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Newly Proposed Hormonal Criteria via Genotypic Proof for Type II 3β-Hydroxysteroid Dehydrogenase Deficiency

2002; Oxford University Press; Volume: 87; Issue: 6 Linguagem: Inglês

10.1210/jcem.87.6.8615

1945-7197

Chantal Lutfallah, Weihua Wang, J. Ian Mason, Ying Chang, Anzar Haider, Barry H. Rich, Mariano Castro‐Magana, Kenneth C. Copeland, Raphael David, Songya Pang,

Sexual Differentiation and Disorders

To define the hormonal criteria via genotypic proof for 3β-hydroxysteroid dehydrogenase (3β-HSD) deficiency in the adrenals and gonads, we investigated the type II 3β-HSD genotype in 55 patients with clinical and/or hormonal presentation suggesting compromised adrenal with or without gonadal 3β-HSD activity. Fourteen patients (11 males and 3 females) had ambiguous genitalia with or without salt wasting and with or without premature pubarche. One female neonate had salt wasting only. Twenty-five children (4 males and 21 females) had premature pubarche only. Fifteen adolescent and adult females had hirsutism with or without menstrual disorder. The type II 3β-HSD gene, including the promoter region up to −1053 base, all exons I, II, III, IV, and exon and intron boundaries, was sequenced in all subjects. Eight patients had a proven or predictably deleterious mutation in both alleles of the type II 3β-HSD gene, and 47 patients had no apparent mutation in the gene. ACTH-stimulated (1 h post iv bolus of 250 μg Cortrosyn) serum 17-hydroxypregnenolone (Δ5–17P) levels and basal and ACTH-stimulated ratios of Δ5–17P to cortisol (F) in the genotypic proven patients were unequivocally higher than those of age-matched or pubic hair stage matched genotype-normal patients or control subjects (n = 7–30 for each group). All other baseline and ACTH-stimulated hormone parameters, including dehydroepiandrosterone (DHEA) levels, ratios of Δ5–17P to 17-OHP and DHEA to androstenedione in the genotype-proven patients, overlapped with the genotype-normal patients or control subjects. The hormonal findings in the genotype-proven patients suggest that the following hormonal criteria are compatible with 3β-HSD deficiency congenital adrenal hyperplasia (numeric and graphic reference standards from infancy to adulthood are provided): ACTH-stimulated Δ5–17P levels in 1) neonatal infants with ambiguous genitalia at or greater than 378 nmol/liter equivalent to or greater than 5.3 sd above the control mean level [95 ± 53 (sd) nmol/liter]; 2) Tanner I children with ambiguous genitalia at or greater than 165 nmol/liter equivalent to or greater than 35 sd above the control mean level [12 ± 4.3 (sd) nmol/liter]; 3) children with premature pubarche at or greater than 294 nmol/liter equivalent to or greater than 54 sd above Tanner II pubic hair stage matched control mean level [17 ± 5 (sd) nmol/liter]; and 4) adults with at or greater than 289 nmol/liter equivalent to or greater than 21 sd above the normal mean level [25 ± 12 (sd) nmol/liter]. ACTH-stimulated ratio of Δ5–17P to F in 1) neonatal infants at or greater than 434 equivalent to or greater than 6.4 sd above the control mean ratio [88 ± 54 (sd)]; 2) Tanner I children at or greater than 216 equivalent to or greater than 23 sd above the control mean ratio [12 ± 9 (sd)]; 3) children with premature pubarche at or greater than 363 equivalent to or greater than 38 sd above the control mean ratio [20 ± 9 (sd)]; and 4) adults at or greater than 4010 equivalent to or greater than 221 sd above the normal mean ratio [29 ± 18 (sd)]. Conversely, the hormonal data in the genotype-normal patients suggest the following hormonal criteria are not consistent with 3β-HSD deficiency congenital adrenal hyperplasia: ACTH-stimulated Δ5–17P levels in children with premature pubarche up to 72 nmol/liter equivalent to up to 11 sd above the control mean level, and in hirsute females up to 150 nmol/liter equivalent to up to 12 sd above the normal female mean level [28 ± 10 (sd) nmol/liter]; and ACTH-stimulated Δ5–17P to F ratio in children with premature pubarche up to 67 equivalent to up to 5 sd above the control mean ratio, and in hirsute females up to 151 equivalent to up to 10 sd above the normal mean ratio [32 ± 12 (sd)]. These findings help define newly proposed hormonal criteria to accurately predict inherited 3β-HSD deficiency.