Molecular evidence of type 2 mosaicism in Gorlin syndrome

Torrelo, Antonio; Hernández‐Martín, Ángela; Bueno, Elena Villamañán; Colmenero, Isabel; Rivera, Isabel; Requena, Luis; Happle, Rudolf; González-Sarmiento, Rogelio

doi:10.1111/bjd.12458

Cited by 41 publications

(34 citation statements)

References 15 publications

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“…It is of note nonetheless that a higher proportion of patients with GS without a pathogenic variant were sporadic (without a positive family history), and thus some may be mosaic for the underlying mutation. Although this is an extremely common mechanism in some other tumour prone syndromes such as neurofibromatosis type 2 (NF2),24 25 it has only reported once in GS 26. In theory, mosaicism should be relatively easy to prove with biopsy material potentially available from more than one BCC, although until recently mutational analysis was difficult on formalin-fixed material and required fresh tissue.…”

Section: Discussionmentioning

confidence: 99%

First evidence of genotype–phenotype correlations in Gorlin syndrome

et al. 2017

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Section: Discussionmentioning

confidence: 99%

First evidence of genotype–phenotype correlations in Gorlin syndrome

et al. 2017

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“…Torrelo et al . reported a girl with paternally inherited BCNS and mosaicism for a second PTCH1 mutation, with asymmetrical palmar pits, hyper‐ and hypotrichosis, skeletal abnormalities and hyper‐ and hypopigmented lesions, confirmed to be BCCs and a basaloid hamartoma …”

Section: Discussionmentioning

confidence: 99%

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

Lovgren

Zhou

Hrčková³

et al. 2019

Br J Dermatol

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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.

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“…Torrelo et al . described a 12‐year‐old girl with congenital, segmentally arranged basal cell carcinomas on the right side of her body (Fig.…”

Section: Autosomal Dominant Disorders Characterized By Multiple Skin mentioning

confidence: 99%

“…Linear arrangement of multiple congenital basal cell carcinomas in a 12‐year‐old girl with type 2 segmental Gorlin syndrome proven by molecular analysis. An ipsilateral jaw cyst that developed during childhood may likewise reflect type 2 segmental mosaicism . (Reproduced with permission from John Wiley & Sons).…”

Section: Autosomal Dominant Disorders Characterized By Multiple Skin mentioning

confidence: 99%

“…[83][84][85] It should be noted, however, that several historical cases of so-called 'unilateral basal cell nevi' can today be categorized as examples of Happle-Tinschert syndrome. 86 Cutaneous T2SM Torrelo et al 10 described a 12-year-old girl with congenital, segmentally arranged basal cell carcinomas on the right side of her body ( Fig. 7).…”

Section: Gorlin Syndromementioning

confidence: 99%

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The concept of type 2 segmental mosaicism, expanding from dermatology to general medicine

Happle

2018

Acad Dermatol Venereol

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In autosomal dominant skin disorders, the well-known type 1 segmental mosaicism reflects heterozygosity for a postzygotic new mutation. By contrast, type 2 segmental mosaicism originates in a heterozygous embryo from an early postzygotic mutational event giving rise to loss of the corresponding wild-type allele, which results in a pronounced segmental involvement being superimposed on the ordinary, non-segmental phenotype. Today, this concept has been proven by molecular analysis in many cutaneous traits. The purpose of this review was to seek publications of cases suggesting an extracutaneous manifestation of type 2 segmental mosaicism. Case reports documenting a pronounced extracutaneous segmental involvement were collected from the literature available in PubMed and from personal communications to the author. Pertinent cases are compared to the description of cutaneous segmental mosaicism of type 1 or type 2 as reported in a given trait. In total, reports suggesting extracutaneous type 2 segmental mosaicism were found in 14 different autosomal dominant skin disorders. In this way, clinical evidence is accumulated that extracutaneous type 2 segmental mosaicism does likewise occur in many autosomal dominant skin disorders. So far, however, molecular proof of this particular form of mosaicism is lacking. The present review may stimulate readers to inform colleagues of other specialties on this new concept, in order to initiate further research in this particular field of knowledge that has important implications for diagnosis, treatment and genetic counselling.

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Molecular evidence of type 2 mosaicism in Gorlin syndrome

Cited by 41 publications

References 15 publications

First evidence of genotype–phenotype correlations in Gorlin syndrome

First evidence of genotype–phenotype correlations in Gorlin syndrome

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

The concept of type 2 segmental mosaicism, expanding from dermatology to general medicine

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