Context: The P450 enzyme aromatase (CYP19) plays a crucial role in the endocrine and paracrine biosynthesis of estrogens from androgens in many diverse estrogen-responsive tissues. Complete aromatase deficiency has been reported in a small number of 46,XX girls with genital ambiguity and absent pubertal development, but it is unknown whether nonclassic phenotypes exist. Objective: The objective of this study was to determine whether variant forms of aromatase insufficiency can occur in humans. Patients and Methods: Four patients (46,XX) from three kindreds with variable degrees of androgenization and pubertal failure were studied using mutational analysis of CYP19 and assay of enzyme activity. Results: Aromatase insufficiency resulting in genital ambiguity at birth, but with variable breast development at puberty (B2-B4), occurred in 46,XX patients from two kindreds who harbored point mutations or single codon deletions (R435C, F234del). Absent puberty with minimal androgenization at birth was found in one girl with a deletion involving exon 5 of CYP19 (exon5del), which would be predicted to lead to an in-frame deletion of 59 amino acids from the enzyme. Functional studies revealed low residual aromatase activity in the cases in which breast development occurred. Conclusions: These studies demonstrate that aromatase mutations can produce variable or "nonclassic" phenotypes in humans. Low residual aromatase activity may be sufficient for breast and uterine development to occur at puberty, despite significant androgenization in utero. Such phenotypic variability may be influenced further by modifying factors such as nonclassic pathways of estrogen synthesis, variability in coregulators, or differences in androgen responsiveness.
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