12625 P450 Side-chain Cleavage Enzyme Deficiency - A Rare Cause Of Congenital Adrenal Hyperplasia And A Newly Described Genetic Variant

Abstract Disclosure: I. Tabatabai: None. N. Meeks, MD: None. J.M. Barker: None. Background: P450 side-chain cleavage enzyme (P450scc) is responsible for the first step in steroidogenesis, converting cholesterol to pregnenolone after cholesterol has been transported into inner mitochondria by StAR. Deficiency in P450scc was first described in 2001 as a cause of primary adrenal insufficiency (PAI) and since then only 40-50 cases have been reported in literature. Clinical Case: A previously healthy 4 month old female born at 36-week gestation presented with 1 week of fatigue, refusal of oral feeds and weight loss. Labs were notable for severe hyponatremia (119 mEq/L), hyperkalemia (6.6 mEq/L), and non-anion gap metabolic acidosis (Bicarbonate 13). Genital exam was normal, newborn screens were normal, and there was no family history of glucocorticoid or mineralocorticoid defects. Further labs revealed hyperreninemic hypoaldosteronism and primary adrenal insufficiency with low aldosterone (2.1 ng/ml, NL >5), elevated plasma renin activity (124 ng/ml/h, NL <58), elevated ACTH (961 pg/ml, NL <48), normal Cortisol on assays not done by mass spectrometry, undetectable 17-OHP, and normal Corticosterone, 11-desoxycortisol, androstenedione, DHEA-S, total testosterone, TSH and T4. She was started on fludrocortisone and kayexalate, then maintenance hydrocortisone was added. ACTH, renin, and electrolytes normalized in the following months and kayexalate was discontinued. She remains on Hydrocortisone and Fludrocortisone and is growing well with normal developmental milestones.A C.A.H. genetic panel revealed two heterozygous mutations in CYP11A1, the gene responsible for P40scc. The first is a known pathogenic loss-of-function mutation (c.835del). The second is a new variant of unknown significance not yet seen in genetic registries, causing a Serine to Leucine shift (c.293C>T). Parent testing showed only a heterozygous c.835del mutation in the mother. Inheritance hypotheses for the new variant include a de novo mutation, paternal germline mosaicism, or a trans-acting gene variant on a different chromosome. Karyotype confirmed 46XX. This was done as p450scc deficiency in XY can cause under-virilization and sex reversal. Conclusion: P450scc deficiency, while rare, is a cause of PAI that is missed by newborn screens which flag elevated 17-OHP, as the deficiency is higher up and all downstream steroid metabolites (i.e. 17-OHP) will not be elevated. Differentiation between StAR and P450scc deficiency can only be done by genetic testing. As this patient is heterozygous for both variants, enzyme function assays of p450scc which are limited to research settings will help determine pathogenicity of this c.293C>T variant and to quantify the degree of enzyme function. Presentation: 6/1/2024