrome (MAIS).[4][10][94][45][100][37][32][101][11] A supplemental system of phenotypic grading that uses seven classes instead of the traditional three was proposed by pediatric endocrinologist Charmian A. Quigley et al. in 1995.[2] The first six grades of the scale, grades 1 through 6, are differentiated by the degree of genital masculinization; grade 1 is indicated when the external genitalia is fully masculinized, grade 6 is indicated when the external genitalia is fully feminized, and grades 2 through 5 quantify four degrees of decreasingly masculinized genitalia that lie in the interim.[2] Grade 7 is indistinguishable from grade 6 until puberty, and is thereafter differentiated by the presence of secondary terminal hair; grade 6 is indicated when secondary terminal hair is present, whereas grade 7 is indicated when it is absent.[2] The Quigley scale can be used in conjunction with the traditional three classes of AIS to provide additional information regarding the degree of genital masculinization, and is particularly useful when the diagnosis is PAIS.[10][102]
#### Complete AIS[edit]
Main article: Complete androgen insensitivity syndrome
#### Partial AIS[edit]
Main article: Partial androgen insensitivity syndrome
#### Mild AIS[edit]
Main article: Mild androgen insensitivity syndrome
## Management[edit]
Management of AIS is currently limited to symptomatic management; no method is currently available to correct the malfunctioning androgen receptor proteins produced by AR gene mutations. Areas of management include sex assignment, genitoplasty, gonadectomy in relation to tumor risk, hormone replacement therapy, genetic counseling, and psychological counseling.
### CAIS[edit]
Main article: Management of Complete Androgen Insensitivity Syndrome
### PAIS[edit]
Main article: Management of Partial Androgen Insensitivity Syndrome
### MAIS[edit]
Main article: Management of Mild Androgen Insensitivity Syndrome
## Epidemiology[edit]
Estimates for the incidence of androgen insensitivity syndrome are based on a relatively small population size, thus are known to be imprecise.[4] CAIS is estimated to occur in one of every 20,400 46,XY births.[103] A nationwide survey in the Netherlands based on patients with genetic confirmation of the diagnosis estimates that the minimal incidence of CAIS is one in 99,000.[61] The incidence of PAIS is estimated to be one in 130,000.[104] Due to its subtle presentation, MAIS is not typically investigated except in the case of male infertility,[81] thus its true prevalence is unknown.[10]
## Controversy[edit]
### Preimplantation genetic diagnosis[edit]
Preimplantation genetic diagnosis (PGD or PIGD) refers to genetic profiling of embryos prior to implantation (as a form of embryo profiling), and sometimes even of oocytes prior to fertilization. When used to screen for a specific genetic sequence, its main advantage is that it avoids selective pregnancy termination, as the method makes it highly likely that a selected embryo will be free of the condition under consideration. [105]
In the UK, AIS appears on a list of serious genetic diseases that may be screened for via PGD.[106] Some ethicists, clinicians, and intersex advocates have argued that screening embryos to specifically exclude intersex traits are based on social and cultural norms as opposed to medical necessity.[107][108][109][110][111][citation needed]
## History[edit]
Recorded descriptions of the effects of AIS date back hundreds of years, although significant understanding of its underlying histopathology did not occur until the 1950s.[4] The taxonomy and nomenclature associated with androgen insensitivity went through a significant evolution that paralleled this understanding.
### Timeline of major milestones[edit]
* 1950: Lawson Wilkins administers daily methyltestosterone to a karyotype|46,XY female patient, who shows no signs of virilization. His experiment is the first documented demonstration of the pathophysiology of AIS.[63][112]
* 1970: Mary F. Lyon and Susan Hawkes reported that a gene on the X chromosome caused complete insensitivity to androgens in mice.[113][114]
* 1981: Barbara Migeon et al. narrowed down the locus of the human androgen receptor gene (or a factor controlling the androgen receptor gene) to somewhere between Xq11 and Xq13.[115][116]
* 1988: The human androgen receptor gene is first cloned and partially analyzed by multiple parties.[117][118] Terry Brown et al. reported the first mutations proven to cause AIS.[10][116]
* 1989: Terry Brown et al. reported the exact locus of the AR gene (Xq11-Xq12),[9] and Dennis Lubahn et al. published its intron-exon boundaries.[119]
* 1994: The androgen receptor gene mutations database was created to provide a comprehensive listing of mutations published in medical journals and conference proceedings.[120]
### Early terminology[edit]
The first descriptions of the effects of AIS appeared in the medical literature as individual case reports or as part of a comprehensive description of intersex physicalities. In 1839, Scottish obstetrician Sir James Young Simpson published one such description[121] in an exhaustive study of intersexuality that has been credited with advancing the medical community's understanding of the subject.[122] Simpson's system of taxonomy, however, was far from the first; taxonomies or descriptions for the classification of intersexuality were developed by Italian physician and physicist Fortuné Affaitati in 1549,[123][124] French surgeon Ambroise Paré in 1573,[122][125] French physician and sexology pioneer Nicolas Venette in 1687 (under the pseudonym Vénitien Salocini),[126][127] and French zoologist Isidore Geoffroy Saint-Hilaire in 1832.[128] All five of these authors used the colloquial term "hermaphrodite" as the foundation of their taxonomies, although Simpson himself questioned the propriety of the word in his publication.[121] Use of the word "hermaphrodite" in the medical literature has persisted to this day,[129][130] although its propriety is still in question. An alternative system of nomenclature has been recently suggested,[131] but the subject of exactly which word or words should be used in its place still one of much debate.[98][132][133][134][135]
"Pudenda pseudo-hermaphroditi ovini." Illustration of ambiguous genitalia from Frederik Ruysch's Thesaurus Anitomicus Octavius, 1709.[136]
### Pseudohermaphroditism[edit]
"Pseudohermaphroditism" has, until very recently,[131] been the term used in the medical literature to describe the condition of an individual whose gonads and karyotype do not match the external genitalia in the gender binary sense. For example, 46,XY individuals who have a female phenotype, but also have testes instead of ovaries—a group that includes all individuals with CAIS, as well as some individuals with PAIS—are classified as having "male pseudohermaphroditism", while individuals with both an ovary and a testis (or at least one ovotestis) are classified as having "true hermaphroditism".[130][131] Use of the word in the medical literature antedates the discovery of the chromosome, thus its definition has not always taken karyotype into account when determining an individual's sex. Previous definitions of "pseudohermaphroditism" relied on perceived inconsistencies between the internal and external organs; the "true" sex of an individual was determined by the internal organs, and the external organs determined the "perceived" sex of an individual.[121][128]
German-Swiss pathologist Edwin Klebs is sometimes noted for using the word "pseudohermaphroditism" in his taxonomy of intersexuality in 1876,[137] although the word is clearly not his invention as is sometimes reported; the history of the word "pseudohermaphrodite" and the corresponding desire to separate "true" hermaphrodites from "false", "spurious", or "pseudo" hermaphrodites, dates back to at least 1709, when Dutch anatomist Frederik Ruysch used it in a publication describing a subject with testes and a mostly female phenotype.[136] "Pseudohermaphrodite" also appeared in the Acta Eruditorum later that same year, in a review of Ruysch's work.[138] Also some evidence indicates the word was already being used by the German and French medical community long before Klebs used it; German physiologist Johannes Peter Müller equated "pseudohermaphroditism" with a subclass of hermaphroditism from Saint-Hilaire's taxonomy in a publication dated 1834,[139] and by the 1840s "pseudohermaphroditism" was appearing in several French and German publications, including dictionaries.[140][141][142][143]
### Testicular feminization[edit]
In 1953, American gynecologist John Morris provided the first full description of what he called "testicular feminization syndrome" based on 82 cases compiled from the medical literature, including two of his own patients.[4][2][144] The term "testicular feminization" was coined to reflect Morris' observation that the testicles in these patients produced a hormone that had a feminizing effect on the body, a phenomenon now understood to be due to the inaction of androgens, and subsequent aromatization of testosterone into estrogen.[4] A few years before Morris published his landmark paper, Lawson Wilkins had shown through experiment that unresponsiveness of the target cell to the action of androgenic hormones was a cause of "male pseudohermaphroditism".[63][112] Wilkins' work, which clearly demonstrated the lack of a therapeutic effect when 46,XY patients were treated with androgens, caused a gradual shift in nomenclature from "testicular feminization" to "androgen resistance".[81]
### Other names[edit]
A distinct name has been given to many of the various presentations of AIS, such as Reifenstein syndrome (1947),[145] Goldberg-Maxwell syndrome (1948),[146] Morris' syndrome (1953),[144] Gilbert-Dreyfus syndrome (1957),[147] Lub's syndrome (1959),[148] "incomplete testicular feminization" (1963),[149] Rosewater syndrome (1965),[150] and Aiman's syndrome (1979).[151] Since it was not understood that these different presentations were all caused by the same set of mutations in the androgen receptor gene, a unique name was given to each new combination of symptoms, resulting in a complicated stratification of seemingly disparate disorders.[63][152]
Over the last 60 years, as reports of strikingly different phenotypes were reported to occur even among members of the same family, and as steady progress was made towards the understanding of the underlying molecular pathogenesis of AIS, these disorders were found to be different phenotypic expressions of one syndrome caused by molecular defects in the androgen receptor gene.[4][11][63][152]
AIS is now the accepted terminology for the syndromes resulting from unresponsiveness of the target cell to the action of androgenic hormones.[4] CAIS encompasses the phenotypes previously described by "testicular feminization", Morris' syndrome, and Goldberg-Maxwell syndrome;[4][153] PAIS includes Reifenstein syndrome, Gilbert-Dreyfus syndrome, Lub's syndrome, "incomplete testicular feminization", and Rosewater syndrome;[152][154][155] and MAIS includes Aiman's syndrome.[156]
The more virilized phenotypes of AIS have sometimes been described as "undervirilized male syndrome", "infertile male syndrome", "undervirilized fertile male syndrome", etc., before evidence was reported that these conditions were caused by mutations in the AR gene.[57] These diagnoses were used to describe a variety of mild defects in virilization; as a result, the phenotypes of some men who have been diagnosed as such are better described by PAIS (e.g. micropenis, hypospadias, and undescended testes), while others are better described by MAIS (e.g. isolated male infertility or gynecomastia).[4][57][58][155][157][158]
## Society and culture[edit]
In the film Orchids, My Intersex Adventure, Phoebe Hart and her sister Bonnie Hart, both women with CAIS, documented their exploration of AIS and other intersex issues.[159]
Recording artist Dalea is a Hispanic-American Activist who is public about her CAIS. She has given interviews about her condition[160][161] and founded Girl Comet, a non-profit diversity awareness and inspiration initiative.[162]
In 2017, fashion model Hanne Gaby Odiele disclosed that they were born with the intersex trait androgen insensitivity syndrome. As a child, they underwent medical procedures relating to the condition,[163] which they said took place without their or their parents' informed consent.[164] They were told about their intersex condition weeks before beginning their modelling career.[164]
In the 1991 Japanese horror novel Ring, by Koji Suzuki (later adapted into Japanese, Korean, and American films), the central antagonist Sadako has this syndrome.[citation needed]
In season 2, episode 13 ("Skin Deep") of the TV series House, the main patient's cancerous testicle is mistaken for an ovary due to the patient's undiscovered CAIS.[citation needed]
In season 2 of the MTV series Faking It, a character has CAIS. The character, Lauren Cooper, played by Bailey De Young, was the first intersex series regular on American television.[165][166]
In season 8, episode 11 ("Delko for the Defense") of the TV series CSI: Miami, the primary suspect has AIS which gets him off a rape charge.[citation needed]
In series 8, episode 5 of Call the Midwife, a woman discovers that she has AIS. She attends a cervical smear and brings up that she has never had a period, and is concerned about having children as she is about to be married. She is then diagnosed with "testicular feminisation syndrome", the old term for AIS.[167]
### People with AIS[edit]
* Kitty Anderson (activist)[168][169]
* Bonnie Hart[170]
* Phoebe Hart[171]
* Maria José Martínez-Patiño[172]
* Hanne Gaby Odiele[173][174]
* Pidgeon Pagonis[175]
* Santhi Soundarajan[176][177]
* Miriam van der Have[178]
* Kimberly Zieselman[179]
#### People with Complete androgen insensitivity syndrome[edit]
* Georgiann Davis[180]
* Seven Graham[181]
#### People with Partial androgen insensitivity syndrome[edit]
* Tony Briffa[182][183]
* Favorinus of Arelate has been described as having partial androgen insensitivity syndrome.[184][185]
* Small Luk[186]
* Eliana Rubashkyn[187][188][189]
* Sean Saifa Wall[190]
## See also[edit]
* Estrogen insensitivity syndrome
* Spinal and bulbar muscular atrophy
## References[edit]
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129. ^ Dorsey FY, Hsieh MH, Roth DR (March 2009). "46,XX SRY-negative true hermaphrodite siblings". Urology. 73 (3): 529–31. doi:10.1016/j.urology.2008.09.050. PMID 19038427.
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144. ^ a b Morris JM (June 1953). "The syndrome of testicular feminization in male pseudohermaphrodites". Am. J. Obstet. Gynecol. 65 (6): 1192–1211. doi:10.1016/0002-9378(53)90359-7. PMID 13057950.
145. ^ Reifenstein EC Jr. (1947). "Hereditary familial hypogonadism". Proc Am Fed Clin Res. 3: 86. PMID 18909356.
146. ^ Goldberg MB, Maxwell A (May 1948). "Male pseudohermaphroditism proved by surgical exploration and microscopic examination; a case report with speculations concerning pathogenesis". J. Clin. Endocrinol. Metab. 8 (5): 367–79. doi:10.1210/jcem-8-5-367. PMID 18863968.
147. ^ Gilbert-Dreyfus S, Sabaoun CI, Belausch J (1957). "Etude d'un cas familial d'androgynoidisme avec hypospadias grave, gynecomastie et hyperoestrogenie". Ann. Endocrinol. 18: 93–101.
148. ^ Lubs HA Jr, Vilar O, Bergenstal DM (September 1959). "Familial male pseudohermaphrodism with labial testes and partial feminization: endocrine studies and genetic aspects". J. Clin. Endocrinol. Metab. 19 (9): 1110–20. doi:10.1210/jcem-19-9-1110. PMID 14418653.
149. ^ Morris JM, Mahesh VB (November 1963). "Further observations on the syndrome, "testicular feminization."". Am. J. Obstet. Gynecol. 87: 731–48. PMID 14085776.
150. ^ Rosewater S, Gwinup G, Hamwi JG (September 1965). "Familial gynecomastia". Annals of Internal Medicine. 63 (3): 377–85. doi:10.7326/0003-4819-63-3-377. PMID 14327504.
151. ^ Aiman J, Griffin JE, Gazak JM, Wilson JD, MacDonald PC (February 1979). "Androgen insensitivity as a cause of infertility in otherwise normal men". N. Engl. J. Med. 300 (5): 223–7. doi:10.1056/NEJM197902013000503. PMID 759869.
152. ^ a b c Simpson JL (2008). "Male Pseudohermaphroditism Due to Androgen Insensitivity or 5α-Reductase Deficiency". Glob. Libr. Women's Med. The Global Library of Women's Medicine. doi:10.3843/GLOWM.10349.
153. ^ Hester JD (2004). "Intersex(e) und alternative Heilungsstrategien – Medizin, soziale Imperative und identitatsstiftende Gegengemeinschaften". Ethik Med. 16: 48–67. doi:10.1007/s00481-004-0284-3. S2CID 5933432.
154. ^ McPhaul MJ (1999). "Molecular defects of the androgen receptor". J. Steroid Biochem. Mol. Biol. 69 (1–6): 315–22. doi:10.1016/S0960-0760(99)00050-3. PMID 10419008. S2CID 1485903.
155. ^ a b Hoff TA, Fuqua SA (2000). "Steroid and nuclear receptor polymorphism variants in hormone resistance and hormone independence". In Miller MS, Cronin MT (eds.). Genetic polymorphisms and susceptibility to disease. Washington, DC: Taylor & Francis. p. 111. ISBN 978-0-7484-0822-1.
156. ^ Sultan C, Lumbroso S, Paris F, Jeandel C, Terouanne B, Belon C, Audran F, Poujol N, Georget V, Gobinet J, Jalaguier S, Auzou G, Nicolas JC (August 2002). "Disorders of androgen action". Semin. Reprod. Med. 20 (3): 217–28. doi:10.1055/s-2002-35386. PMID 12428202.
157. ^ Chu J, Zhang R, Zhao Z, Zou W, Han Y, Qi Q, Zhang H, Wang JC, Tao S, Liu X, Luo Z (January 2002). "Male fertility is compatible with an Arg(840)Cys substitution in the AR in a large Chinese family affected with divergent phenotypes of AR insensitivity syndrome". J. Clin. Endocrinol. Metab. 87 (1): 347–51. doi:10.1210/jc.87.1.347. PMID 11788673.
158. ^ Meschede D, Horst J (May 1997). "The molecular genetics of male infertility". Mol. Hum. Reprod. 3 (5): 419–30. doi:10.1093/molehr/3.5.419. PMID 9239727.
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160. ^ Carter S (31 May 2014). "Challenging Perspectives: Interview Dalea". Vada Magazine. Retrieved 23 January 2017.
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## External links[edit]
Classification
D
* ICD-10: E34.5
* ICD-9-CM: 259.5
* OMIM: 312300 300068
* MeSH: D013734
* DiseasesDB: 29662
External resources
* MedlinePlus: 001180
* eMedicine: ped/2222
* GeneReviews: Androgen insensitivity syndrome
### Information[edit]
* Androgen Insensitivity Syndrome at NIH/UW GeneTests
* Online Mendelian Inheritance in Man (OMIM): Androgen Insensitivity Syndrome - 300068, 313700
* v
* t
* e
Gonadal disorder
Ovarian
* Polycystic ovary syndrome
* Premature ovarian failure
* Estrogen insensitivity syndrome
* Hyperthecosis
Testicular
Enzymatic
* 5α-reductase deficiency
* 17β-hydroxysteroid dehydrogenase deficiency
* aromatase excess syndrome
Androgen receptor
* Androgen insensitivity syndrome
* Familial male-limited precocious puberty
* Partial androgen insensitivity syndrome
Other
* Sertoli cell-only syndrome
General
* Hypogonadism
* Delayed puberty
* Hypergonadism
* Precocious puberty
* Hypoandrogenism
* Hypoestrogenism
* Hyperandrogenism
* Hyperestrogenism
* Postorgasmic illness syndrome
* Cytochrome P450 oxidoreductase deficiency
* Cytochrome b5 deficiency
* Androgen-dependent condition
* Aromatase deficiency
* Complete androgen insensitivity syndrome
* Mild androgen insensitivity syndrome
* Hypergonadotropic hypogonadism
* Hypogonadotropic hypogonadism
* Fertile eunuch syndrome
* Estrogen-dependent condition
* Premature thelarche
* Gonadotropin insensitivity
* Hypergonadotropic hypergonadism
* v
* t
* e
X-linked disorders
X-linked recessive
Immune
* Chronic granulomatous disease (CYBB)
* Wiskott–Aldrich syndrome
* X-linked severe combined immunodeficiency
* X-linked agammaglobulinemia
* Hyper-IgM syndrome type 1
* IPEX
* X-linked lymphoproliferative disease
* Properdin deficiency
Hematologic
* Haemophilia A
* Haemophilia B
* X-linked sideroblastic anemia
Endocrine
* Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy
* KAL1 Kallmann syndrome
* X-linked adrenal hypoplasia congenita
Metabolic
* Amino acid: Ornithine transcarbamylase deficiency
* Oculocerebrorenal syndrome
* Dyslipidemia: Adrenoleukodystrophy
* Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency
* Pyruvate dehydrogenase deficiency
* Danon disease/glycogen storage disease Type IIb
* Lipid storage disorder: Fabry's disease
* Mucopolysaccharidosis: Hunter syndrome
* Purine–pyrimidine metabolism: Lesch–Nyhan syndrome
* Mineral: Menkes disease/Occipital horn syndrome
Nervous system
* X-linked intellectual disability: Coffin–Lowry syndrome
* MASA syndrome
* Alpha-thalassemia mental retardation syndrome
* Siderius X-linked mental retardation syndrome
* Eye disorders: Color blindness (red and green, but not blue)
* Ocular albinism (1)
* Norrie disease
* Choroideremia
* Other: Charcot–Marie–Tooth disease (CMTX2-3)
* Pelizaeus–Merzbacher disease
* SMAX2
Skin and related tissue
* Dyskeratosis congenita
* Hypohidrotic ectodermal dysplasia (EDA)
* X-linked ichthyosis
* X-linked endothelial corneal dystrophy
Neuromuscular
* Becker's muscular dystrophy/Duchenne
* Centronuclear myopathy (MTM1)
* Conradi–Hünermann syndrome
* Emery–Dreifuss muscular dystrophy 1
Urologic
* Alport syndrome
* Dent's disease
* X-linked nephrogenic diabetes insipidus
Bone/tooth
* AMELX Amelogenesis imperfecta
No primary system
* Barth syndrome
* McLeod syndrome
* Smith–Fineman–Myers syndrome
* Simpson–Golabi–Behmel syndrome
* Mohr–Tranebjærg syndrome
* Nasodigitoacoustic syndrome
X-linked dominant
* X-linked hypophosphatemia
* Focal dermal hypoplasia
* Fragile X syndrome
* Aicardi syndrome
* Incontinentia pigmenti
* Rett syndrome
* CHILD syndrome
* Lujan–Fryns syndrome
* Orofaciodigital syndrome 1
* Craniofrontonasal dysplasia
* v
* t
* e
Genetic disorders relating to deficiencies of transcription factor or coregulators
(1) Basic domains
1.2
* Feingold syndrome
* Saethre–Chotzen syndrome
1.3
* Tietz syndrome
(2) Zinc finger
DNA-binding domains
2.1
* (Intracellular receptor): Thyroid hormone resistance
* Androgen insensitivity syndrome
* PAIS
* MAIS
* CAIS
* Kennedy's disease
* PHA1AD pseudohypoaldosteronism
* Estrogen insensitivity syndrome
* X-linked adrenal hypoplasia congenita
* MODY 1
* Familial partial lipodystrophy 3
* SF1 XY gonadal dysgenesis
2.2
* Barakat syndrome
* Tricho–rhino–phalangeal syndrome
2.3
* Greig cephalopolysyndactyly syndrome/Pallister–Hall syndrome
* Denys–Drash syndrome
* Duane-radial ray syndrome
* MODY 7
* MRX 89
* Townes–Brocks syndrome
* Acrocallosal syndrome
* Myotonic dystrophy 2
2.5
* Autoimmune polyendocrine syndrome type 1
(3) Helix-turn-helix domains
3.1
* ARX
* Ohtahara syndrome
* Lissencephaly X2
* MNX1
* Currarino syndrome
* HOXD13
* SPD1 synpolydactyly
* PDX1
* MODY 4
* LMX1B
* Nail–patella syndrome
* MSX1
* Tooth and nail syndrome
* OFC5
* PITX2
* Axenfeld syndrome 1
* POU4F3
* DFNA15
* POU3F4
* DFNX2
* ZEB1
* Posterior polymorphous corneal dystrophy
* Fuchs' dystrophy 3
* ZEB2
* Mowat–Wilson syndrome
3.2
* PAX2
* Papillorenal syndrome
* PAX3
* Waardenburg syndrome 1&3
* PAX4
* MODY 9
* PAX6
* Gillespie syndrome
* Coloboma of optic nerve
* PAX8
* Congenital hypothyroidism 2
* PAX9
* STHAG3
3.3
* FOXC1
* Axenfeld syndrome 3
* Iridogoniodysgenesis, dominant type
* FOXC2
* Lymphedema–distichiasis syndrome
* FOXE1
* Bamforth–Lazarus syndrome
* FOXE3
* Anterior segment mesenchymal dysgenesis
* FOXF1
* ACD/MPV
* FOXI1
* Enlarged vestibular aqueduct
* FOXL2
* Premature ovarian failure 3
* FOXP3
* IPEX
3.5
* IRF6
* Van der Woude syndrome
* Popliteal pterygium syndrome
(4) β-Scaffold factors
with minor groove contacts
4.2
* Hyperimmunoglobulin E syndrome
4.3
* Holt–Oram syndrome
* Li–Fraumeni syndrome
* Ulnar–mammary syndrome
4.7
* Campomelic dysplasia
* MODY 3
* MODY 5
* SF1
* SRY XY gonadal dysgenesis
* Premature ovarian failure 7
* SOX10
* Waardenburg syndrome 4c
* Yemenite deaf-blind hypopigmentation syndrome
4.11
* Cleidocranial dysostosis
(0) Other transcription factors
0.6
* Kabuki syndrome
Ungrouped
* TCF4
* Pitt–Hopkins syndrome
* ZFP57
* TNDM1
* TP63
* Rapp–Hodgkin syndrome/Hay–Wells syndrome/Ectrodactyly–ectodermal dysplasia–cleft syndrome 3/Limb–mammary syndrome/OFC8
Transcription coregulators
Coactivator:
* CREBBP
* Rubinstein–Taybi syndrome
Corepressor:
* HR (Atrichia with papular lesions)
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Androgen insensitivity syndrome | c0936016 | 2,532 | wikipedia | https://en.wikipedia.org/wiki/Androgen_insensitivity_syndrome | 2021-01-18T19:07:35 | {"gard": ["5803"], "mesh": ["D013734"], "umls": ["C0936016", "C0039585"], "icd-9": ["259.5259.5"], "icd-10": ["E34.534.5"], "orphanet": ["754"], "wikidata": ["Q512313"]} |
Rodent-borne viral infectious disease
Lymphocytic choriomeningitis
Other namesBenign lymphocytic meningitis, lymphocytic meningoencephalitis, serous lymphocytic meningitis, la maladie d'Armstrong[1]
SpecialtyInfectious disease
Lymphocytic choriomeningitis (LCM) is a rodent-borne viral infectious disease that presents as aseptic meningitis, encephalitis or meningoencephalitis. Its causative agent is lymphocytic choriomeningitis mammarenavirus (LCMV), a member of the family Arenaviridae. The name was coined by Charles Armstrong in 1934.[2]
Lymphocytic choriomeningitis (LCM) is "a viral infection of the membranes surrounding the brain and spinal cord and of the cerebrospinal fluid".[3] The name is based on the tendency of an individual to have abnormally high levels of lymphocytes during infection. Choriomeningitis is "cerebral meningitis in which there is marked cellular infiltration of the meninges, often with a lymphocytic infiltration of the choroid plexuses".[4]
## Contents
* 1 Signs and symptoms
* 2 Cause
* 2.1 Virus biology
* 2.2 Spread
* 2.2.1 Congenital infection
* 2.2.2 Organ donation
* 3 Diagnosis
* 4 Prevention
* 5 Treatment
* 6 Prognosis
* 7 Epidemiology
* 8 Other animals
* 8.1 Mice
* 8.2 Hamsters
* 8.3 Rats
* 8.4 Primates
* 8.5 Diagnosis
* 8.6 Treatment
* 8.7 Morbidity and mortality
* 8.8 In pets
* 9 Research
* 10 Footnotes
* 11 References
* 12 External links
* 13 Further reading
## Signs and symptoms[edit]
LCMV infection manifests itself in a wide range of clinical symptoms, and may even be asymptomatic for immunocompetent individuals.[5] Onset typically occurs between one or two weeks after exposure to the virus and is followed by a biphasic febrile illness. During the initial or prodromal phase, which may last up to a week, common symptoms include fever, lack of appetite, headache, muscle aches, malaise, nausea, and/or vomiting. Less frequent symptoms include a sore throat and cough, as well as joint, chest, and parotid pain. The onset of the second phase occurs several days after recovery, and consists of symptoms of meningitis or encephalitis. Pathological findings during the first stage consist of leukopenia and thrombocytopenia. During the second phase, typical findings include elevated protein levels, increased leukocyte count, or a decrease in glucose levels of the cerebrospinal fluid).[6]
Occasionally, a patient improves for a few days, then relapses with aseptic meningitis, or very rarely, meningoencephalitis.[7] Patients with meningitis may have a stiff neck, fever, headache, myalgia, nausea and malaise. In some occasions, meningitis occurs without a prodromal syndrome.[7] Meningoencephalitis is characterized by more profound neurological signs such as confusion, drowsiness, sensory abnormalities and motor signs. Under reported complications include myelitis, Guillain–Barré-type syndrome, cranial nerve palsies, transient or permanent hydrocephalus, sensorineural hearing loss, orchitis, arthritis and parotitis.[7] LCMV infections have also been associated with pancreatitis, pneumonitis, myocarditis and pericarditis.[7] The entire illness usually lasts 1 to 3 weeks,[7] nonetheless, temporary or permanent neurological damage is possible in all central nervous system infections, especially in cases of meningoencephalitis. Chronic infections have not been reported in humans and deaths rarely occur.[7]
## Cause[edit]
### Virus biology[edit]
Lymphocytic choriomeningitis mammarenavirus
Negative stain electron micrograph of an arenavirus from a mouse that tested positive for LCM
Virus classification
(unranked): Virus
Realm: Riboviria
Kingdom: Orthornavirae
Phylum: Negarnaviricota
Class: Ellioviricetes
Order: Bunyavirales
Family: Arenaviridae
Genus: Mammarenavirus
Species:
Lymphocytic choriomeningitis mammarenavirus
Synonyms
* Lymphocytic choriomeningitis virus
There are several strains of LCM virus, among which the most widely used are LCMV Armstrong and LCMV Clone 13. Armstrong is the original virus strain which was isolated from the brain by Charles Armstrong in 1934. It triggers a vigorous cytotoxic T lymphocytes(CTL) response and thus, it is cleared rapidly by the host. This is referred to as acute (Armstrong) LCMV infection.[8] On the other hand, Clone 13 is a variant of the Armstrong viral strain, isolated from the spleen and is consequently tropic for visceral organs. It was first isolated from mice which sustained a persistent LCMV infection from birth.[8] This variant potentiates a less vigorous CTL response in the immune system, and thus can ultimately persist in the host organism indefinitely. The latter is referred to as chronic (Clone 13) LCMV infection.[8]
LCMV is a spherical enveloped virus with a diameter between 60 and 300 nm.[9] The helical nucleocapsid contains an RNA genome consisting of two negative single-stranded RNA segments.[9] The negative RNA strand, complementary to the necessary mRNA strand, indicates that it must first be transcribed into a positive mRNA strand before it can be translated into the required proteins. The L strand is ambisense RNA, encoding multiple proteins in opposite directions, separated by an intergenic region. It is approximately 7.2 kb in size and encodes a high-molecular-mass protein (L; 200 kDa) and an 11 kDa small polypeptide Z with unknown function and a ring finger motif.[9] The viral RNA-dependent RNA polymerase is encoded by the L protein which contains conserved characteristic motifs throughout all the RNA-dependent, RNA-polymerases. The S strand is ambisense and approximately 3.4 kb in size.[9] It encodes the two main structural proteins: nucleo-protein (63 kDa) and glycoprotein C (75kDa).[10] The latter undergoes posttranslational cleavage and results in the synthesis of two mature virion glycoproteins, GP-1 (40 to 46 kDa) and GP-2 (35 kDa).[9] The spikes present on the virion envelope are dictated by tetramer formation of GP-1 and GP-2.[9]
When LCMV attacks a cell, the process of replication starts by attachment of the virus to host receptors through its surface glycoproteins.[11] It is then endocytosed into a vesicle inside the host cell and creates a fusion of the virus and vesicle membranes. The ribonucleocapsid is then released in the cytoplasm. The RNA-dependent, RNA-polymerase[11] brought along with the virus initially binds to a promoter on the L and S segments and begins transcription from negative-stranded to a positive-stranded mRNA. The formation of a strong hairpin sequence at the end of each gene terminates transcription.[11] The mRNA strands are capped by the RNA-dependent, RNA-polymerase in the cytoplasm[11] and are then subsequently translated into the four proteins essential for LCMV assembly. The ribonucleocapsid interacts with the Z matrix protein[11] and buds on the cell membrane, releasing the virion out from the infected cell.
The first arenavirus, Lymphocytic choriomeningitis mammarenavirus (LCMV), was isolated in 1933 by Charles Armstrong during a study of an epidemic in St. Louis. Although not the cause of the outbreak, LCMV was found to be a cause of nonbacterial or aseptic meningitis.
In 1996, Peter Doherty and Rolf Zinkernagel shared the Nobel Prize in Medicine and Physiology,[8] for their work with LCMV which led to a fundamental understanding of the adaptive immune response, MHC restriction. In the 1970s, studies concerning the importance of MHC locus were done exclusively in transplantation and tumor rejection. Taking this into consideration, Doherty and Zinkernagel were working on the response of mice to virus infections. They observed that T-cell receptors must recognise a complex of foreign antigen and an MHC antigen in order to destroy infected cells. Their key experiment involved harvesting of splenocytes containing LCMV-specific cytotoxic T lymphocytes(CTL) from an infected mouse strain A.[8] These were then mixed in vitro with virus infected fibroblasts or macrophages from two different mouse strains, A and B. By the method of Cr-release cytotoxicity assay,[8] thereby tagging the CTL with chromium-51 (Cr-51), the CTL destruction of infected cells was quantified by release of Cr-51. The results showed that CTL killed only the infected cells from strain A, and they did not lyse uninfected cells or infected cells from strain B.[8] They concluded that these virus specific CTLs only lyse cells carrying the same molecules of the major histocompatibility site (MHC) as the CTLs themselves. Thus, the virus-specific CTLs are "MHC-restricted".[8] This discovery lead to a greater understanding of an important aspect of the immune system.
### Spread[edit]
LCMV is naturally spread by the common house mouse, Mus musculus.[12] Once infected, these mice can become chronically infected by maintaining virus in their blood or persistently shedding virus in their urine. Chronically infected female mice usually transmit infection to their offspring (vertical transmission), which in turn become chronically infected. Other modes of mouse-to-mouse transmission include nasal secretions, milk from infected dams, bites, and during social grooming within mouse communities. Airborne transmission also occurs.[13]
The virus seems to be relatively resistant to drying and therefore humans can become infected by inhaling infectious aerosolized particles of rodent urine, feces, or saliva, by ingesting food contaminated with virus, by contamination of mucous membranes with infected body fluids, or by directly exposing cuts or other open wounds to virus-infected blood. The only documented cases of transmission from animals have occurred between humans and mice or hamsters.
Cases of lymphocytic choriomeningitis have been reported in North and South America, Europe, Australia, and Japan, particularly during the 1900s.[14][15] However, infection may occur wherever an infected rodent host population exists.[13] LCMV occurs worldwide and its natural host, the rodent, has become established on all continents, except Antarctica.[7]
Seroprevalence is approximately 5% (0.7–4.7%) of the US population. It tends to be more common among lower socio-economic groupings, probably reflecting more frequent and direct contacts with mice. However, obtaining an accurate sense of prevalence by geographic region is difficult due to underreporting.[15]
#### Congenital infection[edit]
Lymphocytic choriomeningitis is a particular concern in obstetrics, as vertical transmission is known to occur. For immunocompetent mothers, there is no significant threat, but the virus has damaging effects upon the fetus. If infection occurs during the first trimester, LCMV results in an increased risk of spontaneous abortion.[14] Later congenital infection may lead to malformations such as intracranial calcifications, hydrocephalus, microcephaly or macrocephaly, intellectual disabilities, and seizures.[16] Other findings include chorioretinal scars, and optic atrophy. Chorioretinitis, which is followed by chorioretinal scarring, is the most common ocular lesion.[7] Mortality among infants is approximately 30%. Among the survivors, two-thirds have lasting neurologic abnormalities.[14]
Other ocular defects including optic atrophy, microphthalmia, vitreitis, leukokoria and cataracts can also be seen. Most of the infants in one case series were of normal birth weight, although 30% were underweight.[7] Aspiration pneumonia can be a fatal complication. Infants who survive may have severe neurological defects including epilepsy, impaired coordination, visual loss or blindness, spastic diplegia or quadriparesis/quadriplegia, delayed development and intellectual disability.[7] Less severe cases with isolated cerebellar hypoplasia and symptoms of ataxia and jitteriness have been reported occasionally.[7] There have also been rare cases with evidence of chorioretinitis but without neurological signs. Systemic signs seem to be rare, but hepatosplenomegaly, thrombocytopenia and hyperbilirubinemia have been documented in a few cases, and skin blisters were reported in one infant.[7]
If a woman has come into contact with a rodent during pregnancy and LCM symptoms are manifested, a blood test is available to determine previous or current infection. A history of infection does not pose a risk for future pregnancies.[17]
#### Organ donation[edit]
Patients infected in solid organ transplants have developed a severe fatal illness, starting within weeks of the transplant.[7] In all reported cases, the initial symptoms included fever, lethargy, anorexia and leukopenia, and quickly progressed to multisystem organ failure, hepatic insufficiency or severe hepatitis, dysfunction of the transplanted organ, coagulopathy, hypoxia, multiple bacteremias and shock.[7] Localized rash and diarrhea were also seen in some patients. Nearly all cases have been fatal.[7]
In May 2005, four solid-organ transplant recipients contracted an illness that was later diagnosed as lymphocytic choriomeningitis. All received organs from a common donor, and within a month of transplantation, three of the four recipients had died as a result of the viral infection.[18] Epidemiologic investigation traced the source to a pet hamster that the organ donor had recently purchased from a Rhode Island pet store.[6] Similar cases occurred in Massachusetts in 2008, and Australia in 2013.[19] There is not a LCMV infection test that is approved by the Food and Drug Administration for organ donor screening. The Morbidity and Mortality Weekly Report advises health-care providers to "consider LCMV infection in patients with aseptic meningitis and encephalitis and in organ transplant recipients with unexplained fever, hepatitis, or multisystem organ failure."[20]
## Diagnosis[edit]
Current or previous infection can be detected through a blood test.[17] However, some authors note that such complement-fixation tests are insensitive and should not be used for diagnosis.[14] Dr. Clare A. Dykewicz, et al. state,
Infection with LCMV should be considered in the differential diagnosis of any compatible, severe viral infection or aseptic meningitis, especially when there is a history of occupational exposure to laboratory rodents. Timeliness of diagnosis is important not only in expediting treatment of infected persons, but also in preventing further LCMV transmission to other workers and animals.[21]
Clinical diagnosis of LCM can be made by the history of prodrome symptoms and by considering the period of time before the onset of meningitis symptoms, typically 15–21 days for LCM.[3]
Pathological diagnosis of congenital infection is performed using either an immunofluorescent antibody (IFA) test or an enzyme immunoassay to detect specific antibody in blood or cerebrospinal fluid. A PCR assay has been recently developed which may be used in the future for prenatal diagnosis; however, the virus is not always present in the blood or CSF when the affected child is born."[14] Diagnoses is subject to methodological shortcomings in regard to specificity and sensitivity of assays used.[22] For this reason, LCMV may be more common than is realized.[14]
Another detection assay is the reverse transcription polymerase chain reaction (RT-PCR) tests which may detect nucleic acids in the blood and cerebrospinal fluid.(CSF)[7] Virus isolation is not used for diagnosis in most cases but it can be isolated from the blood or nasopharyngeal fluid early in the course of the disease,[7] or from CSF in patients with meningitis. LCMV can be grown in a variety of cell lines including BHK21, L and Vero cells, and it may be identified with immuno-fluorescence.[7] A diagnosis can also be made by the intracerebral inoculation of blood or CSF into mice.[7]
## Prevention[edit]
LCMV is susceptible to most detergents and disinfectants including 1% sodium hypochlorite, 70% ethanol, 2% glutaraldehyde and formaldehyde.[7] The effectiveness of infection quickly declines below pH 5.5 and above pH 8.5. In addition, LCMV can also be inactivated by heat, ultraviolet light or gamma irradiation.[7]
Studies have indicated that human infection of the virus occurs primarily during the fall and winter months, presumably due to the movement of mice indoors.[16][23] Several measures can be taken to prevent exposure to LCM from wild rodents in the home. A checklist of precautions is provided by the Centers for Disease Control and Prevention, providing tips for sealing the home to keep rodents out, using traps to eliminate existing rodents, and maintaining a clean, healthy home.[24] New technology reflects a growing trend for more humane means of eliminating rodents. Products include devices that emit ultrasonic sound that allegedly irritates mice and drives them away, and more swift, painless means of death such as mini electrocution or gas chambers. However, the traditional snap trap remains an economic and popular option.[23]
## Treatment[edit]
Treatment is symptomatic and supportive. Children with hydrocephalus often need a ventriculoperitoneal shunt.[7] Nucleoside analog ribavirin is used in some cases due to the inhibitory effect the agent has in vitro on arenaviruses.[14] However, there is not sufficient evidence for efficacy in humans to support routine use.[25] The only survivor of a transplant-associated LCMV infection was treated with ribavirin and simultaneous tapering of the immunosuppressive medications.[7] Early and intravenous ribavirin treatment is required for maximal efficacy, and it can produce considerable side effects.[26] Ribavirin has not been evaluated yet in controlled clinical trials.
Use of ribavirin during pregnancy is generally not recommended, as some studies indicate the possibility of teratogenic effects. If aseptic meningitis, encephalitis, or meningoencephalitis develops in consequence to LCMV, hospitalization and supportive treatment may be required. In some circumstances, anti-inflammatory drugs may also be considered.[14] In general, mortality is less than one percent.[20]
## Prognosis[edit]
Lymphocytic choriomeningitis is not a commonly reported infection in humans, though most infections are mild and are often never diagnosed. Serological surveys suggest that approximately 1–5% of the population in the U.S. and Europe has antibodies to LCMV.[7] The prevalence varies with the living conditions and exposure to mice, and it has been higher in the past due to lower standards of living. The island of Vir in Croatia is one of the biggest described endemic places of origin of LCMV in the world, with IFA testing having found LCMV antibodies in 36% of the population.[27][28] Individuals with the highest risk of infection are laboratory personnel who handle rodents or infected cells.[7] Temperature and time of year is also a critical factor that contributes to the number of LCMV infections, particularly during fall and winter[7] when mice tend to move indoors. Approximately 10–20%[7] of the cases in immunocompetent individuals are thought to progress to neurological disease, mainly as aseptic meningitis. The overall case fatality rate is less than 1%[7] and people with complications, including meningitis, almost always recover completely. Rare cases of meningoencephalitis have also been reported.[7] More severe disease is likely to occur in people who are immunosuppressed.[7]
More than 50 infants with congenital LCMV infection have been reported worldwide.[7] The probability that a woman will become infected after being exposed to rodents, the frequency with which LCMV crosses the placenta, and the likelihood of clinical signs among these infants are still poorly understood. In one study, antibodies to LCMV were detected in 0.8% of normal infants,[7] 2.7% of infants with neurological signs[7] and 30% of infants with hydrocephalus.[7] In Argentina, no congenital LCMV infections were reported among 288 healthy mothers and their infants.[7] However, one study[7] found that two of 95 children in a home for people with severe mental disabilities had been infected with this virus. The prognosis for severely affected infants appears to be poor. In one series, 35% of infants diagnosed with congenital infections had died by the age of 21 months.[7]
Transplant-acquired lymphocytic choriomeningitis proves to have a very high morbidity and mortality rate. In the three clusters reported in the U.S. from 2005 to 2010,[7] nine of the ten infected recipients died.[7] One donor had been infected from a recently acquired pet hamster[7] while the sources of the virus in the other cases were unknown.
## Epidemiology[edit]
LCMV has been isolated from fleas, ticks, cockroaches and Culicoides and Aedes mosquitoes. Ticks, lice and mosquitoes have been shown to transmit this virus mechanically in the laboratory.[7] The presence of LCMV in laboratories may cause serious long-term repercussions to worker safety. In 1989, an outbreak among humans occurred in a US cancer research institute that studied the effects of various therapeutic and diagnostic agents in animal models. Such agents had been developed in the animal care facility, which periodically screened sentinel animals for extraneous infection. Due to an oversight, no sentinel animals were monitored from August 1988 to March 1989. When testing resumed, LCMV antibodies were found in the oldest sentinel hamsters. Several workers reported symptoms consistent with LCMV infection, leading to an investigation. Blood samples were obtained and tested for LCMV antibodies. Of the 82 workers that were tested, seven had definite serologic evidence of past LCMV infection, and two were hospitalized for an acute febrile illness. All seven reported direct contact with the animals at the institute.[21]
An additional hazard associated with LCMV in laboratories misleading experimental results.[21] Interference with research may involve:
[Inhibition of] tumor induction due to polyoma virus, and mammary tumor virus in the mouse, and [interference] with transplantable leukaemia in the guinea pig and the mouse. Infection is associated with depression of cellular immunity in the mouse. Rejection of cutaneous grafts or transplantable tumors may be delayed. In addition, infection will increase the sensitivity of the mouse to ectromelia virus and to bacterial endotoxins.[29]
Reported outbreaks have decreased, perhaps due to improved biohazard management in laboratories. However, it is possible that sporadic cases have been overlooked because of the wide range of clinical presentations. Clare A. Dykewicz, et al. recommend vigilant screening laboratory animals to be used in research facilities either through serum samples or cell line aliquots, as well as ensuring adequate ventilation in housing areas and use of appropriate sanitation products.[21] Other practices to reduce cross-contamination in rodents include washing hands or changing gloves between animal care activities, thoroughly decontaminating cages before reusing them, and avoiding housing healthy rodents in the vicinity of potentially infected rodents.[6]
## Other animals[edit]
Although the house mouse (Mus musculus) is the primary reservoir host for LCMV, it is also often found in the wood mouse (Apodemus sylvaticus) and the yellow-necked mouse (Apodemus flavicollis).[7] Hamster populations can act as reservoir hosts. Other rodents including guinea pigs, rats and chinchillas can be infected but do not appear to maintain the virus.[7] LCMV has been shown to cause illness in New World primates such as macaques, marmosets and tamarins.[7] Infections have also been reported in rabbits, dogs and pigs.[7] After experimental inoculation, the incubation period in adult mice is 5 to 6 days.[7] Congenitally or neonatally infected mice and hamsters do not become symptomatic for several months or longer.[7]
### Mice[edit]
A house mouse Mus musculus
A study conducted by John Hotchin and Heribert Weigand, of the New York State Department of Health, concluded, "The age of the mouse when first exposed to the virus determines its immune response." If LCMV infection occurs in utero or within the first few hours of life, during the immunologically unresponsive period, the mouse will develop immune tolerance. The virus will continue to proliferate for an indefinite time. However, if a mouse is infected after the neonatal period, when the immune system is responsive, the immune response is active. This immunological conflict can result in one of three ways; immunological paralysis, significant or complete suppression of virus with immunity to reinfection, or death. Mice that are infected after the neonatal period often pass through a "runt" stage, which may last for several weeks. Clinical symptoms include excitability, weight loss, and severe retardation of growth and hair development. In general, as the period of time between birth and inoculation decreases, less disease and mortality occurs.[30]
Post mortem lesions in mice show signs of hepatomegaly, splenomegaly, lymphaden opathy, and swollen or shrunken and pitted kidneys due to glomerulonephritis.[7] Histological findings in persistently infected mice often show chronic glomerulonephritis.[7] In these mice, and some hamsters, vasculitis and lymphocytic infiltrates in many organs and tissues including the liver, spleen, lung, kidneys, pancreas, blood vessels, meninges and brain are present.[7]
### Hamsters[edit]
Pathogenesis occurs in the same manner in hamsters as in mice.[31] Symptoms in hamsters are highly variable, and typically indicate that the pet has been infected and shedding the virus for several months. Early signs may include inactivity, loss of appetite, and a rough coat. As the disease progresses, the animal may experience weight loss, hunched posture, inflammation around the eyes, and eventually death. Alternatively, some infected hamsters may be asymptomatic.[32]
### Rats[edit]
Experimental intracerebral infection of suckling rats results in microcephaly, retinitis and the destruction of several brain regions,[7] leading to permanent abnormalities of movement, coordination, vision and behavior.
### Primates[edit]
LCMV causes callitrichid hepatitis[7] in New World primates. The onset of the infection is nonspecific and may include fever, anorexia, dyspnea, weakness and lethargy. Jaundice is characteristic and petechial hemorrhages may develop.[7] Prostration and death usually follow.[7]
Necropsy lesions in primates with callitrichid hepatitis show signs of jaundice, hepatomegaly, splenomegaly, and subcutaneous and intramuscular hemorrhages.[7] Pleural and pericardial effusion, sometimes sanguineous, has also been reported.[7] On histology, multifocal necrosis with acidophilic bodies and mild inflammatory infiltrates are typically found in the liver.[7]
### Diagnosis[edit]
As in humans, the sensitivity of testing methods for rodents contributes to the accuracy of diagnosis. LCMV is typically identified through serology. However, in an endemically infected colony, more practical methods include MAP (mouse antibody production) and PCR testing. Another means of diagnosis is introducing a known naïve adult mouse to the suspect rodent colony. The introduced mouse will seroconvert, allowing use of immunofluorescence antibody (IFA), MFIA or ELISA to detect antibodies.[29]
### Treatment[edit]
Immunosuppressive therapy has been effective in halting the disease for laboratory animals.[31]
### Morbidity and mortality[edit]
LCMV infections are focal[7] Estimates of its prevalence in wild mouse populations range from 0% to 60%, with an average prevalence of 9%.[7] The incidence of LCMV in pet rodents is unknown, yet very few human cases have been associated with exposure to pets.[7] In the transplant-associated cases linked to a pet hamster in 2005, two other hamsters and a guinea pig at the pet shop, and approximately 4%[7] of the hamsters at the distributor, were also infected. Morbidity and mortality rates vary with the species of animal and its age at infection,[7] as well as the strain of the virus and route of exposure. Neonatally and congenitally infected mice remain asymptomatic for many months, but the onset of glomerulonephritis[7] reduces overall life expectancy. The morbidity rate in naturally infected post-neonatal mice is unknown; however, subclinical disease may be the most common form, as few natural outbreaks have been reported.[7] In hamsters, approximately half of all congenitally infected animals[7] clear the virus when they are approximately three months old and remain healthy; the remaining animals develop chronic disease.[7] Hamsters infected as adults usually remain asymptomatic. Callitrichid hepatitis[7] is reported to be highly fatal in naturally infected marmosets and tamarins in zoos. Since 1980, 12 outbreaks with 57 deaths[7] have been reported in the U.S. In experimentally infected rhesusmacaques, three of four animals[7] became fatally ill when inoculation was by the intravenous route. In contrast, inoculation by the intragastric route usually led to asymptomatic infections, with occasional disease and few deaths.[7]
### In pets[edit]
Pet rodents are not known to be natural reservoirs for lymphocytic choriomeningitis virus. However, pets can become vectors if they are exposed to wild house mice in a breeding facility, pet store, or home. Such infections are rare.[32] To date, (January 2017) documented infections in humans have occurred only after introduction to infected mice, guinea pigs, and hamsters, with the majority of cases transmitted by mice. LCMV infection in other animals, including zoo animals, may be possible.[6][22]
In choosing a pet, the CDC advises looking for general indications of health both in the prospective pet and others in the facility. The rodent of choice should be lively and alert, have a glossy coat, breathe normally and have no discharge from eyes or nose. If one of the animals in the facility looks ill, the others may have been exposed, and none of the rodents at that location should be purchased.[32]
Serologic testing is not recommended for pet rodents, as it has been unreliable in detecting antibodies in animals with active infections. For laboratory purposes, immunohistochemistry staining of tissues and virus isolation are used for more accurate testing, but this is unnecessary for the general house pet. The greatest risk of infection to humans occurs shortly after purchase of a pet, so that exposure to the virus, if present, has likely already occurred to existing pet owners. Continued ownership poses negligible additional risk.[6]
The National Center for Infectious Disease suggests the following precautions to reduce the risk of LCMV infection:
* Wash hands with soap and water after handling pet rodents; use waterless alcohol-based hand rubs when soap is not available.
* Keep rodent cages clean and free of soiled bedding.
* Clean the cage in a well-ventilated area or outside.
* Wash hands thoroughly with soap and water after cleaning up pet droppings. Closely supervise young children, especially those less than five years old, when cleaning cages, and make sure they wash their hands immediately after handling rodents and rodent caging or bedding.
* Do not kiss pet rodents or hold them close to your face.[32]
Rodent owners who no longer wish to keep their pet should consult a veterinarian. Pets should not be released into the wild for humane, legal, and ecological reasons. After a rodent has been purchased, it should not be returned to the pet store as it may have been exposed to LCMV through house mice.[5]
## Research[edit]
LCM is the archetypal arenavirus, and was instrumental in research which uncovered the major pathogenetic mechanisms of all arenaviruses.[33]
The field of viral immunology will continue to be uncovered by the model system of LCMV. Specifically, the study of persistent viral infections as well as vaccine development, represent two essential areas.[8] LCMV is already identified as the best model to examine the difference between acute and viral infection in its natural host Mus musculus, the common house mouse. Conveniently, the mouse is also the most widely used genetic model for mammalian genetics. A major phenotypic difference results from only two nucleotide differences[8] between acute LCMV, also known as Armstrong LCMV, and one of its variant, Clone 13, which leads to persistent LCMV infection. One of the nucleotide mutations is in the process of glycoprotein formation and affects tropism.[8] The second base pair mutation affects the polymerase which influences replicative capacity.[8] The mechanism of these mutations and how they confer such a profound physiological difference, acute versus chronic LCMV infection is yet[when?] to be understood.
An important aspect of the present modern society is the thorough understanding of the burden of cancer.[8] In many ways, this disease mirrors persistent viral infection, in the way that it evades and progresses despite the immune system's effort to eliminate it.[8] The LCMV model will be a great path towards advancements in cancer studies. Furthermore, LCMV has been a widely used model system for understanding T cell memory[8] and vaccine synthesis. It was the original model when first studied focused on CD-8 T cells response towards LCMV infection.[8] In addition, a better understanding of CD-4 T cell memory is also a result of studies with LCMV and will continue to contribute to a more efficient mechanism of vaccine formation. Specifically, LCMV has been recently used to quantify the efficiency of a new hydrogen peroxide-based vaccine formation mechanism.[8] The future enhancement of the field of vaccinology will greatly depend on the LCMV model system.
LCMV is a prototype of more severe hemorrhagic fever viruses,[8] especially Lassa virus with the greatest prevalence in sub-Saharan Africa.[8] However, other strains of this virus ( Junin and Machupo viruses)[8] are present in parts of South America and other strains continue to significantly affect the southern African population. Since the modern society continue to become a more inter-connected world, the spread of these virus strains will continue to pose a severe threat around the globe. Understanding the biology of the LCMV model virus will help in advancing the understanding of this important class of viruses and more specifically will give insight into the biology of the Lassa virus which proves to be a growing threat around the world. Furthermore, the United States National Institute for Allergy and Infectious Diseases (NIAID)[8] has appointed the family of arenaviridae to be "Category A Priority Pathogens".[8] This translates to the highest level of importance for the high potential for morbidity and mortality from an infectious agent which is relatively easy to produce and transmit.[8] All in all, the fast advancements in the potential experiments with the LCMV model system will guide future investigators towards the enrichment of biomedical research.
## Footnotes[edit]
1. ^ Beeman op. cit. pp. 305f.
2. ^ Edward A. Beeman: Charles Armstrong, M.D.: A Biography, 2007 pp. 183ff. (also online here (PDF)
3. ^ a b Lasker, Jill S. "Lymphocytic choriomeningitis".
4. ^ "choriomeningitis"
5. ^ a b CDC. "Information for Pet Owners: Reducing the Risk of Becoming Infected with LCMV from Pet Rodents".
6. ^ a b c d e United States. Div of Viral and Rickettsial Diseases, National Center for Infectious Diseases, CDC (August 2005). "Update: interim guidance for minimizing risk for human lymphocytic choriomeningitis virus infection associated with pet rodents". MMWR Morb. Mortal. Wkly. Rep. 54 (32): 799–801. PMID 16107785.
7. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh bi bj bk bl bm bn bo bp bq br The centre for Food Security and Public Health. Institute for International Co-operation and in Animal Biologics. Iowa State University. Ames, Iowa. 2010. http://www.cfsph.iastate.edu/Factsheets/pdfs/lymphocytic_choriomeningitis.pdf
8. ^ a b c d e f g h i j k l m n o p q r s t u v w Zhou X, Ramachandran S, Mann M, Popkin DL (October 2012). "Role of lymphocytic choriomeningitis virus (LCMV) in understanding viral immunology: past, present and future". Viruses. 4 (11): 2650–69. doi:10.3390/v4112650. PMC 3509666. PMID 23202498.
9. ^ a b c d e f Lee, KJ; Novella, IS; Teng, MN; Oldstone, MBA; de la Torre, JC (2000). "NP and L Proteins of Lymphocytic Choriomeningitis Virus (LCMV) Are Sufficient for Efficient Transcription and Replication of LCMV Genomic RNA Analog". Journal of Virology. 74 (8): 3470–7. doi:10.1128/jvi.74.8.3470-3477.2000. PMC 111854. PMID 10729120.
10. ^ [27]
11. ^ a b c d e Swiss Institute of Bioinformatics. Viral Zone "Arenaviridae".
12. ^ Hill, A. Edward (1948). "Benign lymphocytic meningitis". Caribbean Medical Journal. XI (1): 34–7.
13. ^ a b Childs JE, Glass GE, Korch GW, Ksiazek TG, Leduc JW (July 1992). "Lymphocytic choriomeningitis virus infection and house mouse (Mus musculus) distribution in urban Baltimore". Am. J. Trop. Med. Hyg. 47 (1): 27–34. doi:10.4269/ajtmh.1992.47.27. PMID 1636880.
14. ^ a b c d e f g h Jamieson DJ, Kourtis AP, Bell M, Rasmussen SA (June 2006). "Lymphocytic choriomeningitis virus: an emerging obstetric pathogen?". Am. J. Obstet. Gynecol. 194 (6): 1532–6. doi:10.1016/j.ajog.2005.11.040. PMID 16731068.
15. ^ a b CDC. "Lymphocytic choriomeningitis."
16. ^ a b Barton LL, Hyndman NJ (March 2000). "Lymphocytic choriomeningitis virus: reemerging central nervous system pathogen". Pediatrics. 105 (3): E35. doi:10.1542/peds.105.3.e35. PMID 10699137.
17. ^ a b CDC. "Lymphocytic Choriomeningitis Virus (LCMV) and Pregnancy: Facts and Prevention."
18. ^ Emonet S, Retornaz K, Gonzalez JP, de Lamballerie X, Charrel RN (March 2007). "Mouse-to-human transmission of variant lymphocytic choriomeningitis virus". Emerging Infect. Dis. 13 (3): 472–75. doi:10.3201/eid1303.061141. PMC 2725903. PMID 17552104.
19. ^ Transplant patients died from donor's disease—Australian Broadcasting Corporation—Retrieved 7 May 2013.
20. ^ a b Centers for Disease Control and Prevention (July 2008). "Brief report: Lymphocytic choriomeningitis virus transmitted through solid organ transplantation—Massachusetts, 2008". MMWR Morb. Mortal. Wkly. Rep. 57 (29): 799–801. PMID 18650788.
21. ^ a b c d Dykewicz CA, Dato VM, Fisher-Hoch SP, et al. (March 1992). "Lymphocytic choriomeningitis outbreak associated with nude mice in a research institute". JAMA. 267 (10): 1349–53. doi:10.1001/jama.1992.03480100055030. PMID 1740856.
22. ^ a b Craighead, John E. MD. Pathology and Pathogenesis of Human Viral Disease.
23. ^ a b Bauers, Sandy. "House vs. Mouse: The Latest Ideas in Humanely Showing Our Disease-Ridden Fall Visitors the Door."
24. ^ CDC. "Prevent LCMV from wild rodents."p. 1. [1] Archived 10 August 2013 at the Wayback Machine
25. ^ CDC. "Lymphocytic choriomeningitis."
26. ^ Emonet SF, Garidou L, McGavern DB, de la Torre JC (March 2009). "Generation of recombinant lymphocytic choriomeningitis viruses with trisegmented genomes stably expressing two additional genes of interest". Proc. Natl. Acad. Sci. U.S.A. 106 (9): 3473–8. Bibcode:2009PNAS..106.3473E. doi:10.1073/pnas.0900088106. PMC 2651270. PMID 19208813.
27. ^ Kalenić, Smilja (2013). Medicinska mikrobiologija [Medical Microbiology] (in Croatian). Zagreb: Medicinska naklada. ISBN 978-953-176-637-1.
28. ^ Dobec M, Dzelalija B, Punda-Polic V, Zoric I (2006). "High prevalence of antibodies to lymphocytic choriomeningitis virus in a murine typhus endemic region in Croatia". J. Med. Virol. 78 (12): 1643–7. doi:10.1002/jmv.20749. PMID 17063527.
29. ^ a b Charles River Laboratories International. "Lymphocytic Choriomeningitis Virus."
30. ^ Hotchin J, Weigand H (April 1961). "Studies of lymphocytic choriomeningitis in mice. I. The relationship between age at inoculation and outcome of infection". J. Immunol. 86: 392–400. PMID 13716107.
31. ^ a b Vilches, Jose MD ed. Pam Mouser, MD. "Lymphocytic Choriomeningitis."
32. ^ a b c d CDC. "Lymphocytic Choriomeningitis Virus from Pet Rodents."
33. ^ Hotchin J (1977). "Experimental animals and in vitro systems in the study of lymphocytic choriomeningitis virus". Bull. World Health Organ. 55 (5): 599–603. PMC 2366689. PMID 338190.
## References[edit]
* ICTVdB-The Universal Virus Database, version 4. [2]
* Centers for Disease Control and Prevention. Lymphocytic Choriomeningitis Fact Sheet
* CBWInfo (1999). "Safety Precautions for Lymphocytic Choriomeningitis Casualties". Archived from the original on 14 May 2006. Retrieved 11 May 2006.
* "Rodent virus now linked to six deaths—PetSmart in Rhode Island testing animals for rare disease". NBC News. Microsoft. Associated Press. 25 May 2005. Retrieved 11 May 2006.
* "Australian scientists discover new virus". The Age. Fairfax. Australian Associated Press. 22 April 2007. Retrieved 22 April 2007.
* Marrie TJ, Saron MF (January 1998). "Seroprevalence of lymphocytic choriomeningitis virus in Nova Scotia". Am. J. Trop. Med. Hyg. 58 (1): 47–9. doi:10.4269/ajtmh.1998.58.47. PMID 9452291.
* Bauers, Sandy. "House vs. Mouse: The Latest Ideas in Humanely Showing Our Disease-Ridden Fall Visitors the Door." Philadelphia Inquirer 10 Nov. 2006: n.p. Web.
* "choriomeningitis." The American Heritage Medical Dictionary. 2009. Web.
* Craighead, John E. MD. Pathology and Pathogenesis of Human Viral Disease. San Diego, California: Academic, 2000. Print.
* Lasker, Jill S. "Lymphocytic choriomeningitis." The Gale Encyclopedia of Medicine. 2nd ed. 2002. Web.
* "Lymphocytic Choriomeningitis Virus (LCMV)." Centers for Disease Control and Prevention. CDC, n.d. Web. 22 Sept. 2009
* "Lymphocytic Choriomeningitis Virus." Charles River. Charles River Laboratories International, Inc, 2009. Web. 28 Oct 2009.
* "Prevent LCMV from wild rodents." CDC Special Pathogens Branch. CDC. n.d. pdf. 22 Sept. 2009. https://web.archive.org/web/20130810131242/http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/lcmv/prevent.pdf
* United States. National Center for Infectious Diseases. Lymphocytic Choriomeningitis Virus from Pet Rodents. CDC, n.d. Web. 22 Sept. 2009.
* \---. Lymphocytic Choriomeningitis Virus (LCMV) and Pregnancy: Facts and Prevention. CDC, 5 Oct. 2005. Web. 22 Sept. 2009.
* United States. Special Pathogens Branch, Centers for Disease Control and Prevention. Information for Pet Owners: Reducing the Risk of Becoming Infected with LCMV from Pet Rodents. CDC. 6 Sept. 2005. Web. 26 Sept. 2009.
* \---. Lymphocytic choriomeningitis. CDC. 11 October 2007. Web. 26 Sept. 2009.
* Vilches, Jose MD ed. Pam Mouser, MD. "Lymphocytic Choriomeningitis." Animal Disease Diagnostic Laboratory. Animal Disease Diagnostic Laboratory, Purdue University, 2007. Web. 23 September 2009.
* Lee, KJ; Novella, IS; Teng, MN; Oldstone, MBA; de la Torre, JC (2000). "NP and L Proteins of Lymphocytic Choriomeningitis Virus (LCMV) Are Sufficient for Efficient Transcription and Replication of LCMV Genomic RNA Analog". Journal of Virology. 74 (8): 3470–7. doi:10.1128/jvi.74.8.3470-3477.2000. PMC 111854. PMID 10729120.
* Swiss Institute of Bioinformatics. Viral Zone "Arenaviridae"
* Zhou, X; Ramachaundran, S; Mann, M; Popkin, DL (2012). "Role of Lymphocytic Choriomeningitis virus(LCMV) in understanding viral immunology: Past, Present and Future". Viruses. 4 (11): 2650–69. doi:10.3390/v4112650. PMC 3509666. PMID 23202498.
## External links[edit]
* Virus Pathogen Database and Analysis Resource (ViPR): Arenaviridae
## Further reading[edit]
* Palacios, Druce, Du, Tran, Birch, Briese, Conlan, Quan, Hui, Marshall, Simons, Egholm, Paddock, Shieh, Goldsmith, Zaki, Catton, Lipkin (2008). "A New Arenavirus in a Cluster of Fatal Transplant-Associated Diseases". The New England Journal of Medicine. 358 (10): 991–998. doi:10.1056/NEJMoa073785. PMID 18256387.CS1 maint: multiple names: authors list (link)
Classification
D
* ICD-10: A87.2
* ICD-9-CM: 049.0
* MeSH: D008216
* DiseasesDB: 30803
External resources
* eMedicine: med/1350
* v
* t
* e
Infectious diseases – viral systemic diseases
Oncovirus
DNA virus
HBV
Hepatocellular carcinoma
HPV
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Anal cancer
Penile cancer
Vulvar cancer
Vaginal cancer
Oropharyngeal cancer
KSHV
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EBV
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Burkitt's lymphoma
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Follicular dendritic cell sarcoma
Extranodal NK/T-cell lymphoma, nasal type
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HTLV-I
Adult T-cell leukemia/lymphoma
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* Pericarditis
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acute viral
nasopharyngitis/
viral pneumonia
DNA virus
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* EBV infection/Infectious mononucleosis
* Cytomegalovirus
RNA virus
* IV: Human coronavirus 229E/NL63/HKU1/OC43
* Common cold
* MERS coronavirus
* Middle East respiratory syndrome
* SARS coronavirus
* Severe acute respiratory syndrome
* SARS coronavirus 2
* Coronavirus disease 2019
* V, Orthomyxoviridae: Influenza virus A/B/C/D
* Influenza/Avian influenza
* V, Paramyxoviridae: Human parainfluenza viruses
* Parainfluenza
* Human orthopneumovirus
* hMPV
Human
digestive system
Pharynx/Esophagus
* MuV
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* Cytomegalovirus esophagitis
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HEV (E)
HGV (G)
Pancreatitis
* CBV
Urogenital
* BK virus
* MuV
* Mumps
Taxon identifiers
Lymphocytic choriomeningitis mammarenavirus
* Wikidata: Q24719445
* Wikispecies: Lymphocytic choriomeningitis mammarenavirus
* NCBI: 11623
Lymphocytic choriomeningitis virus
* Wikidata: Q19838576
* IRMNG: 11460202
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Lymphocytic choriomeningitis | c0153014 | 2,533 | wikipedia | https://en.wikipedia.org/wiki/Lymphocytic_choriomeningitis | 2021-01-18T18:56:54 | {"mesh": ["D008216"], "umls": ["C0153014"], "wikidata": ["Q1878776"]} |
Cultural belief
Ghost sickness is a cultural belief among some traditional indigenous peoples in North America, notably the Navajo, and some Muscogee and Plains cultures, as well as among Polynesian peoples. People who are preoccupied and/or consumed by the deceased are believed to suffer from ghost sickness. Reported symptoms can include general weakness, loss of appetite, suffocation feelings, recurring nightmares, and a pervasive feeling of terror. The sickness is attributed to ghosts or, occasionally, to witches or witchcraft.[1]
## Contents
* 1 Cultural background
* 2 Cause
* 3 Treatment
* 4 See also
* 5 References
## Cultural background[edit]
In the Muscogee (Creek) culture, it is believed that everyone is a part of an energy called Ibofanga. This energy supposedly results from the flow between mind, body, and spirit. Illness can result from this flow being disrupted. Therefore, their "medicine is used to prevent or treat an obstruction and restore the peaceful flow of energy within a person".[2] Purification rituals for mourning "focus on preventing unnatural or prolonged emotional and physical drain."[2]
The traditional Native American grief resolution process is qualitatively different from those usually seen in mainstream Western cultures. In 1881, there was a federal ban on some of the traditional mourning rituals practised by the Lakota and other tribes. Lakota expert Maria Yellow Horse Brave Heart proposes that the loss of these rituals may have caused the Lakota to be "further predisposed to the development of pathological grief". Some manifestations of unresolved grief include seeking visions of the spirits of deceased relatives, obsessive reminiscing about the deceased, longing for and believing in a reunion with the deceased, fantasies of reappearance of the deceased, and belief in one's ability to project oneself to the past or to the future.[3]
## Cause[edit]
There are a variety of mainstream psychological theories about Ghost Sickness. Putsch states that "Spirits or 'ghosts' may be viewed as being directly or indirectly linked to the cause of an event, accident, or illness".[4] Both Erikson and Macgregor report substantiating evidence of psychological trauma response in ghost sickness, with features including withdrawal and psychic numbing, anxiety and hypervigilance, guilt, identification with ancestral pain and death, and chronic sadness and depression.[5][6][7]
## Treatment[edit]
Religious leaders within the Navajo tribe repeatedly perform ceremonies to eliminate the all-consuming thoughts of the dead.[8]
## See also[edit]
* Complicated grief disorder
## References[edit]
1. ^ Hall, Lena. "Conceptions of Mental Illness: Cultural Perspectives and Treatment Implications". Nova Southeastern University. Archived from the original on August 16, 2013. Retrieved April 1, 2013.
