ESPE Abstracts

Background: X-linked AHC is a rare disorder of the adrenal cortex caused by mutations in the NR0B1 (DAX1) gene. NR0B1 (DAX1) encodes for an orphan nuclear hormone receptor which is expressed in the adrenal, gonad, hypothalamus, and pituitary glands. Hypogonadotropic hypogonadism (HH) is the most frequently observed puberty disorder (absent or delayed puberty) caused by mutations in the NR0B1 (DAX1) gene and is due to impaired gonadotropin synthesis and release.

Objective and hypotheses: The aim of the study was to investigate the clinical phenotype of eight boys with congenital adrenal hypoplasia due to NR0B1 (DAX1) mutation.

Results: All patients had postnatally normal male external genitalia and intrascrotal location of testes apart from one unilateral (patient 6) due to anatomical reasons. A novel mutation c.315G>A (W105X) was detected in patients 1 and 2, a known mutation c.A1319>T (p.Asn440Ile) in exon 2 in patient 3 and a known mutation c.C109>T (p.Gln37X) in exon 1 in patient 4. In patients 5 and 6 a NR0B1 (DAX1) gene deletion coexisted with the deletion of other neighbouring genes (MAGE family genes). Boys 7 and 8 presented coexisting HH but manifested later by lack of spontaneous puberty. Patient 7 had a novel mutation c.T1118>G (p.Ile373Ser) in exon 1 and patient 8 had a known mutation c.A1319>T (p.Asn440Ile) in exon 2. Both had low peak levels of LH and FSH on LHRH test and both had GH deficiency.

Conclusion: The onset of adrenal failure in our patients was in neonatal period but the clinical manifestation of HH was in pubertal period in two of them (six patients are still prepubertal). To date, there is no clear evidence for genotype-phenotype correlation in our group of patients. Genetic counseling in families with congenital adrenal hypoplasia (AHC) patients is mandatory to predict those at risk of HH manifestation later in life.