Monteiro, AF

Osório, T

Rato, M

Saraiva Gil, F

Tavares, E

English

Repositório Comum

CorrespondenceAn extremely rare association of multiple familialtrichoepitheliomas and hereditary multipleosteochondromasMultiple familial trichoepitheliomas (MFT) and hereditary multi-ple osteochondromas (HMO) are both rare and autosomal dom-inant disorders. Herein, we describe the first case with the twogenetic syndromes together.A 35-year-old Caucasian woman, with personal history of mul-tiple excisions of painful osteochondromas in childhood, wasobserved due to a facial dermatosis that appeared 15 yearsago. She indicated that her mother and maternal grandmotherhad multiple osteochondromas, while her paternal grandmotherused to have similar facial lesions. General physical examinationshowed multiple palpable bone masses in the knees, arms, andforearms; short stature; ulnar shortening of the forearm; andulnar deviation of the wrist (Bessel–Hagen deformity). Dermato-logic physical examination revealed multiple, rounded, grouped,firm, and skin-colored papules scattered through the nasolabialsulcus, nose, and frontal region (Fig. 1a). No extrafacial lesionswere observed. Histopathologic examination of two facial lesionsdemonstrated multiple nodular proliferations of uniform basaloidcells with focal peripheral palisading, numerous central keratin-filled cysts, and clefts between stromal elements or betweenstroma and adjacent dermis (Fig. 1b). X-ray images of the shoul-ders, elbows, wrists, and knees were consistent with multipleosteochondromas (Fig. 2). The genetic test found a heterozy-gous mutation in the exon 9 of cylindromatosis gene (CYLD)[c.1112C>A(p.Ser371*)], allowing the clinical diagnosis of MFTand a new heterozygous frameshift mutation never describedbefore in the exostosin-1 gene (EXT1), leading to a change inleucine to cysteine at position 667 [c.2000del (p.Leu667Cys-fs*6)], supporting the clinical diagnosis of HMO. Since childhoodshe periodically visits the orthopedic department and has beensubmitted to multiple surgical excisions of symptomatic osteo-chondromas. Surgical excision and CO2 LASER has been per-formed in a few cutaneous lesions. The patient and theremaining family were referred to the genetic department.Multiple familial trichoepithelioma (OMIM 601606) is charac-terized by multiple skin-colored small papules and nodules usu-ally confined to the nasolabial folds, nose, forehead, and upperlip, with frequent confluence of the lesions.1 Zhang et al.2 identi-fied for the first time mutations in the CYLD gene on chromo-some 16q12-q13, responsible for MFT. The CYLD gene acts asa tumor suppressor and is critical for various signalling path-ways.3 Inactivation of this gene may contribute to oncogenesisby enhancing the degradation of proteins that suppress cell pro-liferation or promote apoptosis.3,4 Simultaneously, it is involvedin the feedback inhibition of RANK signalling pathway in thebone cells.5 Loss of CYLD results in a hyperproduction ofosteoclasts, which is associated with severe bone loss or osteo-porosis.5 The association with bone tumors is not clear.5On the other hand, hereditary multiple osteochondromas(OMIM 133700) are characterized by multiple benign cartilage-capped tumors that grow outward from the metaphyses of longbones.6 Osteochondromas usually continue to grow until pub-erty, and clinical manifestations include short stature, bonedeformities, skeletal abnormalities, compression of adjacent tis-sues, and impaired articular function.7 The two genes responsi-ble for HMO, EXT1, and EXT2, are also tumor suppressorslocated at 8q24.11 and 11p11.2, respectively.6 They encodeglycosyltransferases required for heparin sulphate (HS) biosyn-thesis. Heterozygous loss-of-function mutations lead to dis-turbed interactions and systemic HS deficiency.8 HS is involvedin the regulation signalling of endochondral ossification and,thereby, relevant to the normal skeletal development.9 Addition-ally, HS also plays a vital role in hair follicle morphogenesis.(a) (b)Figure 1 (a) Multiple skin-colored papules and nodules on the face; (b) histological examination of a facial lesion showedmultiple nodular proliferations of uniform basaloid cells with focal peripheral palisading and small keratin-filled cystscompatible with trichoepithelioma (H&E, 940)ª 2018 The International Society of Dermatology International Journal of Dermatology 20181The mutation in EXT gene can lead to a dysregulated hair folli-cle morphogenesis and consequently to the development ofbenign adnexal neoplasm as trichoepitheliomas.10Here we reported for the first time a coexistence of multipletrichoepitheliomas and multiple osteochondromas in a carrier oftwo germline mutations in CYLD and EXT1 genes. The geneticanalysis allowed us to diagnose MFT and HMO, two well-knownhereditary syndromes never described before together in a sin-gle patient and with a new heterozygous frameshift mutation inthe EXT1 gene.Ana F. Monteiro1*, MDFrancisco Saraiva Gil1, MDMargarida Rato1, MDTomas Osorio2, MDErmelindo Tavares3, MD1Dermatovenereology Department, Hospital de SantaremEPE, Santarem, Portugal2Department of Orthopedic Surgery, Unidade Local de Saudedo Baixo Alentejo, EPE – Hospital Jose Joaquim Fernandes,Beja, Portugal3Dermatovenereology Department, Hospital de Vila Francade Xira, Vila Franca de Xira, Portugal*E-mail: anafilipemonteiro@gmail.comFunding: None.Conflicts of interest: None.doi: 10.1111/ijd.14251References1 Kazakov DV. Brooke-Spiegler syndrome and phenotypicvariants: an update. Head Neck Pathol 2016; 10: 125–130.2 Zhang X-J, Liang Y-H, He P-P, et al. Identification of thecylindromatosis tumor-suppressor gene responsible for multiplefamilial trichoepithelioma. J Invest Dermatol 2004; 122: 658–664.3 Ying Z-X, Ma H-Q, Liu Y, et al. A novel mutation of CYLD in aChinese family with multiple familial trichoepithelioma. J EurAcad Dermatol Venereol 2012; 26: 1420–1423.4 Brummelkamp TR, Nijman SMB, Dirac AMG, et al. Loss of thecylindromatosis tumour suppressor inhibits apoptosis byactivating NF-jB. Nature 2003; 424: 797–801.5 Sun S-C. CYLD: a tumor suppressor deubiquitinase regulatingNF-kappaB activation and diverse biological processes. CellDeath Differ 2010; 17: 25–34.6 Li Y, Wang J, Wang Z, et al. A genotype-phenotype study ofhereditary multiple exostoses in forty-six Chinese patients. BMCMed Genet 2017; 18: 126.7 Guo X, Deng Y, Liu H. Clinical characteristics of hereditarymultiple exostoses: a retrospective study of mainland chinesecases in recent 23 years. J Huazhong Univ Sci Technolog MedSci 2014; 34: 42–50.8 Pacifici M. The pathogenic roles of heparan sulfate deficiency inhereditary multiple exostoses. Matrix Biol 2017; in press. https://doi.org/10.1016/j.matbio.2017.12.0119 Matsumoto Y, Matsumoto K, Irie F, et al. Conditional ablation ofthe heparan sulfate-synthesizing enzyme Ext1 leads todysregulation of bone morphogenic protein signaling and severeskeletal defects. J Biol Chem 2010; 285: 19227–19234.10 Coulson-Thomas VJ, Gesteira TF, Esko J, et al. Heparansulfate regulates hair follicle and sebaceous glandmorphogenesis and homeostasis. J Biol Chem 2014; 289:25211–25226.(a) (b) (c)(d)Figure 2 (a) Ulnar shortening of the forearm and ulnar deviation of the wrist (Bessel–Hagen deformity); (b) Shoulders,elbows, and wrists x-ray images showed multiple osteochondromasInternational Journal of Dermatology 2018 ª 2018 The International Society of DermatologyCorrespondence2

An extremely rare association of multiple familial trichoepitheliomas and hereditary multiple osteochondromas

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An extremely rare association of multiple familial trichoepitheliomas and hereditary multiple osteochondromas

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