Waardenburg's syndrome

Waardenburg syndrome (ICD-9-CM 270.2)

Are You Confident of the Diagnosis?

Waardenburg’s syndrome (WS) was first described in 1951 by Waardenburg, a Dutch ophthalmologist. It is an autosomal dominant genetic disorder characterized by piebaldism (congenital poliosis and leukoderma), pigmentary abnormalities of the iris, lateral displacement of the inner canthi of the eyes (dystopia canthorum) and sensorineural deafness. Deafness is associated with the absence of neural-crest derived melanocytes from the stria vascularis of the cochlea, due to failure of melanoblasts to migrate or survive. The disease is classified into 4 clinical types, based on particular clinical characteristics (Table I):

Table I.
Syndrome type Clinical characteristics
WS 1 Hypopigmented patchesSensorineural deafnessHeterochromia iridesDystopia canthorum
WS2 WS1 featuresNo dystopia canthorum
WS3 WS1 features, with musculoskeletal abnormalities
WS4 WS3 features, with Hirschsprung’s diseaseNo deafness

WS type 1: This is the classic form. It is characterized by congenital depigmentation and craniofacial abnormalities. The most common pigmentation abnormality is poliosis, while other less commonly encountered abnormalities include depigmented white patches of skin and pigmentary abnormalities of the iris, such as heterochromia irides (differently colored eyes), partial heterochromia irides (variations of color within an iris), and hypoplastic blue irides. The hallmark craniofacial defect found in virtually all WS1 patients is dystopia canthorum (widely set eyes), which can be measured by the W-index. Moreover, a broadening of the nasal root and synorphrys may be present. Congenital deafness may also exist.

WS type 1: It is characterized by abnormalities associated only with melanocytes. There is no dystopia canthorum. It presents with poliosis, depigmented white patches on the skin, heterochromia irides, and congenital sensorineural deafness.

WS type 3 (Klein-Waardenburg syndrome): It has been regarded as a variant of WS1 and presents with WS1 features with additional axial and limb musculoskeletal anomalies. It has been suggested that homozygous WS1 (as has been reported in offspring form consanguineous heterozygous WS1 parents) may be a cause of WS3.

WS type 4 (Klein-Waardenburg syndrome): It presents with a phenotype similar to that of WS3 but with the additional feature of Hirschsprung’s disease, which manifests with congenital aganglionic megacolon. Hirschsprung’s disease results from deficient neurons of the intestinal neural plexus which, like melanocytes, are derived from the neural crest. There is no deafness.

Diagnosis confirmation

Diagnosis of WS is usually made on clinical grounds, with pigmentary abnormalities being evident at birth. Sensorineural deafness may be confirmed by hearing screening.

Dystopia canthorum is measured by the W-index, contributing to diagnosis.

The W-index: W= X + Y + (A/B)

X= [2A- (0.2119C + 3.909)] /C

Y= [2A- (0.2497B+ 3.909)] /B

A: inner canthal distance

B: interpupillary distance

C: outer canthal distance

The clinical distinction between WS1 and WS2 can be difficult and molecular diagnosis is necessary to differentiate these two types. Mutation analysis of the PAX3 gene is available to establish diagnosis for WS1 and WS3.

WS Consortium diagnostic criteria

As the phenotypes of WS are variable even within a family and may be nonpenetrant in some individuals, in 1992 the WS Consortium developed diagnostic criteria for genetic and phenotypic studies. According to these criteria, for a patient to be diagnosed as affected with WS1, he/she must have either: a) at least 2 of the major criteria, or b) one of the major criteria and 2 of the minor criteria (not including the rare criteria). Furthermore, for a patient to be diagnosed with WS2, there must be 2 major criteria present, with no dystopia canthorum.

Major criteria

  • Poliosis (depigmented hair)

  • congenital sensorineural deafness

  • heterochromia irides

  • positive family history with an affected first-degree relative

  • dystopia canthorum, W index > 1.95

Minor criteria

  • Congenital leukoderma

  • Premature graying of hair

  • Broad nasal root

  • Hypoplasia of alae nasi

  • Synophrys

Differential diagnosis of WS

The differential includes other congenital or acquired disorders characterized by depigmented skin lesions:

  • Acquired depigmentation disorders

  • Vitiligo: it is not present at birth. Usually starts in childhood or young adulthood. Depigmented hair. Depigmented white patches with symmetrical involvement. Tendency for periorificial skin. Koebner phenomenon. May be progressive. Association with autoimmune diseases (Hashimoto thyroiditis, Graves’ disease, alopecia areata, insulin-dependent diabetes mellitus, pernicious anemia).

