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Recognizing rare disorders: aromatase deficiency

Abstract

Aromatase deficiency is rare in humans. Affected individuals cannot synthesize endogenous estrogens. Aromatase is the enzyme that catalyzes conversion of androgens into estrogens, and if aromatase is nonfunctional because of an inactivating mutation, estrogen synthesis cannot occur. If the fetus lacks aromatase activity, dehydroepiandrosterone sulfate produced by the fetal adrenal glands cannot be converted to estrogen by the placenta, so is converted to testosterone peripherally and results in virilization of both fetus and mother. Virilization manifests as pseudohermaphroditism in female infants, with hirsutism and acne in the mother; the maternal indicators resolve following delivery. To date, only seven males and seven females with aromatase deficiency have been reported. Affected females are typically diagnosed at birth because of the pseudohermaphroditism. Cystic ovaries and delayed bone maturation can occur during childhood and adolescence in these girls, who present at puberty with primary amenorrhea, failure of breast development, virilization, and hypergonadotrophic hypogonadism. Affected males, on the other hand, do not present with obvious defects at birth, so are diagnosed much later in life, presenting with clinical symptoms, which include tall stature, delayed skeletal maturation, delayed epiphyseal closure, bone pain, eunuchoid body proportions and excess adiposity. Estrogen replacement therapy reverses the symptoms in male and female patients.

Key Points

  • Aromatase deficiency is rare

  • Aromatase deficiency should be suspected in any pregnancy in which the mother becomes virilized

  • This condition should be suspected when a female newborn presents with ambiguous genitalia

  • When an adult male presents with tall stature, delayed skeletal maturation, delayed epiphyseal closure, eunuchoid body proportions, and undetectable estrogens concomitant with elevated levels of testosterone, aromatase deficiency should be suspected

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Figure 1: Photograph of aromatase-deficient man,11 demonstrating genu valgum

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Acknowledgements

This work was supported by US Public Health Service Grant R37-AG08174, National Health and Medical Research Council (NHMRC) Project Grants 169010 and 338510, and NHMRC Fellowship Award 241024 to MEE Jones. Written consent for publication of the photograph used in Figure 1 was obtained from the patient and clinician involved.

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Correspondence to Margaret EE Jones.

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Jones, M., Boon, W., McInnes, K. et al. Recognizing rare disorders: aromatase deficiency. Nat Rev Endocrinol 3, 414–421 (2007). https://doi.org/10.1038/ncpendmet0477

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