Multiple Familial Trichoepithelioma Research Articles

Differential diagnosis of Brooke–Spiegler syndrome in a young woman with multiple trichoepitheliomas

BrookeSpiegler syndrome (Brooke-Spiegler syndrome; OMIM #605041) is a rare, autosomal dominant inherited monogenic disease caused by mutations in gene CYLD with its different penetrance.
 It is clinically manifested by the development of multiple neoplasms of skin appendages such as spiradenoma, cylindroma, spiradenocylindroma and trichoepithelioma. Several phenotypic variants with mutations in gene CYLD have been described in the scientific literature. They are classic BrookeSpiegler syndrome; multiple familial trichoepithelioma syndrome (multiple trichoepitheliomas without cylindromas, spiradenomas, etc.); familial cylindromatosis (multiple cylindromas on the scalp i.e., "turban tumor"); syndrome of multiple spiradenomas or spiradenocylindromas without other neoplasms of the skin appendages. For four diseases associated with CYLD mutations, the prevalence is 1/1 000 000.
 The scientific literature describes more than 200 cases of BrookeSpiegler syndrome, which is more common in women. Phenotypic manifestations of the CYLD mutation are variable, so there is no reliable statistics on the frequency of occurrence of clinical variants of BrookeSpiegler syndrome. The variety of neoplasms of the skin appendages, the commonality of their histogenesis, the similarity of clinical and histological patterns significantly complicate the diagnosis. Verification of the diagnosis of BrookeSpiegler syndrome is based on histological examination and sequencing of the CYLD gene.

A novel frameshift CYLD mutation in a family with multiple familial trichoepithelioma

A novel frameshift CYLD mutation in a family with multiple familial trichoepithelioma

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>

Multiple Familial Trichoepithelioma with Varied Malignancies.

Multiple Familial Trichoepithelioma with Varied Malignancies.

A de novo missense mutation of the CYLD gene with multiple familial trichoepithelioma.

A 7-year-old Chinese girl presented with a 5-year history of multiple skin-colored papules on the nasal dorsum, nasolabial folds and eyelids, which increased in size and number with age. On cutaneous examination, we observed numerous asymptomatic, firm, skin-colored papules favoring the nasal dorsum, nasolabial folds and eyelids (Fig.1a) Her parents did not show similar eruptions. None of the girl and her parents had any other skin tumors such as cylindromas or spiradenomas. No consanguineous relationship was found in her family.

The E3 ubiquitin ligase MIB2 enhances inflammation by degrading the deubiquitinating enzyme CYLD

The tumor suppressor CYLD is a deubiquitinating enzyme that suppresses polyubiquitin-dependent signaling pathways, including the proinflammatory and cell growth-promoting NF-κB pathway. Missense mutations in the CYLD gene are present in individuals with syndromes such as multiple familial trichoepithelioma (MFT), but the pathogenic roles of these mutations remain unclear. Recent studies have shown that CYLD interacts with a RING finger domain protein, mind bomb homologue 2 (MIB2), in the regulation of NOTCH signaling. However, whether MIB2 is an E3 ubiquitin ligase that acts on CYLD is unknown. Here, using the cell-free-based AlphaScreen and pulldown assays to detect protein-protein interactions, along with immunofluorescence assays and murine Mib2 knockout cells and animals, we demonstrate that MIB2 promotes proteasomal degradation of CYLD and enhances NF-κB signaling. Of note, arthritic inflammation was suppressed in Mib2-deficient mice. We further observed that the ankyrin repeat in MIB2 interacts with the third CAP domain in CYLD and that MIB2 catalyzes Lys-48-linked polyubiquitination of CYLD at Lys-338 and Lys-530. MIB2-dependent CYLD degradation activated NF-κB signaling via tumor necrosis factor alpha (TNFα) stimulation and the linear ubiquitination assembly complex (LUBAC). Mib2-knockout mice had reduced serum interleukin-6 (IL-6) and exhibited suppressed inflammatory responses in the K/BxN serum-transfer arthritis model. Interestingly, MIB2 significantly enhanced the degradation of a CYLDP904L variant identified in an individual with MFT, although the molecular pathogenesis of the disease was not clarified here. Together, these results suggest that MIB2 enhances NF-κB signaling in inflammation by promoting the ubiquitin-dependent degradation of CYLD.

