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Submitted on August 4, 2004
Accepted on November 3, 2004
-Hydroxysteroid Dehydrogenase Deficiency in Patients with Premature Pubarche and Hirsutism Based on HSD3B2 Genotyping
Departamento de Clinica Medica and Departamento de Fisiologia School of Medicine of Ribeirao Preto - University of Sao Paulo, Ribeirao Preto, SP, Brazil, 14049-900; Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular, School of Medicine of University of Sao PauloSao Paulo, SP, Brazil
* To whom correspondence should be addressed. E-mail: castrom{at}fmrp.usp.br.
Congenital adrenal hyperplasia (CAH) due to 3
-hydroxysteroid dehydrogenase/
5-4-isomerase (3HSD), a rare autosomal recessive disorder that affects both sexes, has a heterogeneous clinical presentation ranging from the severe salt-wasting to the nonsalt-wasting forms and results from mutations in the HSD3B2 gene. The hormonal criteria for diagnosing the mild variant of 3HSD deficiency have been controversial because the initial studies were not based on genetic evidence. We investigated the relationship between the hormonal phenotype and HSD3B2 genotype in 22 patients with clinical and/or biochemical features suggestive of 3HSD2 deficiency, including 9 female children with premature pubarche, 12 hirsute females and 1 boy with salt-wasting and ambiguous genitalia. Serum 17-hydroxypregnenolone (5-17P), cortisol (F), 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone (DHEA), and androstenedione (4-A) levels were determined by RIA and were compared with Tanner pubic hair stage-matched control groups. The genomic DNA was extracted and the entire HSD3B2 gene was amplified by PCR followed by automatic sequencing. Besides 2 different mutations previously observed in 3 patients (T259M and G129R/P222Q mutations), we observed the P222Q mutation in the male patient with salt-wasting form of 3HSD2 deficiency. Basal and ACTH-stimulated 5-17P levels (nmol/liter) ranged from 4 to 41 (-0.2 to 14 SD) and 36 to 97 (3.5 to 15.5 SD), respectively, in patients without mutation in HSD3B2 and from 69 to 153 (25 to 57 SD) and 201 to 351 (36 to 65 SD), respectively, in patients with mutation in HSD3B2. Basal and ACTH-stimulated 5-17P to F ratios ranged from 11 to 159 (0.5 to 25 SD) and 42 to 122 (2.4 to 11.3 SD), respectively, in patients without mutation in HSD3B2 and from 181 to 1700 (29 to 282 SD) and 487 to 1523 (52 to 167 SD), respectively, in patients with mutation in HSD3B2. The hormone findings in the genotype-proven patients suggest that the following hormonal criteria are compatible with 3HSD2 deficiency in children with premature pubarche: ACTH-stimulated 5-17P and 5-17P to F ratios at or greater than 201 nmol/liter and 487 nmol/liter, respectively, equivalent to or greater than 36 SD and 52 SD above matched control mean. Basal and ACTH-stimulated 5-17P and 5-17P to F ratios in all genotype-proven patients in childhood were unequivocally higher than the levels of either genotype-normal patients. All the other parameters overlapped between the patients with and without mutations in HSD3B2 gene. In conclusion, genotyping more patients in the present study, we confirm that patients with mutations in HSD3B2 gene have extremely elevated basal and ACTH-stimulated 5-17P levels and 5-17P to F ratios. Therefore, these data refine the hormonal criteria proposed to predict more accurately 3HSD2 deficiency.
HSD deficiency •
mutations •
premature pubarche •
hirsutism
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