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1.
J Cutan Pathol ; 48(12): 1508-1513, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34296453

ABSTRACT

NUT carcinomas are genetically defined epithelial neoplasms. Most tumors harbor fusions of NUTM1 with BRD4 or BRD3. Their histopathologic features have been predominantly reported as undifferentiated or poorly differentiated squamous cell carcinoma, and clinically they tend to be aggressive cancers. However, recent studies have revealed a broader spectrum of NUTM1-rearranged neoplasms with several new fusion partners and associated variable histopathologic phenotypes and clinical behaviors, including benign and malignant cutaneous poroid tumors. We report herein a primary invasive carcinoma of skin adnexal origin with a previously undescribed fusion between BRD3 and NUTM2B. The tumor occurred on the shoulder of a 7-year-old girl and was excised with negative margins. A sentinel lymph node was positive. After follow-up of 23 months, and without systemic treatment, the child remains free of tumor. This case expands the spectrum of NUT carcinomas by including a skin adnexal variant with follicular infundibular differentiation, a novel genomic aberration, and preliminary evidence of a less aggressive clinical course.


Subject(s)
Carcinoma, Skin Appendage/genetics , Carcinoma, Skin Appendage/pathology , Neoplasm Proteins/genetics , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Transcription Factors/genetics , Child , Female , Humans , Oncogene Proteins, Fusion/genetics
2.
Surg Pathol Clin ; 14(2): 251-272, 2021 Jun.
Article in English | MEDLINE | ID: mdl-34023104

ABSTRACT

Cutaneous adnexal tumors recapitulate follicular, sweat gland, and/or sebaceous epithelia, and range from benign tumors to aggressive carcinomas. Adnexal tumors can be hallmarks for inherited tumor syndromes. Oncogenic drivers of adnexal neoplasms modulate intracellular pathways including mitogen-activated protein kinase, phosphoinositide-3-kinase, Wnt/ß-catenin, Hedgehog, nuclear factor κB, and Hippo intracellular signaling pathways, representing potential therapeutic targets. Malignant progression can be associated with tumor suppressor loss, especially TP53. Molecular alterations drive expression of specific diagnostic markers, such as CDX2 and LEF1 in pilomatricomas/pilomatrical carcinomas, and NUT in poromas/porocarcinomas. In these ways, improved understanding of molecular alterations promises to advance diagnostic, prognostic, and therapeutic possibilities for adnexal tumors.


Subject(s)
Carcinoma, Skin Appendage , Neoplasms, Adnexal and Skin Appendage , Skin Neoplasms , Carcinoma, Skin Appendage/genetics , Humans , Molecular Biology , Neoplasms, Adnexal and Skin Appendage/genetics , Skin Neoplasms/genetics
3.
Eur J Dermatol ; 22(3): 299-309, 2012.
Article in English | MEDLINE | ID: mdl-22391625

ABSTRACT

Basal cell carcinoma (BCC) is the commonest cancer in humans. Predisposing factors reflect common genetic variations and environmental influences in most cases. However, an underlying Mendelian disorder should be suspected in a specific subset of patients, namely those with multiple, early onset lesions. Some specific conditions, including Gorlin, Bazex-Dupré-Christol and Rombo syndromes, and Xeroderma Pigmentosum, show BCC as a prominent feature. In addition, BCC may represent a relatively common, although less specific, finding in many other genodermatoses. These include disorders of DNA replication/repair functions (Bloom, Werner, Rothmund-Thomson and Muir-Torre syndromes), genodermatoses affecting the folliculo-sebaceus unit (Brooke-Spiegler, Schöpf-Schulz-Passarge and Cowden syndromes), immune response (cartilage-hair hypoplasia and epidermodysplasia verruciformis) and melanin biosynthesis (oculocutaneous albinism and Hermansky-Pudlak syndrome), and some epidermal nevus syndromes. Further conditions occasionally associated with BCCs exist, but the significance of the association remains to be proven.


Subject(s)
Carcinoma, Basal Cell/genetics , Skin Diseases, Genetic/genetics , Skin Neoplasms/genetics , Basal Cell Nevus Syndrome/epidemiology , Basal Cell Nevus Syndrome/genetics , Carcinoma, Basal Cell/epidemiology , Carcinoma, Skin Appendage/epidemiology , Carcinoma, Skin Appendage/genetics , Comorbidity , Cyanosis/epidemiology , Cyanosis/genetics , DNA Replication , Facial Dermatoses/epidemiology , Facial Dermatoses/genetics , Genetic Testing , Hamartoma Syndrome, Multiple/epidemiology , Hamartoma Syndrome, Multiple/genetics , Histiocytoma, Benign Fibrous/epidemiology , Histiocytoma, Benign Fibrous/genetics , Humans , Hypotrichosis/epidemiology , Hypotrichosis/genetics , Mutation , Nevus, Sebaceous of Jadassohn/epidemiology , Nevus, Sebaceous of Jadassohn/genetics , Rothmund-Thomson Syndrome/epidemiology , Rothmund-Thomson Syndrome/genetics , Skin Diseases, Genetic/epidemiology , Skin Neoplasms/epidemiology , Werner Syndrome/epidemiology , Werner Syndrome/genetics , Xeroderma Pigmentosum/epidemiology , Xeroderma Pigmentosum/genetics
5.
Am J Dermatopathol ; 33(3): 251-65, 2011 May.
Article in English | MEDLINE | ID: mdl-21389835

ABSTRACT

Multiple familial trichoepitheliomas (MFT) constitute an autosomally inherited syndrome possibly related to Brooke-Spiegler syndrome (BSS). Although some early studies suggested a role for the PTCH gene on chromosome 9q22.3 in the etiopathogenesis of MFT, recent studies of occasional patients with the MFT clinical phenotype identified mutations in the CYLD gene on chromosome 16q12-q13, a gene responsible for BSS. A systematic investigation of PTCH and CYLD mutations in patients with MFT has never been performed. Our main objective was to collect a reasonably large series of patients with MFT to (1) study the clinicopathological spectrum of the disease, (2) determine whether the PTCH gene is implicated in the pathogenesis of MFT, and if so (3) determine the relative frequency of CYLD and PTCH mutations, (4) establish if there may be any possible genotype-phenotype correlations, and (5) study the spectrum of somatic mutations. Clinical analysis including family histories, histopathological investigations, and molecular genetic studies were performed. There were 9 female and 7 male patients ranging in age from 11 to 63 years. They presented with multiple, small, discrete and sometimes confluent, skin-colored to pink, asymptomatic nodules preferentially located on the face, being especially prominent and confluent in the nasolabial folds and inner aspects of the eyebrows. A total of 66 conventional trichoepitheliomas (TEs) were studied microscopically. Aside from typical features of TE, some also exhibited variant morphological patterns including areas reminiscent of other benign adnexal neoplasms and melanocytic hyperplasia. In none of the 9 patients tested was a germline mutation of the PTCH gene identified. Germline CYLD mutations were detected in 6 of 13 patients tested (identical in 2 unrelated patients) including 2 novel mutations, whereas the remaining 7 individuals showed wild-type alleles. Two patients with germline wild-type CYLD showed, however, a somatic mutation in the gene (1 duplication, 1 substitution mutation). Neither CYLD nor PTCH germline mutations were found in the 5 patients in whom both genes were analyzed. MFT seems to be a phenotypic variant of BSS. The PTCH gene is rarely, if ever, involved in the pathogenesis of MFT. Absence of a germline mutation of the CYLD gene in cases harboring a somatic mutation may be explained by large deletions in the gene or by mutation in intronic sequences or in the promoter region. Considering our 5 patients with no mutation in either gene, the final possibility is that another, as yet undescribed gene (neither CYLD nor PTCH) is implicated in the pathogenesis of some patients with MFT.


Subject(s)
Carcinoma, Skin Appendage/genetics , Receptors, Cell Surface/genetics , Skin Neoplasms/genetics , Tumor Suppressor Proteins/genetics , Adolescent , Adult , Carcinoma, Skin Appendage/pathology , Child , DNA Mutational Analysis , Deubiquitinating Enzyme CYLD , Female , Gene Expression , Gene Expression Profiling , Humans , Male , Middle Aged , Mutation , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/pathology , Patched Receptors , Patched-1 Receptor , Polymerase Chain Reaction , Skin Neoplasms/pathology , Young Adult
6.
Fam Cancer ; 10(1): 127-32, 2011 Mar.
Article in English | MEDLINE | ID: mdl-20972631

ABSTRACT

Pathogenic mutations in CYLD can be identified in patients affected with Brooke-Spiegler syndrome, (Familial) Cylindromatosis or multiple familial trichoepithelioma. To date, only technologies which are able to identify small point mutations in CYLD, such as sequence and WAVE analysis, were used. Here we describe the identification of a larger rearrangement identified by Quantitative PCR analysis of CYLD, indicating that a combination of these technologies is necessary when searching for pathogenic mutations in CYLD.


