Background: Aromatase deficiency has been associated with disordered sexual development in infancy and delayed puberty later. The condition responds to estradiol treatment with normalization of gonadotropin levels and pubertal development. We report a girl with a novel Aromatase mutation with persistently elevated gonadotropin levels despite adequate estrogen treatment.
Case report: This thirteen and a half year old girl was referred for evaluation of delayed puberty and hypergonadotropic hypogonadism. She had presented to an endocrinologist in the neonatal period with clitoromegaly and labioscrotal fusion and was diagnosed as 21 hydroxylase deficiency due to mildly elevated 17OHP levels. Hydrocortisone treatment was associated with lowering of 17OHP level and discontinuation of the drug. Genetic study excluded the diagnosis of 21 hydroxylase deficiency with normal 17OHP levels despite stopping hydrocortisone. She was referred to our clinic with delayed puberty and growth failure (weight 34.8 kg, -1.98 SDS; height of 149.5 cm -1.48 SDS). Investigations showed high FSH (98 mIU/L) and LH (49 mIU/L) and delayed bone age of 10.98 years. Further assessment confirmed maternal virilization during pregnancy suggesting the possibility of aromatase deficiency. Genetic study identified two novel heterozygous mutations on exon 4 (p.Arg115Ter) and exon 5 (p.Tyr184Ter) of aromatase gene. Pubertal induction was initiated with low dose estradiol valerate (0.25 mg daily) and gradually increased to 1 mg over 2 years. This was associated with increase in body mass index from 15.6 kg/m2 (-1.65 SDS) to 19.7 kg/m2 (-0.14 SDS), breast size from stage II to stage V and bone age from 10.98 years (at chronological age of 13.5 years) to 13 years (at chronological age of 15.5 years). Estradiol replacement was however not associated with reduction in gonadotropin levels (LH 36.97 mIU/L and FSH 106.9 mIU/L) or increase in uterine size and endometrial thickness. This is in contradistinction to previous reports where estradiol treatment resulted in normalization of FSH levels and may be related to reset hypothalamic-pituitary-gonadal axis due to severity of aromatase deficiency in our girl.
Conclusion: Persistent gonadotropin elevation in our case despite adequate estradiol replacement indicates abnormal pituitary responsiveness to estradiol and needs to be further explored.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology