RESUMEN
Heterozygous fumarate hydratase (FH) germline mutations cause hereditary leiomyomatosis and renal cell cancer (HLRCC), an autosomal dominant syndrome characterized by multiple cutaneous piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer. The main objective of our study was to evaluate clinical and genetic data from families suspected of HLRCC on a nationwide level. All families referred for FH mutation analysis in the Netherlands were assessed. We performed FH sequence analysis and multiplex ligation-dependent probe amplification. Families with similar FH mutations were examined for haplotype sharing. In 14 out of 33 families, we identified 11 different pathogenic FH germline mutations, including 4 novel mutations and 1 whole-gene deletion. Clinical data were available for 35 FH mutation carriers. Cutaneous leiomyomas were present in all FH mutation carriers older than 40 years of age. Eleven out of 21 female FH mutation carriers underwent surgical treatment for symptomatic uterine leiomyomas at an average of 35 years. Two FH mutation carriers had papillary type 2 renal cancer and Wilms' tumour, respectively. We evaluated the relevance of our findings for clinical practice and have proposed clinical diagnostic criteria, indications for FH mutation analysis and recommendations for management.
Asunto(s)
Carcinoma de Células Renales/genética , Fumarato Hidratasa , Mutación de Línea Germinal , Neoplasias Renales/genética , Leiomiomatosis , Neoplasias Cutáneas/genética , Neoplasias Uterinas/genética , Adolescente , Adulto , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/enzimología , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Fumarato Hidratasa/genética , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Renales/diagnóstico , Neoplasias Renales/enzimología , Leiomiomatosis/enzimología , Leiomiomatosis/genética , Países Bajos , Linaje , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/enzimología , Síndrome , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/enzimología , Adulto JovenAsunto(s)
Carcinoma de Células Renales/genética , Neoplasias Renales/genética , Leiomiomatosis/genética , Síndromes Neoplásicos Hereditarios/genética , Tumor de Wilms/genética , Adulto , Análisis Mutacional de ADN/métodos , Femenino , Fumarato Hidratasa/genética , Humanos , Mutación Missense , LinajeRESUMEN
NOD2/CARD15 belongs to the N-terminal caspase recruitment domain family of proteins involved in regulating NF-kB activation in response to inflammatory stimuli transduced through Toll-like receptors. Mutations and polymorphisms in the NOD2/CARD15 gene reduce antibacterial responses and are associated with granulomatous inflammatory conditions such as Blau syndrome and early-onset sarcoidosis. The polymorphism R702W (arginine to tryptophan) is strongly associated with susceptibility to Crohn's disease in Caucasian populations. Skin abnormalities (other than cutaneous manifestations of Crohn's disease) have not been previously associated with R702W. We report on a female patient homozygous for R702W who developed granulomatous rosacea at the age of 12 years old. From the occurrence in the context of Crohn associated with R702W, we speculate that granulomatous rosacea may be an entity distinct from other forms of rosacea, which are associated with increased production of antibacterial proteins such as cathelicidin.
Asunto(s)
Enfermedad de Crohn/genética , Proteína Adaptadora de Señalización NOD2/genética , Polimorfismo de Nucleótido Simple , Rosácea/genética , Niño , Enfermedad de Crohn/complicaciones , Femenino , Homocigoto , Humanos , Mutación Missense , Rosácea/complicacionesAsunto(s)
Ictiosis/genética , Lipasa/metabolismo , Errores Innatos del Metabolismo Lipídico/genética , Enfermedades Musculares/genética , Mutación/genética , 1-Acilglicerol-3-Fosfato O-Aciltransferasa , Niño , Consanguinidad , Diagnóstico Diferencial , Hepatomegalia/diagnóstico , Humanos , Lipasa/genética , Errores Innatos del Metabolismo Lipídico/diagnóstico , Masculino , Fenotipo , SíndromeRESUMEN
Multiple cutaneous and uterine leiomyomatosis (MCUL; OMIM 150800) is an autosomal dominantly inherited disease characterized by leiomyomas of the skin and uterine leiomyomas. MCUL can be associated with various types of renal cancer. This syndrome is known as hereditary leiomyomatosis and renal cell cancer (HLRCC; OMIM 605839). Both disorders result from heterozygous germline mutations in the fumarate hydratase (FH) gene.