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

Abstract

Summary Happle–Tinschert syndrome (HTS) and Curry–Jones syndrome (CJS; OMIM 601707) are rare, sporadic, multisystem disorders characterized by hypo‐ and hyperpigmented 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 case of HTS 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, 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 that revealed a case with the same somatic mutation, with 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 of these conditions are caused by somatic mutations in genes of the hedgehog signalling pathway and we therefore propose the unifying term ‘mosaic hedgehog spectrum’. What's already known about this topic? Happle–Tinschert syndrome (HTS) and Curry–Jones syndrome (CJS) are rare mosaic multisystem disorders with linear skin lesions. CJS is characterized by severe constipation, which has not previously been reported in HTS. HTS is characterized by basaloid follicular hamartomas, which are not a recognized feature of CJS. The recurrent mosaic SMO mutation found in CJS was recently reported in a patient with HTS. What does this study add? We describe a patient with HTS and intractable constipation, and a case of CJS with medulloblastoma. Both patients had the same recurrent somatic SMO mutation also found in a case reported as segmental basal cell naevus syndrome. SMO functions in the hedgehog pathway, explaining phenotypic overlap between HTS, CJS and mosaic basal cell naevus syndrome. We propose the term ‘mosaic hedgehog spectrum’ for these overlapping conditions.

Systematized naevoid hypertrichosis may herald Happle–Tinschert syndrome

“…1 To date, fifteen additional cases have been described under this designation. [2][3][4][5] The disorder is caused by a postzygotic mutation in the gene smoothened (SMO). 5,6 In several reports, patches of hypertrichosis have been documented.…”

“…[2][3][4][5] The disorder is caused by a postzygotic mutation in the gene smoothened (SMO). 5,6 In several reports, patches of hypertrichosis have been documented. 1,2 The purpose of this article is to emphasize that such naevoid hypertrichosis may sometimes be a diagnostic marker of HTS.…”

The mosaic hedgehog spectrum: another lesson on the polymorphy of mosaicism

“…4,5 The presented cases further support the notion that CJS and HTS are part of one spectrum, thus underscoring the value of communicating rare and unusual individual observations of mosaic disorders. The authors also point out the overlap with segmental basal cell naevus syndrome, which can occur as a result of mosaicism for PTCH1 mutations, but was also the proposed clinical diagnosis in one previously reported case with the aforementioned recurrent SMO mutation (as reviewed in Lovgren et al 1 ). Based on the obvious phenotypic overlap and the consideration that the gene products of both SMO and PTCH1 function in the hedgehog signalling pathway, the authors propose the term 'mosaic hedgehog spectrum' for these overlapping conditions.…”

“…In this issue of the BJD, Lovgren et al present two unique cases and provide a literature review highlighting the pathogenetic and clinical overlap between Curry-Jones syndrome (CJS) and Happle-Tinschert syndrome (HTS). 1 Both disorders were previously found to be caused by mosaicism for the identical known oncogenic SMO mutation c.1234C>T, p.Leu412Phe. 4,5 The presented cases further support the notion that CJS and HTS are part of one spectrum, thus underscoring the value of communicating rare and unusual individual observations of mosaic disorders.…”

“…This issue of the BJD includes a fascinating case report adding one more piece to the puzzle of human mosaicism. 1 While dermatology has always been pioneering the recognition and delineation of human mosaic disorders, our knowledge of their genetic and molecular basis has only recently experienced a tremendous increase. This was mainly driven by the advent of new (deep) sequencing technologies facilitating the detection of mosaicism at even very low levels.…”