Happle-Tinschert, Curry-Jones and segmental basal cell naevus syndromes: overlapping disorders caused by somatic mutations in hedgehog-signalling genes - the mosaic Hedgehog spectrum.

Happle-Tinschert syndrome (HTS) and Curry-Jones syndrome (CJS; OMIM 601707) are rare, sporadic, multisystem disorders characterised by hypo- and hyper-pigmented skin patches following Blaschko's lines, plus acral skeletal and other abnormalities. The Blaschkoid pattern implies mosaicism, and indeed CJS was found in 2016 to be caused by a recurrent postzygotic mutation in a gene of the hedgehog signalling pathway, namely SMO, c.1234C>T, p.Leu412Phe. More recently the original HTS case was found to carry the same somatic mutation. Despite this genetic and phenotypic overlap, two significant differences remained between the two syndromes. The histological hallmark of HTS, basaloid follicular hamartomas (BFH), is not a feature of CJS. Meanwhile the severe gastrointestinal manifestations regularly reported in CJS, had not been described in HTS. We report a patient whose phenotype was entirely consistent with HTS apart from intractable constipation, and a second patient with classic features of CJS plus early onset medulloblastoma, a feature of basal cell naevus syndrome (BCNS). Both had the same recurrent SMO mutation. This prompted a literature review which revealed a case with the same somatic mutation, basaloid follicular hamartomas and other features of both CJS and BCNS. Segmental BCNS can also be caused by a somatic mutation in PTCH1. We thus demonstrate for the first time phenotypic and genetic overlap between HTS, CJS and segmental BCNS. All these conditions are caused by somatic mutations in genes of the hedgehog signalling pathway and we therefore propose the unifying term "mosaic hedgehog spectrum". This article is protected by copyright. All rights reserved.