Additional phenotypic features of Muenke syndrome in 2 Dutch families

Area of Science:

• Genetics
• Clinical Medicine
• Pediatrics

Background:

• Craniosynostosis syndromes often have underlying genetic causes, with mutations in the FGFR3 gene being common.
• The Pro250Arg mutation in FGFR3 is frequently associated with Muenke syndrome, a specific craniosynostosis syndrome.
• Understanding the full spectrum of clinical findings for specific mutations is crucial for genetic counseling and patient management.

Purpose of the Study:

• To investigate the genotype-phenotype relationship of the Pro250Arg mutation in FGFR3.
• To identify novel clinical characteristics associated with Muenke syndrome.
• To enhance the diagnostic accuracy and genetic counseling for Muenke syndrome patients.

Main Methods:

• Screening of two Dutch families with Muenke syndrome.
• Clinical evaluation for known and additional features of the syndrome.
• Phenotypic analysis correlating with the Pro250Arg mutation in FGFR3.

Main Results:

• Identified new phenotypical findings: frontal sinus hypoplasia, upper eyelid ptosis, dysplastic elbow joints with restricted motion, and mild cutaneous syndactyly.
• Observed incidental findings including polydactyly, severe elbow ankylosis, cervical vertebrae fusion, and epilepsy.
• Upper eyelid ptosis, previously considered pathognomonic for Saethre-Chotzen syndrome, was noted in Muenke syndrome patients.

Conclusions:

• The Pro250Arg mutation in FGFR3 is associated with a broader range of clinical manifestations than previously recognized.
• Phenotypic overlap exists between Muenke syndrome and Saethre-Chotzen syndrome, underscoring the need for genetic testing.
• Accurate genetic diagnosis via DNA analysis is essential for differentiating Muenke syndrome from other craniosynostosis syndromes, even with a family history.