2. ^ a b Walker, Andrea C.; Balk, David E. (2007). "Bereavement Rituals in the Muscogee Creek Tribe". Death Studies. 31 (7): 633–52. doi:10.1080/07481180701405188. PMID 17849603. S2CID 41156151.
3. ^ Brave Heart, Maria Yellow Horse (1998). "The return to the sacred path: Healing the historical trauma and historical unresolved grief response among the Lakota through a psychoeducational group intervention". Smith College Studies in Social Work. 68 (3): 287–305. doi:10.1080/00377319809517532.
4. ^ Putsch, R.W. (2006-2007) Drumlummon Views, retrieved on May 22, 2008
5. ^ Erikson, E. (1959). Identity and the life cycle. Psychological Issues, 7(1). New York: International Universities Press.
6. ^ Macgregor, G. (1975). Warriors without weapons. Chicago: University of Chicago Press. (Original work published 1946)[page needed]
7. ^ Macgregor, G.(1970). Changing society: The Teton Dakotas. InE. Nurge (Ed.),The modern Sioux: Social systems and reservation culture 92-106. Lincoln: University of Nebraska Press.
8. ^ Opler, Morris E.; Bittle, William E. (Winter 1961). "The Death Practices and Eschatology of the Kiowa Apache". Southwestern Journal of Anthropology. 17 (4): 383–94. doi:10.1086/soutjanth.17.4.3628949. JSTOR 3628949.
* v
* t
* e
Ghosts and ghostlore
List of ghosts
Manifestations
* Ancestral spirits
* Haunted locations
* Haunted highways
* Haunted house
* Haunted trains
* Haunted ships
* Hungry ghost
* Phantom vehicle
* Poltergeist
* Residual haunting
* Vengeful ghost
By continent
and culture
African
* South Africa
Asian
* Burmese
* Chinese
* locations
* Ghost Festival
* Tibetan
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* locations
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* locations
* Bengali
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Europe
* France
* Slavic religion
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North America
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* locations
* Day of the Dead
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History
* Mesopotamian
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Parapsychology
* Apparitional experience
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* kaidan
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* Films about ghosts
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* Stories about ghosts
* Halloween
* Samhain
* Paranormal television
Court cases
* Booty v Barnaby
Related
* Fear of ghosts
* Spectrophilia
* Spiritualism
* Spiritism
* The Ghost Club
Category
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Ghost sickness | c0520689 | 2,534 | wikipedia | https://en.wikipedia.org/wiki/Ghost_sickness | 2021-01-18T18:43:12 | {"wikidata": ["Q5557311"]} |
A number sign (#) is used with this entry because of evidence that Meier-Gorlin syndrome-7 (MGORS7) is caused by homozygous or compound heterozygous mutation in the CDC45 gene (603465) on chromosome 22q11.
For a general phenotypic description and a discussion of genetic heterogeneity of Meier-Gorlin syndrome, see 224690.
Clinical Features
Fenwick et al. (2016) studied 15 patients from 12 families with biallelic mutations in the CDC45 gene whose features ranged from syndromic coronal craniosynostosis to severe growth restriction, fulfilling diagnostic criteria for Meier-Gorlin syndrome. There were 10 patients from 8 families who presented with the classic triad of Meier-Gorlin syndrome features, including short stature, microtia, and absent or hypoplastic patellae, but craniosynostosis was also frequent in those patients. The severity of craniosynostosis varied widely, from unilateral or bilateral coronal synostosis to multiple suture involvement, and there was discordance for craniosynostosis in 2 brothers with the same mutation, indicating reduced penetrance for the feature. The remaining 5 patients, who had a primary presentation of craniosynostosis, exhibited mild Meier-Gorlin syndrome features, including hypoplastic ears, mild short stature, and a similar facial gestalt with small mouth. The MGORS feature of patellar hypoplasia, however, was not present in 3 of the 5 patients. Thin eyebrows were observed all 15 patients. Growth failure and microcephaly, evident from birth in almost all patients, were progressive throughout childhood. Anal abnormalities, including imperforate anus or anterior placement, were present in 7 patients from both cohorts.
Molecular Genetics
By whole-genome or exome sequencing in patients with craniosynostosis, Fenwick et al. (2016) identified 2 unrelated patients with syndromic craniosynostosis who were compound heterozygous for mutations in the CDC45 gene (see, e.g., 603465.0001-603465.0004). Screening of CDC45 in a cohort of 467 patients with craniosynostosis revealed 1 more patient with biallelic mutations, and interrogation of exome-sequencing data from 52 patients with primordial dwarfism identified a patient with mutations in CDC45 who had been diagnosed with Meier-Gorlin syndrome. Sequencing of CDC45 in 34 patients with MGORS, who were negative for mutation in known MGORS-associated genes, identified 9 patients from 7 families who were homozygous or compound heterozygous for CDC45 mutations (see, e.g., 603465.0005-603465.0007). In addition, exome sequencing in 2 fetuses from a Dutch family with syndromic craniosynostosis identified a missense variant in CDC45 (A298V; 603465.0008); analysis with MLPA probes revealed deletion of exon 5 of CDC45 on the other allele (603465.0009). The mutations segregated fully with disease in all families for which parental and sib DNA was available for testing.
INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Weight \- Low weight Other \- Growth failure, progressive HEAD & NECK Head \- Craniosynostosis \- Microcephaly, progressive Ears \- Microtia \- Hearing loss Eyes \- Thin eyebrows \- Proptosis \- Strabismus \- Myopia Nose \- Choanal atresia Mouth \- Small mouth \- High palate \- Cleft palate CARDIOVASCULAR Heart \- Atrial septal defect \- Ventricular septal defect \- Atrioventricular canal \- Atrioventricular conduction block RESPIRATORY Lung \- Pulmonary hypoplasia (in 1 patient) CHEST Breasts \- Breast agenesis ABDOMEN Gastrointestinal \- Anterior anus \- Anal stenosis \- Imperforate anus \- Anorectal malformation \- Duodenal stenosis GENITOURINARY External Genitalia (Male) \- Hypospadias \- Micropenis \- Urethral stricture External Genitalia (Female) \- Clitoromegaly Internal Genitalia (Male) \- Undescended testes Ureters \- Vesicoureteral reflux SKELETAL Skull \- Microcephaly, progressive \- Unicoronal or bicoronal craniosynostosis \- Lambdoid or bilateral lambdoid craniosynostosis \- Sagittal craniosynostosis \- Large anterior fontanel \- Copper-beaten appearance of skull Spine \- Scoliosis (in 1 patient) \- C1-C3 fusion (in 1 patient) \- C4-C7 fusion (in 1 patient) \- Thoracic vertebral segmentation defects (in 1 patient) Limbs \- Patellar aplasia/hypoplasia \- Bilateral radial head dislocation \- Bowed legs (in 1 patient) \- Joint laxity (in 1 patient) Hands \- Digital clubbing (in 1 patient) \- Syndactyly of second, third, and fourth fingers, mild (in 1 patient) \- Preaxial polydactyly, bilateral (in 1 patient) Feet \- Syndactyly of second and third toes NEUROLOGIC Central Nervous System \- Developmental delay, mild to severe \- Chiari I malformation (in 1 patient) MOLECULAR BASIS \- Caused by mutation in the cell division cycle 45, S. cerevisiae, homolog-like gene (CDC45L, 603465.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| MEIER-GORLIN SYNDROME 7 | c1868684 | 2,535 | omim | https://www.omim.org/entry/617063 | 2019-09-22T15:47:07 | {"doid": ["0080518"], "mesh": ["C538012"], "omim": ["617063"], "orphanet": ["2554"]} |
ALG12-congenital disorder of glycosylation (ALG12-CDG, also known as congenital disorder of glycosylation type Ig) is an inherited disorder with varying signs and symptoms that can affect several body systems. Individuals with ALG12-CDG typically develop signs and symptoms of the condition during infancy. They may have problems feeding and difficulty growing and gaining weight at the expected rate (failure to thrive). In addition, affected individuals often have intellectual disability, delayed development, and weak muscle tone (hypotonia), and some develop seizures.
Some people with ALG12-CDG have physical abnormalities such as a small head size (microcephaly) and unusual facial features. These features can include folds of skin that cover the inner corners of the eyes (epicanthal folds), a prominent nasal bridge, and abnormally shaped ears. Some males with ALG12-CDG have abnormal genitalia, such as a small penis (micropenis) and undescended testes.
People with ALG12-CDG often produce abnormally low levels of proteins called antibodies (or immunoglobulins), particularly immunoglobulin G (IgG). Antibodies help protect the body against infection by attaching to specific foreign particles and germs, marking them for destruction. A reduction in antibodies can make it difficult for affected individuals to fight infections.
Less common abnormalities seen in people with ALG12-CDG include a weakened heart muscle (cardiomyopathy) and poor bone development, which can lead to skeletal abnormalities.
## Frequency
ALG12-CDG is a rare condition; its prevalence is unknown. Only a handful of affected individuals have been described in the medical literature.
## Causes
Mutations in the ALG12 gene cause ALG12-CDG. This gene provides instructions for making an enzyme that is involved in a process called glycosylation. During this process, complex chains of sugar molecules (oligosaccharides) are added to proteins and fats (lipids). Glycosylation modifies proteins and lipids so they can fully perform their functions. The enzyme produced from the ALG12 gene transfers a simple sugar called mannose to growing oligosaccharides at a particular step in the formation of the sugar chain. Once the correct number of sugar molecules are linked together, the oligosaccharide is attached to a protein or lipid.
ALG12 gene mutations lead to the production of an abnormal enzyme with reduced activity. Without a properly functioning enzyme, mannose cannot be added to the chain efficiently, and the resulting oligosaccharides are often incomplete. Although the short oligosaccharides can be transferred to proteins and fats, the process is not as efficient as with the full-length oligosaccharide. As a result, glycosylation is reduced. The wide variety of signs and symptoms in ALG12-CDG are likely due to impaired glycosylation of proteins and lipids that are needed for normal function of many organs and tissues, including the brain.
### Learn more about the gene associated with ALG12-congenital disorder of glycosylation
* ALG12
## Inheritance Pattern
This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| ALG12-congenital disorder of glycosylation | c2931001 | 2,536 | medlineplus | https://medlineplus.gov/genetics/condition/alg12-congenital-disorder-of-glycosylation/ | 2021-01-27T08:25:00 | {"gard": ["9833", "10307"], "mesh": ["C535745"], "omim": ["607143"], "synonyms": []} |
Idiopathic localized lipodystrophy is a rare, acquired, localized lipodystrophy characterized by asymptomatic, well-demarcated, depressed, lipoatrophic lesions of variable size, with normal overlying skin without antecedent inflammation or a known identifiable cause (autoimmune disease, drug injection, injury, etc).
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Idiopathic localized lipodystrophy | None | 2,537 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=90158 | 2021-01-23T18:20:15 | {"icd-10": ["E88.1"]} |
A number sign (#) is used with this entry because of evidence that neonatal sclerosing cholangitis (NSC) is caused by homozygous or compound heterozygous mutation in the DCDC2 gene (605755) on chromosome 6p22.
Description
Neonatal sclerosing cholangitis is a rare autosomal recessive form of severe liver disease with onset in infancy. Affected infants have jaundice, cholestasis, acholic stools, and progressive liver dysfunction resulting in fibrosis and cirrhosis; most require liver transplantation in the first few decades of life. Cholangiography shows patent biliary ducts, but there are bile duct irregularities (summary by Girard et al., 2016; Grammatikopoulos et al., 2016).
Clinical Features
Girard et al. (2016) reported 4 patients from 2 unrelated consanguineous families with neonatal sclerosing cholangitis. The patients presented with neonatal icterus, cholestasis, acholic stools, and portal hypertension. All were diagnosed with cirrhosis between 2 and 9 months of age. In family 1, the sibs needed liver transplantation at ages 25 and 14 years, respectively, whereas in family 2, 1 sib needed liver transplantation at age 6 years, and the other was on the waiting list at age 3.5 years. Cholangiograms showed patent bile ducts with thin and irregular intrahepatic biliary tree; the patients in family 2 also had extrahepatic bile duct irregularities. Liver biopsy showed cirrhosis and fibrosis. The patients had variable renal involvement: 1 patient had left vesicoureteral reflux with ureteral duplication and a small left kidney, and showed altered renal function after liver transplant associated with septic shock, whereas his sib had normal renal morphology and size, but also developed altered renal function after transplant. In the other family, 1 sib had a hyperechogenic kidney with normal renal function. One of the 4 patients had mild developmental delay; otherwise, none of the patients had additional features, including skin involvement or hearing loss.
Grammatikopoulos et al. (2016) reported 7 patients from 6 unrelated families, 4 of whom were of Greek descent, with neonatal sclerosing cholangitis. The patients presented in the first weeks or years of life (median age of 6 weeks) with jaundice, hepatomegaly, splenomegaly, pale stools, and/or abnormal liver function tests with increased serum GGT (see 612346). Cholangiography confirmed intrahepatic cholangiopathy in all patients. Liver biopsies showed ductular proliferation, portal tract inflammation, and bridging fibrosis, and most patients developed biliary cirrhosis. Other histologic findings included ductal bile plugs, variable ectasia of perihilar bile ducts, absence of bile ducts in areas of fibrosis, and chronic cholestasis. Five patients underwent liver transplantation between 10 and 15 years of age, 1 patient was lost to follow-up at age 6 years, and another died at age 16 years without liver transplantation. Two patients had renal involvement: the patient who died at age 16 without a liver transplant developed end-stage renal disease requiring dialysis before she died, and another patient developed hepatorenal syndrome that resolved after liver transplantation. None of the patients had neurologic involvement or hearing loss.
Inheritance
The transmission pattern of NSC in the families reported by Girard et al. (2016) was consistent with autosomal recessive inheritance.
Molecular Genetics
In 4 patients from 2 unrelated consanguineous families with NSC, Girard et al. (2016) identified 2 different homozygous mutations in the DCDC2 gene (605755.0005 and 605755.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. One was a missense mutation and the other was an in-frame deletion. Patient cells showed loss of DCDC2 immunostaining in the ciliary axoneme of liver cholangiocytes and fewer cilia on cholangiocytes, as well as abnormal accumulation of the mutant protein in the cytoplasm compared to controls.
In 7 patients from 6 unrelated families, many of Greek origin, with NSC, Grammatikopoulos et al. (2016) identified homozygous or compound heterozygous truncating mutations in the DCDC2 gene (see, e.g., 605755.0001; 605755.0002; 605755.0007; 605755.0008). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Parental DNA was only available for 1 patient, but it confirmed segregation of the mutations with the disorder within the family. Patient liver samples showed absence of DCDC2 expression, consistent with a complete loss of function, as well as absence of normally constituted primary cilia in cholangiocytes. The patients were part of a cohort of 12 families with the disorder who underwent whole-exome sequencing; direct sequencing of the DCDC2 gene in 10 patients from 8 additional families did not identify any mutations. Grammatikopoulos et al. (2016) concluded that this disease represents a novel liver-based nonmotile ciliopathy.
INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- No hearing impairment ABDOMEN Liver \- Sclerosing cholangitis \- Hepatomegaly \- Cholestasis \- Portal hypertension \- Irregular bile ducts \- Fibrosis \- Cirrhosis \- Ductal proliferation \- Portal tract inflammation \- Biliary cirrhosis \- Ectasia of perihilar bile ducts \- Absence of bile ducts in area of fibrosis \- Decreased or absent primary cilia on cholangiocytes Spleen \- Splenomegaly Gastrointestinal \- Alcoholic stools \- Pale stools GENITOURINARY Kidneys \- Renal abnormalities (in some patients) \- Renal disease (in some patients) Ureters \- Ureteral abnormalities (in some patients) SKIN, NAILS, & HAIR Skin \- Jaundice \- Pruritis LABORATORY ABNORMALITIES \- Abnormal liver enzymes MISCELLANEOUS \- Onset in infancy \- Progressive disorder \- Most patients require liver transplant in the first or second decades MOLECULAR BASIS \- Caused by mutation in the doublecortin domain-containing protein 2 gene (DCDC2, 605755.0001 ) ▲ 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
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*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
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*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| SCLEROSING CHOLANGITIS, NEONATAL | c4479344 | 2,538 | omim | https://www.omim.org/entry/617394 | 2019-09-22T15:46:02 | {"omim": ["617394"]} |
## Summary
### Clinical characteristics.
Epidermolysis bullosa with pyloric atresia (EB-PA) is characterized by fragility of the skin and mucous membranes, manifested by blistering with little or no trauma; congenital pyloric atresia; and ureteral and renal anomalies (dysplastic/multicystic kidney, hydronephrosis/hydroureter, ureterocele, duplicated renal collecting system, absent bladder). The course of EB-PA is usually severe and often lethal in the neonatal period. Most affected children succumb as neonates; those who survive may have severe blistering with formation of granulation tissue on the skin around the mouth, nose, fingers, and toes, and internally around the trachea. However, some affected individuals have little or no blistering later in life. Additional features shared by EB-PA and the other major forms of EB include congenital localized absence of skin (aplasia cutis congenita) affecting the extremities and/or head, milia, nail dystrophy, scarring alopecia, hypotrichosis, contractures, and dilated cardiomyopathy.
### Diagnosis/testing.
The diagnosis of EB-PA is established in a proband with characteristic clinical findings by molecular genetic testing that identifies biallelic pathogenic variants in one of the genes associated with EB-PA: ITGA6 (~5% of EB-PA), ITGB4 (~80%), or PLEC (~15%). Skin biopsy using transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping can be performed but is no longer the preferred method of diagnosis.
### Management.
Treatment of manifestations: Lance and drain new blisters and dress with three layers (primary: nonadherent; secondary: for stability and protection; tertiary: elastic properties to insure integrity); protect skin from shearing forces; teach caretakers proper handling of infants and children; surgical intervention to correct pyloric atresia; standard treatment for gastroesophageal reflux disease; nutrition consultation to address oral intake and nutritional needs; referral to urology and/or nephrology for renal anomalies and abnormal renal function; tracheostomy when indicated for respiratory failure; psychosocial support, including social services and psychological counseling.
Prevention of primary manifestations: Minimization of new blister formation by wrapping and padding of extremities, use of soft and properly fitted clothing and footwear, avoidance of contact with adhesives and of contact sports and other activities that create friction.
Prevention of secondary complications: Antibiotics and antiseptics to prevent wound infections; attention to fluid and electrolyte balance; additional nutritional support including a feeding gastrostomy when necessary; calcium, vitamin D, zinc, selenium, carnitine, and iron supplements as indicated.
Surveillance: Annual screening for anemia and zinc, vitamin D, and other nutritional deficiencies; periodic echocardiographic screening for dilated cardiomyopathy; bone mineral density scanning for detection of osteopenia and/or osteoporosis.
Agents/circumstances to avoid: Shearing forces on the skin; ordinary medical tape or Band-Aids®; poorly fitting or coarse-textured clothing and footwear.
Pregnancy management: Consider cesarean section to reduce trauma to the skin of an affected fetus during delivery.
### Genetic counseling.
EB-PA is inherited in an autosomal recessive manner. The parents of an affected child are usually obligate heterozygotes (i.e., carriers). Because germline mosaicism and uniparental isodisomy are possible, carrier status of parents needs to be confirmed with molecular genetic testing. At conception, each sib of an affected individual whose parents are both carriers 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 family members at increased risk and prenatal testing or preimplantation genetic testing for pregnancies at increased risk are possible if both pathogenic variants have been identified in the family.
## Diagnosis
### Suggestive Findings
Epidermolysis bullosa with pyloric atresia (EB-PA) should be suspected in newborns with the following clinical features:
* Congenital pyloric atresia with vomiting and abdominal distension resulting from complete obstruction of the gastric outlet. Radiographs reveal that the stomach is distended and filled with air (see Figure 1).
* Fragility of the skin with:
* Blistering with little or no trauma. Blistering may be mild or severe; however, blisters generally heal with no significant scarring.
* Significant oral and mucous membrane involvement
* Large areas of absent skin (aplasia cutis congenital), often with a thin membranous covering, affecting the extremities or head
* Ureteral and renal anomalies, including hydronephrosis, ureterocele, absent bladder, dysplastic kidneys, urinary collecting system/kidney duplication, obstructive uropathy, and glomerulosclerosis
#### Figure 1.
Radiograph of a 36-week gestational-age, one-day-old neonate with EB-PA. Note the single gastric bubble (white arrow).
### Establishing the Diagnosis
The diagnosis of EB-PA is established in a proband by one or both of the following:
* Identification of biallelic pathogenic variants in a gene associated with EB-PA using molecular genetic testing (Table 1)
* Skin biopsy using transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping (See Skin Biopsy.)
Note: Genetic testing is the preferred diagnostic method. Skin biopsy for diagnostic purposes is no longer routinely performed
#### Molecular Genetic Testing
Molecular testing approaches can include use of a multigene panel, more comprehensive genomic testing, and serial single-gene testing.
A multigene panel (including phenotype-focused exome analysis) that includes ITGA6, ITGB4, PLEC, and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
More comprehensive genomic testing including exome sequencing and genome sequencing may also 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.
Serial single-gene testing
* Sequence analysis of ITGB4 may be performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
* If only one no or pathogenic variant in ITGB4 is identified, sequence analysis of PLEC followed by ITGA6 (if only one or no pathogenic variant in PLEC is identified) may be considered next.
### Table 1.
Molecular Genetic Testing Used in Epidermolysis Bullosa with Pyloric Atresia
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Gene 1Proportion of EP-BA Attributed to Pathogenic Variants in Gene 2Proportion of Pathogenic Variants 3 Detectable by Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
ITGA65%5%None reported
ITGB460%~98% 6Rare 7
PLEC15%15%None reported
1\.
See Table A. Genes and Databases for chromosome locus and protein.
2\.
Varki et al [2006]
3\.
See Molecular Genetics for information on allelic variants detected in this gene.
4\.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
5\.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
6\.
50% of persons of Hispanic heritage in the United States have the ITGB4 pathogenic variant p.Cys61Tyr [Varki et al 2006].
7\.
Birnbaum et al [2008], Mencía et al [2016]
#### Skin Biopsy
Examination of a skin biopsy by (1) transmission electron microscopy (TEM) and/or (2) immunofluorescent antibody/antigen mapping is sometimes performed to establish the diagnosis of EB-PA
A punch biopsy that includes the full basement membrane zone is preferred. The biopsy should be taken from the leading edge of a fresh (<12 hours old) blister or from a mechanically induced blister (with a pencil eraser rubbed on the skin). (Older blisters undergo change that may obscure the diagnostic morphology).
Note:
* For TEM
* Specimens must be placed in special fixation medium (e.g., gluteraldehyde) as designated by the laboratory performing the test.
* Formaldehyde-fixed samples cannot be used for electron microscopy.
* For immunofluorescent antibody/antigen mapping
* Specimens should be sent in sterile carrying medium (e.g., Michel's or Zeus’) as specified by the laboratory performing the test.
* Some laboratories prefer flash-frozen tissue.
* In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has the antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific gene products mutated in EB can be assessed.
* Light microscopy is inadequate and unacceptable for the accurate diagnosis of any subtypes of EB.
Transmission electron microscopy (TEM) is used to examine the number and morphology of the basement membrane zone structures – in particular: the number and morphology of anchoring fibrils; the presence of and morphology of hemidesmosomes, anchoring filaments, and keratin intermediate filaments; and the presence of micro-vesicles showing the tissue cleavage plane.
Findings on TEM in EB-PA include the following:
* Cleavage may be within the lamina lucida or just above the hemidesmosomes in the lowest layer of the basal keratinocytes.
* Hemidesmosomes may be reduced in number or dysmorphic [Kunz et al 2000, Jonkman et al 2002, Charlesworth et al 2003, Pasmooij et al 2004].
Immunofluorescent antibody/antigen mapping. Findings include the following:
* Abnormal or absent staining with antibodies to α6β4 integrin in EB-PA and other rare forms of junctional epidermolysis bullosa (JEB) as a result of pathogenic variants in either ITGA6 or ITGB4
* Abnormal or absent staining with antibodies to plectin in EB-PA as a result of PLEC pathogenic variants
Normal staining for other antigens (e.g., collagen VII, laminin 332, keratins 5 and 14) confirms the diagnosis of EB-PA.
Note: Especially in milder forms of EB, indirect immunofluorescent studies are often not sufficient to make the diagnosis because near-normal antigen levels are detected and no cleavage plane is observed. In addition, absence of one hemidesmosomal component (e.g., ITGA6 or ITGB4) may reduce the staining of other hemidesmosomal components as well (e.g., PLEC, COL17). In these cases electron microscopic examination of a skin biopsy must be performed.
## Clinical Characteristics
### Clinical Description
The course of epidermolysis bullosa with pyloric atresia (EB-PA) is usually severe and often lethal in the neonatal period. Most affected children succumb as neonates.
Cutaneous manifestations. Those who survive the neonatal period may have severe blistering with formation of granulation tissue on the skin around the mouth, nose, fingers, and toes, and internally around the trachea. However, some affected individuals have little or no blistering later in life. Many of the findings listed below are present in multiple forms of EB and are not diagnostic of EB-PA.
* Congenital localized absence of skin (aplasia cutis congenita) can be seen in any of the major types of EB and is not a discriminating diagnostic feature of any of these types of EB. Infants with extensive aplasia cutis congenita and blistering or erosions may have fatal infections with sepsis and severe electrolyte imbalance in the first weeks to months of life.
* Milia are small white-topped papules; they are often confused with epidermal cysts.
* Nail dystrophy is defined as changes in size, color, shape, or texture of nails.
* Scarring alopecia is defined as complete loss of scalp hair follicles as a result of scarring and loss of hair follicles.
* Hypotrichosis is defined as reduction in the number of hair follicles in a given area compared to the number of hair follicles in the same area of a normal individual of the same gender.
* Exuberant granulation tissue does not usually appear until the affected child is a few years old and most children with EB-PA do not survive that long.
* Contractures may result from loss of mobility of joints as a result of fibrous tissue scars.
Pyloric atresia may be detected in utero using ultrasound or MRI (see Genetic Counseling, Prenatal Testing and Preimplantation Genetic Testing). Pyloric atresia is evident at birth. It is characterized by vomiting, failure to tolerate any feeding or to pass stool, and a distended abdomen with a large stomach bubble (see Figure 1). Surgical repair of the pyloric atresia is necessary for survival.
Renal and ureteral anomalies can include dysplastic/multicystic kidney, hydronephrosis/hydroureter, acute renal tubular necrosis, obstructive uropathy, ureterocele, duplicated renal collecting system, and absent bladder [Puvabanditsin et al 1997, Kambham et al 2000, Nakano et al 2000, Wallerstein et al 2000, Varki et al 2006, Pfendner et al 2007, Walker et al 2017].
### Genotype-Phenotype Correlations
The forms of EB-PA with the severest cutaneous manifestations are caused by a pathogenic variant on each allele that results in a premature termination codon, although a number of amino acid substitutions also result in a severe phenotype, such as the recurrent ITGB4 variant p.Cys61Tyr, which is common in Hispanic individuals with EB-PA [Varki et al 2006, Masunaga et al 2015, Mutlu et al 2015, Mencía et al 2016, Masunaga et al 2017].
### Penetrance
Pathogenic variants in ITGA6, ITGB4, and PLEC are 100% penetrant in individuals who have biallelic pathogenic variants in the same gene.
### Prevalence
According to the National EB Registry, prevalence of all types of junctional epidermolysis bullosa (JEB) is 0.44 per million in the US population [Fine et al 1999]. Historically, EB-PA was considered a subclass of junctional EB (JEB); however, EB-PA is rare and its prevalence and incidence have not been determined.
Since EB-PA is extremely rare, carrier frequency in the general population is not known; however, it can be conservatively estimated at less than one in 5000 (~10x rarer than Herlitz junctional epidermolysis bullosa [HJEB], the carrier frequency of which is ~1:700).
## Differential Diagnosis
Pyloric atresia. In contrast to pyloric stenosis, which presents insidiously with vomiting, pyloric atresia is present at birth and causes complete obstruction of the gastric outlet. The diagnosis of epidermolysis bullosa with pyloric atresia (EB-PA) should be considered in every neonate with pyloric atresia regardless of the degree of skin blistering.
Epidermolysis bullosa (EB). According to the 2014 classification system, the four major types of EB, caused by pathogenic variants in 18 different genes, are EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler syndrome (KS) [Fine et al 2014]. Classification into major type is based on the location of blistering in relation to the dermal-epidermal junction of skin. Subtypes are predominantly determined by clinical features and supported by molecular diagnosis.
The four major types of EB share easy fragility of the skin (and mucosa in many cases), manifested by blistering with little or no trauma. Although clinical examination is useful in determining the extent of blistering and the presence of oral and other mucous membrane lesions, defining characteristics such as the presence and extent of scarring – especially in young children and neonates ‒ may not be established or significant enough to allow identification of EB type; thus, molecular genetic testing (or less commonly skin biopsy) is usually required to establish the most precise diagnosis. The ability to induce blisters with friction (although the amount of friction can vary) and to enlarge blisters by applying pressure to the blister edge is common to all; mucosal and nail involvement and the presence or absence of milia may not be helpful discriminators.
Post-inflammatory changes, such as those seen in generalized severe EBS (EBS-gen sev), are often mistaken for scarring or mottled pigmentation. Scarring can occur in simplex and junctional EB as a result of infection of erosions or scratching, which further damages the exposed surface. Congenital absence of the skin can be seen in any of the four major types of EB and is not a discriminating diagnostic feature.
Corneal erosions, esophageal strictures, and nail involvement may indicate either DEB or JEB. In milder cases, scarring (especially of the dorsal hands and feet) suggests DEB. Pseudosyndactyly (mitten deformities) resulting from scarring of the hands and feet in older children and adults usually suggests DEB.
Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin that results in nonscarring blisters caused by little or no trauma. The four most common clinical subtypes of EBS range from relatively mild blistering of the hands and feet to more generalized blistering, which can be fatal. Although EB-PA caused by biallelic pathogenic changes in PLEC is classified as a form of EBS, affected individuals are very rare compared to the overwhelming majority of individuals with EB caused by heterozygous (or rarely biallelic) pathogenic variants in KRT5 or KRT14, which encode keratin 5 or 14, respectively. Therefore, the 2014 nomenclature refers to the specific pathogenic variants found in KRT5 or KRT14 (see EBS: Nomenclature).
* In EBS, localized (EBS-loc; previously known as Weber-Cockayne type), blisters are rarely present at birth and may occur on the knees and shins with crawling or on the feet at approximately age 18 months; some individuals manifest the disease in adolescence or early adulthood. Blisters are usually confined to the hands and feet, but can occur anywhere if trauma is significant.
* In EBS, generalized intermediate (EBS-gen intermed; previously known as Koebner type), blisters may be present at birth or develop within the first few months of life. Involvement is more widespread than in EBS-loc, but generally milder than in EBS-gen sev.
* In EBS with mottled pigmentation type (EBS-MP), skin fragility is evident at birth and clinically indistinguishable from EBS-gen sev; over time, progressive brown pigmentation interspersed with depigmented spots develops on the trunk and extremities, the pigmentation disappearing in adult life. Focal palmar and plantar hyperkeratoses may occur.
* In EBS, generalized severe (EBS-gen sev; previously known as Dowling-Meara type), onset is usually at birth; severity varies greatly, both within and among families. Widespread and severe blistering and/or multiple grouped clumps of small blisters are typical and hemorrhagic blisters are common. Improvement occurs during mid- to late childhood. Progressive hyperkeratosis of the palms and soles begins in childhood and may be the major complaint of affected individuals in adult life. Nail dystrophy and milia are common. Both hyperpigmentation and hypopigmentation can occur. Mucosal involvement in EBS-gen sev may interfere with feeding. Blistering can be severe enough to result in neonatal or infant death.
EB caused by pathogenic variants in PLEC. Biallelic and heterozygous pathogenic variants in PLEC, the gene encoding plectin, which is located in the hemidesmosomes of the basement membrane zone of skin and muscle cells, cause cleavage in the basal keratinocyte layer. Hence, these disorders are classified as EBS in the 2014 classification system. In most cases, the associated phenotypes (i.e., EB with muscular dystrophy, EB with pyloric atresia) are more complex:
* EB with muscular dystrophy (EB-MD). See Genetically Related Disorders.
* EB with pyloric atresia (EB-PA) See Clinical Characteristics.
* EB-Ogna. See Genetically Related Disorders.
Junctional EB (JEB) is characterized by fragility of the skin and mucous membranes, manifest by blistering with little or no trauma. Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers, and toes, and internally around the upper airway. Blisters generally heal with no significant scarring. The broad classification of JEB is divided into generalized and localized major subtypes with subordinate phenotypic subtypes. JEB, generalized includes: JEB, generalized severe (JEB-gen sev, formerly Herlitz JEB); JEB, generalized intermediate (JEB-gen intermed); JEB with pyloric atresia (JEB-PA); JEB-late onset (JEB-LO); and JEB with respiratory and renal involvement (JEB-RR).
* In JEB-gen sev, the classic severe form of JEB, blisters are present at birth or become apparent in the neonatal period. Congenital malformations of the urinary tract and bladder may also occur.
* In JEB-gen intermed, the phenotype may be milder with blistering localized to hands, feet, knees, and elbows with or without renal or ureteral involvement. Some individuals never blister after the newborn period.
Additional features shared by JEB and the other major forms of epidermolysis bullosa (EB) include congenital localized absence of skin (aplasia cutis congenita), milia, nail dystrophy, scarring alopecia, hypotrichosis, and joint contractures. Biallelic pathogenic variants in one of the following four genes are known to cause JEB: LAMB3 (70% of all JEB), COL17A1 (12%), LAMC2 (9%), and LAMA3 (9%).
JEB with pyloric atresia has been associated with biallelic pathogenic variants in either α6β4 integrin or plectin; inheritance is autosomal recessive.
Dystrophic EB (DEB). The blister forms below the basement membrane, in the superficial dermis. The basement membrane is attached to the blister roof, resulting in scarring when blisters heal. Pathogenic variants in COL7A1, the gene encoding type VII collagen, have been demonstrated in all forms of DEB, both dominant and recessive [Varki et al 2007].
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with epidermolysis bullosa with pyloric atresia (EB-PA), the following evaluations are recommended, if they were not performed as part of the evaluation that led to the diagnosis:
* Evaluation of the sites of blister formation including skin and oral mucosa
* Tests of renal function including BUN, creatinine, and urinalysis
* Renal ultrasound
* Delineation of involvement of the whole esophagus (with concentration on the upper cervical portion) by barium swallow as needed. Endoscopy can be traumatic and should be avoided if possible.
* Consultation with a clinical geneticist and/or genetic counselor
### Treatment of Manifestations
Skin. New blisters should be lanced and drained to prevent further spread from fluid pressure.
In most cases, dressings for blisters involve three layers:
* A primary nonadherent dressing that does not strip the top layers of the epidermis. Tolerance to different primary layers varies. Primary layers include the following:
* Dressings impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline® gauze, Adaptic®, Xeroform®)
* Nonstick products (e.g., Telfa®, N-terface®)
* Silicone-based products without adhesive (e.g., Mepitel®, Mepilex®)
* Addition of a topical antibiotic or antiseptic such as bacitracin, mupirocin, silver, or honey
* A secondary layer that provides stability for the primary layer and adds padding to allow more activity. Rolls of gauze (e.g., Kerlix® or Conform®) are commonly used.
* A tertiary layer that usually has some elastic properties and ensures the integrity of the dressing (e.g., Coban® or elasticized tube gauze of varying diameters such as Band Net® or Tubifast®).
Gastrointestinal
* Surgical intervention is required to correct pyloric atresia. Many children need medical treatment for gastroesophageal reflux disease.
* Esophageal strictures and webs can be dilated repeatedly to improve swallowing [Azizkhan et al 2007].
* Consultation with a dietitian or nutritionist can be helpful, especially if there is significant mucosal blistering in the mouth preventing adequate oral intake.
Renal. The following are appropriate:
* Referral to an urologist if there are symptoms of difficulty or discomfort with voiding
* Referral to a nephrologist if renal function studies and/or urinalysis are abnormal
Other
* A hoarse cry in an infant should alert the clinician to the possibility of airway obstruction with granulation tissue [Ida et al 2012]. Decisions about tracheostomy should involve the family and take into consideration the medical condition of the infant. Because of the poor prognosis and severe pain and discomfort experienced by these infants, a discussion with the family and hospital ethics committee often helps to determine the type of intervention and comfort care to provide [Yan et al 2007].
* Some children have delays or difficulty walking because of blistering and hyperkeratosis. Appropriate footwear and physical therapy are essential to preserve ambulation.
* Psychosocial support, including social services and psychological counseling, is essential [Lucky et al 2007].
### Prevention of Primary Manifestations
New blister formation can be minimized by wrapping and padding of extremities; use of soft and properly fitted clothing and footwear; and avoidance of: contact with adhesives, contact sports, and other activities that create friction.
### Prevention of Secondary Complications
The most common secondary complication is infection. In addition to wound care, treatment of chronic infection of wounds is a challenge. Many affected individuals become infected with resistant bacteria, most often methicillin-resistant Staphylococcus aureus (MRSA), multidrug resistant Pseudomonas aeruginosa, and Group A beta-hemolytic Streptococci. Both antibiotics and antiseptics need to be employed.
Fluid and electrolyte problems, which can be significant and even life threatening in the neonatal period and in infants with widespread disease, require careful management.
Dilated cardiomyopathy can occur in individuals who survive the neonatal period. The development of dilated cardiomyopathy was associated with nutritional deficiency of carnitine in one study, and it has been postulated that nutritional deficiency of selenium may also contribute [Sidwell et al 2000].
In children who survive the newborn period, nutritional deficiencies must also be addressed when they are identified:
* Calcium and vitamin D replacement for osteopenia and osteoporosis
* Zinc supplementation for wound healing [Mellerio et al 2007]
* Selenium and carnitine replacement for possible prevention of dilated cardiomyopathy
Iron deficiency anemia, a chronic problem, can be treated with oral or intravenous iron infusions and red blood cell transfusions.
### Surveillance
Perform annual screening for iron deficiency anemia with complete blood counts and possibly measurement of serum iron concentration to provide iron supplementation when necessary.
Screen annually for zinc deficiency by measuring serum zinc concentration to provide zinc supplementation when necessary for enhanced wound healing.
Periodic echocardiographic screening to evaluate for the development of dilated cardiomyopathy is appropriate.
Screening with bone mineral density scanning may detect early osteopenia and/ or osteoporosis. No guidelines have been established regarding the age at which this should begin.
### Agents/Circumstances to Avoid
Most persons with EB-PA cannot use ordinary medical tape or Band-Aids®.
Poorly fitting or coarse-textured clothing and footwear should be avoided as they can cause trauma.
In general, activities that traumatize the skin (e.g., hiking, mountain biking, contact sports) should be avoided; affected individuals who are determined to participate in such activities should be encouraged to find creative ways to protect their skin.
### Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Pregnancy Management
Cesarean section is recommended by some obstetricians to reduce trauma to the skin of an affected fetus during delivery.
### Therapies Under Investigation
See Junctional Epidermolysis Bullosa: Management, 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.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Epidermolysis Bullosa with Pyloric Atresia | c1856934 | 2,539 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1157/ | 2021-01-18T21:28:32 | {"mesh": ["C535377"], "synonyms": ["Carmi Syndrome", "EB-PA", "Junctional Epidermolysis Bullosa with Pyloric Atresia", "PA-JEB"]} |
A phenotypic variant of Bartter syndrome presenting antenatally with maternal polyhydramnios, pre-term delivery and postnatally with polyuria, and nephrocalcinosis. Hypokalemic alkalosis, increased levels of plasma renin and aldosterone, low blood pressure and vascular resistance to angiotensin II are characteristically associated. Genotypically they comprise Type 1 and Type 2 Bartter syndrome
## Epidemiology
Prevalence of antenatal Bartter syndrome is not exactly known but it comprises about half the cases of Bartter syndrome.
## Clinical description
Typically, antenatal Bartter syndrome manifests prenatally with maternal polyhydramnios (due to fetal polyuria) usually evident by the end of second trimester, often leading to preterm labour and prematurity. Newborns present with life-threatening polyuria, isosthenuria/hyposthenuria, hyperprostaglandinuria, hypercalciuria and hypokalemic alkalosis. Virtually all patients develop medullary nephrocalcinosis within the first few weeks of life. Patients with type 2 genotype present with a transient hyperkalemic acidosis in the neonatal period; they later manifest with a less severe hypokalemic alkalosis.
## Etiology
Type 1 Bartter syndrome is caused by mutations in the SLC12A1 (15q15-q21) encoding sodium-potassium-chloride co-transporter protein, NKCC2 whereas Type 2 Bartter syndrome is caused by mutations in KCNJ1 (11q24) encoding renal outer medullary potassium channel, ROMK.
## Genetic counseling
The disease is transmitted in an autosomal recessive manner.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Antenatal Bartter syndrome | c1855849 | 2,540 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93604 | 2021-01-23T19:07:44 | {"mesh": ["C537651"], "omim": ["241200", "300971", "601678"], "icd-10": ["E26.8"], "synonyms": ["Bartter syndrome, furosemide type", "Bartter syndrome, furosemide-amiloride type", "Hyperprostaglandin E syndrome"]} |
Biological process of axonal degeneration
Nerve injury
Fluorescent micrographs (100x) of Wallerian degeneration in cut and crushed peripheral nerves. Left column is proximal to the injury, right is distal. A and B: 37 hours post cut. C and D: 40 hours post crush. E and F: 42 hours post cut. G and H: 44 hours post crush.
SpecialtyNeurology
Wallerian degeneration is an active process of degeneration that results when a nerve fiber is cut or crushed and the part of the axon distal to the injury (i.e. farther from the neuron's cell body) degenerates.[1] A related process of dying back or retrograde degeneration known as 'Wallerian-like degeneration' occurs in many neurodegenerative diseases, especially those where axonal transport is impaired such as ALS and Alzheimer's disease.[2] Primary culture studies suggest that a failure to deliver sufficient quantities of the essential axonal protein NMNAT2 is a key initiating event.[3][4]
Wallerian degeneration occurs after axonal injury in both the peripheral nervous system (PNS) and central nervous system (CNS). It occurs in the section of the axon distal to the site of injury and usually begins within 24–36 hours of a lesion. Prior to degeneration, the distal section of the axon tends to remain electrically excitable. After injury, the axonal skeleton disintegrates, and the axonal membrane breaks apart. Axonal degeneration is followed by degradation of the myelin sheath and infiltration by macrophages. The macrophages, accompanied by Schwann cells, serve to clear the debris from the degeneration.[5][6]
Schwann cells respond to loss of axons by extrusion of their myelin sheaths, downregulation of myelin genes, dedifferentiation and proliferation. They finally align in tubes (Büngner bands) and express surface molecules that guide regenerating fibers.[7] Within 4 days of the injury, the distal end of the portion of the nerve fiber proximal to the lesion sends out sprouts towards those tubes and these sprouts are attracted by growth factors produced by Schwann cells in the tubes. If a sprout reaches the tube, it grows into it and advances about 1 mm per day, eventually reaching and reinnervating the target tissue. If the sprouts cannot reach the tube, for instance because the gap is too wide or scar tissue has formed, surgery can help to guide the sprouts into the tubes. Regeneration is efficient in the PNS, with near complete recovery in case of lesions that occur close to the distal nerve terminal. However recovery is hardly observed at all in the spinal cord. One crucial difference is that in the CNS, including the spinal cord, myelin sheaths are produced by oligodendrocytes and not by Schwann cells.
## Contents
* 1 History
* 2 Axonal degeneration
* 3 Myelin clearance
* 3.1 Clearance in PNS
* 3.2 Clearance in CNS
* 4 Regeneration
* 4.1 Schwann cells and endoneural fibroblasts in PNS
* 5 Wallerian degeneration slow
* 5.1 Effects of the WldS mutation
* 6 SARM1
* 7 See also
* 8 References
* 9 External links
## History[edit]
Wallerian degeneration is named after Augustus Volney Waller. Waller experimented on frogs in 1850, by severing their glossopharyngeal and hypoglossal nerves. He then observed the distal nerves from the site of injury, which were separated from their cell bodies in the brain stem.[5] Waller described the disintegration of myelin, which he referred to as "medulla", into separate particles of various sizes. The degenerating axons formed droplets that could be stained, thus allowing for studies of the course of individual nerve fibres.
## Axonal degeneration[edit]
Although most injury responses include a calcium influx signaling to promote resealing of severed parts, axonal injuries initially lead to acute axonal degeneration (AAD), which is rapid separation of the proximal (the part nearer the cell body) and distal ends within 30 minutes of injury.[8] After separation, dystrophic bulb structures form at both terminals and the transected membranes are sealed.[9] A brief latency phase occurs in the distal segment during which it remains electrically excitable and structurally intact.[10] Degeneration follows with swelling of the axolemma, and eventually the formation of bead-like axonal spheroids. The process takes roughly 24 hours in the PNS, and longer in the CNS. The signaling pathways leading to axolemma degeneration are currently poorly understood. However, research has shown that this AAD process is calcium–independent.[11]
Granular disintegration of the axonal cytoskeleton and inner organelles occurs after axolemma degradation. Early changes include accumulation of mitochondria in the paranodal regions at the site of injury. Endoplasmic reticulum degrades and mitochondria swell up and eventually disintegrate. The depolymerization of microtubules occurs and is soon followed by degradation of the neurofilaments and other cytoskeleton components. The disintegration is dependent on Ubiquitin and Calpain proteases (caused by influx of calcium ion), suggesting that axonal degeneration is an active process and not a passive one as previously misunderstood.[12] Thus the axon undergoes complete fragmentation. The rate of degradation is dependent on the type of injury and is also slower in the CNS than in the PNS. Another factor that affects degradation rate is the diameter of the axon: larger axons require a longer time for the cytoskeleton to degrade and thus take a longer time to degenerate.
## Myelin clearance[edit]
Myelin is a phospholipid membrane that wraps around axons to provide them with insulation. It is produced by Schwann cells in the PNS, and by oligodendrocytes in the CNS. Myelin clearance is the next step in Wallerian degeneration following axonal degeneration. The cleaning up of myelin debris is different for PNS and CNS. PNS is much faster and efficient at clearing myelin debris in comparison to CNS, and Schwann cells are the primary cause of this difference. Another key aspect is the change in permeability of the blood-tissue barrier in the two systems. In PNS, the permeability increases throughout the distal stump, but the barrier disruption in CNS is limited to just the site of injury.[11]
### Clearance in PNS[edit]
The response of Schwann cells to axonal injury is rapid. The time period of response is estimated to be prior to the onset of axonal degeneration. Neuregulins are believed to be responsible for the rapid activation. They activate ErbB2 receptors in the Schwann cell microvilli, which results in the activation of the mitogen-activated protein kinase (MAPK).[13] Although MAPK activity is observed, the injury sensing mechanism of Schwann cells is yet to be fully understood. The 'sensing' is followed by decreased synthesis of myelin lipids and eventually stops within 48 hrs. The myelin sheaths separate from the axons at the Schmidt-Lanterman incisures first and then rapidly deteriorate and shorten to form bead-like structures. Schwann cells continue to clear up the myelin debris by degrading their own myelin, phagocytose extracellular myelin and attract macrophages to myelin debris for further phagocytosis.[11] However, the macrophages are not attracted to the region for the first few days; hence the Schwann cells take the major role in myelin cleaning until then.
Schwann cells have been observed to recruit macrophages by release of cytokines and chemokines after sensing of axonal injury. The recruitment of macrophages helps improve the clearing rate of myelin debris. The resident macrophages present in the nerves release further chemokines and cytokines to attract further macrophages. The degenerating nerve also produce macrophage chemotactic molecules. Another source of macrophage recruitment factors is serum. Delayed macrophage recruitment was observed in B-cell deficient mice lacking serum antibodies.[11] These signaling molecules together cause an influx of macrophages, which peaks during the third week after injury. While Schwann cells mediate the initial stage of myelin debris clean up, macrophages come in to finish the job. Macrophages are facilitated by opsonins, which label debris for removal. The 3 major groups found in serum include complement, pentraxins, and antibodies. However, only complement has shown to help in myelin debris phagocytosis.[14]
Murinson et al. (2005)[15] observed that non-myelinated or myelinated Schwann cells in contact with an injured axon enter cell cycle thus leading to proliferation. Observed time duration for Schwann cell divisions were approximately 3 days after injury.[16] Possible sources of proliferation signal are attributed to the ErbB2 receptors and the ErbB3 receptors. This proliferation could further enhance the myelin cleaning rates and plays an essential role in regeneration of axons observed in PNS. Schwann cells emit growth factors that attract new axonal sprouts growing from the proximal stump after complete degeneration of the injured distal stump. This leads to possible reinnervation of the target cell or organ. However, the reinnervation is not necessarily perfect, as possible misleading occurs during reinnervation of the proximal axons to target cells.
### Clearance in CNS[edit]
In comparison to Schwann cells, oligodendrocytes require axon signals to survive. In their developmental stages, oligodendrocytes that fail to make contact to axon and receive axon signals undergo apoptosis.[17]
Experiments in Wallerian degeneration have shown that upon injury oligodendrocytes either undergo programmed cell death or enter a state of rest. Therefore, unlike Schwann cells, oligodendrocytes fail to clean up the myelin sheaths and their debris. In experiments conducted on rats,[18] myelin sheaths were found for up to 22 months. Therefore, CNS rates of myelin sheath clearance are very slow and could possibly be the cause for hindrance in the regeneration capabilities of the CNS axons as no growth factors are available to attract the proximal axons. Another feature that results eventually is Glial scar formation. This further hinders chances for regeneration and reinnervation.
Oligodendrocytes fail to recruit macrophages for debris removal. Macrophage entry in general into CNS site of injury is very slow. In contrast to PNS, Microglia play a vital role in CNS wallerian degeneration. However, their recruitment is slower in comparison to macrophage recruitment in PNS by approximately 3 days. Further, microglia might be activated but hypertrophy, and fail to transform into fully phagocytic cells. Those microglia that do transform, clear out the debris effectively. Differentiating phagocytic microglia can be accomplished by testing for expression of Major histocompatibility complex (MHC) class I and II during wallerian degeneration.[19]The rate of clearance is very slow among microglia in comparison to macrophages. Possible source for variations in clearance rates could include lack of opsonin activity around microglia, and the lack of increased permeability in the blood–brain barrier. The decreased permeability could further hinder macrophage infiltration to the site of injury.[11]
These findings have suggested that the delay in Wallerian degeneration in CNS in comparison to PNS is caused not due to a delay in axonal degeneration, but rather is due to the difference in clearance rates of myelin in CNS and PNS.[20]
## Regeneration[edit]
Regeneration follows degeneration. Regeneration is rapid in PNS, allowing for rates of up to 1 millimeter a day of regrowth.[21] Grafts may also be needed to allow for appropriate reinnervation. It is supported by Schwann cells through growth factors release. CNS regeneration is much slower, and is almost absent in most vertebrate species. The primary cause for this could be the delay in clearing up myelin debris. Myelin debris, present in CNS or PNS, contains several inhibitory factors. The prolonged presence of myelin debris in CNS could possibly hinder the regeneration.[22] An experiment conducted on newts, animals that have fast CNS axon regeneration capabilities, found that Wallerian degeneration of an optic nerve injury took up to 10 to 14 days on average, further suggesting that slow clearance inhibits regeneration.[23]
### Schwann cells and endoneural fibroblasts in PNS[edit]
In healthy nerves, nerve growth factor (NGF) is produced in very small amounts. However, upon injury, NGF mRNA expression increases by five to seven-fold within a period of 14 days. Nerve fibroblasts and Schwann cells play an important role in increased expression of NGF mRNA.[24] Macrophages also stimulate Schwann cells and fibroblasts to produce NGF via macrophage-derived interleukin-1.[25] Other neurotrophic molecules produced by Schwann cells and fibroblasts together include brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, ciliary neurotrophic factor, leukemia inhibitory factor, insulin-like growth factor, and fibroblast growth factor. These factors together create a favorable environment for axonal growth and regeneration.[11] Apart from growth factors, Schwann cells also provide structural guidance to further enhance regeneration. During their proliferation phase, Schwann cells begin to form a line of cells called Bands of Bungner within the basal laminar tube. Axons have been observed to regenerate in close association to these cells.[26] Schwann cells upregulate the production of cell surface adhesion molecule ninjurin further promoting growth.[27] These lines of cell guide the axon regeneration in proper direction. The possible source of error that could result from this is possible mismatching of the target cells as discussed earlier.
Due to lack of such favorable promoting factors in CNS, regeneration is stunted in CNS.
## Wallerian degeneration slow[edit]
Mice belonging to the strain C57BL/Wlds have delayed Wallerian degeneration,[28] and, thus, allow for the study of the roles of various cell types and the underlying cellular and molecular processes. Current understanding of the process has been possible via experimentation on the Wlds strain of mice. The mutation occurred first in mice in Harlan-Olac, a laboratory producing animals the United Kingdom. The Wlds mutation is an autosomal-dominant mutation occurring in the mouse chromosome 4.[29][30] The gene mutation is an 85-kb tandem triplication, occurring naturally. The mutated region contains two associated genes: nicotinamide mononucleotide adenlyl transferase 1 (Nmnat1) and ubiquitination factor e4b (Ube4b). A linker region encoding 18 amino acids is also part of the mutation.[6] The protective effect of the WldS protein has been shown to be due to the NMNAT1 region's NAD+ synthesizing active site.[31]
Although the protein created localizes within the nucleus and is barely detectable in axons, studies suggest that its protective effect is due to its presence in axonal and terminal compartments.[32][33] The protection provided by the WldS protein is intrinsic to the neurons and not surrounding support cells, and is only locally protective of the axon, indicating an intracellular pathway is responsible for mediating Wallerian degeneration.[34][35]
### Effects of the WldS mutation[edit]
The mutation causes no harm to the mouse. The only known effect is that the Wallerian degeneration is delayed by up to three weeks on average after injury of a nerve. At first, it was suspected that the Wlds mutation slows down the macrophage infiltration, but recent studies suggest that the mutation protects axons rather than slowing down the macrophages.[6] The process by which the axonal protection is achieved is poorly understood. However, studies suggest that the Wlds mutation leads to increased NMNAT1 activity, which leads to increased NAD+ synthesis.[31] This in turn activates SIRT1-dependent process within the nucleus, causing changes in gene transcription.[31] NAD+ by itself may provide added axonal protection by increasing the axon's energy resources.[36] More recent work, however, raises doubt that either NMNAT1 or NAD+ can substitute for the full length Wlds gene.[37] These authors demonstrated by both in vitro and in vivo methods that the protective effect of overexpression of NMNAT1 or the addition of NAD+ did not protect axons from degeneration. However, later studies showed that NMNAT1 is protective when combined with an axonal targeting peptide, suggesting that the key to the protection provided by WldS was the combination of NMNAT1's activity and the axonal localization provided by the N-terminal domain of the chimeric protein.[38]
The provided axonal protection delays the onset of Wallerian degeneration. Schwann cell activation should therefore be delayed, as they would not detect axonal degradation signals from ErbB2 receptors. In experiments on Wlds mutated mice, macrophage infiltration was considerably delayed by up to six to eight days.[39] However, once the axonal degradation has begun, degeneration takes its normal course, and, respective of the nervous system, degradation follows at the above-described rates. Possible effects of this late onset are weaker regenerative abilities in the mice. Studies indicate that regeneration may be impaired in WldS mice, but this is likely a result of the environment being unfavorable for regeneration due to the continued existence of the undegenerated distal fiber, whereas normally debris is cleared, making way for new growth.[40]
## SARM1[edit]
Main article: SARM1
The Wallerian degeneration pathway has been further illuminated by the discovery that sterile alpha and TIR motif containing 1 (SARM1) protein plays a central role in the Wallerian degeneration pathway. The gene was first identified in a Drosophila melanogaster mutagenesis screen, and subsequently knockouts of its homologue in mice showed robust protection of transected axons comparable to that of WldS.[41][42]
SARM1 catalyzes the synthesis and hydrolysis of cyclic ADP-ribose (cADPR) from NAD+ to ADP-ribose.[43] SARM1 activation locally triggers a rapid collapse of NAD+ levels in the distal section of the injured axon, which then undergoes degeneration.[44] This collapse in NAD+ levels was later shown to be due to SARM1's TIR domain having intrinsic NAD+ cleavage activity.[45] The SARM1 protein has four domains, a mitochondrial localization signal, an auto-inhibitory N-terminus region consisting of armadillo/HEAT motifs, two sterile alpha motifs responsible for multimerization, and a C-terminus Toll/Interleukin-1 receptor that possesses enzymatic activity.[45] Activation of SARM1 is sufficient to collapse NAD+ levels and initiate the Wallerian degeneration pathway.[44]
The activity of SARM1 helps to explain the protective nature of the survival factor NMNAT2, as NMNAT enzymes have been shown to prevent SARM1-mediated depletion of NAD+.[46] This relationship is further supported by the fact that mice lacking NMNAT2, which are normally not viable, are completely rescued by SARM1 deletion, placing NMNAT2 activity upstream of SARM1.[47] Other pro-degeneration signaling pathways, such as the MAP kinase pathway, have been linked to SARM1 activation. MAPK signaling has been shown to promote the loss of NMNAT2, thereby promoting SARM1 activation, although SARM1 activation also triggers the MAP kinase cascade, indicating some form of feedback loop exists.[48][49] One explanation for the protective effect of the WldS mutation is that the NMNAT1 region, which is normally localized to the soma, substitutes for the labile survival factor NMNAT2 to prevent SARM1 activation when the N-terminal Ube4 region of the WldS protein localizes it to the axon. The fact that the enhanced survival of WldS axons is due to the slower turnover of WldS compared to NMNAT2 also helps explain why SARM1 knockout confers longer protection, as SARM1 will be completely inactive regardless of inhibitor activity whereas WldS will eventually be degraded. Possibles implications of the SARM1 pathway in regard to human health may be found in animal models which exhibit traumatic brain injury, as mice which contain Sarm1 deletions in addition to WldS show decreased axonal damage following injury. [50] Specific mutations in NMNAT2 have linked the Wallerian degeneration mechanism to two neurological diseases.
## See also[edit]
* Axonotmesis
* Connective tissue in the peripheral nervous system
* Diffuse axonal injury
* Digestion chambers
* Nerve injury
* Neuroregeneration
* Peripheral nerve injury
* Primary and secondary brain injury
* Seddon's classification
* Spinal cord injury research
## References[edit]
1. ^ Trauma and Wallerian Degeneration, University of California, San Francisco
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3. ^ Gilley J, Coleman MP (January 2010). "Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons". PLOS Biology. 8 (1): e1000300. doi:10.1371/journal.pbio.1000300. PMC 2811159. PMID 20126265.
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5. ^ a b Waller A (1 January 1850). "Experiments on the Section of the Glossopharyngeal and Hypoglossal Nerves of the Frog, and Observations of the Alterations Produced Thereby in the Structure of Their Primitive Fibres". Philosophical Transactions of the Royal Society of London. 140: 423–429. doi:10.1098/rstl.1850.0021. JSTOR 108444.
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25. ^ Lindholm D, Heumann R, Hengerer B, Thoenen H (November 1988). "Interleukin 1 increases stability and transcription of mRNA encoding nerve growth factor in cultured rat fibroblasts". The Journal of Biological Chemistry. 263 (31): 16348–51. PMID 3263368.
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28. ^ Perry VH, Brown MC, Tsao JW (1 October 1992). "The Effectiveness of the Gene Which Slows the Rate of Wallerian Degeneration in C57BL/Ola Mice Declines With Age". The European Journal of Neuroscience. 4 (10): 1000–2. doi:10.1111/j.1460-9568.1992.tb00126.x. PMID 12106435.
29. ^ Perry, V. H., Lunn, E. R., Brown, M. C., Cahusac, S. and Gordon, S. (1990), Evidence that the Rate of Wallerian Degeneration is Controlled by a Single Autosomal Dominant Gene. European Journal of Neuroscience, 2: 408-413. https://doi.org/10.1111/j.1460-9568.1990.tb00433.x
30. ^ Lyon MF, Ogunkolade BW, Brown MC, Atherton DJ, Perry VH (October 1993). "A gene affecting Wallerian nerve degeneration maps distally on mouse chromosome 4". Proceedings of the National Academy of Sciences of the United States of America. 90 (20): 9717–20. Bibcode:1993PNAS...90.9717L. doi:10.1073/pnas.90.20.9717. PMC 47641. PMID 8415768.
31. ^ a b c Araki T, Sasaki Y, Milbrandt J (August 2004). "Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration". Science. 305 (5686): 1010–3. Bibcode:2004Sci...305.1010A. doi:10.1126/science.1098014. PMID 15310905.
32. ^ Mack TG, Reiner M, Beirowski B, Mi W, Emanuelli M, Wagner D, Thomson D, Gillingwater T, Court F, Conforti L, Fernando FS, Tarlton A, Andressen C, Addicks K, Magni G, Ribchester RR, Perry VH, Coleman MP (December 2001). "Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene". Nature Neuroscience. 4 (12): 1199–206. doi:10.1038/nn770. hdl:1842/737. PMID 11770485. S2CID 8316115.
33. ^ Beirowski B, Babetto E, Gilley J, Mazzola F, Conforti L, Janeckova L, Magni G, Ribchester RR, Coleman MP (January 2009). "Non-nuclear Wld(S) determines its neuroprotective efficacy for axons and synapses in vivo". The Journal of Neuroscience. 29 (3): 653–68. doi:10.1523/JNEUROSCI.3814-08.2009. PMC 6665162. PMID 19158292.
34. ^ Glass JD, Brushart TM, George EB, Griffin JW (May 1993). "Prolonged survival of transected nerve fibres in C57BL/Ola mice is an intrinsic characteristic of the axon". Journal of Neurocytology. 22 (5): 311–21. doi:10.1007/BF01195555. PMID 8315413. S2CID 45871975.
35. ^ Adalbert R, Nógrádi A, Szabó A, Coleman MP (October 2006). "The slow Wallerian degeneration gene in vivo protects motor axons but not their cell bodies after avulsion and neonatal axotomy". The European Journal of Neuroscience. 24 (8): 2163–8. doi:10.1111/j.1460-9568.2006.05103.x. PMID 17074042.
36. ^ Wang J, Zhai Q, Chen Y, Lin E, Gu W, McBurney MW, He Z (August 2005). "A local mechanism mediates NAD-dependent protection of axon degeneration". The Journal of Cell Biology. 170 (3): 349–55. doi:10.1083/jcb.200504028. PMC 2171458. PMID 16043516.
37. ^ Conforti L, Fang G, Beirowski B, Wang MS, Sorci L, Asress S, Adalbert R, Silva A, Bridge K, Huang XP, Magni G, Glass JD, Coleman MP (January 2007). "NAD(+) and axon degeneration revisited: Nmnat1 cannot substitute for Wld(S) to delay Wallerian degeneration". Cell Death and Differentiation. 14 (1): 116–27. doi:10.1038/sj.cdd.4401944. PMID 16645633.
38. ^ Babetto E, Beirowski B, Janeckova L, Brown R, Gilley J, Thomson D, Ribchester RR, Coleman MP (October 2010). "Targeting NMNAT1 to axons and synapses transforms its neuroprotective potency in vivo". The Journal of Neuroscience. 30 (40): 13291–304. doi:10.1523/JNEUROSCI.1189-10.2010. PMC 6634738. PMID 20926655.
39. ^ Fujiki M, Zhang Z, Guth L, Steward O (July 1996). "Genetic influences on cellular reactions to spinal cord injury: activation of macrophages/microglia and astrocytes is delayed in mice carrying a mutation (WldS) that causes delayed Wallerian degeneration". The Journal of Comparative Neurology. 371 (3): 469–84. doi:10.1002/(SICI)1096-9861(19960729)371:3<469::AID-CNE9>3.0.CO;2-0. PMID 8842900.
40. ^ Brown MC, Perry VH, Hunt SP, Lapper SR (March 1994). "Further studies on motor and sensory nerve regeneration in mice with delayed Wallerian degeneration". The European Journal of Neuroscience. 6 (3): 420–8. doi:10.1111/j.1460-9568.1994.tb00285.x. PMID 8019679.
41. ^ Osterloh JM, Yang J, Rooney TM, Fox AN, Adalbert R, Powell EH, Sheehan AE, Avery MA, Hackett R, Logan MA, MacDonald JM, Ziegenfuss JS, Milde S, Hou YJ, Nathan C, Ding A, Brown RH, Conforti L, Coleman M, Tessier-Lavigne M, Züchner S, Freeman MR (July 2012). "dSarm/Sarm1 is required for activation of an injury-induced axon death pathway". Science. 337 (6093): 481–4. Bibcode:2012Sci...337..481O. doi:10.1126/science.1223899. PMC 5225956. PMID 22678360.
42. ^ Gerdts J, Summers DW, Sasaki Y, DiAntonio A, Milbrandt J (August 2013). "Sarm1-mediated axon degeneration requires both SAM and TIR interactions". The Journal of Neuroscience. 33 (33): 13569–80. doi:10.1523/JNEUROSCI.1197-13.2013. PMC 3742939. PMID 23946415.
43. ^ Lee HC, Zhao YJ (2019). "Resolving the topological enigma in Ca 2+ signaling by cyclic ADP-ribose and NAADP". Journal of Biological Chemistry. 294 (52): 19831–19843. doi:10.1074/jbc.REV119.009635. PMC 6937575. PMID 31672920.
44. ^ a b Gerdts J, Brace EJ, Sasaki Y, DiAntonio A, Milbrandt J (April 2015). "SARM1 activation triggers axon degeneration locally via NAD⁺ destruction". Science. 348 (6233): 453–7. Bibcode:2015Sci...348..453G. doi:10.1126/science.1258366. PMC 4513950. PMID 25908823.
