Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency

Abstract

Context:P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available.Objective:The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort.Design:The design of the study was the clinical, biochemical, and genetic assessment including multiplex ligation-dependent probe amplification (MLPA) in 30 PORD patients from 11 countries.Results:We identified 23 P450 oxidoreductase (POR) mutations (14 novel) including an exonic deletion and a partial duplication detected by MLPA. Only 22% of unrelated patients carried homozygous POR mutations. p.A287P was the most common mutation (43% of unrelated alleles); no other hot spot was identified. Urinary steroid profiling showed characteristic PORD metabolomes with variable impairment of 17α-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 18 46,XX and seven of 12 46,XY individuals. Homozygosity for p.A287P was invariably associated with 46,XX DSD but normal genitalia in 46,XY individuals. The majority of patients with mild to moderate skeletal malformations, assessed by a novel scoring system, were compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles.Conclusions:We report clinical, biochemical, and genetic findings in a large PORD cohort and show that MLPA is a useful addition to POR mutation analysis. Homozygosity for the most frequent mutation in Caucasians, p.A287P, allows for prediction of genital phenotype and moderate malformations. Adrenal insufficiency is frequent, easily overlooked, but readily detected by cosyntropin testing.

Genetics of Congenital Adrenal Hyperplasia

“…Adrenal insufficiency is present in the majority of patients. 91 Craniofacial-malformations may also be present and overlap with the Antley-Bixler syndrome (OMIM 201750), a rare craniosynostosis syndrome characterized by radiohumeral synostosis presenting in the perinatal period. 90 The majority of patients with mild to moderate skeletal malformations are compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles.…”

“…94,95 In one study of 30 patients with POR deficiency from 11 countries, 23 POR mutations including a deletion and a partial duplication were detected by MLPA, and only 22% of unrelated patients carried homozygous POR mutations. 91 POR deficiency may present as a form of apparent 17,20 lyase deficiency due to mutations in the POR gene rather than the CYP17A1 gene. 82 …”

Long-term follow-up of a female with congenital adrenal hyperplasia due to P450-oxidoreductase deficiency

“…Our patient carried the p.A287P mutation in homozygosis, which is the most frequent mutation in Caucasians, and it is observed in approximately 43% of nonrelated alleles (8). Our case, and other 46,XX patients who are homozygous for this mutation, presented with external genitalia virilization, in contrast to 46,XY patients who exhibit normal external genitalia.…”

“…The adrenal insufficiency documented by cosyntropin was found in almost all patients in large cohorts, of those 50% needed permanent hydrocortisone (8,13). This phenotype is due to impairment of P450c17 activity with a concomitant deficiency of P450c21.…”

“…However, each enzyme may be differently compromised in a same patient (3,4). This variability in enzymatic impairments produces a wide phenotypic spectrum of clinical manifestations ranging from atypical genitalia in both sexes, adrenocortical insufficiency associated or not to bone malformations, to laboratory abnormalities in the neonatal screening test of asymptomatic newborns (1,(4)(5)(6)(7)(8). A late onset form has also been reported in 46,XX patients with primary amenorrhea and polycystic ovarian morphology (1).…”