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Brooke-Spiegler syndrome (CYLD cutaneous syndrome)

Brooke-Spiegler syndrome (CYLD cutaneous syndrome)
Literature review current through: Aug 2023.
This topic last updated: Oct 21, 2022.

INTRODUCTION — Brooke-Spiegler syndrome (BRSS; MIM #605041), also known as CYLD cutaneous syndrome, is an autosomal dominant disorder characterized by multiple benign skin tumors that develop from adnexal structures of the skin [1,2]. Individuals with BRSS may develop several types of adnexal tumors, most commonly spiradenomas, cylindromas, and trichoepitheliomas (the last called "epithelioma adenoides cysticum" in the first description of the disease) [3-7]. Phenotypic variants of BRSS include multiple familial trichoepithelioma-1 (MFT1; MIM #601606) and familial cylindromatosis (FC; MIM #132700).

This topic will review the genotype and phenotypic variation, diagnosis, and treatment of BRSS. An overview of cutaneous adnexal tumors is presented separately. (See "Cutaneous adnexal tumors".)

EPIDEMIOLOGY — Brooke-Spiegler syndrome (BRSS) is a rare disorder; its exact incidence and prevalence in the population are unknown. BRSS occurs in all ethnic groups and affects both females and males equally, although solitary cylindromas have a female predilection, with a reported ratio of 6:1 to 9:1 [8-10].

PHENOTYPIC VARIANTS — Individuals affected with classic Brooke-Spiegler syndrome (BRSS; MIM #605041) typically develop multiple adnexal cutaneous neoplasms, most commonly spiradenoma, cylindroma, and trichoepithelioma. Individuals with trichoepitheliomas only are recognized as a phenotypic variant of BRSS, multiple familial trichoepithelioma-1 (MFT1; OMIM 601606) [4,5,11-15]. BRSS with cylindromas only, known as familial cylindromatosis (FC; OMIM 132700), is another rare phenotypic variant [16-18]. BRSS with spiradenomas or spiradenocylindromas only have also been reported [19,20].

PATHOGENESIS — Brooke-Spiegler syndrome (BRSS) is caused by mutations within CYLD, a tumor suppressor gene located on chromosome 16q12-q13 encoding an enzyme that interacts with multiple substrates of the nuclear factor kappa B (NF-kB) signaling pathway and downregulates its activity [4,12,16,17,21-26]. Since NF-kB signaling is antiapoptotic, increased transcription via NF-kB leads to uncontrolled cell proliferation and development of tumors associated with BRSS [27]. As classic BRSS, familial cylindromatosis (FC) and multiple familial trichoepithelioma-1 (MFT1) are allelic disorders resulting from mutations in the same gene [28,29].

Susceptibility to BRSS depends on the autosomal dominant inheritance of a germline mutation in CYLD [26]. A second noninherited, somatic mutation, however, is required for the development of skin appendage tumors in BRSS [21,24]. CYLD spans 56 kilobases, contains 20 exons, and encodes a 120 kilodalton enzyme with deubiquitinase activity [5,30,31]. The CYLD enzyme modifies protein substrates by removing Lys63-linked ubiquitin chains [32]. Via such interaction with proteins including tumor necrosis factor (TNF) receptor-associated factors (TRAF2, TRAF3, TRAF6, TRAF7), NF-kB essential modulator (NEMO), and B cell lymphoma 3 (BCL-3) proteins, the enzyme downregulates NF-kB signaling [33,34]. CYLD is highly conserved during evolution, especially exon 9 to 20 at the 3' end, encoding the ubiquitin-specific protease domain. Mutations in this region are associated with increased phenotypic variation and development of different types of cutaneous neoplasms [31].

Germline CYLD mutations are detected in approximately 80 to 85 percent of individuals with classic BRSS and 40 to 50 percent of individuals with MFT1 [4,12,16,21-25]. Cutaneous neoplasms of BRSS also harbor a large spectrum of somatic mutations, representing both loss of heterozygosity (LOH) and sequence alterations [9,35,36]. Somatic mutations often differ among neoplasms that have the same histology in the same individual.

There have been over 100 mutations identified within the CYLD gene; approximately equal numbers were identified in classic BRSS, FC, and MFT1 [37]. Analysis of mutations in relation to clinical phenotypes revealed some correlations with pathogenesis, disease severity, and prognosis [31]. As an example, individuals carrying missense mutations are noted to exhibit milder phenotypes and develop trichoepithelioma only. In contrast, individuals carrying identical nonsense mutations may exhibit very different clinical phenotypes or disease severities, suggesting a possible role of additional disease modifying gene(s). A study comparing a Hungarian and an Anglo-Saxon pedigree with BRSS identified at least three phenotype-modifying genetic variants in TRAF3, signal transducer and activator of transcription 3 (STAT3), and neighbor of BRCA1 (NBR1) [38]. Thus far, the pathogenesis of extracutaneous tumor development and malignant transformation remains unknown.

