ESPE Abstracts

Background: When a baby presents with atypical genitalia, the most important diagnosis to consider is 21-hydroxylase deficiency (21OHD, CAH, 46,XX). However, primary adrenal insufficiency (PAI) can also occur in 46,XY children with differences in sex development (DSD), although this is less common. Known causes of 46,XY DSD-PAI include high blocks in steroidogenesis (STAR, CYP11A1); steroidogenic enzyme defects (HSD3B2, CYP17A1, POR); syndromic associations (Smith-Lemli-Opitz, DHC7R; IMAGe, CDKN1C; MIRAGE, SAMD9), and very rarely, defects in steroidogenic factor-1 (NR5A1). The relative prevalence of these conditions is not known, nor how best to investigate for them in 46,XY DSD.

Methods: Case notes were reviewed of 316 children with 46,XY DSD presenting to a single tertiary centre multidisciplinary team over 25 years. Children were identified who had been diagnosed with PAI and treated with steroid replacement. Clinical, biochemical, and genetic data were obtained. Basal cortisol, standard synacthen-stimulated peak cortisol and incremental rise, and basal ACTH were analysed for those children with PAI, and compared to a “control” group of children being investigated for 46,XY DSD with normal adrenal function (n = 57).

Results: A total of 10 out of 316 (10/316, 3.2%) children with 46,XY DSD were diagnosed with PAI. Five of these children (1.6%) were diagnosed with PAI first: three of them were 46,XY phenotypic girls in whom DSD was not suspected (two with congenital lipoid adrenal hyperplasia (STAR), one with complete 17α-hydroxylase/17,20 lyase deficiency (CYP17A1)) and two of them had syndromic features that led to the diagnosis (Antley-Bixler Syndrome (POR), IMAGe Syndrome (CDKN1C)). Five children (1.6%) presented with 46,XY DSD/genital differences and were diagnosed with PAI through adrenal investigations: two of them had 3β-hydroxysteroid dehydrogenase deficiency type 2 (HSD3B2), two had partial 17a-hydroxylase/17,20 lyase deficiency (CYP17A1), and one had fetal growth restriction/PAI of unknown aetiology. For these five children, basal ACTH (>60 ng/l) had a sensitivity of 100% and specificity of 88%. Specificity was higher if basal cortisol was <150 nmol/l, and if synacthen-stimulated peak or incremental cortisol was suboptimal. Hyperpigmentation, salt loss and ancestral background provided additional clues. Urine steroid profiles and genetic testing were usually diagnostic.

Conclusion: PAI in 46,XY DSD is an important diagnosis to consider with short- and long-term consequences, but it is uncommon (3.2% of our cohort). For those children presenting primarily with DSD/genital differences, basal ACTH is a useful investigation if turn-around time is quick.