Multiple Familial Trichoepitheliomas Research Articles

Multiple Nonfamilial Trichoepitheliomas: A Rare Case with Review of the Literature

Trichoepitheliomas are benign tumors of follicular origin and often appear in childhood or early adolescence. They present as small, firm papulonodular lesions of normal skin color or translucent. The lesions gradually increase in size and then stabilize. They sit electively on the face, mainly in the nasolabial folds, on the forehead, chin, and cheeks, and sometimes on the scalp and neck. Trichoepitheliomas can be divided into three subgroups: multiple familial Trichoepitheliomas, solitary non-hereditary Trichoepitheliomas, and desmoplastic Trichoepitheliomas. Nonfamilial multiple trichoepitheliomas are rarely described. We report a case of a 12-year-old child whose clinical history and clinicopathologic correlation allowed us to retain the diagnosis of multiple non-familial trichoepitheliomas.

The First Case Report of Multiple Familial Trichoepitheliomas Responding Successfully to Topical Benzoyl Peroxide: A Possible Therapeutic Action Underlying Structural Turnover and Antiinflammation.

The First Case Report of Multiple Familial Trichoepitheliomas Responding Successfully to Topical Benzoyl Peroxide: A Possible Therapeutic Action Underlying Structural Turnover and Antiinflammation.

Genetic Testing in CYLD Cutaneous Syndrome: An Update.

CYLD cutaneous syndrome (CCS) is an inclusive label for the inherited skin adnexal tumour syndromes Brooke–Spiegler Syndrome (BSS-OMIM 605041), familial cylindromatosis (FC – OMIM 132700) and multiple familial trichoepitheliomas (MFT-OMIM 601606). All three syndromes arise due to germline pathogenic variants in CYLD, a tumour suppressor gene (OMIM 605018). CCS is transmitted in an autosomal dominant pattern, and has variable expressivity, both of the three syndromic phenotypes, and of the severity of tumour burden. Age-related penetrance figures are not precisely reported. The first tumours typically appear during puberty and progressively accumulate through adulthood. Penetrance is typically high, with equal numbers of males and females affected. Genetic testing is important for confirmation of the clinical diagnosis, genetic counselling and family planning, including preimplantation diagnosis. Additionally, identified CCS patients may be eligible for future clinical trials of non-surgical pre-emptive interventions that aim to prevent tumour growth. In this update, we review the clinical presentations of germline and mosaic CCS. An overview of the germline pathogenic variant spectrum of patients with CCS reveals more than 100 single nucleotide variants and small insertions and deletions in coding exons, most frequently resulting in predicted truncation. In addition, a minority of patients have large deletions involving the CYLD gene, intronic pathogenic variants that affect splicing, or inversions. We discuss germline and somatic testing approaches. Somatic testing of tumour tissue, relevant in mosaic CCS, can reveal recurrently detected pathogenic variants when two or more tumours are tested. This can influence genetic testing of children, who may inherit this as a germline variant, and inform genetic counselling and prenatal diagnosis. Finally, we discuss testing technologies that are currently used, their benefits and limitations, and future directions for genetic testing in CCS.

Multiple familial trichoepitheliomas: a case report

<p class="abstract">Trichoepithelioma is a rare benign adnexal tumor that differentiates towards the folliculo-sebaceous-apocrine unit (trichoblast). It may present as solitary non-familial lesion or multiple lesions as a part of autosomal dominant inherited syndrome known as multiple familial Trichoepithelioma. Multiple familial trichoepithelioma is a relatively rare, disfiguring, benign adnexal neoplasm diagnosed by centrofacial distribution of papules and nodules, positive family history, related histopathological findings and can rarely undergo malignant transformation. Treatment is mainly for cosmetic concern. Here we report a case who presented with multiple skin coloured facial papules and nodules, with a history of similar lesions in other family members. Dermoscopy and histopathology confirmed the diagnosis of trichoepitheliomas.</p>

Giant solitary trichoepithelioma masquerading as basal cell carcinoma

Trichoepithelioma is a rare benign adnexal tumour which can be of solitary non-familial type or multiple familial trichoepitheliomas. Here authors describe a middle-aged patient who presented with a swelling of the left nasolabial region diagnosed clinically as a basal cell carcinoma but proved to be a giant solitary trichoepithelioma (GST) following histopathological examination. This case is presented due to the rarity and the difficulty encountered in diagnosis of the case.

