3?-hydroxysteroid dehydrogenase type II deficiency on newborn screening test / Deficiência de 3?-hidroxiesteroide desidrogenase tipo 2 em teste de triagem neonatal

3b-hydroxysteroid dehydrogenase II (3β-HSD) deficiency represents a rare CAH variant. Newborns affected with its classic form have salt wasting in early infancy and genital ambiguity in both sexes. High levels of 17-hydroxypregnenolone (Δ517OHP) are characteristic, but extra-adrenal conversion to 17-hydroxyprogesterone (17OHP) may lead to positive results on newborn screening tests. Filter paper 17OHP on newborn screening test was performed by immunofluorometric assay, and serum determinations of 17OHP and Δ517OHP, by radioimmunoassay. A 46,XY infant with genital ambiguity and adrenal crisis at three months of age presented a positive result on newborn screening for CAH. Serum determinations of 17OHP and Δ517OHP were elevated, and a high Δ517OHP/cortisol relation was compatible with the diagnosis of 3β-HSD deficiency. Molecular analysis of the HSD3B2 gene from the affected case revealed the presence of the homozygous p.P222Q mutation, whereas his parents were heterozygous for it. We present the first report of 3β-HSD type II deficiency genotype-proven detected at the Newborn Screening Program in Brazil. The case described herein corroborates the strong genotype-phenotype correlation associated with the HSD3B2 p.P222Q mutation, which leads to a classic salt-wasting 3β-HSD deficiency. Further evaluation of 17OHP assays used in newborn screening tests would aid in determining their reproducibility, as well as the potential significance of moderately elevated 17OHP levels as an early indicator to the diagnosis of other forms of classic CAH, beyond 21-hydroxylase deficiency.

A deficiência da enzima 3β-hidroxiesteroide desidrogenase tipo 2 (3β-HSD) representa variante rara de hiperplasia adrenal congenital (HAC). Recém-nascidos afetados com a forma clássica apresentam perda de sal nas primeiras semanas de vida e ambiguidade genital em ambos os sexos. Concentrações elevadas de 17-hidroxipregnenolona (Δ517OHP) são características, porém sua conversão extra-adrenal a 17-hidroxiprogesterona (17OHP) pode resultar em resultados positivos no teste de triagem neonatal. A determinação da concentração de 17OHP obtida em amostra de sangue colhida em papel-filtro para triagem neonatal foi realizada por ensaio imunofluorimétrico, e as concentrações séricas de 17OHP and Δ517OHP, por radioimunoensaio. Um menino, 46,XY, com ambiguidade genital e crise adrenal aos 3 meses de vida, apresentou teste positivo na triagem neonatal para HAC. As concentrações séricas de 17OHP e Δ517OHP estavam aumentadas, bem como a relação Δ517OHP/cortisol, o que foi compatível com o diagnóstico de deficiência de 3β-HSD. A análise molecular do gene HSD3B2 revelou a mutação p.P222Q em homozigose na criança afetada e em heterozigose em seus pais, o que confirmou a deficiência de 3β-HSD com resultado moderadamente elevado na dosagem de 17OHP no “Teste do Pezinho” (Programa de Triagem Neonatal do Distrito Federal, Brasil). Esse caso corrobora a forte correlação genótipo-fenótipo associada à mutação p.P222Q no gene HSD3B2. Estudos futuros para avaliação dos ensaios utilizados na triagem neonatal para determinação de 17OHP poderão auxiliar na determinação do significado potencial de concentrações moderadamente elevadas de 17OHP como um indicador precoce para o diagnóstico de outras formas de HAC clássicas, além da deficiência de 21-hidroxilase.

Late onset adrenal hyperplasia due to 3 beta-hydroxy-delta 5-steroid dehydrogenase deficiency in north Indian hirsute women.

The presence of late onset 3 beta-hydroxy steroid dehydrogenase (3 beta-HSD) type of congenital adrenal hyperplasia was studied in 58 north Indian hirsute women. The age range of these patients was 15 to 42 yr. Fifty two per cent of these patients had body mass index > 25. Basal serum testosterone, luteinizing hormone, follicle stimulating hormone, dehydroepiandrosterone sulphate (DHEAS), and 17 hydroxy progesterone (17 OHP) were estimated. All the patients underwent adrenocorticotropin (ACTH) stimulation test after an overnight dexamethasone suppression for the estimation of DHEAS, 17 OHP, and 17 hydroxy pregnenolone (delta 5-17p). Five (8.6%) hirsute women showed an exaggerated 17 OHP response to ACTH indicating 21-hydroxylase deficiency. Eight (13.8%) hirsute women had elevated basal DHEAS and ACTH-stimulated DHEAS as well as delta 5-17P responses indicative of 3 beta-HSD deficiency. In one patient hirsutism was the presenting manifestation of tumoural hyperandrogenism. Our findings indicate the presence of both 21-hydroxylase and 3 beta-HSD deficiency in north Indian hirsute women, with, 3 beta-HSD deficiency being the major cause of hirsutism in this population.