45. ^ a b Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J (March 2017). "+ Cleavage Activity that Promotes Pathological Axonal Degeneration". Neuron. 93 (6): 1334–1343.e5. doi:10.1016/j.neuron.2017.02.022. PMC 6284238. PMID 28334607.
46. ^ Sasaki Y, Nakagawa T, Mao X, DiAntonio A, Milbrandt J (October 2016). "+ depletion". eLife. 5. doi:10.7554/eLife.19749. PMC 5063586. PMID 27735788.
47. ^ Gilley J, Ribchester RR, Coleman MP (October 2017). "S, Confers Lifelong Rescue in a Mouse Model of Severe Axonopathy". Cell Reports. 21 (1): 10–16. doi:10.1016/j.celrep.2017.09.027. PMC 5640801. PMID 28978465.
48. ^ Yang J, Wu Z, Renier N, Simon DJ, Uryu K, Park DS, Greer PA, Tournier C, Davis RJ, Tessier-Lavigne M (January 2015). "Pathological axonal death through a MAPK cascade that triggers a local energy deficit". Cell. 160 (1–2): 161–76. doi:10.1016/j.cell.2014.11.053. PMC 4306654. PMID 25594179.
49. ^ Walker LJ, Summers DW, Sasaki Y, Brace EJ, Milbrandt J, DiAntonio A (January 2017). "MAPK signaling promotes axonal degeneration by speeding the turnover of the axonal maintenance factor NMNAT2". eLife. 6. doi:10.7554/eLife.22540. PMC 5241118. PMID 28095293.
50. ^ Henninger N, et al. (2016). "Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1". Brain. 139 (4): 1094–1105. doi:10.1093/brain/aww001. PMC 5006226. PMID 26912636.
## External links[edit]
Classification
D
* ICD-10: G58.8
* MeSH: D014855
* Wallerian+Degeneration at the US National Library of Medicine Medical Subject Headings (MeSH)
* v
* t
* e
Physiology of the nervous system
Primarily CNS
* Arousal
* Wakefulness
* Intracranial pressure
* Lateralization of brain function
* Sleep
* Memory
Primarily PNS
* Reflex
* Sensation
Both
Evoked potential
* Bereitschaftspotential
* P300
* Auditory evoked potential
* Somatosensory evoked potentials
* Visual evoked potential
Other short term
* Neurotransmission
* Chronaxie
* Membrane potential
* Action potential
* Postsynaptic potential
* Excitatory
* Inhibitory
Long term
* Axoplasmic transport
* Neuroregeneration/Nerve regeneration
* Neuroplasticity/Synaptic plasticity
* Long-term potentiation
* Long-term depression
Other
* Myelinogenesis
* v
* t
* e
Neurotrauma
Traumatic brain injury
* Intracranial hemorrhage
* Intra-axial
* Intraparenchymal hemorrhage
* Intraventricular hemorrhage
* Extra-axial
* Subdural hematoma
* Epidural hematoma
* Subarachnoid hemorrhage
* Brain herniation
* Cerebral contusion
* Cerebral laceration
* Concussion
* Post-concussion syndrome
* Second-impact syndrome
* Dementia pugilistica
* Chronic traumatic encephalopathy
* Diffuse axonal injury
* Abusive head trauma
* Penetrating head injury
Spinal cord injury
* Anterior spinal artery syndrome
* Brown-Séquard syndrome
* Cauda equina syndrome
* Central cord syndrome
* Paraplegia
* Posterior cord syndrome
* Spinal cord injury without radiographic abnormality
* Tetraplegia (Quadriplegia)
Peripheral nerves
* Nerve injury
* Peripheral nerve injury
* classification
* Wallerian degeneration
* Injury of accessory nerve
* Brachial plexus injury
* Traumatic neuroma
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Wallerian degeneration | c0043020 | 2,541 | wikipedia | https://en.wikipedia.org/wiki/Wallerian_degeneration | 2021-01-18T18:42:12 | {"gard": ["7875"], "mesh": ["D014855"], "wikidata": ["Q1753825"]} |
Dubowitz syndrome is a very rare genetic and developmental disorder with a broad range of signs and symptoms. The typical findings of Dubowitz syndrome include growth failure/short stature, characteristic facial features such as a small triangular face, high sloping forehead, drooping eyelid (ptosis), short eyelids, increased distance between eyes (hypertelorism) broad and flat nasal bridge with a prominent and rounded nasal tip, smaller than normal head (microcephaly), intellectual disability, and eczema, especially on the face and behind the knees. Other common findings are behavioral disorders (hyperactivity, and/or autistic features), speech alterations, scanty or absent hair, foot abnormalities, delayed bone age, bone defects of the lower part of the spine (sacrum and coccyx), testicles that are still not located in the scrotum (cryptorchidism), memory and / or learning problems. There may be an increased risk of having cancer such as leukemia, or lymphoma.
The diagnosis is made based on the symptoms (specially the facial features), but there is no specific laboratory test. The cause is still unknown, but, some people who are diagnosed with the syndrome may have variants (mutations) in the NSUN2 and LIG4 genes, or have loss or gain of microscopic material in some chromosomes (chromosomal microdeletions or microduplications).
Although there is no specific treatment or cure, there are ways to control the symptoms. Often a team of doctors is needed to determine the treatment options for each person.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Dubowitz syndrome | c0175691 | 2,542 | gard | https://rarediseases.info.nih.gov/diseases/6290/dubowitz-syndrome | 2021-01-18T18:00:49 | {"mesh": ["C535718"], "omim": ["223370"], "umls": ["C0175691"], "orphanet": ["235"], "synonyms": ["Intrauterine growth retardation, short stature, microcephaly, mild mental retardation with behavior problems, eczema, and unusual and distinctive faci", "Dwarfism-eczema-peculiar facies syndrome"]} |
A number sign (#) is used with this entry because of evidence that mullerian aplasia and hyperandrogenism can be caused by heterozygous mutation in the WNT4 gene (603490) on chromosome 1p36.
Clinical Features
Biason-Lauber et al. (2004) reported an 18-year-old 46,XX woman, referred for evaluation of primary amenorrhea, who on examination had normal height and weight, acne, Tanner stage 5 pubic hair and breasts with a clitoris of normal size, and a small, short vaginal introitus. Serum androstenedione and dehydroepiandrosterone levels were elevated, and total and free testosterone levels were repeatedly slightly elevated, but levels of LH, FSH, and other sex hormones were all normal. Abdominopelvic MRI revealed that the vagina and uterus were absent, both ovaries were of normal size but ectopic (retroperitoneal), and the right kidney was aplastic with compensatory hypertrophy of the left kidney. The authors noted that this phenotype resembled that of patients with the Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH syndrome; 277000), and was strikingly similar to that of Wnt4 (603490)-knockout female mice.
Biason-Lauber et al. (2007) described a 19.5-year-old 46,XX woman who was referred for primary amenorrhea and dysmorphic features. She was obese and short, and had an abnormal anterior hairline, bushy eyebrows and synophrys, short philtrum, high palate, prominent ears, short neck, brachydactyly, cubitus valgus, and broad chest. Signs of androgen excess were present, including acne on the forehead and chest and mild facial hirsutism. The clitoral size was normal, but the vaginal introitus was small and short. Her total testosterone was repeatedly elevated, but other hormone levels, including androstenedione and dehydroepiandrosterone, were normal. Pelvic ultrasonography revealed uterine agenesis and normal-sized but ectopic ovaries, with a pattern of solid tissue on the left gonad that had no apparent follicular structure, and kidneys of normal size and location.
Philibert et al. (2008) studied a 16-year-old 46,XX girl who presented with primary amenorrhea and clinical hyperandrogenism, with microcystic acne of the face, back, and chest and Tanner IV pubertal development. Hormone analysis showed a high normal testosterone level, slightly elevated androstenedione, and normal dehydroepiandrosterone and 17-alpha-hydroxyprogesterone. The LHRH stimulation test showed an increased LH response, whereas the FSH response was only slightly elevated. Pelvic ultrasonography revealed a hypoplastic uterus, normal left ovary and a 'subnormal' right ovary, with no visible ovarian follicles. At surgery, the fallopian tubes were present but covered with fibrous tissue, and the ovaries were whitish and dystrophic; biopsy of the left ovary revealed only a few follicles.
Molecular Genetics
In an 18-year-old woman with mullerian duct regression, unilateral renal agenesis, and virilization, who was negative for mutation in TCF2 (see 189907.0002), Biason-Lauber et al. (2004) identified a heterozygous missense mutation in the WNT4 gene (E226G; 603490.0001) The mutation was not found in her unaffected mother or sister or in 100 controls; the father was unavailable for study.
In a 19.5-year-old woman with absence of mullerian duct derivatives and clinical and biochemical androgen excess, who was negative for mutation in the TCF2 gene, Biason-Lauber et al. (2007) identified heterozygosity for a missense mutation in the WNT4 gene (R83C; 603490.0003). The mutation was not found in her unaffected mother, sibs, or 100 controls. No mutations in the TCF2 or WNT4 genes were identified in 5 additional patients with varying degrees of mullerian abnormalities but no hyperandrogenism (see MRKH, 277000).
In a 16-year-old girl with uterine hypoplasia, follicle depletion, and hyperandrogenism, Philibert et al. (2008) identified heterozygosity for a missense mutation in the WNT4 gene (L12P; 603490.0004). The mutation was not found in 27 additional adolescent girls with primary amenorrhea, XX karyotype, and mullerian duct abnormalities without hyperandrogenism, or in 100 ethnically matched female controls.
INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Hirsutism GENITOURINARY External Genitalia (Female) \- Normal external genitalia Internal Genitalia (Female) \- Aplasia of Mullerian duct derivatives \- Dysgenesis of Mullerian duct derivatives \- Absent or rudimentary vagina \- Absent or rudimentary uterus \- Functional ovaries Kidneys \- Unilateral renal aplasia (rare) SKIN, NAILS, & HAIR Skin \- Acne Hair \- Hirsutism ENDOCRINE FEATURES \- Hyperandrogenism \- Amenorrhea, primary LABORATORY ABNORMALITIES \- Elevated testosterone \- Elevated androstenedione MISCELLANEOUS \- Normal female secondary sexual characteristics MOLECULAR BASIS \- Caused by mutation in the wingless-type MMTV integration site family, member 4 gene (WNT4, 603490.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| MULLERIAN APLASIA AND HYPERANDROGENISM | c2675014 | 2,543 | omim | https://www.omim.org/entry/158330 | 2019-09-22T16:37:59 | {"mesh": ["C567186"], "omim": ["158330"], "orphanet": ["247768"], "synonyms": ["Alternative titles", "MULLERIAN DUCT FAILURE AND HYPERANDROGENISM"]} |
Crouzon syndrome with acanthosis nigricans (CAN) is a very rare, clinically heterogeneous form of faciocraniostenosis with Crouzon-like features and premature synostosis of cranial sutures (Crouzon disease, see this term), associated with acanthosis nigricans (AN; see this term).
## Epidemiology
CAN has an estimated prevalence of 1/1,000,000 newborns. Fewer than 70 cases have been described in the medical literature. A female-to-male sex ratio of 2.4:1 has been reported.
## Clinical description
All patients have congenital craniofacial abnormalities consistent with classic Crouzon syndrome including craniosynostosis, midface hypoplasia, shallow orbits with exophthalmos, down-slanting palpebral fissures and hypertelorism, maxillary hypoplasia with convex nose and posteriorly angulated ears. The synostosis usually involves the coronal sutures. Cases of cloverleaf skull have also been reported. Patients also develop velvety hyperpigmented skin (AN) within the first decade of life, found primarily in body folds such as the neck, axillae, eyelids, and the perioral, inguinal and perianal areas. The skin disorder is sometimes widespread and develops early compared to classic AN. Craniovertebral junction and vertebral anomalies such as mild alterations of the interpediculate distances of the distal vertebral column are subtle and inconstant. Choanal atresia or stenosis is often present (41%), and is considered highly suggestive of CAN. Other commonly reported signs include hydrocephalus (43%), oral abnormalities such as cleft palate (see this term), dental malocclusion, cementomas of the jaw (34%), and melanocytic nevi (25%). Kidney involvement has also been reported. Some of these specific features are rare in patients with classic Crouzon syndrome. Intellectual disability, hearing loss and speech delay are uncommon. The severity is the same in affected males and females.
## Etiology
CAN is caused by a specific p.Ala391Glu mutation in the fibroblast growth-factor receptor 3 FGFR3 gene (4p16.3), involved in regulation of cell proliferation, differentiation and apoptosis. AN is associated with inadequate stimulation of various fibroblast growth-factor receptors.
## Genetic counseling
Most cases are sporadic, associated with paternal aging, although familial cases consistent with autosomal dominant inheritance have been reported.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Crouzon syndrome-acanthosis nigricans syndrome | c2677099 | 2,544 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93262 | 2021-01-23T16:55:36 | {"mesh": ["C567382"], "omim": ["612247"], "umls": ["C2677099"], "icd-10": ["Q75.1"], "synonyms": ["Crouzon-dermoskeletal syndrome"]} |
A number sign (#) is used with this entry because of evidence that Joubert syndrome-28 (JBTS28) is caused by homozygous or compound heterozygous mutation in the MKS1 gene (609883) on chromosome 17q22.
For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300.
Clinical Features
Romani et al. (2014) reported 2 unrelated patients, a 44-year-old man (COR340) and a 2-year-old child (COR413), with a relatively mild form of Joubert syndrome. Both had developmental delay, oculomotor abnormalities such as nystagmus or oculomotor apraxia, hypotonia and/or ataxia, and the molar tooth sign on brain imaging. In the text, patient COR413 was reported to have normal intellectual abilities, but in Table 1, patient COR413 was noted to have intellectual disability. The 44-year-old man had retinal dystrophy and intellectual disability, but other organ systems were not involved in either case.
Inheritance
The transmission pattern of JBTS28 in the families reported by Romani et al. (2014) was consistent with autosomal recessive inheritance.
Molecular Genetics
In 2 unrelated individuals with JBTS28, Romani et al. (2014) identified biallelic mutations in the MKS1 gene (609883.0010-609883.0012). The mutations segregated with the disorder in the families and were not found in public databases. Functional studies of the variants and studies of patient cells were not performed. The patients were part of a group of 260 JBTS patients who were screened for mutations in ciliopathy genes.
INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Nystagmus \- Oculomotor apraxia \- Retinopathy (1 patient) MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed development \- Intellectual disability (in 1 patient) \- Ataxia \- Molar tooth sign seen on MRI MISCELLANEOUS \- Two unrelated patients have been reported (last curated September 2016) MOLECULAR BASIS \- Caused by mutation in the MKS1 gene (MKS, 609883.0010 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| JOUBERT SYNDROME 28 | c4310705 | 2,545 | omim | https://www.omim.org/entry/617121 | 2019-09-22T15:46:51 | {"doid": ["0110997"], "omim": ["617121", "213300"], "orphanet": ["475", "220493"], "synonyms": ["Cerebelloparenchymal disorder IV", "JS-O", "Classic Joubert syndrome", "Joubert-Boltshauser syndrome", "Joubert syndrome type A", "CPD IV", "Pure Joubert syndrome", "Joubert syndrome with retinopathy"], "genereviews": ["NBK1325"]} |
Tabes dorsalis
Other namesSyphilitic myelopathy
Axial section of the spinal cord showing syphilitic destruction (whitened area, upper center) of the posterior columns which carry sensory information from the body to the brain
SpecialtyNeurology
Tabes dorsalis is a late consequence of neurosyphilis, characterized by the slow degeneration (specifically, demyelination) of the neural tracts primarily in the dorsal root ganglia of the spinal cord (nerve root). These patients have lancinating nerve root pain which is aggravated by coughing, and features of sensory ataxia with ocular involvement.
## Contents
* 1 Signs and symptoms
* 2 Cause
* 3 Treatment
* 4 Prognosis
* 5 Epidemiology
* 6 History
* 7 Notable patients
* 8 See also
* 9 References
* 10 External links
## Signs and symptoms[edit]
Signs and symptoms may not appear for decades after the initial infection and include weakness, diminished reflexes, paresthesias (shooting and burning pains, pricking sensations, and formication), hypoesthesias (abnormally diminished cutaneous, especially tactile, sensory modalities), tabetic gait (locomotor ataxia), progressive degeneration of the joints, loss of coordination, episodes of intense pain and disturbed sensation (including glossodynia), personality changes, urinary incontinence, dementia, deafness, visual impairment, positive Romberg's test, and impaired response to light (Argyll Robertson pupil). The skeletal musculature is hypotonic due to destruction of the sensory limb of the spindle reflex. The deep tendon reflexes are also diminished or absent; for example, the "knee jerk" or patellar reflex may be lacking (Westphal's sign). A complication of tabes dorsalis can be transient neuralgic paroxysmal pain affecting the eyes and the ophthalmic areas, previously called "Pel's crises" after Dutch physician P.K. Pel. Now more commonly called "tabetic ocular crises", an attack is characterized by sudden, intense eye pain, tearing of the eyes and sensitivity to light.[1][2]
"Tabes dorsalgia" is a related lancinating back pain.[citation needed]
"Tabetic gait" is a characteristic ataxic gait of untreated syphilis where the person's feet slap the ground as they strike the floor due to loss of proprioception. In daylight the person can avoid some unsteadiness by watching their own feet.[citation needed]
## Cause[edit]
Tabes dorsalis is caused by demyelination by advanced syphilis infection (tertiary syphilis), when the primary infection by the causative spirochete bacterium, Treponema pallidum, is left untreated for an extended period of time (past the point of blood infection by the organism).[3] The spirochete invades large myelinated fibers, leading to the involvement of the dorsal column medial leminiscus pathway rather than the spinothalamic tract.[citation needed]
## Treatment[edit]
Intravenously administered penicillin is the treatment of choice. Associated pain can be treated with opiates, valproate, or carbamazepine. Those with tabes dorsalis may also require physical therapy and occupational therapy to deal with muscle wasting and weakness. Preventive treatment for those who come into sexual contact with an individual with syphilis is important.[citation needed]
## Prognosis[edit]
Left untreated, tabes dorsalis can lead to paralysis, dementia, and blindness. Existing nerve damage cannot be reversed.[citation needed]
## Epidemiology[edit]
The disease is more frequent in males than in females. Onset is commonly during mid-life. The incidence of tabes dorsalis is rising, in part due to co-associated HIV infection[citation needed].
## History[edit]
Although there were earlier clinical accounts of this disease, and descriptions and illustrations of the posterior columns of the spinal cord, it was the Berlin neurologist Romberg whose account became the classical textbook description, first published in German[4] and later translated into English.[5]
Sir Arthur Conan Doyle, author of the Sherlock Holmes stories, completed his doctorate on tabes dorsalis in 1885.[6]
## Notable patients[edit]
* German storywriter E.T.A. Hoffmann appears to have suffered and died from tabes dorsalis.
* The French novelist Alphonse Daudet kept a journal of the pain he experienced from this condition which was posthumously published as La Doulou (1930) and translated into English as In the Land of Pain (2002) by Julian Barnes.
* Poet Charles Baudelaire contracted syphilis in 1839 and resorted to opium to help alleviate the pain of tabes dorsalis ascending his spine.
* Painter Édouard Manet died of syphilis complications, including tabes dorsalis, in 1883, aged 51.
* Boxer Charley Mitchell
* Meyer Nudelman, the father of author and doctor Sherwin Nuland, who described his father's affliction extensively in his book Lost in America; A Journey with my Father (2003).
## See also[edit]
* General paresis of the insane
* Category:Deaths from tabes dorsalis
## References[edit]
* tabes_dorsalis at NINDS
* 'An Essay Upon the Vasomotor Changes in Tabes Dorsalis' by Arthur Conan Doyle
1. ^ "Pel's Crisis". Retrieved December 14, 2009.[permanent dead link]
2. ^ Basic Clinical Neuroscience, Young, Young, and Tolbert. Lippincott, Williams, and Wilkins, ISBN 978-0-7817-5319-7
3. ^ "NINDS Tabes Dorsalis Information Page". Archived from the original on April 14, 2014. Retrieved April 13, 2014.
4. ^ Romberg, Moritz (1840). Lehrbuch der Nervenkrankheiten des Menschen. Berlin: Duncker.
5. ^ Romberg, Moritz (1853). Tabes dorsalis. Chapter 49 in: A manual of the nervous diseases of man Vol 2 (Translated and edited by EH Sieveking ed.). London: New Sydenham Society. p. 395.
6. ^ Doyle, Arthur C. (April 1885). "An Essay Upon the Vasomotor Changes in Tabes Dorsalis". hdl:1842/418. Cite journal requires `|journal=` (help)
## External links[edit]
Classification
D
* ICD-10: A52.1
* ICD-10-CM: A52.11
* ICD-9-CM: 094.0
* MeSH: D013606
* DiseasesDB: 29061
External resources
* eMedicine: neuro/684
* v
* t
* e
Bacterial diseases due to gram negative non-proteobacteria (BV4)
Spirochaete
Spirochaetaceae
Treponema
* Treponema pallidum
* Syphilis/bejel
* Yaws
* Treponema carateum (Pinta)
* Treponema denticola
Borrelia
* Borrelia burgdorferi/Borrelia afzelii
* Lyme disease
* Erythema migrans
* Neuroborreliosis
* Borrelia recurrentis (Louse borne relapsing fever)
* Borrelia hermsii/Borrelia duttoni/Borrelia parkeri (Tick borne relapsing fever)
Leptospiraceae
Leptospira
* Leptospira interrogans (Leptospirosis)
Chlamydiaceae
Chlamydia
* Chlamydia psittaci (Psittacosis)
* Chlamydia pneumoniae
* Chlamydia trachomatis
* Chlamydia
* Lymphogranuloma venereum
* Trachoma
Bacteroidetes
* Bacteroides fragilis
* Tannerella forsythia
* Capnocytophaga canimorsus
* Porphyromonas gingivalis
* Prevotella intermedia
Fusobacteria
* Fusobacterium necrophorum (Lemierre's syndrome)
* Fusobacterium nucleatum
* Fusobacterium polymorphum
* Streptobacillus moniliformis (Rat-bite fever/Haverhill fever)
* v
* t
* e
Focal lesions of the spinal cord
General
* Myelopathy
* Myelitis
* Spinal cord compression
By location
* Brown-Séquard syndrome
* Posterior cord syndrome
* Anterior cord syndrome
* Central cord syndrome
* Cauda equina syndrome
Other
* Polio
* Demyelinating disease
* Transverse myelitis
* Tropical spastic paraparesis
* Epidural abscess
* Syringomyelia
* Syringobulbia
* Morvan's syndrome
* Sensory ataxia
* Tabes dorsalis
* Abadie's sign
* Subacute combined degeneration of spinal cord
* Vascular myelopathy
* Anterior spinal artery syndrome
* Foix–Alajouanine syndrome
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Tabes dorsalis | c0039223 | 2,546 | wikipedia | https://en.wikipedia.org/wiki/Tabes_dorsalis | 2021-01-18T18:29:41 | {"gard": ["8730"], "mesh": ["D013606"], "umls": ["C0039223"], "wikidata": ["Q2583311"]} |
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It has been suggested that this article be merged with sensory processing disorder. (Discuss) Proposed since July 2020.
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Sensory dysfunction disorder
SpecialtyNeurology
Sensory dysfunction disorder is a reported neurological disorder of information processing, characterized by difficulty in understanding and responding appropriately to sensory inputs.[1] Sensory dysfunction disorder is not recognized by the American Medical Association.[2] "Sensory processing (SP) difficulties have been reported in as many as 95% of children with autism, however, empirical research examining the existence of specific patterns of SP difficulties within this population is scarce."[3]
The brain receives messages from the body's sensory systems, which informs the brain of what is going on around and to a person's body. If one or more of these systems become overstimulated, it may result in what is known as Sensory Dysfunction Disorder.[1] An example of a response to overstimulation is expressed by A. Jean Ayres, in Sensory Integration and the Child: Understanding Hidden Sensory Challenges. She writes, "When the flow of sensations is disorganized, life can be like a rush-hour traffic jam” (p. 289).[4] The following sensory systems are broken down into individual categories to better understand the impact a sensitivity can have on an individual.[2]
## Contents
* 1 Systems
* 1.1 Tactile system
* 1.2 Vestibular system
* 1.3 Proprioceptive system
* 1.4 Olfactory system
* 1.5 Gustatory system
* 1.6 Auditory system
* 1.7 Visual system
* 2 The Mislabeled Child
* 3 The Out-of-Sync Child
* 4 Recognition of the disorder
* 5 References
## Systems[edit]
### Tactile system[edit]
The tactile system is the sense of touch. Someone with Sensory Dysfunction Disorder may have symptoms of not being able to process any form of physical connection. Conversely, a person may need to have some sort of physical connection to soothe an anxiety he or she is experiencing.[2]
### Vestibular system[edit]
The vestibular system includes motor skills, equilibrium, and timing. A child with Sensory Dysfunction Disorder may have a difficult time in sports or sensing the perimeters of his or her surroundings. Sometimes movement for a person can result in a soothing sensation or cause stress, depending on how that individual perceives the information.[2]
### Proprioceptive system[edit]
The proprioceptive system concerns a person's joints and muscles. It tells the brain if a part of the body is moving without actually having to see it. It also controls eating, writing, and using utensils. This sense enables a person to understand the amount of pressure used to carry out routine tasks, such as eating and writing. Bodily pressure is part of this as well; for example, a child may enjoy being held tighter by someone or leaning into things such as walls, desks, and potentially other people.[2]
### Olfactory system[edit]
The olfactory system is considered the sense of smell. People with Sensory Dysfunction Disorder could have difficulty with certain fragrances or odors. Conversely, they may find certain smells to be soothing, and use them to calm themselves.[2]
### Gustatory system[edit]
The Gustatory system concerns a person's taste and sense of smell. A child with Sensory Dysfunction Disorder may not be able to tolerate the texture or taste of certain foods. Their senses may not respond well to food, and they may be unable to smell food that is burning.[2]
### Auditory system[edit]
The auditory system deals with hearing. Children with Sensory Dysfunction Disorder may feel that certain noises are painful or overwhelming. They may need to cover their ears when hearing a sound or in anticipation of what they think will be an offensive sound. They can find certain music to be soothing and become mesmerized by it. However, they may become overstimulated and upset if they hear something for which they are unprepared.[2]
### Visual system[edit]
The visual system involves sight. A child with Sensory Dysfunction Disorder may or may not be able to see an item that is directly in front of them. He or she may be sensitive to certain lighting.[2]
A child who struggles with some sort of sensory sensitivity can also have a difficult time with emotional control.[1] His or her brain may be unable to fully comprehend what is happening in his or her surroundings, which can cause confusion and lead to extreme behavior issues.[1] This could result in intense outbursts and anxiety. During such episodes, children are no longer able to receive any audio information that is generally used to calm them.[1] \- Authored an article, Sensory Dysfunction in Children \- Researched information for article through internet and medical booksde"/> They become unresponsive to any disciplinary actions that may typically be used.[1] Their brain reaches a state of sensory overload and any new information, such as conversation to alter their current state of mind, becomes ineffective. They need to calm themselves and let their brains slow down.[1]
## The Mislabeled Child[edit]
This section's tone or style may not reflect the encyclopedic tone used on Wikipedia. See Wikipedia's guide to writing better articles for suggestions. (July 2020) (Learn how and when to remove this template message)
This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed.
Find sources: "Sensory dysfunction disorder" – news · newspapers · books · scholar · JSTOR (July 2020) (Learn how and when to remove this template message)
The Mislabeled Child, written by Brock Eide, and Fernette Eide, provides information that can improve the messages to the brain for children with Sensory Dysfunction Disorder, so they may become more responsive to their senses that ordinarily overwhelm them. The authors suggest that with specified therapy, namely from Occupational Therapists, messages may be rerouted, creating a new nerve tract through the brain.[1] Treatment of Sensory Dysfunction Disorder has several steps because there are many areas of concern. Treatment can improve with parental involvement and repetition.[1] The Mislabeled Child has compiled a list of steps to help with Sensory Dysfunction Disorder:
1. Making the world more sensory-friendly
2. Managing sensory-seeking behaviors
3. Managing sensory-avoidant behaviors
4. Improving whole-body balance and movement
5. Improving fine-motor function
6. Improving emotional regulation" (p. 314)[1]
Step one is important to a child with sensory dysfunction because this is where they receive their stimuli that can cause them to become overstimulated. Understanding the specific elements that may cause the initial anxiety and removing or altering it, can ease a child's anxiety levels and lessen confusion.[1]
Step two suggests that certain behaviors and activities may be calming for the child. Finding activities that involve movement, whether full motor skills or fine motor skills, can be helpful. Activity and exercise can strengthen these senses.[1]
Step three states that this dysfunction concerns a person's senses, meaning there are specific triggers that may exacerbate behaviors causing the child to stay away from that particular irritant. This could involve the use of a 'sensory diet'. It is noted in the book The Mislabeled Child that "Improving sensitivities in multiple senses often does not require specific desensitization therapies for each one, because our sensory systems are so highly linked, or integrated. Addressing sensitivities in one area often improves sensitivities in many areas" (p. 324).[1]
Step four includes strengthening gross motor skills, which can build better muscle tone through play, enabling children to have more control over their own body. Children may struggle with balance and ability in activities because they lack gross motor skills.[1] As a child's gross motor skills inform the brain about a person's surroundings, the brain becomes confused and inhibits their reactions to their surroundings.
Step five recommends that children who struggle with fine motor skills dealing primarily with their fingers and hands, need to do exercises, such as pinch grip, cutting, and writing, to strengthen them. An Occupational therapist works with the child to develop these skills.[1] Being unable to use their fine motor skills makes it very difficult and frustrating for a child to write properly and can cause the child to avoid doing anything involving handwriting and similar situations.
Lastly, in step six, as the child matures it is important to help him or her to become more aware of how their response to their own senses and learn to understand what their bodies are doing. Once they are able to learn these cues, they can help themselves by knowing when it is time to take a break and regain control over themselves.[1]
## The Out-of-Sync Child[edit]
This section's tone or style may not reflect the encyclopedic tone used on Wikipedia. See Wikipedia's guide to writing better articles for suggestions. (July 2020) (Learn how and when to remove this template message)
This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed.
Find sources: "Sensory dysfunction disorder" – news · newspapers · books · scholar · JSTOR (July 2020) (Learn how and when to remove this template message)
There are ways that children with Sensory Dysfunction Disorder may still have fun. The book The Out-of-Sync Child Has Fun Activities for Kids with Sensory Processing Disorder, written by Carol Stock Kranowitz, M.A., provides different activities for the various sensory systems.[5] These activities can be tools to help strengthen these senses.
## Recognition of the disorder[edit]
The American Psychiatric Association does not recognize Sensory Dysfunction Disorder as a medical diagnosis.[2][6] Daniel Brennan also comments on this in his article "Health and Parenting Sensory Processing Disorder" and further proposes that it is typically paralleled with another disorder such as ADHD, autism spectrum, and countless other disorders, rather than as its own disorder.[2][6]
## References[edit]
1. ^ a b c d e f g h i j k l m n o p Eide, M.D., M.A., Brock, and Fernette Eide, M.D. The Mislabeled Child. New York: Library of Congress Cataloging-in-Publication Data, 2006. Print.
2. ^ a b c d e f g h i j k Emmons, Polly Godwin, and Liz McKendry Anderson. Understanding Sensory Dysfunction: Learning, Development and Sensory Dysfunction in Autism Spectrum Disorders, ADHD, Learning Disabilities and Bipolar Disorder. Philadelphia, PA: Jessica Kingsley Publishers, 2005. Print.
3. ^ Baker, Amy (25 September 2007). "The Relationship Between Sensory Processing Patterns and Behavioural Responsiveness in Autistic Disorder: A Pilot Study". J Autism Dev Disord. 38 (5): 867–875. doi:10.1007/s10803-007-0459-0. PMID 17899349. S2CID 21628554 – via Google Scholar.
4. ^ Ayres, A. Jean Sensory Integration and the Child: Understanding Hidden Sensory Challenges. Los Angeles, CA: Western Psychological Services, 2005. Print.
5. ^ Kranowitz, M.A. Carol Stock. The Out-Of-Sync Child Has Fun Activities for Kids with Sensory Processing Disorder. New York: Penguin Group (USA) Inc., 2003. Print.
6. ^ a b Brennan, M.D. Daniel. "Health & Parenting Sensory Processing Disorder." WebMD. Daniel Brennan, M.D. Osteoarthritis Treatment, 10 May 2014. Web. 6 Nov. 2014.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Sensory dysfunction disorder | None | 2,547 | wikipedia | https://en.wikipedia.org/wiki/Sensory_dysfunction_disorder | 2021-01-18T18:57:42 | {"wikidata": ["Q25048438"]} |
X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia (XMEN) is a rare inherited disorder that affects the immune system. It has been reported in very few patients to date and has only been diagnosed in males. In XMEN, the number of T cells, a type of immune cell, are decreased or don’t work right. Because there are not enough T cells, males with XMEN may have more frequent infections. In addition, they are more likely to get sick from Epstein-Barr virus (EBV), a common virus found in most people. Typically, only people with immune systems that don’t’ work well can develop symptoms from an EBV infection. In males with XMEN, EBV infections lead to abnormal growth of lymph cells and cancer of the lymph system (lymphoma).
XMEN is caused by mutations in the MAGT1 gene, that controls how magnesium gets in and out of the body’s cells. It is inherited in an X-linked pattern in families. XMEN is diagnosed based on the symptoms, and genetic testing for MAGT1 mutations can also be helpful. Treatment for XMEN may include magnesium supplements, chemotherapy for lymphoma, and possible stem cell transplant. Because XMEN has only been diagnosed in a few patients, the long-term outlook for males with XMEN is unknown.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia | c3275445 | 2,548 | gard | https://rarediseases.info.nih.gov/diseases/10907/x-linked-immunodeficiency-with-magnesium-defect-epstein-barr-virus-infection-and-neoplasia | 2021-01-18T17:57:03 | {"omim": ["300853"], "orphanet": ["317476"], "synonyms": ["XMEN", "Immunodeficiency, X-linked, with magnesium defect, epstein-barr virus infection, and neoplasia", "CID due to MAGT1 deficiency", "X-linked magnesium deficiency with Epstein-Barr virus infection and neoplasia", "Combined immunodeficiency due to MAGT1 deficiency"]} |
Narcolepsy is a chronic sleep disorder that disrupts the normal sleep-wake cycle. Although this condition can appear at any age, it most often begins in adolescence.
Narcolepsy is characterized by excessive daytime sleepiness. Affected individuals feel tired during the day, and several times a day they may experience an overwhelming urge to sleep. "Sleep attacks" can occur at unusual times, such as during a meal or in the middle of a conversation. They last from a few seconds to a few minutes and often lead to a longer nap, after which affected individuals wake up feeling refreshed.
Another common feature of narcolepsy is cataplexy, which is a sudden loss of muscle tone in response to strong emotion (such as laughing, surprise, or anger). These episodes of muscle weakness can cause an affected person to slump over or fall, which occasionally leads to injury. Episodes of cataplexy usually last just a few seconds, and they may occur from several times a day to a few times a year. Most people diagnosed with narcolepsy also have cataplexy. However, some do not, which has led researchers to distinguish two major forms of the condition: narcolepsy with cataplexy and narcolepsy without cataplexy.
Narcolepsy also affects nighttime sleep. Most affected individuals have trouble sleeping for more than a few hours at night. They often experience vivid hallucinations while falling asleep (hypnogogic hallucinations) or while waking up (hypnopompic hallucinations). Affected individuals often have realistic and distressing dreams, and they may act out their dreams by moving excessively or talking in their sleep. Many people with narcolepsy also experience sleep paralysis, which is an inability to move or speak for a short period while falling asleep or awakening. The combination of hallucinations, vivid dreams, and sleep paralysis is often frightening and unpleasant for affected individuals.
Some people with narcolepsy have all of the major features of the disorder, while others have only one or two. Most of the signs and symptoms persist throughout life, although episodes of cataplexy may become less frequent with age and treatment.
## Frequency
Narcolepsy affects about 1 in 2,000 people in the United States and Western Europe. However, the disorder is likely underdiagnosed, particularly in people with mild symptoms. Worldwide, narcolepsy appears to be most common in Japan, where it affects an estimated 1 in 600 people.
## Causes
Narcolepsy probably results from a combination of genetic and environmental factors, some of which have been identified, but many of which remain unknown.
In most cases of narcolepsy with cataplexy, and in some cases without cataplexy, sleep abnormalities result from a loss of particular brain cells (neurons) in a part of the brain called the hypothalamus. These cells normally produce chemicals called hypocretins (also known as orexins), which have many important functions in the body. In particular, hypocretins regulate the daily sleep-wake cycle. It is unclear what triggers the death of hypocretin-producing neurons in people with narcolepsy, although evidence increasingly points to an abnormality of the immune system.
Researchers have identified changes in several genes that influence the risk of developing narcolepsy. The most well-studied of these genes is HLA-DQB1, which provides instructions for making part of a protein that plays an important role in the immune system. The HLA-DQB1 gene is part of a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders (such as viruses and bacteria). The HLA-DQB1 gene has many different normal variations, allowing each person's immune system to react to a wide range of foreign proteins. A variation of the HLA-DQB1 gene called HLA-DQB1*06:02 has been strongly associated with narcolepsy, particularly in people who also have cataplexy and a loss of hypocretins. Most people with narcolepsy have the HLA-DQB1*06:02 variation, and many also have specific versions of other, closely related HLA genes. It is unclear how these genetic changes influence the risk of developing the condition.
Variations in several additional genes have also been associated with narcolepsy. Many of these genes are thought to play roles in immune system function. However, variations in these genes probably make only a small contribution to the overall risk of developing narcolepsy. Other genetic and environmental factors are also likely to influence a person's chances of developing this disorder. For example, studies suggest that bacterial or viral infections such as strep throat (streptococcus), colds, and influenza may be involved in triggering narcolepsy in people who are at risk.
### Learn more about the genes associated with Narcolepsy
* HLA-DQA1
* HLA-DQB1
* HLA-DRB1
Additional Information from NCBI Gene:
* CHKB
* CPT1B
* P2RY11
* TNF
* TNFRSF1B
* TRA
## Inheritance Pattern
Most cases of narcolepsy are sporadic, which means they occur in people with no history of the disorder in their family. A small percentage of all cases have been reported to run in families; however, the condition does not have a clear pattern of inheritance. First-degree relatives (parents, siblings, and children) of people with narcolepsy with cataplexy have a 40 times greater risk of developing the condition compared with people in the general population.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Narcolepsy | c0007384 | 2,549 | medlineplus | https://medlineplus.gov/genetics/condition/narcolepsy/ | 2021-01-27T08:25:44 | {"gard": ["7162"], "mesh": ["D002385"], "omim": ["161400", "605841", "609039", "612417", "612851", "614223", "614250"], "synonyms": []} |
Not to be confused with Acne necrotica.
Acne miliaris necrotica
Other namesAcne varioliformis
SpecialtyDermatology
Acne miliaris necrotica is a rare condition consisting of follicular vesicopustules, sometimes occurring as solitary lesions that are usually very itchy.[1] The condition affects middle aged and elderly individuals. Affected areas can include the scalp, frontal hairline, face, and chest.[2][3]
## Contents
* 1 Causes
* 2 Diagnosis
* 3 Treatment
* 3.1 Topical
* 3.2 Systemic
* 4 See also
* 5 References
* 6 External links
## Causes[edit]
It has been hypothesized that the body overreacts to an organism such as the S. aureus bacterium.[2][3]
## Diagnosis[edit]
This section is empty. You can help by adding to it. (September 2017)
## Treatment[edit]
There are multiple medications that are able to treat acne varioliformis.[2][3]
### Topical[edit]
* Clindamycin 1% lotion or Benzoyl peroxide/clindamycin gel
* Erythromycin 2% gel
* 1% hydrocortisone cream
### Systemic[edit]
* Doxycycline 50 mg twice daily
* Isotretinoin 0.5 mg/kg daily
## See also[edit]
* List of cutaneous conditions
## References[edit]
1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. Page 245. ISBN 0-7216-2921-0.
2. ^ a b c "Acne Necrotica (varioliformis)". www.mdedge.com. Archived from the original on 2017-11-09. Retrieved 2017-06-11.
3. ^ a b c "Acne Necrotica (varioliformis)". Clinical Advisor. 2016-12-20. Retrieved 2017-06-11.
## External links[edit]
Classification
D
* ICD-10: L70.2
* ICD-9-CM: 706.0
* v
* t
* e
Disorders of skin appendages
Nail
* thickness: Onychogryphosis
* Onychauxis
* color: Beau's lines
* Yellow nail syndrome
* Leukonychia
* Azure lunula
* shape: Koilonychia
* Nail clubbing
* behavior: Onychotillomania
* Onychophagia
* other: Ingrown nail
* Anonychia
* ungrouped: Paronychia
* Acute
* Chronic
* Chevron nail
* Congenital onychodysplasia of the index fingers
* Green nails
* Half and half nails
* Hangnail
* Hapalonychia
* Hook nail
* Ingrown nail
* Lichen planus of the nails
* Longitudinal erythronychia
* Malalignment of the nail plate
* Median nail dystrophy
* Mees' lines
* Melanonychia
* Muehrcke's lines
* Nail–patella syndrome
* Onychoatrophy
* Onycholysis
* Onychomadesis
* Onychomatricoma
* Onychomycosis
* Onychophosis
* Onychoptosis defluvium
* Onychorrhexis
* Onychoschizia
* Platonychia
* Pincer nails
* Plummer's nail
* Psoriatic nails
* Pterygium inversum unguis
* Pterygium unguis
* Purpura of the nail bed
* Racquet nail
* Red lunulae
* Shell nail syndrome
* Splinter hemorrhage
* Spotted lunulae
* Staining of the nail plate
* Stippled nails
* Subungual hematoma
* Terry's nails
* Twenty-nail dystrophy
Hair
Hair loss/
Baldness
* noncicatricial alopecia: Alopecia
* areata
* totalis
* universalis
* Ophiasis
* Androgenic alopecia (male-pattern baldness)
* Hypotrichosis
* Telogen effluvium
* Traction alopecia
* Lichen planopilaris
* Trichorrhexis nodosa
* Alopecia neoplastica
* Anagen effluvium
* Alopecia mucinosa
* cicatricial alopecia: Pseudopelade of Brocq
* Central centrifugal cicatricial alopecia
* Pressure alopecia
* Traumatic alopecia
* Tumor alopecia
* Hot comb alopecia
* Perifolliculitis capitis abscedens et suffodiens
* Graham-Little syndrome
* Folliculitis decalvans
* ungrouped: Triangular alopecia
* Frontal fibrosing alopecia
* Marie Unna hereditary hypotrichosis
Hypertrichosis
* Hirsutism
* Acquired
* localised
* generalised
* patterned
* Congenital
* generalised
* localised
* X-linked
* Prepubertal
Acneiform
eruption
Acne
* Acne vulgaris
* Acne conglobata
* Acne miliaris necrotica
* Tropical acne
* Infantile acne/Neonatal acne
* Excoriated acne
* Acne fulminans
* Acne medicamentosa (e.g., steroid acne)
* Halogen acne
* Iododerma
* Bromoderma
* Chloracne
* Oil acne
* Tar acne
* Acne cosmetica
* Occupational acne
* Acne aestivalis
* Acne keloidalis nuchae
* Acne mechanica
* Acne with facial edema
* Pomade acne
* Acne necrotica
* Blackhead
* Lupus miliaris disseminatus faciei
Rosacea
* Perioral dermatitis
* Granulomatous perioral dermatitis
* Phymatous rosacea
* Rhinophyma
* Blepharophyma
* Gnathophyma
* Metophyma
* Otophyma
* Papulopustular rosacea
* Lupoid rosacea
* Erythrotelangiectatic rosacea
* Glandular rosacea
* Gram-negative rosacea
* Steroid rosacea
* Ocular rosacea
* Persistent edema of rosacea
* Rosacea conglobata
* variants
* Periorificial dermatitis
* Pyoderma faciale
Ungrouped
* Granulomatous facial dermatitis
* Idiopathic facial aseptic granuloma
* Periorbital dermatitis
* SAPHO syndrome
Follicular cysts
* "Sebaceous cyst"
* Epidermoid cyst
* Trichilemmal cyst
* Steatocystoma
* simplex
* multiplex
* Milia
Inflammation
* Folliculitis
* Folliculitis nares perforans
* Tufted folliculitis
* Pseudofolliculitis barbae
* Hidradenitis
* Hidradenitis suppurativa
* Recurrent palmoplantar hidradenitis
* Neutrophilic eccrine hidradenitis
Ungrouped
* Acrokeratosis paraneoplastica of Bazex
* Acroosteolysis
* Bubble hair deformity
* Disseminate and recurrent infundibulofolliculitis
* Erosive pustular dermatitis of the scalp
* Erythromelanosis follicularis faciei et colli
* Hair casts
* Hair follicle nevus
* Intermittent hair–follicle dystrophy
* Keratosis pilaris atropicans
* Kinking hair
* Koenen's tumor
* Lichen planopilaris
* Lichen spinulosus
* Loose anagen syndrome
* Menkes kinky hair syndrome
* Monilethrix
* Parakeratosis pustulosa
* Pili (Pili annulati
* Pili bifurcati
* Pili multigemini
* Pili pseudoannulati
* Pili torti)
* Pityriasis amiantacea
* Plica neuropathica
* Poliosis
* Rubinstein–Taybi syndrome
* Setleis syndrome
* Traumatic anserine folliculosis
* Trichomegaly
* Trichomycosis axillaris
* Trichorrhexis (Trichorrhexis invaginata
* Trichorrhexis nodosa)
* Trichostasis spinulosa
* Uncombable hair syndrome
* Wooly hair nevus
Sweat
glands
Eccrine
* Miliaria
* Colloid milium
* Miliaria crystalline
* Miliaria profunda
* Miliaria pustulosa
* Miliaria rubra
* Occlusion miliaria
* Postmiliarial hypohidrosis
* Granulosis rubra nasi
* Ross’ syndrome
* Anhidrosis
* Hyperhidrosis
* Generalized
* Gustatory
* Palmoplantar
Apocrine
* Body odor
* Chromhidrosis
* Fox–Fordyce disease
Sebaceous
* Sebaceous hyperplasia
This cutaneous condition article is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Acne miliaris necrotica | c0311216 | 2,550 | wikipedia | https://en.wikipedia.org/wiki/Acne_miliaris_necrotica | 2021-01-18T18:52:05 | {"umls": ["C0311216"], "icd-9": ["706.0"], "icd-10": ["L70.2"], "wikidata": ["Q4674430"]} |
## Description
Achalasia is a primary motor disorder of the esophagus. It is characterized by aperistalsis and a failure of the lower esophageal sphincter to relax due to a loss of inhibitory nitrinergic neurons in the esophageal myenteric plexus. Patients typically present with dysphagia, regurgitation, retrosternal pain, and substantial weight loss (Farrokhi and Vaezi, 2007; summary by Gockel et al., 2010).
Clinical Features
Thibert et al. (1965) described 2 families, each with 2 affected sibs under 16 years of age.
Cloud et al. (1966) observed the disorder in 4 Apache Indian sibs less than 6 years old. Westley et al. (1975) reported 6 cases of achalasia, with symptoms beginning in infancy, in 3 sibships of an Apache Indian kindred.
Koivukangas et al. (1973) found Sjogren syndrome and achalasia in 2 sisters. (The Sjogren syndrome present in this family consisted of the triad of keratoconjunctivitis sicca, xerostomia, and rheumatoid arthritis or other connective tissue disease.)
Vaughan and Williams (1973) described 2 brothers, aged 2 and 8 years, with achalasia. Both presented with pulmonary complications caused by their achalasia. These brothers may have had the syndrome of glucocorticoid deficiency and achalasia (231550) because in the 8-year-old 'the clinical picture was obscured by the fact that the patient was hyperpigmented and had low plasma steroids.' In any case of achalasia in a child, especially if the disorder is familial (and especially if surgery is contemplated), adrenal insufficiency should be considered.
Inheritance
Dayalan et al. (1972) reported 3 documented and 4 probable cases of achalasia among a sibship of 8. The parents were of an uncle-niece consanguineous marriage.
Frieling et al. (1988) described 4 families with multiple cases. Their exhaustive review of the literature found about 5 times as many instances of affected sibs than instances of affected parent/child. There were 3 instances of affected twins; 1 pair was definitely monozygotic and 1 pair was dizygotic, being of unlike sex.
In a study of 1,012 first-degree relatives of 167 patients with achalasia, Mayberry and Atkinson (1989) were unable to detect a single established case of achalasia and none of the 447 sibs of patients with achalasia had the disease, although several had esophageal symptoms. They were able to find a report of only 1 instance of achalasia in monozygotic twins (Stein and Knauer, 1982). Kaar et al. (1991) reported affected brothers.
In a review, Gockel et al. (2010) stated that the inheritance pattern in the majority of cases of isolated achalasia is multifactorial. They also stated that a rare subform of early-onset achalasia probably exists, which is inherited in an autosomal recessive manner.
Molecular Genetics
See 163731.0002 for discussion of a possible association between variation in the NOS1 gene and achalasia.
Mouth \- Xerostomia Inheritance \- Autosomal recessive Eye \- Keratoconjunctivitis sicca GI \- Achalasia Joints \- Rheumatoid arthritis ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| ACHALASIA, FAMILIAL ESOPHAGEAL | c0014848 | 2,551 | omim | https://www.omim.org/entry/200400 | 2019-09-22T16:31:41 | {"doid": ["9164"], "mesh": ["D004931"], "omim": ["200400"], "orphanet": ["930"]} |
This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed.
Find sources: "Scotoma" – news · newspapers · books · scholar · JSTOR (March 2019) (Learn how and when to remove this template message)
Scotoma
Other namesScotomas, scotomata
A depiction of a scintillating scotoma that was almost spiral-shaped, with distortion of shapes but otherwise melting into the background similarly to the physiological blind spot, as may be caused by cortical spreading depression
SpecialtyOphthalmology
A scotoma is an area of partial alteration in the field of vision consisting of a partially diminished or entirely degenerated visual acuity that is surrounded by a field of normal – or relatively well-preserved – vision.
Every normal mammalian eye has a scotoma in its field of vision, usually termed its blind spot. This is a location with no photoreceptor cells, where the retinal ganglion cell axons that compose the optic nerve exit the retina. This location is called the optic disc. There is no direct conscious awareness of visual scotomas. They are simply regions of reduced information within the visual field. Rather than recognizing an incomplete image, patients with scotomas report that things "disappear" on them.[1]
The presence of the blind spot scotoma can be demonstrated subjectively by covering one eye, carefully holding fixation with the open eye, and placing an object (such as one's thumb) in the lateral and horizontal visual field, about 15 degrees from fixation (see the blind spot article). The size of the monocular scotoma is 5×7 degrees of visual angle.
A scotoma can be a symptom of damage to any part of the visual system, such as retinal damage from exposure to high-powered lasers, macular degeneration and brain damage.
The term scotoma is also used metaphorically in several fields. The common theme of all the figurative senses is of a gap not in visual function but in the mind's perception, cognition, or world view. The term is from Greek σκότος/skótos, darkness.
## Contents
* 1 Signs and symptoms
* 2 Causes
* 3 Terminology
* 4 See also
* 4.1 Detection
* 4.2 Types
* 5 References
* 6 External links
## Signs and symptoms[edit]
Symptom-producing, or pathological, scotomata may be due to a wide range of disease processes, affecting any part of the visual system, including the retina (in particular its most sensitive portion, the macula), the optic nerve and even the visual cortex.[2] A pathological scotoma may involve any part of the visual field and may be of any shape or size. A scotoma may include and enlarge the normal blind spot. Even a small scotoma that happens to affect central or macular vision will produce a severe visual disability, whereas a large scotoma in the more peripheral part of a visual field may go unnoticed by the bearer because of the normal reduced optical resolution in the peripheral visual field.
## Causes[edit]
Common causes of scotomata include demyelinating disease such as multiple sclerosis (retrobulbar neuritis), damage to nerve fiber layer in the retina (seen as cotton wool spots[3]) due to hypertension, toxic substances such as methyl alcohol, ethambutol and quinine, nutritional deficiencies, vascular blockages either in the retina or in the optic nerve, stroke or other brain injury, and macular degeneration, often associated with aging. Scintillating scotoma is a common visual aura in migraine.[4] Less common, but important because they are sometimes reversible or curable by surgery, are scotomata due to tumors such as those arising from the pituitary gland, which may compress the optic nerve or interfere with its blood supply.
Rarely, scotomata are bilateral. One important variety of bilateral scotoma may occur when a pituitary tumour begins to compress the optic chiasm (as distinct from a single optic nerve) and produces a bitemporal paracentral scotoma, and later, when the tumor enlarges, the scotomas extend out to the periphery to cause the characteristic bitemporal hemianopsia. This type of visual-field defect tends to be obvious to the person experiencing it but often evades early objective diagnosis, as it is more difficult to detect by cursory clinical examination than the classical or textbook bitemporal peripheral hemianopia and may even elude sophisticated electronic modes of visual-field assessment.
In a pregnant woman, scotomata can present as a symptom of severe preeclampsia, a form of pregnancy-induced hypertension. Similarly, scotomata may develop as a result of the increased intracranial pressure that occurs in malignant hypertension.
The scotoma is also caused by the aminoglycoside antibiotics mainly by Streptomycin.
## Terminology[edit]
Beyond its literal sense concerning the visual system, the term scotoma is also used metaphorically in several fields, including neurology, neuropsychology, psychology, philosophy, and politics. The common theme of all the figurative senses is of a gap not in visual function but in the mind's perception, cognition, or world view. Their concrete connection to the literal sense, however, is by the connection between the nervous system and the mind, via the chain of links from sensory input, to nerve conduction, to the brain, to perception (the processing and interpreting of that input) via the brain-mind correlation, to psychological function. Thus there is not only (or not necessarily) a visual inability to see an aspect of reality but also (or instead) a mental inability to conceive even the possibility of seeing that aspect, due to a cognitive schema that lacks any provision for it.
At the most concrete level, there is neuropsychological scotoma. One example is the hemispatial neglect that is sometimes experienced by people who have had strokes. Another type is the phenomenon of reverse or negative phantom limb, in which nerve injuries to the limbs, such as trauma in which a limb's nerves are severed but the limb is spared from amputation, can affect the mind's body schema in such a way that an existing limb seems to its owner like it should not exist, and its presence thus seems uncanny. Neurologist Oliver Sacks, who experienced a reverse phantom leg that later resolved,[5] considered it a form of spatial neglect in the body schema analogous to hemispatial neglect in that the mind could not conceive of the leg as self because it could not conceive that there was any space for the leg to exist in. Sacks and others agreed that the leg thus seemed like someone else's leg, including sometimes a cadaverous one, which was part of the reason for the dysphoria but not the sole explanation. Even for people who intellectually understood that the leg or hand was supposed to be theirs simply could not believe it emotionally and could not completely reconcile reality with schema, prompting great unease. Given how hard this is to comprehend for a person who has not experienced it, people recently experiencing it for the first time consider it both uncanny and ineffable (as Sacks self-reported and found in others[5]). Sacks also explored the regular type of phantom limb (a positive phantom), which does not produce a neuropsychological scotoma but shares with reverse phantoms the trait that the body schema resists revision despite a person's perfect intellectual awareness and acceptance of the current physical reality (that is, that the amputated limb is gone or that the spared limb is still present). This suggests that aspects of schema in the mind (body schema, world schema) have neurologic bases that cannot be revised by mere intellectual understanding—at least not quickly. Sacks does explore the topic of how people adapt to phantoms over the years and how positive phantom limbs often gradually foreshorten and sometimes disappear; but some remain for the rest of life.[5]
At a higher level of abstraction are what have been called psychological scotomas, in which a person's self-perception of his or her own personality is judged by others to have a gap in perceptive ability. Thus, in psychology, scotoma can refer to a person's inability to perceive personality traits in themselves that are obvious to others. And at the highest abstraction level are what have been called intellectual scotomas, in which a person cannot perceive distortions in their world view that are obvious to others. Thus, in philosophy or politics, a person's thoughts or beliefs might be shaped by an inability to appreciate aspects of social interaction or institutional structure.
## See also[edit]
* Floater
* Scotomization
### Detection[edit]
* Amsler grid
* Horizontal eccentricity
* Visual field test
### Types[edit]
* Binasal hemianopsia
* Bitemporal hemianopsia
* Cortical spreading depression
* Scintillating scotoma
## References[edit]
1. ^ Fletcher, Donald C.; Schuchard, Ronald A.; Renninger, Laura W. (2012-09-01). "Patient awareness of binocular central scotoma in age-related macular degeneration". Optometry and Vision Science. 89 (9): 1395–1398. doi:10.1097/OPX.0b013e318264cc77. ISSN 1538-9235. PMID 22863789.
2. ^ "Bilateral effects of unilateral visual cortex lesions in human", Matthew Rizzo and Donald A. Robin, Brain (1996), 119, pages 951-96.
3. ^ "The role of axoplasmic transport in the pathogenesis of retinal cotton-wool spots", D. McLeod, J. Marshall, E. M. Kohner, and A. C. Bird, Br J Ophthalmol (1977), 61(3), pages 177–191.
4. ^ "Possible Roles of Vertebrate Neuroglia in Potassium Dynamics, Spreading depression, and migraine", Gardner-Medwin, J. Exp. Biol. (1981), 95, pages 111-127 (Figure 4).
5. ^ a b c Sacks, Oliver (1984), A Leg to Stand On, Simon & Schuster, ISBN 978-0671467807.
## External links[edit]
Classification
D
* ICD-10: H53.4, H53.1
* ICD-9-CM: 368.41, 368.42, 368.12
* MeSH: D012607
* v
* t
* e
* Diseases of the human eye
Adnexa
Eyelid
Inflammation
* Stye
* Chalazion
* Blepharitis
* Entropion
* Ectropion
* Lagophthalmos
* Blepharochalasis
* Ptosis
* Blepharophimosis
* Xanthelasma
* Ankyloblepharon
Eyelash
* Trichiasis
* Madarosis
Lacrimal apparatus
* Dacryoadenitis
* Epiphora
* Dacryocystitis
* Xerophthalmia
Orbit
* Exophthalmos
* Enophthalmos
* Orbital cellulitis
* Orbital lymphoma
* Periorbital cellulitis
Conjunctiva
* Conjunctivitis
* allergic
* Pterygium
* Pseudopterygium
* Pinguecula
* Subconjunctival hemorrhage
Globe
Fibrous tunic
Sclera
* Scleritis
* Episcleritis
Cornea
* Keratitis
* herpetic
* acanthamoebic
* fungal
* Exposure
* Photokeratitis
* Corneal ulcer
* Thygeson's superficial punctate keratopathy
* Corneal dystrophy
* Fuchs'
* Meesmann
* Corneal ectasia
* Keratoconus
* Pellucid marginal degeneration
* Keratoglobus
* Terrien's marginal degeneration
* Post-LASIK ectasia
* Keratoconjunctivitis
* sicca
* Corneal opacity
* Corneal neovascularization
* Kayser–Fleischer ring
* Haab's striae
* Arcus senilis
* Band keratopathy
Vascular tunic
* Iris
* Ciliary body
* 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]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Scotoma | c0155012 | 2,552 | wikipedia | https://en.wikipedia.org/wiki/Scotoma | 2021-01-18T18:28:50 | {"mesh": ["D012607"], "umls": ["C0155011", "C0155012"], "wikidata": ["Q950591"]} |
A number sign (#) is used with this entry because cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome (CEDNIK syndrome) is caused by homozygous mutation in the SNAP29 gene (604202) on chromosome 22q11.
Description
CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma) syndrome refers to a unique constellation of clinical manifestations including microcephaly, severe neurologic impairment, psychomotor retardation, failure to thrive, and facial dysmorphism, as well as palmoplantar keratoderma and late-onset ichthyosis. Brain magnetic resonance imaging (MRI) shows various degrees of cerebral dysgenesis including absence of corpus callosum and cortical dysplasia. The syndrome has been found to be uniformly fatal between the ages of 5 and 12 years (Fuchs-Telem et al., 2011).
Clinical Features
Sprecher et al. (2005) described a clinical syndrome in 7 individuals from 2 unrelated consanguineous Arab Muslim families living in northern Israel. After a normal birth, the patients presented during the first 4 months of life with failure to thrive, roving eye movements, and poor head and trunk control. All patients had progressive microcephaly and facial dysmorphism consisting of elongated facies, downward-slanting palpebral fissures, mild hypertelorism, and flat, broad nasal root. Palmoplantar keratosis and ichthyosis appeared between 5 and 11 months of age. By 8 to 15 months, major developmental milestones were not achieved, and all patients had severe psychomotor retardation. Other features included hypoplastic optic discs and sensorineural deafness. MRI showed defects of the corpus callosum and cortical dysplasia with pachygyria and polymicrogyria. Skin biopsy showed clear vesicles in the spinous, granular, and stratum corneum layers, with retained glucosylceramides, suggesting abnormal lamellar granule maturation. Sprecher et al. (2005) concluded that this neurocutaneous syndrome results from abnormal vesicle trafficking, vesicle maturation, and vesicle fusion.
Fuchs-Telem et al. (2011) reported a brother and sister from a consanguineous Pakistani family who both required neonatal tube feeding and had dysmorphic facies with small fontanels, long pointed nose, and small chin, as well as ichthyosis, palmoplantar keratoderma, hearing loss, and severe developmental delay. Brain MRI revealed a small corpus callosum in both sibs as well as other abnormalities, including ventricular asymmetry and frontal cortical dysplasia in the sister and perisylvian polymicrogyria with extensive cortical malformation in the brother.
Mapping
By linkage analysis of families with CEDNIK syndrome, Sprecher et al. (2005) mapped the disorder to a 4-Mb region on chromosome 22q11.2 (maximum multipoint lod score of 4.85 at D22S446).
Molecular Genetics
In affected patients with CEDNIK syndrome, Sprecher et al. (2005) identified a homozygous mutation in the SNAP29 gene (604202.0001).
In a brother and sister from a consanguineous Pakistani family who had features consistent with CEDNIK syndrome, Fuchs-Telem et al. (2011) identified homozygosity for a 1-bp insertion in the SNAP29 gene (604202.0002) that was not found in 200 control chromosomes. DNA from other family members was not available.
INHERITANCE \- Autosomal recessive GROWTH Other \- Failure to thrive HEAD & NECK Head \- Microcephaly, progressive Face \- Long face Ears \- Sensorineural deafness Eyes \- Downslanting palpebral fissures \- Hypertelorism, mild \- Hypoplastic optic discs Nose \- Flat, broad nasal root SKIN, NAILS, & HAIR Skin \- Palmoplantar keratoderma \- Ichthyosis Skin Histology \- Spinous, granular, and stratum corneum layers contain clear vesicles \- Abnormal lamellar granule maturation \- Abnormal distribution of glucosylceramides NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Major developmental milestones are not attained \- Mental retardation, severe \- Roving eye movements (infancy) \- Trunk hypotonia \- Poor head control \- Defects of the corpus callosum seen on MRI \- Cortical dysplasia \- Pachygyria \- Polymicrogyria Peripheral Nervous System \- Peripheral neuropathy \- Areflexia MISCELLANEOUS \- Onset in first months of life MOLECULAR BASIS \- Caused by mutation in the synaptosomal-associated protein 29kD gene (SNAP29, 604202.0001 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| CEREBRAL DYSGENESIS, NEUROPATHY, ICHTHYOSIS, AND PALMOPLANTAR KERATODERMA SYNDROME | c1836033 | 2,553 | omim | https://www.omim.org/entry/609528 | 2019-09-22T16:05:58 | {"doid": ["0060337"], "mesh": ["C537943"], "omim": ["609528"], "orphanet": ["66631"], "synonyms": ["Alternative titles", "CEDNIK SYNDROME"]} |
Heredofamilial amyloidosis
SpecialtyDermatology
Heredofamilial amyloidosis is an inherited condition that may be characterized by systemic or localized deposition of amyloid in body tissues.[1]:522[2]
## See also[edit]
* Amyloidosis
* List of cutaneous conditions
## References[edit]
1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6.
2. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1.
* v
* t
* e
Amyloidosis
Common amyloid forming proteins
* AA
* ATTR
* Aβ2M
* AL
* Aβ/APP
* AIAPP
* ACal
* APro
* AANF
* ACys
* ABri
Systemic amyloidosis
* AL amyloidosis
* AA amyloidosis
* Aβ2M/Haemodialysis-associated
* AGel/Finnish type
* AA/Familial Mediterranean fever
* ATTR/Transthyretin-related hereditary
Organ-limited amyloidosis
Heart
AANF/Isolated atrial
Brain
* Familial amyloid neuropathy
* ACys+ABri/Cerebral amyloid angiopathy
* Aβ/Alzheimer's disease
Kidney
* AApoA1+AFib+ALys/Familial renal
Skin
* Primary cutaneous amyloidosis
* Amyloid purpura
Endocrine
Thyroid
ACal/Medullary thyroid cancer
Pituitary
APro/Prolactinoma
Pancreas
AIAPP/Insulinoma
AIAPP/Diabetes mellitus type 2
This cutaneous condition article is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Heredofamilial amyloidosis | c0740340 | 2,554 | wikipedia | https://en.wikipedia.org/wiki/Heredofamilial_amyloidosis | 2021-01-18T18:52:48 | {"gard": ["6611"], "mesh": ["D028226"], "umls": ["C0206246"], "icd-10": ["E85.2"], "orphanet": ["444116"], "synonyms": [], "wikidata": ["Q5737919"]} |
Blood condition
Eosinophilia
Eosinophils in the peripheral blood of a patient with idiopathic eosinophilia
SpecialtyInfectious disease, hematology
Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 0.5×109/l (500/μL).[1] Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 x 109/L (i.e. 1,500/μL). The hypereosinophilic syndrome is a sustained elevation in this count above 1.5 x 109/L (i.e. 1,500/μl) that is also associated with evidence of eosinophil-based tissue injury.
