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Björnstad syndrome
Other namesBJS[1]
Björnstad syndrome is an autosomal recessive congenital condition involving pili torti,[2] nerve deafness and hair abnormalities.
It was first characterized in 1965, in Oslo, by prof. Roar Theodor Bjørnstad (1908–2002).[3]
It has been mapped to BCS1L.[4] Hearing disabilities related to Björnstad syndrome are congenital, and the severity of the deafness varies from person to person. Pili torti is recognized in early childhood and is characterised by twisted hair shafts and brittle hair.[5] The hearing loss usually becomes evident very early in life, often in the first year. It is caused by mutations in the BCS1L gene which also cause GRACILE syndrome.[6]
## See also[edit]
* GRACILE syndrome
## References[edit]
1. ^ "OMIM Entry - # 262000 - Bjornstad Syndrome; BJS". omim.org. Retrieved 8 April 2019.
2. ^ Siddiqi, Saima; Siddiq, Saadat; Mansoor, Atika; Jaap, Oostrik; Nafees, Ahmad; Syed Ali, Raza Kazmi; Hannie, Kremer; Raheel, Qamar; Margit, Schraders (December 1, 2013). "Novel mutation in AAA domain of BCS1L causing Bjornstad syndrome". Journal of Human Genetics. 12 (58): 819–820. doi:10.1038/jhg.2013.101. PMID 24172246.
3. ^ Bjornstad, R. Pili torti and sensory-neural loss of hearing. Proc. 7th Meeting Northern Derm. Soc., Copenhagen May-29, 1965.
4. ^ Hinson JT, Fantin VR, Schönberger J, et al. (February 2007). "Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome". N. Engl. J. Med. 356 (8): 809–19. doi:10.1056/NEJMoa055262. PMID 17314340.
5. ^ Hinson, J. Travis; Fantin, Valeria R.; Schönberger, Jost; Breivik, Noralv; Siem, Geir; McDonough, Barbara; Sharma, Pankaj; Keogh, Ivan; Godinho, Ricardo; Santos, Felipe; Esparza, Alfonso; Nicolau, Yamileth; Selvaag, Edgar; Cohen, Bruce H.; Hoppel, Charles L.; Tranebjærg, Lisbeth; Eavey, Roland D.; Seidman, J.G.; Seidman, Christine E. (22 February 2007). "Missense Mutations in the BCS1L Gene as a Cause of the Björnstad Syndrome". New England Journal of Medicine. 356 (8): 809–819. doi:10.1056/NEJMoa055262. ISSN 0028-4793. PMID 17314340.
6. ^ "Bjornstad syndrome". NCATS. Genetic and rare diseases information center. Retrieved 17 April 2018.
## External links[edit]
Classification
D
* OMIM: 262000
* MeSH: C537633
* DiseasesDB: 33516
External resources
* Orphanet: 123
* v
* t
* e
Congenital malformations and deformations of skin appendages
Nail disease
* Anonychia
* Leukonychia
* Pachyonychia congenita/Onychauxis
* Koilonychia
Hair disease
* hypotrichosis/abnormalities: keratin disease
* Monilethrix
* IBIDS syndrome
* Sabinas brittle hair syndrome
* Pili annulati
* Pili torti
* Uncombable hair syndrome
* Björnstad syndrome
* Giant axonal neuropathy with curly hair
* hypertrichosis: Zimmermann–Laband syndrome
* v
* t
* e
Disorders of citric acid cycle and electron transport chain
Citric acid cycle
* Pyruvate dehydrogenase deficiency
* Fumarase deficiency
Electron transport chain
* Coenzyme Q10 deficiency
* Björnstad syndrome
* GRACILE syndrome
* Leigh's disease
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
| Björnstad syndrome | c0266006 | 1,400 | wikipedia | https://en.wikipedia.org/wiki/Bj%C3%B6rnstad_syndrome | 2021-01-18T18:30:40 | {"gard": ["22"], "mesh": ["C537633"], "umls": ["C0266006"], "orphanet": ["123"], "wikidata": ["Q4919794"]} |
The syndrome steatocystoma multiplex and natal teeth is characterized by generalized multiple steatocystomas and natal teeth.
## Epidemiology
It has been described a five-generation Chinese family with at least 21 affected patients.
## Genetic counseling
The same condition has been reported in one additional sporadic case. Autosomal dominant inheritance has been suggested.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Steatocystoma multiplex-natal teeth syndrome | c1866650 | 1,401 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3184 | 2021-01-23T16:56:29 | {"gard": ["5004"], "mesh": ["C537487"], "omim": ["184510"], "umls": ["C1866650"], "icd-10": ["L72.2"]} |
A number sign (#) is used with this entry because autosomal recessive deafness-79 (DFNB79) is caused by homozygous mutation in the TPRN gene (613354) on chromosome 9q34.
Clinical Features
Khan et al. (2010) reported 3 consanguineous Pakistani families with severe to profound autosomal recessive prelingual nonsyndromic sensorineural hearing loss.
Li et al. (2010) reported 2 Dutch sibs with DFNB79. Sensorineural hearing loss was diagnosed at age 4 years 3 months and 2 years 9 months, respectively. At these ages, both had delayed speech development, but no other abnormalities. The hearing loss was progressive, becoming profound by age 15 and 26 years, respectively.
Mapping
By genomewide analysis of a consanguineous Pakistani family with autosomal recessive hearing loss, Khan et al. (2010) identified a locus on chromosome 9q34.3 (2-point lod score of 9.43 at marker D9SH159). Two additional large Pakistani families with hearing loss were found to link to the same region. Haplotype analysis of the 3 families refined the candidate region to a 3.84-Mb interval between D9S1818 and D9SH6. The locus was designated DFNB79. Sequencing of candidate genes within this region did not identify any pathogenic mutations.
Molecular Genetics
In affected members of 4 consanguineous Pakistani families with autosomal recessive nonsyndromic deafness-79 (DFNB79; 613307), including the 3 families previously reported by Khan et al. (2010), Rehman et al. (2010) identified 4 different homozygous truncating mutations in the TPRN gene (613354.0001-613354.0004).
Li et al. (2010) also identified homozygous loss of function mutations in the TPRN gene (613354.0004 and 613354.0005) in affected members of a large consanguineous Moroccan family and a Dutch family with DFNB79.
INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Hearing loss, sensorineural, progressive (severe to profound) MISCELLANEOUS \- Dutch, Pakistani, and Moroccan families have been described \- Onset of hearing loss in first decade of life MOLECULAR BASIS \- Caused by mutation in the taperin gene (TPRN, 613354.0001 ) ▲ 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
| DEAFNESS, AUTOSOMAL RECESSIVE 79 | c2750082 | 1,402 | omim | https://www.omim.org/entry/613307 | 2019-09-22T15:59:07 | {"doid": ["0110526"], "mesh": ["C567651"], "omim": ["613307"], "orphanet": ["90636"], "synonyms": ["Autosomal recessive isolated neurosensory deafness type DFNB", "Autosomal recessive isolated sensorineural deafness type DFNB", "Autosomal recessive non-syndromic neurosensory deafness type DFNB"]} |
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Find sources: "Salivary gland tumour" – news · newspapers · books · scholar · JSTOR (July 2016) (Learn how and when to remove this template message)
Salivary gland tumour
Parotid gland tumour
SpecialtyOncology, Oral and maxillofacial surgery, Oral and maxillofacial pathology
Salivary gland tumours or neoplasms are tumours that form in the tissues of salivary glands. The salivary glands are classified as major or minor. The major salivary glands consist of the parotid, submandibular, and sublingual glands. The minor salivary glands consist of 800-1000 small mucus-secreting glands located throughout the lining of the oral cavity.[1]
## Contents
* 1 Presentation
* 2 Diagnosis
* 2.1 Classification
* 3 Treatment
* 4 Epidemiology
* 5 See also
* 6 References
* 7 External links
## Presentation[edit]
Salivary gland tumours usually present as a lump or swelling in the affected gland which may or may not have been present for a long time. The lump may be accompanied by symptoms of duct blockage (e.g. xerostomia). Usually, in their early stages it is not possible to distinguish a benign tumour from a malignant one. One of the key differentiating symptoms of a malignant growth is nerve involvement; for example, signs of facial nerve damage (e.g. facial palsy) are associated with malignant parotid tumours. Facial pain and paraesthesia are also very often associated with malignant tumours.[2] Other red flag symptoms which may suggest malignancy and warrant further investigation are fixation of the lump to the overlying skin, ulceration and induration of the mucosa.[3]
## Diagnosis[edit]
Coronal MRI showing right parotid adenoid cystic carcinoma.
There are many diagnostic methods that can be used to determine the type of salivary gland tumour and if it is benign or malignant. Examples of diagnostic methods include:
Physical exam and history: An exam of the body to check general signs of health. The head, neck, mouth, and throat will be checked for signs of disease, such as lumps or anything else that seems unusual. A history of the patient's health habits and past illnesses and treatments will also be taken.
Endoscopy: A procedure to look at organs and tissues inside the body to check for abnormal areas. For salivary gland cancer, an endoscope is inserted into the mouth to look at the mouth, throat, and larynx. An endoscope is a thin, tube-like instrument with a light and a lens for viewing.
MRI or CT Scan: These tests can confirm the presence of a tumour. An MRI or CT Scan can also show whether metastasis has occurred.[4]
Biopsy: The removal of cells or tissues so they can be viewed under a microscope by a pathologist to check for signs of cancer.[5]
Fine needle aspiration (FNA) biopsy: The removal of tissue or fluid using a thin needle. An FNA is the most common type of biopsy used for salivary gland cancer, and has been shown to produce accurate results when differentiating between benign and malignant tumours.[6]
Radiographs: An OPG (orthopantomogram) can be taken to rule out mandibular involvement. A chest radiograph may also be taken to rule out any secondary tumours.[7]
Ultrasound: Ultrasound can be used to initially assess a tumour that is located superficially in either the submandibular or parotid gland. It can distinguish an intrinsic from an extrinsic neoplasm. Ultrasonic images of malignant tumours include ill-defined margins.[8] Furthermore, high resolution ultrasound can identify the exact tumour location within the parotid gland, its relationship to the retromandibular vein and assist surgical excision.[9]
### Classification[edit]
Due to the diverse nature of salivary gland tumours, many different terms and classification systems have been used. Perhaps the most widely used currently is that system proposed by the World Health Organization in 2004, which classifies salivary neoplasms as primary or secondary, benign or malignant, and also by tissue of origin. This system defines five broad categories of salivary gland neoplasms:[10][11]
Benign tumour of the submandibular gland, also known as pleomorphic adenoma, presented as a painless neck mass in a 40-year-old man. At the left of the image is the white tumor with its characteristic cartilaginous cut surface. To the right is the normally lobated submandibular salivary gland.
Benign epithelial tumors
* Pleomorphic adenoma
* Warthin's tumor
* Myoepithelioma
* Basal cell adenoma
* Oncocytoma
* Canalicular adenoma
* Lymphadenoma
* Sebaceous lymphadenoma
* Nonsebaceous lymphadenoma
* Ductal papilloma
* Inverted ductal papilloma
* Intraductal papilloma
* Sialadenoma papilliferum
* Cystadenoma
* Malignant epithelial tumors
* Acinic cell carcinoma
* Mucoepidermoid carcinoma
* Adenoid cystic carcinoma
* Polymorphous low-grade adenocarcinoma
* Epithelial-myoepithelial carcinoma
* Clear cell carcinoma, not otherwise specified
* Basal cell adenocarcinoma
* Sebaceous carcinoma
* Sebaceous lymphadenocarcinoma
* Cystadenocarcinoma
* Low-grade cribriform cystadenocarcinoma
* Mucinous adenocarcinoma
* Oncocytic carcinoma
* Salivary duct carcinoma
* Salivary duct carcinoma, not otherwise specified
* Adenocarcinoma, not otherwise specified
* Myoepithelial carcinoma
* Carcinoma ex pleomorphic adenoma
* Mammary analogue secretory carcinoma
* Carcinosarcoma
* Metastasizing pleomorphic adenoma
* Squamous cell carcinoma
* Large cell carcinoma
* Lymphoepithelial carcinoma
* Sialoblastoma
* Soft tissue tumors
* Hemangioma
* Hematolymphoid tumors
* Hodgkin lymphoma
* Diffuse large B-cell lymphoma
* Extranodal marginal zone B cell lymphoma
* Secondary tumors (i.e. a tumor which has metastasized to the salivary gland from a distant location)
Others, not included in the WHO classification above, include:[10]
* Intraosseous (central) salivary gland tumors
* Hybrid tumors (i.e. a tumor displaying combined forms of histologic tumor types)
* Hybrid carcinoma
* Others
* Others
* Keratocystoma
* Sialolipoma
## Treatment[edit]
Most patients with early-stage lesions that are resectable generally tend to undergo surgery as their initial therapeutic approach, whereas those with advanced or unresectable cancers tend to be treated with radiotherapy (RT) alone or chemoradiotherapy (CRT), which hampered the comparison of the efficacy of RT alone with that of surgery combined with adjuvant RT. But some effort had been made to reflect the role of surgery in salivary gland tumours.
Specimen from a parotid gland tumour. It was removed by John Hunter from a 37-year-old man called John Burley on 24 October 1785. The tumour weighed over 4 kilograms and took twenty-five minutes to remove. The specimen currently resides in the Hunterian Museum at the Royal College of Surgeons of England
Treatment may include the following:
* Surgery Complete surgical resection, with adequate free margins, is currently the mainstay treatment for salivary gland tumours. However elective treatment of the N0 neck region remains a controversial topic
* Radiotherapy[4] If a salivary gland tumour is cancerous, Radiation Therapy may be necessary
Fast neutron therapy has been used successfully to treat salivary gland tumors,[12] and has shown to be significantly more effective than photons in studies treating unresectable salivary gland tumors.[13][14]
* Chemotherapy Currently little is known about the efficacy of chemotherapy in treating salivary gland tumours. Chemotherapy, which plays an important role in systemic therapy, is generally reserved for the palliative treatment of symptomatic locally recurrent and/or metastatic disease that is not amenable to further surgery or radiation. Conventional chemotherapy regimens, such as cisplatin and 5-FU or CAP (cisplatin, doxorubicin, and cyclophosphamide) are still utilized as first-line therapy for patients with advanced lesions.[15]
Targeted Therapy \- Due to the poor results with chemotherapy, it's urgent to explore novel therapeutic interventions for this disease. And great expectations have been put into individualized therapies: in particular, the EGF receptors family (EGFR and HER2), KIT and androgen receptors are the most commonly investigated molecular targets in SGCs. Their expression seems not to be linked to its pathogenetic role in the development of SGCs, but more to the histogenetic origin of the tumor cells. Various targeted agents, such as imatinib, cetuximab, gefitinib, trastuzumab, had been used for exploring new treatment for salivary gland tumours, but on account of the rare incidence of salivary gland tumours, the number of cases available on targeted therapy for analysis is relatively small.[16]
## Epidemiology[edit]
Little is known about the total incidence of salivary gland tumours as most benign tumours go unrecorded in national cancer registries.[2] The majority of salivary tumours are benign (65-70%).[3] Within the parotid gland 75 - 80% of tumours are benign. Around 50% of the tumours found in the submandibular glands are benign. Sublingual gland tumours are very rare but if present, they are most likely to be malignant.[3][17]
In the United States, salivary gland cancers are uncommon with an incidence rate of 1.7 in 100000 between 2009 and 2013.[18]
## See also[edit]
* Head and neck cancer
* Salivary gland pathology
## References[edit]
1. ^ Shah JP; Patel SG (2001). Cancer of the Head and Neck. PMPH-USA. p. 240. ISBN 978-1-55009-084-0.
2. ^ a b Odell, Edward W. (2017). Cawson's essentials of oral pathology and oral medicine (Ninth ed.). [Edinburgh]: Elsevier Health Sciences. ISBN 978-0702049828. OCLC 960030340.
3. ^ a b c Mehanna, Hisham; McQueen, Andrew; Robinson, Max; Paleri, Vinidh (2012-10-23). "Salivary gland swellings". BMJ. 345: e6794. doi:10.1136/bmj.e6794. ISSN 1756-1833. PMID 23092898. S2CID 373247.
4. ^ a b "Salivary gland tumors: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 2019-10-28.
5. ^ "Salivary Gland Cancer". MedicineNet.
6. ^ Vaishali H Anand et al. FNAC and Histopathology of Salivary Gland Tumors. SEAJCRR. 2014 Feb 3(1):609-618
7. ^ Mounika, C (2016-03-07). "Salivary Gland Tumors". SlideShare.
8. ^ Lee YY, Wong KT, King AD, Ahuja AT (June 2008). "Imaging of salivary gland tumours". Eur J Radiol. 66 (3): 419–36. doi:10.1016/j.ejrad.2008.01.027. PMID 18337041.
9. ^ Psychogios, Georgios; Rueger, Holger; Jering, Monika; Tsoures, Eleni; Künzel, Julian; Zenk, Johannes (September 2019). "Ultrasound can help to indirectly predict contact of parotid tumors to the facial nerve, correct intraglandular localization, and appropriate surgical technique". Head & Neck. 41 (9): 3211–3218. doi:10.1002/hed.25811. ISSN 1043-3074.
10. ^ a b Barnes L (23 December 2008). Surgical Pathology of the Head and Neck. 1 (3rd ed.). Taylor & Francis. p. 511. ISBN 978-0-8493-9023-4.
11. ^ Barnes L (2005). "Chapter 5: Tumors of the salivary glands (chapter authors: Eveson JW, Auclair P, Gnepp DR, El-Naggar AK)" (PDF). Pathology and Genetics of Head and Neck Tumours. International Agency for Research on Cancer, World Health Organization. p. 210. ISBN 978-92-832-2417-4.
12. ^ Douglas JG, Koh WJ, Austin-Seymour M, Laramore GE (September 2003). "Treatment of salivary gland neoplasms with fast neutron radiotherapy". Arch. Otolaryngol. Head Neck Surg. 129 (9): 944–8. doi:10.1001/archotol.129.9.944. PMID 12975266.
13. ^ Laramore GE, Krall JM, Griffin TW, Duncan W, Richter MP, Saroja KR, Maor MH, Davis LW (September 1993). "Neutron versus photon irradiation for unresectable salivary gland tumors: final report of an RTOG-MRC randomized clinical trial. Radiation Therapy Oncology Group. Medical Research Council". Int. J. Radiat. Oncol. Biol. Phys. 27 (2): 235–40. doi:10.1016/0360-3016(93)90233-L. PMID 8407397.
14. ^ Krüll A, Schwarz R, Engenhart R, Huber P, Lessel A, Koppe H, Favre A, Breteau N, Auberger T (1996). "European results in neutron therapy of malignant salivary gland tumors". Bull Cancer Radiother. 83 Suppl: 125–9s. doi:10.1016/0924-4212(96)84897-3. PMID 8949764.
15. ^ Creagan, ET; Woods, JE; Schutt, AJ; O'Fallon, JR (1 December 1983). "Cyclophosphamide, adriamycin, and cis-diamminedichloroplatinum (II) in the treatment of advanced nonsquamous cell head and neck cancer". Cancer. 52 (11): 2007–10. doi:10.1002/1097-0142(19831201)52:11<2007::AID-CNCR2820521106>3.0.CO;2-T. PMID 6684986.
16. ^ Mino M, Pilch BZ, Faquin WC (December 2003). "Expression of KIT (CD117) in neoplasms of the head and neck: an ancillary marker for adenoid cystic carcinoma". Mod. Pathol. 16 (12): 1224–31. doi:10.1097/01.MP.0000096046.42833.C7. PMID 14681323.
17. ^ "About salivary gland cancer | Salivary gland cancer | Cancer Research UK". www.cancerresearchuk.org. Retrieved 2017-11-17.
18. ^ American Cancer Society (2017). Cancer Facts and Figures 2017, Special Section: Rare Cancer in Adults. Atlanta: American Cancer Society.
* v
* t
* e
Oral and maxillofacial pathology
Lips
* Cheilitis
* Actinic
* Angular
* Plasma cell
* Cleft lip
* Congenital lip pit
* Eclabium
* Herpes labialis
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Tongue
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Palate
* Bednar's aphthae
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Oral mucosa – Lining of mouth
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* Verruca vulgaris
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Teeth (pulp, dentin, enamel)
* Amelogenesis imperfecta
* Ankylosis
* Anodontia
* Caries
* Early childhood caries
* Concrescence
* Failure of eruption of teeth
* Dens evaginatus
* Talon cusp
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* Dilaceration
* Discoloration
* Ectopic enamel
* Enamel hypocalcification
* Enamel hypoplasia
* Turner's hypoplasia
* Enamel pearl
* Fluorosis
* Fusion
* Gemination
* Hyperdontia
* Hypodontia
* Maxillary lateral incisor agenesis
* Impaction
* Wisdom tooth impaction
* Macrodontia
* Meth mouth
* Microdontia
* Odontogenic tumors
* Keratocystic odontogenic tumour
* Odontoma
* Dens in dente
* Open contact
* Premature eruption
* Neonatal teeth
* Pulp calcification
* Pulp stone
* Pulp canal obliteration
* Pulp necrosis
* Pulp polyp
* Pulpitis
* Regional odontodysplasia
* Resorption
* Shovel-shaped incisors
* Supernumerary root
* Taurodontism
* Trauma
* Avulsion
* Cracked tooth syndrome
* Vertical root fracture
* Occlusal
* Tooth loss
* Edentulism
* Tooth wear
* Abrasion
* Abfraction
* Acid erosion
* Attrition
Periodontium (gingiva, periodontal ligament, cementum, alveolus) – Gums and tooth-supporting structures
* Cementicle
* Cementoblastoma
* Gigantiform
* Cementoma
* Eruption cyst
* Epulis
* Pyogenic granuloma
* Congenital epulis
* Gingival enlargement
* Gingival cyst of the adult
* Gingival cyst of the newborn
* Gingivitis
* Desquamative
* Granulomatous
* Plasma cell
* Hereditary gingival fibromatosis
* Hypercementosis
* Hypocementosis
* Linear gingival erythema
* Necrotizing periodontal diseases
* Acute necrotizing ulcerative gingivitis
* Pericoronitis
* Peri-implantitis
* Periodontal abscess
* Periodontal trauma
* Periodontitis
* Aggressive
* As a manifestation of systemic disease
* Chronic
* Perio-endo lesion
* Teething
Periapical, mandibular and maxillary hard tissues – Bones of jaws
* Agnathia
* Alveolar osteitis
* Buccal exostosis
* Cherubism
* Idiopathic osteosclerosis
* Mandibular fracture
* Microgenia
* Micrognathia
* Intraosseous cysts
* Odontogenic: periapical
* Dentigerous
* Buccal bifurcation
* Lateral periodontal
* Globulomaxillary
* Calcifying odontogenic
* Glandular odontogenic
* Non-odontogenic: Nasopalatine duct
* Median mandibular
* Median palatal
* Traumatic bone
* Osteoma
* Osteomyelitis
* Osteonecrosis
* Bisphosphonate-associated
* Neuralgia-inducing cavitational osteonecrosis
* Osteoradionecrosis
* Osteoporotic bone marrow defect
* Paget's disease of bone
* Periapical abscess
* Phoenix abscess
* Periapical periodontitis
* Stafne defect
* Torus mandibularis
Temporomandibular joints, muscles of mastication and malocclusions – Jaw joints, chewing muscles and bite abnormalities
* Bruxism
* Condylar resorption
* Mandibular dislocation
* Malocclusion
* Crossbite
* Open bite
* Overbite
* Overeruption
* Overjet
* Prognathia
* Retrognathia
* Scissor bite
* Maxillary hypoplasia
* Temporomandibular joint dysfunction
Salivary glands
* Benign lymphoepithelial lesion
* Ectopic salivary gland tissue
* Frey's syndrome
* HIV salivary gland disease
* Necrotizing sialometaplasia
* Mucocele
* Ranula
* Pneumoparotitis
* Salivary duct stricture
* Salivary gland aplasia
* Salivary gland atresia
* Salivary gland diverticulum
* Salivary gland fistula
* Salivary gland hyperplasia
* Salivary gland hypoplasia
* Salivary gland neoplasms
* Benign: Basal cell adenoma
* Canalicular adenoma
* Ductal papilloma
* Monomorphic adenoma
* Myoepithelioma
* Oncocytoma
* Papillary cystadenoma lymphomatosum
* Pleomorphic adenoma
* Sebaceous adenoma
* Malignant: Acinic cell carcinoma
* Adenocarcinoma
* Adenoid cystic carcinoma
* Carcinoma ex pleomorphic adenoma
* Lymphoma
* Mucoepidermoid carcinoma
* Sclerosing polycystic adenosis
* Sialadenitis
* Parotitis
* Chronic sclerosing sialadenitis
* Sialectasis
* Sialocele
* Sialodochitis
* Sialosis
* Sialolithiasis
* Sjögren's syndrome
Orofacial soft tissues – Soft tissues around the mouth
* Actinomycosis
* Angioedema
* Basal cell carcinoma
* Cutaneous sinus of dental origin
* Cystic hygroma
* Gnathophyma
* Ludwig's angina
* Macrostomia
* Melkersson–Rosenthal syndrome
* Microstomia
* Noma
* Oral Crohn's disease
* Orofacial granulomatosis
* Perioral dermatitis
* Pyostomatitis vegetans
Other
* Eagle syndrome
* Hemifacial hypertrophy
* Facial hemiatrophy
* Oral manifestations of systemic disease
* v
* t
* e
Tumors of lip, oral cavity and pharynx / head and neck cancer
Oral cancer
Salivary gland
malignant epithelial tumors
* Acinic cell carcinoma
* Mucoepidermoid carcinoma
* Adenoid cystic carcinoma
* Salivary duct carcinoma
* Epithelial-myoepithelial carcinoma
* Polymorphous low-grade adenocarcinoma
* Hyalinizing clear cell carcinoma
benign epithelial tumors
* Pleomorphic adenoma
* Warthin's tumor
ungrouped:
* Oncocytoma
Tongue
* Leukoplakia
* Rhabdomyoma
* Oropharynx
## External links[edit]
* Salivary gland cancer entry in the public domain NCI Dictionary of Cancer Terms
Classification
D
* ICD-10: C07-C08, D11
* ICD-9-CM: 142, 210.2
* MeSH: D012468
External resources
* MedlinePlus: 001040
This article incorporates public domain material from the U.S. National Cancer Institute document: "Dictionary of Cancer Terms".
*[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
| Salivary gland tumour | c0036095 | 1,403 | wikipedia | https://en.wikipedia.org/wiki/Salivary_gland_tumour | 2021-01-18T19:10:12 | {"mesh": ["D012468"], "umls": ["C0036095"], "icd-9": ["210.2", "142"], "icd-10": ["D11", "C08", "C07"], "orphanet": ["276142"], "wikidata": ["Q3267772"]} |
A number sign (#) is used with this entry because orofaciodigital syndrome VI (OFD6) is caused by homozygous or compound heterozygous mutation in the C5ORF42 gene (CPLANE1; 614571) on chromosome 5p13.
Mutation in the C5ORF42 gene can also cause Joubert syndrome-17 (JBTS17; 614615), a disorder with overlapping features.
Description
Orofaciodigital syndrome type VI (OFD6), or Varadi syndrome, is a rare autosomal recessive disorder distinguished from other orofaciodigital syndromes by metacarpal abnormalities with central polydactyly and by cerebellar abnormalities, including the molar tooth sign (summary by Doss et al., 1998 and Lopez et al., 2014).
Clinical Features
In 7 children in an inbred Gypsy group, Varadi et al. (1980) delineated a 'new' syndrome of reduplicated big toes, hexadactyly, cleft lip/palate or lingual nodule, and somatic and psychomotor retardation. Some showed absent olfactory bulbs and tracts, cryptorchidism, inguinal hernia, and congenital heart disease. Four of the 6 died within 2 weeks, 1 at 3 years, 1 at 6 years, and the seventh was alive at 3 years. The authors pointed out phenotypic similarities to trisomy 13 but the karyotype was normal and the pedigrees suggested autosomal recessive inheritance. Papp and Varadi (1985) found another case in a sibship of 12 children; a deceased member also had the syndrome.
Munke et al. (1990) presented evidence on the basis of 3 unrelated patients that hypoplastic cerebellar vermis, as demonstrated by magnetic resonance imaging (MRI) as well as by clinical signs of cerebellar defect, is a consistent finding in patients with this disorder, which they referred to as the oral-facial-digital syndrome type VI. Polydactyly of the hands is characterized by a Y-shaped central metacarpal. 'Central polydactyly' of the hands must be the most specific feature of this disorder. Clinically, recurrent episodes of tachypnea and hyperpnea were remarkable features of the cerebellar vermis. Their 3 patients had short stature. In contrast to reported patients who were all severely mentally retarded, 1 of the 3 was of normal intelligence. Munke et al. (1990) proposed that OFD VI was the disorder present in the families reported by Gustavson et al. (1971), Egger et al. (1982), Gencik and Gencikova (1983), Haumont and Pelc (1983), Mattei and Ayme (1983) and Silengo et al. (1987).
Muenke et al. (1991) described detailed studies of a fetus with clinical findings overlapping this disorder, the hydrolethalus syndrome (236680), and the Pallister-Hall syndrome (PHS; 146510). The fetus had many manifestations in common with the twin fetuses reported by Hingorani et al. (1991).
Cleper et al. (1993) reported the cases of 2 male cousins, both the offspring of consanguineous matings, with multiple congenital anomalies. They had an unusual facial appearance. Multiple buccoalveolar frenula and notched inferior alveolar ridges were present at birth. Both had congenital heart anomalies, micropenis, and cryptorchidism. Persistence of Mullerian structures was documented at necropsy in one patient. The surviving patient was mentally retarded and had a unilateral central extra digit with partially formed metacarpal, as well as partial agenesis of the corpus callosum. Bulimia and episodic hyperthermia were attributed to hypothalamic dysfunction. Cleper et al. (1993) pictured a metopic ridge in the forehead of the surviving patient and in the ear an accessory fold between a prominent crus helix and the external meatus. Cleper et al. (1993) suggested that the findings overlapped with those of the Varadi syndrome and Opitz trigonocephaly syndrome (211750). Stephan et al. (1994) suggested that hypothalamic hamartoma is an occasional manifestation of Varadi syndrome.
Toriello (1993) reviewed the clinical overlap observed with the 9 described types of OFD syndromes and with other entities such as Pallister-Hall syndrome and the hydrolethalus syndrome. Shashi et al. (1995) reported 2 brothers with findings overlapping OFD II (252100), OFD VI, and Pallister-Hall syndrome, both of whom had congenital absence of the pituitary gland. Shashi et al. (1995) raised the possibility that this represented a new type of OFD syndrome.
Doss et al. (1998) described the neuropathologic findings in a stillborn, 21-week estimated gestational age, male fetus diagnosed antenatally. Autopsy findings included facial abnormalities, postaxial central polydactyly of the right hand, bilateral bifid toes, and absence of cerebellar vermis with hypoplasia of the hemispheric cortex. Microscopic analysis of the cerebellum demonstrated absence of the subpial granular cell layer and disruption or dysgenesis of the glial architecture. These histopathologic findings suggested that a primary neuronal or glial cell defect, rather than an associated Dandy-Walker malformation, may account for the cerebellar abnormalities in this form of OFD syndrome.
Panigrahi et al. (2013) reported 2 patients with overlapping features of OFD type II and type VI. Y-shaped metacarpal, central polydactyly, and renal disease were characteristic of type VI, whereas face and hand abnormalities and cardiac defect were suggestive of type II. Panigrahi et al. (2013) suggested that types II and VI are part of the same phenotypic spectrum with serious intracranial abnormalities at the more severe end of the spectrum.
Darmency-Stamboul et al. (2013) reported 6 unrelated girls with OFD6. All patients presented with one or more oral malformations, including lobulated tongue, lingual hamartoma, multiple frenula, cleft lip/palate, and upper lip notch. Four patients had pre- or postaxial polydactyly of the hands and/or feet. All had delayed psychomotor development with moderate to severe mental retardation. Other common neurologic abnormalities included ataxia, fine motor difficulties, poor or absent speech, orofacial dyspraxia, and oculomotor apraxia. Four patients had ventilatory disorders. Brain imaging showed cerebellar malformations, brainstem malformations, and cystic dilatation of the posterior fossa; all had the molar tooth sign. These findings indicated that OFD6 should be included among the 'Joubert syndrome-related disorders' (JSRDs). Twin sisters (patients 3 and 4) reported by Darmency-Stamboul et al. (2013), born of consanguineous Turkish parents, were found by Lambacher et al. (2016) to have a homozygous mutation in the TMEM107 gene (E45G; 616183.0003).
Lopez et al. (2014) reported 12 patients, including 8 fetuses, from 9 unrelated families with OFD6. All patients had the molar tooth sign with cerebellar vermis hypoplasia, verified either by brain imaging or neuropathologic examination. Other common features included tongue hamartoma and/or additional frenula and/or upper lip notch, mesoaxial or preaxial polydactyly of the hands or feet, Y-shaped metacarpals, and hypothalamic hamartoma. All 4 surviving patients, including 1 reported by Darmency-Stamboul et al. (2013), had intellectual disability. Atypical features observed in 1 patient each included short femurs, occipital meningocele, and tibial bowing and fibular agenesis. Features common to other ciliopathies, such as polycystic kidney disease or retinal disease, were not present.
Inheritance
Because of the consanguinity in the family reported by Varadi et al. (1980) and because of the involvement of multiple sibs in that and other families, Munke et al. (1990) suggested that OFDS VI is an autosomal recessive disorder.
Molecular Genetics
Valente et al. (2010) reported 2 unrelated Ashkenazi Jewish patients, a 4-year-old boy and a male fetus, with Joubert syndrome-2 (JBTS2; 608091) caused by the same homozygous mutation in the TMEM216 gene (R73L; 613277.0001). In addition to molar tooth sign on brain imaging and polydactyly, the 2 patients had tongue tumors or multiple oral frenula, reminiscent of OFD6.
In 12 patients from 9 of 11 unrelated families with OFD6, Lopez et al. (2014) identified 14 different homozygous or compound heterozygous mutations in the C5ORF42 gene (see, e.g., 614571.0007-614571.0011). Mutations in the first 6 families were found by exome sequencing; in the remaining 3 families, they were found by direct sequencing of the C5ORF42 gene in 9 additional probands with a clinical diagnosis of OFD6 or a similar disorder. Four frameshift, 3 nonsense, 5 missense, and 2 splice site mutations were identified, suggesting that at least 1 truncating mutation is necessary to cause the phenotype. However, functional studies of the variants were not performed.
History
Munke et al. (1990) provided a classification of orofaciodigital syndrome into 7 varieties, following in part the classification of Toriello (1988).
INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Other \- Failure to thrive HEAD & NECK Face \- Micrognathia Ears \- Posteriorly rotated ears \- Low-set ears \- Conductive hearing loss Eyes \- Hypertelorism \- Epicanthal folds \- Nystagmus \- Esotropia Nose \- Broad nasal tip Mouth \- Cleft lip \- Intraoral frenula \- Lobed tongue \- Lingual nodules \- Sublingual nodules \- Notched lip \- High-arched palate \- Cleft palate GENITOURINARY Kidneys \- Renal agenesis \- Renal dysplasia SKELETAL Hands \- Central polydactyly \- Preaxial polydactyly \- Postaxial polydactyly \- Mesoaxial polydactyly \- Clinodactyly \- Syndactyly \- Central Y-shaped metacarpal \- Brachydactyly Feet \- Preaxial polydactyly \- Syndactyly NEUROLOGIC Central Nervous System \- Cerebellar vermis hypoplasia \- Molar tooth sign \- Developmental delay \- Mental retardation \- Hypotonia \- Hypothalamic hamartoma MOLECULAR BASIS \- Caused by mutation in the chromosome 5 open reading frame 42 gene (C5ORF42, 614571.0007 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| OROFACIODIGITAL SYNDROME VI | c2745997 | 1,404 | omim | https://www.omim.org/entry/277170 | 2019-09-22T16:21:24 | {"doid": ["0060376"], "mesh": ["C536531"], "omim": ["277170"], "orphanet": ["2754"], "synonyms": ["Alternative titles", "ORAL-FACIAL-DIGITAL SYNDROME, TYPE VI", "OFDS VI", "VARADI-PAPP SYNDROME", "VARADI SYNDROME", "POLYDACTYLY, CLEFT LIP/PALATE OR LINGUAL LUMP, AND PSYCHOMOTOR RETARDATION"]} |
A number sign (#) is used with this entry because sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) is caused by homozygous or compound heterozygous mutation in the nuclear-encoded DNA polymerase-gamma gene (POLG; 174763).
Recessive mutations in the POLG gene can also cause autosomal recessive progressive external ophthalmoplegia (PEOB; 258450), which shows overlapping features.
Description
SANDO is an autosomal recessive systemic disorder characterized mainly by adult onset of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) resulting from mitochondrial dysfunction and associated with mtDNA depletion in skeletal muscle and peripheral nerve tissue (Fadic et al., 1997). The phenotype varies widely, even within the same family, and can include myopathy, seizures, and hearing loss, but the common clinical feature appears to be sensory ataxia (review by Milone and Massie, 2010).
Spinocerebellar ataxia with epilepsy (SCAE) is a similar disorder with a higher frequency of migraine headaches and seizures (Winterthun et al., 2005).
Clinical Features
Fadic et al. (1997) reported 4 unrelated patients with adult onset of severe sensory ataxic neuropathy in association with dysarthria and chronic progressive external ophthalmoplegia. Patients had ataxic gait, loss of distal proprioception and vibration, areflexia in the lower limbs, positive Romberg sign, and electrophysiologic and pathologic evidence of a peripheral axonal neuropathy. Other variable features included migraine and depression. Skeletal muscle biopsy showed myopathic changes with centralized nuclei and ragged-red fibers. Molecular analysis detected multiple mitochondrial DNA (mtDNA) deletions, ranging in size from 4.5 to 10 kb, in muscle and peripheral nerve. Fadic et al. (1997) proposed the term 'SANDO.'
Rantamaki et al. (2001) reported a family in which 3 of 5 sibs were affected by progressive ataxia starting at age 30 years. Each patient showed gait and limb ataxia, dysarthria, dysphagia, nystagmus, hyporeflexia, decreased vibration and position sense, and mild cognitive impairment. One patient had epilepsy. MRI showed bilateral thalamic lesions and high-intensity signals in the cerebellar white matter. Measurements of sensory action potentials were consistent with a sensory axonal neuropathy and suggested a disorder of the central somatosensory pathways. Postmortem examination of 1 case revealed degenerative pathology and atrophic changes in the thalamus, brainstem, cerebellum, and spinal cord. The authors concluded that the disorder was most consistent with an autosomal recessive pattern of inheritance. Genetic analyses for mutations in the FXN gene (606829), several spinocerebellar ataxias, and mitochondrial diseases were negative, suggesting that this family exhibited a distinct hereditary spinocerebellar ataxia.
Van Goethem et al. (2003) reported a man with SANDO who had been rejected from compulsory military service at the age of 19 years because of a disturbance of balance, which progressed slowly during the third decade and became disabling with frequent falls. He presented at age 39 with moderately severe external ophthalmoparesis, mild dysarthria, and ataxic gait without other muscle weakness. The patient showed thalamic lesions on neuroimaging. The patient's parents, both 70 years of age, were clinically normal, as was his only brother.
Van Goethem et al. (2004) reported 8 patients from 5 European families who presented with sensory ataxia without apparent muscle involvement; 1 of the families had been reported by Rantamaki et al. (2001). In a previously unreported family, a man had an 8-day episode of status epilepticus at age 18 years and an acute psychiatric illness with hyperventilation, gastrointestinal symptoms, and ataxia at age 23. At age 38, he demonstrated gait and limb ataxia, dysarthria, areflexia, distal loss of vibration and proprioception in the lower limbs, a sensory axonal peripheral neuropathy, and increased CSF protein. Other features included severe gastroparesis with progressive weight loss and dilated cardiomyopathy on echocardiogram. At age 38 years, he had an acute episode of stupor, hyperventilation, myoclonus, seizures, and lactic acidosis, and died at age 39 after numerous complications. Blepharoptosis and ophthalmoparesis were never noted. A muscle biopsy at age 34 years showed abnormal mitochondrial inclusions and some evidence of mtDNA deletions. The patient's sister had acute encephalopathy, myoclonus, partial seizures, cortical blindness, stupor, and sudden death at age 17 years. In a consanguineous Belgian family, a brother and sister reported progressive gait unsteadiness beginning in adolescence. By the fifth decade, both patients had ataxic gait, areflexia, distal sensory loss in the lower limbs, axonal neuropathy, and pes cavus. In addition, the sister had gaze-evoked nystagmus, dysarthria, was wheelchair-dependent, and had symmetric cerebellar white matter lesions on MRI. The brother had mild asymptomatic upward gaze paresis, cognitive decline, and cataracts. Two additional unrelated patients had an apparently sporadic disorder with ataxia, axonal neuropathy, dysarthria, and variable eye movement abnormalities. One patient had bilateral cerebellar white matter lesions on MRI. Muscle biopsies of the patients reported by Van Goethem et al. (2004) showed no signs of mitochondrial muscle disease, consistent with the lack of clinical abnormalities. However, some muscle biopsies showed low levels of mtDNA deletions. Extraocular ophthalmoparesis was not a main feature in these patients, only developing later in the disease and often in mild forms. The findings indicated significant phenotypic heterogeneity in patients with recessive mutations in the POLG gene.
Mancuso et al. (2004) reported 2 Italian sibs, a male and a female, with an autosomal recessive neurologic disorder characterized by sensorimotor polyneuropathy, ataxia, and ophthalmoparesis. Onset was in the early twenties with gait disturbances, distal muscle weakness, paresthesias of the lower limbs, and decreased sensation. Bilateral ptosis and ophthalmoplegia were present in both sibs, and the brother also had progressive hearing loss and urinary and erectile dysfunction. Sural nerve biopsy showed loss of myelinated fibers and axonal degeneration without regeneration. Compound heterozygosity for 2 mutations in the POLG gene (174763.0009; 174763.0010) were found in both patients.
### Spinocerebellar Ataxia with Epilepsy
Winterthun et al. (2005) reported 4 unrelated families with a recessively inherited ataxia syndrome characterized by onset of headaches and/or seizures in childhood or adolescence (range 5 to 17 years). By their twenties, all patients developed cerebellar and sensory ataxia, dysarthria, progressive external ophthalmoplegia, and myoclonus. Three patients developed status epilepticus, which was fatal in 1. Several patients showed MRI signal abnormalities deep in the cerebellum and in the thalamus. Muscle biopsies in most patients showed COX-negative fibers, and mtDNA deletions were found in all patients. Affected members from 2 families were homozygous for the same POLG mutation (A467T; 174763.0002), and patients from the remaining 2 families were compound heterozygous for 2 POLG mutations (174763.0013 and 174763.0016). Winterthun et al. (2005) emphasized that migraine, seizures, and myoclonus were especially frequent in this group of patients. Hakonen et al. (2005) referred to this disorder as 'mitochondrial spinocerebellar ataxia-epilepsy syndrome' (MSCAE) or 'mitochondrial recessive ataxia syndrome' (MIRAS).
Bird and Shaw (1978) reported a girl with juvenile-onset progressive myoclonic epilepsy. At age 15 years, she developed an awkward gait, clumsy hand coordination, deteriorating cognition, and nocturnal seizures associated with irregular EEG findings. The disorder was progressive, and she later developed nystagmus, dysarthria, ataxia, fine tremor, loss of distal vibratory sense and reflexes, and pes cavus. Late in the disorder, she developed severe myoclonic jerks and visual impairment, and became bedridden. She died of pneumonia at age 19 years. Neuropathologic examination showed brain atrophy and multifocal lesions in the cerebral cortex characterized by hypertrophic astrocytes, spongy degeneration, and neuronal loss. Fibrillar rod-like structures were seen in the hippocampus. There was widespread loss of Purkinje cells in the cerebellum, neuronal loss and gliosis in the brainstem, including the substantia nigra, and degeneration of the dorsal column of the spinal cord. Family history revealed a younger brother with a similar, but milder, disorder with onset at age 14. He had tremor, mild pes cavus, nystagmus, and peripheral neuropathy. At age 17, he did not have cognitive decline or myoclonic seizures, but he did have EEG abnormalities. Bird and Shaw (1978) noted some phenotypic similarities to the Ramsay-Hunt syndrome (159700) and dentatorubral degeneration (DRPLA; 125370). In the 2 sibs with progressive myoclonic epilepsy originally reported by Bird and Shaw (1978), Tao et al. (2011) identified 2 heterozygous variants on the same allele in the PRICKLE2 gene (R148H and V153I; 608501.0001). An unrelated patient with myoclonic seizures was heterozygous for a different PRICKLE2 variant (V605F; 608501.0002); no further details on this patient were provided. Tao et al. (2011) concluded that PRICKLE signaling is important in seizure prevention, and presented 2 hypotheses: (1) that PRICKLE affects cell polarity and contributes to the development of a functional neural network, and (2) that PRICKLE affects calcium signaling, which may play a role in seizure genesis if disrupted.
By reevaluation of the sibs reported by Bird and Shaw (1978), who were classified as having progressive myoclonic epilepsy-5 (EPM5), Sandford et al. (2016) determined that the 2 heterozygous missense variants in the PRICKLE2 gene identified by Tao et al. (2011) occurred on opposite chromosomes, which would be more consistent with recessive inheritance. Furthermore, in these sibs, Sandford et al. (2016) identified compound heterozygous mutations in the POLG gene (A467T, 174763.0002 on 1 allele, and W748S, 174763.0013 and G497H, 174763.0016 in cis on the other allele). Sandford et al. (2016) concluded that the phenotype resulted from the POLG mutations and not from the PRICKLE2 variants. Sandford et al. (2016) stated that the PRICKLE2 V605F variant reported in an unrelated patient by Tao et al. (2011) appears twice in the ExAC database, and thus is not consistent with its being pathogenic. In a response, Mahajan and Bassuk (2016) maintained that the PRICKLE2 variants identified by Tao et al. (2011) contributed to the phenotype in their patients.
Molecular Genetics
In a patient with SANDO, Van Goethem et al. (2003) identified compound heterozygosity for 2 mutations in the POLG gene (174763.0002; 174763.0005). The finding indicated that SANDO is a variant of autosomal recessive PEO.
In 3 Finnish sibs with SANDO reported by Rantamaki et al. (2001), Van Goethem et al. (2004) identified a homozygous mutation in the POLG gene (W748S; 174763.0013). Another unrelated Finnish patient had the same homozygous mutation. In 3 affected Belgian patients, 2 of whom were sibs, Van Goethem et al. (2004) identified a homozygous mutation in the POLG gene (A467T; 174763.0002). A British patient with sporadic SANDO was compound heterozygous for the W748S and A467T mutations.
Schulte et al. (2009) identified homozygous or compound heterozygous POLG mutations in 9 of 26 patients from 23 families with cerebellar ataxia plus external ophthalmoplegia and/or sensory neuropathy. Two additional patients from this cohort had heterozygous POLG mutations, consistent with PEOA1. Noting that the molecular diagnosis of cerebellar ataxia can be difficult, Schulte et al. (2009) found that for POLG-associated ataxia, the additional presence of ophthalmoplegia had a predictive value of 80%, whereas the presence of neuropathy had a predictive value of 45%.
INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Sensorineural hearing loss \- Vestibular dysfunction Eyes \- Nystagmus \- Upward gaze paresis \- Blepharoptosis \- Ophthalmoparesis, progressive, external \- Cataracts (less common) CARDIOVASCULAR Heart \- Dilated cardiomyopathy (less common) ABDOMEN Gastrointestinal \- Gastroparesis (less common) \- Intestinal pseudo-obstruction (less common) MUSCLE, SOFT TISSUES \- Proximal muscle weakness, mild \- Dysarthria \- Ragged red fibers seen on muscle biopsy \- Increased variation in fiber size \- Necrotic and atrophic fibers with centralized nuclei \- Multiple mitochondrial DNA (mtDNA) deletions (in most cases) \- Decreased activity of cytochrome c oxidase (in most cases) \- Subsarcolemmal accumulations of abnormally shaped mitochondria seen on electron microscopy NEUROLOGIC Central Nervous System \- Gait ataxia, progressive \- Ataxia worsens in the dark \- Positive Romberg sign \- Hyporeflexia \- Areflexia \- Myoclonus (less common) \- Migraine \- Seizures (less common) \- Cognitive impairment, mild \- Bilateral thalamic lesions on MRI \- Cerebellar white matter lesions on MRI \- Atrophic and degenerative changes in the spinal cord Peripheral Nervous System \- Sensory ataxic neuropathy \- Distal sensory impairment to vibration and proprioception \- Sensory axonal neuropathy \- Sural nerve biopsy shows loss of large and small myelinated axons Behavioral Psychiatric Manifestations \- Memory difficulties \- Lack of concentration \- Withdrawal \- Depression LABORATORY ABNORMALITIES \- Mildly increased serum lactate \- Mildly increased serum creatine kinase MISCELLANEOUS \- Young-adult onset (18-30 years) of sensory ataxia \- Later onset of ophthalmoparesis \- Highly variable phenotype MOLECULAR BASIS \- Caused by mutation in the DNA polymerase-gamma gene (POLG, 174763.0002 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS | c1843851 | 1,405 | omim | https://www.omim.org/entry/607459 | 2019-09-22T16:09:15 | {"doid": ["0111276"], "mesh": ["C537583"], "omim": ["607459"], "orphanet": ["70595", "254881", "402082"], "synonyms": ["Alternative titles", "SENSORY ATAXIC NEUROPATHY WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE"], "genereviews": ["NBK26471"]} |
Serositis
SpecialtyRheumatology
Serositis refers to inflammation of the serous tissues of the body, the tissues lining the lungs (pleura), heart (pericardium), and the inner lining of the abdomen (peritoneum) and organs within. It is commonly found with fat wrapping or creeping fat.[1]
## Contents
* 1 Causes
* 2 See also
* 3 References
* 4 External links
## Causes[edit]
Serositis is seen in numerous conditions:[2]
* Lupus erythematosus (SLE), for which it is one of the criteria,
* Rheumatoid arthritis
* Familial Mediterranean fever (FMF)
* Chronic kidney failure
* Juvenile idiopathic arthritis
* Inflammatory bowel disease (especially Crohn's disease)
* Acute appendicitis
* Diffuse cutaneous systemic sclerosis
## See also[edit]
* Hyaloserositis
## References[edit]
1. ^ Bruce G. Wolff; James W. Fleshman; David E. Beck, eds. (2007). "Inflammatory Bowel Disease: Diagnosis and Evaluation". The ASCRS textbook of colon and rectal surgery. Springer. p. 551. ISBN 978-0-387-24846-2. Retrieved 2010-06-15.
2. ^ Causes of Serositis. diagnosispro.com. URL: http://en.diagnosispro.com/differential_diagnosis-for/serositis/11271-154.html Archived 2012-06-29 at Archive.today. Accessed on: June 23, 2008.
## External links[edit]
Classification
D
* ICD-10: K65.8
* MeSH: D012700
This article related to pathology is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Serositis | c0036749 | 1,406 | wikipedia | https://en.wikipedia.org/wiki/Serositis | 2021-01-18T19:07:00 | {"mesh": ["D012700"], "wikidata": ["Q581349"]} |
## Summary
### Clinical characteristics.
Individuals with NGLY1-related congenital disorder of deglycosylation (NGLY1-CDDG) typically display a clinical tetrad of developmental delay / intellectual disability in the mild to profound range, hypo- or alacrima, elevated liver transaminases that may spontaneously resolve in childhood, and a complex hyperkinetic movement disorder that can include choreiform, athetoid, dystonic, myoclonic, action tremor, and dysmetric movements. About half of affected individuals will develop clinical seizures. Other findings may include obstructive and/or central sleep apnea, oral motor defects that affect feeding ability, auditory neuropathy, constipation, scoliosis, and peripheral neuropathy.
### Diagnosis/testing.
The diagnosis of NGLY1-CDDG is established in a proband by the identification of biallelic pathogenic variants in NGLY1 on molecular genetic testing. Typical serum screening tests for congenital disorders of glycosylation (i.e., analysis of serum transferrin glycoforms, N and O glycan profiling) will NOT reliably detect NGLY1-CDDG.
### Management.
Treatment of manifestations: Lubricating eye drops and/or bland ointments for hypolacrima; feeding therapy and/or supplemental tube feeding for those with oromotor deficits and feeding difficulties; adequate access to water and a cool environment (including a cooling vest for those who live in hot climates) for hypohydrosis; vitamin D supplementation for those with vitamin D deficiency; evaluation by a developmental pediatrician and supportive therapies for developmental and cognitive issues; standard treatment for hearing loss, sleep apnea, constipation, scoliosis, and seizure disorder; consideration of referral to a hematologist for abnormal hematologic studies; consideration of referral to a gastroenterologist for elevated liver transaminases.
Surveillance: Annual follow up by a pediatrician/internist, rehabilitation medicine specialist, ophthalmologist, neurologist, and nutritionist is recommended. Periodic evaluation by a developmental pediatrician, gastroenterologist/hepatologist, and audiologist should be considered.
Agents/circumstances to avoid: Hot environment in those with hypohydrosis.
### Genetic counseling.
NGLY1-CDDG is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible if the pathogenic variants in the family are known.
## Diagnosis
Formal diagnostic criteria have not been established.
### Suggestive Findings
NGLY1-related congenital disorder of deglycosylation (NGLY1-CDDG) should be suspected in individuals with the following clinical features and supportive laboratory findings.
Clinical features include:
* Developmental delay / intellectual disability, most often in the severe to profound range
* Hyperkinetic movement disorder
* Hypo- or alacrima
Supportive laboratory findings include elevated ALT and AST during early childhood that spontaneously normalize.
Note: Typical serum screening tests for congenital disorders of glycosylation (i.e., analysis of serum transferrin glycoforms, N and O glycan profiling) will NOT reliably detect NGLY1-CDDG (see Clinical Description, Biochemical).
### Establishing the Diagnosis
The diagnosis of NGLY1-CDDG is established in a proband by the identification of biallelic pathogenic variants in NGLY1 on molecular genetic testing (see Table 1).
#### Recommended Testing
A multigene panel that includes NGLY1 and other genes of interest (see Differential Diagnosis) is recommended (see Table 1). 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.
#### Testing to Consider
Comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if the phenotype alone is insufficient to support gene-targeted testing.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Single-gene testing. Sequence analysis of NGLY1 followed by gene-targeted deletion/duplication analysis (if no pathogenic variant is found) may be considered in a proband with features that are highly suggestive of NGLY1-CDDG. However, because many of the clinical features overlap with those of other intellectual disability / developmental delay syndromes, a multigene panel or comprehensive genomic testing are typically used in lieu of single-gene testing.
### Table 1.
Molecular Genetic Testing Used in NGLY1-Related Congenital Disorder of Deglycosylation
View in own window
Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
NGLY1Sequence analysis 346/46
Gene-targeted deletion/duplication analysis 4Unknown 5
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. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4\.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
5\.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Clinical Characteristics
### Clinical Description
NGLY1-related congenital disorder of deglycosylation (NGLY1-CDDG) is a multisystemic neurodevelopmental disorder in which individuals most commonly exhibit a tetrad of developmental delay / intellectual disability, hyperkinetic movement disorder, hypolacrima, and elevated transaminases during early childhood [Need et al 2012, Enns et al 2014, Heeley & Shinawi 2015, Caglayan et al 2015, Lam et al 2017]. Diagnosis has been achieved at ages ranging from three months to 20 years, mostly through broad molecular testing, such as exome analysis. While most individuals with NGLY1-CDDG survive into early adulthood, with a relatively stable clinical course [Enns et al 2014, Lam et al 2017], death during infancy from unclear causes has been reported. In addition, an affected child died following an infection complicated by uncontrolled seizure activity [Enns et al 2014], and an affected adolescent died from respiratory failure during a respiratory infection [Caglayan et al 2015]. Since so few cases have been identified, understanding of the clinical phenotypic spectrum and natural history continues to evolve.
Growth. In approximately half of individuals with NGLY1-CDDG birth weight is below the tenth centile, while the majority of birth lengths and birth head circumferences are appropriate for gestational age [Lam et al 2017]. Despite a robust appetite, individuals with NGLY1-CDDG develop failure to thrive with weight affected more than length/height. Acquired microcephaly has also been noted in some [Lam et al 2017].
Development. Developmental delay and/or intellectual disability is seen universally in individuals with NGLY1-CDDG. Severity of delay is broad and ranges from individuals having an IQ below average (70s) to individuals with profound intellectual disability. The majority of individuals are nonverbal or can only use single words or phrase speech. Despite lack of verbal communication, they use and benefit from alternate forms of augmentative communication tools, such as switch boards or electronic tablet-based tools. Affected individuals have a consistent developmental profile on the Vineland Adaptive Behavior Scales, Second Edition, in which individuals have relatively strong socialization skills, followed by communication skills, followed by weaknesses in motor skills with fine motor worse than gross motor skills, reflected in low daily living skills [Lam et al 2017].
Neurologic. Approximately half of affected individuals develop clinical seizures. While most develop myoclonic seizures, documented seizure types also include infantile spasms and atonic, tonic, absence, and gelastic seizures. Age of onset ranges from two months to ten years. In some individuals seizures have been intractable, while in others seizures have been controlled with levetiracetam or valproic acid [Lam et al 2017]. Compared to individuals with seizures of different etiologies, those with NGLY1-CDDG have not been more severely affected by any specific antiepileptic medication.
In addition, individuals with NGLY1-CDDG universally exhibit a complex hyperkinetic movement disorder that can include choreiform, athetoid, dystonic, myoclonic, action tremor, and dysmetric movements [Lam et al 2017].
Further findings may include the following:
* CSF laboratory results typically demonstrate:
* Low total protein (from 8 affected individuals, mean protein level was 11 mg/dL, standard error of the mean [SEM] 1) and albumin (from 9 affected individuals, mean 9 mg/dL, SEM 1);
* Low CSF/serum albumin ratios (from 9 affected individuals, mean ratio was 3, SEM 1);
* Low CSF 5-hydroxyindolacetic acid, homovanillic acid, and tetrahydrobiopterin levels, especially in older individuals [Enns et al 2014, Lam et al 2017].
* Brain MRI can show:
* Delayed myelination during early childhood (ages 0-5), but not in older individuals;
* Progressive cerebral and occasional cerebellar atrophy, which correlates with worsening function. In 10/11 affected individuals imaged cerebral volume loss was found; in 4/11 cerebellar volume loss was also seen [Lam et al 2017].
* Brain MRS can be significant for:
* Lower N-acetylaspartylglutamate and N-acetylaspartate levels compared to normal;
* Higher choline and myo-inositol levels, becoming more prominent with increasing age, worsening function, and lower brain volume [Lam et al 2017].
* Nerve conduction studies most often demonstrate an axonal sensorimotor polyneuropathy with additional demyelinative features that are length dependent and appear progressive. Neuropathy has been documented in all nerves tested including the median, ulnar, radial, peroneal, tibial, and sural nerves. Individual testing typically reveals more severe neuropathy in the lower (compared to upper) extremities, with lower amplitudes and slower conduction.
* Needle electromyogram may show neurogenic findings with varying degrees of acute and chronic changes.
* QSWEAT testing can show absent sweat response, more frequently in the lower extremities than in the forearm, suggesting a length-dependent neuropathy [Lam et al 2017].
Ophthalmologic. Most affected individuals, with the exception of the youngest reported person, have evidence of hypo- or alacrima. Corneal findings include neovascularization, pannus formation, and scarring secondary to hypolacrima. Lagophthalmus, ptosis, exotropia and/or esotropia, optic nerve pallor or atrophy, retinal pigmentary changes including pigmentary granularity and pigmentary retinopathy, and cone dystrophy have been observed in individuals with NGLY1-CDDG [Lam et al 2017].
Audiologic. Tympanometry and behavioral hearing thresholds were normal in the individuals who could tolerate and cooperate with these exams. There is a consistent profile on auditory brain stem evoked response showing dyssynchronous and/or absent transmission through the auditory brain stem and/or eighth nerve in most individuals that appears to worsen with age [Lam et al 2017].
Cardiac. Echocardiogram is normal, and electrocardiogram shows heart rates in the low 100s with a minority of affected individuals with a QTcB >440 ms, but a normal QTcF.
Note: The QTcB is the standard clinical correction of the QT interval using Bazett's formula, calculated as QT interval divided by square root of the RR interval. The QtcF is the alternative correction based on Fridericia's formula, which is defined as the QT interval divided by the cube root of the RR interval. The QTcB is believed to overestimate the QT prolongation at higher heart rates, and the QTcF may underestimate the QT prolongation at slower heart rates [FDA 2005].
Sleep. Approximately half of tested individuals with NGLY1-CDDG have also been documented to have mild-to-profound obstructive and/or central sleep apnea [Lam et al 2017].
Feeding. Oral motor defects, including premature spillage, pharyngeal swallow response delays, poor oral bolus formation, weakness of the lips and tongue, dystonic movements of the tongue, and persistent oral reflexes of suckling and suck/swallow are seen in the majority of affected individuals. However, these findings typically do not prohibit oral feeding in the majority of individuals. Enteral feeds have been helpful with nutritional management, although this decision is made on a case-by-case basis [Lam et al 2017].
Gastrointestinal. The majority of affected individuals have some degree of constipation [Enns et al 2014].
Transaminases (AST and ALT):
* Are typically elevated and range from just slightly above the upper limit of normal to >1,000 U/L in the first two years of life;
* Usually normalize by age four years without any specific intervention.
Note: In the few liver biopsies performed, findings have been normal or consistent with microvesicular steatosis, ductular proliferation, focal microvacuolation, and micronodular cirrhosis with bands of fibrosis with regenerative nodules.
Total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels are low in about one third of tested individuals, but particle numbers and sizes of HDL, LDL, and VLDL are normal [Lam et al 2017].
Abdominal ultrasound findings can include splenomegaly, steatosis, coarse or inhomogeneous liver texture, and hepatomegaly.
Fibroscan scores show evidence of liver fibrosis in a few affected individuals [Lam et al 2017].
Hematologic. Coagulation studies in some individuals can be significant for low protein C, factor II, factor IX, factor XI, and fibrinogen levels. However, significant bleeding or clotting episodes have not yet been reported. Complete blood count is generally unremarkable [Lam et al 2017].
Immunologic. Affected individuals typically are reported to have fewer infections than their peers, with the exception of a few individuals with recurrent, more severe, respiratory infections. Antibody titers indicate that individuals with NGLY1-CDDG appear to respond typically to vaccinations, with the exception of rubella and rubeola vaccinations for which titers exhibited out-of-range elevations or were negative (for rubeola) in a majority of tested individuals [Lam et al 2017].
Musculoskeletal findings include delayed bone age despite a normal endocrine evaluation, low bone density in several individuals with a history of recurrent fractures, joint hypermobility, coxa valga, scoliosis, dislocations or subluxations of the hip or shoulder joints, and sclerosis of the phalanges or tarsal bones [Lam et al 2017]. These findings were present even in affected individuals who were ambulatory.
Biochemical findings include the following:
* Carbohydrate-deficient transferrin analysis in blood may show small elevations in mono- and a-oligosaccharides and tri-sialo-oligosaccharides, but not to the levels typically seen in PMM2-CDG.
* O-glycan profiling is normal.
* Urine quantitative mucopolysaccharides can be elevated, but with a normal pattern.
* Free and total carnitine, uric acid, white blood cell CoQ10, plasma amino acids, and urine organic acids are essentially normal.
* Lactate was normal in the majority of affected individuals, but can be mild to moderately elevated (~5 mmol/L) especially in younger affected individuals.
* Lactate to pyruvate ratio is typically normal.
* Urine amino acids can show generalized aminoaciduria, especially in older individuals [Lam et al 2017].
* On liver biopsy, abnormal cristae and mitochondrial proliferation was noted in one individual, while depleted cristae and mitochondrial DNA depletion was seen in another individual [Kong et al 2018].
* On quadriceps muscle biopsy mitochondrial proliferation and mitochondrial DNA proliferation was noted in one affected individual [Kong et al 2018].
### Genotype-Phenotype Correlations
The most common pathogenic variant is c.1201A>T (p.Arg401Ter), accounting for approximately one third of pathogenic alleles. Affected individuals harboring at least one copy of this pathogenic variant tend to have a more severe clinical course with higher scores on the Nijmegen Pediatric CDG Severity scale [Lam et al 2017].
A sib pair with the cryptic pathogenic c.930C>T splice site variant (predicted as a silent p.Gly310=) and a p.Gln208Ter nonsense variant exhibited relatively mild impairment in all domains [Lam et al 2017].
### Nomenclature
NGLY1-CDDG was previously referred to as congenital disorder of glycosylation type Iv (CDG-Iv).
NGLY1-CDDG is the first primary defect of N-linked deglycosylation shown to cause human disease. Following the established nomenclature for congenital disorders of glycosylation, where disorders are formally named with the involved gene (not italicized) followed by -CDG (e.g., PMM2-CDG) [Jaeken et al 2009], the authors propose that this disorder and future disorders of N-linked deglycosylation follow a similar format, except using CDDG instead of CDG.
### Prevalence
A total of 18 individuals from 14 families have been described in the literature [Need et al 2012, Enns et al 2014, Caglayan et al 2015, Heeley & Shinawi 2015, Bosch et al 2016, Lam et al 2017]. However, according to a database maintained by NGLY1.org, biallelic pathogenic variants in NGLY1 coupled with suggestive clinical phenotype have been identified in 46 individuals worldwide. Most of the reported affected individuals have been of northern European background, but this is likely due to ascertainment bias rather than a true increased prevalence in that population. Although not yet reported in the literature, individuals with African and non-white Hispanic background have been confirmed to have NGLY1-CDDG [Lam & Wolfe, personal observation].
## Differential Diagnosis
The tetrad of developmental delay / cognitive impairment, hyperkinetic movement disorder, hypo/alacrima, and elevated transaminases during early childhood is pathognomonic of NGLY1-CDDG [Need et al 2012, Enns et al 2014, Caglayan et al 2015, Heeley & Shinawi 2015, Lam et al 2017]. However, other multisystemic disorders and conditions that feature variable neurologic phenotypes, including seizures, chorea, athetosis, dystonia, myoclonus, tremors, ataxia, and dysmetria, are in the differential diagnosis.
### Table 2.
Disorders to Consider in the Differential Diagnosis of NGLY1-Related Congenital Disorder of Deglycosylation
View in own window
DisorderGene(s)MOIClinical Features
OverlappingDistinguishing
Congenital disorders of glycosylation (CDGs) (see Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview)See
footnote 1AR
XL
* Intrauterine growth restriction
* DD / cognitive impairment
* Neurologic dysfunction
* Liver disease 2
In persons w/NGLY1-CDDG:
* No apparent lipodystrophy or significant cardiac manifestations 3
* Nonspecific brain imaging findings, but usually relatively mild abnormalities 4
Mitochondrial disorders>250
genes 5AR
AD
Maternal
* Multisystem involvement
* Pigmentary retinopathy 6
In some w/NGLY1-CDDG:
* Mild biochemical evidence of mt impairment, especially transient or mildly ↑ blood lactate levels
* Nonspecific electron transport chain abnormalities in skin fibroblasts, muscle, & liver, & mildly abnormal mt morphology on electron microscopy 3, 6
Persons w/NGLY1-CDDG:
* Do not typically have episodes of metabolic decompensation or clinical presentations assoc w/classic mt disorder phenotypes.
* Have normal CSF lactate levels. 6
Neurotransmitter disorders (involving metabolic pathways related to monoamine & amino acid metabolism; e.g., GTPCH1-deficient dopa-responsive dystonia, tyrosine hydroxylase deficiency, aromatic L-amino acid decarboxylase deficiency [OMIM 608643]) 7See
footnote 8.See
footnote 8.On CSF analysis:
* Various combinations of abnormal levels of HVA, 5-HIAA, & biopterin metabolites in neurotransmitter disorders 9, 10
* In some cases, ↓ HVA, 5-HIAA, & tetrahydrobiopterin in NGLY1-CDDG; such findings appear to correlate w/degree of brain atrophy. 11
In persons w/NGLY1-CDDG:
* Oculogyric crises not reported
* No diurnal fluctuation of symptoms
* Peripheral neuropathy common
In persons w/neurotransmitter disorders:
* Alacrima/hypolacrima & liver dysfunction not typically seen
In GTP cyclohydrolase 1-deficient dopa-responsive dystonia:
* Intellectual & cognitive function typically normal
Secondary abnormalities in neurotransmitter metabolitesSee
footnote 8.See
footnote 8.
* ↓ HVA may be present in hypoxic-ischemic encephalopathy, CNS infections, & some genetic disorders. 10
* ↓ HVA & 5-HIAA may occur in hypoxic-ischemic encephalopathy, congenital infections, & some genetic disorders. 12
MECP2-related disordersMECP2XLCognitive impairment, seizures, ataxia, tremors, & acquired microcephaly:
* Are common features in MECP2-related disorders;
* May also be seen in NGLY1-CDDG.
* MECP2-related disorders are classically assoc w/a period of normal development, followed by stagnation & relatively rapid regression in females.
* Persons w/NGLY1-CDDG have neither a period of normal development nor such rapid developmental regression.
Creatine deficiency syndromesGAMT
GATM
SLC6A8AR
XLLike NGLY1-CDDG, disorders of creatine synthesis may be assoc w/DD & cognitive impairment, movement disorders, seizures, & behavior abnormalities.Alacrima & liver disease are not seen in disorders of creatine synthesis.
Triple-A syndrome (OMIM 231550)AAASAR
* Alacrima
* Mild dementia
* Cerebellar ataxia 13
* Triple A syndrome does not feature choreoathetosis.
* Adrenal insufficiency is not a prominent feature of NGLY1-CDDG.
* Persons with Triple A syndrome may have anisocoria.
Alacrima, achalasia, and mental retardation syndrome (AAMR) (OMIM 615510)GMPPAAR
* Alacrima
* ID
* Variable hypotonia
* Ataxia
* Spasticity
* Hearing impairment 14
AAMR:
* Does not feature choreoathetosis.
* May feature anisocoria.
Hereditary sensory and autonomic neuropathy (HSAN)See
footnote
15.See
footnote
16.Alacrima may also be present in some forms of HSAN incl familial dysautonomia (FD) & HSAN type VI (OMIM 614653) 15
* FD & HSAN type VI do not feature choreoathetosis.
* Persons w/HSAN usually have normal cognitive function.
5-HIAA = 5-hydroxyindoleacetic acid; AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; DD = developmental delay; HVA = homovanillic acid; ID = intellectual disability; MOI = mode of inheritance; mt = mitochondrial; XL = X-linked
1\.
See OMIM Phenotypic Series: Congenital disorders of glycosylation, type I and Congenital disorders of glycosylation, type II to view genes associated with these phenotypes.
2\.
Freeze et al [2012]
3\.
Enns et al [2014]
4\.
Some individuals with NGLY1-CDDG have cerebral and cerebellar atrophy, but the cerebellar atrophy is not typically as severe as in the CDGs [Lam et al 2017].
5\.
Alston et al [2017]
6\.
Lam et al [2017], Kong et al [2018]
7\.
Neurotransmitter disorders are associated with a wide spectrum of neurologic abnormalities including seizures, choreoathetosis, dystonia, hypotonia, oculogyric crises, and psychiatric disease [Pons 2009, Marecos et al 2014, Ng et al 2015].
8\.
For more information, see hyperlinked GeneReviews, OMIM entries, and/or citations.
9\.
Pons [2009], Ng et al [2015]
10\.
Genetic disorders that may be associated with low HVA include mitochondrial disorders, glycine encephalopathy, Aicardi-Goutières syndrome, Rett syndrome (see MECP2 Disorders), myotonic dystrophy type 1, and vanishing white matter disease (see Childhood Ataxia with Central Nervous System Hypomyelination/Vanishing White Matter).
11\.
Enns et al [2014], Lam et al [2017]
12\.
