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Partial androgen insensitivity syndrome(PAIS)

MedGen UID:
82785
Concept ID:
C0268301
Disease or Syndrome
Synonyms: ANDROGEN INSENSITIVITY, PARTIAL, WITH OR WITHOUT BREAST CANCER; Androgen resistance syndrome, partial; Gynecomastia, familial; PAIS; Pseudohermaphroditism, Incomplete male, type I; Reifenstein syndrome; Reifenstein syndrome, partial; Type I familial incomplete male pseudohermaphroditism
SNOMED CT: Partial androgen insensitivity syndrome (122811000119101); Reifenstein syndrome (122811000119101); Familial incomplete male pseudohermaphroditism type 1 (122811000119101); PAIS - partial androgen insensitivity syndrome (122811000119101)
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
 
Gene (location): AR (Xq12)
 
Monarch Initiative: MONDO:0010720
OMIM®: 312300
Orphanet: ORPHA90797

Definition

Individuals with androgen insensitivity have a 46,XY karyotype and testes that produce age-appropriate androgen levels but have undermasculinized external genitalia due to defects in androgen action. The phenotype in PAIS varies depending on residual androgen receptor function, ranging from severe undermasculinization presenting as female-like external genitalia to male-appearing genitalia. The typical presentation comprises micropenis, severe hypospadias, and bifid scrotum with or without cryptorchidism (summary by Mongan et al., 2015). [from OMIM]

Additional description

From MedlinePlus Genetics
People with partial androgen insensitivity can have genitalia that look typical for females, genitalia that have both male and female characteristics, or genitalia that look typical for males.  

People with mild androgen insensitivity are born with male-typical sex characteristics, but they are often infertile and tend to experience breast enlargement at puberty.

The partial and mild forms of androgen insensitivity syndrome occur when the body's tissues are partially sensitive to the effects of androgens. 

Complete androgen insensitivity syndrome occurs when the body does not respond to androgens at all. People with this form of the condition have external sex characteristics that are typical of females. Affected individuals do not have a uterus. They have male internal sex organs (testes) that are undescended, which means they are located in the pelvis or abdomen instead of outside the body. As such, affected individuals do not menstruate and are unable to conceive a child (infertile). People with complete androgen insensitivity syndrome also have sparse or absent hair in the pubic area and under the arms.

There are three forms of androgen insensitivity syndrome: complete, partial, and mild.

Androgen insensitivity syndrome is a condition that affects sexual development before birth and during puberty. People with this condition have one X chromosome and one Y chromosome in each cell, which is typical for males. In people with androgen insensitivity syndrome, the body's cells and tissues are unable to respond to certain male sex hormones (called androgens) that are important for normal male sexual development before birth and during puberty. As a result, affected individuals may have external sex characteristics that are typical for females or have features of both male and female sexual development.  https://medlineplus.gov/genetics/condition/androgen-insensitivity-syndrome

Clinical features

From HPO
Azoospermia
MedGen UID:
2150
Concept ID:
C0004509
Disease or Syndrome
Absence of any measurable level of sperm,whereby spermatozoa cannot be observed even after centrifugation of the semen pellet.
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Infertility disorder
MedGen UID:
43876
Concept ID:
C0021359
Finding
Inability to conceive for at least one year after trying and having unprotected sex. Causes of female infertility include endometriosis, fallopian tubes obstruction, and polycystic ovary syndrome. Causes of male infertility include abnormal sperm production or function, blockage of the epididymis, blockage of the ejaculatory ducts, hypospadias, exposure to pesticides, and health related issues.
Male pseudohermaphroditism
MedGen UID:
68666
Concept ID:
C0238395
Congenital Abnormality
Hermaphroditism refers to a discrepancy between the morphology of the gonads and that of the external genitalia. In male pseudohermaphroditism, the genotype is male (XY) and the external genitalia are imcompletely virilized, ambiguous, or complete female. If gonads are present, they are testes.
Absent vas deferens
MedGen UID:
539922
Concept ID:
C0266444
Congenital Abnormality
Aplasia (congenital absence) of the vas deferens.
Bifid scrotum
MedGen UID:
90968
Concept ID:
C0341787
Congenital Abnormality
Midline indentation or cleft of the scrotum.
Perineal hypospadias
MedGen UID:
105292
Concept ID:
C0452148
Congenital Abnormality
Hypospadias with location of the urethral meatus in the perineal region.
Micropenis
MedGen UID:
1633603
Concept ID:
C4551492
Congenital Abnormality
Abnormally small penis. At birth, the normal penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.0-2.5 cm.
Abnormal rib cage morphology
MedGen UID:
871275
Concept ID:
C4025763
Anatomical Abnormality
A morphological anomaly of the rib cage.
Hypogonadism
MedGen UID:
5711
Concept ID:
C0020619
Disease or Syndrome
A decreased functionality of the gonad.
Gynecomastia
MedGen UID:
6694
Concept ID:
C0018418
Disease or Syndrome
Abnormal development of large mammary glands in males resulting in breast enlargement.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Partial androgen insensitivity syndrome in Orphanet.

