Correlation between genotype, phenotype and sex of rearing in 111 patients with partial androgen insensitivity syndrome

Objective Partial androgen insensitivity syndrome (PAIS) is a heterogeneous group of intersex disorders characterized by a typical perineoscrotal hypospadias/micropenis phenotype, and a normal androgen-producing testis. Various mutations in the androgen receptor (AR) are known to cause PAIS. Phenotypic expression is widely variable and there are no agreed guidelines to determine the sex of rearing in individuals with borderline masculinization. We aimed to quantitatively assess the external genital phenotype in relation to AR genotype and sex of rearing and identify criteria that differentiate mutation positive (ARmt) from mutation negative (ARwt) PAIS patients. Patients and design Cases with a diagnosis of PAIS were identified from the Cambridge Intersex Database. An external masculinization score (EMS) was used to quantify the degree of undermasculinization. Family history of AIS and details of the sex of rearing were recorded. Androgen binding was analysed in fibroblasts obtained from genital skin biopsies and mutational analysis of the AR was performed on genomic DNA extracted from peripheral blood. EMS and sex of rearing were compared in cases with similar mutations reported on the McGill International Database. Results Two hundred and sixty-three patients with PAIS were identified. Androgen receptor gene sequencing was performed in 111 patients. Twenty-seven (24%) had mutations. Family history of AIS was present in 61 and 21% of ARmt and ARwt patients, respectively. The median EMS was 3 in both groups. The majority of ARmt patients had abnormal binding and there was a tendency to a higher median testosterone rise on hCG stimulation in ARmt (9.3 nmol/l) compared with ARwt patients (6.9 nmol/l). All patients with EMS of 4 or more were raised as male but there was an overlap of sex of rearing in patients with an EMS less than 4. A wide variation of EMS in relation to genotype and sex of rearing was observed. Conclusion The phenotype in PAIS is extremely variable and is rarely predicted by the AR genotype. Apart from the family history, there are no specific criteria to differentiate ARwt from ARmt. Sex of rearing is not entirely dependent on the EMS. Cultural issues, other modifying genes and response to androgen trials might be influencing factors. Collaborative studies with uniform protocols are needed to investigate infants with PAIS. Documenting phenotype, surgical procedures and outcome criteria are necessary to enable decision-making on the sex of rearing in patients with a lower range EMS.