Abstract 3442: Functional and molecular analysis of the somatic mutations in the NF-κB pathway inhibitor, CYLD, in nasopharyngeal carcinoma

Abstract Background: NF-κB is an important signaling pathway for regulating multiple signaling cascades involved in cancer development such as inflammation, immune response, cell survival, and cell proliferation. Constitutive activation of the NF-κB pathway plays a key role in the development of NPC. Our previous whole-exome sequencing (WES) study in NPC biopsies has identified five mutations in CYLD, including R758Q. As R758X is a mutational hotspot in CYLD, it has been reported in multiple familial trichoepithelioma type 1, Brooke-Spiegler syndrome and familial cylindromatosis. Thus, we attempted to evaluate the functional effect of CYLD WT and R758Q in regulating NF-κB activity in NPC, which is crucial in NPC progression and development. Methods: C17, C666-1 and NPC43 EBV-positive cell lines and HK1 were co-infected by CYLD wild-type (WT) and mutant constructs with a NF-κB specific dual luciferase promoter plasmid. CRISPR-CAS9 system was used to knock out CYLD. The functional role of CYLD was determined by MTT, CFA and wound healing assays. NF-κB downstream targets expression was evaluated by the method of RT-QPCR. Co-immunoprecipitation (Co-IP) experiments were performed with the Sigma Anti-FLAG M2 magnetic beads and the results were confirmed by Western blot analysis. Female athymic BALB/cAnN (nude) mice were utilized to investigate tumorigenicity. NPC cell lines were treated with cisplatin to check cell sensitivity. Results: The reporter assay showed that CYLD can downregulate NF-κB binding activities in comparison to the vector-alone (VA), but R758Q failed to inhibit the NF-κB binding activities. Over-expression of CYLD can suppress NF-κB downstream target genes expression. Knocking out of CYLD results in higher NF-κB downstream genes expression compared with VA, which confirmed that CYLD can suppress NF-κB activity. R758Q increases these genes expression compared with WT. CYLD can suppress cell growth rate, while R758Q promoted cell proliferation and migration compared to WT. Furthermore, WT CYLD can significantly suppress tumor growth rate, whereas R758Q has the same growth rate with VA, consistent with R758Q loss of WT function, causing tumor suppression. Moreover, CYLD can enhance cell sensitivity to cisplatin treatment compared to the VA. Conclusions: These results suggest that CYLD can suppress NF-κB activity compared to VA, while R758Q lost WT function in NPC. CYLD can inhibit tumorigenesis compared to VA, whereas R758Q induces tumor growth compared to WT. The NPC cell line with CYLD WT is more sensitive to cisplatin treatment. Acknowledgement: Research Grants Council Area of Excellence grant AoE-M06/08 to MLL. Citation Format: Mingdan Deng, Wei Dai, Maria Lung. Functional and molecular analysis of the somatic mutations in the NF-κB pathway inhibitor, CYLD, in nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3442.

Marie Unna hereditary hypotrichosis accompanied by multiple familial trichoepithelioma in a Chinese family.

