A diagnosis not to be missed: nonclassic steroid 11β-hydroxylase deficiency presenting with premature adrenarche and hirsutism.
BACKGROUND
Steroid 11β-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia. Milder nonclassic forms are rare and at risk to be missed.


OBJECTIVE
The objective of the study was to demonstrate the challenges in diagnosing nonclassic 11OHD.


METHODS
Patient 1, a 10-year-old boy, presented with high-normal blood pressure and previously unexplained exaggerated adrenarche from age 4 years. Previous tests at the age of 8 years showed normal 17-hydroxyprogesterone concentrations with increased androgens. Patient 2, a 14-year-old female, presented with facial hirsutism, primary amenorrhea, and high-normal blood pressure. Novel CYP11B1 mutations were functionally analyzed in transiently transfected COS7 cells measuring the conversion of 11-deoxycortisol to cortisol by liquid chromatography-tandem mass spectrometry.


RESULTS
Biochemical findings including urinary steroid metabolite analysis by gas chromatography-mass spectrometry were suggestive of 11OHD in all patients. CYP11B1 mutation analysis revealed compound heterozygosity in patient 1 (g.235T>A, p.F79I/g.2608C>T, p.R138C) and a homozygous mutation in patient 2 and two siblings (g.2623C>T, p.R143W). Functional in vitro analysis demonstrated partially impaired CYP11B1 activity compared with wild-type (p.F79I: 8.8% ± 0.8% (SEM); p.R138C: 9.8% ± 0.8%; p.R143W: 10.6% ± 1.2%).


CONCLUSIONS
In addition to nonclassic 21-hydroxylase deficiency and steroid-secreting tumors, nonclassic 11OHD should be considered as an important differential diagnosis in patients with unexplained hyperandrogenism without 46,XX disorder of sex development. Nonclassic 11OHD is likely to be missed when relying on measuring standard steroid hormone panels. This diagnosis needs to be established early in life to avoid long-term health problems such as short stature, hyperandrogenism-related metabolic complications, potentially severe arterial hypertension, and cardiovascular consequences.
MD, FRCPCH, Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom. n.p.krone@bham.ac.uk.
Nicole
N
Reisch
Wolfgang
W
Högler
Silvia
S
Parajes
Ian T
IT
Rose
Vivek
V
Dhir
Joachim
J
Götzinger
Wiebke
W
Arlt
Nils
N
Krone
D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000150:complications / Q000175:diagnosis* / Q000235:genetics; D050499:Adrenarche / Q000235:genetics* / Q000378:metabolism; D002648:Child; D005260:Female; D006628:Hirsutism / Q000150:complications / Q000175:diagnosis* / Q000235:genetics; D006801:Humans; D008297:Male; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics*
D013252:Steroid 11-beta-Hydroxylase