P450c17 deficiency: clinical and molecular characterization of six patients.
BACKGROUND
The characteristics of P450c17 deficiency include 46,XY disorder of sex development, hypertension, hypokalemia, and lack of pubertal development.


OBJECTIVE
To better understand this rare enzymatic deficiency, we analyzed the CYP17A1 gene in six affected patients.


METHODS
We examined six patients, five 46,XY, and one 46,XX (age 9-29 yr) with complete lack of masculinization (female infantile external genitalia, no uterus) and delayed puberty, respectively, and different degrees of hypertension.


METHODS
Genotype-phenotype correlation was measured.


RESULTS
Four homozygote mutations were identified by direct sequencing of the CYP17A1 gene corresponding to an alanin 302-proline (A302P) exchange; the loss of lysine 327 (K327del); the deletion of glutamate 331 (E331del); and the replacement of arginine 416 with a histidine (R416H). Both P450c17 activities were abolished in all the mutant proteins, except one, when expressed in COS1 cells. The E331del-mutated P450c17 retained 17alpha-hydroxylase activity. The mutant proteins were normally expressed, suggesting that the loss of enzymatic activity is not due to defects of synthesis, stability, or localization of P450c17 proteins.


CONCLUSIONS
These studies confirm lack of masculinization in 46,XY individuals as the pathognomic sign of the complete P450c17 deficiency. In XX individuals P450c17 deficiency should be considered in cases of delayed puberty. Age of onset and the severity of hypertension do not seem to be constant. Careful examination of long-term follow-ups in two of our patients suggested to us that estrogen treatment in P450c17-deficient patients might worsen the enzymatic defect, leading to aggravation of the hypertension.
Rosa
S
S
University Children's Hospital, Division of Endocrinology and Diabetology, Steinwiesstrasse 75, 8032 Zurich, Switzerland.
Duff
C
C
Meyer
M
M
Lang-Muritano
M
M
Balercia
G
G
Boscaro
M
M
Topaloglu
A Kemal
AK
Mioni
R
R
Fallo
F
F
Zuliani
L
L
Mantero
F
F
Schoenle
E J
EJ
Biason-Lauber
A
A
D000293:Adolescent; D000328:Adult; D000818:Animals; D001794:Blood Pressure; D019556:COS Cells; D002648:Child; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D017930:Genes, Reporter; D023961:Gonadal Dysgenesis, 46,XX / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D006061:Gonadal Dysgenesis, 46,XY / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D009154:Mutation; D011374:Progesterone / Q000378:metabolism; D011859:Radiography; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D011374:Progesterone; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase