Auditory-pigmentary syndromes are caused by physical absence of melanocytes from the skin, hair, eyes, or the stria vascularis of the cochlea. Dominantly inherited examples with patchy

Waardenburg's syndrome (WS) is an autosomal dominant combination of deafness and pigmentary disturbances, probably caused by defective function of the embryonic neural crest. We have mapped one gene for WS to the distal part of chromosome 2. On the basis of their homologous chromosomal location, their close linkage to an alkaline phosphatase gene, and their related phenotype, we suggested that WS and the mouse mutant Splotch might be homologous. Splotch is caused by mutation in the mouse Pax-3 gene. This gene is one of a family of eight Pax genes known in mice which are involved in regulating embryonic development; each contains a highly conserved transcription control sequence, the paired box. Here we show that some families with WS have mutations in the human homologue of Pax-3. Mutations in a related gene, Pax-6, which, like Pax-3, has both a paired box and a paired-type homeobox sequence, cause the Small-eye mutation in mice and aniridia in man. Thus mutations in the Pax genes are important causes of human developmental defects.

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There has been an increasing awareness of the importance of differentiating NF1 and NF2 in recent years culminating in the mapping of the genes to different chromosomes"q in 1987. In the same year the NIH Consensus Conference statement defined diagnostic criteria for NF1 and NF2.5 The NF2 criteria include distinct ophthalmological findings (posterior subcapsular lenticular opacities), although the frequency of these had been assessed in relatively small numbers of patients at that time.6 The NIH criteria for NFl have been used in a large study and found to be satisfactory,7 but the NF2 criteria have not been similarly assessed.A large clinical and genetic study of NF2 has allowed us to address these and other issues. The study has highlighted the inadequacy of current counselling and screening of at risk relatives. In this paper we present the findings of the study with relevance to genetic counselling, namely, the adequacy of current diagnostic criteria, the natural history of NF2, and suggestion of a screening protocol for at risk subjects. Patients and methodsThe methods of patient ascertainment, clinical assessment, and diagnostic criteria are described in the preceding paper.8 In addition all cases who did not precisely fit the NIH NF2 criteria (table 1), but who were thought to have the disease on clinical grounds were studied to allow evaluation of the diagnostic criteria.