FGFR1 and FGFR2 Mutations in Pfeiffer Syndrome

Abstract

Pfeiffer syndrome (PS) (MIM 101600) is one of the most common syndromic forms of craniosynostosis. It is characterized by craniosysnostosis, midface hypoplasia, broad and medially deviated thumbs, and great toes with partial syndactyly of the digits. Here, we described clinical and genetic features of 12 unrelated Thai individuals with PS. All 12 patients were sporadic, and advanced paternal age was found in 50% of the cases. Polymerase chain reaction sequencing of FGFR1 exon 5 and FGFR2 exons 8, 10, 15, 16, and 17 was performed in all PS patients and revealed 9 recurrent mutations in all patients. Most of the mutations clustered in exons 8 and 10 (9/12) accounting for 75% of PS cases. The most frequently detected mutation, p.S351C, was associated with the severe form of PS in the Thai population. Less frequent mutations in exons 16 (p.K641R) and 17 (p.G663E) were also identified. In addition, the p.P252R mutation in FGFR1 was detected in 1 PS patient with unilateral coronal craniosynostosis expanding the phenotypic spectrum of PS with this particular mutation. Knowing the mutation spectrum of the responsible genes could lead to the most effective strategy in identifying mutations causing Pfeiffer syndrome in the Thai population.

Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway

“…The clinical manifestations of FGFR1 alterations are very heterogeneous since loss‐of‐function mutations in FGFR1 have been linked to Kallman syndrome [Dode et al., ; Albuisson et al., ; Villanueva and de Roux, ], hypogonadotropic hypogonadism with or without anosmia [Costa‐Barbosa et al., ; Vizeneux et al., ; Villanueva et al., ], and Hartsfield syndrome [Simonis et al., ; Hong et al., ]. Gain‐of‐function mutations in FGFR1 have also been identified in about 5% of Pfeiffer syndrome with or without craniosynostosis [Chokdeemboon et al., ]. We describe here one case of FGFR1 mutation (p.Glu692Lys) associated both with Kallmann syndrome and HPE.…”

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

“…It consists of an extracellular region, composed of three immunoglobulin-like domains (IgI, IgII and IgIII), a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain [Coulier et al, 1997]. There is a wide spectrum of mutations in FGFR2 shown to be causative for Pfeiffer syndrome [Kan et al, 2002;Lajeunie et al, 2006;Chokdeemboon et al, 2013]. Most of them affect the third immunoglobulin-like domain (IgIII) of the FGFR2 protein but there are some reported mutations outside of this region [Kan et al, 2002;Lajeunie et al, 2006].…”

“…It was suggested that FGFR1 mutations often result in less severe craniofacial involvement [Muenke et al, 1994;Rossi et al, 2003;Hackett and Rowe 2006]. The majority of cases however are caused by gain of function mutations in FGFR2 [Kan et al, 2002;Lajeunie et al, 2006;Chokdeemboon et al, 2013]. The FGFR2 protein is involved in cell division and regulation of cell growth as well as differentiation [Coulier et al, 1997].…”

Pfeiffer syndrome: oral healthcare management and description of new dental findings in a craniosynostosis

“…Pfeiffer syndrome, also known as archocephalosyndactyly type V or Noack syndrome, is a rare autosomal dominant craniosynostosis first described in 1964 . It is caused by mutations in fibroblast growth factor receptor (FGFR)‐1 on chromosome 8p or FGFR‐2 on chromosome 10q …”