ESPE Abstracts

Background: X-linked congenital adrenal hypoplasia (adrenal hypoplasia congenita, AHC) is a rare life-threating disorder due to pathogenic variants in the NR0B1 gene. It encodes DAX-1, an orphan nuclear hormone receptor, that acts as a transcription factor and is expressed in the adrenals and hypothalamus-pituitary-gonadal (HPG) axis. Therefore, apart from primary adrenal insufficiency, patients present incomplete or absent puberty and infertility due to hypogonadotropic hypogonadism (HH). However other puberty patterns were described including normal puberty, peripheral precocious puberty, ACTH-dependent precocious puberty, and GnRH-dependent precocious puberty. Here, we present a cohort of patients with AHC and different puberty patterns.

Material and methods: 11 patients from 6 families were studied. Pathogenic variants in the NR0B1 gene were identified by direct sequencing and the deletion encompassing NR0B1 and MAGEB1-4 genes by array comparative genomic hybridization.

Results: All patients presented with neonatal onset of adrenal insufficiency with salt-losing. None of the patients exhibited cryptorchidism and/or micropenis – clinical red flags of HH in infancy. One patient presented with acquired cryptorchidism of the left testicle at the age of 10 years and 8 months. Adrenals were described as hypoplastic on ultrasound in 3 out of 11 patients. Five out of 6 patients that achieved pubertal age developed hypogonadotropic hypogonadism and were subsequently treated with testosterone. Remaining patient developed central precocious puberty (CPP) at the age of 8 years and 10 months with fast progression, that was subsequently arrested before final completion (decrease in testicular volume, lack of increase of inhibin B concentration). Hormonal assessment during minipuberty was performed in 3 patients. However, its prognostic value for future puberty is of limited value, as only one patient achieved pubertal age. The hormonal profile was normal (LH 4.2 U/l, FSH 1.8 U/l, testosterone 4.6 nmol/L), however the patient exhibited CPP with subsequent arrest.

Conclusions: Although AHC is mostly associated with HH, different puberty patterns may be observed. It is important to follow-up on HPG function, as it may be disrupted with time. Systematic hormonal assessment of minipuberty in patients suspected of AHC should be performed in order to investigate its prognostic value for future puberty.