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.
"In few cases, mutations in the CYP11A1 (MIM 118485, locus 15q24.1) gene encoding the cytochrome P450 cleavage enzyme have also been reported to cause LCAH (2). The inheritance is autosomal recessive. "
[Show abstract][Hide abstract] ABSTRACT: Lipoid congenital adrenal hyperplasia (LCAH), a rare disorder of steroid biosynthesis, is the most severe form of CAH. We report novel molecular findings of three unrelated infants with LCAH diagnosed at our center. A known missense mutation c.653C>T (p.A218V) and two novel mutations [premature termination c.441G>A (or p.W147X) and frameshift deletion c.del815G (or p.R272PfsX35)] were identified after complete sequencing of the STAR gene. Prenatal diagnosis was carried out for the family with mutation c.815delG by molecular testing wherein the fetus was found to be homozygous for the mutation. This is the first report of molecular diagnosis and prenatal testing for LCAH from India.
Conflict of interest:None declared.
Journal of Clinical Research in Pediatric Endocrinology 06/2013; 5(2):121-4. DOI:10.4274/Jcrpe.927
"The clinical phenotype is similar to congenital lipoid adrenal hyperplasia (CLAH; OMIM #201710) that is caused by deficient mitochondrial cholesterol import due to mutations in the steroidogenic acute regulatory protein (STAR) (2). Severe CYP11A1 deficiency manifests with female external genitalia irrespective of chromosomal sex and with early onset adrenal insufficiency, usually manifesting within the first hours or days of life (3, 4). A milder form of CYP11A1 deficiency has also been described, associated with delayed onset of adrenal insufficiency and variable degrees of 46,XY disorder of sex development (DSD) (5, 6, 7, 8, 9) or also normal male genital development (10). "
[Show abstract][Hide abstract] ABSTRACT: Context
Cytochrome P450 side-chain cleavage enzyme (CYP11A1) catalyses the first and rate-limiting step of steroidogenesis, the conversion of cholesterol to pregnenolone. CYP11A1 deficiency is commonly associated with adrenal insufficiency, and in 46,XY individuals, with variable degrees of disorder of sex development (DSD).
Patient and methods
The patient was born with hyperpigmentation, micropenis, penoscrotal hypospadias, and mild cryptorchidism. Biochemical and hormonal findings were normal except for low testosterone and low-borderline cortisol. However, no short synacthen test was undertaken. Development was unremarkable apart from an episode labeled as sepsis with documented hyperkalemia and elevated C-reactive protein at age 15 days. Diagnosis of 46,XY DSD was made at age 2.5 months. Progression of hyperpigmentation prompted further investigations and the diagnosis of adrenal insufficiency was established at 2 years with raised ACTH, normal renin activity, and failure of cortisol to respond to short synacthen test. Genetic analyses were performed. The novel CYP11A1 mutations were characterized in vitro and in silico.
The patient was compound heterozygous for two novel CYP11A1 mutations, p.R360W and p.R405X. p.R360W retained 30–40% of wild-type activity. In silico analyses confirmed these findings and indicated that p.R405X is severe.
This study demonstrates the pathogenicity of two novel CYP11A1 mutations found in a patient with delayed diagnosis of CYP11A1 deficiency. Patients with partial deficiencies of steroidogenic enzymes are at risk to be misdiagnosed if adrenal function is not assessed. The adrenocortical function should be routinely assessed in all patients with DSD including severe hypospadias of unknown origin to prevent life-threatening adrenal crises.
European Journal of Endocrinology 09/2012; 167(6). DOI:10.1530/EJE-12-0450 · 4.07 Impact Factor
"A urine steroid profile is again a valuable test to cover these possibilities (38, 39, 40). Congenital adrenal hyperplasia due to defects of cholesterol uptake and cholesterol side chain cleavage enzyme (CYP11A1) (41, 42) can be lethal at an early stage, but there are exceptions (43) some present with hypospadias. The infants present as phenotypic females and have an adrenal crisis in the newborn period. "
[Show abstract][Hide abstract] ABSTRACT: Biochemical tests have been the basis for investigations of disorders affecting steroid hormones. In recent years it has been possible however to study the genes that determine functional enzymes, cofactors, receptors, transcription factors and signaling systems that are involved in the process. Analyses of mutations are available as a diagnostic service for only a few of these genes although research laboratories may be able to provide a service. Both biochemical and genetic research have brought to light new disorders. Some genes for transcription factors involved in the development of the endocrine organs have also been identified and patients with defects in these processes have been found. This paper will review general aspects of adrenal disorders with emphasis on clinical and laboratory findings. As with all endocrine investigations there are few single measurements that provide a definitive answer to a diagnosis. Timing of samples in relation to age, gender and time of day needs to be considered.
Conflict of interest:None declared.
Journal of Clinical Research in Pediatric Endocrinology 09/2009; 1(5):209-26. DOI:10.4274/jcrpe.v1i5.209
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