Subject(s)
Gene Rearrangement , Mutation/genetics , Tumor Suppressor Proteins/genetics , Carcinoma, Adenoid Cystic/genetics , Carcinoma, Adenoid Cystic/pathology , Carcinoma, Skin Appendage/genetics , Carcinoma, Skin Appendage/pathology , Deubiquitinating Enzyme CYLD , Female , Humans , Male , Middle Aged , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/pathology , Prognosis , Skin Neoplasms , Syndrome
8.
Mol Cell ; 37(5): 607-19, 2010 Mar 12.
Article in English | MEDLINE | ID: mdl-20227366

ABSTRACT

The mechanism by which Wnt receptors transduce signals to activate downstream beta-catenin-mediated target gene transcription remains incompletely understood but involves Frizzled (Fz) receptor-mediated plasma membrane recruitment and activation of the cytoplasmic effector Dishevelled (Dvl). Here, we identify the deubiquitinating enzyme CYLD, the familial cylindromatosis tumor suppressor gene, as a negative regulator of proximal events in Wnt/beta-catenin signaling. Depletion of CYLD from cultured cells markedly enhances Wnt-induced accumulation of beta-catenin and target gene activation. Moreover, we demonstrate hyperactive Wnt signaling in human cylindroma skin tumors that arise from mutations in CYLD. At the molecular level, CYLD interacts with and regulates K63-linked ubiquitination of Dvl. Enhanced ubiquitination of the polymerization-prone DIX domain in CYLD-deficient cells positively links to the signaling activity of Dvl. Together, our results argue that loss of CYLD instigates tumor growth in human cylindromatosis through a mechanism in which hyperubiquitination of polymerized Dvl drives enhancement of Wnt responses.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Carcinoma, Adenoid Cystic/metabolism , Carcinoma, Skin Appendage/metabolism , Phosphoproteins/metabolism , Protein Processing, Post-Translational , Signal Transduction , Skin Neoplasms/metabolism , Tumor Suppressor Proteins/metabolism , Wnt Proteins/metabolism , beta Catenin/metabolism , Adaptor Proteins, Signal Transducing/genetics , Animals , Carcinoma, Adenoid Cystic/genetics , Carcinoma, Adenoid Cystic/pathology , Carcinoma, Skin Appendage/genetics , Carcinoma, Skin Appendage/pathology , Cell Proliferation , Deubiquitinating Enzyme CYLD , Dishevelled Proteins , HeLa Cells , Humans , Lysine , Mice , Mutation , NF-kappa B/metabolism , Phosphoproteins/genetics , Protein Multimerization , Protein Structure, Tertiary , RNA Interference , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Time Factors , Transcriptional Activation , Transfection , Tumor Necrosis Factor-alpha/metabolism , Tumor Suppressor Proteins/genetics , Ubiquitination , Wnt Proteins/genetics , Wnt3 Protein , beta Catenin/genetics
9.
J Cutan Pathol ; 37(8): 886-90, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20132422

ABSTRACT

The authors report a case of Brooke-Spiegler syndrome (BSS) with a novel germline CYLD mutation and various somatic mutations identified in the lesional tissues. The patient was a 46-year-old man with multiple lesions on the face. The available histopathological material included 24 trichoepitheliomas, 2 large nodular basal cell carcinomas (BCCs), 2 spiradenomas, 1 spiradenocylindroma and 1 trichoblastoma composed of large and small nodules with prominent clear cell differentiation. Whereas one of the two BCCs manifested a conventional morphology, the second neoplasm additionally showed foci with high grade cytological features characterized by marked pleomorphism and numerous mitotic figures. There were also numerous signet ring cells and cells containing intracytoplasmic eosinophilic inclusions. The germline mutation was a substitution mutation c.1684 + 1G> A. Somatic mutations were investigated in eight tissue blocks from which high quality genomic DNA had been successfully extracted. Somatic mutations included loss of heterozygosity (LOH) in four lesions and a single sequence mutation, namely a single base deletion c. 2322delA causing a frameshift mutation E774DfsX2. LOH occurred in both BCCs, one trichoepithelioma and one spiradenoma. In the remaining three lesions, the somatic event remained undetected.


