ESPE Abstracts

Background: CYP11A1 encodes the P450 side chain cleavage (scc) enzyme. This protein localises to the mitochondrial inner membrane and catalyses the conversion of cholesterol to pregnenolone which is the first and rate-limiting step in the synthesis of all steroid hormones. P450scc deficiency is a rare disorder that can present as adrenal insufficiency and varying degrees of disorder in sex development (DSD) in 46XY individuals. Typically, this disorder is caused by biallelic loss of function variants in CYP11A1, either homozygous or compound heterozygous mutations. We describe an infant with 46XY DSD and mild adrenal insufficiency associated with CYP11A1 heterozygous mutation.

Case: A pre-term infant (36/40) with a birth weight of 2.9kg born to non-consanguineous parents, presented on day 1 of life with hypoglycaemia and concerns regarding DSD. Examination showed perineal hypospadias, chordee and cryptorchidism. The karyotype was 46 XY. An ultrasound of pelvis did not show Mullerian structures and demonstrated the presence of bilateral testes in the inguinal region. The plasma electrolytes remained stable. Investigations into the cause of hypoglycaemia showed an inappropriately raised plasma insulin level at the time of hypoglycaemia consistent with hyperinsulinism (HI). The 17 hydroxy progesterone, aldosterone, and renin levels were normal. A short synacthen test showed a suboptimal peak cortisol response of 397nmol/L. The hypoglycaemia was not persistent and completely resolved without specific medical interventions, suggestive of a transient HI picture.

Target sequence analysis of the genes implicated in 46 XY DSD identified a heterozygous frameshift mutation c.835delA p.(lle279Tyrfs*1) in CYP11A1. This variant has previously been reported as pathogenic and in a recessive state has been shown to cause severe adrenal insufficiency and 46XY sex reversal. Heterozygous loss of function of CYP11A1 variants has been rarely reported to cause relatively mild clinical features due to haploinsufficiency. In the absence of other reasons for the mild adrenal insufficiency and undervirilisation seen in our patient, it is possible that the heterozygous CYP11A1 mutation (c.835delA p.(lle279Tyrfs*1)) is contributing to the phenotype.

Conclusion: Recessive (homozygous and compound heterozygous) CYP11A1 mutations are known to result in severe adrenal insufficiency and DSD in 46XY infants. Heterozygous loss of function mutations in CYP11A1 can cause mild adrenal insufficiency and undervirilisation in 46XY infants as seen in our patient. However due to the rarity of such descriptions in the literature, more reported cases and molecular studies might add to the body of evidence.