Bathing suit ichthyosis (BSI) is a striking and unique clinical form of autosomal recessive congenital ichthyosis characterized by pronounced scaling on the bathing suit areas but sparing of the extremities and the central face. Here we report on a series of 10 BSI patients. Our genetic, ultrastructural and biochemical investigations show that BSI is caused by transglutaminase-1 (TGase-1) deficiency. Altogether, we identified 13 mutations in TGM1-among them seven novel missense mutations and one novel nonsense mutation. Structural modeling for the Tyr276Asn mutation reveals that the residue is buried in the hydrophobic interior of the enzyme and that the hydroxyl side chain of Tyr276 is exposed to solvent in a cavity of the enzyme. Cryosections of healthy skin areas demonstrated an almost normal TGase activity, in contrast to the affected BSI skin, which only showed a cytoplasmic and clearly reduced TGase-1 activity. The distribution of TGase-1 substrates in the epidermis of affected skin corresponded to the situation in TGase-1 deficiency. Interestingly, the expression of TGase-3 and cathepsin D was reduced. Digital thermography validated a striking correlation between warmer body areas and presence of scaling in patients suggesting a decisive influence of the skin temperature. In situ TGase testing in skin of BSI patients demonstrated a marked decrease of enzyme activity when the temperature was increased from 25 to 37 degrees C. We conclude that BSI is caused by TGase-1 deficiency and suggest that it is a temperature-sensitive phenotype.
Background Blau syndrome (BS) is a rare monogenic autoinflammatory disease caused by NOD2 mutations. BS classically presents in early childhood as a triad of granulomatous polyarthritis, uveitis and skin involvement. Joint and ocular involvement have been characterized by several cohort studies but only very little data are available on skin lesions. Objectives We aimed to provide a detailed clinical and microscopic analysis of skin manifestations and to study whether they may contribute to an early diagnosis. Methods We conducted a retrospective multicentre study in a French cohort of 21 patients diagnosed with genetically confirmed BS. Results Skin involvement was the first clinical manifestation of BS in 15/16 patients with dermatological manifestations. The presence of skin lesions was associated with significant shorter age at diagnosis (P = 0.03) and diagnostic delay (P = 0.04). Dermatological assessment allowed an earlier diagnosis (P = 0.001) and reduces the diagnostic delay (P = 0.007). Early skin lesions had a homogeneous, stereotypical clinical presentation, namely non‐confluent erythematous or pigmented millimetric papules in 13/14(93%) patients. In contrast, skin lesions occurring during later disease stages had a more heterogeneous clinical presentation, including ichthyosiform dermatosis, panniculitis, livedoid lesions and vasculitis. Whatever their time of occurrence and the clinical aspect, all biopsied showed histologically presence of granuloma. Conclusion Skin involvement in BS is the earliest clinical manifestation of the BS in the large majority of patients. The recognition of dermatological manifestations as granulomatous skin lesions and early dermatological expertise are the key to an early diagnosis of BS. In view of our results, it seems reasonable to propose a simplified view of skin lesions of BS in which the granuloma is the key structure.
Background: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant familial disorder due to FH mutation. Despite a considerable increase in information about the genetic background, inter- and intrafamilial phenotypic variability/penetrance are not well documented. Objective: To describe a large French HLRCC family and provide new data on penetrance and intrafamilial variability. Materials and Methods: The whole family was contacted for clinical examination, skin biopsy, uterine and kidney imagery and molecular analysis. Results: The family included 22 members in 3 generations. The second generation consisted of 13 members who were older than the expected age of onset of disease manifestations. Of the 12 available members of this second generation, 6 (1 man and 5 women, aged 44-57 years) had a novel FH mutation. All had the same mild phenotype with cutaneous asymptomatic leiomyomas, uterine fibroids (if women) and no kidney tumor. The other 6 members not bearing the familial mutation had normal clinical and radiological findings. In this second generation, the penetrance was therefore complete, and there was no intrafamilial variability in the clinical expression of the mutation. Conclusion: This study provides additional data on genotype/phenotype correlation, intrafamilial variability and penetrance that should help to improve prognosis and genetic counseling.
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