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Patients with
biochemical evidence of apparent combined deficiencies of 17a- and 21-hydroxylase have been recognized for almost 2 decades. The
clinical features include infant females born with mildly to moderately
virilized external genitalia in whom virilization does not progress post
partum, to adult women with menstrual irregularities (amenorrhea). Affected
males have normal external genitalia, cryptorchidism, or hypospadias. Serum and
urine glucocorticoid and androgen values are normal or low, while levels of
precursors (progesterone, 17-hydroxyprogesterone, pregnenediol, pregnanediol,
pregnanetriol) are elevated. Recent analysis of the genes encoding the enzyme
proteins (CYP17A1, OMIM 202110, chromosome 10q24.3; CYP21B, OMIM
201910, chromosome 6p21.3) did not disclose any mutations. The Antley-Bixler
syndrome (ABS, OMIM 207410) is characterized by facial (midface hypoplasia with
proptosis, choanal atresia, frontal bossing, dysplastic ears) and skeletal
abnormalities (cranial, humero-radial and radio-ulnar synostoses, femoral and
ulnar bowing, camptodactyly, joint contractures), and in some patients by
genitourinary abnormalities (renal agenesis, vaginal atresia, virilization of
female external genitalia, undermasculination of male genitalia). Heretofore,
ABS has been primarily attributed to mutations in FGFR2.
Steroidogenesis and its impairment in patients affected by apparent combined P450C17 and P450C21
deficiency Serum steroids reported in increased amounts are shown in red, and pathologically
altered urinary steroid metabolites are shown in blue boxes if raised and gray boxes if reduced,
linked to the steroid from which they are derived. Crosses indicate impairment of enzymatic activity.
(Reprinted with permission from: Arlt W, Walker EA, Draper N, et al. Lancet.2004;363:2128-35.Copyright
©2004 Elsevier.)
Fluck et al and Arlt et al reasoned that perhaps the
primary problem in patients with apparent combined deficiencies of 17a- and 21-hydroxylase might be due to
decreased levels of a common co-factor (Figure). Both enzymes require transfer
of electrons to achieve the activated state. The electron donor is cytochrome
P450 oxidoreductase (POR, OMIM 124015, chromosome 7q11.2), a flavoprotein
that contributes electrons to all microsomal P450 enzymes. It does so by
binding to NADPH through its flavin adenine dinucleotide (FAD) domain to which
NADPH contributes 2 electrons; these electrons are then transferred to the
flavin mononucleotide (FMN) domain of POR that, in turn, donates them to
the target P450 enzyme. Mutations in CYP17A1 that involve its binding to
POR lead to decreased 17a-hydroxylase
activity. Accordingly, these investigators analyzed POR in 7 patients
with combined deficiencies of 17a- and
21-hydroxylase deficiency, some of whom had clinical and skeletal anomalies
consistent with ABS. They found compound heterozygous or homozygous
loss-of-function mutations in all patients including: 531TÞG: Tyr178Asp; 731+1GÞA: donor splice site intron 6; *859GÞC: Ala287Pro; *1370GÞA: Arg457His; 1475TÞA: Val492Glu; *1706GÞA:
Cys569Tyr; 1822GÞT: Val608Phe. The Ala287,
Arg457, and Val492 mutations were in the FAD domain that binds
NADPH and, predictably, changed steric conformation or charge leading to
greatly reduced 17a-hydroxylase and
17-20-lyase activities. The Cys569 and Val608 mutations were in
the region that binds NADP+ and resulted in less loss of enzyme
activity. Patients with ABS tended to have the more severe mutations in POR,
while those with the less severe defects only had disordered steroidogenesis.
In no patient studied was a mutation in FGFR2 identified.
Arlt W, Walker EA, Draper N, et al. Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase
and human androgen synthesis: analytical study. Lancet. 2004;363:2128-35.
Fluck CE, Tajima T, Pandey AV, et al. Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nat Genet. 2004;36:228-230.
Editor’s Comment: Pregnant women who are
heterozygous carriers of a loss-of-function mutation in POR may manifest
gestational hyperandrogenism (acne, hirsutism) possibly due to the effects of
both fetal hyperandrogenemia and impaired endogenous steroidogenesis. This
resembles the hyperandrogenism seen in patients with a luteoma of pregnancy or
placental aromatase deficiency. Arlt et al suggest that in the fetus with loss
of POR activity, an alternate pathway of androgen synthesis is pursued: 17a-hydroxyprogesterone is converted to 5a-pregnane-3, 17a-diol-20-one and the latter to androsterone by sequential
actions of 5a-reductase type I, 3a-hydroxysteroid dehydrogenase, and low
levels of 17a-hydroxylase. Since this
pathway disappears in early infancy, virilization does not progress. These data
suggest that ABS is genetically heterogeneous; one type is due to loss of
FGFR2, and is not associated with genital malformation; the second type is due
to loss of POR. POR is required for activity of both adrenal and hepatic
microsomal P450 enzymes. Indeed, in infants of mothers treated with the
antifungal agent fluconazole, that inhibits ergosterol synthesis by interfering
with lanosterol 14a-demethylase
activity, skeletal deformities resembling those in neonates with ABS have been
observed. The skeletal deformities observed in children with deficiency of POR
may reflect an error in this pathway that affects skeletal embryogenesis.
Allen W. Root, MD
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Current GGH - Vol. 24 No. 1
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