Androgen Insensitivity Syndrome - Diagnosis

Diagnosis

The phenotypes that result from the insensitivity to androgens are not unique to AIS, and thus the diagnosis of AIS requires thorough exclusion of other causes. Clinical findings indicative of AIS include the presence of a short vagina or undermasculinized genitalia, partial or complete regression of Müllerian structures, bilateral nondysplastic testes, and impaired spermatogenesis and / or virilization. Laboratory findings include a 46,XY karyotype and normal or elevated postpubertal testosterone, luteinizing hormone, and estradiol levels. The androgen binding activity of genital skin fibroblasts is typically diminished, although exceptions have been reported. Conversion of testosterone to dihydrotestosterone may be impaired. The diagnosis of AIS is confirmed if androgen receptor gene sequencing reveals a mutation, although not all individuals with AIS (particularly PAIS) will have an AR mutation (see Other Causes).

Each of the three types of AIS --- complete, partial, and mild --- has a different list of differential diagnoses to consider. Depending on the form of AIS that is suspected, the list of differentials can include:

1. Chromosomal anomalies:
   1. Klinefelter syndrome (47,XXY karyotype)
   2. Turner syndrome (45,XO karyotype)
   3. Mixed gonadal dysgenesis (45,XO/46,XY karyotype)
   4. Tetragametic chimerism (46,XX/46,XY karyotype)
2. Androgen biosynthetic dysfunction in 46,XY individuals:
   1. Luteinizing hormone (LH) receptor mutations
   2. Smith-Lemli-Opitz syndrome (associated with mental retardation)
   3. Lipoid congenital adrenal hyperplasia
   4. 3β-hydroxysteroid dehydrogenase 2 deficiency
   5. 17α-hydroxylase deficiency
   6. 17,20 lyase deficiency
   7. 17β-hydroxysteroid dehydrogenase deficiency
   8. 5α-reductase deficiency
3. Androgen excess in 46,XX individuals:
   1. 21-hydroxylase deficiency
   2. 3β-hydroxysteroid dehydrogenase 2 deficiency
   3. Cytochrome P450 oxidoreductase deficiency (disorder in mother causes 46,XX fetal virilization)
   4. 11β-hydroxylase deficiency
   5. Aromatase deficiency
   6. Glucocorticoid receptor mutations
   7. Maternal virilizing tumor (e.g. luteoma)
   8. Increased androgen exposure in utero, not otherwise specified (e.g. androgenic drugs)
4. Developmental
   1. Mayer-Rokitansky-Küster-Hauser syndrome (46,XX karyotype)
   2. Swyer syndrome (46,XY karyotype)
   3. XX gonadal dysgenesis (46,XX karyotype)
   4. Leydig cell agenesis or hypoplasia, not otherwise specified (46,XY karyotype)
   5. Absent (vanishing) testes syndrome
   6. Ovotesticular DSD
   7. Testicular DSD (i.e. 46,XX sex reversal)
5. Teratogenic causes (e.g. estrogens, antiestrogens)
6. Other causes:
   1. Frasier syndrome (associated with progressive glomerulopathy)
   2. Denys-Drash syndrome (associated with nephropathy and Wilms tumor)
   3. WAGR syndrome (associated with Wilms tumor and aniridia)
   4. McKusick-Kaufman syndrome (associated with postaxial polydactyly)
   5. Robinow syndrome (associated with dwarfism)
   6. Aarskog-Scott syndrome (associated with facial anomalies)
   7. Hand-foot-genital syndrome (associated with limb malformations)
   8. Popliteal pterygium syndrome (associated with extensive webbing behind knees)
   9. Kallmann syndrome (often associated with anosmia)
   10. Hypospadias not otherwise specified
   11. Cryptorchidism not otherwise specified
   12. vaginal atresia not otherwise specified