Brooke-Spiegler Syndrome Research Articles

Non-Familial and CYLD Gene Mutation Negative Brooke–Spiegler Syndrome Associated with Human Immunodeficiency Virus: A Case Report

Non-Familial and CYLD Gene Mutation Negative Brooke–Spiegler Syndrome Associated with Human Immunodeficiency Virus: A Case Report

Understanding Brooke-Spiegler syndrome and its dermatologic manifestations: A scoping review

Understanding Brooke-Spiegler syndrome and its dermatologic manifestations: A scoping review

Rare Skin Diseases: Turban Tumor (Brooke-Spiegler Syndrome)

The Brooke-Spiegler syndrome is a rare autosomal dominant disorder characterized by development of multiple skin tumours including multiple cylindromas and trichoepitheliomas. Here we describe a case of 68-year-old man admitted at a consultative appointment into the surgical department of Siberian State Medical University with numerous asymptomatic, skin-coloured, dense smooth papulonodular lesions from 2 to 5 mm diameter over the face and with multiple pinkish dense smooth dome-shaped nodules from 1 to 5 cm over the scalp. The patient has noted their appearance since childhood. Earlier, similar lesions have been observed in his father and grandmother. Histopathological examination classified facial lesions as trichoepitheliomas and defined scalp lesions as cylindromas, thereby confirming the diagnosis of Brooke-Spiegler syndrome.

A Misdiagnosed Familiar Brooke-Spiegler Syndrome: Case Report and Review of the Literature.

Aim of the report: Brooke-Spiegler syndrome (BSS) is a rare autosomal dominant disease characterized by the growth of cylindromas, spiradenomas, trichoepitheliomas, or their combination. These neoplasms usually begin in the second decade and progressively increase in number and size over the years. Diagnosis necessitates consideration of family history, clinical examination, histological findings, and genetic analysis. The aim of this paper is to explore the clinical overlap between Brooke-Spiegler syndrome (BSS) and neurofibromatosis type 1 (NF1). We aim to highlight the challenges associated with their differential diagnosis and emphasize the lack of standardized diagnostic criteria and treatment approaches. Case presentation: Hereby, we introduce the case of a 28-year-old male referred for suspicion of neurofibromatosis type 1 (NF1) who initially declined the recommended surgical excision for a scalp mass. After four years, he returned with larger masses of the scalp, and underwent excision of multiple masses, revealing cylindromas, spiradenomas, and spiradenocylindromas. Family history reported similar tumors in his father, who was also diagnosed with NF1 for the presence of multiple subcutaneous lesions on the scalp. Clinical overlap led to a genetic consultation, but testing for CYLD mutations yielded no significant variations. Despite this, the strong family history and consistent findings led to a revised diagnosis of Brooke-Spiegler syndrome, correcting the initial misdiagnosis of NF1 syndrome. Conclusions: Thanks to the evolving landscape of BSS research over the past two decades, its molecular underpinnings, clinical presentation, and histopathological features are now clearer. However, a thorough family history assessment is mandatory when BSS is suspected. It is our belief that a multidisciplinary approach and cooperation between specialists are essential when dealing with BSS. By sharing this case, we hope to underscore the importance of considering BSS as a differential diagnosis, especially in cases with atypical presentations or overlapping features with other syndromes like NF1.

Cylindroma Mimicking Neurofibroma


 Introduction
 
 
 Cylindroma is an appendageal tumour of the skin that is usually benign in nature, arising from pluripotent stem cells in the follicular-sebaceous-apocrine unit. Usually, multiple cylindromas are a component of Brooke-Spiegler syndrome (BSS) or occur only as skin lesions in familial cylindromatosis (FC). The site of the occurrence of tumours in this condition is the scalp.
 
 
 Case Report
 
 
 Here, we are reporting a case of multiple cylindromas in a 47-year-old female who presented with lesions on the face and scalp that were initially suspected to be neurofibroma as there were no features of Brooke-Spiegler syndrome or significant familial history pertaining to this presentation, but the histopathological diagnosis was suggestive of cylindroma.
 
