Homozygous Disruption of P450 Side-Chain Cleavage (CYP11A1) Is Associated with Prematurity, Complete 46,XY Sex Reversal, and Severe Adrenal Failure

Abstract

Disruption of the P450 side-chain cleavage cytochrome (P450scc) enzyme due to deleterious mutations of the CYP11A1 gene is thought to be incompatible with fetal survival because of impaired progesterone production by the fetoplacental unit. We present a 46,XY patient with a homozygous disruption of CYP11A1. The child was born prematurely with complete sex reversal and severe adrenal insufficiency. Laboratory data showed diminished or absent steroidogenesis in all pathways. Molecular genetic analysis of the CYP11A1 gene revealed a homozygous single nucleotide deletion leading to a premature termination at codon position 288. This mutation will delete highly conserved regions of the P450scc enzyme and thus is predicted to lead to a nonfunctional protein. Both healthy parents were heterozygous for this mutation. Our report demonstrates that severe disruption of P450scc can be compatible with survival in rare instances. Furthermore, defects in this enzyme are inherited in an autosomal-recessive fashion, and heterozygote carriers can be healthy and fertile. The possibility of P450scc-independent pathways of steroid synthesis in addition to the current concept of luteoplacental shift of progesterone synthesis in humans has to be questioned.

Early steps in steroidogenesis: intracellular cholesterol trafficking

“…Because the placenta is a fetal tissue, one would expect that human P450scc defi ciency would be incompatible with life, as it would prevent placental progesterone production, causing spontaneous abortion around the middle of pregnancy. Nevertheless, a few patients have now been described with mutations in P450scc that ablate virtually all P450scc activity ( 292,294,321,322 ). It is most likely that these few fetuses with P450scc mutations reached late gestation because of unusually protracted maintenance of the maternal corpus luteum of pregnancy, which normally involutes in the second trimester.…”

Prenatal diagnosis of congenital lipoid adrenal hyperplasia (CLAH) by estriol amniotic fluid analysis and molecular genetic testing

“…Low maternal serum estriol levels and/or discordance of external female genitalia by ultrasound and 46,XY karyotype, especially in Palestinian patients, warrants consideration of CLAH and prompt molecular diagnosis. In addition to CLAH, other mutations in steroidogenic factor 1 (SF-1) and CYP11A1 can also present with adrenal insufficiency and sex reversal in 46,XY infants (Achermann et al, 1999;Hiort et al, 2005).…”

Cytochromes P450: Roles in Diseases

“…It is one of the more essential P450s because placental progesterone produced during steroidogenesis is required to maintain human pregnancy, as it suppresses uterine contractility and prevents spontaneous abortion (4). In very rare cases, however, fetuses with a complete or partial lack of CYP11A1 activity reach late gestation (5)(6)(7)(8)(9)(10)(11), and the babies born have either minimal or no serum concentrations of all steroids. All CYP11A1-deficient individuals develop congenital partial or complete adrenal insufficiency with 46,XY sex reversal (MIM 613743), a severe endocrine disorder lethal without hormone replacement therapy.…”

“…Ten different variations in CYP11A1 were found in individuals with reduced or no cholesterol side chain cleavage activity. These are three homozygous or heterozygous nucleotide insertions or deletions in exons or introns and seven missense mutations, either single homozygous (A359V and L222P) or compound heterozygous (A189V/ R353W, L141W/V4125E, and 835delA/A269V) (5)(6)(7)(8)(9)(10)(11). The A189V mutation does not affect CYP11A1 activity but creates a novel splice site, resulting in truncated inactive protein (6).…”