Background: Over the last 25 years more than 410 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. Mutations in the MC2R were first discovered as causative of FGD in 1993, by candidate gene sequencing.
Objective and methods: To determine the underlying cause of FGD by Sanger, targeted or whole exome sequencing techniques.
Results: A further 8 genes have been identified in our cohort in the temporal order of; MRAP, STAR, MCM4, NNT, TXNRD2, SGPL1 and CYP11A1, made possible through advances in genetic techniques from homozygosity mapping to whole exome sequencing. 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 and the resulting phenotypes are caused by defective ACTH signalling, cholesterol transport, steroidogenesis, cellular redox homeostasis, DNA replication or sphingolipid metabolism. The discovery of such genes, and subsequent functional assays of the respective proteins, have provided some explanation for the variability of the phenotype and association(s) with other co-morbidities. The work has highlighted 'mild' presentations of several adrenal insufficiency disorders, in particular 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 ethnically isolated population with a 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, hypothyroidism, immunodeficiency and neurologic defects.
Conclusion: With recent funding, we are currently analysing the long-term outcome of diagnosed individuals to study the evolution of features such as mineralocorticoid deficiency and pubertal progression. 34% of our cohort remains unsolved, to decipher whether the causative defects are in non-coding parts of known genes, are due to copy number variation or novel genetic aetiologies will form complementary future studies to improve the diagnosis of patients presenting with FGD.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology