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De Novo Heterozygous Mutation in FGFR2 Causing Type II Pfeiffer Syndrome
Rafat Mosalli1,2, Alfia Fatma3, Mohammed A Almatrafi1
1Department of Pediatrics, Umm Al Qura University, Makkah, Saudi Arabia.
Abstract:
Pfeiffer syndrome (PS) is an autosomal dominant disorder with three subtypes stemming from heterozygous mutations in the fibroblast growth factors FGFR1 and FGFR2. The subtypes overlap with heterogeneous clinical manifestations and variable prognosis dependent on neurological and respiratory compromise that impact short- and long-term outcomes and survival. We present a male, term infant with type II PS that was diagnostically suspected antenatally based on three-dimensional ultrasonographic findings that were confirmed postnatally by craniofacial tomography and magnetic resonance imaging. A new generation sequencing panel identified a unique de novo FGFR2, c.335 A > G p. Tyr112Cys variant, the first of its kind, and features that closely aligned with subtype II PS. Initial molecular results categorized the mutation as nonpathogenic, but it was later reclassified as pathogenic. Antenatal, multidisciplinary parental counseling about the tentative diagnosis and prognosis facilitated postnatal decisions that culminated in an informed choice for palliative care and early demise.
Insights
Pfeiffer syndrome (PS) is a genetic disorder caused by FGFR1/FGFR2 mutations. This case highlights a unique FGFR2 variant in a type II PS infant, emphasizing the importance of genetic testing and counseling for prognosis.
Area of Science:
- Genetics and Developmental Biology
- Medical Diagnostics
Background:
- Pfeiffer syndrome (PS) is an autosomal dominant disorder.
- It is caused by mutations in fibroblast growth factor receptors (FGFR1 and FGFR2).
- PS presents with heterogeneous clinical manifestations and variable prognosis.
Observation:
- A male infant presented with features suggestive of type II PS, diagnosed antenatally via ultrasonography.
- Postnatal imaging confirmed craniofacial abnormalities.
- Genetic analysis revealed a novel de novo FGFR2 variant (c.335A>G p.Tyr112Cys).
Findings:
- The identified FGFR2 variant was initially classified as nonpathogenic but later reclassified as pathogenic.
- The clinical presentation closely aligned with subtype II PS.
- This unique variant represents a new mutation associated with Pfeiffer syndrome.
Implications:
- Accurate genetic diagnosis is crucial for understanding PS subtypes and prognosis.
- Multidisciplinary parental counseling is vital for informed decision-making.
- This case underscores the evolving understanding of genotype-phenotype correlations in rare genetic disorders.
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