Eosinophils usually account for less than 7% of the circulating leukocytes.[1] A marked increase in non-blood tissue eosinophil count noticed upon histopathologic examination is diagnostic for tissue eosinophilia.[2] Several causes are known, with the most common being some form of allergic reaction or parasitic infection. Diagnosis of eosinophilia is via a complete blood count (CBC), but diagnostic procedures directed at the underlying cause vary depending on the suspected condition(s). An absolute eosinophil count is not generally needed if the CBC shows marked eosinophilia.[3] The location of the causal factor can be used to classify eosinophilia into two general types: extrinsic, in which the factor lies outside the eosinophil cell lineage; and intrinsic eosinophilia, which denotes etiologies within the eosiniphil cell line.[2] Specific treatments are dictated by the causative condition, though in idiopathic eosinophilia, the disease may be controlled with corticosteroids.[3] Eosinophilia is not a disorder (rather, only a sign) unless it is idiopathic.[3]
Informally, blood eosinophil levels are often regarded as mildly elevated at counts of 500–1,500/μL, moderately elevated between 1,500–5,000/μL, and severely elevated when greater than 5,000/μL. Elevations in blood eosinophil counts can be transient, sustained, recurrent, or cyclical.[4][5]
Eosinophil counts in human blood normally range between 100–500 per/μL. Maintenance of these levels results from a balance between production of eosinophils by bone marrow eosinophil precursor cells termed CFU-Eos and the emigration of circulating eosinophils out of the blood through post-capillary venules into tissues. Eosinophils represent a small percentage of peripheral blood leucocytes (usually less than 8%), have a half-life in the circulation of only 8–18 hours, but persist in tissues for at least several weeks.[6][7]
Eosinophils are one form of terminally differentiated granulocytes; they function to neutralize invading microbes, primarily parasites and helminthes but also certain types of fungi and viruses. They also participate in transplant rejection, Graft-versus-host disease, and the killing of tumor cells. In conducting these functions, eosinophils produce and release on demand a range of toxic reactive oxygen species (e.g. hypobromite, hypobromous acid, superoxide, and peroxide) and they also release on demand a preformed armamentarium of cytokines, chemokines, growth factors, lipid mediators (e.g. leukotrienes, prostaglandins, platelet activating factor), and toxic proteins (e.g. metalloproteinases, major basic protein, eosinophil cationic protein, eosinophil peroxidase, and eosinophil-derived neurotoxin). These agents serve to orchestrate robust immune and inflammatory responses that destroy invading microbes, foreign tissue, and malignant cells. When overproduced and over-activated, which occurs in certain cases of hypereosinophilia and to a lesser extent eosinophilia, eosinophils may misdirect their reactive oxygen species and armamentarium of preformed molecules toward normal tissues. This can result in serious damage to such organs as the lung, heart, kidneys, and brain.[7][8][9]
## Contents
* 1 Pathophysiology
* 2 Diagnosis
* 3 Classification
* 3.1 Primary hypereosinophilia
* 3.1.1 Clonal hypereosinophilia
* 3.1.2 Chronic eosinophilic leukemia (NOS)
* 3.1.3 Familial eosinophilia
* 3.1.4 Idiopathic hypereosinophilia
* 3.1.5 Idiopathic hypereosiophilic syndrome
* 3.2 Secondary hypereosinophilia
* 3.2.1 Infections
* 3.2.2 Autoimmune diseases
* 3.2.3 Allergic diseases
* 3.2.4 Drugs
* 3.2.5 Malignancies
* 3.2.6 Primary immunodeficiency diseases
* 3.2.7 Lymphocyte-variant hypereosinophilia
* 3.2.8 Gleich's syndrome
* 3.2.9 IgG4-related disease
* 3.2.10 Angiolymphoid hyperplasia with eosinophilia
* 3.2.11 Cholesterol embolism
* 3.2.12 Adrenal insufficiency
* 3.3 Organ-restricted hypereosinophilias
* 4 Treatment
* 5 List of causes
* 6 See also
* 7 References
* 8 External links
## Pathophysiology[edit]
IgE-mediated eosinophil production is induced by compounds released by basophils and mast cells, including eosinophil chemotactic factor of anaphylaxis, leukotriene B4 and serotonin mediated release of eosinophil granules occur, complement complex (C5-C6-C7), interleukin 5, and histamine (though this has a narrow range of concentration).[3]
Harm resulting from untreated eosinophilia potentially varies with cause. During an allergic reaction, the release of histamine from mast cells causes vasodilation which allows eosinophils to migrate from the blood and localize in affected tissues. Accumulation of eosinophils in tissues can be significantly damaging. Eosinophils, like other granulocytes, contain granules (or sacs) filled with digestive enzymes and cytotoxic proteins which under normal conditions are used to destroy parasites but in eosinophilia these agents can damage healthy tissues. In addition to these agents, the granules in eosinophils also contain inflammatory molecules and cytokines which can recruit more eosinophils and other inflammatory cells to the area and hence amplify and perpetuate the damage. This process is generally accepted to be the major inflammatory process in the pathophysiology of atopic or allergic asthma.[10]
## Diagnosis[edit]
Diagnosis is by complete blood count (CBC). However, in some cases, a more accurate absolute eosinophil count may be needed.[3] Medical history is taken, with emphasis on travel, allergies and drug use.[3] Specific test for causative conditions are performed, often including chest x-ray, urinalysis, liver and kidney function tests, and serologic tests for parasitic and connective tissue diseases. The stool is often examined for traces of parasites (i.e. eggs, larvae, etc.) though a negative test does not rule out parasitic infection; for example, trichinosis requires a muscle biopsy.[3] Elevated serum B12 or low white blood cell alkaline phosphatase, or leukocytic abnormalities in a peripheral smear indicates a disorder of myeloproliferation.[3] In cases of idiopathic eosinophilia, the patient is followed for complications. A brief trial of corticosteroids can be diagnostic for allergic causes, as the eosinophilia should resolve with suppression of the immune over-response.[3] Neoplastic disorders are diagnosed through the usual methods, such as bone marrow aspiration and biopsy for the leukemias, MRI/CT to look for solid tumors, and tests for serum LDH and other tumor markers.[3]
## Classification[edit]
Based on their causes, hypereosinophilias can be sorted into subtypes. However, cases of eosinophilia, which exhibit eosinophil counts between 500 and 1,500/μL, may fit the clinical criteria for, and thus be regarded as falling into, one of these hypereosinophilia categories: the cutoff of 1,500/μL between hypereosinophilia and eosinophilia is somewhat arbitrary. There are at least two different guidelines for classifying hypereosinophilia/eosinophilia into subtypes. The General Haematoloy and Haemato-oncology Task Forces for the British Committee for Standards in Haematology classifies these disorders into a) Primary, i.e. caused by abnormalities in the eosinophil cell line; b) Secondary, i.e. caused by non-eosinophil disorders; and c) Idiopathic, cause unknown.[4] The World Health Organization classifies these disorders into a) Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1 (i.e. high eosinophil blood counts caused by mutations in the eosinophil cell line of one of these three genes), 'b) Chronic eosinophilic leukemia, and c) the Idiopathic hypereosinophiic syndrome. In the latter classification, secondary hypereosinophilia/eosinophilia is not viewed as a true disorder of eosinophils.[5][11] Here these two classifications are merged and expanded to include the many forms of secondary, i.e. reactive hypereosinophilia/eosinophilia, disorders and also includes another subtype, organ-restricted hypereosinophilias, a disorder in which eosinophil-mediated tissue damage is restricted to one organ and is often but not always associated with increased blood eosinophil counts.[citation needed]
### Primary hypereosinophilia[edit]
Primary hypereosinophilia is due to the development of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a significantly mutated ancestor cell. The clone may prove to be benign, pre-malignant, or overtly malignant. The fundamental driver of these hypereosinophilic (or uncommonly eosinophilic) disorders is the mutation which increases the proliferation, survival, and further mutation of cells descendant from the originally mutated cell. There are several subtypes of primary hypereosinophilia.[citation needed]
#### Clonal hypereosinophilia[edit]
Main article: Clonal hypereosinophilia
Clonal hypereosinophilia is hypereosinophilia caused by a pre-malignant or malignant clone of eosinophils that bear mutations in genes for PDGFRA, PDGFRB, or FGFR1 or, alternatively, a chromosome translocation that creates the PCM1-JAK2 fusion gene. These genes code for dysfunctional protein products capable of enhancing proliferation and/or survival of their parent cells which, in consequence, become an evolving and constantly growing clone of eosinophils. These mutations are recognized by the World Health Association as causing distinct entities differing from idiopathic hypereosinophilia and the idiopathic hypereosinophilic syndrome. Presence of these clones may be associated with tissue injury but in any case suggests specific therapy be directed at reducing the size and suppressing the growth of the eosinophil clone. More recently, mutations in other genes have been described as causing a similar type of clonal hypereosinophilia but have not yet been recognized as entities distinct from idiopathic hypereosinophilia and the idiopathic hyperesoniphilic syndrome. These include gene mutations in JAK2, ABL1, and FLT2 and chromosomal translocations that create the ETV6-ACSL6 fusion gene.[5]
#### Chronic eosinophilic leukemia (NOS)[edit]
Main article: Chronic eosinophilic leukemia
Chronic eosinophilic leukemia, not otherwise specified (i.e. CEL, NOS), is a leukemia-inducing disorder in the eosinophil cell lineage that causes eosinophil blood counts greater than 1,500/μL. The most recent (2017) World health organization criteria specifically excludes from this disorder hypereosinophilia/eosinophilia associated with BCR-ABL1 fusion gene-positive chronic myeloid leukemia, polycythemia vera, essential thrombocytosis, primary myelofibrosis, chronic neutrophilic leukemia, chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia, clonal eosinophilias involving gene rearrangements of PDGFRA, PDGFRB, or FGFR1, and chromosome translocations that form PCM1-JAK2, ETV6-JAK2, or BCR-JAK2 fusion genes. For this diagnosis, immature eosinophil (e.g. myeloblast) cell counts in the bone marrow and peripheral blood must be less than 20% and the chromosomal alterations (inv(16)(p13.1q22)) and t(16;16)(p13;q22) as well as other features diagnostic of acute myelogenous leukemia must be absent. The latter diagnostic features include clonal cytogenetic abnormalities and molecular genetic abnormalities diagnostic for other forms of leukemia or the presence of myeloblast counts greater than 55% in bone marrow or 2% in blood. Chronic eosinophilic leukemia may transform into acute eosinophilic or other types of acute myelogenous leukemia.[5][12]
#### Familial eosinophilia[edit]
Main article: Familial eosinophilia
Familial eosinophilia is a rare congenital disorder characterized by the presence of sustained elevations in blood eosinophil levels that reach ranges diagnostic of eosinophilia or, far more commonly, hypereosinophilia. It is an autosomal dominant disorder in which genetic linkage gene mapping family studies localize the gene responsible for it to chromosome 5 at position q31-q33,[13] between markers D5S642 and D5S816. This region contains a cytokine gene cluster which includes three genes whose protein products function in regulating the development and proliferation of eosinophils viz., interleukin 3, interleukin 5, and colony stimulating factor 2. However, no functional sequence genetic polylmophisms are found within the promoter, exons, or introns, of these genes or within the common gene enhancer for interleukin 3 or colony stimulating factor 2. This suggests that the primary defect in familial eosinophilia is not a mutation in one of these genes but rather in another gene within this chromosome area.[14] Clinical manifestations and tissue destruction related to the eosinophilia in this disorder are uncommon: familial eosinophilia typically has a benign phenotype compared to other congenital and acquired eosinophilic diseases.[15][16][17][18]
#### Idiopathic hypereosinophilia[edit]
Idiopathic hypereosinophilia (also termed hypereosinophilia of undetermined significance, i.e. HEUS) is a disorder characterized by an increase in eosinophil blood counts above 1,500/μL, as detected on at least 2 separate examinations. The disorder cannot be associated with eosinophil-based tissue damage or a primary or secondary cause of eosinophilia. That is, it is a diagnosis of exclusion and has no known cause. Over time, this disorder can resolve into a primary hypereosinphilia, typically clonal hyperesinophilia, chronic eosinphilic leukemia, or an eosinophilia associated with another hematological leukemia. The disorder may also become associated with tissue or organ damage and therefore be diagnosed as the hypereosinophilic syndrome. Idiopathic hyereosinophilia is treated by observation to detect development of the cited more serious disorders.[5][19]
#### Idiopathic hypereosiophilic syndrome[edit]
Main article: Hypereosinophilic syndrome
The idiopathic hypereosinophilic syndrome is a disorder characterized by hypereosiophilia that is associated with eosinophil-based tissue or organ damage. While almost any organ or tissue may be damaged, the lung, skin, heart, blood vessels, sinuses, kidneys, and brain are the most commonly afflicted.[7] The World Health Organization restrict this diagnosis to cases which have no well-defined cause. That is, all cases of secondary (i.e. reactive) eosinophilia (including lymphocyte-variant hypereosinophilia) and primary hypereosinophilia (including chronic eosinophilic leukemia (NOS), clonal eosinophilia, and hypereosinophilia associated with hematological malignancies) are excluded from this diagnosis.[5][7]
### Secondary hypereosinophilia[edit]
Secondary (or reactive) eosinophilias are non-clonal increases in blood eosinophil levels caused by an underlying disease. The pathogenesis of the hypereosinophilia in these diseases is thought to be the release of one or more cytokines (e.g. granulocyte macrophage colony stimulating factor, interleukin 3, interleukin 5) that: a) cause bone marrow precursor cells, i.e. CFU-Eos, to proliferate and mature into eosinophils; b) promote release of bone marrow eosinophils into the circulation, c) stimulate circulating eosinophils to enter tissues and release tissue-injuring agents. These cytokines may be released by the diseased cells or the diseased cells may cause the release of these cytokines by non-diseased cells.[20] Primary disorders associated with and known or presumed to cause hypereosinophilia or eosinophilia are given below.[citation needed]
#### Infections[edit]
Helminths are common causes of hypereosiophilia and eosinophilia in areas endemic to these parasites. Helminths infections causing increased blood eosinophil counts include: 1) nematodes, (i.e. Angiostrongylus cantonensis and Hookworm infections), ascariasis, strongyloidiasis trichinosis, visceral larva migrans, Gnathostomiasis, cysticercosis, and echinococcosis; 2) filarioidea, i.e. tropical pulmonary eosinophilia, loiasis, and onchocerciasis; and 3) flukes, i.e. schistosomiasis, fascioliasis, clonorchiasis, paragonimiasis, and fasciolopsiasis. Other infections associated with increased eosinophil blood counts include: protozoan infections, i.e. Isospora belli and Dientamoeba fragilis) and sarcocystis); fungal infections (i.e. disseminated histoplasmosis, cryptococcosis [especially in cases with central nervous system involvement]), and coccidioides); and viral infections, i.e. Human T-lymphotropic virus 1 and HIV.[7][21]
#### Autoimmune diseases[edit]
Hypereosiophilia or eosinophilia may be associated with the following autoimmune diseases: systemic lupus erythematosus eosinophilic fasciitis, eosinophilic granulomatosis with polyangiitis, dermatomyositis, severe rheumatoid arthritis, progressive systemic sclerosis, Sjögren syndrome, thromboangiitis obliterans, Behçet's disease, IgG4-related disease, inflammatory bowel diseases, sarcoidosis, bullous pemphigoid, and dermatitis herpetiformis.[7]
#### Allergic diseases[edit]
Eosinophilia and comparatively fewer cases of hypereosinophilia are associated with the following known diseases that are known or thought to have an allergic basis: allergic rhinitis, asthma, atopic dermatitis, eosinophilic esophagitis, chronic sinusitis, aspirin-induced asthma, allergic bronchopulmonary aspergillosis, chronic eosinophilic pneumonia, and Kimura's disease.[7][22]
Certain types of food allergy disorders may also be associated with eosinophilia or, less commonly, hypereosinophilia. Allergic eosinophilic esophagitis and the Food protein-induced enterocolitis syndrome are commonly associated with increased blood eosinophil levels.[23][24]
#### Drugs[edit]
A wide range of drugs are known to cause hypereosinophilia or eosinophilia accompanied by an array of allergic symptoms. Rarely, these reactions are severe causing, for example, the drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. While virtually any drug should be considered as a possible cause of these signs and symptoms, the following drugs and drug classes are some of the most frequently reported causes: penicillins, cephalosporins, dapsone, sulfonamides, carbamazepine, phenytoin, lamotrigine, valproic acid, nevirapine, efavirenz, and ibuprofen. These drugs may cause severely toxic reactions such as the DRESS syndrome. Other drugs and drug classes often reported to cause increased blood eosinophil levels accompanied by less severe (e.g. non-DRESS syndrome) symptoms include tetracyclins, doxycycline, linezolid, nitrofurantoin, metronidazole, carbamazepine, phenobarbital, lamotrigine, valproate, desipramine, amitriptyline, fluoxetine, piroxicam, diclofenac, ACE inhibitors, abacavir, nevirapine, ranitidine, cyclosporin, and hydrochlorothiazide.[7][22]
The toxic oil syndrome is associated with hypereosinophilia/eosinophilia and systemic symptoms due to one or more contaminants in rapeseed oil[7][22] and the Eosinophilia–myalgia syndrome, also associated with hypereosinophilia, appears due to trace contaminants in certain commercial batches of the amino acid, L-tryptophan.[7][25]
Allergic reactions to drugs are a common cause of eosinophilia, with manifestations ranging from diffuse maculopapular rash, to severe life-threatening drug reactions with eosinophilia and systemic symptoms (DRESS).[2] Drugs that has, allopurinol, nonsteroidal anti-inflammatory drugs (NSAIDs), some antipsychotics such as risperidone, and certain antibiotics. Phenibut, an analogue of the neurotransmitter GABA, has also been implicated in high doses. The reaction which has been shown to be T-cell mediated may also cause eosinophilia-myalgia syndrome.[2]
#### Malignancies[edit]
Certain malignancies cause a secondary eosinophilia or, less commonly, hypereosinophilia. These increases in blood eosinophils appear due to the release of stimulatory cytokines or invasion of the bone marrow and thereby irritation of resident eosinophils or their precursors. Malignancies associated with these effects include gastric, colorectal, lung, bladder, and thyroid cancers, as well as squamous cell cancers of the cervix, vagina, penis, skin, and nasopharyrnx. Some hematological malignancies are likewise associated with secondary rises in blood eosinophil counts; these include Hodgkin disease, certain T-cell lymphomas, acute myeloid leukemia, the myelodysplastic syndromes, many cases of systemic mastocytosis, chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myelofibrosis, chronic myelomonocytic leukemia, and certain cases of T-lymphoblastic leukemia/lymphoma-associated or myelodysplastic–myeloproliferative syndrome-associated eosinophilias.[7]
Hodgkin lymphoma (Hodgkin's disease) often elicits severe eosinophilia; however, non-Hodgkin lymphoma and leukemia produce less marked eosinophilia.[3] Of solid tumor neoplasms, ovarian cancer is most likely to provoke eosinophilia, though any other cancer can cause the condition.[3] Solid epithelial cell tumors have been shown to cause both tissue and blood eosinophilia, with some reports indicating that this may be mediated by interleukin production by tumor cells, especially IL-5 or IL-3.[2] This has also been shown to occur in Hodgkin lymphoma, in the form of IL-5 secreted by Reed-Sternberg cells.[2] In primary cutaneous T cell lymphoma, blood and dermal eosinophilia are often seen. Lymphoma cells have also been shown to produce IL-5 in these disorders. Other types of lymphoid malignancies have been associated with eosinophilia, as in lymphoblastic leukemia with a translocation between chromosomes 5 and 14 or alterations in the genes which encode platelet-derived growth factor receptors alpha or beta.[2][26] Patients displaying eosinophilia overexpress a gene encoding an eosinophil hematopoietin. A translocation between chromosomes 5 and 14 in patients with acute B lymphocytic leukemia resulted in the juxtaposition of the IL-3 gene and the immunoglobulin heavy-chain gene, causing overproduction production of IL-3, leading to blood and tissue eosinophilia.[2][27]
#### Primary immunodeficiency diseases[edit]
Main article: Primary immunodeficiency
Primary immunodeficiency diseases are inborn errors in the immune system due to defective genes. Certain of these disorders are sometimes or often associated with hypereosinophilia. The list of such disorders includes ZAP70 deficiency (defective ZAP70 gene), CD3gamma chain deficiency (defective CD3G gene), MCHII deficiency (defective RFXANK gene), Wiskott–Aldrich syndrome (defective WAS gene), IPEX syndrome (defective IPEX gene), CD40 gene defect, and autoimmune lymphoproliferative syndrome (defective Fas receptor gene). More than 30 other primary immunodeficiency diseases are sometimes associated with modest increases in eosinophil counts, i.e. eosinophilia.[28] The hyperimmunoglobulin E syndrome is associated with hypereosionphilia or eosinophilia due to mutations in any one of the following genes: STAT3, DOCK8, PGM3, SPINK5, and TYK2 (see mutations in the hymperimmoglobulin E syndrome).[28][29] Omenn syndrome is a severe combined immunodeficiency disease characterized by skin rash, slenomegaly, and lymphadenopathy due to a causative mutation in RAG1, RAG2, or, more rarely, one of several other genes.[28]
#### Lymphocyte-variant hypereosinophilia[edit]
Main article: Lymphocyte-variant hypereosinophilia
Lymphocyte-variant hypereosinophilia is a disorder attributed to the expansion of a cytokine-producing, aberrant population of a particular T-cell phenotype. The disorder is clonal with regard to the production of abnormal T-cell lymphocytes not eosinophils which appear phenotypically normal. The phenotypically aberrant lymphocytes function abnormally by stimulating the proliferation and maturation of bone marrow eosinophil-precursor cells which in studied cases appears due to their excess production of interleukin 5, interleukin 3, or interleukin 13. The disorder is usually indolent but infrequently progresses to T-cell lymphoma or Sezary syndrome. Accumulation of partial deletions in the short arm of chromosome 6, the long arm of chromosome 10, or the acquirement of an extra chromosome (i.e. trisomy) 7) in T-cells or the proliferation of lymphocytes with the CD3 negative, CD41 positive immunophenotype may occur during the disorders progression to lymphoma. Reports on treatment of the disorder are rare. In on study of 16 lymphocyte-variant hypereosinophilia patients with the aberrant CD3 negative, CD41 positive immunophenotype, good responds to corticosteroid drugs were uniform but 16 ultimately required corticosteroid-sparing agents. Hydroxyurea and imatinib are less likely to have efficacy in this variant of hypereosinophilia than in many cases of clonal eosinophilia or chronic eosinophilic leukemia.
#### Gleich's syndrome[edit]
Main article: Gleich's syndrome
Gleich's syndrome, which may be a form of lymphocyte-variant hypereosinophilia, involves hypereosinophilia, elevated blood levels of IgM antibodies, and clonal expansion of T cells. Similar to lymphocyte=variant hypereosinophilia, the increased levels of blood eosinophils in Gleich's syndrome is thought to be secondary to the secretion of eosinophil-stimulating cytokines by a T cell clones.[16]
#### IgG4-related disease[edit]
Main article: IgG4-related disease
IgG4-related disease or Immunoglobulin G4-related disease is a condition dacryoadenitis, sialadenitis, lymphadentitis, and pancreatitis (i.e. inflammation of the lacrimal glands, salivary glands, lymph nodes, and pancreas, respectively) plus retroperitoneal fibrosis. Less commonly, almost any other organ or tissue except joints and brain may be beleaguered by the inflammatory disorder. About 1/3 of cases exhibit eosinophilia or, rarely, hypereosinophilia. This increase in blood eosinophil count is often associated with abnormal T-lymphocyte clones (e.g. increased numbers of CD4 negative, CD7 positive T cells, CD3 negative, CD4 positive T cells, or CD3 positive, CD4 negative, CD8 negative T cells) and is thought to be secondary to these immunological disturbances. The disorder often exhibits are recurrent-relapsing course and is highly responsive to corticosteroids or rituximab as first-line therapy and interferon gamma as second-line therapy.[30]
#### Angiolymphoid hyperplasia with eosinophilia[edit]
Main article: Angiolymphoid hyperplasia with eosinophilia
Angiolymphoid hyperplasia with eosinophilia is a disorder initially classified as a form of IgG4-related diseases but now considered a distinct entity. The disorder involves inflamed benign tumors of the vasculature in skin and, less commonly, other tissues. The tumors consist of histiocytoid endothelial cells prominently infiltrated by lymphocytes and eosinophils and is associated with hypereosinophilia or eosinophilia.[31]
#### Cholesterol embolism[edit]
Main article: Cholesterol embolism
Transient, fluctuating hypereosinophilia occurs in 60%-80% of individuals suffering cholesterol embolisms. In this disorder, cholesterol crystals located in an atherosclerotic plaque of a large artery dislodge, travel downstream in the blood, and clog smaller arteries. This results in obstructive damage to multiple organs and tissues. Afflicted tissues exhibit acute inflammation involving eosinophils, neutrophils, monocytes, lymphocytes, and plasma cells. The cause for this hypereosinophilic response is not known.[32]
#### Adrenal insufficiency[edit]
A class of steroid hormones secreted by the adrenal gland, glucocorticoids, inhibit eosinophil proliferation and survival. In adrenal insufficiency, low levels of these hormones allow increased eosinophil proliferation and survival. This leads to increases in blood eosinophil levels, typically eosinophilia and, less commonly, hypereosinophilia.[33]
### Organ-restricted hypereosinophilias[edit]
Hypereosinophilia may occur in the setting of damage to a single specific organ due to a massive infiltration by eosinophils. This disorder is sub-classified based on the organ involved and is not considered to be a form of primary hypereosinophilia, secondary hypereosinophilia, or the idiopathic hypereosinophilic syndrome because: a) the eosinophils associated with the disorder have not been shown to be clonal in nature; b) a reason for the increase in blood eosinophils has not been determined; c) organ damage has not been shown to be due to eosinophils; and d) the disorder in each individual case typically is limited to the afflicted organ. Examples of organ-restricted hypereosinopilia include eosinophilic myocarditis, eosinophilic esophagitis, eosinophilic gastroenteritis, eosinophilic cystitis, eosinophilic pneumonia, eosinophilic fasciitis, eosinophilic folliculitis, eosinophilic cellulitis, eosinophilic vasculitis, and eosinophilic ulcer of the oral mucosa. Other examples of organ-restricted hepereosinophilia include those involving the heart, kidney, liver, colon, pulmonary pleurae, peritoneum, fat tissue, myometrium, and synovia.[16]
## Treatment[edit]
Treatment is directed toward the underlying cause.[3] However, in primary eosinophilia, or if the eosinophil count must be lowered, corticosteroids such as prednisone may be used. However, immune suppression, the mechanism of action of corticosteroids, can be fatal in patients with parasitosis.[2]
## List of causes[edit]
Eosinophilia can be idiopathic (primary) or, more commonly, secondary to another disease.[2][3] In the Western World, allergic or atopic diseases are the most common causes, especially those of the respiratory or integumentary systems. In the developing world, parasites are the most common cause. A parasitic infection of nearly any bodily tissue can cause eosinophilia.[citation needed] Diseases that feature eosinophilia as a sign include:
* Allergic disorders
* Asthma[34]
* Hay fever[34]
* Drug allergies[34]
* Allergic skin diseases[34]
* Pemphigus[34]
* Dermatitis herpetiformis
* IgG4-related disease
* Parasitic infections[34]
* Addison's disease and stress-induced suppression of adrenal gland function[35]
* Some forms of malignancy
* Acute lymphoblastic leukemia
* Chronic myelogenous leukemia
* Eosinophilic leukemia
* Clonal eosinophilia[18]
* Hodgkin lymphoma[34]
* Some forms of non-Hodgkin lymphoma[34]
* Lymphocyte-variant hypereosinophilia
* Systemic mastocytosis
* Systemic autoimmune diseases[34]
* Systemic lupus erythematosus
* Kimura disease[36]
* Eosinophilic granulomatosis with polyangiitis[37]
* Eosinophilic fasciitis[38]
* Eosinophilic myositis[39]
* Eosinophilic myocarditis[40]
* Eosinophilic esophagitis[41]
* Eosinophilic gastroenteritis[42]
* Cholesterol embolism (transiently)[34]
* Coccidioidomycosis (Valley fever), a fungal disease prominent in the US Southwest.[43]
* Human immunodeficiency virus infection
* Interstitial nephropathy
* Hyperimmunoglobulin E syndrome, an immune disorder characterized by high levels of serum IgE
* Idiopathic hypereosinophilic syndrome.[26]
* Congenital disorders
* Hyperimmunoglobulin E syndrome[39]
* Omenn syndrome[39]
* Familial eosinophilia[17]
## See also[edit]
* Eosinophilia-myalgia syndrome
## References[edit]
1. ^ a b "Eosinophilic Disorders". Merck & Co. Retrieved 2012-11-02.
2. ^ a b c d e f g h i j Simon, Dagmar; HU Simon (16 January 2007). "Eosinophilic Disorders". Journal of Allergy and Clinical Immunology. New York: Elsevier. 119 (6): 1291–300, quiz 1301–2. doi:10.1016/j.jaci.2007.02.010. PMID 17399779. Retrieved 21 October 2010.
3. ^ a b c d e f g h i j k l m n Beers, Mark; Porter, Robert; Jones, Thomas (2006). "Ch. 11". The Merck Manual of Diagnosis and Therapy (18th ed.). Whitehouse Station, New Jersey: Merck Research Laboratories. pp. 1093–6. ISBN 0-911910-18-2.
4. ^ a b Butt NM, Lambert J, Ali S, Beer PA, Cross NC, Duncombe A, Ewing J, Harrison CN, Knapper S, McLornan D, Mead AJ, Radia D, Bain BJ (2017). "Guideline for the investigation and management of eosinophilia" (PDF). British Journal of Haematology. 176 (4): 553–572. doi:10.1111/bjh.14488. PMID 28112388.
5. ^ a b c d e f Gotlib J (2017). "World Health Organization-defined eosinophilic disorders: 2017 update on diagnosis, risk stratification, and management". American Journal of Hematology. 92 (11): 1243–1259. doi:10.1002/ajh.24880. PMID 29044676.
6. ^ Beeken WL, Northwood I, Beliveau C, Baigent G, Gump D (1987). "Eosinophils of human colonic mucosa: C3b and Fc gamma receptor expression and phagocytic capabilities". Clinical Immunology and Immunopathology. 43 (3): 289–300. doi:10.1016/0090-1229(87)90138-3. PMID 2953511.
7. ^ a b c d e f g h i j k Kovalszki A, Weller PF (2016). "Eosinophilia". Primary Care. 43 (4): 607–617. doi:10.1016/j.pop.2016.07.010. PMC 5293177. PMID 27866580.
8. ^ Roufosse F (2013). "L4. Eosinophils: how they contribute to endothelial damage and dysfunction". Presse Médicale. 42 (4 Pt 2): 503–7. doi:10.1016/j.lpm.2013.01.005. PMID 23453213.
9. ^ Long H, Liao W, Wang L, Lu Q (2016). "A Player and Coordinator: The Versatile Roles of Eosinophils in the Immune System". Transfusion Medicine and Hemotherapy. 43 (2): 96–108. doi:10.1159/000445215. PMC 4872051. PMID 27226792.
10. ^ Oxford Respiratory Medicine Library: Asthma, 2nd ed., ed. Graeme P. Currie and John. F. W. Baker, OUP, 2012.
11. ^ Gotlib J (2014). "World Health Organization-defined eosinophilic disorders: 2014 update on diagnosis, risk stratification, and management". American Journal of Hematology. 89 (3): 325–37. doi:10.1002/ajh.23664. PMID 24577808.
12. ^ Helbig G, Soja A, Bartkowska-Chrobok A, Kyrcz-Krzemień S (2012). "Chronic eosinophilic leukemia-not otherwise specified has a poor prognosis with unresponsiveness to conventional treatment and high risk of acute transformation". American Journal of Hematology. 87 (6): 643–5. doi:10.1002/ajh.23193. PMID 22473587.
13. ^ "EOS eosinophilia, familial [Homo sapiens (human)] - Gene - NCBI".
14. ^ http://omim.org/entry/131400
15. ^ Klion AD, Law MA, Riemenschneider W, McMaster ML, Brown MR, Horne M, Karp B, Robinson M, Sachdev V, Tucker E, Turner M, Nutman TB (2004). "Familial eosinophilia: a benign disorder?". Blood. 103 (11): 4050–5. doi:10.1182/blood-2003-11-3850. PMID 14988154.
16. ^ a b c Valent P, Klion AD, Horny HP, Roufosse F, Gotlib J, Weller PF, Hellmann A, Metzgeroth G, Leiferman KM, Arock M, Butterfield JH, Sperr WR, Sotlar K, Vandenberghe P, Haferlach T, Simon HU, Reiter A, Gleich GJ (2012). "Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes". The Journal of Allergy and Clinical Immunology. 130 (3): 607–612.e9. doi:10.1016/j.jaci.2012.02.019. PMC 4091810. PMID 22460074.
17. ^ a b Prakash Babu S, Chen YK, Bonne-Annee S, Yang J, Maric I, Myers TG, Nutman TB, Klion AD (2017). "Dysregulation of interleukin 5 expression in familial eosinophilia". Allergy. 72 (9): 1338–1345. doi:10.1111/all.13146. PMC 5546948. PMID 28226398.
18. ^ a b Reiter A, Gotlib J (2017). "Myeloid neoplasms with eosinophilia". Blood. 129 (6): 704–714. doi:10.1182/blood-2016-10-695973. PMID 28028030.
19. ^ Gotlib J (2015). "World Health Organization-defined eosinophilic disorders: 2015 update on diagnosis, risk stratification, and management". American Journal of Hematology. 90 (11): 1077–89. doi:10.1002/ajh.24196. PMID 26486351.
20. ^ Roufosse F, Cogan E, Goldman M (2004). "Recent advances in pathogenesis and management of hypereosinophilic syndromes". Allergy. 59 (7): 673–89. doi:10.1111/j.1398-9995.2004.00465.x. PMID 15180753.
21. ^ Nunes MC, Guimarães Júnior MH, Diamantino AC, Gelape CL, Ferrari TC (2017). "Cardiac manifestations of parasitic diseases". Heart. 103 (9): 651–658. doi:10.1136/heartjnl-2016-309870. PMID 28285268.
22. ^ a b c Curtis C, Ogbogu PU (2015). "Evaluation and Differential Diagnosis of Persistent Marked Eosinophilia". Immunology and Allergy Clinics of North America. 35 (3): 387–402. doi:10.1016/j.iac.2015.04.001. PMID 26209891.
23. ^ Ho MH, Wong WH, Chang C (2014). "Clinical spectrum of food allergies: a comprehensive review". Clinical Reviews in Allergy & Immunology. 46 (3): 225–40. doi:10.1007/s12016-012-8339-6. PMID 23229594.
24. ^ Manti S, Leonardi S, Salpietro A, Del Campo G, Salpietro C, Cuppari C (2017). "A systematic review of food protein-induced enterocolitis syndrome from the last 40 years". Annals of Allergy, Asthma & Immunology. 118 (4): 411–418. doi:10.1016/j.anai.2017.02.005. PMID 28390583.
25. ^ Oketch-Rabah HA, Roe AL, Gurley BJ, Griffiths JC, Giancaspro GI (2016). "The Importance of Quality Specifications in Safety Assessments of Amino Acids: The Cases of l-Tryptophan and l-Citrulline". The Journal of Nutrition. 146 (12): 2643S–2651S. doi:10.3945/jn.115.227280. PMID 27934657.
26. ^ a b Fathi AT, Dec GW, Richter JM, et al. (February 2014). "Case records of the Massachusetts General Hospital. Case 7-2014. A 27-year-old man with diarrhea, fatigue, and eosinophilia". N. Engl. J. Med. 370 (9): 861–72. doi:10.1056/NEJMcpc1302331. PMID 24571759.
27. ^ Takhar, Rajendra; Motilal, Bunkar; Savita, Arya (2015). "Peripheral eosinophilia in a case of adenocarcinoma lung: A rare association". The Journal of Association of Chest Physicians. 3 (2): 60. doi:10.4103/2320-8775.158859.
28. ^ a b c Navabi B, Upton JE (2016). "Primary immunodeficiencies associated with eosinophilia". Allergy, Asthma, and Clinical Immunology. 12: 27. doi:10.1186/s13223-016-0130-4. PMC 4878059. PMID 27222657.
29. ^ Szczawinska-Poplonyk A, Kycler Z, Pietrucha B, Heropolitanska-Pliszka E, Breborowicz A, Gerreth K (2011). "The hyperimmunoglobulin E syndrome--clinical manifestation diversity in primary immune deficiency". Orphanet Journal of Rare Diseases. 6: 76. doi:10.1186/1750-1172-6-76. PMC 3226432. PMID 22085750.
30. ^ Carruthers MN, Park S, Slack GW, Dalal BI, Skinnider BF, Schaeffer DF, Dutz JP, Law JK, Donnellan F, Marquez V, Seidman M, Wong PC, Mattman A, Chen LY (2017). "IgG4-related disease and lymphocyte-variant hypereosinophilic syndrome: A comparative case series". European Journal of Haematology. 98 (4): 378–387. doi:10.1111/ejh.12842. PMID 28005278.
31. ^ Guo R, Gavino AC (2015). "Angiolymphoid hyperplasia with eosinophilia". Archives of Pathology & Laboratory Medicine. 139 (5): 683–6. doi:10.5858/arpa.2013-0334-RS. PMID 25927152.
32. ^ Zhang J, Zhang HY, Chen SZ, Huang JY (2016). "Anti-neutrophil cytoplasmic antibodies in cholesterol embolism: A case report and literature review". Experimental and Therapeutic Medicine. 12 (2): 1012–1018. doi:10.3892/etm.2016.3349. PMC 4950912. PMID 27446313.
33. ^ Montgomery ND, Dunphy CH, Mooberry M, Laramore A, Foster MC, Park SI, Fedoriw YD (2013). "Diagnostic complexities of eosinophilia". Archives of Pathology & Laboratory Medicine. 137 (2): 259–69. doi:10.5858/arpa.2011-0597-RA. PMID 23368869.
34. ^ a b c d e f g h i j Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson (2007). "Table 12-6". Robbins Basic Pathology (8th ed.). Philadelphia: Saunders. ISBN 978-1-4160-2973-1.
35. ^ Angelis, M; Yu, M; Takanishi, D; Hasaniya, NW; Brown, MR (December 1996). "Eosinophilia as a marker of adrenal insufficiency in the surgical intensive care unit". Journal of the American College of Surgeons. 183 (6): 589–96. PMID 8957461.
36. ^ Boyer, DF (October 2016). "Blood and Bone Marrow Evaluation for Eosinophilia". Archives of Pathology & Laboratory Medicine. 140 (10): 1060–7. doi:10.5858/arpa.2016-0223-RA. PMID 27684977.
37. ^ Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome) at eMedicine
38. ^ Arlettaz L, Abdou M, Pardon F, Dayer E (2012). "[Eosinophllic fasciitis (Shulman disease)]". Revue Médicale Suisse (in French). 8 (337): 854–8. PMID 22594010.
39. ^ a b c Boyer DF (2016). "Blood and Bone Marrow Evaluation for Eosinophilia". Archives of Pathology & Laboratory Medicine. 140 (10): 1060–7. doi:10.5858/arpa.2016-0223-RA. PMID 27684977.
40. ^ Séguéla PE, Iriart X, Acar P, Montaudon M, Roudaut R, Thambo JB (2015). "Eosinophilic cardiac disease: Molecular, clinical and imaging aspects". Archives of Cardiovascular Diseases. 108 (4): 258–68. doi:10.1016/j.acvd.2015.01.006. PMID 25858537.
41. ^ "Eosinophilic Esophagitis". 16 January 2015.
42. ^ Eosinophilic Gastroenteritis at eMedicine
43. ^ Saubolle MA, McKellar PP, Sussland D (January 2007). "Epidemiologic, clinical, and diagnostic aspects of coccidioidomycosis". J. Clin. Microbiol. 45 (1): 26–30. doi:10.1128/JCM.02230-06. PMC 1828958. PMID 17108067.
## External links[edit]
Classification
D
* ICD-10: D72.1
* ICD-9-CM: 288.3
* MeSH: D004802
* DiseasesDB: 4328
* SNOMED CT: 419455006
External resources
* eMedicine: med/685
* Patient UK: Eosinophilia
* Hypereosinophilic Syndrome research in UK
* Hypereosinophilic Syndrome on patient.info
* Hypereosinophilic Syndrome on eMedicine
* Hypereosinophilic Syndrome (HES) on American Academy of Allergy, Asthma & Immunology
* Hypereosinophilic syndrome on Mayo Clinic
* v
* t
* e
Diseases of monocytes and granulocytes
Monocytes and macrophages
↑
-cytosis:
* Monocytosis
* Histiocytosis
* Chronic granulomatous disease
↓
-penia:
* Monocytopenia
Granulocytes
↑
-cytosis:
* granulocytosis
* Neutrophilia
* Eosinophilia/Hypereosinophilic syndrome
* Basophilia
* Bandemia
↓
-penia:
* Granulocytopenia/agranulocytosis (Neutropenia/Severe congenital neutropenia/Cyclic neutropenia
* Eosinopenia
* Basopenia)
Disorder of phagocytosis
Chemotaxis and degranulation
* Leukocyte adhesion deficiency
* LAD1
* LAD2
* Chédiak–Higashi syndrome
* Neutrophil-specific granule deficiency
Respiratory burst
* Chronic granulomatous disease
* Neutrophil immunodeficiency syndrome
* Myeloperoxidase deficiency
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Eosinophilia | c0014457 | 2,555 | wikipedia | https://en.wikipedia.org/wiki/Eosinophilia | 2021-01-18T18:38:32 | {"mesh": ["D004802"], "umls": ["C0014457"], "wikidata": ["Q505142"]} |
An ileosigmoid knot is a form of volvulus in which ileum wraps around the base of the sigmoid and passes beneath itself forming a knot.
The exact cause of this condition is not known. Patients usually present with clinical features of colonic obstruction. Vomiting, abdominal distension, abdominal pain, blood stained stools are frequent symptoms. It is difficult to diagnose this condition before surgery. Raveenthiran described a triad which may be useful in preoperative diagnosis. The triad includes 1). Clinical features suggestive of small bowel obstruction, 2). Radiological features suggestive of large bowel obstruction, 3). Inability to negotiate sigmoidoscope or a flatus tube. This is a surgical emergency that requires urgent resection of gangrenous bowel and untwisting of the volvulus.
## References[edit]
* Raveenthiran V (August 2001). "The ileosigmoid knot: new observations and changing trends". Diseases of the Colon and Rectum. 44 (8): 1196–200. doi:10.1007/BF02234644. PMID 11535862.
This article about a disease, disorder, or medical condition is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Ileosigmoid knot | None | 2,556 | wikipedia | https://en.wikipedia.org/wiki/Ileosigmoid_knot | 2021-01-18T18:49:05 | {"wikidata": ["Q5997595"]} |
Not to be confused with Odontogenic cyst or Glandular odontogenic cyst.
Calcifying odontogenic cyst
Other namesGorlin cyst, calcifying cystic odontogenic tumor[1]
This condition usually affects the jaw area
SpecialtyDentistry
Calcifying odotogenic cyst (COC) is a rare developmental lesion that comes from odontogenic epithelium.[2] It is also known as a calcifying cystic odontogenic tumor, which is a proliferation of odontogenic epithelium and scattered nest of ghost cells and calcifications that may form the lining of a cyst, or present as a solid mass.[3]
It can appear in any location in the oral cavity, but more commonly affects the anterior (front) mandible and maxilla. It is most common in individuals in their 20s to 30s, but can be seen at almost any age, regardless of gender. On dental radiographs, the calcifying odontogenic cyst appears as a unilocular (one circle) radiolucency (dark area). In one-third of cases, an impacted tooth is involved. Histologically, cells that are described as "ghost cells", enlarged eosinophilic epithelial cells without nuclei, are present within the epithelial lining and may undergo calcification.
## Contents
* 1 Signs and symptoms
* 2 Causes
* 3 Mechanism/Pathophysiology
* 3.1 Pathogenesis
* 4 Diagnosis
* 4.1 Radiographic features
* 4.2 CT Scan
* 4.3 Histology
* 5 Treatment
* 6 Prognosis
* 7 Epidemiology
* 8 Research Directions
* 9 See also
* 10 References
* 11 External links
## Signs and symptoms[edit]
Relative incidence of odontogenic cysts.[4] Calcifying odontogenic cyst is labeled at right.
Most calcifying odontogenic cysts appear asymptomatic.[2] They are normally presented as a painless, slow-growing mass on the mandible and/or the maxilla, mostly in the front of the mouth.[5] Symptoms include swelling in the mouth, both inside the bone, in the tooth bearing areas, and outside the bone, in the gingiva. When a COC is located in the maxilla, individuals might complain of nasal stiffness, epistaxis, and headache.
Impacted or displaced teeth are often found due to COC. The diameter of the cyst ranges from 2 to 4 cm and swelling pain may be present. Intrabony (between bone) expansions may produce hard bony expansion and may perforate cortical bones. It can also extend to soft tissue.[6]
## Causes[edit]
It is believed that the calcifying odontogenic cyst arose from odontogenic epithelial remnants (remains) that were trapped within the bones of the maxilla and mandible or gingival tissues.[2] It is associated with impacted and unerupted teeth.
## Mechanism/Pathophysiology[edit]
Calcifying odontogenic cyst can is the presence of a variable number of ghost cells within the epithelial lining. The eosinophilic ghost cells are those that have been changed in a way without a nucleus, but it has been able to maintain its basic cell shape.[7]
The mechanism for the formation of a calcifying odontogenic cyst is controversial, whether the ghost cells change is based on coagulative necrosis (accidental cell death caused by ischemia or infarction)/the build up of enamel protein or it's a form of normal or abnormal keratinization (formation of keratin proteins) of odontogenic epithelium.[7] Large amounts of ghost cells fuse together to form large sheets of material with an undefined shape and are acellular. Calcification of the sheets may occur. It first appears as fine basophilic granules that increase in size and number forming large masses of calcifying material. Eosinophilic dentinoid (abnormal form of dentin) material is present next to a sheet of ghost cells.[7]
Some forms of the cystic type of COC, the epithelial lining proliferates into the lumen (inside space of the cyst) so its filled with masses of ghost cells and dystrophic calcifications.[7]
In a different form, unifocal or multifocal epithelial proliferation (increase in numbers) of the cyst lining into the lumen may look similar to ameloblastoma. These proliferations have a mix of different number of ghost cells.[7]
Neoplastic or solid COC are uncommon. They consist of extraosseous (outside bone) and intraosseous (inside bone) forms. Extraosseous being most common of the two, consists of odontogenic epithelium in the fibrous stroma, with columnar cells and stellate reticulum and ghost cells. Intraosseous consists of ameloblastoma-like strands and epithelium in fibrous connective tissue stroma with ghost cells present.[7]
There are small number of malignant odontogenic ghost cell tumors (odontogenic ghost cell carcinoma). These are aggressive and invade surrounding tissues through cellular pleomorphism and mitotic activity.[7]
### Pathogenesis[edit]
Epithelial lining has ability to induce formation of dental tissues in adjacent connective tissue wall.[6]
## Diagnosis[edit]
### Radiographic features[edit]
These calcifying odontogenic cysts are usually discovered using dental radiographs. They will appear as unilocular (one chamber), multilocular (multiple chambers) or mixed radiolucencies with some radiopaque deposits of differing sizes and opacities.[5] Irregular calcifications may be seen in some cases. They are often located in a periapical or lateral periodontal relationship to adjacent teeth.[2]
### CT Scan[edit]
CT scans can also be used to view the internal structures of the lesions and the involvement of neighboring structures. It is helpful in clinical diagnoses and treatment planning. They reveal vital characteristics that are not shown or detected in a dental radiograph. They are used to confirm the presence of calcifications along the cyst wall that were not detected in the radiographic images.[2]
### Histology[edit]
In general, the epithelium seen is of stratified squamous type and is 5–8 cells thick. Additionally, focal areas of stellate reticulum like cells are seen and near the basement membrane ameloblast-like cells may be seen. Each type of calcifying odontogenic cyst shows special features of which there are three types:[8]
1)Type 1A. Ghost cells and dentinoid are seen.[8]
2)Type 1B. Formation of calcified tissues in the lumen of the cyst wall showing dystrophic calcification. Proliferation of tissues is similar to an Ameloblastic Fibroma.[8]
3)Type 1C. Ameloblast-like proliferation in the connective tissue and lumen of the cyst may be seen.[8]
## Treatment[edit]
The standard treatment of calcifying odontogenic cyst is enucleation and curettage, however it depends on the lesion site and histological pattern. Enucleation followed by the removal of 1 to 2 millimeters layer of bone around the edges of the cystic cavity with a sharp curette or bone bur. The point of this procedure is to remove the epithelial debris that could cause recurrent lesions.[5] Recurrence following enucleation and curretage is rare.[9]
Once treatment is complete, follow-up visits may be required to monitor recurrence of the cyst.[5]
## Prognosis[edit]
The prognosis of a calcifying odontogenic cyst is favorable.[2] It has minimal chance of reccurance after simple surgical removal. There have only been a small number of recurrances reported after enucleation.[7]
## Epidemiology[edit]
About 65% of cases are found in the front of the mouth in the incisor and canine areas. It may occur in individuals aged between infancy to elderly, but the average is 33 years.[7] However, it most commonly occurs in individuals in their twenties to thirties.[2] There is no correlation to gender and race because it can occur in any individual.[2]
## Research Directions[edit]
A calcifying odontogenic cyst is a very uncommon lesion.[10] One researcher stated that he reviewed the COC for 3 year and has only found 51 cases diagnosed as COC.[10] The average number of cases that an oral and maxillofacial surgeon would only see about 1 to 2 cases in their career.[10]
In a case study that was conducted in 2011, a 23 year-old female came with in swelling in the upper right side of the jaw that had been present for about 2 years. Upon examination, there was asymmetry of the face that involved the right midface area.[10] A hard bony expansion could be felt when touching the right maxilla. The radiographic examination showed unilocular, well-circumscribed, round radiolucency in the front, right maxilla extending above the canine to the central incisor (front tooth).[10] Based on clinical and radiographic findings, the diagnosis was considered to be a calcifying odontogenic cyst or calcifying odontogenic tumor. It was treated with an enucleation of the cyst which was 4 to 5 mm in diameters. The specimen was sent for a biopsy and it was revealed that the cyst was indeed a calcifying odontogenic cyst.[10] The purpose of this article was to demonstrate the importance of radiographic and clinical examination for the diagnosis of the COC so proper treatment may be performed as well as histopathological evaluation for confirmation of the diagnosis.
In a 2018 case study, a total of 6,250 oral and maxillofacial lesions were diagnosed during a 26 year study period.[11] Of those 6,250 cases, only 20 cases, or 0.3%, were confirmed diagnoses of COC. Most were found in the mandible and the age ranged from 9 to 58 years. 90% reported no painful symptoms, however, 10% did.[11] In this study, there was a higher prevalence of COC in the posterior mandible, which is about 55% of the cases.[11] This study was compared to other studies, which found the prevalence of COC occurring mostly in the maxilla and the anterior region.[11] The location of the lesion is important for diagnosis because many other bone diseases can be commonly found in the posterior mandible.[11]
## See also[edit]
* Cyst
* Odontogenic cyst
## References[edit]
1. ^ Kler, Shikha; Palaskar, Sangeeta; Shetty, and, Vishwa Parkash; Bhushan, Anju (2009), "Intraosseous calcifying cystic odontogenic tumor", J Oral Maxillofac Pathol, 13 (1): 27–29, doi:10.4103/0973-029X.48753, PMC 3162852, PMID 21886994.
2. ^ a b c d e f g h Zornosa, Ximena; Müller, Susan (2010-07-24). "Calcifying Cystic Odontogenic Tumor". Head and Neck Pathology. 4 (4): 292–294. doi:10.1007/s12105-010-0197-z. ISSN 1936-055X. PMC 2996493. PMID 20658217.
3. ^ Gamoh, Shoko; Akiyama, Hironori; Furukawa, Chisato; Matsushima, Yuki; Iseki, Tomio; Wato, Masahiro; Tanaka, Akio; Morita, Shosuke; Shimizutani, Kimishige (2017-11-01). "Calcifying cystic odontogenic tumor accompanied by a dentigerous cyst: A case report". Oncology Letters. 14 (5): 5785–5790. doi:10.3892/ol.2017.6993. ISSN 1792-1074. PMC 5661555. PMID 29113208.
4. ^ Leandro Bezerra Borges; Francisco Vagnaldo Fechine; Mário Rogério Lima Mota; Fabrício Bitu Sousa; Ana Paula Negreiros Nunes Alves (2012). "Odontogenic lesions of the jaw: a clinical-pathological study of 461 cases". Revista Gaúcha de Odontologia. 60 (1).CS1 maint: multiple names: authors list (link)
5. ^ a b c d Utumi, Estevam Rubens; Pedron, Irineu Gregnanin; Silva, Leopoldo Penteado Nucci da; Machado, Gustavo Grothe; Rocha, André Caroli (September 2012). "Distintas manifestações do tumor odontogênico cístico calcificante". Einstein (São Paulo). 10 (3): 366–370. doi:10.1590/S1679-45082012000300019. ISSN 1679-4508. PMID 23386019.
6. ^ a b Regezi JA, Sciubba J, Jordan RCK (2012-04-15). Oral Pathology: Clinical Pathologic Correlations. Elsevier Health Sciences. p. 259. ISBN 978-1-4557-0269-5.
7. ^ a b c d e f g h i Oral and maxillofacial pathology. Neville, Brad W. (3rd ed.). St. Louis, Mo.: Saunders/Elsevier. 2009. ISBN 978-1-4377-2197-3. OCLC 834142726.CS1 maint: others (link)
8. ^ a b c d Kler, Shikha; Palaskar, Sangeeta; Shetty, Vishwa Parkash; Bhushan, Anju (2009). "Intraosseous calcifying cystic odontogenic tumor". Journal of Oral and Maxillofacial Pathology. 13 (1): 27–29. doi:10.4103/0973-029X.48753. ISSN 0973-029X. PMC 3162852. PMID 21886994.
9. ^ Mervyn Shear; Paul Speight (2008-04-15). Cysts of the Oral and Maxillofacial Regions. John Wiley & Sons. p. 107. ISBN 978-0-470-75972-1.
10. ^ a b c d e f Sonone, Archana; Sabane, V. S.; Desai, Rajeev (2011). "Calcifying Ghost Cell Odontogenic Cyst: Report of a Case and Review of Literature". Case Reports in Dentistry. 2011: 328743. doi:10.1155/2011/328743. ISSN 2090-6447. PMC 3335591. PMID 22567434.
11. ^ a b c d e Arruda, José-Alcides; Silva, Leni-Verônica; Silva, Leorik; Monteiro, João-Luiz; Álvares, Pamella; Silveira, Marcia; Sobral, Ana-Paula (2018-06-01). "Calcifying odontogenic cyst: A 26-year retrospective clinicopathological analysis and immunohistochemical study". Journal of Clinical and Experimental Dentistry. 10 (6): e542–e547. doi:10.4317/jced.54528. ISSN 1989-5488. PMC 6005085. PMID 29930772.
## External links[edit]
Classification
D
* MeSH: D018333
* v
* t
* e
Acquired tooth disease
Hard tissues
* Caries (tooth decay)
* Attrition
* Abrasion
* Erosion
* Hypercementosis
* tooth resorption (External resorption, Internal resorption, Root resorption)
Pulp/periapical (Endodontal)
Pulpal
* External resorption
* Internal resorption
* Irreversible pulpitis
* Reversible pulpitis
* Pulp necrosis
* Pink tooth of Mummery
Periapical
* Acute apical periodontitis
* Chronic apical periodontitis
* Combined periodontic-endodontic lesions
* Fistula
* Periapical abscess
* Phoenix abscess
* Vertical root fracture
Ungrouped
* Pulpitis
* Radicular cyst
* Periapical abscess
Gingiva/periodontal
(Periodontal)
* Gingivitis
* Periodontitis (Chronic periodontitis)
* Periodontal disease
Bone cyst
* Dentigerous cyst
* Calcifying odontogenic cyst
* Glandular odontogenic cyst
Other
* Cracked tooth syndrome
To be grouped
from periodontology
Diagnoses
* Chronic periodontitis
* Localized aggressive periodontitis
* Generalized aggressive periodontitis
* Periodontitis as a manifestation of systemic disease
* Necrotizing periodontal diseases
* Abscesses of the periodontium
* Combined periodontic-endodontic lesions
Pathogenesis
* A. actinomycetemcomitans
* Capnocytophaga sp.
* F. nucleatum
* P. gingivalis
* P. intermedia
* T. forsythia
* T. denticola
Pathologic entities
* Calculus
* Edentulism
* Fremitus
* Furcation defect
* Gingival enlargement
* Gingival pocket
* Gingivitis
* Horizontal bony defect
* Linear gingival erythema
* Occlusal trauma
* Periodontal pocket
* Periodontal disease
* Periodontitis
* Plaque
* Recession
* Vertical bony defect
* v
* t
* e
Cystic diseases
Respiratory system
* Langerhans cell histiocytosis
* Lymphangioleiomyomatosis
* Cystic bronchiectasis
Skin
* stratified squamous: follicular infundibulum
* Epidermoid cyst and Proliferating epidermoid cyst
* Milia
* Eruptive vellus hair cyst
* outer root sheath
* Trichilemmal cyst and Pilar cyst and Proliferating trichilemmal cyst and Malignant trichilemmal cyst
* sebaceous duct
* Steatocystoma multiplex and Steatocystoma simplex
* Keratocyst
* nonstratified squamous: Cutaneous ciliated cyst
* Hidrocystoma
* no epithelium: Pseudocyst of the auricle
* Mucocele
* other and ungrouped: Cutaneous columnar cyst
* Keratin implantation cyst
* Verrucous cyst
* Adenoid cystic carcinoma
* Breast cyst
Human musculoskeletal system
* Cystic hygroma
Human digestive system
* oral cavity: Cysts of the jaws
* Odontogenic cyst
* Periapical cyst
* Dentigerous cyst
* Odontogenic keratocyst
* Nasopalatine duct cyst
* liver: Polycystic liver disease
* Congenital hepatic fibrosis
* Peliosis hepatis
* bile duct: Biliary hamartomas
* Caroli disease
* Choledochal cysts
* Bile duct hamartoma
Nervous system
* Cystic leukoencephalopathy
Genitourinary system
* Polycystic kidney disease
* Autosomal dominant polycystic kidney
* Autosomal recessive polycystic kidney
* Medullary cystic kidney disease
* Nephronophthisis
* Congenital cystic dysplasia
Other conditions
* Hydatid cyst
* Von Hippel–Lindau disease
* Tuberous sclerosis
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Calcifying odontogenic cyst | c0206740 | 2,557 | wikipedia | https://en.wikipedia.org/wiki/Calcifying_odontogenic_cyst | 2021-01-18T19:09:10 | {"mesh": ["D018333"], "wikidata": ["Q5018774"]} |
A transmissible cancer is a cancer cell or cluster of cancer cells that can be transferred between individuals without the involvement of an infectious agent, such as an oncovirus.[1][2] Transmission of cancer between humans is rare.[2] The evolution of transmissible cancer has occurred naturally in other animal species, but—similarly to human cancer transmission—is rare.
## Contents
* 1 Humans
* 2 Other animals
* 2.1 Canine transmissible venereal tumor
* 2.2 Contagious reticulum cell sarcoma
* 2.3 Devil facial tumour disease
* 2.4 Soft-shell clams
* 2.5 Horizontally transmitted cancers
* 3 See also
* 4 References
* 5 External links
## Humans[edit]
In humans, a significant fraction of Kaposi's sarcoma occurring after transplantation may be due to tumorous outgrowth of donor cells.[3] Although Kaposi's sarcoma is caused by a virus (Kaposi's sarcoma-associated herpesvirus), in these cases, it appears likely that transmission of virus-infected tumor cells—rather than the free virus—caused tumors in the transplant recipients.[2]
In 2007, four people received different organ transplants (liver, both lungs and kidneys) from a 53-year-old woman who had recently died from intracranial bleeding. Before transplantation, the organ donor was deemed to have no signs of cancer upon medical examination. Later, the organ recipients developed metastatic breast cancer from the organs and three of them died from the cancer between 2009–2017.[4]
In 2014, a case of parasite-to-host cancer transmission occurred in a 41-year-old man in Colombia with a compromised immune system due to HIV. The man's tumor cells were shown to have originated from the dwarf tapeworm, Hymenolepis nana.[5] In 1990s, an undifferentiated pleomorphic sarcoma was transmitted from a patient to a surgeon when he injured his hand during an operation – within five months a tumor developed on the hand. The tumor was removed.[6] In 1986, a laboratory worker accidentally bruised herself with the needles she was using to inject colonic cancer cells into mice. She developed a small tumor on her hand in two weeks.[7]
## Other animals[edit]
Contagious cancers are known to occur in dogs, Tasmanian devils, Syrian hamsters, and some marine bivalves including soft-shell clams. These cancers have a relatively stable genome as they are transmitted.[8]
Clonally transmissible cancer, caused by a clone of malignant cells rather than a virus,[9] is an extremely rare disease modality,[10] with few transmissible cancers being known.[1] The evolution of transmissible cancer is unlikely, because the cell clone must be adapted to survive a physical transmission of living cells between hosts, and must be able to survive in the environment of a new host's immune system.[11] Animals that have undergone population bottlenecks may be at greater risks of contracting transmissible cancers.[12] Because of their transmission, it was initially thought that these diseases were caused by the transfer of oncoviruses, in the manner of cervical cancer caused by human papillomavirus.[2] However, canine transmissible venereal tumor mutes the expression of the immune response, whereas the Syrian hamster disease spreads due to lack of genetic diversity.[13]
### Canine transmissible venereal tumor[edit]
See also: Canine transmissible venereal tumor
Canine transmissible venereal tumor (CTVT) is sexually transmitted cancer in dogs. It was first described medically by a veterinary practitioner in London in 1810.[14] It was experimentally transplanted between dogs in 1876 by M. A. Novinsky (1841–1914). A single malignant clone of CTVT cells has colonized dogs worldwide, representing the oldest known malignant cell line in continuous propagation,[15] a fact that was uncovered in 2006. Researchers deduced that the CTVT went through 2 million mutations to reach its actual state, and inferred it started to develop in ancient dog species 11 000 years ago.[14]
### Contagious reticulum cell sarcoma[edit]
Contagious reticulum cell sarcoma of the Syrian hamster[16] can be transmitted from one Syrian hamster to another by means of the bite of the mosquito Aedes aegypti.[17]
### Devil facial tumour disease[edit]
See also: Devil facial tumour disease
Devil facial tumour disease (DFTD) is a transmissible parasitic cancer in the Tasmanian devil.[18] Since its discovery in 1996, DFTD has spread and infected 4/5 of all Tasmanian devils and threatens them with extinction.[19] A new DFTD tumor-type cancer was recently uncovered on 5 Tasmanian devils (DFT2), histologically different from DFT1, leading researchers to believe that the Tasmanian devil "is particularly prone to the emergence of transmissible cancers".[14]
### Soft-shell clams[edit]
Soft-shell clams, Mya arenaria, have been found to be vulnerable to a transmissible neoplasm of the hemolymphatic system — effectively, leukemia.[20][21] The cells have infected clam beds hundreds of miles from each other, making this clonally transmissible cancer the only one that does not require contact for transmission.[14]
### Horizontally transmitted cancers[edit]
Horizontally transmitted cancers have also been discovered in three other species of marine bivalves: bay mussels (Mytilus trossulus), common cockles (Cerastoderma edule) and golden carpet shell clams (Polititapes aureus). The golden carpet shell clam cancer was found to have been transmitted from another species, the pullet carpet shell (Venerupis corrugata).[22][23]
## See also[edit]
* Allotransplantation
* Anne-Maree Pearse
## References[edit]
1. ^ a b Ostrander EA, Davis BW, Ostrander GK (January 2016). "Transmissible Tumors: Breaking the Cancer Paradigm". Trends in Genetics. 32 (1): 1–15. doi:10.1016/j.tig.2015.10.001. PMC 4698198. PMID 26686413.
2. ^ a b c d Welsh JS (2011). "Contagious cancer". The Oncologist. 16 (1): 1–4. doi:10.1634/theoncologist.2010-0301. PMC 3228048. PMID 21212437.
3. ^ Barozzi P, Luppi M, Facchetti F, Mecucci C, Alù M, Sarid R, et al. (May 2003). "Post-transplant Kaposi sarcoma originates from the seeding of donor-derived progenitors". Nature Medicine. 9 (5): 554–61. doi:10.1038/nm862. PMID 12692543.
4. ^ Matser YA, Terpstra ML, Nadalin S, Nossent GD, de Boer J, van Bemmel BC, et al. (July 2018). "Transmission of breast cancer by a single multiorgan donor to 4 transplant recipients". American Journal of Transplantation. 18 (7): 1810–1814. doi:10.1111/ajt.14766. PMID 29633548.
5. ^ Muehlenbachs A, Bhatnagar J, Agudelo CA, Hidron A, Eberhard ML, Mathison BA, et al. (November 2015). "Malignant Transformation of Hymenolepis nana in a Human Host". The New England Journal of Medicine. 373 (19): 1845–52. doi:10.1056/NEJMoa1505892. PMID 26535513.
6. ^ Gärtner HV, Seidl C, Luckenbach C, Schumm G, Seifried E, Ritter H, Bültmann B (November 1996). "Genetic analysis of a sarcoma accidentally transplanted from a patient to a surgeon". The New England Journal of Medicine. 335 (20): 1494–6. doi:10.1056/NEJM199611143352004. PMID 8890100.
7. ^ Gugel EA, Sanders ME (December 1986). "Needle-stick transmission of human colonic adenocarcinoma". The New England Journal of Medicine. 315 (23): 1487. doi:10.1056/NEJM198612043152314. PMID 3785302.
8. ^ Weiss RA, Fassati A, Murgia C (2006). "A sexually transmitted parasitic cancer". Retrovirology. 3 (Supplement 1): S92. doi:10.1186/1742-4690-3-S1-S92.
9. ^ Rebbeck CA, Thomas R, Breen M, Leroi AM, Burt A (September 2009). "Origins and evolution of a transmissible cancer". Evolution; International Journal of Organic Evolution. 63 (9): 2340–9. doi:10.1111/j.1558-5646.2009.00724.x. PMID 19453727.
10. ^ Strakova A, Murchison EP (February 2015). "The cancer which survived: insights from the genome of an 11000 year-old cancer" (PDF). Current Opinion in Genetics & Development. 30: 49–55. doi:10.1016/j.gde.2015.03.005. PMID 25867244.
11. ^ Baez-Ortega A, Gori K, Strakova A, Allen JL, Allum KM, Bansse-Issa L, et al. (August 2019). "Somatic evolution and global expansion of an ancient transmissible cancer lineage". Science. 365 (6452): eaau9923. doi:10.1126/science.aau9923. PMC 7116271. PMID 31371581.
12. ^ Belov K (February 2011). "The role of the Major Histocompatibility Complex in the spread of contagious cancers". Mammalian Genome. 22 (1–2): 83–90. doi:10.1007/s00335-010-9294-2. PMID 20963591.
13. ^ Siddle HV, Kreiss A, Eldridge MD, Noonan E, Clarke CJ, Pyecroft S, et al. (October 2007). "Transmission of a fatal clonal tumor by biting occurs due to depleted MHC diversity in a threatened carnivorous marsupial". Proceedings of the National Academy of Sciences of the United States of America. 104 (41): 16221–6. doi:10.1073/pnas.0704580104. PMC 1999395. PMID 17911263.
14. ^ a b c d Harrison C (May 2018). "Clonally transmissible cancers in nature". Cancer Therapy Advisor. Retrieved 2019-10-03.
15. ^ Murgia C, Pritchard JK, Kim SY, Fassati A, Weiss RA (August 2006). "Clonal origin and evolution of a transmissible cancer". Cell. 126 (3): 477–87. doi:10.1016/j.cell.2006.05.051. PMC 2593932. PMID 16901782.
16. ^ Copper HL, Mackay CM, Banfield WG (October 1964). "Chromosome studies of a contagious reticulum cell sarcoma of the Syrian hamster". Journal of the National Cancer Institute. 33 (4): 691–706. doi:10.1093/jnci/33.4.691. PMID 14220251.
17. ^ Banfield WG, Woke PA, Mackay CM, Cooper HL (May 1965). "Mosquito transmission of a reticulum cell sarcoma of hamsters". Science. 148 (3674): 1239–40. doi:10.1126/science.148.3674.1239. PMID 14280009.
18. ^ Pearse AM, Swift K (February 2006). "Allograft theory: transmission of devil facial-tumour disease". Nature. 439 (7076): 549. doi:10.1038/439549a. PMID 16452970.
19. ^ Epstein, Brendan; Jones, Menna; Hamede, Rodrigo; Hendricks, Sarah; McCallum, Hamish; Murchison, Elizabeth P.; Schönfeld, Barbara; Wiench, Cody; Hohenlohe, Paul; Storfer, Andrew (2016-08-30). "Rapid evolutionary response to a transmissible cancer in Tasmanian devils". Nature Communications. 7 (1): 12684. doi:10.1038/ncomms12684. ISSN 2041-1723.
20. ^ Yong E (2015-04-09). "Selfish shellfish cells cause contagious clam cancer". National Geographic. Archived from the original on 2015-09-05. Retrieved 2015-04-10.
21. ^ Metzger MJ, Reinisch C, Sherry J, Goff SP (April 2015). "Horizontal transmission of clonal cancer cells causes leukemia in soft-shell clams". Cell. 161 (2): 255–63. doi:10.1016/j.cell.2015.02.042. PMC 4393529. PMID 25860608.
