Waardenburg Syndrome

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Continuing Education Activity

Waardenburg syndrome is a group of genetic conditions inherited in an autosomal dominant fashion. During embryogenesis, there is an abnormal distribution of melanocytes, which results in patchy areas of depigmentation. This activity reviews the evaluation and treatment of Waardenburg syndrome and highlights the role of the interprofessional team in the care of patients with this condition.


  • Explain the pathophysiology of Waardenburg syndrome.
  • Describe the clinical features of patients presenting with Waardenburg syndrome.
  • Outline the differential diagnosis of patients presenting with Waardenburg syndrome.
  • Review the importance of improving care coordination amongst interprofessional team members to improve outcomes for patients affected by Waardenburg syndrome.


Waardenburg syndrome (WS) is a group of genetic conditions inherited in an autosomal dominant fashion.[1] It is named after Dutch ophthalmologist and geneticist Petrus Johannes Waardenburg, who described it in 1951.[1] During embryogenesis, there is an abnormal distribution of melanocytes, which results in patchy areas of depigmentation. It is a rare disease, caused by loss of pigmentary cells in eyes, skin, stria vascularis of the cochlea, and hair. It is characterized by a broad nasal root, lateral displacement of medial canthi with the dystopia of lacrimal puncta, pigmentary abnormalities of the iris, hypertrichosis of the medial part of the eyebrows, white forelock, and deaf-mutism.[2] 

Several different gene mutations (insertion, deletion, frameshifts, missense, and nonsense mutations) can cause Waardenburg syndrome. There are four clinical variants, type 1 and type 2 are the most common types. Type 1 is due to the mutations in the PAX3 gene, which clinically manifests as congenital deafness (sensorineural), dystopia canthorum (lateral displacement of medial corner of eyes), neural tube defects, cleft palate, and lip with patchy depigmentation of hair and skin. These symptoms are associated with pigmentary abnormalities of the eyes. Type II WS is due to mutations in the MITF gene.[3]

The inner canthi of both eyes are normal but have some other features similar to  type-1. Type-III WS is an extreme presentation of type I with the abnormality of upper limbs. Type IV WS is due to mutations in the genes for one of its receptors, EDNRB or endothelin-3, usually autosomal recessive. As it is a genetic disease, there is no definitive treatment for Waardenburg syndrome, but supportive treatment with cochlear implants and surgery in case of association with Hirschsprung syndrome can be done. Genetic counseling is necessary.[4]


WS is an autosomal dominant disorder. It is caused by mutations in different genes that affect the function of the neural crest.[5] For a child to have the disease, only one affected gene is necessary to pass on. The penetration and expression of different genes are also different. Mutations in the PAX3 gene at chromosome 2q is the cause of type 1 and type 3 syndrome. Mutation in MITF gene chromosome 3q causes type 2A WS. On the other hand, WS type 2B has gene mutations on chromosome 1q, and WS type 2C occurs due to mutation at chromosome 8q. Mutations in the SNAI2 gene at chromosome 8q causes WS Type 2D. Type 4 WS is due to mutations in the genes for one of its receptors, EDNRB or endothelin-3, which is autosomal recessive and a very rare variant.[6]


The prevalence is variable around the world. An estimation of Waardenburg syndrome cases is  1/212,000 individuals in the general population of Netherland (low penetrance about 20%), but the entire syndrome is approximately 1/42,000 globally. Type 1 and 2 are commonly reported worldwide, while type 3 is very rarely reported.[7] Type 4 is reported in around 19% of cases of Waardenburg syndrome. In persons with deaf-mutism, the syndrome is observed in 0.9 to 2.8%. It affects all races worldwide with no gender difference. Waardenburg syndrome can be recognized immediately after birth, but skin changes occur with age. The clinical presentation of the syndrome varies, and most of the time, it is difficult to reach the final diagnosis to get an accurate prevalence.


