Mutations In CYLD Gene Research Articles

Novel CYLD pathogenic variant associated with multiple cylindromas of the scalp-A case report.

Cylindromas are rare, benign adnexal neoplasms primarily found on the scalp and face, with a higher incidence in women and typically manifesting in the second or third decade of life. These tumours can present as single or multiple nodules, with the latter form often linked to CYLD gene mutations, particularly in the context of CYLD cutaneous syndrome. Here, we report a case of a 61-year-old male presenting with multiple cylindromas of the scalp, prompting genetic testing that revealed a novel pathogenic variant in the CYLD gene.

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

Introduction: Multiple familial trichoepithelioma is a rare autosomal dominant genodermatosis caused by a mutation in the CYLD gene. This disease is characterized by the development of multiple skin-colored papules and nodules mainly on the central face. We herein describe a family with multiple familial trichoepithelioma with a novel frameshift mutation in CYLD. Case presentation: The proband was an 8-year-old girl who presented with a 2-year history of numerous progressive, asymptomatic, firm skin-colored papules on her nasal dorsum, nasolabial folds, and eyelids. Histopathological examination was compatible with the typical findings of trichoepithelioma. Her father displayed similar but inconspicuous smaller lesions on the face. Mutation analysis of the proband identified a heterozygous frameshift mutation c.1181_1182insCTTTGAC (p.D394fs) in exon 10 of CYLD. This mutation was also detected in the proband’s father, but not in either her mother or 100 unrelated control individuals Discussion: There is no obvious genotype–phenotype correlation in patients with multiple familial trichoepithelioma. In our study, the girl had a severe clinical appearance characterized by facial disfiguration, whereas her father had inconspicuous smaller lesions despite having the same mutation. We also identified a novel frameshift mutation c.1181_1182insCTTTGAC (p.D394fs) in exon 10 of the CYLD gene. The presence of this mutation leads to premature translation termination and thus to the synthesis of a truncated protein. Conclusion: We found a novel frameshift mutation of the CYLD gene in a Chinese family, thus expanding the database of CYLD gene mutations in multiple familial trichoepithelioma.

Can we clinically identify patients at risk of malignant transformation of skin tumors in Brooke–Spiegler syndrome?

Brooke-Spiegler syndrome (BSS) is a rare inherited autosomal dominant disease characterized by the development of multiple adnexal cutaneous neoplasms. BSS has been linked to mutations in CYLD gene, which is a tumor suppressor gene located on chromosome 16q12-q13. An increased risk of malignant transformation of adnexal cutaneous tumors in BSS patients has been reported. However, no reported genetic markers identify patients at risk of cutaneous malignancy. This study reviews published cases of BSS to investigate the role of clinical parameters as biomarkers of skin malignancy. A comprehensive review of the clinical aspects of BSS is based on 55 case reports. Our analysis revealed only age as a predictor of malignancy; however, this is also a general risk factor for development of malignancy and therefore of limited value as a screening tool. The study highlights the need for standardized clinical follow-up of patients.

Abstract 1722: Spectrum of solid malignancies associated with mutations in CYLD gene

Abstract Introduction: The CYLD gene product is a de-ubiqutinating enzyme involved in regulation of NF-kappaB signaling. Inactivating germline mutations in CYLD are the cause of Brooke-Spiegler syndrome characterized by multiple cutaneous tumors (cylindromas, trichoepitheliomas and spiradenomas) and tumors of salivary glands. Little is known about the role of CYLD in the development of solid organ malignancies. Methods: We retrospectively analyzed CYLD gene mutations detected in a large database of solid tumors genetically profiled (NGS of 592 genes) at a reference laboratory (Caris Life Science, Phoenix, AZ). Results: CYLD pathogenic mutations were identified in 235 tumor samples (0.4% of the tumors analyzed). The most common primary sites included lung (60), endometrium (15) and anus (10). Histologically, the majority of the tumors were classified as squamous (71) and adenocarcinoma (59). A number of mutations were identified, most commonly affecting codons p.N722fs (27), p.S371* (16) and p.P771S/p.P771L (12). 38 cases had only CYLD mutations detected, while the majority of associated mutations occurred in TP53 (45%). Numerous co-occurring pathogenic mutations were present in oncogenes (e.g. PIK3CA in 41, KRAS in 33, BRAF 17) and/or tumor suppressor genes (e.g. APC in 40, PTEN in 36, BRCA2 in 25, RB1 in 23). Conclusion: Our study provides the largest database analysis of CYLD gene mutations in solid tumors and shows the distribution in numerous primary tumor sites previously unrecognized in association with CYLD. Additional studies may reveal unexpected germ-line associations and will be pursued in the future. Citation Format: Michelle Ellis, Jeff Swensen, Zoran Gatalica. Spectrum of solid malignancies associated with mutations in CYLD gene [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 1722.

Frequent and differential mutations of the CYLD gene in basal cell salivary neoplasms: linkage to tumor development and progression

AbstractBasal cell salivary neoplasms display similar cyto-morphologic features and are classified into adenoma and adenocarcinoma based on the presence or absence of tumor invasion at diagnosis. These neoplasms also share considerable phenotypic resemblance and co-exist with certain dermal adnexal tumors harboring the CYLD gene mutations inferring common genetic association. We sequenced the CYLD gene in both basal cell adenomas and adenocarcinomas and correlated the findings with CYLD, NF-κB, and β-catenin expression levels and clinicopathologic factors. Twenty mutations were identified and comprised of 3 synonymous and 17 non-synonymous (missense) types involving the coding exons of the CYLD gene. Mutations in exons 9–11 were identified in both adenomas and adenocarcinomas, while mutations in exons 12–20, encoding the USP domain, were exclusively found in carcinomas. Although no significant correlation between CYLD mutations and expression levels of CYLD, NF-κB, and β-catenin or clinicopathologic parameters was found, basal cell adenocarcinomas with multiple mutations showed reduction in CYLD protein expression and pursued aggressive clinical behavior. Our study revealed high incidence and sequential CYLD mutations in both basal cell adenoma and adenocarcinoma supporting a single neoplastic continuum for their evolution and provides evidence for potential diagnostic and therapeutic utility.

Growing Asymptomatic Nodule on the Ear.

A 56-year-old Caucasian woman presented with a lesion on the right ear of 5-year duration. The site had undergone incision and drainage with no expression of contents followed by a complete excisional punch biopsy 4 years prior to presentation. The patient now presented with recurrence of the lesion, which she reported had been growing in size. Despite its growth, the lesion remained asymptomatic. Physical examination revealed a dermal nodule with a bluish hue and visible telangiectasias on the root of right ear, measuring 1.7 cm in size [Figure 1]. Histopathologic evaluation of a biopsy revealed a dermal-based, well-circumscribed lobulated tumor island composed of basophilic cells with little cytoplasm [Figure 2a]. Higher magnification showed two types of tumor cells – small, dark basaloid cells with scant cytoplasm and small nuclei and slightly larger cells with a more open nuclear chromatin pattern [Figure 2b]. The larger cells surrounded areas of focal ductal differentiation. No atypical features were identified.Figure 1: Dermal nodule with a bluish hue and visible telangiectases on the right root of the earFigure 2: (a) Well-circumscribed lobulated tumor island composed of basophilic cells with little cytoplasm (H and E, original magnification ×20). (b) Close inspection revealing two cell types – small, dark basaloid cells with scant cytoplasm and slightly larger cells with a more open nuclear chromatin pattern. Scattered lymphocytes and hyaline deposits are noted in the tumor nodules (H and E, original magnification ×200)Question What is your diagnosis? Answer Diagnosis: Spiradenoma. Discussion Spiradenomas are well-differentiated, benign dermal neoplasms originating from the sweat glands. They usually present as small solitary nodules that can grow up to several centimeters, typically with a blue, gray, or purple hue and are often strikingly painful in nature.[1] Spiradenomas typically arise on the head, neck, and trunk; however, cases in other areas such as the breast have been reported. Cases of multiple linear, zosteriform, blashkoid, and nevoid spiradenomas have also been reported. It is not uncommon for spiradenomas to occur concomitantly with cylindromas, trichoepitheliomas, and/or trichoblastomas. In particular, patients with Brooke–Spiegler present with multiple spiradenomas, cylindromas, and trichoepitheliomas caused by mutations in the CYLD gene.[2] Histologically, spiradenomas show one or more large, sharply demarcated basophilic nodules of the dermis. Two types of cells are seen in the nodules – small, dark, basaloid cells with hyperchromatic nuclei and cells with larger, pale, ovoid nuclei, which tend to be toward the center of the lesion. Duct-like structures and cystic cavities may be seen. The cystic cavities are usually filled with finely granular eosinophilic material that is diastase resistant and periodic acid-Schiff positive. Historically, spiradenomas were thought to be of eccrine lineage, though many lesions have been shown to demonstrate apocrine differentiation.[3] Clinically, there have been no reported cases on acral skin, further questioning their eccrine origin. Spiradenomas are histologically closely related to cylindromas, often displaying foci of decapitation and tubular patterns with uninterpretable differentiation. Immunohistochemical analysis of several spiradenomas and cylindromas found similar expression patterns of S-100 in the large, pale-staining cells, pointing to eccrine differentiation, and human milk fat globulin (HMFG) and lysozyme in the tubular cells, associated with apocrine differentiation.[4] Classically, spiradenomas also stain positive with CK7, epithelial membrane antigen, and carcinoembryonic antigen, as well the myoepithelial stains p63 and SMA. The pathogenesis of the formation of spiradenomas has not been completely elucidated. Derangements in intercellular bridge proteins that maintain epithelial organization, such as claudin-4, cadherin, and β-catenin, have been suggested as contributing to neoplasm formation. A study of 48 adnexal tumors found intense nuclear immunoreactivity for β-catenin in spiradenomas, in addition to pilomatricomas, suggesting a role of alterations in the β-catenin pathway in the development of spiradenomas.[5] This finding was corroborated in a study by Rajan et al., which also showed that a transition between cylindromas and spiradenomas can occur in patients with CYLD gene mutations.[6] Although spiradenoma is considered to be a benign adnexal neoplasm with low recurrence rate, malignant transformation can occur in longstanding lesions, more commonly in patients over the age of 50. Increased expression of p53 has been observed in malignant spiradenomas, although the significance in the pathophysiology is unclear. Malignant spiradenomas tend to be aggressive tumors with high rates of metastasis and mortality; therefore, conservative surgical excision of spiradenomas is recommended.[7] Given the history of recurrence and growth in size, we recommended conservative management with complete surgical excision of the tumor in our patient, which she agreed to. There has been no evidence of recurrence to date. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Trichoépithéliomes multiples familiaux : nouvelle mutation du gène CYLD

Multiple familial trichoepithelioma (MFT) is an autosomal dominant disease characterized by the development of numerous skin-coloured papules on the central area of the face. It is associated with various CYLD gene mutations that are also responsible for familial cylindromatosis and Brooke-Spiegler syndrome. We report a novel mutation in the CYLD gene in a family with MFT and discuss new developments in therapeutic options. Recent studies indicate that CYLD is a tumour-suppressor gene.

CYLD genes and skin appendage tumors

Cylindromatosis, trichoepithelioma and Brooke-Spiegler syndrome are rare autosomal dominant tumors of skin appendages. As a tumor suppressor, CYLD gene mutation is closely related to the occurrence of these tumors. The CYLD gene encodes a deubiqutination enzyme which can negatively regulate nuclear factor (NF)-κB signaling pathway and suppress the initiation of tumors by deubiquitinating the tumor necrosis factor receptor-associated factor (TRAF) and the regulatory subunit of Ikappa B kinase complex. This review describes the advances in the researches in CYLD gene mutations in, genotype-phenotype correlation in, as well as the treatment of skin appendage tumors. Key words: Genes, CYLD; Neoplasms, adnexal and skin appendage; Genotype; Phenotype

Rare occurrence of biallelic CYLD gene mutations in classical Hodgkin lymphoma

Survival of the malignant Hodgkin and Reed/Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) is dependent on constitutive activation of the nuclear factor kappaB (NF-kappaB) transcription factor. The deubiquitinating enzyme CYLD is a negative regulator of NF-kappaB and known to function as a tumor suppressor. To determine whether CYLD mutations play a role in cHL pathogenesis, we sequenced the gene in cHL cell lines and microdissected HRS cells obtained from lymph-node biopsies. A biallelic inactivation by mutations was found in the cHL cell-line KM-H2. However, the other seven cHL cell lines analyzed and HRS cells of 10 primary cHL cases did not show any mutations. By interphase cytogenetics, a (sub)clonal biallelic CYLD deletion was observed by interphase cytogenetics in 1 of 29 primary cHL, whereas signal patterns indicating decreased CYLD copy numbers were observed in a total of 10 of 29 primary cases. Our results suggest that biallelic CYLD mutations are rarely involved in cHL pathogenesis. Nevertheless, it is remarkable that KM-H2 cells, besides the CYLD mutations, also carry inactivating mutations in the genes of two other NF-kappaB inhibitors, that is, NFKBIA and TNFAIP3, exemplifying that multiple lesions in regulators of this signaling pathway can likely cooperatively contribute to the strong NF-kappaB activity of these cells.

A novel missense mutation of CYLD gene in a Chinese family with multiple familial trichoepithelioma

Multiple familial trichoepithelioma (MFT, OMIM 601606) is an autosomal dominantly inherited disease. It is characterized by numerous skin-colored papules on the central face. Pathogenic mutations in the CYLD gene have been identified. In this report, we identified a novel mutation of CYLD gene in a Chinese family with MFT. It is a novel heterozygous nucleotide G-->A transition at position 2,317 in exon 17 of the CYLD gene. Our study expands the database on the CYLD gene mutations in MFT.

Spiradenocylindroma-Like Basaloid Carcinoma of the Anus and Rectum: Case Report, Including HPV Studies and Analysis of the CYLD Gene Mutations

The authors report a case of basaloid carcinoma involving the anus and rectum of a 57-year-old woman. Microscopically, the tumor showed unusual morphologic features strongly resembling a spiradenocylindroma because it consisted, in most parts, of basaloid cell nodules arranged in a jigsaw-puzzle fashion containing or surrounded by eosinophilic basal membrane material; in addition, there were intratumoral lymphocytes. The overlying squamous epithelium manifested dysplastic changes compatible with in situ squamous carcinoma that gradually became invasive and blended with basaloid cell islands; additionally, there were koilocytes in the squamous epithelium. A molecular biology study identified HPV-16 in the lesional tissue. Analysis of the CYLD gene did not prove any mutation.

A novel mutation in CYLD gene in a family with multiple familiar trichoepitheliomas

A novel mutation in CYLD gene in a family with multiple familiar trichoepitheliomas

Two novel CYLD gene mutations in Chinese families with trichoepithelioma and a literature review of 16 families with trichoepithelioma reported in China

Two novel CYLD gene mutations in Chinese families with trichoepithelioma and a literature review of 16 families with trichoepithelioma reported in China