Subject(s)
Adenoma/genetics , Carcinoma, Adenoid Cystic/genetics , Carcinoma, Basal Cell/genetics , Carcinoma, Skin Appendage/genetics , Facial Neoplasms/genetics , Skin Neoplasms/genetics , Tumor Suppressor Proteins/genetics , Adenoma/pathology , Carcinoma, Adenoid Cystic/pathology , Carcinoma, Basal Cell/pathology , Carcinoma, Skin Appendage/pathology , Deubiquitinating Enzyme CYLD , Facial Neoplasms/pathology , Humans , Loss of Heterozygosity , Male , Middle Aged , Mutation , Pedigree , Skin Neoplasms/pathology , Syndrome
12.
J Med Genet ; 45(5): 298-302, 2008 May.
Article in English | MEDLINE | ID: mdl-18234730

ABSTRACT

BACKGROUND: Germ-line mutations in CYLD are found in patients with familial skin appendage tumours. The protein product functions as a deubiquitinase enzyme, which negatively regulates NF-kappaB and c-Jun N-terminal kinase signalling. Brooke-Spiegler syndrome (BSS) is characterised by cylindromas, trichoepitheliomas and spiradenomas, whereas in familial cylindromatosis (FC) patients present with cylindromas and in multiple familial trichoepitheliomas (MFT) with trichoepitheliomas as the only skin tumour type. Although described as distinct entities, recent studies suggest that they are within the spectrum of a single entity. OBJECTIVE: To investigate the mutation spectrum of CYLD and possible genotype-phenotype correlations. METHODS: 25 families including 13 BSS, 3 FC, and 9 MFT families were examined and evaluated for mutations in the CYLD gene. RESULTS: In total, 18 mutations in CYLD, including 6 novel mutations, were identified in 25 probands (72%). The mutation frequencies among distinct phenotypes were 85% for BSS, 100% for FC, and 44% for MFT. The majority of the mutations were insertions, deletions or nonsense mutations leading to formation of truncated proteins. All mutations were located between exons 9 to 20, encoding the NEMO binding site and the catalytic domain. Genotype-phenotype analysis failed to reveal a correlation between the types of mutations and their location within the gene and the patients' phenotypes and disease severity. CONCLUSIONS: This study provides further evidence on the role of CYLD in the pathogenesis of skin appendage tumours characterised by cylindromas, trichoepitheliomas and/or spiradenomas, but the molecular mechanisms of CYLD in skin tumorigenesis and the reasons for phenotypic variability remain to be explored.


Subject(s)
Carcinoma, Skin Appendage/genetics , Mutation , Skin Neoplasms/genetics , Tumor Suppressor Proteins/genetics , Carcinoma, Skin Appendage/metabolism , Deubiquitinating Enzyme CYLD , Exons , Family , Genotype , Humans , Models, Genetic , Phenotype , Skin Neoplasms/metabolism , Syndrome
13.
Acta Derm Venereol ; 88(1): 43-6, 2008.
Article in English | MEDLINE | ID: mdl-18176750

ABSTRACT

Patients with the autosomal-dominant form of multiple familial trichoepithelioma develop numerous tumours on the face, neck and upper trunk, beginning in childhood. Malignant transformation of such lesions is quite rare; only one case of "malignant trichoepithelioma" has been reported previously, inferring pilomatrix carcinoma on a histological observation. We report here the case of a patient who developed a malignant neoplasm in a long-standing trichoepithelioma lesion on her buttock. Histopathology revealed a transformation zone between the trichoepithelioma and a malignant tumour mass. This case also showed several features of a malignant neoplasm of trichoblastic origin.


