Hypothalamic-pituitary-ovarian axis during infancy, early and late prepuberty in an aromatase-deficient girl who is a compound heterocygote for two new point mutations of the CYP19 gene.

[aromatase deficiency]

A loss of function mutation of the CYP 19 aromatase gene leads to excess circulating androgens in the fetus and in the mother , resulting in ambiguous genitalia in the female fetus . Later on , lack of aromatase is responsible for sexual infantilism , primary amenorrhea , tall stature , and multicystic ovaries , even in preadolescent girls . Up to now , 11 CYP 19 aromatase point mutations and 10 well-documented cases have been reported . In the present case , we are reporting the clinical and hormonal follow-up , from birth to 7 yr of age , of an affected girl with ambiguous genitalia . Gene analysis showed that she was a compound heterozygote for two new CYP 19 aromatase point mutations . In the father 's allele , there was a consensus 5 ' splice donor sequence mutation , GAA -AAA at cDNA position bp 655 in exon 5 , which probably results in a cryptic donor site . In the mother 's allele , there was a base A deletion in exon 9 (Delta A GLU 412 X ), causing a frame shift mutation , and a stop codon after 98 bp (33 codons ) downstream , altering the critical heme-binding region . Basal serum LH and FSH levels were high at 8 d of age (42 .9 and 51 .3 U /liter ), 26 d of age (76 .2 and 119 U /liter ), and 60 d of age (58 .7 and 150 U /liter , respectively ). Both gonadotropins dropped dramatically between the second and fifth months of age (to 1 .79 and 14 .9 U /liter ) but remained higher than in normal control girls (0 .64 and 8 .5 U /liter , respectively ). Serum testosterone (T ) and androstenedione (Delta (4 )A ) levels were high during the first month , but Delta (4 )A was normal at 2 months of age . However , at 5 months of age , along with significant decrements of serum LH and FSH levels and increments in serum Delta (4 )A and T levels , a large ovarian cyst was removed from each gonad . Relatively high levels of T [27 .3 ng /ml (94 .6 nmol /liter ); control , 34 .9 ng /ml (121 nmol /liter )], but not of estradiol [1 .8 ng /ml (6 .6 nmol /liter ); control 62 .9 ng /ml (231 nmol /liter )], and a high T /estradiol ratio [15 .2 ; control < 1 ] were found in the follicular fluid . Serum Delta (4 )A and T levels remained normal from 1 -5 yr of age , but they were high at the last visit (late prepuberty ). A GnRH test was performed at 3 .9 , 6 , and 7 .1 yr of age . At 3 .9 yr , a low prepubertal serum LH peak (2 .12 U /liter ) was found , but at the older ages , higher serum LH peaks (8 .25 and 22 .5 U /liter , respectively ) were observed . Growth pattern and body mass index were normal , but after the age of 5 .2 yr , delays in bone age greater than 2 yr were observed . We concluded that : 1 ) these two new CYP 19 aromatase gene mutations are responsible for the phenotype of aromatase deficiency ; 2 ) in girls , aromatase deficiency results in a decrease of the negative feedback of both serum LH and FSH , which can be detected as early as the second week after birth and persists up to the sixth month of life , and of FSH during the rest of prepuberty ; and 3 ) because large ovarian cysts developed when serum LH and FSH dropped , aromatization of androgens might be required to prevent formation of cystic ovaries .

Diseases
Validation

Diseases presenting "bone age" symptom

achondroplasia

aromatase deficiency

congenital adrenal hyperplasia

cushing syndrome

kabuki syndrome

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