U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

Waardenburg syndrome type 4A(WS4A)

MedGen UID:
341244
Concept ID:
C1848519
Disease or Syndrome
Synonyms: Hirschsprung disease with pigmentary anomaly; Waardenburg Syndrome Type IVA; WAARDENBURG SYNDROME WITH HIRSCHSPRUNG DISEASE, TYPE 4A; WS4A
SNOMED CT: Waardenburg syndrome co-occurrent with Hirschsprung disease (715952000); Waardenburg Shah syndrome (715952000); Waardenburg Hirschsprung syndrome (715952000); Shah Waardenburg syndrome (715952000); Waardenburg syndrome type 4 (715952000)
 
Gene (location): EDNRB (13q22.3)
 
Monarch Initiative: MONDO:0010192
OMIM®: 277580

Definition

Waardenburg syndrome type 4 (WS4), also known as Waardenburg-Shah syndrome, is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes, congenital sensorineural hearing loss, and Hirschsprung disease (reviews by Read and Newton, 1997 and Pingault et al., 2010). WS type 4A is caused by mutation in the EDNRB gene (131244). Clinical Variability of Waardenburg Syndrome Types 1-4 Waardenburg syndrome has been classified into 4 main phenotypes. Type I Waardenburg syndrome (WS1; 193500) is characterized by pigmentary abnormalities of the hair, including a white forelock and premature graying; pigmentary changes of the iris, such as heterochromia iridis and brilliant blue eyes; congenital sensorineural hearing loss; and 'dystopia canthorum.' WS type II (WS2) is distinguished from type I by the absence of dystopia canthorum. WS type III (WS3; 148820) has dystopia canthorum and is distinguished by the presence of upper limb abnormalities. WS type 4 has the additional feature of Hirschsprung disease (reviews by Read and Newton, 1997 and Pingault et al., 2010). Genetic Heterogeneity of Waardenburg Syndrome Type 4 Waardenburg syndrome type 4 is genetically heterogeneous. WS4B (613265) is caused by mutation in the EDN3 gene (131242) on chromosome 20q13, and WS4C (613266) is caused by mutation in the SOX10 gene (602229) on chromosome 22q13. [from OMIM]

Additional description

From MedlinePlus Genetics
Waardenburg syndrome is a group of genetic conditions that can cause hearing loss and changes in coloring (pigmentation) of the hair, skin, and eyes. Although most people with Waardenburg syndrome have normal hearing, moderate to profound hearing loss can occur in one or both ears. The hearing loss is present from birth (congenital). People with this condition often have very pale blue eyes or different colored eyes, such as one blue eye and one brown eye. Sometimes one eye has segments of two different colors. Distinctive hair coloring (such as a patch of white hair or hair that prematurely turns gray) is another common sign of the condition. The features of Waardenburg syndrome vary among affected individuals, even among people in the same family.

There are four recognized types of Waardenburg syndrome, which are distinguished by their physical characteristics and sometimes by their genetic cause. Types I and II have very similar features, although people with type I almost always have eyes that appear widely spaced and people with type II do not. In addition, hearing loss occurs more often in people with type II than in those with type I. Type III (sometimes called Klein-Waardenburg syndrome) includes abnormalities of the arms and hands in addition to hearing loss and changes in pigmentation. Type IV (also known as Waardenburg-Hirschsprung disease or Waardenburg-Shah syndrome) has signs and symptoms of both Waardenburg syndrome and Hirschsprung disease, an intestinal disorder that causes severe constipation or blockage of the intestine.  https://medlineplus.gov/genetics/condition/waardenburg-syndrome