Marie Unna hereditary hypotrichosis (MUHH) and multiple familial trichoepithelioma (MFT) are both autosomal dominant disorders. Recently, certain genes (HR and EPS8L3) have been found to be responsible for MUHH, while CYLD has been demonstrated to be the main pathogenic gene in MFT patients. However, there exist a number of CYLD mutation-negative MFT cases, for which the causative gene has been unknown. Here, we identified a large, five-generation Han Chinese family with several patients presenting with MUHH and MFT. Sanger sequencing of three genes in 13 family members was performed. We found that the c.1A>G mutation in an inhibitory upstream open-reading frame of HR (U2HR) was present in all MUHH patients, while no pathogenic variants were found in the 3'- or 5'-untranslated regions, exons or flanking intronic sequences of EPS8L3 or CYLD in any family members. Subsequently, whole-genome sequencing was performed for five affected and one unaffected family member. We found no CYLD variants but identified an FABP12 variant (rs536105592 G>A) in the patients with both MUHH and MFT. These results suggest that the U2HR mutation was responsible for MUHH and the FABP12 variant may be coincidental in the accompanying MFT in this unique pedigree. This report deepens our understanding of the genetic basis of hair follicle diseases.

Phenotype variability in tumor disorders of the skin appendages associated with mutations in the CYLD gene.

Mutations in the tumor suppressor gene CYLD underlie phenotypically heterogeneous hereditary tumor disorders of the skin appendages. These diseases are inherited autosomal dominantly and include Brooke-Spiegler syndrome (BSS; OMIM 605041), familial cylindromatosis (FC; OMIM 132700) and multiple familial trichoepithelioma (MFT; OMIM 601606). Clinically, cylindromas, trichoepitheliomas and spiradenomas can be found in affected individuals. We sought to elucidate the molecular genetic basis in individuals with newly diagnosed cylindromas, trichoepitheliomas and/or spiradenomas. Mutation analysis using polymerase chain reaction (PCR)-based techniques was performed in seven German patients and one Turkish patient. We detected two missense, two nonsense, two deletions and two duplication mutations in the CYLD gene, of which seven have not yet been reported. No genotype-phenotype correlation was detected amongst the patients. Our data provide additional information on the clinical and molecular genetic heterogeneity of disorders associated with CYLD mutations.

Multiple familial trichoepithelioma: confirmation via dermoscopy.

Trichoepitheliomas are uncommon benign adnexal neoplasms that originate from the hair follicles. Multiple familial trichoepithelioma constitute an autosomal dominant disease characterized by the appearance of multiple flesh-colored, symmetrical papules, tumors and/or nodules in the central face and occasionally on the scalp. Although clinical diagnosis is usually straightforward in light of the family history and naked-eye examination, dermoscopy may aid in its confirmation. Dermoscopy of each papule revealed in-focus arborizing vessels, multiple milia-like cysts and rosettes amidst a whitish background.In a patient with multiple facial papules revealing a dermoscopic appearance described above, the diagnosis of sporadic or familial multiple trichoepithelioma should be considered.

Multiple familial trichoepithelioma: 9 cases from a family

Multiple familial trichoepithelioma: 9 cases from a family

Brooke-Spiegler Syndrome and Phenotypic Variants: An Update.

Brooke-Spiegler syndrome (BSS) is an inherited autosomal dominant disease characterized by the development of multiple adnexal cutaneous neoplasms most commonly spiradenoma, cylindroma, spiradenocylindroma, and trichoepithelioma. Multiple familial trichoepithelioma (MFT) is a phenotypic variant of the disease characterized by the development of numerous trichoepitheliomas (cribriform trichoblastoma) only. Malignant tumors arise in association with preexisting benign cutaneous neoplasms in about 5-10% of the patients . Apart from the skin, major and minor salivary glands have been rarely involved in BSS patients. Extremely rare is the occurrence of breast tumors (cylindroma). The gene implicated in the pathogenesis of the disease is the CYLD gene, a tumor suppressor gene located on chromosome 16q12-q13. Germline CYLD mutations are detected in about 80-85% of patients with the classical BSS phenotype and in about 40-50% of the individuals with the MFT phenotype using a PCR based approach with analysis of exonic sequences and exon-intron junctions of the CYLD gene. There appears to be no genotype-phenotype correlations with respect to the severity of the disease, the possibility of malignant transformation, and development of extracutaneous lesions.