A study profiling 14 benign and malignant tumors in 14 affected individuals revealed recurrent pathogenic variants in DNMT3A (29 percent) and BCOR in addition to CYLD loss in the tumors, suggesting that epigenetic dysregulation may also play a role in the pathogenesis of BRSS [39].

CLINICAL MANIFESTATIONS

Skin tumors — Cutaneous neoplasms in Brooke-Spiegler syndrome (BRSS), including cylindroma, spiradenomas, and trichoepithelioma, first manifest during childhood and early adolescence. These tumors gradually enlarge in size, continue to increase in number throughout the patient's lifetime, and can be disfiguring. The burden of the disease is therefore both physical and psychologic. Although neoplasms with a particular histologic feature may dominate in a specific individual, colocalization of cylindroma, spiradenomas, and trichoepithelioma has been observed frequently in BRSS patients [40,41]:

Cylindroma – Cylindromas are slow-growing, benign tumors that often present on the head and neck as red, pink, or bluish papules or nodules, ranging from a few millimeters to several centimeters in size (picture 1A-B). The confluent distribution and protuberant appearance of cylindromas on the scalp are often referred to as "turban tumors" (picture 2) [42]. The tumors mostly appear around puberty, then increase in number throughout life. Although they are usually painless, pain or paresthesia can occur in the event of nerve compression due to tumor growth. Rapid enlargement, bleeding, and ulceration are concerning characteristics for malignant transformation, reported in 5 to 10 percent of cases [43-47]. (See "Cutaneous adnexal tumors", section on 'Cylindroma and spiradenoma'.)

Spiradenoma – Spiradenomas can present as single or multiple variably sized, well-demarcated, purplish nodules on the head, neck, trunk, or extremities. Spiradenomas associated with BRSS, however, favor the face and scalp and may colocalize with cylindromas as well. The tumors can enlarge to a few centimeters in size and are often painful.

Trichoepithelioma – In individuals with multiple familial trichoepithelioma-1 (MFT1), multiple trichoepitheliomas usually present as discrete, small (2 to 4 mm), confluent, skin-colored papules on the face, concentrating symmetrically around the nose and nasolabial folds (picture 3A-B). The tumors can also extend to the inner aspects of the eyebrows and lateral aspects of the cheeks. The severity of MFT1 also varies, ranging from dozens to hundreds that cause disfigurement. Extensive involvement of the eyelids and external ear canals has also been reported, causing visual impairment and hearing loss. (See "Cutaneous adnexal tumors", section on 'Trichoblastoma and trichoepithelioma'.)

Natural tumor progression studies are difficult to conduct and are therefore limited. A study in which 32 cutaneous and 14 pulmonary cylindromas were followed up in three affected females using a series of high-resolution computed tomography scans demonstrated an average increase in size of 12.6 percent in 30 of 32 cutaneous tumors and of 16.3 percent in all pulmonary tumors within a year. The results of this study indicate that close monitoring and early intervention can be beneficial [48]. Tumors associated with BRSS are generally benign, but malignant transformation can occur in pre-existing neoplasms in 5 to 10 percent of affected individuals [1,43-45,49-51]. Rapid enlargement of trichoepithelioma can be of concern for malignant transformation to basal cell carcinoma (BCC) [44,47,52,53]. Such transformation may be attributed to additional genetic mutation, such as PTCH1 in addition to CYLD [54]. A review of 55 published cases showed that most of the malignant transformations occur after the fourth decade, and age appears to be the only risk factor for transformation [55].

Extracutaneous tumors — Individuals with BRSS may rarely develop extracutaneous tumors in the parotid or in the minor salivary glands, known as membranous basal cell adenoma [1,43,56-58]. In a series of over 100 cases of BRSS/MFT1 with characteristic skin tumors, only two patients with the classic BRSS phenotype developed a salivary gland tumor [1]. Malignant transformation of membranous basal cell adenoma can occur but is very rare [59].

These tumors usually occur later in life, with most cases reported beyond the fourth decade. Significant enlargement of the tumor within the parotid gland can lead to facial nerve damage. Moreover, rapid tumor growth in the parotid has also been associated with malignant transformation [57,58,60].

