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 is possible for pregnancies at increased risk if the CYLD pathogenic variant in the family is known; however, requests for prenatal diagnosis of later-onset diseases are uncommon and require careful genetic counseling.

Suggestive Findings

CYLD cutaneous syndrome should be suspected in an individual with the following findings:

• The presence of one or more cylindromas or spiradenomas on the face and scalp, perinasal trichoepitheliomas, or a combination of these tumor types in an individual
  Cylindromas, spiradenomas, and trichoepitheliomas can be diagnosed clinically but may mimic other skin tumors, thus requiring confirmatory skin biopsy.
• A cylindroma or spiradenoma on the scalp or torso incidentally identified during an imaging study (CT, MRI, and/or PET scan) [Serra et al 1996, Brown et al 2018a]
• A membranous basal cell adenoma-type salivary gland tumor in an individual with a single cylindroma, spiradenoma, or trichoepithelioma

Clinical genetic testing for a germline heterozygous CYLD pathogenic variant should be considered in an individual with the following [Dubois et al 2015]:

• Two or more biopsy-confirmed cylindromas, spiradenomas, or trichoepitheliomas
• A single biopsy-confirmed cylindroma, spiradenoma, or trichoepithelioma in the setting of a first-degree relative who has any one of these biopsy-confirmed tumors

Establishing the Diagnosis

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 [Dubois et al 2015] (see Table 1).

When the phenotypic and laboratory findings suggest the diagnosis of CYLD cutaneous syndrome, molecular genetic testing approaches include single-gene testing or use of a multigene panel.

Single-gene testing. Sequence analysis of CYLD detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis on a peripheral blood sample first.

• If no pathogenic variant is found, and there is no known family history of this condition, it is possible that the proband has mosaicism for a CYLD pathogenic variant.
  If mosaicism is suspected, sequence analysis of CYLD can be performed on two or more skin tumors [Arefi et al 2019].
• Gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications may also be considered, although intragenic deletions and duplications are rare (see Table 1).

A hereditary cancer multigene panel that includes CYLD and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

CYLD cutaneous syndrome (CCS) encompasses the clinical phenotypes described in individuals with germline pathogenic CYLD variants. Historically descriptive names including Brooke-Spiegler syndrome (BSS), familial cylindromatosis (FC), and multiple familial trichoepithelioma (MFT) were assigned on the basis of the predominant tumor type and location; these conditions are now recognized to constitute a clinical spectrum. Individuals with the clinical phenotypes of BSS, FC, and MFT can all present in a single family, and the lack of prognostication offered by these historical labels favors the use of CYLD cutaneous syndrome as a diagnostic term for those with this single gene disorder.

To date, more than 100 pedigrees have been identified with a germline pathogenic variant in CYLD, most of whom have family-specific pathogenic variants with few mutational hot spots identified [Rajan et al 2009a, Grossmann et al 2013, Nagy et al 2015]. The following description of the phenotypic features associated with this condition is based on these reports.

CYLD cutaneous syndrome typically manifests in the second or third decade with the appearance of multiple skin tumors including cylindromas, spiradenomas, and trichoepitheliomas. The first tumor typically presents at puberty, but tumors have been reported to present in children as young as age eight years. Tumors progressively accumulate through adulthood. A female preponderance was reported in early studies of small pedigrees; however, assessment of larger pedigrees supports equal penetrance in both males and females, with increased expressivity in females. The presence of tumors at sites of secondary sexual hair development, the timing of onset, and the gender disparity in severity in females with cylindromas suggest a role of hormonal factors in tumor pathogenesis [Rajan et al 2009b].

Natural history studies in CYLD cutaneous syndrome are limited, but a recent study that followed three affected individuals with a combined total of 32 skin tumors visible on serial CT scans (6.7-23.5 mm across) showed progressive growth in 30 out of 32 lesions over a period of one year [Brown et al 2018b]. The progressive growth of these benign tumors supports the case for considering early excision of skin lesions rather than waiting until a more extensive procedure is required (see Table 5). Affected individuals frequently need repeated procedures due to the development of new tumors and, in some cases, the recurrence of incompletely excised tumors.

Individuals with CYLD cutaneous syndrome may present with more than one tumor type discussed below.

• 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.
• Tumors are often painful and may cause sexual dysfunction when they arise on genital skin.
• Tumors arising within the ear (a favored site for tumor formation) can occlude the external auditory canal and result in conductive hearing loss.
• Although the tumors are usually benign, malignant transformation is recognized, and affected individuals should be guided to report tumors which are rapidly growing, bleeding, ulcerating, or different in appearance from their usual tumors.

