Androgen insensitivity syndrome differential diagnosis: Difference between revisions

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{{Androgen insensitivity syndrome}}
[[Image:Home_logo1.png|right|250px|link=https://www.wikidoc.org/index.php/Androgen_insensitivity_syndrome]]
{{CMG}}; {{AE}} {{ARK}}
{{CMG}}; {{AE}} {{ARK}}


==Overview==
==Overview==
Androgen insensitivity syndrome should be differentiated from other more common forms of male [[undervirilization]], including [[Leydig cell]] [[hypoplasia]], several uncommon defects of [[testosterone]] synthesis, and 5α-reductase deficiency which can produce similar genital anatomy.
Androgen insensitivity syndrome must be differentiated from other conditions based on the genotype, phenotype and developmental characteristics.


==Differentiating Androgen insensitivity syndrome from other Diseases==
==Differentiating Androgen insensitivity syndrome from other Diseases==


*'''Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome''' is diagnosed in [[phenotypic]] females who exhibit [[amenorrhea]] and have a partial or complete absence of the [[cervix]], [[uterus]], and [[vagina]]. Individuals with MRKH can be distinguished from those with CAIS by confirmation of a 46,XX karyotype. <ref name="pmid26586965">{{cite journal| author=Londra L, Chuong FS, Kolp L| title=Mayer-Rokitansky-Kuster-Hauser syndrome: a review. | journal=Int J Womens Health | year= 2015 | volume= 7 | issue=  | pages= 865-70 | pmid=26586965 | doi=10.2147/IJWH.S75637 | pmc=4636170 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26586965  }} </ref>
*[[Mayer-Rokitansky-Hauser syndrome|Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome]]. <ref name="pmid26586965">{{cite journal| author=Londra L, Chuong FS, Kolp L| title=Mayer-Rokitansky-Kuster-Hauser syndrome: a review. | journal=Int J Womens Health | year= 2015 | volume= 7 | issue=  | pages= 865-70 | pmid=26586965 | doi=10.2147/IJWH.S75637 | pmc=4636170 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26586965  }} </ref>


*'''Hypospadias''' resulting from an AR pathogenic variant (and thus a part of the spectrum of PAIS) cannot be distinguished from hypospadias resulting from other (largely undefined) causes by the examination of the genitalia alone. AR variants associated with hypospadias are likely rare.
*[[Hypospadias]]


*'''MAIS''' caused by single-nucleotide variants of AR may be clinically indistinguishable from MAIS caused by expansion of the polymorphic CAG repeat in AR. Pathogenic expansion of this triplet repeat is the cause of spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease (see Genetically Related Disorders).
*Undermasculinization of the external genitalia and pubertal undervirilization


*'''Undermasculinization of the external genitalia and pubertal undervirilization''' are components of many different syndromes that have no etiologic relation to AR. They may or may not have a pathogenic relation to the androgen receptor protein. The one exception is a contiguous gene deletion syndrome that includes the AR locus and results in intellectual disability and genital abnormalities.
*46,XY infants born small for gestational age


*'''46,XY infants born small for gestational age''' may have clinical features of PAIS with no identifiable AR pathogenic variant. It has been suggested that this association be termed ‘XY DSD with fetal growth restriction, as yet unexplained.
*Deficiency of the 5α-reductase enzyme <ref name="pmid22812659">{{cite journal| author=Mendoza N, Motos MA| title=Androgen insensitivity syndrome. | journal=Gynecol Endocrinol | year= 2013 | volume= 29 | issue= 1 | pages= 1-5 | pmid=22812659 | doi=10.3109/09513590.2012.705378 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22812659  }} </ref>


*'''Defciency of the 5α-reductase enzyme:''' Individuals with a defciency in the 5α-reductase enzyme have a blockage during the biosynthesis of testosterone to DHT. These individuals have internal male genitalia (testosterone dependent) and no external genitalia (DHT dependent). Furthermore, they are sexually ambiguous at birth. However, in some, they are entirely female, and virilization occurs during puberty. Patients with 5α-reductase enzyme defciency are diagnosed by confrming the 5α-reductase defciency in fbroblast cultures or by sequencing the SRD5A2 gene. <ref name="pmid22812659">{{cite journal| author=Mendoza N, Motos MA| title=Androgen insensitivity syndrome. | journal=Gynecol Endocrinol | year= 2013 | volume= 29 | issue= 1 | pages= 1-5 | pmid=22812659 | doi=10.3109/09513590.2012.705378 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22812659  }} </ref>
*Leydig cell agenesis due to [[LH]] receptor anomalies:<ref name="pmid22812659">{{cite journal| author=Mendoza N, Motos MA| title=Androgen insensitivity syndrome. | journal=Gynecol Endocrinol | year= 2013 | volume= 29 | issue= 1 | pages= 1-5 | pmid=22812659 | doi=10.3109/09513590.2012.705378 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22812659  }} </ref>