WS is a genetic disorder with autosomal dominant inheritance.[5] There are various hypotheses proposed about the pathogenesis and to explain the different types and clinical features. One hypothesis suggests the abnormal development of the neural crest as causing the syndrome, and it is explained by the deficient neural crest theory. According to this hypothesis, there is an association of Waardenburg syndrome with Hirschsprung syndrome. The first arch syndrome also has features of Waardenburg syndrome.[6] 

A relationship between the intrauterine necrosis theory and Waardenburg syndrome with status dysraphicus has also been proposed. Among all these different hypotheses, none can explain all the features of Waardenburg syndrome. Individuals with deafness account for 50% of inherited causes, in which 70% have different single genes mutations that alone impair the functions of hearing. Syndromic deafness is also sometimes associated with other developmental abnormalities.[3] In Waardenburg syndrome, the genes which cause deafness include MITF and PAX3 in type 2 and type 1 syndrome, respectively. Type 4 WS is due to one of its receptors, EDNRB, or endothelin-3 gene mutations.[4]


The characteristic histopathological finding of Waardenburg syndrome is the absence of melanocytes (few dihydroxyphenylalanine positive cells are present). In the hypopigmented skin, melanosomes or indeterminate dendritic cells in the keratinocytes are present. Langerhans cells are normal in the epidermis, while on the edge of depigmented areas, the number of pigment cells is decreased with many abnormalities of nuclear and cytoplasm. Inside of vacuoles, a clear halo appears with some surrounding melanosomes.[8]

Histopathological findings of ears reveal atrophy of the spinal ganglion, the number of nerve fibers are also decreased with the absence organ of Corti.

History and Physical

Clinically, Waardenburg syndrome can be recognized by specific morphological features that appear after birth. These typical features are white forelock, broad nasal root, and the difference in the color of eyes. According to parents, the child usually does not respond to sounds. Every case of Waardenburg syndrome does not present with all clinical features. Based on genetic and clinical criteria, four types of WS are identified.[1]

Type 1 is characterized by dystopia canthorum, broad nasal root, short philtrum, and short retropositional maxilla. Patients with type 2 Waardenburg syndrome have normally located canthi, sensorineural deafness, and different colored irises. Type 3 WS (also called Klein-Waardenburg syndrome) has the same features as type-1, but musculoskeletal abnormalities are more prominent, like small carpal bones not differentiated fully, aplasia of first and second ribs, sacral cysts, abnormalities of the arms, and hypoplasia of muscles with syndactyly. Some cases of type 3 present with all primary features plus severe skeletal abnormalities, mental disability, and microcephaly. Type 4 WS (also called Shah-Waardenburg syndrome) has the same features as type 2 WS, but it is associated with congenital megacolon (Hirschsprung disease). Pigmentary abnormalities of WS affect skin, hair, and eyes. Skin abnormalities manifest as achromic spots and hyperpigmented macules over normal skin. Eye changes include heterochromia and bilateral isohypochromia. Waardenburg syndrome is a clinical diagnosis, but 2 criteria are used for diagnosis, i.e., major and minor criteria.[9]

Major criteria: Heterochromia, sensorineural deafness, white forelock, lateral displacement of inner canthi of eyes, and a first-degree relative with WS

Minor criteria: Broad nasal root, white macules/patches on the skin, synophrys, premature greying of the scalp hairs, and hypoplasia of nasal alae. For clinical diagnosis of Type 1 WS, two major or one minor and two minor criteria are needed.[10]


Waardenburg syndrome is mostly due to the genes changes in Type 1 and Type 3 due to the point mutations and can be detected by the use of multiplex ligation-dependent probe amplification in specific genes. Other tests include detecting the dystopia canthorum by three intraocular distances: 1)distance between angles of two inner canthi 2)the near papillary distance 3)distance between other canthi angles.[2]

There are no other specific radiological tests for Waardenburg syndrome.[1]

Treatment / Management

WS is a genetic disorder that currently has no definitive treatment.[11] In children with this disease, early diagnosis, and improvement of the deafness and hearing abnormalities are important for mental health development in order to decrease the sense of being ignored by others. The definitive/effective surgical treatment available is cochlear implantation. Sun protection is necessary for hypopigmented patches because these patients are susceptible to sun damage.[12] Genetic counseling is very important for these patients.

