ABSTRACT
ABSTRACT Androgenic insensitivity syndrome is the most common cause of disorders of sexual differentiation in 46,XY individuals. It results from alterations in the androgen receptor gene, leading to a frame of hormonal resistance, which may present clinically under 3 phenotypes: complete (CAIS), partial (PAIS) or mild (MAIS). The androgen receptor gene has 8 exons and 3 domains, and allelic variants in this gene occur in all domains and exons, regardless of phenotype, providing a poor genotype - phenotype correlation in this syndrome. Typically, laboratory diagnosis is made through elevated levels of LH and testosterone, with little or no virilization. Treatment depends on the phenotype and social sex of the individual. Open issues in the management of androgen insensitivity syndromes includes decisions on sex assignment, timing of gonadectomy, fertility, physcological outcomes and genetic counseling.
Subject(s)
Humans , Male , Female , Androgen-Insensitivity Syndrome/genetics , Androgen-Insensitivity Syndrome/therapy , Phenotype , Androgen-Insensitivity Syndrome/physiopathology , Hormone Replacement TherapyABSTRACT
Objective To explore the clinical features and molecular diagnosis of 46, XY disorder of sex development (46, XY DSD).Methods The clinic data of one child with 46, XY DSD raised as female were retrospectively analyzed, and related literatures were reviewed.Results The 11.5-year-old child raised as female visited clinic due to, “accidently found clitoral hypertrophy for half month”. Preliminary series of laboratory examinations supported the diagnosis of 46, XY DSD, high gonadal hormone dysplasia. DNA sequencing of the whole genome exon group showed a heterozygous mutation of c.937C>T, p.Arg313Cys inNR5A1 gene. No abnormality was detected in her father, while her mother was a heterozygous mutation carrier. Conclusions 46, XY DSD can be diagnosed by the whole genome exon gene sequencing.
ABSTRACT
Combined 17alpha-hydroxylase/17,20-lyase deficiency is a rare, autosomal recessive form of congenital adrenal hyperplasia characterized by the coexistence of hypertension, caused by the hyperproduction of mineralocorticoid precursors and DSD in males and sexual infantilism in females, due to impaired production of sex hormones. Several CYP17 mutations resulting in 17alpha-hydroxylase/17,20-lyase deficiency have been reported previously. In the present study, we described a novel CYP17 mutation in two Brazilian sisters with primary amenorrhea, 46,XY karyotype, high basal levels of progesterone (3.4-4.9 ng/mL) and hypokalemic hypertension born to consanguineous parents. After PCR and automatic sequencing of CYP17 coding region, 25 bp duplication at exon 5 was found in the patients. This duplication started at codon 318 resulting in a premature stop codon at position 320 resulting in an ineffective and truncated protein and in accordance with the molecular modeling of P450c17. Therefore we expanded the repertoire of CYP17 mutations describing the largest duplication found in this gene in both sisters, with a clinical phenotype of combined 17alpha-hydroxylase/17,20-lyase deficiency and emphasizes the importance of the P450c 17 molecular modeling to predict the functional effect of these mutations.
A deficiência combinada de 17 alfa-hidroxilase/17,20 liase é uma doença rara, de herança autossômica recessiva, causa de hiperplasia adrenal congênita caracterizada pela presença de hipertensão resultante do acúmulo de precursores mineralocorticóides, distúrbio da diferenciação sexual em homens e infantilismo sexual em mulheres devido à falha na produção de esteróides sexuais. Várias mutações no gene CYP17 resultando em deficiência de 17 alfa-hidroxilase/17,20-liase têm sido descritas. No presente estudo, descrevemos uma nova mutação no CYP17 em duas irmãs, nascidas de pais consangüíneos, com quadro de amenorréia primária, cariótipo 46,XY, dosagens basais elevadas de progesterona (3,4-4,9 ng/mL) e hipertensão hipocalêmica. Após PCR e seqüenciamento automático da região codificadora do CYP17, uma duplicação de 25 pb no exon 5 foi identificada nas pacientes. Esta duplicação inicia-se no códon 318 resultando em parada prematura de leitura no códon 320 gerando uma proteína truncada e inativa conforme predito pela modelagem molecular do P450c17. Com este achado, ampliamos o repertório de mutações do CYP17 descrevendo a maior duplicação descrita até então neste gene em duas irmãs com fenótipo de deficiência combinada de 17 alfa-hidroxilase/17,20-liase e enfatizamos a importância da modelagem molecular do P450c 17 em predizer o efeito funcional destas mutações.