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.
Anales de Pediatría Continuada 01/2011; 9(1):15-30. DOI:10.1016/S1696-2818(11)70003-8
[Show abstract] [Hide abstract]
ABSTRACT: Congenital adrenal hyperplasia (CAH) is one of the most common inherited metabolic disorders. It comprises a group of autosomal recessive disorders caused by the mutations in the genes encoding for steroidogenic enzymes that involved cortisol synthesis. More than 90% of cases are caused by a defect in the enzyme 21-hydroxylase. Four other enzyme deficiencies (cholesterol side-chain cleavage, 17α-hydroxylase [P450c17], 11β-hydroxylase [P450c11β], 3β-hydroxysteroid dehydrogenase) in the steroid biosynthesis pathway, along with one cholesterol transport protein defect (steroidogenic acute regulatory protein), and one electrontransfer protein (P450 oxidoreductase) account for the remaining cases. The clinical symptoms of the different forms of CAH result from the particular hormones that are deficient and those that are produced in excess. A characteristic feature of CAH is genital ambiguity or disordered sex development, and most variants are associated with glucocorticoid deficiency. However, in the rare forms of CAH other than 21-hydroxylase deficiency so-called "atypical CAH", the clinical and hormonal phenotypes can be more complicated, and are not well recognized. This review will focus on the atypical forms of CAH, including the genetic analyses, and phenotypic correlates.03/2015; 20(1):1-7. DOI:10.6065/apem.2015.20.1.1
[Show abstract] [Hide abstract]
ABSTRACT: Congenital lipoid adrenal hyperplasia (lipoid CAH) is the most fatal form of CAH, as it disrupts adrenal and gonadal steroidogenesis. Most cases of lipoid CAH are caused by recessive mutations in the gene encoding steroidogenic acute regulatory protein (StAR). Affected patients typically present with signs of severe adrenal failure in early infancy and 46,XY genetic males are phenotypic females due to disrupted testicular androgen secretion. The StAR p.Q258X mutation accounts for about 70% of affected alleles in most patients of Japanese and Korean ancestry. However, it is more prevalent (92.3%) in the Korean population. Recently, some patients have been showed that they had late and mild clinical findings. These cases and studies constitute a new entity of 'nonclassic lipoid CAH'. The cholesterol side-chain cleavage enzyme, P450scc (CYP11A1), plays an essential role converting cholesterol to pregnenolone. Although progesterone production from the fetally derived placenta is necessary to maintain a pregnancy to term, some patients with P450scc mutations have recently been reported. P450scc mutations can also cause lipoid CAH and establish a recently recognized human endocrine disorder.12/2014; 19(4):179-83. DOI:10.6065/apem.2014.19.4.179