aromatase deficiency

Aromatase deficiency is an inherited endocrine condition that interferes with the body’s ability to convert androgens into estrogens, affecting reproductive, skeletal, and metabolic systems in both sexes. Variants in the CYP19A1 gene disrupt production of the aromatase enzyme, leading to very low estrogen levels and excess androgens before and after birth. Signs can appear in newborns with ambiguous genital development, in adolescent girls who do not start menstruating, or in boys and adults with tall stature, delayed bone maturation, and metabolic concerns. Fewer than one in a million people are thought to be affected worldwide, making it an ultra-rare diagnosis. Severity and symptoms vary widely between individuals.

Presentation differs by age and sex, but several patterns are well recognized. In genetically female newborns, reduced estrogen causes prenatal virilization, so external genitalia may be ambiguous or appear typically male. During adolescence, many girls experience primary amenorrhea and enlarged polycystic ovaries, and they may develop hirsutism because of excess androgens. Genetically male infants may have undescended testes, and older boys often grow unusually tall, with delayed closure of growth plates, macro-orchidism after puberty, and infertility later in life. Across sexes, low estrogen contributes to osteopenia or osteoporosis, bone pain, delayed skeletal maturation, genu valgum, and increased risk of obesity, insulin resistance, type 2 diabetes, and fatty liver disease. Not all individuals experience all features, and severity varies considerably.

Aromatase deficiency results from pathogenic variants in the CYP19A1 gene. This gene provides instructions for making aromatase, the enzyme that converts testosterone and other androgens into estrogens. When both copies of CYP19A1 carry a non-working variant, estrogen production drops sharply while androgen levels rise, creating the hormonal imbalance responsible for the clinical picture. The condition is inherited in an autosomal recessive pattern, meaning an affected individual receives one altered gene from each parent. Parents who each carry one variant are usually healthy but have a 25 percent chance with each pregnancy of having an affected child. Because this condition requires two copies of the variant, it is more common when parents share a common ancestor, which increases the likelihood that both carry the same rare genetic change. Carrier testing and genetic counseling are recommended for parents, siblings, and extended relatives who may be at risk.

Currently, management focuses on supportive care and symptom management. Treatment is tailored to the individual and typically involves a multidisciplinary team that may include endocrinologists, orthopedic specialists, reproductive medicine experts, and metabolic clinicians. Long-term management includes regular surveillance for potential complications. Monitoring bone density, growth parameters, metabolic markers such as blood glucose and lipids, and reproductive health helps detect problems early when intervention is most effective. Patients should discuss options and monitoring schedules with their healthcare team and consider genetic counseling to inform family planning.

The long-term outlook for people with aromatase deficiency depends on the degree of hormonal imbalance, the timing of diagnosis, and access to specialized care. Many individuals can achieve good quality of life when hormonal effects on bone health, growth, and metabolism are recognized and monitored. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with endocrinologists and genetic counselors familiar with this condition to ensure coordinated follow-up and to discuss emerging management options.

Clinical trials are underway exploring new treatment approaches for aromatase deficiency. Individuals interested in research participation can search ClinicalTrials.gov or consult their care team about eligibility.