  • Vogt-Koyanagi-Harada syndrome: a disease complex affecting the eyes, skin, auditory system and central nervous system. Rare in white-skinned individuals. Autoimmune disease. Four successive phases: prodromal phase (fever, headache, vomiting, meningismus, mental status changes), uveitic phase, convalescent phase (vitiligo, poliosis of the scalp, eyebrows, eyelashes and hairs of the axillae), fourth phase of recurrent attacks of uveitis.

2. Congenital depigmentation disorders:

  • Oculocutaneous albinism: Cutaneous sensitivity to ultraviolet radiation, visual defects (nystagmus, photophobia, decreased visual acuity), increased risk of nonmelanoma skin cancers.

  • Hermansky-Pudlak syndrome: Rare, oculocutaneous albinism, platelet storage pool deficiency resulting in bleeding diathesis, ceroid storage disease resulting in pulmonary fibrosis, kidney failure, granulomatous colitis. Fatal in the fourth or fifth decade of life from pulmonary fibrosis.

  • Chediak-Higashi syndrome: Extremely rare, oculocutaneous albinism, neutropenia, recurrent infections, thrombocytopenia, bleeding diathesis, neurologic defects. Fatal in the first decade of life from infections or bleeding.

  • Griscelli syndrome: Extremely rare, oculocutaneous albinism, severe immunodeficiency, neurologic defects. Fatal within the first decade of life.

  • Piebaldism: Presence of hyperpigmented patches within the depigmented lesions. Absence of midfacial lesions, and location of white patches on the trunk and extremities. No iris heterochromia, no deafness.

  • Albinism-deafness syndrome (Woolf syndrome): Extremely rare X-linked recessive disorder. Only affects males. Piebaldism, congenital neural deafness. Some patients have heterochromia irides. The gene has been mapped to Xq26.3-q27.1, but remains unidentified.

  • Tietz-syndrome: severe WS2 phenotype. Tietz syndrome is characterized by severe deafness, generalized albinism with blue eyes, and hypoplasia of the eyebrows. It is caused by a distinct genetic defect of the MITF gene (an in-frame deletion) resulting in greater dysfunction of melanocytes compared to other MITF mutations.

3. Other skin diseases with hypopigmented macules or patches:

  • Hypopigmented mycosis fungoides (MF). This is a rare variant of MF, mainly affecting patients of Asian or African descent. It presents with persistent hypopigmented, usually pruritic, patches, distributed in non-photoexposed areas of the body.

  • Tuberous sclerosis: specific diagnostic criteria must be met for diagnosis. Hypopigmented (off-white) lesions include segmental hypomelanosis, confetti-like hypopigmented macules, ash-leaf macules.

  • Tinea versicolor: cutaneous fungal dermatosis caused by Malassezia furfur. Hypopigmented patches or minimally raised plaques with scaling, most commonly located on the trunk. Recurrence is common.

  • Nevus depigmentosus: Congenital hypopigmented macule or plaque. Stable. Does not cross the midline. It is an expression of mosaicism.

  • Nevus anemicus: congenital, localized vascular disorder. Hypopigmented macule or plaque. Normal melanocytes and melanin. Rubbing the lesion does not cause erythema. Disappears with diascopy.

Who is at Risk for Developing this Disease?

WS is relatively rare, although it is thought to be a more global disease of neural crest development compared to piebaldism. It affects males and females with an equal frequency with an estimated incidence of approximately 1 per 20,000-40,000. There is no racial or ethnic predilection.

What is the Cause of the Disease?

WS is a disorder of melanoblast migration from neural crest to the skin. It is usually inherited in an autosomal dominant way, and autosomal recessive mode of inheritance is relatively rare. WS1 and WS2 are inherited in an autosomal dominant way, WS4 is an autosomal recessive disorder, and WS3 can be either dominant or recessive, depending on the specific gene mutation.

It has been suggested that there are additional clinical types of WS, associated with distinct genotypes.

