2 research outputs found
Differential inhibition of 17alpha-hydroxylase and 17,20-lyase activities by three novel missense CYP17 mutations identified in patients with P450c17 deficiency
The microsomal enzyme cytochrome P450c17 is an important regulator of
steroidogenesis. The enzyme has two functions: 17alpha-hydroxylase and
17,20-lyase activities. These functions determine the ability of adrenal
glands and gonads to synthesize 17alpha-hydroxylated glucocorticoids
(17alpha-hydroxylase activity) and/or sex steroids (17,20-lyase activity).
Both enzyme functions depend on correct steroid binding, but it was
recently shown that isolated lyase deficiency can also be caused by
mutations located in the redox partner interaction domain. In this article
we present the clinical history and molecular analysis of two patients
with combined 17alpha-hydroxylase/17,20-lyase deficiency and four patients
with isolated 17,20-lyase deficiency. In these six patients, four missense
CYP17 mutations were identified. Two mutations were located in the
steroid-binding domain (F114V and D116V), and the other two mutations were
found in the redox partner interaction domain (R347C and R347H). We
investigated the activity of these mutated proteins by transfection
experiments in COS-1 cells using pregnenolone, progesterone, or their
hydroxylated products as a substrate and measuring 17alpha-hydroxylase-
and 17,20-lyase-dependent metabolites in the medium. The mutations in the
steroid-binding domain (F114V and D116V) of P450c17 caused combined,
complete (F114V), or partial (D116V) 17alpha-hydroxylase and 17,20-lyase
deficiencies, whereas mutations in the redox partner interaction domain
(R347C and R347H) displayed less severe 17alpha-hydroxylase deficiency,
but complete 17,20-lyase deficiency. These findings are consistent with
the clinical data and support the observation that the redox partner
interaction domain is essential for normal 17,20-lyase function of
P450c17
Final height in girls with turner syndrome after long-term growth hormone treatment in three dosages and low dose estrogens
Although GH treatment for short stature in Turner syndrome is an accepted
treatment in many countries, which GH dosage to use and which age to start
puberty induction are issues of debate. This study shows final height (FH)
in 60 girls with Turner syndrome treated in a randomized dose-response
trial, combining GH treatment with low dose estrogens at a relatively
young age. Girls were randomly assigned to group A (4 IU/m(2).d;
approximately 0.045 mg/kg/d), group B (first year, 4 IU/m(2).d; thereafter
6 IU/m(2).d), or group C (first year, 4 IU/m(2).d; second year, 6
IU/m(2).d; thereafter, 8 IU/m(2).d). After a minimum of 4 yr of GH
treatment, at a mean age of 12.7 +/- 0.7 yr, low dose micronized
17beta-estradiol was given orally. After a mean duration of GH treatment
of 8.6 +/- 1.9 yr, FH was reached at a mean age of 15.8 +/- 0.9 yr. FH,
expressed in centimeters or SD score, was 157.6 +/- 6.5 or -1.6 +/- 1.0 in
group A, 162.9 +/- 6.1 or -0.7 +/- 1.0 in group B, and 163.6 +/- 6.0 or
-0.6 +/- 1.0 in group C. The difference in FH in centimeters, corrected
for height SD score and age at start of treatment, was significant between
groups A and B [regression coefficient, 4.1; 95% confidence interval (CI),
1.4, 6.9; P < 0.01], and groups A and C (coefficient, 5.0; 95% CI, 2.3,
7.7; P < 0.001), but not between groups B and C (coefficient, 0.9; 95% CI,
-1.8, 3.6). Fifty of the 60 girls (83%) had reached a normal FH (FH SD
score, more than -2). After starting estrogen treatment, the decrease in
height velocity (HV) changed significantly to a stable HV, without
affecting bone maturation (change in bone age/change in chronological
age). The following variables contributed significantly to predicting FH
SD score: GH dose, height SD score (ref. normal girls), chronological age
at start of treatment, and HV in the first year of GH treatment. GH
treatment was well tolerated. In conclusion, GH treatment leads to a
normalization of FH in most girls, even when puberty is induced at a
normal pubertal age. The optimal GH dosage depends on height and age at
the start of treatment and first year HV