Brooke-Spiegler syndrome: report of two cases not associated with a mutation in the CYLD and PTCH tumor-suppressor genes

Brooke-Spiegler syndrome represents an autosomal dominant disease characterized by the occurrence of multiple cylindromas, trichoepitheliomas and (sporadically) spiroadenomas. Patients with Brooke-Spiegler syndrome are also at risk of developing tumors of the major and minor salivary glands. Patients with Brooke-Spiegler syndrome have various mutations in the CYLD gene, a tumor-suppressor gene located on chromosome 16q. To date, 68 unique CYLD mutations have been identified. We describe two families with Brooke-Spiegler syndrome, one with familial cylindromatosis and one with multiple familial trichoepithelioma, which showed wide inter-family phenotypic variability. Analysis of germline mutations of the CYLD and PTCH genes was performed using peripheral blood. In addition, formalin-fixed paraffin-embedded tumor samples were analyzed for PTCH somatic mutations and cylindroma cell cultures were obtained directly from patients for further growth and analysis. Clinically, the major features of Brooke-Spiegler syndrome include the presence of heterogeneous skin tumors and wide inter- and intra-familial phenotypic variability. Histopathologically, both cylindromas and trichoepitheliomas were found in affected individuals. Mutations or loss of heterozygosity was not found in CYLD and PTCH genes. In CYLD and PTCH mutation-negative patients, other genes may be affected and further studies are needed to clarify whether these patients may be affected by de novo germline mutations.     

Multiple linear eccrine spiradenoma associated with multiple trichoepithelioma

A 37-year-old woman had multiple trichoepithelioma of the face which showed typical clinical and histological features, together with multiple papular lesions of 30 years' duration. The lesions were arranged in a linear fashion on her right breast and right upper arm. Microscopic examination of a biopsy specimen revealed typical eccrine spiradenomas. An ultrastructural study of the tumor on the breast revealed that it was composed of two main types of cells: one was a clear cell with low-density cytoplasm and the other was a dark cell with high-density cytoplasm. Some of the clear cells had secretory granule-like structures and/or tono-fibrils, while others had intracytoplasmic cavitations. Neither myoepithelial cells nor Langerhans cells were observed.     

Case of the Brooke-Spiegler syndrome

A 36-year-old woman presented with lesions on her scalp, face and trunk. Histopathological examination of these lesions demonstrated facial trichoepithelioma, and scalp cylindroma. A solitary nodule on the trunk had features of cylindroma, spiradenoma and trichoepithelioma, a previously unreported occurrence. Based on the clinical picture, the diagnosis of Brooke-Spiegler syndrome was established. Genetic studies confirmed the diagnosis, demonstrating a splice site mutation, designated 1518+2T>C, on the CYLD1 gene of chromosome 16q12-q13.     

Multiple hereditary trichoepithelioma and cylindroma (Brooke-Spiegler syndrome).

Three cases of trichoepithelioma associated with cylindroma (Brooke-Spiegler syndrome) in the same family are reported. Three generations were affected. The syndrome usually beginning at puberty is inherited as an irregular autosomal dominant trait.     

A nevoid plaque with histological changes of trichoepithelioma and cylindroma in Brooke-Spiegler syndrome

Brooke-Spiegler syndrome is characterized by the development of multiple trichoepitheliomas and cylindromas. In addition, multiple spiradenomas have been observed in this autosomal-dominant inherited disease. We report a 53-year-old woman with multiple cylindromas on the head and neck and multiple trichoepitheliomas on the face. Additionally, she had had since birth a plaque on the right side of her neck containing two nodules with features of both cylindroma and trichoepithelioma. Immunohistochemical investigations revealed in the basaloid cells of trichoepithelioma an expression of CK5/6, CK 14, CK 17, CK 19 and vim en tin. The cells of the cylindroma lacked vimentin but expressed additionally CK 7, CK 8 and CK 18. The occurrence of cylindroma and trichoepithelioma in a single nevoid plaque from a patient with Brooke-Spiegler syndrome implies an alteration in the stem cells of the folliculosebaceous-apocrine unit and could be characteristic of the disorder.     

New mutation in the CYLD gene within a family with Brooke‐Spiegler syndrome

Brooke‐Spiegler syndrome is a rare, autosomal dominant disease characterized by multiple skin appendage tumors caused by various mutations in the CYLD gene on chromosome 16q12‐q13. We describe a family, in which we performed a molecular‐genetic examination and found a new mutation in exon 19 in the CYLD gene leading to a frameshift. It is important to be aware of this syndrome and its pathogenesis as its phenotypic features can vary so that apparently different diseases are caused by the same genetic defect. In addition, there may be malignant transformation of the generally benign tumors, so that a timely diagnosis is essential for appropriate monitoring and therapy.     

Milialike idiopathic calcinosis cutis and syringoma in Down's syndrome

A 6-year-old girl with Down's syndrome presented milialike whitish small papules on her hands and feet and periorbital syringoma. Histopathological examination of the hand lesion revealed small localized calcium deposits and syringoma in the adjacent upper dermis. This is a very rare but typical case of calcinosis cutis with syringoma in a patient with Down's syndrome.     

