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Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III
K W Gripp1, C A Stolle, D M McDonald-McGinn
1Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia, Pennsylvania 19104, USA.
Insights
This study identifies a novel Ser351Cys mutation in the FGFR2 gene as the first identified cause of Pfeiffer syndrome type III. This genetic finding advances understanding of this rare craniosynostosis disorder.
Area of Science:
- Genetics
- Molecular Biology
- Medical Genetics
Background:
- Pfeiffer syndrome is a rare genetic disorder characterized by craniosynostosis and other skeletal abnormalities.
- Mutations in fibroblast growth factor receptor (FGFR) genes, primarily FGFR1 and FGFR2, are known causes of Pfeiffer syndrome type I.
- Pfeiffer syndrome type III, a severe form, has had its genetic basis less clearly defined.
Observation:
- A patient presented with pansynostosis, hydrocephalus, seizures, extreme proptosis, airway obstruction, intestinal non-rotation, severe developmental delay, bilateral elbow ankylosis, radial head dislocation, and a deviated first toe.
- The patient's phenotype aligned with Pfeiffer syndrome type III but lacked the typical broad thumbs.
- This presentation closely resembled a previously reported case of Pfeiffer syndrome type III with normal thumbs.
Findings:
- A novel Ser351Cys mutation in the FGFR2 gene was identified in the patient.
- This Ser351Cys mutation in FGFR2 is the first reported genetic cause for Pfeiffer syndrome type III.
- The mutation was detected through independent sequence analysis after single-strand conformation polymorphism analysis failed to identify it.
Implications:
- This discovery provides a specific genetic marker for Pfeiffer syndrome type III, aiding in diagnosis and genetic counseling.
- Understanding the role of FGFR2 mutations in Pfeiffer syndrome type III can inform future research into targeted therapies.
- The case highlights the importance of advanced genetic sequencing techniques for identifying mutations missed by other methods.
Abstract:
We present a patient with pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal non-rotation, and severe developmental delay. His skeletal abnormalities include bilateral elbow ankylosis, radial head dislocation, and unilateral broad and deviated first toe. The phenotype of this patient is consistent with that previously reported in Pfeiffer syndrome type III, but is unusual for the lack of broad thumbs. Our patient most closely resembles the case described by Kerr et al. [1996: Am J Med Genet 66:138-143] as Pfeiffer syndrome type III with normal thumbs. Mutations in the genes for fibroblast growth factor receptors (FGFR) 1 and 2 have previously been seen in patients with Pfeiffer syndrome type I. The mutation identified in our patient, Ser351Cys in FGFR2, represents the first reported cause of Pfeiffer syndrome type III. An identical mutation was described once previously by Pulleyn et al., in a patient whose brief clinical description included cloverleaf skull, significant developmental delay, and normal hands and feet [Eur. J. Hum. Genet. 4: 283-291, 1996]. In our patient, previously performed single-strand conformation polymorphism analysis failed to detect a band shift; the mutation was identified only after independent sequence analysis.