The CYLD p.R758X worldwide recurrent nonsense mutation detected in patients with multiple familial trichoepithelioma type 1, Brooke-Spiegler syndrome and familial cylindromatosis represents a mutational hotspot in the gene.

BackgroundMultiple familial trichoepithelioma type 1 (MFT1; MIM 601606), a rare monogenic skin disease with autosomal dominant inheritance, is characterized by the development of multiple skin-colored papules on the central area of the face, frequently occurring in the nasolabial area. The disease is associated with various mutations in the cylindromatosis (CYLD; MIM 605018) gene that are also responsible for familial cylindromatosis (FC) and Brooke-Spiegler syndrome (BSS).MethodsRecently we have identified a Spanish MFT1 pedigree with two affected family members (father and daughter). Direct sequencing of the CYLD gene revealed a worldwide recurrent heterozygous nonsense mutation (c.2272C/T, p.R758X) in the patients.ResultsThis mutation has already been detected in patients with all three clinical variants – BSS, FC and MFT1 – of the CYLD-mutation spectrum. Haplotype analysis was performed for the Spanish patients with MFT1, Dutch patients with FC and an Austrian patient with BSS, all of whom carry the same heterozygous nonsense p.R758X CYLD mutation.ConclusionsOur results indicate that this position is a mutational hotspot on the gene and that patients carrying the mutation exhibit high phenotypic diversity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0346-9) contains supplementary material, which is available to authorized users.

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.

The clinicopathological spectrum of trichoepitheliomas: a retrospective descriptive study.

Trichoepithelioma (TE) is a benign adnexal neoplasm derived from basal cells in the hair follicle. Solitary TE occurs sporadically as opposed to the multiple familial variant that presents as an autosomal dominant genodermatosis. The solitary variant can be confused with basal cell carcinoma both clinically and histologically. Multiple familial TEs are a cosmetically disfiguring condition with limited satisfactory treatment options. Skin biopsies diagnosed as TE from January 1, 2001, to December 31, 2011, were retrieved from the archives of the Division of Anatomical Pathology (University of Stellenbosch and National Health Laboratory Service, Cape Town, South Africa). Clinical and demographic data were retrieved from the patient records at Tygerberg Academic Hospital. Data of patients with solitary TE and multiple TE were compared. Thirty-three biopsy specimens were collected from 30 patients. Twenty patients had solitary TE, nine patients had multiple TEs, and one patient had multiple linear TEs. Multiple TEs started to develop in patients at an average age of 17.3years. Three patients in the study had tumoral TE with a diameter greater than 20mm. One patient had TE associated with a basal cell carcinoma. Multiple TEs were commonly misdiagnosed clinically as tuberous sclerosis and showed a cribriform histopathological tumor pattern in 80% of cases as compared to only 10% of solitary TEs. The current study was confined to a cohort of patients, in the Western Cape Province of South Africa, whose ethnic and geographic origins were not available. The extrapolation of findings from this study to the rest of the South African population may not be valid. A cribriform growth pattern occurs in the majority of cases of multiple TEs.

Multiple familial trichoepithelioma: Report of a Spanish family associated with a mutation in the CYLD gene

Multiple familial trichoepithelioma: Report of a Spanish family associated with a mutation in the CYLD gene

Multiple Familial Trichoepithelioma with an Adjacent Basal Cell Carcinoma, Transformation or Collision - A Case Report and Review of Literature.

Trichoepithelioma is a benign tumor of follicular origin that presents as small, skin-colored papules predominantly on the face. When more than one family member is affected, the disease is known as multiple familial trichoepithelioma (MFT). It is a rare autosomal dominant skin disease. Malignant transformation is very rare. We describe here a case that developed malignant neoplasm in a setting of multiple trichoepithelioma.

Trichoepithelioma and Basal Cell Carcinoma with Squamous Differentiation: Is it Causal or Coincidental?