*'''Leydig cell agenesis due to LH receptor anomalies:''' Individuals with Leydig cell agenesis due to LH receptor anomalies present with sexual ambiguity at birth or with primary amenorrhea and a complete lack of the development of sexual characteristics during puberty. The karyotype of these individuals is 46,XY. Furthermore, the level of testosterone is decreased and the level of LH is elevated in these patients. Leydig cell agenesis due to LH receptor anomalies is diagnosed by detecting mutations in the LHCGR gene. <ref name="pmid22812659">{{cite journal| author=Mendoza N, Motos MA| title=Androgen insensitivity syndrome. | journal=Gynecol Endocrinol | year= 2013 | volume= 29 | issue= 1 | pages= 1-5 | pmid=22812659 | doi=10.3109/09513590.2012.705378 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22812659  }} </ref>
*Monosomy 45,X ([[Turner syndrome]]) <ref name="pmid22812659">{{cite journal| author=Mendoza N, Motos MA| title=Androgen insensitivity syndrome. | journal=Gynecol Endocrinol | year= 2013 | volume= 29 | issue= 1 | pages= 1-5 | pmid=22812659 | doi=10.3109/09513590.2012.705378 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22812659  }} </ref>


*'''Monosomy 45,X (Turner syndrome):'''  Monosomy 45,X is clinically characterized by a delay in the development of puberty, short stature, pterygium colli, a shield chest and primary amenorrhea. Individuals that are mosaic for 45,X and 46,XX may have normal height, menstruate, and become pregnant. <ref name="pmid22812659">{{cite journal| author=Mendoza N, Motos MA| title=Androgen insensitivity syndrome. | journal=Gynecol Endocrinol | year= 2013 | volume= 29 | issue= 1 | pages= 1-5 | pmid=22812659 | doi=10.3109/09513590.2012.705378 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22812659  }} </ref>
*[[Klinefelter syndrome]]
 
*[[Mutations]] in [[SRY]], NR5A1, [[WT1]]
*Klinefelter syndrome
*Mutations in SRY, NR5A1, WT1
*17,20-lyase deficiency
*17,20-lyase deficiency
*3-Beta-Hydroxysteroid Dehydrogenase Deficiency
*[[3 beta-hydroxysteroid dehydrogenase deficiency|3-Beta-Hydroxysteroid Dehydrogenase Deficiency]]
*Congenital Adrenal Hyperplasia
*[[Congenital Adrenal Hyperplasia]]
*17beta-hydroxysteroid dehydrogenase deficiency type 3
*17 beta-hydroxysteroid dehydrogenase deficiency type 3
*Frasier syndrome
*[[Frasier syndrome]]
*17-Hydroxylase Deficiency Syndrome
*[[17 alpha-hydroxylase deficiency]]
*p450 oxidoreductase deficiency
*p450 oxidoreductase deficiency
*Mutations in the luteinizing hormone receptor
*Mutations in the [[luteinizing hormone]] receptor
*Smith-Lemli-Opitz syndrome
*[[Smith-Lemli-Opitz syndrome]]
*Denys-Drash syndrome
*[[Denys-Drash syndrome]]
 
{| class="wikitable"
|-
! rowspan="2" | Disease name
! rowspan="2" | Cause
! colspan="7" | Differentiating
|-
!Findings
![[Uterus]]
![[Breast]] development
![[Testosterone]]
![[LH]]
![[FSH]]
![[Karyotyping]]
|-
|[[Androgen insensitivity syndrome]] 
|
* [[Androgen receptor]] defect
|
* Female [[external genitalia]]
* Resistant to [[testosterone]]
| align="center" style="padding: 5px 5px; background: " |
No
| align="center" style="padding: 5px 5px; background: " |
Yes
| align="center" style="padding: 5px 5px; background: " |
Normal male range
| align="center" style="padding: 5px 5px; background: " |
Normal
| align="center" style="padding: 5px 5px; background: " |
Normal
| align="center" style="padding: 5px 5px; background: " |
[[XY]]
|-
|[[17 alpha-hydroxylase deficiency]]
|
* [[CYP17A1|CYP17A1 gene mutation]]
|
* Female [[external genitalia]]
 