22. ^ Metzger MJ, Villalba A, Carballal MJ, Iglesias D, Sherry J, Reinisch C, et al. (June 2016). "Widespread transmission of independent cancer lineages within multiple bivalve species". Nature. 534 (7609): 705–9. doi:10.1038/nature18599. PMC 4939143. PMID 27338791.
23. ^ Frierman EM, Andrews JD (February 1976). "Occurrence of hematopoietic neoplasms in Virginia oysters (Crassostrea virginica)". Journal of the National Cancer Institute. 56 (2): 319–24. doi:10.1093/jnci/56.2.319. PMID 1255763.
## External links[edit]
* Clonally transmissible cancers at plos.org.
* v
* t
* e
Overview of tumors, cancer and oncology
Conditions
Benign tumors
* Hyperplasia
* Cyst
* Pseudocyst
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Malignant progression
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Viroid
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Satellite
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Other
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Prion
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self-replication
Mobile genetic
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Other aspects
* DNA replication
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* Replicon
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* Provirus
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* Transpoviron
* Repeated sequences in DNA
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Endosymbiosis
* Mitochondrion
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* Chloroplast
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* Organs
* Bacteriome
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Abiogenesis
* Last universal common ancestor
* Earliest known life forms
* ?RNA life
* Ribozyme
* †Protocell
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* Jeewanu
See also
* Organism
* Cell
* Cell division
* Artificial cell
* Non-cellular life
* Synthetic virus
* Viral vector
* Helper dependent virus
* ?Nanobacterium
* ?Nanobe
* Cancer cell
* HeLa
* Clonally transmissible cancer
* v
* t
* e
Life, non-cellular life, and comparable organic structures
Life
* Archaea
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Non-cellular life
Virus
Incl.: viroids,
satellites,
virophages,
virusoids
* Duplodnaviria
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Inc. sed. orders: Ligamenvirales
Inc. sed. families: Alphasatellitidae
* Ampullaviridae
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Inc. sed. genera: Deltavirus
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Other
* Nanobe (?)
Comparable
organic
structures
* Prion
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* Plasmid
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* Ribozyme
* Protocell
* Coacervate
* Proteinoid
* Model lipid bilayer
* Jeewanu
* Sulphobe
* Cancer cell
* HeLa
* Clonally transmissible cancer
* Earliest known life forms
* Biological dark matter
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Clonally transmissible cancer | None | 2,558 | wikipedia | https://en.wikipedia.org/wiki/Clonally_transmissible_cancer | 2021-01-18T18:56:13 | {"wikidata": ["Q247491"]} |
Congenital abnormality involving a single higher shoulder blade
Sprengel's deformity
Other namesSprengel deformity, Sprengel's shoulder, Sprengel shoulder, high scapula
Sprengel's deformity, showing a higher right-sided shoulder blade
SpecialtyMedical genetics
TypesMuscular forms
Sprengel's deformity (also known as high scapula or congenital high scapula) is a rare congenital skeletal abnormality where a person has one shoulder blade that sits higher on the back than the other. The deformity is due to a failure in early fetal development where the shoulder fails to descend properly from the neck to its final position. The deformity is commonly associated with other conditions, most notably Klippel–Feil syndrome, congenital scoliosis, including cervical scoliosis, fused ribs, the presence of an omovertebral bone (an extra bone between the scapula and a cervical vertebra) and spina bifida. The left shoulder is the most commonly affected shoulder, but the condition can be bilateral, meaning that both shoulders are affected.
About 75% of all observed cases are girls. Treatment includes surgery in early childhood and physical therapy. Surgical treatment in adulthood is complicated by the risk of nerve damage when removing the omovertebral bone and when stretching the muscle tissue during relocation of the shoulder.
## Contents
* 1 Presentation
* 2 Diagnosis
* 3 Eponym
* 4 References
* 5 External links
## Presentation[edit]
CT scan showing Sprengel's deformity of the left side (arrow) and fused cervical vertebrae, as seen in Klippel–Feil syndrome
The scapula is small and rotated so that its inferior edge points toward the spine. Sometimes a bony connection is present between the elevated scapula and one of the cervical vertebrae, usually C5 or C6. This connection is known as an omovertebral bone.[citation needed]
There is a high correlation between Sprengel's deformity and Klippel–Feil syndrome.[citation needed]
## Diagnosis[edit]
Sprengel's deformity is inherited in an autosomal dominant manner.
Diagnosis is clinical and can be confirmed by instrumental diagnostics like conventional radiography and CT scan. It may be indicated to perform a genetic analysis, as the deformity may occur under other conditions (see Klippel–Feil syndrome).
## Eponym[edit]
It is named for German surgeon Otto Sprengel, who described it in 1891.[1][2]
## References[edit]
1. ^ synd/2450 at Who Named It?
2. ^ O. K. Sprengel. Die angeborene Verschiebung des Schulterblattes nach oben. Archiv für klinische Chirurgie, Berlin, 1891, 42: 545-549.
## External links[edit]
Classification
D
* ICD-10: Q74.0
* ICD-9-CM: 755.52
* OMIM: 184400
* MeSH: C535802 C535802, C535802
* DiseasesDB: 31521
External resources
* eMedicine: orthoped/445
* 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
This genetic disorder article is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Sprengel's deformity | c0152438 | 2,559 | wikipedia | https://en.wikipedia.org/wiki/Sprengel%27s_deformity | 2021-01-18T18:56:24 | {"gard": ["7693"], "mesh": ["C535802"], "umls": ["C0152438"], "icd-9": ["755.52"], "icd-10": ["Q74.0"], "orphanet": ["3181"], "wikidata": ["Q1850576"]} |
Phantom vibration syndrome or phantom ringing syndrome is the perception that one's mobile phone is vibrating or ringing when it is not. Other terms for this concept include ringxiety (a portmanteau of ring and anxiety), fauxcellarm (a portmanteau of "faux" /fo͜ʊ/ meaning "fake" or "false" and "cellphone" and "alarm" pronounced similarly to "false alarm") and phonetom (a portmanteau of phone and phantom).[1] According to Dr. Michael Rothberg, the term is not a syndrome, but is better characterised as a tactile hallucination since the brain perceives a sensation that is not actually present.[2][3] WebMD published an article on phantom vibration syndrome with Rothberg as a source. [4] Several other articles have been published in 2010s, including in NPR, Bustle, CBS News, and Psychology Today. [5][6][7][8]
Phantom ringing may be experienced while taking a shower, watching television, or using a noisy device. Humans are particularly sensitive to auditory tones between 1,000 and 6,000 hertz, and basic mobile phone ringtones often fall within this range.[1] Phantom vibrations develop after carrying a cell phone set to use vibrating alerts.[9] Researcher Michelle Drouin found that almost 9 of 10 undergraduates at her college experienced phantom vibrations.[10][medical citation needed]
## Contents
* 1 History
* 2 Causes
* 3 Epidemiology
* 4 Management
* 5 References
* 6 Further reading
## History[edit]
In the comic strip Dilbert, cartoonist Scott Adams referenced such a sensation in 1996 as "phantom-pager syndrome".[11] The earliest published use of the term phantom vibration syndrome dates to 2003 in an article entitled "Phantom Vibration Syndrome" published in the New Pittsburgh Courier, written under a pen name of columnist Robert D. Jones. However, it is debated whether earlier noting of the onsets of PVS came from Michael J Lewis of Melbourne, Australia. In the conclusion of the article, Jones wrote, "...should we be concerned about what our mind or body may be trying to tell us by the aggravating imaginary emanations from belts, pockets and even purses? Whether PVS is the result of physical nerve damage, a mental health issue, or both, this growing phenomenon seems to indicate that we may have crossed a line in this 'always on' society."
The first study of the phenomenon was conducted in 2007 by a researcher who coined the term ringxiety to describe it.[9] In 2012, the term phantom vibration syndrome was chosen as the Australian Macquarie Dictionary's word of the year.[12][13]
## Causes[edit]
The cause of phantom vibrations is not known.[9] Preliminary research suggests it is related to over-involvement with one's cell phone.[9] Vibrations typically begin occurring after carrying a phone for between one month and one year.[9] It has been suggested that, when anticipating a phone call, the cerebral cortex may misinterpret other sensory input (such as muscle contractions, pressure from clothing, or music) as a phone vibration or ring tone.[9] This may be understood as a human signal detection issue, with potentially significant influences from psychological attributes.[14] Factors such as experiences, expectations, and psychological states influence the threshold for signal detection.[14] Some phantom vibration experiences may be a type of pareidolia and can therefore be examined as a psychological phenomenon influenced by individual variances in personality, condition, and context.[14] Attachment anxiety can also be seen as a predictor for the frequency of phantom vibration experiences since it is associated with psychological attributes related to insecurity in interpersonal relationships.[14]
## Epidemiology[edit]
In most studies, a majority of cell phone users report experiencing occasional phantom vibrations or ringing, with reported rates ranging from 29.6% to 89%.[9] Once every two weeks is a typical frequency for the sensations, though a minority experience them daily.[9] Some individuals may be seriously bothered by the sensations.[9]
## Management[edit]
Little research has been done on treatment for phantom vibrations.[9] Carrying the cell phone in a different position reduces phantom vibrations for some people.[9] Other methods include turning off the vibration, changing the ringtone or vibration tone, or using a different device altogether.[2]
## References[edit]
1. ^ a b Goodman, Brenda (4 May 2006). "I Hear Ringing and There's No One There. I Wonder Why". The New York Times. p. 1.
2. ^ a b Rothberg, M. B.; Arora, A.; Hermann, J.; Kleppel, R.; Marie, P. S.; Visintainer, P. (2010). "Phantom vibration syndrome among medical staff: a cross sectional survey". BMJ. 341 (dec15 2): c6914. doi:10.1136/bmj.c6914. PMID 21159761.
3. ^ Fischer, Elli (October 3, 2017). "Phonetom Definition". Facebook. Retrieved October 3, 2017. "Phonetom: When you could swear you felt your phone vibrate, but it's not in your pocket."
4. ^ Locke, Tim. "Do You Have 'Phantom Vibration Syndrome'?". WebMD. Retrieved 2019-02-10.
5. ^ "Phantom Phone Vibrations: So Common They've Changed Our Brains?". NPR.org. Retrieved 2019-02-11.
6. ^ Hills, Megan C. "Phantom Ringing Syndrome Is The Weird AF Condition You've Had But Never Heard Of". Bustle. Retrieved 2019-02-11.
7. ^ ""Phantom vibration syndrome" common in cellphone users". www.cbsnews.com. Retrieved 2019-02-11.
8. ^ "Phantom Pocket Vibration Syndrome". Psychology Today. Retrieved 2019-02-11.
9. ^ a b c d e f g h i j k Deb A (2014). "Phantom vibration and phantom ringing among mobile phone users: A systematic review of literature". Asia Pac Psychiatry. 7 (3): 231–9. doi:10.1111/appy.12164. PMID 25408384.CS1 maint: uses authors parameter (link)
10. ^ Rosen, Larry (May 7, 2013). "Phantom Pocket Vibration Syndrome". Psychology Today. Retrieved September 10, 2014. "...According to Dr. Michelle Drouin... 89% of the undergraduates in her study had experienced these phantom vibrations..."
11. ^ Adams, Scott (September 16, 1996). "Dilbert". Retrieved October 16, 2013.
12. ^ Wilson, Aidan (February 7, 2013). "Phantom vibration syndrome: Word of the Year". Crikey.com.au. Retrieved October 9, 2013.
13. ^ Meacham, Merle. "Macquarie Dictionary word of the year archives". Retrieved March 18, 2015.
14. ^ a b c d Kruger, D. J., & Djerf, J. M. (2016). High Ringxiety: Attachment Anxiety Predicts Experiences of Phantom Cell Phone Ringing. Cyberpsychology, Behavior & Social Networking, 19(1), 56-59.
## Further reading[edit]
* Haupt, Angela (June 12, 2007). "Good vibrations? Bad? None at all?". USA Today. McLean, VA: Gannett. ISSN 0734-7456. Retrieved September 4, 2011.
* v
* t
* e
Mobile phones
mobile
networks,
protocols
* Channel capacity
* Frequencies
* Multi-band
* Network operator
* list
* Roaming
* Signal
* SIM card
* dual SIM
* SIM lock
* Standards comparison
* Tethering
* VoIP
* WAP
* XHTML-MP
generations
* analogue:
* 0G
* 1G
* digital:
* 2G
* 3G
* adoption
* 3.5G
* 4G
* 4.5G
* 5G
* 6G
general
operation
* Features
* GSM
* services
* History
* Operating system
* Security
* phone cloning
* Telephony
* airplane mode
* Text messaging
* SMS
* MMS
* RCS
* Spam
* Tracking
* Web browsing
mobile
devices
* Manufacturers
* 3D phone
* Camera phone
* Car phone
* Feature phone
* Projector phone
* Satellite phone
* Smartphone
form factors
* Bar
* Flip
* Phablet
* Slider
* Smartwatch
smartphones
* Android devices
* rooting
* BlackBerry 10
* iPhone
* iOS jailbreaking
* Open-source mobile phones
* Symbian devices
* Windows Phone devices
mobile
specific
software
apps
* Development
* Distribution
* Management
* Cloud computing
commerce
* Banking
* Marketing
* advertising
* campaigns
* Payments
* contactless
* donating
* Ticketing
content
* Blogging
* Email
* Gambling
* Gaming
* Health
* Instant messaging
* Learning
* Music
* News
* Search
* local
* Social
* address book
* Television
culture
* Box breaking
* Charms
* Comics
* Dating
* Japanese culture
* Novels
* Ringtones
* silent mode
* Selfie
* Txt-spk
* Wallpaper
environment
and health
* BlackBerry thumb
* Driving safety
* Electronic waste
* External power supply
* Mental health from overuse
* Phantom vibration syndrome
* Radiation and health
* Recycling
law
* Carrier IQ
* Legality of recording by civilians
* Mobile phones in prison
* Photography and the law
* Telephone tapping
* Texting while driving
* USA use restrictions while driving
* Category
* Portal
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Phantom vibration syndrome | None | 2,560 | wikipedia | https://en.wikipedia.org/wiki/Phantom_vibration_syndrome | 2021-01-18T18:45:46 | {"wikidata": ["Q3242773"]} |
Mucormycosis
Periorbital fungal infection known as mucormycosis, or phycomycosis
SpecialtyInfectious disease
Zygomycosis is the broadest term to refer to infections caused by bread mold fungi of the zygomycota phylum. However, because zygomycota has been identified as polyphyletic, and is not included in modern fungal classification systems, the diseases that zygomycosis can refer to are better called by their specific names: mucormycosis[1] (after Mucorales), phycomycosis[2] (after Phycomycetes) and basidiobolomycosis (after Basidiobolus).[3] These rare yet serious and potentially life-threatening fungal infections usually affect the face or oropharyngeal (nose and mouth) cavity.[4] Zygomycosis type infections are most often caused by common fungi found in soil and decaying vegetation. While most individuals are exposed to the fungi on a regular basis, those with immune disorders (immunocompromised) are more prone to fungal infection.[2][5][6] These types of infections are also common after natural disasters, such as tornadoes or earthquakes, where people have open wounds that have become filled with soil or vegetative matter.[7]
The condition may affect the gastrointestinal tract or the skin. In non-trauma cases, it usually begins in the nose and paranasal sinuses and is one of the most rapidly spreading fungal infections in humans.[2] Common symptoms include thrombosis and tissue necrosis.[8] Treatment consists of prompt and intensive antifungal drug therapy and surgery to remove the infected tissue.[9][10] The prognosis varies vastly depending upon an individual patient's circumstances.[8]
## Contents
* 1 Causes
* 2 Epidemiology
* 3 Other animals
* 4 References
* 5 External links
## Causes[edit]
Micrograph showing a zygomycetes infection.
Pathogenic zygomycosis is caused by species in two orders: Mucorales or Entomophthorales, with the former causing far more disease than the latter.[11] These diseases are known as "mucormycosis" and "entomophthoramycosis", respectively.[12]
* Order Mucorales (mucormycosis)
* Family Mucoraceae
* Absidia (Absidia corymbifera)
* Apophysomyces (Apophysomyces elegans and Apophysomyces trapeziformis)
* Mucor (Mucor indicus)
* Rhizomucor (Rhizomucor pusillus)
* Rhizopus (Rhizopus oryzae)
* Family Cunninghamellaceae
* Cunninghamella (Cunninghamella bertholletiae)
* Family Thamnidiaceae
* Cokeromyces (Cokeromyces recurvatus)
* Family Saksenaeaceae
* Saksenaea (Saksenaea vasiformis)
* Family Syncephalastraceae
* Syncephalastrum (Syncephalastrum racemosum)
* Order Entomophthorales (entomophthoramycosis)
* Family Basidiobolaceae
* Basidiobolus (Basidiobolus ranarum)
* Family Ancylistaceae
* Conidiobolus (Conidiobolus coronatus/Conidiobolus incongruus)
## Epidemiology[edit]
Zygomycosis has been found in survivors of the 2004 Indian Ocean earthquake and tsunami and in survivors of the 2011 Joplin, Missouri tornado.[13]
## Other animals[edit]
The term oomycosis is used to describe oomycete infections.[14] These are more common in animals, notably dogs and horses. These are heterokonts, not true fungi. Types include pythiosis (caused by Pythium insidiosum) and lagenidiosis.
Zygomycosis has been described in a cat, where fungal infection of the tracheobronchus led to respiratory disease requiring euthanasia.[15]
## References[edit]
1. ^ Toro, Carlos; del Palacio, Amalia; Álvarez, Carmen; Rodríguez-Peralto, José Luis; Carabias, Esperanza; Cuétara, Soledad; Carpintero, Yolanda; Gómez, César (1998). "Zigomicosis cutánea por Rhizopus arrhizus en herida quirúrgica" [Cutaneous zygomycosis caused by Rhizopus arrhizus in a surgical wound]. Revista Iberoamericana de Micología (in Spanish). 15 (2): 94–6. PMID 17655419.
2. ^ a b c Auluck, Ajit (2007). "Maxillary necrosis by mucormycosis. a case report and literature review" (PDF). Medicina Oral Patologia Oral y Cirugia Bucal. 12 (5): E360–4. PMID 17767099.
3. ^ Centers for Disease Control and Prevention (1999). "Gastrointestinal Basidiobolomycosis — Arizona, 1994–1999". Morbidity and Mortality Weekly Report. 48 (32): 710–3. PMID 21033182.
4. ^ Nancy F Crum-Cianflone; MD MPH. "Mucormycosis". eMedicine. Retrieved 19 May 2008.
5. ^ "MedlinePlus Medical Encyclopedia: Mucormycosis". Retrieved 19 May 2008.
6. ^ Ettinger, Stephen J.; Feldman, Edward C. (1995). Textbook of Veterinary Internal Medicine (4th ed.). W.B. Saunders Company. ISBN 0-7216-6795-3.[page needed]
7. ^ Draper, Bill; Suhr, Jim (11 June 2011). "Survivors of Joplin tornado develop rare infection". Seattle Post-Intelligencer. Associated Press.
8. ^ a b Spellberg, B.; Edwards, J.; Ibrahim, A. (2005). "Novel Perspectives on Mucormycosis: Pathophysiology, Presentation, and Management". Clinical Microbiology Reviews. 18 (3): 556–69. doi:10.1128/CMR.18.3.556-569.2005. PMC 1195964. PMID 16020690.
9. ^ Spellberg, Brad; Walsh, Thomas J.; Kontoyiannis, Dimitrios P.; Edwards, Jr.; Ibrahim, Ashraf S. (2009). "Recent Advances in the Management of Mucormycosis: From Bench to Bedside". Clinical Infectious Diseases. 48 (12): 1743–51. doi:10.1086/599105. PMC 2809216. PMID 19435437.
10. ^ Grooters, A (2003). "Pythiosis, lagenidiosis, and zygomycosis in small animals". Veterinary Clinics of North America: Small Animal Practice. 33 (4): 695–720. doi:10.1016/S0195-5616(03)00034-2. PMID 12910739.
11. ^ Ribes, J. A.; Vanover-Sams, C. L.; Baker, D. J. (2000). "Zygomycetes in Human Disease". Clinical Microbiology Reviews. 13 (2): 236–301. doi:10.1128/CMR.13.2.236. PMC 100153. PMID 10756000.
12. ^ Prabhu, R. M.; Patel, R. (2004). "Mucormycosis and entomophthoramycosis: A review of the clinical manifestations, diagnosis and treatment". Clinical Microbiology and Infection. 10: 31–47. doi:10.1111/j.1470-9465.2004.00843.x. PMID 14748801.
13. ^ "Joplin toll rises to 151; some suffer from fungus". Associated Press. 10 June 2011 – via Medical Xpress.
14. ^ "Merck Veterinary Manual". Retrieved 4 April 2009.
15. ^ Snyder, Katherine D.; Spaulding, Kathy; Edwards, John (2010). "Imaging diagnosis—tracheobronchial zygomycosis in a cat". Veterinary Radiology & Ultrasound. 51 (6): 617–20. doi:10.1111/j.1740-8261.2010.01720.x. PMID 21158233.
## External links[edit]
Classification
D
* ICD-10: B46
* ICD-9-CM: 117.7
* MeSH: D020096
* DiseasesDB: 31329
External resources
* MedlinePlus: 000649
* eMedicine: med/1513 med/2026 oph/225 ped/1488
* v
* t
* e
Fungal infection and mesomycetozoea
Superficial and
cutaneous
(dermatomycosis):
Tinea = skin;
Piedra (exothrix/
endothrix) = hair
Ascomycota
Dermatophyte
(Dermatophytosis)
By location
* Tinea barbae/tinea capitis
* Kerion
* Tinea corporis
* Ringworm
* Dermatophytids
* Tinea cruris
* Tinea manuum
* Tinea pedis (athlete's foot)
* Tinea unguium/onychomycosis
* White superficial onychomycosis
* Distal subungual onychomycosis
* Proximal subungual onychomycosis
* Tinea corporis gladiatorum
* Tinea faciei
* Tinea imbricata
* Tinea incognito
* Favus
By organism
* Epidermophyton floccosum
* Microsporum canis
* Microsporum audouinii
* Trichophyton interdigitale/mentagrophytes
* Trichophyton tonsurans
* Trichophyton schoenleini
* Trichophyton rubrum
* Trichophyton verrucosum
Other
* Hortaea werneckii
* Tinea nigra
* Piedraia hortae
* Black piedra
Basidiomycota
* Malassezia furfur
* Tinea versicolor
* Pityrosporum folliculitis
* Trichosporon
* White piedra
Subcutaneous,
systemic,
and opportunistic
Ascomycota
Dimorphic
(yeast+mold)
Onygenales
* Coccidioides immitis/Coccidioides posadasii
* Coccidioidomycosis
* Disseminated coccidioidomycosis
* Primary cutaneous coccidioidomycosis. Primary pulmonary coccidioidomycosis
* Histoplasma capsulatum
* Histoplasmosis
* Primary cutaneous histoplasmosis
* Primary pulmonary histoplasmosis
* Progressive disseminated histoplasmosis
* Histoplasma duboisii
* African histoplasmosis
* Lacazia loboi
* Lobomycosis
* Paracoccidioides brasiliensis
* Paracoccidioidomycosis
Other
* Blastomyces dermatitidis
* Blastomycosis
* North American blastomycosis
* South American blastomycosis
* Sporothrix schenckii
* Sporotrichosis
* Talaromyces marneffei
* Talaromycosis
Yeast-like
* Candida albicans
* Candidiasis
* Oral
* Esophageal
* Vulvovaginal
* Chronic mucocutaneous
* Antibiotic candidiasis
* Candidal intertrigo
* Candidal onychomycosis
* Candidal paronychia
* Candidid
* Diaper candidiasis
* Congenital cutaneous candidiasis
* Perianal candidiasis
* Systemic candidiasis
* Erosio interdigitalis blastomycetica
* C. auris
* C. glabrata
* C. lusitaniae
* C. tropicalis
* Pneumocystis jirovecii
* Pneumocystosis
* Pneumocystis pneumonia
Mold-like
* Aspergillus
* Aspergillosis
* Aspergilloma
* Allergic bronchopulmonary aspergillosis
* Primary cutaneous aspergillosis
* Exophiala jeanselmei
* Eumycetoma
* Fonsecaea pedrosoi/Fonsecaea compacta/Phialophora verrucosa
* Chromoblastomycosis
* Geotrichum candidum
* Geotrichosis
* Pseudallescheria boydii
* Allescheriasis
Basidiomycota
* Cryptococcus neoformans
* Cryptococcosis
* Trichosporon spp
* Trichosporonosis
Zygomycota
(Zygomycosis)
Mucorales
(Mucormycosis)
* Rhizopus oryzae
* Mucor indicus
* Lichtheimia corymbifera
* Syncephalastrum racemosum
* Apophysomyces variabilis
Entomophthorales
(Entomophthoramycosis)
* Basidiobolus ranarum
* Basidiobolomycosis
* Conidiobolus coronatus/Conidiobolus incongruus
* Conidiobolomycosis
Microsporidia
(Microsporidiosis)
* Enterocytozoon bieneusi/Encephalitozoon intestinalis
Mesomycetozoea
* Rhinosporidium seeberi
* Rhinosporidiosis
Ungrouped
* Alternariosis
* Fungal folliculitis
* Fusarium
* Fusariosis
* Granuloma gluteale infantum
* Hyalohyphomycosis
* Otomycosis
* Phaeohyphomycosis
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Zygomycosis | c0043541 | 2,561 | wikipedia | https://en.wikipedia.org/wiki/Zygomycosis | 2021-01-18T18:35:25 | {"gard": ["10224"], "mesh": ["D020096"], "icd-9": ["117.7"], "icd-10": ["B46"], "wikidata": ["Q3046374"]} |
Collecting duct carcinoma
Other namesBellini duct carcinoma[1]
Collecting duct carcinoma. H&E stain.
SpecialtyOncology/nephrology
Collecting duct carcinoma in computed tomography
Collecting duct carcinoma (CDC) is a type of kidney cancer that originates in the papillary duct of the kidney. It is rare, accounting for 1-3% of all kidney cancers.[2] It is also recently described; a 2002 review found just 40 case reports worldwide.[3] Previously, due to its location, CDC was commonly diagnosed as renal cell carcinoma or a subtype of renal cell carcinoma.[4] However, CDC does not respond well to chemotherapy drugs used for renal cell carcinoma, and progresses and spreads more quickly.
## Contents
* 1 Signs and symptoms
* 2 Histology
* 3 Treatment
* 4 History
* 5 References
* 6 External links
## Signs and symptoms[edit]
Signs and symptoms are as for kidney cancer.
## Histology[edit]
Histologic examination of collecting duct carcinoma demonstrates an infiltrative lesion with tubulopapillary, irregular channels lined by high grade hobnail cells with marked desmoplastic response and brisk neutrophilic infiltrate.
## Treatment[edit]
This section is empty. You can help by adding to it. (February 2018)
## History[edit]
CDC was thought to be renal cell carcinoma, until "recently developed techniques of lectin histochemistry" helped forward knowledge of kidney duct cancers.[5]
## References[edit]
1. ^ Amin MB, MacLennan GT, Gupta R, Grignon D, Paraf F, Vieillefond A, Paner GP, Stovsky M, Young AN, Srigley JR, Cheville JC (March 2009). "Tubulocystic carcinoma of the kidney: clinicopathologic analysis of 31 cases of a distinctive rare subtype of renal cell carcinoma". Am. J. Surg. Pathol. 33 (3): 384–92. doi:10.1097/PAS.0b013e3181872d3f. PMID 19011562.
2. ^ Fakhrai N, Haitel A, Balassy C, Zielinski CC, Schmidinger M (January 2005). "Major response and clinical benefit following third-line treatment for Bellini duct carcinoma". Wien. Klin. Wochenschr. 117 (1–2): 63–5. doi:10.1007/s00508-004-0289-4. PMID 15986594.
3. ^ Singh I, Nabi G (2002). "Bellini duct carcinoma: review of diagnosis and management" (PDF). Int Urol Nephrol. 34 (1): 91–5. doi:10.1023/A:1021315130481. PMID 12549647.
4. ^ Méjean A, Rouprêt M, Larousserie F, Hopirtean V, Thiounn N, Dufour B (April 2003). "Is there a place for radical nephrectomy in the presence of metastatic collecting duct (Bellini) carcinoma?". J. Urol. 169 (4): 1287–90. doi:10.1097/01.ju.0000050221.51509.f5. PMID 12629344.
5. ^ O Natsume; S Ozono; T Futami & M Ohta (1997). "Bellini duct carcinoma: a case report". Japanese Journal of Clinical Oncology. 27 (2): 107–110. doi:10.1093/jjco/27.2.107. PMID 9152800. Retrieved 2008-06-03.
## External links[edit]
Classification
D
* ICD-10: C64
* MeSH: D002292
External resources
* Orphanet: 247203
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Collecting duct carcinoma | c1266044 | 2,562 | wikipedia | https://en.wikipedia.org/wiki/Collecting_duct_carcinoma | 2021-01-18T18:38:39 | {"gard": ["9573"], "mesh": ["D002292"], "umls": ["C1266044"], "orphanet": ["247203"], "wikidata": ["Q4884045"]} |
A slow-growing type of neuroendocrine tumor that sometimes causes paraneoplastic syndromes
Not to be confused with Chancroid.
Carcinoid is sometimes a type of carcinoma but is more often benign.
Carcinoid
Picture of a carcinoid tumor (center of image) that encroaches into the lumen of the small bowel (pathology specimen). The prominent folds are plicae circulares, a characteristic of the small bowel.
SpecialtyOncology
A carcinoid (also carcinoid tumor) is a slow-growing[1] type of neuroendocrine tumor originating in the cells of the neuroendocrine system. In some cases, metastasis may occur. Carcinoid tumors of the midgut (jejunum, ileum, appendix, and cecum) are associated with carcinoid syndrome.
Carcinoid tumors are the most common malignant tumor of the appendix, but they are most commonly associated with the small intestine, and they can also be found in the rectum and stomach. They are known to grow in the liver, but this finding is usually a manifestation of metastatic disease from a primary carcinoid occurring elsewhere in the body. They have a very slow growth rate compared to most malignant tumors. The median age at diagnosis for all patients with neuroendocrine tumors is 63 years.
## Contents
* 1 Signs and symptoms
* 1.1 Gastrointestinal
* 1.2 Lung
* 1.3 Other sites and metastases
* 1.4 Goblet cell carcinoid
* 2 Cause
* 3 Treatment
* 4 History
* 5 See also
* 6 References
* 7 External links
## Signs and symptoms[edit]
Primary site of a carcinoid cancer of gut
While most carcinoids are asymptomatic through the natural lifetime and are discovered only upon surgery for unrelated reasons (so-called coincidental carcinoids), all carcinoids are considered to have malignant potential.
About 10% of carcinoids secrete excessive levels of a range of hormones, most notably serotonin (5-HT), causing:
* Flushing (serotonin itself does not cause flushing). Potential causes of flushing in carcinoid syndrome include bradykinins, prostaglandins, tachykinins, substance P, and/or histamine, diarrhea, and heart problems. Because of serotonin's growth-promoting effect on cardiac myocytes, a serotonin-secreting carcinoid tumour may cause a tricuspid valve disease syndrome, due to the proliferation of myocytes onto the valve.[citation needed]
* Diarrhea
* Wheezing
* Abdominal cramping
* Peripheral edema
The outflow of serotonin can cause a depletion of tryptophan leading to niacin deficiency. Niacin deficiency, also known as pellagra, is associated with dermatitis, dementia, and diarrhea.
This constellation of symptoms is called carcinoid syndrome or (if acute) carcinoid crisis. Occasionally, haemorrhage or the effects of tumor bulk are the presenting symptoms. The most common originating sites of carcinoid is the small bowel, particularly the ileum; carcinoid tumors are the most common malignancy of the appendix. Carcinoid tumors may rarely arise from the ovary or thymus.[2]
They are most commonly found in the midgut at the level of the ileum or in the appendix. The next most common affected area is the respiratory tract, with 28% of all cases—per PAN-SEER data (1973–1999). The rectum is also a common site.
### Gastrointestinal[edit]
Main article: Small intestine neuroendocrine tumor
Carcinoid tumors are apudomas that arise from the enterochromaffin cells throughout the gut. Over two-thirds of carcinoid tumors are found in the gastrointestinal tract.[3]
### Lung[edit]
Histopathology of a typical carcinoid tumor of the lung, with prominent rosettes.
Main article: Typical lung carcinoid tumor
Carcinoid tumors are also found in the lungs.
### Other sites and metastases[edit]
Metastasis of carcinoid can lead to carcinoid syndrome. This is due to the over-production of many substances, including serotonin, which are released into the systemic circulation, and which can lead to symptoms of cutaneous flushing, diarrhea, bronchoconstriction, and right-sided cardiac valve disease. It is estimated that less than 6% of carcinoid patients will develop carcinoid syndrome, and of these, 50% will have cardiac involvement.[4]
### Goblet cell carcinoid[edit]
Main article: Goblet cell carcinoid
This is considered to be a hybrid between an exocrine and endocrine tumor derived from crypt cells of the appendix. Histologically, it forms clusters of goblet cells containing mucin with a minor admixture of Paneth cells and endocrine cells. The growth pattern is distinctive: typically producing a concentric band of tumor nests interspersed among the muscle and stroma of the appendiceal wall extending up the shaft of the appendix. This makes the lesion difficult to suspect grossly and difficult to measure. Small tumor nests may be camouflaged amongst the muscle or in periappendiceal fat; cytokeratin preparations best demonstrate the tumor cells; mucin stains are also helpful in identifying them. They behave in a more aggressive manner than do classical appendiceal carcinoids. Spread is usually to regional lymph nodes, peritoneum, and particularly the ovary. They do not produce sufficient hormonal substances to cause the carcinoid or other endocrine syndromes. In fact, they more closely resemble exocrine than endocrine tumors. The term 'crypt cell carcinoma' has been used for them, and though perhaps more accurate than considering them carcinoids, has not been a successful competitor.
## Cause[edit]
Carcinoid syndrome involves multiple tumors in one out of five of cases. The incidence of gastric carcinoids is increased in achlorhydria, Hashimoto's thyroiditis, and pernicious anemia.
## Treatment[edit]
Surgery, if feasible, is the only curative therapy. If the tumor has metastasized (most commonly, to the liver) and is considered incurable, there are some promising treatment modalities, such as radiolabeled octreotide[5] (e.g. Lutetium (177Lu) DOTA-octreotate) or the radiopharmaceutical 131I-mIBG (meta iodo benzyl guanidine[5]) for arresting the growth of the tumors and prolonging survival in patients with liver metastases, though these are currently experimental.
Chemotherapy is of little benefit and is generally not indicated. Octreotide or lanreotide (somatostatin analogues) may decrease the secretory activity of the carcinoid, and may also have an anti-proliferative effect. Interferon treatment is also effective, and usually combined with somatostatin analogues.
As the metastatic potential of a coincidental carcinoid is probably low, the current recommendation is for follow up in 3 months with CT or MRI, labs for tumor markers such as serotonin, and a history and physical, with annual physicals thereafter.
## History[edit]
They were first characterized in 1907 by Siegfried Oberndorfer, a German pathologist at the University of Munich, who coined the term karzinoide, or "carcinoma-like", to describe the unique feature of behaving like a benign tumor despite having a malignant appearance microscopically. The recognition of their endocrine-related properties were later described by Gosset and Masson in 1914, and these tumors are now known to arise from the enterochromaffin (EC) and enterochromaffin-like (ECL) cells of the gut. Some sources credit Otto Lubarsch with the discovery.[6]
In 2000, the World Health Organization redefined "carcinoid", but this new definition has not been accepted by all practitioners.[7] This has led to some complexity in distinguishing between carcinoid and other neuroendocrine tumors in the literature. According to the American Cancer Society, the 2000 WHO definition states:[7]
> The WHO now divides these growths into neuroendocrine tumors and neuroendocrine cancers. Neuroendocrine tumors are growths that look benign but that might possibly be able to spread to other parts of the body. Neuroendocrine cancers are abnormal growths of neuroendocrine cells which can spread to other parts of the body.
## See also[edit]
* Carcinoid syndrome
* Don Meyer, head coach emeritus of the Northern State University men's basketball team. Meyer was found to have carcinoid cancer following an automobile accident in September 2009.
* Derrick Bell, Professor and legal scholar, died of carcinoid cancer on October 5, 2011.
## References[edit]
1. ^ Maroun J, Kocha W, Kvols L, et al. (April 2006). "Guidelines for the diagnosis and management of carcinoid tumors. Part 1: The gastrointestinal tract. A statement from a Canadian National Carcinoid Expert Group". Curr Oncol. 13 (2): 67–76. PMC 1891174. PMID 17576444. Archived from the original on 2013-06-10. Retrieved 2008-07-05.
2. ^ Daffner KR, Sherman JC, Gilberto Gonzalez R, Hasserjian RP (2008). "Case 35-2008 — A 65-Year-Old Man with Confusion and Memory Loss". N Engl J Med. 359 (20): 2155–2164. doi:10.1056/NEJMcpc0804643. PMID 19005200.
3. ^ Modlin IM, Lye KD, Kidd M (February 2003). "A 5-decade analysis of 13,715 carcinoid tumors". Cancer. 97 (4): 934–59. doi:10.1002/cncr.11105. PMID 12569593.
4. ^ Fox DJ, Khattar RS (2004). "Carcinoid heart disease: presentation, diagnosis, and management". Heart. 90 (10): 1224–8. doi:10.1136/hrt.2004.040329. PMC 1768473. PMID 15367531.
5. ^ a b "Medical Reviews".
6. ^ Kulke MH, Mayer RJ (March 1999). "Carcinoid tumors". N. Engl. J. Med. 340 (11): 858–68. doi:10.1056/NEJM199903183401107. PMID 10080850.
7. ^ a b "ACS :: What Is a Gastrointestinal Carcinoid Tumor?".
Cunningham JL, Janson ET (2011). "The Hallmarks of Ileal Carcinoids". Eur J Clin Invest. 41 (12): 1353–60. doi:10.1111/j.1365-2362.2011.02537.x. PMID 21605115.
## External links[edit]
Classification
D
* ICD-10: C75, E34.0
* ICD-9-CM: 209.60
* ICD-O: M8240/3
* OMIM: 114900
* MeSH: D002276
* DiseasesDB: 2040
External resources
* MedlinePlus: 000347
* eMedicine: med/271
* v
* t
* e
Glandular and epithelial cancer
Epithelium
Papilloma/carcinoma
* Small-cell carcinoma
* Combined small-cell carcinoma
* Verrucous carcinoma
* Squamous cell carcinoma
* Basal-cell carcinoma
* Transitional cell carcinoma
* Inverted papilloma
Complex epithelial
* Warthin's tumor
* Thymoma
* Bartholin gland carcinoma
Glands
Adenomas/
adenocarcinomas
Gastrointestinal
* tract: Linitis plastica
* Familial adenomatous polyposis
* pancreas
* Insulinoma
* Glucagonoma
* Gastrinoma
* VIPoma
* Somatostatinoma
* Cholangiocarcinoma
* Klatskin tumor
* Hepatocellular adenoma/Hepatocellular carcinoma
Urogenital
* Renal cell carcinoma
* Endometrioid tumor
* Renal oncocytoma
Endocrine
* Prolactinoma
* Multiple endocrine neoplasia
* Adrenocortical adenoma/Adrenocortical carcinoma
* Hürthle cell
Other/multiple
* Neuroendocrine tumor
* Carcinoid
* Adenoid cystic carcinoma
* Oncocytoma
* Clear-cell adenocarcinoma
* Apudoma
* Cylindroma
* Papillary hidradenoma
Adnexal and
skin appendage
* sweat gland
* Hidrocystoma
* Syringoma
* Syringocystadenoma papilliferum
Cystic, mucinous,
and serous
Cystic general
* Cystadenoma/Cystadenocarcinoma
Mucinous
* Signet ring cell carcinoma
* Krukenberg tumor
* Mucinous cystadenoma / Mucinous cystadenocarcinoma
* Pseudomyxoma peritonei
* Mucoepidermoid carcinoma
Serous
* Ovarian serous cystadenoma / Pancreatic serous cystadenoma / Serous cystadenocarcinoma / Papillary serous cystadenocarcinoma
Ductal, lobular,
and medullary
Ductal carcinoma
* Mammary ductal carcinoma
* Pancreatic ductal carcinoma
* Comedocarcinoma
* Paget's disease of the breast / Extramammary Paget's disease
Lobular carcinoma
* Lobular carcinoma in situ
* Invasive lobular carcinoma
Medullary carcinoma
* Medullary carcinoma of the breast
* Medullary thyroid cancer
Acinar cell
* Acinic cell carcinoma
* v
* t
* e
Digestive system neoplasia
GI tract
Upper
Esophagus
* Squamous cell carcinoma
* Adenocarcinoma
Stomach
* Gastric carcinoma
* Signet ring cell carcinoma
* Gastric lymphoma
* MALT lymphoma
* Linitis plastica
Lower
Small intestine
* Duodenal cancer
* Adenocarcinoma
Appendix
* Carcinoid
* Pseudomyxoma peritonei
Colon/rectum
* Colorectal polyp: adenoma, hyperplastic, juvenile, sessile serrated adenoma, traditional serrated adenoma, Peutz–Jeghers
Cronkhite–Canada
* Polyposis syndromes: Juvenile
* MUTYH-associated
* Familial adenomatous/Gardner's
* Polymerase proofreading-associated
* Serrated polyposis
* Neoplasm: Adenocarcinoma
* Familial adenomatous polyposis
* Hereditary nonpolyposis colorectal cancer
Anus
* Squamous cell carcinoma
Upper and/or lower
* Gastrointestinal stromal tumor
* Krukenberg tumor (metastatic)
Accessory
Liver
* malignant: Hepatocellular carcinoma
* Fibrolamellar
* Hepatoblastoma
* benign: Hepatocellular adenoma
* Cavernous hemangioma
* hyperplasia: Focal nodular hyperplasia
* Nodular regenerative hyperplasia
Biliary tract
* bile duct: Cholangiocarcinoma
* Klatskin tumor
* gallbladder: Gallbladder cancer
Pancreas
* exocrine pancreas: Adenocarcinoma
* Pancreatic ductal carcinoma
* cystic neoplasms: Serous microcystic adenoma
* Intraductal papillary mucinous neoplasm
* Mucinous cystic neoplasm
* Solid pseudopapillary neoplasm
* Pancreatoblastoma
Peritoneum
* Primary peritoneal carcinoma
* Peritoneal mesothelioma
* Desmoplastic small round cell tumor
* v
* t
* e
Cancer involving the respiratory tract
Upper RT
Nasal cavity
Esthesioneuroblastoma
Nasopharynx
Nasopharyngeal carcinoma
Nasopharyngeal angiofibroma
Larynx
Laryngeal cancer
Laryngeal papillomatosis
Lower RT
Trachea
* Tracheal tumor
Lung
Non-small-cell lung carcinoma
* Squamous-cell carcinoma
* Adenocarcinoma (Mucinous cystadenocarcinoma)
* Large-cell lung carcinoma
* Rhabdoid carcinoma
* Sarcomatoid carcinoma
* Carcinoid
* Salivary gland–like carcinoma
* Adenosquamous carcinoma
* Papillary adenocarcinoma
* Giant-cell carcinoma
Small-cell carcinoma
* Combined small-cell carcinoma
Non-carcinoma
* Sarcoma
* Lymphoma
* Immature teratoma
* Melanoma
By location
* Pancoast tumor
* Solitary pulmonary nodule
* Central lung
* Peripheral lung
* Bronchial leiomyoma
Pleura
* Mesothelioma
* Malignant solitary fibrous tumor
Authority control
* NDL: 00576160
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Carcinoid | c0007095 | 2,563 | wikipedia | https://en.wikipedia.org/wiki/Carcinoid | 2021-01-18T18:53:20 | {"gard": ["9316"], "mesh": ["D002276"], "umls": ["C0007095"], "icd-9": ["209.60"], "icd-10": ["E34.0", "C75"], "wikidata": ["Q1734755"]} |
Bronchiolitis obliterans is an inflammatory condition that affects the lung's tiniest airways, the bronchioles. In affected people, the bronchioles may become damaged and inflamed leading to extensive scarring that blocks the airways. Signs and symptoms of the condition include a dry cough; shortness of breath; and/or fatigue and wheezing in the absence of a cold or asthma. Many different chemicals (such as nitrogen oxides, ammonia, welding fumes or food flavoring fumes) and respiratory infections can cause lung injury that leads to bronchiolitis obliterans. It can also be associated with rheumatoid arthritis and graft-versus-host disease following a lung or hematopoietic cell transplantation. While there is no way to reverse the disease, treatments are available that may stabilize or slow the progression.
Another similarly named disease, bronchiolitis obliterans organizing pneumonia, is a completely different disease.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Bronchiolitis obliterans | c0006272 | 2,564 | gard | https://rarediseases.info.nih.gov/diseases/9551/bronchiolitis-obliterans | 2021-01-18T18:01:41 | {"mesh": ["D001989"], "umls": ["C0006272"], "synonyms": ["Obliterative bronchiolitis"]} |
This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed.
Find sources: "Spermaturia" – news · newspapers · books · scholar · JSTOR (September 2015) (Learn how and when to remove this template message)
Spermaturia
SpecialtyAndrology, urology
Spermaturia is a human disease characterized by the presence of sperm in the urine.[1]
It can be observed in males of other species and then sometimes diagnosed in veterinary medicine.[2] The cause is most often a retrograde ejaculation. It may be physiological during urination after coitus (postcoital urination).
## See also[edit]
* Spermatorrhea
* Urination and sexual activity
## References[edit]
1. ^ Pedersen, J. L., et al. "Spermaturia and puberty." Archives of Disease in Childhood 69.3 (1993): 384-387.
2. ^ Beatrice, Laura, et al. "Comparison of urine protein-to-creatinine ratio in urine samples collected by cystocentesis versus free catch in dogs." Journal of the American Veterinary Medical Association 236.11 (2010): 1221-1224.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Spermaturia | c1536073 | 2,565 | wikipedia | https://en.wikipedia.org/wiki/Spermaturia | 2021-01-18T18:28:03 | {"umls": ["C1536073"], "wikidata": ["Q1593114"]} |
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. (July 2009) (Learn how and when to remove this template message)
Polymicrogyria
This child presented with seizures. The coronal true inversion recovery sequence shows thickened and disordered cortex in superior frontal and cingulate gyri bilaterally (arrow). There are small convolutions visible at the corticomedullary junction. The appearance is that of cortical dysplasia, with polymicrogyria more likely than pachygyria due to the small convolutions visible. There are also small foci of grey matter signal in the corpus callosum, deep to the dysplastic cortex (double arrows). These probably represent areas of grey matter heterotopia.
SpecialtyNeurology
Polymicrogyria (PMG) is a condition that affects the development of the human brain by multiple small gyri (microgyri) creating excessive folding of the brain leading to an abnormally thick cortex. This abnormality can affect either one region of the brain or multiple regions.
The time of onset has yet to be identified; however, it has been found to occur before birth in either the earlier or later stages of brain development. Early stages include impaired proliferation and migration of neuroblasts, while later stages show disordered post-migration development.
The symptoms experienced differ depending on what part of the brain is affected. There is no specific treatment to get rid of this condition, but there are medications that can control the symptoms such as seizures, delayed development or weakened muscles as some of the noted effects.
## Contents
* 1 Syndromes
* 1.1 Bilateral frontal polymicrogyria (BFP)
* 1.2 Bilateral frontoparietal polymicrogyria (BFPP)
* 1.3 Bilateral perisylvian polymicrogyria (BPP)
* 1.4 Bilateral parasagittal parieto-occipital polymicrogyria (BPOP)
* 1.5 Bilateral generalised polymicrogyria (BGP)
* 1.6 Unilateral polymicrogyria
* 2 Signs and symptoms
* 3 Cause
* 4 Pathology
* 5 Diagnosis
* 5.1 Neuroimaging techniques
* 5.2 Neuropathological techniques
* 6 Treatment
* 7 History
* 8 See also
* 9 References
* 10 External links
## Syndromes[edit]
This section possibly contains original research. Please improve it by verifying the claims made and adding inline citations. Statements consisting only of original research should be removed. (March 2017) (Learn how and when to remove this template message)
Significant technological advances have been made within the past few decades that have allowed more extensive studies to be made regarding syndromes from conditions such as polymicrogyria. Research, imaging, and analysis has shown that distribution of polymicrogryia does not always appear to be random, which revealed different types polymicrogyria. A summary of clinical manifestations of each syndrome can be found below, in the section labelled "Clinical presentation".
### Bilateral frontal polymicrogyria (BFP)[edit]
Polymicrogyria
Other namesPMG
Bilateral Perisylvian Polymicrogyria.
SpecialtyNeurology
BFP appears to be a symmetrical polymicrogyria that extends anteriorly from the frontal poles to the posterior precentral gyrus, and inferiorly to the frontal operculum. Patients who had polymicrogyria distribution similar to this also experienced similar symptoms including delayed motor and language developments, spastic hemiparesis or quadriparesis, and forms of mild mental retardation.
### Bilateral frontoparietal polymicrogyria (BFPP)[edit]
Main article: Bilateral frontoparietal polymicrogyria
BFPP was one of the first discovered forms of polymicrogyria to have a gene identified linking to the syndromes caused. This gene is called GPR56. Symmetrical distribution is also evident in this form, but more distinctly, patients with BFPP were found to have atrophy of the cerebellum and brain stem, as well as bilateral white matter abnormalities. BFPP is characterized by estopia, global development delay, pyramidal signs, cerebral signs, and seizures. Estopia is also known as dysconjugate gaze, and is a common feature of severe static encephalopathy. This differentiates BFPP from the other bilatieral polymicrogyria syndromes.
### Bilateral perisylvian polymicrogyria (BPP)[edit]
BPP is similar to the other types of polymicrogyria in that it is usually symmetrical, but BPP can vary among patients. BPP is characterized by its location; the cerebral cortex deep in the sylvian fissures is thickened and abnormally infolded, as well as the sylvian fissures extending more posteriorly up to the parietal lobes and more vertically oriented.[1] BPP has been classified into a grading system consisting of four different grades that describe that variations in severity:
1. Grade 1: Perisylvian polymicrogyria extends to either one or both poles
2. Grade 2: Perisylvian polymicrogyria extends past the perisylvian region, but not to either of the poles
3. Grade 3: Perisylvian polymicrogyria is contained in the perisylvian region only
4. Grade 4: Perisylvian polymicrogyria is contained in the posterior perisylvian region only
The grades move from most severe (Grade 1) to least severe (Grade 4). Although BFPP was the first form of polymicrogyria to be discovered, BPP was the first form to be described and is also the most common form of polymicrogyria. The clinical characterizations of BPP "include pseudobulbar palsy with diplegia of the facial, pharyngeal and masticory muscles (facio-pharyngo-glosso-masticatory paresis), pyramidal signs, and seizures."[1] These can result in drooling, feeding issues, restricted tongue movement, and dysarthria.[1] Disorders in language development have also been associated with BPP, but the extent of language disorder depends on the severity of cortical damage. Patients who suffer from BPP can also have pyramidal signs that vary in severity, and can be either unilateral or bilateral.[1]
The sodium channel SCN3A has been implicated in BPP.[2]
### Bilateral parasagittal parieto-occipital polymicrogyria (BPOP)[edit]
BPOP is located in the parasagittal and mesial regions of the parieto-occipital cortex. This form has been associated with IQ scores that range from average intelligence to mild mental retardation, seizures, and cognitive slowing. The age of seizure onset has been found to occur anywhere from 20 months to 15 years, and in most cases the seizures were intractable (meaning hard to control).[1]
### Bilateral generalised polymicrogyria (BGP)[edit]
BGP is most severe in the perisylvian regions, but occurs in a generalised distribution. Associated factors include a reduced volume of white matter and ventriculomegaly. BGP tends to show excessively folded and fused gyri of an abnormally thin cerebral cortex, and an absence of the normal six-layered structure. The abnormally thin cortex is a key factor that distinguishes this form of polymicrogyria from the others, which are characterized by an abnormally thick cortex. Most of the patients have cognitive and motor delay, spastic hemi- or quadriparesis, and seizures in varying degrees. The seizures also vary at age of onset, type, and severity. There have been pseudobulbar signs reported with BGP, which are also seen in patients suffering from BPP. This association leads to the belief that there is overlap between patients suffering from BGP and patients suffering from grade 1 BPP.[1]
### Unilateral polymicrogyria[edit]
The region in which unilateral polymicrogyria occurs has been generalized into different cortical areas. Features associated with this form of polymicrogyria are similar to the other forms and include spastic hemiparesis, mental retardation in variable degrees, and seizures. The features depend on the exact area and extent to which polymicrogyria has affected the cortex. Patients who have unilateral polymicrogyria have been reported to also have electrical status epilepticus during sleep (EPES), and all suffered from seizures.[1]
## Signs and symptoms[edit]
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The diagnosis of PMG is merely descriptive and is not a disease in itself, nor does it describe the underlying cause of the brain malformation.
Polymicrogyria may be just one piece of a syndrome of developmental abnormalities, because children born with it may suffer from a wide spectrum of other problems, including global developmental disabilities, mild to severe intellectual disabilities, motor dysfunctions including speech and swallowing problems, respiratory problems, and seizures. Though it is difficult to make a predictable prognosis for children with the diagnosis of PMG, there are some generalized clinical findings according to the areas of the brain that are affected.
* Bilateral frontal polymicrogyria (BFP) – Cognitive and motor delay, spastic quadriparesis, epilepsy
* Bilateral frontoparietal polymicrogyria (BFPP) – Severe cognitive and motor delay, seizures, dysconjugate gaze, cerebellar dysfunction
* Bilateral perisylvian polymicrogyria (BPP) – Pseudobulbar signs, cognitive impairment, epilepsy, some with arthrogryposis or lower motor neuron disease
* Bilateral parasagittal parieto-occipital polymicrogyria (BPPP) – Partial seizures, some with mental retardation
* Bilateral generalized polymicrogyria (BGP) – Cognitive and motor delay of variable severity, seizures
## Cause[edit]
The cause of polymicrogyria is unclear. It is currently classified as resulting from abnormalities during late neuronal migration or early cortical organization of fetal development. Evidence for both genetic and non-genetic causes exists. Polymicrogyria appears to occur around the time of neuronal migration or early cortical development. Non-genetic causes include defects in placental oxygenation and in association with congenital infections, particularly cytomegalovirus.[citation needed]
An association with the gene WDR62 and SCN3A has been identified.,[3][4][5][2] as well as other ion channels.[6]
## Pathology[edit]
Polymicrogyria is a disorder of neuronal migration, resulting in structurally abnormal cerebral hemispheres. The Greek roots of the name describe its salient feature: many [poly] small [micro] gyri (convolutions in the surface of the brain). It is also characterized by shallow sulci, a slightly thicker cortex, neuronal heterotopia and enlarged ventricles. When many of these small folds are packed tightly together, PMG may resemble pachygyria (a few "thick folds" - a mild form of lissencephaly).[citation needed]
The pathogenesis of polymicrogyria is still being researched for understanding though it is historically heterogeneous-4. It results from both genetic and destructive events. While polymicrogyria is associated with genetic mutations, none of these are the sole cause of this abnormality. The cortical development of mammals requires specific cell functions that all involve microtubules, whether it is because of mitosis, specifically cell division, cell migration or neurite growth. Some mutations that affect the role of microtubules and are studied as possible contributors, but not causes, to polymicrogyria include TUBA1A and TUBB2B.[7] TUBB2B mutations are known to contribute to polymicrogyria either with or without congenital fibrosis or the external ocular muscles, as well as bilateral perisylvian.[citation needed]
GPR56 protein structuregreen: signal peptideyellow: N-Glycosylation siteblue: GPS motiforange bracket: 108-177 aa STPpink bracket: 27-160 aa Ligand binding domain Referenced article: Singer K, Luo R, Jeong SJ, Piao X (2013). "GPR56 and the developing cerebral cortex: cells, matrix, and neuronal migration". Mol. Neurobiol. 47 (1): 186–96. doi:10.1007/s12035-012-8343-0. PMC 3538897. PMID 23001883.
The gene GPR56 is a member of the adhesion G protein-coupled receptor family and is directly related to causing Bilateral frontoparietal polymicrogyria, (BFPP)-6. Other genes in the G protein-coupled receptor family have effects with this condition as well such as the outer brain development, but not enough is known to carry out all the research properly so the main focus is starting with the specific GR56 gene within this category. This malformation of the brain is a result of numerous small gyri taking over the surface of the brain that should otherwise be normally convoluted. This gene is currently under studies to help identify and contribute to the knowledge about this condition. It is studied to provide information on the causes along with insight into the mechanisms of normal cortical development and the regional patterning of the cerebral cortex using magnetic resonance imagine, MRI. Specifically found to polymicrogyria due to mutation of this gene are myelination defects. GPR56 is observed to be important for myelinations due to a mutation in this gene results in reduced white matter volume and signal changes as shown in MRI's. While the cellular roles of GPR56 in myelination remains unclear, this information will be used to further other studies done with this gene.[citation needed]
Another gene that has been associated with this condition is GRIN1 and GRIN2B.[8][6]
## Diagnosis[edit]
The effects of polymicrogyria (PMG) can be either focal or widespread. Although both can have physiological effects on the patient, it is hard to determine PMG as the direct cause because it can be associated with other brain malformations. Most commonly, PMG is associated with Aicardi and Warburg micro syndromes.[9] These syndromes both have frontoparieto polymicrogyria as their anomalies. To ensure proper diagnosis, doctors thus can examine a patient through neuroimaging or neuropathological techniques.[9]
### Neuroimaging techniques[edit]
Pathologically, PMG is defined as “an abnormally thick cortex formed by the piling upon each other of many small gyri with a fused surface.”[10] To view these microscopic characteristics, magnetic resonance imaging (MRI) is used. First physicians must distinguish between polymicrogyria and pachygyria. Pachygria leads to the development of broad and flat regions in the cortical area, whereas the effect of PMG is the formation of multiple small gyri. Underneath a computerized tomography (CT scan) scan, these both appear similar in that the cerebral cortex appears thickened. However, MRI with a T1 weighted inversion recovery will illustrate the gray-white junction that is characterized by patients with PMG.[9] An MRI is also usually preferred over the CT scan because it has sub-millimeter resolution. The resolution displays the multiple folds within the cortical area, which is continuous with the neuropathology of an infected patient.[citation needed]
### Neuropathological techniques[edit]
Gross examination exposes a pattern of many small gyri clumped together, which causes an irregularity in the brain surface.[9] The cerebral cortex, which in normal patients is six cell layers thick, is also thinned. As mentioned prior, the MRI of an affected patient shows what appears to be a thickening of the cerebral cortex because of the tiny folds that aggregate causing a more dense appearance. However, gross analysis shows that an affected patient can have as few as one to all six of these layers missing.[9]
## Treatment[edit]
The Polymicrogyria (PMG) malformation cannot be reversed, but the symptoms can be treated. The removal of affected areas through hemispherectomy has been used in some cases to reduce the amount a seizure activity. Few patients are candidates for surgery.[11] The global developmental delay that affects 94% can also be mitigated in some patients with occupational, physical, and speech therapies. The important aspect to realize is PMG affects each patient differently and treatment options and mitigation techniques will vary.[12] Many services are available to help, most children's hospitals can direct caregivers guidance where to get the information they need to seek assistance.[citation needed]
## History[edit]
Limited information was known about cerebral disorders until the development of modern technologies. Brain imaging and genetic sequencing greatly increased the information known about polymicrogyria within the past decade.[13] Understanding about development, classification and localization of the disorder have greatly improved.[13] For instance, localization of specific cortex regions affected by the disease was determined. This allowed for clinical symptoms of patients to be linked with localized cortex areas affected.[13] A gene that was identified to be a contributor to Bilateral frontoparietal polymicrogyria was GPR56[citation needed].
## See also[edit]
* Bilateral frontoparietal polymicrogyria (genetic lesion)
* Augmentative and alternative communication
* Epilepsy Phenome/Genome Project
## References[edit]
1. ^ a b c d e f g Jansen, A.; Andermann, E. (1 May 2005). "Genetics of the polymicrogyria syndromes". Journal of Medical Genetics. 42 (5): 369–378. doi:10.1136/jmg.2004.023952. PMC 1736054. PMID 15863665.
2. ^ a b Smith, RS; Kenny, CJ; Ganesh, V; Jang, A; Borges-Monroy, R; Partlow, JN; Hill, RS; Shin, T; Chen, AY; Doan, RN; Anttonen, AK; Ignatius, J; Medne, L; Bönnemann, CG; Hecht, JL; Salonen, O; Barkovich, AJ; Poduri, A; Wilke, M; de Wit, MCY; Mancini, GMS; Sztriha, L; Im, K; Amrom, D; Andermann, E; Paetau, R; Lehesjoki, AE; Walsh, CA; Lehtinen, MK (5 September 2018). "Sodium Channel SCN3A (NaV1.3) Regulation of Human Cerebral Cortical Folding and Oral Motor Development". Neuron. 99 (5): 905–913.e7. doi:10.1016/j.neuron.2018.07.052. PMC 6226006. PMID 30146301.
3. ^ Bhat, V; Girimaji, SC; Mohan, G; Arvinda, HR; Singhmar, P; Duvvari, MR; Kumar, A (Apr 15, 2011). "Mutations in WDR62, encoding a centrosomal and nuclear protein, in Indian primary microcephaly families with cortical malformations". Clinical Genetics. 80 (6): 532–40. doi:10.1111/j.1399-0004.2011.01686.x. PMID 21496009.
4. ^ Murdock DR, Clark GD, Bainbridge MN, Newsham I, Wu YQ, Muzny DM, Cheung SW, Gibbs RA, Ramocki MB (2011). "Whole-exome sequencing identifies compound heterozygous mutations in WDR62 in siblings with recurrent polymicrogyria". Am J Med Genet A. 155 (9): 2071–2077. doi:10.1002/ajmg.a.34165. PMC 3616765. PMID 21834044.
5. ^ Smith RS, Kenny CJ, Ganesh V, Jang A, Borges-Monroy R, Partlow JN, Hill RS, Shin T, Chen AY, Doan RN, Anttonen AK, Ignatius J, Medne L, Bönnemann CG, Hecht JL, Salonen O, Barkovich AJ, Poduri A, Wilke M, de Wit MCY, Mancini GMS, Sztriha L, Im K, Amrom D, Andermann E, Paetau R, Lehesjoki AE, Walsh CA, Lehtinen MK (2018). "Sodium Channel SCN3A (NaV1.3) Regulation of Human Cerebral Cortical Folding and Oral Motor Development". Neuron. 99 (5): 905–913.e7. doi:10.1016/j.neuron.2018.07.052. PMC 6226006. PMID 30146301.CS1 maint: multiple names: authors list (link)
6. ^ a b Smith, RS; Walsh, CA (February 2020). "Ion Channel Functions in Early Brain Development". Trends in Neurosciences. 43 (2): 103–114. doi:10.1016/j.tins.2019.12.004. PMID 31959360.
7. ^ Kato, Mitsuhiro (2015-01-01). "Genotype-phenotype correlation in neuronal migration disorders and cortical dysplasias". Frontiers in Neuroscience. 9: 181. doi:10.3389/fnins.2015.00181. ISSN 1662-4548. PMC 4439546. PMID 26052266.
8. ^ Fry AE, Fawcett KA, Zelnik N, Yuan H, Thompson BAN, Shemer-Meiri L, Cushion TD, Mugalaasi H, Sims D, Stoodley N, Chung SK, Rees MI, Patel CV, Brueton LA, Layet V, Giuliano F, Kerr MP, Banne E, Meiner V, Lerman-Sagie T, Helbig KL, Kofman LH, Knight KM, Chen W, Kannan V, Hu C, Kusumoto H, Zhang J, Swanger SA, Shaulsky GH, Mirzaa GM, Muir AM, Mefford HC, Dobyns WB, Mackenzie AB, Mullins JGL, Lemke JR, Bahi-Buisson N, Traynelis SF, Iago HF, Pilz DT (2018) De novo mutations in GRIN1 cause extensive bilateral polymicrogyria. Brain doi: 10.1093/brain/awx358
9. ^ a b c d e Chang, Bernard; Walsh, Christopher A.; Apse, Kira; Bodell, Adria (1993-01-01). Pagon, Roberta A.; Adam, Margaret P.; Ardinger, Holly H.; Wallace, Stephanie E.; Amemiya, Anne; Bean, Lora J.H.; Bird, Thomas D.; Fong, Chin-To; Mefford, Heather C. (eds.). Polymicrogyria Overview. Seattle (WA): University of Washington, Seattle. PMID 20301504.
10. ^ Squier, Waney; Jansen, Anna (2014-01-01). "Polymicrogyria: pathology, fetal origins and mechanisms". Acta Neuropathologica Communications. 2: 80. doi:10.1186/s40478-014-0080-3. ISSN 2051-5960. PMC 4149230. PMID 25047116.
11. ^ Epilepsia Vol. 57, Iss. 1
12. ^ Journal of Medical Genetics; London Vol. 42, Iss. 5,
13. ^ a b c Barkovich, A. James (2010-06-01). "Current concepts of polymicrogyria". Neuroradiology. 52 (6): 479–487. doi:10.1007/s00234-009-0644-2. ISSN 1432-1920. PMC 2872023. PMID 20198472.
## External links[edit]
Classification
D
* ICD-10: Q04.3
* ICD-9-CM: 742.2
* MeSH: D054220
* DiseasesDB: 33975
External resources
* GeneReviews: Polymicrogyria Overview
* Orphanet: 35981
* Scholia: Q2991265
* v
* t
* e
Congenital malformations and deformations of nervous system
Brain
Neural tube defect
* Anencephaly
* Acephaly
* Acrania
* Acalvaria
* Iniencephaly
* Encephalocele
* Chiari malformation
Other
* Microcephaly
* Congenital hydrocephalus
* Dandy–Walker syndrome
* other reduction deformities
* Holoprosencephaly
* Lissencephaly
* Microlissencephaly
* Pachygyria
* Hydranencephaly
* Septo-optic dysplasia
* Megalencephaly
* Hemimegalencephaly
* CNS cyst
* Porencephaly
* Schizencephaly
* Polymicrogyria
* Bilateral frontoparietal polymicrogyria
Spinal cord
Neural tube defect
* Spina bifida
* Rachischisis
Other
* Currarino syndrome
* Diastomatomyelia
* Syringomyelia
*[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
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Polymicrogyria | c0266464 | 2,566 | wikipedia | https://en.wikipedia.org/wiki/Polymicrogyria | 2021-01-18T19:06:30 | {"gard": ["12271"], "mesh": ["D065706"], "umls": ["C0266464"], "icd-9": ["742.2"], "orphanet": ["35981"], "wikidata": ["Q2991265"]} |
A number sign (#) is used with this entry because of evidence that joint laxity, short stature, and myopia (JLSM) is caused by homozygous mutation in the GZF1 gene (613842) on chromosome 20p11.
Clinical Features
Patel et al. (2017) studied 5 affected individuals from 2 consanguineous Saudi families with joint laxity, short stature, and severe myopia with prominent eyes. An affected sister and brother in the first family exhibited multiple joint dislocations, involving the elbows, hips, knees, and ankles, as well as pectus carinatum and talipes equinovarus. The 16-year-old sister had severe kyphoscoliosis with compromised lung function, and progressive hearing loss. Her 2.5-year-old brother had only mild cervical kyphosis and no hearing loss. In the second family, 3 affected brothers exhibited joint laxity and mild pectus carinatum; 1 brother also had mild scoliosis and another had bilateral talipes equinovarus. All 3 brothers had severe myopia, 2 of whom also had retinal detachment and iris and chorioretinal coloboma, and 1 brother had hearing loss. Patel et al. (2017) considered the phenotype in the 2 families to be consistent with an autosomal recessive form of Larsen syndrome (see 150250), although they observed a number of clinical and radiologic differences between their patients and previously reported patients. The authors stated that the most striking difference was the severe eye phenotype in their patients, noting that eye involvement is unusual in Larsen syndrome.
