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Waardenburg syndrome type 1

  • Author(s): Karaman, Ali, MD
  • Aliagaoglu, Cihangir, MD
  • et al.
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Waardenburg syndrome type 1
Ali Karaman MD1, Cihangir Aliagaoglu, MD2
Dermatology Online Journal 12 (3): 21

1. Department of Genetics, State Hospital, Erzurum, Turkey. alikaramandr@hotmail.com
2. Department of Dermatology, State Hospital, Erzurum, Turkey




Abstract

Waardenburg syndrome (WS) is a rare disease characterized by sensorineural deafness in association with pigmentary anomalies and defects of neural-crest-derived tissues. Depending on additional symptoms, WS is classified into four types, WS1, WS2, WS3 and WS4. WS1 and WS3 are attributed to mutations in PAX3, whereas WS2 is heterogenous, being caused by mutations in the microphthalmia-associated transcription factor gene in some but not all affected families. WS4 is attributed to mutations in the endothelin-3 or the endothelin-B receptor genes and SOX10 gene. WS1 is an auditory-pigmentary disorder comprising sensorineural hearing loss and pigmentary disturbances of the iris, hair, and skin, along with dystopia canthorum. We report a case with a confirmed diagnosis of WS1 and review the relevant literature for this rare disorder.


Waardenburg syndrome (WS) is a rare (1/40,000) disease characterized by sensorineural deafness in association with pigmentary anomalies and defects of neural-crest-derived tissues. Depending on additional symptoms, WS is classified into four types, WS1, WS2, WS3 and WS4. WS1 and WS3 are associated with mutations in PAX3, whereas WS2 is heterogenous, being associated with mutations in the microphthalmia-associated transcription factor (MITF) gene in some but not all affected families. WS4 is attributed to mutations in the endothelin-3 (EDNB) or the endothelin-B receptor (EDNRB) genes and SOX10 gene. WS1 is an auditory-pigmentary disorder comprising sensorineural hearing loss and pigmentary disturbances of the iris, hair, and skin, along with dystopia canthorum (lateral displacement of the inner canthi). We report a case with a confirmed diagnosis of WS1 and review the relevant literature for this rare disorder.


Clinical synopsis

A 3-year-old girl who suffers from congenital deafness and mutism was admitted to our pediatric outpatient clinic. Her prenatal, natal and postnatal histories were within normal limits. She was the third child of nonconsanguinous parents. She has two healthy sisters and three healthy brothers. Her height and weight were under the third percentile, indicating growth retardation. Mental and motor development of the patient were appropriate to her age.

Physical examination revealed characteristic sapphire-blue irises, dystopia canthorum, high broad nasal root, synophrys, low anterior hairline, mild frontal bossing and deaf-mutism (Fig. 1). There was an area of skin hypopigmentation (congenital leukoderma) on the forearm (Fig. 2). There was no physical abnormality in temporal bone computerized tomographic scans. The hearing of the child could not be examined with pure tone audiometry. Bilateral hearing loss was noted on auditory brainstem response. However, there were no signs or symptoms of Hirschsprung aganglionosis. No chromosomal abnormality was found.


Figure 1Figure 2

Comment

Waardenburg set forth this pattern of malformation in 1951. He found this syndrome in 1.4 per cent of congenitally deaf children and from these data estimated the incidence to be about 1 in 42,000 in Holland [1]. Waardenburg syndrome (WS) is classified into four types: type I is with dystopia canthorum, type 2 is without dystopia canthorum, type 3 is pseudo WS and type 4 is with Hirschsprung disease. Dystopia canthorum is the most distinguishing feature of WS type I. Phenotypic features of WS help to make an early diagnosis of this syndrome among deaf-mute children [2]. WS 1 is characterized by lateral displacement of medial canthi (dystopia canthorum), prominent broad nasal root, medial brushy eyebrows (synophrys), congenital deafness, pigmentary disorders of eyes, hair, and skin, heterochromic irides, white forelock, and hypomelanotic macules [2, 3]. However, the patients rarely exhibit all the clinical signs. WS equally affects both sexes and all races, with no sex difference among persons with congenital deaf-mutism. Among deaf-mutes WS has been observed in 0.9-2.8 percent of cases [4].