Genetic disorders that may be associated with low HVA and 5-HIAA include mitochondrial disease, Niemann-Pick disease type C, Alexander disease, glycine encephalopathy, pontocerebellar hypoplasia type 2 (see TSEN54-Related Pontocerebellar Hypoplasia), Rett syndrome (see MECP2 Disorders), Smith-Lemli-Opitz syndrome, urea cycle disorders [Molero-Luis et al 2013, Ng et al 2015].
13\.
Tullio-Pelet et al [2000], Handschug et al [2001]
14\.
Koehler et al [2013]
15\.
Anderson et al [2001], Edvardson et al [2012]
16\.
See OMIM Phenotypic Series: Hereditary sensory and autonomic neuropathy to view genes and modes of inheritance associated with these phenotypes.
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with NGLY1-related congenital disorder of deglycosylation (NGLY1-CDDG), the evaluations summarized in Table 3 (if not performed as part of the initial evaluation that led to diagnosis) are recommended.
### Table 3.
Recommended Evaluations Following Initial Diagnosis of NGLY1-CDDG
View in own window
System/ConcernEvaluationComment
EyesOphthalmologic eval for hypolacrima & retinal disease
ENT/MouthAuditory brain stem evoked potentials
RespiratorySleep studyIf review of systems reveals snoring or symptoms concerning for sleep apnea
GastrointestinalNutrition eval to optimize intakeFeeding & swallowing eval if indicated
* Transaminase levels
* Eval for constipation
Consultation w/gastroenterologist or hepatologist as needed
MusculoskeletalRadiologic & orthopedic assessment incl DEXA scanTo evaluate bone health & help manage scoliosis, coxa valga, &/or contractures
SkinQSWEAT analysis to evaluate for hypohydrosis
Neurologic
* Neurologic & neurodevelopmental eval of cognitive abilities
* Nerve conduction study
EndocrinologicVitamin D levelTo assess for vitamin D deficiency
Hematologic/
LymphaticProtein C; factor II, IX, XI; fibrinogen levelsConsultation w/hematologist if abnormal
Miscellaneous/
OtherSpeech & language evalReferral to speech therapist if indicated
Rehabilitation team evalReferral for OT &/or PT if indicated
Consultation w/clinical geneticist &/or genetic counselor
OT = occupational therapy; PT = physical therapy
### Treatment of Manifestations
Treatment and quality of life can be optimized when care is provided by specialists in biochemical genetics, neurology, developmental pediatrics, ophthalmology, gastroenterology, orthopedics, and rehabilitation medicine who are knowledgeable about NGLY1-CDDG.
### Table 4.
Treatment of Manifestations in Individuals with NGLY1-CDDG
View in own window
Manifestation/ConcernTreatmentConsiderations/Other
HypolacrimaLubricating eye drops &/or bland ointments
Hearing lossStandard treatmentSee Hereditary Hearing Loss and Deafness Overview.
Sleep apneaRoutine management
Oromotor deficits leading to feeding problemsFeeding therapy; supplemental tube feeding if indicatedReferral to gastroenterologist
ConstipationStandard managementReferral to gastroenterologist if refractory to typical medical management
Abnormal hematologic &/or gastroenterologic labsFollow up w/hematologist & gastroenterologist
Scoliosis & osteopeniaRoutine management
HypohydrosisAdequate access to water & cool environment (AC, wet T-shirt, &/or spray bottle of water)Cooling vests may be helpful in hot climates.
SeizuresStandard treatmentReferral to neurologist for those w/refractory or severe seizures
Vitamin D deficiencySupplemental vitamin D
Any condition requiring surgical interventionSurgery best performed in centers w/surgeons & anesthesiologists experienced in care of those w/metabolic disorders & special needs
AC = air conditioning
#### Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.
Ages 5-21 years
* In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
* Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
* Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
* Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
#### Motor Dysfunction
Gross motor dysfunction
* Physical therapy is recommended to maximize mobility.
* Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
* For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox®, anti-parkinsonian medications, or orthopedic procedures.
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.
Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended for affected individuals who have difficulty feeding due to poor oral motor control.
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.
### Surveillance
In the absence of formal surveillance guidelines, the authors recommend the following:
* Annual follow up by:
* Pediatrician or internist
* Physical medicine and rehabilitation medicine
* Ophthalmology
* Neurology
* Nutrition
* Follow up as recommended by:
* Developmental pediatrician
* Gastroenterologist/hepatologist
* Audiologist
* Clinical or biochemical geneticist
### Agents/Circumstances to Avoid
Hot environment should be avoided by those with hypohydrosis.
### Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Therapies Under Investigation
No FDA-approved treatments for NGLY1-CDDG exist.
Enzyme replacement therapy is currently being evaluated in the pre-clinical arena.
Pre-clinical screens for Endo-Beta-N-Acetylglucosaminidase (ENGase) inhibitors are underway [Bi et al 2017].
Large-scale compound screens on model organisms and cell lines are being evaluated.
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| NGLY1-Related Congenital Disorder of Deglycosylation | c3808991 | 1,407 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK481554/ | 2021-01-18T21:09:11 | {"mesh": ["C000626124"], "synonyms": ["NGLY1-CDDG", "NGLY1 Deficiency", "NGLY1-Related Disorder"]} |
Pyridoxal 5'-phosphate-dependent epilepsy is a condition that involves seizures beginning soon after birth or, in some cases, before birth. The seizures typically involve irregular involuntary muscle contractions (myoclonus), abnormal eye movements, and convulsions. Most babies with this condition are born prematurely and may have a temporary, potentially toxic, increase in lactic acid in the blood (lactic acidosis). Additionally, some infants have a slow heart rate and a lack of oxygen during delivery (fetal distress).
Anticonvulsant drugs, which are usually given to control seizures, are ineffective in people with pyridoxal 5'-phosphate-dependent epilepsy. Instead, individuals with this type of epilepsy are medically treated with large daily doses of pyridoxal 5'-phosphate (a form of vitamin B6). If left untreated, people with this condition can develop severe brain dysfunction (encephalopathy), which can lead to death. Even though seizures can be controlled with pyridoxal 5'-phosphate, neurological problems such as developmental delay and learning disorders may still occur.
## Frequency
Pyridoxal 5'-phosphate-dependent epilepsy is a rare condition; approximately 14 cases have been described in the scientific literature.
## Causes
Mutations in the PNPO gene cause pyridoxal 5'-phosphate-dependent epilepsy. The PNPO gene provides instructions for producing an enzyme called pyridoxine 5'-phosphate oxidase. This enzyme is involved in the conversion (metabolism) of vitamin B6 derived from food (in the form of pyridoxine and pyridoxamine) to the active form of vitamin B6 called pyridoxal 5'-phosphate (PLP). PLP is necessary for many processes in the body including protein metabolism and the production of chemicals that transmit signals in the brain (neurotransmitters).
PNPO gene mutations result in a pyridoxine 5'-phosphate oxidase enzyme that is unable to metabolize pyridoxine and pyridoxamine, leading to a deficiency of PLP. A shortage of PLP can disrupt the function of many other proteins and enzymes that need PLP in order to be effective. It is not clear how the lack of PLP affects the brain and leads to the seizures that are characteristic of pyridoxal 5'-phosphate-dependent epilepsy.
### Learn more about the gene associated with Pyridoxal 5'-phosphate-dependent epilepsy
* PNPO
## 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
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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
| Pyridoxal 5'-phosphate-dependent epilepsy | c1864723 | 1,408 | medlineplus | https://medlineplus.gov/genetics/condition/pyridoxal-5-phosphate-dependent-epilepsy/ | 2021-01-27T08:24:33 | {"gard": ["10730"], "mesh": ["C566449"], "omim": ["610090"], "synonyms": []} |
A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome (chr2:59.0-61.5 Mb; involving chromosome 2p16.1-p15).
Description
Chromosome 2p16.1-p15 deletion syndrome is a neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, and variable but distinctive dysmorphic features, including microcephaly, bitemporal narrowing, smooth and long philtrum, hypertelorism, downslanting palpebral fissures, broad nasal root, thin upper lip, and high palate. Many patients have behavioral disorders, including autistic features, as well as structural brain abnormalities, such as pachygyria or hypoplastic corpus callosum. Those with deletions including the BCL11A gene (606557) also have persistence of fetal hemoglobin (HbF), which is asymptomatic and does not affected hematologic parameters or susceptibility to infection (summary by Funnell et al., 2015).
Point mutation in the BCL11A gene causes intellectual developmental disorder with persistence of fetal hemoglobin (617101), which shows overlapping features.
See also fetal hemoglobin quantitative trait locus-5 (HBFQTL5; 142335).
Clinical Features
Rajcan-Separovic et al. (2007) reported 2 unrelated children, a boy and a girl, with a de novo interstitial microdeletion at chromosome 2p16.1-p15 associated with a similar phenotype characterized by mental retardation, autistic features, and dysmorphic features. Dysmorphic craniofacial features included progressive microcephaly, flat occiput, bitemporal narrowing, widened inner canthal distance, small palpebral fissures, ptosis, downslanting palpebral fissures, long and straight eyelashes, broad and high nasal root, wide and prominent nasal tip, elongated smooth philtrum, high palate, large ears, and everted lower lips. Additional features included optic nerve hypoplasia, hydronephrosis, digital camptodactyly, widely spaced nipples, and lower limb spasticity. Brain MRI showed cortical dysplasia/pachygyria.
De Leeuw et al. (2008) reported an additional male patient with 2p16.1-p15 deletion syndrome. He had delayed psychomotor development, mental retardation, optic nerve hypoplasia, a narrow receding forehead, widened inner canthal distance, short and downslanting palpebral fissures, high nasal bridge, low-set large ears, and small mouth with high palate. The thorax was broad with increased internipple distance. Renal ultrasound showed multiple cysts.
Chabchoub et al. (2008) reported a 16-year-old Belgian boy with 2p16.1-p15 deletion syndrome. He had mild mental retardation without autistic features. Dysmorphic features included high forehead, downslanting palpebral fissures, large ears, broad nasal root with prominent tip, and a smooth upper vermilion border of the mouth with everted upper lip. Other features included pectus excavatum, small testes, arachnodactyly, and mild kyphoscoliosis. He also had multiple cardiac valvular defects.
Liang et al. (2009) reported a 4.5-year-old Japanese girl with 2p16.1-p15 microdeletion syndrome. She showed intrauterine and postnatal growth retardation and severely delayed psychomotor development with an IQ of about 20. Short stature and microcephaly were noted. Dysmorphic facial features included hypertelorism, epicanthal folds, broad nasal bridge, retrognathia, and low-set ears. She had generalized hypotonia, spasticity, attention deficit, metatarsus adductovarus, and bilateral optic atrophy. Brain imaging showed no abnormalities. Comparative genomic hybridization array analysis showed a de novo heterozygous 3.2-Mb deletion at chromosome 2p16.1-p15 on the paternally-derived chromosome.
Felix et al. (2010) reported a 4-year-old girl with a de novo heterozygous 3.35-Mb deletion at 2p16.1-p15 on the paternal chromosome. She had pre- and postnatal growth deficiency, microcephaly, and developmental delay. Dysmorphic features included micrognathia, high and broad nasal root, smooth philtrum, long eyelashes, high palate, and camptodactyly. She also had gastroesophageal reflux and 2 febrile seizures. Brain imaging was normal.
Prontera et al. (2011) and Piccione et al. (2012) independently reported a total of 3 children with developmental delay and dysmorphic features associated with variable de novo heterozygous deletions of 2p16.1-p15. Each patient also had additional copy number variations of other chromosomes that may have contributed to the phenotype. Dysmorphic features were variable, but included flat facial profile, trigonocephaly, bitemporal narrowing, smooth and long philtrum, hypertelorism, strabismus, epicanthal folds, large, low-set, or posteriorly rotated ears, thin upper lip, everted lower lip, and high palate. Other features included short stature, hypotonia, and hypogonadism. One patient had cerebral atrophy and hypoplasia of the corpus callosum on brain imaging. Funnell et al. (2015) found that the 3 patients reported by Prontera et al. (2011) and Piccione et al. (2012) had increased fetal hemoglobin levels (7.3%, 4.8%, and 6.2%, respectively) compared to controls, although additional hematologic parameters in these patients were largely normal.
Basak et al. (2015) reported 3 unrelated children with 3 different de novo heterozygous deletions at 2p16.1-p15 (440 kb, 1 Mb, and 874 kb, respectively) that commonly deleted only the BCL11A gene. All children had a neurodevelopmental disorder characterized by moderate to severe developmental delay, autism spectrum disorder, hypotonia, and dysmorphic facial features. Two had microcephaly and normal brain structure, whereas the third had a normal head circumference with a posterior fossa malformation. In addition, all 3 patients had persistence of fetal hemoglobin (HbF), which was elevated at 23.8%, 16.1%, and 29.7%, respectively. None had changes in any hematologic parameters or evidence of impaired immune function. Mononuclear cells from 2 of the patients showed haploinsufficiency for BCL11A and increased mRNA levels of the HbF-encoding genes HBG1 (142200) and HBG2 (142250) compared to controls. The findings implicated BCL11A as a key neurodevelopmental gene in addition to its role in silencing HbF. Moreover, Basak et al. (2015) concluded that the findings demonstrated that haploinsufficiency of BCL11A may be sufficient to allow persistence of HbF at a high enough level to ameliorate beta-thalassemia (613985) or sickle cell disease (603903).
Balci et al. (2015) reported a 3-year-old girl with moderate developmental delay and dysmorphic features associated with a heterozygous de novo 0.875-Mb deletion at 2p16.1 including the BCL11A gene. In addition to characteristic dysmorphic features observed with this disorder, she also had brain malformations, including cerebral atrophy, enlarged ventricles, and hypoplasia of the corpus callosum, amygdala, pons, and cerebellum.
Mapping
Rajcan-Separovic et al. (2007) found that the 2p16.1-p15 deletion in 2 affected individuals measured 4.5 Mb and 5.7 Mb, respectively. In another patient, De Leeuw et al. (2008) narrowed the candidate region to a 3.9-Mb interval within the deletion regions described by Rajcan-Separovic et al. (2007).
In a patient with dysmorphic facial features and mild mental retardation, Chabchoub et al. (2008) identified a 570-kb deletion at chromosome 2p15. Compared with previously reported cases, the authors concluded that a candidate gene(s) in the 570-kb region was most likely responsible for the facial dysmorphism features and proposed a role for the VRK2 gene (602169) on chromosome 2p16.1 for autism and neuroectodermal developmental disorders in the patients of Rajcan-Separovic et al. (2007).
In an affected girl, Felix et al. (2010) was able to refine the critical region for the 2p16.1-p15 deletion syndrome to a 3.35-Mb region (chr2:59.13-62.48) that did not include the VRK2 gene. The girl had facial dysmorphism and developmental delay, but MRI did not show brain abnormalities, such as cortical dysplasia.
Cytogenetics
Peter et al. (2014) reported an 11-year-old boy with mild intellectual disability and a severe speech sound disorder associated with a de novo heterozygous 203-kb deletion at 2p16.1 including only the BCL11A gene (606557). It was the smallest deletion of this region yet reported. He had some features associated with larger deletions of 2p16-p15, including abnormal muscle tone and delayed motor development, but lacked other significant features, such as craniofacial or skeletal anomalies and optic nerve impairment. His language difficulties were significant and included poor expressive speech, dysarthria in the orofacial region, and childhood apraxia of speech. Peter et al. (2014) suggested a specific role for the BCL11A gene in language development, and noted that this gene falls within a locus for susceptibility to dyslexia (DYX3; 604254) on chromosome 2p16-p15. The patient also had a 343-kb duplication on 2q13 and an 80-kb duplication on 6p25.3.
Molecular Genetics
Funnell et al. (2015) concluded that increased HbF in patients with 2p16.1-p15 deletion syndrome is due to haploinsufficiency of the BCL11A gene. Erythroblasts from these patients had significantly reduced BCL11A transcript levels. Funnell et al. (2015) noted that the patient reported by Prontera et al. (2011) had a 3.5-Mb deletion that was downstream of the BCL11A gene; however, BCL11A expression was significantly decreased in patient cells, suggesting that there are downstream regulatory elements within the deleted region that are required for full gene expression.
INHERITANCE \- Isolated cases GROWTH Height \- Short stature HEAD & NECK Head \- Microcephaly \- Brachycephaly Face \- Receding, short forehead \- Bitemporal narrowing \- Smooth, long philtrum \- Retrognathia Ears \- Large ears \- Low-set ears \- Posteriorly rotated ears \- Hearing loss, sensorineural (reported in 1 patient) Eyes \- Telecanthus \- Widened inner canthal distance \- Short palpebral fissures \- Downslanting palpebral fissures \- Ptosis \- Epicanthal folds \- Strabismus \- Long, straight eyelashes \- Optic nerve hypoplasia Nose \- Broad nasal root \- High nasal root \- Depressed nasal root \- Prominent nasal tip Mouth \- Smooth upper vermilion border \- Thin upper lip \- Everted lower lip \- High narrow palate CARDIOVASCULAR Heart \- Valvular defects (reported in 1 patient) RESPIRATORY \- Frequent upper respiratory infections Larynx \- Laryngomalacia (reported in 1 patient) CHEST Ribs Sternum Clavicles & Scapulae \- Pectus excavatum Breasts \- Widely spaced nipples ABDOMEN Gastrointestinal \- Feeding difficulties GENITOURINARY External Genitalia (Male) \- Small testes \- Micropenis \- Cryptorchidism Kidneys \- Hydronephrosis SKELETAL Spine \- Kyphoscoliosis (reported in 1 patient) Hands \- Camptodactyly \- Arachnodactyly Feet \- Metatarsus adductus \- Calcaneovalgus SKIN, NAILS, & HAIR Hair \- Long, straight eyelashes MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Mental retardation \- Spasticity of the lower limbs \- Cortical dysplasia \- Pachygyria \- Cerebral atrophy \- Enlarged ventricles \- Hypoplasia of the corpus callosum \- Hypoplasia of the cerebellum \- Hypoplasia of the pons Behavioral Psychiatric Manifestations \- Autistic features \- Attention deficit VOICE \- Nasal speech ENDOCRINE FEATURES \- Hypogonadism HEMATOLOGY \- Elevated fetal hemoglobin (HbF) (in patients with deletion of the BCL11A gene) MISCELLANEOUS \- Onset at birth or early infancy \- Brain malformations are variable MOLECULAR BASIS \- A contiguous gene deletion syndrome caused by a deletion (3.9 Mb) of chromosome 2p16.1-p15 ▲ 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
| CHROMOSOME 2p16.1-p15 DELETION SYNDROME | c2675875 | 1,409 | omim | https://www.omim.org/entry/612513 | 2019-09-22T16:01:29 | {"doid": ["0060415"], "mesh": ["C567289"], "omim": ["612513"], "orphanet": ["261349"]} |
A number sign (#) is used with this entry because mevalonic aciduria (MEVA) is caused by homozygous or compound heterozygous mutation in the mevalonate kinase gene (MVK; 251170) on chromosome 12q24.
Description
Mevalonic aciduria, the first recognized defect in the biosynthesis of cholesterol and isoprenoids, is a consequence of a deficiency of mevalonate kinase (ATP:mevalonate 5-phosphotransferase; EC 2.7.1.36). Mevalonic acid accumulates because of failure of conversion to 5-phosphomevalonic acid, which is catalyzed by mevalonate kinase. Mevalonic acid is synthesized from 3-hydroxy-3-methylglutaryl-CoA, a reaction catalyzed by HMG-CoA reductase (142910).
Mevalonic aciduria is characterized by dysmorphology, psychomotor retardation, progressive cerebellar ataxia, and recurrent febrile crises, usually manifesting in early infancy, accompanied by hepatosplenomegaly, lymphadenopathy, arthralgia, and skin rash. The febrile crises are similar to those observed in hyperimmunoglobulinemia D and to periodic fever syndrome (HIDS; 260920), which is also caused by mutation in the MVK gene (summary by Prietsch et al., 2003).
Clinical Features
Hoffmann et al. (1986) delineated this inborn error of metabolism in a boy who came to their attention at age 2 years and in an unborn female sib. The boy presented with severe failure to thrive, developmental delay, anemia, hepatosplenomegaly, central cataracts, and dysmorphic facies. In the urine, they found massive quantities of mevalonic acid, a precursor of cholesterol and nonsterol isoprenes: 46,000 and 56,200 mmol per mole of creatinine, as compared with 0.2-0.3 mmol per mole in normal children. In plasma, the concentration of mevalonic acid was about 9,000 times normal. The activity of mevalonate kinase, the enzyme that catalyzes the first step in mevalonate metabolism, was severely deficient in the patient's fibroblasts, lymphocytes, and lymphoblasts, and was about half-normal in each parent. The proband died at 24.5 months. In the mother's next pregnancy, the concentration of mevalonic acid was found to be very high in the amniotic fluid. A therapeutic abortion was performed at 19 weeks. The fetus was female and seemingly normal. Defects in synthetic pathways such as this are fewer than defects in catabolic pathways. As in the porphyrias and in glutathione synthetase deficiency (266130), feedback inhibition is lacking because the final product is underproduced. This leads to overproduction and massive urinary excretion of intermediates such as delta-aminolevulinic acid and porphyrins in porphyrias and 5-oxoproline in glutathione synthetase deficiency. The failure to thrive may have been due to loss of almost 9 grams daily of mevalonic acid in the urine.
Berger et al. (1985) described a milder case of mevalonic aciduria, with cerebellar ataxia. In the family first reported by Hoffmann et al. (1986), Gibson et al. (1987) found enzyme levels indicating heterozygosity in 1 sib of the proband, both parents, and 3 other relatives of each of the parents. Gibson et al. (1988) documented mevalonate kinase deficiency in an 8-year-old child who presented with cerebellar ataxia, hypotonia, and mevalonic aciduria. Heterozygotes showed intermediate levels of the enzyme in cultured skin fibroblasts and transformed lymphoblasts. Mancini et al. (1993) described the disorder in 2 girls and 1 boy, the offspring of parents related as first cousins once removed. All 3 showed failure to thrive, susceptibility to infections, hepatosplenomegaly, cataract, and psychomotor retardation. Dysmorphic features included microcephaly, triangular face, and hypoplastic alae nasi. Urinary organic acid analysis by gas chromatography/mass spectrometry invariably demonstrated a high urinary excretion of mevalonic acid. Mevalonate kinase activity assayed in fibroblasts was very low.
To establish the clinical and biochemical phenotype of mevalonic aciduria, a consortium of authors (Hoffmann et al., 1993) assembled their experience with 11 patients, including attempts at therapeutic intervention. Varying degrees of severity of clinical illness were observed despite uniform, virtual absence of residual activity of mevalonate kinase. The most severely affected patients had profound developmental delay, dysmorphic features, cataracts, hepatosplenomegaly, lymphadenopathy, and anemia, as well as diarrhea and malabsorption, and died in infancy. Less severely affected patients had psychomotor retardation, hypotonia, myopathy, and ataxia. All patients had recurrent crises in which there was fever, lymphadenopathy, increase in size of liver and spleen, arthralgia, edema, and a morbilliform rash. Neuroimaging studies revealed selective and progressive atrophy of the cerebellum. Mevalonic acid concentrations were grossly elevated in body fluids in all patients. Concentrations of plasma cholesterol were normal or only slightly reduced. Concentrations of ubiquinone-10 in plasma were found to be decreased in most patients. Abnormalities such as hypoglycemia, metabolic acidosis, or lactic acidemia, the usual concomitants of disorders of organic acid metabolism, were conspicuously absent.
Hinson et al. (1998) reported 2 additional patients with MVK deficiency. Both patients presented in infancy, one with severe normocytic anemia, petechiae, cutaneous extramedullary hematopoiesis, hepatosplenomegaly, leukocytosis, and recurrent febrile episodes, and the other with minor anomalies, hepatosplenomegaly, anemia, thrombocytopenia, recurrent febrile crises, and facial rashes. Neither patient had significant neurologic abnormalities. The authors noted that MVK deficiency can mimic congenital infections, myelodysplastic syndromes, or chronic leukemia, and emphasized the importance of considering this diagnosis in patients with hematologic abnormalities.
Prietsch et al. (2003) reported a 15-year-old girl and her 14-year-old brother with mevalonic aciduria, previously described by Hoffmann et al. (1993), in whom the phenotype shifted with age, with ataxia becoming the predominant clinical manifestation and febrile attacks occurring less frequently as they grew older. Both sibs showed marked elevations of immunoglobulin D (IgD) and also exhibited short stature, kyphoscoliosis, obesity, and delayed psychomotor development. Additional findings included the development of nuclear cataract and retinal dystrophy in both patients; electroretinography in the brother showed undetectable scotopic and photopic responses. Prietsch et al. (2003) also described a 6-year-old boy whose mevalonic aciduria was discovered on metabolic screening at 5.5 years of age due to mild psychomotor retardation and general 'clumsiness.' He never underwent febrile crises and his IgD levels were repeatedly normal. MRI showed severe cerebellar atrophy, consistent with his predominant symptom of moderate cerebellar ataxia. Ophthalmologic examination showed retinal dystrophy with field constriction and lack of dark adaptation, primarily in the retinal periphery, as well as thinned retinal vessels, uneven retinal surface reflections, and moderate optic atrophy, but no bone-spicule pigmentation. Prietsch et al. (2003) stated that this was the first report of adolescent MEVA patients, and that in patients who survive infancy, the predominant findings include short stature, ataxia caused by cerebellar atrophy, and ocular involvement with retinal dystrophy. They noted that recurrent febrile crises seem to diminish with increasing age and might not be an obligatory finding, and they suggested that IgD elevation might be a secondary phenomenon linked to recurrent febrile crises.
Mandey et al. (2006) reviewed aspects of mevalonate kinase deficiency (MKD), of which classic mevalonic aciduria and the autoinflammatory hyperimmunoglobulinemia D and periodic fever syndrome (HIDS; 260920) represent the severe and mild clinical ends of the spectrum. Patients with the HIDS phenotype typically present only with recurrent episodes of fever and associated inflammatory symptoms, whereas patients with mevalonic aciduria show, in addition to these episodes, developmental delay, dysmorphic features, ataxia, cerebellar atrophy, and psychomotor retardation and may die in early childhood (Hoffmann et al., 1993). Cells from patients with the HIDS phenotype still contain residual mevalonate kinase enzyme activities from 1 to 8% of the activities of control cells, while in cells from patients with the mevalonic aciduria phenotype the enzyme activity is below the level of detection. This difference in residual enzyme activity is also reflected in the occurrence of high levels of mevalonic acid in plasma, urine, and tissues of patients with the mevalonic aciduria phenotype and low to moderately increased levels of mevalonic acid in patients with the HIDS presentation.
Molecular Genetics
For a complete discussion of the molecular genetics of mevalonic aciduria and other manifestations of mevalonate kinase deficiency, see the entry for the mevalonate kinase gene (MVK; 251170).
In 2 adolescent sibs with mevalonic aciduria, in whom symptomatology had gradually shifted from febrile crises to ataxia, and who also exhibited nuclear cataract and retinal dystrophy, Prietsch et al. (2003) identified homozygosity for a missense mutation in the MVK gene (A334T; 251170.0006). In a 6-year-old boy with mevalonic aciduria, who had cerebellar ataxia but no febrile crises or elevated IgD, and who also showed retinal dystrophy, Prietsch et al. (2003) identified compound heterozygosity for the A334T mutation and a 1-bp insertion (251170.0016).
INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Other \- Failure to thrive HEAD & NECK Head \- Microcephaly \- Dolichocephaly \- Wide, irregular fontanels Face \- Triangular face Ears \- Low-set ears \- Posteriorly rotated ears Eyes \- Downslanting palpebral fissures \- Blue sclerae \- Central cataracts \- Nystagmus \- Nuclear cataract (in some patients) Retinal dystrophy (in some patients) \- Undetectable rod and cone responses on electroretinography \- Attenuation of retinal vessels \- Moderate atrophy of optic disc ABDOMEN Liver \- Fluctuating hepatomegaly Spleen \- Fluctuating splenomegaly Gastrointestinal \- Vomiting \- Diarrhea SKELETAL Spine \- Kyphoscoliosis (in some patients) Limbs \- Arthralgias SKIN, NAILS, & HAIR Skin \- Morbilliform rash \- Edema NEUROLOGIC Central Nervous System \- Psychomotor retardation \- Hypotonia \- Progressive ataxia (onset second year of life) \- Developmental delay \- Cerebellar atrophy \- Cerebral atrophy \- Agenesis of cerebellar vermis HEMATOLOGY \- Normocytic hypoplastic anemia \- Leukocytosis \- Thrombocytopenia IMMUNOLOGY \- Elevated IgD LABORATORY ABNORMALITIES \- Elevated serum creatine kinase \- Elevated transaminases \- Serum cholesterol low or normal \- Elevated leukotriene E(4) \- Decreased ubiquinone-10 \- Elevated urinary mevalonic acid MISCELLANEOUS \- Recurrent febrile crises with lymphadenopathy, hepatosplenomegaly, vomiting, and diarrhea \- Onset of crises in early childhood \- Febrile crises decrease with age, with ataxia becoming the predominant symptom (in some patients) \- Rash, edema, and arthralgia may occur during crisis \- Allelic to hyperimmunoglobulinemia D syndrome (HIDS, 260920 ) MOLECULAR BASIS \- Caused by mutation in the mevalonate kinase gene (MVK, 251170.0001 ) ▲ 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
| MEVALONIC ACIDURIA | c0342731 | 1,410 | omim | https://www.omim.org/entry/610377 | 2019-09-22T16:04:39 | {"doid": ["0050452"], "mesh": ["D054078"], "omim": ["610377"], "orphanet": ["29"]} |
A number sign (#) is used with this entry because of evidence that autosomal recessive hereditary spastic paraplegia-76 (SPG76) is caused by homozygous or compound heterozygous mutation in the CAPN1 gene (114220) on chromosome 11q13.
Description
Spastic paraplegia-76 is an autosomal recessive neurologic disorder characterized by young-adult onset of slowly progressive spasticity of the lower limbs resulting in gait difficulties. Most affected individuals have upper limb involvement and additional features such as foot deformities and dysarthria. Cognition is unaffected (summary by Gan-Or et al., 2016).
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).
Clinical Features
Gan-Or et al. (2016) reported 3 families, 2 consanguineous Moroccan families and 1 nonconsanguineous North American family, with spastic paraplegia. The clinical features of 8 patients were reported in detail. The average age at onset was 28.5 years (range 19 to 39); all affected individuals had spasticity and hyperreflexia of the lower limbs, 7 had hyperreflexia of the upper limbs, 6 had dysarthria, and 3 had ataxia. Six patients had foot deformities, including pes cavus or pes valgus, 2 had abnormal bladder function, and 2 had distal sensory impairment. The motor impairment was mild to moderate, and 2 patients had started using a cane to aid in walking. There were no other neurologic abnormalities.
Inheritance
The transmission pattern of SPG76 in the families reported by Gan-Or et al. (2016) was consistent with autosomal recessive inheritance.
Molecular Genetics
In affected members of 3 unrelated families with SPG76, Gan-Or et al. (2016) identified homozygous or compound heterozygous mutations in the CAPN1 gene (114220.0001-114220.0004). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. One of the mutations was a missense mutation, whereas the others were nonsense, frameshift, or splice site mutations. Functional studies of the variants and studies of patient cells were not performed, but knockdown of the Capn1 gene in animal models resulted in disruption of neuronal patterning and neurodegeneration (see ANIMAL MODEL).
Animal Model
Gan-Or et al. (2016) found that RNAi knockdown of the Capn1 gene in C. elegans resulted in neurodegeneration of GABAergic motor neurons and an age-dependent paralysis phenotype. Loss of Capn1 in Drosophila led to locomotor defects, axonal abnormalities, and age-dependent negative geotaxis. The axons appeared to have larger diameters and increased levels of acetylated tubulin. Morpholino knockdown of capn1a in zebrafish resulted in disruption of brain development, particularly of branchiomotor neuron migration and positioning, as well as disorganization of the microtubule network with abnormal accumulation of axonal acetylated tubulin as well as depletion of acetylated tubulin. These animal models supported a neuroprotective role of Capn1.
INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Nystagmus (1 patient) GENITOURINARY Bladder \- Abnormal bladder function (in some patients) SKELETAL Feet \- Pes cavus \- Pes valgus NEUROLOGIC Central Nervous System \- Spastic paraplegia (upper limbs may be affected) \- Hyperreflexia \- Extensor plantar responses \- Dysarthria \- Dysmetria (in some patients) \- Ataxia (in some patients) Peripheral Nervous System \- Sensory axonal neuropathy (in some patients) \- Distal sensory impairment (in some patients) MISCELLANEOUS \- Average age at onset 28.5 years (range 19 to 39) \- Three families have been reported (last curated May 2016) MOLECULAR BASIS \- Caused by mutation in the calpain 1 gene (CAPN1, 114220.0001 ) ▲ 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
| SPASTIC PARAPLEGIA 76, AUTOSOMAL RECESSIVE | c4310800 | 1,411 | omim | https://www.omim.org/entry/616907 | 2019-09-22T15:47:50 | {"doid": ["0110821"], "omim": ["616907"], "orphanet": ["488594"], "synonyms": ["SPG76"]} |
Hypocementosis is a reduction in the amount of cementum on a tooth root. It is a feature of conditions such as cleidocranial dysplasia and hypophosphatasia.[1]
## References[edit]
1. ^ Ireland R (25 March 2010). A Dictionary of Dentistry. Oxford University Press. p. 180. ISBN 978-0-19-953301-5.
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Oral and maxillofacial pathology
Lips
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Teeth (pulp, dentin, enamel)
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Periodontium (gingiva, periodontal ligament, cementum, alveolus) – Gums and tooth-supporting structures
* Cementicle
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* Epulis
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* Gingival enlargement
* Gingival cyst of the adult
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* Gingivitis
* Desquamative
* Granulomatous
* Plasma cell
* Hereditary gingival fibromatosis
* Hypercementosis
* Hypocementosis
* Linear gingival erythema
* Necrotizing periodontal diseases
* Acute necrotizing ulcerative gingivitis
* Pericoronitis
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* Aggressive
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* Chronic
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Periapical, mandibular and maxillary hard tissues – Bones of jaws
* Agnathia
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* Odontogenic: periapical
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* Median mandibular
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Temporomandibular joints, muscles of mastication and malocclusions – Jaw joints, chewing muscles and bite abnormalities
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Salivary glands
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Orofacial soft tissues – Soft tissues around the mouth
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* Perioral dermatitis
* Pyostomatitis vegetans
Other
* Eagle syndrome
* Hemifacial hypertrophy
* Facial hemiatrophy
* Oral manifestations of systemic disease
This dentistry article is a stub. You can help Wikipedia by expanding it.
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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
| Hypocementosis | None | 1,412 | wikipedia | https://en.wikipedia.org/wiki/Hypocementosis | 2021-01-18T18:42:09 | {"wikidata": ["Q20707496"]} |
A number sign (#) is used with this entry because of evidence that omodysplasia-2 (OMOD2) is caused by heterozygous mutation in the FZD2 gene (600667) on chromosome 17q21.
Description
Omodysplasia-2 is a rare autosomal dominant skeletal dysplasia characterized by shortened humeri, dislocated radial heads, shortened first metacarpals, craniofacial dysmorphism, and variable genitourinary anomalies (Saal et al., 2015).
For a discussion of genetic heterogeneity of OMOD, see 258315.
Clinical Features
Under the designation omodysplasia, Maroteaux et al. (1989) described 3 cases of a 'new' congenital bone disorder associating facial anomalies (depressed nasal bridge, broad base of the nose, and long philtrum) with short humeri. (Omodysplasia etymologically means shoulder dysplasia: the 'omo' comes from the Greek word for shoulder.) The complex skeletal abnormalities consisted of a defect in the growth of the distal end of the humerus, a hypoplastic everted condyle, a proximal radioulnar diastasis, and an anterolateral dislocation of the head of the radius. A mother and her infant son were 2 of the 3 cases. Two other cases had micromelic dwarfism due to shortness of the long bones, particularly the femora; Maroteaux et al. (1989) considered that these cases represented variable expression of the same disorder; see OMOD1 (258315).
Venditti et al. (2002) described a family with mother-to-son transmission of omodysplasia. The mother, who had originally been diagnosed with Robinow syndrome (180700), had shortened humeri, shallow olecranon fossae with partially subluxed radii, shortened first metacarpals, and small, laterally displaced patellas. She also had a large forehead, hypertelorism, a depressed nasal bridge, maxillary hypoplasia, and hypoplastic genitalia. Her intellectual and motor development were normal. Prenatal ultrasound of her son at 13 to 14 weeks showed delayed humeral ossification. A repeat study at 20 weeks showed shortened humeri and genitalia that were not assignable to either gender. At birth, he was noted to have facial and skeletal features similar to those of his mother and hypoplastic genitalia with a small penis, bifid scrotum, and undescended testes.
Gordon et al. (2014) provided long-term observation of a 48-year-old woman with omodysplasia, who was first evaluated at age 9 years. She had short stature, prominent forehead, flat face, rhizomelic shortening of the upper and lower extremities, and inability to pronate and supinate the forearms. Radiographs revealed shortening of the humeri and ulnas, bowing and dislocation of the radial heads, short fifth metacarpals, and symmetric coxa valga. At age 11 years, 6 to 8 permanent teeth were extracted to relieve dental crowding due to a small maxilla and mandible. Radiographic evaluation at age 16 confirmed marked symmetric shortening of all tubular bones in the upper limbs; bones in the lower limbs were considered to be normal. At age 25, the patient underwent laparotomy for suspected ectopic pregnancy and was found to have a bicornuate uterus. Examination at age 48 showed low-set, posteriorly angulated ears with a Darwinian tubercle and overfolded helix, downslanting palpebral fissures, upturned short nose with broad base and hypoplastic alae, and underdeveloped but long philtrum. She had several small frenula between lower lip and gums, slightly tethered tongue, and hypoplastic uvula. Her thumbs were short and proximally implanted due to short first metacarpals. The authors stated that mild rhizomelic shortening of the lower extremities had not previously been reported in omodysplasia.
Saal et al. (2015) reported a mother and daughter with omodysplasia. Both had short humeri and radial dislocation with limitation of movement, and the daughter also showed widening of the femoral neck and lateral uncovering of the femoral head bilaterally, shortening of the ulnas and fibulas, and short first metacarpals. Both patients exhibited facial dysmorphism, including round face, frontal bossing, flat nasal bridge, and long philtrum, and the mother also had bilateral cleft lip and cleft palate. In addition, the mother showed hypoplastic genitalia and a didelphic uterus.
Molecular Genetics
In a mother and daughter with omodysplasia, Saal et al. (2015) performed next-generation exome sequencing and identified heterozygosity for a nonsense mutation in the FZD2 gene (W548X; 600667.0001) that was not found in the mother's unaffected parents or in an in-house database or in public variant databases. Functional analysis showed that the mutant protein had reduced ability to interact with downstream targets and, in contrast to wildtype FZD2, could not facilitate the cellular response to canonical WNT (see 164820) signaling.
INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Long philtrum \- Frontal bossing Nose \- Depressed nasal bridge \- Bifid nasal tip \- Cleft lip \- Cleft palate GENITOURINARY External Genitalia (Male) \- Small penis External Genitalia (Female) \- Hypoplastic genitalia Internal Genitalia (Male) \- Cryptorchidism Internal Genitalia (Female) \- Didelphic uterus SKELETAL Limbs \- Rhizomelic arm shortening \- Short, curved humeri \- Hypoplastic distal humeri \- Dislocated radial head (anteriorly and laterally) \- Limited elbow flexion/extension \- Radioulnar diastasis Hands \- Short first metacarpal MOLECULAR BASIS \- Caused by mutation in the frizzled class receptor 2 gene (FZD2, 600667.0001 ) ▲ 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
| OMODYSPLASIA 2 | c2750355 | 1,413 | omim | https://www.omim.org/entry/164745 | 2019-09-22T16:37:08 | {"doid": ["0060288"], "mesh": ["C567664"], "omim": ["164745"], "orphanet": ["93328", "2733"], "synonyms": ["Alternative titles", "OMODYSPLASIA, AUTOSOMAL DOMINANT"]} |
A number sign (#) is used with this entry because molybdenum cofactor deficiency of complementation group A (MOCODA) is caused by homozygous or compound heterozygous mutation in the MOCS1 gene (603707) on chromosome 6p21.
Description
Molybdenum cofactor deficiency (MOCOD) is a rare autosomal recessive metabolic disorder characterized by onset in infancy of poor feeding, intractable seizures, and severe psychomotor retardation. Characteristic biochemical abnormalities include decreased serum uric acid and increased urine sulfite levels due to the combined enzymatic deficiency of xanthine dehydrogenase (XDH; 607633) and sulfite oxidase (SUOX; 606887), both of which use molybdenum as a cofactor. Most affected individuals die in early childhood (summary by Reiss, 2000; Reiss et al., 2011).
### Genetic Heterogeneity of Molybdenum Cofactor Deficiency
See also MOCOD, complementation group B (MOCODB; 252160), caused by mutation in the MOCS2 gene (602708) on chromosome 5q11; and MOCOD, complementation group C (MOCODC; 615501), caused by mutation in the GPHN gene (603930) on chromosome 14q24.
Clinical Features
Duran et al. (1978) reported a female infant with a combination of sulfite oxidase deficiency (272300) and xanthine oxidase deficiency (278300). She presented at age 10 days with poor feeding, tonic-clonic seizures, EEG abnormalities, and dysmorphic features, including frontal bossing, asymmetry of the skull, and subtle medio-facial dysplasia. She also had nystagmus, enophthalmos, and dislocated lenses. Laboratory studies showed low serum uric acid, and urinary analysis showed increased excretion of xanthine, hypoxanthine, S-sulfocysteine, and taurine. At age 14 months, she was noted to have excretion of xanthine stones. At age 2 years, she had poor head control, hypertonia, no reaction to light, and essentially no psychomotor development. Xanthine oxidase activity was demonstrated to be absent in patient cells, but sulfite oxidase activity was difficult to determine. However, the excretion of sulfur-containing metabolites was consistent with decreased sulfite oxidase activity. Serum molybdenum concentration was normal. Johnson et al. (1980) reported further studies on the patient reported by Duran et al. (1978), who was bedridden and had not achieved any milestones by age 3 years. Hepatic tissue from the patient showed deficient activities of both sulfite oxidase and xanthine dehydrogenase, secondary to deficient synthesis of the molybdenum cofactor. Molybdenum was absent in the liver sample despite normal serum levels of the metal; however, the active molybdenum cofactor was not detectable in the liver. The clinical features were attributed mainly to the deficiency of sulfite oxidase; urinary xanthine stones were presumably the only manifestation of the xanthine oxidase deficiency. There was also indirect biochemical evidence of aldehyde oxidase (AOX1; 602841) deficiency. Johnson et al. (1980) concluded that the patient had a primary defect in an essential step of the biosynthesis of the active molybdenum cofactor.
Beemer (1981) identified this disorder in a second patient, a male newborn, whose parents were born in the same region of Holland as the parents of the first patient, with at least 2 links between the pedigrees. By 1983, according to Wadman et al. (1983), there were more cases of sulfite oxidase deficiency due to a defect in the molybdenum cofactor than cases of isolated sulfite oxidase deficiency. Convulsions, feeding difficulties, mental retardation, and lens dislocation occurred in both the isolated and the combined forms. In the combined form, abnormal muscle tone, myoclonic spasms, and an abnormal physiognomy had also been reported.
Endres et al. (1988) reported a newborn infant with seizures and spastic tetraparesis at the age of 1 week who excreted excessive amounts of sulfite, taurine, S-sulfocysteine and thiosulfate, characteristic of sulfite oxidase deficiency. In addition, increased renal excretion of xanthine and hypoxanthine combined with a low serum and urinary uric acid was consistent with xanthine dehydrogenase deficiency. Both deficiencies were established at the enzyme level. Attempts at treatment were unsuccessful. The patient developed a severe neurologic syndrome, brain atrophy, and lens dislocation, and died at the age of 22 months.
Slot et al. (1993) reported 2 unrelated patients with MOCOD who presented with neonatal convulsions. The parents in one case were second cousins. One infant died at the age of 10 days and was found to have severe loss of neocortical neurons, predominantly affecting the deeper layers, well-established gliosis of the white matter, and areas of cystic lysis in the white matter. In the case of the second infant, death occurred at the age of about 1 year. Postmortem examination, like clinical examination, disclosed no lens luxation.
Parini et al. (1997) described a patient with molybdenum cofactor deficiency in which lens dislocation developed late (at the age of 8 years) and was preceded by bilateral spherophakia. The authors hypothesized that the cause of spherophakia in this disorder is an abnormal relaxation of the zonular fibers, which eventually causes lens dislocation.
Patients with MOCOD have recognizable dysmorphic facial features, including long face with puffy cheeks, widely spaced eyes, elongated palpebral fissures, thick lips, long philtrum, and small nose. Some patients develop progressive microcephaly, whereas others have macrocephaly secondary to hydrocephalus. Neuropathologic findings include brain atrophy, neuronal loss, astrocytic gliosis, cystic changes in the subcortical white matter, thin corpus callosum, enlarged ventricles, and demyelination (summary by Johnson and Duran, 2001).
Mechler et al. (2015) reported a natural history of molybdenum cofactor deficiency with pooled data. Of 82 children, 70% were classified as MOCD not otherwise specified because the molecular basis was not known; 15% were MOCODA, 10% were MOCODB, and 6% were MOCODC. In this cohort, 42% were female, 45% were male, and 13% were of unknown sex. Affected sibs were present in 38%, absent in 60%, and unknown in 2%. At last follow-up, 51% were alive and 49% had died. The median survival overall was 36 months. The initial cardinal disease features at onset were seizures (72%) as well as feeding difficulties (25%) and hypotonia (11%). In addition, developmental delay (9%), hemiplegia (2%), lens dislocation (2%), and hyperreflexia (1%) were reported. Reported median age of onset of the disease was the first day of life; the median age at diagnosis was 4.5 months. The median time to diagnosis (diagnostic delay) was 89 days.
Biochemical Features
Johnson and Rajagopalan (1982) showed that urothione, a sulfur-containing pterin, is the normal metabolic degradation product of the molybdenum cofactor that is deficient in this disorder. Roesel et al. (1986) found no detectable urinary urothione in a patient with combined xanthine and sulfite oxidase deficiency.
From studies of cocultured fibroblasts from affected individuals, Johnson et al. (1989) identified 2 complementation groups, A and B. Coculture of group A and group B cells, without heterokaryon formation, led to the appearance of active sulfite oxidase. Use of conditioned media indicated that a relatively stable form of diffusible precursor produced by group B cells could be used to repair sulfite oxidase in group A recipient cells. Although the extremely low level of precursor produced by group B cells precluded its direct characterization, studies with a heterologous in vitro reconstitution system suggested that the precursor that accumulates in group B cells is the same as a molybdopterin precursor identified in a molybdopterin mutant of Neurospora crassa, and that a converting enzyme is present in group A cells which catalyzes an activation reaction analogous to that of a converting enzyme identified in a molybdopterin mutant of E. coli.
Inheritance
The transmission pattern of molybdenum cofactor deficiency is consistent with autosomal recessive inheritance (summary by Reiss, 2000).
Diagnosis
Wadman et al. (1983) called attention to a very simple screening test for urinary sulfite, which was originally developed for the semiquantitative determination of sulfite in wine and fruit juices and is available as a 'strip test.' Aukett et al. (1988) described a patient presenting with seizures at age 4 weeks in whom the stick sulfite test, by 2 techniques, was negative. They suggested that low serum urate may be a better pointer to the diagnosis than the sulfite test.
Coskun et al. (1998) presented a case of MOCOD and stressed the value of serum uric acid concentration in reaching the diagnosis. A very low serum uric acid level reflects the deficiency of xanthine dehydrogenase, one of the enzymes whose function is affected in this disorder.
### Prenatal Diagnosis
Gray et al. (1990) described prenatal diagnosis by demonstrating sulfite oxidase deficiency in uncultured chorionic villus material.
Reiss et al. (1999) pointed out that since 1983 the prenatal diagnosis of molybdenum cofactor deficiency had been made by measurement of sulfite oxidase activity, but no enzymatic carrier diagnosis was possible. With the cloning of the MOCS1 gene, it was possible for Reiss et al. (1999) to perform enzymatic and molecular genetic analysis in parallel after chorionic villus sampling in a Danish family. The sulfite oxidase activity in uncultured CVS material was found to be normal. A MOCS1 splice site mutation (603707.0004), found to be homozygous in the proband, was found to be heterozygous in cultured chorionic cells. This confirmed that the fetus was not affected, since heterozygous carriers of the molybdenum cofactor deficiency do not display any symptoms.
Mapping
By use of homozygosity mapping in 2 unrelated consanguineous kindreds of Israeli Arab origin, Shalata et al. (1998) demonstrated linkage of MOCODA to an 8-cM region on chromosome 6p21.3, between markers D6S1641 and D6S1672. Linkage analysis generated the highest combined lod score, 3.6, at a recombination fraction of 0.0, with marker D6S1575. In 1 extensive kindred, 11 homozygotes in 9 sibships related as cousins were reported. The first affected member of this family had been reported by Van Gennip et al. (1994). In a second kindred, 2 sibs were homozygous. An immediate benefit of the mapping effort was the ability to perform prenatal diagnosis and carrier detection by use of microsatellite markers.
Molecular Genetics
In 2 unrelated patients with molybdenum cofactor deficiency of complementation group A, Reiss et al. (1998) identified 2 different homozygous truncating mutations in the MOCS1 gene (603707.0001 and 603707.0002); one mutation occurred in the MOCS1A transcript and the other occurred in the MOCS1B transcript. These findings indicated the existence of a eukaryotic mRNA which, as a single and uniform transcript, guides the synthesis of 2 different enzymatic polypeptides with disease-causing potential. Thus the MOCS1 gene is bicistronic.
In an initial cohort of 24 patients with molybdenum cofactor deficiency, Reiss et al. (1998) identified 13 different mutations on 34 of the 48 chromosomes, giving a mutation detection rate of 70%. Five mutations were observed in more than 1 patient and together accounted for two-thirds of detected mutations. All patients with identified mutations were either homozygous or compound heterozygous for mutations in either of the 2 open reading frames corresponding to MOCS1A and MOCS1B, respectively.
Reiss (2000) reviewed the genetics of molybdenum cofactor deficiency. Both MOCS1 and MOCS2 have an unusual bicistronic architecture, have identical very low expression profiles, and show extremely conserved C-terminal ends in their 5-prime open reading frames. MOCS1 mutations are responsible for two-thirds of cases. Reiss (2000) pointed out that all described MOCS1 and MOCS2 mutations affect one or several highly conserved motifs. No missense mutations of a less conserved residue were identified. This mirrors the absence of mild or partial forms of MoCo deficiency and supports the hypothesis of a qualitative 'yes or no' mechanism rather than quantitative kinetics for MoCo function, i.e., this function is either completely abolished or sufficient for a normal phenotype. The minimal expression of the MOCS genes concurs with this theory and would predict a low level of transfected or expressing cells that would be adequate for somatic gene therapy. Furthermore, precursor-producing cells seem to be capable of feeding their precursor-deficient neighbor cells (Johnson et al., 1989).
Reiss and Johnson (2003) collected a total of 32 different disease-causing mutations in the MOCS1, MOCS2, or GPHN genes, including several common to more than 1 family, that had been identified in molybdenum cofactor-deficient patients and their relatives.
Nomenclature
The mutations of MOCS1 causing molybdenum cofactor deficiency occur in either the MOCS1A or MOCS1B isoforms, and similarly the mutations in MOCS2 can occur in either the MOCS2A or MOSC2B isoforms. The form of molybdenum cofactor deficiency caused by mutation in MOCS1 is called here complementation group A (not type A); molybdenum cofactor deficiency due to mutation in MOCS2 is referred to as complementation group B; and molybdenum cofactor deficiency due to mutation in the GPHN gene is referred to as complementation group C.
Animal Model
Lee et al. (2002) constructed a transgenic mouse model of molybdenum cofactor deficiency in which the MOCS1 gene was disrupted by homologous recombination with a targeting vector. As in humans, heterozygous mice displayed no symptoms, but homozygous animals died between days 1 and 11 after birth. Biochemical analysis of these animals showed that molybdopterin and active cofactor were undetectable. The animals did not possess any sulfite oxidase or xanthine dehydrogenase activity. No organ abnormalities were observed and the synaptic localization of inhibitory receptors, which was found to be disturbed in molybdenum cofactor-deficient mice with a Geph mutation, appeared normal.
Schwarz et al. (2004) described the isolation of a pterin intermediate from bacteria that was successfully used for the therapy of molybdenum cofactor deficiency in a mouse model. An intermediate of this pathway, designated 'precursor Z,' is more stable than the cofactor itself and has an identical structure in all phyla. Schwarz et al. (2004) overproduced precursor Z in E. coli and injected purified precursor Z-deficient knockout mice, which displayed a phenotype resembling the human deficiency state. Precursor Z-substituted mice reached adulthood and fertility. Biochemical analyses further suggested that the described treatment may lead to the alleviation of most symptoms associated with human molybdenum cofactor deficiency.
The mouse model of MoCo deficiency type A (Lee et al., 2002; Schwarz et al., 2004) showed the biochemical characteristics of sulfite and xanthine intoxication and a failure to survive more than 2 weeks after birth. Kugler et al. (2007) constructed an expression cassette for the gene MOCS1 which, by alternative splicing, facilitates the expression of the proteins MOCS1A and MOCS1B, both of which are necessary for the formation of a first intermediate, cyclic pyranopterin monophosphate (cPMP), within the biosynthetic pathway leading to active MoCo. A recombinant adeno-associated virus (AAV) vector was used to express the artificial MOCS1 minigene in an attempt to cure the lethal MOCS1-deficient phenotype. The vector was used to transduce Mocs1-deficient mice at both 1 and 4 days after birth or, after a pretreatment with purified cPMP, at 40 days after birth. They found that all deficient animals injected with control AAV-enhanced green fluorescent protein vector died approximately 8 days after birth or after withdrawal of cPMP supplementation, whereas AAV-MOCS1-transduced animals showed significantly increased longevity. A single intrahepatic injection of AAV-MOCS1 resulted in fertile adult animals without any pathologic phenotypes.
INHERITANCE \- Autosomal recessive GROWTH Other \- Poor growth HEAD & NECK Head \- Frontal bossing \- Microcephaly \- Macrocephaly Face \- Long face \- Puffy cheeks \- Long philtrum Eyes \- Dislocated lenses \- Spherophakia \- Nystagmus \- Elongated palpebral fissures \- Widely spaced eyes Nose \- Small nose Mouth \- Thick lips ABDOMEN Gastrointestinal \- Poor feeding SKELETAL Skull \- Asymmetric skull MUSCLE, SOFT TISSUES \- Myoclonic spasms NEUROLOGIC Central Nervous System \- Absent or delayed psychomotor development, severe \- Seizures, intractable \- Opisthotonos \- Hypertonicity \- Spastic quadriplegia \- Cerebral atrophy \- Thinning of the corpus callosum \- Gliosis \- Demyelination \- Axonal loss \- Cystic lysis of the deep white matter \- Enlarged ventricles LABORATORY ABNORMALITIES \- Hypouricemia \- Increased urinary xanthine \- Increased urinary hypoxanthine \- Increased urinary S-sulfocysteine \- Increased urinary taurine \- Xanthine stones \- Decreased xanthine dehydrogenase activity \- Decreased sulfite oxidase activity \- Molybdenum cofactor deficiency MISCELLANEOUS \- Onset at birth or in early infancy \- Progressive disorder \- Most affected patients die in childhood MOLECULAR BASIS \- Caused by mutation in the molybdenum cofactor synthesis gene 1 (MOCS1, 603707.0001 ) ▲ 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
| MOLYBDENUM COFACTOR DEFICIENCY, COMPLEMENTATION GROUP A | c1854988 | 1,414 | omim | https://www.omim.org/entry/252150 | 2019-09-22T16:24:59 | {"doid": ["0111164"], "mesh": ["C565372"], "omim": ["252150"], "orphanet": ["833", "99732", "308386"], "synonyms": ["MOCOD", "Alternative titles", "Combined deficiency of sulfite oxidase, xanthine dehydrogenase and aldehyde oxidase", "SULFITE OXIDASE, XANTHINE DEHYDROGENASE, AND ALDEHYDE OXIDASE, COMBINED DEFICIENCY OF"]} |
Primary peritoneal carcinoma
Micrograph of a serous carcinoma, which may arise from the peritoneal lining
SpecialtyOncology
Primary peritoneal cancer or carcinoma is also known as serous surface papillary carcinoma, primary peritoneal carcinoma, extra-ovarian serous carcinoma, primary serous papillary carcinoma, psammomacarcinoma. It was historically classified under "carcinoma of unknown primary" (CUP). Primary peritoneal cancer (PPC, or PPCa)[1] is a cancer of the cells lining the peritoneum, or abdominal cavity.
Histomorphological and molecular biological characteristics suggest that serous carcinomas, which include ovarian serous carcinoma, uterine serous carcinoma, Fallopian tube serous carcinoma, cervical serous carcinoma, and primary peritoneal serous carcinoma really represent one entity.[2]
## Contents
* 1 Genetic causes
* 2 Prognosis
* 3 References
* 4 External links
## Genetic causes[edit]
Although the precise causes are not known, a link with certain variants of BRCA1/2 has been described.[3] Furthermore, women with BRCA1/2 mutation have a 5% risk of developing primary peritoneal cancer even after prophylactic oophorectomy.
Primary peritoneal carcinoma shows similar rates of tumor suppressor gene dysfunction (p53, BRCA, WT1) as ovarian cancer and can also show an increased expression of HER-2/neu.
An association with vascular endothelial growth factor has been observed.[4]
## Prognosis[edit]
Prognosis and treatment is the same as for the most common type of ovarian cancer, which is epithelial ovarian cancer.[5][6]
The median survival of primary peritoneal carcinomas is usually shorter by 2–6 months time when compared with serous ovarian cancer. Studies show median survival varies between 11.3–17.8 months. One study reported 19-40 month median survival (95% CI) with a 5-year survival of 26.5%.[citation needed]
Elevated albumin levels have been associated with a more favorable prognosis.[7]
## References[edit]
1. ^ Jaaback KS, Ludeman L, Clayton NL, Hirschowitz L (2006). "Primary peritoneal carcinoma in a UK cancer center: comparison with advanced ovarian carcinoma over a 5-year period". Int. J. Gynecol. Cancer. 16 Suppl 1: 123–8. doi:10.1111/j.1525-1438.2006.00474.x. PMID 16515579.
2. ^ Dubeau, L. (Dec 2008). "The cell of origin of ovarian epithelial tumours". Lancet Oncol. 9 (12): 1191–7. doi:10.1016/S1470-2045(08)70308-5. PMC 4176875. PMID 19038766.
3. ^ "Gynecologic Cancer Treatment — Primary Peritoneal Cancer — Dana-Farber Cancer Institute".
4. ^ Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI (November 2007). "Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study". J. Clin. Oncol. 25 (33): 5165–71. doi:10.1200/JCO.2007.11.5345. PMID 18024863.
5. ^ "New Drug Combination for Ovarian and Primary Peritoneal Cancers - National Cancer Institute".
6. ^ "eMedicine — Peritoneal Cancer : Article by Wissam Bleibel".
7. ^ Alphs HH, Zahurak ML, Bristow RE, Díaz-Montes TP (December 2006). "Predictors of surgical outcome and survival among elderly women diagnosed with ovarian and primary peritoneal cancer". Gynecol. Oncol. 103 (3): 1048–53. doi:10.1016/j.ygyno.2006.06.019. PMID 16876237.
## External links[edit]
Classification
D
* ICD-10: C48.1-C48.2
* ICD-9-CM: 158
* MeSH: D010534
* 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
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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
| Primary peritoneal carcinoma | c1514428 | 1,415 | wikipedia | https://en.wikipedia.org/wiki/Primary_peritoneal_carcinoma | 2021-01-18T18:36:00 | {"umls": ["C1514428"], "icd-9": ["158"], "icd-10": ["C48.1", "C48.2"], "orphanet": ["168829"], "wikidata": ["Q1816041"]} |
A number sign (#) is used with this entry because of evidence that susceptibility to schizophrenia-19 (SCZD19) is conferred by heterozygous mutation in the RBM12 gene (607179) on chromosome 20q11.
Clinical Features
Steinberg et al. (2017) reported a large Icelandic family in which 6 individuals were diagnosed with schizophrenia, 2 with schizoaffective disorder, and 3 with psychotic bipolar disorder. There were multiple additional family members without frank psychosis who had various psychiatric disorders and impaired cognition. A second family of Finnish descent contained 4 affected sibs, including 3 diagnosed with schizophrenia and 1 with schizoaffective disorder.
Inheritance
The transmission pattern of SCZD19 in one of the families reported by Steinberg et al. (2017) was consistent with autosomal dominant inheritance with incomplete penetrance.
Molecular Genetics
In affected members of 2 unrelated families, of Icelandic and Finnish descent, respectively, with SCZD19, Steinberg et al. (2017) identified heterozygous truncating mutations in the RBM12 gene (G793X, 607179.0001 and c.2532delT, 607179.0002). The mutations were found by genome or exome sequencing, and there was evidence of incomplete penetrance. In the Icelandic family, statistical analysis showed a significant association between the variant and psychotic disorders (p = 2.2 x 10(-4)). Further studies revealed 22 obligate carriers of the variant, all of whom were descendants from the same Icelandic couple, who did not have frank psychosis. However, the carriers were found to have a higher rate of psychiatric disorders (odds ratio of 4.21, p = 0.028) as well as impaired cognition (p = 0.028) compared to noncarriers. The carriers also had lesser educational attainment and were more likely to receive disability compared to noncarriers. Studies of patient cells showed that the G793X mutation resulted in the production of a stable truncated protein lacking a predicted RNA-recognition motif. Functional studies of the variant found in the Finnish family were not performed.
INHERITANCE \- Autosomal dominant NEUROLOGIC Central Nervous System \- Cognitive impairment Behavioral Psychiatric Manifestations \- Schizophrenia \- Schizoaffective disorder \- Mood disorders MISCELLANEOUS \- Incomplete penetrance \- Two unrelated families of Icelandic and Finnish descent have been reported MOLECULAR BASIS \- Susceptibility conferred by mutation in the RNA-binding motif protein 12 gene (RBM12, 607179.0001 ) ▲ 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
| SCHIZOPHRENIA 19 | c4539944 | 1,416 | omim | https://www.omim.org/entry/617629 | 2019-09-22T15:45:18 | {"omim": ["617629"], "synonyms": ["Alternative titles", "SCHIZOPHRENIA 19 WITH OR WITHOUT AN AFFECTIVE DISORDER"]} |
Paternal 20q13.2q13.3 microdeletion syndrome is a recently described syndrome characterized by severe pre- and post-natal growth retardation, microcephaly, intractable feeding difficulties, mild psychomotor retardation, hypotonia and facial dysmorphism.
## Epidemiology
It has been reported in 2 unrelated patients.
## Clinical description
Facial dysmorphism includes high forehead, broad nasal bridge, thin upper lip, small chin and malformed ears. In addition, the patients presented with skin, iris and hair hypopigmentation and abnormal adipose tissue distribution.
## Etiology
The syndrome is caused by an interstitial deletion of paternal origin at 20q13.2q13.3. In the 2 cases, the deletion was approximately 4.5Mb in size and encompassed the GNAS imprinted locus; the loss of the paternally expressed GNAS gene might account for the severe pre- and post-natal retardation and intractable feeding difficulties observed in the patients.
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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
| Paternal 20q13.2q13.3 microdeletion syndrome | c4510306 | 1,417 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=261304 | 2021-01-23T17:22:38 | {"icd-10": ["Q93.5"], "synonyms": ["Paternal del(20)(q13.2q13.3)", "Paternal monosomy 20q13.2q13.3"]} |
Medical term for seeing everything tinted in blue
Cyanopsia is a medical term for seeing everything tinted with blue. It is also referred to as blue vision. Cyanopsia often occurs for a few days, weeks, or months after removal of a cataract from the eye. Cyanopsia also sometimes occurs as a side effect of taking sildenafil Cialis, or Levitra.[1]
Cyanopsia is a medical symptom and not a sign. It is a purely subjective state and can be caused by a physical or functional abnormality of the eye, a physical or functional abnormality of the brain, or be purely psychological. Cyanopsia, if unaccompanied by any other sign or symptom, is not an indication of any disease or disorder. Unless it causes an impairment or significant distress, it is not in and of itself diagnostically relevant.
## Contents
* 1 Cyanopsia after cataract removal
* 2 Cyanopsia from sildenafil
* 3 See also
* 4 References
* 5 External links
## Cyanopsia after cataract removal[edit]
The eye's lens is normally tinted yellow. This reduces the intensity of blue light reaching the retina. When the lens is removed because of cataract, it is usually replaced by an artificial intraocular lens; these artificial lenses are clear, allowing more intense blue light than usual to fall on the retina, leading to the phenomenon.
Hayashi and Hayashi (2006) compared visual function in people given yellow-tinted intraocular lenses with that in people given non-tinted intraocular lenses. Those with the yellow-tinted lenses were less likely to report cyanopsia than those with the clear lenses. Hayashi and Hayashi found no differences in visual acuity or in contrast sensitivity between the two groups. They also found that no one reported cyanopsia three months after the cataract operation, suggesting that some form of neural adaptation or colour constancy had taken place.[2]
## Cyanopsia from sildenafil[edit]
The author of Viagra and vision attributes cyanopsia after taking sildenafil to diminished enzyme activity, thereby sensitizing the retinal rod cells.[1] Rod cells are most sensitive to light of wavelengths near 498 nm; such light appears blue-green. When light levels are low enough for both rods and cone cells to be active (mesopic vision) the enhanced rod activity induces the bluish visual tint.
## See also[edit]
* Xanthopsia
## References[edit]
1. ^ a b "Viagra and Vision". (n.d.). Author. Retrieved January 31, 2008
2. ^ Hayashi, K., & Hayashi, H. (2006). Visual function in patients with yellow tinted intraocular lenses compared with vision in patients with non-tinted intraocular lenses. British Journal of Ophthalmology, 90, 1019-1023.
## External links[edit]
* https://web.archive.org/web/20070524033238/http://www.psych.ucalgary.ca/PACE/VA-LAB/Brian/acquired.htm for illustrations of various colour deficiencies including cyanopsia.
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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
| Cyanopsia | c0854725 | 1,418 | wikipedia | https://en.wikipedia.org/wiki/Cyanopsia | 2021-01-18T18:48:12 | {"umls": ["C0854725"], "wikidata": ["Q5197477"]} |
## Summary
The purpose of this overview is to increase the awareness of clinicians regarding the genetic causes of holoprosencephaly and to inform genetic counseling of family members.
The following are the goals of this overview.
### Goal 1.
Describe the clinical characteristics of holoprosencephaly.
### Goal 2.
Review the genetic causes of holoprosencephaly.
### Goal 3.
Provide an evaluation strategy to identify (when possible) the genetic cause of holoprosencephaly in a proband.
### Goal 4.
Inform genetic counseling of family members of an individual with holoprosencephaly.
## Diagnosis
## Clinical Characteristics
## Differential Diagnosis
## Management
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Holoprosencephaly Overview | None | 1,419 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1530/ | 2021-01-18T21:19:36 | {"synonyms": []} |
X-linked sideroblastic anemia is a constitutional microcytic, hypochromic anemia of varying severity that is clinically characterized by manifestations of anemia and iron overload and that may respond to treatment with pyridoxine and folic acid.
## Epidemiology
Prevalence is unknown. Around 200 cases and fewer than 100 unrelated probands are described in the literature.
## Clinical description
The anemia can present at any age from birth to the 9th decade. Some patients are asymptomatic and are detected incidentally by hematological screening or through a family study. Clinical features are those of anemia and/or iron overload such as pallor, fatigue, weakness. Breathlessness, mild splenomegaly, cardiac problems, abnormal liver function, hyperglycemia, glucose intolerance and skin hyperpigmentation are seen more rarely.
## Etiology
SA is due to inherited or de novo mutations in the ALAS2 gene (Xp11.21) encoding the erythroid form of delta amino levulinic acid synthase (ALAS2), which altered function leads to impaired heme synthesis. The increased ineffective and expanded erythropoiesis leads to increased absorption of dietary iron and a risk of iron overload. Female carriers are usually unaffected, however, one quarter of probands are female who have X-chromosome inactivation skewed against the unaffected allele and almost half of the female probands have macrocytic rather than microcytic red blood cells due to the heterozygous inheritance of a severe/null allele.
## Diagnostic methods
Diagnosis requires a full blood and reticulocyte count, measurement of iron stores, exclusion of thalassemia as a cause, bone marrow aspirate showing ringed sideroblasts, and mutation analysis of the ALAS2 gene.
## Differential diagnosis
The differential diagnosis should include other types of inherited sideroblastic anemia and in case of macrocytic red cells in females also acquired myelodysplasia (refractory anemia with ringed sideroblasts or RARS (see these terms). Most female carriers show some evidence of microcytic, hypochromic red blood cells but hematological parameters cannot be relied upon for genetic counseling purposes and DNA analysis is required
## Antenatal diagnosis
Prenatal diagnosis is rarely indicated or requested, but should be offered in case of family history.
## Genetic counseling
Genetic counseling for the family of affected individuals is recommended, as early diagnosis in a child may be of great benefit for treatment of anemia and prevention of iron overload, the main cause of early death in the past.
## Management and treatment
Treatment is supportive and involves hematological monitoring, the surveillance of iron levels, lifetime pyridoxine supplementation in those who respond and folic acid supplementation. Pyridoxine response varies in degree and is rarely complete. Prophylactic occasional phlebotomy can be performed to prevent iron overload, if anemia is very mild or corrected by pyridoxine. If iron overload has already developed, phlebotomy, iron chelation or a combination of both can be used to normalize iron levels. In some cases iron depletion may simultaneously increase the hemoglobin level. Blood transfusions may be needed on occasion but are only required on a regular basis for those most severely affected.
## Prognosis
Prognosis is variable but for patients with pyridoxine-responsive anemia whose iron stores are kept low, normal life expectancy should be achievable
*[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
| X-linked sideroblastic anemia | c4551511 | 1,420 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=75563 | 2021-01-23T19:11:19 | {"gard": ["9456"], "mesh": ["C536761"], "omim": ["300751"], "icd-10": ["D64.0"], "synonyms": ["XLSA"]} |
Pontocerebellar hypoplasia
Other namesNon-syndromic pontocerebellar hypoplasia
Pontocerebellar hypoplasia is inherited in an autosomal recessive manner
SpecialtyNeurology
TreatmentThere is no known treatment.
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare neurodegenerative disorders caused by genetic mutations and characterised by progressive atrophy of various parts of the brain such as the cerebellum or brainstem (particularly the pons).[1] Where known, these disorders are inherited in an autosomal recessive fashion. There is no known cure for PCH.[2]
## Contents
* 1 Signs and symptoms
* 2 Causes
* 3 Mechanism
* 4 Diagnosis
* 4.1 Classification
* 5 Treatment
* 6 Outcomes
* 7 See also
* 8 References
* 9 External links
## Signs and symptoms[edit]
There are different signs and symptoms for different forms of pontocerebellar hypoplasia, at least six of which have been described by researchers. All forms involve abnormal development of the brain, leading to slow development, movement problems, and intellectual impairment.[2]
* Facial features (dysmorphism) of patients with one form of pontocerebellar hypoplasia due to mutations in the CASK gene. A and B: patient at 1 year (A) and 4 years (B). C: patient, 18 months. D: patient, 13 years. E: patient, 13 years. F: patient, 12 years. Note minor facial dysmorphism: round face, small chin, well-drawn eyebrows in the younger patients; longer face, high and large nasal bridge, long nose, protruding maxilla, in the older patients.