Twelve Years' Observation of Multiple Familial Trichoepithelioma with Squamous Carcinoma.

Long-standing trichoepithelioma lesion on scalp with 12 years follow-up. The patient was observed for 12 years, and the carcinoma recurred 3 times during 8 years after surgical excision and radiation therapy. Malignant transformation may occur in multiple familial trichoepitheliomas; Moderate radiation therapy should be given for malignant transformation patients with lower radiation dose and shorter time. Removing the trichoepithelioma as soon as possible if the tumor suddenly or continuously increased is recommended.

Nonfamilial Multiple Trichoepithelioma: Few and Far Between.

Trichoepithelioma is a rare benign adnexal tumor which may be of solitary nonfamilial type or multiple familial trichoepitheliomas. Here, we describe a rare presentation of nonfamilial case of trichoepithelioma in a 50-year-old female with multiple skin colored facial papules and nodules over the face, upper back, and extremities.

Clinical, Histological and Dermoscopic Findings in Familial Cylindromatosis: a Report of Two Cases

Abstract Cylindromas are benign appendage tumors mainly found on the scalp, but they can occur on any hair-bearing skin. Mutations in the cylindromatosis (CYLD) gene, a tumor suppressor gene located on chromosome 16q12–13, are responsible for multiple cylindromas, which are usually inherited in an autosomal dominant way, as in familial cylindromatosis and Brooke-Spiegler syndrome. The latter is characterized by the presence of multiple cylindromas, multiple trichoepitheliomas and spiradenomas. Based on genetic studies and the identification of heterozygous mutations in the same CYLD gene in familial cylindromatosis, multiple familial trichoepitheliomas, and the Brooke–Spiegler syndrome, it is suggested that these three conditions have the same genetic basis and are phenotypic expressions of the same disease. The diagnosis of each of the tree conditions is based on the dominant tumor type: cylindroma in familiar cyindromas, trichoepithelioma in multiple familial trichoepitheliomas, or a variety of skin appendage tumors including cylindromas, spiradenomas and trichoepitheliomas in Brooke-Spiegler syndrome. The onset of the disease is usually in the early adulthood, but may also occur in childhood or adolescence. We report on two sisters, 37 and 43 years of age, with multiple cylindromas on the face and the scalp. Both patients reported that their mother also had multiple tumors on her head. Dermoscopy revealed arborizing vessels on a white-ivory or pink background, resembling dermoscopic features of basal cell carcinoma, though histopathological analysis revealed cylindroma. In conclusion, in this study we report two cases of a very rare familial cylindromatosis, presenting with multiple benign cylidromas with dermoscopic features of basal cell carcinoma. All patients with multiple cylindromas in familial cylindromatosis should be counseled about increased risk for developing further tumors. Systemic and multidisciplinary approach with follow up is strongly recommended.

CYLD GeneticTesting for Brooke-Spiegler Syndrome, Familial Cylindromatosis and Multiple Familial Trichoepitheliomas.

The clinical presentation of multiple, rare, skin appendage tumours called cylindromas has been attributed to germline mutations in the tumour suppressor gene <i>CYLD</i> (OMIM 605018). Brooke-Spiegler Syndrome (BSS), familial cylindromatosis (FC) and multiple familial trichoepitheliomas (MFT) (OMIM #605041, #132700, #601606 respectively) differ due to the types of other skin appendage tumour seen together with cylindroma, such as spiradenoma and trichoepithelioma. Previously thought to be separate entities, they are now viewed as allelic variants with overlapping phenotypes, supported by mutation analysis of <i>CYLD</i> . The conditions display autosomal dominant inheritance and affected individuals develop multiple benign skin tumours most commonly on the head and neck. <i>CYLD</i> testing can be performed using PCR and Sanger sequencing for patients with: 1. Multiple cylindromas, spiradenomas or trichoepitheliomas. 2. A single cylindroma, spiradenoma or trichoepithelioma and an affected first-degree relative with any of these tumours. 3. An asymptomatic family member at 50% risk with a known mutation in the family.