Subject(s)
Carcinoma, Skin Appendage/pathology , Cell Transformation, Neoplastic , Skin Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Carcinoma, Skin Appendage/genetics , Female , Hair Follicle/pathology , Humans , Male , Middle Aged , Prognosis , Skin Neoplasms/genetics
14.
J Invest Dermatol ; 128(3): 587-93, 2008 Mar.
Article in English | MEDLINE | ID: mdl-17851586

ABSTRACT

Brooke-Spiegler syndrome, familial cylindromatosis, and familial trichoepithelioma are autosomal-dominant genetic predispositions for benign tumors of skin appendages caused by mutations in the CYLD gene localized on chromosome 16q12-q13. The encoded protein functions as ubiquitin-specific protease (UBP), which negatively regulates NF-kappaB and c-Jun N-terminal kinase (JNK) signaling. We investigated five families affected with these skin neoplasms and identified four premature stop codons and the novel missense mutation D681G in a family in which 11 of 12 investigated tumors were trichoepitheliomas. CYLD protein harboring this missense mutation had a significant reduced ability to inhibit TNF receptor-associated factor (TRAF)2- and TRAF6-mediated NF-kappaB activation, tumor necrosis factor-alpha (TNFalpha)-induced JNK signaling, and to deubiquitinate TRAF2. CYLD-D681G was coimmunoprecipitated by TRAF2, but was unable to cleave K63-linked polyubiquitin chains. Aspartic acid 681 is highly conserved in CYLD homologues and other members of the UBP family, but does not belong to the Cys and His boxes providing the CYLD catalytic triad (Cys601, His871, and Asp889). As reported previously, the homologous residue D295 of HAUSP/USP-7 forms a hydrogen bond with the C-terminal end of ubiquitin and is important for the enzymatic activity. These results underline that D681 in CYLD is required for cleavage of K63-linked polyubiquitin chains.


Subject(s)
Carcinoma, Adenoid Cystic/genetics , Mutation, Missense , Skin Neoplasms/genetics , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Adult , Amino Acid Sequence , Biopsy , Carcinoma, Adenoid Cystic/metabolism , Carcinoma, Adenoid Cystic/pathology , Carcinoma, Skin Appendage/genetics , Carcinoma, Skin Appendage/metabolism , Carcinoma, Skin Appendage/pathology , Cell Line, Tumor , Codon, Terminator , Deubiquitinating Enzyme CYLD , Female , Humans , Male , Molecular Sequence Data , Pedigree , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , TNF Receptor-Associated Factor 2/metabolism , TNF Receptor-Associated Factor 6/metabolism , Ubiquitin/metabolism
15.
Exp Dermatol ; 15(12): 966-70, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17083363

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.


Subject(s)
Carcinoma, Adenoid Cystic/genetics , Carcinoma, Skin Appendage/genetics , Codon, Nonsense , Skin Neoplasms/genetics , Tumor Suppressor Proteins/genetics , Adult , Carcinoma, Adenoid Cystic/pathology , Carcinoma, Skin Appendage/pathology , China , DNA Mutational Analysis , Deubiquitinating Enzyme CYLD , Family Health , Female , Humans , Male , Neoplasms, Multiple Primary/genetics , Neoplasms, Multiple Primary/pathology , Pedigree , Phenotype , Skin Neoplasms/pathology
16.
Clin Genet ; 70(3): 246-9, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16922728

ABSTRACT

Brooke-Spiegler syndrome (BSS), familial cylindromatosis (FC), and multiple familial trichoepithelioma (MFT), originally described as distinct inherited disorders, are characterized by a variety of skin appendage neoplasms. Mutations in the CYLD gene are found in individuals with these syndromes. We describe a single family with affected members exhibiting either the FC or the MFT phenotypes associated with a mutation in the CYLD gene. These findings support the notion that BSS, FC, and MFT represent phenotypic variation of a single defect. Of interest, one of the affected individuals described in this report exhibits a severe phenotype illustrating the morbidity of the disorder.


Subject(s)
Carcinoma, Skin Appendage/genetics , Skin Neoplasms/genetics , Tumor Suppressor Proteins/genetics , Aged , Carcinoma, Skin Appendage/pathology , Deubiquitinating Enzyme CYLD , Female , Humans , Male , Middle Aged , Mutation , Pedigree , Phenotype , Skin Neoplasms/pathology , Syndrome
17.
Br J Dermatol ; 155(1): 182-5, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16792771

