ESPE Abstracts

Background and objective: The first and rate-limiting step of steroidogenesis is the conversion of cholesterol to pregnanolone which is catalyzed by the P450scc side chain cleavage enzyme (encoded by CYP11A1 gene-SCC). Homozygous recessive mutations of the CYP11A1 gene cause a global steroid hormone deficiency thereby disorders of sexual development in 46, XY individuals with a variable phenotype depending on the mutation characteristics. About 60 cases of SCC deficiency due to CYP11A1 gene mutation have been reported so far. The most common mutation is the c.1351C>T (p.R451W) mutation, which has been detected in 12 cases. We, herein, present the clinical characteristics of 14 cases presented with adrenal insufficiency due to p.R451W mutation in the CYP 11A1 gene.

Design and method: Data were retrospectively collected from tertiary pediatric endocrine centers using a standardized proforma. Family history, presenting age, clinical, biochemical, and hormonal characteristics, treatment options, and the follow-up characteristics obtained during their latest follow-up visits were recorded.

Results: 14 patients (M/F:7/7) from 10 consanguineous Turkish families were recruited. The mean age of the diagnosis was 3.8±2.4(Range: 1.04-8.5 years). All of the male subjects were completely virilized with no sign of DSD. The main presenting complaints were signs and symptoms of primary adrenal insufficiency. However, despite having signs and symptoms 3 subjects were diagnosed when investigated due to the history of their affected siblings. While glucocorticoid deficiency (elevated ACTH, low cortisol) was present in all cases, none of the male cases had undervirilization excluding androgen deficiency. Mild mineralocorticoid (MC) deficiency was detected in 10/14 of the cases which were recovered in 2 subjects during follow-up. More strikingly, one patient with no MC deficiency at presentation had developed a salt-wasting adrenal crisis during acute illness. Although a deterioration was detected in height SDS, there was not a statistically significant difference between height SDS at presentation (-0.64±1.4), at the latest follow-up visit(-0.90±1.4), and target height SDS (-0.63±0.6).

Conclusion: In the present largest case series with a p.R451W mutation in the CYP11A1 gene our results confirmed a milder phenotype for all steroid hormones. Particularly lack of virilization defect in male subjects, and lack of salt-wasting crisis until a relatively late age of diagnosis suggested mild MC and androgen deficiency. Nevertheless, lack of MC deficiency at presentation does not exclude the risk of developing a salt-wasting adrenal crisis. Therefore special caution requires for patients with no MC replacement, particularly during acute illnesses.