View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Repositório Institucional dos Hospitais da Universidade de Coimbra 67 DOI: http://dx.doi.org/10.3315/jdcr.2015.1208 Brooke-Spiegler Syndrome – an underrecognized cause of multiple familial scalp tumors: report of a new germline mutation André Castro Pinho, Miguel José Pinto Gouveia, Ana Rita Portelinha Gameiro, José Carlos Pereira Silva Cardoso, Maria Margaria Martins Gonçalo Dermatology Department of Centro Hospitalar e Universitário de Coimbra, Portugal. Corresponding author: Abstract André Castro Pinho, MD Background: Brooke-Spiegler syndrome (BSS) is probably an underdiagnosed ge- Dermatology Department nodermatosis that predisposes for the development of cylindromas, spiradeno- mas and trichoepitheliomas mainly of the head and neck. Wide phenotypic varia- Hospitais da Universidade de Coimbra bility regarding the number and type of lesions can be observed within a family. Centro Hospitalar e Universitário Mutations of the CYLD gene are identified in the vast majority of cases and play de Coimbra a key role in BSS pathogenesis. Praceta Mota Pinto, 3000-075 Coimbra, Main observations: Two first degree relatives with numerous erythematous te- Portugal langiectatic nodules of the scalp present for decades, with recurring tendency re- gardless the multiple previous excisions. Histopathological review of the lesions E-mail: [email protected] revealed predominantly "spiradenocylindromas" in the proband and cylindromas in her sister. The suspicion of BSS was confirmed after detection of a new non- sense germline mutation of CYLD (c.1783C>T pGln 595*) in the proband. Conclusions: BSS diagnosis can be challenging and is based on clinical-patholo- gical correlation, positive familial association and identification of CYLD mutations. CYLD exerts antineoplastic effects by downregulating intracellular NF-κB signal- ling pathways. The reported mutation affecting the ubiquitin-specific protease do- Key words: main leads to a truncated and catalytically inactive enzyme. Despite the expanding list of CYLD mutations no firm genotype-phenotype correlation is known so far. CYLD protein, cylindroma, dermosco- Early recognition and treatment of BSS avoid disfiguring changes like "turban tu- py, gene, mutation, spiradenoma mor". (J Dermatol Case Rep. 2015; 9(3): 67-70) Introduction (CYLD) tumor-suppressor gene. Different manifestations of each can be present to a variable degree within a single family.1-3 Brooke-Spiegler syndrome (BSS; OMIM 605041) is a rare Apart from skin adnexal tumors, an increased incidence hereditary disorder characterized by predisposition for mul- of salivary gland, parathyroid and ovarian neoplasms has tiple skin adnexal tumors derived from the folliculo-seba- been found in patients with BSS, as well as inflammatory ceous-apocrine unit, specifically cylindromas, spiradeno- disorders such as ulcerative colitis. This probably reflects mas and trichoepitheliomas.1,2 the physiological importance and ubiquity of CYLD protein These tumors that are uncommon in the general popula- expression.1,5,6 tion, begin during adolescence, typically involving the scalp, Despite the growing number of mutations reported over face and neck, and gradually increase in number and size the last decade, there is no defined genotype-phenotype throughout life.3,4 correlation in BSS.1,3,7 The two ends within the phenotypic spectrum of BSS are We describe two members of a family affected by multiple familial cylindromatosis (FC; OMIM 132700) and multiple nodular scalp lesions, present for decades and with clinical familial trichoepithelioma (MFT; MIM 601606), allelic disor- and histological features consistent with BSS and confirmed ders that share germline mutations of the cylindromatosis after identification of a new germline mutation of CYLD gene. J Dermatol Case Rep 2015 3, pp 67-70 Brooke-Spiegler Sydrome – an underrecognized cause of multiple familial scalp tumors, Pinho et al. 68 Figure 1 Scalp lesions. Confluent erythema- tous telangiectatic nodules and pa- pules on the scalp of the proband, consistent with spiradenocylindro- mas and cylindromas. Case reports Proband: An 80-year-old Portuguese Caucasian woman presented with multiple slowly growing papules and nodu- les of the scalp, some episodically painful, which started du- ring adolescence. Thirteen lesions were excised in a general surgery department, due to pain and aesthetic discomfort, but a dermatology evaluation was requested due to the emer- gence of new scalp lesions. Clinical examination showed multiple aggregated erythematous telangiectatic papules and nodules on the scalp, sometimes lobulated, with elastic con- sistency ranging in size from 1x1 to 2x3 cm (Fig. 1). Most le- sions shared