* Magnetic resonance imaging (MRI) examples of patients with pontocerebellar hypoplasia with CASK mutations. A. Sagittal images showing different degrees of hypoplasia (incomplete formation) of the pons and vermis (parts of the brain). Numbers represent different patients. Figure 9a shows an MRI of a patient at age 4 months and figure 9b shows the same patient at age 11 years. There is no progression of the lesions between successive MRI in patient 9. Note that in all patients, the pons is very small but has a relative sparing of its bulging, mainly in its superior part. Hypoplasia predominates at the lower part of the pons. Vermis hypoplasia is very variable, severe in patient 13, very slight in patient 10-11-12 and also predominates at the inferior part. B. Coronal images showing varying degrees of cerebellar hemispheric (one of two halves of a part of the brain) hypoplasia. Hemispheres are frequently asymmetric. Note that the vermis does not protrude from the hemispheres indicating similar involvement of the vermis and the hemispheres. This pattern is different from that of PCH2 in which the vermis is relatively spared leading to the classic image of a "dragonfly", the protruding vermis being the body of the dragonfly and the hemispheres, the wings.
The following values seem to be aberrant in children with CASK gene defects: lactate, pyruvate, 2-ketoglutaric acid, adipic acid, and suberic acid which seems to support the thesis that CASK affects mitochondrial function.[3]
## Causes[edit]
Pontocerebellar hypoplasia is caused by mutations in genes including VRK1 (PCH1); TSEN2, TSEN34 (PCH2); RARS2 (PCH6); and TSEN54 (PCH2 and PCH4). The genes associated with PCH3 and PCH5 have not yet been identified.[2]
The mutated genes in PCH are autosomal recessive, which means that parents of an affected child each carry only one copy of the damaged gene. In each parent the other copy performs its proper function and they display no signs of PCH. A child inheriting two damaged copies of the gene will be affected by PCH.[2]
## Mechanism[edit]
Mutations in the genes that cause PCH produce faults in the production of chemicals, usually enzymes, that are required for the development of nerve cells (neurons) and for properly processing RNA, which is needed for any cell to function normally. The exact mechanism by which PCH affects the development of the cerebellum and pons is not well understood.[2]
## Diagnosis[edit]
### Classification[edit]
Pontocerebellar hypoplasia is classified as follows:[4]
Type OMIM Gene Locus Distinctive features Alternate names
PCH1A 607596 VRK1 14q32 Infantile onset anterior horn cell degeneration resulting in progressive muscle atrophy; resembles infantile spinal muscular atrophy[5] Spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH)
PCH1B 614678 EXOSC3 9p13.2 Cerebellar and spinal motor neuron degeneration beginning at birth and resulting in decreased body tone, respiratory insufficiency, muscle atrophy, progressive microcephaly and global developmental delay[6]
PCH2A 277470 TSEN54 17q25.1 Dyskinetic movements, seizures (frequently) Volendam neurodegenerative disease
PCH2B 612389 TSEN2 3p25.2
PCH2C 612390 TSEN34 19q13.42
PCH2D 613811 SEPSECS 4p15.2 Progressive cerebello-cerebral atrophy (PCCA)
PCH2E 615851 VPS53 17p13.3 Profound mental retardation, progressive microcephaly, spasticity, and early-onset epilepsy[7]
PCH2F 617026 TSEN15 1q25.3 Variable neurologic signs and symptoms, including cognitive and motor delay, poor or absent speech, seizures, and spasticity
PCH3 608027 PCLO 7q11–q21 Seizures, short stature, optic atrophy, progressive microcephaly, severe developmental delay; described only in a handful of cases.[8] CLAM-PCH, cerebellar atrophy with progressive microcephaly
PCH4 225753 TSEN54 17q25.1 Severe prenatal form of PCH2 with excess fluid in the amniotic sac, muscle contractures, brief involuntary muscle twitching, brief episodes without breathing, and early death following birth
PCH5 610204 TSEN54 17q25.1 Severe prenatal form, described in one family Olivopontocerebellar hypoplasia (OPCH)
PCH6 611523 RARS2 6q15 Severe encephalopathy in the newborn with hypotonia, and inconstantly: intractable seizures, edema, increased lactate blood levels, mitochondrial respiratory chain defects
PCH7 614969 TOE1 1p34.1 Hypotonia, apneic episodes, seizures, vanishing testis[9][10]
PCH8 614961 CHMP1A 16q24.3 Severe psychomotor retardation, abnormal movements, hypotonia, spasticity, and variable visual defects[11]
PCH9 615809 AMPD2 1p13.3 Severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy, thin corpus callosum, and delayed myelination[12]
PCH10 615803 CLP1 11q12.1 Severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy and delayed myelination[13]
Pontine and cerebellar hypoplasia is also observed in certain phenotypes of X-linked mental retardation – so called MICPCH.
Another gene that has been associated with this condition is coenzyme A synthase (COASY).[14]
## Treatment[edit]
This section is empty. You can help by adding to it. (December 2017)
## Outcomes[edit]
The severity of different forms of PCH varies, but many children inheriting the mutated gene responsible do not survive infancy[15] or childhood; nevertheless, some individuals born with PCH have reached adulthood.[2]
## See also[edit]
* Mental retardation and microcephaly with pontine and cerebellar hypoplasia
## References[edit]
1. ^ Millen KJ, Gleeson JG (February 2008). "Cerebellar development and disease". Curr Opin Neurobiol. 18 (1): 12–9. doi:10.1016/j.conb.2008.05.010. PMC 2474776. PMID 18513948.
2. ^ a b c d e f "Pontocerebellar hypoplasia". Genetics Home Reference. U.S. National Library of Medicine. December 2009. Retrieved 20 September 2014.
3. ^ Mukherjee, K; Slawson, JB; Christmann, BL; Griffith, LC (2014). "Neuron-specific protein interactions of Drosophila CASK-β are revealed by mass spectrometry". Frontiers in Molecular Neuroscience. 7: 58. doi:10.3389/fnmol.2014.00058. PMC 4075472. PMID 25071438.
4. ^ Online Mendelian Inheritance in Man (OMIM): [1]
5. ^ Online Mendelian Inheritance in Man (OMIM): 607596
6. ^ Online Mendelian Inheritance in Man (OMIM): 614678
7. ^ Online Mendelian Inheritance in Man (OMIM): 615851
8. ^ Online Mendelian Inheritance in Man (OMIM): 608027
9. ^ Anderson, C; Davies, JH; Lamont, L; Foulds, N (April 2011). "Early pontocerebellar hypoplasia with vanishing testes: A new syndrome?". American Journal of Medical Genetics Part A. 155A (4): 667–72. doi:10.1002/ajmg.a.33897. PMID 21594990.
10. ^ Namavar, Y; Barth, PG; Poll-The, BT; Baas, F (2011). "Classification, diagnosis and potential mechanisms in pontocerebellar hypoplasia". Orphanet Journal of Rare Diseases. 6: 50. doi:10.1186/1750-1172-6-50. PMC 3159098. PMID 21749694.
11. ^ Online Mendelian Inheritance in Man (OMIM): 614961
12. ^ Online Mendelian Inheritance in Man (OMIM): 615809
13. ^ Online Mendelian Inheritance in Man (OMIM): 615803
14. ^ van Dijk T, Ferdinandusse S, Ruiter JPN, Alders M, Mathijssen IB, Parboosingh JS, Innes AM, Meijers-Heijboer H, Poll-The BT, Bernier FP, Wanders RJA, Lamont RE, Baas F (2018) Biallelic loss of function variants in COASY cause prenatal onset pontocerebellar hypoplasia, microcephaly, and arthrogryposis. Eur J Hum Genet doi: 10.1038/s41431-018-0233-0
15. ^ Basson MA, Wingate RJ (September 2013). "Congenital hypoplasia of the cerebellum: developmental causes and behavioral consequences". Front Neuroanat. 7: 29. doi:10.3389/fnana.2013.00029. PMC 3759752. PMID 24027500.
## External links[edit]
Classification
D
* ICD-10: Q04.3
* MeSH: C580383 C580383, C580383
External resources
* Orphanet: 98523
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Diseases of the nervous system, primarily CNS
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* For more detailed coverage, see Template:Demyelinating diseases of CNS
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* Intracranial hypertension
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* Brain herniation
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SA
* Friedreich's ataxia
* Ataxia–telangiectasia
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* UMN only:
* Primary lateral sclerosis
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* LMN only:
* Distal hereditary motor neuronopathies
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* SMA
* SMAX1
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* SMA-PCH
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* both:
* Amyotrophic lateral sclerosis
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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
| Pontocerebellar hypoplasia | c0266468 | 1,421 | wikipedia | https://en.wikipedia.org/wiki/Pontocerebellar_hypoplasia | 2021-01-18T19:08:05 | {"gard": ["10977", "8168"], "mesh": ["C580383"], "umls": ["C0266468"], "orphanet": ["98523"], "wikidata": ["Q1698867"]} |
Benign rolandic epilepsy (BRE) is the most common form of childhood epilepsy. It is referred to as "benign" because most children outgrow the condition by puberty. This form of epilepsy is characterized by seizures involving a part of the brain called the rolandic area. These seizures typically begin between the ages of 3 and 12 years and occur during the nighttime. Other features of BRE include headaches or migraines and behavioral and/or learning differences. BRE is thought to be a genetic disorder because most affected individuals have a family history of epilepsy. Treatment for BRE may depend on the symptoms and severity in each person. Because BRE resolves on its own before adulthood, many children with BRE who have infrequent seizures that only occur at night do not take anti-epileptic drugs (AEDs). However, there have been studies suggesting that BRE may cause lasting cognitive or behavioral problems in some people. Medication is more likely to be recommended in children with frequent or daytime seizures, cognitive impairment, or a learning disorder. Each family must consult with their physician(s) and make their own decision about whether to treat BRE.
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*[AA]: Adrenergic agonist
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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
| Benign rolandic epilepsy (BRE) | c2363129 | 1,422 | gard | https://rarediseases.info.nih.gov/diseases/10287/benign-rolandic-epilepsy-bre | 2021-01-18T18:01:49 | {"mesh": ["D019305"], "omim": ["117100"], "synonyms": ["Benign rolandic epilepsy of childhood (BREC)", "Benign epilepsy with centro-temporal spikes (BECTS)", "Benign epilepsy of childhood with centrotemporal spikes (BECCT)"]} |
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: "Splenic sequestration crisis" – news · newspapers · books · scholar · JSTOR (February 2019) (Learn how and when to remove this template message)
Splenic sequestration crisis (SSC) is a life-threatening illness common in pediatric patients with homozygous sickle cell disease and beta thalassemia. Up to 30% of these children may develop SSC with a mortality rate of up to 15%. This crisis occurs when splenic vaso-occlusion causes a large percentage of total blood volume to become trapped within the spleen. Clinical signs include severe, rapid drop in hemoglobin leading to hypovolemic shock and death. Pediatric patients with sickle cell disease and beta thalassemia experience multiple splenic infarcts, resulting in splenic fibrosis and scarring. Over time, this leads to a small, auto infarcted spleen typically by the time patients reach adulthood. Splenic sequestration crisis can only occur in functioning spleens which may be why this crisis is rarely seen in adults. However, late adolescent or adult patients in this group who maintain splenic function may develop splenic sequestration crisis.[1]
## References[edit]
1. ^ Chapman, J; Azevedo, AM (2018). "Splenomegaly". Treasure Island (FL): StatPearls Publishing. PMID 28613657. Retrieved 2019-02-26 – via NCBI Bookshelf.
* v
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Human spleen
Structure
* Hilum
* Trabeculae
Red pulp
* Cords of Billroth
* Marginal zone
White pulp
* Periarteriolar lymphoid sheaths
* Germinal center
Blood flow
* Trabecular arteries
* Trabecular veins
Pain
* Splenomegaly
* Splenic abscess
* Splenic infarction
* Spleen rupture
* Splenic injury
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*[AA]: Adrenergic agonist
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*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Splenic sequestration crisis | c1536066 | 1,423 | wikipedia | https://en.wikipedia.org/wiki/Splenic_sequestration_crisis | 2021-01-18T19:03:21 | {"wikidata": ["Q63430622"]} |
A rare, autosomal recessive, multiple congenital anomalies/dysmorphic syndrome characterized mainly by developmental delay, variable intellectual disability, microcephaly, cerebellar hypoplasia, dysmorphic features (central incisors macrodontia and slender fingers), short stature and variable congenital anomalies.
## Epidemiology
To date, ten patients carrying biallelic BRF1 variants have been reported in the literature.
## Clinical description
The clinical features of the syndrome include developmental delay and intellectual disability. Congenital microcephaly is present in all patients with [occipital frontal circumference recorded and with progressive deceleration. Postnatal growth retardation occurred in all patients with height last evaluation between -2.5 and -5 SD. The most constant dysmorphic features include central incisors macrodontia and slender fingers. Laryngomalacia, tracheomalacia, congenital heart defect, sensorineural hearing impairment and inner ear malformation have been reported. Brain malformations, as detected on magnetic resonance imaging, may include cerebellar hypoplasia, corpus callosum hypoplasia and, more variably, enlarged cisterna magna and enlarged lateral ventricles.
## Etiology
The disorder is due to biallelic variants in the BRF1 (14q32.33) gene; the pathogenic variants reported are missense variants, with only one frameshift mutation identified. All variants affect protein residues located within the cyclin 2 protein domain.
## Diagnostic methods
All patients reported had been diagnosed by next generation sequencing.
## Differential diagnosis
The disorder is distinguished from other intellectual disability syndromes mainly by short stature and progressive microcephaly. Prominent upper incisors is a remarkable sign.
## Antenatal diagnosis
Where the mutations has been identified previously in a proband, prenatal molecular genetic testing could be offered.
## Genetic counseling
The pattern of inheritance is autosomal recessive. Families with an affected child should be counselled that there is a recurrence risk of 25% for each pregnancy.
## Management and treatment
Standard management is indicated for intellectual disability and postnatal growth retardation. Echocardiography, abdominal ultrasound and hearing evaluation is recommended at birth. Surveillance should include frequent monitoring of growth and development. Regular ophthalmological follow up is recommended.
## Prognosis
Patients reported with poor prognosis are related to complex heart defects.
* European Reference Network
*[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
| Cerebellar-facial-dental syndrome | c4015495 | 1,424 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=444072 | 2021-01-23T18:21:40 | {"omim": ["616202"], "icd-10": ["Q87.0"], "synonyms": ["Cerebellofaciodental syndrome"]} |
Hecht (1971) described a family, presumably his own, in which a male and 2 sons of his brother had exquisite sensitivity to insect stings. This is a situation of possible genetic sensitivity to an environmental insult, comparable to familial farmer's lung and pulmonary edema of mountaineers (178400), as well as to less esoteric and more clearly established examples such as favism, suxamethonium sensitivity, and malignant hyperpyrexia of anesthesia.
Inheritance \- Autosomal dominant Skin \- Hypersensitivity to insect stings ▲ Close
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*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| INSECT STINGS, HYPERSENSITIVITY TO | c1840171 | 1,425 | omim | https://www.omim.org/entry/147540 | 2019-09-22T16:39:24 | {"omim": ["147540"]} |
## Description
Age-related cataracts are one of the leading causes of visual impairment and blindness among the elderly worldwide. Among age-related cataracts, cortical opacities rank as the second most common type (Iyengar et al., 2004).
The preferred title/symbol of this entry was formerly 'Cataract, Age-Related Cortical, 1; ARCC1.'
Mapping
To identify susceptibility loci for cortical cataracts, Iyengar et al. (2004) genotyped a subset of families from the Beaver Dam Eye Study (performed in the population of Beaver Dam, Wisconsin) and did a model-free genomewide linkage analysis for markers linked to a quantitative measure of cortical opacity. They obtained evidence for linkage at marker D1S1622 on chromosome 1p35 (P less than 0.0002) and at marker D6S1053 on chromosome 6q12 (p less than 0.00008) in the initial scan. Five additional regions ( on chromosomes 1q31, 2p24, 2q11, 4q28, and 15q13) had suggestive linkage (p equal to or less than 0.01 or lod equal to or more than 1.18). The region on 6p12-q12 was selected for fine mapping, which showed that significant evidence of linkage remained for marker D6S1053 in this region (p less than 0.00005). Few regions identified in this scan had previously been implicated in congenital or age-related cataracts.
Inheritance
Congdon et al. (2005) quantified the risk for age-related cortical cataract and posterior subcapsular cataract (PSC) associated with having an affected sib after adjusting for known environmental and personal risk factors. Multivariate analysis revealed the magnitude of heritability for ARCC to be 24%, whereas that for PSC was not statistically significant (4%). The model revealed that increasing age, female gender, a history of diabetes, and black race increased the odds of ARCC, whereas higher levels of provitamin A were protective. A history of diabetes and steroid use increased the odds for PSC. Congdon et al. (2005) concluded that there is a significant genetic effect for ARCC but not for PSC.
Pathogenesis
Tan et al. (2007) studied the association of statin use with long-term incident cataract in the Blue Mountains Eye Study cohort. After controlling for age, gender, and other factors, statin use was found to reduce by 50% the risk of cataract development, principally nuclear or cortical cataract subtypes.
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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
| CATARACT 28 | c1836942 | 1,426 | omim | https://www.omim.org/entry/609026 | 2019-09-22T16:06:50 | {"mesh": ["C563812"], "omim": ["609026"], "synonyms": ["Alternative titles", "CATARACT, AGE-RELATED CORTICAL, 1"]} |
## Summary
### Clinical characteristics.
Coffin-Siris syndrome (CSS) is classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, distinctive facial features, hypotonia, hirsutism/hypertrichosis, and sparse scalp hair. Congenital anomalies can include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Other findings commonly include feeding difficulties, slow growth, ophthalmologic abnormalities, and hearing impairment.
### Diagnosis/testing.
Before the molecular basis was known, the diagnosis of CSS was based on clinical findings. With the recent detection of heterozygous pathogenic variants in ARID1A, ARID1B, SMARCA4, SMARCB1, SMARCE1, or SOX11 in some (but not all) individuals with CSS, the diagnostic features have become more clearly described for classic cases. A few individuals diagnosed with CSS on a clinical basis have been found to have pathogenic variants in SMARCA2 or PHF6; on reevaluation, the phenotype of these individuals was most consistent with Nicolaides-Baraitser syndrome or Borjeson-Forssman-Lehmann syndrome, respectively.
### Management.
Treatment of manifestations: Occupational, physical, and/or speech therapies to optimize developmental outcomes. Feeding therapy, nutritional supplementation and/or gastrostomy tube placement as needed to meet nutritional needs. Routine management of ophthalmologic abnormalities and hearing loss.
Surveillance: Yearly evaluation by a developmental pediatrician to assess developmental progress and therapeutic and educational interventions; follow up with a gastroenterologist and feeding specialists as needed to monitor feeding and weight gain. Routine follow up of ophthalmologic and/or audiologic abnormalities.
### Genetic counseling.
CSS caused by a heterozygous pathogenic variant in one of six genes (ARID1A, ARID1B, SMARCA4, SMARCB1, SMARCE1, and SOX11) is inherited in an autosomal dominant manner, but most commonly results from a de novo pathogenic variant. If the pathogenic variant has been identified in a family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
## Diagnosis
Formal diagnostic criteria for Coffin-Siris syndrome (CSS) have not been established; however, several key features are useful in making a clinical diagnosis.
### Suggestive Findings
Coffin-Siris syndrome (CSS) should be suspected in individuals with the following findings [Fleck et al 2001, Schrier et al 2012, Kosho et al 2014b, Santen et al 2014]:
* Fifth-digit nail / distal phalanx hypoplasia/aplasia. Typically, individuals with a clinical diagnosis of CSS have either aplasia or hypoplasia of the distal phalanx or absence of the nail, typically involving the fifth finger, but other digits may also be affected (Figure 1C, D, E, F). Toes can also be affected, where the finding tends to involve multiple digits.
* Developmental or cognitive delay of variable degree
* Facial features [Schrier et al 2012]. Individuals with typical features demonstrate a wide mouth with thick, everted upper and lower lips, broad nasal bridge with broad nasal tip, thick eyebrows, and long eyelashes. Together, these features can give a suggestion of coarseness in individuals with CSS (Figure 1A, B).
* Hypotonia that is central in origin
* Hirsutism/hypertrichosis. Hair growth in atypical areas (e.g., the back) or excessive hair growth on the arms or face
* Sparse scalp hair, especially in infancy, particularly in the temporal regions
#### Figure 1.
Coffin-Siris syndrome classic features Facial features (i.e., bushy eyebrows, coarse facies, and thick, everted lips) in (A) a clinically diagnosed boy age five years and (B) a clinically diagnosed man age 29 years
### Establishing the Diagnosis
The diagnosis of CSS is established in a proband with identification of a heterozygous pathogenic variant in one of the genes listed in Table 1.
Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing:
* Serial single-gene testing in the order in which pathogenic variants most commonly occur may be considered:
1.
Sequence analysis for ARID1B is performed first, followed by deletion/duplication testing if no pathogenic variant is found.
2.
If no ARID1B pathogenic variant is identified, sequence analysis followed by deletion/duplication testing should be performed on the other genes (in order of the likelihood of identifying a pathogenic variant: SMARCA4, SMARCB1, ARID1A, PHF6, SMARCE1, SOX11, SMARCA2).
Note: Evidence indicates that pathogenic variants in SMARCA4, SMARCB1, and SMARCE1 act through a gain-of-abnormal-function mechanism, suggesting that large pathogenic deletions or duplications are unlikely to occur; however, in-frame deletions or duplications of relevant domains may be pathogenic; one such deletion in SMARCA4 has been reported (see Table 1 and Molecular Genetics).
* A multigene panel that includes ARID1B, SMARCA4, SMARCB1, ARID1A, PHF6, SMARCE1, SOX11, SMARCA2 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 provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
* More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel; see A multigene panel) fails to confirm a diagnosis in an individual with features of CSS. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
### Table 1.
Molecular Genetic Testing Used in Coffin-Siris Syndrome
View in own window
Gene 1Proportion of CSS Attributed to Pathogenic Variants in Gene 2Proportion of Pathogenic Variants 3 Detected by Method 4
Sequence analysis 5Gene-targeted deletion/duplication analysis 6
ARID1A8/172 (5%)8/80/8
ARID1B64/172 (37%)59/643/60 7
SMARCA2 85/172 (2%)4/51/5
SMARCA412/172 (7%)12/120/12
SMARCB112/171 (7%)12/120/13
SMARCE13/171 (2%)3/30/3
SOX112/92 (2%) 95/12 10Unknown 11; 7 individuals w/deletions & a CSS phenotype have been reported 12
PHF6 132/37 (5%) 142/20/2
Unknown 1569/172 (40%)NA
1\.
See Table A. Genes and Databases for chromosome locus and protein.
2\.
Numbers represent a compilation of unique cases in reports of cohorts of clinically ascertained patients with CSS [Tsurusaki et al 2012, Santen et al 2013, Wieczorek et al 2013, Tsurusaki et al 2014b] except as indicated with a footnote.
3\.
See Molecular Genetics for information on allelic variants detected in these genes.
4\.
Number of individuals with an identified pathogenic variant / number of individuals tested
5\.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
6\.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Mosaic pathogenic variants have been noted for ARID1A [Santen et al 2013, Wieczorek et al 2013].
7\.
Microdeletions of chromosome 6q25.3 that include ARID1B have been reported in: (a) children with CSS ascertained prior to the understanding of the molecular basis of CSS [Tsurusaki et al 2012]; (b) children ascertained with a microdeletion containing ARID1B and secondarily noted to have features similar to CSS [Santen et al 2012]; and (c) individuals with mildly or variably syndromic intellectual disability [Nagamani et al 2009, Halgren et al 2012, Hoyer et al 2012, Michelson et al 2012] for whom available clinical information is insufficient to determine the similarity to CSS. Of note, these individuals may have complex clinical findings due to the involvement of additional genes surrounding the ARID1B locus.
8\.
Reevaluation of an individual initially thought to have CSS concluded that findings were more consistent with Nicolaides-Baraitser syndrome [Tsurusaki et al 2012, Van Houdt et al 2012]; however, since a number of individuals with SMARCA2 pathogenic variants were initially ascertained as CSS, the authors have included these numbers for comparison purposes. See Differential Diagnosis.
9\.
Tsurusaki et al [2014a]
10\.
Tsurusaki et al [2014a], Hempel et al [2016]
11\.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
12\.
Hempel et al [2016]
13\.
Individuals initially ascertained as CSS when younger have been found to have pathogenic variants in PHF6. Most of these have acquired facial features more consistent with Borjeson-Forssman-Lehmann syndrome as they age [Wieczorek et al 2013]. See Differential Diagnosis.
14\.
Wieczorek et al [2013]
15\.
In these studies, approximately 40% (69/172) of individuals with CSS did not have a pathogenic variant in one of the known genes [Tsurusaki et al 2012, Santen et al 2013, Wieczorek et al 2013, Tsurusaki et al 2014b].
Karyotype and chromosomal microarray (CMA). Many individuals who present with congenital anomalies and developmental delay have their chromosomes evaluated through karyotype and/or CMA as part of the initial evaluation. If an individual presenting with features of CSS does not have a pathogenic variant identified by the testing described, a karyotype and/or CMA should be considered based on the occurrence of rare rearrangements that have been reported to cause CSS [Backx et al 2011, Halgren et al 2012, Malli et al 2014].
## Clinical Characteristics
### Clinical Description
The following information has been compiled from data included in two reports by the Coffin-Siris Syndrome International Collaborators [Kosho et al 2014b, Santen et al 2014]. This section focuses on features common to the molecular subtypes; the findings that vary in frequency or severity between genetic etiologies are noted in Genotype-Phenotype Correlations.
#### Early Characteristics
Prenatal findings are typically unremarkable, with growth within normal limits. Rarely, CNS or cardiac anomalies, IUGR, and microcephaly have been noted.
Infancy. Although many individuals with Coffin-Siris syndrome (CSS) may not be clinically distinguishable at birth, several of the congenital anomalies may be noted:
* Hypoplasia of the fifth digits/nails. Most individuals have at a minimum brachydactyly of the fifth digit (seen in 65% of affected infants) and hypoplasia of one or more nails (80%). It should be noted that some individuals with a molecularly confirmed diagnosis of CSS have little or no fifth digit involvement.
* Dysmorphic facial features (~30% at birth). Because facial features typically coarsen over time, the characteristic facies may not be apparent until later in childhood.
* Hirsutism often noted
* Malformations affecting the CNS and cardiac and genitourinary systems (see Findings in Childhood)
* Other findings appearing in infancy that may be the first indication of CSS:
* Feeding problems (90%) and slow growth
* Hypotonia (75%)
* Seizures (50%)
* Hearing impairment (45%)
* Visual impairment (~40%)
#### Findings in Childhood
Developmental delays. The developmental/cognitive delay is typically apparent when delayed developmental milestones are noted and/or formal cognitive testing is performed.
* On average, children with CSS learn to sit at 12 months, walk at 30 months, and speak their first words at 24 months.
* Expressive language is more severely affected than receptive language, with no speech in a significant subset of individuals.
* Intellectual disability is present in most and typically moderate to severe (IQ range: 40 to 69); however, IQ as high as 97 has been reported [Santen et al 2012].
* Behavioral abnormalities include hyperactivity (~10%), aggressiveness (~10%), and occasionally autistic features.
Brain/CNS issues
* CNS malformations include Dandy-Walker variant, gyral simplification, and agenesis of the corpus callosum.
* Seizures and tics. A variety of types of seizures are reported. There is no typical age of onset for seizures or tics.
* Hypotonia (75%), noted in infancy, is typically persistent.
Facial features (see Figure 1)
* Coarse facies (95%)
* Thick eyebrows (90%)
* Prominent eyelashes (85%)
* Flat nasal bridge (50%)
* Short nose (50%)
* Anteverted nares (50%)
* Broad nasal tip (75%)
* Wide nasal base (50%)
* Thick alae nasi (70%)
* Broad philtrum (70%)
* Wide mouth (80%)
* Thin vermilion of the upper lip (50%)
* Thick vermilion of the lower lip (80%)
Musculoskeletal findings
* Small nails on 5th finger or toe (80%)
* Clinodactyly (40%)
* Delayed bone age (40%)
* Joint laxity (66%)
* Scoliosis (30%)
* Hernias (10%)
Skin and hair findings
* Hypertrichosis (95%) may appear in areas unexpected for an individual’s ethnicity (i.e., back, shoulders).
* A low anterior hairline is common (75%).
* Sparse scalp hair (60%); hair may appear at an appropriate age but may be very thin.
Feeding difficulties. Children may have oral aversion or difficulty feeding in the absence of any evident intestinal malformations.
Growth issues
* Weight and height is below the 50th percentile for most, and below the 5th percentile for 20%.
* Bone age typically lags about two to three years behind chronologic age.
* Dentition is delayed (40%).
Hearing impairment (45%) is often associated with recurrent upper respiratory tract infections.
Ophthalmologic abnormalities
* Ptosis (50%)
* Strabismus (50%)
* Myopia (20%)
Frequent infections (60%). These are poorly characterized, but often are consistent with upper respiratory viral infections.
Malformations
* Cardiac anomalies (35%) including ventricular septal defects, atrial septal defects, tetralogy of Fallot, and patent ductus arteriosus
* Renal and genitourinary malformations (~35%) including cryptorchidism most commonly, but also horseshoe kidney, hypospadias, and other abnormalities
Tumor risk. Although pathogenic variants in a subset of the genes causing CSS have been implicated in tumorigenesis (see Cancer and Benign Tumors), data on tumor risk in CSS are lacking. Tumors have been reported in three individuals with CSS:
* Hepatoblastoma was reported in one of eight individuals with an ARID1A pathogenic variant [Tsurusaki et al 2012, Kosho et al 2014b].
* An individual with a 4.2-Mb deletion that included (among 14 genes) ARID1B developed papillary thyroid cancer [Vengoechea et al 2014].
* Multiple studies have reported an individual who has CSS, schwannomatosis, and a pathogenic variant in SMARCB1 [Carter et al 2012, Schrier et al 2012, Gossai et al 2015].
#### Prognosis
In the absence of long-term studies, information on life span in individuals with Coffin-Siris syndrome is not available. Children have been reported to die of aspiration pneumonia and/or seizures, although this is not common [Schrier et al 2012]. Efforts are in progress by the Coffin-Siris Syndrome International Consortium [Kosho et al 2014a] to better understand prognosis in individuals with CSS.
### Genotype-Phenotype Correlations
Genotype-phenotype correlations have been seen in clinically diagnosed individuals with pathogenic variants in ARID1A, ARID1B, SMARCA4, SMARCB1, SMARCE1, and SOX11 [Wieczorek et al 2013, Kosho et al 2014b, Santen et al 2014, Tsurusaki et al 2014a, Hempel et al 2016].
ARID1A. Individuals with a pathogenic variant in ARID1A displayed a wide spectrum of severity; some exhibited only mild intellectual disability while others had severe intellectual disability. Some individuals also had serious medical complications (e.g., aspiration pneumonia, seizures) leading to death.
ARID1B. Individuals with pathogenic ARID1B variants are typically at the milder end of the spectrum of CSS and often have normal growth. Moderately severe feeding problems are noted in two thirds, seizures in one third, and hypoplasia of the corpus callosum in one third. Facial gestalt is consistent with CSS, albeit at times milder, with hypertelorism and anteverted nares more commonly noted. Distal digital hypoplasia is usually limited to the fifth digit.
SMARCA4. Individuals with a pathogenic variant in SMARCA4 appear to have growth impairment that is mild prenatally and mild to moderate postnatally; sucking/feeding difficulty is almost always observed. While individuals can sometimes have severe developmental delays, significant behavioral challenges tend to be more characteristic. Facial features have demonstrated less coarseness, while hypoplastic fifth fingers or toes and hypoplastic fifth fingernails or toenails are a near-constant finding (and hypoplasia of other fingernails or toenails an occasional finding). Prominence of interphalangeal joints and distal phalanges is also noted in some.
SMARCB1. Individuals with a pathogenic variant in SMARCB1 typically have a more severely affected phenotype and all have growth impairment, usually mild prenatally and moderate to severe postnatally, with sucking/feeding difficulty. Structural CNS abnormalities with hypotonia and seizures are typical findings accompanied by severe developmental delay/intellectual disability; individuals are typically nonverbal. Typical skeletal findings include hypoplastic fifth fingers or toes, hypoplastic other fingernails or toenails, prominent distal phalanges, and scoliosis. Some individuals may walk independently. Gastrointestinal complications and hernia as well as cardiovascular and genitourinary complications are common.
SMARCE1. Individuals with pathogenic SMARCE1 variants tend to have severe intellectual disability, typical facial gestalt, and hypoplastic or absent fifth finger- and toenails associated with hypoplasia of other nails. The hands are characterized by long and slender fingers. Individuals are typically small for gestational age and have postnatal short stature and severe microcephaly, complex congenital heart defects, feeding difficulties, and seizures.
SOX11. Individuals display mild to severe intellectual and developmental delay, along with fifth-digit nail and distal phalangeal hypoplasia. Neurodevelopmental abnormalities tend to be more prevalent than organ-system or physical complications.
### Penetrance
Penetrance for Coffin-Siris syndrome appears to be complete.
More females than males with CSS were reported in the literature prior to 2001 [Fleck et al 2001]; however, in cases of molecularly confirmed CSS, male:female ratios are similar [Kosho et al 2014b, Santen et al 2014]. No evidence exists for X-linked dominant, sex-limited, or mitochondrial inheritance.
### Prevalence
Fewer than 200 individuals with molecularly confirmed Coffin-Siris syndrome have been reported, indicating that the diagnosis is rare. However, this is likely an underestimate, as not all individuals may have come to medical attention.
In addition, the identification of a pathogenic variant in ARID1B in some members of a large cohort with intellectual disability [Hoyer et al 2012] suggests that the prevalence of pathogenic variants in genes associated with CSS (and possibly of subtle phenotypic features of CSS) may be higher than currently appreciated among those with intellectual disability.
## Differential Diagnosis
Nicolaides-Baraitser syndrome (NCBRS) is characterized by sparse scalp hair, prominence of the interphalangeal joints and distal phalanges due to decreased subcutaneous fat, characteristic coarse facial features, microcephaly, seizures, and developmental delay/intellectual disability. Developmental delay / intellectual disability is severe in nearly half of individuals with NCBRS, moderate in a third, and mild in the remainder. Nearly a third never develop speech. Of note, after heterozygous SMARCA2 pathogenic variants were identified in NCBRS [Van Houdt et al 2012], reevaluation of an individual initially thought to have CSS determined that findings were more consistent with NCBRS [Tsurusaki et al 2012]. Inheritance is autosomal dominant; to date, all affected individuals have had a de novo SMARCA2 pathogenic variant.
Borjeson-Forssman-Lehmann syndrome (BFLS) (OMIM 301900) is typically characterized by males with severe intellectual disability, epilepsy, hypogonadism, hypometabolism, marked obesity, swelling of subcutaneous tissue of face, narrow palpebral fissure, and large but not deformed ears. Females with pathogenic variants in PHF6, which causes BFLS, demonstrate some phenotypic overlap with individuals with CSS [Wieczorek et al 2013]. The two syndromes, however, are still considered distinctly separate entities [Zweier et al 2013].
ARID2-related intellectual disability (OMIM 617808). Pathogenic variants in ARID2 have been identified in several individuals with a Coffin-Siris-like phenotype. Shang et al identified four individuals with de novo loss-of-function ARID2 variants in a cohort of 970 individuals with neurodevelopmental disorders and previously nondiagnostic testing [Shang et al 2015]. An additional three individuals with syndromic intellectual disability have been reported [Bramswig et al 2017, Van Paemel et al 2017]. An ARID2 de novo missense variant has also been reported in an individual with autism [Iossifov et al 2014]
Most individuals with ARID2 pathogenic variants demonstrate intellectual disability, hypotonia, and behavioral anomalies. Birth defects are not common. Several individuals have demonstrated very mild hypoplasia of the fifth fingernails and hypoplasia of the fifth toenails. Individuals with ARID2 pathogenic variants share some facial features with each other: coarse features, frontal bossing and high forehead, narrow palpebral fissures, flat nasal bridge, slightly broad nose with upturned nasal tip and thick, anteverted alae nasi, prominent philtrum, and a large mouth with a thick lower vermilion. While some of these features demonstrate overlap with Coffin-Siris syndrome, an assessment of a larger cohort of individuals with ARID2 pathogenic variants will be needed to determine whether it is clinically similar to or distinct from Coffin-Siris syndrome.
Mosaic trisomy 9. An individual with mosaic trisomy 9 had features similar to those of CSS, including facial features (wide, bulbous nose), hirsutism, and hypoplasia of the fifth digits [Kushnick & Adessa 1976].
Brachymorphism-onychodysplasia-dysphalangism (BOD) syndrome (OMIM 113477) is characterized by short stature, tiny dysplastic nails, short fifth fingers, a wide mouth with broad nose, and mild intellectual deficits [Verloes et al 1993, Elliott & Teebi 2000]. This latter characteristic is most likely to distinguish individuals with BOD syndrome from those with CSS, as the cognitive disability in CSS is nearly always moderate to severe. Inheritance appears to be autosomal dominant.
DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures) syndrome. Features in common with CSS include hypoplastic terminal phalanges and/or nail anomalies, deafness, and neurologic abnormalities. DOORS syndrome is inherited in an autosomal recessive manner and is caused by biallelic pathogenic variants in TBC1D24. (See TBC1D24-Related Disorders.)
Fetal alcohol spectrum (FAS). Small nails, prenatal and postnatal growth retardation, dysmorphic facial features, and cognitive disabilities may be seen in FAS.
Fetal hydantoin/phenytoin embryopathy. Small nails with hypoplasia of distal phalanges, dysmorphic facial features, digitalized thumbs, low hairline, short or webbed neck, growth retardation, and cognitive disabilities have been described in this syndrome, caused by prenatal exposure to phenytoin.
Mabry syndrome (hyperphosphatasia with mental retardation syndrome 1; OMIM 239300). Mabry syndrome is characterized by delayed development, seizures, coarse facial features, hypoplastic fifth digits, and elevated serum concentrations of alkaline phosphatase [Gomes & Hunter 1970, Kruse et al 1988, Thompson et al 2010]. It is inherited in an autosomal recessive manner and caused by biallelic pathogenic variants in PIGV [Krawitz et al 2010].
Cornelia de Lange syndrome (CdLS). Classic CdLS is characterized by distinctive craniofacial features (arched eyebrows, synophrys, upturned nose, small teeth, microcephaly); growth retardation; and limb anomalies, which can at times include fifth finger hypoplasia similar to CSS. Other findings may include cardiac defects, gastrointestinal anomalies, and genitourinary malformations. Pathogenic variants in NIPBL, SMC1A, SMC3, HDAC8, or RAD21 are causative. CdLS is inherited in an autosomal dominant (NIPBL, SMC3, and RAD21) or X-linked (SMC1A and HDAC8) manner.
4q deletion syndrome. This chromosome deletion syndrome results in a characteristic curved, volar, fifth-digit nail, which may resemble a hypoplastic distal phalanx.
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with Coffin-Siris syndrome (CSS), the following evaluations are recommended:
* Consultation with a clinical geneticist and/or genetic counselor
* Neurologic and/or developmental examination to record developmental milestones and identify neurologic symptoms or deficits
* Evaluation for occupational, speech, or physical therapy as needed
* Gastrointestinal evaluation for feeding difficulties or poor growth
* Dietary evaluation by a nutritionist as needed
* Ophthalmologic examination, including a dilated fundus examination and visual acuity
* Audiology evaluation with auditory brain stem response testing and otoacoustic emission testing to assess for hearing loss
* Echocardiogram to evaluate for structural cardiac defects
* Renal ultrasonography to evaluate for structural kidney or genitourinary anomalies
### Treatment of Manifestations
The following are appropriate:
* Occupational, physical, and/or speech therapies to optimize developmental outcomes
* Feeding therapy, nutritional supplementation, and/or gastrostomy tube placement as needed to meet nutritional needs
* Spectacles as needed to correct refractive errors and surgery as needed for strabismus and/or ptosis
* Hearing aids as needed
### Prevention of Secondary Complications
Therapies and interventions which can prevent secondary complications mirror the recommended treatments for an individual’s particular needs. This may include developmental therapies, appropriate cardiac, gastrointestinal, and neurologic evaluations and treatments, and ophthalmologic and audiologic surveillance.
### Surveillance
Surveillance includes the following:
* Yearly evaluation by a developmental pediatrician to assess developmental progress and therapeutic and educational interventions
* Annual follow up with a gastroenterologist and feeding specialists as needed to monitor feeding and weight gain
* Regular follow up of ophthalmologic and/or audiologic abnormalities
Because of the rarity of tumors in CSS, the utility of tumor surveillance has not been determined.
### Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Pregnancy Management
As no females with CSS have been reported to reproduce, potential complications of pregnancy are unknown.
### Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Coffin-Siris Syndrome | c0265338 | 1,427 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK131811/ | 2021-01-18T21:33:55 | {"mesh": ["C536436"], "synonyms": ["Fifth Digit Syndrome"]} |
Four members of a family, father, daughter and 2 sons, presented with papulonodular eruptions, symmetric arthritis and ocular lesions. Zayid and Farraj (1973) described this condition as similar to, but distinct from, multicentric reticulohistiocytosis. The 4 affected family members showed multiple benign cutaneous histiocytic nodules on the face and limbs (no xanthelasmas or mucosal lesions were noted) and symmetric destructive seronegative rheumatoidlike polyarthritis. The father and 2 sons showed ocular lesions, including glaucoma, uveitis and cataracts. Histologically, skin lesions were described as 'granulomatous' with heavy, diffuse, chronic inflammatory infiltrate and increased vascularity, but no multinucleated giant cells were seen. Joint deformities were severe and response to steroid therapy was minimal. Onset was in early childhood for the sibs and in adolescence for the father. The similarities to and differences from dermochondrocorneal dystrophy of Francois (221800) should be noted. The disorder described in entry 186580 also has some similarities.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| HISTIOCYTIC DERMATOARTHRITIS | c1840551 | 1,428 | omim | https://www.omim.org/entry/142730 | 2019-09-22T16:40:10 | {"mesh": ["C564183"], "omim": ["142730"]} |
Iron-deficiency anemia
Other namesIron-deficiency anaemia
Red blood cells
SpecialtyHematology
SymptomsFeeling tired, weakness, shortness of breath, confusion, pallor[1]
ComplicationsHeart failure, arrhythmias, frequent infections[2]
CausesIron deficiency[3]
Diagnostic methodBlood tests[4]
TreatmentDietary changes, medications, surgery[3]
MedicationIron supplements, vitamin C, blood transfusions[5]
Frequency1.48 billion (2015)[6]
Deaths54,200 (2015)[7]
Iron-deficiency anemia is anemia caused by a lack of iron.[3] Anemia is defined as a decrease in the number of red blood cells or the amount of hemoglobin in the blood.[3] When onset is slow, symptoms are often vague such as feeling tired, weak, short of breath, or having decreased ability to exercise.[1] Anemia that comes on quickly often has more severe symptoms, including: confusion, feeling like one is going to pass out or increased thirst.[1] Anemia is typically significant before a person becomes noticeably pale.[1] Children with iron deficiency anemia may have problems with growth and development.[3] There may be additional symptoms depending on the underlying cause.[1]
Iron-deficiency anemia is caused by blood loss, insufficient dietary intake, or poor absorption of iron from food.[3] Sources of blood loss can include heavy periods, childbirth, uterine fibroids, stomach ulcers, colon cancer, and urinary tract bleeding.[8] Poor absorption of iron from food may occur as a result of an intestinal disorder such as inflammatory bowel disease or celiac disease, or surgery such as a gastric bypass.[8] In the developing world, parasitic worms, malaria, and HIV/AIDS increase the risk of iron deficiency anemia.[9] Diagnosis is confirmed by blood tests.[4]
Iron deficiency anemia [10]can be prevented by eating a diet containing sufficient amounts of iron or by iron supplementation.[11] Foods high in iron include meat, nuts, spinach, and foods made with iron-fortified flour.[12] Treatment may include dietary changes and dealing with underlying causes, for example medical treatment for parasites or surgery for ulcers.[3] Iron supplements and vitamin C may be recommended.[5] Severe cases may be treated with blood transfusions or iron injections.[3]
Iron-deficiency anemia affected about 1.48 billion people in 2015.[6] A lack of dietary iron is estimated to cause approximately half of all anemia cases globally.[13] Women and young children are most commonly affected.[3] In 2015, anemia due to iron deficiency resulted in about 54,000 deaths – down from 213,000 deaths in 1990.[7][14]
## Contents
* 1 Signs and symptoms
* 1.1 Child development
* 2 Cause
* 2.1 Parasitic disease
* 2.2 Blood loss
* 2.2.1 Menstrual bleeding
* 2.2.2 Gastrointestinal bleeding
* 2.3 Diet
* 2.4 Iron malabsorption
* 2.5 Pregnant women
* 2.6 Children
* 2.7 Blood donation
* 2.8 Hepcidin
* 3 Mechanism
* 4 Diagnosis
* 4.1 Blood tests
* 4.2 Screening
* 5 Treatment
* 6 Epidemiology
* 7 References
* 8 External links
## Signs and symptoms[edit]
Iron-deficiency anemia may be present without a person experiencing symptoms.[15] If symptomatic, patients may present with the sign of pallor (reduced oxyhemoglobin in skin or mucous membranes), and the symptoms of fatigue, lightheadedness, decreased exercise tolerance, headache, and weakness.[15] None of these symptoms (or any of the others below) are sensitive or specific. The symptom most suggestive of iron deficiency anemia in children is pallor of mucous membranes (primarily the conjunctiva). Even so, a large study showed that pallor of the mucous membranes is only 28% sensitive and 87% specific (with high predictive value) in distinguishing children with anemia (defined as hemoglobin < 11.0 g/dl) and 49% sensitive and 79% specific in distinguishing severe anemia (hemoglobin < 7.0 g/dl).[16] Thus, this sign is reasonably predictive when present, but not helpful when absent, as only one-third to one-half of children who are anemic (depending on severity) will show pallor.
Iron deficiency anemia tends to develop slowly; therefore the body has time to adapt, and the disease often goes unrecognized for some time.[17] In severe cases, shortness of breath can occur.[18] Pica may also develop; of which consumption of ice, known as pagophagia, has been suggested to be the most specific for iron deficiency anemia.[17]
Other possible symptoms and signs of iron-deficiency anemia include:[3][17][18][19]
Koilonychia (spoon-shaped nails)
* Irritability
* Angina (chest pain)
* Palpitations (feeling that the heart is skipping beats or fluttering)
* Breathlessness
* Tingling, numbness, or burning sensations
* Glossitis (inflammation or infection of the tongue)
* Angular cheilitis (inflammatory lesions at the mouth's corners)
* Koilonychia (spoon-shaped nails) or nails that are brittle
* Poor appetite
* Dysphagia (difficulty swallowing) due to formation of esophageal webs (Plummer–Vinson syndrome)
* Restless legs syndrome[20]
### Child development[edit]
Iron-deficiency anemia is associated with poor neurological development, including decreased learning ability and altered motor functions.[21][22] This is because iron deficiency impacts the development of the cells of the brain called neurons. When the body is low on iron, the red blood cells get priority on iron and it is shifted away from the neurons of the brain. Exact causation has not been established, but there is a possible long-term impact from these neurological issues.[22]
## Cause[edit]
A diagnosis of iron-deficiency anemia requires further investigation into its cause.[23] It can be caused by increased iron demand, increased iron loss, or decreased iron intake.[24] Increased iron demand often occurs during periods of growth, such as in children and pregnant women.[25] For example, during stages of rapid growth, babies and adolescents may outpace their dietary intake of iron which can result in deficiency in the absence of disease or a grossly abnormal diet.[24] Iron loss is typically from blood loss.[25] One example of blood loss is by chronic gastrointestinal blood loss, which could be linked to a possible cancer.[23] In women of childbearing age, heavy menstrual periods can be a source of blood loss causing iron-deficiency anemia.[23] People who do not consume much iron in their diet, such as vegans or vegetarians, are also at increased risk of developing iron deficiency anemia.[15]
### Parasitic disease[edit]
The leading cause of iron-deficiency anemia worldwide is a parasitic disease known as a helminthiasis caused by infestation with parasitic worms (helminths); specifically, hookworms. The hookworms most commonly responsible for causing iron-deficiency anemia include Ancylostoma duodenale, Ancylostoma ceylanicum, and Necator americanus.[23][26] The World Health Organization estimates that approximately two billion people are infected with soil-transmitted helminths worldwide.[27] Parasitic worms cause both inflammation and chronic blood loss by binding to a human's small-intestinal mucosa, and through their means of feeding and degradation, they can ultimately cause iron-deficiency anemia.[17][26]
### Blood loss[edit]
Red blood cells contain iron, so blood loss also leads to a loss of iron. There are several causes of blood loss including menstrual bleeding, gastrointestinal bleeding, stomach ulcers, and bleeding disorders.[28] The bleeding may occur quickly or slowly. Slow, chronic blood loss within the body — such as from a peptic ulcer, angiodysplasia, inflammatory bowel disease, a colon polyp or gastrointestinal cancer (e.g., colon cancer)— can cause iron-deficiency anemia.
#### Menstrual bleeding[edit]
Menstrual bleeding is a common cause of iron deficiency anemia in women of child-bearing age.[28] Women with menorrhagia (heavy menstrual periods) are at risk of iron-deficiency anemia because they are at higher-than-normal risk of losing a larger amount blood during menstruation than is replaced in their diet. Most women lose about 40 mL of blood per cycle. Iron is lost with the blood. Some birth control methods, such as pills and IUDs, may decrease the amount of blood, therefore iron lost during a menstrual cycle.[28] Intermittent iron supplementation may be as effective a treatment in these cases as daily supplements and reduce some of the adverse effects of long term daily supplements.[29]
#### Gastrointestinal bleeding[edit]
The most common cause of iron deficiency anemia in men and post-menopausal women is gastrointestinal bleeding.[28] There are many sources of gastrointestinal tract bleeding including the stomach, esophagus, small intestine, and the large intestine (colon). Gastrointestinal bleeding can result from regular use of some groups of medication, such as non-steroidal anti-inflammatory drugs (e.g. aspirin), as well as antiplatelets such as clopidogrel and anticoagulants such as warfarin; however, these are required in some patients, especially those with states causing a tendency to form blood clots. Colon cancer is another potential cause gastrointestinal bleeding, thus iron deficiency anemia. Typically colon cancer occurs in older individuals[30] In addition, some bleeding disorders can cause gastrointestinal bleeding.[28] Two examples of bleeding disorders are von Willebrand disease and polycythemia vera.[28]
### Diet[edit]
In many countries, wheat flour is fortified with iron.[31]
The body normally gets the iron it requires from foods. If a person consumes too little iron, or iron that is poorly absorbed (non-heme iron), they can become iron deficient over time. Examples of iron-rich foods include meat, eggs, leafy green vegetables and iron-fortified foods. For proper growth and development, infants and children need iron from their diet.[32] For children, a high intake of cow's milk is associated with an increased risk of iron-deficiency anemia.[33] Other risk factors for iron-deficiency anemia include low meat intake and low intake of iron-fortified products.[33]
The National Academy of Medicine updated Estimated Average Requirements and Recommended Dietary Allowances in 2001. The current EAR for iron for women ages 14–18 is 7.9 mg/day, 8.1 for ages 19–50 and 5.0 thereafter (post menopause). For men the EAR is 6.0 mg/day for ages 19 and up. The Recommended Dietary Allowance is 15.0 mg/day for women ages 15–18, 18.0 for 19–50 and 8.0 thereafter. For men, 8.0 mg/day for ages 19 and up. (Recommended Dietary Allowances are higher than Estimated Average Requirements so as to identify amounts that will cover people with higher than average requirements.) The Recommended Dietary Allowance for pregnancy is 27 mg/day, and for lactation, 9 mg/day. For children ages 1–3 years it is 7 mg/day, 10 for ages 4–8 and 8 for ages 9–13.[34] The European Food Safety Authority refers to the collective set of information as Dietary Reference Values, with Population Reference Intakes instead of Recommended Dietary Allowances, and Average Requirements instead of Estimated Average Requirements. For women the Population Reference Intake is 13 mg/day ages 15–17 years, 16 mg/day for women ages 18 and up who are premenopausal and 11 mg/day postmenopausal. For pregnancy and lactation, 16 mg/day. For men the Population Reference Intake is 11 mg/day ages 15 and older. For children ages 1 to 14 the Population Reference Intake increases from 7 to 11 mg/day. The Population Reference Intakes are higher than the US Recommended Dietary Allowances, with the exception of pregnancy.[35]
### Iron malabsorption[edit]
Iron from food is absorbed into the bloodstream in the small intestine, primarily in the duodenum.[36] Iron malabsorption is a less common cause of iron-deficiency anemia, but many gastrointestinal disorders can reduce the body's ability to absorb iron.[37] There are different mechanisms that may be present.
In celiac disease, abnormal changes in the structure of the duodenum can decrease iron absorption.[38] Abnormalities or surgical removal of the stomach can also lead to malabsorption by altering the acidic environment needed for iron to be converted into its absorbable form.[37] If there is insufficient production of hydrochloric acid in the stomach, hypochlorhydria/achlorhydria can occur (often due to chronic H. pylori infections or long-term proton-pump inhibitor therapy), inhibiting the conversion of ferric iron to the absorbable ferrous iron.[38]
Bariatric surgery is associated with an increased risk of iron deficiency anemia due to malabsorption of iron.[39] During a Roux-en-Y anastamosis, which is commonly performed for weight management and diabetes control, the stomach is made into a small pouch and this is connected directly to the small intestines further downstream (bypassing the duodenum as a site of digestion). About 17-45% of people develop iron deficiency after a Roux-en-Y gastric bypass.[40]
### Pregnant women[edit]
Without iron supplementation, iron-deficiency anemia occurs in many pregnant women because their iron stores need to serve their own increased blood volume, as well as be a source of hemoglobin for the growing baby and for placental development.[32] Other less common causes are intravascular hemolysis and hemoglobinuria. Iron deficiency in pregnancy appears to cause long-term and irreversible cognitive problems in the baby.[41]
Iron deficiency affects maternal well-being by increasing risks for infections and complications during pregnancy.[42] Some of these complications include pre-eclampsia, bleeding problems, and perinatal infections.[42] Pregnancies where iron deficiency is present can lead to improper development of fetal tissues.[43] Oral iron supplementation during the early stages of pregnancy is suggested to decrease the adverse effects of iron-deficiency anemia throughout pregnancy and to decrease the negative impact that iron deficiency has on fetal growth.[42] Iron deficiency can lead to premature labor and to problems with neural functioning, including delays in language and motor development in the infant.[42]
Some studies show that women pregnant during their teenage years can be at greater risk of iron-deficiency anemia due to an already increased need for iron and other nutrients during adolescent growth spurts.[42]
### Children[edit]
Babies are at increased risk of developing iron deficiency anemia due to their rapid growth.[25] Their need for iron is greater than they are getting in their diet.[25] Babies are born with iron stores; however, these iron stores typically run out by 4–6 months of age. In addition, infants who are given cow's milk too early can develop anemia due to gastrointestinal blood loss.[25]
Children who are at risk for iron-deficiency anemia include:[44]
* Preterm infants
* Low birth weight infants
* Infants fed with cow's milk under 12 months of age
* Breastfed infants who have not received iron supplementation after age 6 months, or those receiving non-iron-fortified formulas
* Children between the ages of 1 to 5 years old who receive more than 24 ounces (700 mL) of cow milk per day
* Children with low socioeconomic status
* Children with special health care needs
* Children of Hispanic ethnicity[45]
* Children who are overweight[45]
### Blood donation[edit]
Frequent blood donors are also at risk for developing iron deficiency anemia.[46] When whole blood is donated, approximately 200 mg of iron is also lost from the body.[28] The blood bank screens people for anemia before drawing blood for donation. If the patient has anemia, blood is not drawn.[28] Less iron is lost if the person is donating platelets or white blood cells.[28]
### Hepcidin[edit]
Decreased levels of serum and urine hepcidin are early indicators of iron deficiency.[47] Hepcidin concentrations are also connected to the complex relationship between malaria and iron deficiency.[48]
## Mechanism[edit]
Anemia can result from significant iron deficiency.[37] When the body has sufficient iron to meet its needs (functional iron), the remainder is stored for later use in cells, mostly in the bone marrow and liver.[37] These stores are called ferritin complexes and are part of the human (and other animals) iron metabolism systems. Men store about 3.5 g of iron in their body, and women store about 2.5 g.[15]
Hepcidin is a peptide hormone produced in the liver that is responsible for regulating iron levels in the body. Hepcidin decreases the amount of iron available for erythropoesis (red blood cell production).[39] Hepcidin binds to and induces the degradation of ferroportin, which is responsible for exporting iron from cells and mobilizing it to the bloodstream.[39] Conditions such as high levels of erythropoesis, iron deficiency and tissue hypoxia inhibit hepcidin expression.[39] Whereas systemic infection or inflammation (especially involving the cytokine IL-6) or increased circulating iron levels stimulate hepcidin expression.[39]
Iron is a mineral that is important in the formation of red blood cells in the body, particularly as a critical component of hemoglobin.[23] About 70% of the iron found in the body is bound to hemoglobin.[15] Iron is primarily absorbed in the small intestine, in particular the duodenum and jejunum. Certain factors increase or decrease absorption of iron. For example, taking Vitamin C with a source of iron is known to increase absorption. Some medications such as tetracyclines and antacids can decrease absorption of iron.[15] After being absorbed in the small intestine, iron travels through blood, bound to transferrin, and eventually ends up in the bone marrow, where it is involved in red blood cell formation.[23] When red blood cells are degraded, the iron is recycled by the body and stored.[23]
When the amount of iron needed by the body exceeds the amount of iron that is readily available, the body can use iron stores (ferritin) for a period of time, and red blood cell formation continues normally.[37] However, as these stores continue to be used, iron is eventually depleted to the point that red blood cell formation is abnormal.[37] Ultimately, anemia ensues, which by definition is a hemoglobin lab value below normal limits.[3][37]
## Diagnosis[edit]
Blood smear of a person with iron-deficiency anemia at 40X enhancement
Conventionally, a definitive diagnosis requires a demonstration of depleted body iron stores obtained by bone marrow aspiration, with the marrow stained for iron.[49][50] However, with the availability of reliable blood tests that can be more readily collected for iron-deficiency anemia diagnosis, a bone marrow aspiration is usually not obtained.[51] Furthermore, a study published April 2009 questions the value of stainable bone marrow iron following parenteral iron therapy.[52] Once iron deficiency anemia is confirmed, gastrointestinal blood loss is presumed to be the cause until proven otherwise since it can be caused by an otherwise asymptomatic colon cancer. Initial evaluation must include esophagogastroduodenoscopy and colonoscopy to evaluate for cancer or bleeding of the gastrointestinal tract.
A thorough medical history is important to the diagnosis of iron-deficiency anemia. The history can help to differentiate common causes of the condition such as a menstruation in woman or the presence of blood in the stool.[53] A travel history to areas in which hookworms and whipworms are endemic may also be helpful in guiding certain stool tests for parasites or their eggs.[54] Although symptoms can play a role in identifying iron-deficiency anemia, they are often vague, which may limit their contribution to determining the diagnosis.
### Blood tests[edit]
Change in lab values in iron deficiency anemia Change Parameter
↓ ferritin, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin
↑ total iron-binding capacity, transferrin, red blood cell distribution width
Anemia is often discovered by routine blood tests. A sufficiently low hemoglobin by definition makes the diagnosis of anemia, and a low hematocrit value is also characteristic of anemia. Further studies will be undertaken to determine the anemia's cause. If the anemia is due to iron deficiency, one of the first abnormal values to be noted on a complete blood count, as the body's iron stores begin to be depleted, will be a high red blood cell distribution width, reflecting an increased variability in the size of red blood cells.[17][23]
A low mean corpuscular volume also appears during the course of body iron depletion. It indicates a high number of abnormally small red blood cells. A low mean corpuscular volume, a low mean corpuscular hemoglobin or mean corpuscular hemoglobin concentration, and the corresponding appearance of red blood cells on visual examination of a peripheral blood smear narrows the problem to a microcytic anemia (literally, a small red blood cell anemia).[17]
The blood smear of a person with iron-deficiency anemia shows many hypochromic (pale, relatively colorless) and small red blood cells, and may also show poikilocytosis (variation in shape) and anisocytosis (variation in size).[17][51] Target cells may also be seen. With more severe iron-deficiency anemia, the peripheral blood smear may show hypochromic, pencil-shaped cells and, occasionally, small numbers of nucleated red blood cells.[55] The platelet count may be slightly above the high limit of normal in iron-deficiency anemia (termed a mild thrombocytosis), but severe cases can present with thrombocytopenia (low platelet count).[56]
Iron-deficiency anemia is confirmed by tests that include serum ferritin, serum iron level, serum transferrin, and total iron binding capacity. A low serum ferritin is most commonly found. However, serum ferritin can be elevated by any type of chronic inflammation and thus is not consistently decreased in iron-deficiency anemia.[23] Serum iron levels may be measured, but serum iron concentration is not as reliable as the measurement of both serum iron and serum iron-binding protein levels.[19] The percentage of iron saturation (or transferrin saturation index or percent) can be measured by dividing the level of serum iron by total iron binding capacity and is a value that can help to confirm the diagnosis of iron-deficiency anemia; however, other conditions must also be considered, including other types of anemia.[19]
Another finding that can be used is the level of red blood cell distribution width.[57] During haemoglobin synthesis, trace amounts of zinc will be incorporated into protoporphyrin in the place of iron which is lacking. Protoporphyrin can be separated from its zinc moiety and measured as free erythrocyte protoporphyrin, providing an indirect measurement of the zinc-protoporphyrin complex. The level of free erythrocyte protoporphyrin is expressed in either μg/dl of whole blood or μg/dl of red blood cells. An iron insufficiency in the bone marrow can be detected very early by a rise in free erythrocyte protoporphyrin.
Further testing may be necessary to differentiate iron-deficiency anemia from other disorders, such as thalassemia minor.[58] It is very important not to treat people with thalassemia with an iron supplement, as this can lead to hemochromatosis. A hemoglobin electrophoresis provides useful evidence for distinguishing these two conditions, along with iron studies.[19][59]
### Screening[edit]
It is unclear if screening pregnant women for iron-deficiency anemia during pregnancy improves outcomes in the United States.[60] The same holds true for screening children who are 6 to 24 months old.[61] Even so, screening is a Level B recommendation suggested by the US Preventative Services Task Force in pregnant women without symptoms and in infants considered high risk. Screening is done with either a hemoglobin or hematocrit lab test.[45]
## Treatment[edit]
See also: Iron deficiency and Lucky iron fish
Ascorbic acid
Ferric derisomaltose (Monoferric) was approved in the United States in January 2020, for the treatment of iron deficiency anemia.[62][63]
Treatment should take into account the cause and severity of the condition.[5] If the iron-deficiency anemia is a result of blood loss or another underlying cause, treatment is geared toward addressing the underlying cause.[5] Most cases of iron deficiency anemia are treated with oral iron supplements.[64] In severe acute cases, treatment measures are taken for immediate management in the interim, such as blood transfusions or intravenous iron.[5]
For less severe cases, treatment of iron-deficiency anemia includes dietary changes to incorporate iron-rich foods into regular oral intake and oral iron supplementation.[5] Foods rich in ascorbic acid (vitamin C) can also be beneficial, since ascorbic acid enhances iron absorption.[5] Oral iron supplements are available in multiple forms. Some are in the form of pills and some are drops for children.[5] Most forms of oral iron replacement therapy are absorbed well by the small intestine; however, there are certain preparations of iron supplements that are designed for longer release in the small intestine than other preparations.[64] Oral iron supplements are best taken up by the body on an empty stomach because food can decrease the amount of iron absorbed from the small intestine.[64] The dosing of oral iron replacement therapy is as much as 100-200 mg per day in adults and 3-6 mg per kilogram in children.[39] This is generally spread out as 3-4 pills taken throughout the day.[64] The various forms of treatment are not without possible adverse side effects. Iron supplementation by mouth commonly causes negative gastrointestinal effects, including constipation, nausea, vomiting, metallic taste to the oral iron and dark colored stools.[65][39] Constipation is reported by 15-20% of patients taking oral iron therapy.[64] Preparations of iron therapy that take longer to be absorbed by the small intestine (extended release iron therapy) are less likely to cause constipation.[64] It can take six months to one year to get blood levels of iron up to a normal range and provide the body with iron stores.[64] Oral iron replacement may not be effective in cases of iron deficiency due to malabsorption, such as celiac disease, inflammatory bowel disease, or H. pylori infection; these cases would require treatment of the underlying disease to increase oral absorption or intravenous iron replacement.[39]
As iron-deficiency anemia becomes more severe, if the anemia does not respond to oral treatments, or if the treated person does not tolerate oral iron supplementation, then other measures may become necessary.[5][65] Two options are intravenous iron injections and blood transfusion.[64] Intravenous can be for people who do not tolerate oral iron, who are unlikely to respond to oral iron, or who require iron on a long-term basis.[64] For example, people receiving dialysis treatment who are also getting erythropoietin or another erythropoiesis-stimulating agent are given parenteral iron, which helps the body respond to the erythropoietin agents to produce red blood cells.[65][66][39]
Intravenous iron can induce an allergic response that can be as serious as anaphylaxis, although different formulations have decreased the likelihood of this adverse effect.[65] In certain cases intravenous iron is both safer and more effective than the oral route.[67] For patients with severe anemia such as from blood loss, or who have severe symptoms such as cardiovascular instability, a blood transfusion may be considered.[64]
## Epidemiology[edit]
Deaths due to iron-deficiency anaemia per million persons in 2012
no data
0
1
2-3
4-5
6-8
9-12
13-19
20-30
31-74
75-381
Disability-adjusted life year for iron-deficiency anemia per 100,000 inhabitants in 2004.[68]
no data
less than 50
50-100
100-150
150-200
200-250
250-300
300-350
350-400
400-450
450-500
500-1000
more than 1000
A moderate degree of iron-deficiency anemia affects approximately 610 million people worldwide or 8.8% of the population.[69] It is slightly more common in females (9.9%) than males (7.8%).[69] Up to 15% of children ages 1–3 years have iron deficiency anemia.[45] Mild iron deficiency anemia affects another 375 million.[69] Iron deficiency affects up to 52% of pregnant women worldwide.[42]
The prevalence of iron deficiency as a cause of anemia varies among countries; in the groups in which anemia is most common, including young children and a subset of non-pregnant women, iron deficiency accounts for a fraction of anemia cases in these groups (25% and 37%, respectively).[70] Iron deficiency is common in pregnant women.[71]
Within the United States, iron-deficiency anemia affects about 2% of adult males, 10.5% of Caucasian women, and 20% of African-American and Mexican-American women.[72]
A map provides a country-by-country listing of what nutrients are fortified into specified foods. Some of the Sub-Saharan countries shown in the deaths from iron-deficiency anemia map from 2012 are as of 2018 fortifying foods with iron.[31]
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64. ^ a b c d e f g h i j Adamson JW (2014). Iron Deficiency and Other Hypoproliferative Anemias. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 19e New York, NY: McGraw-Hill.
65. ^ a b c d Kasper D, Fauci A, Hauser S, Longo D, Jameson JL, Loscalzo J (2015). "126". Harrison's Principles of Internal Medicine (19th ed.). ISBN 978-0-07-180215-4.
66. ^ "KDIGO clinical practice guideline for anemia in chronic kidney disease". Agency for Healthcare Research and Quality. August 2012. Archived from the original on 2017-12-07. Retrieved 2017-12-06.
67. ^ Auerbach M, Deloughery T (December 2016). "Single-dose intravenous iron for iron deficiency: a new paradigm". Hematology. American Society of Hematology. Education Program. 2016 (1): 57–66. doi:10.1182/asheducation-2016.1.57. PMC 6142502. PMID 27913463.
68. ^ "Mortality and Burden of Disease Estimates for WHO Member States in 2002" (xls). World Health Organization. 2002. Archived from the original on 2013-01-16.
69. ^ a b c Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. (GBD 2013 Mortality and Causes of Death Collaborators) (December 2012). "Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010". Lancet. 380 (9859): 2163–96. doi:10.1016/S0140-6736(12)61729-2. PMC 6350784. PMID 23245607.
70. ^ Petry N, Olofin I, Hurrell RF, Boy E, Wirth JP, Moursi M, et al. (November 2016). "The Proportion of Anemia Associated with Iron Deficiency in Low, Medium, and High Human Development Index Countries: A Systematic Analysis of National Surveys". Nutrients. 8 (11): 693. doi:10.3390/nu8110693. PMC 5133080. PMID 27827838.
71. ^ Sifakis S, Pharmakides G (2000). "Anemia in pregnancy". Annals of the New York Academy of Sciences. 900 (1): 125–36. Bibcode:2000NYASA.900..125S. doi:10.1111/j.1749-6632.2000.tb06223.x. PMID 10818399. S2CID 6740558.
72. ^ Killip S, Bennett JM, Chambers MD (March 2007). "Iron deficiency anemia". American Family Physician. 75 (5): 671–8. PMID 17375513. Archived from the original on 11 March 2016.
## External links[edit]
Classification
D
* ICD-10: D50
* ICD-9-CM: 280
* MeSH: D018798
* DiseasesDB: 6947
External resources
* MedlinePlus: 000584
* eMedicine: med/1188
* The Importance of Iron – From IronTherapy.Org
* Interactive material on Iron Metabolism – From IronAtlas.com
* Establishing the cause of anemia – From AnaemiaWorld.com
* Handout: Iron Deficiency Anemia – From the National Anemia Action Council
* NPS News 70: Iron deficiency anaemia: NPS – Better choices, Better health – From the National Prescribing Service
* v
* t
* e
Diseases of red blood cells
↑
Polycythemia
* Polycythemia vera
↓
Anemia
Nutritional
* Micro-: Iron-deficiency anemia
* Plummer–Vinson syndrome
* Macro-: Megaloblastic anemia
* Pernicious anemia
Hemolytic
(mostly normo-)
Hereditary
* enzymopathy: Glucose-6-phosphate dehydrogenase deficiency
* glycolysis
* pyruvate kinase deficiency
* triosephosphate isomerase deficiency
* hexokinase deficiency
* hemoglobinopathy: Thalassemia
* alpha
* beta
* delta
* Sickle cell disease/trait
* Hereditary persistence of fetal hemoglobin
* membrane: Hereditary spherocytosis
* Minkowski–Chauffard syndrome
* Hereditary elliptocytosis
* Southeast Asian ovalocytosis
* Hereditary stomatocytosis
Acquired
AIHA
* Warm antibody autoimmune hemolytic anemia
* Cold agglutinin disease
* Donath–Landsteiner hemolytic anemia
* Paroxysmal cold hemoglobinuria
* Mixed autoimmune hemolytic anemia
* membrane
* paroxysmal nocturnal hemoglobinuria
* Microangiopathic hemolytic anemia
* Thrombotic microangiopathy
* Hemolytic–uremic syndrome
* Drug-induced autoimmune
* Drug-induced nonautoimmune
* Hemolytic disease of the newborn
Aplastic
(mostly normo-)
* Hereditary: Fanconi anemia
* Diamond–Blackfan anemia
* Acquired: Pure red cell aplasia
* Sideroblastic anemia
* Myelophthisic
Blood tests
* Mean corpuscular volume
* normocytic
* microcytic
* macrocytic
* Mean corpuscular hemoglobin concentration
* normochromic
* hypochromic
Other
* Methemoglobinemia
* Sulfhemoglobinemia
* Reticulocytopenia
*[v]: 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
| Iron-deficiency anemia | c0162316 | 1,429 | wikipedia | https://en.wikipedia.org/wiki/Iron-deficiency_anemia | 2021-01-18T18:34:29 | {"mesh": ["D018798"], "umls": ["C0162316"], "icd-10": ["D50"], "wikidata": ["Q954674"]} |
Glycine encephalopathy (GE) is an inborn error of glycine metabolism characterized by accumulation of glycine in body fluids and tissues, including the brain, resulting in neurometabolic symptoms of variable severity.
## Epidemiology
In Finland, an incidence at birth of 1/55,000 is reported and in British Columbia, Canada, 1/63,000, with a calculated carrier rate of 1/125.
## Clinical description
Three forms of GE have been recognized based on the age of onset: neonatal, infantile and atypical glycine encephalopathy (see these terms). Most patients have the life-threatening neonatal form and present mild to severe disease manifestations starting within a few days of birth including lethargy or even coma, hypotonia, hiccups, myoclonic jerks, and breathing/swallowing disorders, with subsequent intellectual deficit, spasticity and intractable seizures. A smaller proportion of patients show developmental delay and generally mild seizures in the infantile period, while others do not develop symptoms until late infancy or adulthood. Although patients usually have either a mild or severe course, there is a continuous clinical spectrum. Some patients develop choreic movements. Atypical glycine encephalopathy indicates hyperglycinemic patients whose clinical presentations are different from those of neonatal or infantile form, for example, transient or late-onset hyperglycinemia and patients with spastic paraparesis.
## Etiology
Mutations in two genes are known to cause glycine encephalopathy: GLDC (9p22) and AMT (3p21.2-p21.1). These genes encode the P-protein and T-protein components of the enzymatic glycine cleavage system (GCS), respectively. Although GCSH is another GCS gene, no mutations have been identified in neonatal or infantile forms. Deficient GCS activity results in defective glycine metabolism and accumulation of the amino acid in body tissues. In some patients with deficient GCS enzyme activity no mutation could be identified by exon sequencing analysis of any GCS gene. The vast majority of patients have no detectable enzyme activity. Etiology of atypical forms remains largely unknown.
## Diagnostic methods
GE should be suspected in cases of elevated glycine levels in blood and cerebrospinal fluid (CSF). Increased CSF-to-plasma glycine ratios also suggest the diagnosis. Measurement of GCS activity of biopsied liver sample or by 13C-glycine breath test and genetic testing may confirm diagnosis. Brain MRI may reveal hypogenesis of corpus callosum, abnormal gyrus, and hypogenesis of cerebellum in the neonatal form. Suppression burst and hypsarrhythmia are common in EEG. Subsequently, delayed myelination and atrophy may be observed.
## Differential diagnosis
Differential diagnosis includes organic acidemias that may present hyperglycinemia such as D-glyceric acidemia, propionic acidemia, methylmalonic acidemia, isovaleric acidemia, and ketoacidosis due to beta-ketothiolase deficiency (see these terms). Conditions characterized by neonatal seizures should also be considered. Valproate treatment may cause hyperglycinemia.
## Antenatal diagnosis
Prenatal diagnosis for at-risk pregnancies can be performed either by molecular genetic testing of the causative genes or by GCS enzyme analysis of chorionic villi sample.
## Genetic counseling
Glycine encephalopathy is inherited in an autosomal recessive manner.
## Management and treatment
The following tests should be used to guide treatment: brain MRI, EEG, and developmental and neurological assessment. There are only supportive and symptomatic measures for GE including antiepileptics for seizure control, placement of a gastrostomy tube for swallowing disorders, and treatment for gastroesophageal reflux. Sodium benzoate is used to reduce plasma glycine levels. NMDA receptor antagonists may ameliorate neurological symptoms although it remains to be established whether they improve long term outcome.
## Prognosis
Prognosis depends on disease severity. Most patients with neonatal or infantile forms have a severe outcome. In the neonatal form, early death sometimes occurs due to apnea. Prognosis in atypical cases is variable.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Glycine encephalopathy | c0751748 | 1,430 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=407 | 2021-01-23T18:31:58 | {"gard": ["7219"], "mesh": ["D020158"], "omim": ["605899"], "umls": ["C0751748"], "icd-10": ["E72.5"], "synonyms": ["NKA", "Non-ketotic hyperglycinemia"]} |
Isolated aniridia is a congenital bilateral ocular malformation characterized by the complete or partial absence of the iris.
## Epidemiology
The annual incidence is estimated at 1/ 64,000- 1/ 96,000.
## Clinical description
Isolated aniridia can occur in association with a range of other ocular anomalies including cataract, glaucoma (usually occurring during adolescence), corneal pannus, optic nerve hypoplasia, absence of macular reflex, ectopia lentis, nystagmus, and photophobia, all of which generally result in poor vision.
## Etiology
Aniridia is due to mutations in the PAX6 gene (11p13) encoding a transcriptional regulator involved in oculogenesis. PAX6 mutations result in alterations in corneal cytokeratin expression, cell adhesion and glycoconjugate expression.
## Diagnostic methods
Diagnosis is based on ophthalmological examination and is confirmed by mutation detection of the PAX6 gene.
## Antenatal diagnosis
Antenatal diagnosis is only possible when the underlying genetic defect is known. It is performed by invasive procedures like chorionic villus sampling (CVS) or amniocentesis and molecular analysis of fetal DNA.
## Genetic counseling
Aniridia is inherited in an autosomal dominant manner with high penetrance and variable expression. About two-thirds of affected children have an affected parent and one-third of cases occur in sporadic form.
## Management and treatment
A regular follow-up is necessary. Intraocular pressure should be measured yearly for detection of glaucoma. Keratolimbal allograft (a stem cell transplantation technique) has been evaluated as a treatment of the aniridic keratopathy, which is a major cause of vision loss in aniridia patients. Glaucoma drainage is used to treat secondary angle closure glaucoma.
## Prognosis
Aniridia results in poor vision, the mean visual acuity being around 0,19 in young adulthood.
*[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
| Isolated aniridia | c0003076 | 1,431 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=250923 | 2021-01-23T17:27:58 | {"gard": ["5816"], "mesh": ["D015783"], "omim": ["106210", "617141", "617142"], "umls": ["C0003076"], "icd-10": ["Q13.1"]} |
Congenital coronary artery aneurysm is a rare congenital coronary artery malformation defined as a more than 1.5 fold the normal size dilatation of a coronary artery segment with no identified underlying inflammatory or connective tissue disease. It may be asymptomatic or may present with angina pectoris, myocardial infarction, sudden cardiac death, fistula formation, pericardial tamponade, compression of surrounding structures, or congestive heart failure.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Congenital coronary artery aneurysm | c0340627 | 1,432 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=95491 | 2021-01-23T17:08:59 | {"icd-10": ["Q24.5"], "synonyms": ["Congenital coronary aneurysm"]} |
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. (August 2012) (Learn how and when to remove this template message)
Papuloerythroderma of Ofuji
SpecialtyDermatology
Papuloerythroderma of Ofuji is a rare disorder most commonly found in Japan, characterized by pruritic papules that spare the skinfolds, producing bands of uninvolved cutis, creating the so-called deck-chair sign. Frequently there is associated blood eosinophilia. Skin biopsies reveal a dense lymphohistiocytic infiltrate, eosinophils in the papillary dermis, and increased Langerhans cells (S-100 positive). Systemic steroids are the treatment of choice and may result in long-term remissions.[1]:57[2]
It was characterized in 1984.[3][4]
Use of PUVA in treatment has been described.[5]
## See also[edit]
* Pruritus
* List of cutaneous conditions
* Erythroderma
## References[edit]
1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
2. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1.
3. ^ Torchia D, Miteva M, Hu S, Cohen C, Romanelli P (March 2010). "Papuloerythroderma 2009: Two New Cases and Systematic Review of the Worldwide Literature 25 Years after Its Identification by Ofuji et al". Dermatology. 220 (4): 311–320. doi:10.1159/000301915. PMID 20339287.
4. ^ Ofuji S, Furukawa F, Miyachi Y, Ohno S (1984). "Papuloerythroderma". Dermatologica. 169 (3): 125–30. doi:10.1159/000249586. PMID 6148269.
5. ^ Günter Burg; Werner Kempf (2005). Cutaneous Lymphomas. Informa Health Care. pp. 365–. ISBN 978-0-8247-2997-4. Retrieved 30 May 2010.
## External links[edit]
Classification
D
* ICD-10: L30.8 (ILDS L30.806)
* MeSH: C535953
* v
* t
* e
Dermatitis and eczema
Atopic dermatitis
* Besnier's prurigo
Seborrheic dermatitis
* Pityriasis simplex capillitii
* Cradle cap
Contact dermatitis
(allergic, irritant)
* plants: Urushiol-induced contact dermatitis
* African blackwood dermatitis
* Tulip fingers
* other: Abietic acid dermatitis
* Diaper rash
* Airbag dermatitis
* Baboon syndrome
* Contact stomatitis
* Protein contact dermatitis
Eczema
* Autoimmune estrogen dermatitis
* Autoimmune progesterone dermatitis
* Breast eczema
* Ear eczema
* Eyelid dermatitis
* Topical steroid addiction
* Hand eczema
* Chronic vesiculobullous hand eczema
* Hyperkeratotic hand dermatitis
* Autosensitization dermatitis/Id reaction
* Candidid
* Dermatophytid
* Molluscum dermatitis
* Circumostomy eczema
* Dyshidrosis
* Juvenile plantar dermatosis
* Nummular eczema
* Nutritional deficiency eczema
* Sulzberger–Garbe syndrome
* Xerotic eczema
Pruritus/Itch/
Prurigo
* Lichen simplex chronicus/Prurigo nodularis
* by location: Pruritus ani
* Pruritus scroti
* Pruritus vulvae
* Scalp pruritus
* Drug-induced pruritus
* Hydroxyethyl starch-induced pruritus
* Senile pruritus
* Aquagenic pruritus
* Aquadynia
* Adult blaschkitis
* due to liver disease
* Biliary pruritus
* Cholestatic pruritus
* Prion pruritus
* Prurigo pigmentosa
* Prurigo simplex
* Puncta pruritica
* Uremic pruritus
Other
* substances taken internally: Bromoderma
* Fixed drug reaction
* Nummular dermatitis
* Pityriasis alba
* Papuloerythroderma of Ofuji
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
| Papuloerythroderma of Ofuji | c0406305 | 1,433 | wikipedia | https://en.wikipedia.org/wiki/Papuloerythroderma_of_Ofuji | 2021-01-18T18:42:28 | {"gard": ["8534"], "mesh": ["C535953"], "umls": ["C0406305"], "icd-10": ["L30.8"], "wikidata": ["Q7133231"]} |
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: "Murine typhus" – news · newspapers · books · scholar · JSTOR (January 2019) (Learn how and when to remove this template message)
Murine typhus
Other namesEndemic typhus
Chest Xray of a 40 yr old male in acute respiratory distress syndrome as a complication of murine typhus
SpecialtyInfectious disease
Murine typhus is a form of typhus transmitted by fleas (Xenopsylla cheopis), usually on rats. (This is in contrast to epidemic typhus, which is usually transmitted by lice.) Murine typhus is an under-recognized entity, as it is often confused with viral illnesses. Most people who are infected do not realize that they have been bitten by fleas. Historically term "hunger-typhus" was used for instance in accounts by British POWs in Germany at the end of World War I when they described conditions in Germany.[citation needed]
## Contents
* 1 Signs and symptoms
* 2 Causes
* 3 Diagnosis
* 4 Treatment
* 5 See also
* 6 References
* 7 External links
## Signs and symptoms[edit]
Symptoms of endemic typhus include headache, fever, muscle pain, joint pain, nausea and vomiting. 40–50% of patients will develop a discrete rash six days after the onset of signs. Up to 45% will develop neurological signs such as confusion, stupor, seizures or imbalance.
Symptoms may resemble those of measles, rubella, or possibly Rocky Mountain spotted fever. These symptoms are likely caused by a vasculitis caused by the rickettsia.
## Causes[edit]
It is caused by the bacterium Rickettsia typhi, and is transmitted by the fleas that infest rats. While rat fleas are the most common vectors, cat fleas and mouse fleas are less common modes of transmission. These fleas are not affected by the infection. Human infection occurs because of flea-fecal contamination of the bites on human skin. Rats, cats, opossums maintain the rickettsia colonization by providing it with a host for its entire life cycle. Rats can develop the infection, and help spread the infection to other fleas that infect them, and help multiply the number of infected fleas that can then infect humans.
Less often, endemic typhus is caused by Rickettsia felis and transmitted by fleas carried by cats or opossums.
In the United States of America, murine typhus is found most commonly in southern California,[1] Texas and Hawaii. In some studies, up to 13% of children were found to have serological evidence of infection.[2]
## Diagnosis[edit]
As of 2014[update], early diagnosis continued to be based on clinical suspicion, and treatment of the disease is indicated even before laboratory results confirm its presence. Because of the lag between the onset of infection and the appearance of antibodies in a blood test, serologic tests are merely confirmatory and retrospective. Weil-Felix agglutination reactions are not sensitive to the disease. Indirect fluorescence antibody assays that are specific to R. typhi antigens are the recommended route for detection and diagnosis: diagnostic titers are present in half of all cases within the first week of infection and in nearly all cases by day-15. The sharing of antigens by rickettsiae means routine serologic evaluation will not distinguish between murine typhus and epidemic typhus. Bacterial cultures are rarely performed because although they are highly accurate for diagnosis, the biohazard risk of generating them is often considered too high.[3]
## Treatment[edit]
The disease can be fatal if left untreated, but endemic typhus is highly treatable with antibiotics. Most people recover fully, but death may occur in the elderly, severely disabled or patients with a depressed immune system. The most effective antibiotics include tetracycline and chloramphenicol. In United States, CDC recommends solely doxycycline.[4]
## See also[edit]
* List of mites associated with cutaneous reactions
## References[edit]
1. ^ "Murine (endemic) Typhus" (PDF). California Department of Public Health. Retrieved 30 May 2012.
2. ^ The Pediatric Infectious Disease Journal (Impact Factor: 3.57). 07/2000; 19(6):535−8.
3. ^ John E. Bennett; Raphael Dolin; Martin J. Blaser (2014-09-02). Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases E-Book. Elsevier Health Sciences. p. 2223. ISBN 978-0-323-26373-3.
4. ^ "Murine Typhus". Centers for Disease Control and Prevention. 7 March 2017. Retrieved 15 July 2017.
## External links[edit]
Classification
D
* ICD-10: A75.2
* ICD-9-CM: 081.0
* MeSH: D014437
* DiseasesDB: 32211
External resources
* Orphanet: 83315
* v
* t
* e
Proteobacteria-associated Gram-negative bacterial infections
α
Rickettsiales
Rickettsiaceae/
(Rickettsioses)
Typhus
* Rickettsia typhi
* Murine typhus
* Rickettsia prowazekii
* Epidemic typhus, Brill–Zinsser disease, Flying squirrel typhus
Spotted
fever
Tick-borne
* Rickettsia rickettsii
* Rocky Mountain spotted fever
* Rickettsia conorii
* Boutonneuse fever
* Rickettsia japonica
* Japanese spotted fever
* Rickettsia sibirica
* North Asian tick typhus
* Rickettsia australis
* Queensland tick typhus
* Rickettsia honei
* Flinders Island spotted fever
* Rickettsia africae
* African tick bite fever
* Rickettsia parkeri
* American tick bite fever
* Rickettsia aeschlimannii
* Rickettsia aeschlimannii infection
Mite-borne
* Rickettsia akari
* Rickettsialpox
* Orientia tsutsugamushi
* Scrub typhus
Flea-borne
* Rickettsia felis
* Flea-borne spotted fever
Anaplasmataceae
* Ehrlichiosis: Anaplasma phagocytophilum
* Human granulocytic anaplasmosis, Anaplasmosis
* Ehrlichia chaffeensis
* Human monocytotropic ehrlichiosis
* Ehrlichia ewingii
* Ehrlichiosis ewingii infection
Rhizobiales
Brucellaceae
* Brucella abortus
* Brucellosis
Bartonellaceae
* Bartonellosis: Bartonella henselae
* Cat-scratch disease
* Bartonella quintana
* Trench fever
* Either B. henselae or B. quintana
* Bacillary angiomatosis
* Bartonella bacilliformis
* Carrion's disease, Verruga peruana
β
Neisseriales
M+
* Neisseria meningitidis/meningococcus
* Meningococcal disease, Waterhouse–Friderichsen syndrome, Meningococcal septicaemia
M−
* Neisseria gonorrhoeae/gonococcus
* Gonorrhea
ungrouped:
* Eikenella corrodens/Kingella kingae
* HACEK
* Chromobacterium violaceum
* Chromobacteriosis infection
Burkholderiales
* Burkholderia pseudomallei
* Melioidosis
* Burkholderia mallei
* Glanders
* Burkholderia cepacia complex
* Bordetella pertussis/Bordetella parapertussis
* Pertussis
γ
Enterobacteriales
(OX−)
Lac+
* Klebsiella pneumoniae
* Rhinoscleroma, Pneumonia
* Klebsiella granulomatis
* Granuloma inguinale
* Klebsiella oxytoca
* Escherichia coli: Enterotoxigenic
* Enteroinvasive
* Enterohemorrhagic
* O157:H7
* O104:H4
* Hemolytic-uremic syndrome
* Enterobacter aerogenes/Enterobacter cloacae
Slow/weak
* Serratia marcescens
* Serratia infection
* Citrobacter koseri/Citrobacter freundii
Lac−
H2S+
* Salmonella enterica
* Typhoid fever, Paratyphoid fever, Salmonellosis
H2S−
* Shigella dysenteriae/sonnei/flexneri/boydii
* Shigellosis, Bacillary dysentery
* Proteus mirabilis/Proteus vulgaris
* Yersinia pestis
* Plague/Bubonic plague
* Yersinia enterocolitica
* Yersiniosis
* Yersinia pseudotuberculosis
* Far East scarlet-like fever
Pasteurellales
Haemophilus:
* H. influenzae
* Haemophilus meningitis
* Brazilian purpuric fever
* H. ducreyi
* Chancroid
* H. parainfluenzae
* HACEK
Pasteurella multocida
* Pasteurellosis
* Actinobacillus
* Actinobacillosis
Aggregatibacter actinomycetemcomitans
* HACEK
Legionellales
* Legionella pneumophila/Legionella longbeachae
* Legionnaires' disease
* Coxiella burnetii
* Q fever
Thiotrichales
* Francisella tularensis
* Tularemia
Vibrionaceae
* Vibrio cholerae
* Cholera
* Vibrio vulnificus
* Vibrio parahaemolyticus
* Vibrio alginolyticus
* Plesiomonas shigelloides
Pseudomonadales
* Pseudomonas aeruginosa
* Pseudomonas infection
* Moraxella catarrhalis
* Acinetobacter baumannii
Xanthomonadaceae
* Stenotrophomonas maltophilia
Cardiobacteriaceae
* Cardiobacterium hominis
* HACEK
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| Murine typhus | c0041472 | 1,434 | wikipedia | https://en.wikipedia.org/wiki/Murine_typhus | 2021-01-18T19:02:59 | {"mesh": ["D014437"], "icd-9": ["081.0"], "icd-10": ["A75.2"], "orphanet": ["83315"], "synonyms": ["Endemic typhus", "Flea-borne typhus"], "wikidata": ["Q3084532"]} |
A number sign (#) is used with this entry because of evidence that X-linked mental retardation-63 can be caused by mutation in the ACSL4 (300157) gene.
Clinical Features
Raynaud et al. (2000) reported a 4-generation family with nonspecific nonsyndromic X-linked mental retardation. Affected males showed nonprogressive mental retardation ranging from severe to moderate, without seizures, whereas carrier females showed highly variable cognitive capacities, ranging from moderate mental retardation to normal intelligence.
Mapping
Raynaud et al. (2000) reported a 4-generation family with nonspecific nonsyndromic X-linked mental retardation mapped between DXS990 and DXS1227 (Xq21.33-q27.1) with a maximum lod at theta = 0.0 of 2.14 at DXS1001.
Molecular Genetics
In the proband of the family reported by Raynaud et al. (2000) as MRX63, Meloni et al. (2002) identified a mutation in the ACSL4 gene (300157.0001). The proband of a second affected family carried a mutation in the 3-prime splice site of intron 10 of the ACSL4 gene (300157.0002). Mental retardation was severe. Six of 6 informative carrier females in family MRX63 showed completely skewed X inactivation in leukocytes. Similarly, 3 of 3 carrier females from 2 different families with ATS-MR (300194) showed completely skewed X inactivation in leukocytes, as did the carrier mother of the proband of the second family.
In a family with nonsyndromic X-linked mental retardation (MRX68), Longo et al. (2003) identified a mutation in the ACSL4 gene (300157.0003). Neurocognitive levels ranged from mild to moderate in affected males and were borderline in female carriers. X-inactivation studies in the female carriers showed 100% skewed inactivation in all of them.
Animal Model
Zhang et al. (2009) demonstrated that the Drosophila ACSL-like protein, Acsl, and ACSL4 are highly conserved, allowing ACSL4 to substitute for Acsl in organismal viability, lipid storage, and the neural wiring in the visual center. In neurodevelopment, production of decapentaplegic (Dpp), a BMP-like protein in Drosophila, diminished specifically in the larval brain of Drosophila Acsl mutants. Consistent with the Dpp reduction, the number of glial cells and neurons dramatically decreased and the retinal axons mistargeted in the visual cortex. All of these defects in Drosophila brain were rescued by the wildtype ACSL4 but not by the mutant products found in nonsyndromic X-linked mental retardation patients. Expression of an MRX63-associated ACSL4 mutant form in a wildtype background led to lesions in the visual center, suggesting a dominant-negative effect. Zhang et al. (2009) proposed a connection between ACSL4 and the BMP pathway in neurodevelopment.
INHERITANCE \- X-linked dominant HEAD & NECK Head \- Microcephaly (in some patients) NEUROLOGIC Central Nervous System \- Mental retardation, moderate to severe \- Language impairment (in some patients) \- Hypotonia in childhood (in some patients) \- Increased reflexes Behavioral Psychiatric Manifestations \- Anxiety \- Autistic features \- Executive function disorder LABORATORY ABNORMALITIES \- Female carriers show skewed X inactivation in leukocytes MOLECULAR BASIS \- Caused by mutation in the acyl-CoA synthetase long-chain family member 4 gene (ACSL4, 300157.0001 ) ▲ Close
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*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| MENTAL RETARDATION, X-LINKED 63 | c2931498 | 1,435 | omim | https://www.omim.org/entry/300387 | 2019-09-22T16:20:24 | {"doid": ["0050776"], "mesh": ["C567906"], "omim": ["300387"], "orphanet": ["777"], "synonyms": ["Alternative titles", "MENTAL RETARDATION, X-LINKED 68"]} |
Familial scaphocephaly syndrome, McGillivray type is a rare newly described craniosynostosis (see this term) syndrome characterized by scaphocephaly, macrocephaly, severe maxillary retrusion, and mild intellectual disability.
## Epidemiology
It has been reported in 11 patients from a three-generation family.
## Clinical description
The patients had variable dysmorphic features including high forehead, marked midface hypoplasia with severe maxillary retrusion, relative or absolute prognathism, and malocclusion. More severely affected patients were male and had intellectual disability.
## Etiology
Molecular analysis revealed a K526E mutation of the fibroblast growth factor receptor 2 gene, FGFR2.
## Genetic counseling
In this family, findings are consistent with autosomal dominant inheritance.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
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*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
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*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Familial scaphocephaly syndrome, McGillivray type | c1865070 | 1,436 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=168624 | 2021-01-23T18:42:21 | {"mesh": ["C566511"], "omim": ["609579"], "umls": ["C1865070"], "icd-10": ["Q87.0"], "synonyms": ["Scaphocephaly-macrocephaly-maxillary retrusion-intellectual disability syndrome"]} |
Raccoon eyes
Other namesPanda eyes
Bilateral raccoon eyes
SpecialtyNeurosurgery
Raccoon eyes (also known in the United Kingdom and Ireland as panda eyes) or periorbital ecchymosis is a sign of basal skull fracture or subgaleal hematoma, a craniotomy that ruptured the meninges, or (rarely) certain cancers.[1][2] Bilateral hemorrhage occurs when damage at the time of a facial fracture tears the meninges and causes the venous sinuses to bleed into the arachnoid villi and the cranial sinuses. In lay terms, blood from skull fracture seeps into the soft tissue around the eyes. Raccoon eyes may be accompanied by Battle's sign, an ecchymosis behind the ear. These signs may be the only sign of a skull fracture, as it may not show on an X-ray. They may not appear until up to two hours after the injury.[3] It is recommended that the patient not blow their nose, cough vigorously, or strain to prevent further tearing of the meninges.[4]
Raccoon eyes may be bilateral or unilateral.[5] If bilateral, it is highly suggestive of basilar skull fracture, with a positive predictive value of 85%. They are most often associated with fractures of the anterior cranial fossa.[6][7]
Raccoon eyes may also be a sign of disseminated neuroblastoma[8] or of amyloidosis (multiple myeloma). It also can be temporary result of rhinoplasty.
Depending on cause, raccoon eyes always require urgent consultation and management, that is surgical (facial fracture or post-craniotomy) or medical (neuroblastoma or amyloidosis).
## See also[edit]
* Periorbital dark circles
* Periorbital puffiness
* Battle's sign
## References[edit]
1. ^ Herbella, FA; Mudo M; Delmonti C; Braga FM; Del Grande JC (December 2001). "'Raccoon eyes' (periorbital haematoma) as a sign of skull base fracture". Injury. 32 (10): 745–47. doi:10.1016/S0020-1383(01)00144-9. PMID 11754879.
2. ^ EMT Prehospital Care (4th Edition)
3. ^ Handbook of Signs & Symptoms (Third Edition)
4. ^ Nursing: Interpreting Signs and Symptoms
5. ^ "Skull fractures. Step-by-step diagnostic approach". Best Practice, BMJ.
6. ^ "BMJ Best Practice". bestpractice.bmj.com.
7. ^ Visual Diagnosis in Emergency and Critical Care Medicine, Christopher P. Holstege, Alexander B. Baer, Jesse M. Pines, William J. Brady, p. 228
8. ^ Gumus K (2007). "A child with raccoon eyes masquerading as trauma". Int Ophthalmol. 27 (6): 379–81. doi:10.1007/s10792-007-9089-y. PMID 17534581. S2CID 5921.
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*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
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| Raccoon eyes | c2053461 | 1,437 | wikipedia | https://en.wikipedia.org/wiki/Raccoon_eyes | 2021-01-18T18:58:00 | {"umls": ["C2053461"], "wikidata": ["Q1047245"]} |
A number sign (#) is used with this entry because autosomal recessive hereditary thrombophilia due to protein C deficiency is caused by homozygous or compound heterozygous mutation in the PROC gene (612283) on chromosome 2q14.
See also autosomal dominant thrombophilia due to protein C deficiency (THPH3; 176860), an allelic disorder caused by heterozygous mutation in the PROC gene.
Description
Autosomal recessive protein C deficiency resulting from homozygous or compound heterozygous PROC mutations is a thrombotic condition that can manifest as a severe neonatal disorder or as a milder disorder with late-onset thrombophilia (Millar et al., 2000).
Clinical Features
Branson et al. (1983) reported a newborn male infant with intractable purpura fulminans, which reflected massive subcutaneous thrombosis. His mother had heterozygous protein C deficiency. This was the first instance in which protein C deficiency was implicated in disseminated intravascular coagulation (DIC).
Seligsohn et al. (1984) studied an Arab-Israeli family in which 2 sibs with first-cousin parents died with massive venous thrombosis in the neonatal period. Both parents and several other relatives, who were heterozygous carriers, had had no thrombotic episodes.
Marlar (1985) diagnosed complete deficiency of protein C in 5 infants. The major symptom was massive subcutaneous thrombosis that usually started within the first 24 hours of life.
Peters et al. (1988) described a patient with neonatal purpura fulminans and severe bilateral vitreous hemorrhages. The patient showed reduced protein C antigen levels with undetectable activity levels. Infusions of fresh frozen plasma were given for 8 months.
Gruppo et al. (1988) reported a child who had renal vein thrombosis as a newborn and iliofemoral thrombosis at the age of 6 years. Protein C levels and anticoagulant activity were decreased to 47% and 14% of normal, respectively. A 3-year-old asymptomatic sib had a similar reduction of PROC anticoagulant activity. The mother had type I protein C deficiency with a proportionate reduction in immunologic protein levels (59%) and anticoagulant activity (52%), whereas the father had type II PROCC deficiency with normal immunologic protein levels (102%), and low anticoagulant function (50%). Electrophoretic studies showed an abnormal protein C in the father and both children. Gruppo et al. (1988) concluded that the children were compound heterozygous for the 2 different types of PROC deficiency inherited from each of the parents.
Tuddenham et al. (1989) reported a consanguineous family in which 2 members had homozygous protein C deficiency. Both presented in the second half of their first year of life with recurrent rapidly disappearing ecchymotic skin lesions, DIC, and venous thrombosis. The authors noted that homozygous deficiency usually presents in the neonatal period. Successful treatment was achieved by frequent infusions of plasma or prothrombin complex with warfarin maintenance.
Dreyfus et al. (1991) stated that at least 19 cases of life-threatening neonatal thrombosis and purpura fulminans had been described.
Fong et al. (2010) reported 2 sisters with autosomal recessive protein C deficiency who had extensive bilateral periventricular hemorrhagic infarction causing spastic cerebral palsy. The older sister presented at 20 months with cortical visual blindness, spastic diplegia, and purpura fulminans. The younger sister presented at age 3 days with apneas and multifocal seizures. At age 2 years, she had global developmental delay, cortical visual blindness, spastic quadriplegia, epilepsy, and purpura fulminans. Neuroimaging of both sibs showed findings consistent with bilateral cerebral intramedullary venous thrombosis occurring at under 28 weeks' gestation for the older sister and around time of birth for the younger sister. Laboratory studies showed severe qualitative reduction in plasma protein C anticoagulant activity.
### Clinical Variability
Melissari and Kakkar (1989) reported 2 unrelated families in which 4 adults had severe protein C deficiency with less than or equal to 5% of normal plasma levels. Newborn deaths were reported in the first family but not in the second family. Adult patients developed thrombotic symptoms mainly in their early twenties, characterized by recurrent superficial and deep iliofemoral vein thromboses and pulmonary emboli. Other clinical features included generalized peritonitis due to massive mesenteric vein thrombosis, thrombosis of the cavernous sinus, renal vein thrombosis, and priapism. In the second family, 5 individuals died of intravascular abdominal thrombosis at about 40 years of age. Massive thromboembolic episodes were associated with a compensated DIC syndrome. Clinical symptoms could be controlled by long-term administration of low molecular weight heparin alone or in combination with low dose warfarin.
Tripodi et al. (1990) reported a family in which 2 protein C deficiency homozygotes with similarly low protein C levels had mild disease. One had recurrent venous thrombosis starting at the age of 28 years, and the other was still asymptomatic at 38 years despite exposure to thrombotic risk factors. A review of 13 additional homozygotes revealed a highly variable phenotypic expression, which the authors subdivided into 2 groups. In the first group, affected homozygotes from 8 kindreds presented at birth with unmeasurable protein C levels and life-threatening thrombosis, whereas affected homozygous individuals of 1 kindred had very low levels of protein C and delayed onset of thrombosis at about 10 months of age. In a second group of 4 kindreds, homozygotes had very low, but measurable, protein C levels and survived into adulthood with histories of moderately severe thrombosis. Tripodi et al. (1990) noted that the findings in their family demonstrated that protein C levels lower than 10% are compatible with a negative history for thrombosis, not only in the neonatal period but also during adulthood. These results suggested that other factors need to interact for full clinical penetrance of the defect in some homozygotes.
Clinical Management
Marlar (1985) noted that treatment of affected infants with heparin, antiplatelet drugs, or both, was not effective. The only successful treatment was protein C replacement using fresh frozen plasma or factor IX concentrate.
In a newborn Chinese boy with homozygous protein C deficiency, Dreyfus et al. (1991) found that long-term therapy with concentrated protein C was well tolerated.
Muller et al. (1996) described the successful use of protein C concentrate in a homozygous protein C-deficient infant for 8 months until oral anticoagulation was initiated. The availability of a protein C concentrate purified by monoclonal antibody allowed specific replacement of protein C, thus avoiding problems of fluid overload from use of fresh frozen plasma. An occlusive-hydrocolloid bandage was effective in local treatment of skin lesions.
Angelis et al. (2001) reported en bloc heterotopic auxiliary liver and bilateral renal transplantation in a patient with homozygous protein C deficiency.
Molecular Genetics
Among 9 unrelated patients with severe autosomal recessive protein C deficiency, Millar et al. (2000) identified 13 different biallelic mutations, including 8 novel mutations (see, e.g., 612283.0004) in the PROC gene.
Genotype/Phenotype Correlations
Millar et al. (2000) found that plasma protein C activity levels ranged from 1 to 8% among 9 patients with severe recessive protein C deficiency, but there was not a clear correlation between residual enzyme activity and clinical thrombosis. Several patients with 0 to 1% protein activity had neonatal purpura fulminans, but 1 patient with 1% activity did not have a thrombotic episode until age 11. Conversely, a patient with 8% activity developed neonatal symptoms. However, the patient with 8% activity was also found to be homozygous for the factor V Leiden (612309.0001) mutation, which likely influenced the severity of the clinical phenotype. Another patient with 1% protein C activity and heterozygosity for the factor V Leiden mutation had a severe fatal neonatal course.
INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Neonatal vitreous hemorrhages CARDIOVASCULAR Vascular \- Superficial thrombophlebitis \- Deep venous thrombosis \- Intraabdominal venous thrombosis RESPIRATORY Lung \- Pulmonary embolism SKIN, NAILS, & HAIR Skin \- Neonatal purpura fulminans NEUROLOGIC Central Nervous System \- Spastic cerebral palsy \- Developmental delay \- Seizures \- Periventricular hemorrhagic infarction LABORATORY ABNORMALITIES \- Plasma protein C deficiency MISCELLANEOUS \- May be lethal in infancy if untreated \- Variable severity \- Occasional late-onset of symptoms with homozygosity (e.g. 612283.0005 protein C deficiency, homozygous) \- See also autosomal dominant form ( 176860 ) MOLECULAR BASIS \- Caused by mutation in the protein C gene (PROC, 612283.0003 ) ▲ Close
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*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| THROMBOPHILIA DUE TO PROTEIN C DEFICIENCY, AUTOSOMAL RECESSIVE | c2930896 | 1,438 | omim | https://www.omim.org/entry/612304 | 2019-09-22T16:01:52 | {"mesh": ["C535424"], "omim": ["612304"], "orphanet": ["745"], "synonyms": ["Alternative titles", "PROTEIN C DEFICIENCY, AUTOSOMAL RECESSIVE", "PROC DEFICIENCY, AUTOSOMAL RECESSIVE"]} |
## Description
Familial male hypogonadism is a highly heterogeneous category from which some disorders such as Reifenstein syndrome (312300), Kallmann syndrome (see 308700), isolated gonadotropin deficiency, and some other entities can be separated. The presence of an autosomal recessive form is suggested by the occurrence of parental consanguinity (Nowakowski and Lenz, 1961).
Clinical Features
Ferriman (1954) described a possibly distinct form in 2 sons of first-cousin parents. First-degree hypospadias, small penis, gynecomastia, markedly diminished secondary sexual characteristics, and normal-sized testes were described. In all respects except the parental consanguinity suggesting recessive inheritance, the disorder clinically resembled Reifenstein syndrome (312300).
Cytogenetics
In a Caucasian male with hypogonadism and testicular atrophy, Quintero-Rivera et al. (2007) identified an apparently balanced translocation t(8;10)(p11.2;p13), which was also found in his mother and maternal grandmother. There were no known genes disrupted by the 8p11 breakpoint; however, FISH mapping with overlapping BAC clones of the 10p13 breakpoint demonstrated disruption of the NMT2 gene (603801) between exons 1 and 3. The authors suggested that dysfunctional N-myristolylation is a possible mechanism for testicular failure, either directly or in concert with viral insults.
GU \- Male hypogonadism \- Hypospadias \- Small penis \- Normal-sized testes Misc \- Markedly diminished secondary sexual characteristics Thorax \- Gynecomastia Inheritance \- Autosomal recessive ▲ Close
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*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| HYPOGONADISM, MALE | c0151721 | 1,439 | omim | https://www.omim.org/entry/241100 | 2019-09-22T16:26:36 | {"doid": ["1924"], "mesh": ["D005058"], "omim": ["241100"], "icd-10": ["E29.1"]} |
A number sign (#) is used with this entry because nonspherocytic hemolytic anemia can be caused by homozygous or compound heterozygous mutation in the PHI gene (GPI; 172400) on chromosome 19q13.
Clinical Features
Baughan et al. (1968) found deficiency of erythrocyte GPI in an adolescent boy with lifelong nonspherocytic hemolytic anemia. The autohemolysis pattern conformed to Dacie type I. Both parents, a sib, and 5 other relatives showed intermediate enzyme levels. The proband showed low enzyme in leukocytes and no detectable enzyme in plasma. The deficiency occurs in leukocytes and plasma as well as in erythrocytes but the only clinical manifestation is hemolytic anemia.
Paglia et al. (1969) found deficiency of red cell and leukocyte glucosephosphate isomerase in 3 sibs with hemolytic anemia. The anemia was ameliorated by splenectomy. Heterozygotes could be identified.
Detter et al. (1968) found that the parents of a patient with hemolytic anemia had different electrophoretic variants of PHI, each associated with reduced enzyme activity. Thus, the patient was a genetic compound. Blume et al. (1972) also described a patient with hemolytic anemia who was a genetic compound for 2 forms of GPI. The variant inherited from the mother had no detectable activity. That inherited from the father and designated GPI Los Angeles had residual activity and electrophoretic and thermolability peculiarities. A patient homozygous for GPI Winnipeg was also described. Nakashima et al. (1973) described 2 Japanese families with nonspherocytic hemolytic anemia due to GPI deficiency. Each family demonstrated a 'new' variety of mutant enzyme with deficiency of catalytic function.
Beutler et al. (1974) described a 13-year-old girl with chronic nonspherocytic hemolytic anemia who appeared to be homozygous for a deficient GPI allele, which the authors designated GPI Elyria. The girl's parents were related.
Schroter et al. (1985) described a patient with severe enzyme deficiency in red cells, granulocytes and muscle. The mutant enzyme, called GPI Homburg, had nearly normal stability, normal kinetic properties, and decreased electrophoretic mobility. The proband was a boy with transfusion-requiring, recurrent, spontaneous hemolytic crises beginning at the age of 3 and relieved by splenectomy at age 5 years. At age 13, however, he still had mild hemolytic anemia and moderate icterus and showed several pigment gallstones. Involvement of the neuromuscular system was indicated by muscle weakness, a mixed sensory and cerebellar ataxia, and mental retardation. Although granulocyte function appeared not to be altered in vivo, decreased production of superoxide anion and reduced bactericidal activity was observed in vitro.
Ravindranath et al. (1987) reported a consanguineous family from southern India in which 5 of 6 pregnancies resulted either in stillbirth or in early neonatal death (one with hydrops). The sixth child was delivered early, noted to have hydrops fetalis, and successfully treated with exchange transfusion in the immediate postnatal period. The hemolytic anemia was subsequently shown to be due to GPI deficiency and was clinically ameliorated by splenectomy at the age of 3 years.
Shalev et al. (1993) reported what they claimed to be the first instance of GPI deficiency causing hereditary nonspherocytic hemolytic anemia in an Ashkenazi Jew. The biophysical characteristics of the GPI variant, which they called GPI Mount Scopus, were slow electrophoretic mobility, presence of only 1 of the 2 electrophoretic bands normally present, and extreme thermolability.
Diagnosis
Blume and Beutler (1972) developed a simple screening test for GPI deficiency.
Molecular Genetics
In a patient with chronic hemolytic anemia associated with severe deficiency of red cell glucose phosphate isomerase, Walker et al. (1993) identified compound heterozygosity for 2 mutations in the GLI gene (172400.0001-172400.0002).
In the patient described by Schroter et al. (1985) with GPI Homburg, Kugler et al. (1998) identified compound heterozygosity for 2 mutations in the GLI gene (172400.0006-172400.0007).
Animal Model
Merkle and Pretsch (1993) reported enzymatic and hematologic studies on mice homozygous for one or the other of 2 mutations in the GPI gene found in mutagenicity experiments.
Neuro \- Mixed sensory and cerebellar ataxia \- Mental retardation Lab \- Phosphohexose isomerase deficiency \- Glucosephosphate isomerase deficiency \- Normal osmotic fragility \- Reduced leukocyte superoxide anion production \- Reduced leukocyte bactericidal activity Inheritance \- Autosomal recessive Skin \- Jaundice Muscle \- Muscle weakness Misc \- Response to splenectomy \- Stillbirth or early neonatal death ( ? recessive) GI \- Pigment gallstones \- Splenomegaly \- Cholecystitis Heme \- Nonspherocytic hemolytic anemia \- Spontaneous hemolytic crises ▲ Close
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*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| HEMOLYTIC ANEMIA, NONSPHEROCYTIC, DUE TO GLUCOSE PHOSPHATE ISOMERASE DEFICIENCY | c3150730 | 1,440 | omim | https://www.omim.org/entry/613470 | 2019-09-22T15:58:34 | {"doid": ["2861"], "omim": ["613470"], "orphanet": ["712"], "synonyms": []} |
A number sign (#) is used with this entry because Allan-Herndon-Dudley syndrome (AHDS) is caused by mutation in the MCT8 gene (SLC16A2; 300095) on chromosome Xq13.
Clinical Features
Allan et al. (1944) described a kindred of 24 males affected by severe mental retardation spanning 6 generations. The patients had hypotonia at birth, but otherwise appeared normal. By 6 months, they developed an inability to hold up the head, leading to the family's description of the patients as having a 'limber-neck.' Motor development was markedly reduced, few ever walked, and most had generalized muscular atrophy, joint contractures, and hyporeflexia as adults. At least 15 women of reproductive age or younger were potential heterozygotes. Stevenson et al. (1990) restudied this family, extending the typical X-linked recessive pedigree pattern with 5 additional affected males in 2 generations. In all, 29 males were affected in 7 generations. Clinical features included severe mental retardation, dysarthria, ataxia, athetoid movements, muscle hypoplasia, and spastic paraplegia with hyperreflexia, clonus, and Babinski reflexes. The facies appeared elongated with normal head circumference, bitemporal narrowing, and large, simple ears. Contractures developed at both small and large joints. Statural growth was normal and there was no macroorchidism. Longevity was not impaired. High-resolution chromosome analysis, serum creatine kinase, and amino acids were normal.
In 2 ostensibly unrelated Jamaican black families living in Birmingham, England, Bundey and Hill (1975) found 3 cases of severe microcephaly with spastic quadriplegia beginning between 4 and 16 months of age. The authors concluded that Roboz and Pitt (1969) and perhaps others had reported the same condition. The paper by Bundey and Hill (1975) was not published, but the patients were referred to by Bundey and Griffiths (1977). The microcephaly was 'postnatal;' head circumference was normal at birth and at 7 months. There were no neonatal problems. The first abnormalities noted by the parents were unresponsiveness and delayed milestones. On reevaluation of the family, Bundey et al. (1991) concluded that the disorder may represent the Allan-Herndon syndrome.
Bialer et al. (1992) restudied a family reported in abstract by Davis et al. (1981). Clinical characteristics of 8 living affected males included severe mental retardation, spastic paraplegia, dysarthria, muscle wasting, scoliosis, broad shallow pectus excavatum, long face, large ears with minor modeling anomalies, foot deformities, joint contractures, and neck drop, which was illustrated by photographs with the head hanging forward when the patients were in the sitting position. Bialer et al. (1992) suggested that the unusual appearance of the ears was due to abnormalities of ear muscle development in utero. Similarly, the long thin face, which from some of the photographs might be called myopathic, and asthenic body habitus were possibly due to muscle hypoplasia. Bialer et al. (1992) suggested that this was the second reported family with AHDS.
Passos-Bueno et al. (1993) reported a large Brazilian family in which 7 males had a severe form of X-linked mental retardation with severe generalized muscle atrophy. Affected individuals were never able to hold their head against gravity, to sit unsupported, or to walk or speak. All had urinary and fecal incontinence. The disorder was not progressive, and the oldest patient was 47 years old. Passos-Bueno et al. (1993) noted the phenotypic similarity to the family reported by Allan et al. (1944). Zorick et al. (2004) reported additional clinical findings identified in 2 of the patients from the family reported by Passos-Bueno et al. (1993). Features included spastic paraplegia, joint contractures, chest malformation, scoliosis, and facial dysmorphism, all of which were consistent with AHDS.
Dumitrescu et al. (2004) reported 2 unrelated families in which males showed neurologic abnormalities from infancy, including global developmental delay, central hypotonia, spastic quadriplegia, dystonic movements, rotary nystagmus, and impaired gaze and hearing. Serum thyroxine (T4) was decreased, TSH was normal to mildly increased, and serum T3 was increased. Some female family members had mild serum thyroid hormone abnormalities but no neurologic manifestations.
Friesema et al. (2004) reported 5 unrelated boys, aged 18 months to 6 years, who had a disorder characterized by severe proximal hypotonia with poor head control and inability to stand, involuntary writhing movements, and severe mental retardation with lack of speech and basic communication skills. Serum T4 and free T4 were at the lower limits of normal, and serum TSH ranged from normal to high. Serum T3 concentrations were greatly increased.
Schwartz et al. (2005) summarized clinical features of AHDS. Infancy and childhood are marked by hypotonia, weakness, reduced muscle mass, and delay of developmental milestones. Facial manifestations are not distinctive, but the face tends to be elongated with bifrontal narrowing, and the ears are often simply formed or cupped. Some patients have myopathic facies. Generalized weakness is manifested by excessive drooling, forward positioning of the head and neck, failure to ambulate independently, or ataxia in those who do ambulate. Speech is dysarthric or absent altogether. Hypotonia gives way in adult life to spasticity. The hands exhibit dystonic and athetoid posturing and fisting. Cognitive development is severely impaired. No major malformations occur, intrauterine growth is not impaired, and head circumference and genital development are usually normal. Behavior tends to be passive, with little evidence of aggressive or disruptive behavior. Although clinical signs of thyroid dysfunction are usually absent in affected males, the disturbances in blood levels of thyroid hormones suggest the possibility of systematic detection through screening of high-risk populations. Schwartz et al. (2005) stated that the pattern of findings in their patients with AHDS was the same as that in other individuals reported by Dumitrescu et al. (2004) and Friesema et al. (2004). Dumitrescu et al. (2004) had reported rotary nystagmus, disconjugate eye movements, and feeding difficulties in 2 affected boys from different kindreds, findings that were not noted in other reports.
Using magnetic resonance imaging (MRI) and MR spectroscopy, Sijens et al. (2008) found that compared with controls, 2 children with MCT8 mutations had increased choline and myoinositol and decreased N-acetyl aspartate in supraventricular gray and white matter, phenomena associated with the degree of dysmyelinization. The authors concluded that different mutations in the MCT8 gene lead to differences in the severity of the clinical spectrum, dysmyelinization, and MR spectroscopy-detectable changes in brain metabolism.
Vaurs-Barriere et al. (2009) identified mutations in the MCT8 gene in 6 (11%) of 53 families in which a male was affected with a hypomyelinating leukodystrophy of unknown etiology. The 12 patients initially presented a Pelizaeus-Merzbacher (312080)-like phenotype with a later unusual improvement of MRI white matter changes, but absence of clinical improvement. All patients presented before age 6 months with delayed motor development associated with nystagmus and/or choreoathetosis and ataxia progressing to para- or quadriplegia and dystonia. There was poor head control and lack of language acquisition. MRI showed myelin defects affecting the first myelinated areas before age 2 years, which appeared to improve with age, but was not associated with neurologic improvement. These findings were consistent with an overall delay in myelination rather than persistent hypomyelination, as seen in classic PMD. Thyroid parameters in the 3 patients available for serum dosages showed increased T3, decreased T4, and normal TSH. Vaurs-Barriere et al. (2009) concluded that males with a PMD-like phenotype should be screened for MCT mutations.
Papadimitriou et al. (2008) reported an 11-month-old boy referred for severe hypotonia and global developmental delay. He had decreased muscle strength, hyperactive deep tendon reflexes, severe head lag, was unable to sit independently. Although he showed no signs of thyroid dysfunction, and thyrotropin was within the reference range, laboratory studies showed high serum triiodothyronine (T3), low thyroxine (T4), and mildly increased serum lactate. The increased serum lactate was considered to be consistent with peripheral thyrotoxicosis. Brain MRI showed decreased myelination of the subcortical tissue and thalamus. Family history was significant for a maternal uncle with an unidentified neurologic disorder leading to death at age of 8 years, and a brother with muscular hypotonia since birth and death at age 9 months. Treatment with T4 did not improve the patient's neurologic condition. Genetic analysis confirmed a defect in the MCT8 gene.
Mapping
Schwartz et al. (1990) presented linkage data on the original family reported by Allan et al. (1944). A putative AHDS disease locus was identified on chromosome Xq21 near marker DYX1 (maximum multipoint lod score of 3.58).
Bialer et al. (1992) linked the family reported by Davis et al. (1981) to Xq21 with a maximum lod score of 2.88 at marker DXS72. A maximum multipoint lod score of 4.14 was obtained showing close linkage to DXS72, a position slightly more proximal in Xq21 than was suggested by the data from the original AHDS family.
Schwartz (1993) noted that 35% (10 of 43) of mapped mental retardation loci on the X chromosome show linkage to markers in the region Xq12-q21. The observation of males with cytogenetically visible deletions in Xq21 and mental retardation is consistent with the clustering of X-linked mental retardation entities to Xq12-q21. The mental retardation is invariably associated with some other entity, usually choroideremia (CHM; 303100), but sometimes both choroideremia and X-linked deafness (DFN3; 304400). Molecular analysis of 4 males with mental retardation and deletions of Xq21 led May et al. (1995) to place the putative MR region in Xq21.1 between DXS233 and the CHM locus.
Zorick et al. (2004) reported fine mapping of a large Brazilian family originally reported by Passos-Bueno et al. (1993). A critical region was identified between markers at Xp11.2 and Xq13, thus showing overlap with the candidate AHDS region identified by Schwartz et al. (1990) and Bialer et al. (1992).
Bohan and Azizi (2004) suggested that AHDS is a fourth locus for X-linked spastic paraplegia, distinct from SPG1 (303350), SPG2 (312920) and Pelizaeus-Merzbacher disease (PMD; 312080), and SPG16 (300266). The authors noted that the X-linked SPG families reported by Claes et al. (2000) (see 300534) and Starling et al. (2002) suggested linkage to the AHDS region on Xq21. Bohan and Azizi (2004) proposed the term 'SPG22' for the locus at Xq21 that encompasses the AHDS region. In a reply, Fink (2004) stated that AHDS could be considered a form of complicated SPG, but noted that the family reported by Starling et al. (2002) had a pure form of the disorder (SPG34; 300750).
Cytogenetics
Frints et al. (2008) reported a woman with full-blown AHDS associated with a de novo translocation t(X;9)(q13.2;p24) that interrupted the SLC16A2 gene. Patient fibroblasts showed complete loss of protein expression due to nonrandom X inactivation. The patient was severely developmentally retarded. She had axial hypotonia, spastic paraplegia, and athetoid movements of the upper limbs. Dysmorphic facial features included hypotonia, long palpebral fissures, midface hypoplasia, anteverted nares with bulbous nasal tip, and elongated open mouth with prominent teeth. Other features included scoliosis, contractures of the knees and ankles, and increased serum T3.
Molecular Genetics
In affected members of 2 unrelated families in which males had mental retardation associated with increased serum T3, Dumitrescu et al. (2004) identified 2 different mutations in the SLC16A2 gene (300095.0001; 300095.0002). Heterozygous females had a milder thyroid phenotype with no neurologic deficits.
In 2 young boys with highly elevated serum T3 and severe mental retardation, Friesema et al. (2003) identified 2 different mutations in the MCT8 gene (300095.0003; 300095.0004).
Friesema et al. (2004) identified mutations in the MCT8 gene in 5 unrelated boys with severe neurologic abnormalities and increased serum T3 (see, e.g., 300095.0005-300095.0006).
The identification by Dumitrescu et al. (2004) and Friesema et al. (2004) of mutations in the SLC16A2 gene, encoding monocarboxylate transporter-8 (MCT8), in males with hypotonia, involuntary movements, and mental retardation made that gene an attractive candidate for the site of the mutation in Allan-Herndon-Dudley syndrome. Schwartz et al. (2005) found that each of 6 large families with Allan-Herndon-Dudley had mutations in MCT8. One essential function of the protein encoded by this gene appeared to be the transport of triiodothyronine into neurons. Abnormal transporter function was reflected in elevated free triiodothyronine and lowered free thyroxine levels in the blood.
In affected members of a large Brazilian family with AHDS originally reported by Passos-Bueno et al. (1993), Maranduba et al. (2006) identified a mutation in the SLC16A2 gene (300095.0011). Serum T3 and free T3 levels were elevated in all affected males, whereas normal levels were found among obligate female carriers.
Among 13 families with X-linked mental retardation, 401 male sibships with mental retardation, and 47 male patients with sporadic AHDS-like clinical features, Frints et al. (2008) identified 2 patients with pathogenic SLC16A2 mutations. The authors concluded that SLC16A2 mutations are not a common cause of X-linked mental retardation.
Pathogenesis
Capri et al. (2013) found that the pathogenicity of SLC16A2 mutations could be evaluated in both patient fibroblasts and JEG3 human placental choriocarcinoma cells by measuring T3 uptake activity. Fibroblasts from 6 unrelated patients with SLC16A2 mutations showed significantly decreased T3 uptake (about 50%) compared to controls, but the amount of uptake did not accurately reflect phenotype severity. In contrast, the decrease in T3 uptake in JEG3 cells transfected with the mutations did correlate with phenotypic severity: those with a severe phenotype showed a greater than 80% decrease in T3 uptake, whereas an intermediate decrease (mean -66.11%) was associated with a milder phenotype. Capri et al. (2013) noted that transfected JEG3 cells represent a good alternative cell model from patient cells because T3 transport relies mainly on expression of the SLC16A2 transporter after transfection, whereas patient fibroblasts may also express other transporters.
INHERITANCE \- X-linked HEAD & NECK Head \- Microcephaly Face \- Elongated face \- Bitemporal narrowing Ears \- Large ears \- Simple ears \- Pinna modeling anomalies \- Prominent antihelix \- Flattened antihelix Eyes \- Nystagmus, rotary (in some patients) \- Disconjugate eye movements CHEST Ribs Sternum Clavicles & Scapulae \- Pectus excavatum, broad, shallow ABDOMEN Gastrointestinal \- Poor feeding SKELETAL \- Joint contractures (small and large joints affected) Spine \- Scoliosis Feet \- Flat feet \- Lateral deviation of great toe NEUROLOGIC Central Nervous System \- Neonatal hypotonia \- Hypotonia, proximal, severe \- Inability to hold neck up ('limber neck') onset at 6 months \- Neck drop \- Delayed psychomotor development, severe \- Spastic paraplegia \- Spastic quadriplegia \- Ataxia \- Inability to walk \- Inability to stand \- Dystonic posturing of the hands \- Involuntary writhing movements \- Generalized muscle atrophy \- Dysarthria \- Drooling \- Mental retardation, severe \- Inability to communicate \- No gaze contact \- Lack of communication \- Clonus \- Hyperreflexia \- Extensor plantar responses \- Delayed myelination \- Leukodystrophy and white matter changes, which improve with age Behavioral Psychiatric Manifestations \- Irritability LABORATORY ABNORMALITIES \- Decreased serum thyroxine (T4) \- Decreased serum free thyroxine \- Normal or mildly increased thyroid-stimulating hormone (TSH) \- Increased serum triiodothyronine (T3) \- Decreased serum rT3 MISCELLANEOUS \- Onset at birth \- Heterozygous females may have milder thyroid phenotype and no neurologic abnormalities \- No peripheral signs of hypothyroidism MOLECULAR BASIS \- Caused by mutation in the monocarboxylate transporter 8 gene (MCT8, 300095.0001 ) ▲ 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
| ALLAN-HERNDON-DUDLEY SYNDROME | c0795889 | 1,441 | omim | https://www.omim.org/entry/300523 | 2019-09-22T16:20:08 | {"doid": ["0050631"], "mesh": ["C537047"], "omim": ["300523"], "orphanet": ["280270", "59"], "synonyms": ["Alternative titles", "MONOCARBOXYLATE TRANSPORTER 8 DEFICIENCY", "ALLAN-HERNDON SYNDROME", "MENTAL RETARDATION, X-LINKED, WITH HYPOTONIA", "T3 RESISTANCE", "TRIIODOTHYRONINE RESISTANCE", "PMLD", "MENTAL RETARDATION AND MUSCULAR ATROPHY"], "genereviews": ["NBK26373"]} |
## Clinical Features
Goodpasture syndrome is an autoimmune disease of lung and kidney. Viral and streptococcal infections and exposure to hydrocarbon fumes have been suggested as possible causes. Three familial instances (Gossain et al., 1972; Maddock et al., 1967), including a pair of identical twins (D'Apice et al., 1978), have been reported. One twin had pumped gasoline in a filling station for 2 weeks before onset; the other twin had, 5 days before onset, started a job spraying ball-bearings with a fine mist of mineral turpentine. The host factor might be immune response genes. Maddock et al. (1967) described the Goodpasture syndrome in 2 male first cousins.
Pathogenesis
Turner et al. (1992) demonstrated that the Goodpasture antigen is the alpha-3 chain of type IV collagen (COL4A3; 120070).
Hudson et al. (2003) reviewed extensively the biology of type IV collagen and its relation to Goodpasture syndrome. They pointed to the existence of 2 forms: the antineutrophil cytoplasmic autoantibody (ANCA)-negative form, present in 75% of cases, and the ANCA-positive form, present in 25% of cases. Both have autoantibodies to the NC1 domain of the alpha-3 chain of type IV collagen, but the ANCA-positive form also has antibodies to myeloperoxidase. The Goodpasture syndrome occurring posttransplantation in cases of Alport syndrome shows alloantibodies to NC1 domains of alpha-3, alpha-4, and alpha-5 chains of type IV collagen.
Pedchenko et al. (2010) analyzed circulating autoantibodies in 57 patients with Goodpasture disease and kidney-bound antibodies in 14 patients. Autoantibodies to both the COL4A3 and COL4A5 (303630) NC1 monomers were bound in the kidneys and lungs, indicating roles for those monomers as autoantigens. The antibodies bound to distinct epitopes encompassing region E(A) in the COL4A5 NC1 monomer and regions E(A) and E(B) in the COL4A3 NC1 monomer, but they did not bind to the native crosslinked COL4A3-COL4A4 (120131)-COL4A5 NC1 hexamer. Pedchenko et al. (2010) concluded that the development of Goodpasture disease may be considered an autoimmune 'conformeropathy' that involves perturbation of the quaternary structures of the COL4A3-COL4A4-COL4A5 NC1 hexamer, inducing a pathogenic conformational change in the COL4A3 NC1 and COL4A5 NC1 subunits, which in turn elicits an autoimmune response.
Ooi et al. (2017) showed that autoreactive alpha-3(135-145)-specific T cells expand in patients with Goodpasture disease and, in alpha-3(135-145)-immunized HLA-DR15 transgenic mice, alpha-3(135-145)-specific T cells infiltrate the kidney and mice develop Goodpasture disease. HLA-DR15 and HLA-DR1 exhibit distinct peptide repertoires and binding preferences and present the Goodpasture epitope in different binding registers. HLA-DR15-alpha-3(135-145) tetramer-positive T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-alpha-3(135-145) tetramer-positive T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4+Foxp3+ regulatory T cells (Treg cells) expressing tolerogenic cytokines. HLA-DR1-induced Treg cells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15+ and HLA-DR1+ healthy human donors display altered alpha-3(135-145)-specific T-cell antigen receptor usage. Moreover, patients with Goodpasture disease display a clonally expanded alpha-3(135-145)-specific CD4+ T-cell repertoire. Ooi et al. (2017) concluded that they provided a mechanistic basis for the dominantly protective effect of HLA in autoimmune diseases, whereby HLA polymorphism shapes the relative abundance of self-epitope-specific Treg cells that leads to protection or causation of autoimmunity.
Animal Model
Kalluri et al. (1997) developed a new mouse model of human anti-glomerular basement disease (GBM) to characterize better the genetic determinants of cell-mediated injury. The findings in studies of the model suggested that anti-GBM antibodies in mice facilitate disease only in MHC haplotypes capable of generating nephritogenic lymphocytes with special T-cell repertoires.
INHERITANCE \- Autosomal recessive RESPIRATORY \- Dyspnea Lung \- Hemoptysis \- Pulmonary hemorrhage \- Pulmonary infiltrates GENITOURINARY Kidneys \- Glomerulonephritis \- Renal insufficiency IMMUNOLOGY \- Autoimmune disease LABORATORY ABNORMALITIES \- Circulating antibodies to alpha-3 chain of type IV collagen \- Hematuria \- Proteinuria ▲ 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
| GOODPASTURE SYNDROME | c0403529 | 1,442 | omim | https://www.omim.org/entry/233450 | 2019-09-22T16:27:24 | {"doid": ["9808"], "mesh": ["D019867"], "omim": ["233450"], "icd-9": ["446.21"], "icd-10": ["M31.0"], "orphanet": ["375"]} |
Obstructive uropathy
SpecialtyUrology
Obstructive uropathy is a structural or functional hindrance of normal urine flow,[1] sometimes leading to renal dysfunction (obstructive nephropathy).
It is a very broad term, and does not imply a location or cause.
## Contents
* 1 Symptoms
* 2 Causes
* 3 Diagnosis
* 4 Treatment
* 5 References
* 6 External links
## Symptoms[edit]
Symptoms, less likely in chronic obstruction, are pain radiating to the T11 to T12 dermatomes, anuria, nocturia, or polyuria.
## Causes[edit]
It can be caused by a lesion at any point in the urinary tract.[2]
Causes include urolithiasis,[3] posterior urethral valves and ureteral herniation.[3]
## Diagnosis[edit]
Diagnosis is based on results of bladder catheterization, ultrasonography, CT scan, cystourethroscopy, or pyelography, depending on the level of obstruction.
## Treatment[edit]
Treatment, depending on cause, may require prompt drainage of the bladder via catheterization, medical instrumentation, surgery (e.g., endoscopy, lithotripsy), hormonal therapy, or a combination of these modalities.
Treatment of the obstruction at the level of the ureter:
* Open surgery.
* Less invasive treatment: laparoscopic correction.
* Minimal invasive treatment: Overtoom procedure:[4] dilatation with cutting balloon catheter followed by introduction of the pyeloplasty balloon catheter.[5] This balloon is inflated with pure contrast agent via the pusher and remains in situ in the ureter to keep the previous treated stricture dilated while the expanded urothelium heals. Urine can drain through the central channel of this catheter.
## References[edit]
1. ^ Definition: obstructive uropathy from Online Medical Dictionary.
2. ^ Kumar, Vinay; Fausto, Nelson; Fausto, Nelso; Robbins, Stanley L.; Abbas, Abul K.; Cotran, Ramzi S. (2005). Robbins and Cotran Pathologic Basis of Disease (7th ed.). Philadelphia, Pa.: Elsevier Saunders. p. 1012. ISBN 978-0-7216-0187-8.
3. ^ a b Tsai PJ, Lin JT, Wu TT, Tsai CC (September 2008). "Ureterosciatic hernia causes obstructive uropathy". J Chin Med Assoc. 71 (9): 491–3. doi:10.1016/S1726-4901(08)70155-2. PMID 18818145.[dead link]
4. ^ Treatment of ureteropelvic junction obstruction using a detachable inflatable stent: initial experience Archived 2014-01-09 at the Wayback Machine by Timotheus T C Overtoom, Peter L Vijverberg, Hendrik W van Es, Sandrine van Selm, Hans P M van Heesewijk
5. ^ "Overtoom balloon". www.overtoomballoon.com. Retrieved 2016-10-15.
## External links[edit]
Classification
D
* ICD-10: N13
* ICD-9-CM: 599.60
External resources
* MedlinePlus: 000507
* eMedicine: radio/804
* v
* t
* e
Diseases of the urinary tract
Ureter
* Ureteritis
* Ureterocele
* Megaureter
Bladder
* Cystitis
* Interstitial cystitis
* Hunner's ulcer
* Trigonitis
* Hemorrhagic cystitis
* Neurogenic bladder dysfunction
* Bladder sphincter dyssynergia
* Vesicointestinal fistula
* Vesicoureteral reflux
Urethra
* Urethritis
* Non-gonococcal urethritis
* Urethral syndrome
* Urethral stricture
* Meatal stenosis
* Urethral caruncle
Any/all
* Obstructive uropathy
* Urinary tract infection
* Retroperitoneal fibrosis
* Urolithiasis
* Bladder stone
* Kidney stone
* Renal colic
* Malakoplakia
* Urinary incontinence
* Stress
* Urge
* Overflow
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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
| Obstructive uropathy | c0477731 | 1,443 | wikipedia | https://en.wikipedia.org/wiki/Obstructive_uropathy | 2021-01-18T18:34:25 | {"umls": ["C0477731"], "wikidata": ["Q2013137"]} |
## Clinical Features
Verloes et al. (1989) reported a brother and sister and probably a third sib with a seemingly characteristic and previously undescribed syndrome. Microcephaly was severe and there was also microphthalmia, brachydactyly with clinodactyly 5, delayed growth in puberty, and severe mental retardation. The third and probably identically affected sib died at the age of 15 months from the consequences of a complex cyanotic heart defect.
Bottani and Verloes (1995) stated that the condition in the boy reported by Verloes et al. (1989) had been 'very stable' over the previous 8 years; however, the girl died suddenly and unexpectedly, with no autopsy. Bottani and Verloes (1995) suggested that the disorder they described might be the same as the growth-mental deficiency syndrome of Myhre (139210).
Farrell (1997) described a 23-year-old male with microphthalmia, severe developmental delay, conductive hearing loss, marked short stature of prenatal onset, and radiographic skeletal changes. His height was 107 cm (50th centile for 5 years). The facial view at age 23 years looked like that of a young child.
Cytogenetics
Verloes et al. (2000) used subtelomeric probes to reinvestigate the family initially published as GOMBO syndrome by Verloes et al. (1989). They identified a cryptic translocation resulting in 3p monosomy and 22q trisomy. The karyotype was 46,XY,ish der(3),t(3;22)(p25;q13).
Limbs \- Brachydactyly \- Clinodactyly Neuro \- Severe mental retardation Inheritance \- Autosomal recessive Growth \- Delayed pubertal growth Cardiac \- Congenital heart defect HEENT \- Microcephaly \- Microphthalmia ▲ 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
| GOMBO SYNDROME | c1856274 | 1,444 | omim | https://www.omim.org/entry/233270 | 2019-09-22T16:27:23 | {"mesh": ["C537284"], "omim": ["233270"], "synonyms": ["Alternative titles", "GROWTH RETARDATION, OCULAR ABNORMALITIES, MICROCEPHALY, BRACHYDACTYLY, AND OLIGOPHRENIA"]} |
Plant disease that primarily affects Bananas
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Panama disease
Common namesPanama disease
Fusarium wilt of banana
Vascular wilt of banana
Causal agentsFusarium oxysporum f.sp. cubense
Hostsbanana
Vectorswater, soil residues, replanting of suckers, farming tools and transport, leaf trash
EPPO CodeFUSACB
DistributionIndonesia, China, Malaysia, Australia, the Philippines, Jordan, Vietnam, Laos, Pakistan, Lebanon, Mozambique, Oman
Panama disease (or Fusarium wilt) is a plant disease that infects banana plants (Musa spp.). It is a wilting disease caused by the fungus Fusarium oxysporum f. sp. cubense (Foc). The pathogen is resistant to fungicides and its control is limited to phytosanitary measures.[1]
During the 1950s, an outbreak of Panama disease almost wiped out the commercial Gros Michel banana production. The Gros Michel banana was the dominant cultivar of bananas, and Fusarium wilt inflicted enormous costs and forced producers to switch to other, disease-resistant cultivars. Currently, a new outbreak of Panama disease caused by the strain Tropical Race 4 (TR4) threatens the production of the Cavendish banana, today's most popular cultivar.
## Contents
* 1 Distribution
* 2 Symptoms
* 3 Classification and host range
* 4 Disease cycle
* 5 History
* 5.1 Gros Michel devastation era
* 5.2 TR4 devastation era
* 5.3 Australian quarantine
* 5.4 Spread to Colombia
* 6 Disease management
* 6.1 Banana breeding impeded by triploidy
* 7 See also
* 8 References
* 9 Bibliography
* 10 External links
## Distribution[edit]
Not all banana-producing countries have been affected by the outbreak of Panama disease. Tropical Race 4 (TR4) was first identified in Taiwan,[2] and from there rapidly spread to Indonesia, China, Malaysia, Australia and the Philippines.[3] The disease was then identified in Jordan in 2013.[4] TR4 later spread to Vietnam[5] and Laos,[6] as well as to the Middle East being reported in Pakistan and Lebanon.[7] In 2015, the disease then spread to Africa, being informally announced in Mozambique and Oman.[3] In August 2019, TR4 arrived in Colombia, a country in Latin America, the region comprising the world's biggest banana exporters.[8]
## Symptoms[edit]
Two external symptoms help characterize Panama disease of banana:
* Yellow leaf syndrome, the yellowing of the border of the leaves which eventually leads to bending of the petiole.[1]
* Green leaf syndrome, which occurs in certain cultivars, marked by the persistence of the green color of the leaves followed by the bending of the petiole as in yellow leaf syndrome. Internally, the disease is characterized by a vascular discoloration. This begins in the roots and rhizomes with a yellowing that proceeds to a reddish-brown color in the pseudostem, as the pathogen blocks the plant's nutrient and water transport.[1][9]
* With proceeding infection, the banana pseudostem can split and eventually, the whole plant collapses.[1]
External symptoms often get confused with the symptoms of bacterial wilt of banana, but ways to differentiate between the two diseases include:
* Fusarium wilt proceeds from older to younger leaves, but bacterial wilt is the opposite.
* Fusarium wilt has no symptoms on the growing buds or suckers, no exudates visible within the plant, and no symptoms in the fruit. Bacterial wilt can be characterized by distorted or necrotic buds, bacterial ooze within the plant, and fruit rot and necrosis.[9]
Once a banana plant is infected, recovery is rare, but if it does occur, any new emerging suckers will already be infected and can propagate disease if planted.[9]
## Classification and host range[edit]
Fusarium oxysporum f. sp. cubense (Foc) is a member of the Fusarium oxysporum species complex, a group of ascomycete fungi with morphological similarities.[10][11] Based on their different host species, the plant pathogenic fungi of this species complex are divided into approximately 150 special forms (formae specialis, f.sp.).[12] Fusarium oxysprorum f.sp. cubense mainly infects banana (Musa) species. The special form cubense has been subdivided into four different races, that each attack a different group of banana genotypes.
* Race 1 was involved in the 1960s Panama disease outbreak which destroyed much of the Gros Michel banana plantations in Central America. In addition to Gros Michel, Race 1 also attacks other members of the banana AAB genomic group, including Abacá, Maqueño, the Silk subgroup, the Pome subgroup, Pisang Awak, Ducasse, and Lady Finger.[13] Cavendish cultivars are resistant to Race 1.