Differential Diagnosis

Differential diagnosis of Waardenburg syndrome include:

  • Piebaldism: It is a genetic disorder characterized by depigmentation of skin and hair.[13]
  • Tietz syndrome: A rare disorder present with musculoskeletal abnormalities.
  • Oculocutaneous albinism: A disorder characterized by the absence of melanocytes. It clinically presents as depigmentation of skin and hairs with a change of eye color.
  • Vogt-Koyanagi-Harada disease: Usually affects the skin, eyes, ear, and nervous system.
  • Vitiligo: It clinically presents as multiple depigmented patches of skin and hair.


WS is a chronic condition. Life expectancy in children with Waardenburg syndrome is normal. Morbidity is related to the defect of neural crest-derived tissues, including mental disability, deafness and, ocular disorders (cataracts), skeletal anomalies, and psychiatric disorders.[14]


A complication of type 1 Waardenburg syndrome is blepharophimosis. Type 2 complications include sensorineural deafness (70%) Type 3 is associated with skeletal abnormalities, and the severe form presents with mental disability and microcephaly. Hirschsprung syndrome is the main complication of type 4 Waardenburg syndrome.[15]


Consultations with geneticists are important as type I Waardenburg syndrome is an autosomal dominant disease, and some affected persons have relatives with the same disease. Even if prenatal tests determine the positive gene pathology, it still cannot predict the severity of its clinical expression. An interprofessional approach is needed to manage all the complications of the disease.

Deterrence and Patient Education

Life expectancy is normal in children with Waardenburg syndrome. Genetic counseling is necessary because one affected gene can pass the syndrome to the next generation. As there is no definitive treatment, the family and the patient's awareness regarding symptomatic treatment is also very important. Morbidity is related only to neural crest defects.[16]

Enhancing Healthcare Team Outcomes

WS is a difficult condition to manage, and its management is best done by an interprofessional team to deal with all the complications. Consider the impact of WS on psychosocial functioning and quality-of-life and remember that it may be accompanied by psychiatric disorders. The dermatologist, psychiatrist, ophthalmologist, nuerologists and rheumatologist need to work as a team while treating such patients. Dermatology specialty-trained nurses can also help by counseling the patient, providing direction on medical management, and monitoring and charting for any complication. Close communication between interprofessional team members is vital to improve the outcomes.[17]



Ryan K. Mui


Sadia Masood


7/4/2023 12:28:59 AM



Sil A, Panigrahi A. Visual Dermatology: Waardenburg Syndrome Type II. Journal of cutaneous medicine and surgery. 2020 May/Jun:24(3):305. doi: 10.1177/1203475420902048. Epub     [PubMed PMID: 32421428]


Grewal PS, Knight H, Michaelides M. Asymmetric choroidal hypopigmentation in a Son and mother with Waardenburg syndrome type I. Ophthalmic genetics. 2020 Jun:41(3):284-287. doi: 10.1080/13816810.2020.1750037. Epub 2020 Apr 13     [PubMed PMID: 32281454]


Ren SM, Kong XD, Wu QH, Jiao ZH, Chen C, Qin ZB. [Analysis of genetic variation in patients with Waardenburg syndrome type Ⅱ by next generation sequencing]. Zhonghua yi xue za zhi. 2020 Mar 24:100(11):853-858. doi: 10.3760/cma.j.cn112137-20190730-01692. Epub     [PubMed PMID: 32234158]

Level 2 (mid-level) evidence


Yu Y, Liu W, Chen M, Yang Y, Yang Y, Hong E, Lu J, Zheng J, Ni X, Guo Y, Zhang J. Two novel mutations of PAX3 and SOX10 were characterized as genetic causes of Waardenburg Syndrome. Molecular genetics & genomic medicine. 2020 May:8(5):e1217. doi: 10.1002/mgg3.1217. Epub 2020 Mar 13     [PubMed PMID: 32168437]


