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Aromatase deficiency

MedGen UID:
743307
Concept ID:
C1960539
Disease or Syndrome
Synonyms: Familial gynecomastia, due to increased aromatase activity; Increased aromatase activity; Pseudohermaphroditism, female, due to placental aromatase deficiency
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele). [HPO:curators]
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Maternal virilization due to placental aromatase deficiency (427627006)
 
Gene (location): CYP19A1 (15q21.2)
OMIM®: 613546

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 GHR
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.  https://ghr.nlm.nih.gov/condition/aromatase-deficiency

Clinical features

Ovarian cyst
MedGen UID:
14540
Concept ID:
C0029927
Disease or Syndrome
A cyst that arises from the ovary. Representative examples include simple, complex, corpus luteum, and endometrioid cysts. Symptoms include pelvic and abdominal pain and irregular periods.
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.
Hypergonadotropic hypogonadism
MedGen UID:
184926
Concept ID:
C0948896
Disease or Syndrome
Ovarian or testicular dysfunction associated with high levels of gonadotropins.
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.
Primary amenorrhea
MedGen UID:
115918
Concept ID:
C0232939
Disease or Syndrome
Abnormally late or absent menarche in a female with normal secondary sexual characteristics.
Hypergonadotropic hypogonadism
MedGen UID:
184926
Concept ID:
C0948896
Disease or Syndrome
Ovarian or testicular dysfunction associated with high levels of gonadotropins.

Recent clinical studies

Etiology

Zhu WJ, Cheng T, Zhu H, Han B, Fan MX, Gu T, Zhao SX, Liu Y, Cheng KX, Song HD, Qiao J
Mol Cell Endocrinol 2016 Sep 15;433:66-74. Epub 2016 May 30 doi: 10.1016/j.mce.2016.05.025. PMID: 27256151
Marino R, Perez Garrido N, Costanzo M, Guercio G, Juanes M, Rocco C, Ramirez P, Warman DM, Ciaccio M, Pena G, Feyling JG, Miras M, Rivarola MA, Belgorosky A, Saraco N
J Clin Endocrinol Metab 2015 Feb;100(2):E301-7. Epub 2014 Nov 21 doi: 10.1210/jc.2014-2967. PMID: 25415177
Baykan EK, Erdoğan M, Özen S, Darcan Ş, Saygılı LF
J Clin Res Pediatr Endocrinol 2013;5(2):129-32. doi: 10.4274/Jcrpe.970. PMID: 23748068Free PMC Article
Hertig A, Liere P, Chabbert-Buffet N, Fort J, Pianos A, Eychenne B, Cambourg A, Schumacher M, Berkane N, Lefevre G, Uzan S, Rondeau E, Rozenberg P, Rafestin-Oblin ME
Am J Obstet Gynecol 2010 Nov;203(5):477.e1-9. Epub 2010 Aug 5 doi: 10.1016/j.ajog.2010.06.011. PMID: 20691412
Rochira V, Zirilli L, Madeo B, Aranda C, Caffagni G, Fabre B, Montangero VE, Roldan EJ, Maffei L, Carani C
Bone 2007 Jun;40(6):1662-8. Epub 2007 Feb 27 doi: 10.1016/j.bone.2007.01.022. PMID: 17400043

Diagnosis

Unal E, Yıldırım R, Taş FF, Demir V, Onay H, Haspolat YK
J Clin Res Pediatr Endocrinol 2018 Nov 29;10(4):377-381. Epub 2018 Mar 19 doi: 10.4274/jcrpe.0011. PMID: 29553041Free PMC Article
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
Sudeep K, Abraham J, Seshadri L, Seshadri MS
J Assoc Physicians India 2013 May;61(5):340-3. PMID: 24482950
Baykan EK, Erdoğan M, Özen S, Darcan Ş, Saygılı LF
J Clin Res Pediatr Endocrinol 2013;5(2):129-32. doi: 10.4274/Jcrpe.970. PMID: 23748068Free PMC Article
Verma N, Jain V, Birla S, Jain R, Sharma A
J Pediatr Endocrinol Metab 2012;25(11-12):1185-90. doi: 10.1515/jpem-2012-0152. PMID: 23329769