Molecular Genetics
By combined autozygome and exome sequencing in 2 consanguineous Saudi families with short stature, joint laxity, and severe myopia, Patel et al. (2017) identified homozygous mutations in the GZF1 gene: a nonsense mutation (E289X; 613842.0001) in one family and a frameshift mutation (613842.0002) in the other. The mutations were confirmed by Sanger sequencing and segregated fully with disease in each family. Neither mutation was found in 2,379 Saudi exomes or the ExAC database.
INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Ears \- Hearing loss (in some patients) Eyes \- Exophthalmos \- Severe myopia \- Retinal detachment (in some patients) \- Iris coloboma (in some patients) \- Chorioretinal coloboma (in some patients) \- Glaucoma (in 1 patient) Neck \- Short neck RESPIRATORY Lung \- Restrictive lung disease CHEST Ribs Sternum Clavicles & Scapulae \- Pectus carinatum SKELETAL \- Osteopenia Spine \- Progressive kyphoscoliosis Limbs \- Hyperextensibility of joints \- Multiple large joint dislocations (in some patients) Feet \- Talipes equinovarus (in some patients) MOLECULAR BASIS \- Caused by mutation in the GDNF-inducible zinc finger protein-1 gene (GZF1, 613842.0001 ) ▲ Close
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| JOINT LAXITY, SHORT STATURE, AND MYOPIA | c4540020 | 2,567 | omim | https://www.omim.org/entry/617662 | 2019-09-22T15:45:15 | {"omim": ["617662"], "orphanet": ["527450"], "synonyms": []} |
Distal myopathy with posterior leg and anterior hand involvement, also named distal ABD-filaminopathy, is a neuromuscular disease characterized by a progressive symmetric muscle weakness of anterior upper and posterior lower limbs.
## Epidemiology
It has been described in several members of an Australian and an Italian family.
## Clinical description
The disease usually manifests during the third decade of life with thenar muscle weakness resulting in reduced grip strength. The disease is slowly progressive and generally proceeds with calf muscle weakness appearing during the fourth decade and proximal muscles becoming perceptibly affected in the fifth decade. The tibial anterior muscle is spared, so is respiratory function. Mild cardiomyopathy can sometimes be observed.
## Etiology
The disease is due to mutations on the actin-binding domain of the FLNC gene that encodes filamin C, a muscle specific filamin that is also associated with myofibrillar myopathy when mutations affect other parts of the protein. The disease mechanism seems to be linked to an increased actin-binding affinity of filamin C.
## Genetic counseling
Transmission is autosomal dominant.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Distal myopathy with posterior leg and anterior hand involvement | c3279722 | 2,568 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=63273 | 2021-01-23T18:19:43 | {"omim": ["614065"], "icd-10": ["G71.0"], "synonyms": ["Distal ABD-filaminopathy"]} |
## Description
Parietal foramina-3 is a nonsyndromic developmental defect characterized by symmetrical oval holes in the parietal bone (Chen et al., 2003).
For a discussion of genetic heterogeneity of parietal foramina, see 168500.
Clinical Features
Chen et al. (2003) reported a large Chinese pedigree in which 15 individuals spanning 4 generations had typical features of nonsyndromic PFM.
Inheritance
The transmission pattern of parietal foramina in the family described by Chen et al. (2003) was consistent with autosomal dominant inheritance.
Mapping
By genomewide scanning in a Chinese family segregating PFM, Chen et al. (2003) identified a putative locus, termed PFM3, on chromosome 4q21-q23 (maximum 2-point lod score of 3.87 at marker D4S2961; maximum multipoint lod score of 6.17 between D4S2986 and D4S421). Haplotype analysis refined PFM3 to a 20-cM interval between D4S2964 and D4S2961. The authors excluded mutations in the BMPR1B (603248), SPP1 (166490), and IBSP (147563) genes.
INHERITANCE \- Autosomal dominant SKELETAL Skull \- Symmetrical, oval parietal bone defects \- Cranium bifidum SKIN, NAILS, & HAIR Skin \- Scalp defect MISCELLANEOUS \- Genetic heterogeneity (see PFM1, 168500 ) ▲ 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
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| PARIETAL FORAMINA 3 | c1868598 | 2,569 | omim | https://www.omim.org/entry/609566 | 2019-09-22T16:05:54 | {"doid": ["0060285"], "mesh": ["C566826"], "omim": ["609566"], "orphanet": ["60015"]} |
Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly is a rare, central nervous system malformation syndrome characterized by progressive microcephaly with profound motor delay and intellectual disability, associated with hypertonia, spasticity, clonus, and seizures, with brain imaging revealing severe cerebral and cerebellar atrophy, and poor myelination.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly | c3150921 | 2,570 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=402364 | 2021-01-23T17:54:13 | {"gard": ["10995"], "omim": ["613668"], "icd-10": ["Q04.3"]} |
Death of a region of brain cells due to poor blood flow
For other uses, see Stroke (disambiguation).
Stroke
Other namesCerebrovascular accident (CVA), cerebrovascular insult (CVI), brain attack
CT scan of the brain showing a prior right-sided ischemic stroke from blockage of an artery. Changes on a CT may not be visible early on.[1]
SpecialtyNeurology, stroke medicine
SymptomsInability to move or feel on one side of the body, problems understanding or speaking, dizziness, loss of vision to one side[2][3]
ComplicationsPersistent vegetative state[4]
CausesIschemic (blockage) and hemorrhagic (bleeding)[5]
Risk factorsHigh blood pressure, tobacco smoking, obesity, high blood cholesterol, diabetes mellitus, previous TIA, end-stage kidney disease, atrial fibrillation[2][6][7]
Diagnostic methodBased on symptoms with medical imaging typically used to rule out bleeding[8][9]
Differential diagnosisLow blood sugar[8]
TreatmentBased on the type[2]
PrognosisAverage life expectancy 1 year[2]
Frequency42.4 million (2015)[10]
Deaths6.3 million (2015)[11]
A stroke is a medical condition in which poor blood flow to the brain causes cell death.[5] There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding.[5] Both cause parts of the brain to stop functioning properly.[5] Signs and symptoms of a stroke may include an inability to move or feel on one side of the body, problems understanding or speaking, dizziness, or loss of vision to one side.[2][3] Signs and symptoms often appear soon after the stroke has occurred.[3] If symptoms last less than one or two hours, the stroke is a transient ischemic attack (TIA), also called a mini-stroke.[3] A hemorrhagic stroke may also be associated with a severe headache.[3] The symptoms of a stroke can be permanent.[5] Long-term complications may include pneumonia and loss of bladder control.[3]
The main risk factor for stroke is high blood pressure.[6] Other risk factors include tobacco smoking, obesity, high blood cholesterol, diabetes mellitus, a previous TIA, end-stage kidney disease, and atrial fibrillation.[2][6][7] An ischemic stroke is typically caused by blockage of a blood vessel, though there are also less common causes.[12][13][14] A hemorrhagic stroke is caused by either bleeding directly into the brain or into the space between the brain's membranes.[12][15] Bleeding may occur due to a ruptured brain aneurysm.[12] Diagnosis is typically based on a physical exam and supported by medical imaging such as a CT scan or MRI scan.[8] A CT scan can rule out bleeding, but may not necessarily rule out ischemia, which early on typically does not show up on a CT scan.[9] Other tests such as an electrocardiogram (ECG) and blood tests are done to determine risk factors and rule out other possible causes.[8] Low blood sugar may cause similar symptoms.[8]
Prevention includes decreasing risk factors, surgery to open up the arteries to the brain in those with problematic carotid narrowing, and warfarin in people with atrial fibrillation.[2] Aspirin or statins may be recommended by physicians for prevention.[2] A stroke or TIA often requires emergency care.[5] An ischemic stroke, if detected within three to four and half hours, may be treatable with a medication that can break down the clot.[2] Some hemorrhagic strokes benefit from surgery.[2] Treatment to attempt recovery of lost function is called stroke rehabilitation, and ideally takes place in a stroke unit; however, these are not available in much of the world.[2]
In 2013, approximately 6.9 million people had an ischemic stroke and 3.4 million people had a hemorrhagic stroke.[16] In 2015, there were about 42.4 million people who had previously had a stroke and were still alive.[10] Between 1990 and 2010 the number of strokes which occurred each year decreased by approximately 10% in the developed world and increased by 10% in the developing world.[17] In 2015, stroke was the second most frequent cause of death after coronary artery disease, accounting for 6.3 million deaths (11% of the total).[11] About 3.0 million deaths resulted from ischemic stroke while 3.3 million deaths resulted from hemorrhagic stroke.[11] About half of people who have had a stroke live less than one year.[2] Overall, two thirds of strokes occurred in those over 65 years old.[17]
## Contents
* 1 Classification
* 1.1 Definition
* 1.2 Ischemic
* 1.3 Hemorrhagic
* 2 Signs and symptoms
* 2.1 Early recognition
* 2.2 Subtypes
* 2.3 Associated symptoms
* 3 Causes
* 3.1 Thrombotic stroke
* 3.2 Embolic stroke
* 3.3 Cerebral hypoperfusion
* 3.4 Venous thrombosis
* 3.5 Intracerebral hemorrhage
* 3.6 Other
* 3.7 Silent stroke
* 4 Pathophysiology
* 4.1 Ischemic
* 4.2 Hemorrhagic
* 5 Diagnosis
* 5.1 Physical examination
* 5.2 Imaging
* 5.3 Underlying cause
* 5.4 Misdiagnosis
* 6 Prevention
* 6.1 Risk factors
* 6.1.1 Blood pressure
* 6.1.2 Blood lipids
* 6.1.3 Diabetes mellitus
* 6.1.4 Anticoagulation drugs
* 6.1.5 Surgery
* 6.1.6 Diet
* 6.2 Women
* 6.3 Previous stroke or TIA
* 7 Management
* 7.1 Ischemic stroke
* 7.1.1 Thrombolysis
* 7.1.2 Endovascular treatment
* 7.1.3 Craniectomy
* 7.2 Hemorrhagic stroke
* 7.3 Stroke unit
* 7.4 Rehabilitation
* 7.4.1 Physical and occupational therapy
* 7.4.2 Speech and language therapy
* 7.4.3 Devices
* 7.4.4 Physical fitness
* 7.4.5 Other therapy methods
* 7.5 Self-management
* 8 Prognosis
* 8.1 Physical effects
* 8.2 Emotional and mental effects
* 9 Epidemiology
* 10 History
* 11 Research
* 12 See also
* 13 References
* 14 Further reading
* 15 External links
## Classification
There are two main categories of strokes. Ischemic (top), typically caused by a blood clot in an artery (1a) resulting in brain death to the affected area (2a). Hemorrhagic (bottom), caused by blood leaking into or around the brain from a ruptured blood vessel (1b) allowing blood to pool in the affected area (2b) thus increasing the pressure on the brain.
A slice of brain from the autopsy of a person who had an acute middle cerebral artery (MCA) stroke
Strokes can be classified into two major categories: ischemic and hemorrhagic.[18] Ischemic strokes are caused by interruption of the blood supply to the brain, while hemorrhagic strokes result from the rupture of a blood vessel or an abnormal vascular structure. About 87% of strokes are ischemic, the rest being hemorrhagic. Bleeding can develop inside areas of ischemia, a condition known as "hemorrhagic transformation." It is unknown how many hemorrhagic strokes actually start as ischemic strokes.[2]
### Definition
In the 1970s the World Health Organization defined stroke as a "neurological deficit of cerebrovascular cause that persists beyond 24 hours or is interrupted by death within 24 hours",[19] although the word "stroke" is centuries old. This definition was supposed to reflect the reversibility of tissue damage and was devised for the purpose, with the time frame of 24 hours being chosen arbitrarily. The 24-hour limit divides stroke from transient ischemic attack, which is a related syndrome of stroke symptoms that resolve completely within 24 hours.[2] With the availability of treatments that can reduce stroke severity when given early, many now prefer alternative terminology, such as brain attack and acute ischemic cerebrovascular syndrome (modeled after heart attack and acute coronary syndrome, respectively), to reflect the urgency of stroke symptoms and the need to act swiftly.[20]
### Ischemic
Main articles: Cerebral infarction and Brain ischemia
In an ischemic stroke, blood supply to part of the brain is decreased, leading to dysfunction of the brain tissue in that area. There are four reasons why this might happen:
1. Thrombosis (obstruction of a blood vessel by a blood clot forming locally)
2. Embolism (obstruction due to an embolus from elsewhere in the body),[2]
3. Systemic hypoperfusion (general decrease in blood supply, e.g., in shock)[21]
4. Cerebral venous sinus thrombosis.[22]
A stroke without an obvious explanation is termed cryptogenic (of unknown origin); this constitutes 30–40% of all ischemic strokes.[2][23]
There are various classification systems for acute ischemic stroke. The Oxford Community Stroke Project classification (OCSP, also known as the Bamford or Oxford classification) relies primarily on the initial symptoms; based on the extent of the symptoms, the stroke episode is classified as total anterior circulation infarct (TACI), partial anterior circulation infarct (PACI), lacunar infarct (LACI) or posterior circulation infarct (POCI). These four entities predict the extent of the stroke, the area of the brain that is affected, the underlying cause, and the prognosis.[24][25] The TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification is based on clinical symptoms as well as results of further investigations; on this basis, a stroke is classified as being due to (1) thrombosis or embolism due to atherosclerosis of a large artery, (2) an embolism originating in the heart, (3) complete blockage of a small blood vessel, (4) other determined cause, (5) undetermined cause (two possible causes, no cause identified, or incomplete investigation).[26] Users of stimulants such as cocaine and methamphetamine are at a high risk for ischemic strokes.[27]
### Hemorrhagic
Main articles: Intracerebral hemorrhage and Subarachnoid hemorrhage
CT scan of an intraparenchymal bleed (bottom arrow) with surrounding edema (top arrow)
There are two main types of hemorrhagic stroke:[28][29]
* Intracerebral hemorrhage, which is basically bleeding within the brain itself (when an artery in the brain bursts, flooding the surrounding tissue with blood), due to either intraparenchymal hemorrhage (bleeding within the brain tissue) or intraventricular hemorrhage (bleeding within the brain's ventricular system).
* Subarachnoid hemorrhage, which is basically bleeding that occurs outside of the brain tissue but still within the skull, and precisely between the arachnoid mater and pia mater (the delicate innermost layer of the three layers of the meninges that surround the brain).
The above two main types of hemorrhagic stroke are also two different forms of intracranial hemorrhage, which is the accumulation of blood anywhere within the cranial vault; but the other forms of intracranial hemorrhage, such as epidural hematoma (bleeding between the skull and the dura mater, which is the thick outermost layer of the meninges that surround the brain) and subdural hematoma (bleeding in the subdural space), are not considered "hemorrhagic strokes".[30]
Hemorrhagic strokes may occur on the background of alterations to the blood vessels in the brain, such as cerebral amyloid angiopathy, cerebral arteriovenous malformation and an intracranial aneurysm, which can cause intraparenchymal or subarachnoid hemorrhage.[citation needed]
In addition to neurological impairment, hemorrhagic strokes usually cause specific symptoms (for instance, subarachnoid hemorrhage classically causes a severe headache known as a thunderclap headache) or reveal evidence of a previous head injury.
## Signs and symptoms
Stroke symptoms typically start suddenly, over seconds to minutes, and in most cases do not progress further. The symptoms depend on the area of the brain affected. The more extensive the area of the brain affected, the more functions that are likely to be lost. Some forms of stroke can cause additional symptoms. For example, in intracranial hemorrhage, the affected area may compress other structures. Most forms of stroke are not associated with a headache, apart from subarachnoid hemorrhage and cerebral venous thrombosis and occasionally intracerebral hemorrhage.[citation needed]
### Early recognition
Various systems have been proposed to increase recognition of stroke. Different findings are able to predict the presence or absence of stroke to different degrees. Sudden-onset face weakness, arm drift (i.e., if a person, when asked to raise both arms, involuntarily lets one arm drift downward) and abnormal speech are the findings most likely to lead to the correct identification of a case of stroke, increasing the likelihood by 5.5 when at least one of these is present. Similarly, when all three of these are absent, the likelihood of stroke is decreased (– likelihood ratio of 0.39).[31] While these findings are not perfect for diagnosing stroke, the fact that they can be evaluated relatively rapidly and easily make them very valuable in the acute setting.
A mnemonic to remember the warning signs of stroke is FAST (facial droop, arm weakness, speech difficulty, and time to call emergency services),[32] as advocated by the Department of Health (United Kingdom) and the Stroke Association, the American Stroke Association, the National Stroke Association (US), the Los Angeles Prehospital Stroke Screen (LAPSS)[33] and the Cincinnati Prehospital Stroke Scale (CPSS).[34] Use of these scales is recommended by professional guidelines.[35] FAST is less reliable in the recognition of posterior circulation strokes.[36]
For people referred to the emergency room, early recognition of stroke is deemed important as this can expedite diagnostic tests and treatments. A scoring system called ROSIER (recognition of stroke in the emergency room) is recommended for this purpose; it is based on features from the medical history and physical examination.[35][37]
### Subtypes
If the area of the brain affected includes one of the three prominent central nervous system pathways—the spinothalamic tract, corticospinal tract, and the dorsal column–medial lemniscus pathway, symptoms may include:
* hemiplegia and muscle weakness of the face
* numbness
* reduction in sensory or vibratory sensation
* initial flaccidity (reduced muscle tone), replaced by spasticity (increased muscle tone), excessive reflexes, and obligatory synergies.[38]
In most cases, the symptoms affect only one side of the body (unilateral). Depending on the part of the brain affected, the defect in the brain is usually on the opposite side of the body. However, since these pathways also travel in the spinal cord and any lesion there can also produce these symptoms, the presence of any one of these symptoms does not necessarily indicate a stroke. In addition to the above CNS pathways, the brainstem gives rise to most of the twelve cranial nerves. A brainstem stroke affecting the brainstem and brain, therefore, can produce symptoms relating to deficits in these cranial nerves:[citation needed]
* altered smell, taste, hearing, or vision (total or partial)
* drooping of eyelid (ptosis) and weakness of ocular muscles
* decreased reflexes: gag, swallow, pupil reactivity to light
* decreased sensation and muscle weakness of the face
* balance problems and nystagmus
* altered breathing and heart rate
* weakness in sternocleidomastoid muscle with inability to turn head to one side
* weakness in tongue (inability to stick out the tongue or move it from side to side)
If the cerebral cortex is involved, the CNS pathways can again be affected, but also can produce the following symptoms:
* aphasia (difficulty with verbal expression, auditory comprehension, reading and writing; Broca's or Wernicke's area typically involved)
* dysarthria (motor speech disorder resulting from neurological injury)
* apraxia (altered voluntary movements)
* visual field defect
* memory deficits (involvement of temporal lobe)
* hemineglect (involvement of parietal lobe)
* disorganized thinking, confusion, hypersexual gestures (with involvement of frontal lobe)
* lack of insight of his or her, usually stroke-related, disability
If the cerebellum is involved, ataxia might be present and this includes:
* altered walking gait
* altered movement coordination
* vertigo and or disequilibrium
### Associated symptoms
Loss of consciousness, headache, and vomiting usually occur more often in hemorrhagic stroke than in thrombosis because of the increased intracranial pressure from the leaking blood compressing the brain.
If symptoms are maximal at onset, the cause is more likely to be a subarachnoid hemorrhage or an embolic stroke.
## Causes
### Thrombotic stroke
Illustration of an embolic stroke, showing a blockage lodged in a blood vessel.
In thrombotic stroke, a thrombus[39] (blood clot) usually forms around atherosclerotic plaques. Since blockage of the artery is gradual, onset of symptomatic thrombotic strokes is slower than that of a hemorrhagic stroke. A thrombus itself (even if it does not completely block the blood vessel) can lead to an embolic stroke (see below) if the thrombus breaks off and travels in the bloodstream, at which point it is called an embolus. Two types of thrombosis can cause stroke:
* Large vessel disease involves the common and internal carotid arteries, the vertebral artery, and the Circle of Willis.[40] Diseases that may form thrombi in the large vessels include (in descending incidence): atherosclerosis, vasoconstriction (tightening of the artery), aortic, carotid or vertebral artery dissection, various inflammatory diseases of the blood vessel wall (Takayasu arteritis, giant cell arteritis, vasculitis), noninflammatory vasculopathy, Moyamoya disease and fibromuscular dysplasia.
* Small vessel disease involves the smaller arteries inside the brain: branches of the circle of Willis, middle cerebral artery, stem, and arteries arising from the distal vertebral and basilar artery.[41] Diseases that may form thrombi in the small vessels include (in descending incidence): lipohyalinosis (build-up of fatty hyaline matter in the blood vessel as a result of high blood pressure and aging) and fibrinoid degeneration (a stroke involving these vessels is known as a lacunar stroke) and microatheroma (small atherosclerotic plaques).[42]
Sickle-cell anemia, which can cause blood cells to clump up and block blood vessels, can also lead to stroke. A stroke is the second leading cause of death in people under 20 with sickle-cell anemia.[43] Air pollution may also increase stroke risk.[44]
### Embolic stroke
An embolic stroke refers to an arterial embolism (a blockage of an artery) by an embolus, a traveling particle or debris in the arterial bloodstream originating from elsewhere. An embolus is most frequently a thrombus, but it can also be a number of other substances including fat (e.g., from bone marrow in a broken bone), air, cancer cells or clumps of bacteria (usually from infectious endocarditis).[45]
Because an embolus arises from elsewhere, local therapy solves the problem only temporarily. Thus, the source of the embolus must be identified. Because the embolic blockage is sudden in onset, symptoms usually are maximal at the start. Also, symptoms may be transient as the embolus is partially resorbed and moves to a different location or dissipates altogether.
Emboli most commonly arise from the heart (especially in atrial fibrillation) but may originate from elsewhere in the arterial tree. In paradoxical embolism, a deep vein thrombosis embolizes through an atrial or ventricular septal defect in the heart into the brain.[45]
Causes of stroke related to the heart can be distinguished between high and low-risk:[46]
* High risk: atrial fibrillation and paroxysmal atrial fibrillation, rheumatic disease of the mitral or aortic valve disease, artificial heart valves, known cardiac thrombus of the atrium or ventricle, sick sinus syndrome, sustained atrial flutter, recent myocardial infarction, chronic myocardial infarction together with ejection fraction <28 percent, symptomatic congestive heart failure with ejection fraction <30 percent, dilated cardiomyopathy, Libman-Sacks endocarditis, Marantic endocarditis, infective endocarditis, papillary fibroelastoma, left atrial myxoma and coronary artery bypass graft (CABG) surgery.
* Low risk/potential: calcification of the annulus (ring) of the mitral valve, patent foramen ovale (PFO), atrial septal aneurysm, atrial septal aneurysm with patent foramen ovale, left ventricular aneurysm without thrombus, isolated left atrial "smoke" on echocardiography (no mitral stenosis or atrial fibrillation), complex atheroma in the ascending aorta or proximal arch.
Among those who have a complete blockage of one of the carotid arteries, the risk of stroke on that side is about one percent per year.[47]
A special form of embolic stroke is the embolic stroke of undetermined source (ESUS). This subset of cryptogenic stroke is defined as a non-lacunar brain infarct without proximal arterial stenosis or cardioembolic sources. About one out of six ischemic strokes could be classified as ESUS.[48]
### Cerebral hypoperfusion
Cerebral hypoperfusion is the reduction of blood flow to all parts of the brain. The reduction could be to a particular part of the brain depending on the cause. It is most commonly due to heart failure from cardiac arrest or arrhythmias, or from reduced cardiac output as a result of myocardial infarction, pulmonary embolism, pericardial effusion, or bleeding.[citation needed] Hypoxemia (low blood oxygen content) may precipitate the hypoperfusion. Because the reduction in blood flow is global, all parts of the brain may be affected, especially vulnerable "watershed" areas—border zone regions supplied by the major cerebral arteries. A watershed stroke refers to the condition when the blood supply to these areas is compromised. Blood flow to these areas does not necessarily stop, but instead it may lessen to the point where brain damage can occur.
### Venous thrombosis
Cerebral venous sinus thrombosis leads to stroke due to locally increased venous pressure, which exceeds the pressure generated by the arteries. Infarcts are more likely to undergo hemorrhagic transformation (leaking of blood into the damaged area) than other types of ischemic stroke.[22]
### Intracerebral hemorrhage
It generally occurs in small arteries or arterioles and is commonly due to hypertension,[49] intracranial vascular malformations (including cavernous angiomas or arteriovenous malformations), cerebral amyloid angiopathy, or infarcts into which secondary hemorrhage has occurred.[2] Other potential causes are trauma, bleeding disorders, amyloid angiopathy, illicit drug use (e.g., amphetamines or cocaine). The hematoma enlarges until pressure from surrounding tissue limits its growth, or until it decompresses by emptying into the ventricular system, CSF or the pial surface. A third of intracerebral bleed is into the brain's ventricles. ICH has a mortality rate of 44 percent after 30 days, higher than ischemic stroke or subarachnoid hemorrhage (which technically may also be classified as a type of stroke[2]).
### Other
Other causes may include spasm of an artery. This may occur due to cocaine.[50]
### Silent stroke
A silent stroke is a stroke that does not have any outward symptoms, and people are typically unaware they have had a stroke. Despite not causing identifiable symptoms, a silent stroke still damages the brain and places the person at increased risk for both transient ischemic attack and major stroke in the future. Conversely, those who have had a major stroke are also at risk of having silent strokes.[51] In a broad study in 1998, more than 11 million people were estimated to have experienced a stroke in the United States. Approximately 770,000 of these strokes were symptomatic and 11 million were first-ever silent MRI infarcts or hemorrhages. Silent strokes typically cause lesions which are detected via the use of neuroimaging such as MRI. Silent strokes are estimated to occur at five times the rate of symptomatic strokes.[52][53] The risk of silent stroke increases with age, but may also affect younger adults and children, especially those with acute anemia.[52][54]
## Pathophysiology
### Ischemic
Micrograph showing cortical pseudolaminar necrosis, a finding seen in strokes on medical imaging and at autopsy. H&E-LFB stain.
Micrograph of the superficial cerebral cortex showing neuron loss and reactive astrocytes in a person that has had a stroke. H&E-LFB stain.
Ischemic stroke occurs because of a loss of blood supply to part of the brain, initiating the ischemic cascade.[55] Brain tissue ceases to function if deprived of oxygen for more than 60 to 90 seconds[citation needed], and after approximately three hours will suffer irreversible injury possibly leading to the death of the tissue, i.e., infarction. (This is why fibrinolytics such as alteplase are given only until three hours since the onset of the stroke.) Atherosclerosis may disrupt the blood supply by narrowing the lumen of blood vessels leading to a reduction of blood flow, by causing the formation of blood clots within the vessel, or by releasing showers of small emboli through the disintegration of atherosclerotic plaques.[56] Embolic infarction occurs when emboli formed elsewhere in the circulatory system, typically in the heart as a consequence of atrial fibrillation, or in the carotid arteries, break off, enter the cerebral circulation, then lodge in and block brain blood vessels. Since blood vessels in the brain are now blocked, the brain becomes low in energy, and thus it resorts to using anaerobic metabolism within the region of brain tissue affected by ischemia. Anaerobic metabolism produces less adenosine triphosphate (ATP) but releases a by-product called lactic acid. Lactic acid is an irritant which could potentially destroy cells since it is an acid and disrupts the normal acid-base balance in the brain. The ischemia area is referred to as the "ischemic penumbra".[57]
As oxygen or glucose becomes depleted in ischemic brain tissue, the production of high energy phosphate compounds such as adenosine triphosphate (ATP) fails, leading to failure of energy-dependent processes (such as ion pumping) necessary for tissue cell survival. This sets off a series of interrelated events that result in cellular injury and death. A major cause of neuronal injury is the release of the excitatory neurotransmitter glutamate. The concentration of glutamate outside the cells of the nervous system is normally kept low by so-called uptake carriers, which are powered by the concentration gradients of ions (mainly Na+) across the cell membrane. However, stroke cuts off the supply of oxygen and glucose which powers the ion pumps maintaining these gradients. As a result, the transmembrane ion gradients run down, and glutamate transporters reverse their direction, releasing glutamate into the extracellular space. Glutamate acts on receptors in nerve cells (especially NMDA receptors), producing an influx of calcium which activates enzymes that digest the cells' proteins, lipids, and nuclear material. Calcium influx can also lead to the failure of mitochondria, which can lead further toward energy depletion and may trigger cell death due to programmed cell death.[58]
Ischemia also induces production of oxygen free radicals and other reactive oxygen species. These react with and damage a number of cellular and extracellular elements. Damage to the blood vessel lining or endothelium is particularly important. In fact, many antioxidant neuroprotectants such as uric acid and NXY-059 work at the level of the endothelium and not in the brain per se. Free radicals also directly initiate elements of the programmed cell death cascade by means of redox signaling.[59]
These processes are the same for any type of ischemic tissue and are referred to collectively as the ischemic cascade. However, brain tissue is especially vulnerable to ischemia since it has little respiratory reserve and is completely dependent on aerobic metabolism, unlike most other organs.
In addition to damaging effects on brain cells, ischemia and infarction can result in loss of structural integrity of brain tissue and blood vessels, partly through the release of matrix metalloproteases, which are zinc- and calcium-dependent enzymes that break down collagen, hyaluronic acid, and other elements of connective tissue. Other proteases also contribute to this process. The loss of vascular structural integrity results in a breakdown of the protective blood brain barrier that contributes to cerebral edema, which can cause secondary progression of the brain injury.[citation needed]
### Hemorrhagic
Hemorrhagic strokes are classified based on their underlying pathology. Some causes of hemorrhagic stroke are hypertensive hemorrhage, ruptured aneurysm, ruptured AV fistula, transformation of prior ischemic infarction, and drug-induced bleeding.[60] They result in tissue injury by causing compression of tissue from an expanding hematoma or hematomas. In addition, the pressure may lead to a loss of blood supply to affected tissue with resulting infarction, and the blood released by brain hemorrhage appears to have direct toxic effects on brain tissue and vasculature.[43][61] Inflammation contributes to the secondary brain injury after hemorrhage.[61]
## Diagnosis
A CT showing early signs of a middle cerebral artery stroke with loss of definition of the gyri and grey white boundary
Dens media sign in a patient with middle cerebral artery infarction shown on the left. Right image after 7 hours.
Stroke is diagnosed through several techniques: a neurological examination (such as the NIHSS), CT scans (most often without contrast enhancements) or MRI scans, Doppler ultrasound, and arteriography. The diagnosis of stroke itself is clinical, with assistance from the imaging techniques. Imaging techniques also assist in determining the subtypes and cause of stroke. There is yet no commonly used blood test for the stroke diagnosis itself, though blood tests may be of help in finding out the likely cause of stroke.[62]
### Physical examination
A physical examination, including taking a medical history of the symptoms and a neurological status, helps giving an evaluation of the location and severity of a stroke. It can give a standard score on e.g., the NIH stroke scale.
### Imaging
For diagnosing ischemic (blockage) stroke in the emergency setting:[63]
* CT scans (without contrast enhancements)
sensitivity= 16% (less than 10% within first 3 hours of symptom onset)
specificity= 96%
* MRI scan
sensitivity= 83%
specificity= 98%
For diagnosing hemorrhagic stroke in the emergency setting:
* CT scans (without contrast enhancements)
sensitivity= 89%
specificity= 100%
* MRI scan
sensitivity= 81%
specificity= 100%
For detecting chronic hemorrhages, MRI scan is more sensitive.[64]
For the assessment of stable stroke, nuclear medicine scans SPECT and PET/CT may be helpful. SPECT documents cerebral blood flow and PET with FDG isotope the metabolic activity of the neurons.
CT scans may not detect an ischemic stroke, especially if it is small, of recent onset, or in the brainstem or cerebellum areas. A CT scan is more to rule out certain stroke mimics and detect bleeding.[9]
### Underlying cause
12-lead ECG of a patient with a stroke, showing large deeply inverted T-waves. Various ECG changes may occur in people with strokes and other brain disorders.
When a stroke has been diagnosed, various other studies may be performed to determine the underlying cause. With the current treatment and diagnosis options available, it is of particular importance to determine whether there is a peripheral source of emboli. Test selection may vary since the cause of stroke varies with age, comorbidity and the clinical presentation. The following are commonly used techniques:
* an ultrasound/doppler study of the carotid arteries (to detect carotid stenosis) or dissection of the precerebral arteries;
* an electrocardiogram (ECG) and echocardiogram (to identify arrhythmias and resultant clots in the heart which may spread to the brain vessels through the bloodstream);
* a Holter monitor study to identify intermittent abnormal heart rhythms;
* an angiogram of the cerebral vasculature (if a bleed is thought to have originated from an aneurysm or arteriovenous malformation);
* blood tests to determine if blood cholesterol is high, if there is an abnormal tendency to bleed, and if some rarer processes such as homocystinuria might be involved.
For hemorrhagic strokes, a CT or MRI scan with intravascular contrast may be able to identify abnormalities in the brain arteries (such as aneurysms) or other sources of bleeding, and structural MRI if this shows no cause. If this too does not identify an underlying reason for the bleeding, invasive cerebral angiography could be performed but this requires access to the bloodstream with an intravascular catheter and can cause further strokes as well as complications at the insertion site and this investigation is therefore reserved for specific situations.[65] If there are symptoms suggesting that the hemorrhage might have occurred as a result of venous thrombosis, CT or MRI venography can be used to examine the cerebral veins.[65]
### Misdiagnosis
Among people with ischemic strokes, misdiagnosis occurs 2 to 26% of the time.[66] A "stroke chameleon" (SC) is stroke which is diagnosed as something else.[66][67]
People not having a stroke may also be misdiagnosed as a stroke. Giving thrombolytics (clot-busting) in such cases causes intracerebral bleeding 1 to 2% of the time, which is less than that of people with strokes. This unnecessary treatment adds to health care costs. Even so, the AHA/ASA guidelines state that starting intravenous tPA in possible mimics is preferred to delaying treatment for additional testing.[66]
Women, African-Americans, Hispanic-Americans, Asian and Pacific Islanders are more often misdiagnosed for a condition other than stroke when in fact having a stroke. In addition, adults under 44 years-of-age are seven times more likely to have a stroke missed than are adults over 75 years-of-age. This is especially the case for younger people with posterior circulation infarcts.[66] Some medical centers have used hyperacute MRI in experimental studies for persons initially thought to have a low likelihood of stroke. And in some of these persons, strokes have been found which were then treated with thrombolytic medication.[66]
## Prevention
Given the disease burden of strokes, prevention is an important public health concern.[68] Primary prevention is less effective than secondary prevention (as judged by the number needed to treat to prevent one stroke per year).[68] Recent guidelines detail the evidence for primary prevention in stroke.[69] In those who are otherwise healthy, aspirin does not appear beneficial and thus is not recommended.[70] In people who have had a myocardial infarction or those with a high cardiovascular risk, it provides some protection against a first stroke.[71][72] In those who have previously had a stroke, treatment with medications such as aspirin, clopidogrel, and dipyridamole may be beneficial.[71] The U.S. Preventive Services Task Force (USPSTF) recommends against screening for carotid artery stenosis in those without symptoms.[73]
### Risk factors
The most important modifiable risk factors for stroke are high blood pressure and atrial fibrillation although the size of the effect is small with 833 people have to be treated for 1 year to prevent one stroke.[74][75] Other modifiable risk factors include high blood cholesterol levels, diabetes mellitus, end-stage kidney disease,[7] cigarette smoking[76][77] (active and passive), heavy alcohol use,[78] drug use,[79] lack of physical activity, obesity, processed red meat consumption,[80] and unhealthy diet.[81] Smoking just one cigarette per day increases the risk more than 30%.[82] Alcohol use could predispose to ischemic stroke, as well as intracerebral and subarachnoid hemorrhage via multiple mechanisms (for example, via hypertension, atrial fibrillation, rebound thrombocytosis and platelet aggregation and clotting disturbances).[83] Drugs, most commonly amphetamines and cocaine, can induce stroke through damage to the blood vessels in the brain and acute hypertension.[84][85] Migraine with aura doubles a person's risk for ischemic stroke.[86][87] Untreated, celiac disease regardless of the presence of symptoms can be an underlying cause of stroke, both in children and adults.[88]
High levels of physical activity reduce the risk of stroke by about 26%.[89] There is a lack of high quality studies looking at promotional efforts to improve lifestyle factors.[90] Nonetheless, given the large body of circumstantial evidence, best medical management for stroke includes advice on diet, exercise, smoking and alcohol use.[91] Medication is the most common method of stroke prevention; carotid endarterectomy can be a useful surgical method of preventing stroke.
#### Blood pressure
High blood pressure accounts for 35–50% of stroke risk.[92] Blood pressure reduction of 10 mmHg systolic or 5 mmHg diastolic reduces the risk of stroke by ~40%.[93] Lowering blood pressure has been conclusively shown to prevent both ischemic and hemorrhagic strokes.[94][95] It is equally important in secondary prevention.[96] Even people older than 80 years and those with isolated systolic hypertension benefit from antihypertensive therapy.[97][98][99] The available evidence does not show large differences in stroke prevention between antihypertensive drugs—therefore, other factors such as protection against other forms of cardiovascular disease and cost should be considered.[100][101] The routine use of beta-blockers following a stroke or TIA has not been shown to result in benefits.[102]
#### Blood lipids
High cholesterol levels have been inconsistently associated with (ischemic) stroke.[95][103] Statins have been shown to reduce the risk of stroke by about 15%.[104] Since earlier meta-analyses of other lipid-lowering drugs did not show a decreased risk,[105] statins might exert their effect through mechanisms other than their lipid-lowering effects.[104]
#### Diabetes mellitus
Diabetes mellitus increases the risk of stroke by 2 to 3 times. While intensive blood sugar control has been shown to reduce small blood vessel complications such as kidney damage and damage to the retina of the eye it has not been shown to reduce large blood vessel complications such as stroke.[106][107]
#### Anticoagulation drugs
Oral anticoagulants such as warfarin have been the mainstay of stroke prevention for over 50 years. However, several studies have shown that aspirin and other antiplatelets are highly effective in secondary prevention after a stroke or transient ischemic attack.[71] Low doses of aspirin (for example 75–150 mg) are as effective as high doses but have fewer side effects; the lowest effective dose remains unknown.[108] Thienopyridines (clopidogrel, ticlopidine) might be slightly more effective than aspirin and have a decreased risk of gastrointestinal bleeding, but are more expensive.[109] Both aspirin and clopidogrel may be useful in the first few weeks after a minor stroke or high risk TIA.[110] Clopidogrel has less side effects than ticlopidine.[109] Dipyridamole can be added to aspirin therapy to provide a small additional benefit, even though headache is a common side effect.[111] Low-dose aspirin is also effective for stroke prevention after having a myocardial infarction.[72]
Those with atrial fibrillation have a 5% a year risk of stroke, and this risk is higher in those with valvular atrial fibrillation.[112] Depending on the stroke risk, anticoagulation with medications such as warfarin or aspirin is useful for prevention.[113] Except in people with atrial fibrillation, oral anticoagulants are not advised for stroke prevention—any benefit is offset by bleeding risk.[114]
In primary prevention, however, antiplatelet drugs did not reduce the risk of ischemic stroke but increased the risk of major bleeding.[115][116] Further studies are needed to investigate a possible protective effect of aspirin against ischemic stroke in women.[117][118]
#### Surgery
Carotid endarterectomy or carotid angioplasty can be used to remove atherosclerotic narrowing of the carotid artery. There is evidence supporting this procedure in selected cases.[91] Endarterectomy for a significant stenosis has been shown to be useful in preventing further strokes in those who have already had one.[119] Carotid artery stenting has not been shown to be equally useful.[120][121] People are selected for surgery based on age, gender, degree of stenosis, time since symptoms and the person's preferences.[91] Surgery is most efficient when not delayed too long—the risk of recurrent stroke in a person who has a 50% or greater stenosis is up to 20% after 5 years, but endarterectomy reduces this risk to around 5%. The number of procedures needed to cure one person was 5 for early surgery (within two weeks after the initial stroke), but 125 if delayed longer than 12 weeks.[122][123]
Screening for carotid artery narrowing has not been shown to be a useful test in the general population.[124] Studies of surgical intervention for carotid artery stenosis without symptoms have shown only a small decrease in the risk of stroke.[125][126] To be beneficial, the complication rate of the surgery should be kept below 4%. Even then, for 100 surgeries, 5 people will benefit by avoiding stroke, 3 will develop stroke despite surgery, 3 will develop stroke or die due to the surgery itself, and 89 will remain stroke-free but would also have done so without intervention.[91]
#### Diet
Nutrition, specifically the Mediterranean-style diet, has the potential for decreasing the risk of having a stroke by more than half.[127] It does not appear that lowering levels of homocysteine with folic acid affects the risk of stroke.[128][129]
### Women
A number of specific recommendations have been made for women including taking aspirin after the 11th week of pregnancy if there is a history of previous chronic high blood pressure and taking blood pressure medications during pregnancy if the blood pressure is greater than 150 mmHg systolic or greater than 100 mmHg diastolic. In those who have previously had preeclampsia other risk factors should be treated more aggressively.[130]
### Previous stroke or TIA
Keeping blood pressure below 140/90 mmHg is recommended.[131] Anticoagulation can prevent recurrent ischemic strokes. Among people with nonvalvular atrial fibrillation, anticoagulation can reduce stroke by 60% while antiplatelet agents can reduce stroke by 20%.[132] However, a recent meta-analysis suggests harm from anticoagulation started early after an embolic stroke.[133] Stroke prevention treatment for atrial fibrillation is determined according to the CHA2DS2–VASc score. The most widely used anticoagulant to prevent thromboembolic stroke in people with nonvalvular atrial fibrillation is the oral agent warfarin while a number of newer agents including dabigatran are alternatives which do not require prothrombin time monitoring.[131]
Anticoagulants, when used following stroke, should not be stopped for dental procedures.[134]
If studies show carotid artery stenosis, and the person has a degree of residual function on the affected side, carotid endarterectomy (surgical removal of the stenosis) may decrease the risk of recurrence if performed rapidly after stroke.
## Management
### Ischemic stroke
Aspirin reduces the overall risk of recurrence by 13% with greater benefit early on.[135] Definitive therapy within the first few hours is aimed at removing the blockage by breaking the clot down (thrombolysis), or by removing it mechanically (thrombectomy). The philosophical premise underlying the importance of rapid stroke intervention was summed up as Time is Brain! in the early 1990s.[136] Years later, that same idea, that rapid cerebral blood flow restoration results in fewer brain cells dying, has been proved and quantified.[137]
Tight blood sugar control in the first few hours does not improve outcomes and may cause harm.[138] High blood pressure is also not typically lowered as this has not been found to be helpful.[139][140] Cerebrolysin, a mix of pig brain tissue used to treat acute ischemic stroke in many Asian and European countries, does not improve outcomes and may increase the risk of severe adverse events.[141]
#### Thrombolysis
Thrombolysis, such as with recombinant tissue plasminogen activator (rtPA), in acute ischemic stroke, when given within three hours of symptom onset, results in an overall benefit of 10% with respect to living without disability.[142][143] It does not, however, improve chances of survival.[142] Benefit is greater the earlier it is used.[142] Between three and four and a half hours the effects are less clear.[144][145][146] The AHA/ASA recommend it for certain people in this time frame.[147] A 2014 review found a 5% increase in the number of people living without disability at three to six months; however, there was a 2% increased risk of death in the short term.[143] After four and a half hours thrombolysis worsens outcomes.[144] These benefits or lack of benefits occurred regardless of the age of the person treated.[148] There is no reliable way to determine who will have an intracranial bleed post-treatment versus who will not.[149] In those with findings of savable tissue on medical imaging between 4.5 hours and 9 hours or who wake up with a stroke, alteplase results in some benefit.[150]
Its use is endorsed by the American Heart Association, the American College of Emergency Physicians and the American Academy of Neurology as the recommended treatment for acute stroke within three hours of onset of symptoms as long as there are no other contraindications (such as abnormal lab values, high blood pressure, or recent surgery). This position for tPA is based upon the findings of two studies by one group of investigators[151] which showed that tPA improves the chances for a good neurological outcome. When administered within the first three hours thrombolysis improves functional outcome without affecting mortality.[152] 6.4% of people with large strokes developed substantial brain bleeding as a complication from being given tPA thus part of the reason for increased short term mortality.[153] The American Academy of Emergency Medicine had previously stated that objective evidence regarding the applicability of tPA for acute ischemic stroke was insufficient.[154] In 2013 the American College of Emergency Medicine refuted this position,[155] acknowledging the body of evidence for the use of tPA in ischemic stroke;[156] but debate continues.[157][158] Intra-arterial fibrinolysis, where a catheter is passed up an artery into the brain and the medication is injected at the site of thrombosis, has been found to improve outcomes in people with acute ischemic stroke.[159]
#### Endovascular treatment
Mechanical removal of the blood clot causing the ischemic stroke, called mechanical thrombectomy, is a potential treatment for occlusion of a large artery, such as the middle cerebral artery. In 2015, one review demonstrated the safety and efficacy of this procedure if performed within 12 hours of the onset of symptoms.[160][161] It did not change the risk of death, but reduced disability compared to the use of intravenous thrombolysis which is generally used in people evaluated for mechanical thrombectomy.[162][163] Certain cases may benefit from thrombectomy up to 24 hours after the onset of symptoms.[164]
#### Craniectomy
Strokes affecting large portions of the brain can cause significant brain swelling with secondary brain injury in surrounding tissue. This phenomenon is mainly encountered in strokes affecting brain tissue dependent upon the middle cerebral artery for blood supply and is also called "malignant cerebral infarction" because it carries a dismal prognosis. Relief of the pressure may be attempted with medication, but some require hemicraniectomy, the temporary surgical removal of the skull on one side of the head. This decreases the risk of death, although some people – who would otherwise have died – survive with disability.[165]
### Hemorrhagic stroke
People with intracerebral hemorrhage require supportive care, including blood pressure control if required. People are monitored for changes in the level of consciousness, and their blood sugar and oxygenation are kept at optimum levels. Anticoagulants and antithrombotics can make bleeding worse and are generally discontinued (and reversed if possible).[citation needed] A proportion may benefit from neurosurgical intervention to remove the blood and treat the underlying cause, but this depends on the location and the size of the hemorrhage as well as patient-related factors, and ongoing research is being conducted into the question as to which people with intracerebral hemorrhage may benefit.[166]
In subarachnoid hemorrhage, early treatment for underlying cerebral aneurysms may reduce the risk of further hemorrhages. Depending on the site of the aneurysm this may be by surgery that involves opening the skull or endovascularly (through the blood vessels).[167]
### Stroke unit
Ideally, people who have had a stroke are admitted to a "stroke unit", a ward or dedicated area in a hospital staffed by nurses and therapists with experience in stroke treatment. It has been shown that people admitted to a stroke unit have a higher chance of surviving than those admitted elsewhere in hospital, even if they are being cared for by doctors without experience in stroke.[2][168] Nursing care is fundamental in maintaining skin care, feeding, hydration, positioning, and monitoring vital signs such as temperature, pulse, and blood pressure.[169]
### Rehabilitation
Stroke rehabilitation is the process by which those with disabling strokes undergo treatment to help them return to normal life as much as possible by regaining and relearning the skills of everyday living. It also aims to help the survivor understand and adapt to difficulties, prevent secondary complications, and educate family members to play a supporting role. Stroke rehabilitation should begin almost immediately with a multidisciplinary approach. The rehabilitation team may involve physicians trained in rehabilitation medicine, neurologists, clinical pharmacists, nursing staff, physiotherapists, occupational therapists, speech-language pathologists, and orthotists. Some teams may also include psychologists and social workers, since at least one-third of affected people manifests post stroke depression. Validated instruments such as the Barthel scale may be used to assess the likelihood of a person who has had a stroke being able to manage at home with or without support subsequent to discharge from a hospital.[170]
Stroke rehabilitation should be started as quickly as possible and can last anywhere from a few days to over a year. Most return of function is seen in the first few months, and then improvement falls off with the "window" considered officially by U.S. state rehabilitation units and others to be closed after six months, with little chance of further improvement.[medical citation needed] However, some people have reported that they continue to improve for years, regaining and strengthening abilities like writing, walking, running, and talking.[medical citation needed] Daily rehabilitation exercises should continue to be part of the daily routine for people who have had a stroke. Complete recovery is unusual but not impossible and most people will improve to some extent: proper diet and exercise are known to help the brain to recover.
#### Physical and occupational therapy
Physical and occupational therapy have overlapping areas of expertise; however, physical therapy focuses on joint range of motion and strength by performing exercises and relearning functional tasks such as bed mobility, transferring, walking and other gross motor functions. Physiotherapists can also work with people who have had a stroke to improve awareness and use of the hemiplegic side. Rehabilitation involves working on the ability to produce strong movements or the ability to perform tasks using normal patterns. Emphasis is often concentrated on functional tasks and people's goals. One example physiotherapists employ to promote motor learning involves constraint-induced movement therapy. Through continuous practice the person relearns to use and adapt the hemiplegic limb during functional activities to create lasting permanent changes.[171] Physical therapy is effective for recovery of function and mobility after stroke.[172] Occupational therapy is involved in training to help relearn everyday activities known as the activities of daily living (ADLs) such as eating, drinking, dressing, bathing, cooking, reading and writing, and toileting. Approaches to helping people with urinary incontinence include physical therapy, cognitive therapy, and specialized interventions with experienced medical professionals, however, it is not clear how effective these approaches are at improving urinary incontinence following a stroke.[173]
Treatment of spasticity related to stroke often involves early mobilizations, commonly performed by a physiotherapist, combined with elongation of spastic muscles and sustained stretching through various different positions.[38] Gaining initial improvement in range of motion is often achieved through rhythmic rotational patterns associated with the affected limb.[38] After full range has been achieved by the therapist, the limb should be positioned in the lengthened positions to prevent against further contractures, skin breakdown, and disuse of the limb with the use of splints or other tools to stabilize the joint.[38] Cold in the form of ice wraps or ice packs have been proven to briefly reduce spasticity by temporarily dampening neural firing rates.[38] Electrical stimulation to the antagonist muscles or vibrations has also been used with some success.[38] Physical therapy is sometimes suggested for people who experience sexual dysfunction following a stroke.[174]
#### Speech and language therapy
Speech and language therapy is appropriate for people with the speech production disorders: dysarthria[175] and apraxia of speech,[176] aphasia,[177] cognitive-communication impairments, and problems with swallowing. Speech and language therapy for aphasia following stroke compared to no therapy improves functional communication, reading, writing and expressive language. There may be benefit in high intensity and high doses over a longer period, but these higher intensity doses may not be acceptable to everyone.[172]
People who have had a stroke may have particular problems, such as dysphagia, which can cause swallowed material to pass into the lungs and cause aspiration pneumonia. The condition may improve with time, but in the interim, a nasogastric tube may be inserted, enabling liquid food to be given directly into the stomach. If swallowing is still deemed unsafe, then a percutaneous endoscopic gastrostomy (PEG) tube is passed and this can remain indefinitely. Swallowing therapy has mixed results as of 2018.[178]
#### Devices
Often, assistive technology such as wheelchairs, walkers and canes may be beneficial. Many mobility problems can be improved by the use of ankle foot orthoses.[179]
#### Physical fitness
A stroke can also reduce people's general fitness.[180] Reduced fitness can reduce capacity for rehabilitation as well as general health.[181] Physical exercises as part of a rehabilitation program following a stroke appear safe.[180] Cardiorespiratory fitness training that involves walking in rehabilitation can improve speed, tolerance and independence during walking, and may improve balance.[180] There are inadequate long-term data about the effects of exercise and training on death, dependence and disability after a stroke.[180] The future areas of research may concentrate on the optimal exercise prescription and long-term health benefits of exercise. The effect of physical training on cognition also may be studied further.
The ability to walk independently in their community, indoors or outdoors, is important following stroke. Although no negative effects have been reported, it is unclear if outcomes can improve with these walking programs when compared to usual treatment.[182]
#### Other therapy methods
Some current and future therapy methods include the use of virtual reality and video games for rehabilitation. These forms of rehabilitation offer potential for motivating people to perform specific therapy tasks that many other forms do not.[183] While virtual reality and interactive video gaming are not more effective than conventional therapy for improving upper limb function, when used in conjunction with usual care these approaches may improve upper limb function and ADL function.[184] There are inadequate data on the effect of virtual reality and interactive video gaming on gait speed, balance, participation and quality of life.[184] Many clinics and hospitals are adopting the use of these off-the-shelf devices for exercise, social interaction, and rehabilitation because they are affordable, accessible and can be used within the clinic and home.[183]
Mirror therapy is associated with improved motor function of the upper extremity in people who have had a stroke.[185]
Other non-invasive rehabilitation methods used to augment physical therapy of motor function in people recovering from a stroke include transcranial magnetic stimulation and transcranial direct-current stimulation.[186] and robotic therapies.[187] Constraint‐induced movement therapy (CIMT), mental practice, mirror therapy, interventions for sensory impairment, virtual reality and a relatively high dose of repetitive task practice may be effective in improving upper limb function. However, further primary research, specifically of CIMT, mental practice, mirror therapy and virtual reality is needed.[188]
### Self-management
A stroke can affect the ability to live independently and with quality. Self-management programs are a special training that educates stroke survivors about stroke and its consequences, helps them acquire skills to cope with their challenges, and helps them set and meet their own goals during their recovery process. These programs are tailored to the target audience, and led by someone trained and expert in stroke and its consequences (most commonly professionals, but also stroke survivors and peers). A 2016 review reported that these programs improve the quality of life after stroke, without negative effects. People with stroke felt more empowered, happy and satisfied with life after participating in this training.[189]
## Prognosis
Disability affects 75% of stroke survivors enough to decrease their ability to work.[190] Stroke can affect people physically, mentally, emotionally, or a combination of the three. The results of stroke vary widely depending on size and location of the lesion.[191]
### Physical effects
Some of the physical disabilities that can result from stroke include muscle weakness, numbness, pressure sores, pneumonia, incontinence, apraxia (inability to perform learned movements), difficulties carrying out daily activities, appetite loss, speech loss, vision loss and pain. If the stroke is severe enough, or in a certain location such as parts of the brainstem, coma or death can result. Up to 10% of people following a stroke develop seizures, most commonly in the week subsequent to the event; the severity of the stroke increases the likelihood of a seizure.[192][193] An estimated 15% of people experience urinary incontinence for more than a year following a stroke.[173] 50% of people have a decline in sexual function (sexual dysfunction) following a stroke.[174]
### Emotional and mental effects
Emotional and mental dysfunctions correspond to areas in the brain that have been damaged. Emotional problems following a stroke can be due to direct damage to emotional centers in the brain or from frustration and difficulty adapting to new limitations. Post-stroke emotional difficulties include anxiety, panic attacks, flat affect (failure to express emotions), mania, apathy and psychosis. Other difficulties may include a decreased ability to communicate emotions through facial expression, body language and voice.[194]
Disruption in self-identity, relationships with others, and emotional well-being can lead to social consequences after stroke due to the lack of ability to communicate. Many people who experience communication impairments after a stroke find it more difficult to cope with the social issues rather than physical impairments. Broader aspects of care must address the emotional impact speech impairment has on those who experience difficulties with speech after a stroke.[195] Those who experience a stroke are at risk of paralysis which could result in a self disturbed body image which may also lead to other social issues.[196]
30 to 50% of stroke survivors suffer post-stroke depression, which is characterized by lethargy, irritability, sleep disturbances, lowered self-esteem and withdrawal.[197] Depression can reduce motivation and worsen outcome, but can be treated with social and family support, psychotherapy and, in severe cases, antidepressants. Psychotherapy sessions may have a small effect on improving mood and preventing depression after a stroke,[198] however psychotherapy does not appear to be effective at treating depression after a stroke.[199] Antidepressant medications may be useful for treating depression after a stroke.[199]
Emotional lability, another consequence of stroke, causes the person to switch quickly between emotional highs and lows and to express emotions inappropriately, for instance with an excess of laughing or crying with little or no provocation. While these expressions of emotion usually correspond to the person's actual emotions, a more severe form of emotional lability causes the affected person to laugh and cry pathologically, without regard to context or emotion.[190] Some people show the opposite of what they feel, for example crying when they are happy.[200] Emotional lability occurs in about 20% of those who have had a stroke. Those with a right hemisphere stroke are more likely to have an empathy problems which can make communication harder.[201]
Cognitive deficits resulting from stroke include perceptual disorders, aphasia,[202] dementia,[203][204] and problems with attention[205] and memory.[206] A stroke sufferer may be unaware of his or her own disabilities, a condition called anosognosia. In a condition called hemispatial neglect, the affected person is unable to attend to anything on the side of space opposite to the damaged hemisphere.Cognitive and psychological outcome after a stroke can be affected by the age at which the stroke happened, pre-stroke baseline intellectual functioning, psychiatric history and whether there is pre-existing brain pathology.[207]
## Epidemiology
Stroke deaths per million persons in 2012
58–316
317–417
418–466
467–518
519–575
576–640
641–771
772–974
975-1,683
1,684–3,477
Disability-adjusted life year for cerebral vascular disease per 100,000 inhabitants in 2004.[208]
no data
<250
250–425
425–600
600–775
775–950
950–1125
1125–1300
1300–1475
1475–1650
1650–1825
1825–2000
>2000
Stroke was the second most frequent cause of death worldwide in 2011, accounting for 6.2 million deaths (~11% of the total).[209] Approximately 17 million people had a stroke in 2010 and 33 million people have previously had a stroke and were still alive.[17] Between 1990 and 2010 the number of strokes decreased by approximately 10% in the developed world and increased by 10% in the developing world.[17] Overall, two-thirds of strokes occurred in those over 65 years old.[17] South Asians are at particularly high risk of stroke, accounting for 40% of global stroke deaths.[210]
It is ranked after heart disease and before cancer.[2] In the United States stroke is a leading cause of disability, and recently declined from the third leading to the fourth leading cause of death.[211] Geographic disparities in stroke incidence have been observed, including the existence of a "stroke belt" in the southeastern United States, but causes of these disparities have not been explained.
The risk of stroke increases exponentially from 30 years of age, and the cause varies by age.[212] Advanced age is one of the most significant stroke risk factors. 95% of strokes occur in people age 45 and older, and two-thirds of strokes occur in those over the age of 65.[43][197] A person's risk of dying if he or she does have a stroke also increases with age. However, stroke can occur at any age, including in childhood.
Family members may have a genetic tendency for stroke or share a lifestyle that contributes to stroke. Higher levels of Von Willebrand factor are more common amongst people who have had ischemic stroke for the first time.[213] The results of this study found that the only significant genetic factor was the person's blood type. Having had a stroke in the past greatly increases one's risk of future strokes.
Men are 25% more likely to suffer strokes than women,[43] yet 60% of deaths from stroke occur in women.[200] Since women live longer, they are older on average when they have their strokes and thus more often killed.[43] Some risk factors for stroke apply only to women. Primary among these are pregnancy, childbirth, menopause, and the treatment thereof (HRT).
## History
Hippocrates first described the sudden paralysis that is often associated with stroke.
Episodes of stroke and familial stroke have been reported from the 2nd millennium BC onward in ancient Mesopotamia and Persia.[214] Hippocrates (460 to 370 BC) was first to describe the phenomenon of sudden paralysis that is often associated with ischemia. Apoplexy, from the Greek word meaning "struck down with violence", first appeared in Hippocratic writings to describe this phenomenon.[215][216] The word stroke was used as a synonym for apoplectic seizure as early as 1599,[217] and is a fairly literal translation of the Greek term. The term apoplectic stroke is an archaic, nonspecific term, for a cerebrovascular accident accompanied by haemorrhage or haemorrhagic stroke.[218] Martin Luther was described as having an apoplectic stroke that deprived him of his speech shortly before his death in 1546.[219]
In 1658, in his Apoplexia, Johann Jacob Wepfer (1620–1695) identified the cause of hemorrhagic stroke when he suggested that people who had died of apoplexy had bleeding in their brains.[43][215] Wepfer also identified the main arteries supplying the brain, the vertebral and carotid arteries, and identified the cause of a type of ischemic stroke known as a cerebral infarction when he suggested that apoplexy might be caused by a blockage to those vessels.[43] Rudolf Virchow first described the mechanism of thromboembolism as a major factor.[220]
The term cerebrovascular accident was introduced in 1927, reflecting a "growing awareness and acceptance of vascular theories and (...) recognition of the consequences of a sudden disruption in the vascular supply of the brain".[221] Its use is now discouraged by a number of neurology textbooks, reasoning that the connotation of fortuitousness carried by the word accident insufficiently highlights the modifiability of the underlying risk factors.[222][223][224] Cerebrovascular insult may be used interchangeably.[225]
The term brain attack was introduced for use to underline the acute nature of stroke according to the American Stroke Association,[225] which has used the term since 1990,[226] and is used colloquially to refer to both ischemic as well as hemorrhagic stroke.[227]
## Research
As of 2017, angioplasty and stents were under preliminary clinical research to determine the possible therapeutic advantages of these procedures in comparison to therapy with statins, antithrombotics, or antihypertensive drugs.[228]
## See also
* Cerebrovascular disease
* Dejerine–Roussy syndrome
* Functional Independence Measure
* Lipoprotein(a)
* Mechanism of anoxic depolarization in the brain
* Ultrasound-enhanced systemic thrombolysis
* Weber's syndrome
* World Stroke Day
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213. ^ Bongers TN, de Maat MP, van Goor ML, Bhagwanbali V, van Vliet HH, Gómez García EB, et al. (November 2006). "High von Willebrand factor levels increase the risk of first ischemic stroke: influence of ADAMTS13, inflammation, and genetic variability". Stroke. 37 (11): 2672–7. doi:10.1161/01.STR.0000244767.39962.f7. PMID 16990571.
214. ^ Ashrafian H (April 2010). "Familial stroke 2700 years ago". Stroke. 41 (4): e187, author reply e188. doi:10.1161/STROKEAHA.109.573170. PMID 20185778.
215. ^ a b Thompson JE (August 1996). "The evolution of surgery for the treatment and prevention of stroke. The Willis Lecture". Stroke. 27 (8): 1427–34. doi:10.1161/01.STR.27.8.1427. PMID 8711815.
216. ^ Kopito, Jeff (September 2001). "A Stroke in Time". MERGINET.com. 6 (9). Archived from the original on 2012-12-08.
217. ^ R. Barnhart, ed. The Barnhart Concise Dictionary of Etymology (1995)
218. ^ "Apoplectic Stroke". TheFreeDictionary.com. Retrieved 13 December 2020.
219. ^ Brecht, Martin. Martin Luther. tr. James L. Schaaf, Philadelphia: Fortress Press, 1985–93, 3:369–79.
220. ^ Schiller F (April 1970). "Concepts of stroke before and after Virchow". Medical History. 14 (2): 115–31. doi:10.1017/S0025727300015325. PMC 1034034. PMID 4914683.
221. ^ Finger S, Boller F, Tyler KL (2010). Handbook of Clinical Neurology. North-Holland Publishing Company. p. 401. ISBN 978-0-444-52009-8. Archived from the original on 12 October 2013. Retrieved 1 October 2013.
222. ^ Scadding JW (2011). Clinical Neurology. CRC Press. p. 488. ISBN 978-0-340-99070-4. Archived from the original on 12 October 2013. Retrieved 1 October 2013.
223. ^ Sirven JI, Malamut BL (2008). Clinical Neurology of the Older Adult. Lippincott Williams & Wilkins. p. 243. ISBN 978-0-7817-6947-1. Archived from the original on 12 October 2013. Retrieved 1 October 2013.
224. ^ Kaufman DM, Milstein MJ (5 December 2012). Kaufman's Clinical Neurology for Psychiatrists. Elsevier Health Sciences. p. 892. ISBN 978-1-4557-4004-8. Archived from the original on 12 October 2013. Retrieved 1 October 2013.
225. ^ a b Mosby's Medical Dictionary, 8th edition. Elsevier. 2009.
226. ^ "What is a Stroke/Brain Attack?" (PDF). National Stroke Association. Archived (PDF) from the original on 19 October 2013. Retrieved 27 February 2014.
227. ^ Segen's Medical Dictionary. Farlex, Inc. 2010.
228. ^ Morris, Dylan R.; Ayabe, Kengo; Inoue, Takashi; Sakai, Nobuyuki; Bulbulia, Richard; Halliday, Alison; Goto, Shinya (1 March 2017). "Evidence-Based Carotid Interventions for Stroke Prevention: State-of-the-art Review". Journal of Atherosclerosis and Thrombosis. 24 (4): 373–387. doi:10.5551/jat.38745. ISSN 1340-3478. PMC 5392474. PMID 28260723.
## Further reading
* Mohr JP, Choi D, Grotta J, Wolf P (2004). Stroke: Pathophysiology, Diagnosis, and Management. New York: Churchill Livingstone. ISBN 978-0-443-06600-9. OCLC 50477349.
* Warlow CP, van Gijn J, Dennis MS, Wardlaw JM, Bamford JM, Hankey GJ, Sandercock PA, Rinkel G, Langhorne P, Sudlow C, Rothwell P (2008). Stroke: Practical Management (3rd ed.). Wiley-Blackwell. ISBN 978-1-4051-2766-0.
## External links
Wikimedia Commons has media related to Stroke.
* Stroke at Curlie
* DRAGON Score for Post-Thrombolysis
* THRIVE score for stroke outcome
* National Institute of Neurological Disorders and Stroke
Classification
D
* ICD-10: I61-I64ner
* ICD-9-CM: 434.91
* OMIM: 601367
* MeSH: D020521
* DiseasesDB: 2247
External resources
* MedlinePlus: 000726
* eMedicine: neuro/9 emerg/558 emerg/557 pmr/187
* Patient UK: Stroke
* v
* t
* e
Cerebrovascular diseases including stroke
Ischaemic stroke
Brain
* Anterior cerebral artery syndrome
* Middle cerebral artery syndrome
* Posterior cerebral artery syndrome
* Amaurosis fugax
* Moyamoya disease
* Dejerine–Roussy syndrome
* Watershed stroke
* Lacunar stroke
Brain stem
* Brainstem stroke syndrome
* Medulla
* Medial medullary syndrome
* Lateral medullary syndrome
* Pons
* Medial pontine syndrome / Foville's
* Lateral pontine syndrome / Millard-Gubler
* Midbrain
* Weber's syndrome
* Benedikt syndrome
* Claude's syndrome
Cerebellum
* Cerebellar stroke syndrome
Extracranial arteries
* Carotid artery stenosis
* precerebral
* Anterior spinal artery syndrome
* Vertebrobasilar insufficiency
* Subclavian steal syndrome
Classification
* Brain ischemia
* Cerebral infarction
* Classification
* Transient ischemic attack
* Total anterior circulation infarct
* Partial anterior circulation infarct
Other
* CADASIL
* Binswanger's disease
* Transient global amnesia
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General
* Intracranial hemorrhage
Aneurysm
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Other
* Cerebral vasculitis
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* v
* t
* e
Diseases of the nervous system, primarily CNS
Inflammation
Brain
* Encephalitis
* Viral encephalitis
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* Encephalitis lethargica
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* For more detailed coverage, see Template:Demyelinating diseases of CNS
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Headache
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* For more detailed coverage, see Template:Headache
Cerebrovascular
* TIA
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* For more detailed coverage, see Template:Cerebrovascular diseases
Other
* Sleep disorders
* For more detailed coverage, see Template:Sleep
CSF
* Intracranial hypertension
* Hydrocephalus
* Normal pressure hydrocephalus
* Choroid plexus papilloma
* Idiopathic intracranial hypertension
* Cerebral edema
* Intracranial hypotension
Other
* Brain herniation
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Both/either
Degenerative
SA
* Friedreich's ataxia
* Ataxia–telangiectasia
MND
* UMN only:
* Primary lateral sclerosis
* Pseudobulbar palsy
* Hereditary spastic paraplegia
* LMN only:
* Distal hereditary motor neuronopathies
* Spinal muscular atrophies
* SMA
* SMAX1
* SMAX2
* DSMA1
* Congenital DSMA
* Spinal muscular atrophy with lower extremity predominance (SMALED)
* SMALED1
* SMALED2A
* SMALED2B
* SMA-PCH
* SMA-PME
* Progressive muscular atrophy
* Progressive bulbar palsy
* Fazio–Londe
* Infantile progressive bulbar palsy
* both:
* Amyotrophic lateral sclerosis
Authority control
* GND: 4052588-0
* NDL: 00969244
* NSK: 000173178
*[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
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Stroke | c0038454 | 2,571 | wikipedia | https://en.wikipedia.org/wiki/Stroke | 2021-01-18T18:39:27 | {"mesh": ["D020521"], "wikidata": ["Q12202"]} |
A rare form of mucopolysaccharidosis characterized by abnormal storage of hyaluronan in lysosomes due to deficiency of hyaluronidase 1. Clinical manifestations include knee and/or hip pain associated with swelling, diffuse joint involvement with proliferative synovitis and occurrence of multiple periarticular soft-tissue masses, short stature, and dysmorphic craniofacial features (such as flattened nasal bridge, bifid uvula, and cleft palate).
