FGFR2 mutation in a patient without typical features of Pfeiffer syndrome – The emerging role of combined NGS and phenotype based strategies

Abstract

Pfeiffer syndrome (MIM: #101600) is a rare autosomal dominant disorder classically characterized by limb and craniofacial anomalies. It is caused by heterozygous mutations in the fibroblast growth factor receptors types 1 and 2 (FGFR1 and FGFR2). We applied a next generation sequencing (NGS) panel approach comprising all 2877 genes currently known to be causative for one or more Mendelian diseases combined with the phenotype based computational tool PhenIX (Phenotypic Interpretation of eXomes). We report on a patient presenting with multiple anomalies of hands and feet including brachydactyly and symphalangism. No clinical diagnosis could be established based on the clinical findings and testing of several genes associated with brachydactyly and symphalangism failed to identify mutations. Via next generation sequencing (NGS) panel approach we then identified a novel de novo missense FGFR2 mutation affecting an amino acid reported to be mutated in Pfeiffer syndrome. Since our patient shows typical radiological findings of Pfeiffer syndrome in hands and feet but at the same time lacks several characteristic features such as clinical signs of craniosynostosis and prominent eyes we suggest introducing the term "FGFR2 associated phenotypes" for similar cases. Our results highlight the emerging role of combined NGS and phenotype based bioinformatics strategies to establish clinical diagnoses.

Variable prenatal presentation of Pfeiffer syndrome: Suggested aids to prenatal sonographic diagnosis

“…In 2 of our cases (cases and ), craniosynostosis was not present on prenatal US. Most reported cases of PS without craniosynostosis have a FGFR1 gene mutation . In addition to our 2 cases with FGFR2 mutations without prenatal craniosynostosis, we identified 1 case of PS with FGFR2 mutation reported without craniosynostosis at 18 and 20 WG and with onset of cloverleaf skull at 36 WG.…”

“…In 2 of our cases (cases 2 and 4), craniosynostosis was not present on prenatal US. Most reported cases of PS without craniosynostosishave a FGFR1 gene mutation 2,7,14. In addition to our 2 cases with FGFR2 mutations without prenatal craniosynostosis, we identified 1…”

“…Brahman provided the first sonographic observation of craniosynostosis, in 1979, describing “Kleeblattschädel syndrome,” then Salvo in 1981 . Pfeiffer syndrome is known for its clinical variability and expressivity, even in the same family; thus, the prenatal diagnosis of PS may be challenging. Our findings confirm this as we have demonstrated the variability in the prenatal presentation with craniosynostosis found postnatally in 3 of 4 cases, but only detected prenatally in 2, abnormalities of thumbs and big toes only detected in 3 out of 4 cases on prenatal ultrasound, and other cardinal signs such as sacral appendage, vertebral fusion, and coronal clefts only seen prenatally in 1 case.…”

“…Pfeiffer syndrome is known for its variable clinical expression. Because typical radiological findings such as craniosynostosis may be lacking, prenatal diagnosis might be challenging.…”

Genome sequencing in families with congenital limb malformations

“…In all four cases, we classified the variants as (likely) pathogenic according to the criteria of the American College of Medical Genetics and Genomics (ACMG), based on the type of variant and the phenotype of the patient. All variants were inherited (note that the mother of I8, was not radiographically phenotyped, which is necessary to diagnose mild FGFR2 -associated phenotypes (Flöttmann et al 2015 )).…”