dermoscopic features of cylindromas with ar- borizing telangiectasia and scattered white globules on a mil- ky to salmon-pink background (Fig. 2). Excisional biopsy of three nodules revealed, in all of them, a predominant spira- denoma pattern, with multiple inter-anastomosing trabecu- Figure 3 lae composed of a biphasic cell population (small cells with Spiradenoma pattern. Multiple inter-anastomosing trabeculae hyperchromatic nuclei at the periphery and clear larger cells composed of small cells with hyperchromatic nuclei at the peri- phery and clear larger cells at the centre. Sparse lymphocytic infiltrate. Figure 2 Figure 4 Dermatoscopic features of cylindroma within a scalp nodule. Ar- Cylindroma pattern. Nests of basaloid cells in a "jigsaw" puzzle borizing telangiectasia more pronounced at the periphery, scat- pattern surrounded by a thick hyaline membrane. Tendency for tered white globules at the centre and a salmon-pink background. palisading of epithelial darker cells at the periphery. J Dermatol Case Rep 2015 3, pp 67-70 69 Brooke-Spiegler Sydrome – an underrecognized cause of multiple familial scalp tumors, Pinho et al. at the centre) surrounded by a highly vascularized hyaline tion in exon 11 (aa 595), at the beginning of ubiquitin-spe- stroma and with a sparse lymphocytic infiltrate (Fig. 3). Areas cific protease (USP) domain (aa 583-956) leads to the pro- of cylindroma were also seen, with nests of basaloid cells in duction of a truncated and catalytically inactive enzyme. The close apposition in a jigsaw puzzle-like pattern surrounded subsequent loss of heterozygosity of wild-type allele at CYLD by a thick hyaline membrane (Fig. 4). Histopathological re- locus, or the (more frequent) occurrence of other somatic view of previously excised lesions confirmed the presence mutations of CYLD may be responsible for the development of mainly "spiradenocylindromas", and less often cylindro- of the lesions described.1,7 mas and spiradenomas, raising the suspicion of BSS. As in our cases, the lesions more frequently found in BSS Case 2: The 77-year-old sister of the proband also presen- cases are cylindromas and spiradenomas. These closely-re- ted similar scalp lesions for decades: aggregated erythema- lated tumors share the same anatomical distribution, have tous nodules with 2 to 3 cm in diameter, with smooth telan- controversial histogenesis and can occur close together in giectatic surface. Lesions began in the second decade of life the same patient. They are usually poorly differentiated, and and five of them had already been removed in another hospital show overlapping cytomorphological and immunohistoche- for esthetical reasons, with no histological evaluation known. mical features of apocrine and eccrine lineage.8,9 Two further symptomatic nodules that were excised corre- Nevertheless, Sellheyer recently proposed that spiradeno- sponded to typical cylindromas histologically. mas and cylindromas are not sudoriparous but poorly diffe- Within the family, four of ten uncles had a history of mul- rentiated follicular tumors derived from the hair follicle bul- tiple scalp lesions. Patients’ offspring were, so far, not affec- ge. He based his proposal on the increased expression of ted by similar lesions. CD200 in both types of lesions whereas, in his extensive stu- In the presence of multiple adnexal scalp tumors with hi- dy, he had shown that tumors classified as eccrine in line- stological features of cylindroma and spiradenoma in two age (hidradenoma, poroma, dermal duct tumor, and hidro- first-degree relatives we considered the diagnosis of BSS. acanthoma simplex) were CD200 negative.9 The proband was assessed for CYLD gene germline muta- Cylindromas are benign basaloid painless tumors distri- tion in peripheral blood sample. A heterozygous nonsense buted preferentially over the areas that are rich in hair follic- mutation was detected in exon 11 of CYLD gene, responsi- les and sebaceous glands, typically begin during puberty al- ble for the introduction of a premature stop codon at posi- though sometimes earlier, grow slowly and affect mainly wo- tion 595 amino acid (c.1783C>T pGln 595*). men, with a ratio 6-9:1.1,3,8,10 Clinically they consist of no- Patients referred no other complaints and clinical and ul- dular erythematous lesions with overlying telangiectasia and trasound evaluation of salivary glands as well as abdominal variable size distributed over the scalp, face and neck, whe- ultrasound were normal. reas the trunk, extremities and the pubic region are less af- fected.3,10 Multiple cylindromas may coalesce in the scalp and form the so-called turban tumor.1,7,10 Malignant trans- Discussion formation of cylindromas may occur with an aggressive be- haviour in the context