WS type 1 and 3 result from mutations of the PAX3 transcription factor gene which has been mapped to human chromosome 2q35-q37.3. The importance of PAX3 for the expression of MITF, with consequent effects on melanocyte survival during development, seems to be responsible for pigmentary defects of WS1 and WS3. PAX3 also seems to be involved in the development of bony and cartilaginous structures of the face from neural crest-derived cell types, as well as in skeletal development.

WS type 2 has been attributed to a mutation of the MITF which is located on chromosome 3p12. Additionally, mutations in the SLUG gene have been reported, although there are cases of WS2 with no mutations in MITF or other known pigmentation genes, suggesting additional roles for yet unidentified genes. The restricted phenotype of WS2 may also be explained by the fact that MITF appears to be important for the development and function solely of the melanocytic lineage.

WS type 4 is caused by a heterozygous mutation of the SOX10 gene or homozygous mutations either in the gene encoding the peptide ligand endothelin-3 (EDN3) or its receptor (EDNRB). These genes are important determinants of the development of the neural crest-derived enteric nervous system cells that innervate the distal part of the colon. The transcription factor SOX10/PAX3 binds to the promoter of the MITF gene to express the MITF which in turn stimulates the expression of KIT. Therefore, WS4 can be a result of a defect of any one of these transcription factors that can reduce c-KIT production.

Systemic Implications and Complications

Apart from cutaneous involvement, WS may affect:

  • The ear, causing sensorineural deafness. The patient population with WS accounts for approximately 2% of congenitally deaf children.

  • Musculoskeletal abnormalities: Limb abnormalities

  • Hirschsprung’s disease: The disorder is a neurocristopathy, caused by defects in migration, proliferation and/or survival of neural crest cells that normally give rise to all neurons and supporting cells of the enteric nervous system, resulting in a form of structural intestinal obstruction.

  • Neurologic abnormalities: Peripheral demyelinating neuropathy, central demyelinating leukodystrophy, Waardenburg syndrome, Hirschprung Disease (PCWH). A subset of WS4 patients, carrying mutations in the SOX10 gene, may exhibit neurological abnormalities. SOX10 plays a key role in the development of neural-crest-derived tissues, such as melanocytes, autonomic and enteric nervous systems, as well as glial cells of the central nervous system.

  • Cleft lip and palate

A screening program in Colombia identified 95 affected WS patients among 1,763 deaf individuals. 62% had WS2 and 38% WS1. In addition to sensorineural deafness in all, the most frequent features were broad nasal root (58.9%), a first degree relative affected (37.9%), heterochromia irides (36.8%), skin hypopigmentation (31.6%), white forelock (28%), intense blue iris (27.4%) and hypoplasia alae nasi (1.1%). The majority of individuals had normal psychomotor development (87%) while developmental delay was found in 13%.

Mortality risk in WS patients is similar to that of the general population.

Treatment Options

Treatment options are summarized in Table II.

Table II.
Medical Treatment Surgical Procedures Physical Modalities
Not successful Cochlear implantation Cosmetic camouflage for pigmentary abnormalities

Optimal Therapeutic Approach for this Disease

Explain the natural history of WS to the patient. It is a stable, noncontagious disease.

Medical treatments are not effective for WS.

Surgery may be beneficial for severe dystopia canthorum, cleft lip or palate, and Hirschsprung’s disease.

Children with WS exhibit normal inner ear anatomy and perform well when they receive cochlear implantation and auditory rehabilitation.

Cosmetic camouflage may be used for limited skin depigmentation

Optimal therapeutic approach for WS requires a multidisciplinary approach including:

  • a geneticist (for molecular diagnosis),

  • audiologist (for hearing evaluations),

  • otorynolaryngologist (chochlear implantation),

  • dermatologist (for hair and skin pigmentary abnormalities),

  • ophthalmologist (for ophthalmologic studies)

  • orthopedist (for limb abnormalities),

  • neurosurgeon (for neural tube defects),

  • plastic surgeon (for cleft lip or palate) and

  • gastroenterologist (for Hirschsprung’s disease)

Patient Management

Genetic counseling should highlight the following:

  • Patients with WS1 and WS2 have a 50% chance in each pregnancy to have an affected offspring

  • In patients with WS3 or WS4, inheritance depends on the type of the underlying mutation, and requires molecular testing.

