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Aromatase Deficiency in a Female Who Is Compound Heterozygote for Two New Point Mutations in the P450_arom Gene: Impact of Estrogens on Hypergonadotropic Hypogonadism, Multicystic Ovaries, and Bone Densitometry in Childhood¹

Division of Paediatric Endocrinology, University Children’s Hospital (P.E.M., B.K.) and Policlinic of Medicine, University Hospital (K.L., P.J.), 3010 Bern, Switzerland; and Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University (N.Y., N.H.),Toyake, Aichi, Japan

Address all correspondence and requests for reprints to: P.E. Mullis, Paediatric Endocrinology, University Children’s Hospital, Inselspital, CH-3010 Bern, Switzerland. E-mail: primus.mullis{at}insel.unibe.ch

We report on a female who is compound heterozygote for two new point mutations in the CYP19 gene. The allele inherited from her mother presented a base pair deletion (C) occurring at P408 (CCC, exon 9), causing a frameshift that results in a nonsense codon 111 bp (37 aa) further down in the CYP19 gene. The allele inherited from her father showed a point mutation from G->A at the splicing point (canonical GT to mutational AT) between exon and intron 3. This mutation ignores the splice site and a stop codon 3 bp downstream occurs.

Aromatase deficiency was already suspected because of the marked virilization occurring prepartum in the mother, and the diagnosis was confirmed shortly after birth. Extremely low levels of serum estrogens were found in contrast to high levels of androgens. Ultrasonographic follow-up studies revealed persistently enlarged ovaries (19.5–22 mL) during early childhood (2 to 4 yr) which contained numerous large cysts up to 4.8 x 3.7 cm and normal-appearing large tertiary follicles already at the age of 2 yr. In addition, both basal and GnRH-induced FSH levels remained consistently strikingly elevated. Low-dose estradiol (E₂) (0.4 mg/day) given for 50 days at the age of 36/12 yr resulted in normalization of serum gonadotropin levels, regression of ovarian size, and increase of whole body and lumbar spine (L1-L4) bone mineral density. The FSH concentration and ovarian size returned to pretreatment levels shortly (150 days) after cessation of E₂ therapy. Therefore, we recommend that affected females be treated with low-dose E₂ in amounts sufficient to result in physiological prepubertal E₂ concentrations using an ultrasensitive estrogen assay. However, E₂ replacement needs to be adjusted throughout childhood and puberty to ensure normal skeletal maturation and adequate adolescent growth spurt, normal accretion of bone mineral density, and, at the appropriate age, female secondary sex maturation.

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