IMPE Abstracts

Adrenal hypoplasia congenita due to NR0B1 pathogenic variations accounts for more than 50% of children with primary adrenal insufficiency. Although more than 230 different deleterious variations have already been described, no genotype-phenotype correlation had been defined so far. Frequently, clinical manifestations include salt-losing adrenal failure, in association with hypogonadotropic hypogonadism (HH) at puberty and infertility at adulthood. We report a case of an adopted boy with X-linked congenital adrenal hypoplasia who had the first onset of adrenal crisis at 2 weeks of life, requiring replacement therapy with mineralocorticod and glucocorticoid for 4 months. For 3 years he did well, remaining without treatment when, at almost 4 years of age, the disorder was definitely reintroduced. The long follow-up showed his evolution to hypogonadotropic hypogonadism. Molecular studies on NR0B1revealed a novel and deleterious deletion-inversion-deletion complex rearrangement, characterized by deletion of the intergenic region (between Cxorf 21 and NR0B1 genes) and 5'UTR region, inversion of part of exon 1, deletion of the final portion of exon 1 and exon 2 and beginning of the 3'UTR region, maintenance of part of the intergenic sequence (between genes MAGEB1 and NR0B1, telomeric sense), large posterior deletion, in the same sense. The path taken to reach molecular diagnosis was challenging and involved several molecular biology techniques. Electrophoresis analysis could identify the deletions, confirmed by MLPA (multiplex ligation-dependent probe amplification). Sanger sequencing identified the presence of the inversion. Using the array-CGH technique, we were able to delimit the size of the deletions, but only with whole genome sequencing (WGS) were we able to detail the rearrangement with its breakpoints. Several authors have highlighted the frequent presence of complex rearrangements on the X chromosome due to the local genomic architecture, composed of repeat sequences such as LCRs (low copy repeats, Alu elements etc.). Evaluating the breakpoints in our patient, we assumed that it is a non-recurrent rearrangement, not yet described, by a probable mechanism of DNA replication-based mechanism of fork stalling and template switching (FoSTeS), microhomolgy-mediated break induction (MMBIR), a new mechanism suposed to explain most non-recurrent genomic rearrangements associated with an X-linked disorder. The importance of describing this type of structural change is to help us to understand the local architecture and the particular mechanisms for rearrangement formation, contributing to guide studies about the potential causes of human disease.