Human FGFR2 Mutation in 46,XY Gonadal Dysgenesis

Program: Late-Breaking Abstracts
Session: SUN-LB-Late-Breaking Poster Session 2
Bench to Bedside
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-LB-09
Stefan Bagheri-Fam1, Makoto Ono1, Gerd Scherer2, Oliver Bartsch3, Veraragavan Eswarakumar4 and Vincent R Harley*5
1Prince Henry's Institute of Medical Research, Australia, 2Institute of Human Genetics and Anthropology, 3Institute of Human Genetics, Mainz University, 4School of Medicine, Yale University, 5Prince Henry's Institute of Medical Research, Clayton VIC, Australia
Disorders of sex development are genetically heterogeneous and occur in common and rare forms. 46,XY gonadal dysgenesis affects testis development and is associated with gonadal cancer and genital defects ranging from ambiguous genitalia to complete male-to-female sex reversal. A molecular diagnosis is made in only 20% of cases. Fibroblast Growth Factor Receptor 2 (FGFR2) is important for testis development in mice, but there has been no evidence reported for such a role in humans. FGFR2 mutations lead to various craniosynostosis syndromes, including Crouzon syndrome, defined by associated features.  Here we report the first case of Crouzon syndrome with XY male-to-female sex reversal. The female Crouzon patient presented at the age of 15 years with primary amenorrhea, bilateral malignant ovarian tumors (dysgerminoma developed from gonadoblastoma), severe craniosynostosis requiring surgery, short stature, and limited movement/synostosis of elbows and was diagnosed with 46,XY gonadal dysgenesis. DNA sequencing revealed the heterozygous missense mutation, c.1025G>C (p.Cys342Ser) in FGFR2, within the FGFR2c isoform. Substitution of Cysteine 342 with Serine or with other amino acids occur in Crouzon, Pfeiffer and Antley-Bixler syndromes, resulting in constitutively activated FGFR2 and bone overgrowth. To investigate whether an FGFR2c-Cys342Ser mutation could cause XY sex reversal, we analysed a knock-in mouse model (Fgfr2cC342Y) carrying a functionally identical substitution, Cys342Tyr. In this model, the spectrum of craniofacial phenotypes closely parallels that in Crouzon patients. Immunofluorescence analysis of testicular and ovarian markers revealed that the gonads of XY Fgfr2cC342Y/C342Y embryos display sex reversal to varying extents, from hypoplastic testes with small areas of ovarian tissue to ovaries with small areas of testicular tissue. These gonadal abnormalities phenocopy those observed in Fgfr2 knockout mice lacking functional FGFR2. We speculate therefore that in the Crouzon patient there is loss of FGFR2c activity in the gonads during fetal development. This supports an earlier proposal that constitutive activation of FGFR2c caused by the Cys342Tyr mutation can result in loss-of-function dependent on tissue context. Whether an identical FGFR2c Cys342 substitution causes Crouzon or Pfeiffer syndrome is believed to be dependent upon additional sequence variations. We conclude that in the XY female Crouzon patient the FGFR2c-Cys342Ser mutation is the primary driver of gonadal dysgenesis, with genetic background exerting specific effects which define a rare form of Crouzon syndrome.  However Crouzon patients may be at increased risk of testicular abnormalities (i.e. small testes), hitherto overlooked. Our results exemplify the need to screen for FGFR2 mutations in 46,XY gonadal dysgenesis cases without craniosynostosis.

Nothing to Disclose: SB, MO, GS, OB, VE, VRH

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm