RESUMO
BACKGROUND: The renal form of pseudohypoaldosteronism type 1 (PHA1) is a rare disease characterized by congenital mineralocorticoid resistance of the kidney. Twenty-two different loss-of-function mutations in the mineralocorticoid receptor gene have been described in families with PHA1. These mutations were not recurrent and resulted in a large phenotypic variability. OBJECTIVE: The objective of this study is to analyze the recurrence of an inactivating mutation in the mineralocorticoid receptor gene in unrelated families with autosomal dominant PHA1. PATIENTS: Seventeen members from three unrelated families with autosomal dominant PHA1 were studied, including 11 affected patients with variable clinical manifestations. Fifty healthy subjects were used as controls. METHODS: Genomic DNA was extracted, and the entire coding region of the mineralocorticoid receptor gene was submitted to automatic sequencing. Four dinucleotide microsatellite markers spanning a region of 3.2 cM in the human mineralocorticoid receptor gene locus, and two intragenic polymorphisms were used for haplotype analysis. RESULTS: A heterozygous point mutation at codon 947 (c.2839C>T) changing arginine to stop codon (R947X) was found in the three families. Different haplotypes segregated with the R947X mutation in each family, demonstrating the absence of a founder effect for this mutation. CONCLUSION: Codon 947 of the mineralocorticoid receptor is the first mutational hot spot for autosomal dominant PHA1.
Assuntos
Mutação Puntual , Pseudo-Hipoaldosteronismo/genética , Receptores de Mineralocorticoides/genética , 17-alfa-Hidroxiprogesterona/sangue , Aldosterona/sangue , DNA/química , DNA/genética , Feminino , Humanos , Hidrocortisona/sangue , Lactente , Recém-Nascido , Masculino , Repetições de Microssatélites , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Genético , Pseudo-Hipoaldosteronismo/sangue , Pseudo-Hipoaldosteronismo/patologia , Renina/sangueRESUMO
OBJECTIVES: To test the sensitivities of recently published American recommendations predicting occult intracranial lesion (OICL) in girls with central precocious puberty (CPP), and to validate a previously derived diagnosis rule predicting OICL based on age at puberty onset and estradiol (E2) level. STUDY DESIGN: A retrospective, multicenter, hospital-based, cohort study was performed, including all girls with CPP seen in 7 centers in 6 European countries during given periods. American recommendations and the previously derived diagnosis rule were tested. RESULTS: Girls with CPP (n=443), including 35 with OICL, were recruited. American recommendations did not identify all OICL. Previously identified independent risk factors for OICL were confirmed: age <6 years (adjusted odds ratio 20.5; 95% CI, 8.1-52.1) and E2 >45th percentile (3.0; 95% CI, 1.3-7.1). The previously derived diagnosis rule had 100% sensitivity (95% CI, 90-100): all girls with OICL had either an age <6 years or an E2 level >45th percentile. The specificity was 39% (95% CI, 34-44). CONCLUSIONS: American recommendations do not seem safe to select European girls with CPP who require brain imaging. In settings where systematic brain imaging is not possible, the proposed diagnosis rule could safely help to avoid more than one third of unnecessary brain imaging.
Assuntos
Encefalopatias/epidemiologia , Árvores de Decisões , Puberdade Precoce/epidemiologia , Encefalopatias/complicações , Encefalopatias/diagnóstico , Criança , Europa (Continente) , Medicina Baseada em Evidências , Feminino , Humanos , Imageamento por Ressonância Magnética , Seleção de Pacientes , Puberdade Precoce/etiologia , Estudos Retrospectivos , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios XRESUMO
We report an estimated prevalence of precocious puberty of 1 in 5 to 6 girls with Williams syndrome (18.3%). Mean menarcheal age of 86 girls with Williams syndrome was 11.5 +/- 1.7 (+/-SD) years. Distribution of menarcheal age was significantly different from that in normal girls (12.9 +/- 1.1 years; n = 759).