Unilateral syringoma of the face associated with hyperthyroidism

Syringomas are benign tumors derived from the intraepidermal portion of eccrine sweat ducts. They usually occur on the periobital area, but have also been found on the scalp, forehead, cheeks, axillae, abdomen, extremities, genitalia, and buttocks. We describe a patient with an unusual presentation of unilateral syringoma of the face associated with hyperthyroidism.     

Diverse phenotype of Brooke-Spiegler syndrome associated with a nonsense mutation in the CYLD tumor suppressor gene

Abstract:  Brooke–Spiegler syndrome (BSS) is an autosomal dominant disease characterized by cylindromas, trichoepitheliomas and occasionally spiradenomas. The disease gene was mapped to 16q12-13, and mutations in the CYLD gene were identified in families with BSS. In the present report, we describe a large consanguineous Chinese family with BSS showing an intra-family phenotypic variability. Clinically, some affected individuals only revealed discrete small skin-coloured tumors whereas the proband showed an expansion of multiple large tumors on the back of nose and numerous dome-shaped papules on her scalp. Histologically, both trichoepitheliomas and cylindromas were found in the affected individuals. By sequence analysis, we identified a recurrent mutation 2272C>T (R758X) of the CYLD gene in the affected individuals of this family, which was previously identified in other ethnic families with familial cylindromatosis. Our result provided additional information for phenotype–genotype correlation in BSS.     

14例小汗腺螺旋腺瘤临床及病理特征分析

回顾性分析2015-2019年我院皮肤科确诊为小汗腺螺旋腺瘤的14例患者的临床及病理资料,并复习相关文献.结果示14例小汗腺螺旋腺瘤患者中,男5例,女9例,中位发病年龄为40.5岁.10例患者皮疹发生于躯干.皮损形态为皮色、红色、蓝色、浅褐色的皮下包块或结节,且多伴疼痛.14例患者临床首诊均误诊,误诊为表皮囊肿6例、色...     

Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-phenotype correlation

Brooke-Spiegler syndrome (BSS), familial cylindromatosis (FC), and multiple familial trichoepithelioma (MFT), originally described as distinct entities, share overlapping clinical findings. Patients with BSS are predisposed to multiple skin appendage tumors such as cylindroma, trichoepithelioma, and spiradenoma. FC, however, is characterized by cylindromas and MFT by trichoepitheliomas as the only tumor type. These disorders have recently been associated with mutations in the CYLD gene. In this report, we describe three families with BSS, one with FC, and two with MFT phenotypes associated with novel and recurrent mutations in CYLD. We provide evidence that these disorders represent phenotypic variation of a single entity and lack genotype-phenotype correlation.     

Familial syringoma: Report of two cases with a published work review and the unique association with steatocystoma multiplex

Syringoma is a benign neoplasm of eccrine origin. Clinically, it manifests as small skin-colored to yellowish soft papules usually localized around the eyes and on the upper cheeks of middle-aged women. Familial cases have rarely been reported and may be inherited as an autosomal dominant trait or result from either germ line or somatic mutations. Syringoma can coexist with various conditions, notably Down syndrome. Herein, we report a family with multiple syringomas affecting members of three following generations and describe in detail a 36-year-old woman and her 17-year-old son. In the latter, steatocystoma multiplex, which is regarded as a benign cystic neoplasm of the folliculosebaceous unit or a nevoid malformation differentiated in the direction of the sebaceous duct, was associated. Acral distribution of steatocystoma multiplex and its presentation as subcutaneous nodules in this patient were unique.     

Follicular stem cell marker PHLDA1 (TDAG51) is superior to cytokeratin-20 in differentiating between trichoepithelioma and basal cell carcinoma in small biopsy specimens

Background: Biopsies submitted to dermatopathologists are becoming increasingly smaller in size and thus the available diagnostic material is reduced. The distinction between trichoepithelioma and basal cell carcinoma remains challenging, particularly if tissue is limited. Merkel cells, which can be highlighted by means of cytokeratin‐20 (CK20) immunostaining, are used as a surrogate marker for the diagnosis of trichoepithelioma, as Merkel cells commonly colonize trichoepithelioma but are generally lacking in basal cell carcinomas. In the current study, we examined the expression of a recently characterized follicular stem cell marker, PHLDA1 (pleckstrin homology‐like domain, family A, member 1), also known as TDAG51 (T‐cell death‐associated gene 51). Methods: Using standard immunohistochemical techniques, we examined 19 trichoepitheliomas and 11 basal cell carcinomas for the expression of PHLDA1 and compared it with CK20 expression. Results: All 19 trichoepitheliomas were immunoreactive for PHLDA1 and all 11 basal cell carcinomas lacked PHLDA1 expression. Two of eleven basal cell carcinomas harbored CK20‐positive Merkel cells. Three trichoepitheliomas lacked secondary CK20‐positive cells. Conclusions: Our results suggest that PHLDA1 represents a practical and easily used tool that can be applied to the differentiation of trichoepithelioma and basal cell carcinoma in small biopsy specimens. Rather than searching for CK20‐positive Merkel cells, assessing PHLDA1 expression allows the differential diagnosis between trichoepithelioma and basal cell carcinoma to be solved at scanning magnification. Sellheyer K, Nelson P. Follicular stem cell marker PHLDA1 (TDAG51) is superior to cytokeratin‐20 in differentiating between trichoepithelioma and basal cell carcinoma in small biopsy specimens.