Alehabib E, Alinaghi S, Pourfatemi F, Darvish H. Incomplete penetrance of MITF gene c.943C}T mutation in an extended family with Waardenburg syndrome type II. International journal of pediatric otorhinolaryngology. 2020 Aug:135():110014. doi: 10.1016/j.ijporl.2020.110014. Epub 2020 Apr 21     [PubMed PMID: 32422366]


Li S, Guo M, Ruan B, Liu Y, Cui X, Han W, Li R. A Novel PAX3 Mutation in a Chinese Family with Waardenburg Syndrome Type 1. Genetic testing and molecular biomarkers. 2020 May:24(5):249-255. doi: 10.1089/gtmb.2019.0231. Epub 2020 Apr 3     [PubMed PMID: 32250160]


Apaydin F,Bereketoglu M,Turan O,Hribar K,Maassen MM,Günhan O,Zenner HP,Pfister M, [Waardenburg syndrome. A heterogenic disorder with variable penetrance]. HNO. 2004 Jun     [PubMed PMID: 15029423]


Ez-Zahraoui M, Lezrek O, Cherkaoui O. [Waardenburg syndrome type 1]. Journal francais d'ophtalmologie. 2019 Jan:42(1):94-95. doi: 10.1016/j.jfo.2018.03.028. Epub 2018 Dec 13     [PubMed PMID: 30554874]


Astakhov YS, Tultseva SN, Lisochkina AB, Takhtaev YV, Astakhov SY, Shakhnazarova AA. [Ophthalmologic manifestations of Waardenburg syndrome]. Vestnik oftalmologii. 2019:135(6):91-99. doi: 10.17116/oftalma201913506191. Epub     [PubMed PMID: 32015313]


Gowda VK, Srinivas S, Srinivasan VM. Waardenburg Syndrome Type I. Indian journal of pediatrics. 2020 Mar:87(3):244. doi: 10.1007/s12098-019-03170-5. Epub 2020 Jan 27     [PubMed PMID: 31989460]


Ren S, Chen X, Kong X, Chen Y, Wu Q, Jiao Z, Shi H. Identification of six novel variants in Waardenburg syndrome type II by next-generation sequencing. Molecular genetics & genomic medicine. 2020 Mar:8(3):e1128. doi: 10.1002/mgg3.1128. Epub 2020 Jan 20     [PubMed PMID: 31960627]


Wallis KE, Blum NJ, Waryasz SA, Augustyn M. Bilateral Cochlear Implants: Maximizing Expected Outcomes. Journal of developmental and behavioral pediatrics : JDBP. 2018 Feb/Mar:39(2):177-179. doi: 10.1097/DBP.0000000000000547. Epub     [PubMed PMID: 29324475]


Shah M, Patton E, Zedek D. Piebaldism. StatPearls. 2023 Jan:():     [PubMed PMID: 31334958]


Minami SB, Nara K, Mutai H, Morimoto N, Sakamoto H, Takiguchi T, Kaga K, Matsunaga T. A clinical and genetic study of 16 Japanese families with Waardenburg syndrome. Gene. 2019 Jul 1:704():86-90. doi: 10.1016/j.gene.2019.04.023. Epub 2019 Apr 10     [PubMed PMID: 30978479]


Raissi D, Christie A, Applegate K. Waardenburg Syndrome and Left Persistent Superior Vena Cava. Journal of clinical imaging science. 2018:8():44. doi: 10.4103/jcis.JCIS_31_18. Epub 2018 Nov 15     [PubMed PMID: 30546928]


Boutkhil M, Benchekroun Belabess S, El Ikhloufi M, Taouri N, Cherkaoui O. [Waardenburg syndrome, a family story]. Journal francais d'ophtalmologie. 2019 Sep:42(7):e319-e324. doi: 10.1016/j.jfo.2018.12.026. Epub 2019 May 24     [PubMed PMID: 31130388]


Shrinkhal, Singh A, Mittal SK, Agrawal A, Verma R, Yadav P. Waardenburg syndrome with dry eyes: A rare association. Taiwan journal of ophthalmology. 2019 Jul-Sep:9(3):198-201. doi: 10.4103/tjo.tjo_103_18. Epub 2019 Sep 12     [PubMed PMID: 31572658]