 
 Discussion
 
 
 These are skin appedegeal tumours which commonly occur in the face and scalp. Their presentation resembles that of Neurofibromatosis and hence histopathological examination holds significance here. The main modality of treatment is excision of the lesions with management of the vascularity around the lesions, if present. 

Dermal cylindroma – An update and a series of uncommon clinical presentations

Objectives: Dermal cylindroma is an uncommon adnexal tumor. Although frequently occurring in the head-and-neck region as a firm nodule with smooth surface, the tumor may rarely occur on other body sites and present atypically. Material and Methods: Patients files from the department during the years 2003–2022 have been analyzed. Clinical data, histopathology, and treatment were collected with a focus on atypical presentations. A short literature review has been performed using PUBMED. Results: We identified six adult Caucasian patients with Fitzpatrick skin type II–III aged between 42 and 74 years, two females and four males. We observed cylindroma of the auricle and the lower leg. One tumor presented as a flat plaque and another one was pedunculated with a mushroom-like shape. Two patients had syndromic cylindroma. One patient presented only with multiple cylindromas of the scalp but no other associated adnexal tumors of Brooke-Spiegler syndrome, while the second one developed multiple malignant tumors of skin and parotid glands. Conclusion: Dermal cylindroma rarely occurs outside the scalp. The clinical presentation is variable. Syndromic cases may present either oligosymptomatic or with multiple associated malignant tumors.

Brooke-Spiegler syndrome: radiotherapy as the last resort?

To describe the case of successful radiotherapeutic treatment of awoman 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 afollow-up period of 14and 11years, 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 amatter 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.

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.

Chronicles of A.I. Pospelov Moscow Society of Dermatovenereologists and Cosmetologists (MSDC was founded on October 4, 1891). Bulletin of the MSDC № 1149

On October 18, 2022, the 1149th meeting of the A.I. Pospelov Moscow Society of Dermatovenerologists and Cosmetologists (MSDC) took place. The meeting was held in a face-to-face format. There were 128 participants in total. Accepted as a member of the MSDC 53 people.
 Two clinical cases are presented for discussion: trichoadenoma ― a rare benign follicular tumor consisting of strands of epithelial cells and keratinizing cysts embedded in the sclerotic stroma, and Dariers follicular dyskeratosis ― hereditary dermatosis characterized by the formation of follicular hyperkeratotic vegetative papules on seborrheic areas of the skin caused by a violation of the keratinization process by the type of dyskeratosis.
 Scientific reports were devoted to the analysis of differential diagnosis and therapeutic tactics in BrookeSpiegler syndrome (multiple cylindromes and trichoepitheliomas), the mechanisms of action and effectiveness of zinc pyrithione as a means of controlling colonization of the hairy skin by fungi-commensals of the genus Malassezia, as well as the most urgent problems of modern medicine ― the features of the course of chronic-severe dermatoses after SARS-CoV-2 infection (COVID-19) and an increase in the incidence of mucormycosis, which is a marker of immune breakdown that occurs immediately after COVID-19 infections.

Dermoscopy of Cylindroma in Fitzpatrick Type IV Skin: A Case Report and Review of Literature.

Dermoscopy of Cylindroma in Fitzpatrick Type IV Skin: A Case Report and Review of Literature.

Facial Trichoepitheliomas Revealing the Rare Brooke-Spiegler Syndrome.

Facial Trichoepitheliomas Revealing the Rare Brooke-Spiegler Syndrome.

