Mutation analysis in the family of a child with 21-hydroxylase deficiency showed that the father and affected child were homozygous for a mutation, A/C655G, believed to activate a cryptic splice site in intron 2 of the 21-hydroxylase gene. The father, who was clinically asymptomatic, showed no biochemical evidence of disease. These results create problems for the management of future pregnancies in such families and for the interpretation of the risk associated with carrier status for this mutation.
An 18-year-old woman with primary amenorrhoea and pubertal delay was investigated for mild labile hypertension and secondary hypogonadism. Low renin and normal aldosterone levels combined with evidence of primary adrenal insufficiency suggested partial 17-alpha hydroxylase enzyme deficiency. The diagnosis was confirmed by measurement of 24-hour urine steroid metabolites and whole gene sequencing of CYP17A1 that demonstrated c.160_162delTTC (p.Phe54del) homozygous mutation. Ultrasound showed bilateral small ovaries with multiple cysts. The serum anti-mullerian hormone concentration was unremarkable at 6.6 (normal <12.6 ng/ml) but the outlook for her future ovulatory potential is uncertain. Dexamethasone 0.25 mg pre-bed and hydrocortisone 5 mg on waking normalised her hormonal profile and her blood pressure without side-effects.
Summary Objective Fertility in women with classical congenital adrenal hyperplasia (CAH) has been reported low; however, the true pregnancy rate for women trying to conceive with this condition is unknown. Our aim was to calculate pregnancy rate for women with CAH calculated as a proportion of those who had attempted conception. Fertility expressed as live birth rate is also calculated. Patients One hundred and six women with classical CAH followed in a multidisciplinary service [81 salt‐losing (SL) and 25 nonsalt‐losing (NSL) form]. Results Twenty‐five (23·6%) women with CAH women considered motherhood, 23 had actively tried conception of whom 21 (91·3%) achieved 34 pregnancies. Pregnancy rate is no different from that in the normal population (95%). Pregnancy rates were similar in the SL (88·9%) and NSL (92·9%) subgroups but those with NSL‐CAH were more likely to seek motherhood than those with SL‐CAH (16/25 vs. 9/81). Optimized glucocorticoid and mineralocorticoid regimes during fertility monitoring resulted spontaneous conception in nearly all recent cases. Fertility rate was 0·25 live births per woman compared with 1·8 in the UK population ( P < 0·001). Conclusion We report a normal pregnancy rate (91·3%) for women with classical CAH, similar in SL and NSL subgroups. Fertility rate, however, remains much lower than in general population.
Variations in phenotype in 21-hydroxylase deficiency (21OHD) have cautioned against initiating treatment in the absence of abnormal clinical features. We report 2 Caucasian brothers with compound heterozygous mutations of the CYP21 gene and mild clinical and biochemical features of late-presenting 21OHD. The index case presented aged 8.5 years with mild genital virilization and bone age advanced by 5 years. Elevated basal and synacthen-stimulated 17-hydroxyprogesterone (17OHP; 22.4 and 246 nmol/l) and androstenedione (10.9 and 19.9 nmol/l) levels confirmed 21OHD. His younger brother was investigated at age 7.3 years, and although examination showed normal pre-pubertal genitalia, basal and synacthen-stimulated 17OHP (32.4 and 281 nmol/l) and androstenedione (6.2 and 9.0 nmol/l) were abnormal, and bone age was advanced by 1.5 years. Because of actual or incipient virilization, both patients were treated with glucocorticoid replacement 8–12 mg/m<sup>2</sup>/day. This decision is discussed in the context of published guidelines for the management of 21OHD.
DNA was analysed from 33 patients with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency. In each case Southern blots were prepared from a number of restriction enzyme digests and hybridised with probes for both the 21-hydroxylase and the adjacent fourth component of complement (C4). Evidence for deletion of the active 21-hydroxylase gene (CYP21B) was found in 13 cases and in 10 of these the deletion included the adjacent C4B gene, leading to a hybrid CYP21A/CYP21B gene. Deletion of CYP21B alone was found in one patient, the remaining two cases appearing to have the active gene replaced by the inactive pseudogene. Duplications of the CYP21A-C4B region and deletion of the pseudogene are also described. In a further 12 cases no gross abnormality could be found.
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