Novel and recurrent non-truncating mutations of the MITF basic domain: genotypic and phenotypic variations in Waardenburg and Tietz syndromes.

The microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor, which regulates melanocyte development and the biosynthetic melanin pathway. A notable relationship has been described between non-truncating mutations of its basic domain and Tietz syndrome, which is characterized by albinoid-like hypopigmentation of the skin and hair, rather than the patchy depigmentation seen in Waardenburg syndrome, and severe hearing loss. Twelve patients with new or recurrent non-truncating mutations of the MITF basic domain from six families were enrolled in this study. We observed a wide range of phenotypes and some unexpected features. All the patients had blue irides and pigmentation abnormalities that ranged from diffuse hypopigmentation to Waardenburg-like patches. In addition, they showed congenital complete hearing loss, diffuse hypopigmentation of the skin, freckling and ocular abnormalities, more frequently than patients with MITF mutations outside the basic domain. In conclusion, the non-truncating mutations of the basic domain do not always lead to Tietz syndrome but rather to a large range of phenotypes. Sun-exposed freckles are interestingly observed more frequently in Asian populations. This variability argues for the possible interaction with modifier loci.

Cardiac conduction alterations in a French family with amyloidosis of the Finnish type with the p.Asp187Tyr mutation in the GSN gene.

Familial amyloidosis of the Finnish type (FAF) is a rare autosomal-dominant disorder caused by the accumulation of a 71-amino acid amyloidogenic fragment of mutant gelsolin, an actin-modulating protein. The main symptoms include corneal lattice dystrophy, progressive cranial and peripheral neuropathy, and skin changes. To date, only two mutations in the GSN gene have been described: the p.Asp187Asn mutation in most patients and the p.Asp187Tyr mutation in a Danish and Czech family. We report on the third family with the p.Asp187Tyr mutation and the first French FAF family. Severe cardiac conduction alterations in three patients were mainly caused by cardiac sympathetic denervation. These findings demonstrate the cardiological involvement of the FAF phenotype and suggest that cardiological follow-up is required in FAF patients.

Complete germline deletion of the STK11 gene in a family with Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal-dominant inherited disorder characterised by multiple gastrointestinal hamartomatous polyps, melanin spots of the oral mucosa and digits, and an increased risk for various neoplasms. The PJS results from germline alterations of the STK11/LKB1 tumour suppressor gene, located on 19p13.3, and encoding a serine/threonine kinase. The detection of STK11 germline mutations, in only 50-70% of PJS families, has suggested a genetic heterogeneity of the disease. We report the case of a family with typical features of PJS, including gastrointestinal hamartomatous, breast cancers and melanin spots of the oral mucosa. Quantitative multiplex PCR of short fluorescent fragments (QMPSF) of the 19p13 region allowed us to identify an approximately 250 kb heterozygous deletion removing entirely the STK11 locus. This report, which constitutes the first description of a complete germline deletion of STK11, shows that the presence of such large genomic deletions should be considered in PJS families without detectable point mutations of STK11.