* Race 2 infects cooking bananas with ABB genome and the Bluggoe subgroup.[10]
* Race 3 infecting Heliconia spp. is no longer considered pathogenic to bananas,[1] but included into the Fusarium oxysporum f.sp. heliconiae.[10]
* Race 4 is the causal agent of the current Panama disease outbreak since it is pathogenic to the currently used Cavendish cultivars (AAA genome). Race 4 is further subdivided into Tropical Race 4 (TR4) and Subtropical Race 4 (STR4). The latter only infects Cavendish and Race 1 and 2 susceptibles under abiotic stress.[14]
## Disease cycle[edit]
Modern commercially farmed banana plants are reproduced asexually, by replanting the plant's basal shoot that grows after the original plant has been cut down. Being triploid, the fruit contains no seeds, and the male flower does not produce pollen suitable for pollination, prohibiting sexual reproduction. This causes all bananas of a single breed to be nearly genetically identical. The fungus easily spreads from plant to plant because the individual plants' defenses are nearly identical.[15]
The disease is dispersed by spores or infected material that travel in surface water or farming activities. One of the biggest issues in spreading the disease is the means by which new banana plants are planted. Suckers are taken from one plant and clonally propagated to grow new trees. About 30 to 40% of suckers from a diseased plant are infected and not all show symptoms, so the chance of growing a new, already infected plant is fairly high. Finally, the disease is known to infect certain weeds without showing symptoms, meaning it can survive in the absence of banana plants and remain undetected in a place where bananas are planted later.[16]
FOC is thought to persist only asexually, as no sexual phase (teleomorph) has been observed. Recombination events may occur via somatic hybridisation and the parasexual cycle.[17]
This means that the survival and dispersal of the disease relies on purely asexual spores and structures. The disease survives in chlamydospores which are released as the plant dies and can survive in the soil for up to 30 years. When the environment is ideal and there are host roots available (fungus is attracted to root exudates), these chlamydospores will germinate and hyphae will penetrate the roots, initiating infection. There is an increase in the number of symptomatic plants when inflorescences emerge and the highest disease incidence occurs right before harvest.[16] Once infected, microconidia are produced and proliferate within the vessels of the plant's vascular system. Macroconidia are another asexual spore that tends to be found on the surface of plants killed by Panama disease.[18] Infection is systemic, moving through the vascular system and causing yellowing and buckling that starts in older leaves and progresses to younger leaves until the entire plant dies.[16]
## History[edit]
### Gros Michel devastation era[edit]
The Gros Michel was the only type of banana eaten in the United States from the late 19th century until after World War II. The disease was serious and diagnosed in Panama banana plantations of Central America. Over several decades, the fungus spread from Panama to neighboring countries, moving north through Costa Rica to Guatemala and south into Colombia and Ecuador.
The banana industry was in a serious crisis, so a new banana thought to be immune to Panama disease was found and adopted, the Cavendish. In a few years, the devastated plantations resumed business as usual, and the transition went smoothly in the American market. Shortly thereafter, Malaysia entered the banana-growing business. Cavendish banana plantations were new to that country in the 1980s, but they rapidly expanded to meet the demand. Thousands of acres of rain forests and former palm oil plantations were shifted to banana production. Within a few years, though, the new plants began to die. While it took several years to find, the cause was ultimately attributed back to the Panama disease. Although the Cavendish was then thought to be immune, it was immune only to the strain of the fungus that destroyed the Gros Michel. The version that annihilated the Gros Michel was found only in the Western Hemisphere, but the version found in Malaysian soil was different, and the Cavendish is susceptible to it. It killed and spread faster, inspiring more panic than its earlier counterpart in Panama. The newly discovered strain of F. oxysporum was named tropical race 4 (TR4).
### TR4 devastation era[edit]
Tropical Race 4 (TR4) was discovered in Taiwan in 1989.[19] In July 2013, members of OIRSA, a Latin American regional organisation for plant and animal health, produced a contingency plan specific to TR4 for its nine member countries (Belize, Costa Rica, Dominican Republic, El Salvador, Guatemala, Honduras, Mexico, Nicaragua and Panama), the plan is only available in Spanish.[20] In March 2015, Latin America growers met to create a regional defense effort and planned to meet again in September or October of that year. No specific regional measures are in place. Ecuadorian growers requested the government to fumigate all containers.[21]
Scientists are trying to modify the banana plant to make it resist Panama disease and many other serious banana afflictions ranging from fungal, bacterial, and viral infections to nematodes and beetles. Researchers are combing remote jungles searching for new wild bananas. Hybrid bananas are being created in the hope of generating a new variety with strong resistance to diseases. Some[who?] believe the best hope for a more resilient banana is through genetic engineering. However, the resulting fruit also needs to taste good, ripen in a predictable amount of time, travel long distances undamaged, and be easy to grow in great quantities. Currently, no cultivar or hybrid meets all of these criteria.
### Australian quarantine[edit]
In Queensland, a farm in Tully, 1500 km north of Brisbane, was quarantined and some plants were destroyed after TR4 was detected on March 3, 2015. After an initial shutdown of the infected farm, truckloads of fruit left in April with harvesting allowed to resume under strict biosecurity arrangements. The government says it is not feasible to eradicate the fungus. Researchers like Wageningen's Kema say the disease will continue to spread, despite efforts to contain it, as long as susceptible varieties are being grown.[22] The disease was again detected in Tully in July 2017, prompting Biosecurity Queensland to impose quarantine conditions.[23]
### Spread to Colombia[edit]
In August 2019, authorities in Colombia declared a national emergency after confirming that the Panama disease had reached Latin America. "Once you see it, it is too late, and it has likely already spread outside that zone without recognition," said one expert quoted by National Geographic.[8]
## Disease management[edit]
Currently, fungicides and other chemical and biological control agents have proven fairly unsuccessful, or only successful in vitro or in greenhouses, in the face of Panama disease of bananas. The most commonly used practices include mostly sanitation and quarantine practices to prevent the spread of Panama disease out of infected fields. However, the most effective tool against Panama disease is the development of banana plants resistant to Fusarium oxysporum f. sp. cubense.[9] The clonal reproduction of banana has led to a consequential lack of other varieties. Efforts are being made to produce resistant varieties, but with bananas being triploids which do not produce seeds, this is not an easy task. Creating clones from tissue cultures, rather than suckers, has proven somewhat successful in breeding resistant varieties, although these tend to have decreased success in stress-tolerance, yield, or other beneficial traits necessary for commercial varieties.[16] Nevertheless, these efforts are leading to the best control measure for Panama disease of banana.
Recently,[when?] an R gene (RGA2) was transformed into Cavendish bananas which showed disease resistance to Fusarium wilt tropical race 4. One specific transformed line, which consisted of eight plants, showed resistance in the field for all of them. The field trial lasted three years and the plants exhibited a yield drag.[clarification needed][24]
Taiwanese researchers believe that the onset of TR4 was linked to soil degradation caused by the use of chemical fertilizers.[25]
### Banana breeding impeded by triploidy[edit]
One major impediment to breeding bananas is polyploidy; Gros Michel and Cavendish bananas are triploid and thus attempts at meiosis in the plant's ovules cannot produce a viable gamete. Only rarely does the first reduction division in meiosis in the plants' flowers tidily fail completely, resulting in a euploid triploid ovule, which can be fertilized by normal haploid pollen from a diploid banana variety; a whole stem of bananas would contain only a few seeds and sometimes none. As a result, the resulting new banana variety is tetraploid, and thus contains seeds; the market for bananas is not accustomed to bananas with seeds. Experience showed that where both meiosis steps failed, causing a heptaploid seedling, or when the seedling is aneuploid, results are not as good.[citation needed]
Second-generation breeding using those new tetraploids as both parents has tended not to yield good results, because the first generation contains the Gros Michel triploid gene set intact (plus possibly useful features in the added fourth chromosome set), but in the second generation, the Gros Michel gene set has been broken up by meiosis.
The Honduras Foundation for Agricultural Research cultivates several varieties of the Gros Michel. They have succeeded in producing a few seeds by hand-pollinating the flowers with pollen from diploid seeded bananas.[26]
## See also[edit]
* List of banana and plantain diseases
* Black sigatoka (a leaf-spot disease of banana plants caused by the ascomycete fungus Mycosphaerella fijiensis (Morelet))
## References[edit]
1. ^ a b c d e Ploetz, R. C. (2015). "Fusarium Wilt of Banana." Phytopathology 105(12): 1512-1521.
2. ^ Ploetz, R. C. (2006). "Panama disease, an old nemesis rears its ugly head: part 2, the cavendish era and beyond." Plant Health Progress: 1-17.
3. ^ a b Ordonez, N., M. F. Seidl, C. Waalwijk, A. Drenth, A. Kilian, B. P. Thomma, R. C. Ploetz and G. H. Kema (2015). "Worse comes to worst: bananas and Panama disease—when plant and pathogen clones meet." PLoS pathogens 11(11): e1005197.
4. ^ Garcia-Bastidas, F., N. Ordonez, J. Konkol, M. Al-Qasim, Z. Naser, M. Abdelwali, N. Salem, C. Waalwijk, R. C. Ploetz and G. H. J. Kema (2014). "First Report of Fusarium oxysporum f. sp cubense Tropical Race 4 Associated with Panama Disease of Banana outside Southeast Asia." Plant Disease 98(5): 694-694.
5. ^ Hung, T. N., N. Q. Hung, D. Mostert, A. Viljoen, C.-P. Chao and A. Molina (2017). "First report of Fusarium wilt on Cavendish bananas, caused by Fusarium oxysporum f. sp. cubense tropical race 4 (VCG 01213/16), in Vietnam." Plant Disease: PDIS-08-17-1140-PDN.
6. ^ Chittarath, K., D. Mostert, K. S. Crew, A. Viljoen, G. Kong, A. Molina and J. E. Thomas (2017). "First report of Fusarium oxysporum f. sp. cubense tropical race 4 (VCG 01213/16) associated with Cavendish bananas in Laos." Plant Disease: PDIS-08-17-1197-PDN.
7. ^ Ordonez, L. N., F. Garcia-Bastidas, H. B. Laghari, M. Y. Akkary, E. N. Harfouche, B. N. al Awar and G. H. J. Kema (2016). "First Report of Fusarium oxysporum f. sp cubense Tropical Race 4 Causing Panama Disease in Cavendish Bananas in Pakistan and Lebanon." Plant Disease 100(1): 209-210.
8. ^ a b Karp, Myles (12 August 2019). "The banana is one step closer to disappearing". National Geographic. Retrieved 16 August 2019.
9. ^ a b c d Perez-Vincent, Luis; Dita, Miguel A.; Martinez-de la Parte, Einar (May 2014). Technical Manual: Prevention and diagnostic of Fusarium Wilt (Panama disease) of banana caused by Fusarium oxysporum f. sp. cubense Tropical Race 4 (TR4). Food and Agriculture Organization of the United Nations.
10. ^ a b c Ploetz, R. C. (2006). "Fusarium wilt of banana is caused by several pathogens referred to as Fusarium oxysporum f. sp. cubense." Phytopathology 96(6): 653-656.
11. ^ Snyder, W. C. and H. Hansen (1940). "The species concept in Fusarium." American Journal of Botany: 64- 67.
12. ^ Baayen, R. P., K. O'Donnell, P. J. M. Bonants, E. Cigelnik, L. Kroon, E. J. A. Roebroeck and C. Waalwijk (2000). "Gene genealogies and AFLP analyses in the Fusarium oxysporum complex identify monophyletic and nonmonophyletic formae speciales causing wilt and rot disease." Phytopathology 90(8): 891-900.
13. ^ Drenth, A. and D. I. Guest (2016). Fungal and Oomycete Diseases of Tropical Tree Fruit Crops. Annual Review of Phytopathology, Vol 54. J. E. Leach and S. Lindow. 54: 373-395.
14. ^ Ploetz, R. C. (2005). "Panama disease, an old nemesis rears its ugly head: part 1, the beginnings of the banana export trades." Plant Health Progress(December): 1-10.
15. ^ Burton, Reg (2015-03-04). "Panama disease threatens NQ bananas". Fairfax Media.
16. ^ a b c d Hwang, Shin-Chuan; Ko, Wen-Hsuing (June 2004). "Cavendish Banana Cultivars Resistant to Fusarium Wilt Acquired through Somaclonal Variation in Taiwan". Plant Disease. 88 (6): 580–588. doi:10.1094/pdis.2004.88.6.580. PMID 30812575.
17. ^ M J Carlile, S C Watkinson, G W Gooday, 2001, Parasites and Mutualistic Symbionts in 'The Fungi (Second Edition)' Eds: same as authors, Academic Press, pp 363-460,
18. ^ "Fusarium oxysporum f. sp. cubense". ProMusa. July 2017. Retrieved 25 October 2017.
19. ^ REYNOLDS, MATT. "A Fungus Could Wipe Out the Banana Forever". Wired. Retrieved 26 February 2020.
20. ^ https://www.oirsa.org/contenido/biblioteca/PlandecontingenciacontraFocR4TOIRSA.pdf
21. ^ "Tropical race 4 - TR4".
22. ^ Sedgman, Phoebe. "There Might Be No Saving the World's Top Banana". Bloomberg.com. Retrieved 2015-06-06.
23. ^ McKillop, Charlie (13 July 2017). "Panama disease outbreak on Queensland banana farm prompts quarantine restrictions". Australian Broadcasting Corporation. Retrieved 27 July 2017.
24. ^ Dale, James; et al. (November 14, 2017). "Transgenic Cavendish bananas with resistance to Fusarium wilt tropical race 4". Nature Communications. 8 (1): 1496. Bibcode:2017NatCo...8.1496D. doi:10.1038/s41467-017-01670-6. ISSN 2041-1723. PMC 5684404. PMID 29133817.
25. ^ Chia-nan, Lin. "ICDF is helping other nations with banana disease". taipeitimes.com. Taipei Times. Retrieved 1 March 2020.
26. ^ Carla Helfferich (1990). "Battling for Bananas". Alaska Science Forum. Archived from the original on 2008-02-23. Retrieved 2008-06-02.
## Bibliography[edit]
* “
## External links[edit]
* https://fusariumwilt.org/index.php/en/about-fusarium-wilt/
* "Fusarium wilt of banana" on ProMusa's Musapedia
* Can This Fruit be Saved? (discusses the disease threat to banana crops)
* Fusarium Wilt - A global threat to the banana
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Panama disease | None | 1,445 | wikipedia | https://en.wikipedia.org/wiki/Panama_disease | 2021-01-18T19:06:47 | {"wikidata": ["Q3240031"]} |
Polymyositis is a type of inflammatory myopathy, which refers to a group of muscle diseases characterized by chronic muscle inflammation and weakness. The muscles affected by polymyositis are the skeletal muscles (those involved with making movements) on both sides of the body. Although the disease can affect people of all ages, most cases are seen in adults between the ages of 31 and 60 years. The disease is more common among women and among black individuals.
The exact cause of polymyositis is unknown. The disease shares many characteristics with autoimmune disorders, which occur when the immune system mistakenly attacks healthy body tissues. In some cases, the disease may be associated with viral infections, connective tissue disorders, or an increased risk for malignancies (cancer). Diagnosis is based on a clinical examination that may include laboratory tests, imaging studies, electromyography, and a muscle biopsy. Although there is no cure for polymyositis, treatment with corticosteroids or immunosuppressants can improve muscle strength and function.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Polymyositis | c0085655 | 1,446 | gard | https://rarediseases.info.nih.gov/diseases/7425/polymyositis | 2021-01-18T17:58:15 | {"mesh": ["D017285"], "umls": ["C0085655"], "synonyms": []} |
GATA2 deficiency
Other namesGATA2 haploinsufficiency, GATA2 deficiency syndrome
GATA2 deficiency is a grouping of several disorders caused by common defect, viz., familial or sporadic inactivating mutations in one of the two parental GATA2 genes. These autosomal dominant mutations cause a reduction, i.e. a haploinsufficiency, in the cellular levels of the gene's product, GATA2. The GATA2 protein is a transcription factor critical for the embryonic development, maintenance, and functionality of blood-forming, lymphatic-forming, and other tissue-forming stem cells. In consequence of these mutations, cellular levels of GATA2 are deficient and individuals develop over time hematological, immunological, lymphatic, or other presentations that may begin as apparently benign abnormalities but commonly progress to severe organ (e.g. lung) failure, opportunistic infections, virus infection-induced cancers, the myelodysplastic syndrome, and/or leukemia. GATA2 deficiency is a life-threatening and precancerous condition.[1][2]
The various presentations of GATA2 deficiency include: 1) Monocytopenia and Mycobacterium Avium Complex/Dendritic Cell, Monocyte, B and NK Lymphocyte deficiency (i.e. MonoMAC or MonoMAC/DCML); 2) Emberger syndrome; 3) familial myelodysplastic syndrome/acute myeloid leukemia (i.e. familial MDS/AML); 3) chronic myelomonocytic leukemia (i.e. CMML); and 4) other anomalies such as aplastic anemia, chronic neutropenia, and wide-ranging immunological defects.[2] Each of these presentations is characterized by a specific constellation of signs and symptoms but often includes signs and symptoms more characteristic of other GATA2 deficiency presentations. Furthermore, individuals with identical GATA2 gene mutations can exhibit very different presentations.[1][2][3][4]
Prior to 2011, MonoMAC and the Emberger syndrome were clinically defined as unrelated genetic disorders. In 2011, however, all cases of both disorders were found to be caused by inactivating mutations in the GATA2 gene. Subsequently, some but not all cases of an expanding list of other well-defined disorders have been attributed to inactivating GATA2 mutations. While MonoMAC, the Emberger syndrome, and the growing list of all other disorders marked by inactivating GATA2 gene mutations are now being classified as a single clinical entity termed GATA2 deficiency, MonoMAC and the Emberger syndrome are sometimes still regarded as separate clinical entities.[2] Here, GATA2 deficiency is taken to include all disorders caused by inactivating GATA2 mutations. Defined as such, GATA2 deficiency is an unexpectedly common underlying cause for a growing list of disorders. Importantly, however, its treatment differs critically from that used to treat cases of these disorders which are not due to GATA2 deficiency.[2]
## Contents
* 1 Presentations
* 1.1 MonoMAC
* 1.2 Emberger Syndrome
* 1.3 Familial MDS/AML
* 1.4 Congenital neutropenia
* 1.5 Other presentations
* 1.6 Symptoms
* 2 Genetics
* 2.1 GATA2 transcription factor
* 2.2 GATA2 gene mutations
* 2.3 Non-mutational GATA2 deficiency
* 2.4 Other genetic abnormalities
* 3 Pathophysiology
* 3.1 Blood defects
* 3.2 Immunologic defects
* 3.3 Lymphedema
* 3.4 Hearing loss
* 3.5 Other defects
* 4 Diagnosis
* 5 Treatment
* 5.1 Family counseling
* 5.2 Prevention of complications
* 5.3 Bone marrow transplantation
* 5.3.1 Clinical trials
* 6 Prognosis
* 7 History
* 8 References
## Presentations[edit]
The presentations of GATA2 deficiency commonly fall into various categories with MonoMAC and Emberger syndrome in the past and sometimes even currently being considered as separate entities. In most cases, the age of onset and initial signs and symptoms are variable with each presentation often being accompanied by signs or symptoms more typical of other presentations. Nonetheless, most cases of the deficiency exhibit a combination of signs and symptoms that fit the following presentations.
### MonoMAC[edit]
Main article: MonoMAC
Individuals afflicted with MonoMAC commonly present in early adulthood afflicted with one or more of the opportunistic infections listed in the above Signs and symptoms section and have profoundly low numbers of circulating monocytes which may have existed for many years before symptoms developed.[5] These individuals also have low numbers of two other types of circulating blood cells viz., B lymphocytes and NK cells. Other presentations and/or developments (see Signs and symptoms) include: 1) pulmonary alveolar proteinosis; 2) tumors caused by opportunistic viral infections; 3) autoimmunity disturbances; and 4) the myelodysplastic syndrome, acute myeloblastic leukemia, or chronic myelomonocytic leukemia.[5][6]
### Emberger Syndrome[edit]
Main article: Emberger syndrome
Emberger syndrome presents as early as infancy but more typically in childhood or early adulthood with lymphedema of the lower limbs or testes, i.e. hydrocele, and congenital sensorineural hearing loss. Afflicted individuals may also exhibit one or more of the dysplasias listed in the above "Signs and symptoms" section. These presentations typically occur alongside of or are followed by hematologic abnormalities including but often only after many years or decades seriously life-threatening myelodysplastic syndrome and/or acute myeloid leukemia.[2][7][8] Individuals afflicted by the syndrome may also exhibit increased susceptibility to opportunistic viral infections, particularly in individuals that have Null mutations (i.e. mutations that cause complete lose of a functional gene product) in the GATA2 gene.[9]
### Familial MDS/AML[edit]
Main article: Myelodysplastic syndrome
Familial MDS/AML is an inherited predisposition to develop MDS, i.e. a disorder characterized by the development of a genetically distinct subpopulation (i.e. clone) of bone marrow hematopoietic stem cells, decreased levels of one or more types of circulating blood cells, and an increased risk of progressing to leukemia, particularly AML.[10] GATA2 deficiency commonly presents as MDS in childhood (usually >4 years of age) and adolescent (generally <18 years of age) individuals and as such is the most common germline mutation responsible for familial MDS/AML in this age group.[11] Inactivating GATA2 mutations appear responsible for ~15% in cases of advanced familial MDS (i.e. cases in which hematologic blast cells are ≥2% in blood or ≥2% but ≤20% in bone marrow) and in 4% of cases diagnosed as low-grade familial MDS (i.e. blast cells are <2% in blood or <5% in blood). Individuals exhibiting >20% blast cells in blood or bone marrow are diagnosed as having AML. Thus, GATA2 deficiency may also present as AML that was preceded by MPS.[10][11][12] In about 70% of the cases, the inactivating GATA2 mutations found in Familial MDS/AML are associated with advanced disease and exhibit monosomy of their 7 chromosome.[11] GATA2 deficiency-induced familial MDS/AML is often diagnosed in one member of a family that has other members with identical GATA2 gene mutations but either are classified as having another type of GATA2 deficiency presentation or have no signs or symptoms whatsoever of GATA2 deficiency.[2][11]
### Congenital neutropenia[edit]
Main article: Neutropenia
Congenital neutropenia refers to an assorted group of diseases that share a common set of signs and symptoms, viz., neutropenia, i.e. a low circulating blood neutrophil count, increased susceptibility to infections, various organ dysfunctions, and an extraordinarily high risk of developing leukemia.[13] A small percentage of individuals with familial or sporadic GATA2 deficiency present in their childhood with asymptomatic mild neutropenia but no other discernible hematological abnormalities except perhaps monocytopenia and macrocytosis, i.e. enlarged red blood cells. This presentation often persists for years but commonly progresses to include thrombocytopenia, increases susceptibility to infections due to, e.g. atypical mycobacteria or human papillomavirus, dysfunction of non-hematological organs, MDS, and leukemia (primarily AML and less commonly CMML). It is estimated that by age 30, 60% of these individuals develop leukemia.[2][4][9][13] Some of these individuals have large deletion mutations that span the GATA2 along with nearby genes and exhibit in addition to hematological defects various developmental abnormalities, neurological abnormalities, and/or body dysmorphic disorders.[14]
### Other presentations[edit]
Main article: Aplastic anemia
Main article: Bone marrow failure
Main article: Humoral immune deficiency
Main article: Monocytosis
Main article: Chronic myelomonocytic leukemia
GATA2 deficiency has been diagnosed in up to 10% of individuals presenting with aplastic anemia. It is also the most common cause of hereditary bone marrow failure and may present with this disorder. GATA 2 deficiency has been diagnosed in rare cases presenting as humoral immune deficiency due to B cell depletion, severe Epstein–Barr virus infection, or Epstein-Barr associated cancers. In all of these presentations, individuals may have or develop other manifestations of the deficiency and are of particularly high risk for developing AML or CMML.[1][2][15]
Rare cases of individuals with GATA2 deficiency may also present with extreme monocytosis (i.e. increases in circulating blood monocytes) or CMML, i.e. monocytosis plus the presence of abnormal (blasts) in the circulation and/or bone marrow. GATA2 deficient individuals who develop CMML often exhibit mutations in one of their ASXL1 genes. Since mutations in this gene are associated with CMML independently of GATA2 mutations, ASXL1 mutations may promote the development of CMML in GATA2 deficiency.[1][2][15]
### Symptoms[edit]
The age of onset of the GATA2 deficiency is variable with rare individuals showing first signs or symptoms in their infancy and others showing first symptoms or signs at almost any time thereafter including their later years. Rare individuals with inactivating GATA2 mutations may never develop symptoms, i.e. the disorder has a very high but nonetheless incomplete degree of penetrance.[7][16][8] This variability can occur between members of the same family who are documented to have the same GATA2 mutation.[17] The many signs and symptoms that are the direct or indirect consequences of GATA2 deficiency organized based on the types of involvement are:[1][16][18][8][5][6]
* Hematologic: Aplastic anemia, chronic neutropenia, monocytopenia, monocytosis (rarely), thrombocytopenia (which unlike other hematologic findings is most often due to autoimmunity), bone marrow failure, myelodysplastic syndrome, acute myeloid leukemia, chronic myelomonocytic leukemia, case reports of chronic lymphocytic leukemia and large granular lymphocytic leukemia.
* Lymphatic: lymphedema, i.e. fluid retention and tissue swelling caused by a compromised lymphatic system of the lower extremities (often complicated by deep vein thrombosis and cellulitis), lymphedema in other sites such as the face or testes (i.e. hydrocele).
* Immunologic: Increased susceptibility to infections caused by human papillomavirus, Herpes simplex, Varicella zoster virus, Epstein–Barr virus, cytomegalovirus, Molluscum contagiosum virus, nontuberculous mycobacteria, other bacteria, various aspergillus fungus species, various Candida fungus species, and histoplasma capsulatum;
* Tumors: Increased incidence of human papillomavirus-induced (e.g. Bowenoid papulosis, warts, etc.)) and Epstein-Barr virus-associated (e.g. nasopharynx cancer, T cell non-Hodgkin lymphoma ) benign and malignant tumors.
* Cancers: Increased incidence of metastatic melanoma, cervical carcinoma, Bowen disease of the vulva, spindle cell sarcoma of the liver, head and neck cancers, leiomyosarcoma, pancreas cancer, kidney cancer, and breast cancer.
* Autoimmunity: Erythema nodosum, panniculitis, lupus erythematosus-like reactions, autoimmune thrombocytopenia, chronic arthritis, arthralgias, primary biliary cirrhosis, aggressive multiple sclerosis.
* Lung: Pulmonary alveolar proteinosis (unlike most other cases of pulmonary alveolar proteinosis, the GATA2 deficiency-induced lung disorder is not caused by autoimmunity to or other causes for sharp reductions in granulocyte-macrophage colony stimulating factor); cryptogenic organizing pneumonia-like disease, pulmonary artery hypertension; pulmonary ventilation and diffusion defects as defined by pulmonary function testing that may lead to respiratory failure.
* Neuorlogic: Sensorineural hearing loss mainly for high frequencies.
* Heart: Endocarditis (may reflect GATA2 deficiency in the endocardium and/or impaired overlap with GATA4 function, which is involved in the embryonic development of this organ).
* Thyroid gland: Idiopathic (i.e. unknown cause) hypothyroidism.
* Reproductive: High rate of miscarriage.
* Body dysmorphic disorders: Hypotelorism, epicanthic folds, webbed neck, small palpebral fissures, ptosis, strabismus, urogenital malformations.
* Emotional and behavioral disorders: Autism spectrum disorders, chronic headache.
## Genetics[edit]
### GATA2 transcription factor[edit]
The GATA2 transcription factor contains two zinc finger (i.e. ZnF) motifs. C-ZnF is located toward the protein's C-terminus and is responsible for binding to specific DNA sites. N-ZnF is located toward the proteins N-terminus and is responsible for interacting with various other nuclear proteins that regulate its activity. The transcription factor also contains two transactivation domains and one negative regulatory domain which interact with nuclear proteins to up-regulate and down-regulate, respectively, its activity.[19] In promoting haematopoiesis (i.e. maturation of hematological and immunological cells), GATA2 interacts with other transcription factors (viz., RUNX1, SCL/TAL1, GFI1, GFI1b, MYB, IKZF1, Transcription factor PU.1, LYL1) and cellular receptors (viz., MPL, GPR56).[20]
GATA2 binds to a specific nucleic acid sequence viz., (T/A(GATA)A/G), on the promoter and enhancer sites of its target genes and in doing so either stimulates or suppresses the expression of these target genes. However, there are thousands of sites in human DNA with this nucleotide sequence but, for unknown reasons, GATA2 binds to <1% of these. Furthermore, all members of the GATA transcription factor family bind to this same nucleotide sequence and in doing so may in certain instances serve to interfere with GATA2 binding or even displace the GATA2 that is already bound to these sites. For example, displacement of GATA2 bond to this sequence by the GATA1 transcription factor appears important for the normal development of some types of hematological stem cells. This displacement phenomenon is termed the "GATA switch". In all events, the actions of GATA2 in regulating its target genes is extremely complex and not fully understood.[1][19][20][21]
### GATA2 gene mutations[edit]
Inactivating mutations in the GATA2 gene are the primary cause of GATA2 deficiency disorders. This gene is a member of the evolutionarily conserved GATA transcription factor gene family. All vertebrate species tested so far, including humans and mice, express 6 GATA genes, GATA1 through GATA6.[22] The human GATA2 gene is located on the long (or "q") arm of chromosome 3 at position 21.3 (i.e. the 3q21.3 locus). It consists of 8 exons.[23] Two sites, one more toward the 5' end, the second more toward the 3' end of the gene code for two Zinc finger structural motifs, ZF1 and ZF2, respectively, of the GATA2 transcription factor. ZF1 and ZF2 are critical for regulating the ability of GATA2 transcription factor to stimulate its target genes.[19][20]
The GATA2 gene has at least five separate sites which bind nuclear factors that regulate its expression. One particularly important such site is located in intron 4\. This site, termed the 9.5 kb enhancer, is located 9.5 kilobases (i.e. kb) down-stream from the gene's transcript initiation site and is a critically important enhancer of the gene's expression.[19] Regulation of GATA2 expression is highly complex. For example, in hematological stem cells, GATA2 transcription factor itself binds to one of these sites and in doing so is part of functionally important positive feedback autoregulation circuit wherein the transcription factor acts to promote its own production; in a second example of a positive feed back circuit, GATA2 stimulates production of Interleukin 1 beta and CXCL2 which act indirectly to simulate GATA2 expression. In an example of a negative feedback circuit, the GATA2 transcription factor indirectly causes activation of the G protein-coupled receptor, GPR65, which then acts, also indirectly, to repress GATA2 gene expression.[19][20] In a second example of negative feed-back, GATA2 transcription factor stimulates the expression of the GATA1 transcription factor which in turn can displace GATA2 transcription factor from its gene-stimulating binding sites thereby limiting GATA2's actions (see GATA2 switch in "GATA2 transcription factor" section).[21]
The human GATA2 gene is expressed in hematological bone marrow cells at the stem cell and later progenitor cell stages of their development. Increases and/or decreases in the gene's expression regulate the self-renewal, survival, and progression of these immature cells toward their final mature forms viz., erythrocytess, certain types of lymphocytes (i.e. B cells, NK cells, and T helper cells), monocytes, neutrophils, platelets, plasmacytoid dendritic cells, macrophages and mast cells.[19][16][18] The gene is likewise critical for the formation of the lymphatic system, particularly for the development of its valves. The human gene is also expressed in endothelium, some non-hematological stem cells, the central nervous system, and, to lesser extents, prostate, endometrium, and certain cancerous tissues.[1][22][19]
Scores of different types of inactivating GATA mutations have been associated with GATA2 deficiency; these include frameshift, point, insertion, splice site and deletion mutations scattered throughout the gene but concentrated in the region encoding the GATA2 transcription factor's ZF1, ZF2, and 9.5 kb sites. Rare cases of GATA2 deficiency involve large mutational deletions that include the 3q21.3 locus plus contiguous adjacent genes; these mutations seem more likely than other types of GATA mutations to cause increased susceptibilities to viral infections, developmental lymphatic disorders, and neurological disturbances.[1][16]
### Non-mutational GATA2 deficiency[edit]
Analyses of individuals with AML have discovered many cases of GATA2 deficiency in which one parental GATA2 gene was not mutated but silenced by hypermethylation of its gene promoter. Further studies are required to define the involvement of this hypermethylation-induced form of GATA2 deficiency in other disorders as well to integrate it into the diagnostic category of GATA2 deficiency.[15]
### Other genetic abnormalities[edit]
GATA2 deficiency disorders are variably associated with secondary genetic abnormalities. Monosomy of chromosome 7 (i.e. lose of one of the two chromosomes 7) or deletion of the "q" (i.e. short arm) of one chromosome 7 are the most common abnormal karyotypes (i.e. abnormal chromosome number or appearance) associated with GATA2 deficiency, occurring in ~41% of cases; less common abnormal karyotypes associated with the deficiency include chromosome 8 trisomy (8% of cases) and, rarely, chromosome 21 monosomy.[1] GATA2 deficiency is also associated with somatic mutations in at least three other genes viz., ASXL1, SETBP1, and STAG2.[2][19] Independently of GATA2 mutations and the development of GATA2 deficiency, ASXL1 mutations are associated with MDS, AML, CMML, chronic lymphocytic leukemia, myeloproliferative neoplasm, and cancers of the breast, cervix, and liver,[24] SETBP1 mutations are associated with atypical MDS, CMML, chronic myelogenous leukemia, and chronic neutrophilic leukemia,[1][25] and STAG2 mutations are associated with MDS, AML, CMML, chronic myelogenous leukemia, and cancers of the bladder, stomach, colon, rectum, and prostate gland.[26] The roles, if any, of these karyotypes and somatic mutations on the development, types of presentation, and progression of GATA2 deficiency are unclear and require further study.[1][2][19]
## Pathophysiology[edit]
### Blood defects[edit]
Deletion of both Gata2 genes in mice is lethal by day 10 of embryogenesis due to a total failure in the formation of mature blood cells. Inactivation of one mouse Gata2 gene is neither lethal nor associated with most of the signs of human GATA2 deficiency; however, these animals do show a ~50% reduction in their hematopoietic stem cells along with a reduced ability to repopulate the bone marrow of mouse recipients. The latter findings, human clinical studies, and experiments on human tissues support the conclusion that in humans both parental GATA2 genes are required for sufficient numbers of hematopoietic stem cells to emerge from the hemogenic endothelium during embryogenesis and for these cells and subsequent progenitor cells to survive, self-renew, and differentiate into mature cells.[19][16][15] As GATA2 deficient individuals age, their deficiency in hematopoietic stem cells worsens, probably as a result of factors such as infections or other stresses. In consequence, the signs and symptoms of their disease appear and/or become progressively more severe.[9]
MonoMAC-afflicted individuals exhibit reduced levels of common lymphoid progenitor cells (i.e. a heterogenous group of precursors to various lymphocyte types) and granulocyte-macrophage progenitor cells (i.e. precursors to granulocytes and monocytes).[27] In mice and presumably humans, GATA2 deficiency also leads to reduced levels of early erythrocyte stem cells.[28] While our understanding of human hematopoiesis is incomplete, it is proposed that these or related progenitor cell reductions causes a progressively worsening depletion of circulating and/or tissue bound B cells, NK cells, T helper cells, monocytes, plasmacytoid dendritic cells, neutrophils, and/or red blood cells. In consequence, GATA2 deficient individuals may exhibit the clinically significant disorders of chronic neutropenia, aplastic anemia, bone marrow failure, or the myelodysplastic syndrome.[20][16][18] However, the role of GATA2 deficiency in leading to a leukemias is not understood, particularly since mutations which increase the activity of this transcription factor appear to be associated with the progression of non-familial AML as well as development of the blast crisis in chronic myelogenous leukemia.[20][9]
### Immunologic defects[edit]
The depletion of hematologic cells, particularly dendritic cells, caused by GATA2 deficiency (see previous section) also appears responsible for the development of defective innate and adaptive immune responses. In consequence, these individuals become increasing susceptibility to infectious agents and to cancers caused by infective agents. This defect in mounting immune responses is mostly restricted to new antigenic challenges. That is, secondary immune responses to which individuals had mounted effective primary immune responses before GATA2 deficiency paralyzed their immune system generally remain intact. Immune system deterioration would also appear responsible for the development of the pathological autoimmune reactions which afflicted individuals may mount against their own tissues.[20][16][18]
### Lymphedema[edit]
The GATA2 transcription factor contributes to controlling the expression of two genes, PROX1 and FOXC2, which are required for the proper development of the lymphatic system, particularly lymph vessel valves. It is proposed that GATA2 deficiency causes a failure to develop competent valves and/or vessels in the lymphatic system and thereby leads to lymphedema.[2]
### Hearing loss[edit]
GATA2 deficiency-induced abnormalities in the lymphatic system are also proposed to be responsible for a failure in generating the perilymphatic space around the inner ear's semicircular canals, which in turn underlies the development of sensorineural hearing loss in GATA2 deficient individuals, particularly those diagnosed with the Emberger syndrome.[2]
### Other defects[edit]
The pathophysiology behind the other defects associated with GATA2 deficiency such as hypothyroidism, endocarditis, pulmonary alveolar proteinosis; cryptogenic organizing pneumonia-like disease, pulmonary hypertension, pulmonary ventilator and diffusion defects, miscarriages, etc., is as yet undefined. It is possible that many of these other defects are secondary, i.e. associated with GATA2 deficiency but not a direct result of low cellular levels of the GATA2 transcription factor.
## Diagnosis[edit]
Individuals with GATA2 deficiency commonly exhibit abnormalities in their circulating blood cells (see above "Hematologic" section of Signs and symptoms) that may precede other signs and symptoms of the disease by years. Their bone marrow typically shows significant reductions in one or more types of blood cell lines (i.e. hypocellularity) with characteristic dysplastic features of increased sizes of cells in the red blood cell line (i.e. macrocytic erythropoiesis), small or enlarged megakaryocytes, abnormalities in the maturation of cells in the granulocyte cell line, fibrosis consisting of reticular fibers, increased numbers of T cells containing numerous large granules in their cytoplasm, and in advanced cases increases in blast cell numbers. The bone marrow in advanced cases may also exhibit increase in cellularity, i.e. hypercellularity.[11] GATA2 deficient individuals often have highly increased blood levels of FMS-like tyrosine kinase 3 ligand[15] However, these as well as other features are diagnostic of a hematologic disorder but not necessarily of GATA2 deficiency. DNA sequencing of the full GATA2 gene coding region including the intron4 enhancer by Sanger sequencing or high-throughput methods along with DNA copy number analysis and karyotyping should establish the presence of GATA2 gene mutations; comparison of detected gene mutations to the list of inactivating GATA2 gene mutations plus the clinical presentation and family history are essentials in making the diagnosis of GATA2 deficiency.[7][29]
## Treatment[edit]
The various interventions recommended for GATA2 deficiency fall into three categories: family counseling, prevention of the disease's many complications, and bone marrow transplantation in an effort to restore GATA2-sufficient stem cells. However, due to the uncommonness of, and only recent appreciation for, the disease, standard phase 2 clinical trials to establish the efficacy of a drug(s), and/or non-drug treatment regiments against an appropriate placebo treatment regimen have not been reported.
### Family counseling[edit]
Family members of an individual(s) diagnosed with an inactivating GATA2 gene mutation should be told of their chances of having this mutation, advised of the consequences of this mutation, recommended to be tested for the mutation, warned that they are not suitable donors for any GATA2 deficient individual, and offered long term follow up of their mutation.[1][2][19][15][29][30]
### Prevention of complications[edit]
Recommendations for individuals exhibiting susceptibility to the infectious complications of GATA2 deficiency (e.g. MonoMAC-afflicted individuals) include: early vaccination for papillomavirus, early vaccination or prophylaxis drug treatment for nontuberculosus mycobacteria, and, perhaps, prophylaxis drug treatment (e.g. Azithromycin) for bacteria.[15][31] Standard methods are recommended for the prevention of deep vein thrombosis and/or the embolism that occur in lymphedema of the lower extremities and for the blood hypercoagulability state complicating GATA2 insufficiency presentations such as the Emberger syndrome.[7] GATA2 deficient individuals should be routinely monitored by: a) frequent complete blood counts and when indicated bone marrow examinations to detect progression of their disorder to more MDS or leukemia; b) and clinical evaluation of respiratory function and when indicated lung function tests to detect deterioration of lung function; and c) clinical evaluation analyses to determine the infection susceptibility, tumor formation, and the worsening function of other organs.[1][2][19][15][29][30]
### Bone marrow transplantation[edit]
Many authorities currently recommend GATA2 deficiency be treated by a moderately but not maximally aggressive myeloablative conditioning regimen to remove native bone marrow stem/progenitor cells followed by hematopoietic stem cell transplantation to repopulate the bone marrow with GATA2 sufficient stem cells.[1][2][19][15][30][29] The use of this procedure should be anticipatory and occur before the development of a hyperellular bone marrow or a bone marrow or blood populated by an excess of progenitor cells (i.e. blast cells >2% to 5%). These developments are often followed by transformation of the disorder to a leukemia.[10][19] This regiment should also be performed before the development of severe systemic infections, tumors, or deterioration in lung function. disease. While it takes up to 3.5 years for this regiment to fully re-institute good immune function, it significantly reduces susceptibility to infections and infection-induced tumor formation.[19] The regimen also improves or normalizes lung function in cases of pulmonary alveolar proteinosis and pulmonary artery hypertension and may halt the progression or improve the function of other organs directly injured by GATA2 deficiency.[19][15][9]
#### Clinical trials[edit]
Many reports on the recommended treatment of GATA2 deficiency follow an NIH clinical trial termed "A Pilot and Feasibility Study of Reduced-Intensity Hematopoietic Stem Cell Transplant regimen for Patients With GATA2 Mutations". This trial used a regimen of medication (cyclophosphamide, fludarabine) and total body irradiation conditioning followed by allogenic hematopoietic Stem Cell Transplant on 10 patients. The trial had 8 disease-free survivors and obtained an overall survival 76 months with a range of 18 to 95 months.[32] An NIH intervention study is in the process of recruiting and treating 144 individuals with GATA2 deficiency to determine the success of a treatment regimen consisting of medication (fludarabine, busulfan, cyclophosphamide) and total body irradiation conditioning followed by allogenic hematopoietic stem cell transplantation.[33]
## Prognosis[edit]
Overall survival in a NIH study using a modest conditioning regimen followed by hematologic stem cell transplantation in GATA2 deficient patients afflicted with immune deficiencies was 54% at 4 years; GATA2 deficient children transplanted for MDS with monosomy 7 experienced a 5-year survival of 68%.[19][2]
## History[edit]
In 2011, all cases of the previously described disorders of Emberger syndrome[7] and MonoMAC[34] as well as some cases of the previously described disorder of familial MDS/AML[35] were discovered to be due to inactivating mutations in the GATA2 gene. Subsequently, numerous studies discovered that a significant percentage of many other well-known hematological, immunological, autoimmune, and infectious diseases were associated with, and apparently due to, inactivating mutations in the GATA2 gene.[1][2]
## References[edit]
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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
| GATA2 deficiency | c3280030 | 1,447 | wikipedia | https://en.wikipedia.org/wiki/GATA2_deficiency | 2021-01-18T18:46:50 | {"gard": ["13373"], "mesh": ["D000077428"], "umls": ["C3280030"], "wikidata": ["Q55612175"]} |
Congenital herpesviral (herpes simplex) infection
SpecialtyPediatrics
Neonatal herpes simplex is a rare but serious condition, usually caused by vertical transmission of the herpes simplex virus from mother to newborn. Around 1 in every 3,500 babies in the United States contract the infection.[1]
## Contents
* 1 Signs and symptoms
* 2 Cause
* 2.1 Risk factors
* 2.2 Transmission
* 3 Treatment
* 4 Epidemiology
* 5 See also
* 6 References
* 7 Further reading
* 8 External links
## Signs and symptoms[edit]
Neonatal herpes manifests itself in three forms: skin, eye, and mouth herpes (SEM, sometimes referred to as "localized"); disseminated herpes (DIS); and central nervous system herpes (CNS).[2]
* SEM herpes is characterized by external lesions but no internal organ involvement. Lesions are likely to appear on trauma sites such as the attachment site of fetal scalp electrodes, forceps, or vacuum extractors that are used during delivery; in the margin of the eyes; in the nasopharynx; and in areas associated with trauma or surgery (including circumcision).[3]
* DIS herpes affects internal organs, particularly the liver.[citation needed]
* CNS herpes is an infection of the nervous system and the brain that can lead to encephalitis. Infants with CNS herpes present with seizures, tremors, lethargy, and irritability. They feed poorly, have unstable temperatures, and their fontanelle (soft spot of the skull) may bulge.[4]
CNS herpes is associated with higher morbidity, while DIS herpes has a higher mortality rate. These categories are not mutually exclusive and there is often overlap of two or more types. SEM herpes has the best prognosis of the three, however if left untreated it may progress to disseminated or CNS herpes with attendant increases in mortality and morbidity.[citation needed]
Death from neonatal HSV disease in the U.S. is currently decreasing; the current death rate is about 25%, down from as high as 85% in untreated cases just a few decades ago. Other complications from neonatal herpes include prematurity, with approximately 50% of cases having a gestation of 38 weeks or less, and concurrent sepsis in approximately one-quarter of cases that further clouds speedy diagnosis.[citation needed]
## Cause[edit]
### Risk factors[edit]
Maternal risk factors for neonatal HSV-1 include: White non-Hispanic race,[5] young maternal age (<25), primary infection in third trimester,[6] first pregnancy, HSV (1&2) seronegativity,[4][7] a discordant partner,[8] gestation <38 weeks,[6] and receptive oral sex in the third trimester.[9]
Neonatal HSV-2 maternal risk factors: Black race,[10] young maternal age (<21),[4][6] a discordant partner, primary or non-primary first episode infection in the third trimester,[11] four or more lifetime sexual partners,[10] lower level of education,[10] history of previous STD, history of pregnancy wastage, first viable pregnancy, and gestation <38 weeks.[4][6]
### Transmission[edit]
The majority of cases (85%) occur during birth when the baby comes in contact with infected genital secretions in the birth canal, most common with mothers that have newly been exposed to the virus (mothers that had the virus before pregnancy have a lower risk of transmission). An estimated 5% are infected in utero, and approximately 10% of cases are acquired postnatally. Detection and prevention is difficult because transmission is asymptomatic in 60–98% of cases.[12]
Post-natal transmission incidences can happen from a source other than the mother, such as an Orthodox Jewish mohel with herpetic gingivostomatitis who performs oral suction on a circumcision wound without using a prophylactic barrier to prevent contact between the baby's penis and the mohel's mouth.[13][14][15]
## Treatment[edit]
Reductions in morbidity and mortality are due to the use of antiviral treatments such as vidarabine and acyclovir.[2][16][17][18] However, morbidity and mortality still remain high due to diagnosis of DIS and CNS herpes coming too late for effective antiviral administration; early diagnosis is difficult in the 20–40% of infected neonates that have no visible lesions.[19] A recent large-scale retrospective study found disseminated NHSV patients least likely to get timely treatment, contributing to the high morbidity/mortality in that group.[20]
Harrison's Principles of Internal Medicine recommends that pregnant women with active genital herpes lesions at the time of labor be delivered by caesarean section. Women whose herpes is not active can be managed with acyclovir.[21] The current practice is to deliver women with primary or first episode non-primary infection via caesarean section, and those with recurrent infection vaginally (even in the presence of lesions) because of the low risk (1–3%) of vertical transmission associated with recurrent herpes.[citation needed]
## Epidemiology[edit]
Neonatal HSV rates in the U.S. are estimated to be between 1 in 3,000 and 1 in 20,000 live births. Approximately 22% of pregnant women in the U.S. have had previous exposure to HSV-2, and an additional 2% acquire the virus during pregnancy, mirroring the HSV-2 infection rate in the general population.[22] The risk of transmission to the newborn is 30–57% in cases where the mother acquired a primary infection in the third trimester of pregnancy. Risk of transmission by a mother with existing antibodies for both HSV-1 and HSV-2 has a much lower (1–3%) transmission rate. This in part is due to the transfer of a significant titer of protective maternal antibodies to the fetus from about the seventh month of pregnancy.[4][23] However, shedding of HSV-1 from both primary genital infection and reactivations is associated with higher transmission from mother to infant.[4]
HSV-1 neonatal herpes is extremely rare in developing countries because development of HSV-1 specific antibodies usually occurs in childhood or adolescence, precluding a later genital HSV-1 infection. HSV-2 infections are much more common in these countries. In industrialized nations, the adolescent HSV-1 seroprevalence has been dropping steadily for the last 5 decades. The resulting increase in the number of young women becoming sexually active while HSV-1 seronegative has contributed to increased HSV-1 genital herpes rates, and as a result, increased HSV-1 neonatal herpes in developed nations. A study in the United States from 2003–2014 using large administrative databases showed increasing trends in incidence of neonatal HSV from 7.9 to 10 cases per 100,000 live births and mortality of 6.5%. Babies of decreased gestational age and those of African American race had higher incidences of neonatal HSV. Another study from Canada showed similar results, with an incidence of 5.9 per 100,000 live births and a case fatality of 15.5%.[24] A three-year study in Canada (2000–2003) revealed a neonatal HSV incidence of 5.9 per 100,000 live births and a case fatality rate of 15.5%. HSV-1 was the cause of 62.5% of cases of neonatal herpes of known type, and 98.3% of transmission was asymptomatic.[12] Asymptomatic genital HSV-1 has been shown to be more infectious to the neonate, and is more likely to produce neonatal herpes than HSV-2.[4][25] However, with prompt application of antiviral therapy, the prognosis of neonatal HSV-1 infection is better than that for HSV-2.[citation needed]
## See also[edit]
* Disseminated herpes zoster
* Herpes simplex
* Herpesviral encephalitis
* TORCH complex
## References[edit]
1. ^ "Neonatal herpes simplex". Boston Children's Hospital. 14 July 2009. Archived from the original on 20 February 2014. Retrieved 2 February 2014.
2. ^ a b Kimberlin, David W.; Whitley, Richard J. (2005). "Neonatal herpes: What have we learned". Seminars in Pediatric Infectious Diseases. 16 (1): 7–16. doi:10.1053/j.spid.2004.09.006. PMID 15685144.
3. ^ Prober, Charles G. (1997). "Herpes simplex virus". In Long, Sarah S.; Pickering, Larry K.; Prober, Charles G. (eds.). Principles and Practices of Pediatric Infectious Diseases (3rd rev. ed.). New York: Churchhill Livingstone. p. 1138.
4. ^ a b c d e f g Brown, Zane A.; Wald, Anna; Morrow, Rhoda Ashley; Selke, Stacy; Zeh, Judith; Corey, Lawrence (January 2003). "Effect of Serologic Status and Cesarean Delivery on Transmission Rates of Herpes Simplex Virus From Mother to Infant". . 289 (2): 203–209. doi:10.1001/jama.289.2.203. PMID 12517231.
5. ^ Xu, Fujie; Markowitz, Lauri E.; Gottlieb, Sami L.; Berman, Stuart M. (1 January 2007). "Seroprevalence of herpes simplex virus types 1 and 2 in pregnant women in the United States". American Journal of Obstetrics and Gynecology. 196 (1): 43.e1–6. doi:10.1016/j.ajog.2006.07.051. PMID 17240228.
6. ^ a b c d Whitley, Richard (June 2004). "Neonatal herpes simplex virus infection". Current Opinion in Infectious Diseases. 17 (3): 243–246. doi:10.1097/00001432-200406000-00012. PMID 15166828. S2CID 8336377.
7. ^ Nahmias, Andre J. (August 2004). "Neonatal HSV infection Part II: Obstetric considerations -- a tale of hospitals in two cities (Seattle and Atlanta, USA)". Herpes. 11 (2): 41–44. PMID 15955267.
8. ^ Baker, David A. (December 2005). "Risk factors for herpes simplex virus transmission to pregnant women: A couples study". American Journal of Obstetrics and Gynecology. 193 (6): 1887–1888. doi:10.1016/j.ajog.2005.08.007. PMID 16325587.
9. ^ Nahmias, Andre J. (August 2004). "Neonatal HSV infection Part I: continuing challenges" (PDF). Herpes. 11 (2): 33–7. PMID 15955265. Archived from the original (PDF) on 2009-04-12. Retrieved 2009-05-20.
10. ^ a b c Mertz, Gregory J. (December 1993). "Epidemiology of genital herpes infections". Infectious Disease Clinics of North America. 7 (4): 825–839. PMID 8106731.
11. ^ Gardella, Carolyn; Brown, Zane A.; Wald, Anna; Morrow, Rhoda Ashley; Selke, Stacy; Krantz, Elizabeth; Corey, Lawrence; et al. (August 2005). "Poor correlation between genital lesions and detection of herpes simplex virus in women in labor". . 106 (2): 268–274. doi:10.1097/01.AOG.0000171102.07831.74. PMID 16055574. S2CID 23039017.
12. ^ a b Kropp, Rhonda Y.; Wong, Thomas; Cormier, Louise; Ringrose, Allison; Burton, Sandra; Embree, Joanne E.; Steben, Marc; et al. (June 2006). "Neonatal Herpes Simplex Virus Infections in Canada: Results of a 3-Year National Prospective Study". . 117 (61): 1955–1962. doi:10.1542/peds.2005-1778. PMID 16740836. S2CID 9632498.
13. ^ https://abcnews.go.com/Health/baby-dies-herpes-virus-ritual-circumcision-nyc-orthodox/story?id=15888618
14. ^ https://www.independent.co.uk/news/world/americas/herpes-babies-jewish-circumcision-ritual-link-rabbis-infants-a7620446.html
15. ^ https://www.timesofisrael.com/4-ny-babies-get-herpes-from-jewish-circumcision-rite-in-past-6-months/
16. ^ Kesson, Alison M. (2001). "Management of neonatal herpes simplex virus infection". Paediatric Drugs. 3 (2): 81–90. doi:10.2165/00128072-200103020-00001. PMID 11269641. S2CID 22544225.
17. ^ "The Merck Manual, Neonatal Herpes Simplex Virus (HSV) Infection".
18. ^ Brocklehurst, Peter; Kinghorn, George R.; Carney, Orla; Helsen, K.; Ross, Emma; Ellis, E; Shen, R. N.; Cowan, Frances M.; Mindel, Adrian; et al. (1998). "A randomised placebo controlled trial of suppressive acyclovir in late pregnancy in women with recurrent genital herpes infection". British Journal of Obstetrics and Gynaecology. 105 (3): 275–280. doi:10.1111/j.1471-0528.1998.tb10086.x. PMID 9532986.
19. ^ Jacobs, Richard F. (1998). "Neonatal herpes simplex virus infections". Seminars in Perinatology. 22 (1): 64–71. doi:10.1016/S0146-0005(98)80008-6. PMID 9523400.
20. ^ Caviness, A Chantal; Demmler, Gail J.; Selwyn, Beatrice J. (May 2008). "Clinical and Laboratory Features of Neonatal Herpes Simplex Virus Infection: A Case-Control Study". Pediatric Infectious Disease Journal. 27 (5): 425–430. doi:10.1097/INF.0b013e3181646d95. PMID 18360301. S2CID 13294240.
21. ^ Kasper, Dennis L.; Braunwald, Eugene; Fauci, Anthony S.; Hauser, Stephen L.; Longo, Dan L.; Jameson, J. Larry (2005). "Medical Disorders During Pregnancy". Harrison's Principles Of Internal Medicine (16th ed.). McGraw-Hill Medical Publishing Division.
22. ^ Brown, Zane A.; Gardella, Carolyn; Wald, Anna; Morrow, Rhoda Ashley; Corey, Lawrence (2005). "Genital herpes complicating pregnancy". Obstetrics and Gynecology. 106 (4): 845–856. doi:10.1097/01.AOG.0000180779.35572.3a. PMID 16199646. S2CID 8768010.
23. ^ Brown, Zane A.; Benedetti, Jacqueline; Ashley, Rhoda; Burchett, Sandra; Selke, Stacy; Berry, Sylvia; Vontver, Louis A.; Corey, Lawrence (May 1991). "Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor". New England Journal of Medicine. 324 (18): 1247–1252. doi:10.1056/NEJM199105023241804. PMID 1849612.
24. ^ Donda, Keyur; Sharma, Mayank; Amponsah, Jason K.; Bhatt, Parth; Chaudhari, Riddhi; Okaikoi, Michael; Dapaah-Siakwan, Fredrick (25 March 2019). "Trends in the incidence, mortality, and cost of neonatal herpes simplex virus hospitalizations in the United States from 2003 to 2014". Journal of Perinatology. 39 (5): 697–707. doi:10.1038/s41372-019-0352-7. PMID 30911082. S2CID 85494894.
25. ^ Brown, Elizabeth L.; Gardella, Carolyn; Malm, Gunilla; Prober, Charles G.; Forsgren, Marianne; Krantz, Elizabeth M.; Arvin, Ann M.; Yasukawa, Linda L.; Mohan, Kathleen; Brown, Zane; Corey, Lawrence; Wald, Anna (2007). "Effect of maternal herpes simplex virus (HSV) serostatus and HSV type on risk of neonatal herpes". Acta Obstetricia et Gynecologica Scandinavica. 86 (5): 523–529. doi:10.1080/00016340601151949. PMID 17464578.
## Further reading[edit]
* Knezevic, Aleksandra; Martic, Jelena; Stanojevic, Maja; Jankovic, Sasa; Nedeljkovic, Jasminka; Nikolic, Ljubica; Pasic, Srdjan; Jankovic, Borisav; Jovanovic, Tanja (1 February 2007). "Disseminated Neonatal Herpes Caused by Herpes Simplex Virus Types 1 and 2". Emerging Infectious Diseases. 13 (2): 302–304. doi:10.3201/eid1302.060907. PMC 2725876. PMID 17479897.
## External links[edit]
Classification
D
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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
| Neonatal herpes simplex | c0495407 | 1,448 | wikipedia | https://en.wikipedia.org/wiki/Neonatal_herpes_simplex | 2021-01-18T18:37:38 | {"gard": ["1486"], "umls": ["C2931185", "C0495407", "C0276225", "C4275250"], "icd-9": ["771.2"], "icd-10": ["P35.2"], "orphanet": ["293"], "wikidata": ["Q3134326"]} |
X-linked dominant chondrodysplasia Chassaing-Lacombe type is a rare genetic bone disorder characterized by chondrodysplasia, intrauterine growth retardation (IUGR), hydrocephaly and facial dysmorphism in the affected males.
## Epidemiology
Prevalence is unknown. To date, 10 patients (4 males and 6 females) in a single family have been reported through 4 generations.
## Clinical description
Three male fetuses were diagnosed prenatally on ultrasonography (skeletal abnormalities and hydrocephaly) leading to termination of the pregnancies. The fourth affected male died at 6 days of life. The disease is severe and probably lethal in males, in whom the clinical picture includes short hands, brachydactyly, hydrocephaly and facial dysmorphism, including frontal bossing, low-set ears, short flat nose and microphthalmia. Other signs may include cerebellar hypoplasia and hyperkeratotic skin. X-rays show severe platyspondyly due to delayed ossification of the vertebrae, thin ribs, moderate shortening of the long bones, hypoplastic iliac wings, poorly ossified pubis, brachydactyly of the fingers and/or toes with cupped metacarpals, metatarsals, and phalanges and hypoplastic square calcaneus. The clinical picture in females is less severe and comprises short stature (128-151 cm), rhizomelic shortening of the limbs, short hands, brachymesophalangia of the 3rd and 4th toes, and may be associated with body asymmetry and mild cognitive impairment.
## Etiology
X-linked dominant chondrodysplasia Chassaing-Lacombe type is due to a mutation in the histone deacetylase 6 HDAC6 gene (Xp11.3-q13.1) that causes a nucleotide substitution in the 3' untranslated region (UTR) of the HDAC6 transcript. This mutation lies in the seed sequence of microRNA-433 (hsa-miR-433) and abolishes the post-transcriptional regulation of HDAC6 expression by hsa-miR-433, resulting in the overexpression of the HDAC6 protein.
## Genetic counseling
Inheritance is X-linked 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
| X-linked dominant chondrodysplasia, Chassaing-Lacombe type | c3275476 | 1,449 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=163966 | 2021-01-23T19:11:49 | {"omim": ["300863"], "icd-10": ["Q87.8"], "synonyms": ["X-linked dominant chondrodysplasia-hydrocephaly-microphthalmia syndrome"]} |
Familial transthyretin amyloidosis (FTA) is a rare inherited condition characterized by abnormal build-up of a protein called amyloid in the body's organs and tissues. Symptoms start in adulthood and get worse over time. Signs and symptoms depend on where the amyloid protein is building up. Amyloid build-up in the nerves of the peripheral nervous system causes a loss of sensation in the lower limbs, feet, and hands (peripheral neuropathy). Amyloid build-up can also affect the involuntary body functions, such as blood pressure, heart rate, and digestion. Other areas of the body that may be affected are the heart, kidneys, eyes, and gastrointestinal tract.
FTA is caused by changes (mutations) in the TTR gene. Inheritance is autosomal dominant, but not all people with a TTR gene mutation will develop FTA. Diagnosis of FTA is suspected by signs and symptoms and confirmed by tissue biopsy and genetic testing.
Primary treatment is a liver transplantation. This procedure removes the main source of amyloid from the body, but amyloid may still build-up in the heart, brain, and eyes. New medications have become available that block the formation of amyloid and may provide an alternative to liver transplant. Other treatments include heart and/or kidney transplantation, putting in a pacemaker, replacing the fluid in the eye (vitrectomy), and various medications. FTA is typically a fatal condition, but life expectancy depends on many factors.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Familial transthyretin amyloidosis | c2751492 | 1,450 | gard | https://rarediseases.info.nih.gov/diseases/656/familial-transthyretin-amyloidosis | 2021-01-18T18:00:31 | {"mesh": ["C567782"], "omim": ["105210"], "umls": ["C2751492"], "synonyms": ["Amyloidosis, hereditary, transthyretin-related", "Transthyretin amyloidosis", "Familial amyloid polyneuropathy", "Amyloidosis Transthyretin related", "Transthyretin amyloid neuropathy", "TTR amyloid neuropathy", "Transthyretin amyloid polyneuropathy", "Hereditary ATTR amyloidosis"]} |
A rare neurological disease which is a circadian rhythm sleep disorder characterized by non-synchronization to a 24-hour day leading to insomnia and daytime sleepiness with sometimes severe associated manifestations.
## Epidemiology
Approximately half of all people with complete blindness are thought to be affected by non-24 hour disorder. Rare cases are found in partially blind subjects. The disorder may be largely underdiagnosed in blind individuals. Sighted individuals with the disorder are far less numerous and about 100 cases have been reported in the medical literature to date.
## Clinical description
Non-24 hour sleep-wake syndrome can occur at any age in sighted individuals but often develops in childhood. In blind people, it can occur at any age. In affected patients, the circadian system does not synchronize with the 24-hour day. Patients have gradual delays in sleep onset time from one day to the next. Sleep onset therefore occurs later and later during the night and then eventually during the daytime. In rare cases, sleep onset time moves backward from one day to the next. Constant and changing misalignment between the patient's circadian rhythm and standard times can result in fragmented sleep and signs of sleepiness when the patient attempts to maintain a regular 24h sleep-wake cycle. These manifestations include diurnal sleepiness, nocturnal insomnia, and fatigue. Other repercussions may include headaches, depression, difficulty concentrating, confusion, memory disorders, decreased appetite, ataxia, and psychological difficulties (loneliness, isolation). At certain times, the sleep pattern coincides with standard times providing temporary remission of symptoms.
## Etiology
Defective functioning of the suprachiasmatic nucleus (SCN) located in the hypothalamus, which controls circadian rhythms, is thought to underlie the disorder, especially in sighted patients. The circadian clock has a slight deviation from 24h (generally 24.2h) which is corrected in healthy people by environmental time cues (including the solar light-dark cycle). Core body temperature cycle and production of melatonin are also affected. Absence of perception of light in completely blind subjects is thought to lead to failed sleep training. Abnormal development of the brain, trauma, and iatrogenic factors may play a role in sighted patients with non-24 disorder.
## Diagnostic methods
The diagnosis is based on recurrent or relapsing insomnia and daytime drowsiness. The disorder should be suspected in blind individuals with recurrent insomnia and daytime sleepiness. At certain times, the sleep pattern coincides with standard times due to misalignment between the 24-hour light-dark cycle and the undeveloped endogeneous circadian rhythm. Symptoms persist for at least 3 months. Daily sleep logs and actigraphy, for at least 14 days, demonstrates a pattern of sleep and wake times that delay each day with a circadian period that is usually longer than 24 hours. A non-24-hour pattern of cortisol or melatonin secretion may assist diagnosis.
## Differential diagnosis
Differential diagnoses include delayed sleep phase disorder, irregular sleep-wake disorder, sleep apnea syndrome, Kleine Levin syndrome, and idiopathic hypersomnia.
## Management and treatment
Some patients may find relief by following their own changing sleep-wake cycle. This is however generally not compatible with regular occupational and social constraints. Phototherapy in the morning and scototherapy late in the day has been found to successfully improve sleep cycles in some sighted patients. Melatonin can also be used to this end in both sighted and blind patients. Hypnotics and/or stimulants may also play a role in the management. Tasimelteon, a melatonin-receptor agonist, is used for treatment of non-24 hour disorder in blind patients without light perception.
## Prognosis
Without treatment, this disorder disrupts social, emotional and occupational functioning and may be severely debilitating.
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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
| Non-24-hour sleep-wake syndrome | c0751759 | 1,451 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=73267 | 2021-01-23T17:52:35 | {"gard": ["10949"], "mesh": ["D020178"], "umls": ["C0751759"], "icd-10": ["G47.2"], "synonyms": ["Hypernychthemeral syndrome"]} |
Spondyloepiphyseal dysplasia, Reardon type is an extremely rare type of spondyloepiphyseal dysplasia (see this term) described in several members of a single family to date and characterized by short stature, vertebral and femoral abnormalities, cervical instability and neurologic manifestations secondary to anomalies of the odontoid process.
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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
| Spondyloepiphyseal dysplasia, Reardon type | c1833603 | 1,452 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=163662 | 2021-01-23T16:58:21 | {"mesh": ["C563472"], "omim": ["600561"], "umls": ["C1833603"], "icd-10": ["Q77.7"]} |
Calcification occurring in degenerated or necrotic tissue
Amyloidosis, dystrophic calcification
Dystrophic calcification (DC) is the calcification occurring in degenerated or necrotic tissue, as in hyalinized scars, degenerated foci in leiomyomas, and caseous nodules. This occurs as a reaction to tissue damage,[1] including as a consequence of medical device implantation. Dystrophic calcification can occur even if the amount of calcium in the blood is not elevated (a systemic mineral imbalance would elevate calcium levels in the blood and all tissues) and cause metastatic calcification. Basophilic calcium salt deposits aggregate, first in the mitochondria, then progressively throughout the cell. These calcifications are an indication of previous microscopic cell injury, occurring in areas of cell necrosis when activated phosphatases bind calcium ions to phospholipids in the membrane.
## Contents
* 1 Calcification in dead tissue
* 2 Calcification in degenerated tissue
* 3 See also
* 4 References
## Calcification in dead tissue[edit]
1. Caseous necrosis in T.B. is most common site of dystrophic calcification.
2. Liquefactive necrosis in chronic abscesses may get calcified.
3. Fat necrosis following acute pancreatitis or traumatic fat necrosis in breasts results in deposition of calcium soaps.
4. Infarcts may undergo D.C.
5. Thrombi, especially in veins, may produce phlebolithis.
6. Haematomas in the vicinity of bones may undergo D.C.
7. Dead parasites like schistosoma eggs may calcify.
8. Congenital toxoplasmosis, CMV or rubella may be seen on X-ray as calcifications in the brain.
Density-Dependent Colour Scanning Electron Micrograph SEM (DDC-SEM) of cardiovascular calcification, showing in orange calcium phosphate spherical particles (denser material) and, in green, the extracellular matrix (less dense material).[2]
## Calcification in degenerated tissue[edit]
1. Dense scars may undergo hyaline degeneration and calcification.
2. Atheroma in aorta and coronaries frequently undergo calcification.[2][3]
3. Cysts can show calcification.
4. Calcinosis cutis is condition in which there are irregular nodular deposits of calcium salts in skin and subcutaneous tissue.
5. Senile degenerative changes may be accompanied by calcification.
6. The inherited disorder pseudoxanthoma elasticum may lead to angioid streaks with calcification of Bruch's membrane, the elastic tissue below the retinal ring.
## See also[edit]
* Calcinosis
* Monckeberg's arteriosclerosis
## References[edit]
1. ^ "Cell Injury".
2. ^ a b Bertazzo, Sergio; Gentleman, Eileen; Cloyd, Kristy L.; Chester, Adrian H.; Yacoub, Magdi H.; Stevens, Molly M. (Jun 2013). "Nano-analytical electron microscopy reveals fundamental insights into human cardiovascular tissue calcification". Nature Materials. 12 (6): 576–583. Bibcode:2013NatMa..12..576B. doi:10.1038/nmat3627. PMC 5833942. PMID 23603848.
3. ^ Miller, Jordan D. (Jun 2013). "Cardiovascular calcification: Orbicular origins". Nature Materials. 12 (6): 476–478. Bibcode:2013NatMa..12..476M. doi:10.1038/nmat3663. PMID 23695741.
* v
* t
* e
Electrolyte imbalances
Sodium
* High
* Salt poisoning
* Low
* Hypotonic
* Isotonic
* Cerebral salt-wasting syndrome
Potassium
* High
* Low
Chloride
* High
* Low
Calcium
* High
* Low
* Symptoms and signs
* Chvostek sign
* Trousseau sign
* Milk-alkali syndrome
* Disorders of calcium metabolism
* Calcinosis (Calciphylaxis, Calcinosis cutis)
* Calcification (Metastatic calcification, Dystrophic calcification)
* Familial hypocalciuric hypercalcemia
Phosphate
* High
* Low
Magnesium
* High
* Low
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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
| Dystrophic calcification | c0333582 | 1,453 | wikipedia | https://en.wikipedia.org/wiki/Dystrophic_calcification | 2021-01-18T19:01:45 | {"umls": ["C0333582"], "wikidata": ["Q3650238"]} |
A number sign (#) is used with this entry because of evidence that DFNB37 is caused by homozygous mutation in the gene encoding myosin VI (MYO6; 600970) on chromosome 6q14.
Clinical Features
Ahmed et al. (2003) reported a Pakistani family in which 6 individuals had bilateral, profound, congenital sensorineural hearing loss segregating as an autosomal recessive disorder. Vestibular dysfunction and mild facial dysmorphism also occurred in the family, and one hearing impaired individual had retinitis pigmentosa along with a vestibular abnormality; however, the other clinical phenotypes were mild and did not occur in all deaf individuals.
Mapping
In a Pakistani family with congenital sensorineural hearing loss, Ahmed et al. (2003) found linkage of deafness to markers at chromosome 6q13 (maximum lod = 7.10 at theta = 0.0). Haplotype analysis defined a region between D6S1282 and D6S460. Using markers in this interval to screen 250 Pakistani and 100 Indian families segregating autosomal recessive deafness, they identified 2 additional linked families with severe to profound hearing loss.
Molecular Genetics
Ahmed et al. (2003) screened for mutations in the MYO6 gene in 3 families with autosomal recessive deafness linked to 6q13 and identified mutations in all 3 (607821.0002-607821.0004).
INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Hearing loss, sensorineural, bilateral (severe to profound) \- Vestibular dysfunction (in 2 patients) Eyes \- Retinitis pigmentosa (in 1 patient) \- Congenital stationary night blindness (in 1 patient) MISCELLANEOUS \- Based on one report of 3 consanguineous Pakistani families (last curated August 2015) \- Eye and vestibular findings were found in some members of one family MOLECULAR BASIS \- Caused by mutation in the myosin VI gene (MYO6, 600970.0002 ) ▲ 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
| DEAFNESS, AUTOSOMAL RECESSIVE 37 | c1843028 | 1,454 | omim | https://www.omim.org/entry/607821 | 2019-09-22T16:08:44 | {"doid": ["0110495"], "mesh": ["C564331"], "omim": ["607821"], "orphanet": ["90636"], "synonyms": ["Autosomal recessive isolated neurosensory deafness type DFNB", "Autosomal recessive isolated sensorineural deafness type DFNB", "Autosomal recessive non-syndromic neurosensory deafness type DFNB"], "genereviews": ["NBK1434"]} |
A number sign (#) is used with this entry because of evidence that intellectual developmental disorder with neuropsychiatric features (IDDNPF) is caused by homozygous mutation in the SLC45A1 gene (605763) on chromosome 1p36.
Description
Intellectual developmental disorder with neuropsychiatric features is an autosomal recessive disorder characterized by moderate intellectual disability, relatively mild seizures, and neuropsychiatric abnormalities, such as anxiety, obsessive-compulsive behavior, and autistic features. Mild facial dysmorphic features may also be present (summary by Srour et al., 2017).
