Multiple Facial Trichoepitheliomas and Vulval Cysts: Extending the Phenotypic Spectrum in CYLD Cutaneous Syndrome

Trichoepitheliomas are small benign skin tumors exhibiting hair follicle differentiation seen in the autosomal dominant condition multiple familial trichoepithelioma (MFT; OMIM 601606). Multiple familial trichoepithelioma is associated with germline mutations in the cylindromatosis (CYLD) gene, a tumor suppressor gene, in 44% of cases.¹ Mutations in this gene are also responsible for familial cylindromatosis (FC; OMIM 132700) and Brooke-Spiegler syndrome (BSS; OMIM 605041). The term CYLD cutaneous syndrome has been proposed to encompass this variation.² We report a unique case of multiple trichoepitheliomas in combination with epidermoid cysts of the vulva in association with a novel pathogenic mutation in CYLD, extending the phenotypic spectrum.

A woman in her late 20s presented with multiple, asymptomatic papules on the sides of the nose, cheek and upper lip (Figure, A), present since her mid-teenage years. In addition, she had multiple pink vulval nodules (Figure, B), present since her mid-20s. These nodules developed recurrent infections, leading to rupture and discharge. There was no family history of either facial or genital lesions on her mother’s side; her father was not available for clinical assessment. Biopsy from a facial skin-colored papule revealed trichoepithelioma. Histology of the nodules from the labia majora showed multiple epidermal inclusion cysts and milia. She underwent curettage and cautery of facial lesions, with good cosmesis, and following excision of her labial nodules, is symptom free after a follow-up period of 2 years. Her clinical presentation prompted genetic testing for CYLD mutations, and comparison of vulval phenotypes in other genotyped CYLD mutation carriers.

Genetic analysis revealed a novel heterozygous duplication mutation in exon 8 of the CYLD gene—NM_015247.2(CYLD_v001):c.966dupG;NM_015247.2(CYLD_i001): p.(Ser323Valfs*13)—with an insertion of a base pair resulting in a frameshift mutation. The patient’s mother did not share the same mutation. Retrospective review of 5 genotyped CYLD mutation carriers who attended for excision of vulval tumors was undertaken and summarized. Human subjects research ethics committee approval was obtained for this work (REC Ref:06/Q1001/59). Multiple epidermoid cysts were not noted on the vulval skin in 5 patients with CYLD cutaneous syndrome, nor within the pathological specimens excised (Table). Patients 1 through 3 had undergone scalp removal for multiple cylindromas, indicative of a severe phenotype. Patient 5, who has the MFT phenotype, developed a pubic cylindroma, a finding not previously reported in association with MFT.

The finding of the combination of multiple vulval epidermoid cysts and facial trichoepitheliomas represents a novel facet of CYLD cutaneous syndrome and is consistent with the spectrum of hair follicle–related tumors and milia seen in affected patients.² Genital cylindromas and spiradenomas are recognized but underreported in CYLD cutaneous syndrome; we previously noted tumors were present on pubic and genital skin in 42% of 26 affected individuals.³ Nonetheless, it remains a possibility, that the presence of vulval cysts may be coincidental. Deep phenotyping in larger cohorts of patients is needed to clarify this.

CYLD is a tumor suppressor that negatively regulates a range of oncogenic signaling pathways that are relevant in hair follicle biology, such as NF-κB, Wnt, and Notch.² Approximately 100 mutations in CYLD have been identified, but there is little in the way of genotype-phenotype correlation.^4-6 Ninety-nine percent of reported mutations are located within exons 9 through 20, which encode the catalytic domains of the enzyme, so our mutation is unusual in that it is located in exon 8 (Figure, C).

The clinical relevance is that this novel phenotype should prompt genetic testing for CYLD mutations. If positive, this will inform genetic counselling, despite the limitation that this precludes prognostication of severity,³ as unaffected progeny of affected probands can be reassured if they are found not to have inherited the familial mutation.

Corresponding Author: Neil Rajan, MBBS, PhD, Institute of Genetic Medicine, Newcastle University, NE1 3BZ, England (neil.rajan@ncl.ac.uk).

Accepted for Publication: January 29, 2017.

Published Online: April 19, 2017. doi:10.1001/jamadermatol.2017.0321

Author Contributions: Drs Dubois and Rajan had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Dubois, Alonso-Sanchez, Rajan.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Dubois, Bajaj, Rajan.

Critical revision of the manuscript for important intellectual content: All authors.

Obtained funding: Rajan.

Administrative, technical, or material support: Rajan.

Supervision: Alonso-Sanchez, Bajaj, Rajan.

Conflict of Interest Disclosures: None reported.

Funding/Support: Dr Rajan is a Wellcome Trust–funded Intermediate Fellow.

Role of the Funder/Sponsor: The Wellcome Trust had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We are grateful to Valerie Wilson, PhD, for her expert technical assistance; Ms Wilson did not receive compensation for her contributions. We are also indebted to the patients who have supported this work.