Aromatase deficiency

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Aromatase deficiency is a condition characterized by reduced levels of the female sex hormone estrogen and increased levels of the male sex hormone testosterone.

Females with aromatase deficiency have a typical female chromosome pattern (46,XX) but are born with external genitalia that do not appear clearly female or male. These individuals typically have normal internal reproductive organs, but develop ovarian cysts early in childhood, which impair the release of egg cells from the ovaries (ovulation). In adolescence, most affected females do not develop secondary sexual characteristics, such as breast growth and menstrual periods. They tend to develop acne and excessive body hair growth (hirsutism).

Men with this condition have a typical male chromosome pattern (46,XY) and are born with male external genitalia. Some men with this condition have decreased sex drive, abnormal sperm production, or testes that are small or undescended (cryptorchidism).

There are other features associated with aromatase deficiency that can affect both males and females. Affected individuals are abnormally tall because of excessive growth of long bones in the arms and legs. The abnormal bone growth results in slowed mineralization of bones (delayed bone age) and thinning of the bones (osteoporosis), which can lead to bone fractures with little trauma. In affected individuals, the body does not respond correctly to the hormone insulin, so people with aromatase deficiency can have abnormally high blood sugar (glucose), a condition known as hyperglycemia. In addition, people with armoatase deficiency can have excessive weight gain and a fatty liver.

Women who are pregnant with fetuses that have aromatase deficiency often experience mild symptoms of the disorder even though they themselves do not have the disorder. These women may develop hirsutism, acne, an enlarged clitoris (clitoromegaly), and a deep voice. These features can appear as early as 12 weeks of pregnancy and go away soon after delivery.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Mutations in the CYP19A1 gene cause aromatase deficiency. The CYP19A1 gene provides instructions for making an enzyme called aromatase. This enzyme converts a class of hormones called androgens, which are involved in male sexual development, to different forms of estrogen. In females, estrogen guides female sexual development before birth and during puberty. In both males and females, estrogen plays a role in regulating bone growth and blood glucose levels. During fetal development, aromatase converts androgens to estrogens in the placenta, which is the link between the mother's blood supply and the fetus. This conversion in the placenta prevents androgens from directing sexual development in female fetuses. After birth, the conversion of androgens to estrogens takes place in multiple tissues.

CYP19A1 gene mutations that cause aromatase deficiency decrease or eliminate aromatase activity. A shortage of functional aromatase results in an inability to convert androgens to estrogens before birth and throughout life. As a result, there is a decrease in estrogen production and an increase in the levels of androgens, including testosterone. In affected individuals, these abnormal hormone levels lead to impaired female sexual development, unusual bone growth, insulin resistance, and other signs and symptoms of aromatase deficiency. In women who are pregnant with an affected fetus, excess androgens in the placenta pass into the woman's bloodstream, which may cause her to have temporary signs and symptoms of aromatase deficiency.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

The prevalence of aromatase deficiency is unknown; approximately 20 cases have been described in the medical literature.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Ambiguous genitalia, female · Very frequent (99-80%)

Ambiguous genitalia in an individual with XX genetic gender.

Bone pain · Very frequent (99-80%)

An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to bone.

Cryptorchidism · Very frequent (99-80%)

Testis in inguinal canal. That is, absence of one or both testes from the scrotum owing to failure of the testis or testes to descend through the inguinal canal to the scrotum.

Delayed skeletal maturation · Very frequent (99-80%)

A decreased rate of skeletal maturation. Delayed skeletal maturation can be diagnosed on the basis of an estimation of the bone age from radiographs of specific bones in the human body.

Eunuchoid habitus · Very frequent (99-80%)

A body habitus that is tall, slim and underweight, with long legs and long arms (i.e., arm span exceeds height by 5 cm or more).

Female pseudohermaphroditism · Very frequent (99-80%)

Hermaphroditism refers to a discrepancy between the morphology of the gonads and that of the external genitalia. In female pseudohermaphroditism, the genotype is female (XX) and the gonads are ovaries, but the external genitalia are virilized.

Genu valgum · Very frequent (99-80%)

The legs angle inward, such that the knees are close together and the ankles far apart.

Growth delay · Very frequent (99-80%)

A deficiency or slowing down of growth pre- and postnatally.

Other findings in the same source

From: Orphanet

Additional reported features include Hypergonadotropic hypogonadism (Very frequent (99-80%)); Hyperlipidemia (Very frequent (99-80%)); Maternal virilization in pregnancy (Very frequent (99-80%)); Obesity (Very frequent (99-80%)); Osteopenia (Very frequent (99-80%)); Osteoporosis (Very frequent (99-80%)); Tall stature (Very frequent (99-80%)); Delayed epiphyseal ossification (Very frequent (99-80%)); Enlarged polycystic ovaries (Very frequent (99-80%)); Female infertility (Very frequent (99-80%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Aromatase deficiency is Endocrinology, with a endocrinologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which hormone or metabolic finding is important in this case?
• How should test timing and current medicines be taken into account?
• What follow-up would show whether the care plan is working?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Aromatase deficiency. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.