Cylindromas

Cylindromas are well-circumscribed, smooth, pale pink nodular tumors, often with arborizing vessels visible. The tumors are slow growing and vary in size from a few millimeters to >5 mm (see Figure 1a). The finding of mixed cylindroma and spiradenoma histology within a single tumor is common in CYLD cutaneous syndrome, and the two terms have been used to describe variants of the same tumor [Rajan et al 2011a].

Figure 1

A. Cylindroma demonstrating a well-circumscribed pink nodular lesion with arborizing blood vessels visible on the surface B. Confluent scalp cylindromas in a severely affected individual with CYLD cutaneous syndrome

Confluent scalp tumors. In severe cases, tumors may cover most of the scalp, referred to as confluent scalp tumors (see Figure 1b).

• Early surgical intervention may prevent or delay confluent scalp tumors.
• One study of two families reported that confluent scalp tumors affected up to one in four individuals with a heterozygous germline pathogenic CYLD variant [Rajan et al 2009a].

Pulmonary cylindromas. Single or multiple pulmonary cylindromas that originate from the skin have been described in three individuals with CYLD cutaneous syndrome [Vernon et al 1988, Brown et al 2018b]. In these cases, there is no history of a primary malignant cutaneous cylindroma in the skin, lymph node disease is absent, and pulmonary histology is benign, leading them to be categorized as "benign" metastases.

• One individual presented at age 64 with breathlessness on exertion and was found to have multiple pulmonary tumors. This individual required serial monitoring with pulmonary imaging, and received endocopic laser ablation to maintain large airway patency.
• A second individual had four asymptomatic pulmonary tumors discovered incidentally on a chest radiograph at age 80 years. The tumors were histologically confirmed on autopsy.
• Whole-exome and genome sequencing have shown pulmonary cylindromas to harbor an additional pathogenic variant in AKT1 and a UV mutation signature confirming cutaneous origin [Davies et al 2019].
• The true prevalence of pulmonary cylindromas in individuals with CYLD cutaneous syndrome is not known, as prospective radiologic imaging studies of large numbers of affected individuals have yet to be performed.
• Currently, there are no routine surveillance imaging guidelines that can be recommended; however clinicians who care for individuals with CYLD cutaneous syndrome need to be aware that these tumors do arise and may need to be monitored to determine rate of growth, and that surgical interventions may be necessary to ablate pulmonary tumors that threaten large airway patency.

Histopathology. The histologic appearance of well-circumscribed cylindrical nests of basaloid cells in the dermis led to the term "cylindroma." Each cluster consists of darker, basophilic cells at the periphery, and larger pale cells centrally and is surrounded by a thick, hyaline membrane consisting of extracellular matrix proteins (including collagen IV and VII and laminin-332) in the basement membrane of the skin (see Figure 2a).

Figure 2

A. Histopathology of cylindroma B. Histopathology of spiradenoma

Spiradenomas

Spiradenomas are nodular tumors that are often blue/black in color. They tend to be painful and can grow up to 10 cm in diameter (see Figure 3).

Figure 3.

Spiradenoma: a well-circumscribed nodular lesion (excision specimen) with characteristic blue/black appearance Rajan & Ashworth [2015]; republished with permission of author.

Histopathology. Spiradenomas are relatively disorganized histologically when compared to cylindromas and consist of sheets of epithelial cells associated with a lymphocytic infiltrate (mixed T and B cells). Some affected individuals present with histologic features of both cylindroma and spiradenoma within a single tumor specimen, giving rise to the term spiradenocylindroma. In addition, there is evidence that histologically organized cylindroma and histologically disorganized spiradenoma represent extremes of a spectrum of histophenotype of the same tumor [Rajan et al 2011a] (see Figure 2b).

Trichoepitheliomas

Trichoepitheliomas are skin-colored papules or firm nodules, mainly found on the central face (see Figure 4). They are often symmetrically distributed and usually no more than 2-5 mm across.

Figure 4.

Trichoepithelioma: small skin-colored papules with a predilection for the central face Rajan & Ashworth [2015]; republished with permission of author.

Histopathology. Trichepitheliomas demonstrate clusters of basaloid germinative cells with keratinizing cystic spaces and superficial follicular differentiation surrounded by a fibrocytic stroma. Intra-stromal clefts and mesenchymal papillary buds may be seen.

