Songya Pang

Mutations in the type II 3β-hydroxysteroid dehydrogenase gene in a patient with classic salt-wasting 3β-hydroxysteroid dehydrogenase deficiency congenital adrenal hyperplasia

ABSTRACT: Inherited adrenal and gonadal 3β-hydroxy-steroid dehydrogenase (3β-HSD) deficiency is most likely caused by a mutation of the type II 3β-HSD gene. Cloning and sequencing of exons I-II, III, and IV and portions of the adjacent introns, amplified by polymerase chain reaction using primers specific for the type II gene, in one male pseudohermaphrodite with salt-wasting classic 3β-HSD deficiency congenital adrenal hyperplasia revealed the same mutation in all nine clones of exon IV consisting of a missense mutation at codon 248 [GTC (Val) AAC (Asn)] followed by a frameshift mutation at codon 249 [CGA (Arg) TA], resulting in a stop codon TAG, and normal sequences of exon I-II and III and the adjacent portions of introns. The same codon 248 and 249 mutations were found on one clone of his mothers DNA, but two other clones revealed normal sequences. These data indicate a homozygous combined missense/frameshift mutation in exon IV of the type II 3β-HSD gene resulting in severe salt-wasting adrenal and gonadal 3β-HSD deficiency in the patient.

Carriers for type II 3β‐hydroxysteroid dehydrogenase (HSD3B2) deficiency can only be identified by HSD3B2 genotype study and not by hormone test

objective We investigated adrenal steroidogenic function relevant to 3β‐hydroxysteroid dehydrogenase (HSD3B2) activity in vivo and HSD3B2 genotype in clinically normal family members of patients with HSD3B2 genotype‐proven HSD3B2 deficiency congenital adrenal hyperplasia (CAH) to determine whether genotype‐proven carriers for HSD3B2 deficiency exhibit decreased enzyme activity analogous to the mildly decreased adrenal 21‐hydroxylase activity in the carriers of CYP21 gene mutation.

HORMONAL MONITORING AND SIDE EFFECTS OF PRENATAL DEXAMETHASONE (DEX) TREATMENT FOR 21-HYDROXYIASE DEFICIENCY CONGENITAL ADRENAL HYPERPIASIA (CAH)

Maternal Dex therapy for fetal CAH at 1-1.5 mg daily initiated between 5-8 weeks gestation and continued to birth, resulted in normal genital outcome, mild virilization, and significant genital virilization in the three CAH newborns treated, and significant side effects in the three mothers, including excess weight gain (9-26 Ibs greater at 35-37 weeks gestation compared to previous full-term pregnancies), glucose intolerance, facial hirsutism, and Cushingoid features including moon-face, plethora, markedly discolored striae on arms, abdomen, breast, and thighs, which resulted in permanent scarring. In addition, hypertension, epigastric pain, and emotional lability were noted, but not consistently. Amniotic fluid 17-OH Progesterone, androstenedione, and testosterone, were elevated in all three Dex treated cases. Maternal EI level was consistently suppressed in the case with the normal genital outcome, and were initially unsuppressed in the cases with mild and severe genital virilization.Conclusion: Dex therapy for prenatal treatment of CAH at a dose of 1-1.5 mg daily was associated with significant maternal side effects. Amniotic fluid steroid levels may not be useful, while maternal serum E1 level may be useful for therapeutic monitoring of fetal CAH, this however requires further investigation.

3α-Androstanediol Glucuronide in Virilizing Congenital Adrenal Hyperplasia: A Useful Serum Metabolic Marker of Integrated Adrenal Androgen Secretion

To determine whether serum 3 alpha-androstanediol glucuronide (3AG) reflects the overall effect of integrated adrenal androgen secretion in the virilizing form of congenital adrenal hyperplasia (CVAH), circadian levels (0800, 1200, 1600, and 2000 h) of serum 3AG and 17-hydroxyprogesterone (17OHP) or 11-deoxycortisol (S), androstenedione (A), testosterone (T), and 24-h urinary 17-ketosteroids (17KS) were examined in seven patients (pts) with classical 21-hydroxylase deficiency (21OHD) and one pt with classical 11 beta-hydroxylase deficiency (11 beta OHD). Hormonal studies were conducted during the second day of dexamethasone (Dex) administration (2 mg/day). In five poorly controlled CVAH pts, including the 11 beta OHD pt, highly elevated baseline morning (AM) serum 17OHP or S as well as A levels, and elevated AM T levels in three pts decreased markedly in the evening (PM), while elevated serum 3AG showed no significant circadian changes; 17KS levels were markedly elevated for age. During Dex, moderately or slightly elevated AM 17OHP, A, or T in two to four pts with 21OHD decreased to the normal range in the PM. In the pt with 11 beta OHD, S, A, and T levels were suppressed. 3AG levels were modestly elevated or normal, without circadian changes, in these pts; 17KS levels were elevated or normal. In two other 21OHD pts, modestly elevated AM baseline 17OHP and A levels decreased in the PM; elevated AM T decreased in one pt in the PM; modestly elevated 3AG levels showed no circadian changes; 17KS levels were modestly elevated. During Dex, normal or slightly elevated serum steroids and 17KS levels were associated with normal or high normal 3AG levels without circadian changes. In one postpubertal female with 21OHD, modestly elevated AM baseline 17OHP levels decreased at 2000 h; normal A and T levels throughout the day and low normal 17KS were associated with slightly low 3AG levels, without circadian variation. During Dex treatment, normal 17OHP, A, T, and low 17KS levels were associated with low 3AG levels without circadian variation. In all pts as a group, an excellent correlation (r = 0.9) was found between either 0800 h or mean, or 2000 h serum 3AG levels and 17KS. In addition, AM and PM serum 3AG levels in five normal women were similar. We conclude that the high correlation between serum 3AG and urinary 17KS and the absence of a significant circadian variation in 3AG indicate that serum 3AG, regardless of sample time, is a useful metabolic index of integrated adrenal androgen secretion in CVAH.

ACTH AND ADRENAL STEROID REPONSE TO CORTICOTRCPIN RELEASING FACTOR (CRF) STIMULATION IN PATIENTS WITH A GENETIC DEFECT IN ADRENAL STEROIDOGENESIS

To investigate the pathophysiology of hypothalamic-pituitary-adrenal axis in patients (pt) with a mild defect in adrenal steroidogenesis, ACTH and adrenal steroid response (180 min) to ovine CRF (1 ug/kg IV bolus at 1600 hr) in 3 pt with late diagnosis of 11β-hydroxylase (11β-OH) deficiency (def) and in 7 pt with late-onset 21-hydroxylase def (21-OH) or 3β-ol dehydrogenase def (3β-HSD) were compared with the responses in 8 controls. In all pt, levels of adrenal precursor steroids proximal to the particular enzyme block were high following CRF. Basal and CRF-stimulated ACTH & F levels were normal irrespective of enzyme def or magnitude of the rise of the precursor steroid in all pt but 2 (11β-OH def) in whom ACTH response to CRF was high and F response low, with lower precursor steroid response than in the pt with normal ACTH and F.Conclusion: In pt with defects in adrenal steroidogenesis, compensatory ACTH hypersecretion occurs only when F secretion is inadequate. Normal ACTH secretion is seen in pt with normal F secretion despite increased precursor steroids. Mechanism for normal F without excess ACTH remains to be defined.