ECCRINE SPIRADENOMA : CASE REPORT WITH AN UNUSUAL CLININAL PRESENTATION

Eccrine spiradenoma is one of the rare, benign dermal neoplasm showing eccrine sweat gland differentiation. The literature search accounts for less than 100 reported cases of eccrine spiradenoma. Clinically, the lesion presents as solitary, intradermal, circumscribed, round or oval, firm, painful or tender nodule measuring from 0.3 - 5 cm in diameter. Rarely if ES, presents as multiple lesions, in combination with other types of adnexal tumors such as cylindromas & trichoepitheliomas, it can be considered as a part of the Brooke-Spiegler syndrome. Majority of these tumours appear on the head/face & upper trunk region of the body. Spiradenomas arise in early adulthood in most instances with few reports also of congenital cases and no sex predilection seen. The definitive diagnosis is made by excisional biopsy of the tumour. Complete tumor excision with clear surgical margins is considered the primary treatment for these cases. Here, we present a rare case report of a 58 years old male presenting with a soft, cystic lesion in the left lumbar region of the abdomen for past 2 years duration. Surgical excision of the tumour was done with clear margins and the specimen was sent for histopathological examination. Due to the overlapping histomorphological features, this tumour is often confused with cylindromas and trichoepitheliomas along with other vascular tumours. Eccrine Spiradenoma, although a benign tumour, but malignant transformation has been described especially in long-standing cases or multiple lesions. So, early diagnosis is very important to prevent recurrence and to identify any onset of malignant transformation.

Genotípus-fenotípus összefüggések feltárása, funkcionális vizsgálatok és terápiás fejlesztések monogénes bőrbetegségekben

Genetic and genomic research over the past 10 years resulted in huge advances in the understanding of monogenic skin diseases: 35 new diseases have been described and 131 new pathogenic genes have been identified with our contribution: with the first description of cutaneous teleangiectasia and familial oropharyngeal cancer syndrome and the identification of the USB1 gene. We demonstrated that familial cylindromatosis, multiple familial trichoepitheliomatosis, and Brooke-Spiegler syndrome are not different entities but the clinical variants of the same disease, the CYLD cutaneous syndrome. Regarding therapeutic developments, we contributed to the development of future drug therapies replacing the original cell therapy of intradermal allogeneic fibroblast injections.

Metastatic Spiradenocarcinoma Managed With PD-1 Inhibition.

Spiradenomas are rare skin adnexal tumors, usually benign, appearing in early adulthood. The etiology of this tumor is still debated. The tumor suppressor gene CYLD, responsible for the Brooke-Spiegler syndrome, causes spiradenomas, trichoepitheliomas, and cylindromas. With time, spiradenomas can degenerate into aggressive spiradenocarcinomas. With only 117 malignant cases reported, treatment recommendations are based on case reports and expert opinion. There is no standard of care beyond surgical resection for localized disease and no guidelines for management of metastatic disease. With the advent of immunotherapy and PD-1 inhibition, we present the first reported case of a metastatic spiradenocarcinoma managed with pembrolizumab.

Malignant eccrine spiradenocylindroma and parotid gland involvement in Brooke Spiegler syndrome.

Brooke-Spiegler syndrome is a rare disorder, characterized by the development of skin adnexal tumors, including cylindromas, trichoepitheliomas, spiradenomas. Although these neoplasms are benign in most patients, a malignant transformation can rarely occur. Furthermore, an occasional association between cutaneous adnexal tumors and basal cell adenoma as well as adenocarcinoma of the parotid gland has been rarely described, with approximately 20 cases reported. We report a case of BSS presenting with a malignant eccrine spiradenocylindroma, in a patient with previous history of parotid basal cell tumor.

Giant Vascular Cylindroma in a Case of Brooke-Spiegler Syndrome.

Giant Vascular Cylindroma in a Case of Brooke-Spiegler Syndrome.

176 Identification of putative phenotype-modifying genetic factors associated with phenotypic diversity in Brooke-Spiegler syndrome

Brooke-Spiegler syndrome (BSS; OMIM 605041) is a rare monogenic skin disease characterized by the development of skin appendage tumors caused by mutations in the cylindromatosis (CYLD) gene. Despite the described phenotypes and reports of the underlying CYLD mutations, it has been difficult to establish genotype–phenotype correlations in BSS. We recently investigated two BSS pedigrees (Hungarian with Bukovinian origin and Anglo-Saxon), in which the affected family members exhibit striking differences in their phenotypes — despite carrying the same disease-causing mutation (c.2806C>T, p.Arg936Ter) of the CYLD gene.

173 TRAF3 and NBR1 both influence the effect of 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.

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.

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.