Endocrine Abstracts (2019) 65 P48 | DOI: 10.1530/endoabs.65.P48

Twenty-five years of familial glucocorticoid deficiency: genotypic and phenotypic variability

CJ Smith, AV Maharaj, R Prasad, C Hughes, Y Qamar, AJL Clark, LF Chan & LA Metherell

William Harvey Research Institute, London, UK

Within the last 25 years more than 400 cases with suspected Familial Glucocorticoid Deficiency (FGD) have been referred to our centre for genetic testing. All cases had low or undetectable serum cortisol paired with an elevated plasma ACTH level. Our patient cohort comprises 352 families from 30 different nationalities and ranges from neonates to patients in their eighties. In 1993 the first gene defect, in MC2R, was discovered by candidate gene sequencing. Subsequently 8 further genes have been identified in our cohort by Next Generation Sequencing technologies, in temporal order; MRAP, STAR, MCM4, NNT, TXNRD2, SGPL1 and CYP11A1. MC2R mutations account for 25% of cases, MRAP for 20%, NNT for 8%, STAR for 7%, CYP11A1 for 3% and MCM4, TXNRD2 and SGPL1 each for 1%. These genes are involved in diverse pathways with phenotypes resulting from defective ACTH signalling, cholesterol transport, steroidogenesis, cellular redox homeostasis, DNA replication or sphingolipid metabolism. Functional assays of the proteins these genes encode, have provided some explanation for the variability of the phenotype and association(s) with other co-morbidities. The work has highlighted non-classical presentations of lipoid congenital adrenal hyperplasia and P450 side-chain-cleavage enzyme deficiency with partial loss-of-function variants in STAR and CYP11A1 respectively. In addition, a few cases have revealed syndromic disease exemplified by the MCM4 variant causing natural killer (NK) cell and glucocorticoid deficiency with DNA repair defect and SGPL1 mutations which cause a syndrome of primary adrenal insufficiency, progressive renal dysfunction plus in some cases ichthyosis, acanthosis, immunodeficiency and neurologic defects. The finding of further gene defects; novel genetic aetiologies, Copy Number Variation or non-coding variation in known genes will improve the diagnosis for the 40% of patients presenting with FGD who currently have no genetic cause identified.

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