Statistics from Altmetric.com
Editor,—Waardenburg syndrome (WS) is a typical auditory pigmentary syndrome with affected individuals showing varying combinations of sensorineural hearing loss, patchy abnormal pigmentation of the eyes, hair and skin, and various defects of neural crest derived tissues.1-3
This syndrome is both clinically and genetically heterogeneous and is clinically classified into four types.3 Mutations of thePAX3 gene have been identified in WS type 1 and 3, while those of either the endothelin B receptor gene, the endothelin-3 gene or the soxio gene have been identified in WS type 4.4-6 WS type 2 is a heterogeneous group, with about 10% of cases caused by mutations in MITF. But MITF mutations are obviously not the major cause of WS type 2 and for most cases the genetic basis is as yet unknown.
The diagnostic criteria for WS type 2 proposed by Liuet al 1 include, in addition to congenital sensorineural hearing loss and pigmentary disturbances of the hair, pigmentary disturbances of the iris but not of the fundus.
In the two affected boys of the Turkish family presented here, the pattern of fundus pigmentation was one of the most striking clinical features, with dense hyperpigmented areas next to hypopigmented areas. We want to emphasise the importance of a thorough observation of the clinical phenotype and especially of the pattern of fundus pigmentation in WS type 2.
A Turkish family presented with two of three sons showing clinical symptoms of WS type 2. Firstly, the 5 year old boy, the youngest of three children of a non-consanguineous couple, was referred for ophthalmological evaluation because of constant esotropia in the left eye. The child has worn hearing aids since the age of 16 months; the first reliable audiogram at age 3 years showed profound sensorineural hearing loss which had not changed over the past years. Best corrected visual acuity was right eye 20/20 and left eye 20/400. Cycloplegic refraction showed anisohypermetropia (right eye +2.5D and left eye +4.5D). He had bilateral dark brown irides and strabismus convergens in the left eye (Fig 1, top). The pattern of fundus pigmentation was of a distinctly abnormal type in both eyes. Areas of hypopigmentation on the posterior pole as well as nasally passed over to areas with pigmentary mottling and spots of hyperpigmentation temporally in the right eye. In the left eye, these areas of hyperpigmentation were more extensive in the peripapillary region, nasally, and in the whole fundus periphery, respectively (Fig 1, centre). Audiometry showed profound bilateral sensorineural hearing loss (Fig 1, bottom).
As the parents also reported congenital deafness in the second son with “two different coloured eyes,” we asked them to bring the other family members for examination. The second son, a 7 year old boy, showed complete iris heterochromia with a dark brown iris right and a brilliant blue iris left (Fig 2, top). Cycloplegic refraction revealed an anisohypermetropia (right eye +0.5D and left eye +5.5D), best corrected visual acuity was 20/20 right eye and 20/200 left eye. Severe fundus pigmentary disturbances were found in the left (blue) eye, with extensive albinoid areas nasally and on the posterior pole, whereas the temporal region showed a homogeneous area of dense hyperpigmentation. In the right (dark brown) eye, the pigmentary disturbances were less extensive with a hyperpigmented peripapillary ring and pigmentary mottling especially in the nasal region (Fig 2, centre). Conventional audiological examinations showed bilateral senorineural hearing loss with moderate impairment on the right and total deafness on the left side (Fig 2, bottom).
Ophthalmological and audiological evaluations made of the father, the eldest brother, and a son of the father‘s first marriage were within normal limits. The mother showed pigmentary mottling in the periphery of the fundus only. No other associated abnormalities (such as hair or skin hypopigmentation, medial eyebrow flare, broad and high nasal root, hypoplasia of alae nasi, or premature greying of hair) were found among the family members. To calculate the W index, a biometric index for dystopia canthorum, we used dystopia indices for WS as reported by Arias,7 based upon the inner canthal, interpupillary, and outer canthal distances. The W index for this family was 1.45, indicating that none of the individuals had dystopia canthorum. This was consistent with the clinical picture of WS type 2.
The genomic DNA samples, tested for mutations in thePAX3 and MITFgenes as described elsewhere,4 showed no abnormally migrating bands.
Given the classic symptoms of WS type 2 expressed in this Turkish family, we had the opportunity to make some interesting observations on the clinical findings in this syndrome.
In the genomic DNA samples of this family no abnormally migrating bands in the MITF gene or the PAX 3 gene were seen. Only about 10% of patients who fulfil the diagnostic criteria for WS type 2 have an MITF mutation and for most cases the genetic basis is as yet unknown.4-6 8Dominantly inherited examples of auditory pigmentary syndromes with patchy depigmentation of the skin, hair, eyes or the stria vascularis of the cochlea are usually labelled as Waardenburg syndromes.1 3 Expression of clinical findings is extremely variable1 2 and the evaluation of a correct history of pedigree was difficult in this family because of the fact that most of the other family members were living in the Turkey. However, the fundal pigmentary changes of the mother were distinct enough to mark her as affected.
Complete heterochromia irides and especially the brilliant sapphire-blue eye colour have been noted rarely in non-Waardenburg people.2 Slit lamp examination of the left iris of the second son showed a thick iris of a brilliant blue colour without any hypoplastic structures or transillumination defects. It is generally assumed that in WS type 2 only the mesodermal component of the iris is involved owing to a lack of melanocytes in the mesodermal part of the iris.
Congenital deafness is clinically the most serious symptom. WS type 2 individuals were found to have a greater incidence of deafness, more severe and more often bilateral forms of deafness.2Hearing impairment can be explained by a lack of melanocytes in the stria vascularis of the cochleae. These two affected boys showed bilateral sensorineural hearing loss. Interestingly, we found that the audiological results are paralleled by the pattern of fundus pigmentation. While the youngest boy with bilateral brown irides and marked bilateral pigmentary abnormalities of the fundus had profound bilateral hearing loss (Fig 1), the 7 year old boy with heterochromia irides showed different degrees in the severity of fundus anomalies and hearing loss: the moderate degree of hearing loss of the right ear correlated with mild irregularities of pigmentation of the homolateral fundus, total deafness left correlated with severe homolateral fundus pigmentary disturbances and the brilliant blue iris (Fig 2).
The pattern of fundus pigmentation is not considered as part of diagnostic criteria for WS type 2.1 However, in our family, abnormalities in fundus pigmentation seem to constitute an integral part of this syndrome. Fundi in patients with WS were described as “patchy hypopigmentation,” “pigmentary mottling,” or “albinoid in type” in most cases.9 10 Only Goldberg9 reported “blond next to hyperpigmented areas” in a black boy. In the two affected boys, dense hyperpigmented areas next to marked hypopigmented areas were one of the most impressive clinical findings. This picture seems to be the result of a localised accumulation of pigmented melanocytes which were handicapped in their determined homogeneous distribution.
In conclusion, we have presented a Turkish WS type 2 family in which no mutations of the MITF gene could be found. The affected family members showed a conspicuous fundus picture with ipsilateral connections between iris, fundus, and perhaps, inner ear pigmentation. Therefore, one might suggest, that the clinical signs in WS type 2 could be a consequence of a failure in distribution of pigmented melanocytes in their final location. The genetic basis, as yet unknown for most cases of WS type 2, might be found in a very late step of the pigmentation pathway.