Professional guidelines

PubMed

Mathews R, Nelson CP, Gearhart JP, Vander Kolk CA
Urology 2005 Jul;66(1):180-4. doi: 10.1016/j.urology.2005.01.063. PMID: 15992898
Deeb A, Mason C, Lee YS, Hughes IA
Clin Endocrinol (Oxf) 2005 Jul;63(1):56-62. doi: 10.1111/j.1365-2265.2005.02298.x. PMID: 15963062
Lobaccaro JM, Belon C, Lumbroso S, Olewniczack G, Carré-Pigeon F, Job JC, Chaussain JL, Toublanc JE, Sultan C
Clin Endocrinol (Oxf) 1994 Mar;40(3):297-302. doi: 10.1111/j.1365-2265.1994.tb03922.x. PMID: 7910529

Recent clinical studies

Etiology

Guaragna-Filho G, Guerra-Junior G, Tadokoro-Cuccaro R, Hughes IA, Barros BA, Hiort O, Balsamo A, Guran T, Holterhus PM, Hannema S, Poyrazoglu S, Darendeliler F, Bryce J, Ahmed SF, Quigley CA
Sex Dev 2023;17(1):16-25. Epub 2023 Mar 14 doi: 10.1159/000526997. PMID: 36917969
Liu Q, Yin X, Li P
Reprod Biol Endocrinol 2020 Apr 28;18(1):34. doi: 10.1186/s12958-020-00593-0. PMID: 32345305Free PMC Article
Sezgin T, Dönmez Mİ, Dirican A, Deniz İ, Savut B
Endocr J 2019 Jun 28;66(6):575-577. Epub 2019 Mar 28 doi: 10.1507/endocrj.EJ18-0578. PMID: 30918167
Hughes IA, Werner R, Bunch T, Hiort O
Semin Reprod Med 2012 Oct;30(5):432-42. Epub 2012 Oct 8 doi: 10.1055/s-0032-1324728. PMID: 23044881
Sultan C
Ann Genet 1986;29(1):5-10. PMID: 3521447

Diagnosis

Guaragna-Filho G, Guerra-Junior G, Tadokoro-Cuccaro R, Hughes IA, Barros BA, Hiort O, Balsamo A, Guran T, Holterhus PM, Hannema S, Poyrazoglu S, Darendeliler F, Bryce J, Ahmed SF, Quigley CA
Sex Dev 2023;17(1):16-25. Epub 2023 Mar 14 doi: 10.1159/000526997. PMID: 36917969
Babu R, Shah U
J Pediatr Urol 2021 Feb;17(1):39-47. Epub 2020 Nov 12 doi: 10.1016/j.jpurol.2020.11.017. PMID: 33246831
Liu Q, Yin X, Li P
Reprod Biol Endocrinol 2020 Apr 28;18(1):34. doi: 10.1186/s12958-020-00593-0. PMID: 32345305Free PMC Article
Hughes IA, Werner R, Bunch T, Hiort O
Semin Reprod Med 2012 Oct;30(5):432-42. Epub 2012 Oct 8 doi: 10.1055/s-0032-1324728. PMID: 23044881
Sultan C
Ann Genet 1986;29(1):5-10. PMID: 3521447

