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

Abstract

SUMMARYP450 oxidoreductase deficiency (PORD) is a variant of congenital adrenal hyperplasia that is caused by POR gene mutations. The POR gene encodes a flavor protein that transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH) to all microsomal cytochrome P450 type II (including 21-hydroxylase, 17α-hydroxylase 17,20 lyase and aromatase), which is fundamental for their enzymatic activity. POR mutations cause variable impairments in steroidogenic enzyme activities that result in wide phenotypic variability ranging from 46,XX or 46,XY disorders of sexual differentiation, glucocorticoid deficiency, with or without skeletal malformations similar to Antley-Bixler syndrome to asymptomatic newborns diagnosed during neonatal screening test. Little is known about the PORD long-term evolution. We described a 46,XX patient with mild atypical genitalia associated with severe bone malformation, who was diagnosed after 13 years due to sexual infantilism. She developed large ovarian cysts and late onset adrenal insufficiency during follow-up, both of each regressed after hormone replacement therapies. We also described a late surgical approach for the correction of facial hypoplasia in a POR patient. Arch Endocrinol Metab. 2016;60(5):500-4

Clinical characteristics of cytochrome P450 oxidoreductase deficiency: a nationwide survey in Japan

“…The median age at diagnosis was 0.21 years (range, 0-25 years), and the median age at the time of the survey was 12.1 years (range, 0.7-46.1 years). Nine patients were diagnosed with PORD at >2 years of age (Patients 9,10,11,14,19,20,21,22,and 23). Five patients (Patients 9, 11, 14, 19, and 22) were diagnosed with PORD after 2004, which was the first year of publication of PORD.…”

“…Maternal virilization (40.8%) has been described in mothers during pregnancies of PORD-affected fetuses [3]. Hyperandrogenic manifestations in mothers have also been described during pregnancies of PORDaffected fetuses and range from acne to hirsutism until the appearance of virilization signs such as deepening of the voice [14]. A single multicenter study of 20 pregnant women showed that the presence of maternal virilization and severe birth defects detected by fetal ultrasound may be the fundamental characteristics of fetuses with PORD [12].…”

Classic congenital adrenal hyperplasia and its impact on reproduction

“…17a-Hydroxylase/17,20 lyase deficiency accounts for <1% of all CAH cases (32); however, it is the second most frequent adrenal enzymatic defect in the Brazilian population owing to gene founder effect mutations (33). 46,XX patients present with normal prenatal sexual development, resulting in normal internal and external genitalia (34)(35)(36). The diagnosis is generally recognized at puberty, when patients develop hypergonadotropic hypogonadism, usually associated with hypokalemic hypertension, secondary to the deficiency of sex steroids and the accumulation of the following precursors: 11-deoxycorticosterone, corticosterone, and 18-deoxycorticosterone, respectively.…”

“…There are few reports about gonadal function in female patients with POR deficiency (43-45). Recently we described the long-term follow-up of a 46,XX patient who presented with partial pubertal development (breasts TII), infantile uterus, and a large ovarian cyst (2.8 cm) at 14 years of age; menses only occurred after E replacement, and the ovarian cyst regressed (46).…”

Loss of multiple enzyme activities due to the human genetic variation P284T in NADPH cytochrome P450 oxidoreductase

“…Human POR deficiency (PORD, OMIM: 613537 and 201750) is a form of congenital adrenal hyperplasia, initially described in patients with altered steroidogenesis Flück et al, 2007;Flück and Pandey, 2011;Flück and Pandey, 2013;Pandey and Flück, 2013;Fukami and Ogata, 2014;Pandey and Sproll, 2014;Flück and Pandey, 2019) followed by several reports with a broad spectrum of disorders (Adachi et al, 2004;Arlt et al, 2004;Pandey and Flück, 2013;Flück and Pandey, 2014;Pandey and Sproll, 2014;Oldani et al, 2015;Bonamichi et al, 2016;Nakanishi et al, 2016;Burkhard et al, 2017;Flück and Pandey, 2019). Congenital adrenal hyperplasia is an inborn error of adrenal steroid biosynthesis affecting the production of glucocorticoids (Miller and Fluck, 2014;Fluck, 2017).…”