Unusual Clinical Scenarios to Consider in Patient Management

Although poliosis is characteristically a congenital finding that may be associated with Waardenburg syndrome, rarely poliosis may be acquired, even due to plucking of hair. When assessing the differential diagnosis including vitiligo and Vogt-Koyanagi-Harada syndorme, inquire about this history.

What is the Evidence?

Dessinioti, C, Stratigos, AJ, Rigopoulos, D, Katsambas, AD. “A review of genetic disorders of hypopigmentation: lessons learned from the biology of melanocytes”. Exp Dermatol. vol. 18. 2009. pp. 741-9. (A comprehensive review of the basic concepts of melanocyte biology and of molecular defects in melanocyte development and function resulting in the development of hypopigmentary hereditary skin diseases, including Waardenburg's syndrome, piebaldism, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, oculocutaneous albinism and Griscelli syndrome.)

Spritz, RA, Nordlund, JJ, Boissy, RE, Hearing, VJ, King, RA, Oetting, WS, Ortonne, JP. “Genetic hypomelanoses: disorders characterized by congenital white spotting- piebaldism, Waardenburg syndrome, and related genetic disorders of melanocyte development-clinical aspects”. The pigmentary system: physiology and pathophysiology. 2006. pp. 541-50. (This book encompasses the physiology of the pigmentary system, as well as the pathophysiology, clinical presentation and treatment strategies of congenital and acquired disorders of pigmentation (hypopigmentation, depigmentation, hyperpigmentation). The specific chapter focuses on the clinical presentations of disorders characterized by congenital white spotting, such as piebaldism, Waardenburg syndrome, and the albinism-deafness syndrome.)

Farrer, LA, Grundfast, KM, Amos, J. “Waardenburg syndrome (WS) type I is caused by defects at multiple loci, one of which is near ALPP at chromosome 2: first report of the WS consortium”. Am J Hum Genet. vol. 50. 1992. pp. 902-13. Development of diagnostic criteria for WS1.

Deka, RC, Sikka, K, Chaturvedy, G. “Cochlear implantation in Waardenburg syndrome: the Indian scenario”. Acta Otolaryngol. vol. 130. 2010. pp. 1097-100. (Cochlear implantation is beneficial for children with WS.)

Pingault, V, Ente, D, Dastot-Le Moal, F. “Review and update of mutations causing Waardenburg syndrome”. Hum Mutat. vol. 31. 2010. pp. 391-406. (An update on all WS genes and mutation databases and a discussion of the applications in diagnostics and genetic counseling in WS patients.)

Tamayo, ML, Gelvez, N, Rodriguez, M. “Screening program for Waardenburg syndrome in Colombia: clinical definition and phenotypic variability”. Am J Med Genet A. vol. 146A. 2008. pp. 1026-31. (Data on 95 WS patients identified among 1,763 deaf individuals in Columbia, showing inter-and intrafamilial variability in the phenotypic manifestations and variable expression of the disease.)

Qari, MS, Lin, N, Demierre, MF. “Hypopigmented mycosis fungoides and literature review”. J Cut Med Surg. vol. 4. 2000. pp. 142-8. (Four cases of hypopigmented MF are reported and the literature is reviewed.)

Touraine, RL, Attie-Bitach, T, Manceau, E. “Neurological phenotype in Waardenburg Syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain”. Am J Hum Genet. vol. 66. 2000. pp. 1496-1503. (The presentation of three unrelated WS4 patients with growth retardation and neurological phenotype with impairment of the central and autonomous nervous systems. A SOX10 mutation was identified in these patients.)

Takeda, K, Shibahara, S, Nordlund, JJ, Goissy, RE, Hearing, VJ, King, RA, Oetting, WS, Ortonne, JP. “Transcriptional regulation of melanocyte function”. The pigmentary system: physiology and pathophysiology. 2006. pp. 242-260. (A thorough review of the topic).

Horner, ME, Abramson, AK, Warren, RB. “The spectrum of oculocutaneous disease. Part I. Infectious, inflammatory, and genetic causes of oculocutaneous disease”. J Am Acad Dermatol. vol. 70. 2014. pp. e1-25. (This review paper summarizes eye findings in oculocutaneous genodermatoses and recommendations on when to refer to an ophthalmologist if a patient has signs/symptoms of ocular disease.)