A Clinicopathologic and Molecular Biologic Study of Patients Presenting With Few Adnexal Tumors (Two to Four) From the Morphological Spectrum of Brooke–Spiegler Syndrome

We report 11 individuals, each presenting with few (2-4) adnexal neoplasms histologically confirmed as belonging to the spectrum of lesions typical for Brooke-Spiegler syndrome (BSS) and/or multiple familial trichoepitheliomas. These include spiradenoma, cylindroma, spiradenocylindroma, and trichoblastoma variants. Our objective was to clarify whether this is merely a sporadic, albeit unusual, occurrence of multiple neoplasms in these patients or whether they are related to BSS and its phenotypic variant, multiple familial trichoepithelioma. Six patients presented with 2 neoplasms, 4 had 3 lesions and the last had 4 lesions. In none was there any family history of similar lesions. The 28 neoplasms consisted of 7 spiradenomas, 6 cylindromas, 5 spiradenocylindromas, and 11 trichoblastomas (6 trichoepitheliomas and 5 with mixed patterns). In 1 patient only with 2 spiradenomas, both tumors harbored identical CYLD sequence alterations (c.1112C>A/S371X) in the CYLD gene and both showed loss of heterozygosity on chromosome 16q. The remaining cases yielded neither germ line nor somatic alterations in CYLD. It is concluded that the presentation with few (2-4) cylindromas, spiradenomas, spiradenocylindromas, and trichoepitheliomas is a sporadic occurrence, and that these patients do not have any relationship to BSS.

Novel and Recurrent Germline and Somatic Mutations in a Cohort of 67 Patients From 48 Families With Brooke–Spiegler Syndrome Including the Phenotypic Variant of Multiple Familial Trichoepitheliomas and Correlation With the Histopathologic Findings in 379 Biopsy Specimens

Brooke-Spiegler syndrome (BSS) is a rare, inherited, autosomal dominant disorder characterized by development of multiple adnexal cutaneous neoplasms including spiradenoma, cylindroma, spiradenocylindroma, and trichoepithelioma. The syndrome of multiple familial trichoepitheliomas (MFT) is considered a phenotypic variant of BSS in which patients present with trichoepitheliomas only. We studied germline and somatic mutations of the CYLD gene by direct sequencing in patients with BSS (n = 49) and MFT (n = 18) using peripheral blood and 90 samples of frozen or formalin-fixed paraffin-embedded tumor tissue selected from 379 available histology specimens. Germline CYLD mutations were found in 51 patients (76%) from 36 families (75%). Germline CYLD mutations were found in 43 of the 49 patients with BSS (88%) but in only 8 of 18 MFT cohort (44%). Twenty-one frameshift, 15 nonsense, 3 missense, and 4 splice site mutations were found in patients with BSS, whereas 1 frameshift, 5 nonsense, and 2 splice site mutations were identified in the MFT cohort. Five novel mutations were identified including 4 frameshift mutations (c.1027dupA/p.T343NfsX7, c.2155dupA/p.M719NfsX5, c.2288_2289delTT/p.F763X, and c.2641delG/p.D881TfsX32) and 1 nonsense mutation (c.2713C>T/p. Q905X). Of the 76 tumors from 32 patients with a germline CYLD mutation, 12 were spiradenomas, 15 spiradenocylindromas, 26 cylindromas, 15 trichoepitheliomas, and 7 were other tumor types. Somatic mutations were detected in 67 specimens of these 76 tumors (88%). Of the 67 somatic mutations, 21 (31%) represented a sequence alteration and 46 (69%) showed loss of heterozygosity. In the remaining 9 cases (12%), the somatic changes remained unknown. A germline CYLD mutation was not detected in 14 tumor samples from 8 patients. In these 14 tumors, somatic mutations were identified in 6 samples (43%), all consisting of sequence alterations (1 sample showed 2 different sequence alterations). In the remaining 8 samples (53%), neither germline nor somatic mutations were found in the lesional tissue. Our study increases the catalog of known CYLD mutations in patients with BSS/MFT to 86 and documents the variability of somatic mutations that may occur in them. We confirm the absence of firm genotype-phenotype correlations and the existence of a subset of patients with BSS/MFT who lack a demonstrable germline CYLD mutation. Further studies are needed to explain the reasons for this phenomenon.

Brooke-Spiegler syndrome

Note Familial cylindromatosis/Turban tumor syndrome and multiple familial trichoepitheliomas were considered as separate diseases; it is now known that they are allelic diseases and represent two ends of the Brooke-Spiegler syndrome spectrum (Welch et al., 1968; Young et al., 2006). Familial cylindromatosis/Turban tumor syndrome is characterized by cylindromas and multiple familial trichoepitheliomas by trichoepitheliomas as the only tumor type.

Multiple familial trichoepitheliomas in association with squamous cell carcinoma

Multiple familial trichoepitheliomas in association with squamous cell carcinoma

Multiple (Familial) Trichoepitheliomas: A Clinicopathological and Molecular Biological Study, Including CYLD and PTCH Gene Analysis, of a Series of 16 Patients: Erratum

Multiple (Familial) Trichoepitheliomas: A Clinicopathological and Molecular Biological Study, Including CYLD and PTCH Gene Analysis, of a Series of 16 Patients: Erratum

Multiple (Familial) Trichoepitheliomas: A Clinicopathological and Molecular Biological Study, Including CYLD and PTCH Gene Analysis, of a Series of 16 Patients

Multiple familial trichoepitheliomas (MFT) constitute an autosomally inherited syndrome possibly related to Brooke-Spiegler syndrome (BSS). Although some early studies suggested a role for the PTCH gene on chromosome 9q22.3 in the etiopathogenesis of MFT, recent studies of occasional patients with the MFT clinical phenotype identified mutations in the CYLD gene on chromosome 16q12-q13, a gene responsible for BSS. A systematic investigation of PTCH and CYLD mutations in patients with MFT has never been performed. Our main objective was to collect a reasonably large series of patients with MFT to (1) study the clinicopathological spectrum of the disease, (2) determine whether the PTCH gene is implicated in the pathogenesis of MFT, and if so (3) determine the relative frequency of CYLD and PTCH mutations, (4) establish if there may be any possible genotype-phenotype correlations, and (5) study the spectrum of somatic mutations. Clinical analysis including family histories, histopathological investigations, and molecular genetic studies were performed. There were 9 female and 7 male patients ranging in age from 11 to 63 years. They presented with multiple, small, discrete and sometimes confluent, skin-colored to pink, asymptomatic nodules preferentially located on the face, being especially prominent and confluent in the nasolabial folds and inner aspects of the eyebrows. A total of 66 conventional trichoepitheliomas (TEs) were studied microscopically. Aside from typical features of TE, some also exhibited variant morphological patterns including areas reminiscent of other benign adnexal neoplasms and melanocytic hyperplasia. In none of the 9 patients tested was a germline mutation of the PTCH gene identified. Germline CYLD mutations were detected in 6 of 13 patients tested (identical in 2 unrelated patients) including 2 novel mutations, whereas the remaining 7 individuals showed wild-type alleles. Two patients with germline wild-type CYLD showed, however, a somatic mutation in the gene (1 duplication, 1 substitution mutation). Neither CYLD nor PTCH germline mutations were found in the 5 patients in whom both genes were analyzed. MFT seems to be a phenotypic variant of BSS. The PTCH gene is rarely, if ever, involved in the pathogenesis of MFT. Absence of a germline mutation of the CYLD gene in cases harboring a somatic mutation may be explained by large deletions in the gene or by mutation in intronic sequences or in the promoter region. Considering our 5 patients with no mutation in either gene, the final possibility is that another, as yet undescribed gene (neither CYLD nor PTCH) is implicated in the pathogenesis of some patients with MFT.

Germline and somatic mutations in the CYLD and PTCH genes in patients with multiple familial trichoepitheliomas: Is there a third gene implicated in the pathogenesis of the disease?

Germline and somatic mutations in the CYLD and PTCH genes in patients with multiple familial trichoepitheliomas: Is there a third gene implicated in the pathogenesis of the disease?

