Endocrine Abstracts

Genetic variants causing adrenal insufficiency (AI) are either disrupting corticosteroid production exclusively leading to isolated AI or they are causing additional organ malfunctions as part of a syndromic form of AI. In isolated AI, genetic disorders may affect structure and function of the adrenal cortex or adrenal steroidogenesis specifically, but often also lead to overall disturbances of steroidogenesis affecting other steroid organs (mainly the gonads or the placenta). This can then result in a disorder of sex development (DSD, e.g. congenital adrenal hyperplasia (CAH)) as steroid hormone biosynthesis, regulation and metabolism rely on a common gene network. Nevertheless, cell- and tissue-specific expression and regulation of steroidogenic genes leads to organ-specific steroid production. Genetic variants in core genes of steroid hormone biosynthesis may therefore be recognized by characteristic clinical phenotypes and changes of steroid profiles. However, considerable overlap exists. Although syndromic forms of AI seem easier to recognize through their broader range of typically involved organ systems, this remains theory in many cases. Syndromes with primary AI can manifest similar, oligosymptomatic or atypical mainly because the typical spectrum may only develop over time or simply because the phenotype is only recognized when searched for. Molecular disease mechanisms causing genetic forms of primary AI are manifold and include disorders of steroidogenesis, adrenal dysgenesis (e.g. IMAGe, MIRAGE), familial glucocorticoid deficiency (e.g. MC2R/MRAP, OXPHOS system and ROS detoxification (NNT), metabolic (e.g. SGPL1) and autoimmune disorders (AIRE). Remarkably, only a few variants in genes critically involved in adrenal development, as revealed by basic research studies, have been identified in humans with dysgenetic, syndromic AI. It is highly likely that pathogenic variants of genes essential for adrenal development and beyond are embryonic lethal and thus go undetected. For instance, a homozygous mutation in WNT4 has been found in three fetuses with SERKAL syndrome, characterized by female sex reversal and dysgenesis of kidneys, adrenals, and lungs. In a recent study, we reported a homozygous splice variant in the LGR4 gene within a highly consanguineous family. Offspring with this variant either died in utero or at birth from adrenal salt-wasting crises. Only three affected children survived the neonatal period, and they required early steroid replacement therapy. These survivors manifested symptoms including adrenal insufficiency, hearing loss, nail anomalies, short stature, delayed puberty, and mental retardation. LGR4 is the R-spondin-dependent receptor that stimulates the WNT/β-catenin signaling in the adrenal cortex, playing a crucial role in adrenal cortex zona glomerulosa formation and function, thus aldosterone synthesis.

Key learning points: - Genetic forms of (primary) adrenal insufficiency may manifest isolated or as syndromic forms.

- Clinical characteristics may overlap that a genetic diagnosis is mostly necessary.

- Genotype-phenotype correlation is also variable.

- Genes and pathways involved in adrenal development are excellent candidates for explaining adrenal disorders, but seldom found in patients.

A variant in LGR4, an R-spondin stimulated receptor for activating WNT/β-catenin signaling, has been found in several members of a consanguineous family presenting with a novel syndromic form of isolated mineralocorticoid deficiency.