Therapy

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
Chen Z, Wang O, Nie M, Elison K, Zhou D, Li M, Jiang Y, Xia W, Meng X, Chen S, Xing X
Mol Cell Endocrinol 2015 Jan 5;399:32-42. Epub 2014 Oct 6 doi: 10.1016/j.mce.2014.09.016. PMID: 25301327Free PMC Article
Baykan EK, Erdoğan M, Özen S, Darcan Ş, Saygılı LF
J Clin Res Pediatr Endocrinol 2013;5(2):129-32. doi: 10.4274/Jcrpe.970. PMID: 23748068Free PMC Article
Verma N, Jain V, Birla S, Jain R, Sharma A
J Pediatr Endocrinol Metab 2012;25(11-12):1185-90. doi: 10.1515/jpem-2012-0152. PMID: 23329769
Zirilli L, Maffei L, Meunier PJ, Chavassieux P, Carani C, Rochira V
Bone 2009 Nov;45(5):827-32. Epub 2009 Apr 5 doi: 10.1016/j.bone.2009.03.672. PMID: 19345749

Prognosis

Marino R, Perez Garrido N, Costanzo M, Guercio G, Juanes M, Rocco C, Ramirez P, Warman DM, Ciaccio M, Pena G, Feyling JG, Miras M, Rivarola MA, Belgorosky A, Saraco N
J Clin Endocrinol Metab 2015 Feb;100(2):E301-7. Epub 2014 Nov 21 doi: 10.1210/jc.2014-2967. PMID: 25415177
Chen Z, Wang O, Nie M, Elison K, Zhou D, Li M, Jiang Y, Xia W, Meng X, Chen S, Xing X
Mol Cell Endocrinol 2015 Jan 5;399:32-42. Epub 2014 Oct 6 doi: 10.1016/j.mce.2014.09.016. PMID: 25301327Free PMC Article
Verma N, Jain V, Birla S, Jain R, Sharma A
J Pediatr Endocrinol Metab 2012;25(11-12):1185-90. doi: 10.1515/jpem-2012-0152. PMID: 23329769
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
Fukami M, Hasegawa T, Horikawa R, Ohashi T, Nishimura G, Homma K, Ogata T
Pediatr Res 2006 Feb;59(2):276-80. doi: 10.1203/01.pdr.0000195825.31504.28. PMID: 16439592

Clinical prediction guides

Zhu WJ, Cheng T, Zhu H, Han B, Fan MX, Gu T, Zhao SX, Liu Y, Cheng KX, Song HD, Qiao J
Mol Cell Endocrinol 2016 Sep 15;433:66-74. Epub 2016 May 30 doi: 10.1016/j.mce.2016.05.025. PMID: 27256151
Marino R, Perez Garrido N, Costanzo M, Guercio G, Juanes M, Rocco C, Ramirez P, Warman DM, Ciaccio M, Pena G, Feyling JG, Miras M, Rivarola MA, Belgorosky A, Saraco N
J Clin Endocrinol Metab 2015 Feb;100(2):E301-7. Epub 2014 Nov 21 doi: 10.1210/jc.2014-2967. PMID: 25415177
Chen Z, Wang O, Nie M, Elison K, Zhou D, Li M, Jiang Y, Xia W, Meng X, Chen S, Xing X
Mol Cell Endocrinol 2015 Jan 5;399:32-42. Epub 2014 Oct 6 doi: 10.1016/j.mce.2014.09.016. PMID: 25301327Free PMC Article
Rochira V, Zirilli L, Maffei L, Premrou V, Aranda C, Baldi M, Ghigo E, Aimaretti G, Carani C, Lanfranco F
J Clin Endocrinol Metab 2010 Apr;95(4):1626-33. Epub 2010 Feb 17 doi: 10.1210/jc.2009-1743. PMID: 20164294
Zirilli L, Maffei L, Meunier PJ, Chavassieux P, Carani C, Rochira V
Bone 2009 Nov;45(5):827-32. Epub 2009 Apr 5 doi: 10.1016/j.bone.2009.03.672. PMID: 19345749

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