Jervell and Lange-Nielsen syndrome: Difference between revisions
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== Differentiating Jervell and Lange-Nielsen syndrome from other Diseases == | == Differentiating Jervell and Lange-Nielsen syndrome from other Diseases == | ||
* Jervell and Lange-Nielsen syndrome (JLNS) must be differentiated from [[Romano-Ward syndrome]], [[Timothy syndrome]], [[Andersen-Tawil syndrome]], [[Brugada syndrome]], and [[Sudden infant death syndrome]] ([[Sudden infant death syndrome|SIDS]]).<ref name="pmid20301308">{{cite journal| author=Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K et al.| title=GeneReviews® | journal= | year= 1993 | volume= | issue= | pages= | pmid=20301308 | doi= | pmc= | url= }}</ref><ref name="pmid11710892">{{cite journal| author=Ackerman MJ, Siu BL, Sturner WQ, Tester DJ, Valdivia CR, Makielski JC et al.| title=Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. | journal=JAMA | year= 2001 | volume= 286 | issue= 18 | pages= 2264-9 | pmid=11710892 | doi=10.1001/jama.286.18.2264 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11710892 }}</ref><ref name="pmid17210839">{{cite journal| author=Arnestad M, Crotti L, Rognum TO, Insolia R, Pedrazzini M, Ferrandi C et al.| title=Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. | journal=Circulation | year= 2007 | volume= 115 | issue= 3 | pages= 361-7 | pmid=17210839 | doi=10.1161/CIRCULATIONAHA.106.658021 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17210839 }}</ref><ref name="pmid11136691">{{cite journal| author=Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C et al.| title=Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. | journal=Circulation | year= 2001 | volume= 103 | issue= 1 | pages= 89-95 | pmid=11136691 | doi=10.1161/01.cir.103.1.89 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11136691 }}</ref><ref name="pmid16012827">{{cite journal| author=Wedekind H, Bajanowski T, Friederich P, Breithardt G, Wülfing T, Siebrands C et al.| title=Sudden infant death syndrome and long QT syndrome: an epidemiological and genetic study. | journal=Int J Legal Med | year= 2006 | volume= 120 | issue= 3 | pages= 129-37 | pmid=16012827 | doi=10.1007/s00414-005-0019-0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16012827 }}</ref> | * Jervell and Lange-Nielsen syndrome (JLNS) must be differentiated from [[Romano-Ward syndrome]], [[Timothy syndrome]], [[Andersen-Tawil syndrome]], [[Brugada syndrome]], and [[Sudden infant death syndrome]] ([[Sudden infant death syndrome|SIDS]]).<ref name="pmid20301308">{{cite journal| author=Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K et al.| title=GeneReviews® | journal= | year= 1993 | volume= | issue= | pages= | pmid=20301308 | doi= | pmc= | url= }}</ref><ref name="pmid11710892">{{cite journal| author=Ackerman MJ, Siu BL, Sturner WQ, Tester DJ, Valdivia CR, Makielski JC et al.| title=Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. | journal=JAMA | year= 2001 | volume= 286 | issue= 18 | pages= 2264-9 | pmid=11710892 | doi=10.1001/jama.286.18.2264 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11710892 }}</ref><ref name="pmid17210839">{{cite journal| author=Arnestad M, Crotti L, Rognum TO, Insolia R, Pedrazzini M, Ferrandi C et al.| title=Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. | journal=Circulation | year= 2007 | volume= 115 | issue= 3 | pages= 361-7 | pmid=17210839 | doi=10.1161/CIRCULATIONAHA.106.658021 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17210839 }}</ref><ref name="pmid11136691">{{cite journal| author=Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C et al.| title=Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. | journal=Circulation | year= 2001 | volume= 103 | issue= 1 | pages= 89-95 | pmid=11136691 | doi=10.1161/01.cir.103.1.89 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11136691 }}</ref><ref name="pmid16012827">{{cite journal| author=Wedekind H, Bajanowski T, Friederich P, Breithardt G, Wülfing T, Siebrands C et al.| title=Sudden infant death syndrome and long QT syndrome: an epidemiological and genetic study. | journal=Int J Legal Med | year= 2006 | volume= 120 | issue= 3 | pages= 129-37 | pmid=16012827 | doi=10.1007/s00414-005-0019-0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16012827 }}</ref><ref name="pmid27761167">{{cite journal| author=Juang JJ, Horie M| title=Genetics of Brugada syndrome. | journal=J Arrhythm | year= 2016 | volume= 32 | issue= 5 | pages= 418-425 | pmid=27761167 | doi=10.1016/j.joa.2016.07.012 | pmc=5063259 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27761167 }}</ref> | ||
== Epidemiology and Demographics == | == Epidemiology and Demographics == | ||
Revision as of 15:44, 20 November 2019
| Jervell and Lange-Nielsen syndrome | |
| ICD-9 | 426.82 |
|---|---|
| OMIM | 220400 |
| DiseasesDB | 7249 |
| MeSH | D029593 |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Synonyms and keywords:Autosomal recessive long QT syndrome (LQTS), cardioauditory syndrome, cardioauditory syndrome of Jervell and Lange-Nielsen, deafness, congenital, and functional heart disease, Jervell and Lange-Nielsen (JLNS), surdocardiac syndrome
Overview
Jervell and Lange-Nielsen syndrome is a rare autosomal recessive condition that leads to sensorineural deafness, abnormal ventricular myocardial repolarization with results in long QT syndrome (LQTS) and other cardiac events. Jervell and Lange-Nielsen syndrome is due to KCNQ1 or KCNE1 gene mutations. The range of symptoms and severity of symptoms in Jervell and Lange-Nielsen syndrome differs from patient to patient.
