What are the other Names for this Condition? (Also known as/Synonyms)

• Congenital Estrogen Deficiency

What is Aromatase Deficiency? (Definition/Background Information)

• Aromatase Deficiency disrupts the synthesis of estradiol, resulting in hirsutism of mothers during gestation of an affected child; pseudohermaphroditism and virilization in women; and tall stature, osteoporosis and obesity in men
• Affected female newborns present with different degrees of ambiguous genitalia, virilization and non-palpable gonads, in one case female genitalia were present. Female internal genitalia differentiation is unaffected
• Ovarian cystic follicles may appear in childhood, even at birth, or adolescence when patients manifest primary amenorrhea and no pubertal growth spurt. Breasts remain hypoplastic after initial development during puberty, while pubic hairs develop in a normal fashion. Males may present with cryptorchidism, but are generally asymptomatic until after puberty when patients present with bone pain and tall stature
• The pubertal growth spurt is absent, but linear growth continues due to incomplete epiphyseal closure and progressive genu valgum, eunuchoid proportion of the skeleton and osteoporosis manifest
• For these reasons the diagnosis is often overlooked in men. Metabolic co-morbidities may manifest as obesity, steatohepatitis, insulin resistance with acanthosis nigricans and dyslipidemia. Fertility is partially or completely disrupted in male patients
• In female patients, differential diagnosis includes congenital adrenal hyperplasia; in male patients, estrogen resistance syndrome 46,XY disorder of sex development due to isolated 17, 20 lyase deficiency, congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency and congenital hypogonadotropic hypogonadism 
• During the third trimester of gestation, mothers exhibit severe acne, deep voice and in some cases clitoral enlargement and hirsutism, symptoms resolve spontaneously post-partum
• Genetic testing is recommended in these cases. Genetic testing is recommended for families who have had one affected child, transmission is autosomal recessive

(Source: Aromatase Deficiency; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Who gets Aromatase Deficiency? (Age and Sex Distribution)

• Aromatase Deficiency is a rare congenital disorder and less than 20 cases are described in the medical literature
• The presentation of symptoms may occur at birth
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Aromatase Deficiency? (Predisposing Factors)

• A positive family history may be an important risk factor, since Aromatase Deficiency can be inherited
• Currently, no other risk factors have been clearly identified for the disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Aromatase Deficiency? (Etiology)

• Aromatase (CYP19A1, 15q21.1), or cytochrome P450, synthesizes estradiol from androgens. Several null mutations have been identified, placental expression of aromatase converts androgens to estradiol; excess androgens affect both the mother and fetal development
• One reported case of a promoter region mutation exclusively inhibited placental expression
• Genetic testing is recommended for families who have had one affected child with Aromatase Deficiency, transmission is autosomal recessive

(Source: Aromatase Deficiency; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Aromatase Deficiency?

The signs and symptoms of Aromatase Deficiency may include:

Very frequently present symptoms in 80-99% of the cases:

• Ambiguous genitalia, female
• Bone pain
• Cryptorchidism
• Delayed epiphyseal ossification
• Delayed skeletal maturation
• Enlarged polycystic ovaries
• Eunuchoid habitus
• Female infertility
• Female pseudohermaphroditism
• Genu valgum
• Growth delay
• Hypergonadotropic hypogonadism
• Hyperlipidemia
• Male infertility
• Maternal virilization in pregnancy
• Obesity
• Osteopenia
• Osteoporosis
• Primary amenorrhea
• Tall stature

Frequently present symptoms in 30-79% of the cases:

• Acanthosis nigricans
• Generalized hirsutism
• Hepatic steatosis
• Insulin resistance
• Macroorchidism, postpubertal
• Type II diabetes mellitus

(Source: Aromatase Deficiency; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

How is Aromatase Deficiency Diagnosed?

• Females are generally diagnosed at birth. Male patients are usually diagnosed during adulthood due to continuing linear growth in height and unfused epiphyses are revealed by hand radiographs
• Measurement of serum estradiol, testosterone and luteinizing hormone may be followed by genetic testing

(Source: Aromatase Deficiency; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Aromatase Deficiency?

The complications of Hoyeraal Hreidarsson Syndrome may include:

• Uncontrolled diabetes and associated complications
• Infertility
• Emotional stress

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Aromatase Deficiency Treated?

• Female patients are candidates for surgical modification of genitalia depending on the degree of ambiguity and must be monitored for ovarian cysts. Upon puberty, daily treatment with estrogen must be administered (0.625 mg/twice weekly increasing to daily) and may be supplemented with progesterone-like hormone and monthly treatments of gonadotrophin-releasing hormone antagonists
• Adult men should be treated immediately upon diagnosis: daily transdermal administration of up to 50 µg of estradiol (serum estradiol at 40 pg/ml) for 6-9 months to complete skeletal maturation. Upon epiphyseal closure, estradiol replacement may be reduced to 25 µg daily
• Hypocaloric diet should be complemented with calcium, vitamin D and physical activity. Dyslipidemia, glucose intolerance or insulin resistance must be treated symptomatically

(Source: Aromatase Deficiency; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

How can Aromatase Deficiency be Prevented?

Currently, Aromatase Deficiency may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Aromatase Deficiency? (Outcomes/Resolutions)

• Lifetime hormone replacement therapy is obligatory. In male patients with late diagnosis, skeletal defects remain even after successful hormonal treatment and may require surgical correction
• Furthermore, adiposity and fertility defects are not alleviated by estradiol treatment

(Source: Aromatase Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Additional and Relevant Useful Information for Aromatase Deficiency:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/