* [[Primary amenorrhea]]
* [[Hypertension]]
* Absence of secondary [[sexual characteristics]]
* Minimal [[body hair]]
| align="center" style="padding: 5px 5px; background: " |
No
| align="center" style="padding: 5px 5px; background: " |
No
| align="center" style="padding: 5px 5px; background: " |
Low
| align="center" style="padding: 5px 5px; background: " |
Normal
| align="center" style="padding: 5px 5px; background: " |
Normal
| align="center" style="padding: 5px 5px; background: " |
[[XY]]
|-
|[[Gonadal dysgenesis]]
|
* Mutations in [[SRY]], FOG2/ZFPM2, and WNT1
|
* Female [[external genitalia]]
* Intact [[Mullerian ducts]]
* [[Streak gonads]]
* [[karyotyping ]]
| align="center" style="padding: 5px 5px; background: " |
Yes
| align="center" style="padding: 5px 5px; background: " |
Yes
| align="center" style="padding: 5px 5px; background: " |
Low
| align="center" style="padding: 5px 5px; background: " |
High
| align="center" style="padding: 5px 5px; background: " |
High
| align="center" style="padding: 5px 5px; background: " |
[[XY]]
|-
|[[Testicular regression syndrome]]
|
* Loss of [[testicular]] function and tissue early in development
|
* Female phenotype with atrophic [[Mullerian ducts]].
| align="center" style="padding: 5px 5px; background: " |
No
| align="center" style="padding: 5px 5px; background: " |
No
| align="center" style="padding: 5px 5px; background: " |
Low
| align="center" style="padding: 5px 5px; background: " |
High
| align="center" style="padding: 5px 5px; background: " |
High
| align="center" style="padding: 5px 5px; background: " |
[[XY]]
|-
|[[LH receptor|LH receptor defects]]
|
* [[LH receptor]] [[gene]] [[mutation]] on [[chromosome 2]]
|
* Female [[external genitalia]]
* Lack a [[uterus]] and [[fallopian tubes]]
* [[Epididymis]] and [[vas deferens]] may be present
* Laboratory:
** Unresponsiveness to [[hCG]]
** Normal levels of [[testosterone]] precursors (produced in the [[adrenal glands]]).
| align="center" style="padding: 5px 5px; background: " |
No
| align="center" style="padding: 5px 5px; background: " |
No
| align="center" style="padding: 5px 5px; background: " |
Low
| align="center" style="padding: 5px 5px; background: " |
High
| align="center" style="padding: 5px 5px; background: " |
High
| align="center" style="padding: 5px 5px; background: " |
[[XY]]
|-
|[[5-alpha-reductase deficiency|5-alpha-reductase type 2 deficiency]]
|
* [[Autosomal recessive]]
|
* Female [[external genitalia or ambiguous]]
* Bilateral testes and normal [[testosterone]] formation
 
* Impaired external [[virilization]] during [[embryogenesis]]
* Defective conversion of [[testosterone]] to [[DHT]].
* [[Testosterone]]:[[DHT]] ratio is >10:1
| align="center" style="padding: 5px 5px; background: " |
No
| align="center" style="padding: 5px 5px; background: " |
No
| align="center" style="padding: 5px 5px; background: " |
Normal male range
| align="center" style="padding: 5px 5px; background: " |
High to normal
| align="center" style="padding: 5px 5px; background: " |
High to normal
| align="center" style="padding: 5px 5px; background: " |
[[XY]]
|-
|[[Mullerian agenesis]]
|
* Mutations in ''[[WNT4]]''
|
* Normal female [[genitalia]]
* Normal [[breast]] development
| align="center" style="padding: 5px 5px; background: " |
No
| align="center" style="padding: 5px 5px; background: " |
Yes
| align="center" style="padding: 5px 5px; background: " |
Normal [[female]] range
| align="center" style="padding: 5px 5px; background: " |
Normal
| align="center" style="padding: 5px 5px; background: " |
Normal
| align="center" style="padding: 5px 5px; background: " |
[[XX]]
|-
|[[Ovarian insufficiency|Primary ovarian insufficiency]]
|
* [[Genetic defects]] such as [[turner syndrome]], [[fragile X syndrome]], some other chromosomal defects
|
* Normal [[female genitalia]]
| align="center" style="padding: 5px 5px; background: " |
Yes
| align="center" style="padding: 5px 5px; background: " |
Yes
| align="center" style="padding: 5px 5px; background: " |
Normal female range
| align="center" style="padding: 5px 5px; background: " |
High
| align="center" style="padding: 5px 5px; background: " |
High
| align="center" style="padding: 5px 5px; background: " |
[[XX]]
|-
|[[Hypogonadotropic hypogonadism]]
|
* Functional, sellar masses
|
* Normal [[female genitalia]],
 
