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Aromatase deficiency

MedGen UID:
743307
Concept ID:
C1960539
Disease or Syndrome
Synonyms: Increased aromatase activity; Pseudohermaphroditism, female, due to placental aromatase deficiency
SNOMED CT: Maternal virilization due to placental aromatase deficiency (427627006)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): CYP19A1 (15q21.2)
 
Monarch Initiative: MONDO:0013301
OMIM®: 613546
Orphanet: ORPHA91

Definition

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). [from OMIM]

Additional description

From MedlinePlus Genetics
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.  https://medlineplus.gov/genetics/condition/aromatase-deficiency

Clinical features

From HPO
Ovarian cyst
MedGen UID:
14540
Concept ID:
C0029927
Disease or Syndrome
The presence of one or more cysts of the ovary.
Primary amenorrhea
MedGen UID:
115918
Concept ID:
C0232939
Disease or Syndrome
Abnormally late or absent menarche in a female with normal secondary sexual characteristics.
Female pseudohermaphroditism
MedGen UID:
65964
Concept ID:
C0238394
Congenital Abnormality
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.
Delayed skeletal maturation
MedGen UID:
108148
Concept ID:
C0541764
Finding
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.
Hypergonadotropic hypogonadism
MedGen UID:
184926
Concept ID:
C0948896
Disease or Syndrome
Reduced function of the gonads (testes in males or ovaries in females) associated with excess pituitary gonadotropin secretion and resulting in delayed sexual development and growth delay.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAromatase deficiency

Professional guidelines

PubMed

Fukami M, Nishimura G, Homma K, Nagai T, Hanaki K, Uematsu A, Ishii T, Numakura C, Sawada H, Nakacho M, Kowase T, Motomura K, Haruna H, Nakamura M, Ohishi A, Adachi M, Tajima T, Hasegawa Y, Hasegawa T, Horikawa R, Fujieda K, Ogata T
J Clin Endocrinol Metab 2009 May;94(5):1723-31. Epub 2009 Mar 3 doi: 10.1210/jc.2008-2816. PMID: 19258400
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Diabet Med 2007 Dec;24(12):1491-5. Epub 2007 Nov 1 doi: 10.1111/j.1464-5491.2007.02304.x. PMID: 17976198

Recent clinical studies

Etiology

Berkane N, Liere P, Lefevre G, Alfaidy N, Nahed RA, Vincent J, Oudinet JP, Pianos A, Cambourg A, Rozenberg P, Galichon P, Rousseau A, Simon T, Schumacher M, Chabbert-Buffet N, Hertig A
Placenta 2018 Sep;69:40-49. Epub 2018 Jul 7 doi: 10.1016/j.placenta.2018.07.004. PMID: 30213483
De Sanctis V, Marsella M, Soliman A, Yassin M
Pediatr Endocrinol Rev 2014 Feb;11 Suppl 2:263-73. PMID: 24683950
Gennari L, Merlotti D, Nuti R
Adv Clin Chem 2011;54:129-64. doi: 10.1016/b978-0-12-387025-4.00006-6. PMID: 21874760
Kaňová N, Bičíková M
Physiol Res 2011;60(2):243-52. Epub 2010 Nov 29 doi: 10.33549/physiolres.932078. PMID: 21114372
Czajka-Oraniec I, Simpson ER
Endokrynol Pol 2010 Jan-Feb;61(1):126-34. PMID: 20205115

Diagnosis

Berkane N, Liere P, Lefevre G, Alfaidy N, Nahed RA, Vincent J, Oudinet JP, Pianos A, Cambourg A, Rozenberg P, Galichon P, Rousseau A, Simon T, Schumacher M, Chabbert-Buffet N, Hertig A
Placenta 2018 Sep;69:40-49. Epub 2018 Jul 7 doi: 10.1016/j.placenta.2018.07.004. PMID: 30213483
Bulun SE
Fertil Steril 2014 Feb;101(2):323-9. doi: 10.1016/j.fertnstert.2013.12.022. PMID: 24485503Free PMC Article
Pienkowski C, Cartault A, Carfagna L, Ernoult P, Vial J, Lemasson F, Le Mandat A, Galinier P, Tauber M
Endocr Dev 2012;22:101-111. Epub 2012 Jul 25 doi: 10.1159/000326627. PMID: 22846524
Belgorosky A, Guercio G, Pepe C, Saraco N, Rivarola MA
Horm Res 2009;72(6):321-30. Epub 2009 Oct 21 doi: 10.1159/000249159. PMID: 19844120
Rochira V, Carani C
Nat Rev Endocrinol 2009 Oct;5(10):559-68. Epub 2009 Aug 25 doi: 10.1038/nrendo.2009.176. PMID: 19707181

Therapy

Szulc P
Best Pract Res Clin Endocrinol Metab 2022 Mar;36(2):101624. Epub 2022 Feb 4 doi: 10.1016/j.beem.2022.101624. PMID: 35165044
Miedlich SU, Karamooz N, Hammes SR
Bone 2016 Dec;93:181-186. Epub 2016 Sep 29 doi: 10.1016/j.bone.2016.09.024. PMID: 27693882
Fukami M, Miyado M, Nagasaki K, Shozu M, Ogata T
Pediatr Endocrinol Rev 2014 Mar;11(3):298-305. PMID: 24716396
Zajac JD, Fui MN
Adv Exp Med Biol 2012;769:153-68. PMID: 23560310
Czajka-Oraniec I, Simpson ER
Endokrynol Pol 2010 Jan-Feb;61(1):126-34. PMID: 20205115

Prognosis

Li H, Fu S, Dai R, Sheng Z, Liu W
Zhong Nan Da Xue Xue Bao Yi Xue Ban 2022 Jun 28;47(6):794-800. doi: 10.11817/j.issn.1672-7347.2022.210401. PMID: 35837780
Gibb FW, Dixon JM, Clarke C, Homer NZ, Faqehi AMM, Andrew R, Walker BR
J Clin Endocrinol Metab 2019 Sep 1;104(9):3670-3678. doi: 10.1210/jc.2018-02339. PMID: 30920624Free PMC Article
Vandenput L, Ohlsson C
Nat Rev Endocrinol 2009 Aug;5(8):437-43. Epub 2009 Jun 16 doi: 10.1038/nrendo.2009.112. PMID: 19528961
Pepe CM, Saraco NI, Baquedano MS, Guercio G, Vaiani E, Marino R, Pandey AV, Flück CE, Rivarola MA, Belgorosky A
Clin Endocrinol (Oxf) 2007 Nov;67(5):698-705. Epub 2007 Jul 2 doi: 10.1111/j.1365-2265.2007.02948.x. PMID: 17608756
Bulun SE
J Clin Endocrinol Metab 1996 Mar;81(3):867-71. doi: 10.1210/jcem.81.3.8772541. PMID: 8772541

Clinical prediction guides

Berkane N, Liere P, Lefevre G, Alfaidy N, Nahed RA, Vincent J, Oudinet JP, Pianos A, Cambourg A, Rozenberg P, Galichon P, Rousseau A, Simon T, Schumacher M, Chabbert-Buffet N, Hertig A
Placenta 2018 Sep;69:40-49. Epub 2018 Jul 7 doi: 10.1016/j.placenta.2018.07.004. PMID: 30213483
Gennari L, Nuti R, Bilezikian JP
J Clin Endocrinol Metab 2004 Dec;89(12):5898-907. doi: 10.1210/jc.2004-1717. PMID: 15579733
Carreau S, Lambard S, Delalande C, Denis-Galeraud I, Bilinska B, Bourguiba S
Reprod Biol Endocrinol 2003 Apr 11;1:35. doi: 10.1186/1477-7827-1-35. PMID: 12747806Free PMC Article
Carreau S, Bourguiba S, Lambard S, Galeraud-Denis I, Genissel C, Levallet J
Mol Cell Endocrinol 2002 Jul 31;193(1-2):137-43. doi: 10.1016/s0303-7207(02)00107-7. PMID: 12161013
Grumbach MM, Auchus RJ
J Clin Endocrinol Metab 1999 Dec;84(12):4677-94. doi: 10.1210/jcem.84.12.6290. PMID: 10599737

Recent systematic reviews

Yami Channaiah C, Memon SS, Sarathi V, Lila AR, Barnabas R, Raghav D, Bhandare VV, Arya S, Thakkar H, Patil VA, Karlekar M, Kunwar A, Bandgar T
Ann Endocrinol (Paris) 2024 Feb;85(1):48-55. Epub 2023 Jun 20 doi: 10.1016/j.ando.2023.05.010. PMID: 37348676
Fan L, Zhang B, Li L, Gong C
Clin Endocrinol (Oxf) 2020 Dec;93(6):687-695. Epub 2020 Jul 27 doi: 10.1111/cen.14277. PMID: 32623730

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