ABSTRACT

BACKGROUND: Familial cylindromatosis is a rare genetic disorder, giving rise to neoplasms of the skin appendages. We have recently shown that loss of the cylindromatosis tumour suppressor gene leads to activation of NF-kappaB, a transcription factor having antiapoptotic activity. This provides a possible explanation for the deregulated growth of cylindromas. In cell-based assays, salicylate can prevent NF-kappaB activation caused by loss of the cylindromatosis gene, suggesting that salicylic acid application might be a potential treatment for cylindromatosis. OBJECTIVES: To assess the effectiveness of topical application of salicylic acid on familial cylindromas. METHODS: Cylindromas in five patients from four different cylindromatosis families were treated with twice daily and then once daily topical salicylic acid. Clinical response was determined by serial tumour measurements. RESULTS: In total 17 cylindromas in five patients were studied: 12 target lesions and five control lesions. The median size of the cylindromas was 1.0 cm (range, 0.6-2.8 cm). Two of the 12 cylindromas showed a complete remission. Another eight lesions showed some response, but not sufficient to qualify as partial remission. The control lesions remained stable or increased in size. CONCLUSIONS: Salicylic acid is a well-tolerated and potential new treatment for cylindromatosis.


Subject(s)
Carcinoma, Adenoid Cystic/drug therapy , Carcinoma, Skin Appendage/drug therapy , Keratolytic Agents/administration & dosage , Neoplastic Syndromes, Hereditary/drug therapy , Salicylic Acid/administration & dosage , Administration, Topical , Carcinoma, Adenoid Cystic/genetics , Carcinoma, Adenoid Cystic/metabolism , Carcinoma, Skin Appendage/genetics , Carcinoma, Skin Appendage/metabolism , Female , Follow-Up Studies , Genes, Tumor Suppressor , Humans , I-kappa B Kinase/metabolism , Keratolytic Agents/therapeutic use , NF-kappa B/metabolism , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/metabolism , Pilot Projects , Remission Induction , Salicylic Acid/therapeutic use
18.
J Med Genet ; 42(11): 811-9, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16272260

ABSTRACT

In the past decade the molecular basis of many inherited syndromes has been unravelled. This article reviews the clinical and genetic aspects of inherited syndromes that are characterised by skin appendage neoplasms, including Cowden syndrome, Birt-Hogg-Dube syndrome, naevoid basal cell carcinoma syndrome, generalised basaloid follicular hamartoma syndrome, Bazex syndrome, Brooke-Spiegler syndrome, familial cylindromatosis, multiple familial trichoepitheliomas, and Muir-Torre syndrome.


Subject(s)
Carcinoma, Skin Appendage/genetics , Carcinoma, Skin Appendage/pathology , Genetic Predisposition to Disease , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Female , Genetic Linkage , Humans , Male , Neoplastic Syndromes, Hereditary/genetics , Syndrome
19.
J Invest Dermatol ; 124(5): 919-20, 2005 May.
Article in English | MEDLINE | ID: mdl-15854031

ABSTRACT

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.


Subject(s)
Carcinoma, Adenoid Cystic/genetics , Carcinoma, Skin Appendage/genetics , Mutation , Neoplasms, Multiple Primary/genetics , Skin Neoplasms/genetics , Tumor Suppressor Proteins/genetics , Deubiquitinating Enzyme CYLD , Genotype , Humans , Phenotype , Syndrome
20.
J Invest Dermatol ; 121(4): 732-4, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14632188

ABSTRACT

Brooke-Spiegler syndrome (BSS, familial cylindromatosis or turban tumor syndrome) is an inherited disease characterized by neoplasms of the skin appendages such as cylindroma, trichoepithelioma, and spiradenoma. The disease has been mapped to 16q12-13, and mutations in the CYLD gene have been identified in families with this disorder. Of interest, multiple familial trichoepithelioma (MFT) has been described as a distinct disorder characterized by the familial occurrence of trichoepitheliomas. MFT has been mapped to 9p21; however, to date a candidate gene has not been identified. In this report, we describe a four-generation family with BSS presenting predominantly with trichoepitheliomas (resembling MFT phenotype). We identified a novel missense mutation in the CYLD gene, designated E474G, in the affected individuals of this family. Our findings exemplify clinical heterogeneity within BSS and extend the body of evidence that mutations in CYLD are implicated in this disease. Although not conclusive, these findings suggest that BSS and MFT may represent a single entity.


Subject(s)
Carcinoma, Adenoid Cystic/genetics , Carcinoma, Skin Appendage/genetics , Mutation, Missense , Skin Neoplasms/genetics , Tumor Suppressor Proteins/genetics , Deubiquitinating Enzyme CYLD , Family Health , Female , Humans , Male , Pedigree , Phenotype
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