Therapy

Tack LJW, Maris E, Looijenga LHJ, Hannema SE, Audi L, Köhler B, Holterhus PM, Riedl S, Wisniewski A, Flück CE, Davies JH, T'Sjoen G, Lucas-Herald AK, Evliyaoglu O, Krone N, Iotova V, Marginean O, Balsamo A, Verkauskas G, Weintrob N, Ellaithi M, Nordenström A, Verrijn Stuart A, Kluivers KB, Wolffenbuttel KP, Ahmed SF, Cools M
Horm Res Paediatr 2018;90(4):236-246. Epub 2018 Oct 18 doi: 10.1159/000493645. PMID: 30336477
Gaspari L, Paris F, Philibert P, Audran F, Orsini M, Servant N, Maïmoun L, Kalfa N, Sultan C
Eur J Endocrinol 2011 Oct;165(4):579-87. Epub 2011 Jul 25 doi: 10.1530/EJE-11-0580. PMID: 21788424
Bhangoo A, Paris F, Philibert P, Audran F, Ten S, Sultan C
Asian J Androl 2010 Jul;12(4):561-6. Epub 2010 Mar 22 doi: 10.1038/aja.2010.6. PMID: 20305676Free PMC Article
Menon PS, Khatwa UA
Indian J Pediatr 2000 Jun;67(6):455-60. doi: 10.1007/BF02859468. PMID: 10932967
Lee PA, Danish RK, Mazur T, Migeon CJ
Johns Hopkins Med J 1980 Nov;147(5):175-81. PMID: 7441936

Prognosis

Kumar A, Sharma R, Faruq M, Kumar M, Sharma S, Werner R, Hiort O, Vandana J
Sex Dev 2022;16(1):34-45. Epub 2021 Oct 22 doi: 10.1159/000519047. PMID: 34689141
Peng Y, Zhu H, Han B, Xu Y, Liu X, Song H, Qiao J
Front Endocrinol (Lausanne) 2021;12:731107. Epub 2021 Nov 18 doi: 10.3389/fendo.2021.731107. PMID: 34867780Free PMC Article
Batista RL, Yamaguchi K, Rodrigues ADS, Nishi MY, Goodier JL, Carvalho LR, Domenice S, Costa EMF, Kazazian HH, Mendonca BB
J Clin Endocrinol Metab 2019 Dec 1;104(12):6385-6390. doi: 10.1210/jc.2019-00144. PMID: 31393562Free PMC Article
Lek N, Tadokoro-Cuccaro R, Whitchurch JB, Mazumder B, Miles H, Prentice P, Bunch T, Zielińska K, Metzler V, Mongan NP, Heery DM, Hughes IA
EBioMedicine 2018 Oct;36:401-409. Epub 2018 Oct 11 doi: 10.1016/j.ebiom.2018.09.047. PMID: 30316867Free PMC Article
Mazur T
Arch Sex Behav 2005 Aug;34(4):411-21. doi: 10.1007/s10508-005-4341-x. PMID: 16010464

Clinical prediction guides

Guaragna-Filho G, Guerra-Junior G, Tadokoro-Cuccaro R, Hughes IA, Barros BA, Hiort O, Balsamo A, Guran T, Holterhus PM, Hannema S, Poyrazoglu S, Darendeliler F, Bryce J, Ahmed SF, Quigley CA
Sex Dev 2023;17(1):16-25. Epub 2023 Mar 14 doi: 10.1159/000526997. PMID: 36917969
Liu Q, Yin X, Li P
J Endocrinol Invest 2023 Jan;46(1):151-158. Epub 2022 Aug 16 doi: 10.1007/s40618-022-01894-4. PMID: 35974208Free PMC Article
Kumar A, Sharma R, Faruq M, Kumar M, Sharma S, Werner R, Hiort O, Vandana J
Sex Dev 2022;16(1):34-45. Epub 2021 Oct 22 doi: 10.1159/000519047. PMID: 34689141
Batista RL, Rodrigues AS, Machado AZ, Nishi MY, Cunha FS, Silva RB, Costa EMF, Mendonca BB, Domenice S
J Pediatr Endocrinol Metab 2018 Jan 26;31(2):223-228. doi: 10.1515/jpem-2017-0095. PMID: 29267169
Sultan C
Ann Genet 1986;29(1):5-10. PMID: 3521447

Recent systematic reviews

Babu R, Shah U
J Pediatr Urol 2021 Feb;17(1):39-47. Epub 2020 Nov 12 doi: 10.1016/j.jpurol.2020.11.017. PMID: 33246831
Islam R, Lane S, Williams SA, Becker CM, Conway GS, Creighton SM
Clin Endocrinol (Oxf) 2019 Aug;91(2):237-244. Epub 2019 May 2 doi: 10.1111/cen.13994. PMID: 31004515

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