Androgen insensitivity syndrome differential diagnosis

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

• Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome.

• Hypospadias

• Undermasculinization of the external genitalia and pubertal undervirilization

• 46,XY infants born small for gestational age

• Deficiency of the 5α-reductase enzyme

• Leydig cell agenesis due to LH receptor anomalies:

• Monosomy 45,X (Turner syndrome)

• 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