A few cases of cylindromas of the breast have also been reported [61].

Pulmonary cylindromas have been rarely reported in affected individuals [62]. Chest imaging could be considered in affected patients with respiratory symptoms. Since some patients remain asymptomatic, the prevalence is unclear. These pulmonary tumors may be single or multiple. A whole genome sequencing of pulmonary cylindromas demonstrated a pathogenic variant in AKT1 in addition to biallelic mutations in CYLD [39]. Interestingly, ultraviolet mutational signatures were identified in these tumors, suggesting they were originated from skin.

PATHOLOGY — Skin neoplasms in Brooke-Spiegler syndrome (BRSS) are histologically identical to their sporadic counterparts [1,40,63]. Combined histologic features of different tumors are observed frequently on tissue biopsies from patients with BRSS [40,41,53]. "Hybrid" tumors exhibiting features of both cylindroma and spiradenoma especially have been reported [40,41].

Histologically, spiradenomas are composed of dense, small, diffused, basaloid cells intermixed with paler cells and lymphocytes (picture 4A-B). The basaloid cells are often clustered into dermal nodules extending to the subcutis [3]. Tubular structures comprised of periodic acid-Schiff (PAS)-positive hyaline basal membrane material as well as focal ductal differentiation are often noted [64]. Spiradenomas can occasionally transform into spiradenocarcinomas [20,44,65]. (See "Cutaneous adnexal tumors", section on 'Cylindroma and spiradenoma'.)

Cylindromas are histologically characterized as nonencapsulated dermal nodules of epithelial cells. Islands of tumor cells are often arranged in a distinctive "jigsaw puzzle" pattern outlined by eosinophilic, membrane-like hyaline basement material that is PAS positive (picture 5). Within each "tumor island," large cells containing abundant cytoplasm often cluster in the center, whereas small, monomorphic, basaloid, hyperchromatic cells gather at the periphery. In contrast to spiradenomas, the presence of lymphocytes within cylindroma is usually scarce. Immunohistochemical evaluation confirmed that spiradenoma and cylindroma are originated from sebaceous and follicular differentiated stem cells with positive CD200 stains, a well-recognized immunohistochemical marker for hair follicle bulge [66].

Trichoepithelioma (cribriform trichoblastoma) is a biphasic neoplasm with histologic features of dual differentiation toward follicular germinative epithelium and specific follicular stroma [46,53]. The characteristic histopathology demonstrates basaloid cells with peripheral palisading that are arranged in nests or cribriform patterns surrounded by dense stroma and fibroblasts. Areas with ductal differentiation and lymphocyte infiltration resembling spiradenoma have also been observed on biopsies from patients with multiple familial trichoepithelioma-1 (MFT1). Small and large, nodular trichoblastomas can be seen occasionally [67].

DIAGNOSIS — The diagnosis of Brooke-Spiegler syndrome (BRSS) is suspected in a patient presenting with multiple benign cutaneous adnexal tumors (cylindroma, spiradenoma, and/or trichoepithelioma) that occurred at an early age and with a family history of similar multiple tumors suggesting an autosomal dominant pattern of inheritance. Histologic evaluation of tissue biopsies from the cutaneous tumors is required for the diagnosis of the specific tumor type. The presence of more than one type of adnexal tumor on the same tissue biopsy is suggestive of BRSS.

The definitive diagnosis of BRSS is based on the combination of the following:

Early age of onset for skin neoplasms and progression of disease over time

Family history of similar neoplasms and inheritance pattern

Histopathologic findings on tissue biopsy

Association with tumors in the parotid or other minor salivary glands

Genetic testing demonstrating a germline mutation in CYLD

Clinical genetic testing for a germline CYLD pathogenic variant should be considered for individuals with two or more biopsy-confirmed cylindromas, spiradenomas, or trichoepitheliomas alone or in combination. As some affected individuals may not develop skin tumors until the fourth decade, genetic testing in unaffected individuals with a family history of BRSS can help facilitate early diagnosis and family planning. Genetic testing may also be considered for children and young adults who have a single biopsy-proved cylindroma, spiradenoma, or trichoepithelioma and a first-degree relative with multiple of these adnexal tumors.

If no germline pathogenic variant is identified and the affected individual has no known family history, genetic mosaicism should be considered. Sequencing analysis of CYLD should be performed on skin tumors instead of peripheral blood or saliva only [68].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of solitary or multiple skin neoplasms on the head and neck includes:

Basal cell carcinoma – The distinction of trichoepithelioma from basal cell carcinoma (BCC) can be difficult clinically and pathologically, but the histologic finding of a fibrotic stroma and the lack of retraction of tumor stroma from parenchyma can be used to distinguish trichoepithelioma from BCC. In addition, mitotic figures are rare in trichoepitheliomas but common in BCC. (See "Epidemiology, pathogenesis, clinical features, and diagnosis of basal cell carcinoma" and "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis".)

