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Review
. 2021 Oct 29:14:427-444.
doi: 10.2147/TACG.S288274. eCollection 2021.

Genetic Testing in CYLD Cutaneous Syndrome: An Update

Nikoletta Nagy  1   2 , Anna Dubois  3 , Marta Szell  1   2 , Neil Rajan  3   4
Affiliations
Review

Genetic Testing in CYLD Cutaneous Syndrome: An Update

Nikoletta Nagy et al. Appl Clin Genet. .

Abstract

CYLD cutaneous syndrome (CCS) is an inclusive label for the inherited skin adnexal tumour syndromes Brooke-Spiegler Syndrome (BSS-OMIM 605041), familial cylindromatosis (FC - OMIM 132700) and multiple familial trichoepitheliomas (MFT-OMIM 601606). All three syndromes arise due to germline pathogenic variants in CYLD, a tumour suppressor gene (OMIM 605018). CCS is transmitted in an autosomal dominant pattern, and has variable expressivity, both of the three syndromic phenotypes, and of the severity of tumour burden. Age-related penetrance figures are not precisely reported. The first tumours typically appear during puberty and progressively accumulate through adulthood. Penetrance is typically high, with equal numbers of males and females affected. Genetic testing is important for confirmation of the clinical diagnosis, genetic counselling and family planning, including preimplantation diagnosis. Additionally, identified CCS patients may be eligible for future clinical trials of non-surgical pre-emptive interventions that aim to prevent tumour growth. In this update, we review the clinical presentations of germline and mosaic CCS. An overview of the germline pathogenic variant spectrum of patients with CCS reveals more than 100 single nucleotide variants and small insertions and deletions in coding exons, most frequently resulting in predicted truncation. In addition, a minority of patients have large deletions involving the CYLD gene, intronic pathogenic variants that affect splicing, or inversions. We discuss germline and somatic testing approaches. Somatic testing of tumour tissue, relevant in mosaic CCS, can reveal recurrently detected pathogenic variants when two or more tumours are tested. This can influence genetic testing of children, who may inherit this as a germline variant, and inform genetic counselling and prenatal diagnosis. Finally, we discuss testing technologies that are currently used, their benefits and limitations, and future directions for genetic testing in CCS.

Keywords: CYLD gene testing.

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Conflict of interest statement

The authors declare no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Cylindromas: germline and mosaic presentations. (A) Cylindromas and spiradenomas progressively grow and form a confluent mass, as seen in this severely affected patient with CCS. (B) Mosaic presentations of unilateral cylindromas, that may warrant skin biopsy and genetic testing to determine a recurrently detected pathogenic variant across multiple tumours. Image (B) reprinted from J Am Acad Dermatol, 81, Arefi M, Wilson V, Muthiah S et al. Diverse presentations of cutaneous mosaicism occur in CYLD cutaneous syndrome and may result in parent-to-child transmission. 1300–1307, Copyright (2019), with permission from Elsevier.
Figure 2
Figure 2
Skin tumours frequently seen in CCS. (A) Cylindroma. (B) Spiradenoma indicated by black arrow. (C) Trichoepithelioma indicated by white arrows. Reprinted from Dermatol Clin, 35 (1), Dubois A, Hodgson K, Rajan N. Understanding Inherited Cylindromas: Clinical Implications of Gene Discovery. 61–71, Copyright (2017), with permission from Elsevier.
Figure 3
Figure 3
Pulmonary and cutaneous cylindromas visualised radiologically and endoscopically. (A) Spatial location of cutaneous CCS tumours seen on a CT with contrast indicated in green, and pulmonary CCS tumours indicated in yellow. Adapted from (B) Intra bronchial CCS tumour visualised during bronchoscopy. Adapted with permission from Brown SM, Arefi M, Stones R, et al. Inherited pulmonary cylindromas: extending the phenotype of CYLD mutation carriers. Br J Dermatol. 2018;179:662–668. © 2018 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.
Figure 4
Figure 4
CYLD gene pathogenic variants identified to date. (A) Exonic locations of CYLD pathogenic variants in CCS patients; note a predisposition to the 3’ end of the gene, from which the catalytic domains are encoded. (B) Frameshift and nonsense pathogenic variants resulting in a predicted truncating protein are the most frequent mutation type seen.
Figure 5
Figure 5
A suggested testing strategy for CCS that addresses germline and mosaic presentations. *RNA from blood leucocytes require special collection tubes; **in principle such a patient may still yet harbour a germline pathogenic variant, and it remains the clinician’s decision if she would prefer to pursue GERMLINE testing first.
Figure 6
Figure 6
An overview of risk of transmission of germline and mosaic variants in CCS.
See this image and copyright information in PMC

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