NIH Rare Diseases :
52
The following summary is from Orphanet , a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 91 Definition A rare disorder that 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. Epidemiology Fewer than 20 cases have been reported to date. Clinical description 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. 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. Diagnostic methods 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 . Differential diagnosis In female patients, differential diagnosis includes congenital adrenal hyperplasia (see this term); 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 (see these terms). Antenatal diagnosis 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 counseling Genetic testing is recommended for families who have had one affected child, transmission is autosomal recessive . Management and treatment 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 ?g 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 ?g daily. Hypocaloric diet should be complemented with calcium, vitamin D and physical activity. Dyslipidemia, glucose intolerance or insulin resistance must be treated symptomatically. Prognosis 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. Visit the Orphanet disease page for more resources.
MalaCards based summary :
Aromatase Deficiency, also known as
congenital estrogen deficiency, is related to
lipoid congenital adrenal hyperplasia and
amenorrhea. An important gene associated with Aromatase Deficiency is
CYP19A1 (Cytochrome P450 Family 19 Subfamily A Member 1), and among its related pathways/superpathways are
Steroid hormone biosynthesis and
Ovarian steroidogenesis. Affiliated tissues include
bone,
breast and
ovary, and related phenotypes are
delayed skeletal maturation and
genu valgum
Genetics Home Reference :
25
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 (ambiguous genitalia). 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. Males and females with aromatase deficiency can have abnormally high blood sugar (hyperglycemia) because the body does not respond correctly to the hormone insulin. In addition, they 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.
OMIM :
56
Aromatase deficiency is a rare autosomal recessive disorder in which individuals cannot synthesize endogenous estrogens. If a fetus lacks aromatase activity, dehydroepiandrosterone sulfate produced by the fetal adrenal glands cannot be converted to estrogen by the placenta, and 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. Affected females are usually 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 hypergonadotropic hypogonadism. Affected males do not present with obvious defects at birth. Their clinical symptoms include tall stature, delayed skeletal maturation, delayed epiphyseal closure, bone pain, eunuchoid body proportions, and excess adiposity. Estrogen replacement therapy reverses the symptoms in males and females (summary by Jones et al., 2007).
(613546)
KEGG :
36
Aromatase deficiency is a rare autosomal recessive syndrome, caused by mutations in CYP19A1 gene. Aromatase, encoded by the CYP19A1, catalyses the biosynthesis of estrogens. Due to estrogen deficiency, disorders of sex development and progressive virilization at puberty develop in females. In the males, prepubertal development is normal. Delayed epiphyseal closure, eunuchoid body habitus, osteopenia, and osteoporosis develop in both genders.
UniProtKB/Swiss-Prot :
73
Aromatase deficiency: A rare disease in which fetal androgens are not converted into estrogens due to placental aromatase deficiency. Thus, pregnant women exhibit a hirsutism, which spontaneously resolves after post-partum. At birth, female babies present with pseudohermaphroditism due to virilization of extern genital organs. In adult females, manifestations include delay of puberty, breast hypoplasia and primary amenorrhoea with multicystic ovaries.
Wikipedia :
74
Aromatase deficiency is a very rare condition characterised by the extremely low or absence of the...
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Rare infertility disorders 
