Patients with 46,XY gonadal dysgenesis (GD) exhibit genital anomalies, which range from hypospadias to complete male-to-female sex reversal. A molecular diagnosis is made in only 30% of cases. Our study identifies FGFR2c as a novel 46,XY GD locus. Human FGFR2 mutations cause various craniosynostosis syndromes including Crouzon, Pfeiffer, and Apert syndrome. Here, we describe a patient whose features we would suggest represent a new syndrome, craniosynostosis with XY male-to-female sex reversal or CSR. The patient was chromosomally XY, but presented as a phenotypic female due to complete GD, and was also diagnosed with Crouzon-like syndrome. DNA sequencing identified the FGFR2 heterozygous missense mutation, c.1025G>C (p.C342S), affecting the 2c splice isoform. Substitution of C342 by S or other amino acids (R/F/W/Y) occurs frequently in Crouzon and Pfeiffer syndrome leading to ligand-independent receptor activation. We show that the ‘knock-in’ Crouzon mouse model Fgfr2cC342Y/C342Y carrying a C342Y substitution displays variable XY gonadal sex reversal. This suggests that the C342 substitution contributed to XY sex reversal in the patient. Despite FGFR2c-C342Y being widely considered a gain-of-function mutation, the gonadal abnormalities in XY Fgfr2cC342Y/C342Y mice phenocopy those observed in Fgfr2 knockout mice. We demonstrate that sex reversal in XY Fgfr2cC342Y/- mice is rescued by wildtype FGFR2 in Fgfr2cC342Y/+ mice. This implies that ligand-independent signaling by FGFR2c-C342Y displays qualitatively different biological activities to wildtype FGFR2c, resulting in reduced ability to promote testis development. In conclusion, our study identifies the first FGFR2 mutation in 46,XY GD. Diagnosis of 46,XY GD should be widened to encompass FGF-signaling components.