Sporadic Kindler Syndrome with a novel mutation / Sindrome de Kindler esporadica com uma mutacao nao descrita previamente

We report the case of a 28-year-old woman with Kindler syndrome, a rare form of epidermolysis bullosa. Clinically, since childhood, she had widespread pigmentary changes in her skin as well as photosensitivity and fragility of the skin and mucous membranes. The mucosal involvement led to an erosive stomatitis as well as esophageal, anal and vaginal stenoses, requiring surgical intervention. The diagnosis of Kindler syndrome was confirmed by DNA sequencing with compound heterozygosity for a nonsense/frameshift combination of mutations (p.Arg110X; p.Ala289GlyfsX7) in the FERMT1 gene.

Nós relatamos uma paciente feminina de 28 anos com Síndrome de Kindler, uma forma rara de Epidermólise Bolhosa. Clinicamente, ela apresentava alterações cutâneas pigmentares disseminadas, fotossensibilidade e fragilidade da pele e das mucosas desde a infância. O envolvimento mucoso levou à estomatite erosiva e a estenoses esofágica, anal e vaginal, as quais necessitaram de intervenções cirúrgicas. O diagnóstico de Síndrome de Kindler foi confirmado por sequenciamento de DNA, que demonstrou heterozigose composta uma combinação de mutações uma nonsense e outra frameshift (p.Arg110X; p.Ala289GlyfsX7) no gene FERMT1.

Advances in understanding the genetic basis of inherited single gene skin barrier disorders: new clues to key genes that may be involved in the pathogenesis of atopic dermatitis

Increasing knowledge of genomic DNA sequences and genetic databases has led to the characterization of the molecular basis of several inherited skin disorders. In this review we summarize some of the major recent discoveries that have been made in defining the pathogenic mutations that cause inherited disorders of the skin barrier leading to skin scaling or increased transepidermal water loss in either rare disorders (NethertonÆs syndrome or harlequin ichthyosis) or more common genodermatoses (ichthyosis vulgaris). These molecular breakthroughs have led to more accurate diagnoses, better genetic counselling and, where appropriate, the feasibility of DNA-based prenatal diagnosis, as well as the possibility of developing newer forms of treatment, including gene or protein therapy. Identifying the molecular basis of these conditions, especially ichthyosis vulgaris, has also provided dramatic new insight into the genetic abnormalities in the common disorder, atopic dermatitis. Thus research on the relatively rare single gene inherited skin disorders not only has benefits for patients and their families with these uncommon conditions but also has the potential to yield fresh and significant new information about very common skin diseases.

O maior conhecimento sobre as de sequências genômicas de DNA e as bases de dados genéticas levou à caracterização da base molecular de várias doenças hereditárias de pele. Nesta revisão resumimos algumas das descobertas recentes mais importantes quanto à definição das mutações patogênicas que causam as doenças hereditárias da barreira cutânea, levando a descamação ou aumento da perda hídrica transepidérmica, seja em doenças raras, (síndrome de Netherton ou ictiose em Arlequim) ou genodermatoses mais comuns (ictiose vulgar). Estas descobertas moleculares têm conduzido a diagnósticos mais acurados, melhor aconselhamento genético e, quando apropriado, à possibilidade de diagnóstico pré-natal baseado em DNA, assim como desenvolvimento de novas formas de tratamento, incluindo terapia gênica ou proteica. A identificação da base molecular destas doenças, especialmente ictiose vulgar, também propiciou importante entendimento das anormalidades genéticas de doença comum, a dermatite atópica. Assim, as pesquisas em doenças hereditárias monogênicas de pele relativamente raras não apenas trazem benefícios para os pacientes e familiares, mas também têm o potencial de trazer informações novas e significativas sobre doenças de pele muito comuns.

Las epidermolisis bullosas distróficas en México: 2470insG representa la mutación mas común en 21 familias / 2470insG, represents the commonest mutation in Mexican patients with dystrophic bullous epidermolysis: a study of 21 families

Antecedentes: Las epidermolisis ampollosas congénitas son enfermedades caracterizadas por ampollas en piel y mucosas al mínimo traumatismo. Son tres tipos: simple, unión y distrófica. Las epidermolisis ampollosas distróficas (EAD) son causadas por mutaciones en el gen COL 7Al que codifica la producción del colágeno tipo VII localizado en las fibrillas de anclaje de la unión dermoepidérmica. Objetivo: Determinar las bases moleculares de las EAD en México. Material y métodos: se analizaron ADN de 21 familias mexicanas con EAD. Se realizó reacción en cadena de la polimerasa, estudios de heteroduplex secuenciación de nucleótidos en ADN de los pacientes. Resultados: Se detectó 59 de 67 mutaciones en 36 pacientes. Se encontraron seis mutaciones de tipo codón de terminación prematuro, substitución de glicina, remoción de intrones de novo y depleción interna. La mutación comúnmente más encontrada fue la 2470insG, en 21 (58.35%) de 36 pacientes. Conclusiones: En pacientes con EAD, la mutación 2470insG es la más frecuente en México. Recomendamos analizar esta mutación a Mexicanos con EAD como primera opción. Estos resultados son útiles para clasificar los subtipos de EAD, dar asesoramiento genético, así como para entender un poco más la fisiopatología de esta enfermedad mecano ampollosa.

BACKGROUND: Type VII collagen gene (COL 7 Al) mutations are the cause of dystrophic epidermolysis bullosa (DEB), but most mutations are specific to individual families and there is limited data on the nature of COL 7 Al mutations in certain ethnic populations. OBJECTIVE: To determine the molecular basis of DEB in Mexican patients and describe the most frequent mutation among this ethnic population. METHODS: Most subjects were approached at FUNDACION DEBRA MEXICO AC. Molecular analysis was performed by polymerase chain reaction (PCR) of genomic DNA using COL 7 A l-specific primers, heteroduplex analysis, and direct nucleotide sequencing. RESULTS: Fifty nine of 67 COL 7 Al possible mutations (88%) were identified; 36 individuals (31 recessive, five dominant) from 21 families. Recessive mutations included six frameshift mutations, four silent glycine substitutions and two splice site mutations. CONCLUSIONS: The present study informs a different kind of mutation observed in our patient population. Only two mutations informed in this study had been described earlier among another ethnic group. The most frequent mutation was 2470insG, affecting 21 (58.3%) out of 36 patients with DEB. These new data will be helpful in facilitating the accurate diagnosis of an DEB subtype, and will add further insight into the pathophysiology of this mechanobullous disease.