*[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
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Hyaluronidase deficiency | c1291490 | 2,572 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=67041 | 2021-01-23T17:24:13 | {"mesh": ["C563209"], "omim": ["601492"], "umls": ["C1291490"], "icd-10": ["E76.2"], "synonyms": ["MPS9", "MPSIX", "Mucopolysaccharidosis type 9", "Mucopolysaccharidosis type IX"]} |
Not to be confused with Dyskaryosis.
Dyskeratosis is abnormal keratinization occurring prematurely within individual cells or groups of cells below the stratum granulosum.[1]
Dyskeratosis congenita is congenital disease characterized by reticular skin pigmentation, nail degeneration, and leukoplakia on the mucous membranes associated with short telomeres.[2]
## See also[edit]
* Skin lesion
* Skin disease
* List of skin diseases
## References[edit]
1. ^ Kumar, Vinay; Fausto, Nelso; Abbas, Abul (2004) Robbins & Cotran Pathologic Basis of Disease (8th ed.). Saunders. Page 1392. ISBN 0-7216-0187-1.
2. ^ Mason PJ, Bessler M (2011). "The genetics of dyskeratosis congenita". Cancer Genetics. 204 (12): 635–645. doi:10.1016/j.cancergen.2011.11.002. PMC 3269008. PMID 22285015.
* v
* t
* e
Skin lesion terminology
Macroscopic
Primary lesions
* flat
* Macule
* Patch
* elevated
* Papule
* Nodule
* Plaque
* fluid
* Vesicle
* Bulla
* Pustule
* Ulcer
* Erosion
* Telangiectasia
* Special initial lesions : Burrow
* Tunnel
* Comedo
* Scutulum
* Target lesion
* Herald patch
* Wheal
Secondary lesions
* Scale
* Crust
* Lichenification
* Excoriation
* Induration
* Atrophy
Microscopic
* keratin: Hyperkeratosis
* Parakeratosis
* Dyskeratosis
* Hypergranulosis
* Acanthosis
* Papillomatosis
* Acantholysis
* Spongiosis
* Hydropic swelling
* Exocytosis
* Vacuolization
* Erosion
* Ulceration
* Lentiginous
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Dyskeratosis | c0334061 | 2,573 | wikipedia | https://en.wikipedia.org/wiki/Dyskeratosis | 2021-01-18T19:01:50 | {"umls": ["C0334061"], "wikidata": ["Q2897327"]} |
Partial unilateral lentiginosis
Other namesSegmental lentiginosis[1]
SpecialtyDermatology
Partial unilateral lentiginosis is a cutaneous condition characterized by lentigines located on only one half of the body.[1]:686[2]
## See also[edit]
* Lentigo
* 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. pp. 1727–8. ISBN 978-1-4160-2999-1.
2. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6.
This cutaneous condition article is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Partial unilateral lentiginosis | c0406809 | 2,574 | wikipedia | https://en.wikipedia.org/wiki/Partial_unilateral_lentiginosis | 2021-01-18T18:32:42 | {"umls": ["C0406809"], "wikidata": ["Q7140392"]} |
Clavicle fracture
Other namesBroken collarbone[1]
X-ray of a left clavicle fracture
SpecialtyEmergency medicine
SymptomsPain, decreased ability to move the affected arm[1]
ComplicationsPneumothorax, injury to the nerves or blood vessels in the area, unpleasant appearance[2]
Usual onsetSudden[3]
TypesType I (middle 3rd), Type II (lateral 3rd), Type III (medial third)[3]
CausesFall onto a shoulder, outstretched arm, or direct trauma[1][3]
Diagnostic methodBased on symptoms, confirmed with X-rays[2]
TreatmentPain medication, sling, surgery[1][2]
PrognosisUp to five months for complete healing[3]
Frequency5% of adult fractures, 13% of children's fractures[1][3]
A clavicle fracture, also known as a broken collarbone, is a bone fracture of the clavicle.[1] Symptoms typically include pain at the site of the break and a decreased ability to move the affected arm.[1] Complications can include a collection of air in the pleural space surrounding the lung (pneumothorax), injury to the nerves or blood vessels in the area, and an unpleasant appearance.[2]
It is often caused by a fall onto a shoulder, outstretched arm, or direct trauma.[1][3] The fracture can also occur in a baby during childbirth.[1] The middle section of the clavicle is most often involved.[3] Diagnosis is typically based on symptoms and confirmed with X-rays.[2]
Clavicle fractures are typically treated by putting the arm in a sling for one or two weeks.[1][2] Pain medication such as paracetamol (acetaminophen) may be useful.[1] It can take up to five months for the strength of the bone to return to normal.[3] Reasons for surgical repair include an open fracture, involvement of the nerves or blood vessels, or shortening of the clavicle by more than 1.5 cm in a young person.[1][4]
Clavicle fractures most commonly occur in people under the age of 25 and those over the age of 70.[2][3] Among the younger group males are more often affected than females.[3] In adults they make up about 5% of all fractures while in children they represent about 13% of fractures.[1][3]
## Contents
* 1 Signs and symptoms
* 2 Mechanism
* 2.1 Anatomy
* 3 Diagnosis
* 4 Treatment
* 4.1 Nonoperative
* 4.2 Surgical
* 5 Prognosis
* 6 Epidemiology
* 7 History
* 8 References
* 9 External links
## Signs and symptoms[edit]
* Pain, particularly with arm movement or on the front part of upper chest
* Swelling
* Often, after the swelling has subsided, the fracture can be felt through the skin.
* Sharp pain when any movement is made
* Referred pain: dull to extreme ache in and around clavicle area, including surrounding muscles
* Possible nausea, dizziness, and/or spotty vision due to extreme pain
## Mechanism[edit]
The location of the clavicles
Clavicle fractures are commonly known as a breaking of the collarbone, and they are usually a result of injury or trauma. The most common type of fracture occurs when a person falls horizontally on the shoulder or with an outstretched hand. A direct hit to the collarbone can also cause a break. In most cases, the direct hit occurs from the lateral side towards the medial side of the bone. The muscles involved in clavicle fractures include the deltoid, trapezius, subclavius, sternocleidomastoid, sternohyoid, and pectoralis major muscles. The ligaments involved include the conoid ligament and trapezoid ligament. Incidents that may lead to a clavicle fracture include automobile accidents, biking accidents (especially common in mountain biking), horizontal falls on the shoulder joint, or contact sports such as football, rugby, hurling, or wrestling.[citation needed]
It is most often fractured in the middle third of its length which is its weakest point. The lateral fragment is depressed by the weight of the arm and is pulled medially and forward by the strong adductor muscles of the shoulder joint, especially the pectoralis major. The part of the clavicle near the center of the body is tilted upwards by the sternocleidomastoid muscle. Children and infants are particularly prone to it. Newborns often present clavicle fractures following a difficult delivery[citation needed].
After fracture of the clavicle, the sternocleidomastoid muscle elevates the medial fragment of the bone. The trapezius muscle is unable to hold up the distal fragment owing to the weight of the upper limb, thus the shoulder droops. The adductor muscles of the arm, such as the pectoralis major, may pull the distal fragment medially, causing the bone fragments to override.[citation needed]
### Anatomy[edit]
Illustration showing fracture of clavicle
The clavicle is the bone that connects the trunk of the body to the arm, and it is located directly above the first rib. A clavicle is located on each side of the front, upper part of the chest. The clavicle consists of a medial end, a shaft, and a lateral end. The medial end connects with the manubrium of the sternum and gives attachments to the fibrous capsule of the sternoclavicular joint, articular disc, and interclavicular ligament. The lateral end connects at the acromion of the scapula which is referred to as the acromioclavicular joint. The clavicle forms a slight S-shaped curve where it curves from the sternal end laterally and anteriorly for near half its length, then forming a posterior curve to the acromion of the scapula.[citation needed]
## Diagnosis[edit]
The basic method to check for a clavicle fracture is by an X-ray of the clavicle to determine the fracture type and extent of injury. In former times, X-rays were taken of both clavicle bones for comparison purposes. Due to the curved shape in a tilted plane X-rays are typically oriented with ~15° upwards facing tilt from the front. In more severe cases, a computerized tomography (CT) or magnetic resonance imaging (MRI) scan is taken. However, the standard method of diagnosis through ultrasound imaging performed in the emergency room may be equally accurate in children.[5]
## Treatment[edit]
Medication may be prescribed for pain. It is unclear if surgery or conservative management is superior.[6]
Antibiotics and tetanus vaccination may be used if the bone breaks through the skin however this is uncommon.[7] Often, they are treated without surgery. In severe cases, surgery may be done.
### Nonoperative[edit]
The arm is usually supported by an external immobilizer to keep the joint stable and decrease the risk of further damage. The two most common types of fixation are the figure-of-eight splint that wraps the shoulders to keep them forced back and a simple sling, often called collar 'n' cuff. The primary indication is pain relief. Type of sling used does not seem to affect the results as far as healing is concerned but patient satisfaction is lower with the figure-of-eight bandage. No difference in functional outcome has been reported between the two types of immobilization.[8]
Current practice for simple fractures without great displacement is generally to provide a sling, and pain relief, and to allow the bone to heal itself, monitoring progress with X-rays every week or few weeks if necessary. Surgery is employed in 5–10% of cases. However, a meta-analysis of 2 144 midshaft clavicle fractures supports primary plate fixation of completely displaced midshaft clavicular fractures in active adult patients.[9]
If the fracture is at the lateral end, the risk of nonunion is greater than if the fracture is of the shaft.[10]
### Surgical[edit]
X-ray of the above comminuted fracture treated with an intramedullary fixation device
For breaks in the middle of the clavicle in children surgery resulted in faster recover but more complications.[11] The evidence for different types of surgery for breaks of the middle part of the clavicle is poor as of 2015.[12]
Surgery may be considered when one or more of the following is presents
* Comminution with separation (bone is broken into multiple pieces)
* Skin penetration (open fracture)
* Associated nervous and vascular trauma (brachial plexus or supraclavicular nerves)
* Nonunion after several months (3–6 months, typically)
* Displaced distal third fractures (high risk of nonunion)
* Although shortening (as a result of overlap of fracture ends) has often been suggested as an indication for surgery, a review found that people treated without surgery for shortening of mid shaft clavicle fractures did not affect outcomes.[13]
A discontinuity in the bone shape often results from a clavicular fracture, visible through the skin, if not treated with surgery. Surgical procedures often call for open reduction internal [plate] fixation where an anatomically shaped titanium or steel plate is affixed along the superior aspect of the bone by several screws. In some cases, the plate is removed after healing due to discomfort, to avoid tissue aggravation, osteolysis or subacromial impingement. This is especially important with a special type of fixation plate called hook plate.[14] With anatomical plates plate removal is considered an elective procedure that is rarely necessary. An alternative to plate fixation is elastic TEN intramedullary nailing. These devices are implanted within the clavicle's canal to support the bone from the inside. Typical surgical complications are infection, neurological symptoms distal the incision (sometimes to the extremity), and nonunion of the bone (failure of the bone to properly fuse together).[citation needed]
## Prognosis[edit]
Healing time varies based on age, health, complexity, and location of the break, as well as the bone displacement. For adults, one to several weeks of sling immobilization is normally employed to allow for pain relief, initial bone and soft tissue healing; teenagers require slightly less, while children can often achieve the same level in two weeks. During this period, patients may remove the sling to practice passive pendulum range of motion exercises to reduce atrophy in the elbow and shoulder, but they are often minimized to 15–20° off vertical. Depending on the severity of fracture, a person can begin to use the arm if comfortable with movement and no pain results. The final goal is to be able to have full range of motion with no pain; therefore, if any pain occurs, allowing for more recovery time is best. Depending on severity of the fracture, athletes involved in contact sports may need a longer period of rest to heal to avoid refracturing bone. A person should be able to return unrestricted to any sports or work by 3 months after the injury.[citation needed]
## Epidemiology[edit]
Clavicle fractures occur at 30–64 cases per 100,000 a year and are responsible for 2.6–5.0% of all fractures.[15] This type of fracture occurs more often in males.[15] About half of all clavicle fractures occur in children under the age of seven and is the most common pediatric fracture. Clavicle fractures involve roughly 5% of all fractures seen in hospital emergency admissions. Clavicles are the most commonly broken bone in the human body.[16]
## History[edit]
Hippocrates, 4th century BC:
> When, then, a [clavicle] fracture has recently taken place, the patients attach much importance to it, as supposing the mischief greater than it really is, and the physicians bestow great pains in order that it may be properly bandaged; but in a little time the patients, having no pain, nor finding any impediment to their walking or eating, become negligent; and the physicians finding they cannot make the parts look well, take themselves off, and are not sorry at the neglect of the patient, and in the meantime the callus is quickly formed.[17]
The management of skeletal injuries in ancient Egypt – Collar bone: "If thou examinest a man having a break in his collar bone and shouldst thou find his collar bone short and separated from its fellow, I will treat. Place him prostrate on his back with something folded between his shoulder blades; thou shouldst spread out with his two shoulders to stretch apart his collar bone until the break falls in its place."[18]
## References[edit]
1. ^ a b c d e f g h i j k l m "Clavicle Fracture (Broken Collarbone)-OrthoInfo - AAOS". orthoinfo.aaos.org. Dec 2016. Archived from the original on 4 September 2017. Retrieved 26 September 2017.
2. ^ a b c d e f g Pecci M, Kreher JB (January 2008). "Clavicle fractures". American Family Physician. 77 (1): 65–70. PMID 18236824.
3. ^ a b c d e f g h i j k Paladini P, Pellegrini A, Merolla G, Campi F, Porcellini G (January 2012). "Treatment of clavicle fractures". Translational Medicine @ UniSa. 2: 47–58. PMC 3728778. PMID 23905044.
4. ^ Ropars M, Thomazeau H, Huten D (February 2017). "Clavicle fractures". Orthopaedics & Traumatology, Surgery & Research. 103 (1S): S53–S59. doi:10.1016/j.otsr.2016.11.007. PMID 28043849.
5. ^ Cross KP, Warkentine FH, Kim IK, Gracely E, Paul RI (July 2010). "Bedside ultrasound diagnosis of clavicle fractures in the pediatric emergency department". Academic Emergency Medicine. 17 (7): 687–93. doi:10.1111/j.1553-2712.2010.00788.x. PMID 20653581.
6. ^ Lenza, Mário; Buchbinder, Rachelle; Johnston, Renea V; Ferrari, Bruno AS; Faloppa, Flávio (22 January 2019). "Surgical versus conservative interventions for treating fractures of the middle third of the clavicle". Cochrane Database of Systematic Reviews. 2019 (1): CD009363. doi:10.1002/14651858.CD009363.pub3. PMC 6373576. PMID 30666620.
7. ^ Zlowodzki M, Zelle BA, Cole PA, Jeray K, McKee MD (August 2005). "Treatment of acute midshaft clavicle fractures: systematic review of 2144 fractures: on behalf of the Evidence-Based Orthopaedic Trauma Working Group". Journal of Orthopaedic Trauma. 19 (7): 504–7. doi:10.1097/01.bot.0000172287.44278.ef. PMID 16056089.
8. ^ Lenza M, Faloppa F (December 2016). "Conservative interventions for treating middle third clavicle fractures in adolescents and adults". The Cochrane Database of Systematic Reviews. 12: CD007121. doi:10.1002/14651858.CD007121.pub4. PMC 6463869. PMID 27977849.
9. ^ Zlowodzki M, Zelle BA, Cole PA, Jeray K, McKee MD (August 2005). "Treatment of acute midshaft clavicle fractures: systematic review of 2144 fractures: on behalf of the Evidence-Based Orthopaedic Trauma Working Group". Journal of Orthopaedic Trauma. 19 (7): 504–7. doi:10.1097/01.bot.0000172287.44278.ef. PMID 16056089.
10. ^ Khan LA, Bradnock TJ, Scott C, Robinson CM (February 2009). "Fractures of the clavicle". The Journal of Bone and Joint Surgery. American Volume. 91 (2): 447–60. doi:10.2106/JBJS.H.00034. PMID 19181992. S2CID 39095274.
11. ^ Gao, B; Dwivedi, S; Patel, S; Nwizu, C; Cruz AI, Jr (15 July 2019). "Operative Vs. Non-operative Management of Displaced Midshaft Clavicle Fractures in Pediatric and Adolescent Patients: A Systematic Review and Meta-Analysis". Journal of Orthopaedic Trauma. doi:10.1097/BOT.0000000000001580. PMID 31343597.
12. ^ Lenza M, Faloppa F (May 2015). "Surgical interventions for treating acute fractures or non-union of the middle third of the clavicle". The Cochrane Database of Systematic Reviews. 5 (5): CD007428. doi:10.1002/14651858.CD007428.pub3. PMID 25950424.
13. ^ Malik, Shahbaz S.; Tahir, Muaaz; Jordan, Robert W.; Malik, Sheraz S.; Saithna, Adnan (August 2019). "Is shortening of displaced midshaft clavicle fractures associated with inferior clinical outcomes following nonoperative management? A systematic review" (PDF). Journal of Shoulder and Elbow Surgery. 28 (8): 1626–1638. doi:10.1016/j.jse.2018.12.017. PMID 30929954.
14. ^ Tiren D, van Bemmel AJ, Swank DJ, van der Linden FM (January 2012). "Hook plate fixation of acute displaced lateral clavicle fractures: mid-term results and a brief literature overview". Journal of Orthopaedic Surgery and Research. 7: 2. doi:10.1186/1749-799X-7-2. PMC 3313877. PMID 22236647.
15. ^ a b Malik S, Chiampas G, Leonard H (November 2010). "Emergent evaluation of injuries to the shoulder, clavicle, and humerus". Emergency Medicine Clinics of North America. 28 (4): 739–63. doi:10.1016/j.emc.2010.06.006. PMID 20971390.
16. ^ Snell RS (2010-03-10). "Chapter 9: The upper Limb". Clinical Anatomy by Regions (8th ed.). Lippincott Williams & Wilkins. p. 433. ISBN 978-0-7817-6404-9.
17. ^ "The Internet Classics Archive | On the Articulations by Hippocrates". classics.mit.edu. Archived from the original on 26 February 2017. Retrieved 26 October 2017.
18. ^ Said GZ (28 September 2007). "The management of skeletal injuries in ancient Egypt" (PDF). Archived from the original on 28 September 2007.CS1 maint: bot: original URL status unknown (link)
## External links[edit]
* Details from AAOS
Classification
D
* ICD-10: S42.0
* ICD-9-CM: 810
External resources
* MedlinePlus: 001588
* eMedicine: orthoped/50
* v
* t
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Fractures and cartilage damage
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* Trimalleolar fracture
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Crus fracture:
* Patella fracture
Femoral fracture:
* Hip fracture
Foot fracture
* Lisfranc
* Jones
* March
* Calcaneal
*[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
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Clavicle fracture | c0159658 | 2,575 | wikipedia | https://en.wikipedia.org/wiki/Clavicle_fracture | 2021-01-18T18:37:49 | {"icd-9": ["810"], "icd-10": ["S42.0"], "wikidata": ["Q1746068"]} |
Insulinoma is a type of pancreatic neuroendocrine tumor (pancreatic NET), which refers to a group of rare tumors that form in the hormone-making cells of the pancreas. Insulinomas, specifically, produce too much insulin, a hormone that reduces the level of sugar in the blood by helping it move into cells. As a result, people with insulinomas generally have very low blood sugar levels which can be associated with anxiety, confusion, hunger, a fast heart rate, and sweating. In severe cases, it can lead to seizures, coma or even death. Ninty percent of insulinomas are benign (noncancerous). In most cases, the underlying cause of insulinoma is unknown. However, people with specific genetic syndromes such as multiple endocrine neoplasia type I, Von Hippel-Lindau syndrome, Neurofibromatosis type 1, and tuberous sclerosis are at risk of insulinomas and other endocrine tumors. Treatment generally includes surgery to remove the tumor.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Insulinoma | c0021670 | 2,576 | gard | https://rarediseases.info.nih.gov/diseases/3010/insulinoma | 2021-01-18T17:59:46 | {"mesh": ["D007340"], "umls": ["C0021670"], "synonyms": []} |
Corneal dystrophy
Corneal dystrophy, Gelatinous drop-like
SpecialtyOphthalmology
Corneal dystrophy is a group of rare hereditary disorders characterised by bilateral abnormal deposition of substances in the transparent front part of the eye called the cornea.[1][2][3]
## Contents
* 1 Signs and symptoms
* 2 Genetics
* 3 Pathophysiology
* 4 Diagnosis
* 4.1 Differential diagnosis
* 4.2 Classification
* 4.2.1 Epithelial and subepithelial dystrophies
* 4.2.2 Bowman Layer dystrophies
* 4.2.3 Stromal dystrophies
* 4.2.4 Endothelial dystrophies
* 5 Treatment
* 6 See also
* 7 References
## Signs and symptoms[edit]
Corneal dystrophy may not significantly affect vision in the early stages. However, it does require proper evaluation and treatment for restoration of optimal vision. Corneal dystrophies usually manifest themselves during the first or second decade but sometimes later. It appears as grayish white lines, circles, or clouding of the cornea. Corneal dystrophy can also have a crystalline appearance.
There are over 20 corneal dystrophies that affect all parts of the cornea. These diseases share many traits:
* They are usually inherited.
* They affect the right and left eyes equally.
* They are not caused by outside factors, such as injury or diet.
* Most progress gradually.
* Most usually begin in one of the five corneal layers and may later spread to nearby layers.
* Most do not affect other parts of the body, nor are they related to diseases affecting other parts of the eye or body.
* Most can occur in otherwise totally healthy people, male or female.
Corneal dystrophies affect vision in widely differing ways. Some cause severe visual impairment, while a few cause no vision problems and are diagnosed during a specialized eye examination by an ophthalmologist. Other dystrophies may cause repeated episodes of pain without leading to permanent loss of vision.[4]
## Genetics[edit]
Different corneal dystrophies are caused by mutations in the CHST6, KRT3, KRT12, PIP5K3, SLC4A11, TACSTD2, TGFBI, and UBIAD1 genes. Mutations in TGFBI which encodes transforming growth factor beta induced cause several forms of corneal dystrophies including granular corneal dystrophy, lattice corneal dystrophy, epithelial basement membrane dystrophy, Reis-Bucklers corneal dystrophy, and Thiel–Behnke dystrophy.
Corneal dystrophies may have a simple autosomal dominant, autosomal recessive or rarely X-linked recessive Mendelian mode of inheritance:
Name Inheritance Gene locus Gene
Superficial corneal dystrophies
Meesmann dystrophy AD 12q13, 17q12 KRT3, KRT12
Reis-Bücklers corneal dystrophy AD 5q31 TGFBI
Gelatinous drop-like corneal dystrophy AR 1p32 TACSTD2
Stromal corneal dystrophies
Macular dystrophy AR 16q22 CHST6
Granular dystrophy AD 5q31 TGFBI
Lattice dystrophy AD 5q31, 9q34 TGFBI, GSN (gene)
Schnyder corneal dystrophy AD 1p34.1–p36 UBIAD1
Congenital stromal corneal dystrophy AD 12q13.2 DCN
Fleck corneal dystrophy AD 2q35 PIP5K3
Posterior dystrophies
Fuchs dystrophy AD 1p34.3,13pTel-13q12.13, 18q21.2–q21.32, 20p13-p12, 10p11.2 COL8A, SLC4A11, TCF8, TCF4
posterior polymorphous corneal dystrophy AD 20p11.2, 1p34.3-p32.3, 10p11.2 COL8A2, TCF8,OVOL2, GRHL2
Congenital hereditary endothelial dystrophy AR 20p13-p12 SLC4A11
## Pathophysiology[edit]
A corneal dystrophy can be caused by an accumulation of extraneous material in the cornea, including lipids and cholesterol crystals.
## Diagnosis[edit]
Diagnosis can be established on clinical grounds and this may be enhanced with studies on surgically excised corneal tissue and in some cases with molecular genetic analyses. As clinical manifestations widely vary with the different entities, corneal dystrophies should be suspected when corneal transparency is lost or corneal opacities occur spontaneously, particularly in both corneas, and especially in the presence of a positive family history or in the offspring of consanguineous parents.
Superficial corneal dystrophies \- Meesmann dystrophy is characterized by distinct tiny bubble-like, punctate opacities that form in the central corneal epithelium and to a lesser extent in the peripheral cornea of both eyes during infancy that persists throughout life. Symmetrical reticular opacities form in the superficial central cornea of both eyes at about 4–5 years of age in Reis-Bücklers corneal dystrophy. Patient remains asymptomatic until epithelial erosions precipitate acute episodes of ocular hyperemia, pain, and photophobia. Visual acuity eventually becomes reduced during the second and third decades of life following a progressive superficial haze and an irregular corneal surface. In Thiel–Behnke dystrophy, sub-epithelial corneal opacities form a honeycomb-shaped pattern in the superficial cornea. Multiple prominent gelatinous mulberry-shaped nodules form beneath the corneal epithelium during the first decade of life in Gelatinous drop-like corneal dystrophy which cause photophobia, tearing, corneal foreign body sensation and severe progressive loss of vision. Lisch epithelial corneal dystrophy is characterized by feather shaped opacities and microcysts in the corneal epithelium that are arranged in a band-shaped and sometimes whorled pattern. Painless blurred vision sometimes begins after sixty years of life.
Corneal stromal dystrophies \- Macular corneal dystrophy is manifested by a progressive dense cloudiness of the entire corneal stroma that usually first appears during adolescence and eventually causing severe visual impairment. In Granular corneal dystrophy multiple small white discrete irregular spots that resemble bread crumbs or snowflakes become apparent beneath Bowman zone in the superficial central corneal stroma. They initially appear within the first decade of life. Visual acuity is more or less normal. Lattice dystrophy starts as fine branching linear opacities in Bowman's layer in the central area and spreads to the periphery. Recurrent corneal erosions may occur. The hallmark of Schnyder corneal dystrophy is the accumulation of crystals within the corneal stroma which cause corneal clouding typically in a ring-shaped fashion.
Posterior corneal dystrophies \- Fuchs corneal dystrophy presents during the fifth or sixth decade of life. The characteristic clinical findings are excrescences on a thickened Descemet membrane (cornea guttae), generalized corneal edema and decreased visual acuity. In advanced cases, abnormalities are found in the all layers of the cornea. In posterior polymorphous corneal dystrophy small vesicles appear at the level of Descemet membrane. Most patients remain asymptomatic and corneal edema is usually absent. Congenital hereditary endothelial corneal dystrophy is characterized by a diffuse ground-glass appearance of both corneas and markedly thickened (2–3 times thicker than normal) corneas from birth or infancy.
### Differential diagnosis[edit]
Main differential diagnosis include various causes of monoclonal gammopathy, lecithin-cholesterol-acyltransferase deficiency, Fabry disease, cystinosis, tyrosine transaminase deficiency, systemic lysosomal storage diseases, and several skin diseases (X-linked ichthyosis, keratosis follicularis spinolosa decalvans).
Historically, an accumulation of small gray variable shaped punctate opacities of variable shape in the central deep corneal stroma immediately anterior to Descemet membrane were designated deep filiform dystrophy and cornea farinata because of their resemblance to commas, circles, lines, threads (filiform), flour (farina) or dots. These abnormalities are now known to accompany X-linked ichthyosis, steroid sulfatase deficiency, caused by steroid sulfatase gene mutations and are currently usually not included under the rubric of the corneal dystrophies.
In the past, the designation vortex corneal dystrophy (corneal verticillata) was applied to a corneal disorder characterized by the presence of innumerable tiny brown spots arranged in curved whirlpool-like lines in the superficial cornea. An autosomal dominant mode of transmission was initially suspected, but later it was realized that these individuals were affected hemizygous males and asymptomatic female carriers of an X-linked systemic metabolic disease caused by a deficiency of α-galactosidase, known as Fabry disease.[3]
### Classification[edit]
Corneal dystrophies were commonly subdivided depending on its specific location within the cornea into anterior, stromal, or posterior according to the layer of the cornea affected by the dystrophy.
In 2015 the ICD3 classification was published.[5] and has classified disease into four groups as follows:
#### Epithelial and subepithelial dystrophies[edit]
* Epithelial basement membrane dystrophy
* Epithelial recurrent erosion dystrophies (Franceschetti corneal dystrophy, Dystrophia Smolandiensis, and Dystrophia Helsinglandica)
* Subepithelial mucinous corneal dystrophy
* Meesmann corneal dystrophy
* Lisch epithelial corneal dystrophy
* Gelatinous drop-like corneal dystrophy
#### Bowman Layer dystrophies[edit]
* Reis–Bücklers corneal dystrophy
* Thiel–Behnke corneal dystrophy
* Stromal dystrophies-
* TGFB1 corneal dystrophies
* Lattice corneal dystrophy, type 1 variants (III, IIIA, I/IIIA, IV) of lattice corneal dystrophy
* Granular corneal dystrophy, type 1
* Granular corneal dystrophy, type 2
#### Stromal dystrophies[edit]
* Macular corneal dystrophy
* Schnyder crystalline corneal dystrophy
* Congenital stromal corneal dystrophy
* Fleck corneal dystrophy
* Posterior amorphous corneal dystrophy
* Central cloudy dystrophy of François
* Pre-Descemet corneal dystrophy
#### Endothelial dystrophies[edit]
* Fuchs' dystrophy
* Posterior polymorphous corneal dystrophy
* Congenital hereditary endothelial dystrophy
* X-linked endothelial corneal dystrophy
The following (now historic) classification was by Klintworth:[3]
Superficial dystrophies:
* Epithelial basement membrane dystrophy
* Meesmann juvenile epithelial corneal dystrophy
* Gelatinous drop-like corneal dystrophy
* Lisch epithelial corneal dystrophy
* Subepithelial mucinous corneal dystrophy
* Reis-Bucklers corneal dystrophy
* Thiel–Behnke dystrophy
Stromal dystrophies:
* Lattice corneal dystrophy
* Granular corneal dystrophy
* Macular corneal dystrophy
* Schnyder crystalline corneal dystrophy
* Congenital stromal corneal dystrophy
* Fleck corneal dystrophy
Posterior dystrophies:
* Fuchs' dystrophy
* Posterior polymorphous corneal dystrophy
* Congenital hereditary endothelial dystrophy
## Treatment[edit]
Early stages may be asymptomatic and may not require any intervention. Initial treatment may include hypertonic eyedrops and ointment to reduce the corneal edema and may offer symptomatic improvement prior to surgical intervention.
Suboptimal vision caused by corneal dystrophy may be helped with scleral contact lenses but eventually usually requires surgical intervention in the form of corneal transplantation. Penetrating keratoplasty, a common type of corneal transplantation, is commonly performed for extensive corneal dystrophy.
With penetrating keratoplasty (corneal transplant), the long-term results are good to excellent. Recent surgical improvements have been made which have increased the success rate for this procedure. However, recurrence of the disease in the donor graft may happen. Superficial corneal dystrophies do not need a penetrating keratoplasty as the deeper corneal tissue is unaffected, therefore a lamellar keratoplasty may be used instead.
Phototherapeutic keratectomy (PTK) can be used to excise or ablate the abnormal corneal tissue. Patients with superficial corneal opacities are suitable candidates for this procedure.[3]
## See also[edit]
* Recurrent corneal erosion
* Keratoconus
* Keratoglobus
* Corneal dystrophies in dogs
* Dyskeratosis corneal and photophobia in XLPDR
## References[edit]
1. ^ Basic&Clinical Science Course; External disease and cornea (2011-2012 ed.). American Academy of Ophthalmology. 2012. ISBN 9781615251155.
2. ^ Weiss JS, Møller HU, Lisch W, Kinoshita S, Aldave AJ, Belin MW, Kivelä T, Busin M, Munier FL, Seitz B, Sutphin J, Bredrup C, Mannis MJ, Rapuano CJ, Van Rij G, Kim EK, Klintworth GK (December 2008). "The IC3D classification of the corneal dystrophies". Cornea. 27 (Suppl 2): S1–83. doi:10.1097/ICO.0b013e31817780fb. PMC 2866169. PMID 19337156.
3. ^ a b c d Klintworth GK (2009). "Corneal dystrophies". Orphanet J Rare Dis. 4 (1): 7. doi:10.1186/1750-1172-4-7. PMC 2695576. PMID 19236704.
4. ^ "Facts About the Cornea and Corneal Disease". National Eye Institute. Archived from the original on 2005-03-27.
5. ^ Weis JS (2015). "IC3D Classification of Corneal Dystrophies—Edition 2". Cornea. 34 (2): 117–159. doi:10.1097/ICO.0000000000000307. hdl:11392/2380137. PMID 25564336.
* v
* t
* e
Types of corneal dystrophy
Epithelial and subepithelial
* Epithelial basement membrane dystrophy
* Gelatinous drop-like corneal dystrophy
* Lisch epithelial corneal dystrophy
* Meesmann corneal dystrophy
* Subepithelial mucinous corneal dystrophy
Bowman's membrane
* Reis–Bucklers corneal dystrophy
* Thiel-Behnke dystrophy
Stroma
* Congenital stromal corneal dystrophy
* Fleck corneal dystrophy
* Granular corneal dystrophy
* Lattice corneal dystrophy
* Macular corneal dystrophy
* Posterior amorphous corneal dystrophy
* Schnyder crystalline corneal dystrophy
Descemet's membrane and
endothelial
* Congenital hereditary endothelial dystrophy
* Fuchs' dystrophy
* Posterior polymorphous corneal dystrophy
* X-linked endothelial corneal dystrophy
* v
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* Diseases of the human eye
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*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Corneal dystrophy | c0010036 | 2,577 | wikipedia | https://en.wikipedia.org/wiki/Corneal_dystrophy | 2021-01-18T18:49:49 | {"mesh": ["D003317"], "umls": ["C0010036", "C0010035"], "orphanet": ["34533"], "wikidata": ["Q2044949"]} |
Axenfeld-Rieger syndrome is a group of disorders that mainly affects the development of the eye. Common eye symptoms include cornea defects and iris defects. People with this syndrome may have an off-center pupil (corectopia) or extra holes in the eyes that can look like multiple pupils (polycoria). About 50% of people with this syndrome develop glaucoma, a condition that increases pressure inside of the eye, and may cause vision loss or blindness. Click here to view a diagram of the eye.
Even though Axenfeld-Rieger syndrome is primarily an eye disorder, this syndrome can affect other parts of the body. Most people with this syndrome have distinctive facial features and many have issues with their teeth, including unusually small teeth (microdontia) or fewer than normal teeth (oligodontia). Some people have extra folds of skin around their belly button, heart defects, or other more rare birth defects.
There are three types of Axenfeld-Rieger syndrome and each has a different genetic cause. Axenfeld-Rieger syndrome type 1 is caused by mutations in the PITX2 gene. Axenfeld-Rieger syndrome type 3 is caused by mutations in the FOXC1 gene. The gene that causes Axenfeld-Rieger syndrome type 2 is not known, but it is located on chromosome 13. Axenfeld-Rieger syndrome has an autosomal dominant pattern of inheritance. Treatment depend on the symptoms.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Axenfeld-Rieger syndrome | c0265341 | 2,578 | gard | https://rarediseases.info.nih.gov/diseases/5701/axenfeld-rieger-syndrome | 2021-01-18T18:01:54 | {"mesh": ["C535679"], "omim": ["602482", "180500", "601499"], "umls": ["C0265341"], "orphanet": ["782"], "synonyms": ["Rieger syndrome", "Iridogoniodysgenesis with somatic anomalies", "Goniodysgenesis hypodontia"]} |
Bosley-Salih-Alorainy syndrome (BSAS) is characterized by variable horizontal gaze dysfunction, profound and bilateral sensorineural deafness associated commonly with severe inner ear maldevelopment, cerebrovascular anomalies (ranging from unilateral internal carotid artery hypoplasia to bilateral agenesis), cardiac malformation, developmental delay and occasionally autism. The syndrome is caused by homozygous mutations in the HOXA1 gene (7p15.2) and is transmitted in an autosomal recessive manner. The syndrome overlaps clinically and genetically with Athabaskan brain dysfunction syndrome (ABDS,). However unlike ABDS, BSAS does not manifest central hypoventilation.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Bosley-Salih-Alorainy syndrome | c1832216 | 2,579 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=69737 | 2021-01-23T18:40:39 | {"mesh": ["C535397"], "omim": ["601536"], "umls": ["C1832216"], "icd-10": ["Q87.8"]} |
Autosomal inheritance is much rarer than X-linked (309300). Megalocornea is often found in the Marfan syndrome (154700).
HEENT \- Large cornea Inheritance \- Autosomal recessive much rarer than 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
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| MEGALOCORNEA | c0344530 | 2,580 | omim | https://www.omim.org/entry/249300 | 2019-09-22T16:25:29 | {"doid": ["0060305"], "mesh": ["C562829"], "omim": ["249300"]} |
Macroovalocytes are enlarged, oval-shaped erythrocytes (red blood cells). They are not seen in healthy blood, and are most commonly seen in megaloblastic anemia.[1] In most instances, the macroovalocyte morphology is due to megaloblastic erythropoiesis (Vitamin B-12 or folate deficiency) but may be seen with dyserythropoiesis. Although macroovalocytes are characteristic in these deficiency states, they are not pathognomonic. Poikilocytosis is often present, particularly in more advanced cases. If associated with hypersegmented granulocytes in the absence of other causes (e.g. drugs), the findings are essentially diagnostic of Vitamin B-12 or folate deficiency.[2]
## References[edit]
1. ^ http://medical-dictionary.thefreedictionary.com/macroovalocyte
2. ^ "Archived copy". Archived from the original on 2012-08-05. Retrieved 2010-01-18.CS1 maint: archived copy as title (link)
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Macroovalocyte | None | 2,581 | wikipedia | https://en.wikipedia.org/wiki/Macroovalocyte | 2021-01-18T19:05:47 | {"wikidata": ["Q6725490"]} |
Hydrocephalus-cleft palate-joint contractures syndrome is a rare genetic disorder characterized by a buildup of fluid in the brain (hydrocephalus) due to a brain abnormality called Dandy-Walker malformation, cleft palate, and stiff or "frozen" joints (contractures). Less than 20 cases of hydrocephalus-cleft palate-joint contractures syndrome have been reported. Other symptoms might include: thin fingers with absent knuckles and reduced creases over the joints, ear abnormalities, heart defects, and clubfoot. The cause of hydrocephalus-cleft palate-joint contractures syndrome is not known, but it is likely genetic due to reports of affected family members and likely autosomal dominant inheritance. Treatment is specific to the symptoms present in each individual and might include surgical correction of birth defects such as cleft palate and clubfoot.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Hydrocephalus-cleft palate-joint contractures syndrome | c0220686 | 2,582 | gard | https://rarediseases.info.nih.gov/diseases/5642/hydrocephalus-cleft-palate-joint-contractures-syndrome | 2021-01-18T17:59:56 | {"mesh": ["C535332"], "omim": ["147800"], "umls": ["C0220686"], "orphanet": ["916"], "synonyms": ["Aase-Smith syndrome I", "Joint contractures with other abnormalities"]} |
Hereditary neuropathy with liability to pressure palsies (HNPP) is a disorder that affects peripheral nerves, causing the nerves to be highly sensitive to pressure. Symptoms usually begin during adolescence or early adulthood but may develop anytime from childhood to late adulthood. Symptoms vary in severity. While some people never realize they have the disorder, others experience prolonged disability. The most common problem sites involve nerves in the wrists, elbows, and knees; however, the fingers, shoulders, hands, feet, and scalp can also be affected. Symptoms associated with HNPP occur in episodes, due to pressure on any single peripheral nerve. Symptoms may include numbness, tingling, and/or loss of muscle function (palsy), pain in the limbs (especially the hands), carpal tunnel syndrome (impairing the ability to use the fingers, hands, and wrists), and foot drop (making it hard or impossible to walk, climb stairs, or drive). Some people experience fatigue, generalized weakness, muscle cramps, pain in the muscles or bones, or lower back pain. An episode of symptoms associated with HNPP can last from several minutes to days or even months. Most people completely recover after an episode, but repeated episodes can cause permanent muscle weakness or loss of sensation.
HNPP is most often caused by the loss of one copy (a deletion) of the PMP22 gene, but it may also be cause by a mutation within this gene. It is inherited in an autosomal dominant manner. The diagnosis is made based on the symptoms present, electrodiagnostic testing, and genetic testing. HNPP is thought to be underdiagnosed, and it may be misdiagnosed as another disorder such as Charcot-Marie Tooth disease.
There is currently no standard medical treatment for HNPP. Management generally involves strategies to avoid or modify positions (such as leaning on the elbows) and activities that cause symptoms, and using splints or pads on the wrists or arms to avoid pressure on the nerves. An ankle-foot orthosis may be needed permanently for those with a residual foot drop. Management of pain may include over-the-counter pain medicines and/or prescription drugs used for peripheral neuropathy. Special work or school accommodations may be necessary. While the long-term outlook (prognosis) regarding quality of life depends on the frequency and severity of episodes and whether pain and disability persist, HNPP does not affect life expectancy.
*[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
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Hereditary neuropathy with liability to pressure palsies | c0393814 | 2,583 | gard | https://rarediseases.info.nih.gov/diseases/5221/hereditary-neuropathy-with-liability-to-pressure-palsies | 2021-01-18T18:00:02 | {"mesh": ["C536965"], "omim": ["162500"], "umls": ["C0393814"], "orphanet": ["640"], "synonyms": ["HNPP", "Polyneuropathy, familial recurrent", "Tomaculous neuropathy"]} |
Lethal arthrogryposis with anterior horn cell disease
Other namesVuopala disease
Lethal arthrogryposis with anterior horn cell disease is inherited in an autosomal recessive manner
Lethal arthrogryposis with anterior horn cell disease (LAAHD) is an autosomal recessive genetic disorder characterized by reduced mobility of the foetus and early death.
## Contents
* 1 Presentation
* 2 Molecular genetics
* 3 Diagnosis
* 4 Treatment
* 5 Epidemiology
* 6 References
* 7 External links
## Presentation[edit]
LAAHD resembles LCCS1 disease but the phenotype is milder, with survival beyond 32nd gestational week. However, the foetuses are often stillborn or survive only few minutes. The movements of the foetus during pregnancy are scanty and stiff, often only in upper limbs. The malpositions are distal. The inwards spiral and especially the elbow contractures are less severe than in LCCS1 disease. Some patients have intrauterine long bone fractures. Skeletal muscles are affected and show neurogenic atrophy. The size and shape of spinal cord at different levels are normal but anterior horn motoneurons are diminished in number and degenerated.[1]
## Molecular genetics[edit]
LAAHD disease results from compound heterozygosity of GLE1FinMajor and a missense point mutation in exon 13 (6 cases in 3 families) or a missense mutation in exon 16 ( seven cases in 3 families). One of the latter cases survived 12 weeks, mostly under artificial respiration.[2]
## Diagnosis[edit]
This section is empty. You can help by adding to it. (July 2017)
## Treatment[edit]
This section is empty. You can help by adding to it. (July 2017)
## Epidemiology[edit]
LAAHD is one of approximately 40 Finnish heritage diseases. Families affected by these diseases come from different parts of Finland, and birthplaces of the ancestors of affected individuals do not show geographic clustering.[citation needed]
## References[edit]
1. ^ Vuopala K, Ignatius J, Herva R (1995). "Lethal arthrogryposis with anterior horn cell disease". Hum Pathol. 26 (1): 12–19. doi:10.1016/0046-8177(95)90109-4. PMID 7821908.
2. ^ Nousiainen HO, Kestilä M, Pakkasjärvi N, Honkala H, Kuure S, Tallila J, Vuopala K, Ignatius J, Herva R, Peltonen L (February 2008). "Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease". Nature Genetics. 40 (2): 155–157. doi:10.1038/ng.2007.65. PMC 2684619. PMID 18204449.
## External links[edit]
Classification
D
* OMIM: 611890
* MeSH: C567502
External resources
* Orphanet: 53696
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Lethal arthrogryposis with anterior horn cell disease | c2678471 | 2,584 | wikipedia | https://en.wikipedia.org/wiki/Lethal_arthrogryposis_with_anterior_horn_cell_disease | 2021-01-18T18:58:47 | {"mesh": ["C567502"], "umls": ["C2678471"], "orphanet": ["53696"], "wikidata": ["Q6533261"]} |
Potassium aggravated myotonia is a group of diseases that causes tensing and stiffness (myotonia) of skeletal muscles, which are the muscles used for movement. The three types of potassium-aggravated myotonia include myotonia fluctuans, myotonia permanens, and acetazolamide-sensitive myotonia. Potassium aggravated myotonia is different from other types of myotonia because symptoms get worse when an affected individual eats food that is rich in potassium. Symptoms usually develop during childhood and vary, ranging from infrequent mild episodes to long periods of severe disease. Potassium aggravated myotonia is an inherited condition that is caused by changes (mutations) in the SCN4A gene. Treatment begins with avoiding foods that contain large amounts of potassium; other treatments may include physical therapy (stretching or massages to help relax muscles) or certain medications (such as mexiletine, carbamazapine, or acetazolamide).
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Potassium aggravated myotonia | c0856123 | 2,585 | gard | https://rarediseases.info.nih.gov/diseases/4459/potassium-aggravated-myotonia | 2021-01-18T17:58:13 | {"omim": ["608390"], "orphanet": ["612"], "synonyms": ["Myotonia fluctuans", "Myotonia permanens", "Myotonia congenita, atypical", "Myotonia congenita, acetazolamide-responsive"]} |
A rare constitutional hemolytic anemia characterized by a low 6-phosphogluconate dehydrogenase activity in the erythrocytes, which clinically manifests with a well-compensated chronic nonspherocytic hemolytic anemia and transient hemolytic periods with jaundice.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| 6-phosphogluconate dehydrogenase deficiency | None | 2,586 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99135 | 2021-01-23T19:06:38 | {"icd-10": ["D55.1"]} |
This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed.
Find sources: "Greenstick fracture" – news · newspapers · books · scholar · JSTOR (August 2014) (Learn how and when to remove this template message)
Greenstick fracture
Greenstick fractures on X-ray.
SpecialtyOrthopedics
Pediatrics
A greenstick fracture is a fracture in a young, soft bone in which the bone bends and breaks. Greenstick fractures occur most often during infancy and childhood when bones are soft. The name is by analogy with green (i.e., fresh) wood which similarly breaks on the outside when bent.
## Contents
* 1 Signs and symptoms
* 2 Risk factors
* 3 Diagnosis
* 4 Treatment
* 5 Fossil record
* 6 References
* 7 External links
## Signs and symptoms[edit]
Some clinical features of a greenstick fracture are similar to those of a standard long bone fracture – greenstick fractures normally cause pain at the injured area. As these fractures are specifically a pediatric problem, an older child will be protective of the fractured part and babies may cry inconsolably. As per a standard fracture, the area may be swollen and either red or bruised. Greenstick fractures are stable fractures as a part of the bone remains intact and unbroken so this type of fracture normally causes a bend to the injured part, rather than a distinct deformity, which is problematic. Symptoms include pain in the area and can start from overuse in that specific bone. This can be a very gradual chronic pain or pain from a specific injury.
## Risk factors[edit]
The greenstick fracture pattern occurs as a result of bending forces. Activities with a high risk of falling are risk factors. Non-accidental injury more commonly causes spiral (twisting) fractures but a blow on the forearm or shin could cause a greenstick fracture. The fracture usually occurs in children and teens because their bones are flexible, unlike adults whose more brittle bones usually break.
## Diagnosis[edit]
Projectional radiography is generally preferable.
## Treatment[edit]
Removable splints result in better outcomes than casting in children with torus fractures of the distal radius.[1] If a person is doing better after 4 weeks, repeat X rays are not needed.[2]
## Fossil record[edit]
Main article: Paleopathology
Evidence for greenstick fractures found in the fossil record is studied by paleopathologists, specialists in ancient disease and injury. Greenstick fractures (willow breaks) have been reported in fossils of the large carnivorous dinosaur Allosaurus fragilis.[3]
Greenstick fractures are found in the fossil remains of Lucy, the most famous specimen of Australopithecus afarensis, discovered in Ethiopia in 1974. Analysis of bone fracture patterns, which include a large number of greenstick fractures in the forearms, lower limbs, pelvis, thorax and skull, suggest that Lucy died from a vertical fall and impact with the ground.[4]
## References[edit]
1. ^ Firmin F, Crouch R (July 2009). "Splinting versus casting of "torus" fractures to the distal radius in the paediatric patient presenting at the emergency department (ED): a literature review". Int Emerg Nurs. 17 (3): 173–8. doi:10.1016/j.ienj.2009.03.006. PMID 19577205.
2. ^ "Five Things Physicians and Patients Should Question" (PDF). Choosing Wisely. Retrieved 15 February 2018.
3. ^ Molnar, R. E., 2001, Theropod paleopathology: a literature survey: In: Mesozoic Vertebrate Life, edited by Tanke, D. H., and Carpenter, K., Indiana University Press, p. 337-363.
4. ^ Kappelman, John; Ketcham, Richard; Pearce, Stephen; Todd, Lawrence; Akins, Wiley; Colbert, Matthew; Feseha, Mulugeta; Maisano, Jessica; Witzel, Adrienne (2016). "Perimortem fractures in Lucy suggest mortality from fall out of tall tree". Nature. 537 (7621): 503–507. Bibcode:2016Natur.537..503K. doi:10.1038/nature19332. PMID 27571283.
## External links[edit]
Wikimedia Commons has media related to Greenstick fractures.
* Radiology Greenstick vs Torus Fractures
* v
* t
* e
Fractures and cartilage damage
General
* Avulsion fracture
* Chalkstick fracture
* Greenstick fracture
* Open fracture
* Pathologic fracture
* Spiral fracture
Head
* Basilar skull fracture
* Blowout fracture
* Mandibular fracture
* Nasal fracture
* Le Fort fracture of skull
* Zygomaticomaxillary complex fracture
* Zygoma fracture
Spinal fracture
* Cervical fracture
* Jefferson fracture
* Hangman's fracture
* Flexion teardrop fracture
* Clay-shoveler fracture
* Burst fracture
* Compression fracture
* Chance fracture
* Holdsworth fracture
Ribs
* Rib fracture
* Sternal fracture
Shoulder fracture
* Clavicle
* Scapular
Arm fracture
Humerus fracture:
* Proximal
* Supracondylar
* Holstein–Lewis fracture
Forearm fracture:
* Ulna fracture
* Monteggia fracture
* Hume fracture
* Radius fracture/Distal radius
* Galeazzi
* Colles'
* Smith's
* Barton's
* Essex-Lopresti fracture
Hand fracture
* Scaphoid
* Rolando
* Bennett's
* Boxer's
* Busch's
Pelvic fracture
* Duverney fracture
* Pipkin fracture
Leg
Tibia fracture:
* Bumper fracture
* Segond fracture
* Gosselin fracture
* Toddler's fracture
* Pilon fracture
* Plafond fracture
* Tillaux fracture
Fibular fracture:
* Maisonneuve fracture
* Le Fort fracture of ankle
* Bosworth fracture
Combined tibia and fibula fracture:
* Trimalleolar fracture
* Bimalleolar fracture
* Pott's fracture
Crus fracture:
* Patella fracture
Femoral fracture:
* Hip fracture
Foot fracture
* Lisfranc
* Jones
* March
* Calcaneal
*[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
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Greenstick fracture | c0332716 | 2,587 | wikipedia | https://en.wikipedia.org/wiki/Greenstick_fracture | 2021-01-18T18:46:53 | {"umls": ["C0332716"], "wikidata": ["Q1552265"]} |
## Description
Hypertrichosis is defined as hair growth that is excessive for a particular site of the body or age of the patient and that is not hormone-dependent (summary by Fantauzzo et al., 2012).
### Genetic Heterogeneity of Congenital Generalized Hypertrichosis
HTC1 has been mapped to chromosome 8q. HTC2 (307150) is caused by palindrome-mediated interchromosomal insertion at chromosome Xq27. HTC3 (135400), which can occur with or without associated gingival hyperplasia, is caused by deletion or duplication at chromosome 17q24 or by mutation in the ABCA5 gene (612503) on chromosome 17q24.
Also see lanugo-like generalized congenital hypertrichosis (145700).
Clinical Features
Baumeister et al. (1993) found 9 observations of a unique form of hypertrichosis which they suggested should be called Ambras syndrome in reference to the first documented case. Furthermore, they reinvestigated a Greek girl with this disorder, described as a newborn by Sigalas et al. (1990). The girl was found to have a pericentric inversion (8)(p11.2q22). Her persistent generalized hypertrichosis was most excessive on the face, ears, and shoulders. The fine silky hair was of the vellus, not the lanugo type. Baumeister et al. (1993) stated that the first well-documented observation concerned a man named Petrus Gonzales, who was born in the Canary Islands in 1556. (Wiesner-Hanks (2009) stated that Petrus Gonzales was born in 1537.) Two daughters, a son, and a grandchild were similarly affected. The family was also referred to as 'the family of Ambras,' after the castle near Innsbruck where their portraits are still shown (e.g., Cockayne, 1933). One of the documented reports selected by Baumeister et al. (1993) was that by Macias-Flores et al. (1984) of a family in which X-linked dominant inheritance was suggested (307150). Figuera and Cantu (1994) insisted that the disorder in the kindred reported by Macias-Flores et al. (1984) was clinically and genetically distinct from the Ambras syndrome. In the apparently X-linked disorder, the overgrowth of hair involves mainly the upper part of the body and the hair is short and curly without other alterations, while in Ambras syndrome, there is a more diffuse distribution of the hypertrichosis, the hair is fine and long, other skin appendages are involved, and dysmorphic features are present.
Balducci et al. (1998) likewise described Ambras syndrome associated with an inversion of chromosome 8 but a paracentric rather than pericentric inversion: inv(8)(q12q22). The girl presented in the newborn period with abundant dark hair on the face and ears, shoulders and arms; the other parts of the body were covered with fine, lightly pigmented hair. No alterations were found in plasma antigen levels.
Baumeister (2000) suggested that the patient reported by Balducci et al. (1998) had hypertrichosis universalis (145700) and not Ambras syndrome. He stated that Ambras syndrome differs from other forms of congenital hypertrichosis by its associated anomalies and its pattern of hair distribution, especially on the face. The forehead, eyelids, nose (an especially important site of involvement), cheeks, and preauricular regions are uniformly covered with hair, reaching a length of several decimeters if not shaved. The hypertrichosis of the external ears is typical; if not cut, long curls protrude from the external auditory canal. In the patient reported by Balducci et al. (1998), the facial hair was not uniformly distributed; it was accentuated in the frontal, temporal, and preauricular regions. Hypertrichosis of the nose was not present and hypertrichosis of the ears was not prominent. Baumeister (2000) provided a photograph of a 16-year-old boy with extraordinary facial hypertrichosis.
In a rebuttal to Baumeister (2000), Cianfarani (2000) pointed out that in both the case reported by Balducci et al. (1998) and that reported by Baumeister et al. (1993) there was a chromosome abnormality involving 8q22. He pointed out further that 'modern genetics teaches us that identical mutations result in highly variable combinations of clinical features: phenotypic heterogeneity.'
Population Genetics
Fantauzzo et al. (2012) stated that hereditary hypertrichoses are very rare, affecting as few as 1 in 1 billion individuals.
Cytogenetics
Tadin et al. (2001) found that the rearrangement of chromosome 8 in patient 'SS-1,' originally reported by Balducci et al. (1998), was more complex than initially reported. They detected an insertion of the q23-q24 region into a more proximal region of the long arm of chromosome 8 as well as a large deletion in 8q23. Given the large number of breakpoints and the presence of a substantial deletion, it was surprising that the proposita did not show anomalies other than those characteristic of Ambras syndrome.
Baumeister (2002) reiterated his insistence that the patient studied by Balducci et al. (1998) and reinvestigated by Tadin et al. (2001) did not have Ambras syndrome because she did not present with hypertrichosis of the ears and the pattern of hair distribution in general was not identical to that previously described. Baumeister (2002) stated that his position was further strengthened by the finding of Tadin et al. (2001) that the rearrangement in the patient originally reported by Balducci et al. (1998) did not involve 8q22.
In a patient (ME-1) with Ambras syndrome associated with a de novo pericentric inversion of chromosome 8 first described by Baumeister et al. (1993), Tadin-Strapps et al. (2004) cloned the breakpoints of the inversion and generated a detailed physical map. To determine the precise nature of the rearrangement, they used FISH analysis. Analysis of transcripts mapped to the vicinity of the breakpoints showed that the inversion did not disrupt a gene, and suggested that the phenotype was caused by a position effect.
Fantauzzo et al. (2008) analyzed the cytogenetic breakpoints of 3 patients with hypertrichosis universalis congenita, Ambras type, including patients ME-1 and SS-1, originally reported by Baumeister et al. (1993) and Balducci et al. (1998), respectively. They identified a pericentric inversion in chromosome 8q23.1 that lies 7.3 Mb downstream of the TRPS1 gene (604386) in patient ME-1, a 6.7-Mb deletion that encompasses the TRPS1 gene in patient SS-1, and a 1.5-Mb deletion in chromosome 8q24.1 that lies 2.1 Mb upstream of the TRPS1 gene in patient BN-1. There was no overlap between the breakpoints in the 3 patients, so the authors defined the entire 11.5-Mb interval between markers RH62506 and D8S269 containing 20 genes, including the TRPS1 gene, as the candidate interval. Southern blot analysis was suggestive of deletion of TRPS1 in patient SS-1, and no RNA was available for patient BN-1. Quantitative RT-PCR demonstrated significant downregulation of TRPS1 in patient ME-1, suggesting that the inversion breakpoint 7.3 Mb downstream from the TRPS1 gene reduced expression, consistent with a position effect. Fantauzzo et al. (2008) suggested that position effect causing downregulation of TRPS1 expression is the probable cause of hypertrichosis in Ambras syndrome.
Animal Model
Fantauzzo et al. (2008) analyzed koala ('Koa') mice, which represent a mouse model of hypertrichosis and have a semidominant, radiation-induced chromosomal inversion near the mouse ortholog of Trps1, and found that the proximal breakpoint of the Koa inversion is located 791 kb upstream of the Trps1 gene. Quantitative RT-PCR, in situ hybridization, and immunofluorescence analysis revealed that Trps1 expression levels are reduced in Koa mutant mice at the sites of pathology for the phenotype, including muzzle and dorsal skin and cells surrounding the developing vibrissae follicles. Fantauzzo et al. (2008) determined that the Koa inversion created a new Sp1 binding site and translocated additional Sp1 binding sites within a highly conserved stretch spanning the proximal breakpoint, providing a potential mechanism for a position effect.
Hair \- Persistent generalized hypertrichosis, esp. face, ears, and shoulders Inheritance \- Autosomal dominant ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| HYPERTRICHOSIS UNIVERSALIS CONGENITA, AMBRAS TYPE | c1840362 | 2,588 | omim | https://www.omim.org/entry/145701 | 2019-09-22T16:39:48 | {"doid": ["0111060"], "mesh": ["C536605"], "omim": ["145701"], "orphanet": ["1023", "2222"], "synonyms": ["Alternative titles", "AMBRAS SYNDROME", "HYPERTRICHOSIS, CONGENITAL GENERALIZED"]} |
Necrobiotic xanthogranuloma (NXG) is a rare, chronic form of non-Langerhans histiocytosis usually found in older adults. Xanthogranulomas are lesions made of immune cells known as a histiocytes. The term necrobiotic refers to the buildup of broken down collagen fibers that can be seen under a microscope. The typical lesion is a yellow, thickened, or raised lesion (plaque) located around the eyes. In most cases the lesions are associated with conditions in which abnormal proteins are found in the blood (monoclonal gammopathies). NXG is also sometimes associated with blood cancers or lymphoproliferative disorders. As these blood disorders may arise years after the first NXG lesions appear, lifelong follow-up may be recommended. Approximately 50% of people with NXG have problems with their eyes, such as burning or itching, blurred vision, double vision, bulging of the eyeball, drooping of the eyelid, and restricted eye movement. In most cases, other parts of the body, such as the trunk, legs, face, and arms, are also involved. Internal organs may sometimes be affected. Treatment of NXG can be challenging, but is usually necessary to minimize the risk of skin ulcers and scarring. First-line therapy may include drugs used to treat cancer (such as chlorambucil and melphalan). Additional treatment options include corticosteroids, intravenous immunoglobulin, lenalidomide, interferon, radiation therapy, and surgery. In some cases, the symptoms of NXG may return after treatment. If NXG is associated with a blood cancer or a lymphoproliferative disorder, treatment focuses on the blood disorder.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Necrobiotic xanthogranuloma | c1275339 | 2,589 | gard | https://rarediseases.info.nih.gov/diseases/10951/necrobiotic-xanthogranuloma | 2021-01-18T17:58:47 | {"mesh": ["D058252"], "orphanet": ["158011"], "synonyms": ["NXG"]} |
Monosomy 22q13.3 syndrome (deletion 22q13.3 syndrome or Phelan-McDermid syndrome) is a chromosome microdeletion syndrome characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, and minor dysmorphic features.
## Epidemiology
Due to lack of clinical recognition and often insufficient laboratory testing, the syndrome is underdiagnosed and its true incidence remains unknown.
## Clinical description
The deletion occurs with equal frequency in males and females and has been reported in mosaic and non-mosaic forms. Common physical traits include long eye lashes, large or unusual ears, relatively large hands, dysplastic toenails, full brow, dolicocephaly, full cheeks, bulbous nose, and pointed chin. Behavior is autistic-like with decreased perception of pain and habitual chewing or mouthing.
## Etiology
The loss of 22q13.3 can result from a simple deletion, translocation, ring chromosome formation or, less commonly, from structural changes affecting the long arm of chromosome 22, specifically the region containing the SHANK3 gene.
## Diagnostic methods
The diagnosis of monosomy 22q13.3 syndrome should be considered in all cases of hypotonia of unknown etiology and in individuals with absent speech. Although the deletion can sometimes be detected by high resolution chromosome analysis, fluorescence in situ hybridization (FISH) or array comparative genomic hybridization (CGH) is recommended for confirmation.
## Differential diagnosis
Differential diagnosis includes syndromes associated with hypotonia, developmental delay, speech delay and/or autistic-like behavior (Prader-Willi, Angelman, Williams, Smith-Magenis, Fragile X, Sotos, FG, trichorhinophalangeal and velocardiofacial syndromes, autism spectrum disorders and cerebral palsy; see these terms).
## Antenatal diagnosis
Prenatal diagnosis should be offered for future pregnancies in families with inherited rearrangements.
## Genetic counseling
Genetic counseling is recommended and laboratory studies of the parents should be considered to identify cryptic rearrangements and detect parental mosaicism.
## Management and treatment
ndividuals with monosomy 22q13.3 should have routine examinations by the primary care physician, as well as genetic evaluations with referral to specialists if neurological, gastrointestinal, renal, or other systemic problems are suspected. Affected individuals benefit from early intervention programs, intense occupational and communication therapies, adaptive exercise and sport programs, and other therapies to strengthen their muscles and increase their communication skills.
## Prognosis
No apparent life-threatening organic abnormalities accompany the diagnosis of monosomy 22q 13.3.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Monosomy 22q13.3 | c1853490 | 2,590 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=48652 | 2021-01-23T19:09:49 | {"gard": ["10130"], "mesh": ["C536801"], "omim": ["606232"], "umls": ["C1853490"], "icd-10": ["Q93.5"], "synonyms": ["22q13.3 deletion", "Phelan-McDermid syndrome"]} |
Encephalocraniocutaneous lipomatosis
Other namesHaberland syndrome,[1]
SpecialtyNeurology
Encephalocraniocutaneous lipomatosis (ECCL), is a rare condition primarily affecting the brain, eyes, and skin of the head and face.[2] It is characterized by unilateral subcutaneous and intracranial lipomas, alopecia, unilateral porencephalic cysts, epibulbar choristoma and other ophthalmic abnormalities.
It was named after Haberland and Perou who first described it.[3]
## Contents
* 1 History
* 2 See also
* 3 References
* 4 External links
## History[edit]
This condition was first described in 1970.
## See also[edit]
* Nevus psiloliparus
## References[edit]
1. ^ Koishi, Giovanna Negrisoli; Yoshida, Mauricio; Alonso, Nivaldo; Matushita, Hamilton; Goldenberg, Dov (2008). "Encephalocraniocutaneous lipomatosis (haberland's syndrome): a case report of a neurocutaneous syndrome and a review of the literature". Clinics. 63 (3): 406–408. doi:10.1590/S1807-59322008000300020. PMC 2664244. PMID 18568254.
2. ^ Reference, Genetics Home. "ECCL". Genetics Home Reference. Retrieved 22 September 2017.
3. ^ Haberland, C; Perou, M (February 1970). "Encephalocraniocutaneous lipomatosis. A new example of ectomesodermal dysgenesis". Archives of Neurology. 22 (2): 144–55. doi:10.1001/archneur.1970.00480200050005. ISSN 0003-9942. PMID 4902772.
## External links[edit]
Classification
D
* ICD-10: E88.2
* OMIM: 613001
* MeSH: C535736
External resources
* Orphanet: 2396
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Phakomatosis
Angiomatosis
* Sturge–Weber syndrome
* Von Hippel–Lindau disease
Hamartoma
* Tuberous sclerosis
* Hypothalamic hamartoma (Pallister–Hall syndrome)
* Multiple hamartoma syndrome
* Proteus syndrome
* Cowden syndrome
* Bannayan–Riley–Ruvalcaba syndrome
* Lhermitte–Duclos disease
Neurofibromatosis
* Type I
* Type II
Other
* Abdallat–Davis–Farrage syndrome
* Ataxia telangiectasia
* Incontinentia pigmenti
* Peutz–Jeghers syndrome
* Encephalocraniocutaneous lipomatosis
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*[c.]: circa
*[AA]: Adrenergic agonist
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*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Encephalocraniocutaneous lipomatosis | c0406612 | 2,591 | wikipedia | https://en.wikipedia.org/wiki/Encephalocraniocutaneous_lipomatosis | 2021-01-18T19:00:47 | {"gard": ["2108"], "mesh": ["C535736"], "umls": ["C0406612"], "icd-10": ["E88.2"], "orphanet": ["2396"], "wikidata": ["Q17540092"]} |
A number sign (#) is used with this entry because of evidence that X-linked deafness-1 (DFNX1) is caused by loss-of-function mutation in the PRPS1 gene (311850) on chromosome Xq22.
Loss-of-function PRPS1 mutations, resulting in decreased enzyme activity, can also cause X-linked recessive Charcot-Marie-Tooth disease-5 (CMTX5; 311070) and Arts syndrome (ARTS; 301835). There is considerable phenotypic overlap between DFNX1, CMTX5, and Arts syndrome, as well as intrafamilial variability depending on gender, X-inactivation ratio, residual enzyme activity, and additional factors. Males tend to be more severely affected than females in all 3 disorders, although some females can show severe features. These disorders are best considered as representing a phenotypic spectrum (summary by Almoguera et al., 2014; Synofzik et al., 2014).
