Cytochrome P450 Oxidoreductase Deficiency in Three Patients Initially Regarded as Having 21-Hydroxylase Deficiency and/or Aromatase Deficiency: Diagnostic Value of Urine Steroid Hormone Analysis

Abstract

ABSTRACT:In this study, we report on three Japanese patients with cytochrome P450 oxidoreductase (POR) deficiency (PORD). Case one was a 46,XY patient who was found to have mildly increased 17␣-hydroxyprogesterone (17-OHP) by the neonatal mass screening. There was no maternal virilization during pregnancy, and he had no skeletal or genital abnormality. Thus, he was initially diagnosed as having nonclassical 21-hydroxylase deficiency (21-OHD). Cases two and three were 46,XX patients who were identified because of severely virilized external genitalia and maternal virilization during pregnancy. In case two, the neonatal mass screening was normal, and she had no skeletal abnormality except for mild adduction of bilateral third toes. Thus, she was initially diagnosed as having aromatase deficiency. In case three, the neonatal mass screening showed moderately increased 17-OHP, and no skeletal lesion other than rigid second metacarpophalangeal joints was identified in early infancy. Thus, she was initially suspected as having 21-OHD and/or aromatase deficiency. Subsequently, endocrine studies including urine steroid hormone analysis were performed for the assessment of glucocorticoid treatment in case one and for the virilized genitalia in cases two and three, showing adrenal and/or gonadal dysfunction characteristic of PORD. Thus, molecular analysis of POR was carried out, demonstrating homozygosity for R457H in cases one through three. The results imply that clinical features in PORD can be similar to those in 21-OHD or aromatase deficiency, and that comprehensive assessment of the pregnant course, physical examination, and adrenal and gonadal function studies is essential for the precise diagnosis of PORD. (Pediatr Res 59: 276-280, 2006)

46,XX DSD and Antley-Bixler syndrome due to novel mutations in the cytochrome P450 oxidoreductase gene

“…However, dihydroepiandrosterone (DHEA), DHEA-sulphate and androstenedione levels are generally low or normal due to the low 17,20-lyase activity of CYP17A1. This hormonal profile, which is usually observed in patients with PORD, including this patient, indicates that the 21-hydroxylation activity by CYP21A2 is as diminished as the 17-hydroxylation activity by CYP17A1 (4,6,18,25).…”

“…Considering that p.Arg223* is a null allele in the compound heterozygosis with p.Met408Lys, it can be inferred that the residual activity of p.Met408Lys missense carrying allele is defining the patient's phenotype. Different from the most studied p.Ala287Pro and p.Arg457His mutations, which have been frequently observed in Japanese patients and are related to severe inborn skeletal malformations (6,10,18), p.Met408Lys seems to be more deleterious to POR activity related to the androgenic pathway than to skeletal development, since the patient presented severe virilizition and no signs of skeletal malformations at birth. Krone and cols.…”

“…However, most authors agree with drug administration only in case of moderate to severe stress, especially for those patients who do not present adequate cortisol response to ACTH stimulus, as was the case of our patient (11,18,(21)(22)(23)(24)(25). Therefore, glucocorticoid was only administrated upon stress situations.…”

“…The reported patient did not present neonatal signs of skeletal malformations; however, during childhood, she developed a few osteoarticular abnormalities, such as carpal and tarsal synostosis, reduced skull diameter and "hammered-silver" appearance (suggestive of craniosynostosis), and limited forearm pronosupination, indicating that periodic clinical and image evaluations were necessary (6,10,11,17,18). Considering that p.Arg223* is a null allele in the compound heterozygosis with p.Met408Lys, it can be inferred that the residual activity of p.Met408Lys missense carrying allele is defining the patient's phenotype.…”

Severity of Virilization of External Genitalia in Japanese Patients with Salt-wasting 21-hydroxylase Deficiency

“…Some authors have shown the existence of a backdoor pathway in the human fetal adrenal gland (Arlt et al 2004;Fukami et al 2006;Homma et al 2006). There are two options for 17OHP: 5α -reduction and entry into the backdoor (Hanley and Arlt 2006).…”