暂无摘要。

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.
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.
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.
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, 30 × 2 Gy can result in long-term tumor control, while other dose prescriptions may be adequate for tumors in other locations.

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.

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.
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.
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.
Our study expands the types of mutations in CCS and will undoubtedly provide valuable information for genetic counseling for families affected by the condition.

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.

OBJECTIVE: 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.
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.

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.