Concomitant mutations in the P450 oxidoreductase and androgen receptor genes presenting with 46,XY disordered sex development and androgenization at adrenarche.
BACKGROUND
Undervirilization in males, i.e. 46,XY disordered sex development (46,XY DSD), is commonly caused by either lack of androgen action due to mutant androgen receptor (AR) or deficient androgen synthesis, e.g. due to mutations in 17alpha-hydroxylase (CYP17A1). Like all other microsomal cytochrome P450 (CYP) enzymes, CYP17A1 requires electron transfer from P450 oxidoreductase (POR).


OBJECTIVE
The objective of the study was to analyze the clinical and biochemical phenotype in a 46,XY individual carrying concomitant POR and AR mutations and to dissect their impact on phenotypic expression.


METHODS
We characterized the clinical and biochemical phenotype, genetic identification, and functional analysis of POR missense mutation by yeast micrososomal coexpression assays for CYP17A1, CYP21A2 and CYP19A1 activities.


RESULTS
The patient presented neonatally with 46,XY DSD and was diagnosed as partial androgen insensitivity syndrome carrying a disease causing AR mutation (p.Q798E). She was raised as a girl and gonadectomized at the age of 4 yr. At 9 yr progressive clitoral enlargement prompted reassessment. Urinary steroid analysis was indicative of POR deficiency, but surprisingly androgen production was normal. Genetic analysis identified compound heterozygous POR mutations (p.601fsX12/p.Y607C). In vitro analysis confirmed p.Y607C as a pathogenic mutation with differential inhibition of steroidogenic CYP enzymes.


CONCLUSIONS
Both mutant AR and POR are likely to contribute to the neonatal presentation with 46,XY DSD. Virilization at the time of adrenarche appears to suggest an age-dependent, diminishing disruptive effect of both mutant proteins. This case further highlights the importance to assess both gonadal and adrenal function in patients with 46,XY DSD.
Idkowiak
Jan
J
Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom.
Malunowicz
Ewa M
EM
Dhir
Vivek
V
Reisch
Nicole
N
Szarras-Czapnik
Maria
M
Holmes
Donna M
DM
Shackleton
Cedric H L
CH
Davies
John D
JD
Hughes
Ieuan A
IA
Krone
Nils
N
Arlt
Wiebke
W
D050499:Adrenarche / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002648:Child; D005260:Female; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D046468:Sexual Development / Q000235:genetics; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D014770:Virilism / Q000235:genetics* / Q000378:metabolism
D011944:Receptors, Androgen; D010088:Oxidoreductases; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase
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