XY DSD With Normal Testosterone, Normal Precursors and Normal DHT
A defect in androgen signalling is most likely due to dysfunction of the androgen receptor protein (AR) and gene variants resulting in a complete lack of function of the AR cause Complete Androgen Insensitivity Syndrome (CAIS). This presents in the newborn infant as a discordance between a female phenotype and a prenatal karyotype of 46, XY, a postnatal check because of a positive family history, or as inguinal or labial swellings in a girl. CAIS usually presents in adolescence as primary amenorrhoea with normal breast development and absent uterus. The presence of pubic hair is often reported in CAIS and should not be used to exclude the diagnosis. AR gene variants that result in some residual AR function and varying degrees of androgenization cause partial androgen insensitivity syndrome (PAIS). Although children with AIS typically have normal testosterone and DHT response to hCG stimulation and a normal urinary steroid profile, some demonstrate a poor response to hCG stimulation. The serum AMH concentration is normal or may even be elevated. LH levels are increased in the face of normal or elevated serum testosterone, reflecting a state of androgen resistance. A family history of X-linked inheritance is informative although one-third of cases are the result of spontaneous new gene variants.
A functional assessment of androgen sensitivity may include assessing the clinical effect of a short course of testosterone or dihydrotestosterone applied on the phallus or by the effect of systemic testosterone following hCG stimulation. However, there is no consensus on the choice of androgen, dosage, method of administration, timing and duration of treatment as well as the definition of an optimal response in the growth of the phallus. Androgen sensitivity can be also assessed by measuring change in androgen responsive circulating proteins such as SHBG following androgen exposure but this is rarely performed in clinical practice as the response can be very variable. There may be other methods of assessing tissue responsiveness to androgens including the measurement of androgen responsive proteins in genital skin fibroblasts or the assessment of the androgen responsive transcriptome but their clinical utility requires further exploration. AR analysis may reveal a causative gene variant in over 90% of cases with a CAIS phenotype but given that only 20% of cases with a PAIS phenotype have a variant in the coding region of AR, there is a need to improve the diagnosis of this condition especially as it has been reported that the gene variants in AR may exist beyond the coding sequence. A number of newborns with XY DSD are loosely labelled as 'PAIS' when no conclusive biochemical or genetic abnormalities are identified in gonadal function, androgen synthesis or androgen action. However, the term PAIS should only be used in the context of a molecular confirmation of a likely causative AR variant as there is great prognostic value in having a genetically confirmed diagnosis of PAIS. The majority of infants with XY DSD encountered in a DSD clinic and who are systematically investigated do not have an endocrine disorder of androgen synthesis and do not have a variant in AR. Whilst in some of them, there may be other phenotypic clues, such as in the case of persistent Mullerian duct syndrome, in others, the aetiology may only become clear with further clinical follow-up. The use of HTS in such cases has also started to identify variants in a wide range of genes that may have a role to play in genital tubercle development or testis migration.
Clin Endocrinol. 2021;95(6):818-840. © 2021 Blackwell Publishing