Clinical Features
Srour et al. (2017) reported 2 adult sisters, born of consanguineous Palestinian parents, and 2 young brothers, born of consanguineous parents from the United Arab Emirates, with a similar neurologic disorder. The 2 sisters, aged 22 and 20 years, showed moderate intellectual disability from early childhood, but attended special schools and could read and write and speak simply. Both developed focal seizures later in childhood, at 4.5 and 11 years, respectively, that occasionally turned into secondary generalized seizures, but could be controlled with medication. Neurologic examination showed some slowing in finger-to-nose testing and rapid alternating movements. The women also had neuropsychiatric abnormalities, including obsessive-compulsive disorder, anxiety, and repetitive behaviors; 1 had autistic features. Both were noted to have mild dysmorphic features, such as downslanting palpebral fissures, smooth philtrum, and thin upper lip. Brain imaging was normal. CSF glucose levels and the CSF:blood glucose levels, studied in 1 patient, were normal. The 2 boys from the second family, aged 11 months and 8 years, were more severely affected. They had global developmental delay. The older boy walked at age 2.5 years, was nonverbal, could not understand simple instructions, had autistic features, and was not toilet-trained. He had 2 seizures in infancy, but not after age 12 months. EEG showed enhanced spike-and-slow-wave activity in the left occipital region during sleep, as well as slowing of the background in the left occipital region. The 11-month-old boy had global developmental delay and hypotonia with inability to sit, but could fix and follow visually; he had not had any seizures. Both patients had mild dysmorphic features, including triangular face, downslanting eyes, arched eyebrows, widely spaced eyes, depressed nasal bridge, smooth philtrum, and thin lips. The older boy had a single kidney and hyperparathyroidism, and the younger boy had evidence of nephrocalcinosis, which resolved, but it was not clear whether these abnormalities were related to the SLC45A1 mutation.
Inheritance
The transmission pattern of IDDNPF in the families reported by Srour et al. (2017) was consistent with autosomal recessive inheritance.
Molecular Genetics
In 4 patients from 2 unrelated consanguineous families with IDDNPF, Srour et al. (2017) identified homozygous missense mutations in the SLC45A1 gene (605763.0001 and 605763.0002). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro functional expression studies in COS-7 cells showed that the mutations resulted in decreased glucose transport compared to controls. Srour et al. (2017) noted that although a homozygous missense variant (I56T) in the SLC45A1 gene had been reported in a 5-year-old girl with developmental delay, ataxia, and Dandy-Walker malformation by Anazi et al. (2017), functional studies of that variant showed that it did not have a significant effect on glucose transporter activity, suggesting that it is not pathogenic.
INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Triangular face \- Smooth philtrum Eyes \- Downslanting palpebral fissures \- Hypertelorism \- Arched eyebrows Nose \- Depressed nasal bridge Mouth \- Thin lips MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed development \- Intellectual disability, moderate \- Seizures, well-controlled Behavioral Psychiatric Manifestations \- Neuropsychiatric abnormalities \- Obsessive-compulsive tendencies \- Anxiety MISCELLANEOUS \- Two consanguineous families have been reported (last curated June 2017) MOLECULAR BASIS \- Caused by mutation in the solute carrier 45, member 1 gene (SLC45A1, 605763.0001 ) ▲ 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
| INTELLECTUAL DEVELOPMENTAL DISORDER WITH NEUROPSYCHIATRIC FEATURES | c4479636 | 1,455 | omim | https://www.omim.org/entry/617532 | 2019-09-22T15:45:37 | {"omim": ["617532"]} |
## Description
N-glycolylneuraminic acid (NeuGc), a sialic acid involved in cell-cell recognition and cell-pathogen interactions, is abundantly expressed in most mammals but is not detectable in humans. The expression of NeuGc is controlled by cytidine monophospho-N-acetylneuraminic acid (CMP-NeuAc) hydroxylase activity, which in humans is inactivated by a deletion in the CMAHP pseudogene that renders the enzyme nonfunctional (summary by Irie et al., 1998).
Cloning and Expression
The sialic acids are a family of acidic sugars typically found in the outer portion of the cell surface and in secreted glycoconjugates of all vertebrates. Cell membrane sialic acid is involved in cell-cell and cell-pathogen interactions and in binding of cells to the extracellular matrix. The 2 most common forms of sialic acid found in mammalian cells are N-acetylneuraminic acid (Neu5Ac) and its hydroxylated derivative, N-glycolylneuraminic acid (Neu5Gc). The conversion of Neu5Ac to Neu5Gc can positively or negatively affect interactions involving several of the known endogenous and exogenous receptors for sialic acid, such as CD22 (107266), myelin-associated glycoprotein (MAG; 159460), sialoadhesin (SN; 600751), and the influenza A virus hemagglutinin. Even in animals with large amounts of Neu5Gc in other tissues, its level in the brain is always very low. A major biochemical difference between the great apes and humans is the loss of activity of the enzyme CMP-N-acetylneuraminic acid hydroxylase in the human. This enzyme converts the nucleotide sugar donor CMP-Neu5Ac to CMP-Neu5Gc in other animals. Loss of hydroxylase activity provides a potential explanation for the finding that although the body fluids and tissues of all the great apes (chimpanzee, bonobo, gorilla, and orangutan) express high levels of Neu5Gc, corresponding samples from humans contain low or undetectable levels of this sialic acid (Muchmore et al., 1998). To explore the basis of this deficiency in the human, Chou et al. (1998) cloned the human and chimpanzee cDNAs encoding the CMP-Neu5Ac hydroxylase. They found that the human lineage had suffered a genetic mutation in the coding region of this cDNA. Although the chimpanzee cDNA was similar to the murine homolog, the human cDNA contained a 92-bp deletion in the 5-prime region, resulting in a frameshift mutation and premature termination of the coding sequence. The genomic DNA showed evidence of this deletion. Genomic PCR analysis indicated that this deletion did not occur in any of the African great apes. Thus, the lineage leading to modern humans suffered a mutation sometime after the common ancestor with the chimpanzee and bonobo, potentially affecting recognition by a variety of endogenous and exogenous sialic acid-binding lectins. Also, the expression of Neu5Gc previously reported in human fetuses and tumors, as well as the traces detected in some normal adult humans, must be mediated by an alternate pathway. Thus, this situation is similar to those of the urate oxidase (UOX; 191540) and gulonolactone oxidase (GULOP; 240400) genes, which in most mammals are involved in uric acid and vitamin C metabolism, respectively, but in the human are nonfunctional.
Kawano et al. (1995) cloned and sequenced mouse CMP-NeuAc hydroxylase cDNAs.
By RT-PCR using primers based on the sequence of the mouse CMP-NeuAc hydroxylase gene, Irie et al. (1998) isolated a HeLa cell cDNA encoding human CMP-NeuAc hydroxylase. They identified the same 5-prime 92-bp deletion in the human CMP-sialic acid hydrolase gene as Chou et al. (1998) and determined that this deletion corresponds to an exon that is present in the mouse gene. Northern blot analysis revealed that, like the mouse enzyme, human CMP-NeuAc hydroxylase mRNA is expressed in many human tissues, but not brain. The human CMP-NeuAc hydroxylase protein expressed in COS-7 cells exhibited no enzymatic activity, and a mouse hydroxylase mutant lacking the same N-terminal domain was also inactive. A chimera composed of the human hydroxylase and the N-terminal portion of the mouse hydroxylase displayed enzyme activity. The results of Irie et al. (1998) indicated that the human CMP-NeuAc hydroxylase is inactive because it lacks an N-terminal domain that is essential for enzyme activity, and that the absence of NeuGc in human glycoconjugates is due to a deletion in the CMAH gene.
Evolution
Plasmodium falciparum, the major worldwide cause of malaria mortality, causes no severe infection in chimpanzees. Conversely, Plasmodium reichenowi, a morphologically identical and genetically similar parasite, infects chimpanzees but not humans. Martin et al. (2005) expressed recombinant Plasmodium erythrocyte-binding antigens specific for chimpanzee or human erythrocytes and found that enhancing Neu5Gc on human glycophorin A (GYPA; 617922) markedly reduced binding by the P. falciparum antigen, which preferentially interacts with Neu5Ac. They found that the New World Aotus (owl) monkey, which can be infected by P. falciparum, expresses primarily Neu5Ac. Lack of Neu5Gc resulted in poor binding of the chimpanzee P. reichenowi parasite by human and owl monkey red cells. Martin et al. (2005) proposed that their results have implications for the prehistory of hominids and for the genetic origins and recent emergence of P. falciparum as a major human pathogen.
Mapping
By somatic cell hybrid analysis and fluorescence in situ hybridization, Chou et al. (1998) localized the CMP-Neu5Ac hydroxylase gene to 6p23-p22 in both humans and great apes, which does not correspond to known chromosomal rearrangements that occurred during hominoid evolution. By fluorescence in situ hybridization, Irie and Suzuki (1998) mapped the human and mouse CMP-NeuAc hydroxylase genes to 6p22.3-p22.2 and chromosome 13A3, respectively; these regions show homology of synteny.
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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
| CYTIDINE MONOPHOSPHO-N-ACETYLNEURAMINIC ACID HYDROXYLASE, PSEUDOGENE | None | 1,456 | omim | https://www.omim.org/entry/603209 | 2019-09-22T16:13:18 | {"omim": ["603209"], "synonyms": ["Alternative titles", "CMAH", "CMP-NeuAc HYDROXYLASE", "CMP-Neu5Ac HYDROXYLASE", "CMP-SIALIC ACID HYDROXYLASE"]} |
Intracranial arteriovenous malformations (AVMs) are abnormal connections between the arteries and veins in the brain. Most people with brain or spinal AVMs experience few, if any, major symptoms. About 12 percent of people with this condition experience symptoms that vary greatly in severity. Seizures and headaches are the most common symptoms of AVMs but individuals can also experience a wide range of other neurological symptoms. AVMs can cause hemorrhage (bleeding) in the brain, which can be fatal. Symptoms can appear at any age, but are most often noticed when people are in their twenties, thirties, or forties. The cause of AVMs is not yet well understood but it is believed that AVMs result from mistakes that occur during embryonic or fetal development. Medication is used to treat general symptoms such as headache, back pain, and seizures caused by AVMs. However, the best treatment for AVMs is often surgery or sterotactic radiosurgery.
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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
| Intracranial arteriovenous malformation | c0007772 | 1,457 | gard | https://rarediseases.info.nih.gov/diseases/3020/intracranial-arteriovenous-malformation | 2021-01-18T17:59:45 | {"mesh": ["D002538"], "umls": ["C0007772"], "orphanet": ["46724"], "synonyms": ["Intracranial AVM", "Cerebral arteriovenous malformation"]} |
A rare, systemic amyloidosis characterized by a triad of ophthalmologic, neurologic and dermatologic findings due to the deposition of gelsolin amyloid fibrils in these tissues. Clinical manifestations include corneal lattice dystrophy, cranial neuropathy, especially affecting the facial nerve, bulbar signs, cutis laxa, increased skin fragility, and less commonly peripheral neuropathy and renal failure.
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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
| AGel amyloidosis | c0936273 | 1,458 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=85448 | 2021-01-23T19:04:58 | {"gard": ["2339"], "mesh": ["D028227"], "omim": ["105120"], "umls": ["C0936273"], "icd-10": ["E85.1"], "synonyms": ["Familial amyloid polyneuropathy type IV", "Familial amyloidosis, Finnish type", "Gelsolin amyloidosis", "Hereditary amyloidosis, Finnish type"]} |
A number sign (#) is used with this entry because of evidence that maturity-onset diabetes of the young type 7 (MODY7) is caused by heterozygous mutation in the KLF11 gene (603301) on chromosome 2p25.
For a phenotypic description and a discussion of genetic heterogeneity of MODY, see 606391.
Molecular Genetics
Neve et al. (2005) sequenced the KLF11 gene in 190 probands of families with early-onset type II diabetes mellitus and identified a SNP (A349S; 603301.0001) in affected members of a 4-generation family and another SNP (T220M; 603301.0002) in affected members of 2 unrelated multigenerational families. In 1 of the latter families, the T220M variant was not found in a diabetic sib with disease onset at a later age. Neither variant was found in 313 patients with late-onset type II diabetes or in 313 normoglycemic individuals.
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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
| MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 7 | c0342276 | 1,459 | omim | https://www.omim.org/entry/610508 | 2019-09-22T16:04:26 | {"doid": ["0111106"], "mesh": ["C562772"], "omim": ["610508"], "orphanet": ["552"], "genereviews": ["NBK500456"]} |
A number sign (#) is used with this entry because hereditary paragangliomas-3 (PGL3) is caused by heterozygous mutation in the SDHC gene (602413) on chromosome 1q23, which encodes subunit C of the succinate dehydrogenase complex.
For a phenotypic description and a discussion of genetic heterogeneity of familial paragangliomas, see PGL1 (168000).
Mapping
In a large German family with autosomal dominant hereditary paraganglioma, Niemann et al. (1999) excluded linkage to PGL1 and PGL2 (601650), suggesting the existence of a third locus. There was no evidence of maternal imprinting.
Niemann et al. (2001) described a family with maternally transmitted paraganglioma. The diagnosis had been histologically proven in 5 patients, and 1 patient had imaging findings consistent with a paraganglioma. Linkage studies indicated mapping to chromosome 1q21-q23.
Molecular Genetics
In affected members of a family with PGL3, Niemann and Muller (2000) identified a heterozygous mutation in the SDHC gene (602413.0001).
Baysal et al. (2004) described a family with PGL3 in which an 8,372-bp deletion in the SDHC gene (602413.0003) was transmitted both maternally and paternally, without evidence of genomic imprinting. They also identified the deletion in an unrelated sporadic case. They concluded that hereditary paraganglioma with imprinted transmission is restricted to SDHD (602690) among complex II genes.
Schiavi et al. (2005) identified mutations in the SDHC gene in 5 (4%) of 121 index patients with head and neck paragangliomas from a European registry. Clinically, 4 patients had jugular paragangliomas, and 1 had a carotid body tumor. All were benign, and none were multifocal. None of the mutation carriers or their carrier family members had signs of pheochromocytoma. Of 371 patients with sporadic pheochromocytomas, there were none with SDHC mutations, 21 with SDHB (185470) mutations, and 21 with SDHD (602690) mutations. Schiavi et al. (2005) concluded that SDHC-associated tumors are not likely to be pheochromocytomas and are less likely to be malignant or multifocal compared to SDHB- or SDHD-associated tumors.
Population Genetics
Hensen et al. (2012) determined the mutation frequency of 4 succinate dehydrogenase genes in a total of 1,045 patients from 340 Dutch families with paraganglioma and pheochromocytoma. Mutations were identified in 690 cases from 239 families. The most commonly affected gene in mutation carriers was SDHD (87.1%), followed by SDHAF2 (613019) (6.7%), SDHB (5.9%), and SDHC (0.3%). Almost 70% of all carriers had the founder mutation D92Y (602690.0004) in SDHD; approximately 89% of all SDH mutation carriers had 1 of 6 Dutch founder mutations. The dominance of SDHD mutations was unique to the Netherlands, contrasting with the higher prevalence of SDHB mutations found elsewhere.
INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Pulsatile tinnitus (tympanic paraganglioma) CARDIOVASCULAR Heart \- Palpitations (with pheochromocytoma) \- Tachycardia (with pheochromocytoma) Vascular \- Hypertension (with pheochromocytoma) RESPIRATORY Larynx \- Vocal cord paralysis (caused by tumor impingement) SKIN, NAILS, & HAIR Skin \- Diaphoresis (with pheochromocytoma) NEUROLOGIC Central Nervous System \- Headache (with pheochromocytoma) \- Cranial nerve palsies can arise with head and neck paragangliomas Behavioral Psychiatric Manifestations \- Anxiety (with pheochromocytoma) VOICE \- Hoarse voice (caused by tumor impingement) \- Loss of voice NEOPLASIA \- Paragangliomas \- Multiple tumors \- Paragangliomas, head and neck \- Chemodectomas \- Carotid body tumors \- Glomus jugular tumors \- Pheochromocytoma, adrenal \- Pheochromocytoma, extraadrenal \- Rarely malignant LABORATORY ABNORMALITIES \- Elevated catecholamines (in patients with pheochromocytoma) MISCELLANEOUS \- Cells of origin are part of the diffuse neuroendocrine system (DNES) \- Adult onset, wide range of age \- Signs and symptoms depend on tumor location and activity \- See also PGL1 ( 168000 ) MOLECULAR BASIS \- Caused by mutations in the succinate dehydrogenase complex subunit C gene (SDHC, 602413.0001 ) ▲ 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
| PARAGANGLIOMAS 3 | c1854336 | 1,460 | omim | https://www.omim.org/entry/605373 | 2019-09-22T16:11:23 | {"doid": ["0050773"], "mesh": ["C565335"], "omim": ["605373"], "orphanet": ["29072"], "synonyms": ["Alternative titles", "Familial pheochromocytoma-paraganglioma", "GLOMUS TUMORS, FAMILIAL, 3"], "genereviews": ["NBK1548"]} |
By polyacrylamide gel electrophoresis, Ziomek and Szewczuk (1978) demonstrated polymorphism of Co(2+)-activated acylase of human liver, kidney and small intestine as well as serum from patients with viral hepatitis. Family studies were not reported. This enzyme is an N-acylamino acid amidohydrolase that cleaves the low molecular weight carboxylic acids from acylated amino acids. It is distinct from aminoacylases 1 and 2 (104620).
*[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
| ACYLASE, COBALT-ACTIVATED | c0110356 | 1,461 | omim | https://www.omim.org/entry/102590 | 2019-09-22T16:45:22 | {"omim": ["102590"]} |
Unplanned event that did not result in injury, illness, or damage but had the potential to do so
"Close call" redirects here. For the film, see Close Call.
A near miss, "near hit", "close call", or "nearly a collision" is an unplanned event that has the potential to cause, but does not actually result in human injury, environmental or equipment damage, or an interruption to normal operation.[citation needed]
OSHA defines a near miss as an incident in which no property was damaged and no personal injury was sustained, but where, given a slight shift in time or position, damage or injury easily could have occurred. Near misses also may be referred to as close calls, near accidents, accident precursors, injury-free events and, in the case of moving objects, near collisions.[citation needed]
A near miss is often an error, with harm prevented by other considerations and circumstances.[1]
The phrase "near miss" should not be confused with the phrase "nearly a miss" which would imply a collision.
## Contents
* 1 Causes
* 2 Reporting, analysis and prevention
* 3 Safety improvements by reports
* 3.1 Aviation
* 3.2 Fire-rescue services
* 3.3 Law enforcement and public safety
* 3.4 Healthcare
* 3.5 Rail
* 4 See also
* 5 References
* 6 External links
## Causes[edit]
There are factors for a near miss related to the operator, and factors related to the context. Fatigue is an example for the former. The risk of a car crash after a more than 24h shift for physicians has been observed to increase by 168%, and the risk of near miss by 460%.[2] Factors relating to the context include time pressures, unfamiliar settings, and in the case of health care, diverse patients, and increased patient-to-nurse staffing ratio increases.[3]
## Reporting, analysis and prevention[edit]
Most safety activities are reactive and not proactive. Many organizations wait for losses to occur before taking steps to prevent a recurrence. Near miss incidents often precede loss producing events but are largely ignored because nothing (no injury, damage or loss) happened. Employees are not enlightened to report these close calls as there has been no disruption or loss in the form of injuries or property damage. Thus, many opportunities to prevent the accidents that the organization has not yet had are lost. Recognizing and reporting near miss incidents can make a major difference to the safety of workers within organizations. History has shown repeatedly that most loss producing events (accidents) were preceded by warnings or near accidents, sometimes also called close calls, narrow escapes or near hits.[4]
In terms of human lives and property damage, near misses are cheaper, zero-cost learning opportunities (compared to learning from actual injury or property loss events)
Getting a very high number of near misses is the goal as long as that number is within the organization's ability to respond and investigate - otherwise it is merely a paperwork exercise and a waste of time; it is possible to achieve a ratio of 100 near misses reported per loss event.[5]
Achieving and investigating a high ratio of near misses will find the causal factors and root causes of potential future accidents, resulting in about 95% reduction in actual losses.[5]
An ideal near miss event reporting system includes both mandatory (for incidents with high loss potential) and voluntary, non-punitive reporting by witnesses. A key to any near miss report is the "lesson learned". Near miss reporters can describe what they observed of the beginning of the event, and the factors that prevented loss from occurring.
The events that caused the near miss are subjected to root cause analysis to identify the defect in the system that resulted in the error and factors that may either amplify or ameliorate the result.[citation needed]
To prevent the near miss from happening again, the organization must institute teamwork training, feedback on performance and a commitment to continued data collection and analysis, a process called continuous improvement.[citation needed]
Near misses are smaller in scale, relatively simpler to analyze and easier to resolve. Thus, capturing near misses not only provides an inexpensive means of learning, but also has some equally beneficial spin offs:[citation needed]
* Captures sufficient data for statistical analysis; trending studies.
* Provides immense opportunity for "employee participation," a basic requirement for a successful workplace health and safety program. This embodies principles of behavior shift, responsibility sharing, awareness, and incentives.
* One of the primary workplace problems near miss incident reporting attempts to solve directly or indirectly is to try to create an open culture whereby everyone shares and contributes in a responsible manner. Near-Miss reporting has been shown to increase employee relationships and encourage teamwork in creating a safer work environment.[6]
## Safety improvements by reports[edit]
Reporting of near misses by observers is an established error reduction technique in many industries and organizations:
### Aviation[edit]
In the United States, the Aviation Safety Reporting System (ASRS) has been collecting confidential voluntary reports of close calls from pilots, flight attendants, air traffic controllers since 1976. The system was established after TWA Flight 514 crashed on approach to Dulles International Airport near Washington, D.C., killing all 85 passengers and seven crew in 1974. The investigation that followed found that the pilot misunderstood an ambiguous response from the Dulles air traffic controllers, and that earlier another airline had told its pilots, but not other airlines, about a similar near miss. The ASRS identifies deficiencies and provides data for planning improvements to stakeholders without regulatory action. Some familiar safety rules, such as turning off electronic devices that can interfere with navigation equipment, are a result of this program. Due to near miss observations and other technological improvements, the rate of fatal accidents has dropped about 65 percent, to one fatal accident in about 4.5 million departures, from one in nearly 2 million in 1997.[7]
In the United Kingdom, an aviation near miss report is known as an "airprox", an air proximity hazard,[8] by the Civil Aviation Authority. Since reporting began, aircraft near misses continue to decline.[9]
### Fire-rescue services[edit]
The rate of fire fighter fatalities and injuries in the United States is unchanged for the last 15 years despite improvements in personal protective equipment, apparatus and a decrease in structure fires.[10] In 2005, the National Fire Fighter Near-Miss Reporting System was established, funded by grants from the U.S. Fire Administration and Fireman’s Fund Insurance Company, and endorsed by the International Associations of Fire Chiefs and Fire Fighters. Any member of the fire service community is encouraged to submit a report when he/she is involved in, witnesses, or is told of a near-miss event. The report may be anonymous, and is not forwarded to any regulatory agency.[11]
### Law enforcement and public safety[edit]
A total of 1,439 U.S. law enforcement officers died in the line of duty during the past 10 years, an average of one death every 61 hours or 144 per year. There were 123 law enforcement officers killed in the line of duty in 2015.[12] In 2014, the Law Enforcement Officer (LEO) Near Miss Reporting System was established, with funding support from the U.S. Department of Justice's Office of Community Oriented Policing Services (COPS Office).[13] Since its launch, the LEO Near Miss system has established endorsements and partnerships with the National Law Enforcement Officers' Memorial Fund (NLEOMF), the International Association of Chiefs of Police (IACP), the International Association of Directors of Law Enforcement Standards and Training (IADLEST), the Officer Down Memorial Page (ODMP) and the Below 100 organization.[13] The Police Foundation, a national, independent non-profit organization, operates the system and has received additional support from the Motorola Solutions Foundation.[14] Law enforcement members are to submit voluntary reports when involved in or having witnessed or become aware of a near-miss event. Near miss reports take minutes to submit, can be submitted anonymously and are not forwarded to regulatory or investigative agencies, but are used to provide analysis, policy and training recommendations to the law enforcement community.
### Healthcare[edit]
AORN, a US-based professional organization of perioperative registered nurses, has put in effect a voluntary near miss reporting system called SafetyNet covering medication or transfusion reactions, communication or consent issues, wrong patient or procedures, communication breakdown or technology malfunctions. An analysis of incidents allows safety alerts to be issued to AORN members.[15]
The United States Department of Veterans Affairs (VA) and the National Aeronautics and Space Administration (NASA) developed the Patient Safety Reporting System modeled upon the Aviation Safety Reporting System to monitor patient safety through voluntary, confidential reports.[16]
### Rail[edit]
CIRAS (the Confidential Incident Reporting and Analysis System) is a confidential reporting system modelled upon ASRS and originally developed by the University of Strathclyde for use in the Scottish rail industry. However, after the Ladbroke Grove rail crash, John Prescott mandated its use throughout the whole UK rail industry. Since 2006 CIRAS has been run by an autonomous Charitable trust.[17]
## See also[edit]
* 1983 Soviet nuclear false alarm incident
* Aviation safety – A state in which risks associated with aviation are at an acceptable level
* Confidential incident reporting – System to allow safety problems to be reported in confidence
* Error – Deviation from what is correct
* Hazard analysis – The identification of present hazards as the first step in a process to assess risk
* Maternal near miss – Event in which a pregnant woman comes close to death but does not die
* Patient safety – The prevention, reduction, reporting, and analysis of medical error
* Road traffic safety – Methods and measures for reducing the risk of death and injury on roads
* Root cause – Earliest, most basic cause of a specified outcome
* Root cause analysis – Method of identifying the fundamental causes of faults or problems
* Safety engineering – Engineering discipline which assures that engineered systems provide acceptable levels of safety
* Separation (aeronautics) – Concept of keeping aircraft at least a minimum distance apart to reduce the risk of collision or wake turbulence
## References[edit]
1. ^ My Near Miss DANIELLE OFRI, MAY 28, 2013
2. ^ When Doctors Don't Sleep, Talk of the Nation, National Public Radio, 13 December 2006.
3. ^ Aiken LH, Clarke SP, Sloane DM, Sochalski J, Silber JH; Clarke; Sloane; Sochalski; Silber (2002). "Hospital nurse staffing and patient mortality, nurse burnout, and job dissatisfaction". JAMA. 288 (16): 1987–93. doi:10.1001/jama.288.16.1987. PMID 12387650.CS1 maint: multiple names: authors list (link)
4. ^ McKinnon, Ron C. Safety Management: Near Miss Identification, Recognition, and Investigation.
5. ^ a b "Gains from Getting Near Misses Reported" (PDF). Process Improvement Institute. Cite journal requires `|journal=` (help)
6. ^ "Near-Miss Incident Reporting – It's About Trust". CLMI Safety Training. n.d. Cite journal requires `|journal=` (help)
7. ^ Wald, Matthew L. (October 1, 2007). "Fatal Airplane Crashes Drop 65%". The New York Times. Retrieved 2007-10-01.
8. ^ "Air Proximity Hazard" (PDF). Archived from the original (PDF) on August 1, 2014. Retrieved August 29, 2014.
9. ^ Civil Aviation Authority: UK Airprox Board Archived 2006-08-13 at the Wayback Machine, Retrieved July 16, 2006
10. ^ National Fire Fighter Near-Miss Reporting System (www.firefighternearmiss.com): FAQ Archived 2006-07-18 at the Wayback Machine Retrieved July 16, 2006
11. ^ Mandak, Joe (September 18, 2005). "Database seeks to lower firefighter deaths". USA Today. Retrieved 2006-07-08.
12. ^ "National Law Enforcement Officers Memorial Fund: Law Enforcement Facts". www.nleomf.org. Retrieved 2016-11-14.
13. ^ a b "LEO Near Miss". www.leonearmiss.org. Retrieved 2016-11-14.
14. ^ "Police Foundation Receives Public Safety Grant Award from Motorola Solutions Foundation". www.policefoundation.org. Retrieved 2016-11-14.
15. ^ AORN: SafetyNet Archived 2006-07-17 at the Wayback Machine Retrieved on July 16, 2006
16. ^ L. A. Lenert, MD, MS, H. Burstin, MD, MPH, L. Connell, MA, RN, J. Gosbee, MD, MS, and G. Phillips (1 January 2002). "Federal Patient Safety Initiatives Panel Summary". J Am Med Inform Assoc. 9 (6 Suppl 1): s8–s10. doi:10.1197/jamia.M1217. PMC 419408. PMID 12386172.CS1 maint: multiple names: authors list (link)
17. ^ CIRAS Charitable Trust CIRAS website, Retrieved December 20th, 2006
## External links[edit]
* Columbia Journalism Review:‘Near Miss’
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*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Near miss (safety) | None | 1,462 | wikipedia | https://en.wikipedia.org/wiki/Near_miss_(safety) | 2021-01-18T18:34:40 | {"wikidata": ["Q1674639"]} |
Ellsworth (1927) found displacement of the carpal bone group on the radius and ulna. The distal epiphyses of these bones were misshapen. Five females in 4 generations were affected in a pattern equally consistent with either autosomal or X-linked inheritance. Carpal bossing appears to be the same trait as Ellsworth described. A prominence is produced by a double beak between the third metacarpal and the capitate bone of the wrist. Photographs and x-rays were presented by Larson et al. (1958), who estimated that it is present in about 26% of adults but only 1 of 50 children under 15 years of age. The genetics has not been worked out. Both genetic and environmental (e.g., occupational) factors may be involved. Surana (1973) described carpal bossing (which is probably a better term than carpal displacement) in several members of 3 generations, with male-to-male transmission. Clinically, they showed a small bony prominence on the third metacarpal-carpal joint. Roentgenograms of the wrist in marked palmar flexion showed a bony overgrowth of the dorsal aspect of both the capitate and the third metacarpal at the joint margin producing a characteristic double beak. All affected persons were asymptomatic. Surana (1973) stated that this trait was first described by Fiolle (1931) as 'carpe bossu.'
Limbs \- Carpal bossing Radiology \- Misshapen distal carpal epiphyses Inheritance \- Autosomal dominant ▲ Close
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*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| CARPAL DISPLACEMENT | c1861847 | 1,463 | omim | https://www.omim.org/entry/115400 | 2019-09-22T16:43:40 | {"omim": ["115400"], "synonyms": ["Alternative titles", "CARPAL BOSSING"]} |
Juvenile Paget disease is a very rare form of Paget disease of the bone characterized by a general increase in bone turnover with increased bone resorption and deposition, resulting in cortical and trabecular thickening, and clinically presenting as progressive skeletal deformities, growth impairment, fractures, vertebral collapse, skull enlargement and sensorineural hearing loss.
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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
| Juvenile Paget disease | c0268414 | 1,464 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2801 | 2021-01-23T18:45:29 | {"gard": ["2831"], "mesh": ["C537701"], "omim": ["239000"], "umls": ["C0268414"], "icd-10": ["M88.0", "M88.8", "M88.9"], "synonyms": ["Familial osteoectasia", "Hereditary hyperphosphatasia", "Hyperostosis corticalis deformans juvenilis", "JPG"]} |
Beta-mannosidosis is a very rare lysosomal storage disease characterized by developmental delay of varying severity and hearing loss, but that can manifest a wide phenotypic heterogeneity.
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*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
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*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Beta-mannosidosis | c2931893 | 1,465 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=118 | 2021-01-23T18:56:50 | {"gard": ["869"], "mesh": ["D044905"], "omim": ["248510"], "umls": ["C0342849", "C2931893"], "icd-10": ["E77.1"], "synonyms": ["Beta-mannosidase deficiency"]} |
Bleeding from a laceration in the mucosa at the junction of the stomach and esophagus
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: "Mallory–Weiss syndrome" – news · newspapers · books · scholar · JSTOR (October 2015) (Learn how and when to remove this template message)
Mallory–Weiss syndrome
Other namesGastro-esophageal laceration syndrome
Mallory–Weiss tear affecting the esophageal side of the gastroesophageal junction
SpecialtyGastroenterology
Mallory–Weiss syndrome or gastro-esophageal laceration syndrome refers to bleeding from a laceration in the mucosa at the junction of the stomach and esophagus. This is usually caused by severe vomiting because of alcoholism or bulimia,[1] but can be caused by any condition which causes violent vomiting and retching such as food poisoning. The syndrome presents with hematemesis. The laceration is sometimes referred to as a Mallory-Weiss tear.
## Contents
* 1 Signs and symptoms
* 2 Causes
* 3 Diagnosis
* 4 Treatment
* 5 History
* 6 See also
* 7 References
* 8 External links
## Signs and symptoms[edit]
Mallory–Weiss syndrome often presents as an episode of vomiting up blood (hematemesis) after violent retching or vomiting, but may also be noticed as old blood in the stool (melena), and a history of retching may be absent.
In most cases, the bleeding stops spontaneously after 24–48 hours, but endoscopic or surgical treatment is sometimes required. The condition is rarely fatal.[citation needed]
## Causes[edit]
It is often associated with alcoholism[2] and eating disorders and there is some evidence that presence of a hiatal hernia is a predisposing condition. Forceful vomiting causes tearing of the mucosa at the junction. NSAID abuse is also a rare association.[3] In rare instances some chronic disorders like Ménière's disease that cause long term nausea and vomiting could be a factor.
The tear involves the mucosa and submucosa but not the muscular layer (contrast to Boerhaave syndrome which involves all the layers).[4] Most patients are between the ages of 30 and 50 years, although it has been reported in infants aged as young as 3 weeks, as well as in older people [5][6] Hyperemesis gravidarum, which is severe morning sickness associated with vomiting and retching in pregnancy, is also a known cause of Mallory-Weiss tear.[7]
## Diagnosis[edit]
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Definitive diagnosis is by endoscopy.[8] Proper history taking by the medical doctor to distinguish other conditions that cause haematemesis but definitive diagnosis is by conducting esophagogastroduodenoscopy.
## Treatment[edit]
Treatment is usually supportive as persistent bleeding is uncommon. However cauterization or injection of epinephrine[9] to stop the bleeding may be undertaken during the index endoscopy procedure. Very rarely embolization of the arteries supplying the region may be required to stop the bleeding. If all other methods fail, high gastrostomy can be used to ligate the bleeding vessel. The tube will not be able to stop bleeding as here the bleeding is arterial and the pressure in the balloon is not sufficient to overcome the arterial pressure.
## History[edit]
The condition was first described in 1929 by G. Kenneth Mallory and Soma Weiss in 15 alcoholic patients.[10]
## See also[edit]
* Boerhaave syndrome – Full thickness esophageal ruptures also often secondary to vomiting/retching.
* Hematemesis
## References[edit]
1. ^ Sattar, Husain A. (2011). Fundamentals of Pathology. Pathoma, LLC. ISBN 9780983224600.
2. ^ Caroli A, Follador R, Gobbi V, Breda P, Ricci G (1989). "[Mallory-Weiss syndrome. Personal experience and review of the literature]". Minerva Dietologica e Gastroenterologica (in Italian). 35 (1): 7–12. PMID 2657497.
3. ^ R, Eslava García; Jl, Negrete Pardo; P, Muñoz Kim; S, García (April 1990). "[Mallory-Weiss Syndrome. Surgical Treatment After Sclerotherapy. Presentation of a Case and Review of the Literature]". Revista de Gastroenterologia de Mexico. 55 (2): 75–7. PMID 2287873.
4. ^ Boerhaave Syndrome at eMedicine
5. ^ Ba¸k-Romaniszyn, L.; Małecka-Panas, E.; Czkwianianc, E.; Płaneta-Małecka, I. (1999-03-01). "Mallory–Weiss syndrome in children". Diseases of the Esophagus. 12 (1): 65–67. doi:10.1046/j.1442-2050.1999.00006.x. ISSN 1120-8694. PMID 10941865.
6. ^ Kitagawa, Takashi; Takano, Hideya; Sohma, Mitsuhiro; Mutoh, Eiji; Takeda, Shouzo (1994). "Clinical Study of Mallory-Weiss Syndrome in the Aged Patients Over 75 Year. Mainly Five Cases Induced by the Endoscopic Examination". Nippon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics. 31 (5): 374–379. doi:10.3143/geriatrics.31.374. ISSN 0300-9173. PMID 8072208.
7. ^ Parva M, Finnegan M, Keiter C, Mercogliano G, Perez CM (August 2009). "Mallory-Weiss tear diagnosed in the immediate postpartum period: a case report". J Obstet Gynaecol Can. 31 (8): 740–3. doi:10.1016/S1701-2163(16)34280-3. PMID 19772708.
8. ^ Hastings, Paul R.; Peters, Kenneth W.; Cohn, Isidore (November 1981). "Mallory-Weiss syndrome". The American Journal of Surgery. 142 (5): 560–562. doi:10.1016/0002-9610(81)90425-6. PMID 7304810.
9. ^ Gawrieh S, Shaker R (2005). "Treatment of actively bleeding Mallory-Weiss syndrome: epinephrine injection or band ligation?". Current Gastroenterology Reports. 7 (3): 175. doi:10.1007/s11894-005-0030-0. PMID 15913474. S2CID 195343875.
10. ^ Weiss S, Mallory GK (1932). "Lesions of the cardiac orifice of the stomach produced by vomiting". Journal of the American Medical Association. 98 (16): 1353–5. doi:10.1001/jama.1932.02730420011005.
## External links[edit]
Classification
D
* ICD-10: K22.6
* ICD-9-CM: 530.7
* MeSH: D008309
* DiseasesDB: 7803
External resources
* MedlinePlus: 000269
* eMedicine: ped/1359
* Patient UK: Mallory–Weiss syndrome
* v
* t
* e
Diseases of the digestive system
Upper GI tract
Esophagus
* Esophagitis
* Candidal
* Eosinophilic
* Herpetiform
* Rupture
* Boerhaave syndrome
* Mallory–Weiss syndrome
* UES
* Zenker's diverticulum
* LES
* Barrett's esophagus
* Esophageal motility disorder
* Nutcracker esophagus
* Achalasia
* Diffuse esophageal spasm
* Gastroesophageal reflux disease (GERD)
* Laryngopharyngeal reflux (LPR)
* Esophageal stricture
* Megaesophagus
* Esophageal intramural pseudodiverticulosis
Stomach
* Gastritis
* Atrophic
* Ménétrier's disease
* Gastroenteritis
* Peptic (gastric) ulcer
* Cushing ulcer
* Dieulafoy's lesion
* Dyspepsia
* Pyloric stenosis
* Achlorhydria
* Gastroparesis
* Gastroptosis
* Portal hypertensive gastropathy
* Gastric antral vascular ectasia
* Gastric dumping syndrome
* Gastric volvulus
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*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Mallory–Weiss syndrome | c0024633 | 1,466 | wikipedia | https://en.wikipedia.org/wiki/Mallory%E2%80%93Weiss_syndrome | 2021-01-18T18:58:53 | {"gard": ["6967"], "mesh": ["D008309"], "icd-9": ["530.7"], "icd-10": ["K22.6"], "wikidata": ["Q1632678"]} |
A number sign (#) is used with this entry because Chediak-Higashi syndrome (CHS) is caused by homozygous or compound heterozygous mutation in the lysosomal trafficking regulator gene (LYST; 606897) on chromosome 1q42.
Clinical Features
The features of Chediak-Higashi syndrome are decreased pigmentation of hair and eyes (partial albinism), photophobia, nystagmus, large eosinophilic, peroxidase-positive inclusion bodies in the myeloblasts and promyelocytes of the bone marrow, neutropenia, abnormal susceptibility to infection, and peculiar malignant lymphoma. Death often occurs before the age of 7 years. (See Hermansky-Pudlak syndrome (203300), a similar but distinct entity.) Kritzler et al. (1964) found the karyotype normal in a 16-year-old patient. Glycolipid inclusions were described in histiocytes, renal tubular epithelium, and neurons. Heterozygotes were identifiable by the presence of a granular anomaly of the lymphocytes. The patient died of massive gastrointestinal hemorrhage. Leukemia and lymphoma have been observed (Efrati and Jonas, 1958).
Windhorst et al. (1966) found large lysosomal granules in leukocytes and giant melanosomes in melanocytes. For this reason, Leader et al. (1966) referred to the condition as 'hereditary leukomelanopathy.' Hargis and Prieur (1985), who studied CHS in cats, quoted White (1966) as providing evidence that many of the enlarged granules in CHS cells are derived from lysosomes. Sheramata et al. (1971) described 3 brothers, aged 31, 34 and 38, who had this disorder and a neurologic picture resembling spinocerebellar degeneration. Neutrophils are deficient in chemotactic and bactericidal activities. Microtubular abnormalities have been demonstrated (Oliver and Zurier, 1976) and ascorbic acid corrects certain functional abnormalities of the cells (Boxer et al., 1976).
Siccardi et al. (1978) described a 4-year-old Italian boy with recurrent infections. Both he and his healthy father had a severe isolated defect in bactericidal activity of circulating neutrophils. The parents of the proband were first cousins once removed. The proband had silvery-blond hair, individual hairs showing silver and blond banding, as well as a slate-gray generalized hyperpigmentation of the skin. Generalized lymph node enlargement and hepatosplenomegaly were present. The boy died at age 4 years and 9 months, following cerebral hemorrhage (probably secondary to thrombocytopenia caused by hypersplenism). No autopsy was performed. Obviously there were similarities to and differences from the Chediak-Higashi syndrome. Inoue et al. (1991) reported the occurrence of sclerosing stromal tumor of the ovary in a 13-year-old girl with CHS.
Spritz (1999) stated that about 85 to 90% of CHS patients eventually develop a strange lymphoproliferative syndrome, the so-called 'accelerated phase' of the disorder, characterized by generalized lymphohistiocytic infiltrates, fever, jaundice, hepatosplenomegaly, lymphadenopathy, pancytopenia, and bleeding. Management of this phase is quite difficult (Bejaoui et al., 1989). Most patients ultimately require bone marrow transplantation, without which mean survival is only about 3.1 years, death usually resulting from pyogenic infections or hemorrhage (Blume and Wolff, 1972). Patients who do not develop an accelerated phase tend to have fewer or no infections, but usually develop progressively debilitating neurologic manifestations (Misra et al., 1991; Uyama et al., 1994).
Spritz (1999) provided a comprehensive review.
Tardieu et al. (2005) reported 3 patients with CHS who underwent successful bone marrow transplantation (BMT) in childhood with sustained mixed chimerism and no subsequent recurrent infections or hemophagocytic syndrome. At the age of 20 to 24 years, each patient developed neurologic symptoms combining difficulty walking, loss of balance, and tremor. Examination revealed cerebellar ataxia and signs of peripheral neuropathy. Electrophysiologic studies showed motor-sensory axonal neuropathy, there was axon loss on peripheral nerve biopsy, and cerebellar atrophy was detected on brain MRI. Tardieu et al. (2005) reviewed the neurologic status of 4 other patients with CHS who had undergone BMT: 1 began having gait abnormality, falls when walking, and decreased cognitive abilities at the age of 21; 3 other patients, aged 17, 14, and 2 years, had borderline low IQ scores but normal neurologic examinations. Tardieu et al. (2005) noted that the neurologic symptoms observed were identical to those in adults with mild CHS who did not undergo BMT, and concluded that the symptoms most likely resulted from steady long-term progression, despite BMT, of the lysosomal defect in neurons and glial cells.
### Clinical Variability
Shimazaki et al. (2014) reported 2 brothers, born of consanguineous Japanese parents, who presented with gait abnormalities due to spastic paraplegia, cerebellar ataxia, and peripheral neuropathy at ages 48 and 58 years, respectively. Brain MRI showed cerebellar atrophy. Neither patient had pigmentary abnormalities of the skin or eyes, clinical features of immunodeficiency, or a bleeding tendency. Peripheral blood showed giant granules in granulocytes and reduced NK cell activity. Linkage analysis combined with exome sequencing identified a homozygous missense mutation in the LYST gene (c.4189T-G, F1397V); functional studies of the variant were not performed. The report expanded the phenotypic spectrum of CHS to include a late-onset, slowly progressive, mainly neurologic disorder.
Clinical Management
In a girl with Chediak-Higashi syndrome, Aslan et al. (1996) reported on the temporary success (11 months) of high-dose methylprednisolone during the 'accelerated phase' of her condition after unsuccessful treatment with vincristine, prednisolone, ascorbic acid, and antibiotics (ceftriaxone, netilmicin, and co-trimoxazole). After a second trial of high-dose methylprednisolone was unsuccessful, splenectomy continued the child's survival for an additional 29 months. The patient died of neutropenic septicemia. Atypically, this child had pulmonary involvement and no evidence of lymphohistiocytic infiltration in the rectum and sigmoid colon with biopsy proven intestinal polyposis.
Biochemical Features
Ganz et al. (1988) demonstrated deficiency of cathepsin G (116830) and elastase (130130) in all 3 patients with CHS whom they studied. Cathepsin G is a constituent of the azurophil granule; defensins, which are also constituents, were normal or only mildly decreased in the CHS patients. Elastase has an ancillary microbicidal/cytotoxic action. In another disorder with frequent and severe bacterial infections, namely, specific granule deficiency (SGD; 245480), Ganz et al. (1988) found almost complete deficiency of defensins.
In cells from patients with the Chediak-Higashi syndrome, Faigle et al. (1998) found that peptide loading onto major histocompatibility complex class II molecules and antigen presentation were strongly delayed. Results of other studies suggested that the product of the LYST gene (606897) is required for sorting endosomal resident proteins into late multivesicular endosomes by a mechanism involving microtubules.
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA4; 123890) plays a major role in the regulation of T-cell activation. Its membrane expression is highly regulated by endocytosis and trafficking through the secretory lysosome pathway. Chediak-Higashi syndrome is caused by mutations in the lysosomal trafficking regulator gene LYST. It results in defective membrane targeting of the proteins present in secretory lysosomes, and it is associated with a variety of features, including a lymphoproliferative syndrome with hemophagocytosis in the human. 'Beige' mice, the murine equivalent of CHS, present similar characteristics but do not develop the lymphoproliferative syndrome. Barrat et al. (1999) showed that intracellular trafficking of CTLA4 is impaired in the T cells of CHS patients and results in defective cell surface expression of this molecule. In contrast, little is defective in CTLA4 trafficking in 'beige' mouse T cells, and membrane expression of CTLA4 is normal. They proposed that the defective surface expression of CTLA4 by CHS T cells is involved in the generation of lymphoproliferative disease.
Inheritance
Dufourcq-Lagelouse et al. (1999) reported the case of a unique patient with CHS, who was homozygous for a stop codon in the LYST gene and who had a normal 46,XY karyotype. The mother was found to be a carrier of the mutation, whereas the father had 2 normal LYST alleles. Nonpaternity was excluded by analysis of microsatellite markers from different chromosomes. The results of 13 informative microsatellite markers spanning the entire chromosome 1 revealed that the proband had a maternal isodisomy of chromosome 1 encompassing the LYST mutation. The proband's clinical presentation also confirmed the absence of imprinted genes on chromosome 1. No clinical abnormalities other than those related to the LYST mutation were found.
Manoli et al. (2010) reported an 8-month-old boy with severe Chediak-Higashi syndrome and early developmental delay who was homozygous for a truncating mutation in the LYST gene, resulting from paternal isodisomy of chromosome 1. The patient's fibroblasts expressed no detectable protein. In addition to classic features of CHS, the patient had hypotonia and developmental delay. However, both parents also had cognitive delay, and comparative genomic hybridization showed that the patient had an interstitial duplication of chromosome 6q14 inherited from his father, which likely contributed to the additional features and/or more severe phenotype.
Other Features
Penner and Prieur (1987) found close morphologic similarities of the CHS fibroblasts from humans, cats, mink, and cattle. Mice homozygous for the 'beige' (bg) gene have a selective deficiency of NK (natural killer) lymphocytes and an increased susceptibility to transplanted tumors. Patients with the homologous Chediak-Higashi syndrome appear to have the same defect of NK cells (Roder et al., 1980). Perou et al. (1997) showed that the mutation in the bg allele is the result of a LINE-1 (see 151626) retrotransposition. Penner and Prieur (1987) found a lack of complementation when human CHS fibroblasts were fused with cat CHS fibroblasts, and also when human CHS fibroblasts were fused with mink CHS fibroblasts. This suggested that the disease has the same cause in these 3 species. NK cells are thought to have an important role in surveillance against tumor development. Virelizier and Griscelli (1980) simultaneously demonstrated the defect in NK cells. They could not modify the NK activity of CHS leukocytes by prolonged in vitro incubation with interferon, or by in vivo administration of interferon. Bone marrow transplantation, however, restored NK activity. Both spontaneous levels of NK activity and its in vitro activation by interferon were restored. Neutrophils kill their targets by means of 2 distinct classes of effector substances: reactive oxygen intermediates (ROI) and microbicidal/cytotoxic proteins. Myeloperoxidase deficiency (254600) and chronic granulomatous disease (306400) are examples of deficient ROI production by polymorphonuclear leukocytes.
Mapping
In the mouse, the analog of CHS (beige) is linked to the TCRG locus (see 186970) on mouse chromosome 13 (Holcombe et al., 1987). The 2 loci show a frequency of recombination of 0.025. However, Holcombe et al. (1987) found nonlinkage in man between TCRG and the Chediak-Higashi syndrome; lod scores were negative through a full range of recombination values and were less than -2.0 at theta = 0.20 and lower. Jenkins et al. (1991) predicted that the CHS1 gene may reside on distal 1q because in the mouse the homologous condition to Chediak-Higashi syndrome shows linkage to the nidogen gene (131390) which is located on human 1q.
Fukai et al. (1996) carried out homozygosity mapping in 4 inbred probands with classic childhood CHS using markers derived from the human chromosome segment 1q42-q44. The lod score between markers in this region (e.g., D1S235, D1S1594, and D1S204) and CHS in the inbred kindreds was 4.82. Fukai et al. (1996) also studied several inbred patients with the atypical adult form of CHS. None of these individuals were homozygous for markers in distal 1q. This finding suggested to the authors that at least some cases of CHS may represent a genetic entity with a different map location.
Barrat et al. (1996) mapped the CHS locus by linkage analysis to a 5-cM interval on chromosome 1q42.1-q42.2. The highest lod score (5.38 at theta = 0) was obtained with the marker D1S235. They used haplotype analysis to define D1S2680 as the telomeric flanking marker and D1S163 as the centromeric flanking marker. The 9 families used in this study were from 7 different countries. There was consanguinity in 5 of the families. Barrat et al. (1996) identified 3 YAC clones which covered the entire region in a contig.
Kunieda et al. (2000) demonstrated linkage between the CHS locus and marker loci on the proximal end of bovine chromosome 28.
Molecular Genetics
Barbosa et al. (1997) identified novel mutations in the coding region of the LYST gene in 3 CHS patients (606897.0006-606897.0007). Karim et al. (1997) reported 2 homozygous LYST mutations in 2 affected patients (606897.0004-606897.0005).
Genotype/Phenotype Correlations
Karim et al. (2002) performed mutation analysis of 21 unrelated patients with the childhood, adolescent, and adult forms of CHS. In patients with severe childhood CHS, they found only functionally null mutant LYST alleles, whereas in patients with the adolescent and adult forms of CHS, they also found missense mutant alleles that likely encode LYST polypeptides with partial function.
Animal Model
Man, mouse, cattle, mink, and killer whale are known to be affected. Kahraman and Prieur (1990) stated that this disorder has been identified in 10 species, including humans. Kahraman and Prieur (1990) succeeded in prenatal diagnosis of the disorder in cats by demonstrating abnormally large lysosomes (stained for acid phosphatase) in cultured amniotic fluid cells. In mink and cattle, the disorder is autosomal recessive (Padgett et al., 1964).
Chediak-Higashi syndrome in Japanese black cattle is a hereditary disease with prolonged bleeding time and partial albinism. Kunieda et al. (2000) demonstrated linkage between the CHS locus and marker loci on the proximal end of bovine chromosome 28. They also showed that the bovine LYST gene is on chromosome 28 using a bovine/murine somatic cell hybrid panel.
History
This disorder was first reported by Beguez-Cesar (1943), a Cuban pediatrician. Chediak (1952) and Higashi (1954) gave further descriptions. Sato (1955) reported 'Chediak and Higashi's disease,' the probable identity of 'a new leucocyte anomaly (Chediak)' and 'congenital gigantism of peroxidase granules (Higashi)'. Donohue and Bain (1957) used the specific designation Chediak-Higashi syndrome.
INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Reduced visual acuity \- Photophobia \- Nystagmus \- Strabismus \- Reduced iris pigmentation \- Macular hypoplasia Mouth \- Gingivitis \- Pseudomembranous sloughing of buccal mucosa ABDOMEN Liver \- Hepatomegaly \- Jaundice Spleen \- Splenomegaly SKIN, NAILS, & HAIR Skin \- Mild/severe skin hypopigmentation \- Jaundice Skin Histology \- Giant melanosomes in melanocytes Hair \- Mild hair hypopigmentation MUSCLE, SOFT TISSUES \- Muscle weakness \- Giant granules in muscle cells NEUROLOGIC Central Nervous System \- Mental deficiency \- Progressive intellectual decline \- Neurodegeneration \- Cranial nerve palsies \- Decreased deep tendon reflexes \- Markedly delayed nerve conduction velocities \- Tremor \- Abnormal gait \- Seizures \- Diffuse brain and spinal cord atrophy on brain CT/MRI \- Giant granules in Schwann cells Peripheral Nervous System \- Progressive peripheral neuropathy \- Foot drop HEMATOLOGY \- Anemia \- Thrombocytopenia \- Leukopenia \- Giant inclusion bodies present in most granulated cells IMMUNOLOGY \- Recurrent cutaneous and systemic pyogenic infections \- Absent natural killer cell cytotoxicity \- Normal B cell function \- Decreased neutrophil and monocyte migration and chemotaxis \- Lymphadenopathy in late phase \- Generalized lymphohistiocytic infiltrates in late phase \- Erythrophagocytosis in late phase MOLECULAR BASIS \- Caused by mutation in the lysosomal trafficking regulator gene (CHS1, 606897.0001 ) ▲ 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
| CHEDIAK-HIGASHI SYNDROME | c0007965 | 1,467 | omim | https://www.omim.org/entry/214500 | 2019-09-22T16:29:47 | {"doid": ["2935"], "mesh": ["D002609"], "omim": ["214500"], "icd-10": ["E70.330", "D72.0"], "orphanet": ["167"], "genereviews": ["NBK5188"]} |
Secondary hyperparathyroidism
Other namesSHPT
Thyroid and parathyroid.
SpecialtyEndocrinology
Secondary hyperparathyroidism is the medical condition of excessive secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia (low blood calcium levels), with resultant hyperplasia of these glands. This disorder is primarily seen in patients with chronic kidney failure. It is sometimes abbreviated "SHPT" in medical literature.
## Contents
* 1 Signs and symptoms
* 2 Cause
* 3 Diagnosis
* 4 Treatment
* 5 Prognosis
* 6 See also
* 7 References
* 8 External links
## Signs and symptoms[edit]
Bone and joint pain are common, as are limb deformities. The elevated PTH has also pleiotropic effects on the blood, immune system, and neurological system.[citation needed]
## Cause[edit]
Chronic kidney failure is the most common cause of secondary hyperparathyroidism. Failing kidneys do not convert enough vitamin D to its active form, and they do not adequately excrete phosphate. When this happens, insoluble calcium phosphate forms in the body and removes calcium from the circulation. Both processes lead to hypocalcemia and hence secondary hyperparathyroidism. Secondary hyperparathyroidism can also result from malabsorption (chronic pancreatitis, small bowel disease, malabsorption-dependent bariatric surgery) in that the fat-soluble vitamin D can not get reabsorbed. This leads to hypocalcemia and a subsequent increase in parathyroid hormone secretion in an attempt to increase the serum calcium levels. A few other causes can stem from inadequate dietary intake of calcium, a vitamin D deficiency, or steatorrhea.[1]
## Diagnosis[edit]
The PTH is elevated due to decreased levels of calcium or 1,25-dihydroxy-vitamin D3. It is usually seen in cases of chronic kidney disease or defective calcium receptors on the surface of parathyroid glands.[citation needed]
## Treatment[edit]
If the underlying cause of the hypocalcemia can be addressed, the hyperparathyroidism will resolve. In people with chronic kidney failure, treatment consists of dietary restriction of phosphorus; supplements containing an active form of vitamin D, such as calcitriol, doxercalciferol, paricalcitol; and phosphate binders, which are either calcium-based and non-calcium based.[citation needed]
Extended Release Calcifediol was recently approved by the FDA as a treatment for secondary hyperparathyroidism (SHPT) in adults with stage 3 or 4 chronic kidney disease (CKD) and low vitamin D blood levels (25-hydroxyvitamin D less than 30 ng/mL). It can help treat SHPT by increasing Vitamin D levels and lowering parathyroid hormone or PTH. It is not indicated for people with stage 5 CKD or on dialysis.[citation needed]
In the treatment of secondary hyperparathyroidism due to chronic kidney disease on dialysis calcimimetics do not appear to affect the risk of early death.[2] It does decrease the need for a parathyroidectomy but caused more issues with low blood calcium levels and vomiting.[2]
Most people with hyperparathyroidism secondary to chronic kidney disease will improve after renal transplantation, but many will continue to have a degree of residual hyperparathyroidism (tertiary hyperparathyroidism) post-transplant with associated risk of bone loss, etc.[citation needed]
## Prognosis[edit]
If left untreated, the disease will progress to tertiary hyperparathyroidism, where correction of the underlying cause will not stop excess PTH secretion, i.e. parathyroid gland hypertrophy becomes irreversible. In contrast with secondary hyperparathyroidism, tertiary hyperparathyroidism is associated with hypercalcemia rather than hypocalcemia.[citation needed]
## See also[edit]
* Primary hyperparathyroidism
* Tertiary hyperparathyroidism
## References[edit]
1. ^ Robbins and Cotran pathologic basis of disease. Kumar, Vinay, 1944-, Abbas, Abul K.,, Aster, Jon C.,, Perkins, James A. (Ninth ed.). Philadelphia, PA. 2014. p. 1103. ISBN 9781455726134. OCLC 879416939.CS1 maint: others (link)
2. ^ a b Ballinger, AE; Palmer, SC; Nistor, I; Craig, JC; Strippoli, GF (9 December 2014). "Calcimimetics for secondary hyperparathyroidism in chronic kidney disease patients". The Cochrane Database of Systematic Reviews. 12 (12): CD006254. doi:10.1002/14651858.CD006254.pub2. PMID 25490118.
## External links[edit]
Classification
D
* ICD-10: E21.1
* ICD-9-CM: 252.02, 588.81
* MeSH: D006962
* DiseasesDB: 6301
External resources
* MedlinePlus: 000318
* v
* t
* e
Parathyroid disease
Hypoparathyroidism
* Pseudohypoparathyroidism
* Pseudopseudohypoparathyroidism
Hyperparathyroidism
* Primary
* Secondary
* Tertiary
* Osteitis fibrosa cystica
Other
* Parathyroiditis
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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
| Secondary hyperparathyroidism | c0020503 | 1,468 | wikipedia | https://en.wikipedia.org/wiki/Secondary_hyperparathyroidism | 2021-01-18T18:42:17 | {"mesh": ["D006962"], "umls": ["C0020503"], "icd-9": ["588.81", "252.02"], "icd-10": ["E21.1"], "wikidata": ["Q3622611"]} |
Throckmorton's reflex
Differential diagnosispyramidal tract lesions
Throckmorton's reflex is a clinical sign in which pressure over the dorsal side of the metatarsophalangeal joint of the big toe elicits a plantar reflex. It is found in patients with pyramidal tract lesions, and is one of a number of Babinski-like responses.[1]
The sign is named after Tom Bentley Throckmorton.[2]
## References[edit]
1. ^ Kumar SP; Ramasubramanian D (December 2000). "The Babinski sign--a reappraisal". Neurol India. 48 (4): 314–8. PMID 11146592. Retrieved 2009-04-13.
2. ^ T.B. Throckmorton. A new method for eliciting the extensor toe reflex. Journal of the American Medical Association, Chicago, 1911, 56: 1311.
## External links[edit]
Throckmorton's reflex at Who Named It?
This medical sign article is a stub. You can help Wikipedia by expanding it.
* v
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* e
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Throckmorton's reflex | None | 1,469 | wikipedia | https://en.wikipedia.org/wiki/Throckmorton%27s_reflex | 2021-01-18T18:56:01 | {"wikidata": ["Q7798325"]} |
Genetic disorder
Hyperglycerolemia
SpecialtyMedical genetics
Hyperglycerolemia, also known as Glycerol kinase deficiency (GKD), is a genetic disorder where the enzyme glycerol kinase is deficient resulting in a build-up of glycerol in the body. Glycerol kinase is responsible for synthesizing triglycerides and glycerophospholipids in the body. Excess amounts of glycerol can be found in the blood and/ or urine. Hyperglycerolmia occurs more frequently in males. Hyperglycerolemia is listed as a “rare disease” which means it affects less than 200,000 people in the US population, or less than about 1 in 1500 people.
## Contents
* 1 Signs and symptoms
* 2 Cause
* 3 Mechanism
* 4 Diagnosis
* 5 Treatment
* 6 Research
* 7 See also
* 8 References
* 9 External links
## Signs and symptoms[edit]
The Human Phenotype Ontology provided the following list of symptoms and signs for hyperglycerolemia:[1] Abnormality of metabolism/homeostasis, Cognitive Deficit, EMG abnormality, Muscular Hypotonia, Myopathy, Neurological speech impairment, Primary adrenal insufficiency, Short stature, Cryptorchidism, EEG abnormality, Lumbar Hyperlordosis, Reduced bone mineral density, Scoliosis, Seizures, Abnormal facial shape, and Adrenal insufficiency. Adrenal insufficiency is associated with the genetic disease X-linked adrenal hypoplasia congenita.[2] If the glycerol kinase gene is deleted then the NROB1 gene is also often deleted, which causes X-linked adrenal hypoplasia congenita.[3]
## Cause[edit]
Hyperglycerolemia is caused by excess glycerol in the bloodstream. People with more severe cases of glycerol kinase deficiency may have a deletion of the GK gene that is large enough to see by routine cytogenetic evaluation.[4] It has been found an x-linked recessive inheritance pattern of the trait when a study was conducted on a grandfather and grandson. In addition, there is a high prevalence of [diabetes mellitus] in this family.[5] There is no known prevention for hyperglycerolemia because it is caused by a mutation or deletion of an individual's genetic code.
## Mechanism[edit]
Hyperglycerolemia or Glycerol kinase deficiency, is caused by a rare X-linked recessive genetic disorder caused by a mutation or a deletion in the glycerol kinase gene, located at the locus Xp21.3 of the X chromosome between base pairs 30,653,358 to 30,731,461.[6] Glycerol kinase catalyzes the phosphorylation of glycerol by ATP, yielding ADP and glycerol-3-phosphate.[7] It is more common in males because they only have one X chromosome, whereas females rarely manifest the disease because they have two X chromosomes. If hyperglycerolemia is caused by a mutation in the glycerol kinase gene then it generally causes an isolated glycerol kinase deficiency, resulting in the inability to synthesize triglycerides and glycerophospholipids. If hyperglycerolemia results from a deletion of the glycerol kinase gene then it often is part of a contiguous gene deletion syndrome with associated Duchenne muscular dystrophy and adrenal hypoplasia congenita.[8]
## Diagnosis[edit]
Glycerol and glycerol kinase activity analyses are usually not offered by routine general medical laboratories.[9] To diagnose hyperglycerolemia, blood and urine can be tested for the amounts of glycerol present. There are three clinical forms of GKD: infantile, juvenile, and adult. The infantile form is associated with severe developmental delay and results in a syndrome with Xp21 gene deletion with congenital adrenal hypoplasia and/or Duchenne muscular dystrophy. The infantile diagnosis is made by measuring plasma glycerol and is characterized by glycerol levels between 1.8 and 8.0 mmol/L and glyceroluria more than 360 mmol/24h.[9] To confirm the diagnosis, genetic testing of the Xp21 gene is definitive.[9] Children with GKD have severe hypoglycemic episodes and profound metabolic acidosis, or are completely symptom free. Individuals who are unable to form glucose from the glycerol released during triglyceride catabolism also the hypoglycemic episodes often disappear during adolescence.[9] Patients with the juvenile and adult forms often have no symptoms and are diagnosed fortuitously when a medical professional tests for another medical condition. The juvenile form is an uncommon form characterized by Reye syndrome-like clinical manifestations including episodic vomiting, acidemia, and disorders of consciousness.[10]
## Treatment[edit]
In adults, fibrates and statins have been prescribed to treat hyperglycerolemia by lowering blood glycerol levels. Fibrates are a class of drugs that are known as amphipathic carboxylic acids that are often used in combination with Statins. Fibrates work by lowering blood triglyceride concentrations. When combined with statins, the combination will lower LDL cholesterol, lower blood triglycerides and increase HDL cholesterol levels.[11] If hyperglycerolemia is found in a young child without any family history of this condition, then it may be difficult to know whether the young child has the symptomatic or benign form of the disorder.[1] Common treatments include: a low-fat diet, IV glucose if necessary, monitor for insulin resistance and diabetes, evaluate for Duchenne muscular dystrophy, adrenal insufficiency & developmental delay.[9] The Genetic and Rare Diseases Information Center (GARD) does not list any treatments at this time.[1]
## Research[edit]
According to Clinicaltrials.gov, there are no current studies on hyperglycerolemia. Clinicaltrials.gov is a service of the U.S. National Institutes of Health. Recent research shows patients with high concentrations of blood triglycerides have an increased risk of coronary heart disease. Normally, a blood glycerol test is not ordered. The research was about a child having elevated levels of triglycerides when in fact the child had glycerol kinase deficiency. This condition is known as pseudo-hypertriglyceridemia, a falsely elevated condition of triglycerides.[12] Another group treated patients with elevated concentrations of blood triglycerides with little or no effect on reducing the triglycerides. A few laboratories can test for high concentrations of glycerol, and some laboratories can compare a glycerol-blanked triglycerides assay with the routine non-blanked method.[13] Both cases show how the human body may exhibit features suggestive of a medical disorder when in fact it is another medical condition causing the issue.
## See also[edit]
* Hypertriglyceridemia
## References[edit]
1. ^ a b c U.S. Department of Health & Human Services (n.d.), Genetic and Rare Diseases Information Center. Retrieved from https://rarediseases.info.nih.gov/gard/2807/disease/resources/1
2. ^ Domenice S, Latronico AC, Brito VN, Arnhold IJ, Kok F, Mendonca BB (September 2001). "Adrenocorticotropin-dependent precocious puberty of testicular origin in a boy with X-linked adrenal hypoplasia congenita due to a novel mutation in the DAX1 gene". J. Clin. Endocrinol. Metab. 86 (9): 4068–71. doi:10.1210/jc.86.9.4068. PMID 11549627.
3. ^ Tabarin A, Achermann JC, Recan D, Bex V, Bertagna X, Christin-Maitre S, Ito M, Jameson JL, Bouchard P (February 2000). "A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism". J. Clin. Invest. 105 (3): 321–8. doi:10.1172/JCI7212. PMC 377437. PMID 10675358
4. ^ Blau, N., Duran, M., Blaskovics, K.M., & Gibson, K.M. (2012). Physician's guide to the laboratory diagnosis of metabolic diseases. New York, NY: Springer.
5. ^ Rose, C. I., & Haines, D. S. (1978). Familial hyperglycerolemia. Journal of Clinical Investigation, 61(1), 163.
6. ^ Genetics Home Reference (n.d.), GK. Retrieved from http://ghr.nlm.nih.gov/gene/GK
7. ^ Glycerol Kinase (n.d.). Retrieved from http://omim.org/entry/300474
8. ^ Huq, A. M., Lovell, R. S., Ou, C. N., Beaudet, A. L., & Craigen, W. J. (1997). X-linked glycerol kinase deficiency in the mouse leads to growth retardation, altered fat metabolism, autonomous glucocorticoid secretion and neonatal death. Human molecular genetics, 6(11), 1803-1809.
9. ^ a b c d e Arrobas-Velilla, T., Mondéjar-García, R., Gómez-Gerique, J. A., Díaz, I. C., Mengibar, M. C., de Diego, A. O., & Fabiani-Romero, F. (2013). Pseudo-hypertriglyceridaemia or hyperglycerolemia?. Clínica e Investigación en Arteriosclerosis, 25(3), 123-126.
10. ^ Orphanet (n.d.), The Portal for Rare Diseases and Orphan Drugs. Retrieved from http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=284411
11. ^ Medicinenet.com (n.d.), Retrieved from http://www.medicinenet.com/fibrates/article.htm,
12. ^ Fabiani, R. F., Bermúdez, D. L. V. J., González, M. C., Gentil, G. J., Oribe, A., & Cruz, C. (2009, July). [Hyperglycerolemia, a pseudo-hypertriglyceridemia: a case report]. In Anales de pediatria (Barcelona, Spain: 2003) (Vol. 71, No. 1, pp. 68-71)
13. ^ Backes, J. M., Dayspring, T., Mieras, T., & Moriarty, P. M. (2012). Pseudohypertriglyceridemia: Two cases of probable glycerol kinase deficiency. Journal of clinical lipidology, 6(5), 469-473.
## External links[edit]
Classification
D
* ICD-10: E74.8
* OMIM: 307030
* MeSH: C538138
* DiseasesDB: 29827
* Hyperglycerolemia at Online Mendelian Inheritance in Man
*[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
| Hyperglycerolemia | c0574108 | 1,470 | wikipedia | https://en.wikipedia.org/wiki/Hyperglycerolemia | 2021-01-18T19:01:02 | {"gard": ["2807"], "mesh": ["C538138"], "orphanet": ["408"], "wikidata": ["Q17120992"]} |
Caffey disease is a bone disorder that most often occurs in babies. It is characterized by the excessive formation of new bone (hyperostosis) in the jaw, shoulder blades, collarbones, and shafts of long bones in the arms and legs. Affected bones may double or triple in width. In some cases, two bones that are next to each other may become fused. Caffey disease is caused by a mutation in the COL1A1 gene. It is inherited in an autosomal dominant pattern, but not all people who inherit the mutation develop signs and symptoms. This is due to incomplete penetrance.
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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
| Caffey disease | c0020497 | 1,471 | gard | https://rarediseases.info.nih.gov/diseases/1051/caffey-disease | 2021-01-18T18:01:40 | {"mesh": ["D006958"], "omim": ["114000"], "umls": ["C0020497"], "orphanet": ["1310"], "synonyms": ["Infantile cortical hyperostosis"]} |
A rare syndromic genetic deafness characterized by congenital hearing loss, atresia or stenosis of the external auditory canal, dilated internal auditory canal, malformation of the inner ear (incomplete separation of the cochlea basal turn from the fundus of the internal auditory canal), in combination with abnormal auricular shape and facial dysmorphism (including thick eyebrows, ptosis, broad nasal root, and telecanthus). Intelligence is normal and developmental delay is absent.
*[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
| X-linked external auditory canal atresia-dilated internal auditory canal-facial dysmorphism syndrome | None | 1,472 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=500188 | 2021-01-23T19:11:51 | {"omim": ["301018"]} |
Restrictive cardiomyopathy
Other namesObliterative cardiomyopathy, infiltrative cardiomyopathy, constrictive cardiomyopathy[1]
Micrograph of cardiac amyloidosis, a cause of restrictive cardiomyopathy. Congo red stain.