Clinical features

From HPO
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Aganglionic megacolon
MedGen UID:
5559
Concept ID:
C0019569
Disease or Syndrome
The disorder described by Hirschsprung (1888) and known as Hirschsprung disease or aganglionic megacolon is characterized by congenital absence of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses of the gastrointestinal tract. Patients are diagnosed with the short-segment form (S-HSCR, approximately 80% of cases) when the aganglionic segment does not extend beyond the upper sigmoid, and with the long-segment form (L-HSCR) when aganglionosis extends proximal to the sigmoid (Amiel et al., 2008). Total colonic aganglionosis and total intestinal HSCR also occur. Genetic Heterogeneity of Hirschsprung Disease Several additional loci for isolated Hirschsprung disease have been mapped. HSCR2 (600155) is associated with variation in the EDNRB gene (131244) on 13q22; HSCR3 (613711) is associated with variation in the GDNF gene (600837) on 5p13; HSCR4 (613712) is associated with variation in the EDN3 gene (131242) on 20q13; HSCR5 (600156) maps to 9q31; HSCR6 (606874) maps to 3p21; HSCR7 (606875) maps to 19q12; HSCR8 (608462) maps to 16q23; and HSCR9 (611644) maps to 4q31-q32. HSCR also occurs as a feature of several syndromes including the Waardenburg-Shah syndrome (277580), Mowat-Wilson syndrome (235730), Goldberg-Shprintzen syndrome (609460), and congenital central hypoventilation syndrome (CCHS; 209880). Whereas mendelian modes of inheritance have been described for syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. Isolated HSCR appears to be of complex nonmendelian inheritance with low sex-dependent penetrance and variable expression according to the length of the aganglionic segment, suggestive of the involvement of one or more genes with low penetrance. The development of surgical procedures decreased mortality and morbidity, which allowed the emergence of familial cases. HSCR occurs as an isolated trait in 70% of patients, is associated with chromosomal anomaly in 12% of cases, and occurs with additional congenital anomalies in 18% of cases (summary by Amiel et al., 2008).
Leukodystrophy
MedGen UID:
6070
Concept ID:
C0023520
Disease or Syndrome
Leukodystrophy refers to deterioration of white matter of the brain resulting from degeneration of myelin sheaths in the CNS. Their basic defect is directly related to the synthesis and maintenance of myelin membranes. Symmetric white matter involvement at MRI is a typical finding in patients with leukodystrophies.
Spastic paraparesis
MedGen UID:
52432
Concept ID:
C0037771
Sign or Symptom
Mild or moderate loss of motor function accompanied by spasticity in the lower extremities. This condition is a manifestation of CENTRAL NERVOUS SYSTEM DISEASES that cause injury to the motor cortex or descending motor pathways.
Polyneuropathy
MedGen UID:
57502
Concept ID:
C0152025
Disease or Syndrome
A generalized disorder of peripheral nerves.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Premature graying of hair
MedGen UID:
75524
Concept ID:
C0263498
Finding
Development of gray hair at a younger than normal age.
White forelock
MedGen UID:
91023
Concept ID:
C0344312
Finding
A triangular depigmented region of white hairs located in the anterior midline of the scalp.
Hypopigmented skin patches
MedGen UID:
373164
Concept ID:
C1836735
Finding
White eyelashes
MedGen UID:
332275
Concept ID:
C1836736
Finding
White color (lack of pigmentation) of the eyelashes.
White eyebrow
MedGen UID:
373165
Concept ID:
C1836737
Finding
White color (lack of pigmentation) of the eyebrow.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Heterochromia iridis
MedGen UID:
98395
Concept ID:
C0423318
Finding
Heterochromia iridis is a difference in the color of the iris in the two eyes.
Blue irides
MedGen UID:
108297
Concept ID:
C0578626
Finding
A markedly blue coloration of the iris.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Recent clinical studies

Etiology

Pingault V, Zerad L, Bertani-Torres W, Bondurand N
J Med Genet 2022 Feb;59(2):105-114. Epub 2021 Oct 19 doi: 10.1136/jmedgenet-2021-108105. PMID: 34667088Free PMC Article
Leechawengwongs E, Tison BE, Gopalakrishna GS, Reid BS, Bacino CA, Haws AL, Finegold MJ, Shearer WT
J Allergy Clin Immunol 2013 Jan;131(1):251-5. Epub 2012 Nov 21 doi: 10.1016/j.jaci.2012.08.053. PMID: 23177999
Khong HT, Rosenberg SA
Cancer Res 2002 Jun 1;62(11):3020-3. PMID: 12036907Free PMC Article
Verastegui C, Bille K, Ortonne JP, Ballotti R
J Biol Chem 2000 Oct 6;275(40):30757-60. doi: 10.1074/jbc.C000445200. PMID: 10938265
Touraine RL, Attié-Bitach T, Manceau E, Korsch E, Sarda P, Pingault V, Encha-Razavi F, Pelet A, Augé J, Nivelon-Chevallier A, Holschneider AM, Munnes M, Doerfler W, Goossens M, Munnich A, Vekemans M, Lyonnet S
Am J Hum Genet 2000 May;66(5):1496-503. Epub 2000 Apr 4 doi: 10.1086/302895. PMID: 10762540Free PMC Article

