Aromatase Excess Syndrome (AEXS), sometimes referred to as Familial Aromatase Excess Syndrome (FAES), is a rare genetic disorder characterized by the body’s overproduction of the female sex hormone estrogen. This condition stems from an overactive aromatase enzyme, which leads to abnormally high levels of circulating estrogen in both biological sexes. The fundamental issue in AEXS is a significant endocrine imbalance, where this excessive estrogen signaling disrupts the body’s normal development and physiology, leading to wide-ranging effects.
The Biological Mechanism of Aromatase Excess
The core biological function of the aromatase enzyme is to synthesize estrogen by converting a class of hormones known as androgens. Specifically, aromatase catalyzes the conversion of testosterone into the potent estrogen estradiol, and androstenedione into estrone. This enzyme is encoded by the CYP19A1 gene and is present in various tissues, including fat cells, skin, liver, and muscle.
In individuals with Aromatase Excess Syndrome, genetic changes cause the aromatase enzyme to be hyperactive, functioning at an excessively high rate. This enhanced activity leads to a significantly increased conversion of available androgens into estrogens, resulting in hyperestrogenemia, or chronic estrogen excess. The overexpression of the enzyme effectively drains the body’s supply of androgens, further contributing to the hormonal imbalance.
Genetic Basis and Inheritance
Aromatase Excess Syndrome is caused by specific gain-of-function mutations within the CYP19A1 gene, which is located on chromosome 15. The term “gain-of-function” signifies that the mutation enhances the normal activity of the gene product, leading to the overproduction of the aromatase enzyme and chronic hyperestrogenemia.
The condition follows an autosomal dominant pattern of inheritance, meaning a child only needs to inherit one copy of the mutated CYP19A1 gene from a parent to develop the syndrome. The mutations often involve large-scale genetic rearrangements, such as duplications, deletions, or inversions of the genetic material surrounding the gene. These structural changes can lead to the recruitment of novel gene promoters, resulting in the inappropriate or excessive transcription of the CYP19A1 gene. The severity of the clinical symptoms is often linked to the specific type of genetic rearrangement.
Clinical Manifestations
The chronic excess of estrogen in AEXS leads to distinct physical changes, with the presentation differing significantly between males and females due to their baseline hormonal environments.
Manifestations in Males
For males, the most common and noticeable symptom is the onset of gynecomastia, or breast enlargement, which typically begins in the pre- or peripubertal period. This development is a direct result of estrogen stimulating breast tissue growth. Another significant manifestation is an accelerated rate of bone maturation, often referred to as advanced bone age. Estrogen has a powerful role in regulating bone growth and is responsible for the final closure of the growth plates, or epiphyses, in long bones. In AEXS, the continuous high estrogen signal causes the growth plates to fuse prematurely. While affected males may experience an early growth spurt, this premature epiphyseal closure ultimately results in a short adult stature.
Manifestations in Females
Affected females generally present with symptoms that are less severe or noticeable, but they still experience the effects of chronic estrogen exposure. Some females develop isosexual precocious puberty, which is the early onset of puberty with appropriate secondary sexual characteristics, such as breast development (macromastia when excessive). They may also experience irregular menstrual cycles due to the constant, unregulated hormonal signal. Similar to males, females with AEXS face advanced bone maturation, leading to a reduced final adult height. The excessive estrogen levels can also cause an enlarged uterus.
Diagnosis and Management
The process of diagnosing Aromatase Excess Syndrome begins with a high index of clinical suspicion, especially when a patient, particularly a male, presents with early-onset gynecomastia and a family history of similar symptoms. Initial laboratory testing involves measuring circulating sex hormone levels to detect the characteristic profile of elevated estrogen and estrone, often accompanied by normal or low androgen levels.
A definitive diagnosis relies on genetic testing. Genetic analysis is necessary to confirm the presence of a gain-of-function mutation or genomic rearrangement in the CYP19A1 gene. This molecular confirmation identifies the specific alteration causing excessive aromatase activity, which is particularly helpful in cases where the hormonal profile is ambiguous or when diagnosing a sporadic case.
The primary method for managing AEXS involves the use of medications known as Aromatase Inhibitors (AIs), such as anastrozole or letrozole. These drugs work by directly blocking the action of the overactive aromatase enzyme, preventing the conversion of androgens into estrogens. Reducing the overall estrogen load effectively halts or reverses the progression of symptoms, particularly gynecomastia and accelerated bone maturation, helping to preserve the patient’s final adult height.