Trichoepitheliomas (TEs) are benign cutaneous tumors that occur either as solitary non-familial or multiple familial. We report a case of multiple familial trichoepithelioma (MFT) in a 55-year-old female patient and her son who came with complaints of single ulcerated mass involving the left nasolabial fold and cheek. She had multiple papules and nodules all over the face and neck since 25 years. Histopathological examination of an ulcerated lesion revealed features of basal cell carcinoma (BCC) with squamous differentiation, which was confirmed by immunohistochemistry. A skin biopsy obtained from the papule on neck showed features of TE. However, whether BCC developed independently or by transformation from TE was uncertain. Her 36-year-old son presented with similar lesions on the face and a skin biopsy showed features of TE. Though malignant transformation of TE is quite rare, awareness of the potential for evolution of carcinoma in patients with MFT is important for management of these patients.

Large germline deletions of the CYLD gene in patients with Brooke-Spiegler syndrome and multiple familial trichoepithelioma.

Brooke-Spiegler syndrome (BSS) and its phenotypic variants, multiple familial trichoepithelioma (MFT) and familial cylindromatosis, are rare autosomal dominant hereditary diseases. They are characterized by the presence of multiple adnexal tumors, especially cylindromas, spiradenomas, spiradenocylindromas, and trichoepitheliomas. Implicated in the pathogenesis of the disease is the gene CYLD, which is localized on the long arm of chromosome 16. This gene encodes an evolutionarily conserved protein belonging to the deubiquitinating enzymes family, which plays a key role in many signaling pathways, especially in NF-κB, JNK, and Wnt. Less than 90 germline mutations of CYLD have been identified in patients with BSS/MFT. These mutations are mostly small alterations in the coding sequence and at exon-intron junction sites. One patient with an intronic mutation and another with a large CYLD deletion have also been recorded. In this study, the authors have analyzed a cohort of 14 patients with BSS/MFT from 13 families for large genome rearrangements by array comparative genome hybridization followed by confirmatory sequencing. We identified 2 large deletions, namely c.-34111_*297858del378779 and c.914-6398_1769del13642ins20 in patients with MFT and BSS, respectively. All other analyzable patients did not reveal any copy number alteration. It is concluded that the large rearrangements are relatively rare in patients without a germline CYLD mutation demonstrable by conventional sequencing. The pathogenetic mechanisms in patients with BSS/MFT lacking germline sequence alterations or large rearrangements in the CYLD gene remain to be clarified.

A novel frameshift mutation in the cylindromatosis (CYLD) gene in a Chinese family with multiple familial trichoepithelioma

Multiple familial trichoepithelioma (MFT) (OMIM: 601606) is an autosomal dominantly inherited disorder characterized by numerous, skin-colored papules and nodules with pilar differentiation. Recently, several mutations in the cylindromatosis (CYLD) gene have been reported in MFT. In this study, a mutation analysis of the CYLD was conducted in a Chinese pedigree of typical MFT. Affected individuals were identified through probands from Shanxi Province, China. Lesional skin biopsy of the proband revealed the typical histopathological characteristics of trichoepithelioma. Individuals belonging to five consecutive generations were similarly affected, which indicated an autosomal dominant inheritance pattern. Genomic DNA was extracted from peripheral blood lymphocytes using standard phenol/chloroform extraction method. All the coding exons (4-20) and exon-intron boundaries of the CYLD gene were amplified by polymerase chain reaction (PCR). Direct sequencing of all PCR products amplified from the complete coding regions of the CYLD gene was performed to identify mutations. Sequencing of the CYLD gene was performed in a further 100 unrelated, unaffected control individuals to exclude the possibility of polymorphism. A novel heterozygous frameshift mutation c.1169_1170delCA (p.Thr390Argfs) was identified in exon 10 of the CYLD gene in the affected family members. This mutation was also detected in unaffected family members, but not in the unrelated, healthy individuals who were also analyzed. Our study expands the database on the CYLD gene mutations in MFT and should be useful in providing genetic counseling and prenatal diagnosis for families affected by MFT.