medwireNews: Researchers present “clear evidence” that mutations in the androgen receptor gene (AR) forecast worse outcomes in patients with partial androgen insensitivity syndrome (PAIS).

The analysis of 52 patients identified in the international disorders of sexual development (DSD) registry found clear differences between boys with and without AR mutations at diagnosis, yet those with mutations had poorer outcomes, being more likely to require multiple surgical procedures.

“Not only does the study raise concerns about the long-term outcome in those men with PAIS but it also strengthens the clinical rationale for the routine genetic analysis of AR in boys where there is a clinical suspicion of PAIS”, say Faisal Ahmed (University of Glasgow, UK) and co-researchers.

At presentation, the 29 patients with mutations were of a similar age to the 23 without, had similar External Masculinisation Scores, and were as likely to have hypospadias, undescended testis and micropenis. The only clinical difference was that 24% of the boys with mutations had gynaecomastia, compared with none of those without mutations; by their early 20s, this had progressed to 100% versus 9%.

Biochemical characteristics were also similar at presentation. Testosterone levels tended to be higher in patients with versus without AR mutations, and the ratio of testosterone to serum luteinizing hormone was significantly higher (1.9 versus 0.9), but the team notes “a large overlap between the two groups”.

Although a similar proportion of patients with and without mutations presented with hypospadias (69 and 87%, respectively), their repair was a more straightforward process in the latter group. Just one of this group needed three or more operations, compared with seven patients with mutations, one of whom needed 10 operations.

Furthermore, by a median age of 21 years, hypospadias was still present in 35% of patients with mutations, compared with just 15% of patients without mutations at a median age of 24 years.

“Given that the relative proportions of the type of hypospadias was similar in the two study groups and that the cases were spread over all the centers, the different outcome cannot be due to case or operator bias”, write the researchers in The Journal of Clinical Endocrinology & Metabolism.

“Thus, the poor results are more likely to be related to defective androgen signaling and its links to tissue healing.”

They therefore suggest that AR testing should be routine in PAIS patients, as the identification of any mutation may be “sufficient to predict poor prognosis” and could “guide the clinician towards a different approach to surgical management and may also allow improved preparation and counseling of the patient.”

By Eleanor McDermid

J Clin Endrocrinol Metab 2016; Advance online publication

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