The diagnosis in patients with classic features of WS or in families with affected relatives is not difficult. There are five major and five minor diagnostic criteria for Waardenburg syndrome. Major criteria include sensorineural hearing loss, iris pigmentary abnormality (two eyes different color or iris bicolor or characteristic brilliant blue iris), hair hypopigmentation (white forelock or white hairs at other sites on the body), dystopia canthorum (lateral displacement of inner canthi, W index greater than 1.95) and first-degree relative previously diagnosed with Waardenburg syndrome. Minor criteria include skin hypopigmentation (congenital leukoderma/white skin patches), which is frequently present in WS1 on the face, trunk, or limbs (30-36 %)[5], medial eyebrow flare (synophrys), broad nasal root, hypoplasia alae nasi, and premature graying of the hair (before age 30) . Diagnostic criteria for WS1 have been proposed by the Waardenburg Consortium [6]. An individual must have two major or one major plus two minor criteria to be considered.

Because dystopia canthorum is the single most distinguishing feature of WSI, there have been a variety of indices devised to diagnose lateral displacement of the inner canthi. One of them is the W index, developed by Arias and Mota [7]. We calculated the W index to be 2.11 (indicates dystopia canthorum). Three major (sensorineural hearing loss, characteristic blue eyes, and dystopia canthorum) and four minor (synophrys, skin hypopigmentation (congenital leukoderma), premature graying of the hair, and broad nasal root) criteria were found in our patient. According to these criteria the child diagnosed as WS I. Neither parents nor any other member of the family had any history of pigmentary abnormalities, congenital deafness or findings suggesting WS. Therefore, the observed patterns of anomalies in this patient are probably the result of a new mutation within gene.

Deafness is the most serious feature of WS. There are different combinations of hearing loss: unilateral or bilateral; severe or moderate; total or partial. Waardenburg syndrome accounts for approximately 2-3 percent of the population with profound congenital deafness. Also, deafness is a present feature in approximately 25 percent of WS I and in 50 percent of WS II [8, 9, 10].

Both the auditory and the pigmentary abnormalities of WS could be explained by a failure of proper melanocyte differentiation. Melanocytes are required in the stria vascularis for normal cochlear function. With the exception of those in the retina, melanocytes are derived from the embryonic neural crest. Other tissues derived from the neural crest that are involved in WS1 and the rarer WS3 and WS4 variants include the frontal bone, limb muscles, and enteric ganglia. The findings are consistent with defective melanocyte migration or function that results in defective development of the stria vascularis leading to sensorineural hearing loss. Histopathologic examination of the inner ears of persons with Waardenburg syndrome shows absent organs of corti, atrophy of the spinal ganglion, and reduced numbers of nerve fibers [8, 9, 10,11]. Mutations in multiple genes cause the various forms of WS [12, 13, 14, 15]. Most, if not all, cases of WS1 are attributed to mutations in the PAX3 gene located on chromosome band 2q35. H within PAX3 causing WS1 were first described in 1992 [12, 13]. PAX3 is one of a family of nine human PAX coding for DNA-binding that is expressed in the early embryo. The PAX are defined by the presence of a paired box (128 amino acid DNA-binding domain). In addition, the PAX3 also contains a homeobox. The PAX3 has ten with the paired box in 2-4 and the homeobox in 5 and 6 [15].

Mutations in the microphthalmia-associated transcription factor (MITF) gene, located on chromosome band 3p14.1-p12.3, are responsible for some cases of WS2. Other cases of WS2 have been linked to another locus on band 1p; still others remain unlinked to either locus. Evidence exists that the MITF gene transactivates the tyrosinase gene, which is involved in melanocyte differentiation [15]. A study by Watanabe in 1998 showed that PAX3 transactivates the MITF promoter. Mutations in the PAX3 gene, therefore, could affect regulation of the MITF gene, leading to abnormalities of melanocyte differentiation [16].

WS4 is caused by homozygous mutations in either the endothelin-3 (EDN3) or the endothelin-B receptor (EDNRB) genes [17]. Heterozygous mutations in either gene cause isolated Hirschsprung disease. Heterozygous mutations in the SOX10 gene are also reported to be associated with WS4 [18]. Bondurand et al. have shown that an interaction occurs among PAX3, SOX10, and MITF in the regulation of melanocyte development that affects a molecular pathway leading to the auditory-pigmentary abnormalities seen in WS [19].

Occasional findings have been associated with WS1 [20]. Spina bifida and cleft lip and palate have been described in multiple families. The finding of spina bifida in several families with WS1 is not surprising given that WS is considered a neurocristopathy with the PAX3 being expressed in the neural crest. Vestibular symptoms including vertigo, dizziness, and balance difficulties have been reported in WS1, even without hearing loss [21].

Waardenburg syndrome can be diagnosed easily in the first few months of life because of prominent phenotypic features. Earlier diagnosis means a more successful rehabilitation of hearing [4]. Folic acid supplementation in pregnancy has been recommended for women at increased risk of having a child with WS1, given the possibly increased risk of neural tube defects associated with WS1 [22].

References

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