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.
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.
GAB2 is a scaffold protein with diverse upstream and downstream effectors. MAPK and PI3K signaling pathways are known effectors of GAB2. It is amplified and overexpressed in a variety of human tumors ...including melanoma. Here we show a previously undescribed role for GAB2 in NRAS-driven melanoma. Specifically, we found that GAB2 is co-expressed with mutant NRAS in melanoma cell lines and tumor samples and its expression correlated with metastatic potential. Co-expression of GAB2(WT) and NRAS(G12D) in melanocytes and in melanoma cells increased anchorage-independent growth by providing GAB2-expressing cells a survival advantage through upregulation of BCL-2 family of anti-apoptotic factors. Of note, collaboration of GAB2 with mutant NRAS enhanced tumorigenesis in vivo and led to an increased vessel density with strong CD34 and VEGFR2 activity. We found that GAB2 facilitiated an angiogenic switch by upregulating HIF-1α and VEGF levels. This angiogenic response was significantly suppressed with the MEK inhibitor PD325901. These data suggest that GAB2-mediated signaling cascades collaborate with NRAS-driven downstream activation for conferring an aggressive phenotype in melanoma. Second, we show that GAB2/NRAS signaling axis is non-linear and non-redundant in melanocytes and melanoma, and thus are acting independent of each other. Finally, we establish a link between GAB2 and angiogenesis in melanoma for the first time. In conclusion, our findings provide evidence that GAB2 is a novel regulator of tumor angiogenesis in NRAS-driven melanoma through regulation of HIF-1α and VEGF expressions mediated by RAS-RAF-MEK-ERK signaling.
Pachyonychia congenita (PC) is a rare genodermatosis affecting the nails, skin, oral mucosae, larynx, hair, and teeth. Pathogenic mutations in keratins K6a or K16 are associated with the PC-1 ...phenotype whereas K6b and K17 mutations are associated with the PC-2 phenotype. Analysis of clinical, pathological, and genetic data from the literature and two research registries reveal that >97% of PC cases exhibit fingernail and toenail thickening, and painful plantar keratoderma. Prospective evaluation of 57 PC patients from 41 families revealed variable clinical findings: hyperhidrosis (79%), oral leukokeratosis (75%), follicular keratosis (65%), palmar keratoderma (60%), cutaneous cysts (35%), hoarseness or laryngeal involvement (16%), coarse or twisted hair (26%), early primary tooth loss (14%), and presence of natal or prenatal teeth (2%). Stratification of these data by keratin mutation confirmed the increased incidence of cyst formation and natal teeth among PC-2 patients, although cysts were more commonly seen in PC-1 than previously reported (25%–33%). Previously unreported clinical features of PC include development of painful oral and nipple lesions during breastfeeding, copious production of waxy material in ears, and inability to walk without an ambulatory aid (50%). Possible pathogenic mechanisms are discussed with respect to the clinicopathologic and genetic correlations observed.
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.
To investigate the mutation spectrum of CYLD and possible genotype-phenotype correlations.
25 families including 13 BSS, 3 FC, and 9 MFT families were examined and evaluated for mutations in the CYLD gene.
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.
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.
CONTEXT PTEN,a tumour suppressor gene located on chromosome 10q23, develops somatic mutations in various tumours and tumour cell lines including brain, endometrium, prostate, breast, kidney, thyroid, ...liver, and melanoma. OBJECTIVES To investigate the mutational profile of this gene further, as well as its role in tumour progression in melanoma. DESIGN, SETTINGS We examined 21 metastatic melanoma samples for 10q23 allelic losses andPTEN sequence alterations. Additionally, we screened these samples for mutations inCDKN2A, a gene in which alterations are well documented in primary melanoma as well as in the germline of familial melanoma. RESULTS Loss of heterozygosity (LOH) at 10q23 was observed in 33% (7/21) of the samples tested. We identified four sequence alterations in PTEN(19%) and two in CDKN2A (9.5%). Of interest, only one case showed mutations in both genes. CONCLUSIONS These data support the notion that PTEN alterations occur in some metastatic melanomas, and that mutation of this gene plays a role in the progression of some forms of melanoma.
Summary
Background. Premature ageing of the skin (photoageing) results from the action of ultraviolet radiation (UVR) on skin. One of the histopathological findings of photoageing is the presence of ...solar elastosis in the dermis. Skin pigmentation is protective against UVR.
Aim. To evaluate the presence of solar elastosis in dark‐skinned people.
Methods. Normal facial skin biopsies of 147 dark‐skinned and 140 light‐skinned people were examined histopathologically for solar elastosis. The degree of solar elastosis was graded on a five‐point scale by a panel of dermatopathologists blinded to patient demographics.
Results. There were 112 of 140 (80%) light‐skinned and 50 of 147 (34%) dark‐skinned patients with high‐grade solar elastosis. In the dark‐skinned patient group, high‐grade solar elastosis was seen in 29 of 61 (47.5%) Hispanic and 5 of 49 (10.2%) African American subjects.
Conclusions. Dark‐skinned people are not completely protected from the effects of UVR.
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.
Cowden syndrome (CS) and Bannayan-Zonana syndrome (BZS) are two hamartoma syndromes with distinct phenotypic features. Although partial clinical overlap exists between CS and BZS, they are considered ...to be separate entities. PTEN has been identified as the susceptibility gene for both disorders, suggesting allelism. We have identified a germline mutation, R335X, in PTEN in a family consisting of two female members with the phenotypic findings of CS and two male members with the phenotypic findings of BZS. To our knowledge, this is the first report that shows the presence of separate subjects with CS and with BZS in a single family associated with a single germline PTEN mutation.
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