Waardenburg Syndrome, Type 2e

A number sign (#) is used with this entry because Waardenburg syndrome type 2E (WS2E) is caused by heterozygous mutations in the SOX10 gene (602229) on chromosome 22q13.

Description

Waardenburg syndrome type 2 is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes; congenital sensorineural hearing loss; and the absence of 'dystopia canthorum,' the lateral displacement of the inner canthus of each eye, which is seen in some other forms of WS (review by Read and Newton, 1997). Individuals with WS type 2E, which is caused by mutation in the SOX10 gene (602229), may have neurologic abnormalities, including mental impairment, myelination defects, and ataxia. Waardenburg syndrome type 2 is genetically heterogeneous (see WS2A; 193510).

For a description of other clinical variants of Waardenburg syndrome, see WS1 (193500), WS3 (148820), and WS4 (277580).

Clinical Features

Hennekam and Gorlin (1996) described a girl with bilateral sensorineural hearing loss, completely white anterior scalp hair, multiple freckles, and hypopigmentation of the right hand and foot and left fingers and toes. She also had nystagmus that spontaneously disappeared before 2 years of age and dental anomalies, including delayed tooth eruption and malpositioned teeth. She had mild learning difficulties and hypertonia of the limbs.

Bondurand et al. (2007) described 5 patients with type 2 Waardenburg syndrome who carried deletions in the SOX10 gene. All presented with white forelock and/or skin hypopigmentation and deafness ranging from severe to profound. Two patients had hypoplastic irides, 1 had sapphire blue irides, and 1 had hypopigmented irides. One patient had mental retardation with autism, and another had thumb duplication and congenital heart disease; these features were thought to result from deletion of additional genes.

Iso et al. (2008) reported a Japanese female infant with light blue eyes, hypopigmented irides, and a piece of white hair forelock. She did not have dystopia canthorum, broad nasal root, or Hirschsprung disease. Ophthalmologic examination revealed bilateral ocular albinism with hypopigmented fundus and hypochromic iris. At 3.5 months of age, auditory brainstem response studies showed bilateral severe sensorineural deafness. The phenotype was consistent with type 2 Waardenburg syndrome.

Sznajer et al. (2008) described a boy with Waardenburg syndrome. Clinical features included white matter anomalies, mental retardation with autistic-like behavior, vivid blue eyes, bilateral complete agenesis of the semicircular canals, and lack of Hirschsprung disease. Sznajer et al. (2008) identified a de novo mutation in the SOX10 gene (602229.0017).

Barnett et al. (2009) reported a 21-month-old boy with Waardenburg syndrome type 2E caused by a heterozygous mutation in the SOX10 gene (Q174P; 602229.0018). He had sensorineural deafness, fair skin and hair pigmentation, multiple tiny lentigines, cafe-au-lait spots, and light blue irides, but no evidence of Hirschsprung disease. He also showed neurologic involvement, with hypotonia, poor vision with intermittent nystagmus in early life, inability to fix or follow, and increased muscle tone. Brain imaging showed absence of the cochlear nerves, absence of the olfactory bulbs, and brain hypomyelination.

Elmaleh-Berges et al. (2013) retrospectively reviewed imaging studies from 14 Waardenburg probands who all had different mutations in the SOX10 gene, including 2 patients with WS2E; 6 with WS4C, 1 of whom was previously reported by Pingault et al. (2002); and 6 with PCWH, 2 of whom were previously reported by Pingault et al. (2002) and 1 by Bondurand et al. (2007). The patients, who underwent imaging for cochlear implant evaluation, a diagnosis of hearing loss, and/or evaluation of neurologic impairment, all had bilateral temporal bone abnormalities; the most frequent pattern consisted of agenesis or hypoplasia of one or more semicircular canals, an enlarged vestibule, and a cochlea with a reduced size and sometimes abnormal shape, but with normal partition. Three patients lacked a cochlear nerve, bilaterally in 2 patients with PCWH. Associated abnormalities observed when adequate MRI sequences were available included agenesis of the olfactory bulbs in 7 (88%) of 8 patients, hypoplastic or absent lacrimal glands in 11 (79%) of 14 patients, hypoplastic parotid glands in 12 (86%) of 14 patients, and white matter signal anomalies in 7 (54%) of 13 patients. These associated abnormalities were variably present in patients with all 3 SOX10-related Waardenburg diagnoses, except for the 2 patients with WS2E, who had normal lacrimal and parotid glands.

From a systematic literature search, Song et al. (2016) determined that the prevalence of hearing loss in patients with Waardenburg syndrome differed according to the genotype: the prevalence in those with WS2 due to SOX10 mutations was 100%.

Molecular Genetics

In a girl with a mild form of Waardenburg syndrome type 2E reported by Hennekam and Gorlin (1996), Bondurand et al. (1999) identified a heterozygous mutation in the SOX10 gene (S135T; 602229.0005).

Using a combination of semiquantitative fluorescence multiplex polymerase chain reaction and fluorescence in situ hybridization, Bondurand et al. (2007) identified heterozygous SOX10 deletions in 5 of 30 patients with Waardenburg syndrome type 2; no SOX10 point mutations were identified by DNA sequencing of the 3 SOX10 coding exons. One deletion removed exon 3 (602229.0013), another removed exon 4 (602229.0014), and the other 3 deletions included the entire SOX10 gene as well as other genes. Neurologic phenotypes reminiscent of that observed in variant WS4, i.e., PCWH syndrome (peripheral demyelinating neuropathy, central demyelinating leukodystrophy, WS, and Hirschsprung disease; see 609136) were observed in 2 WS2-affected patients with SOX10 deletions.

In a Japanese girl with Waardenburg syndrome type 2E, Iso et al. (2008) identified a heterozygous mutation in the SOX10 gene (602229.0015). She had ocular albinism, a white forelock, and sensorineural deafness.

Pingault et al. (2013) analyzed the SOX10 gene in 17 patients with hypogonadotropic hypogonadism and anosmia who had been diagnosed with Kallmann syndrome (see 147950) but who also exhibited at least 1 Waardenburg-like feature, and identified heterozygous SOX10 mutations in 6 of them (see, e.g., 602229.0023). One of the mutation-positive patients was reported to have early graying and deafness and therefore fulfilled the diagnostic criteria for type 2 WS, but no pigmentation defects had been reported in the other cases. Clinical reevaluation of 4 SOX10-mutated probands confirmed the absence of pigmentation disturbances in 3, whereas the fourth proband had developed a white forelock in his twenties. Analysis of SOX10 in 86 more patients with hypogonadotropic hypogonadism and anosmia, 20 of whom had various nonolfactory, nonreproductive associated anomalies, revealed heterozygous mutations in 2 patients; 1 of the 2 had hypoacusis and the other had normal hearing but showed macroscelia. Pingault et al. (2013) stated that there was no evidence to indicate why a given SOX10 mutation might be associated with hypogonadotropic hypogonadism and anosmia, and also noted that anosmia and hypogonadism might be underestimated in Waardenburg syndrome because individuals usually do not spontaneously complain of anosmia and WS is often diagnosed in childhood.