CYLD Cutaneous Syndrome

Clinical characteristics: CYLD cutaneous syndrome (CCS) typically manifests in the second or third decade with the appearance of multiple skin tumors including cylindromas, spiradenomas, trichoepitheliomas, and rarely, membranous basal cell adenoma of the salivary gland. The first tumor typically develops at puberty and tumors progressively accumulate through adulthood. Females often have more tumors than males. Tumors typically arise on the scalp and face but can also arise on the torso and sun-protected sites, such as the genital and axillary skin. A minority of individuals develop salivary gland tumors. Rarely, pulmonary cylindromas can develop in large airways and compromise breathing. Although the tumors are usually benign, malignant transformation is recognized.

Diagnosis / testing: The diagnosis of CYLD cutaneous syndrome is established in a proband with multiple skin tumors (histologically confirmed cylindromas, spiradenomas, and/or trichoepitheliomas) and/or by identification of a germline heterozygous pathogenic variant in CYLD by molecular genetic testing.

Management: Treatment of manifestations: Removal of cylindromas, spiradenomas, and trichoepitheliomas is by conventional surgery. Ideally, as much normal scalp and skin should be preserved. "Scalp-sparing" strategies include early primary excision with direct skin closure, tumor enucleation followed by direct skin closure, and excision followed by secondary intention healing techniques. Hyfrecation or laser ablation of selected small tumors may be considered. Mohs micrographic surgery for recurrence of tumors after failure of primary surgical excision may have limited benefit. Multidisciplinary team management of tumors that have undergone malignant transformation is recommended.

Prevention of primary manifestations: Appropriate precautions against UV-related skin damage are recommended.

Surveillance: Annual or more frequent full skin examination by a dermatologist, with assessment of tumor burden and rate of new tumor development, and for signs/symptoms of malignant transformation (rapid tumor growth, bleeding, ulceration, or appearance that is different from an affected individual's usual tumors).

Agents/circumstances to avoid: Radiotherapy should be avoided as it causes DNA damage and may result in further tumor formation or malignant transformation of existing lesions.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

Genetic counseling: Germline pathogenic variants in CYLD are inherited in an autosomal dominant manner. Most individuals with CYLD cutaneous syndrome inherit it from a parent. The degree of severity can vary within families; for example, a mildly affected parent may have a more severely affected child or vice versa. Offspring of an individual with CYLD cutaneous syndrome have a 50% chance of inheriting the variant. Prenatal testing for a pregnancy at increased risk is possible if the CYLD pathogenic variant in the family is known; however, requests for prenatal testing for later-onset diseases are uncommon and require careful genetic counseling.