The portal for rare diseases and orphan drugs

To date, more than 200 cases of Brooke-Spiegler syndrome (or CYLD Cutaneous Syndrome, CCS) have been reported in the literature. Increased severity in females is recognized.

CCS typically manifests in adolescence and early adulthood with the appearance of multiple skin tumours including cylindromas, spiradenomas and trichoepitheliomas. Tumour development is progressive and can affect the head and neck as well as torso. Cylindromas present as different sized pink nodules on the scalp which can become confluent (historically called ''turban tumour''). Spiradenomas are painful blue nodules that can measure several centimeters across. Trichoepitheliomas manifest as skin colored papules or firm nodules, bilateral and symmetrically distributed, preferring the central face region, particularly the nose and the surrounding skin. Patients may also develop small milia on the skin of the face. Mosaic presentations are recognised, with risk of genetic transmission to children. A minority of patients can also get major and minor salivary glands neoplasms, usually membranous basal cell adenoma. Malignancies arising in preexisting spiradenoma, cylindroma and spiradenocylindroma have been reported. Malignant tumours may be aggressive carcinomas with local infiltrative growth or metastases. Rarely, skin cylindromas may metastasise to the lung without involvement of lymph nodes (pulmonary cylindromas). Malignant metastases to bone, lung and the liver have been reported.

CCS is due to germline mutations in the CYLD gene (16q12-q13), a tumour suppressor gene which encodes a protein that plays a key role in negatively regulating several signaling pathways, such as NF-KB, JNK, Wnt, TGFB and TRK.

Diagnosis of CCS is based mainly on clinical examination, family history and skin biopsy. Histopathologic findings of cylindromas, spiradenomas and trichoepitheliomas are consistent with CCS. CYLD gene testing is now performed in affected individuals that fit clinical diagnostic criteria.

Differential clinical diagnosis for multiple skin and/or scalp tumours include Birt-Hogg-Dubé syndrome, neurofibromatosis type 1, Cowden syndrome, tuberous sclerosis complex, Marie-Unna hypotrichosis, basal cell naevus syndrome, pilar cysts, multiple syringomas. These can be usually excluded following clinical examination and skin biopsy of a tumour, followed by dermatopathological assessment.

CCS is inherited as an autosomal dominant trait with high penetrance and variable expressivity. Prognostication regarding severity, tumour type, or clinical presentation is currently not possible in confirmed CYLD mutation carriers.

Removal of cylindroma, spiradenoma, and trichoepithelioma is by conventional surgery. For an optimal outcome, as much normal scalp and skin as possible must remain in place. '' Scalp-sparing'' strategies include early primary excision with direct skin closure, tumour enucleation followed by direct skin closure, and excision followed by secondary intention healing techniques. Hyfrecation for selected small tumours and laser ablation of smaller lesions may be considered. Mohs micrographic surgery for recurrent benign tumours after primary surgical excision may have limited benefit, and lead to unnecessarily large surgical defects. Multidisciplinary skin cancer team management of tumours that have undergone malignant transformation is advised, and such a team may include a dermatologist, plastic surgeon, oncologist, radiologist and pathologist. Radiotherapy should be avoided as this may cause additional new tumours, and may increase risk of maligant transformation. Although malignant transformation is uncommon, patients are advised to report tumours that grow rapidly, or ulcerate and bleed. These features should prompt excision and histological assessment.

Tumours observed in CCS are usually benign and most patients have a normal life span. The development of malignant tumours may shorten lifespan.