* Delayed [[puberty]]
| align="center" style="padding: 5px 5px; background: " |
Yes
| align="center" style="padding: 5px 5px; background: " |
No
| align="center" style="padding: 5px 5px; background: " |
Normal female range
| align="center" style="padding: 5px 5px; background: " |
Low
| align="center" style="padding: 5px 5px; background: " |
Normal
| align="center" style="padding: 5px 5px; background: " |
[[XX]]
|-
| align="center" style="padding: 5px 5px; background: " |
[[Turner syndrome]]
|
* Chromosomal
|
* Female [[external genitalia]]
| align="center" style="padding: 5px 5px; background: " |
Yes
| align="center" style="padding: 5px 5px; background: " |
Yes
| align="center" style="padding: 5px 5px; background: " |
Normal [[female]] range
| align="center" style="padding: 5px 5px; background: " |
High
| align="center" style="padding: 5px 5px; background: " |
High
| align="center" style="padding: 5px 5px; background: " |
[[Turner syndrome|45 XO]]
|-
|3-beta-hydroxysteroid dehydrogenase type 2 deficiency
|
* HSD3B2  [[gene]] [[mutation]]
|
* [[Undervirilization]] in 46,XY individuals due to a block in [[testosterone]] biosynthesis.
* Mild [[virilization]] in 46,XX individuals
| align="center" style="padding: 5px 5px; background: " |
Yes in [[female]]
| align="center" style="padding: 5px 5px; background: " |
Yes in [[female]]
| align="center" style="padding: 5px 5px; background: " |
Low
| align="center" style="padding: 5px 5px; background: " |
Normal
| align="center" style="padding: 5px 5px; background: " |
Normal
| align="center" style="padding: 5px 5px; background: " |
[[XY]] and [[XX]]
|}


==References==
==References==

Latest revision as of 22:44, 25 February 2019

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2]

Overview

Androgen insensitivity syndrome must be differentiated from other conditions based on the genotype, phenotype and developmental characteristics.

Differentiating Androgen insensitivity syndrome from other Diseases

  • Undermasculinization of the external genitalia and pubertal undervirilization
  • 46,XY infants born small for gestational age
  • Deficiency of the 5α-reductase enzyme [2]
  • Leydig cell agenesis due to LH receptor anomalies:[2]
Disease name Cause Differentiating
Findings Uterus Breast development Testosterone LH FSH Karyotyping
Androgen insensitivity syndrome 

No

Yes

Normal male range

Normal

Normal

XY

17 alpha-hydroxylase deficiency

No

No

Low

Normal

Normal

XY

Gonadal dysgenesis
  • Mutations in SRY, FOG2/ZFPM2, and WNT1

Yes

Yes

Low

High

High

XY

Testicular regression syndrome
  • Loss of testicular function and tissue early in development

No

No

Low

High

High

XY

LH receptor defects

No

No

Low

High

High

XY

5-alpha-reductase type 2 deficiency

No

No

Normal male range

High to normal

High to normal

XY

Mullerian agenesis

No

Yes

Normal female range

Normal

Normal

XX

Primary ovarian insufficiency

Yes

Yes

Normal female range

High

High

XX

Hypogonadotropic hypogonadism
  • Functional, sellar masses

Yes

No

Normal female range

Low

Normal

XX

Turner syndrome

  • Chromosomal

Yes

Yes

Normal female range

High

High

45 XO

3-beta-hydroxysteroid dehydrogenase type 2 deficiency

Yes in female

Yes in female

Low

Normal

Normal

XY and XX

References

  1. Londra L, Chuong FS, Kolp L (2015). "Mayer-Rokitansky-Kuster-Hauser syndrome: a review". Int J Womens Health. 7: 865–70. doi:10.2147/IJWH.S75637. PMC 4636170. PMID 26586965.
  2. 2.0 2.1 2.2 Mendoza N, Motos MA (2013). "Androgen insensitivity syndrome". Gynecol Endocrinol. 29 (1): 1–5. doi:10.3109/09513590.2012.705378. PMID 22812659.

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