Androgen insensitivity syndrome differential diagnosis

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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 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.

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.

• 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.

• 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 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 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.

• 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 deficiency are diagnosed by confrming the 5α-reductase defciency in fibroblast cultures or by sequencing the SRD5A2 gene.

• 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.

• 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.

• Klinefelter syndrome
• Mutations in SRY, NR5A1, WT1
• 17,20-lyase deficiency
• 3-Beta-Hydroxysteroid Dehydrogenase Deficiency
• Congenital Adrenal Hyperplasia
• 17 beta-hydroxysteroid dehydrogenase deficiency type 3
• Frasier syndrome
• 17 alpha-hydroxylase deficiency
• p450 oxidoreductase deficiency
• Mutations in the luteinizing hormone receptor
• Smith-Lemli-Opitz syndrome
• Denys-Drash syndrome

Disease name	Cause	Differentiating
		Findings	Uterus	Breast development	Testosterone	LH	FSH	Karyotyping
Androgen insensitivity syndrome	Androgen receptor defect	Female external genitalia Resistant to testosterone	No	Yes	Normal male range	Normal	Normal	XY
17 alpha-hydroxylase deficiency	CYP17A1 gene mutation	Female external genitalia Primary amenorrhea Hypertension Absence of secondary sexual characteristics Minimal body hair	No	No	Low	Normal	Normal	XY
Gonadal dysgenesis	Mutations in SRY, FOG2/ZFPM2, and WNT1	Female external genitalia Intact Mullerian ducts Streak gonads karyotyping	Yes	Yes	Low	High	High	XY
Testicular regression syndrome	Loss of testicular function and tissue early in development	Female phenotype with atrophic Mullerian ducts.	No	No	Low	High	High	XY
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).	No	No	Low	High	High	XY
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	No	No	Normal male range	High to normal	High to normal	XY
Mullerian agenesis	Mutations in WNT4	Normal female genitalia Normal breast development	No	Yes	Normal female range	Normal	Normal	XX
Primary ovarian insufficiency	Genetic defects such as turner syndrome, fragile X syndrome, some other chromosomal defects	Normal female genitalia	Yes	Yes	Normal female range	High	High	XX
Hypogonadotropic hypogonadism	Functional, sellar masses	Normal female genitalia, Delayed puberty	Yes	No	Normal female range	Low	Normal	XX
Turner syndrome	Chromosomal	Female external genitalia	Yes	Yes	Normal female range	High	High	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	Yes in female	Yes in female	Low	Normal	Normal	XY and XX