Differential diagnosis

Waardenburg syndrome type I (WS1) needs to be differentiated from other causes of congenital, non-progressive sensorineural hearing loss and from other forms of Waardenburg syndrome.

Waardenburg syndrome type II (WS2). WS1 is distinguished from WS2 by the presence in WS1 of lateral displacement of the inner canthi (dystopia canthorum). If the average W index across a family is less than 1.95, the diagnosis is WS2. Sensorineural hearing loss and heterochromia iridum are the two most characteristic features of WS2. Both are more common in WS2 than WS1. White forelock and leukoderma are both more common in WS1 than in WS2.

Waardenburg syndrome type IV (WS4). Individuals having a rare combination of pigmentary abnormalities, hearing loss, and Hirschsprung disease have WS4.

Piebaldism has some pigmentary features in common with Waardenburg syndrome. A white forelock is commonly seen along with absent pigmentation of the medial forehead and eyebrows. Absent pigmentation of the chest, abdomen, and limbs is also common. A characteristic feature is hyperpigmented borders surrounding the unpigmented areas. Heterochromia irides and sensorineural deafness are rarely described. This disorder has shown genetic heterogeneity with dominant loss-of-function variants/whole-gene deletions described involving the KIT proto-oncogene. Heterozygous pathogenic variants in SNAI2 have also been implicated as an etiology in some individuals with piebaldism. Checkout pickaloan uk for more details.


Waadernburg syndrome (WS) is an autosomal dominant disease clinically and genetically heterogeneous. It is characterized by non-progressive sensorineuronal hearing loss of variable degree and anomalous pigmentation (of the eyes, skin and stria vascularis of cochlear duct) caused by melanocytes absence. The syndrome is caused by mutations in genes that regulate the melanocytes differentiation from the neural crest during embriogenetic development. The main characteristics of Waardenburg syndrome (WS) include: a wide bridge of the nose; pigmentary disturbances such as two different colored eyes, white forelock and eyelashes and premature graying of the hair; and some degree of cochlear deafness. The disease was named for Petrus Johannes Waardenburg, a Dutch ophthalmologist (1886-1979) who was the first to notice that people with two different colored eyes frequently had hearing problems.

Type I of the disorder is characterized by displacement of the fold of the eyelid, while Type II does not include this feature, but instead has a higher frequency of deafness.

The discovery of the human gene that causes Type I WS came about after scientists speculated that the gene that causes ‘splotch mice’ (mice with a splotchy coat coloring) might be the same gene that causes WS in humans. They located the human gene to chromosome 2 and found it was the same as mouse Pax3. Pax3 is one of a family of eight mouse Pax genes that are involved in regulating embryonic development at the level of transcription.


DYSTOPIA CANTHORUM Dystopia canthorum is the most penetrant feature of WS1, being present in 99% of those affected. Dystopia presents with the appearance of blepharophimosis and with fusion of the inner eyelids medially leading to a reduction in the medial sclerae. The inferior lachrymal ducts are displaced laterally, with the punctae opposite the cornea. Not only the inner canthal, but also the interpupillary and outer canthal distances are greater than normal, indicating a degree of hypertelorism. In the majority of affected subjects dystopia is readily recognised, but our experience shows that clinical impression is not altogether reliable. Subjects with WS2 risk being misdiagnosed as WS1 if there is mild hypertelorism. It is much better to rely on a biometric index. The W index is the best of several broadly equivalent indices9 (the bizarre numbers in the formula come from a discriminant analysis). Such indices are based upon the inner canthal, interpupillary, and outer canthal distances. Indices based on these three measurements are more reliable than those based upon two measures alone, although if there is strabismus the interpupillary distance cannot be used. The indices depend upon the relationship between the measurements rather than absolute measures, and so should be unaffected by age, race, or sex.


A broad, high nasal root, medial hypertrichosis and synophyrys, and hypoplasia of the alae nasi are features associated with dystopia canthorum in WS1 (table 3). Other facial features described include a patent metopic suture and square jaw. “l Strabismus may be more common with WS1 than normally.


Iris heterochromia may be complete or partial. In complete heterochromia each iris is a different colour, while in partial heterochromia the differently coloured area of the iris is sharply demarcated from the remainder and is usually, but not invariably, a radial segment. Partial heterochromia may be unilateral or bilateral and, if bilateral, may be symmetrical or asymmetrical.  Hypoplastic blue irises are found where there is deficient iris stroma, and mainly in association with a severe or profound hearing loss.


A distinctive white forelock is usually described, but the forelock may be red or black. The site of the forelock is usually in the midline but it may be elsewhere on the head. It may vary in size from a few hairs to a clump of hair and, if present at birth, may persist or disappear only to reappear later, usually in the teens, when it is considered to represent early graying. Complete depigmentation of the hair may occur in the teens and the hair may be sparse and of poor quality. The premature greying signifying WS is defined by the Waardenburg Consortium as predominance of white hairs appearing before the age of 30 years with the white hairs appearing in the midline. Pigmentation defects can affect the eyebrows and eyelashes as well as scalp hair.


Hypopigmentation of the skin is congenital and may be found on the face, trunk, or limbs. It may be associated with an adjacent white forelock. Hyperpigmentation has also been described” and this may develop after birth ina previously hypopigmented area. Arias3 noted that hypopigmented areas frequently had hyperpigmented borders. If depigmented patches are extensive, piebaldism (owing to mutation in the KIT gene) should be suspected, especially if the patient has normal hearing.


The hearing loss in Waardenburg syndrome is sensorineural, congenital, and usually nonprogressive. It may be unilateral or bilateral and can vary in degree from slight to profound.  include low frequency and U shaped losses, bilateral or unilateral, and sometimes a combination of a low frequency sensorineural hearing loss in one ear and a profound loss in the other. Radiological investigation of the auditory system has indicated a normal temporal bone or dysplasia of the lateral semicircular canal associated with a normal bony cochlea. The histological appearance of one temporal bone studied by Fisch” was consistent with the auditory features of type I being caused by a cochleosaccular degeneration.

Other associated conditions

A long list of other conditions have been reported in association with Waardenburg syndrome. It is difficult to disentangle to what extent these additional conditions are true rare manifestations of WS (type I or II), coincidental findings, or features of other neurocristopathies that are really separate syndromes. WS1 carries a small but definite risk of spina bifida and with cleft lip/palate.Hirschsprung disease (HSCR) is unquestionably associated with Waardenburg syndrome in WS4, which as described below is recessive and caused by mutations in the EDN3 and EDNRB genes. Whether there is also an association with other forms of Waardenburg syndrome is less clear. Most reports of WS-HSCR patients date from before the distinction was made between WS1 and WS2. One might expect WS1, as a neurocristopathy, to be the form associated with HSCR, but in fact any association that may exist of WS with HSCR is with type II WS.


There are no specific treatment options available for this syndrome the thing that we can do is only to manage the auditory disabilities in patients with waardenberg syndrome and other symptomatic care.