SpecialtyCardiology
Restrictive cardiomyopathy (RCM) is a form of cardiomyopathy in which the walls of the heart are rigid (but not thickened).[2][3] Thus the heart is restricted from stretching and filling with blood properly. It is the least common of the three original subtypes of cardiomyopathy: hypertrophic, dilated, and restrictive.[1]
It should not be confused with constrictive pericarditis, a disease which presents similarly but is very different in treatment and prognosis.[1]
## Contents
* 1 Signs and symptoms
* 2 Causes
* 3 Mechanism
* 4 Diagnosis
* 5 Treatment
* 6 Epidemiology
* 7 References
* 8 External links
## Signs and symptoms[edit]
Untreated hearts with RCM often develop the following characteristics:[citation needed]
* M or W configuration in an invasive hemodynamic pressure tracing of the RA
* Square root sign of part of the invasive hemodynamic pressure tracing Of The LV
* Biatrial enlargement
* Thickened LV walls (with normal chamber size)
* Thickened RV free wall (with normal chamber size)
* Elevated right atrial pressure (>12mmHg),
* Moderate pulmonary hypertension,
* Normal systolic function,
* Poor diastolic function, typically Grade III - IV Diastolic heart failure.
Those afflicted with RCM will experience decreased exercise tolerance, fatigue, jugular venous distention, peripheral edema, and ascites.[3] Arrhythmias and conduction blocks are common.
## Causes[edit]
RCM can be caused by genetic or non-genetic factors.[4][5][6] Thus it is possible to divide the causes into primary and secondary.[7] The common modern organization is into Infiltrative, storage diseases, non-infiltrative, and endomyocardial etiologies:[8]
* Infiltrative
* Amyloidosis
* Sarcoidosis
* Primary hyperoxaluria
* Storage diseases
* Fabry disease
* Gaucher disease
* Hereditary hemochromatosis
* Glycogen storage disease
* Mucopolysaccharidosis type I (Hurler syndrome)
* Mucopolysaccharidosis type II (Hunter syndrome)
* Niemann-Pick disease
* Non-infiltrative
* Idiopathic
* Diabetic cardiomyopathy
* Scleroderma
* Myofibrillar myopathies
* Pseudoxanthoma elasticum
* Sarcomeric protein disorders
* Werner's syndrome
* Endomyocardial
* Carcinoid heart disease
* Endomyocardial fibrosis
* Idiopathic
* Hypereosinophilic syndrome
* Chronic eosinophilic leukemia
* Drugs (serotonin, methysergide, ergotamine, mercurial agents, busulfan)
* Endocardial fibroelastosis
* Consequence of cancer or cancer therapy
* Metastatic cancer
* Drugs (anthracyclines)
* Radiation
The most common cause of restrictive cardiomyopathy is amyloidosis.[3]
## Mechanism[edit]
Rhythmicity and contractility of the heart may be normal, but the stiff walls of the heart chambers (atria and ventricles) keep them from adequately filling, reducing preload and end-diastolic volume. Thus, blood flow is reduced, and blood volume that would normally enter the heart is backed up in the circulatory system. In time, restrictive cardiomyopathy patients develop diastolic dysfunction and eventually heart failure.
## Diagnosis[edit]
Diagnosis is typically made via echocardiography. Patients will demonstrate normal systolic function, diastolic dysfunction, and a restrictive filling pattern.[8] 2-dimensional and Doppler studies are necessary to distinguish RCM from constrictive pericarditis. Cardiac MRI and transvenous endomyocardial biopsy may also be necessary in some cases.[3][8] Reduced QRS voltage on EKG may be an indicator of amyloidosis-induced restrictive cardiomyopathy.[8]
## Treatment[edit]
Treatment of restrictive cardiomyopathy should focus on management of causative conditions (for example, using corticosteroids if the cause is sarcoidosis), and slowing the progression of cardiomyopathy.[8] Salt-restriction, diuretics, angiotensin-converting enzyme inhibitors, and anticoagulation may be indicated for managing restrictive cardiomyopathy.[9]
Calcium channel blockers are generally contraindicated due to their negative inotropic effect, particularly in cardiomyopathy caused by amyloidosis.[10][11] Digoxin, calcium channel blocking drugs and beta-adrenergic blocking agents provide little benefit, except in the subgroup of restrictive cardiomyopathy with atrial fibrillation.[12] Vasodilators are also typically ineffective because systolic function is usually preserved in cases of RCM.[3]
Heart failure resulting from restrictive cardiomyopathy will usually eventually have to be treated by cardiac transplantation or left ventricular assist device.[9]
## Epidemiology[edit]
Endomyocardial fibrosis is generally limited to the tropics and sub-saharan Africa.[8] The highest incidence of death caused by cardiac sarcoidosis is found in Japan.[13]
## References[edit]
1. ^ a b c Hancock, EW (September 2001). "Differential diagnosis of restrictive cardiomyopathy and constrictive pericarditis". Heart. 86 (3): 343–9. doi:10.1136/heart.86.3.343 (inactive 2021-01-15). PMC 1729880. PMID 11514495.CS1 maint: DOI inactive as of January 2021 (link)
2. ^ "restrictive cardiomyopathy" at Dorland's Medical Dictionary
3. ^ a b c d e Pathophysiology of heart disease : a collaborative project of medical students and faculty. Lilly, Leonard S., Harvard Medical School. (5th ed.). Baltimore, MD: Wolters Kluwer/Lippincott Williams & Wilkins. 2011. ISBN 978-1605477237. OCLC 649701807.CS1 maint: others (link)
4. ^ Brodehl, Andreas; Ferrier, Raechel A.; Hamilton, Sara J.; Greenway, Steven C.; Brundler, Marie-Anne; Yu, Weiming; Gibson, William T.; McKinnon, Margaret L.; McGillivray, Barbara (March 2016). "Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy". Human Mutation. 37 (3): 269–279. doi:10.1002/humu.22942. ISSN 1098-1004. PMID 26666891. S2CID 35455240.
5. ^ Brodehl, Andreas; Gaertner-Rommel, Anna; Klauke, Bärbel; Grewe, Simon Andre; Schirmer, Ilona; Peterschröder, Andreas; Faber, Lothar; Vorgerd, Matthias; Gummert, Jan (2017). "The novel αB-crystallin (CRYAB) mutation p.D109G causes restrictive cardiomyopathy". Human Mutation. 38 (8): 947–952. doi:10.1002/humu.23248. ISSN 1098-1004. PMID 28493373. S2CID 13942559.
6. ^ Brodehl, Andreas; Pour Hakimi, Seyed Ahmad; Stanasiuk, Caroline; Ratnavadivel, Sandra; Hendig, Doris; Gaertner, Anna; Gerull, Brenda; Gummert, Jan; Paluszkiewicz, Lech; Milting, Hendrik (2019-11-11). "Restrictive Cardiomyopathy is Caused by a Novel Homozygous Desmin (DES) Mutation p.Y122H Leading to a Severe Filament Assembly Defect". Genes. 10 (11): 918. doi:10.3390/genes10110918. ISSN 2073-4425. PMC 6896098. PMID 31718026.
7. ^ Crawford, Michael H. (2003). Current diagnosis & treatment in cardiology. New York: Lange Medical Books/McGraw-Hill. pp. 188. ISBN 978-0-8385-1473-3.
8. ^ a b c d e f Muchtar, Eli; Blauwet, Lori A.; Gertz, Morie A. (2017-09-15). "Restrictive Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy". Circulation Research. 121 (7): 819–837. doi:10.1161/CIRCRESAHA.117.310982. ISSN 0009-7330. PMID 28912185.
9. ^ a b "Restrictive Cardiomyopathy Treatment & Management". 2014-12-18. Retrieved 2015-06-10. Cite journal requires `|journal=` (help)
10. ^ Pollak, A; Falk, R H (1993-08-01). "Left ventricular systolic dysfunction precipitated by verapamil in cardiac amyloidosis". Chest. 104 (2): 618–620. doi:10.1378/chest.104.2.618. ISSN 0012-3692. PMID 8339658.
11. ^ Gertz, Morie A.; Falk, Rodney H.; Skinner, Martha; Cohen, Alan S.; Kyle, Robert A. (1985-06-01). "Worsening of congestive heart failure in amyloid heart disease treated by calcium channel-blocking agents". American Journal of Cardiology. 55 (13): 1645. doi:10.1016/0002-9149(85)90995-6. ISSN 0002-9149. PMID 4003314.
12. ^ Artz, Gregory; Wynne, Joshua (October 2000). "Restrictive Cardiomyopathy". Current Treatment Options in Cardiovascular Medicine. 2 (5): 431–438. doi:10.1007/s11936-000-0038-6. ISSN 1092-8464. PMID 11096547. S2CID 45162583.
13. ^ Hulten, Edward; Aslam, Saira; Osborne, Michael; Abbasi, Siddique; Bittencourt, Marcio Sommer; Blankstein, Ron (February 2016). "Cardiac sarcoidosis—state of the art review". Cardiovascular Diagnosis and Therapy. 6 (1): 50–63. doi:10.3978/j.issn.2223-3652.2015.12.13. ISSN 2223-3652. PMC 4731586. PMID 26885492.
## External links[edit]
Classification
D
* ICD-10: I42.5
* ICD-9-CM: 425.4
* MeSH: D002313
* DiseasesDB: 11390
External resources
* MedlinePlus: 000189
* eMedicine: med/291
* Overview at Merck Manual
* v
* t
* e
Cardiovascular disease (heart)
Ischaemic
Coronary disease
* Coronary artery disease (CAD)
* Coronary artery aneurysm
* Spontaneous coronary artery dissection (SCAD)
* Coronary thrombosis
* Coronary vasospasm
* Myocardial bridge
Active ischemia
* Angina pectoris
* Prinzmetal's angina
* Stable angina
* Acute coronary syndrome
* Myocardial infarction
* Unstable angina
Sequelae
* hours
* Hibernating myocardium
* Myocardial stunning
* days
* Myocardial rupture
* weeks
* Aneurysm of heart / Ventricular aneurysm
* Dressler syndrome
Layers
Pericardium
* Pericarditis
* Acute
* Chronic / Constrictive
* Pericardial effusion
* Cardiac tamponade
* Hemopericardium
Myocardium
* Myocarditis
* Chagas disease
* Cardiomyopathy
* Dilated
* Alcoholic
* Hypertrophic
* Tachycardia-induced
* Restrictive
* Loeffler endocarditis
* Cardiac amyloidosis
* Endocardial fibroelastosis
* Arrhythmogenic right ventricular dysplasia
Endocardium /
valves
Endocarditis
* infective endocarditis
* Subacute bacterial endocarditis
* non-infective endocarditis
* Libman–Sacks endocarditis
* Nonbacterial thrombotic endocarditis
Valves
* mitral
* regurgitation
* prolapse
* stenosis
* aortic
* stenosis
* insufficiency
* tricuspid
* stenosis
* insufficiency
* pulmonary
* stenosis
* insufficiency
Conduction /
arrhythmia
Bradycardia
* Sinus bradycardia
* Sick sinus syndrome
* Heart block: Sinoatrial
* AV
* 1°
* 2°
* 3°
* Intraventricular
* Bundle branch block
* Right
* Left
* Left anterior fascicle
* Left posterior fascicle
* Bifascicular
* Trifascicular
* Adams–Stokes syndrome
Tachycardia
(paroxysmal and sinus)
Supraventricular
* Atrial
* Multifocal
* Junctional
* AV nodal reentrant
* Junctional ectopic
Ventricular
* Accelerated idioventricular rhythm
* Catecholaminergic polymorphic
* Torsades de pointes
Premature contraction
* Atrial
* Junctional
* Ventricular
Pre-excitation syndrome
* Lown–Ganong–Levine
* Wolff–Parkinson–White
Flutter / fibrillation
* Atrial flutter
* Ventricular flutter
* Atrial fibrillation
* Familial
* Ventricular fibrillation
Pacemaker
* Ectopic pacemaker / Ectopic beat
* Multifocal atrial tachycardia
* Pacemaker syndrome
* Parasystole
* Wandering atrial pacemaker
Long QT syndrome
* Andersen–Tawil
* Jervell and Lange-Nielsen
* Romano–Ward
Cardiac arrest
* Sudden cardiac death
* Asystole
* Pulseless electrical activity
* Sinoatrial arrest
Other / ungrouped
* hexaxial reference system
* Right axis deviation
* Left axis deviation
* QT
* Short QT syndrome
* T
* T wave alternans
* ST
* Osborn wave
* ST elevation
* ST depression
* Strain pattern
Cardiomegaly
* Ventricular hypertrophy
* Left
* Right / Cor pulmonale
* Atrial enlargement
* Left
* Right
* Athletic heart syndrome
Other
* Cardiac fibrosis
* Heart failure
* Diastolic heart failure
* Cardiac asthma
* Rheumatic fever
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Restrictive cardiomyopathy | c0007196 | 1,473 | wikipedia | https://en.wikipedia.org/wiki/Restrictive_cardiomyopathy | 2021-01-18T18:44:27 | {"mesh": ["D002313"], "umls": ["C0007196"], "icd-9": ["425.4"], "orphanet": ["75249", "217632"], "wikidata": ["Q2151267"]} |
## Description
The hairy ears trait consists of long hairs growing from the helix of the pinna; see Dronamraju (1964) and Stern et al. (1964).
Clinical Features
Stern and Tokunaga (1965) collected data on 261 adult Japanese males, aged 20 to 91 years, living in Japan or in California. Only a single man had hairy ear rims. This low frequency stood in contrast to a high frequency of hairs in the meatus of the ear.
Population Genetics
Abbie (1965) found hairy pinnae in 37 of 189 adult full-Aboriginal Australian males, giving an overall incidence of 19.6% but with much regional variation, from 5.3 to 34.3%. Hairy pinnae were more common in western and southwestern Aborigines than in those of the north and northeast.
Inheritance
Controversy has prevailed as to whether hairy ears is Y-linked (see 425500) or autosomal, or perhaps both (in different families).
Among 500 individuals screened in an outpatient dermatology clinic in Madras, India, Kamalam and Thambiah (1990) found that 83 adult males (16.6%) and 2 adult females (0.4%) had hairy ears. Family study in 5 probands (3 males and 2 females) suggested an autosomal dominant sex-limited inheritance of this entity.
History
A probably unrelated 'hairy ears' (Eh) mutation originated in the mouse in a neutron irradiation experiment at Oak Ridge National Laboratory (Davisson et al., 1990). Subsequent linkage studies with Eh and other loci on mouse chromosome 15 suggested that it is associated with a chromosomal rearrangement that inhibits recombination.
INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Long hairs growing from helix of pinna ▲ 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
| HAIRY EARS | c0263482 | 1,474 | omim | https://www.omim.org/entry/139500 | 2019-09-22T16:40:27 | {"mesh": ["C562484"], "omim": ["139500"], "synonyms": ["Alternative titles", "HYPERTRICHOSIS PINNAE AURIS"]} |
A number sign (#) is used with this entry because benign familial neonatal seizures-2 (BFNS2) is caused by heterozygous mutation in the KCNQ3 gene (602232) on chromosome 8q24.
Description
Benign familial neonatal seizures-2 is an autosomal dominant neurologic condition characterized by onset of clonic or tonic-clonic seizures in the first few days of life. Seizures tend to last for about a minute, may occur several times a day, and are responsive to medication. Almost all patients have full remission within the first months of life, although some rare patients may have a few seizures later in childhood. EEG, brain imaging, and psychomotor development are usually normal (summary by Fister et al., 2013).
For a general phenotypic description and a discussion of genetic heterogeneity of benign familial neonatal seizures, see BFNS1 (121200).
Clinical Features
Ryan et al. (1991) reported a large 3-generation family of Mexican American origin in which 14 individuals had benign neonatal epilepsy manifest as clonic seizures. All affected individuals had onset of seizures between the second and fourteenth day of life, and none had seizures after 2 months of age. EEG and brain imaging were normal, and all patients showed normal intellectual development.
Hirose et al. (2000) reported a Japanese family in which several members had onset of clonic or tonic-clonic seizures in the first week of life. Seizures disappeared by 2 weeks of life in all affected individuals except 2: these 2 patients had complex partial seizures with occasional secondary generalization at ages 6 months and 3 years, respectively. None of the patients showed intellectual delay.
Li et al. (2008) reported a 3-generation Chinese family in which 7 individuals had benign neonatal seizures. Affected individuals developed afebrile seizures between 2 and 3 days after birth, followed by remission during 1 month without recurrence. Most patients had partial clonic seizures that lasted from 30 seconds to 1 minute and occurred from 1 to 10 times a day. One patient had paroxysmal squeals. EEG and brain imaging were normal in all patients studied.
Fister et al. (2013) reported a mother and daughter of Slovenian descent with BFNS2. The patients developed focal clonic seizures on the third and fifth days of life, respectively. The seizures in the daughter lasted from thirty seconds to 2 minutes. At age 2.5 years, she was seizure-free and developing normally. The mother had recurrence of seizures at age 3 weeks, but thereafter was seizure-free and had normal development. The seizures in both patients were responsive to phenobarbital.
Inheritance
The transmission pattern of benign neonatal seizures in the families reported by Ryan et al. (1991), Hirose et al. (2000), and Li et al. (2008) was consistent with autosomal dominant inheritance.
Mapping
Using dinucleotide repeat markers distributed throughout the genome to analyze an affected family reported by Ryan et al. (1991), Lewis et al. (1993) demonstrated linkage of benign neonatal epilepsy to markers D8S284 and D8S256 on chromosome 8q (maximum pairwise lod score of 4.43). Multipoint analysis placed the BFNS2 locus in the interval spanned by D8S198-D8S274. The kindred was of Mexican American ancestry.
Molecular Genetics
In an affected member of the large BFNC family previously reported by Ryan et al. (1991) and Lewis et al. (1993), Charlier et al. (1998) identified a mutation in the KCNQ3 gene (G263V; 602232.0001) that cosegregated with the BFNC phenotype.
In affected members of a Japanese family with BFNS2, Hirose et al. (2000) identified a heterozygous missense mutation in the KCNQ3 gene (W309R; 602232.0002).
In affected members of a Chinese family with benign neonatal seizures, Li et al. (2008) identified a heterozygous mutation in the KCNQ3 gene (R330C; 602232.0003). The mutation, which was found by linkage analysis followed by candidate gene sequencing, segregated with the disorder in the family. Fister et al. (2013) identified a heterozygous R330C mutation in the KCNQ3 gene in a Slovenian mother and daughter with benign neonatal seizures-2.
INHERITANCE \- Autosomal dominant NEUROLOGIC Central Nervous System \- Seizures, afebrile \- Focal clonic seizures \- Generalized tonic-clonic seizures \- Increased risk of seizures in childhood or adulthood (11-16%) \- Normal psychomotor development MISCELLANEOUS \- Onset of seizures at 2-8 days of life \- Most remit by 2 months MOLECULAR BASIS \- Caused by mutation in the potassium voltage-gated channel, KQT-like subfamily, member 3 gene (KCNQ3, 602232.0001 ) ▲ 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
| SEIZURES, BENIGN FAMILIAL NEONATAL, 2 | c0220669 | 1,475 | omim | https://www.omim.org/entry/121201 | 2019-09-22T16:42:56 | {"doid": ["14264"], "mesh": ["D020936"], "omim": ["121201"], "orphanet": ["1949"], "synonyms": ["Alternative titles", "CONVULSIONS, BENIGN FAMILIAL NEONATAL, 2"], "genereviews": ["NBK201978"]} |
GM1 gangliosidosis is an inherited lysosomal storage disorder that progressively destroys nerve cells (neurons) in the brain and spinal cord. The condition may be classified into three major types based on the general age that signs and symptoms first appear: classic infantile (type 1); juvenile (type 2); and adult onset or chronic (type 3). Although the types differ in severity, their features may overlap significantly. GM1 gangliosidosis is caused by mutations in the GLB1 gene and is inherited in an autosomal recessive manner. Treatment is currently symptomatic and supportive.
*[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
| GM1 gangliosidosis | c0085131 | 1,476 | gard | https://rarediseases.info.nih.gov/diseases/10891/gm1-gangliosidosis | 2021-01-18T18:00:16 | {"mesh": ["D016537"], "orphanet": ["354"], "synonyms": ["Beta galactosidase 1 deficiency", "GLB 1 deficiency", "Beta-galactosidosis"]} |
Heckenlively and Weleber (1986) described 2 families with a 'new' form of X-linked cone dystrophy characterized by a peculiar greenish-golden tapetal-like sheen of large areas of the retina; onset of symptoms in the third decade; gradual loss of vision with development of macular lesions in older patients; defective color vision; elevated cone thresholds on dark adaptometry; and abnormalities of the cone-mediated electroretinogram. One patient developed rhegmatogenous retinal detachment in one eye. Although the disorder was different from Oguchi disease (258100) in clinical features and mode of inheritance, the patients showed the Mizuo-Nakamura phenomenon as in Oguchi disease: fading of the retinal sheen with clearer revealing of choroidal structures, on dark adaptation.
Eyes \- Cone dystrophy \- Greenish-golden tapetal-like retinal sheen \- Defective color vision \- Gradual visual loss \- Late macular lesions \- Retinal detachment Misc \- Onset in third decade Lab \- Elevated cone thresholds on dark adaptometry \- Abnormal cone-mediated electroretinogram \- Fading of retinal sheen with clearer choroidal structures on dark adaptation Inheritance \- ? X-linked ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| CONE DYSTROPHY, X-LINKED, WITH TAPETAL-LIKE SHEEN | c0271092 | 1,477 | omim | https://www.omim.org/entry/304030 | 2019-09-22T16:18:28 | {"omim": ["304030"], "orphanet": ["1871"]} |
A number sign (#) is used with this entry because Joubert syndrome-17 (JBTS17) is caused by compound heterozygous mutation in the C5ORF42 gene (CPLANE1; 614571) on chromosome 5p13.
Mutation in the C5ORF42 gene can also cause orofaciodigital syndrome VI (OFD6; 277170), a disorder with overlapping features.
For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300.
Clinical Features
Joubert et al. (1969) described 4 French Canadian sibs, born of distantly related parents, with a severe neurologic disorder characterized by episodic hyperpnea, abnormal eye movements, ataxia, and global psychomotor retardation. Partial or complete agenesis of the cerebellar vermis was demonstrated by autopsy or pneumoencephalogram. One patient also had an occipital meningomyelocele. The oldest living sib was 8 years old.
Srour et al. (2012) reported 10 patients from 7 French Canadian families with Joubert syndrome. Two sibs were part of the original family described by Joubert et al. (1969). All patients showed global developmental delay, with the onset of independent walking between 30 months and 8 years of age. Cognitive impairment was present in all individuals but was variable, ranging from borderline intelligence to mild intellectual disability. Most also showed oculomotor apraxia and breathing abnormalities, mainly episodic hyperventilation. Two individuals had limb abnormalities; 1 had preaxial and postaxial polydactyly, and another had syndactyly of the third and fourth fingers on 1 hand. Brain MRI showed the molar tooth sign in all patients examined. None had evidence of retinal or kidney involvement.
In a comprehensive study of 279 patients from 232 unrelated families with Joubert syndrome in whom a genetic basis was determined by molecular analysis of 27 candidate genes, Bachmann-Gagescu et al. (2015) found a significant association between mutations in the C5ORF42 gene and polydactyly (odds ratio (OR) of 2.7).
Molecular Genetics
In affected individuals from 7 French Canadian families with Joubert syndrome-17, Srour et al. (2012) identified 6 different potentially pathogenic mutations in the C5ORF42 gene (614571.0001-614571.0006). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Three of the mutations were found in multiple families, and haplotype analysis showed that each was linked to a distinct haplotype. The higher frequency of these mutations in the Lower St. Lawrence region might be explained by a founder effect with the coincidental occurrence of the 3 mutations in the same group of settlers, or by multiple regional founder effects corresponding to sequential pioneer fronts.
Animal Model
Using fetal ultrasound biomicroscopy, Damerla et al. (2015) screened N-ethylnitrosourea-generated mouse mutants for congenital heart disease and identified 'heart under glass' (hug) mutant mice with agenesis of the rib cage. Hug mutants had multiple developmental defects that caused prenatal mortality, including skeletal dysplasia, craniofacial defects, polydactyly, cystic kidneys, and cerebellar hypoplasia. Hug mutants and cultured fibroblasts showed perturbed hedgehog signaling (see SHH, 600725). However, hug cochlea had normal stereocilia and kinocilia, and hug neural tube had normal dorsoventral patterning. Damerla et al. (2015) identified the hug mutation as a homozygous 757T-C transition in the C5orf42 gene that results in a ser253-to-phe (S253F) substitution in a highly conserved residue in the Jbts17 protein.
INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Oculomotor apraxia RESPIRATORY \- Hyperventilation, episodic \- Abnormal breathing pattern SKELETAL Hands \- Polydactyly (in some) \- Syndactyly (in some) Feet \- Polydactyly (in some) NEUROLOGIC Central Nervous System \- Global developmental delay \- Ataxia \- Molar tooth sign \- Cerebellar vermis hypoplasia \- Cerebellar vermis agenesis MISCELLANEOUS \- Reported in individuals of French Canadian origin MOLECULAR BASIS \- Caused by mutation in the chromosome 5 open reading frame 42 gene (C5ORF42, 614571.0001 ) ▲ 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
| JOUBERT SYNDROME 17 | c3553264 | 1,478 | omim | https://www.omim.org/entry/614615 | 2019-09-22T15:54:41 | {"doid": ["0110986"], "omim": ["614615", "213300"], "orphanet": ["475"], "synonyms": ["CPD IV", "Cerebelloparenchymal disorder IV", "Classic Joubert syndrome", "Joubert syndrome type A", "Joubert-Boltshauser syndrome", "Pure Joubert syndrome"], "genereviews": ["NBK1325"]} |
## Clinical Features
Cramer (1947) and Ribble (1931) observed affected sisters, and Warr (1938) described parental consanguinity. The primary dentition was not affected and no associated abnormalities were noted.
Gorlin (1979) knew of at least 8 reports of complete absence of the permanent dentition with the entire primary dentition present and erupted at a normal time. Gorlin (1979) and Gorlin et al. (1980) presented evidence of autosomal recessive inheritance, including multiple affected sibs and consanguineous parents.
On the basis of 2 families in which both parents had pegged or missing maxillary lateral incisors (150400), Witkop (1987) concluded that agenesis of the permanent teeth can be an expression of the homozygous state of the mutated gene. In the patients that he observed, the permanent molar teeth were present.
Hoo (2000) reported a family with 2 sibs with anodontia of permanent teeth. Both parents had normal dentition, but the paternal grandmother, her twin sister, and a paternal aunt all had only 2 maxillary incisors, and the maternal grandmother had only 2 mandibular incisors. The author concluded that this family provides further evidence for the hypothesis of Witkop (1987) that anodontia of permanent teeth is a homozygous state of the gene responsible for pegged or missing maxillary lateral incisors.
Molecular Genetics
In patients with a recessive form of ectodermal dysplasia (OODD; 257980) caused by mutation in the WNT10A gene (606268), Bohring et al. (2009) observed a pattern of tooth anomalies comparable to that seen in patients with anodontia of permanent dentition and selective tooth agenesis-4 (150400).
History
Based on a description by Plutarch, Bartsocas (1980) suggested that Pyrrhus (c.318-272 B.C.), King of Epirus, had this disorder. Furthermore, he concluded that there were no other 'cases' in the family (which included Alexander the Great), thus supporting autosomal recessive inheritance.
Inheritance \- Autosomal recessive Teeth \- Anodontia, permanent dentition \- Primary dentition unaffected \- Pegged or missing maxillary lateral incisors in heterozygotes ▲ 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
| ANODONTIA OF PERMANENT DENTITION | c0399352 | 1,479 | omim | https://www.omim.org/entry/206780 | 2019-09-22T16:30:56 | {"doid": ["13714"], "mesh": ["D000848"], "omim": ["206780"], "orphanet": ["99797"], "synonyms": ["Alternative titles", "TEETH, PERMANENT, ABSENCE OF"]} |
Neurologically-based disability beginning before adulthood
For disabilities caused by mental disorders, see Mental disorder § Disability.
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Find sources: "Developmental disability" – news · newspapers · books · scholar · JSTOR (November 2014) (Learn how and when to remove this template message)
Developmental Disability
SpecialtyPsychiatry, Clinical psychology
Developmental disability is a diverse group of chronic conditions that are due to mental or physical impairments that arise before adulthood. Developmental disabilities cause individuals living with them many difficulties in certain areas of life, especially in "language, mobility, learning, self-help, and independent living".[1] Developmental disabilities can be detected early on and persist throughout an individual's lifespan. Developmental disability that affects all areas of a child's development is sometimes referred to as global developmental delay.
The most common developmental disabilities are:
* Down syndrome is a condition in which people are born with an extra copy of chromosome 21. Normally, a person is born with two copies of chromosome 21. However, if they are born with Down syndrome, they have an extra copy of this chromosome. This extra copy affects the development of the body and brain, causing physical and mental challenges for the individual.
* Fragile X syndrome (FXS) is thought to cause autism and intellectual disability, usually among boys.
* Pervasive developmental disorders (PDD) are a group of developmental disabilities that can cause significant social, communication and behavioral challenges.
* Fetal alcohol spectrum disorders (FASD) are a group of conditions that can occur in a person whose mother drank alcohol during pregnancy.
* Cerebral palsy (CP) is a group of disorders that affect a person’s ability to move and maintain balance and posture. CP is the most common motor disability in childhood.[1]
* Intellectual disability, also (sometimes proscriptively) known as mental retardation, is defined as an IQ below 70 along with limitations in adaptive functioning and onset before the age of 18 years.[2]
* Attention Deficit Hyperactivity Disorder or simply known as ADHD is a neurodevelopmental disorder characterized by executive dysfunction. Primarily in attention span, cognition, self-control, and emotional regulation.
## Contents
* 1 Causes
* 2 Diagnosis and quantification
* 3 Associated issues
* 3.1 Physical health issues
* 3.2 Mental health issues (dual diagnoses)
* 3.3 Abuse and vulnerability
* 3.4 Challenging behavior
* 4 Societal attitudes
* 5 Services and support
* 5.1 Education and training
* 5.2 At-home and community support
* 5.3 Residential accommodation
* 5.4 Employment support
* 5.5 Day services
* 5.6 Advocacy
* 5.7 Other types of support
* 6 See also
* 7 References
* 8 Further reading
* 9 External links
## Causes[edit]
The causes of developmental disabilities are varied and remain unknown in a large proportion of cases. Even in cases of known etiology the line between "cause" and "effect" is not always clear, leading to difficulty in categorizing causes.[3]
Genetic factors have long been implicated in the causation of developmental disabilities. There is also a large environmental component to these conditions, and the relative contributions of nature versus nurture have been debated for decades.[4]
Preterm birth is known to be a predictor for potential developmental disabilities later in childhood, which further complicates the question of nature versus nurture, as
> premature birth could already have resulted from earlier and longer existing difficulties. Second, being born at such an immature gestation could immediately have damaged the main organs (lungs and brain) or, third, such damage could arise in the neonatal period, for instance from the necessary intrusive treatment. Furthermore, exhaustion resulting from adaptation or stress could damage or disturb development. In addition, the highly stimulating hospital environment and the lack of social interactive experiences with the mother or the abundant interaction with others could add to the risk. In short, many reasons are conceivable that by itself or in different combinations could result in developmental problems of very preterm children
[5]
Current theories on causation focus on genetic factors, and over 1,000 known genetic conditions include developmental disabilities as a symptom.[6]
Developmental disabilities affect between 1 and 2% of the population in most western countries, although many government sources acknowledge that statistics are flawed in this area.[7] The worldwide proportion of people with developmental disabilities is believed to be approximately 1.4%.[8] It is twice as common in males as in females, and some researchers have found that the prevalence of mild developmental disabilities is likely to be higher in areas of poverty and deprivation, and among people of certain ethnicities.[9]
## Diagnosis and quantification[edit]
Developmental disabilities can be initially suspected when a child does not reach expected child development stages. Subsequently, a differential diagnosis may be used to diagnose an underlying disease, which may include a physical examination and genetic tests.
The degree of disability can be quantified by assigning a developmental age to a person, which is age of the group into which test scores place the person. This, in turn, can be used to calculate a developmental quotient (DQ) as follows:[10][11]
D Q = D e v e l o p m e n t a l a g e C h r o n o l o g i c a l a g e ∗ 100 {\displaystyle DQ={\frac {Developmental\ age}{Chronological\ age}}*100}
## Associated issues[edit]
### Physical health issues[edit]
There are many physical health factors associated with developmental disabilities. For some specific syndromes and diagnoses, these are inherent, such as poor heart function in people with Down syndrome. People with severe communication difficulties find it difficult to articulate their health needs, and without adequate support and education might not recognize ill health. Epilepsy, sensory problems (such as poor vision and hearing), obesity and poor dental health are over-represented in this population.[12] Life expectancy among people with developmental disabilities as a group is estimated at 20 years below average, although this is improving with advancements in adaptive and medical technologies, and as people are leading healthier, more fulfilling lives,[13] and some conditions (such as Freeman–Sheldon syndrome) do not impact life expectancy.
### Mental health issues (dual diagnoses)[edit]
Mental health issues, and psychiatric illnesses, are more likely to occur in people with developmental disabilities than in the general population. A number of factors are attributed to the high incidence rate of dual diagnoses:
* The high likelihood of encountering traumatic events throughout their lifetime (such as abandonment by loved ones, abuse, bullying and harassment)[14]
* The social and developmental restrictions placed upon people with developmental disabilities (such as lack of education, poverty, limited employment opportunities, limited opportunities for fulfilling relationships, boredom)
* Biological factors (such as brain injury, epilepsy, illicit and prescribed drug and alcohol misuse)[15]
* Developmental factors (such as lack of understanding of social norms and appropriate behavior, inability of those around to allow/understand expressions of grief and other human emotions)
* External monitoring factor: all federal- or state-funded residences are required to have some form of behavioral monitoring for each person with developmental disability at the residence. With this information psychological diagnoses are more easily given than with the general population that has less consistent monitoring.
* Access to health care providers: in the United States, all federal- or state-funded residences require the residents to have annual visits to various health care providers. With consistent visits to health care providers more people with developmental disabilities are likely to receive appropriate treatment than the general population that is not required to visit various health care providers.
These problems are exacerbated by difficulties in diagnosis of mental health issues, and in appropriate treatment and medication, as for physical health issues.[16][17]
### Abuse and vulnerability[edit]
Abuse is a significant issue for people with developmental disabilities, and as a group they are regarded as vulnerable people in most jurisdictions. Common types of abuse include:
* Physical abuse (withholding food, hitting, punching, pushing, etc.)
* Neglect (withholding help when required, e.g., assistance with personal hygiene)
* Sexual abuse is associated with psychological disturbance. Sequeira, Howlin & Hollins found that sexual abuse was associated with increased rates of mental illness and behavioural problems, including symptoms of post-traumatic stress. Psychological reactions to abuse were similar to those observed in the general population, but with the addition of stereotypical behaviour. The more serious the abuse, the more severe the symptoms that were reported.[18][19]
* Psychological or emotional abuse (verbal abuse, shaming and belittling)
* Constraint and restrictive practices (turning off an electric wheelchair so a person cannot move)
* Financial abuse (charging unnecessary fees, holding onto pensions, wages, etc.)
* Legal or civil abuse (restricted access to services)
* Systemic abuse (denied access to an appropriate service due to perceived support needs)
* Passive neglect (a caregiver's failure to provide adequate food, shelter)
Lack of education, lack of self-esteem and self-advocacy skills, lack of understanding of social norms and appropriate behavior and communication difficulties are strong contributing factors to the high incidence of abuse among this population.
In addition to abuse from people in positions of power, peer abuse is recognized as a significant, if misunderstood, problem. Rates of criminal offense among people with developmental disabilities are also disproportionately high, and it is widely acknowledged that criminal justice systems throughout the world are ill-equipped for the needs of people with developmental disabilities—as both perpetrators and victims of crime.[20][21][22] Failings in care have been identified in one in eight deaths of people with learning difficulties under NHS England.[23]
### Challenging behavior[edit]
Main article: Challenging behaviour
Some people with developmental disabilities (particularly Autism) exhibit challenging behavior, defined as "culturally abnormal behaviour(s) of such intensity, frequency or duration that the physical safety of the person or others is placed in serious jeopardy, or behaviour which is likely to seriously limit or deny access to the use of ordinary community facilities".[24] Common types of challenging behavior include self-injurious behavior (such as hitting, headbutting, biting), aggressive behavior (such as hitting others, shouting, screaming, spitting, kicking, swearing, hairpulling), inappropriate sexualized behavior (such as public masturbation or groping), behavior directed at property (such as throwing objects and stealing) and stereotyped behaviors (such as repetitive rocking, echolalia or elective incontinence). Such behaviors can be assessed to suggest areas of further improvement, using assessment tools such as the Nisonger Child Behavior Rating Form (NCBRF).
Challenging behavior in people with developmental disabilities may be caused by a number of factors, including biological (pain, medication, the need for sensory stimulation), social (boredom, seeking social interaction, the need for an element of control, lack of knowledge of community norms, insensitivity of staff and services to the person's wishes and needs), environmental (physical aspects such as noise and lighting, or gaining access to preferred objects or activities), psychological (feeling excluded, lonely, devalued, labelled, disempowered, living up to people's negative expectations) or simply a means of communication. A lot of the time, challenging behavior is learned and brings rewards and it is very often possible to teach people new behaviors to achieve the same aims. Challenging behavior in people with developmental disabilities can often be associated with specific mental health problems.[25]
Experience and research suggests that what professionals call "challenging behavior" is often a reaction to the challenging environments that those providing services create around people with developmental disabilities. "Challenging behavior" in this context is a method of communicating dissatisfaction with the failure of those providing services to focus on what kind of life makes most sense to the person, and is often the only recourse a developmentally disabled person has against unsatisfactory services or treatment and the lack of opportunities made available to the person. This is especially the case where the services deliver lifestyles and ways of working that are centered on what suits the service provider and its staff, rather than what best suits the person.
In general, behavioral interventions or what has been termed applied behavior analysis has been found to be effective in reducing specific challenging behavior.[26] Recently, efforts have been placed on developing a developmental pathway model in the behavior analysis literature to prevent challenging behavior from occurring.[27] This method is controversial according to the Autistic Self Advocacy Network, saying that this type of therapy can lead to the development of Post Traumatic Stress Disorder and worsening of symptoms later in life.[28]
## Societal attitudes[edit]
Throughout history, people with developmental disabilities have been viewed as incapable and incompetent in their capacity for decision-making and development. Until the Enlightenment in Europe, care and asylum was provided by families and the Church (in monasteries and other religious communities), focusing on the provision of basic physical needs such as food, shelter and clothing. Stereotypes such as the dimwitted village idiot, and potentially harmful characterizations (such as demonic possession for people with epilepsy) were prominent in social attitudes of the time.
Early in the twentieth century, the eugenics movement became popular throughout the world. This led to the forced sterilization and prohibition of marriage for the developmentally disabled in most of the developed world and was later used by Hitler as rationale for the mass murder of mentally challenged individuals during the Holocaust. The eugenics movement was later thought to be seriously flawed and in violation of human rights and the practice of forced sterilization and prohibition from marriage was discontinued by most of the developed world by the mid 20th century.
The movement towards individualism in the 18th and 19th centuries, and the opportunities afforded by the Industrial Revolution, led to housing and care using the asylum model. People were placed by, or removed from, their families (usually in infancy) and housed in large institutions (of up to 3,000 people, although some institutions were home to many more, such as the Philadelphia State Hospital in Pennsylvania which housed 7,000 people through the 1960s), many of which were self-sufficient through the labor of the residents. Some of these institutions provided a very basic level of education (such as differentiation between colors and basic word recognition and numeracy), but most continued to focus solely on the provision of basic needs. Conditions in such institutions varied widely, but the support provided was generally non-individualized, with aberrant behavior and low levels of economic productivity regarded as a burden to society. Heavy tranquilization and assembly line methods of support (such as "birdfeeding" and cattle herding)[clarification needed] were the norm, and the medical model of disability prevailed. Services were provided based on the relative ease to the provider, not based on the human needs of the individual.[citation needed]
Ignoring the prevailing attitude, Civitans adopted service to the developmentally disabled as a major organizational emphasis in 1952. Their earliest efforts included workshops for special education teachers and daycamps for disabled children, all at a time when such training and programs were almost nonexistent.[29] In the United States, the segregation of people with developmental disabilities wasn't widely questioned by academics or policy-makers until the 1969 publication of Wolf Wolfensberger's seminal work "The Origin and Nature of Our Institutional Models",[30] drawing on some of the ideas proposed by SG Howe 100 years earlier. This book posited that society characterizes people with disabilities as deviant, sub-human and burdens of charity, resulting in the adoption of that "deviant" role. Wolfensberger argued that this dehumanization, and the segregated institutions that result from it, ignored the potential productive contributions that all people can make to society. He pushed for a shift in policy and practice that recognized the human needs of "retardates" and provided the same basic human rights as for the rest of the population.
The publication of this book may be regarded as the first move towards the widespread adoption of the social model of disability in regard to these types of disabilities, and was the impetus for the development of government strategies for desegregation.[citation needed]Successful lawsuits against governments and an increasing awareness of human rights and self-advocacy also contributed to this process, resulting in the passing in the U.S. of the Civil Rights of Institutionalized Persons Act in 1980.
From the 1960s to the present, most U.S. states have moved towards the elimination of segregated institutions. Along with the work of Wolfensberger and others including Gunnar and Rosemary Dybwad,[31] a number of scandalous revelations around the horrific conditions within state institutions created public outrage that led to change to a more community-based method of providing services.[32] By the mid-1970s, most governments had committed to de-institutionalization, and had started preparing for the wholesale movement of people into the general community, in line with the principles of normalization. In most countries, this was essentially complete by the late 1990s, although the debate over whether or not to close institutions persists in some states, including Massachusetts.[32]
Individuals with developmental disabilities are not fully integrated into society.[citation needed] Person Centered Planning and Person Centered Approaches are seen as methods of addressing the continued labeling and exclusion of socially devalued people, such as people with a developmental disability label, encouraging a focus on the person as someone with capacities and gifts, as well as support needs.
## Services and support[edit]
Today, support services are provided by government agencies, non-governmental organizations and by private sector providers. Support services address most aspects of life for people with developmental disabilities, and are usually theoretically based in community inclusion, using concepts such as social role valorization and increased self-determination (using models such as Person Centred Planning).[33] Support services are funded through government block funding (paid directly to service providers by the government), through individualized funding packages (paid directly to the individual by the government, specifically for the purchase of services) or privately by the individual (although they may receive certain subsidies or discounts, paid by the government). There also are a number of non-profit agencies dedicated to enriching the lives of people living with developmental disabilities and erasing the barriers they have to being included in their community.[34]
### Education and training[edit]
See also: Special education
Education and training opportunities for people with developmental disabilities have expanded greatly in recent times, with many governments mandating universal access to educational facilities, and more students moving out of special schools and into mainstream classrooms with support.
Post-secondary education and vocational training is also increasing for people with these types of disabilities, although many programs offer only segregated "access" courses in areas such as literacy, numeracy and other basic skills. Legislation (such as the UK's Disability Discrimination Act 1995) requires educational institutions and training providers to make "reasonable adjustments" to curriculum and teaching methods in order to accommodate the learning needs of students with disabilities, wherever possible. There are also some vocational training centers that cater specifically to people with disabilities, providing the skills necessary to work in integrated settings, one of the largest being Dale Rogers Training Center in Oklahoma City. (See also Intensive interaction)
### At-home and community support[edit]
Many people with developmental disabilities live in the general community, either with family members, in supervised-group homes or in their own homes (that they rent or own, living alone or with flatmates). At-home and community supports range from one-to-one assistance from a support worker with identified aspects of daily living (such as budgeting, shopping or paying bills) to full 24-hour support (including assistance with household tasks, such as cooking and cleaning, and personal care such as showering, dressing and the administration of medication). The need for full 24-hour support is usually associated with difficulties recognizing safety issues (such as responding to a fire or using a telephone) or for people with potentially dangerous medical conditions (such as asthma or diabetes) who are unable to manage their conditions without assistance.
In the United States, a support worker is known as a Direct Support Professional (DSP). The DSP works in assisting the individual with their ADLs and also acts as an advocate for the individual with a developmental disability, in communicating their needs, self-expression and goals.
Supports of this type also include assistance to identify and undertake new hobbies or to access community services (such as education), learning appropriate behavior or recognition of community norms, or with relationships and expanding circles of friends. Most programs offering at-home and community support are designed with the goal of increasing the individual's independence, although it is recognized that people with more severe disabilities may never be able to achieve full independence in some areas of daily life.
### Residential accommodation[edit]
Some people with developmental disabilities live in residential accommodation (also known as group homes) with other people with similar assessed needs. These homes are usually staffed around the clock, and usually house between 3 and 15 residents. The prevalence of this type of support is gradually decreasing, however, as residential accommodation is replaced by at-home and community support, which can offer increased choice and self-determination for individuals. Some U.S. states still provide institutional care, such as the Texas State Schools.[35] The type of residential accommodation is usually determined by the level of developmental disability and mental health needs.[36]
### Employment support[edit]
Employment support usually consists of two types of support:
* Support to access or participate in integrated employment, in a workplace in the general community. This may include specific programs to increase the skills needed for successful employment (work preparation), one-to-one or small group support for on-the-job training, or one-to-one or small group support after a transition period (such as advocacy when dealing with an employer or a bullying colleague, or assistance to complete an application for a promotion).
* The provision of specific employment opportunities within segregated business services. Although these are designed as "transitional" services (teaching work skills needed to move into integrated employment), many people remain in such services for the duration of their working life. The types of work performed in business services include mailing and packaging services, cleaning, gardening and landscaping, timberwork, metal fabrication, farming, and sewing.
Workers with developmental disabilities have historically been paid less for their labor than those in the general workforce, although this is gradually changing with government initiatives, the enforcement of anti-discrimination legislation and changes in perceptions of capability in the general community.
In the United States, a variety of initiatives have been launched in the past decade to reduce unemployment among workers with disabilities—estimated by researchers at over 60%.[37] Most of these initiatives are directed at employment in mainstream businesses. They include heightened placement efforts by the community agencies serving people with developmental disabilities, as well as by government agencies.
Additionally, state-level initiatives are being launched to increase employment among workers with disabilities. In California, the state senate in 2009 created the Senate Select Committee on Autism and Related Disorders. The Committee has been examining additions to existing community employment services, and also new employment approaches. Committee member Lou Vismara, chairman of the MIND Institute at University of California, Davis, is pursuing the development of a planned community for persons with autism and related disorders in the Sacramento region.[38] Another committee member, Michael Bernick, the former director of the state labor department, has established a program at the California state university system, starting at California State University East Bay, to support students with autism on the college level.[39] Other Committee efforts include mutual support employment efforts, such as disability job networks, job boards, and identifying business lines that build on the strengths of persons with disabilities.
Though efforts are being made to integrate individuals with developmental disabilities into the workforce, businesses are still reluctant to employ individuals with IDD because of their poor communication skills and emotional intelligence.[40] High functioning individuals with developmental disabilities can find it difficult to work in an environment that requires teamwork and direct communication due to their lack of social awareness. Working with employers to better understand the disorders and barriers that may come from the struggles associated with them, can greatly impact the quality of life for these individuals.
### Day services[edit]
Non-vocational day services are usually known as day centers, and are traditionally segregated services offering training in life skills (such as meal preparation and basic literacy), center-based activities (such as crafts, games and music classes) and external activities (such as day trips). Some more progressive day centers also support people to access vocational training opportunities (such as college courses), and offer individualized outreach services (planning and undertaking activities with the individual, with support offered one-to-one or in small groups).
Traditional day centers were based on the principles of occupational therapy, and were created as respite for family members caring for their loved ones with disabilities. This is slowly changing, however, as programs offered become more skills-based and focused on increasing independence.
### Advocacy[edit]
Advocacy is a burgeoning support field for people with developmental disabilities. Advocacy groups now exist in most jurisdictions, working collaboratively with people with disabilities for systemic change (such as changes in policy and legislation) and for changes for individuals (such as claiming welfare benefits or when responding to abuse). Most advocacy groups also work to support people, throughout the world, to increase their capacity for self-advocacy, teaching the skills necessary for people to advocate for their own needs.
### Other types of support[edit]
Other types of support for people with developmental disabilities may include:
* Therapeutic services, such as speech therapy, occupational therapy, physical therapy, massage, aromatherapy, art, dance/movement or music therapy
* Supported holidays
* Short-stay respite services (for people who live with family members or other unpaid carers)
* Transport services, such as dial-a-ride or free bus passes
* Specialist behavior support services, such as high-security services for people with high-level, high-risk challenging behaviors
* Specialist relationships and sex education.
Programs are set up around the country in hopes to educate individuals with and without developmental disabilities. Studies have been done testing specific scenarios on how what is the most beneficial way to educate people. Interventions are a great way to educate people, but also the most time consuming. With the busy schedules that everybody has, it is found to be difficult to go about the intervention approach. Another scenario that was found to be not as beneficial, but more realistic in the time sense was Psychoeducational approach. They focus on informing people on what abuse is, how to spot abuse, and what to do when spotted. Individuals with developmental disabilities don't only need the support programs to keep them safe, but everybody in society needs to be aware of what is happening and how to help everybody prosper.[41]
## See also[edit]
* American Coalition of Citizens with Disabilities
* Behavioral cusp
* Disability abuse
* List of disability rights activists
* List of disability rights organizations
## References[edit]
1. ^ a b Center for Disease Control and Prevention. (2013). Developmental disabilities. Retrieved October 18, 2013
2. ^ DSM-IV - Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, published by the American Psychiatric Association (APA, 1994)
3. ^ Improving health outcomes for children and youth with developmental disabilities, A literature review/Surrey Place Services 2013
4. ^ Finucane, B.(2012) Introduction to special issue on developmental disabilities. National Society of Genetic Counselors, Inc. 749-751.
5. ^ Anneloes L. van Baar, PhD, Aleid G. van Wassenaer, MD, PhD, Judy M. Briët, PhD, Friedo W. Dekker, PhD, Joke H. Kok, MD, PhD, Very Preterm Birth is Associated with Disabilities in Multiple Developmental Domains, Journal of Pediatric Psychology, Volume 30, Issue 3, April/May 2005, Pages 247–255, https://doi.org/10.1093/jpepsy/jsi035
6. ^ "OMIM - Online Mendelian Inheritance in Man". omim.org. Retrieved 2019-10-23.
7. ^ Larson, S., Lakin, C., Anderson, L., Kwak, N., Lee, J., & Anderson, D. (2000). "Prevalence of Mental Retardation and/or Developmental Disabilities: Analysis of the 1994/1995 NHIS-D". MR/DD Data Brief, April 2000, Volume 2, No. 1. 106: 231. doi:10.1352/0895-8017(2001)106<0231:POMRAD>2.0.CO;2.CS1 maint: multiple names: authors list (link)
8. ^ "Enable, Scotland -".
9. ^ "Valuing People — A New Strategy for Learning Disability for the 21st Century". Secretary of State (UK) for Health. March 2001. p. 16.
10. ^ "Definition of DEVELOPMENTAL QUOTIENT". Merriam-Webster Dictionary. Retrieved 2014-11-09.
11. ^ "developmental quotient (DQ)". TheFreeDictionary.com. Retrieved 2014-11-09., in turn citing Mosby's Medical Dictionary, 8th edition.
12. ^ "Health Guidelines for Adults with an Intellectual Disability". St. George's University of London/Down's Syndrome Association. Archived from the original on 2009-05-04. Retrieved 2006-02-11.
13. ^ "Health and People with Intellectual Disability". NSW Council for Intellectual Disability. Archived from the original on 2006-03-03. Retrieved 2006-02-11.
14. ^ Martorell, A.; Tsakanikos E. (2008). "Traumatic experiences and life events in people with intellectual disability" (PDF). Current Opinion in Psychiatry. 21 (5): 445–448. doi:10.1097/YCO.0b013e328305e60e. PMID 18650684. S2CID 16804572.
15. ^ Chaplin, E.; Gilvarry, C.; Tsakanikos E. (2011). "Recreational substance use patterns in adults with intellectual disability and co-morbid psychopathology". Research in Developmental Disabilities. 32 (6): 2981–6. doi:10.1016/j.ridd.2011.05.002. PMID 21640553.
16. ^ "Learning Disabilities: Mental Health Problems". Mind (UK National Association for Mental Health).
17. ^ Sally-Ann Cooper. "CLASSIFICATION AND ASSESSMENT OF PSYCHIATRIC DISORDERS IN ADULTS WITH LEARNING [INTELLECTUAL] DISABILITIES". St. George's. Archived from the original on 2009-04-15. Retrieved 2006-02-11.
18. ^ Psychological disturbance associated with sexual abuse in people with learning disabilities. Case-control study. / Sequeira, H; Howlin, P; Hollins, S.In: British Journal of Psychiatry, Vol. 183, No. NOV., 11.2003, p. 451–456.
19. ^ "The British Journal of Psychiatry". Cambridge Core. Retrieved 2019-10-23.
20. ^ "Sexual Abuse FAQ". Archived from the original (DOC) on 2007-01-06. Retrieved 2006-02-11.
21. ^ "Family Violence and People with a Mental Handicap". National Clearinghouse on Family Violence. Public Health Agency of Canada.
22. ^ "Criminal Justice FAQ". The Arc of the United States. Archived from the original (DOC) on 2007-01-06. Retrieved 2006-02-11.
23. ^ Failings in learning disability deaths, report finds BBC
24. ^ Emerson, E. 1995. Challenging behaviour: analysis and intervention with people with learning difficulties. Cambridge: Cambridge University Press
25. ^ Hemmings, C.; Underwood, L.; Tsakanikos E.; Holt, G.; Bouras, N. (2008). "Clinical predictors of challenging behaviour in intellectual disability". Social Psychiatry and Psychiatric Epidemiology. 43 (10): 824–830. doi:10.1007/s00127-008-0370-9. PMID 18488127. S2CID 37301668.
26. ^ Neef, N. A. (2001). "The Past and Future of Behavior Analysis in Developmental Disabilities: When Good News is Bad and Bad News is Good. The Behavior Analyst Today, 2 (4) '": 336–343. Cite journal requires `|journal=` (help)
27. ^ Roane, H.S., Ringdahl, J.E., Vollmer, T.R., Whitmarsh, E.L. and Marcus, B.A. (2007). A Preliminary Description of the Occurrence of Proto-injurious Behavior in Typically Developing Children. Journal of Early and Intensive Behavior Intervention, 3(4), 334-347. [1]
28. ^ Kupferstein, H. (2018), "Evidence of increased PTSD symptoms in autistics exposed to applied behavior analysis", Advances in Autism, Vol. 4 No. 1, pp. 19-29. https://doi.org/10.1108/AIA-08-2017-0016 https://www.emerald.com/insight/content/doi/10.1108/AIA-08-2017-0016/full/html
29. ^ Armbrester, Margaret E. (1992). The Civitan Story. Birmingham, AL: Ebsco Media. pp. 74–75.
30. ^ Wolf Wolfensberger (January 10, 1969). "The Origin and Nature of Our Institutional Models". Changing Patterns in Residential Services for the Mentally Retarded. President's Committee on Mental Retardation, Washington, D.C.
31. ^ "Archived copy". Archived from the original on 2010-07-11. Retrieved 2010-06-29.CS1 maint: archived copy as title (link)
32. ^ a b "Archived copy". Archived from the original on 2010-07-11. Retrieved 2010-06-29.CS1 maint: archived copy as title (link)
33. ^ Kormann & Petronko (2003). "Crisis and Revolution in Developmental Disabilities: The Dilemma of Community Based Services. The Behavior Analyst Today, 3 (4,": 434–443. Cite journal requires `|journal=` (help)
34. ^ "Home".
35. ^ Texas Department of Aging and Disability Services Archived February 6, 2007, at the Wayback Machine
36. ^ Chaplin, E., Paschos, D. O’Hara, J., McCarthy, J., Holt, G.Bouras, N. Tsakanikos E. (2010). Mental ill-health and care pathways in adults with intellectual disability across different residential settings. Research in Developmental Disabilities, 31, 458-63
37. ^ Richard Burkhauser; Mary Daly (2002). "United States Disability Policy in a Changing Environment". Journal of Economic Perspectives. 16 (1).
38. ^ "With Housing that Caters to All, We all Win". Sacramento Bee. 2008-09-18. Archived from the original on 2011-05-26. Retrieved 2011-05-14.
39. ^ "College for Autistics". San Francisco Chronicle. 2009-08-04. Retrieved 2011-05-14.
40. ^ Lewis, G. (2014). Business is still scared of autism. People Management, 32.
41. ^ Lund, Emily. Hammond, Marilyn. “Single-Session Intervention for Abuse Awareness Among People with Developmental Disabilities.” Sexuality and Disability 32.1 (n.d.): 99-105. Proquest Central. Web. 24 April 2014.
## Further reading[edit]
* Developmental-Behavioral Pediatrics, 4th Edition \- Expert Consult — Online and Print By William B. Carey, MD, Allen C. Crocker, MD, Ellen Roy Elias, MD, Heidi M. Feldman, MD, PhD and William L. Coleman, MD
* Advocacy and Learning Disability[permanent dead link]. Barry Gray and Robin Jackson (Eds) London: Jessica Kingsley Publishers, 2002
* US Administration on Developmental Disabilities fact sheet
* A Short History of the Treatment of Persons with Mental Retardation
* Real Lives: Contemporary supports to people with mental retardation (1998)
* Rights of People with Intellectual Disabilities: Access to Education and Employment, bilingual reports on 14 European countries
* Australian Institute of Health and Welfare paper The Definition and Prevalence of Intellectual Disability in Australia
* 2001 New Zealand Snapshot of Intellectual Disability
* People with Intellectual Disabilities: from Invisible to Visible Citizens of the EU Accession Countries
* Policy brief: Education and Employment in the UK
* The American Bar Association's paper Invisible Victims: Violence against persons with developmental disabilities
* Persons With Intellectual Disability Who Are Incarcerated For Criminal Offences (Canadian paper)
* 'Fighting to keep 'em in', Ragged Edge magazine January 1998
* Wishart, G.D. (2003) The Sexual Abuse of People with Learning Difficulties: Do We Need A Social Model Approach To Vulnerability? Journal of Adult Protection, Volume 5 (Issue 3)
* Piper, Julia (2007). "The Case of the Pillow Angel". The Triple Helix Cambridge Michaelmas
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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
| Developmental disability | c0085996 | 1,480 | wikipedia | https://en.wikipedia.org/wiki/Developmental_disability | 2021-01-18T18:33:41 | {"mesh": ["D002658"], "wikidata": ["Q1142806"]} |
A congenital vascular bone syndrome (CVBS) characterized by the presence of a vascular malformation in a limb, mainly of the arteriovenous type, which results in overgrowth of the affected limb.
## Epidemiology
Prevalence is unknown but around 1,000 cases have been reported in the literature so far.
## Clinical description
The affected limb may show overgrowth in comparison with the contralateral limb and the extent of this limb length discrepancy (LLD) may vary from a slight difference to 10 cm or more. The growth effect may be manifested in only one bone (mainly the femur or tibia) or, in some cases, affect the whole limb. The LLD may become apparent during infancy, childhood or adolescence and is clearly visible by comparison of the level of the gluteal and posterior knee folds. Collateral signs may include a cutaneous nevus, dilated superficial veins, limb enlargement, skin warming, dermatitis, ulcers and bleeding. However, these signs are not always present. The existence of AV fistulas around or inside the bone is now being widely accepted as the main cause of bone overgrowth and the older theory that venostasis may cause the bone growth alterations is being largely discounted. The arteriovenous malformations (AVMs) may affect bone metabolism, stimulating limb elongation during the growing period. After the physiologic end of bone growth, no further change in bone length is possible. Some cases of CVBS with venous anomalies (such as deep venous aplasia) have been observed but angiographic studies demonstrated that in these cases opening of an AV communication resulted in stimulation of the bone growth.
## Etiology
Recently, several different molecules with both angiogenic and osteogenic activity have been identified and their role in CVBS needs to be investigated.
## Diagnostic methods
Diagnosis is made by clinical examination with a combination of plain X-ray studies (preferably in the standing position to identify the LLD and any changes in bone structure), and various techniques for detecting and establishing the site of the AVM: duplex scan, angiography (although it may fail to demonstrate intraosseous fistulas), angioscintigraphy (whole blood pool scan), a labeled microspheres test, direct percutaneous puncture of abnormal bone areas with contrast injection, and angio-MRI, -CT and -3D CT scans.
## Differential diagnosis
The differential diagnosis should include venous dysplasias, lymphedema and bone tumors.
## Genetic counseling
Although Angioosteohypertrophic syndrome generally appears to be sporadic, autosomal dominant inheritance has been noted in a few families.
## Management and treatment
In childhood, during the growth period, treatment of the AVM should be performed and may lead to spontaneous correction of the LLD. Intraosseous AVMs should be treated by direct puncture and occlusion, or possibly by catheter embolization, but surgery should be avoided as the risk of hemorrhage is high. Soft tissue fistulas can be treated by catheter embolization or by surgery with resection of the fistulous area, alone or in combination with endovascular procedures. Orthopedic procedures should stop the bone elongation during the growth period or correct the LLD in adults. Epiphyseal staples are also effective at stopping growth. Contralateral limb elongation using the Ilizarov technique is feasible in adults.
## Prognosis
If recognized early and treaded correctly during childhood, results may be good or excellent. In adults, orthopedic interventions are able to correct the LLD.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Angioosteohypertrophic syndrome | c0022739 | 1,481 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2346 | 2021-01-23T18:29:23 | {"gard": ["3122"], "mesh": ["D007715"], "omim": ["149000", "608354", "608355"], "umls": ["C0022739", "C2931360"], "icd-10": ["Q87.2"], "synonyms": ["Klippel-Trénaunay-Weber syndrome"]} |
Ear-patella-short stature syndrome is an association of malformations including bilateral microtia (severe hypoplasia of ear pinnae), absent patellae, short stature, poor weight gain, and characteristic facial features such as high forehead, micrognathism with full lips and small mouth, and accentuated nasolabial folds (smile wrinkles linking the nostrils to the labial commissure).
## Epidemiology
Ear-patella-short stature syndrome is a rare condition, with less than 50 cases reported in the literature.
## Clinical description
Other skeletal anomalies include dislocation of the elbow, slender ribs and long bones, abnormal modelling of the glenoid fossas with hooked clavicles, and clinodactyly. Bone age is significantly delayed and long bone epiphyses are flattened. Hypoplastic genitalia have been reported in affected boys and girls. Some patients have severe deafness, which may impair neuromotor and mental development, and cognitive ability may be subnormal.
## Etiology
The etiology remains unknown: all genes evaluated in affected patients were normal.
## Diagnostic methods
Neuroradiographic imaging and functional inner ear investigations are recommended in the diagnostic workup.
## Genetic counseling
Reports of parental consanguinity in some cases, the equal sex ratio, and the occurrence of affected sibs provide strong evidence for an autosomal recessive mode of inheritance.
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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
| Ear-patella-short stature syndrome | c1868684 | 1,482 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2554 | 2021-01-23T19:02:49 | {"gard": ["2033"], "mesh": ["C538012"], "omim": ["224690", "613800", "613803", "613804", "613805", "616835", "617063"], "umls": ["C1868684"], "icd-10": ["Q87.1"], "synonyms": ["Meier-Gorlin syndrome"]} |
A number sign (#) is used with this entry because molybdenum cofactor deficiency of complementation group B (MOCODB) is caused by homozygous or compound heterozygous mutation in the MOCS2 gene (603708) on chromosome 5q11.
Description
Molybdenum cofactor deficiency is a rare autosomal recessive metabolic disorder characterized by neonatal onset of intractable seizures, opisthotonus, and facial dysmorphism associated with hypouricemia and elevated urinary sulfite levels. Affected individuals show severe neurologic damage and often die in early childhood (summary by Reiss et al., 1999).
For a general phenotypic description and a discussion of genetic heterogeneity of MOCOD, see MOCODA (252150), which is clinically indistinguishable from MOCODB.
Clinical Features
Leimkuhler et al. (2005) reported a 9-month-old Mexican infant with an unusual phenotype of molybdenum cofactor deficiency involving static encephalopathy, microcephaly, and dysmorphic features, but no evidence of seizure disorder, lens dislocation, or progressive psychomotor retardation. On examination, the patient had spastic quadriparesis, opisthotonos, nystagmus, and irritability; brain MRI revealed diffuse cerebral atrophy, gliotic white matter, and a thinned corpus callosum.
Hahnewald et al. (2006) reported a Senegalese male infant with molybdenum cofactor deficiency. The child was born to a nonconsanguineous couple and appeared healthy at birth. From the third day of life, he developed feeding difficulties, hypotonia, and drug-resistant tonic and clonic seizures, and he had elevated sulfite and diminished uric acid in urine. He died 21 days after birth from cardiorespiratory arrest.
Molecular Genetics
In 7 of 8 patients with MOCOD who were negative for mutations in the MOCS1 gene and in whom fibroblast studies confirmed complementation group B, Reiss et al. (1999) identified biallelic mutations in the MOCS2 gene (see, e.g., 603708.0001-603708.0005). A 2-bp deletion (726del; 603708.0001) accounted for 50% (7 of 14) of identified alleles.
Reiss (2000) reviewed the genetics of molybdenum cofactor deficiency. Both MOCS1 and MOCS2 have an unusual bicistronic architecture, have identical very low expression profiles, and show extremely conserved C-terminal ends in their 5-prime open reading frames. MOCS1 mutations are responsible for two-thirds of cases. Reiss (2000) pointed out that all described MOCS1 and MOCS2 mutations affect one or several highly conserved motifs. No missense mutations of a less conserved residue were identified. This mirrored the absence of mild or partial forms of MoCo deficiency and supported the hypothesis of a qualitative 'yes or no' mechanism rather than quantitative kinetics for MoCo function, i.e., this function is either completely abolished or sufficient for a normal phenotype. The minimal expression of the MOCS genes concurs with this theory and would predict a low level of transfected or expressing cells that would be adequate for somatic gene therapy. Furthermore, precursor-producing cells seem to be capable of feeding their precursor-deficient neighbor cells (Johnson et al., 1989).
Reiss and Johnson (2003) collected a total of 32 different disease-causing mutations in the MOCS1, MOCS2, or GPHN (603930) genes, including several common to more than 1 family, that had been identified in molybdenum cofactor-deficient patients and their relatives.
In a Mexican infant with MOCODB, Leimkuhler et al. (2005) identified a mutation of the normal stop codon (X189Y; 603708.0008) in the MOCS2 gene.
In a Senegalese boy with molybdenum cofactor deficiency, Hahnewald et al. (2006) identified a 23-bp deletion at nucleotide 148 in exon 1a of the MOCS2 gene (603708.0009).
Genotype/Phenotype Correlations
Johnson et al. (2001) reported a 4-year-old patient with mild features of molybdenum cofactor deficiency. The patient had mild developmental delay, but no seizures or lens dislocation. Genetic analysis identified compound heterozygous mutations in the MOSC2 gene (Q6X; 603708.0006 and V7F; 603708.0007). The authors postulated that a low level of residual molybdopterin synthase activity derived from the V7F allele may have been responsible for the milder clinical symptoms.
INHERITANCE \- Autosomal recessive GROWTH Other \- Poor growth HEAD & NECK Head \- Frontal bossing \- Microcephaly \- Macrocephaly Face \- Long face \- Puffy cheeks \- Long philtrum Eyes \- Dislocated lenses \- Spherophakia \- Nystagmus \- Elongated palpebral fissures \- Widely spaced eyes Nose \- Small nose Mouth \- Thick lips ABDOMEN Gastrointestinal \- Poor feeding SKELETAL Skull \- Asymmetric skull MUSCLE, SOFT TISSUES \- Myoclonic spasms NEUROLOGIC Central Nervous System \- Absent or delayed psychomotor development, severe \- Seizures, intractable \- Opisthotonos \- Hypertonicity \- Spastic quadriplegia \- Cerebral atrophy \- Thinning of the corpus callosum \- Gliosis \- Demyelination \- Axonal loss \- Cystic lysis of the deep white matter \- Enlarged ventricles LABORATORY ABNORMALITIES \- Hypouricemia \- Increased urinary xanthine \- Increased urinary hypoxanthine \- Increased urinary S-sulfocysteine \- Increased urinary taurine \- Xanthine stones \- Decreased xanthine dehydrogenase activity \- Decreased sulfite oxidase activity \- Molybdenum cofactor deficiency MISCELLANEOUS \- Onset at birth or in early infancy \- Progressive disorder \- Most affected patients die in childhood MOLECULAR BASIS \- Caused by mutation in the molybdenum cofactor synthesis gene 2 (MOCS2, 603708.0001 ) ▲ 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
| MOLYBDENUM COFACTOR DEFICIENCY, COMPLEMENTATION GROUP B | c1854989 | 1,483 | omim | https://www.omim.org/entry/252160 | 2019-09-22T16:25:10 | {"doid": ["0111163"], "mesh": ["C565373"], "omim": ["252160"], "orphanet": ["833", "99732", "308393"], "synonyms": ["Combined deficiency of sulfite oxidase, xanthine dehydrogenase and aldehyde oxidase", "MOCOD"]} |
Gastric erosion occurs when the mucous membrane lining the stomach becomes inflamed. Specifically, the term "erosion," in this context means damage that is limited to the mucosa (which consists of three distinct layers: The epithelium (in the case of a healthy stomach, this is non-ciliated simple columnar epithelium), basement membrane, and lamina propria). An erosion is different from an ulcer. An "ulcer" is an area of damage to the gastrointestinal wall (in this case the gastric wall) that extends deeper through the wall than an erosion (an ulcer can extend anywhere from beyond the lamina propria to right through the wall, potentially causing a perforation). See gastrointestinal wall.
Some drugs, as tablets, can irritate this mucous membrane, especially drugs taken for arthritis and muscular disorders, steroids, and aspirin. A gastric erosion may also occur because of emotional stress, or as a side effect of burns or stomach injuries. See acute gastritis.
## Symptoms[edit]
There is basically one symptom of gastric erosion: bleeding from the area where the stomach lesion is. Bowel movements may contain blood. Vomit may be bloody as well, but a gastric erosion may not cause vomiting. Blood may be black because it will be partially digested. Loss of blood may cause one to develop anemia.
## Risks[edit]
Anemia and other problems related to blood loss may occur. Sometimes a person with a gastric erosion will experience severe bleeding all at once; red (bloody) vomiting and/or black bowel movements may occur.
## Sources[edit]
* "Gastric Erosion." Encyclopædia Britannica, Micropaedia. Encyclopædia Britannica Inc., 1998 ed.
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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
| Gastric erosion | c0341177 | 1,484 | wikipedia | https://en.wikipedia.org/wiki/Gastric_erosion | 2021-01-18T18:38:57 | {"umls": ["C0341177"], "wikidata": ["Q5526781"]} |
Adenine phosphoribosyltransferase deficiency
Other namesAPRT deficiency or 2,8 Dihydroxyadenine urolithiasis
Dihydroxyadenine, an insoluble purine
SpecialtyEndocrinology
Adenine phosphoribosyltransferase deficiency is an autosomal recessive[1] metabolic disorder associated with a mutation in the enzyme adenine phosphoribosyltransferase.[2]
## Contents
* 1 Signs and symptoms
* 2 Genetics
* 2.1 Characteristics
* 3 Diagnosis
* 4 Treatment
* 5 References
* 6 External links
## Signs and symptoms[edit]
Most patients with APRT deficiency have repeated episodes of kidney stones that are not detected by a conventional x-ray study. However, all stones are easily detected by other medical imaging methods such as ultrasound or computerized tomography (CT) scan. A minority of patients develop symptoms of kidney failure. Kidney stones are often associated with severe loin or abdominal pain. Symptoms associated with kidney failure are largely nonspecific such as increased fatigue and weakness, poor appetite, and weight loss. Children with the disease may have similar symptoms as adults. In young children, APRT deficiency can cause reddish-brown diaper spots.[citation needed]
## Genetics[edit]
Adenine phosphoribosyltransferase deficiency has an autosomal recessive pattern of inheritance.
APRT deficiency is inherited in an autosomal recessive manner.[1] This means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.
### Characteristics[edit]
The disorder results in accumulation of the insoluble purine 2,8-dihydroxyadenine.[3] It can result in nephrolithiasis (kidney stones), acute renal failure and permanent kidney damage.