Historical Perspective
- Jervell and Lange-Nielsen syndrome (JLNS) was first discovered by Anton Jervell a Norwegian physician and Fred Lange-Nielsen a Norwegian doctor and jazz musician, in 1957.[1][2]
Classification
- Jervell and Lange-Nielsen syndrome (JLNS) may be classified according into two subtypes:[3][4][5][6]
| Type | Chromosome Locus | Gene Mutation | Protein Involved |
| Jervell and Lange-Nielsen syndrome 1 | 11p15.5-p15.4 | KCNQ1 | Potassium voltage-gated channel subfamily KQT member 1 |
| Jervell and Lange-Nielsen syndrome 2 | 21q22.12 | KCNE1 | Potassium voltage-gated channel subfamily E member 1 |
Pathophysiology
Physiology
The normal physiology of KCNQ1 and KCNE1 genes can be understood as follows:[7]
- Both KCNQ1 and KCNE1 genes encodes for the slow potassium channel currents of the cochlea and the heart.
- Normally the slow potassium channel currents were stimulated by the sound, when stimulated the potassium from the scala media passes the action potential through the apex of the hair cells.
- The potassium action potential then depolarises the hair cells.
- Once depolarised there is a release calcium-channel-induced release of neurotransmitter.
- The neurotransmitter then passes along with the auditory nerve and then depolarizes and the currents are sent centrally where they are received as sound.
Pathogenesis
- It is understood that Jervell and Lange-Nielsen syndrome (JLNS) is the result of mutations in the gene KCNQ1 and KCNE1.[8]
- KCNQ1 gene normally consists of 16 exons and have a general spanning of 400 kb.[9][10][11][12]
- The normal gene product of KCNQ1 gene is potassium voltage-gated channel subfamily KQT member 1.
- When KCNQ1 gene undergoes frameshift mutation it results in yielding truncated protein.
- Then the truncated protein either delete or duplicate the exons of the KCNQ1 gene and results in abnormal gene product which is known to result in long QT syndrome.
- KCNE1 gene normally consists of 3 exons and have a general spanning of 40 kb.[13][14][15][16][17]
- The normal gene product of KCNE1 gene is potassium voltage-gated channel subfamily E member 1.
- Potassium voltage-gated channel subfamily E member 1 is also called as minK potassium channel protein beta subunit.[18]
- When KCNE1 gene undergoes missense mutation it results in yielding truncated protein.
- Then the truncated protein results in impairing potassium channel function, which is known to result in long QT syndrome.
Genetics
- Jervell and Lange-Nielsen syndrome (JLNS) is transmitted in a autosomal recessive pattern.[19]
- Jervell and Lange-Nielsen syndrome appear to have low penetrance.[20]
- Genes involved in the pathogenesis of Jervell and Lange-Nielsen syndrome (JLNS) include:
Causes
Genetic Causes
Differentiating Jervell and Lange-Nielsen syndrome from other Diseases
- Jervell and Lange-Nielsen syndrome (JLNS) must be differentiated from Romano-Ward syndrome, Timothy syndrome, Andersen-Tawil syndrome, Brugada syndrome, and Sudden infant death syndrome (SIDS).[21][22][23][24][25][26]
Epidemiology and Demographics
Incidence
- The incidence of Jervell and Lange-Nielsen syndrome (JLNS) is approximately 1 per 100,000 individuals in Norway.[27]
- The incidence of Jervell and Lange-Nielsen syndrome (JLNS) is approximately 1 per 100,000 individuals in Sweden.
- It is estimated that Jervell and Lange-Nielsen syndrome (JLNS) affects 166,000 to 625,000 children worldwide.
Prevalence
- The prevalence of Jervell and Lange-Nielsen syndrome (JLNS) is approximately 1:200,000 individuals in Norway.[1]
Age
- The incidence of Jervell and Lange-Nielsen syndrome (JLNS) increases with age; the median age at diagnosis is 6.8 years.[28][29]
- The exact time of presentation in Jervell and Lange-Nielsen syndrome (JLNS) is highly variable.
Gender
- Jervell and Lange-Nielsen syndrome (JLNS) affects men and women equally. But the severity of cardiac events is much more common in men.
Risk Factors
- The most potent risk factor in the development of Jervell and Lange-Nielsen syndrome (JLNS) is KCNQ1 and KCNE1 genes mutation.
Screening
- According to the American College of Medical Genetics, screening for Jervell and Lange-Nielsen syndrome (JLNS) by hearing evaluation which is standard and electrocardiograms is recommended among patients with a family history.[30][31][32][33]
Natural History, Complications and Prognosis
Natural History
- The symptoms of Jervell and Lange-Nielsen syndrome (JLNS) usually develop in the first or second of life, and start with symptoms such as hearing loss and syncope.
Complications
- Common complications of Jervell and Lange-Nielsen syndrome (JLNS) include:
Prognosis
- Depending on the severity of the genetic mutation at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as poor as most of the untreated patients die around the age of 15 years.[34]
- The prognosis varies with the gender, gene mutation and baseline QTc interval.
Diagnosis
Diagnostic Study of Choice
- Molecular genetic testing is the gold standard test for the diagnosis of Jervell and Lange-Nielsen syndrome (JLNS).
- The following result of molecular genetic testing is confirmatory of Jervell and Lange-Nielsen syndrome (JLNS):
- KCNQ1 or KCNE1 pathogenic variants identification
OR
[Name of the investigation] must be performed when:
- The patient presents with [symptom/sign 1], [symptom/sign 2], and [symptom/sign 3].
- A [name of test] is positive for [sign 1], [sign 2], and [sign 3] in the patient.
History and Symptoms
Common Symptoms
Common symptoms of Jervell and Lange-Nielsen syndrome (JLNS) include:
- Congenital Deafness: Usually identified at the time of birth, most commonly sensorineural hearing loss
- Syncope: Due to abnormal heart rhythm
- Seizures: Most commonly grand mal seizures
- Palpitations
- Mild to moderate chest pain
- Ventricular fibrillation
- Sudden cardiac death
Less Common Symptoms
Less common symptoms of [disease name] include
- [Symptom 1]
- [Symptom 2]
- [Symptom 3]
Treatment
References
- ↑ 1.0 1.1 Tranebjaerg L, Bathen J, Tyson J, Bitner-Glindzicz M (1999). "Jervell and Lange-Nielsen syndrome: a Norwegian perspective". Am J Med Genet. 89 (3): 137–46. PMID 10704188.
- ↑ Schwartz, Peter J.; Spazzolini, Carla; Crotti, Lia; Bathen, Jørn; Amlie, Jan P.; Timothy, Katherine; Shkolnikova, Maria; Berul, Charles I.; Bitner-Glindzicz, Maria; Toivonen, Lauri; Horie, Minoru; Schulze-Bahr, Eric; Denjoy, Isabelle (2006). "The Jervell and Lange-Nielsen Syndrome". Circulation. 113 (6): 783–790. doi:10.1161/CIRCULATIONAHA.105.592899. ISSN 0009-7322.
- ↑ Tyson J, Tranebjaerg L, McEntagart M, Larsen LA, Christiansen M, Whiteford ML; et al. (2000). "Mutational spectrum in the cardioauditory syndrome of Jervell and Lange-Nielsen". Hum Genet. 107 (5): 499–503. doi:10.1007/s004390000402. PMID 11140949.
- ↑ Schwartz PJ, Spazzolini C, Crotti L, Bathen J, Amlie JP, Timothy K; et al. (2006). "The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome". Circulation. 113 (6): 783–90. doi:10.1161/CIRCULATIONAHA.105.592899. PMID 16461811.
- ↑ Tranebjaerg L, Bathen J, Tyson J, Bitner-Glindzicz M (1999). "Jervell and Lange-Nielsen syndrome: a Norwegian perspective". Am J Med Genet. 89 (3): 137–46. PMID 10704188.
- ↑ ACMG (2002) Genetics Evaluation Guidelines for the Etiologic Diagnosis of Congenital Hearing Loss. Genetic Evaluation of Congenital Hearing Loss Expert Panel. ACMG statement. Genet Med 4 (3):162-71. DOI:10.1097/00125817-200205000-00011 PMID: 12180152
- ↑ Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K; et al. (1993). "GeneReviews®". PMID 20301579.
- ↑ Tranebjaerg L, Bathen J, Tyson J, Bitner-Glindzicz M (1999). "Jervell and Lange-Nielsen syndrome: a Norwegian perspective". Am J Med Genet. 89 (3): 137–46. PMID 10704188.
- ↑ Wang Z, Li H, Moss AJ, Robinson J, Zareba W, Knilans T; et al. (2002). "Compound heterozygous mutations in KvLQT1 cause Jervell and Lange-Nielsen syndrome". Mol Genet Metab. 75 (4): 308–16. doi:10.1016/S1096-7192(02)00007-0. PMID 12051962.
- ↑ Abbott GW, Xu X, Roepke TK (2007). "Impact of ancillary subunits on ventricular repolarization". J Electrocardiol. 40 (6 Suppl): S42–6. doi:10.1016/j.jelectrocard.2007.05.021. PMC 2128763. PMID 17993327.
- ↑ Abbott GW, Goldstein SA (2002). "Disease-associated mutations in KCNE potassium channel subunits (MiRPs) reveal promiscuous disruption of multiple currents and conservation of mechanism". FASEB J. 16 (3): 390–400. doi:10.1096/fj.01-0520hyp. PMID 11874988.
- ↑ Nishimura M, Ueda M, Ebata R, Utsuno E, Ishii T, Matsushita K; et al. (2017). "A novel KCNQ1 nonsense variant in the isoform-specific first exon causes both jervell and Lange-Nielsen syndrome 1 and long QT syndrome 1: a case report". BMC Med Genet. 18 (1): 66. doi:10.1186/s12881-017-0430-7. PMC 5465588. PMID 28595573.
- ↑ Lewis A, McCrossan ZA, Abbott GW (2004). "MinK, MiRP1, and MiRP2 diversify Kv3.1 and Kv3.2 potassium channel gating". J Biol Chem. 279 (9): 7884–92. doi:10.1074/jbc.M310501200. PMID 14679187.
- ↑ Lu Y, Mahaut-Smith MP, Huang CL, Vandenberg JI (2003). "Mutant MiRP1 subunits modulate HERG K+ channel gating: a mechanism for pro-arrhythmia in long QT syndrome type 6". J Physiol. 551 (Pt 1): 253–62. doi:10.1113/jphysiol.2003.046045. PMC 2343156. PMID 12923204.
- ↑ Anantharam A, Abbott GW (2005). "Does hERG coassemble with a beta subunit? Evidence for roles of MinK and MiRP1". Novartis Found Symp. 266: 100–12, discussion 112-7, 155–8. PMID 16050264.
- ↑ Abbott GW, Goldstein SA (2002). "Disease-associated mutations in KCNE potassium channel subunits (MiRPs) reveal promiscuous disruption of multiple currents and conservation of mechanism". FASEB J. 16 (3): 390–400. doi:10.1096/fj.01-0520hyp. PMID 11874988.
- ↑ Abbott GW, Xu X, Roepke TK (2007). "Impact of ancillary subunits on ventricular repolarization". J Electrocardiol. 40 (6 Suppl): S42–6. doi:10.1016/j.jelectrocard.2007.05.021. PMC 2128763. PMID 17993327.
- ↑ McCrossan ZA, Roepke TK, Lewis A, Panaghie G, Abbott GW (2009). "Regulation of the Kv2.1 potassium channel by MinK and MiRP1". J Membr Biol. 228 (1): 1–14. doi:10.1007/s00232-009-9154-8. PMC 2849987. PMID 19219384.