Diagnosis

Wang Y, Chai Y, Zhang P, Zang W
BMC Med Genomics 2023 Jun 26;16(1):147. doi: 10.1186/s12920-023-01572-1. PMID: 37365589Free PMC Article
Ng BW, Lee JS, Toh TH, Ngu LH
BMJ Case Rep 2022 Jun 20;15(6) doi: 10.1136/bcr-2022-250360. PMID: 35725288Free PMC Article
Pingault V, Zerad L, Bertani-Torres W, Bondurand N
J Med Genet 2022 Feb;59(2):105-114. Epub 2021 Oct 19 doi: 10.1136/jmedgenet-2021-108105. PMID: 34667088Free PMC Article
Wang X, Lin XJ, Tang X, Chai YC, Yu DH, Chen DY, Wu H
Int J Pediatr Otorhinolaryngol 2017 Nov;102:114-118. Epub 2017 Sep 4 doi: 10.1016/j.ijporl.2017.08.012. PMID: 29106856
Mahmoudi A, Rami M, Khattala K, Elmadi A, Afifi MA, Youssef B
Pan Afr Med J 2013;14:60. Epub 2013 Feb 12 doi: 10.11604/pamj.2013.14.60.1543. PMID: 23565307Free PMC Article

Prognosis

Rankine-Mullings AE, Serjeant G, Ramsay Z, Hanchard NA, Asnani M
J Med Case Rep 2019 Jan 13;13(1):10. doi: 10.1186/s13256-018-1953-z. PMID: 30636638Free PMC Article
Núñez-Ramos R, Fernández RM, González-Velasco M, Ruiz-Contreras J, Galán-Gómez E, Núñez-Núñez R, Borrego S
Pediatr Dev Pathol 2017 Jan-Feb;20(1):28-37. doi: 10.1177/1093526616683883. PMID: 28276298
Gupta R, Sharma SB, Mathur P, Agrawal LD
Indian Pediatr 2014 Dec;51(12):1013-4. doi: 10.1007/s13312-014-0549-y. PMID: 25560164
Mahmoudi A, Rami M, Khattala K, Elmadi A, Afifi MA, Youssef B
Pan Afr Med J 2013;14:60. Epub 2013 Feb 12 doi: 10.11604/pamj.2013.14.60.1543. PMID: 23565307Free PMC Article
Unzicker A, Pingault V, Meyer T, Rauthe S, Schütz A, Kunzmann S
Eur J Pediatr 2011 Nov;170(11):1475-80. Epub 2011 Aug 6 doi: 10.1007/s00431-011-1539-x. PMID: 21822601

Clinical prediction guides

Wang Y, Chai Y, Zhang P, Zang W
BMC Med Genomics 2023 Jun 26;16(1):147. doi: 10.1186/s12920-023-01572-1. PMID: 37365589Free PMC Article
Pingault V, Zerad L, Bertani-Torres W, Bondurand N
J Med Genet 2022 Feb;59(2):105-114. Epub 2021 Oct 19 doi: 10.1136/jmedgenet-2021-108105. PMID: 34667088Free PMC Article
Gupta R, Sharma SB, Mathur P, Agrawal LD
Indian Pediatr 2014 Dec;51(12):1013-4. doi: 10.1007/s13312-014-0549-y. PMID: 25560164
Fernández RM, Núñez-Ramos R, Enguix-Riego MV, Román-Rodríguez FJ, Galán-Gómez E, Blesa-Sánchez E, Antiñolo G, Núñez-Núñez R, Borrego S
Am J Med Genet A 2014 Feb;164A(2):542-7. Epub 2013 Dec 5 doi: 10.1002/ajmg.a.36302. PMID: 24311220
Verastegui C, Bille K, Ortonne JP, Ballotti R
J Biol Chem 2000 Oct 6;275(40):30757-60. doi: 10.1074/jbc.C000445200. PMID: 10938265

Supplemental Content

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...