Primary cutaneous adenoid cystic carcinoma. (See "Cutaneous adnexal tumors", section on 'Adenoid cystic carcinoma'.)

Cutaneous metastasis of adenoid carcinoma of the salivary gland. (See "Salivary gland tumors: Epidemiology, diagnosis, evaluation, and staging".)

Syringoma – Although eruptive syringomas also present as multiple small, flesh-colored papules on the face, the distribution is usually around the periorbital area (picture 6). (See "Cutaneous adnexal tumors", section on 'Syringoma'.)

Trichofolliculoma – Trichofolliculoma most often presents as a solitary lesion on the cheek of older adult individuals (picture 7). (See "Cutaneous adnexal tumors", section on 'Trichofolliculoma'.)

Cutaneous metastasis of visceral organ carcinoma (picture 8) – Immunohistochemical markers like epithelial membrane antigen, low molecular weight keratin (S-100), and carcinoembryonic antigen can be applied to distinguish cutaneous metastasis from adnexal tumors. (See "Cutaneous manifestations of internal malignancy", section on 'Cutaneous metastases'.)

Multiple trichoepitheliomas can occur in or mimic other genetic syndromes, including:

Bazex-Dupré-Christol syndrome (also called Bazex syndrome [BZX] or follicular atrophoderma and basal cell carcinomas) is an X-linked dominant disorder characterized by congenital hypotrichosis, follicular atrophoderma, milia, and basal cell carcinomas [69,70]. It should not be confused with acrokeratosis paraneoplastica, also called Bazex syndrome, an unrelated, rare paraneoplastic syndrome. (See "Cutaneous manifestations of internal malignancy".)

Nevoid basal cell nevus syndrome is not typically associated with trichoepitheliomas. However, an inexperienced pathologist may misdiagnose skin tag-like basal cell nevi as multiple trichoepitheliomas, especially in a young child [71]. (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)".)

Rombo syndrome, which shows vermiculate atrophoderma, milia, hypotrichosis, BCC, and peripheral vasodilation [72]. (See "Keratosis pilaris atrophicans", section on 'Atrophoderma vermiculatum'.)

MANAGEMENT

Surgical excision of skin tumors — Surgical removal of skin tumors is the mainstay of treatment for patients with Brooke-Spiegler syndrome (BRSS). Since the tumors are benign in the vast majority of cases, complete excision may not be necessary once the diagnosis is confirmed histologically. Surgical removal of benign neoplasms is mainly aimed at minimizing symptoms and improving function and cosmesis.

Destructive therapies, including curettage, cryosurgery, electric cautery, and laser resurfacing, have also been used to treat cylindromas, spiradenomas, and trichoepitheliomas [73-80]. Because BRSS patients usually develop multiple neoplasms throughout their lifetime, repeated procedures may be needed.

The management of tumors that have undergone malignant transformation requires a multidisciplinary approach involving a dermatologist, a pathologist, an oncologist, and other specialists as indicated. Standard excision with appropriate margins is recommended [78]. Mohs micrographic surgery should be considered for tissue sparing, especially for tumors on the head and neck [81]. Appropriate radioimaging studies should be obtained if there are clinical concerns of tumor invasion and metastasis.

Investigational therapies — The tumor suppressor CYLD is a deubiquitinating enzyme that downregulates nuclear factor kappa B (NF-kB) signaling by removing Lys-63-linked ubiquitin chains from TRAF2, TRAF6, and IKBKG (NEMO) [34,82]. Based on the observation that activated NF-kB signaling due to CYLD mutations leads to increased transcription, cell proliferation, and tumor formation, agents acting as inhibitors of the NF-kB signaling pathway may be potential targeted treatments for BRSS [33,34,83]. In vitro studies have demonstrated that NF-kB signaling can be downregulated by anti-inflammatory agents, such as salicylate [84]. However, in a small study of five patients with 12 cylindromas, daily application of topical salicylic acid induced a complete regression in only two tumors after 16 and 24 weeks of treatment, respectively [85].

Blockage of tumor necrosis factor (TNF)-mediated NF-kB activation with oral aspirin and subcutaneous adalimumab in combination with laser resurfacing was attempted in a single patient with multiple familial trichoepitheliomas [86]. Although some beneficial effect was noted in areas that had not undergone laser treatment, the efficacy of anti-TNF therapy alone remains to be determined.