Clinicopathologic features of malignant tumors in patients affected with Brooke-Spiegler syndrome, including the multiple familial trichoepitheliomas variant

Clinicopathologic features of malignant tumors in patients affected with Brooke-Spiegler syndrome, including the multiple familial trichoepitheliomas variant

Spectrum of Tumors With Follicular Differentiation in a Patient With the Clinical Phenotype of Multiple Familial Trichoepitheliomas: A Clinicopathological and Molecular Biological Study, Including Analysis of the CYLD and PTCH Genes

We report a patient with multiple trichoepitheliomas whose biopsy material also demonstrated a range of other neoplasms with follicular differentiation, including small nodular trichoblastoma, small nodular basal cell carcinoma (BCC), and areas resembling infundibulocystic BCC/basaloid follicular hamartoma. These were all intimately associated with otherwise typical trichoepitheliomas that dominated the microscopic appearances. Peripheral blood and tumor tissues of the patient and his 2 daughters, who apparently had a milder phenotype, were studied for alterations in the CYLD and PTCH genes, but mutations or loss of heterozygosity was not found in either gene. The occurrence of multiple follicular neoplasms within a single lesion adds evidence that, although in most cases BCC and trichoblastoma are distinct lesions, the 2 neoplasms do encompass a morphological spectrum of follicular differentiation, which is probably more overtly expressed in syndromic patients.

Tumor Mapping in 2 Large Multigenerational Families With CYLD Mutations

To comprehensively ascertain the extent and severity of clinical features in affected individuals from 2 large families with proven heterozygous mutations in the CYLD locus and to correlate these findings with the 3 appendageal tumor predisposition syndromes (familial cylindromatosis, Brooke-Spiegler syndrome, and multiple familial trichoepitheliomas) known to be associated with such germline mutations. Interfamilial and intrafamilial observational study. Tertiary genetic and dermatology referral center. Thirty-four individuals recruited from 2 large multigenerational families with CYLD mutations. Clinical details, history, and tumor maps were obtained from all participants; in 18, the information was corroborated by detailed clinical examination. Tumor density, distribution and histologic findings, associated medical conditions, patient symptoms, and impact of disease on quality of life. The severity of penetrance and phenotype varied within families. Although an approximately equal female to male predisposition was noted, 5 women and 1 man (of 26 patients surveyed [23%]) had undergone total scalp removal. The average age at onset was 16 years (range, 8-30 years). Symptoms reported by affected patients included painful tumors (in 12 of 23 patients [52%] who answered the question), conductive deafness, and sexual dysfunction. Of the 26 surveyed patients, tumors were noted on the scalp in 21 (81%), on the trunk in 18 (69%), and in the pubic area in 11 (42%). Tumor mapping provided clinical evidence that correlated with hormonally stimulated hair follicles being particularly vulnerable to loss of heterozygosity and tumor induction. The burden of disease at sites other than the head and neck appears to be underreported in the literature and greatly affects quality of life. Differentiation between the clinical diagnoses has little prognostic or clinical utility in genetic counseling, even within individuals from the same family. Thus, we suggest an encompassing diagnosis of "CYLD cutaneous syndrome." Finally, the clinical distribution of tumors suggests that hormonal factors may play an important role in tumor induction in these patients.

Basal cell carcinomas arising within multiple trichoepitheliomas

Although trichoepitheliomas (TEs) are commonly regarded as benign tumors of follicular origin, the natural history of multiple familial trichoepitheliomas (MFT) and their risk for malignancy has been unclear. We describe a 57-year-old male with numerous skin-colored firm papules and plaques present on the central face since 6 years of age. Recently, some lesions had enlarged and ulcerated. Other family members were similarly affected. Biopsies from multiple lesions showed TEs both alone and associated with basal cell carcinoma (BCC) in the same section, suggesting the secondary development of BCCs within TEs. Many prior reports of BCCs arising within TEs in patients with presumed MFT were likely misdiagnosed cases of nevoid BCC. This report is a compelling example of MFT in which BCCs evolved secondarily. Awareness of the potential for the evolution of carcinoma in patients with MFT is important in the management of these patients.