Background: Mutations in the side chain cleavage enzyme, (CYP11A1) cause congenital adrenal insufficiency, with complete or partial 46XY sex reversal. The disorder manifests with adrenal and gonadal insufficiencies along with derangements of the renin/angiotensin system.
Objective and hypotheses: To obtain a genetic diagnosis in six patients with adrenal insufficiency of unknown aetiology. Patients 1 and 2 are sisters with ACTH resistance, having high ACTH levels, low glucocorticoids, no response to exogenous ACTH and no pigmentation. Patients 3 and 4 have FGD and subclinical hypothyroidism. The patients are adult now and female patient 4 has suffered three miscarriages. Patient 5, with a diagnosis of lipoid adrenal hyperplasia, presented with adrenal failure in early life with mineralocorticoid and glucocorticoid deficiency and had big adrenals in the neonatal period. Patient 6 had a salt wasting early neonatal history and was hyperpigmented in infancy. He was treated as a case of Addisons disease despite normal renin and aldosterone levels.
Method: Whole exome sequencing was undertaken on genomic DNA of the patients. Variants in seven genes; MC2R, MRAP, STAR, CYP11A1, NNT, MCM4 and TXNRD2 were assessed for causality.
Results: All patients had CYP11A1 mutations; homozygous A359V (patients 1 and 2), compound heterozygous mutations I279Yfs*9 and *122Rext*68 (patients 3 and 4), compound heterozygous R120Q and Q395K (patient 5) and compound heterozygous E314K and an exon5/intron5 splice site mutation (patient 6). The A359V and I279Yfs*9 mutations have been previously reported and in homozygosity shown to cause severe cases of CAH, all other variants were novel, with the exception of the E314K (aka rs6161 with a minor allele frequency 0.001).
Conclusion: The presentation varied between cases, ranging from a patient with neonatal salt wasting/adrenal crisis and large adrenals to a pair of non-pigmented sisters aged 2 and 4 years on glucocorticoid replacement alone. These cases emphasize the utility of whole exome sequencing as a tool for improved diagnosis and therefore patient management/genetic counselling in the endocrine clinic.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology