Prenatal diagnosis of congenital adrenal hyperplasia caused by P450 oxidoreductase deficiency.
BACKGROUND
Mutations in the electron donor enzyme P450 oxidoreductase (POR) result in congenital adrenal hyperplasia with apparent combined 17α-hydroxylase/17,20 lyase and 21-hydroxylase deficiencies, also termed P450 oxidoreductase deficiency (PORD). Major clinical features present in PORD are disordered sex development in affected individuals of both sexes, glucocorticoid deficiency, and multiple skeletal malformations.


OBJECTIVE
The objective of the study was to establish a noninvasive approach to prenatal diagnosis of PORD including assessment of malformation severity to facilitate optimized prenatal diagnosis and timely treatment.


METHODS
We analyzed 20 pregnancies with children homozygous or compound heterozygous for disease-causing POR mutations and 1 pregnancy with a child carrying a heterozygous POR mutation by recording clinical and biochemical presentations and fetal ultrasound findings. In 4 of the pregnancies (3 homozygous and 1 heterozygous for disease-causing POR mutations), prenatal analysis of steroid metabolite excretion in maternal urine was carried out by gas chromatography/mass spectrometry during gestational weeks 11-23.


RESULTS
Pregnancy complications in our cohort included maternal virilization (6 of 20) with onset in the second trimester. Seven pregnant women presented with low unconjugated estriol at prenatal screening (triple or quadruple antenatal screening test). Overt dysmorphic features were noted in 19 of the 20 babies at birth but observed in only 5 by prenatal ultrasound. These 5 had the most severe malformation phenotypes and poor outcome, whereas the other babies showed normal development. Steroid profiling of maternal urine revealed significantly increased steroids of fetal origin, namely the pregnenolone metabolite epiallopregnanediol and the androgen metabolite androsterone, with concomitant low values for estriol. Diagnostic steroid ratios conclusively indicated PORD as early as gestational week 12. In the heterozygous pregnancy, steroid ratios were only slightly elevated and estriol excretion was normal.


CONCLUSIONS
Prenatal diagnosis in PORD is readily established via urinary steroid metabolite analysis of maternal urine. Visible malformations at prenatal ultrasound predict a severe malformation phenotype.
Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom.
Nicole
N
Reisch
Jan
J
Idkowiak
Beverly A
BA
Hughes
Hannah E
HE
Ivison
Omar A
OA
Abdul-Rahman
Laura G
LG
Hendon
Ann Haskins
AH
Olney
Shelly
S
Nielsen
Rachel
R
Harrison
Edward M
EM
Blair
Vivek
V
Dhir
Nils
N
Krone
Cedric H L
CH
Shackleton
Wiebke
W
Arlt
D000015:Abnormalities, Multiple / Q000000981:diagnostic imaging* / Q000235:genetics; D000312:Adrenal Hyperplasia, Congenital / Q000175:diagnosis / Q000235:genetics / Q000652:urine; D000738:Androsterone / Q000652:urine; D004964:Estriol / Q000652:urine; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008403:Mass Screening / Q000379:methods*; D010641:Phenotype; D011237:Predictive Value of Tests; D011247:Pregnancy; D011262:Pregnancy Trimester, Second / Q000235:genetics; D011276:Pregnanediol / Q000652:urine; D011296:Prenatal Diagnosis / Q000379:methods*; D011859:Radiography; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics / Q000652:urine*; D013255:Steroid 21-Hydroxylase / Q000235:genetics / Q000652:urine*; D016216:Ultrasonography, Prenatal; D014770:Virilism / Q000175:diagnosis / Q000235:genetics
D000738:Androsterone; D013255:Steroid 21-Hydroxylase; D013254:Steroid 17-alpha-Hydroxylase; D004964:Estriol; D011276:Pregnanediol