RESUMO
11beta-Hydroxylase deficiency is a common form of congenital adrenal hyperplasia causing virilization of the female fetus and hypertension. DNA analysis of the gene (CYP11B1) encoding 11beta-hydroxylase has been reported previously to be effective in the prenatal diagnosis of one affected female fetus. In that case, prenatal treatment with dexamethasone resulted in normal female genitalia. We now report five new pregnancies that underwent prenatal diagnosis for 11beta-hydroxylase deficiency. In the first family, the proband is homozygous for a T318M mutation and all fetuses from four subsequent pregnancies are carriers. In a second family, the mother is homozygous for a A331V mutation and was started on dexamethasone, but identification of a homozygous normal fetus led to the discontinuation of treatment. In another family, the fetus was a male homozygous for R384Q and treatment was discontinued. Lastly, a novel G444D mutation in exon 8 was identified and proven to reduce 11beta-hydroxylase activity.
Assuntos
Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/genética , Cromossomos Humanos Par 8/genética , Doenças Fetais/diagnóstico , Doenças Fetais/genética , Esteroide 11-beta-Hidroxilase/genética , Adolescente , Hiperplasia Suprarrenal Congênita/terapia , Amniocentese , Criança , Amostra da Vilosidade Coriônica , Consanguinidade , Análise Mutacional de DNA , Dexametasona/uso terapêutico , Feminino , Doenças Fetais/tratamento farmacológico , Triagem de Portadores Genéticos/métodos , Glucocorticoides/uso terapêutico , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Linhagem , Gravidez , Diagnóstico Pré-Natal , Virilismo/genética , Virilismo/prevenção & controleRESUMO
Blood pressure is determined by the product of cardiac output, intravascular volume, and peripheral resistance. Because hormones are involved in blood pressure regulation and affect these parameters, hypertension is a prominent feature of certain adrenal enzymatic abnormalities. In this report, two steroid-dependent forms of genetic low-renin hypertension are examined: 11beta-hydroxylase deficiency and apparent mineralocorticoid excess. 11beta-Hydroxylation is an enzymatic function necessary for the biosynthesis of cortisol by the zona fasciculata (ZF) of the adrenal cortex. Defects in this step lead to the abnormally increased production by the ZF of the steroid 11-deoxycorticosterone (DOC), a moderately potent mineralocorticoid, which causes sodium retention and volume expansion that result in hypertension. Further, the excess production of adrenal androgens leads to virilization, prenatally in the genetic female, and postnatally in both sexes. The disorder of 11beta-hydroxylase deficiency is due to an autosomal recessive defect of the enzyme protein-encoding gene CYP11B1. Numerous mutations in CYP11B1 causing 11beta-hydroxylase deficiency have been characterized. Apparent mineralocorticoid excess is a potentially fatal genetic disorder causing severe juvenile hypertension, pre- and postnatal growth failure, and low to undetectable levels of potassium, renin, and aldosterone. It is caused by autosomal recessive mutations in the HSD11B2 gene, which result in a deficiency of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2).
Assuntos
Hiperplasia Suprarrenal Congênita , Hipertensão/etiologia , Mineralocorticoides/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2 , Pré-Escolar , Citocromo P-450 CYP11B2/genética , Humanos , Hidroxiesteroide Desidrogenases/genética , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/fisiopatologia , Erros Inatos do Metabolismo/terapia , Mutação/fisiologiaRESUMO
Congenital adrenal hyperplasia (CAH) consists of autosomal recessive disorders of cortisol biosynthesis, which in the majority of cases result from 21-hydroxylase deficiency. Another enzymatic defect causing CAH is 11beta-hydroxylase deficiency. In both forms, the resulting excessive androgen secretion causes genital virilization of the female fetus. For over 10 yr female fetuses affected with 21-hydroxylase deficiency have been safely and successfully prenatally treated with dexamethasone. We report here the first successful prenatal treatment with dexamethasone of an affected female with 11beta-hydroxylase deficiency CAH. The family had two girls affected with 1beta-hydroxylase deficiency born with severe ambiguous genitalia who were both homozygous for the T318M mutation in the CYP11B1 gene, which codes for the 11beta-hydroxylase enzyme. In the third pregnancy in this family, the female fetus was treated in utero by administering dexamethasone to the mother, starting at 5 weeks gestation. The treatment was successful, as the newborn was not virilized and had normal female external genitalia. A second family with two affected sons was also studied in preparation for a future pregnancy. We report a novel 1-bp deletion in codon 394 (R394delta1) in the CYP11B1 gene in this family.
Assuntos
Hiperplasia Suprarrenal Congênita , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Dexametasona/uso terapêutico , Glucocorticoides/uso terapêutico , Diagnóstico Pré-Natal , Virilismo/prevenção & controle , Hiperplasia Suprarrenal Congênita/genética , Amostra da Vilosidade Coriônica , Consanguinidade , Análise Mutacional de DNA , Dexametasona/administração & dosagem , Feminino , Doenças Fetais/diagnóstico , Doenças Fetais/tratamento farmacológico , Doenças Fetais/genética , Idade Gestacional , Glucocorticoides/administração & dosagem , Humanos , Masculino , Troca Materno-Fetal , Mutação de Sentido Incorreto , Linhagem , Gravidez , Esteroide 11-beta-Hidroxilase/genética , Virilismo/embriologia , Virilismo/etiologiaRESUMO
Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency (21-OHD) is the most common inherited defect of adrenal steroid biosynthesis. At least 36 mutations in the CYP21 gene, which is mapped to chromosome 6p21.3, have been described. We performed genetic analysis of the CYP21 gene in a patient with classic 21-OHD CAH and her family. The entire exonic coding regions and intronic regions, as well as the -1 kb 5' upstream promoter region, were thoroughly sequenced and analyzed. Despite extensive sequencing, no mutation was found in this 3.7 kb area. The 11beta-hydroxylase defect, closely mimicking the clinical and biochemical phenotype of classic 21-OHD, was excluded by directly sequencing 2.6 kb covering the entire coding of the CYP11B1 gene. Herein we describe a phenotypically and hormonally affected patient with classic simple virilizing 21-OHD CAH who lacks a mutation in the entire CYP21 gene and coding region of the CYP11B1 gene.