Increased NF-kB signaling via Akt-dependent activation of the mechanistic target of rapamycin (mTOR) gene is often seen in human cancer cells as well as animal models [87]. Inhibition of mTOR activation therefore may reduce signaling via NF-kB and reduce tumor cell proliferation [87]. Topical sirolimus, an mTOR protein inhibitor, was used successfully as a maintenance therapy in a young child with multiple trichoepitheliomas refractory to repeated laser resurfacing; in addition, early initiation of topical treatment was beneficial for her sibling with the same condition [88]. Similar benefits have been observed in an adult case series as well [89].

One study demonstrated that tumors with somatic CYLD mutations have impaired tropomyosin kinase (TRK) signaling, and that in cell cultures from CYLD mutant tumors, treatment with the TRK inhibitor molecule lestaurtinib reduced colony formation and proliferation of tumor cells [90]. However, lestaurtinib, an orphan drug used for the treatment of acute myeloid leukemia, has not been used in patients with CYLD neoplasms. Pegcantratinib 0.5%, a topical tropomyosin receptor kinase inhibitor, showed no effect in reducing tumor size in 15 patients with 150 CYLD tumors [91]. Investigators attributed lack of response to possible low drug concentration in the tumors.

This condition can be distressful for severely affected patients. Ongoing clinical trials available for patients can be searched for online.

GENETIC COUNSELING — Once the diagnosis of Brooke-Spiegler syndrome (BRSS) is confirmed, genetic counseling should be considered for affected individuals and families. The risk of inheritance, transmission, and options for genetic testing for patients and family members should be evaluated and addressed appropriately. The offspring of an affected individual carrying the CYLD germline mutation have a 50 percent chance of inheriting the variant, although the clinical severity may be unknown [2].

Sporadic mosaic BRSS may also have gonadal mosaicism. There is a risk of parent-to-child transmission, but it is lower than that associated with germline mutations.

PROGNOSIS AND FOLLOW-UP — Although the majority of neoplasms associated with Brooke-Spiegler syndrome (BRSS) are benign, malignant transformation does occur in 5 to 10 percent of cases [1,43-45,49-51]. Lifetime clinical monitoring is therefore recommended. Dermal cylindroma that is recalcitrant to surgery is reported to have a higher propensity to undergo malignant transformation [45].

PREVENTION AND SURVEILLANCE — Precautions against ultraviolet light and ionizing radiation exposure should be taken to minimize additional DNA damage, which may lead to increased risks of tumorigenesis and/or neoplasm malignant transformation [2]. Routine total skin examination including oral mucosa is recommended to assess burden and severity of cutaneous tumors as well as to ensure timely diagnosis should malignant transformation occur [48]. Radiologic evaluation for pulmonary involvement should be considered if any concerning respiratory symptoms develop [62].

SUMMARY AND RECOMMENDATIONS

Definition and phenotypic variants – Brooke-Spiegler syndrome (BRSS) is a rare autosomal dominant disorder characterized by multiple benign skin tumors that develop from adnexal structures of the skin. Phenotypic variants of BRSS are familial cylindromatosis (FC) and multiple familial trichoepithelioma-1 (MFT1). Cutaneous neoplasms of BRSS also harbor a large spectrum of somatic mutations, even among tumors with similar histology. (See 'Introduction' above and 'Phenotypic variants' above.)

Skin tumors – Cutaneous neoplasms, including cylindroma, spiradenoma, and trichoepithelioma, first manifest during childhood and early adolescence. These tumors gradually enlarge in size, continue to increase in number throughout the patient's lifetime, and can be disfiguring (picture 2). Tumors associated with BRSS are generally benign, but malignant transformation may occur. (See 'Clinical manifestations' above.)

Diagnosis – The diagnosis of BRSS is based upon the combination of the presence of multiple skin tumors with histologic features of cylindroma, spiradenoma, or trichoepithelioma and a family history of a similar condition. Genetic testing demonstrating a germline mutation in CYLD can confirm the diagnosis. (See 'Diagnosis' above.)

Management – Surgical removal of cutaneous tumors is the mainstay of treatment for patients with BRSS, with the aim of minimizing symptoms and improving function and cosmesis. Nonsurgical destructive therapies, including curettage, cryosurgery, electric cautery, and laser resurfacing, have also been used for multiple small tumors. (See 'Management' above.)

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Topic 15522 Version 6.0

References

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