More than 300 individuals with this disease have been reported world-wide but it is not known how common this medical problem truly is. Patients with the disease deficiency lack the enzyme adenine phosphoribosyltransferase and therefore have difficulties breaking down dietary substances called purines, resulting in accumulation of a compound called 2,8-dihydroxyadenine (2,8-DHA) that is excreted by the kidneys. Up to 70% of affected patients, have red hair or relatives with this hair color.
## Diagnosis[edit]
This section is empty. You can help by adding to it. (June 2017)
## Treatment[edit]
This section is empty. You can help by adding to it. (June 2017)
## References[edit]
1. ^ a b Kamatani, N (December 1996). "Adenine phosphoribosyltransferase(APRT) deficiency" (Free full text). Nippon Rinsho. Japanese Journal of Clinical Medicine. 54 (12): 3321–7. ISSN 0047-1852. PMID 8976113.
2. ^ Terai, C; Hakoda, M; Yamanaka, H; Kamatani, N; Okai, M; Takahashi, F; Kashiwazaki, S (November 1995). "Adenine phosphoribosyltransferase deficiency identified by urinary sediment analysis: cellular and molecular confirmation". Clinical Genetics. 48 (5): 246–50. doi:10.1111/j.1399-0004.1995.tb04098.x. ISSN 0009-9163. PMID 8825602.
3. ^ Funato, T; Nishiyama, Y; Ioritani, N; Matsuki, R; Yoshida, K; Kaku, M; Sasaki, T; Ideguchi, H; Ono, J (2000). "Detection of mutations in adenine phosphoribosyltransferase (APRT) deficiency using the LightCycler system". Journal of Clinical Laboratory Analysis. 14 (6): 274–9. doi:10.1002/1098-2825(20001212)14:6<274::AID-JCLA5>3.0.CO;2-2. ISSN 0887-8013. PMC 6808163. PMID 11138609.
## External links[edit]
Classification
D
* ICD-10: E79
* ICD-9-CM: 277.2
* OMIM: 102600
* MeSH: C538228 C538228, C538228
* DiseasesDB: 32632
External resources
* Orphanet: 976
* Adenine phosphoribosyltransferase deficiency at NIH's Office of Rare Diseases
* v
* t
* e
Inborn error of purine–pyrimidine metabolism
Purine metabolism
Anabolism
* Adenylosuccinate lyase deficiency
* Adenosine Monophosphate Deaminase Deficiency type 1
Nucleotide salvage
* Lesch–Nyhan syndrome/Hyperuricemia
* Adenine phosphoribosyltransferase deficiency
Catabolism
* Adenosine deaminase deficiency
* Purine nucleoside phosphorylase deficiency
* Xanthinuria
* Gout
* Mitochondrial neurogastrointestinal encephalopathy syndrome
Pyrimidine metabolism
Anabolism
* Orotic aciduria
* Miller syndrome
Catabolism
* Dihydropyrimidine dehydrogenase deficiency
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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
| Adenine phosphoribosyltransferase deficiency | c0268120 | 1,485 | wikipedia | https://en.wikipedia.org/wiki/Adenine_phosphoribosyltransferase_deficiency | 2021-01-18T19:08:43 | {"gard": ["10666", "546"], "mesh": ["C538228"], "umls": ["C0268120", "C3665382"], "icd-9": ["277.2"], "icd-10": ["E79"], "orphanet": ["976"], "wikidata": ["Q4682223"]} |
A rare neuroendocrine tumor arising from chromaffin cells of the adrenal medulla (pheochromocytoma) or from sympathetic and parasympathetic ganglia (paraganglioma). These tumors are most often benign and may produce catecholamines in excess causing hypertension and sometimes severe acute cardiovascular complications.
## Epidemiology
Pheochromocytomas and paragangliomas (PPGL) are rare, occurring in 0.1 to 0.6% of patients with hypertension and 5% with adrenal incidentaloma. The incidence is approximately 0.57 per 100,000 person-years (0.46 for pheochromocytomas and 0.11 for paragangliomas).
## Clinical description
The symptomatology may be related to hypersecretion of catecholamines. It is variable, fluctuating, non-specific and even sometimes completely non-existent. Hypertension is the most common sign and can be permanent (50-60%) or paroxysmal (35%) and associated with orthostatic hypotension. Blood pressure can also be normal, especially in patients with low or no hypersecretion. A sudden discharge of catecholamines can cause paroxysmal symptoms that may or not occur concomitantly: headache (60-90%), sweating (55-75%), and palpitations (50-70%). The specificity and sensitivity of this triad for the diagnosis of pheochromoctyoma and/or catecholamines-producing paraganglioma are 94% and 91% respectively. Ten to 15% of PPGL are diagnosed after an acute cardiomyopathy, the most frequent being the Takotsubo cardiomyopathy. The others symptoms, less frequent, are general impairment, weight loss, constipation, anxiety, hyperglycemia and nausea. Head and neck paraganglioma are classically non-secreting tumors: the discovery could be made because of the palpation of a cervical mass or a swelling sometimes pulsatile, tinnitus, hypoacousia or even paralysis of the cranial nerves (dysphonia, dysphagia...). In genetically determined forms, others tumors or signs may be associated. For instance, gastrointestinal stromal tumors in patients with Carney-Stratakis syndrome.
## Etiology
About 40% of PPGL occur in the context of an autosomal inherited syndrome. More than 15 predisposing genes have been identified (SDHA, SDHB, SDHC, SDHD, RET, VHL, NF1, TMEM127, MAX, FH...). About 60% are sporadic but up to 30% of sporadic tumors actually carry somatic mutations in these known susceptibility genes.
## Diagnostic methods
The diagnosis of secreting PPGL is based on plasma free metanephrines or 24-hour urinary fractionated metanephrines measurements. A radiological evaluation is necessary to locate the tumor with conventional and nuclear medicine imaging. Biopsy should not be performed due to the high risk of acute catecholamines-induced hypertensive crisis and of hematoma. An early onset and/or the presence of multiple, extra-adrenal PPGL, bilateral pheochromocytoma or of metastases suggest a genetic form.
## Differential diagnosis
In patients with paroxysmal symptoms, main differential diagnoses are panic disorder, hot flashes, carcinoid syndrome.
## Antenatal diagnosis
Prenatal diagnosis is not performed except for patients with VHL disease. Genetic testing may be offered to children at risk over 6 years old.
## Genetic counseling
Genetic testing is recommended for all patients diagnosed with PPGL because 40% of cases occur in the context of an autosomal inherited syndrome. Moreover, patient follow-up is adapted according to the mutated gene (for example, intensive follow-up for SDHB mutation because the risk of malignancy is increased). It is also important to offer screening to first-degree relatives of mutation-carriers.
## Management and treatment
For catecholamines-producing PPGL, referral treatment is surgical excision. Patients need to undergo preoperative alpha-adrenergic blockade and rehydration for preventing hypertensive crisis during surgery. In case of tachycardia, a cardioselective beta-blocker can be added in a second step. Radiotherapy can be proposed for non-functioning paragangliomas of the skull base and neck. Indeed, the risk of neurovascular damage is important with surgery. For metastatic PPGL, there is no consensus. The therapeutic decision requires a multidisciplinary discussion by an expert team (surgery, metabolic or conventional radiotherapy, embolization, chemotherapy, targeted therapy...). Patients management should be organized in a referral center.
## Prognosis
The acute cardiovascular complications (sudden death, acute stress cardiomyopathy, myocardial infarction, heart failure...) represent the most frequent causes of morbi-mortality. Moreover, a metastatic evolution or a recurrence can be observed in about 15% of the cases, especially in cases of genetic predisposition.
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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
| Pheochromocytoma-paraganglioma | None | 1,486 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=573163 | 2021-01-23T17:10:24 | {} |
For a general phenotypic description and a discussion of genetic heterogeneity of lung cancer, see 211980.
Mapping
In a genomewide association study of 3,259 patients with lung cancer and 4,159 controls, McKay et al. (2008) found a significant association between lung cancer and 2 SNPs, rs402710 and rs2736100 on chromosome 5p15.33 (p = 2 x 10(-7) and p = 4 x 10(-6), respectively). The findings were replicated in 2,899 cases and 5,573 controls (p = 7 x 10(-5) and p = 0.016 for the 2 SNPs, respectively). The susceptibility region on chromosome 5p15 contains 2 genes, TERT (187270) and CLPTM1L (612585), suggesting that 1 or both may have a role in lung cancer etiology.
Wang et al. (2008) found a significant association between rs401681 on chromosome 5p15.33 and lung cancer susceptibility in a genomewide association study of 5,095 cases of lung cancer and 5,200 controls. The findings were replicated in an additional 2,484 cases and 3,036 controls (p value = 7.90 x 10(-9)). The A allele of rs401681 was associated with decreased risk of lung cancer. The SNP is located within intron 13 of the CLPTM1L gene.
Given the relevance of the 5p15.33 region to cancer biology, and following confirmation of association of SNPs within the region with risk of basal cell carcinoma (605462), Rafnar et al. (2009) assessed the association of the SNP rs401681 with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls. They found association of the C allele with lung cancer (OR = 1.15, p = 7.2 x 10(-8)) and weaker associations with urinary bladder, prostate, and cervix cancer. Notably, most of these cancer types have a strong environmental component to their risk. The lung cancer study included 4,265 patients and 34,666 controls.
In a genomewide association study of lung cancer and its major histologic types involving 515,922 SNPs and 5,739 lung cancer cases and 5,848 controls, Landi et al. (2009) found an association between TERT SNP rs2736100 and the risk of adenocarcinoma (odds ratio, 1.23; corrected p = 3.02 x 10(-7)). Metaanalysis combining their results with summary data from 10 previous studies for a total of 13,300 cases and 19,666 controls replicated the finding (odds ratio, 1.24; corrected p = 3.74 x 10(-14)). Landi et al. (2009) concluded that the previously identified association of rs2736100 on chromosome 5p15.33 with lung cancer risk is confined to the adenocarcinoma histologic type, and noted that rs2736100 is located in intron 2 of TERT within a putative regulatory region.
Hu et al. (2011) performed a genomewide association scan of 5,408 subjects (2,331 individuals with lung cancer and 3,077 controls) followed by a 2-stage validation among 12,722 subjects (6,313 cases and 6,409 controls). The combined analyses identified 6 well-replicated SNPs with independent effects and significant lung cancer associations. Hu et al. (2011) confirmed the locus at 5p15.33 in the TERT-CLPTM1L region characterized by rs465498 and rs2736100 (p = 1.2 x 10(-20) and p = 1.0 x 10(-27), respectively). The authors also confirmed an associated SNP, rs4488809 (see LNCR5, 614210), located in the first intron of TP63 (603273) on chromosome 3q28 (p = 7.2 x 10(-26)).
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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
| LUNG CANCER SUSCEPTIBILITY 3 | c2675497 | 1,487 | omim | https://www.omim.org/entry/612571 | 2019-09-22T16:01:09 | {"omim": ["612571"], "synonyms": ["Alternative titles", "ADENOCARCINOMA OF LUNG, SUSCEPTIBILITY TO"]} |
Audioanalgesia
MeSHD001297
[edit on Wikidata]
Audioanalgesia (also known as audio-analgesia) is the relief of pain using white noise or music without using pharmacological agents while doing painful medical procedures such as dental treatments. It was first introduced by Gardner and Licklider in 1959.[1][2]
There are many studies of this technique in dental,[3] obstetric,[4] and palliative care[5] contexts. The most recent review reports mixed results for effectiveness.[6] This questionable pain management strategy might prove useful in distraction and sensory confusion, but only when combined with actual pain relief medications. There is no research to suggest these dubious results will ever be effective other than as a means of self-distraction. This measure is similar to breathing exercises during cramps before administration of epidurals.
It has also been suggested that music may stimulate the production of endorphins and catecholamines.[citation needed]
## See also[edit]
* Anesthesia
## References[edit]
1. ^ Gardner, WJ; Licklider JC (1959). "Auditory analgesia in dental operations". J Am Dent Assoc. 59 (6): 1144–1149. doi:10.14219/jada.archive.1959.0251. PMID 13826544.
2. ^ Gardner, W. J., Licklider, J. C. R., & Weisz, A. Z. (1960). Suppression of Pain by Sound. Science, 132, 32-33.
3. ^ British Dental Journal
4. ^ P. Simkin, A. Bolding "Update on nonpharmacologic approaches to relieve labor pain and prevent suffering" Journal of Midwifery & Women's Health, Volume 49, no. 6, p. 489-504 online version Archived July 7, 2011, at the Wayback Machine
5. ^ Phillip J. Wiffen, "Evidence-Based Pain Management and Palliative Care" Journal of Pain & Palliative Care Pharmacotherapy Volume 18, Issue 1, 2004, Pages 79 – 85 Cochrane Library
6. ^ "A survey investigation of the effects of music listening on chronic pain" Laura A. Mitchell et al, Psychology of Music abstract
## Further reading[edit]
* Weisbrod, R. L. (1969). "Audio analgesia revisited". Anesthesia Progress. 16 (1): 8–14. PMC 2235527. PMID 5250548.
* "Nonpharmacologic Approaches to Relieve Labor Pain: Music and Audioanalgesia". Medscape Today. WebMD. Retrieved 2009-06-23.
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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
| Audioanalgesia | None | 1,488 | wikipedia | https://en.wikipedia.org/wiki/Audioanalgesia | 2021-01-18T19:09:00 | {"mesh": ["D001297"], "wikidata": ["Q4819894"]} |
Idiopathic pneumonia syndrome
SpecialtyPulmonology
Idiopathic pneumonia syndrome is a set of pneumonia-like symptoms that occur with no sign of infection in the lung. Idiopathic pneumonia syndrome is a serious condition that can occur after a stem cell transplant. It occurs between 2.2 and 15 percent of hematopoietic stem cell transplants. The incubation period ranges between 4 and 106 days, but mostly is about 22 days from transplant.[1]
## Contents
* 1 Symptoms
* 2 Risk factors
* 3 Diagnosis
* 4 Treatment
* 5 References
## Symptoms[edit]
The symptoms are like pneumonia, and include fever, chills, coughing, and breathing problems. Lack of oxygen may also occur.[1]
## Risk factors[edit]
Risk factors for IPS can be old age, graft vs host disease, multi organ failure, and multiple organ failure.[1]
## Diagnosis[edit]
This section is empty. You can help by adding to it. (February 2019)
## Treatment[edit]
Treatment is only supportive, with steroids showing no effect. The need for mechanical ventilation is indicative of a poor prognosis. Steroids are often used, though often without effect.[1]
## References[edit]
1. ^ a b c d "Idiopathic pneumonia syndrome following hematopoietic stem cell transplantation". doi:10.3233/PIC-14098. PMC 6530755. Cite journal requires `|journal=` (help)
* Idiopathic pneumonia syndrome entry in the public domain NCI Dictionary of Cancer Terms
This article incorporates public domain material from the U.S. National Cancer Institute document: "Dictionary of Cancer Terms".
* v
* t
* e
Pneumonia
Infectious pneumonias
* Bacterial pneumonia
* Viral pneumonia
* Fungal pneumonia
* Parasitic pneumonia
* Atypical pneumonia
* Community-acquired pneumonia
* Healthcare-associated pneumonia
* Hospital-acquired pneumonia
* Ventilator-associated pneumonia
* Severe acute respiratory syndrome
Pneumonias caused by
infectious or noninfectious agents
* Aspiration pneumonia
* Lipid pneumonia
* Eosinophilic pneumonia
* Bronchiolitis obliterans organizing pneumonia
Noninfectious pneumonia
* Chemical pneumonitis
* Idiopathic pneumonia syndrome
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
| Idiopathic pneumonia syndrome | c1504431 | 1,489 | wikipedia | https://en.wikipedia.org/wiki/Idiopathic_pneumonia_syndrome | 2021-01-18T19:05:07 | {"umls": ["C1504431"], "wikidata": ["Q5988895"]} |
Inflammatory condition of the retina of the eye
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. (January 2013) (Learn how and when to remove this template message)
Multiple evanescent white dot syndrome (MEWDS) is an uncommon inflammatory condition of the retina that typically affects otherwise healthy young females in the second to fourth decades of life.
The typical patient with MEWDS is a healthy middle aged female age 15-50. There is a gender disparity as women are affected with MEWDS four times more often than men. Roughly 30% of patients have experienced an associated viral prodrome. Patients present with acute, painless, unilateral change in vision. [1]
## Contents
* 1 Presentation
* 2 Cause
* 3 Diagnosis
* 4 Treatment
* 5 References
## Presentation[edit]
Patients commonly present with acute unilateral painless decreased vision and photopsias.[2] Presentations like central or paracentral scotoma, Floaters and dyschromatopsia are less common.[2] An antecedent viral prodrome occurs in approximately one-third of cases. Myopia is commonly seen in patients.
Eye exam during the acute phase of the disease reveals multiple discrete white to orange spots at the level of the RPE or deep retina, typically in a perifoveal location (around the fovea). Optic disc oedema may also seen occasionally.[2]
## Cause[edit]
The etiology of multiple evanescent white dot syndrome is currently unknown.[2]
## Diagnosis[edit]
* Visual field abnormalities are variable and include generalized depression of visual field, paracentral or peripheral scotoma and enlargement of the blind spot.
* Fluorescein angiography of the eye reveals characteristic punctate hyperfluorescent lesions in a wreath-like configuration surrounding the fovea.
* Indocyanine green angiography reveals hypofluorescent lesions in a greater number compared with other studies.
* Fundus autofluorescence (FAF) has been shown to be a noninvasive method to demonstrate the subretinal spots in MEWDS.
## Treatment[edit]
MEWDS is a self limited disease with excellent visual recovery within 2-10 weeks. However residual symptoms including photopsia may persist for months.
## References[edit]
1. ^ Brian Toussaint MD (December 6, 2014). [Multiple_Evanescent_White_Dot_Syndrome "Multiple Evanescent White Dot Syndrome"] Check `|url=` value (help). EyeWiki.
2. ^ a b c d John F, Salmon (13 December 2019). "Uveitis". Kanski's clinical ophthalmology : a systematic approach (9th ed.). Elsevier. p. 484. ISBN 978-0-7020-7711-1.
3. ^ Basic and Clinical Science Course; Intraocular inflammation and uveitis (2011-2012 ed.). American Academy of Ophthalmology. 2012. ISBN 978-1615251162.
4. ^ Basic and Clinical Science Course; Retina and vitreous (2011-2012 ed.). American Academy of Ophthalmology. 2012. ISBN 978-1615251193.
5. ^ Myron, Yanoff (2008). Ophthalmology (3rd ed.). Mosby. ISBN 978-0323057516.
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*[DOR]: δ-opioid receptor
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*[NET]: Norepinephrine transporter
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| Multiple evanescent white dot syndrome | c0730322 | 1,490 | wikipedia | https://en.wikipedia.org/wiki/Multiple_evanescent_white_dot_syndrome | 2021-01-18T19:02:48 | {"umls": ["C0730322"], "wikidata": ["Q6934930"]} |
Multilocular cystic renal neoplasm of low malignant potential is a rare subtype of clear cell renal cell carcinoma with distinct pathological features of cysts lined by occasionally flattened cuboidal clear cells and septa containing aggregates of epithelial cells with clear cytoplasm, and excellent prognosis. The tumor usually presents as an asymptomatic, unilateral, solitary lesion, macroscopically consisting of numerous, fluid-filled, septated cysts of variable size. Rarely, the symptoms typically associated with renal tumors (flank pain, hematuria, palpable mass) may be present.
*[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
| Multilocular cystic renal neoplasm of low malignant potential | c0346249 | 1,491 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=319287 | 2021-01-23T17:52:39 | {"icd-10": ["C64"], "synonyms": ["MCRCC", "Multilocular clear cell adenocarcinoma", "Multilocular clear cell carcinoma", "Multilocular clear cell renal cell adenocarcinoma", "Multilocular clear cell renal cell carcinoma", "Multilocular cystic renal cell adenocarcinoma", "Multilocular cystic renal cell carcinoma"]} |
Benign adult familial myoclonic epilepsy (BAFME) is an inherited epileptic syndrome characterized by cortical hand tremors, myoclonic jerks and occasional generalized or focal seizures with a non-progressive or very slowly progressive disease course, and no signs of early dementia or cerebellar ataxia.
## Epidemiology
Worldwide prevalence is unknown but an estimated prevalence of 1/35,000 was reported in Japan.
## Clinical description
BAFME usually presents in the second decade of life (but age of onset can range from age 11-50) with a minor cortical hand tremor. The tremor consists of continuous, arrhythmic fine twitching in the hands that is exacerbated by fatigue or emotional stress. There is no progression of severity in these tremors until after the age of 70. Myoclonus usually appears around the same age as the cortical tremor and consists of erratic, arrhythmic, segmental jerks of the upper limbs heightened by posture and action. Rare tonic-clonic seizures are also a manifestation of BAFME (peak age of onset being 30), occurring after the appearance of tremors and myoclonus and often precipitated by photic stimulation, emotional stress and sleep deprivation. Some patients from families mapped on chromosome 2p11.1-q12.2 present with drug-resistant complex partial seizures and focal EEG abnormalities. At an advanced age, a worsening of the myoclonus is possible as well as difficulty walking and mild ataxia.
## Etiology
BAFME has been mapped to at least 4 different chromosomal loci. The identified chromosomal loci linked to BAFME are: 8q23.3-q24.11 in Japanese families (BAFME type 1), 2p11.1-q12.2 in Italian families (BAFME type 2), 5p15.31-p15.1 in a French family (BAFME type 3) and 3q26.32-q28 in a Thai family (BAFME type 4). In addition, a consanguineous Egyptian family with focal epilepsy, neuropsychiatric features, borderline cognitive level, and myoclonus, resembling BAFME but inherited in an autosomal recessive manner was recently described. A homozygous deletion in the CNTN2 (1q32.1) gene encoding contactin 2 was found to be responsible.
## Diagnostic methods
Diagnosis is based on clinical and electrophysiological findings. Electroencephalographic (EEG) findings include a photomyoclonic response along with abnormality of polyspikes and waves. Patients also display extremely enlarged cortical components of somatosensory evoked potentials and an enhanced C-reflex. Jerk-locked average analysis reveals positive-negative, biphasic spikes preceding myoclonus.
## Differential diagnosis
BAFME must be differentiated from epilepsy syndromes with prominent myoclonus features. Patients may easily be misdiagnosed as having juvenile myoclonic epilepsy (JME; see this term) due to the occurence of myoclonic jerks and generalized tonic-clonic seizures. However, JME differs clinically from BAFME by the absence of cortical tremor, the mainly proximal myoclonic jerks, and seizures typically occurring at awakening. The absence of ataxia and dementia, the adult onset, and the usually benign outcome of epilepsy differentiates BAFME from progressive myoclonic epilepsies.
## Genetic counseling
BAFME is transmitted autosomal dominantly and penetrance is high. Genetic counseling is possible when a family member has the disease and presymptomatic diagnosis may be done in young patients from families mapped on any of the 3 loci, based on electrophysiological findings.
## Management and treatment
Cortical tremor (unlike essential tremor) usually has a poor response to beta blockers but improves with antiepileptic drugs. As alcohol aggravates these tremors, it should be avoided. Valproate, levetiracetam, and benzodiazepines are most beneficial in the treatment of cortical tremors and myoclonus due to their combined antiepileptic and antimyoclonic effects. In some cases, epilepsy may be difficult to treat.
## Prognosis
BAFME has no effect on life expectancy. With successful treatment, patients are often relieved from their symptoms.
*[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
| Benign adult familial myoclonic epilepsy | c1832841 | 1,492 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=86814 | 2021-01-23T19:08:50 | {"mesh": ["C563399"], "omim": ["601068", "607876", "613608", "615127", "615400"], "icd-10": ["G40.3"], "synonyms": ["ADCME", "Autosomal dominant cortical myoclonus and epilepsy", "BAFME", "Benign adult familial myoclonus epilepsy", "FAME", "FCMTE", "Familial adult myoclonic epilepsy", "Familial cortical myoclonic tremor and epilepsy"]} |
For other uses, see Piedra (disambiguation).
Piedra
Other namesTrichosporosis[1]:312
SpecialtyDermatology
Piedra is a hair disease caused by a fungus, which causes formation of nodules on the hair shaft.[2][3]
Types include:
* White piedra
* Black piedra
## References[edit]
1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0.
2. ^ "Piedra" at Dorland's Medical Dictionary
3. ^ Veasey JV, Avila RB, Miguel BAF, Muramatu LH. White piedra, black piedra, tinea versicolor, and tinea nigra: contribution to the diagnosis of superficial mycosis. An Bras Dermatol. 2017 May-Jun;92(3):413-416. doi:10.1590/abd1806-4841.20176018 PMID 29186263
## External links[edit]
Classification
D
* ICD-9-CM: 111.2-111.3
* MeSH: D010854
* SNOMED CT: 402135006
External resources
* eMedicine: derm/788
* 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
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* White superficial onychomycosis
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* Epidermophyton floccosum
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* Trichophyton rubrum
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Other
* Hortaea werneckii
* Tinea nigra
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* Black piedra
Basidiomycota
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* Trichosporon
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and opportunistic
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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
| Piedra | c0031898 | 1,493 | wikipedia | https://en.wikipedia.org/wiki/Piedra | 2021-01-18T18:53:54 | {"mesh": ["D010854"], "icd-9": ["111.2", "111.3"], "wikidata": ["Q10863066"]} |
Familial hyperaldosteronism is a group of inherited conditions in which the adrenal glands, which are small glands located on top of each kidney, produce too much of the hormone aldosterone. Aldosterone helps control the amount of salt retained by the kidneys. Excess aldosterone causes the kidneys to retain more salt than normal, which in turn increases the body's fluid levels and blood pressure. People with familial hyperaldosteronism may develop severe high blood pressure (hypertension), often early in life. Without treatment, hypertension increases the risk of strokes, heart attacks, and kidney failure.
Familial hyperaldosteronism is categorized into three types, distinguished by their clinical features and genetic causes. In familial hyperaldosteronism type I, hypertension generally appears in childhood to early adulthood and can range from mild to severe. This type can be treated with steroid medications called glucocorticoids, so it is also known as glucocorticoid-remediable aldosteronism (GRA). In familial hyperaldosteronism type II, hypertension usually appears in early to middle adulthood and does not improve with glucocorticoid treatment. In most individuals with familial hyperaldosteronism type III, the adrenal glands are enlarged up to six times their normal size. These affected individuals have severe hypertension that starts in childhood. The hypertension is difficult to treat and often results in damage to organs such as the heart and kidneys. Rarely, individuals with type III have milder symptoms with treatable hypertension and no adrenal gland enlargement.
There are other forms of hyperaldosteronism that are not familial. These conditions are caused by various problems in the adrenal glands or kidneys. In some cases, a cause for the increase in aldosterone levels cannot be found.
## Frequency
The prevalence of familial hyperaldosteronism is unknown. Familial hyperaldosteronism type II appears to be the most common variety. All types of familial hyperaldosteronism combined account for fewer than 1 out of 10 cases of hyperaldosteronism.
## Causes
The various types of familial hyperaldosteronism have different genetic causes. Familial hyperaldosteronism type I is caused by the abnormal joining together (fusion) of two similar genes called CYP11B1 and CYP11B2, which are located close together on chromosome 8. These genes provide instructions for making two enzymes that are found in the adrenal glands.
The CYP11B1 gene provides instructions for making an enzyme called 11-beta-hydroxylase. This enzyme helps produce hormones called cortisol and corticosterone. The CYP11B2 gene provides instructions for making another enzyme called aldosterone synthase, which helps produce aldosterone. When CYP11B1 and CYP11B2 are abnormally fused together, too much aldosterone synthase is produced. This overproduction causes the adrenal glands to make excess aldosterone, which leads to the signs and symptoms of familial hyperaldosteronism type I.
Familial hyperaldosteronism type III is caused by mutations in the KCNJ5 gene. The KCNJ5 gene provides instructions for making a protein that functions as a potassium channel, which means that it transports positively charged atoms (ions) of potassium into and out of cells. In the adrenal glands,the flow of ions through potassium channels produced from the KCNJ5 gene is thought to help regulate the production of aldosterone. Mutations in the KCNJ5 gene likely result in the production of potassium channels that are less selective, allowing other ions (predominantly sodium) to pass as well. The abnormal ion flow results in the activation of biochemical processes (pathways) that lead to increased aldosterone production, causing the hypertension associated with familial hyperaldosteronism type III.
The genetic cause of familial hyperaldosteronism type II is unknown.
### Learn more about the genes associated with Familial hyperaldosteronism
* CYP11B1
* CYP11B2
* KCNJ5
## Inheritance Pattern
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Familial hyperaldosteronism | c1260386 | 1,494 | medlineplus | https://medlineplus.gov/genetics/condition/familial-hyperaldosteronism/ | 2021-01-27T08:25:17 | {"gard": ["2789", "12362", "2790"], "mesh": ["C563177"], "omim": ["103900", "605635", "613677"], "synonyms": []} |
A number sign (#) is used with this entry because dyschromatosis symmetrica hereditaria (DSH) is caused by heterozygous mutation in the DSRAD gene (ADAR; 146920) on chromosome 1q21.
Description
Dyschromatosis symmetrica hereditaria (DSH), also called symmetric dyschromatosis of the extremities and symmetric or reticulate acropigmentation of Dohi (Komaya, 1924), is characterized by hyperpigmented and hypopigmented macules on the face and dorsal aspects of the extremities that appear in infancy or early childhood. DSH generally shows an autosomal dominant pattern of inheritance with high penetrance. The condition has been reported predominantly in Japanese and Chinese individuals.
### Review of Reticulate Pigment Disorders
Muller et al. (2012) reviewed the spectrum of reticulate pigment disorders of the skin, tabulating all reported cases of patients with Dowling-Degos disease (see DDD1; 179850), reticulate acropigmentation of Kitamura (RAK; 615537), reticulate acropigmentation of Dohi (RAD), Galli-Galli disease (GGD), and Haber syndrome (HS). Of 82 cases, 26 (31.7%) were clinically diagnosed as DDD, 13 (15.9%) as RAD, 11 (13.4%) as GGD, 8 (9.8%) as RAK, and 8 (9.8%) as HS; in addition, 16 (19.5%) of the cases showed overlap between DDD and RAK. Muller et al. (2012) also published photographs of an affected individual exhibiting an overlap of clinical features of DDD, GGD, RAD, and RAK. The authors noted that in reticulate disorders of the skin, the main disease entity is DDD, with a subset of cases exhibiting acantholysis (GGD), facial erythema (HS), or an acral distribution (RAD; RAK). Muller et al. (2012) concluded that all reticulate pigment diseases of the skin are varying manifestations of a single entity.
### Genetic Heterogeneity of Reticulate Pigment Disorders
For a discussion of genetic heterogeneity of reticulate pigment disorders, see 179850.
Clinical Features
Patrizi et al. (1994) described a 9-year-old Caucasian girl with a mixture of hyperpigmented and hypopigmented macules on the backs of the feet. Two brothers had the same lesions, and all had small freckle-like pigmented macules on their face. The father showed large symmetrical hypopigmented vitiligo-like macules which had been present on the backs of his hands and the tops of his feet since childhood. Large symmetrical hypopigmented vitiligo-like macules were found also around his eyes and mouth, on his knees, and on his penis. These hypopigmented macules had progressively widened after the age of 28 years. The 9-year-old daughter had, since the age of 7 years, also shown a neurologic disorder diagnosed as idiopathic torsion dystonia. In all 4 patients, no cellular abnormality in DNA repair was demonstrated, thus excluding a mild form of xeroderma pigmentosum. Torsion dystonia (TYD1; 128100) maps to 9q34. Because of the family of Patrizi et al. (1994), the DSH gene was hypothesized to be located on chromosome 9, but studies of 3 Japanese families with DSH by Kono et al. (2000) excluded chromosome 9.
Oyama et al. (1999) reported a Japanese family with DSH. The proband was an 11-year-old male, born following a normal pregnancy and delivery. At the age of 1 year, he developed pea-sized pigmented macules on the face. The small hyperpigmented and hypopigmented macules spread gradually on the dorsal aspects of the extremities. The number of skin lesions increased until he was 4 years of age. The mother, a 50-year-old woman, had had an asymptomatic mixture of hyperpigmented and hypopigmented small macules on the backs of her hands and feet as well as scattered small pigmented macules on her face since childhood. Her father, twin brothers of her father, and her grandmother had also had the same skin lesions.
Oyama et al. (1999) reviewed 185 cases of DSH reported since 1923. The differential diagnosis was considered to include dyschromatosis universalis hereditaria (DUH; 127500). DUH was once considered to be a generalized form of DSH; however, Suenaga (1952) pointed out that skin lesions in DUH appear predominantly on the trunk. DSH can closely resemble a mild form of xeroderma pigmentosum (see 278700).
In Italy, Danese et al. (1997) observed a family with affected members in at least 3 generations. The proband was a 21-year-old white woman who had progressive reticulate hyper- and hypopigmentation on the volar surface of the forearms and the dorsa of the hands. There were no pits or breaks in the epidermal ridge pattern on the palms.
Urabe and Hori (1997) described a Japanese family with DSH with an autosomal recessive inheritance pattern. Alfadley et al. (2000) described 3 black sibs from the Middle East, a 20-year-old male and his 19- and 18-year-old sisters, who had progressive reticulate hyperpigmented and hypopigmented macules over the dorsa of hands and feet, which began in early childhood. There were no palmar pits or breaks of the epidermal rete ridge pattern, nor was there a family history of any pigmentary skin disease. Findings from 3 skin biopsies from 1 patient were consistent with DSH. These finding suggested to the authors that DSH may be inherited in an autosomal recessive manner.
Chao et al. (2006) reported 3 affected members of a Taiwanese family segregating DSH. Strict avoidance of sunlight by the proband and her affected daughter led to improvement in the skin lesions.
Population Genetics
Miyamura et al. (2003) stated that the prevalence of DSH in the Japanese population is estimated to be 1.5 per 100,000.
Mapping
Zhang et al. (2003) performed a genomewide search in 2 large Chinese families with DSH and identified a locus at chromosome 1q11-q21 with a cumulative maximum 2-point lod score of 8.85 at marker D1S2343 (recombination fraction = 0.00). Haplotype analyses indicated that the disease gene is located within the 11.6-cM region between markers D1S2696 and D1S2635.
Miyamura et al. (2003) performed a genomewide search in 3 families with DSH and mapped the DSH locus to 1q21.3, within a 500-kb critical region bounded proximally by IL6R (147880) and distally by KCNN3 (602983).
Miyamura et al. (2003) suggested that the patients reported by Xing et al. (2003) showing linkage to 6q24.2-q25.2 in fact had dyschromatosis universalis hereditaria, as indicated by photographs showing dyschromatosis over most of their entire bodies.
Molecular Genetics
In affected members of 4 Japanese families segregating DSH, Miyamura et al. (2003) identified heterozygous mutations in the ADAR gene (146920.0001-146920.0004).
In affected members of 6 Chinese multigeneration families and 2 sporadic patients with DSH, Zhang et al. (2004) identified 7 novel heterozygous mutations in the ADAR gene.
INHERITANCE \- Autosomal dominant SKIN, NAILS, & HAIR Skin \- Hyperpigmented/hypopigmented macules (dorsum hands and feet, face) MISCELLANEOUS \- Onset in infancy and early childhood \- New skin lesions stop appearing before adolescence \- Majority of cases in Japan MOLECULAR BASIS \- Caused by mutation in the adenosine deaminase, RNA-specific gene (ADAR, 601059.0001 ) ▲ 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
| DYSCHROMATOSIS SYMMETRICA HEREDITARIA | c0406775 | 1,495 | omim | https://www.omim.org/entry/127400 | 2019-09-22T16:42:05 | {"doid": ["0060257"], "mesh": ["C535729"], "omim": ["127400"], "orphanet": ["41"], "synonyms": ["Alternative titles", "DYSCHROMATOSIS SYMMETRICA HEREDITARIA 1", "RETICULATE ACROPIGMENTATION OF DOHI", "SYMMETRIC DYSCHROMATOSIS OF THE EXTREMITIES"]} |
Central pontine myelinolysis
Other namesOsmotic demyelination syndrome, central pontine demyelination
Axial fat-saturated T2-weighted image showing hyperintensity in the pons with sparing of the peripheral fibers, the patient was an alcoholic admitted with a serum Na of 101 treated with hypertonic saline, he was left with quadriparesis, dysarthria, and altered mental status
SpecialtyNeurology
CausesAlcoholism, malnutrition
Central pontine myelinolysis (CPM) is a neurological condition involving severe damage to the myelin sheath of nerve cells in the pons (an area of the brainstem). It is predominately iatrogenic (treatment-induced), and is characterized by acute paralysis, dysphagia (difficulty swallowing), dysarthria (difficulty speaking), and other neurological symptoms.
Central pontine myelinolysis was first described as a disorder in 1959. The original paper described four cases with fatal outcomes, and the findings on autopsy. The disease was described as a disease of alcoholics and malnutrition.[1] ‘Central pontine’ indicated the site of the lesion and ‘myelinolysis’ was used to emphasise that myelin was affected. The authors intentionally avoided the term ‘demyelination’ to describe the condition, in order to differentiate this condition from multiple sclerosis and other neuroinflammatory disorders.[2]
Since this original description, demyelination in other areas of the central nervous system associated with osmotic stress has been described outside the pons (extrapontine).[3] Osmotic demyelination syndrome (ODS) is the term used for both central pontine myelinolysis and extrapontine myelinolysis.[4]
Central pontine myelinolysis, and osmotic demyelination syndrome, present most commonly as a complication of treatment of patients with profound hyponatremia (low sodium), which can result from a varied spectrum of conditions, based on different mechanisms. It occurs as a consequence of a rapid rise in serum tonicity following treatment in individuals with chronic, severe hyponatremia who have made intracellular adaptations to the prevailing hypotonicity.[5][6]
## Contents
* 1 Signs and symptoms
* 2 Causes
* 3 Pathophysiology
* 4 Diagnosis
* 5 Treatment
* 6 Prognosis
* 7 References
* 8 External links
## Signs and symptoms[edit]
T2 weighted magnetic resonance scan image showing bilaterally symmetrical hyperintensities in caudate nucleus (small, thin arrow), putamen (long arrow), with sparing of globus pallidus (broad arrow), suggestive of extrapontine myelinolysis (osmotic demyelination syndrome)
Symptoms depend on the regions of the brain involved. Prior to its onset, patients may present with the neurological signs and symptoms of hyponatraemic encephalopathy such as nausea and vomiting, confusion, headache and seizures. These symptoms may resolve with normalisation of the serum sodium concentration. Three to five days later, a second phase of neurological manifestations occurs correlating with the onset of myelinolysis. Observable immediate precursors may include seizures, disturbed consciousness, gait changes, and decrease or cessation of respiratory function.[7][8]
The classical clinical presentation is the progressive development of spastic quadriparesis, pseudobulbar palsy, and emotional lability (pseudobulbar affect), with other more variable neurological features associated with brainstem damage. These result from a rapid myelinolysis of the corticobulbar and corticospinal tracts in the brainstem.[9]
In about ten per cent of people with CPM, extrapontine myelinolysis (EPM) is also found. In these cases symptoms of Parkinson's disease may be generated.[1]
## Causes[edit]
Loss of myelinated fibers at the basilar part of the pons in the brainstem (Luxol-Fast blue stain)
The most common cause is overly rapid correction of low blood sodium levels (hyponatremia).[10] Apart from rapid correction of hyponatraemia, there are case reports of central pontine myelinolysis in association with hypokalaemia, anorexia nervosa when feeding is started, patients undergoing dialysis and burn victims. There is a case report of central pontine myelinolysis occurring in the context of refeeding syndrome, in the absence of hyponatremia.[2]
It has also been known to occur in patients suffering withdrawal symptoms of chronic alcoholism.[1] In these instances, occurrence may be entirely unrelated to hyponatremia or rapid correction of hyponatremia. It could affect patients who take some prescription medicines that are able to cross the blood-brain barrier and cause abnormal thirst reception - in this scenario the CPM is caused by polydipsia leading to low blood sodium levels (hyponatremia).[citation needed]
In schizophrenic patients with psychogenic polydipsia, inadequate thirst reception leads to excessive water intake, severely diluting serum sodium.[11] With this excessive thirst combined with psychotic symptoms, brain damage such as CPM[12] may result from hyperosmolarity caused by excess intake of fluids, (primary polydipsia) although this is difficult to determine because such patients are often institutionalised and have a long history of mental health conditions.[13]
It has been observed following hematopoietic stem cell transplantation.[14]
CPM may also occur in patients prone to hyponatraemia affected by:
* Severe liver disease (e.g., cirrhosis)
* Liver transplant[15][16][17]
* Alcoholism
* Hypokalemia
* People with serum sodium <105 mEq/L
* Severe burns[18][19]
* Malnutrition
* Anorexia nervosa[20][21][22]
* Severe electrolyte disorders
* HIV/AIDS
* hyperemesis gravidarum[23][24]
* Hyponatremia due to peritoneal dialysis
* Wernicke encephalopathy[25]
## Pathophysiology[edit]
The currently accepted theory states that the brain cells adjust their osmolarities by changing levels of certain osmolytes like inositol, betaine, and glutamine in response to varying serum osmolality. In the context of chronic low plasma sodium (hyponatremia), the brain compensates by decreasing the levels of these osmolytes within the cells, so that they can remain relatively isotonic with their surroundings and not absorb too much fluid. The reverse is true in hypernatremia, in which the cells increase their intracellular osmolytes so as not to lose too much fluid to the extracellular space.[citation needed]
With correction of the hyponatremia with intravenous fluids, the extracellular tonicity increases, followed by an increase in intracellular tonicity. When the correction is too rapid, not enough time is allowed for the brain's cells to adjust to the new tonicity, namely by increasing the intracellular osmoles mentioned earlier. If the serum sodium levels rise too rapidly, the increased extracellular tonicity will continue to drive water out of the brain's cells. This can lead to cellular dysfunction and CPM.[26][27]
## Diagnosis[edit]
It can be diagnosed clinically in the appropriate context, but may be difficult to confirm radiologically using conventional imaging techniques. Changes are more prominent on MRI than on CT, but often take days or weeks after acute symptom onset to develop. Imaging by MRI typically demonstrates areas of hyperintensity on T2-weighted images.[citation needed]
## Treatment[edit]
To minimise the risk of this condition developing from its most common cause, overly rapid reversal of hyponatremia, the hyponatremia should be corrected at a rate not exceeding 10 mmol/L/24 h or 0.5 mEq/L/h; or 18 mEq/L/48hrs; thus avoiding demyelination.[27] No large clinical trials have been performed to examine the efficacy of therapeutic re-lowering of serum sodium, or other interventions sometimes advocated such as steroids or plasma exchange.[27] Alcoholic patients should receive vitamin supplementation and a formal evaluation of their nutritional status.[28][29]
Once osmotic demyelination has begun, there is no cure or specific treatment. Care is mainly supportive. Alcoholics are usually given vitamins to correct for other deficiencies. The favourable factors contributing to the good outcome in CPM without hyponatremia were: concurrent treatment of all electrolyte disturbances, early intensive care unit involvement at the advent of respiratory complications, early introduction of feeding including thiamine supplements with close monitoring of the electrolyte changes and input.[2]
Research has led to improved outcomes.[30] Animal studies suggest that inositol reduces the severity of osmotic demyelination syndrome if given before attempting to correct chronic hyponatraemia.[31] Further study is required before using inositol in humans for this purpose.
## Prognosis[edit]
Though traditionally the prognosis is considered poor, a good functional recovery is possible. All patients at risk of developing refeeding syndrome should have their electrolytes closely monitored, including sodium, potassium, magnesium, glucose and phosphate.[2] Recent data indicate that the prognosis of critically ill patients may even be better than what is generally considered,[32] despite severe initial clinical manifestations and a tendency by the intensivists to underestimate a possible favorable evolution.[33] While some patients die, most survive and of the survivors, approximately one-third recover; one-third are disabled but are able to live independently; one-third are severely disabled.[34] Permanent disabilities range from minor tremors and ataxia to signs of severe brain damage, such as spastic quadriparesis and locked-in syndrome.[35] Some improvements may be seen over the course of the first several months after the condition stabilizes.
The degree of recovery depends on the extent of the original axonal damage.[26]
## References[edit]
1. ^ a b c Yoon B, Shim YS, Chung SW (2008). "Central Pontine and Extrapontine Myelinolysis After Alcohol Withdrawal". Alcohol. 43 (6): 647–9. doi:10.1093/alcalc/agn050. PMID 18678596.
2. ^ a b c d Bose, P; Kunnacherry, A; Maliakal, P (19 September 2011). "Central pontine myelinolysis without hyponatraemia". The Journal of the Royal College of Physicians of Edinburgh. 41 (3): 211–214. doi:10.4997/JRCPE.2011.305. PMID 21949915.
3. ^ Gocht A, Colmant HJ (1987). "Central pontine and extrapontine myelinolysis: a report of 58 cases". Clin. Neuropathol. 6 (6): 262–70. PMID 3322623.
4. ^ Lampl C, Yazdi K (2002). "Central pontine myelinolysis". Eur. Neurol. 47 (1): 3–10. doi:10.1159/000047939. PMID 11803185. S2CID 46885398. Archived from the original on 2012-03-06.
5. ^ Babar, S. (October 2013). "SIADH Associated With Ciprofloxacin". Annals of Pharmacotherapy. 47 (10): 1359–1363. doi:10.1177/1060028013502457. ISSN 1060-0280. PMID 24259701. S2CID 36759747.
6. ^ https://academic.oup.com/alcalc/article/43/6/647/249472
7. ^ Musana AK, Yale SH (August 2005). "Central pontine myelinolysis: case series and review". WMJ. 104 (6): 56–60. PMID 16218318.
8. ^ Odier C, Nguyen DK, Panisset M (July 2010). "Central pontine and extrapontine myelinolysis: from epileptic and other manifestations to cognitive prognosis". J. Neurol. 257 (7): 1176–80. doi:10.1007/s00415-010-5486-7. PMID 20148334. S2CID 25301314.
9. ^ Karp BI, Laureno R (November 1993). "Pontine and extrapontine myelinolysis: a neurologic disorder following rapid correction of hyponatremia". Medicine (Baltimore). 72 (6): 359–73. doi:10.1097/00005792-199311000-00001. PMID 8231786. S2CID 24829955.
10. ^ Bernsen HJ, Prick MJ (September 1999). "Improvement of central pontine myelinolysis as demonstrated by repeated magnetic resonance imaging in a patient without evidence of hyponatremia". Acta Neurol Belg. 99 (3): 189–93. PMID 10544728.
11. ^ Donald, Hutcheon. "Psychogenic Polydipsia (Excessive Fluid seeking Behaviour)" (PDF). American Psychological Society Divisions.
12. ^ Lim, Leslie; Krystal, Andrew (2007-06-01). "Psychotic disorder in a patient with central and extrapontine myelinolysis". Psychiatry and Clinical Neurosciences. 61 (3): 320–322. doi:10.1111/j.1440-1819.2007.01648.x. ISSN 1440-1819. PMID 17472602.
13. ^ Melissa, Gill; MacDara, McCauley; Melissa, Gill; MacDara, McCauley (2015-01-21). "Psychogenic Polydipsia: The Result, or Cause of, Deteriorating Psychotic Symptoms? A Case Report of the Consequences of Water Intoxication". Case Reports in Psychiatry. 2015: 846459. doi:10.1155/2015/846459. ISSN 2090-682X. PMC 4320790. PMID 25688318.
14. ^ Lim KH, Kim S, Lee YS, et al. (April 2008). "Central pontine myelinolysis in a patient with acute lymphoblastic leukemia after hematopoietic stem cell transplantation: a case report". J. Korean Med. Sci. 23 (2): 324–7. doi:10.3346/jkms.2008.23.2.324. PMC 2526450. PMID 18437020. Archived from the original on 2009-02-27.
15. ^ Singh N, Yu VL, Gayowski T (March 1994). "Central nervous system lesions in adult liver transplant recipients: clinical review with implications for management". Medicine (Baltimore). 73 (2): 110–8. doi:10.1097/00005792-199403000-00004. PMID 8152365. S2CID 37808180.
16. ^ Kato T, Hattori H, Nagato M, Kiuchi T, Uemoto S, Nakahata T, Tanaka K (April 2002). "Subclinical central pontine myelinolysis following liver transplantation". Brain Dev. 24 (3): 179–82. doi:10.1016/S0387-7604(02)00013-X. PMID 11934516. S2CID 22140717.
17. ^ Martinez AJ, Estol C, Faris AA (May 1988). "Neurologic complications of liver transplantation". Neurol Clin. 6 (2): 327–48. doi:10.1016/S0733-8619(18)30873-9. PMID 3047544.
18. ^ McKee AC, Winkelman MD, Banker BQ (August 1988). "Central pontine myelinolysis in severely burned patients: relationship to serum hyperosmolality". Neurology. 38 (8): 1211–7. doi:10.1212/wnl.38.8.1211. PMID 3399069. S2CID 42068902.
19. ^ Winkelman MD, Galloway PG (September 1992). "Central nervous system complications of thermal burns. A postmortem study of 139 patients". Medicine (Baltimore). 71 (5): 271–83. doi:10.1097/00005792-199209000-00002. PMID 1522803. S2CID 12872586.
20. ^ Sugimoto T, Murata T, Omori M, Wada Y (March 2003). "Central pontine myelinolysis associated with hypokalaemia in anorexia nervosa". J. Neurol. Neurosurg. Psychiatry. 74 (3): 353–5. doi:10.1136/jnnp.74.3.353. PMC 1738317. PMID 12588925.
21. ^ Keswani SC (April 2004). "Central pontine myelinolysis associated with hypokalaemia in anorexia nervosa". J. Neurol. Neurosurg. Psychiatry. 75 (4): 663, author reply 663. PMC 1739009. PMID 15026526. Retrieved 2014-05-29.
22. ^ Leroy S, Gout A, Husson B, de Tournemire R, Tardieu M (June 2012). "Centropontine myelinolysis related to refeeding syndrome in an adolescent suffering from anorexia nervosa". Neuropediatrics. 43 (3): 152–4. doi:10.1055/s-0032-1307458. PMID 22473289.
23. ^ Bergin PS, Harvey P (August 1992). "Wernicke's encephalopathy and central pontine myelinolysis associated with hyperemesis gravidarum". BMJ. 305 (6852): 517–8. doi:10.1136/bmj.305.6852.517. PMC 1882865. PMID 1393001.
24. ^ Sutamnartpong P, Muengtaweepongsa S, Kulkantrakorn K (January 2013). "Wernicke's encephalopathy and central pontine myelinolysis in hyperemesis gravidarum". J Neurosci Rural Pract. 4 (1): 39–41. doi:10.4103/0976-3147.105608. PMC 3579041. PMID 23546346.
25. ^ Kishimoto Y, Ikeda K, Murata K, Kawabe K, Hirayama T, Iwasaki Y (2012). "Rapid development of central pontine myelinolysis after recovery from Wernicke encephalopathy: a non-alcoholic case without hyponatremia". Intern. Med. 51 (12): 1599–603. doi:10.2169/internalmedicine.51.7498. PMID 22728498.
26. ^ a b Medana IM, Esiri MM (March 2003). "Axonal damage: a key predictor of outcome in human CNS diseases". Brain. 126 (Pt 3): 515–30. doi:10.1093/brain/awg061. PMID 12566274.
27. ^ a b c Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn E, Ichai C, Joannidis M, Soupart A, Zietse R, Haller M, van der Veer S, Van Biesen W, Nagler E (2014). "Clinical practice guideline on diagnosis and treatment of hyponatremia". European Journal of Endocrinology. 170 (3): G1–G47. doi:10.1530/eje-13-1020. PMID 24569125.
28. ^ Kleinschmidt-DeMasters BK, Norenberg MD (March 1981). "Rapid correction of hyponatremia causes demyelination: relation to central pontine myelinolysis". Science. 211 (4486): 1068–70. Bibcode:1981Sci...211.1068K. doi:10.1126/science.7466381. PMID 7466381.
29. ^ Laureno R (1980). "Experimental pontine and extrapontine myelinolysis". Trans Am Neurol Assoc. 105: 354–8. PMID 7348981.
30. ^ Brown WD (December 2000). "Osmotic demyelination disorders: central pontine and extrapontine myelinolysis". Curr. Opin. Neurol. 13 (6): 691–7. doi:10.1097/00019052-200012000-00014. PMID 11148672. S2CID 36063964.
31. ^ Silver SM, Schroeder BM, Sterns RH, Rojiani AM (2006). "Myoinositol administration improves survival and reduces myelinolysis after rapid correction of chronic hyponatremia in rats". J Neuropathol Exp Neurol. 65 (1): 37–44. doi:10.1097/01.jnen.0000195938.02292.39. PMID 16410747.
32. ^ Louis G, Megarbane B, Lavoué S, Lassalle V, Argaud L, Poussel JF, Georges H, Bollaert PE (March 2012). "Long-term outcome of patients hospitalized in intensive care units with central or extrapontine myelinolysis*". Critical Care Medicine. 40 (3): 970–2. doi:10.1097/CCM.0b013e318236f152. PMID 22036854. S2CID 205542487.
33. ^ Young GB (March 2012). "Central pontine myelinolysis: a lesson in humility*". Critical Care Medicine. 40 (3): 1026–7. doi:10.1097/CCM.0b013e31823b8e0b. PMID 22343870.
34. ^ Abbott R, Silber E, Felber J, Ekpo E (October 2005). "Osmotic demyelination syndrome". BMJ. 331 (7520): 829–30. doi:10.1136/bmj.331.7520.829. PMC 1246086. PMID 16210283.
35. ^ Luzzio, Christopher (17 November 2015). "Central Pontine Myelinolysis". Medscape. Retrieved 14 March 2017.
## External links[edit]
Classification
D
* ICD-10: G37.2
* MeSH: D017590
* SNOMED CT: 6807001
* MedPix Images of Osmotic Myelinolysis
* v
* t
* e
Multiple sclerosis and other demyelinating diseases of the central nervous system
Signs and symptoms
* Ataxia
* Depression
* Diplopia
* Dysarthria
* Dysphagia
* Fatigue
* Incontinence
* Nystagmus
* Optic neuritis
* Pain
* Uhthoff's phenomenon
Investigations and diagnosis
* Multiple sclerosis diagnosis
* McDonald criteria
* Poser criteria
* Clinical
* Clinically isolated syndrome
* Expanded Disability Status Scale
* Serological and CSF
* Oligoclonal bands
* Radiological
* Radiologically isolated syndrome
* Lesional demyelinations of the central nervous system
* Dawson's fingers
Approved[by whom?] treatment
* Management of multiple sclerosis
* Alemtuzumab
* Cladribine
* Dimethyl fumarate
* Fingolimod
* Glatiramer acetate
* Interferon beta-1a
* Interferon beta-1b
* Mitoxantrone
* Natalizumab
* Ocrelizumab
* Ozanimod
* Siponimod
* Teriflunomide
Other treatments
* Former
* Daclizumab
* Multiple sclerosis research
Demyleinating diseases
Autoimmune
* Multiple sclerosis
* Neuromyelitis optica
* Diffuse myelinoclastic sclerosis
Inflammatory
* Acute disseminated encephalomyelitis
* MOG antibody disease
* Balo concentric sclerosis
* Marburg acute multiple sclerosis
* Neuromyelitis optica
* Diffuse myelinoclastic sclerosis
* Tumefactive multiple sclerosis
* Experimental autoimmune encephalomyelitis
Hereditary
* Adrenoleukodystrophy
* Alexander disease
* Canavan disease
* Krabbe disease
* Metachromatic leukodystrophy
* Pelizaeus–Merzbacher disease
* Leukoencephalopathy with vanishing white matter
* Megalencephalic leukoencephalopathy with subcortical cysts
* CAMFAK syndrome
Other
* Central pontine myelinolysis
* Marchiafava–Bignami disease
* Mitochondrial DNA depletion syndrome
Other
* List of multiple sclerosis organizations
* List of people with multiple sclerosis
* Multiple sclerosis drug pipeline
* Pathophysiology
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Central pontine myelinolysis | c0206083 | 1,496 | wikipedia | https://en.wikipedia.org/wiki/Central_pontine_myelinolysis | 2021-01-18T18:45:11 | {"gard": ["8749"], "mesh": ["D017590"], "umls": ["C0206083"], "wikidata": ["Q190370"]} |
For a phenotypic description and a discussion of genetic heterogeneity of malignant hyperthermia, see MHS1 (145600).
By linkage studies in 3 families, Sudbrak et al. (1993) excluded linkage either to chromosome 19 or 17q, thus suggesting the existence of a third locus for malignant hyperthermia susceptibility.
In MHS families linked to neither chromosome 17 nor chromosome 19, Iles et al. (1994) found linkage with no recombination to markers flanking the CACNA2D1 gene (114204) on chromosome 7. Since this gene encodes a subunit of the L-type voltage-dependent calcium channel that is intimately associated at the skeletal muscle triadic junctions with the ryanodine receptor (RYR1; 180901), it is possible that the mutation is located in this gene. In affected members of a family linked to the MHS3 locus by Iles et al. (1994), Schleithoff et al. (1999) did not identify any pathogenic mutations in the coding region of the CACNA2D1 gene.
Neuro \- Hyperthermia Inheritance \- Autosomal dominant form (unlinked to 19q or 17q) \- heterogeneous Metabolic \- Lactic acidosis Misc \- Precipitated by general anesthesia \- Hypertonicity of voluntary muscles \- Response to Dantrolene sodium Lab \- Elevated blood CPK, phosphate and potassium Muscle \- Myopathy \- Rhabdomyolysis may follow severe exercise in hot conditions, neuroleptic drugs, alcohol, or infections ▲ 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
| MALIGNANT HYPERTHERMIA, SUSCEPTIBILITY TO, 3 | c0024591 | 1,497 | omim | https://www.omim.org/entry/154276 | 2019-09-22T16:38:34 | {"mesh": ["D008305"], "omim": ["154276"], "orphanet": ["423"], "synonyms": ["Alternative titles", "MHS3"], "genereviews": ["NBK1146"]} |
Form of dwarfism that results in a smaller body size in all stages of life
Primordial dwarfism
SpecialtyMedical genetics
Primordial dwarfism (PD) is a form of dwarfism that results in a smaller body size in all stages of life beginning from before birth.[1] More specifically, primordial dwarfism is a diagnostic category including specific types of profoundly proportionate dwarfism, in which individuals are extremely small for their age, even as a fetus. Most individuals with primordial dwarfism are not diagnosed until they are about 3–5 years of age.
Medical professionals typically diagnose the fetus as being small for gestational age, or as showing intrauterine growth restriction when an ultrasound is conducted. Typically, people with primordial dwarfism are born with very low birth weights. After birth, growth continues at a much slower rate, leaving individuals with primordial dwarfism perpetually years behind their peers in stature and in weight.
Most cases of short stature are caused by skeletal or endocrine disorders. The five subtypes of primordial dwarfism are among the most severe forms of the 200 types of dwarfism.
There are as yet no effective treatments for primordial dwarfism. It is rare for individuals affected by primordial dwarfism to live past the age of 30.[2] In the case of microcephalic osteodysplastic primordial dwarfism type 2 (MOPDII), there can be increased risk of vascular problems, which may cause premature death.[3]
## Contents
* 1 Causes
* 2 Diagnosis
* 2.1 Types
* 3 Notable cases
* 4 See also
* 5 References
## Causes[edit]
It is known that PD is caused by inheriting a mutant gene from each parent.[4] The lack of normal growth in the disorder is not due to a deficiency of growth hormone, as in hypopituitary dwarfism. Administering growth hormone, therefore, has little or no effect on the growth of the individual with primordial dwarfism, except in the case of Russell–Silver syndrome (RSS). Individuals with RSS respond favorably to growth hormone treatment. Children with RSS that are treated with growth hormone before puberty may achieve several inches of additional height. In January 2008, it was published that mutations in the pericentrin gene (PCNT) were found to cause primordial dwarfism.[5] Pericentrin has a role in cell division, proper chromosome segregation and cytokinesis.
Another gene that has been implicated in this condition is DNA2.[6] Mutations in this gene have been implicated in Seckel syndrome.
## Diagnosis[edit]
Since primordial dwarfism disorders are extremely rare, misdiagnosis is common. Because children with PD do not grow like other children, poor nutrition, a metabolic disorder, or a digestive disorder may be diagnosed initially. The correct diagnosis of PD may not be made until the child is 5 years old and it becomes apparent that the child has severe dwarfism.[citation needed]
### Types[edit]
Name OMIM Description
Seckel syndrome 210600 People with Seckel syndrome are noted to have microcephaly. Many also suffer from scoliosis, hip dislocation, delayed bone age, radial head dislocation, and seizures. Mutations in patients with Seckel syndrome have recently been identified in the gene encoding centrosomal protein CEP152 which is also mutated in some cases of primary isolated microcephaly.
Microcephalic osteodysplastic primordial dwarfism type I (MODPD1) (Taybi–Linder syndrome) 210710 This form of primordial dwarfism is often shortened to ODPDI. The corpus callosum of the brain is often undeveloped (called agenesis of the corpus callosum) and patients are known to have seizures and apnea. Hair thinness is also common, including scalp, hair, eyelashes and eyebrows. They suffer skeletally from short vertebrae, elongated clavicles, bent femora and hip displacement. Like those with Seckel syndrome, they also often have microcephaly. This syndrome is due to mutations in the RNU4ATAC gene. This gene, located on the long arm of chromosome 2 (2q14), encodes a small nuclear RNA component of the U12 dependent spliceosome.
Microcephalic osteodysplastic primordial dwarfism type II (MODPD2) 210720 Those who have ODPDII often have additional medical problems as compared with the other types, such as a squeaky voice, microdontia, widely spaced primary teeth, poor sleep patterns (in early years), delayed mental development, frequent sickness, breathing problems, eating problems, hyperactivity, farsightedness, brain aneurysms, and do not respond to hormone therapy because primordial dwarfism is not caused by a lack of any growth hormone. After reviewing X-rays, it is also found that many have dislocated joints, scoliosis and delayed bone age as well as microcephaly. They will not reach the size of an average newborn until they are between the ages of 3 and 5. This condition is due to mutations in the PCNT gene located on the long arm of chromosome 21 (21q22). It encodes a protein known as pericentrin.
Silver–Russell dwarfism (Russell-Silver Syndrome) 180860 The final height of those with Russell–Silver syndrome often exceeds the height of others with primordial dwarfism, and they tend to have dysmorphic features. Some phenotypes (characteristics) of people who have Russell–Silver syndrome are inadequate catch-up growth in first 2 years, body asymmetry, lack of appetite, low-set posteriorly rotated ears, clinodactly (inward curving) of the 5th finger, webbed toes, non-descended testicles, weak muscle tone, delayed bone age, downturned corners of mouth and thin upper lip, hypospadias, high pitched voice, small chin, delayed closure of the fontanel, hypoglycemia, and a bossed forehead. Their heads may appear to be triangular shaped and large for their small body size.
Meier–Gorlin syndrome 224690 Individuals with Meier-Gorlin syndrome often have small ears and no kneecaps. They are also found to have curved clavicles, narrow ribs, and elbow dislocation. Like Russell–Silver syndrome, they usually exceed the height of those with Seckel syndrome and ODPDI and II. It is also known as "ear, patella, short stature syndrome" (EPS). Mutations in patients with Meier-Gorlin syndrome have recently been identified in a series of genes involved in chromosomal replication, specifically in the pre-replication complex. Specific genes include origin recognition complex genes ORC1, ORC4 and ORC6, as well as other replication genes CDT1 and CDC6.
## Notable cases[edit]
* Nelson de la Rosa – actor linked to the USA baseball team Boston Red Sox
* Lucía Zárate – Mexican entertainer and first person identified to have MOPD II
* Weng Weng – Filipino actor and martial artist
* Aditya Dev – world's smallest bodybuilder
* Gul Mohammed – former smallest man of all time
* He Pingping – world's shortest ambulatory man until his death in 2010
* Khagendra Thapa Magar – world's shortest man from his 18th birthday on 14 October 2010 to 13 June 2011
* Chandra Bahadur Dangi – smallest man of all time[7]
* Caroline Crachami – known as the "Sicilian Fairy" and famously displayed in the Hunterian Museum in Scotland
* Bridgette Jordan and Brad Jordan – siblings.[8]
## See also[edit]
* Gigantism
* Dwarfism
* Psychogenic dwarfism
* List of people with dwarfism
## References[edit]
1. ^ Fima Lifshitz (2007). Pediatric Endocrinology: Growth, adrenal, sexual, thyroid, calcium, and fluid balance disorders. CRC Press. pp. 15–. ISBN 978-1-4200-4270-2. Retrieved 7 January 2011.
2. ^ As seen on the 2006 TLC/Channel Four program on primordial dwarfism, The Smallest People in the World,
3. ^ American Journal of Medical Genetics
4. ^ National Geographic Channel Presents: Science of Dwarfism
5. ^ Rauch, A.; Thiel, C.T.; Schindler, D.; Wick, U.; Crow, Y.J.; Ekici, A.B.; Van Essen, A.J.; Goecke, T.O.; Al-gazali, L.; Chrzanowska, K.H.; et al. (2008). "Mutations in the Pericentrin (PCNT) Gene Cause Primordial Dwarfism". Science. 319 (5864): 816–9. Bibcode:2008Sci...319..816R. doi:10.1126/science.1151174. PMID 18174396.
6. ^ Tarnauskaitė Ž, Bicknell LS, Marsh JA, Murray JE, Parry DA, Logan CV, Bober MB, de Silva DC, Duker AL, Sillence D, Wise C, Jackson AP, Murina O, Reijns MAM (2019) Biallelic variants in DNA2 cause microcephalic primordial dwarfism. Hum Mutat
7. ^ "72-year-old Nepalese man from remote mountain village declared shortest human on record". The Washington Post. Retrieved 2012-02-28.[dead link]
8. ^ "Smallest Siblings In the World Bridgette and Brad Jordan" Retrieved on 10 February 2019.
* v
* t
* e
Growth and height disorder due to endocrine malfunction
* Dwarfism
* Primordial dwarfism
* Laron syndrome
* Psychosocial
* Ateliosis
* Gigantism
* v
* t
* e
Congenital abnormality syndromes
Craniofacial
* Acrocephalosyndactylia
* Apert syndrome
* Carpenter syndrome
* Pfeiffer syndrome
* Saethre–Chotzen syndrome
* Sakati–Nyhan–Tisdale syndrome
* Bonnet–Dechaume–Blanc syndrome
* Other
* Baller–Gerold syndrome
* Cyclopia
* Goldenhar syndrome
* Möbius syndrome
Short stature
* 1q21.1 deletion syndrome
* Aarskog–Scott syndrome
* Cockayne syndrome
* Cornelia de Lange syndrome
* Dubowitz syndrome
* Noonan syndrome
* Robinow syndrome
* Silver–Russell syndrome
* Seckel syndrome
* Smith–Lemli–Opitz syndrome
* Snyder–Robinson syndrome
* Turner syndrome
Limbs
* Adducted thumb syndrome
* Holt–Oram syndrome
* Klippel–Trénaunay–Weber syndrome
* Nail–patella syndrome
* Rubinstein–Taybi syndrome
* Gastrulation/mesoderm:
* Caudal regression syndrome
* Ectromelia
* Sirenomelia
* VACTERL association
Overgrowth syndromes
* Beckwith–Wiedemann syndrome
* Proteus syndrome
* Perlman syndrome
* Sotos syndrome
* Weaver syndrome
* Klippel–Trénaunay–Weber syndrome
* Benign symmetric lipomatosis
* Bannayan–Riley–Ruvalcaba syndrome
* Neurofibromatosis type I
Laurence–Moon–Bardet–Biedl
* Bardet–Biedl syndrome
* Laurence–Moon syndrome
Combined/other,
known locus
* 2 (Feingold syndrome)
* 3 (Zimmermann–Laband syndrome)
* 4/13 (Fraser syndrome)
* 8 (Branchio-oto-renal syndrome, CHARGE syndrome)
* 12 (Keutel syndrome, Timothy syndrome)
* 15 (Marfan syndrome)
* 19 (Donohue syndrome)
* Multiple
* Fryns 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
| Primordial dwarfism | c0342573 | 1,498 | wikipedia | https://en.wikipedia.org/wiki/Primordial_dwarfism | 2021-01-18T18:45:16 | {"mesh": ["C537404"], "icd-9": ["253.3"], "wikidata": ["Q2289761"]} |
A rare, genetic proximal spinal muscular atrophy characterized by degeneration of alpha motor neurons in the anterior horns of the spinal cord and lower brain stem manifesting with onset of progressive proximal muscle weakness (legs greater than arms) between 18 months and adulthood. Motor development is heterogeneous but walking is typically acquired.
## Epidemiology
The average prevalence at birth of proximal spinal muscular atrophy (SMA) is estimated between 1/12,000, of which more than 10% account for type 3.
## Clinical description
The disease manifests between 18 months of age and adulthood, typically presenting with frequent falls, difficulty climbing steps and proximal weakness. Patients are subdivided based on age of onset: early onset is between 18 months and 3 years of age (type 3a) and is associated with a plateau in motor development, reduced or absent reflexes, finger polymyoclonus tremor and, frequently, loss of ambulation before or around puberty. Later onset (type 3b), between 3 and 21 years of age, is associated with comparatively milder decline in gross motor function. The muscle weakness predominantly affects the legs and hip muscles and then progresses to the shoulders and arms. Abnormal gait characteristics are common in order to compensate for weakness. Typically, patients are spared scoliosis and respiratory muscle weakness but these may be a feature after loss of ambulation. Cognition is normal.
## Etiology
The disease is a result of degeneration and loss of the lower motor neurons in the spinal cord and the brain stem nuclei. Causal homozygous mutations/deletions in the SMN1 gene (5q12.2-q13.3) are responsible. SMN1encodes the survival motor neuron protein (SMN) which is known to participate in critical pathways related to RNA processing and transport. Modifier genes include SMN2 (5q13.2), a homologous centromeric copy of SMN1, and NAIP (5q13.1), encoding neuronal apoptosis inhibitory protein. Type 3 is associated with 3-4 copy numbers of SMN2.
## Diagnostic methods
The disease is suspected based on clinical history and examination. The gold standard in diagnosis is genetic testing of SMN1 deletion/mutation. Muscle biopsy and electromyography should not be performed in a typical presentation.
## Differential diagnosis
Differential diagnoses include other disorders of the peripheral nervous system including myopathies or muscular dystrophies (dystrophinopathies, limb girdle muscular dystrophy, metabolic myopathies, or inflammatory myopathies), inflammatory neuropathies (Guillain-Barré syndrome), neuromuscular junction disorders (myasthenia gravis or congenital myasthenic syndromes), and other motor neuron disorders (non-5q form of SMA or late onset hexosaminidase A deficiency).
## Antenatal diagnosis
Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villus samples.
## Genetic counseling
Transmission is autosomal recessive but around 2% of cases are caused by de novo mutations. Genetic counseling should be offered to patients and their families.
## Management and treatment
Symptomatic management is multidisciplinary and aims to improve quality of life. Physiotherapy and occupational therapies are recommended and include exercise programs. Clinical evaluations should include timed function tests including the six-minute walk test. Nusinersen, an antisense oligonucleotide, is approved for treatment of SMA in Europe and the USA. Real world data following commercial availability of the drug suggest efficacy in type 3 children and adult patients.
## Prognosis
A wheelchair may be required during childhood for some patients (more commonly those with type 3a), whilst others retain the ability to walk into adulthood. Progression is slow and life expectancy is typically normal. Data on long-term outcomes with nusinersen treatment are not currently available.
* European Reference Network
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
| Proximal spinal muscular atrophy type 3 | c0152109 | 1,499 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=83419 | 2021-01-23T18:23:25 | {"gard": ["198"], "mesh": ["D014897"], "omim": ["253400"], "umls": ["C0152109"], "icd-10": ["G12.1"], "synonyms": ["Juvenile spinal muscular atrophy", "Kugelberg-Welander disease", "SMA type 3", "SMA type III", "SMA-III", "SMA3"]} |
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