Background: CYP11A1 gene encodes the cholesterol side-chain cleavage enzyme, P450scc, which plays a key role in the initial steps of steroidogenesis. CYP11A1 insufficiency lead to a variable phenotype ranging from severe early onset primary adrenal insufficiency (PAI) in the neonatal period,with 46,XY DSD; to late-onset PAI with normal genitalia.
Objective: Detail the phenotype of a family sharing newly described compound heterozygous mutations1 in CYP11A1, identified by HaloPlex targeted capture array.
Family study: This non-consanguineous Scottish family comprised unaffected parents and two sisters with three affected brothers (II-2, II-3 and II-5). Learning difficulties were present in the mother, II-2 and II-3. All siblings were born at term, birthweight 2.6 (II-2), 2.5 (II-3) and 2.8 kg (II-5). II-5 was diagnosed first aged 3.7 years following a number of "febrile" convulsions and was found to be hyperpigmented with sodium 129mmol/l, potassium 5.9mmol/l, renin 1209 µU/l (NR:9-50), ACTH 1089 mU/l (N<20), and basal/peak cortisol after synacthen 174/178 nmol/l. Assessment in II-2 and II-3 at 8 and 9 years showed that they too were deeply pigmented with normal electrolytes but high ACTH and renin; basal/peak cortisol 339/389 and 278/289 nmol/l. An X-linked disorder was considered likely, but DAX-1 and adrenoleukodystrophy studies were negative.Conventional glucocorticoid and mineralocorticoid replacement for unclassified PAI was given. All three brothers completed puberty- delayed in II-2 and II-3 with G2/G4-5 at 13.1/16.9 and 14.2/17 years. Genetic analysis during adulthood revealed compound heterozygosity of the CYP11A1 gene with an rs6161 variant (c.940G>A, p.Glu314Lys) affecting splicing and another disruptive variant causing frameshift and premature stop codon (c.790_802del, K264Lfs*5)1. At last review aged 32, 36 and 37 years the brothers were stable on hydrocortisone and fludrocortisone replacement, had scanty body hair but normal pubic hair, normal testicular volumes (15-20 ml), normal serum testosterone (27.2, 33.3 and 24.7nmol/L) but FSH values 41.2, 9.3 and 13.8 u/L. II-3 suffered from epilepsy and died shortly after from a prolonged convulsion. II-5 had undergone orchidectomy for suspected malignancy aged 25 years with initial histology reported as showing nodular Leydig cell hyperplasia, revised to testicular adrenal rest tumour (TART) when the diagnosis came to light.
Conclusion: Partial CYP11A1 defect is emerging as a surprisingly common cause of previously undiagnosed PAI. This kinship demonstrates the importance of studying other family members when PAI presents and of precise diagnosis, which could have identified TART as the cause of testicular enlargement thus avoiding orchidectomy in the younger brother.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology