INTRODUCTION AND MOLECULAR PATHOGENESIS

CYLD cutaneous syndrome is an autosomal-dominant disorder characterized by multiple adnexal neoplasms and is now recognized as a single disease spectrum encompassing Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma [1–3]. CYLD is identified as a tumor-suppressor gene on chromosome 16q12-q13, and germline truncating or loss-of-function variants underlie inherited disease [2–4]. The encoded deubiquitinase normally restrains proliferative and survival signaling, particularly NF-κB and Wnt/β-catenin pathways; loss of CYLD enhances NF-κB activity and Wnt signaling through dysregulated ubiquitination of signaling intermediates, including Dishevelled [4–6]. Tumor development follows a second-hit model [4]. Recent sequencing studies suggest that recurrent mutations in epigenetic regulators such as DNMT3A and BCOR may cooperate with CYLD loss in tumor progression [7]. More recent integrative molecular profiling has reinforced this model, identifying a low-mutational-burden landscape centered on CYLD, DNMT3A, and BCOR in CCS tumors [8]. Despite high penetrance, clinical expression is variable, and these syndromes are best regarded as phenotypic variants along one CYLD-dysfunction spectrum [1–3,7].

CLINICOPATHOLOGIC FEATURES

CYLD cutaneous syndrome causes benign adnexal tumors derived from hair follicle-associated structures, which usually appear as slow-growing dermal nodules beneath an intact epidermis [1,3,9]. The three principal lesion types are cylindromas, spiradenomas, and trichoepitheliomas, which may occur separately or as hybrid tumors within the same patient [1,9]. Cylindromas, the signature lesions of familial cylindromatosis and Brooke-Spiegler syndrome, show basaloid islands arranged in a classic jigsaw pattern and surrounded by a thick PAS-positive hyaline basement membrane. On the scalp, they may coalesce into large “turban tumors” [1,9,10]. Spiradenomas are often deeper, violaceous, and painful with dual-cell lobules, duct-like structures, and prominent lymphoid infiltrates [1,9]. Trichoepitheliomas typically present as multiple small pearly papules on the central face and show follicular germ-like lobules, horn cysts, and (primitive) papillary mesenchyme [1–3]. In addition to cutaneous disease, rare extracutaneous manifestations such as parotid membranous basal cell adenoma and pulmonary cylindromas have been reported [1,3,11]. A recent systematic review further emphasized that salivary-gland involvement in CCS is predominantly parotid, often multifocal, and clinically significant because malignant cases have also been described [12].

Clinical expression usually begins around puberty or in early adulthood and progresses cumulatively throughout life, although severity is highly variable even within families [1,3]. Lesions are concentrated on the head and neck, particularly the scalp and central face, though the trunk, flexures, and other sites may also be involved [3,10]. Brooke-Spiegler syndrome denotes the mixed phenotype with cylindromas, spiradenomas, and trichoepitheliomas; familial cylindromatosis is dominated by scalp cylindromas; and multiple familial trichoepithelioma is characterized by numerous facial papules, although these patterns are still best regarded as variants along a single CYLD-dysfunction spectrum [1–3]. Malignant transformation is uncommon and is typically heralded by rapid enlargement, ulceration, and/or bleeding. Malignant cylindroma or spiradenocarcinoma may show infiltrative growth, necrosis, marked atypia, and metastatic potential. In such cases, the need for lifelong surveillance and a low threshold for biopsy of changing lesions becomes paramount [3,13].

MANAGEMENT AND OUTCOMES

Management of CYLD cutaneous syndrome remains largely procedural as no available therapy reliably prevents new lesion formation. Symptomatic, enlarging, or cosmetically burdensome tumors are typically treated with local excision, enucleation, or ablative approaches such as CO2 laser, electrodesiccation, or related resurfacing techniques, whereas larger scalp burdens may require staged excision or grafting [3,14,15]. Mohs micrographic surgery is generally reserved for malignant transformation or selected lesions in function-critical sites rather than routine high-burden disease [3]. Because treated lesions may be cleared while adjacent CYLD-mutant adnexal units continue to generate new tumors, most patients require repeated interventions over time [3,15].

Medical therapy is best viewed as adjunctive rather than definitive. Topical salicylic acid has shown only modest benefit, while case reports and small series describe partial responses with imiquimod-based regimens, topical sirolimus, low-dose aspirin or anti-inflammatory strategies, and other multimodal combinations [16–20]. Interest has increasingly shifted toward pathway-directed and investigational approaches, including TRK signaling, precision-oncology medicine, and other downstream mediators of CYLD loss, all of which remain early and not yet practice-changing [21–23]. Indeed, in clinical practice, optimal care is individualized and multimodal, balancing lesion control, scarring, recurrence, treatment burden, and psychosocial impact. Visible facial and scalp disease can substantially affect self-esteem and social functioning regardless of age, so supportive measures such as camouflage, wigs, counseling, and shared decision-making are important components of long-term management [3,11,18].

CONCLUSION

CYLD cutaneous syndrome is best understood as a single inherited adnexal tumor spectrum encompassing Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma. Advances in molecular genetics have clarified the central role of germline CYLD loss, the requirement for somatic second hits, and the contribution of dysregulated survival and proliferative signaling to tumor development [1–7]. Clinicopathologic correlation remains essential, as lesion morphology, anatomic distribution, and interval change guide diagnosis, surveillance, and biopsy of suspicious lesions [1–3,9,10,13]. Although malignant transformation is uncommon, the lifelong burden of recurrent cutaneous tumors and repeated procedures can be substantial [3,13].

At present, management remains primarily procedural, with excision and ablative strategies forming the cornerstone of care and medical therapies serving mainly adjunctive roles [3,11,14–19]. Investigational pathway-directed and precision-oncology approaches are promising but remain early, and no current therapy reliably prevents continued lesion formation across susceptible skin [7,13,21–23]. For this reason, optimal care is longitudinal, multimodal, and patient-centered, integrating tumor control with cosmetic, functional, and psychosocial outcomes [3,11,18]. This review acknowledges both the progress made in defining CYLD-associated disease and the continued need for more effective disease-modifying therapies.