Key Points
Disease summary:
Waardenburg syndrome types 1 to 4 are a group of auditory-pigmentary syndromes that comprise sensorineural hearing loss (due to the absence of melanocytes in the stria vascularis of the cochlea), and hypomelanosis of the eyes, hair, and/or skin.
Since Waardenburg syndrome types 1 to 4 are disorders related to neural crest cells and their derivatives, they are considered to be neurocristopathies.
Hereditary basis:
Waardenburg syndrome is one of the most common syndromic causes of hearing loss and accounts for approximately 2% to 5% of all congenital sensorineural hearing loss.
Waardenburg syndrome demonstrates both inter- and intrafamilial variable expressivity, as well as locus and allelic heterogeneity.
Waardenburg syndrome type 1 (WS1), Waardenburg syndrome type 2 (WS2), and Waardenburg syndrome type 3 (WS3) are transmitted in an autosomal dominant manner, while Waardenburg syndrome type 4 (WS4) is inherited either as an autosomal recessive condition, with mutations within the endothelin-3 (EDN3) or endothelin-B receptor (EDNRB) genes, or as an autosomal dominant condition with heterozygous mutations within the SRY-related HMG-box 10 (SOX10) gene.
Differential diagnosis:
Well over 400 genetic syndromes that include hearing loss have been described. While nonsyndromic hearing loss accounts for the vast majority of hearing loss, syndromic hearing impairment is thought to account for up to 30% of prelingual deafness.
Piebaldism [MIM 172800] is an autosomal dominant condition that has a clinical phenotype similar to that of Waardenburg syndrome. A white forelock is commonly seen along with absent pigmentation of the medial forehead, eyebrows, chest, abdomen, and limbs. A characteristic feature is hyperpigmented borders surrounding the hypopigmented areas. In contrast to Waardenburg syndrome, hearing loss is not characteristic of this syndrome.
Tietze syndrome [MIM 103500] is an autosomal dominant condition characterized by congenital hearing loss and uniform hypopigmentation. Tietze syndrome is allelic to WS2 with heterozygous mutations within the MITF gene described in affected individuals. In contrast to WS2, the Tietze phenotype does not include heterochromia.
Craniofacial-deafness-hand syndrome [MIM 122880] is an autosomal dominant condition with characteristic facial features, profound sensorineural hearing loss, and radiologic abnormalities of the maxilla, nasal bones, and hands. This condition is also allelic to WS1 and WS3 with a heterozygous mutation within the PAX3 gene described in an affected individual.
Diagnostic Criteria and Clinical Characteristics
An individual must have two major criteria or one major and two minor criteria:
Major criteria
Congenital sensorineural hearing loss
Hair hypopigmentation
White forelock
White hairs within eyebrow, eyelashes
Pigmentation abnormality of the iris
Complete heterochromia iridum (irides of different color)
Partial or segmental heterochromia (two different colors in same iris, typically brown and blue)
Hypoplastic blue irides, or brilliant blue (sapphire) irides
Dystopia canthorum: W index >1.95∗
First-degree relative (parent, sibling, or offspring) with WS1 as defined by the above criteria
Minor criteria
Skin hypopigmentation (congenital leukoderma)
Synophrys or medial eyebrow flare
Broad high nasal root, prominent columella
Hypoplasia of the alae nasi
Premature graying of the hair (before age 30 years)
∗W index: The measurements necessary to calculate the W index (in mm) are as follows: inner canthal distance (a), interpupillary distance (b), and outer canthal distance (c).
Calculate X = (2a − 0.2119c + 3.909)/c
Calculate Y = (2a − 0.2479b + 3.909)/b
Calculate W = X + Y + a/b
An abnormal W index result is greater than 1.95.
An individual must have two criteria:
Congenital sensorineural hearing loss
Hair hypopigmentation
White forelock
White hairs within eyebrow, eyelashes
Pigmentation abnormality of the iris
Complete heterochromia iridum (irides of different color)
Partial or segmental heterochromia (two different colors in same iris, typically brown and blue)
Hypoplastic blue irides, or brilliant blue (sapphire) irides
First-degree relative (parent, sibling, or offspring) with WS2 as defined by the above criteria
And the absence of
Dystopia canthorum: Thus, W-index should be less than 1.95.
An individual must have the presence of
WS1 features (+ dystopia canthorum)
And
Skeletal abnormalities
Axial or limb anomalies
Hypoplasia of the musculoskeletal system
Flexion contractures of the fingers
Fusion of the carpal bones
Syndactyly
An individual must have the presence of
Waardenburg syndrome features (+/− dystopia canthorum)
And
Intestinal dysfunction: often presents as chronic unremitting constipation
Hirschsprung disease
Total colonic aganglionosis: includes the entire large intestine
Long segment colonic aganglionosis: proximal to the sigmoid colon
Short segment colonic aganglionosis: restricted to the rectosigmoid colon
Chronic intestinal pseudo-obstruction∗
∗Chronic intestinal pseudo-obstruction is defined as repetitive episodes or continuous symptoms of bowel obstruction, in the absence of a mechanical occluding lesion.
Refer to Table 153-1.
Dystopia canthorum is observed in virtually all individuals with WS1. The hearing loss observed in 60% of patients with WS1 is typically congenital, sensorineural, nonprogressive, and unilateral or bilateral. Most often the hearing loss is bilateral and profound (>100 dB). The majority of individuals with WS1 have either a classic white forelock (observed in ∼45% of affected individuals) or premature graying of the scalp hair. The classic white forelock and congenital leukoderma are more common in WS1 than WS2. While the classic forelock is most commonly in the midline, the patch of white hair may also be elsewhere. Other associated features occurring rarely include cleft lip and/or palate and spina bifida.
The main distinguishing feature between WS2 and WS1 is the absence of dystopia canthorum. Hearing loss and heterochromia iridum are the two most characteristic features of WS2. Both features are more common in WS2 than WS1.
WS3 is an allelic disorder to WS1 caused by mutations in the PAX3 gene. Skeletal malformations in WS3 range from minimal contractures of the fingers with or without syndactyly to hypoplasia of the upper limbs and/or pectoral girdle. Other skeletal abnormalities observed in affected individuals include hypoplastic or absent terminal phalanges of the toes.
Intestinal dysfunction is a feature unique to this type of Waardenburg syndrome. All forms of Hirschsprung disease have been described in individuals with WS4, with total colonic aganglionosis being the most prevalent. Symptoms of short segment Hirschsprung disease include chronic constipation, malabsorption, and enterocolitis. Long-segment Hirschsprung disease presents with intestinal obstruction findings such as bilious vomiting, abdominal distention, inability to feed orally in the first few days of life, and delayed meconium passage. Neurologic symptoms including peripheral demyelinating neuropathy and central neuropathy are typically only observed in affected individuals with terminal SOX10 mutations. In addition, the penetrance of Hirschsprung disease is close to 100% in individuals with SOX10 mutations, whereas it is not as prevalent in individuals with EDN3 or ENDRB mutations. Other dysautonomic features including asialia, alacrima, and reduced sweating may also be observed in affected individuals with SOX10 mutations.
| Percent of Affected Individuals | ||
|---|---|---|
| Clinical Findings | WS1 | WS2 |
Sensorineural hearing loss | 47%-58% | 77%-80% |
White forelock | 43%-48% | 16%-23% |
Complete heterochromia irides | 15%-31% |
