Rare Pulmonology News

Disease Profile

Aromatase deficiency

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of onset

All ages

ageofonset-all.svg

ICD-10

E25.8

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

no.svg

Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

rnn-autosomalrecessive.svg

X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

no.svg

X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

no.svg

Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

no.svg

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

no.svg

Not applicable

no.svg

Other names (AKA)

Congenital estrogen deficiency

Categories

Congenital and Genetic Diseases; Endocrine Diseases; Female Reproductive Diseases;

Summary

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
orphanet

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 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.

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.

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Ambiguous genitalia, female
Atypical appearance of female genitals
0000061
Bone pain
0002653
Cryptorchidism
Undescended testes
Undescended testis

[ more ]

0000028
Delayed epiphyseal ossification
0002663
Delayed skeletal maturation
Delayed bone maturation
Delayed skeletal development

[ more ]

0002750
Enlarged polycystic ovaries
Enlarged ovaries with cysts
0008675
Eunuchoid habitus
0003782
Female infertility
0008222
Female pseudohermaphroditism
0010458
Genu valgum
Knock knees
0002857
Growth delay
Delayed growth
Growth deficiency
Growth failure
Growth retardation
Poor growth
Retarded growth

[ more ]

0001510
Hypergonadotropic hypogonadism
0000815
Hyperlipidemia
Elevated lipids in blood
0003077
Male infertility
0003251
Maternal virilization in pregnancy
0008072
Obesity
Having too much body fat
0001513
Osteopenia
0000938
Osteoporosis
0000939
Primary amenorrhea
0000786
Tall stature
Increased body height
0000098
30%-79% of people have these symptoms
Acanthosis nigricans
Darkened and thickened skin
0000956
Generalized hirsutism
Excessive hairiness over body
0002230
Hepatic steatosis
Fatty infiltration of liver
Fatty liver

[ more ]

0001397
Insulin resistance
Body fails to respond to insulin
0000855
Macroorchidism, postpubertal
0002050
Type II diabetes mellitus
Noninsulin-dependent diabetes
Type 2 diabetes
Type II diabetes

[ more ]

0005978
Percent of people who have these symptoms is not available through HPO
Autosomal recessive inheritance
0000007
Ovarian cyst
0000138

Learn more

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference contains information on Aromatase deficiency. This website is maintained by the National Library of Medicine.

In-Depth Information

  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Aromatase deficiency. Click on the link to view a sample search on this topic.