ESPE Abstracts (2016) 86 P-P1-19

Heterozygous Mutations in CYP11A1 Gene can Cause Life-Threatening Salt Wasting and Failure to Thrive

Dimitrios T. Papadimitrioua,b, Christina Bothoua, Patrick J. Willemsc, Diagoras Zarganisa, Vassiliki Papaevangeloub & Anastasios Papadimitrioub


aAthens Medical Center, Athens, Greece; bAttikon University Hospital, Athens, Greece; cGenetic Diagnostic Network (GENDIA), Antwerp, Belgium


Background: Cytochrome P450 side-chain cleavage enzyme (CYP11A1 gene) catalyses the conversion of cholesterol to pregnenolone in steroidogenic cells, the first step in the biosynthesis of all steroid hormones. SCC deficiency has been established as an autosomal recessive disorder caused by inactivating homozygous or compound heterozygous mutations in the CYP11A1 gene, with a wide phenotypic spectrum ranging from prematurity, complete underandrogenization and severe early-onset adrenal failure, to term birth with clitoromegaly and later-onset adrenal failure. No patient with P450scc deficiency has been described with the massive adrenal enlargement typical of congenital lipoid adrenal hyperplasia.

Objective and hypotheses: A 3-month-old boy (46, XY) was admitted with extreme failure to thrive (3.2 kg – born 40 weeks 2.98 kg), hyponatremia, hyperkalemia, hypocortisolemia<3 mcg/dl with inappropriately elevated ACTH>50 pg/ml and undetectable adrenal androgens (DHEA-S), whereas male mini-puberty was normally expressed. Ultrasound showed normal adrenals. Five years later one of his twin sisters presented adrenal crisis with hyponatremia–hyperkalemia inside the neonatal ICU shortly after birth.

Method: Direct sequencing of the entire coding region and all the intron–exon boundaries of the CYP11A1 gene was performed.

Results: A novel heterozygous CYP11A1 c.235G>A missense variant was identified in exon 1 leading to the substitution of a valine by an isoleucine on amino acid position 79 to the patient, to one of his sisters and his father who suffered from failure to thrive during the first year of life and survived, according to his mother, grace to intensive feeding. Ffludrocortisone 100 μg twice daily immediately restored electrolytes and resolved failure to thrive. The boy needed proper hydrocortisone replacement for 4 years, but his sister on a need-only basis. Fludrocortisone was gradually diminished and discontinued at 5.5 years. The next year however despite low normal sodium (136 mmol/l) and high normal potassium levels (5.1 mmol/l), height velocity dropped from 6.5 to 3.5 cm/yr with an elevated renin which reached a plateau at a compensating drop from 837 to 224 ng/ml, similar to what is observed in primary hypoaldosteronism.

Conclusion: A novel heterozygous mutation in CYP11A1 gene can cause early onset adrenal insufficiency with life-threatening failure to thrive.

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