Brooke-Spiegler syndrome: radiotherapy as the last resort?

PURPOSE: To describe the case of successful radiotherapeutic treatment of a woman suffering from Brooke-Spiegler syndrome who had multiple disfiguring cylindromas on the entire scalp and further tumors on the trunk. METHODS: After decades of treatment with conventional therapies including surgery and topically applied salicylic acid, the 73-year-old woman agreed to undergo radiotherapeutic treatment. She received 60 Gy to the scalp and 36 Gy to painful nodules in the lumbar spine region. RESULTS: Over a follow-up period of 14 and 11 years, respectively, the scalp nodules almost completely regressed, while the lumbar nodules became painless and considerably smaller. Apart from alopecia, no late adverse effects of treatment remain. CONCLUSION: This case should remind us of the potential role that radiotherapy could play in treating Brooke-Spiegler syndrome. The required dose for treatment of such extensive disease is still a matter of debate due to the scarcity of radiotherapeutic experience. This case demonstrates that for scalp tumors, 30â€¯× 2 Gy can result in long-term tumor control, while other dose prescriptions may be adequate for tumors in other locations.

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.

Tricoepitelioma múltiple familiar. Reporte de un caso / Multiple family trichoepithelioma. Case study

El tricoepitelioma es un tumor benigno poco frecuente que se origina en el folículo piloso, puede ser único o múltiple, siendo la forma múltiple de presentación esporádica o familiar. El tricoepitelioma múltiple familiar se inicia durante la adolescencia y se presenta como neoformaciones múltiples progresivas, confluentes y deformantes sobre el rostro, suelen desencadenar trastornos ansiosos en los jóvenes afectados. El diagnóstico se realiza mediante historia clínica y examen físico, el abordaje siempre debe ser médico quirúrgico. Se informa el caso de una joven portadora de tricoepitelioma múltiple familiar que se trató de forma conjunta con el servicio de psiquiatría.(AU)

Trichoepithelioma is a rare benign tumour originating from the hair follicle. It can take a single or multiple form. The multiple form has a sporadic or family presentation. Multiple family trichoepithelioma appears during adolescence and presents as gradual multiple neoformations that are confluent and deforming on the face, which could trigger anxiety disorders in the young people affected. Diagnosis is by medical history and physical examination and the strategy must always be both medical and surgical. We report the case of a teenage girl diagnosed with familial multiple trichoepithelioma treated together with the psychiatry service.(AU)

TRAF3 and NBR1 both influence the effect of the disease-causing CYLD(Arg936X) mutation on NF-κB activity.

Recently described Hungarian and Anglo-Saxon pedigrees that are affected by CYLD cutaneous syndrome (syn: Brooke-Spiegler syndrome (BSS)) carry the same disease-causing mutation (c.2806C>T, p.Arg936X) of the cylindromatosis (CYLD) gene but exhibit striking phenotypic differences. Using whole exome sequencing, missense genetic variants of the TRAF3 and NBR1 genes were identified in the affected family members of the Hungarian pedigree that are not present in the Anglo-Saxon pedigree. This suggested that the affected proteins (TRAF3 and NBR1) are putative phenotype-modifying factors. An in vitro experimental system was set up to clarify how wild type and mutant TRAF3 and NBR1 modify the effect of CYLD on the NF-κB signal transduction pathway. Our study revealed that the combined expression of mutant CYLD(Arg936X) with TRAF3 and NBR1 caused increased NF-κB activity, regardless of the presence or absence of mutations in TRAF3 and NBR1. We concluded that increased expression levels of these proteins further strengthen the effect of the CYLD(Arg936X) mutation on NF-κB activity in HEK293 cells and may explain the phenotype-modifying effect of these genes in CYLD cutaneous syndrome. These results raise the potential that detecting the levels of TRAF3 and NBR1 might help explaining phenotypic differences and prognosis of CCS.

A novel large deletion of the CYLD gene causes CYLD cutaneous syndrome in a Chinese family.

BACKGROUND: CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) is a rare autosomal dominant hereditary disease characterized by multiple adnexal skin tumors including cylindromas, spiradenomas, and trichoepitheliomas. More than 100 germline mutations of the cylindromatosis (CYLD) gene have been reported in CCS and most of them are frameshift mutations or small alterations. METHODS: We identified a large, three-generation Chinese family with CCS, which consisted of 18 living family members, including six affected individuals. To explore the molecular biology of this family, we carried out targeted next-generation sequencing and Affymetrix CytoScan HD SNP array to analyze the mutation in the CYLD gene. RESULTS: A novel large deletion mutation, NC_000016.9:g.(50826498_50827517)_(50963389-50967346)del was found in the proband of this family. This deletion results in the loss of a nearly 140 kb fragment of the CYLD gene, spanning exons 17 ~ 20, which represent the coding regions of the ubiquitin-specific protease domain. Further quantitative polymerase chain reaction proved that all patients and two proband-related family members carried this large deletion. CONCLUSIONS: Our study expands the types of mutations in CCS and will undoubtedly provide valuable information for genetic counseling for families affected by the condition.

Tricoepitelioma múltiple familiar: a propósito de un caso / Familial multiple trichoepithelioma: a case report

El Tricoepitelioma Múltiple Familiar (TMF) constituye una rara enfermedad autosómica dominante, se caracteriza por la aparición de múltiples pápulas color piel, monomorfas, simétricas, ubicadas en la región central de la cara. El diagnóstico es histopatológico, donde se encuentran tricoepiteliomas, los cuales son neoplasias anexiales benignas que se originan en los folículos pilosos. La condición es de comportamiento indolente, pero con una importante repercusión estética y de difícil manejo. Al ser esta una entidad poco frecuente, el objetivo de este artículo es actualizar los aspectos más relevantes de esta enfermedad. Se presenta el caso de una paciente de 23 años con lesiones faciales típicas en quien se confirmó el diagnostico de TMF

Familial Multiple Trichoepithelioma (FMT) is a rare autosomal dominant disease, characte-rized by the appearance of multiple papules of skin color, monomorphic, symmetrical and located in the central region of the face. The diagnosis is based on histopathological features of trichoepitheliomas, which are benign adnexal neoplasms that originate in the hair follicles. The condition has an indolent behavior but it has an important aesthetic repercussion and it's difficult to treat. As this is a rare entity, the objective of this article is to update the most relevant aspects of this disease. We present the case of a 23 year old patient with typical facial lesions in whom the diagnosis of FMT was confirmed.

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.

A case of Brooke-Spiegler syndrome with a novel mutation in the CYLD gene in a patient with aggressive non-Hodgkin's lymphoma.

PURPOSE: Brooke-Spiegler syndrome (BSS, familial cylindromatosis) is a rare hereditary disease characterized by multiple tumors of the skin appendages predominantly located in the head and neck region, such as cylindromas, trichoepitheliomas, or spiradenomas. It is caused by an autosomal dominant mutation in the CYLD gene, mapped on chromosome 16q12-13. Association with secondary malignant neoplasms has been reported. Until now 51 different mutations in 73 families have been reported; 41 % of them constitute frameshift mutations, resulting in an interruption of the expression of the gene product CYLD. CYLD is a deubiquitinating enzyme and plays an important role in (NF)-κB pathway signaling, a central pathway for apoptosis regulation. Mutation-induced loss of function leads to constitutive activation of NF-κB. METHODS: Here, we report the case of a 48-year-old female patient diagnosed with an abdominal aggressive non-Hodgkin's lymphoma. The patient presented with multiple cylindromas of the capillitium. The patient's mother also has a mild form of late-onset cylindromas. Due to the typical clinical features indicating BSS, genotyping from peripheral blood was performed. A c.2465insAACA mutation in exon 17 of the CYLD gene, leading to a frameshift, was detected in the patient and in the patient's mother. RESULTS/CONCLUSIONS: This is the first description of this hereditary mutation in exon 17 of the CYLD gene. There have been several reports on patients with CYLD mutations and different types of malignancies. However, a coincidence with aggressive non-Hodgkin's lymphoma has not been reported yet.

Brooke-Spiegler syndrome presenting multiple concurrent cutaneous and parotid gland neoplasms: cytologic findings on fine-needle sample and description of a novel mutation of the CYLD gene.

Multiple dermal cylindromas and membranous basal cell adenoma of parotid gland in a 67-year-old woman with Brooke-Spiegler syndrome (BSS) were examined by fine-needle cytology. Histology, immunochemistry, and CYLD germline mutation testing were also performed. Cytomorphology and immunochemistry of the two lesions showed basaloid neoplasms, remarkably similar, composed by proliferating epithelial cells of basal type accompanied by a smaller proportion of myoepithelial cells. CYLD gene showed a novel germline splice acceptor site mutation (c.2042-1G>C) with skipping of the entire exon 15. The occurrence of analogous tumors, dermal cylindromas, and membranous basal cell adenoma of the parotid gland, in the same patient may result from the action of a single gene on ontogenetically similar stem cells. Therefore, patients with BSS should be offered a genetic counselling for an early and correct diagnosis.