Characterization of a novel CYP19A1 (aromatase) R192H mutation causing virilization of a 46,XX newborn, undervirilization of the 46,XY brother, but no virilization of the mother during pregnancies.

[aromatase deficiency]

P 450 aromatase (CYP 19 A 1 ) is essential for the biosynthesis of estrogens from androgen precursors . Mutations in the coding region of CYP 19 A 1 lead to autosomal recessive aromatase deficiency . To date over 20 subjects have been reported with aromatase deficiency which may manifest during fetal life with maternal virilization and virilization of the external genitalia of a female fetus due to low aromatase activity in the steroid metabolizing fetal -placental unit and thus high androgen levels . During infancy , girls often have ovarian cysts and thereafter fail to enter puberty showing signs of variable degree of androgen excess . Moreover , impact on growth , skeletal maturation and other metabolic parameters is seen in both sexes .We found a novel homozygous CYP 19 A 1 mutation in a 46 ,XX girl who was born at term to consanguineous parents . Although the mother did not virilize during pregnancy , the baby was found to have a complex genital anomaly at birth (enlarged genital tubercle , fusion of labioscrotal folds ) with elevated androgens at birth , normalizing thereafter . Presence of 46 ,XX karyotype and female internal genital organs (uterus , vagina ) together with biochemical findings and follow-up showing regression of clitoral hypertrophy , as well as elevated FSH suggested aromatase deficiency . Interestingly , her older brother presented with mild hypospadias and bilateral cryptorchidism and was found to carry the same homozygous CYP 19 A 1 mutation . To confirm the clinical diagnosis , genetic , functional and computational studies were performed .Genetic analysis revealed a homozygous R 192 H mutation in the CYP 19 A 1 gene . This novel mutation was characterized for its enzymatic activity (Km , Vmax ) in a cell model and found to have markedly reduced catalytic activity when compared to wild-type aromatase ; thus explaining the phenotype . Computational studies suggest that R 192 H disrupts the substrate access channel in CYP 19 A 1 that may affect binding of substrates and exit of catalytic products .R 192 H is a novel CYP 19 A 1 mutation which causes a severe phenotype of aromatase deficiency in a 46 ,XX newborn and maybe hypospadias and cryptorchidism in a 46 ,XY , but no maternal androgen excess during pregnancy .

Diseases
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Diseases presenting "thereafter fail to enter puberty showing signs of variable degree of androgen excess" symptom

aromatase deficiency

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