Endocrine Abstracts

Introduction: FKBP prolyl isomerase 4, encoded by the gene FKBP4, is a member of the FK506-binding protein family and is presumed to be a regulator of the androgen receptor (AR) pathway. Mutations in FKBP4 have been proposed to cause Androgen Insensitivity Syndrome (AIS), with only one case reported in the literature so far.

Aim: To report the clinical, biochemical and genetic findings in an infant with 46, XY DSD a homozygous variant in the FKBP4 gene.

Case report: The baby (46,XY) was born prematurely at 27 weeks of gestation and noted to have severe undermasculinisation (minimal phallus with 0.5 cm in length, urethral meatus at the base, unfused labioscrotal folds, and right-side undescended testis with left testis in the groin; external masculinisation score=1). There were no obvious dysmorphic features. Endocrine work for DSD (at term) revealed a baseline testosterone (T) level of 0.5 nmol/l, raising to 15.5 nmol/l post hCG stimulation. Ultrasound imaging detected both testes at the inguinal ring and no evidence of Mullerian structures. A next-generation multi-gene DSD sequencing panel did not detect any variants associated with DSD, including the AR gene. In the absence of a molecular diagnosis of CAIS and intense consultation with the parents who have traditional, non-binary values, the gender was assigned as male. However, subsequent whole-exome sequencing revealed a homozygous splice variant in FKBP4 (c.106-2A>G). We did not observe any masculinisation of the external genitalia following three monthly injections of 25 mg testosterone IM. At 12 months of age, the child underwent a Ross procedure for severe aortic and mitral regurgitation. There is a significant global developmental delay with delayed myelination on MRI brain imaging.

Summary and conclusion: We report a case with 46,XY DSD with a splice variant in FKBP4. The case highlights management challenges in 46,XY DSD when there is discordance between a clinical phenotype of AIS in the absence of an established molecular cause. Given the known role of FKB4 in the regulation of androgen receptor signalling, FKBP4 deficiency might extend the molecular spectrum of AIS, but functional studies and data on long-term outcomes are needed.