- ↑ Priori SG, Napolitano C, Schwartz PJ (1999). "Low penetrance in the long-QT syndrome: clinical impact". Circulation. 99 (4): 529–33. doi:10.1161/01.cir.99.4.529. PMID 9927399.
- ↑ Berge KE, Haugaa KH, Früh A, Anfinsen OG, Gjesdal K, Siem G; et al. (2008). "Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers". Scand J Clin Lab Invest. 68 (5): 362–8. doi:10.1080/00365510701765643. PMID 18752142.
- ↑ Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K; et al. (1993). "GeneReviews®". PMID 20301308.
- ↑ Ackerman MJ, Siu BL, Sturner WQ, Tester DJ, Valdivia CR, Makielski JC; et al. (2001). "Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome". JAMA. 286 (18): 2264–9. doi:10.1001/jama.286.18.2264. PMID 11710892.
- ↑ Arnestad M, Crotti L, Rognum TO, Insolia R, Pedrazzini M, Ferrandi C; et al. (2007). "Prevalence of long-QT syndrome gene variants in sudden infant death syndrome". Circulation. 115 (3): 361–7. doi:10.1161/CIRCULATIONAHA.106.658021. PMID 17210839.
- ↑ Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C; et al. (2001). "Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias". Circulation. 103 (1): 89–95. doi:10.1161/01.cir.103.1.89. PMID 11136691.
- ↑ Wedekind H, Bajanowski T, Friederich P, Breithardt G, Wülfing T, Siebrands C; et al. (2006). "Sudden infant death syndrome and long QT syndrome: an epidemiological and genetic study". Int J Legal Med. 120 (3): 129–37. doi:10.1007/s00414-005-0019-0. PMID 16012827.
- ↑ Juang JJ, Horie M (2016). "Genetics of Brugada syndrome". J Arrhythm. 32 (5): 418–425. doi:10.1016/j.joa.2016.07.012. PMC 5063259. PMID 27761167.
- ↑ Berge KE, Haugaa KH, Früh A, Anfinsen OG, Gjesdal K, Siem G; et al. (2008). "Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers". Scand J Clin Lab Invest. 68 (5): 362–8. doi:10.1080/00365510701765643. PMID 18752142.
- ↑ Rohatgi RK, Sugrue A, Bos JM, Cannon BC, Asirvatham SJ, Moir C; et al. (2017). "Contemporary Outcomes in Patients With Long QT Syndrome". J Am Coll Cardiol. 70 (4): 453–462. doi:10.1016/j.jacc.2017.05.046. PMID 28728690.
- ↑ Garson A, Dick M, Fournier A, Gillette PC, Hamilton R, Kugler JD; et al. (1993). "The long QT syndrome in children. An international study of 287 patients". Circulation. 87 (6): 1866–72. doi:10.1161/01.cir.87.6.1866. PMID 8099317.
- ↑ Chang RK, Lan YT, Silka MJ, Morrow H, Kwong A, Smith-Lang J; et al. (2014). "Genetic variants for long QT syndrome among infants and children from a statewide newborn hearing screening program cohort". J Pediatr. 164 (3): 590-5.e1-3. doi:10.1016/j.jpeds.2013.11.011. PMC 3943925. PMID 24388587.
- ↑ Berge KE, Haugaa KH, Früh A, Anfinsen OG, Gjesdal K, Siem G; et al. (2008). "Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers". Scand J Clin Lab Invest. 68 (5): 362–8. doi:10.1080/00365510701765643. PMID 18752142.
- ↑ Uysal F, Turkgenc B, Toksoy G, Bostan OM, Evke E, Uyguner O; et al. (2017). ""Homozygous, and compound heterozygous mutation in 3 Turkish family with Jervell and Lange-Nielsen syndrome: case reports"". BMC Med Genet. 18 (1): 114. doi:10.1186/s12881-017-0474-8. PMC 5644177. PMID 29037160.
- ↑ Olsson KS, Wålinder O, Jansson U, Wilbe M, Bondeson ML, Stattin EL; et al. (2017). "Common founder effects of hereditary hemochromatosis, Wilson´s disease, the long QT syndrome and autosomal recessive deafness caused by two novel mutations in the WHRN and TMC1 genes". Hereditas. 154: 16. doi:10.1186/s41065-017-0052-2. PMC 5735936. PMID 29270100.
- ↑ Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K; et al. (1993). "GeneReviews®". PMID 20301579.