Another allelic disorder, PRPS-related gout (300661), results from increased PRPS1 enzyme activity. Some affected patients also have neurologic symptoms, including sensorineural deafness.
Clinical Features
Tyson et al. (1996) reevaluated a 4-generation British American family with congenital profound sensorineural hearing loss in males, similar to that ascribed to the previously unmapped locus DFN2. In this family, female carriers had a mild/moderate hearing loss affecting the high frequencies.
Liu et al. (2010) studied 14 affected and 29 unaffected members of a large 5-generation Chinese family segregating X-linked nonsyndromic hearing loss. Age at onset of hearing impairment was between 5 and 15 years for males and in the fifth decade for females. Affected males exhibited symmetric, progressive, severe-to-profound hearing loss with flat-shaped audio profiles at 24 years to 50 years of age. Obligate female carriers had either symmetric or asymmetric hearing loss that varied from mild to moderate in degree.
Synofzik et al. (2014) reported a German family with variable manifestations of PRPS1 deficiency, illustrating that the disorder can present as a continuous spectrum of clinical features, even within the same family. A 42-year-old woman had only prelingual-onset hearing loss without symptoms of neurologic dysfunction, consistent with DFNX1, whereas her 36-year-old brother had a protracted form of Arts syndrome, including prelingual sensorineural hearing loss. Brain imaging in both patients showed mild cerebellar and parietal cortical atrophy. The mother of these sibs had no hearing deficit or neurologic dysfunction at age 66. Genetic analysis identified a missense mutation in the PRPS1 gene (Q277P; 311850.0019) that was heterozygous in the females and hemizygous in the male proband. Erythrocyte PRPS1 activity was not detectable in the proband, was decreased in the sister, and was normal in the mother. X-chromosome inactivation was extremely skewed in the sister with DFNX1 (94%; 6%), but only moderately skewed in the mother (80%; 20%). The findings indicated that females with DFNX1 can also show early-onset hearing loss starting at birth.
Mapping
By linkage analysis using polymorphic microsatellite markers in a 4-generation British American family with congenital sensorineural hearing loss, Tyson et al. (1996) found that the DFN2 locus maps to Xq22. A maximum 2-point lod score of 2.91 at theta = 0.0 was observed with a fully informative dinucleotide repeat at COL4A5 (303630), which had previously been mapped to Xq22, and flanking recombinations were observed at DXS990 and DXS1001.
In a large 5-generation Chinese family segregating X-linked nonsyndromic hearing loss, Liu et al. (2010) performed linkage analysis and obtained a maximum 2-point lod score of 4.25 with marker DXS8096 (theta = 0). Recombination events defined a 5.4-cM critical interval between DXS8020 and DXS8055, overlapping the DFN2 locus.
Molecular Genetics
In a large 5-generation Chinese family segregating X-linked nonsyndromic hearing loss mapping to the DNF2 locus, Liu et al. (2010) analyzed 14 candidate genes and identified a missense mutation in the PRPS1 gene (D65N; 311850.0013) that cosegregated with the phenotype. Analysis of the PRPS1 gene in the British American DFN2 family previously reported by Tyson et al. (1996) revealed a different missense mutation (A87T; 311850.0014); missense mutations were also detected in DFN2 families previously reported by Manolis et al. (1999) and Cui et al. (2004) (311850.0015 and 311850.0016, respectively).
In 2 Italian brothers with postlingual DFNX1, Robusto et al. (2015) identified a hemizygous missense mutation in the PRPS1 gene (A113S; 311850.0021). The mother, who had late-onset moderate hearing loss, was heterozygous for the mutation. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Erythrocyte PRPS1 activity was mildly decreased in the 2 affected males (25-35% of normal controls).
Nomenclature
Petersen et al. (2008) proposed the designation DFNX1 for this locus.
History
There are many early reports of an X-linked form of congenital deafness (e.g., Dow and Poynter, 1930; Mitsuda et al., 1952; Stevenson, cited by Deraemaeker, 1958; Deraemaeker, 1958; Sataloff et al., 1955; Parker, 1958; Fraser, 1965). In the family reported by Dow and Poynter (1930), 4 affected males married deaf-mute women who probably had the autosomal recessive form of the disease because no children were affected. The deafness is of the sensorineural type.
William Wilde (1815-1876), the father of Oscar Wilde and a distinguished ear, nose, and throat surgeon, conducted a large survey of deafness in Ireland in 1851 (Wilde, 1853). In his report he noted that 'the proportion of male deaf mutes exceeds the female considerably but it differs somewhat in the 2 great classes of congenital and acquired deafness.' In the Wilde data, the ratio of males to females was 100:75 for congenital deafness and 100:91 for acquired deafness. Reardon (1990) reanalyzed the data from the Wilde survey and suggested that 5% of congenital male deafness was the result of X-linked inheritance. The result correlated well with the estimate of Fraser (1965) that X-linked inheritance accounts for 6.2% of male genetic deafness.
Wellesley and Goldblatt (1992) reported a kindred in which 5 male members of 3 generations connected through normal females had an identical nonprogressive isolated form of sensorineural hearing loss. Audiograms in 2 brothers, who were noted at age 3 and 4, respectively, to have speech difficulties, showed hearing loss in the 1,500-8,000 Hz range. A maternal uncle had not been aware of any hearing problem, but was found on audiogram to have hearing loss in the 4,000-8,000 Hz range. Two maternal great-uncles who had worked in the motor industry and had received compensation for apparent work-related noise damage had only a vague history of poor hearing; their audiograms showed identical hearing loss to that in the young brothers. Wellesley and Goldblatt (1992) noted that the finding of only affected males with no male-to-male transmission supports X-linked inheritance.
Many families with congenital sensorineural deafness are found to have the gusher-deafness syndrome (304400) with typical radiologic changes in the temporal bone (Reardon et al., 1991). Some congenital sensorineural deafness may represent the entity that Lalwani et al. (1994) found to be linked to Xp21.2; see 300030.
Willems (2000) reviewd the genetic causes of nonsyndromic sensorineural hearing loss.
INHERITANCE \- X-linked HEAD & NECK Ears \- Hearing loss, sensorineural MISCELLANEOUS \- Variable age at onset, ranging from prelingual at birth to fifth decade \- Males tend to have earlier onset than females MOLECULAR BASIS \- Caused by mutation in the phosphoribosylpyrophosphate synthetase-1 gene (PRPS1, 311850.0013 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| DEAFNESS, X-LINKED 1 | c1844677 | 2,592 | omim | https://www.omim.org/entry/304500 | 2019-09-22T16:18:26 | {"doid": ["0050566"], "mesh": ["C564433"], "omim": ["304500"], "orphanet": ["90625"], "synonyms": ["X-linked isolated sensorineural hearing loss type DFN", "X-linked isolated sensorineural deafness type DFN", "Alternative titles", "X-linked isolated neurosensory hearing loss type DFN", "X-linked non-syndromic neurosensory deafness type DFN", "X-linked non-syndromic neurosensory hearing loss type DFN", "X-linked non-syndromic sensorineural hearing loss type DFN", "DEAFNESS, X-LINKED 2, SENSORINEURAL CONGENITAL", "X-linked isolated neurosensory deafness type DFN"], "genereviews": ["NBK1434", "NBK57098"]} |
Genetic disorder in Quarter Horses and draft horses
Equine polysaccharide storage myopathy (EPSM, PSSM, EPSSM) is an inheritable glycogen storage disease of horses that causes exertional rhabdomyolysis. It is currently known to affect the following breeds American Quarter Horses, American Paint Horses, Warmbloods, Cobs, Dales Ponies, Thoroughbreds, Arabians, New Forest ponies, and a large number of Heavy horse breeds. While incurable, PSSM can be managed with appropriate diet and exercise. There are currently 2 subtypes, known as Type 1 PSSM and Type 2 PSSM.
## Contents
* 1 Pathophysiology of glycogen storage disorders and sub-typing of PSSM
* 1.1 Type 1 PSSM
* 1.2 Glycogen branching enzyme deficiency
* 1.3 Type 2 PSSM
* 2 Presentation
* 3 Clinical signs
* 3.1 Variability in phenotype and modifying genes
* 4 Diagnosis
* 5 Management
* 5.1 Effect on metabolism
* 5.2 Diet
* 5.3 Exercise
* 6 References
## Pathophysiology of glycogen storage disorders and sub-typing of PSSM[edit]
A representation of glucose molecules linked by α-1,4-glycosidic bonds, with a single α-1,6-glycosidic bond leading to a branch off of the chain.
Glycogen is a molecular polymer of glucose (a polysaccharide) used to store energy, and is important for maintaining glucose homeostasis in the blood, as well as for providing energy for skeletal muscle and cardiac muscle contraction. Molecules of glucose are linked into linear chains by α-1,4-glycosidic bonds. Additionally, branches of glucose are formed off of the chain by α-1,6-glycosidic bonds. 2 molecules of glucose are joined into an α-1,4-glycosidic bonds by an enzyme known as glycogen synthase. This bond may be broken by amylase when the body wishes to break down glycogen into glucose for energy. Glycogen branching enzyme is responsible for the required α-1,6-glycosidic bonds needed to start a branch off of these linear chains.
Any disruption to this system results in a glycogen storage disease. There are currently 2 subcategories of glycogen storage diseases in horses: Type 1 polysaccharide storage myopathy, glycogen branching enzyme deficiency, and Type 2 polysaccharide storage myopathy.
### Type 1 PSSM[edit]
Type 1 PSSM is caused by an autosomal dominant genetic mutation known as GSY1. This mutation causes an up-regulation of glycogen synthase, and high levels of glycogen synthase relative to glycogen branching enzyme (GBE). This altered ratio of glycogen synthase to GBE results in glycogen molecules with long chains and few branches, making these molecules somewhat amylase resistant.[1] The GSY1 mutation is associated with altered glucose metabolism (but normal glycogen metabolism), as well as accumulation of high levels of glycogen and abnormal polysaccharide in the muscles of the horse.[2] Additionally, some horses have been shown to have insulin sensitivity, which improves glucose uptake by muscle cells and contributes to excessive glycogen storage that is already elevated secondary to the GSY1 mutation.[2]
### Glycogen branching enzyme deficiency[edit]
Main article: Glycogen branching enzyme deficiency
Low levels of glycogen branching enzyme leads to a condition known as glycogen-branching enzyme deficiency. This condition is caused by a mutation of the GBE1 gene responsible for producing the glycogen branching enzyme. Subsequently, glycogen molecules are produced with few branches, which greatly decreasing the number of nonreducing ends, drastically slowing the rate as which the molecule can be synthesized or broken down. This causes low levels of muscle glycogen that is very resistant to amylase.[1] This disease is usually seen in Quarter Horse foals and is fatal.
### Type 2 PSSM[edit]
Type 2 PSSM is a category for disorders that lead to abnormal deposition of glycogen in the skeletal muscles of the horse that is not due to mutations in GSY1 or GBE1.[1]
## Presentation[edit]
The Belgian Draft is one breed with a very high prevalence of PSSM in their population.
PSSM is most prevalent in American Quarter Horses and their related breeds (Paint horse, Appaloosa, Appendix Quarter Horse), Draft horse breeds (especially Belgian Draft and Percherons), and Warmblood breeds.[3] The Belgian Draft been shown to have a 36% prevalence of PSSM.[4] Other breeds that have been diagnosed with PSSM include the Arabian, Lipizzaner, Morgan, Mustang, Peruvian Paso, Rocky Mountain Horse, Standardbred, Tennessee Walking Horse, Thoroughbred, and National Show Horse.[3] It has been suggested that the GSY1 mutation provided some benefit to hard working animals with poor-quality diets, and is now damaging members of those "thrifty" breeds that are managed with moderate to low levels of work and diets high in non-structural carbohydrates.[1]
PSSM Type 1 (homozygous or heterozygous for the GSY1 mutation) is more common in Quarter Horses and their related breeds, and draft breeds, while PSSM Type 2 (negative for the GSY1 mutation) is more commonly seen in other breeds, including warmbloods. There is no sex predilection to the disease.[1]
## Clinical signs[edit]
Horses with Type 1 PSSM usually appear normal at rest, but show signs of exertional rhabdomyolysis ("tying up") such as shortened stride, stiffness, firm musculature, sweating, pain or reluctance to exercise, when asked to perform light work.[1] While episodes of exertional rhabdomyolysis is one of the most frequent signs associated with affected horses (reported in ~37% of affected animals), other common signs include gait abnormalities, shifting lameness, muscle weakness that may result in an inability to rise, colic-like pain, and muscle fasciculation, atrophy, and/or stiffness (most commonly seen in the semimembranosus, semitendinosus, and longissimus muscles).[3][5]
These clinical signs usually first become apparent when the horse is placed into training as a young animal; however, affected horses will show histological changes consistent with muscle damage at one month of age, and may also show elevations in creatine kinase (CK), an enzyme that elevates with muscle damage.[6] Concurrent illness, such as respiratory or gastrointestinal infection, can lead to elevations in CK and potentially life-threatening rhabdomyolysis, even without exercise.[1][6] Horses with PSSM often have a persistently elevated CK at rest, which differentiates the disease from recurrent exertional rhabdomyolysis, in which horses have normal CK concentrations between episodes.[7]
### Variability in phenotype and modifying genes[edit]
Some affected animals may remain subclinical, others may have mild signs that do not impede athletic performance, while some horses will have clinical signs that prevent any forced exercise. Rarely, horses will die from acute episodes of rhabdomyolysis. The reason for such variability of phenotype is not fully understood. Temperament, gender, and body type have no effect on degree of clinical signs.[1] However, environmental factors such as diet and exercise, whether the horse is heterozygous or homozygous for the mutated GSY1 allele, and the presence of modifying genes all play a role.[8] Additionally, some affected horses may have PSSM Type 2, which will produce different cellular changes and subsequently different phenotypic effects.[1]
One such modifying genes is RYR1, which is responsible for calcium regulation in muscle cells. RYR1 mutation causes malignant hyperthermia, a rare but potentially fatal disorder usually associated with anesthesia. While RYR1 mutation is rare in horses, including the general Quarter Horse population, it is much more common in Quarter Horses with GSY1 mutation. Horses with both mutations are more likely to have a severe PSSM phenotype, including higher levels of blood creatine kinase (CK), more severe exercise intolerance, more severe episodes of rhabdomyolysis (more frequent muscle fasciculations, more frequent episodes that are not associated with exercise, acute death), and poor response to PSSM treatment.[8]
Additionally, defects in both GSY1 and the SCNA4 gene, responsible for hyperkalemic periodic paralysis (HYPP) in Quarter Horses and related breeds, has been found in 14% of Halter horses.[9] A combination of both of these genes can cause severe rhabdomyolysis should the horse become recumbent due to an HYPP attack.[1]
## Diagnosis[edit]
A genetic test is available for Type 1 PSSM. This test requires a blood or hair sample, and is less-invasive than muscle biopsy. However, it may be less useful for breeds that are more commonly affected by Type 2 PSSM, such as light horse breeds. Often a muscle biopsy is recommended for horses displaying clinical signs of PSSM but who have negative results for GYS1 mutation.
A muscle biopsy may be taken from the semimembranosis or semitendinosis (hamstring) muscles. The biopsy is stained for glycogen, and the intensity of stain uptake in the muscle, as well as the presence of any inclusions, helps to determine the diagnosis of PSSM. This test is the only method for diagnosing Type 2 PSSM. Horses with Type 1 PSSM will usually have between 1.5-2 times the normal levels of glycogen in their skeletal muscle.[10] While abnormalities indicating muscle damage can be seen on histologic sections of muscle as young as 1 month of age, abnormal polysaccharide accumulation may take up to 3 years to develop.[6]
## Management[edit]
### Effect on metabolism[edit]
Horses with PSSM have elevated levels of muscle glycogen at rest. During exercise, glycogen levels are depleted faster than is seen in unaffected horses, and are reduced down to levels considered normal for a resting non-PSSM horse. This demonstrates that glycogen metabolism is actually normal in these animals.[11] However, PSSM horses synthesize muscle glycogen at double the rate of a normal horse once exercise has ceased, which leads to elevated muscle glycogen.[2] The exact mechanism of abnormal glucose metabolism has not yet been established, but it may have similarities to phosphofructokinase deficiency in humans.[2]
Quarter Horse-related breeds with PSSM show insulin sensitivity, which improves glucose uptake by cells, and these horses clear the blood of glucose more quickly after eating than unaffected horses.[12] This provides easy access to glucose by the muscles, which can then use the substrate to produce glycogen. The GYS1 defect, which up-regulates the glycogen synthase enzyme, allows the muscles to use this glucose to rapidly produce glycogen for storage in the muscle.[13] Surprisingly, increased insulin sensitivity is not seen in draft horse breeds.[14]
Dietary and exercise manipulation may be used to counteract these metabolic changes. Approximately 50% of horses that adhere to the dietary recommendations, and 90% of horses that adhere to both dietary and exercise recommendations, have few to no episodes of exertional rhabdomyolysis.[13]
### Diet[edit]
For most horses, diet has a significant impact on the degree of clinical signs. PSSM horses fed diets high in nonstructural carbohydrates (NSC), which stimulate insulin secretion, have been shown to have increased severity of rhabdomyolysis with exercise.[1] Current recommendations for horses with PSSM include a low-starch, high-fat diet. Low-starch diets produce low blood glucose and insulin levels after eating, which may reduce the amount of glucose taken up by the muscle cells. High fat diets increase free fatty acid concentrations in the blood, which may promote the use of fat for energy (via free fatty acid oxidation) over glucose metabolism. Horses with the most severe clinical signs often show the greatest improvement on the diet.[11]
Dietary recommendations usually include a combination of calorie restriction, reduction of daily NSC content, and an increase in dietary fat. Diet recommendations need to be balanced with the animal's body condition score and exercise level, as it may be beneficial to wait on increasing dietary fat after an obese animal has lost weight.[13] The diet should have <10% of digestible energy coming from NSC, and 15-20% of daily digestible energy coming from fat.[15]
### Exercise[edit]
Horses with PSSM show fewer clinical signs if their exercise is slowly increased over time (i.e. they are slowly conditioned). Additionally, they are much more likely to develop muscle stiffness and rhabdomyolysis if they are exercised after prolonged stall rest.[6]
Horses generally have fewer clinical signs when asked to perform short bouts of work at maximal activity level (anaerobic exercise), although they have difficulty achieving maximal speed and tire faster than unaffected horses. They have more muscle damage when asked to perform lower intensity activity over a longer period of time (aerobic activity),[1] due to an energy deficit in the muscle.[16]
## References[edit]
Wikimedia Commons has media related to Equine polysaccharide storage myopathy.
1. ^ a b c d e f g h i j k l Mickelson JR, Valberg SJ (2015). "The Genetics of Skeletal Muscle Disorders in Horses". Annu. Rev. Anim. Biosci. 3: 197–217. doi:10.1146/annurev-animal-022114-110653. PMID 25387114.
2. ^ a b c d Annandale, E. J.; Valberg, S. J.; Mickelson, J. R.; Seaquist, E. R. (October 2004). "Insulin sensitivity and skeletal muscle glucose transport in horses with equine polysaccharide storage myopathy". Neuromuscular Disorders. 14 (10): 666–674. doi:10.1016/j.nmd.2004.05.007. PMID 15351424.
3. ^ a b c McCue ME, Ribeiro WP, Valberg SJ (August 2006). "Prevalence of polysaccharide storage myopathy in horses with neuromuscular disorders". Equine Veterinary Journal. 38 (S36): 340–344. doi:10.1111/j.2042-3306.2006.tb05565.x. PMID 17402444.
4. ^ Firshman AM, Baird JD, Valberg JS (December 15, 2005). "Prevalences and clinical signs of polysaccharide storage myopathy and shivers in Belgian Draft Horses". JAVMA. 227 (12): 1958–1964. doi:10.2460/javma.2005.227.1958. PMID 16379634.
5. ^ Valentine BA (2003). "Equine polysaccharide storage myopathy". Equine Veterinary Education. 15 (5): 254–262. doi:10.1111/j.2042-3292.2003.tb00537.x.
6. ^ a b c d De La Corte FD, Valberg SJ, MacLeay JM, Mickelson JR (2002). "Developmental Onset of Polysaccharide Storage Myopathy in 4 Quarter Horse Foals". Journal of Veterinary Internal Medicine. 16 (5): 581–587. doi:10.1111/j.1939-1676.2002.tb02391.x.
7. ^ Finno CJ, SPier SJ, Valberg SJ (2009). "Equine diseases caused by known genetic mutations". The Veterinary Journal. 179 (3): 336–347. doi:10.1016/j.tvjl.2008.03.016. PMID 18472287.
8. ^ a b McCue ME, Valberg SJ, Jackson M, Borgia L, Lucio M, Mickelson JR (January 2009). "Polysaccharide storage myopathy phenotype in quarter horse-related breeds is modified by the presence of an RYR1 mutation". Neuromuscular Disorders. 19 (1): 37–43. doi:10.1016/j.nmd.2008.10.001. PMID 19056269.
9. ^ Tryon RC, Penedo CT, McCue ME, et al. (January 2009). "Evaluation of allele frequencies of inherited disease genes in subgroups of American Quarter Horses". JAVMA. 234 (1): 120–125. doi:10.2460/javma.234.1.120. PMID 19119976.
10. ^ Valberg SJ, Cardinet III GH, Carlson GP, DiMauro S (1992). "Polysaccharide storage myopathy associated with recurrent exertional rhabdomyolysis in horses". Neuromuscular Disorders. 2 (5–6): 351–359. doi:10.1016/S0960-8966(06)80006-4.
11. ^ a b Ribeiro WP, Valberg SJ, Pagan JD, Gustavsson BE (2004). "The Effect of Varying Dietary Starch and Fat Content on Serum Creatine Kinase Activity and Substrate Availability in Equine Polysaccharide Storage Myopathy". J Vet Intern Med. 18 (6): 887–894. doi:10.1111/j.1939-1676.2004.tb02637.x.
12. ^ Corte FD, Valberg SJ, Mickelson JR, Hower-Moritz M (July 1999). "Blood glucose clearance after feeding and exercise in polysaccharide storage myopathy". Equine Veterinary Journal. 31 (S30): 324–328. doi:10.1111/j.2042-3306.1999.tb05242.x.
13. ^ a b c Valberg, Stephanie; James Mickelson. "Polysaccharide Storage Myopathy (PSSM) in horses". University of Minnesota Equine Center. University of Minnesota. Retrieved 15 June 2015.
14. ^ Firshman AM, Valberg SJ, et al. (June 2008). "Insulin sensitivity in Belgian horses with polysaccharide storage myopathy". American Journal of Veterinary Research. 69 (6): 816–823. doi:10.2460/ajvr.69.6.818. PMID 18518664.
15. ^ Firshman AM, Valberg SJ, Bender JB, Finno CJ (October 2003). "Epidemiologic characteristics and management of polysaccharide storage myopathy in Quarter Horses". American Journal of Veterinary Research. 64 (10): 1319–1327. doi:10.2460/ajvr.2003.64.1319.
16. ^ Annandale EJ, Valberg SJ, Essen-Gustavsson B (May 2005). "Effects of submaximal exercise on adenine nucleotide concentrations in skeletal muscle fibers of horses with polysaccharide storage myopathy". Am. J. Vet. Res. 66 (5): 839–845. doi:10.2460/ajvr.2005.66.839.
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*[AA]: Adrenergic agonist
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*[HAART]: highly active antiretroviral therapy
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| Equine polysaccharide storage myopathy | c1319005 | 2,593 | wikipedia | https://en.wikipedia.org/wiki/Equine_polysaccharide_storage_myopathy | 2021-01-18T18:45:23 | {"wikidata": ["Q16992706"]} |
Subacute sclerosing panencephalitis (SSPE) a rare condition that is caused by a measles infection acquired earlier in life. Signs and symptoms of the condition primarily affect the central nervous system and often develop approximately 7 to 10 years after a person recovers from the measles. Affected people may initially experience behavioral changes, dementia, and disturbances in motor function. In the late stages of the disease, affected people often progress to a comatose state, and then to a persistent vegetative state. Ultimately, many people with SSPE succumb to fever, heart failure, or the brain's inability to continue controlling the autonomic nervous system. It is unclear why some people develop SSPE after they have seemingly recovered from the measles while others do not. Researchers suspect that SSPE may be due to an abnormal immune response or a mutant form of the measles virus that causes a persistent infection within the central nervous system. Treatment is supportive and primarily based on the signs and symptoms present in each person. Recent studies have shown that certain medications (called antiviral and immunomodulatory drugs) may slow the progression of the condition, although the best treatment regimen and their long-term effects in people with SSPE are currently unknown.
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*[MOR]: μ-opioid receptor
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| Subacute sclerosing panencephalitis | c0038522 | 2,594 | gard | https://rarediseases.info.nih.gov/diseases/7708/subacute-sclerosing-panencephalitis | 2021-01-18T17:57:29 | {"mesh": ["D013344"], "omim": ["260470"], "umls": ["C0038522"], "orphanet": ["2806"], "synonyms": ["SSPE", "Dawson disease", "Dawson Encephalitis"]} |
Abortion in the Federated States of Micronesia is only legal if the abortion will save the woman's life.[1]
## History[edit]
Before the Federated States of Micronesia gained sovereignty in 1986, its laws followed the codes set in place by the Trust Territory of the Pacific Islands, meaning the territory legally observed abortion laws in the United States.[1] With independence, the nation was authorized to set its own laws regarding abortion, and government officials priotized local customs in court cases that charged abortion as a criminal act.[1]
### Local abortion practice[edit]
In the Federated States of Micronesia, women have traditionally induced abortion with local herbs, by inserting foreign bodies into the womb, or through ritual bathing and massages.[1] The rate of local remedies for abortion is difficult to determine because cases are only reported when the abortion leads to severe injury, hospitalization, and death.[1]
## References[edit]
1. ^ a b c d e Division, United Nations Dept of Economic and Social Affairs Population (2001-01-01). Abortion Policies: A Global Review. United Nations Publications. ISBN 9789211513615.
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A number sign (#) is used with this entry because of evidence that the phenotype is a contiguous gene deletion syndrome involving chromosome 3pter-p25.
Description
Characteristic features of the distal 3p- syndrome include low birth weight, microcephaly, trigonocephaly, hypotonia, psychomotor and growth retardation, ptosis, telecanthus, downslanting palpebral fissures, and micrognathia. Postaxial polydactyly, renal anomalies, cleft palate, congenital heart defects (especially atrioventricular septal defects), preauricular pits, sacral dimple, and gastrointestinal anomalies are variable features. Although intellectual deficits are almost invariably associated with cytogenetically visible 3p deletions, rare patients with a 3p26-p25 deletion and normal intelligence or only mild abnormalities have been described (summary by Shuib et al., 2009).
Clinical Features
Verjaal and De Nef (1978) reported a male infant with failure to thrive who had an asymmetric skull flattened on the left posterior side, triangular facies, low anterior hairline, ptosis, epicanthic folds, malformed ears with bilateral indentation of lobules and a pit in the right anterior helix, downturned mouth with thin lips, high-arched palate, arched eyebrows, prominent nose with fleshy tip, micrognathia, and retrognathia. He had poorly developed external genitalia, with small penis and hypoplastic scrotum, and undescended testicles were palpable in the inguinal canals. Muscle hypoplasia of both upper arms was striking, and on both hands, the second finger was curved over the third, with the fifth finger curved inwardly over the fourth finger. He had rocker bottom feet, with a supplementary toe laterally on each foot and partial syndactyly of the second and third toes, and the right fifth toe was larger than the fourth. Over time, severe mental and physical retardation became evident, and hearing and sight were defective, although no anatomic or structural lesion was seen on ophthalmoscopic examination. G-banded chromosome analysis revealed a de novo heterozygous deletion of the short arm of chromosome 3: 46,XY,del(3)(p25). Verjaal and De Nef (1978) stated that this was the first report of monosomy 3p25.
Schwyzer et al. (1987) described a 13-month-old girl with growth and developmental retardation who had terminal deletion of the short arm of chromosome 3, with a breakpoint at 3p25. Features present in the patient that were characteristic of the 3p- syndrome included low birth weight, microcephaly, brachy-trigonocephaly, high and narrow forehead with a prominent metopic suture, epicanthic folds, upslanting palpebral fissures, ptosis, depressed nasal bridge, anteverted nares, and small mandible. She had an anteriorly placed anus, but lacked the postaxial polydactyly that had been observed in about half of patients with 3p- reported at that time. Ophthalmoscopic evaluation at age 9 months revealed a prominent and possibly edematous optic disc and a poorly differentiated macula with absence of central and wall reflexes; electroretinography (ERG) was normal. Reviewing the findings in 13 previously reported patients, Schwyzer et al. (1987) emphasized that it was a pattern, rather than 1 or a few specific dysmorphisms and malformations, that was characteristic of terminal 3p deletion. A feature that appeared to be underreported was trigonocephaly, which was specifically mentioned in only 1 report but, Schwyzer et al. (1987) noted, was evident in published photographs of at least 4 other patients.
Ramer et al. (1989) reported an unrelated female and male infant with identical deletions of the terminal portion of chromosome 3p, involving 3pter-p25. The female infant was small at birth and had periorbital edema, edema of hands and feet, and bilateral postaxial polydactyly. Examination at 5 months of age while hospitalized for growth failure and developmental delay revealed craniofacial manifestations, including scalp hypotrichosis, low posterior hairline, brachycephaly, midface hypoplasia, upslanting palpebral fissures with telecanthus, flat nasal bridge with a short upturned nose, simple philtrum with thin upper lip, micrognathia, and small cupped ears. Hands were small with bilateral simian crease and clinodactyly of the fifth fingers. Feet had a 'rocker bottom' configuration and incurving of the fourth and fifth toes. She had hypotonia in the upper limbs with hyperreactive deep tendon reflexes. On barium studies, she was found to have malrotation of the colon which was surgically corrected. Renal ultrasound showed abnormal positioning of the kidneys, mimicking 'horseshoe' kidney without a connecting isthmus. Audiometry was suggestive of moderate bilateral sensorineural hearing loss. Ophthalmologic examination demonstrated blepharophimosis, telecanthus, and possible nanophthalmos in addition to ptosis. Heart and brain were structurally normal by echocardiography and CT scan, respectively. The male patient was small, with weight, length, and occipital-frontal circumference all 2.5 SD below the mean at 13 months of age. He had low-set ears with posterior angulation and folded helices, long philtrum with thin upper lip, highly arched palate, and micrognathia. Evaluation of a heart murmur by electrocardiography revealed a complete endocardial cushion defect. Cranial ultrasound was normal. Chromosome analysis revealed an identical deletion of the terminal portion of chromosome 3p in each: p25[del(3)(p25pter)]. Ramer et al. (1989) reviewed 10 previously reported patients with deletion of bands p25pter and noted that they had a high frequency of growth failure, severe developmental retardation, and serious structural heart defects; the most frequently documented craniofacial anomalies included ptosis, synophrys, hypertelorism, thin upper lip, micrognathia, malformed or apparently low-set ears, and triangular face.
Narahara et al. (1990) studied 2 unrelated female infants with monosomy for the distal portion of chromosome 3p. One patient, with a 46,XX,del(3)(p25.3) karyotype, showed the characteristic clinical manifestations of the 3p- syndrome, including growth failure, mental retardation, microcephaly with a flat occiput, triangular face, synophrys, blepharoptosis, hypertelorism, broad and flat nose, long philtrum, downturned mouth, micrognathia, apparently low-set and malformed ears, finger abnormalities, and deafness. The other patient, who had a 46,XX,r(3)(p26.1q29) karyotype, had a nonspecific phenotype with mental retardation, growth failure, and microcephaly. Narahara et al. (1990) reviewed 16 previously reported cases with deficiency of distal 3p and suggested that deficiency of the 3p25.3 band was critical to produce the main clinical manifestations of the del(3p) syndrome.
Nienhaus et al. (1992) described a male infant with monosomy for distal 3p, involving deletion of 3pter-p25. At birth he was noted to have an unusual craniofacial appearance, with midface hypoplasia, flat nasal bridge with upturned nostrils, hypertelorism, ptosis, bilateral epicanthus, and periorbital edema; his mouth was downturned with thin lips, long philtrum, high-arched palate, and slight micrognathia, and he had low-set and malformed ears. In contrast to previously described cases, there was no microcephaly, the occiput was prominent, and he had unusually wide cranial sutures. In addition, he had postaxial hexadactyly of all limbs. Cardiac catheterization confirmed a congenital heart defect, consisting of atrial septal defect, ventricular septal defect, and patent ductus arteriosus, He had a small penis, hypospadias, and a skin dimple over the sacrum. The infant died of heart failure due to his serious congenital heart defect at 4 weeks of age. Review of 14 previously reported cases of 3p- syndrome showed the most frequent features (occurring in at least 10 of 15 patients) to be microcephaly, blepharoptosis, epicanthal folds, flat nasal bridge with upturned nostrils, long philtrum, and polydactyly.
Mowrey et al. (1993) studied a male infant who had a terminal deletion of 3p that encompassed all of 3p26 and most or all of 3p25. The infant had low birth weight and length, and the newborn period was complicated by pneumonia and apneic episodes. Examination revealed microcephaly, flattened nasal bridge, hypertelorism, blepharophimosis, narrow palpebral fissures, long philtrum, micrognathia, and small C-shaped ears. Retinal exam demonstrated bilateral macular hypoplasia. At 5.5 months of age, the patient developed increased upper respiratory secretions with difficulty breathing; the patient died at home 2 weeks later. At autopsy, marked hypoplasia of all organs was noted, with hypomyelination of white matter and multiple renal cortical microcysts. Testes were high in the inguinal canals with no changes in the urogenital tract.
Kariya et al. (2000) reported a boy with deletion of the short arm of chromosome 3 who had respiratory distress at birth and minor craniofacial anomalies, including long philtrum, thin lips, flat occiput, high broad forehead, hypertelorism, bilateral ptosis, upturned nose, high-arched palate, micrognathia, retrognathia, preauricular pit, and ear malformation. Despite good sucking, the patient exhibited a swallowing disturbance and was fed by nasogastric tube. Abdominal sonography and ophthalmologic and otoscopic examination were normal, as was CT scan of the temporal bone. Auditory brainstem evoked responses were absent at 1 month and 10 months of age, and he never showed any reaction to visual or auditory stimulation during his life. Brain imaging showed a hypoplastic corpus callosum and enlargement of the lateral ventricle. He had a severely abnormal EEG with low voltage and irregular wave pattern, and began having frequent seizures at the age of 6 months. Psychomotor retardation was observed. He died of kidney and heart failure with fever at 2 years of age.
Kuechler et al. (2015) reported 4 unrelated patients with de novo heterozygous nonrecurrent microdeletions of chromosome 3p25.3 from a cohort of 301 individuals with developmental delay who underwent copy number analysis of exome sequence data. In addition to delayed psychomotor development and poor or absent speech, the patients had common dysmorphic facial features, including mild hypertelorism, strabismus, tubular nose with prominent columella, anteverted nares, broad nasal tip, long philtrum, thin upper lip, downturned corners of the mouth, and striking eyebrows that were full, straight, or arched. All also had short stature and hypotonia, and 3 developed microcephaly during the first year of life. Two patients had seizures, 1 had febrile seizures, 2 patients had postaxial polydactyly, and 2 had tapering fingers. Three patients had not learned to walk independently at ages 1.5 to 6 years.
Molecular Genetics
In a boy with 3p- syndrome, Angeloni et al. (1999) found that the break was distal to the von Hippel-Lindau syndrome gene (VHL; 608537), removing marker D3S18 and the CALL gene (CHL1; 607416). The authors suggested that deletion of 1 copy of the CALL gene might be responsible for mental defects in patients with 3p- syndrome.
Green et al. (2000) studied 10 individuals with chromosome 3pter-p25 deletions, 5 of whom had congenital heart disease. Congenital heart defects, typically AVSD (see AVSD2; 606217), occur in approximately one-third of individuals with 3p- syndrome (Phipps et al., 1994; Drumheller et al., 1996). Green et al. (2000) identified a susceptibility locus for AVSD in cytogenetic band 3p25, bounded by markers at D3S1263 and D3S3594, an interval of 3.7 cM.
Cargile et al. (2002) stated that all reported cases of terminal 3p deletion involved, at a minimum, the loss of chromosomal material telomeric to 3p25.3. Cargile et al. (2002) defined a minimum candidate region conferring the common features of the syndrome by study of a patient with clinical findings consistent with terminal 3p deletion who had an interstitial deletion involving a 4.5-Mb interval between markers D3S3630 and D3S1304. Cargile et al. (2002) noted that the CALL gene was outside the area of deletion in this patient, but the ITPR1 gene (147265), encoding an intracellular calcium channel expressed in the brain, was located in the critical region and might be a good candidate gene for mental retardation.
Endris et al. (2002) performed molecular analysis in a patient with a balanced de novo translocation t(X;3)(p11.2;p25), hypotonia, and severe mental retardation, features characteristic of 3p- syndrome. The translocation breakpoint on the X chromosome was located outside of any coding region; however, the breakpoint on chromosome 3 interrupted a previously unknown gene which Endris et al. (2002) designated MEGAP, 'mental disorder-associated GAP protein' (SRGAP3; 606525). Noting that MEGAP is highly expressed in fetal and adult brain tissue, Endris et al. (2002) suggested that the phenotype they observed in their patient was caused by misregulation of neuronal signal-transduction machinery controlling the correct migration of neurons and their axonal connectivity, and proposed that haploinsufficiency of MEGAP leads to the abnormal development of neuronal structures that are important for normal cognitive function.
Fernandez et al. (2004) identified a boy with characteristic physical features of 3p deletion syndrome and both verbal and nonverbal developmental delay who carried a de novo balanced translocation t(3;10)(p26;q26). Fine mapping of this rearrangement demonstrated that the translocation breakpoint on chromosome 3 fell within the minimum candidate region for 3p deletion syndrome and disrupted the CNTN4 (607280) mRNA transcript at 3p26.3-p26.2. This transcript is a member of the immunoglobulin superfamily of neuronal cell adhesion molecules involved in axon growth, guidance, and fasciculation in the central nervous system (CNS). The results demonstrated the association of CNTN4 disruption with the 3p deletion syndrome phenotype and strongly suggested a causal relationship. In an addendum, the authors stated that the patient they described met clinical criteria for an autism spectrum disorder (see 209850), with impaired social functioning, language delay, and repetitive behaviors.
Takagishi et al. (2006) analyzed a chromosome 3p25 deletion in a mother and daughter that had minimal phenotypic effect. The mother had only minor dysmorphism, including simple-formed ears, high-arched palate, fourth and fifth toe clinodactyly, and a history of moderate scoliosis that required bracing. Her daughter, examined at 15 months of age, had ears that were simple but normal in size, a 'somewhat high' palate, mild hypotonia with mild joint laxity, and fourth and fifth toe clinodactyly; she exhibited no developmental delay. Cytogenetic analysis revealed a terminal 3pter-p25.3 deletion in both mother and daughter. Takagishi et al. (2006) concluded that the 3p25 deletion syndrome might have a much broader phenotypic spectrum than previously recognized.
Malmgren et al. (2007) performed fine mapping in 3 patients with distal 3p deletions, including the female patient originally reported by Ramer et al. (1989). The deletions ranged in size from 10.2 Mb to 11 Mb and encompassed 47 to 51 known genes, including VHL. The location of the proximal breakpoint in 1 of the patients suggested that the previously identified critical region for heart defects might be narrowed down to 0.45 Mb; Malmgren et al. (2007) also concluded that deletion of the ATP2B2 gene (108733) alone, previously suggested as a candidate for the hearing impairment in this syndrome, is not sufficient. Comparison with 9 previously characterized 3p deletion cases showed no common breakpoint. Malmgren et al. (2007) noted that most of the characteristic symptoms, such as growth retardation, feeding problems, hypotonia, microcephaly, and the very characteristic facial features, were present in almost all patients, including the 1 with the smallest interstitial deletion (Cargile et al., 2002).
Shuib et al. (2009) analyzed 14 patients with cytogenetically detectable deletions of 3p25, 10 of whom had previously been reported (Green et al., 2000; Zatyka et al., 2005) and found that deletion size ranged from 6 to 12 Mb. Assuming complete penetrance, a candidate critical region for a congenital heart disease susceptibility gene was refined to approximately 200 kb, and a candidate critical region for mental retardation was mapped to an approximately 1-Mb interval containing the SRGAP3 gene but excluding other 3p neurodevelopmental genes including CHL1, CTN4, LRRN1, and ITPR1. Shuib et al. (2009) suggested that SRGAP3 is the major determinant of mental retardation in distal 3p deletions.
Kuechler et al. (2015) reported 4 unrelated patients with intellectual disability and dysmorphic features associated with 4 different de novo heterozygous nonrecurrent deletions of chromosome 3p25.3. The deletions ranged in size from 148 kb, containing 4 genes, to 11.16 Mb, containing 71 genes. The common minimal region included the entire SETD5 gene (615743), as well as part of the THUMPD3 and LHFPL4 (610240) genes and the noncoding antisense RNA SETD5-AS1. Functional studies were not performed, but the findings were consistent with haploinsufficiency as the disease mechanism. Mutations in the SETD5 gene are associated with MRD23 (615761), which shows some overlapping clinical features. Kuechler et al. (2015) concluded that deletion of the SETD5 gene is most likely the largest contributor to the core phenotype in 3p25 deletion syndrome.
Mattioli et al. (2017) presented evidence that the BRPF1 gene (602410) on chromosome 3p26 also contributes to the phenotype of the 3p deletion syndrome. They identified 2 unrelated patients with 3p25 deletions including BRPF1 and several other genes, but not SETD5. These patients had mild intellectual disability, ptosis or blepharophimosis, and a roundish face. A genotype/phenotype comparison of patients with deletions affecting either BRPF1 or SETD5 and those with deletions affecting both genes suggested that disruption of either gene causes mild to moderate intellectual disability, whereas disruption of both genes causes more severe intellectual disability. Features enriched in patients with BRPF1 disruption included ptosis and/or blepharophimosis, strabismus, short stature, and small head size.
INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature Weight \- Low birth weight Other \- Postnatal growth retardation HEAD & NECK Head \- Microcephaly (up to -3.4 SD) \- Brachycephaly \- Trigonocephaly \- Flat occiput Face \- Triangular face \- Mandible small \- Micrognathia \- Retrognathia \- Long philtrum Ears \- Low-set ears \- Poorly shaped ears \- Preauricular pits \- Preauricular fistulas \- Hearing loss (in some patients) Eyes \- Synophrys \- Arched eyebrows \- Hypertelorism \- Periorbital fullness \- Ptosis \- Upslanting palpebral fissures \- Blepharophimosis \- Epicanthal folds \- Strabismus \- Macular hypoplasia (rare) Nose \- Prominent nasal bridge (in some patients) \- Flat nasal bridge \- Broad nasal bridge \- Tubular nose \- Prominent columella \- Broad nasal tip \- Anteverted nares Mouth \- Downturned corners of mouth \- Thin lips \- High-arched palate CARDIOVASCULAR Heart \- Congenital heart disease (in some patients) \- Atrioventricular septal defect (in some patients) ABDOMEN Gastrointestinal \- Feeding problems GENITOURINARY Internal Genitalia (Male) \- Cryptorchidism (in some patients) Kidneys \- Renal malformation (in some patients) SKELETAL Skull \- Prominent metopic suture Spine \- Sacral dimple Hands \- Postaxial polydactyly \- Tapering fingers Feet \- Postaxial polydactyly MUSCLE, SOFT TISSUES \- Muscle hypotonia \- Muscle hypertonicity \- Spasticity NEUROLOGIC Central Nervous System \- Psychomotor retardation, severe to profound \- Poor or absent speech \- Seizures (rare) MISCELLANEOUS \- Contiguous gene deletion syndrome MOLECULAR BASIS \- Caused by deletion of 6-12Mb on 3pter-p25 ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| CHROMOSOME 3pter-p25 DELETION SYNDROME | c0795806 | 2,596 | omim | https://www.omim.org/entry/613792 | 2019-09-22T15:57:32 | {"doid": ["0060417"], "mesh": ["C536804"], "omim": ["613792"], "orphanet": ["1620"], "synonyms": ["Telomeric monosomy 3p", "3p- SYNDROME", "Alternative titles", "Distal 3p deletion", "3p- syndrome", "Monosomy 3pter"]} |
Meesmann corneal dystrophy (MECD) is a rare genetic condition affecting the clear front covering of the eye (cornea). It is characterized by the development of multiple tiny round cysts in the outermost layer of the cornea (corneal epithelium). Over time, these cysts can break open (rupture) and cause irritation and erosions. Symptoms usually appear around adulthood and may include light sensitivity (photophobia), redness, and pain. Vision remains good in most individuals, but some individuals can have temporary episodes of blurred vision. MECD can be caused by mutations in the either the KRT3 gene or the KRT12 gene and is inherited in an autosomal dominant fashion. While there is no cure for MECD, symptoms are usually effectively managed with use of lubricating eye drops.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Meesmann corneal dystrophy | c0339277 | 2,597 | gard | https://rarediseases.info.nih.gov/diseases/9688/meesmann-corneal-dystrophy | 2021-01-18T17:59:11 | {"mesh": ["D053559"], "omim": ["122100"], "orphanet": ["98954"], "synonyms": ["Meesmann corneal epithelial dystrophy", "Corneal dystrophy, juvenile epithelial of Meesmann", "Juvenile hereditary epithelial dystrophy", "Meesman dystrophy"]} |
## Summary
### Clinical characteristics.
ZAP70-related combined immunodeficiency (ZAP70-related CID) is a cell-mediated immunodeficiency caused by abnormal T-cell receptor (TCR) signaling. Affected children usually present in the first year of life with recurrent bacterial, viral, and opportunistic infections, diarrhea, and failure to thrive. Severe lower-respiratory infections and oral candidiasis are common. Affected children usually do not survive past their second year without hematopoietic stem cell transplantation (HSCT).
### Diagnosis/testing.
The diagnosis of ZAP70-related CID is suggested by low to absent CD8+ T cells in an individual with normal CD3+ and CD4+ T-cell counts. Additional supportive laboratory features include absent proliferation of CD4+ T cells in response to mitogens and antigens, and absent ZAP-70 protein expression. The diagnosis is established in a proband by identification of biallelic pathogenic variants in ZAP70 on molecular genetic testing.
### Management.
Treatment of manifestations: Supportive care includes immediate intravenous immunoglobulin (IVIG) and antibacterial, antifungal, antiviral, and Pneumocystis jiroveci prophylaxis to control and reduce the occurrence of infections.
Prevention of primary manifestations: Allogeneic HSCT to reconstitute the immune system, preferably prior to the onset of infections.
Prevention of secondary complications: Use of irradiated, leukoreduced, cytomegalovirus (CMV)-safe blood products; deferment of immunizations until immune reconstitution; consideration for formula feeds in place of breast feeding until CMV status of mother is known.
Surveillance: Individuals with milder findings or those who have not undergone HSCT need to be monitored for worsening of immune function with periodic assessment of clinical status and functional lymphocyte responsiveness. Following a successful HSCT, the following should be routinely monitored: growth, psychomotor development, complete blood counts, liver and renal function, immune status, donor and recipient chimerism, development of post-transplant complications.
Agents/circumstances to avoid: Non-irradiated blood products; live viral, live mycobacterial, and live bacterial vaccinations; contaminated water sources; exposure to fungus-enriched environments (e.g., construction sites, agricultural areas with active soil disruption, mulch, hay).
Evaluation of relatives at risk: Because the outcome of HSCT in children with ZAP70-related CID is significantly improved by performing HSCT prior to the onset of severe infections, early testing of at-risk sibs should be considered. In addition, any sibs considered as bone marrow donors must be evaluated for ZAP70-related CID prior to donation.
### Genetic counseling.
ZAP70-related CID 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 a carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known.
## Diagnosis
### Suggestive Findings
ZAP70-related combined immunodeficiency (ZAP70-related CID) should be suspected in individuals who present with the following findings within the first two years of life:
* Recurrent viral, bacterial, and opportunistic infections
* Chronic diarrhea and failure to thrive
* Characteristic results of lymphocyte subset analysis of CD3, CD4, and CD8 T cells, lymphocyte functional testing, and ZAP-70 protein expression (see Lymphocyte development and numbers)
Note: Individuals with non-classic ZAP70-related CID may present at an older age with symptoms of autoimmunity, lymphoproliferation, and/or immune dysregulation with or without evidence of immunodeficiency.
Lymphocyte development and numbers. In ZAP70-related CID, total lymphocyte counts can range from normal to high.
* Thymic architecture is largely preserved in individuals with ZAP70-related CID; however, compared to controls, a smaller medullary zone, decreased numbers of AIRE+ medullary thymic epithelial cells, and decreased numbers of dendritic cell numbers may be seen [Poliani et al 2013].
* T-cell counts:
* CD3+ cell counts are typically normal.
* CD4+ cell counts are normal or elevated and may account for 60%-80% of the lymphocytes in individuals with ZAP70-related CID. Numbers of CD4+ recent thymic emigrants may be decreased [Hauck et al 2015].
* CD8+ cells are absent or extremely low, often comprising only 0%-2% of the child's total T-cell count in individuals with ZAP70-related CID [Arpaia et al 1994, Noraz et al 2000].
* Numbers of regulatory T cells may be normal or decreased [Poliani et al 2013, Hauck et al 2015].
* B cell counts and NK cell counts are normal.
Lymphocyte function. T-cell responses to stimuli that act through the T-cell receptor (TCR) are absent or severely diminished:
* Absent or decreased proliferation to CD3 antibody [Roifman et al 2010]
* Absent or decreased proliferation of CD4+ cells in response to mitogens (e.g., PHA, ConA) [Roifman et al 2012]
* Intact proliferative response to mitogenic stimuli that bypass the TCR (e.g., PMA/Ionomycin) [Elder et al 1994, Elder 1997]
* Normal TCR Vβ repertoire in both CD4+ and CD8+ T cells [Roifman et al 2010]
* In CD4 cells: limited differentiation into Th2 cells and resistance to Fas-induced cell death [Roifman et al 2010]
* In regulatory T cells: potentially decreased expression of CTLA4 and TGFB leading to increased risk of autoimmunity [Roifman et al 2010]
ZAP-70 protein expression. Testing of CD4+ T cells reveals absence or near absence of ZAP-70 protein in most affected individuals. Recent reports suggest that the amount of residual ZAP-70 protein expression influences the clinical phenotype [Picard et al 2009, Chan et al 2016, Gavino et al 2017]. Expression of Syk, a related tyrosine kinase important in T-cell signaling, may partially compensate for ZAP-70 signaling in some individuals [Toyabe et al 2001, Hauck et al 2015].
Immunoglobulin concentrations and function
* Immunoglobulin levels vary by individual. Many affected individuals have severe hypogammaglobulinemia, but normal immunoglobulins or elevated IgA, IgM, and/or IgE can also be seen [Turul et al 2009, Cuvelier et al 2016].
* Although functional antibody responses to immunization are present in a few persons [Turul et al 2009, Hauck et al 2015], this finding does not indicate that all specific antigenic responses are intact.
Newborn screening. The utility of TREC screening for individuals with ZAP70-related CID continues to be controversial. Although some have shown that TREC levels in individuals with confirmed ZAP70-related CID are very low compared to age-matched controls [Roifman et al 2010, Roifman et al 2012, Aluri et al 2017], others have shown that a substantial portion of individuals with ZAP70-related CID have TREC levels above the cutoffs used for newborn screening and could be missed [Grazioli et al 2014, Jilkina et al 2014, Hauck et al 2015, Schroeder et al 2016]. Therefore, newborn screening results must be interpreted with caution in individuals with clinical findings consistent with ZAP70-related CID or in populations with a high prevalence of ZAP70-related CID.
### Establishing the Diagnosis
The diagnosis of ZAP70-related CID is established in a proband by identification of biallelic pathogenic variants in ZAP70 on molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
* Single-gene testing. Sequence analysis of ZAP70 is performed.
Note: (1) No deletions or duplications of ZAP70 have been reported. (2) Targeted analysis for the c.1624-11G>A variant can be performed first in individuals of Mennonite ancestry.
* A multigene panel that includes ZAP70 and other genes of interest (see Differential Diagnosis) may also be considered.
Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene varies by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
### Table 1.
Molecular Genetic Testing Used in ZAP70-Related Combined Immunodeficiency
View in own window
Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
ZAP70Sequence analysis 344/44 4
Gene-targeted deletion/duplication analysis 5Unknown 6
1\.
See Table A. Genes and Databases for chromosome locus and protein.
2\.
See Molecular Genetics for information on allelic variants detected in this gene.
3\.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4\.
Arpaia et al [1994], Chan et al [1994], Elder et al [1994], Matsuda et al [1999], Meinl et al [2000], Noraz et al [2000], Barata et al [2001], Elder et al [2001], Toyabe et al [2001], Fagioli et al [2003], Picard et al [2009], Turul et al [2009], Santos et al [2010], Newell et al [2011], Hönig et al [2012], Roifman et al [2012], Karaca et al [2013], Kim et al [2013], Grazioli et al [2014], Akar et al [2015], Hauck et al [2015], Cuvelier et al [2016], Esenboga et al [2016], Schroeder et al [2016], Aluri et al [2017], Gavino et al [2017], Shirkani et al [2017]
5\.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
6\.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Clinical Characteristics
### Clinical Description
Individuals with ZAP70-related CID characteristically present in the first two years of life with recurrent bacterial, viral (including live-virus vaccine strains), and opportunistic infections, diarrhea, and failure to thrive. Severe lower-respiratory infections are seen, most notably Pneumocystis jiroveci infections and viral infections. Oral candidiasis is also common [Cuvelier et al 2016, Schroeder et al 2016].
Other presentations have also been reported:
* Reports of milder phenotypes in sibs of children who had died from ZAP70-related CID include a child age five months with recurrent lower-respiratory disease but no severe infections [Turul et al 2009] and a child with persistent dermatitis resistant to therapy [Katamura et al 1999].
* A child age nine years with a ZAP70 hypomorphic intronic pathogenic variant had an attenuated clinical and immunologic phenotype [Picard et al 2009] (see Genotype-Phenotype Correlations).
* A child age 11 months with ZAP70-related CID presented with lymphoma [Newell et al 2011].
* BCG-related complications including axillary lymphadenitis or disseminated mycobacterial disease following BCG vaccination may be presenting features [Santos et al 2010, Esenboga et al 2016].
* Two individuals presented with recurrent infections and silent brain infarcts; one also had congenital nephrotic syndrome and autoimmune hemolytic anemia [Akar et al 2015].
* An individual with isolated treatment-refractory immune thrombocytopenia (ITP) has been described [Cuvelier et al 2016].
* Two sibs had refractory autoimmune features including nephrotic syndrome/proteinuria, bullous pemphigoid, and colitis; one also developed autoantibodies to factor VIII caused by a hypomorphic and weakly activating ZAP70 pathogenic variant [Chan et al 2016].
* An adult with a history of infantile-onset colitis, recurrent respiratory-tract infections, mucocutaneous candidiasis, HSV stomatitis, VZV infection, EBV lymphoproliferative disorder, recurrent CMV viremia, polyomaviremia, and epidermodysplasia verruciformis-like lesions due to HHV-23 was recently reported. A novel pathogenic variant (c.1272C>T) that leads to an altered splice site and low levels of wild-type ZAP-70 protein was identified in this individual [Gavino et al 2017].
The long-term prognosis of untreated ZAP70-related CID is death from infection. Affected children have a declining quality of life and usually do not survive past their second year without hematopoietic stem cell transplantation (HSCT).
### Genotype-Phenotype Correlations
There is very little genotype-phenotype correlation reported in ZAP70-related CID; however, the amount of residual ZAP-70 protein expressed may modulate the clinical phenotype, as suggested by the following:
* A child with a hypomorphic intronic pathogenic variant (c.837+121G>A in intron 7) who had had chronic eczema from age two months and recurrent infections from age two years. The frequency of infections declined at age six following introduction of co-trimoxazole and IVIG prophylaxis. Of note, an older sib with a history of multiple infections had died at age one year [Picard et al 2009].
* Two sibs with refractory autoimmune features including nephrotic syndrome/proteinuria, bullous pemphigoid, and colitis. One sib also developed autoantibodies to factor VIII. These sibs had compound heterozygous ZAP70 pathogenic variants including a hypomorphic variant (c.574C>T) and a weakly activating variant (c.1079G>C) [Chan et al 2016].
### Nomenclature
ZAP70-related combined immunodeficiency may also be referred to as zeta-associated protein 70 deficiency or immunodeficiency 48.
### Prevalence
ZAP70-related CID was first described in 1994 in three individuals of Mennonite descent [Arpaia et al 1994]. Since that time, more than 50 affected individuals have been described in the literature [Arpaia et al 1994, Chan et al 1994, Elder et al 1994, Elder et al 1995, Gelfand et al 1995, Katamura et al 1999, Matsuda et al 1999, Meinl et al 2000, Noraz et al 2000, Barata et al 2001, Elder et al 2001, Toyabe et al 2001, Fagioli et al 2003, Picard et al 2009, Turul et al 2009, Santos et al 2010, Newell et al 2011, Hönig et al 2012, Roifman et al 2012, Karaca et al 2013, Kim et al 2013, Grazioli et al 2014, Akar et al 2015, Hauck et al 2015, Cuvelier et al 2016, Esenboga et al 2016, Schroeder et al 2016, Aluri et al 2017, Gavino et al 2017, Shirkani et al 2017].
The prevalence of ZAP70-related CID is unknown but much lower than that of all forms of SCID, which is estimated at 1:50,000. Prevalence is higher in the Canadian Mennonite population, where a c.1624-11G>A pathogenic variant resulting in destabilization of the ZAP-70 protein is frequently seen [Arpaia et al 1994, Jilkina et al 2014, Cuvelier et al 2016, Schroeder et al 2016].
## Differential Diagnosis
Human immunodeficiency virus infection. Infants positive for human immunodeficiency virus (HIV+) may present with recurring infections and failure to thrive similar to CID. Individuals with HIV have CD4+ lymphopenia, in contrast to the CD8+ lymphopenia in individuals with ZAP70-related CID. In a neonate, the definitive diagnosis of HIV should be made by detection of cell-associated human immunodeficiency proviral DNA by polymerase chain reaction (PCR) amplification. See Table 2 for additional considerations.
### Table 2.
Combined Immunodeficiencies in the Differential Diagnosis of ZAP70-Related CID
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DisorderGene InvolvedMode of
InheritanceLymphocyte Phenotype
TBNKOther
ZAP70-related CIDZAP70AR+++CD4+/CD8-
Familial CD8 deficiencyCD8AAR+++CD4+/CD8–
CD25 deficiencyIL2RAAR+++CD4–/CD8+
MHC II deficiency (BLS)See Major histocompatibility complex class II deficiencyAR+++CD4–/CD8+
BLS = bare lymphocyte syndrome; MHC II = major histocompatibility complex class II
Familial CD8 deficiency (OMIM 608957) may have a presentation similar to ZAP70-related CID; the diagnosis can be confirmed with CD8A molecular genetic testing. The two individuals reported with this disease had recurring infections from early childhood and lived past their twenties [de la Calle-Martin et al 2001, Mancebo et al 2008].
CD25 deficiency (OMIM 606367) also presents with recurring infections early in life with low to normal T-cell counts. However, the T cells are CD4–/CD8+. The diagnosis can be confirmed with molecular genetic testing of IL2RA (CD25), which encodes the interleukin-2 receptor alpha chain.
Major histocompatibility complex (MHC) class II deficiency (also known as bare lymphocyte syndrome) (OMIM 209920) may have normal or elevated T-cell counts; however, the T cells are CD4–/CD8+. As in other forms of CID, pathologic findings manifest within the first year of life. Major histocompatibility complex II expression is decreased. Molecular genetic testing may reveal pathogenic variants in RFX5, RFXAP, CIITA, or RFXANK, the four genes in which pathogenic variants are known to cause this disorder.
Table 3 differentiates several forms of combined immunodeficiency. Since CID presents as a phenotypically heterogeneous class of diseases, it is useful to recognize forms that present with low to normal T-cell counts. Lymphocyte subset testing and molecular genetic testing can implicate or rule out these other forms of CID.
### Table 3.
T-Cell-Negative Forms of CID in the Differential Diagnosis of ZAP70-Related CID
View in own window
DisorderGene(s) InvolvedMode of
InheritanceDefectLymphocyte Phenotype
TBNK
ZAP70-related CIDZAP70ARDecreased protein expression+++
JAK3-related SCID (OMIM 600802)JAK3AR–+–
IL7R-related SCID (OMIM 608971)IL7RAR–++
CD45 deficiency (OMIM 608971)PTPRCAR–+–
ADA deficiencyADAARDecreased protein production–––
RAG1/2 deficiency (OMIIM 601457)RAG1, RAG2AR––+
SCID Athabascan (OMIM 602450)DCLRE1CAR––+
X-linked SCIDIL2RGXLDysfunctional receptor–+–
Omenn syndrome (OMIM 603554). Some individuals with ZAP70-related CID can present with Omenn syndrome-like features including rash, lymphadenopathy, hepatosplenomegaly, and eosinophilia.
## Management
### Evaluations Following Initial Diagnosis
The care of individuals diagnosed with ZAP70-related CID is best managed with a multidisciplinary team of providers including hematology/oncology/bone marrow transplantation, immunology, genetics, and infectious disease specialists. To establish the extent of disease and needs in an individual diagnosed with ZAP70-related combined immunodeficiency (CID), the following evaluations are recommended:
* Assessment of growth
* Evaluation for common and opportunistic viral, bacterial, and fungal disease-causing agents
* Complete metabolic panel (liver and renal function), complete blood count (CBC) with differential and platelet count, lymphocyte subsets and mitogen proliferation, and quantitative immunoglobulins
* Consultation with a clinical geneticist and/or genetic counselor
* Consultation with a clinical immunologist
* Consultation for hematopoietic stem cell transplantation
### Treatment of Manifestations
Treatment relies on prompt reconstitution of the individual's immune system (see Prevention of Primary Manifestations).
Supportive treatment includes IVIG and antibacterial, antifungal, antiviral, and Pneumocystis jiroveci prophylaxis to control and reduce the occurrence of infections.
### Prevention of Primary Manifestations
The only curative therapy for ZAP70-related CID is allogeneic hematopoietic stem cell transplantation (HSCT). Extrapolated data show that the outcome of HSCT in children with SCID is significantly improved by performing HSCT prior to the onset of infections [Pai et al 2014]. Children with ZAP70-related CID have been successfully transplanted using a variety of donors including haploidentical donors and unrelated umbilical cord blood [Noraz et al 2000, Elder et al 2001, Hönig et al 2012, Cuvelier et al 2016].
* Outcomes are the best with HLA-matched, related donors.
* If an HLA-matched, related donor is not available, alternatives include:
* Matched unrelated donor;
* Umbilical cord blood donor;
* Haploidentical parental bone marrow or mobilized peripheral blood stem cells that have been T-cell depleted.
* In contrast to individuals with SCID, individuals with ZAP70-related CID are typically treated with a chemotherapeutic conditioning regimen prior to HSCT, although some individuals have received unconditioned transplants with variable success, suggesting that conditioning may not be essential in some circumstances [Hönig et al 2012, Kim et al 2013, Cuvelier et al 2016].
* The largest series of eight individuals with ZAP70-related CID who received HSCT using a variety of stem cell sources showed the following:
* All individuals were alive at a median of 13.5 years of follow up.
* Two-thirds of the individuals who did not receive conditioning failed to have myeloid engraftment but have maintained stable mixed chimerism. In addition, three individuals who received stem cells from a matched sib did not receive conditioning prior to transplant and achieved engraftment.
* 75% of individuals developed acute graft-versus-host disease (GVHD) and 50% developed chronic GVHD.
* Seven of eight individuals achieved freedom from IVIG and show evidence of class switching with resolution of dysregulated immunoglobulin production and six of the eight show evidence of antibody production to both protein and polysaccharide vaccines.
* Two individuals receiving myeloablative conditioning have developed premature ovarian failure.
* Cellular reconstitution following HSCT takes up to one year, while restoration of humoral immunity can take significantly longer, and may not occur in some individuals.
* Complications from HSCT include graft-versus-host disease, failure to reconstitute the humoral immune compartment, graft failure over time, and post-transplant lymphoproliferative disease [Skoda-Smith et al 2001, Dvorak & Cowan 2008, Pai et al 2014].
* Affected individuals with poor humoral reconstitution are maintained on long-term immunoglobulin replacement.
Individuals who do not undergo HSCT require close monitoring for worsening of immune function manifested by increased susceptibility to severe or opportunistic infections (see also Surveillance). If clinical status worsens, rapid transition to HSCT should be considered.
### Prevention of Secondary Complications
The following are appropriate:
* Use of irradiated, leukoreduced, cytomegalovirus (CMV)-safe blood products
* Delay of immunizations until immune reconstitution
* Consideration for formula feeds in place of breast feeding until CMV status of mother is known. Caution should be taken to assess the quality of the water source for the infant formula.
### Surveillance
Following a successful HSCT, the following should be routinely monitored:
* Growth
* Psychomotor development
* Complete blood counts
* Liver and renal function
* Immune status
* Donor and recipient chimerism
* Development of post-transplant complications, particularly chronic graft-versus-host disease, decreased bone density, pulmonary and cardiac function, and gonadal function
Individuals with milder findings or those who have not undergone HSCT also need to be monitored for worsening of immune function with periodic assessment of clinical status and functional lymphocyte responsiveness.
### Agents/Circumstances to Avoid
Individuals with ZAP70-related CID should avoid the following:
* Non-irradiated blood products
* Live virus vaccinations
* Mycobacterium bovis (BCG) vaccine against tuberculosis, Salmonella typhi (Ty21a) vaccine against typhoid fever, and Vibrio cholerae (CVD 103-HgR) vaccine against cholera, which may be part of the routine vaccination schedule in countries where these diseases are endemic
* Contaminated water sources
* Exposure to fungus-enriched environments (e.g., construction sites, agricultural areas with active soil disruption, mulch, hay)
### Evaluation of Relatives at Risk
Because the outcome of HSCT in children with ZAP70-related CID is significantly improved by performing HSCT prior to the onset of severe infections, early testing of at-risk sibs should be considered. In addition, any sibs considered as bone marrow donors must be evaluated for ZAP70-related CID prior to donation.
* If the ZAP70 pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
* If the pathogenic variants in the family are not known, CBC, quantitative immunoglobulins, and lymphocyte subsets and proliferation can be used to clarify the genetic status (immunologic status) of at-risk sibs.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Pregnancy Management
Appropriately screened blood products should be available, if needed, during the course of the pregnancy and delivery.
### Therapies Under Investigation
Gene therapy. Gene therapy has not been performed in ZAP70-related CID. Experimental studies utilizing gene therapy have been conducted on murine models [Adjali et al 2005, Irla et al 2008] as well as human cells in vitro [Steinberg et al 2000, Kofler et al 2004, Gavino et al 2017]. Nonviral transfer methods (e.g., electro-gene transfer) have also been used to correct ZAP-70 deficiency in a murine model [Irla et al 2008].
Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| ZAP70-Related Combined Immunodeficiency | None | 2,598 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK20221/ | 2021-01-18T20:47:57 | {"synonyms": []} |
Mesomelic dysplasia, Savarirayan type is characterised by severely hypoplastic and triangular-shaped tibiae, and absence of the fibulae. So far, two sporadic cases have been described. Moderate mesomelia of the upper limbs, proximal widening of the ulnas, pelvic anomalies and marked bilateral glenoid hypoplasia were also reported.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Mesomelic dysplasia, Savarirayan type | c1854470 | 2,599 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=85170 | 2021-01-23T17:39:38 | {"gard": ["10584"], "mesh": ["C565349"], "omim": ["605274"], "umls": ["C1854470"], "icd-10": ["Q78.8"], "synonyms": ["Mesomelic dysplasia with absent fibulas and triangular tibias", "Triangular tibia-fibular aplasia syndrome"]} |
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