RESUMEN
HNF1B encodes for a transcription factor involved in the early development of the kidney, pancreas, liver and genital tract. Mutations in HNF1B are dominantly inherited and consist of whole-gene deletion, or small mutation. De novo mutation occurs in half of tested kindreds. HNF1B-related disease combines renal and non-renal manifestations. Renal involvement is heterogeneous and may escape early recognition. During fetal life and childhood, it mostly consists of hyperechogenic kidneys or bilateral renal cystic hypodysplasia. The adult phenotype encompasses tubulointerstitial profile at presentation and slowly progressive renal decline (-2 ml/min/year). Renal involvement includes renal cysts (mostly few cortical cysts), a solitary kidney, pelvi-caliceal abnormalities, hypokalemia and hypomagnesemia related to tubular leak, and more rarely, Fanconi syndrome and chromophobe renal carcinoma. The latter warrants ultrasound screening. Extrarenal phenotype consists of diabetes mellitus (MODY-5), exocrine pancreas failure and pancreas atrophy; fluctuation liver tests abnormalities; diverse genital tract abnormalities in females or infertility in males; and mild mental retardation in rare individuals. Phenotype heterogeneity within families is striking. Individuals progressing to end-stage renal disease are eligible for kidney transplantation (or combined pancreas and kidney transplantation for diabetic individuals). While HNF1B disease was still unknown one decade ago, it has emerged as the second most prevalent dominantly inherited kidney disease. Data available pave the way for early recognition and improved specific management, including genetic counselling.
Asunto(s)
Factor Nuclear 1-beta del Hepatocito/genética , Enfermedades Renales/genética , Diabetes Mellitus Tipo 2/genética , Heterocigoto , Humanos , Hepatopatías/genética , Mutación , Enfermedades Pancreáticas/genética , Anomalías Urogenitales/genéticaRESUMEN
Human mitochondrial DNA (mt DNA) lesions can cause a heterogeneous group of mitochondrial degenerative disorders. We report on a 5-year-old patient suffering from the full-blown picture of Pearson syndrome. His symptoms started in the first year of life with failure to thrive, followed by chronic diarrhoea and lactic acidosis at 18 months of age. Analysis of mitochondrial DNA revealed large amounts of mt DNA molecules with a 2.7 kb deletion in all tissues examined. The diagnosis of Pearson syndrome was made initially in the absence of haematological disturbances. In the following months neutropenia, sideroblastic anaemia and hypoparathyroidism developed. Daily administration of dichloroacetate (DCA) and bicarbonate controls the lactic acidosis, while episodic treatments with filgastrim (Neupogen) reverse episodes of severe neutropenia. Calcium and vitamin D supplementation compensate for the hypoparathyroidism. Chronic administration of DCA and supportive treatment for a long period help to stabilize patients with multiorgan dysfunction.
Asunto(s)
Anomalías Múltiples/genética , Enfermedades de la Médula Ósea/genética , ADN Mitocondrial , Enfermedades Pancreáticas/genética , Eliminación de Secuencia , Anomalías Múltiples/tratamiento farmacológico , Acidosis Láctica/tratamiento farmacológico , Acidosis Láctica/genética , Southern Blotting , Enfermedades de la Médula Ósea/patología , Preescolar , Diarrea/tratamiento farmacológico , Diarrea/genética , Insuficiencia de Crecimiento/genética , Humanos , Masculino , Enfermedades Pancreáticas/tratamiento farmacológico , Mapeo Restrictivo , SíndromeRESUMEN
Familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI), an autosomal recessive disorder characterized by unregulated insulin secretion, is linked to chromosome 11p14-15.1. The newly cloned high-affinity sulfonylurea receptor (SUR) gene, a regulator of insulin secretion, was mapped to 11p15.1 by means of fluorescence in situ hybridization. Two separate SUR gene splice site mutations, which segregated with disease phenotype, were identified in affected individuals from nine different families. Both mutations resulted in aberrant processing of the RNA sequence and disruption of the putative second nucleotide binding domain of the SUR protein. Abnormal insulin secretion in PHHI appears to be caused by mutations in the SUR gene.