Other Findings

Salivary lesions. Affected individuals are also at risk of developing tumors of the salivary glands, typically membranous basal cell adenoma (MBCA) [Jungehülsing et al 1999] usually after age 40 years.

• These tumors typically present as a lump in the parotid gland, may be bilateral, and warrant a biopsy to confirm the diagnosis.
• MBCA is a benign entity which may be managed surgically, but recurs in up to 25% of affected individuals [Zarbo 2002] (see also Malignant transformation).

Malignant transformation has been (rarely) reported in preexisting spiradenomas, cylindromas, spiradenocylindromas, and MBCA [Hyman et al 1988, Kazakov 2016]. Malignant tumors tend to be aggressive carcinomas with frequent local infiltrative growth or metastases.

• Transcalvarial invasion is uncommon, but has been observed [Serracino & Kleinschmidt-Demasters 2013].
• Malignant metastases to bone, lung, and liver have been reported [Gerretsen et al 1993].
• Death from metastatic disease has been described in affected individuals in the early fifth decade [Kazakov et al 2009].
• Malignant histopathology. Four diverse histologic patterns of malignant cylindroma or spiradenoma have been described [Kazakov et al 2009], including:
  • Salivary gland type basal cell adenocarcinoma-like pattern, low-grade
  • Salivary gland type basal cell adenocarcinoma-like pattern, high-grade
  • Invasive adenocarcinoma, not otherwise specified
  • Sarcomatoid (metaplastic) carcinoma

Other skin lesions and malignancies

• Affected individuals may also develop small milia cysts on the skin of the face [Bajwa et al 2018].
• Vulval cysts consisting histologically of multiple epidermal inclusion cysts and milia were reported in one affected female [Dubois et al 2017].
• Squamous cell carcinoma [Ganguly et al 2012, Ma et al 2016] and follicular squamous cell carcinoma [Dubois et al 2018] arising in individuals with CYLD cutaneous syndrome have been described in isolated reports.
• Basal cell carcinoma (BCC) is the most common human cancer, and coexistence in individuals with CYLD cutaneous syndrome may be coincidental or related to overlap in the appearance of each under the microscope. However, in a recent study of a large South American family with CYLD cutaneous syndrome, BCC was a reported in 25% of affected family members from this kindred [Arruda et al 2019].

Segmental disease due to mosaic pathogenic CYLD variants should be considered when individuals develop unilateral clusters of any cylindromas, spiradenomas, or trichoepitheliomas [Arefi et al 2019]. Findings may include skin lesions arranged in a linear fashion [Furuichi et al 2012] following embryologic skin development lines (lines of Blaschko). The presentation of unilateral clusters may reflect either a pathogenic CYLD variant in the skin alone (late postzygotic mosaicism) or a pathogenic variant in both the blood and the skin (early postzygotic mosaicism) (see Figure 5 below) [Arefi et al 2019].

Figure 5.

Mosaic presentations of CYLD cutaneous syndrome Arefi et al [2019]; published under Creative Commons license.

Genotype-Phenotype Correlations

No convincing genotype-phenotype correlations have been identified. There is a suggestion that individuals with pathogenic missense variants may have a milder phenotype; however, as missense variants constitute a minority of pathogenic variants in affected individuals (most have pathogenic truncating variants, which can also result in a mild phenotype), further studies are needed to investigate this hypothesis [Nagy et al 2015].

Nomenclature

Historically, descriptive names including Brooke-Spiegler syndrome (BSS), familial cylindromatosis (FC), and multiple familial trichoepithelioma (MFT) were assigned on the basis of the predominant tumor type and location. These conditions are now recognized to constitute a clinical spectrum and individuals with the clinical phenotypes of BSS, FC, and MFT can all present in a single family. The lack of prognostication offered by these historic labels favors the use of CYLD cutaneous syndrome as a diagnostic term for individuals with this single-gene disorder.

Outdated terms previously used in the literature to refer to CYLD cutaneous syndrome include the following:

• Ancell-Spiegler cylindromas
• Dermal eccrine cylindroma
• Turban tumor syndrome (now denoted as confluent scalp tumors)

Prevalence

The true prevalence of CYLD cutaneous syndrome is unknown but may be in the order of more than 1:100,000 population [Rajan & Ashworth 2015].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CYLD cutaneous syndrome (CCS), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations