FGFR2mutation in 46,XY sex reversal with craniosynostosis

Abstract

Patients with 46,XY gonadal dysgenesis (GD) exhibit genital anomalies, which range from hypospadias to complete male-to-female sex reversal. However, a molecular diagnosis is made in only 30% of cases. Heterozygous mutations in the human FGFR2 gene cause various craniosynostosis syndromes including Crouzon and Pfeiffer, but testicular defects were not reported. Here, we describe a patient whose features we would suggest represent a new FGFR2-related syndrome, craniosynostosis with XY male-to-female sex reversal or CSR. The craniosynostosis patient was chromosomally XY, but presented as a phenotypic female due to complete GD. DNA sequencing identified the FGFR2c heterozygous missense mutation, c.1025G>C (p.Cys342Ser). Substitution of Cys342 by Ser or other amino acids (Arg/Phe/Try/Tyr) has been previously reported in Crouzon and Pfeiffer syndrome. We show that the 'knock-in' Crouzon mouse model Fgfr2c(C342Y/C342Y) carrying a Cys342Tyr substitution displays XY gonadal sex reversal with variable expressivity. We also show that despite FGFR2c-Cys342Tyr being widely considered a gain-of-function mutation, Cys342Tyr substitution in the gonad leads to loss of function, as demonstrated by sex reversal in Fgfr2c(C342Y/-) mice carrying the knock-in allele on a null background. The rarity of our patient suggests the influence of modifier genes which exacerbated the testicular phenotype. Indeed, patient whole exome analysis revealed several potential modifiers expressed in Sertoli cells at the time of testis determination in mice. In summary, this study identifies the first FGFR2 mutation in a 46,XY GD patient. We conclude that, in certain rare genetic contexts, maintaining normal levels of FGFR2 signaling is important for human testis determination.

Long‐term outcomes and molecular analysis of a large cohort of patients with 46,XY disorder of sex development due to partial gonadal dysgenesis

“…FGFR2 variants most commonly cause craniosynostosis syndromes without any gonadal phenotype. Although there is one report of a heterozygous FGFR2 p.Cys342Tyr variant that was associated with complete gonadal dysgenesis and no report of patients with PGD . The FGFR2 p.Ser453Leu allelic variant found in one of our families is located in the hotspot region for pathogenic variants responsible for craniosynostosis phenotypes; however, our patients and their mother did not have any skull problems.…”

Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

“…Consistent with a conserved role for FGF9/FGFR2 signaling in human gonadal development, a heterozygous missense mutation (c.1025G>C, p.Cys342Ser) in the FGFR2c gene was associated with complete 46,XY gonadal dysgenesis with a female phenotype [90]. No information about fertility potential was reported for the patient with this specific mutation who was gonadectomized at age 15 years due to bilateral dysgerminoma.…”

Corrigendum: Corrigendum for: Disorders of sex development: The evolving role of genomics in diagnosis and gene discovery, 108:337–350 (10.1002/bdrc.21148)

“…However, this group also concentrated their analysis on known DSD genes, narrowing their focus to NR5A1 as a key candidate for 46,XX DSD (Baetens et al, ). WES has also been used to validate the existence of potential genetic modifiers in patients, which could sensitize an individual to DSD (Bagheri‐Fam et al, ). WES will allow for the discovery of novel genes related to DSD, however, the current trend to only analyze known DSD genes to ease the bioinformatic analysis only hampers the potential of WES for novel gene discovery.…”