Is Bilateral Clubfoot Typically Syndromic?
Bilateral clubfoot is NOT typically syndromic—approximately 66-80% of cases are isolated (idiopathic), while only 20-33% are associated with genetic syndromes or chromosomal abnormalities. 1, 2
Epidemiology of Isolated vs. Syndromic Clubfoot
The majority of clubfoot cases (approximately 80%) occur as isolated birth defects without underlying genetic syndromes, according to whole exome sequencing studies of patients with idiopathic clubfoot 3
In prenatal diagnosis studies, 66.6% of prenatally diagnosed clubfoot cases were isolated, while 33.3% were complex (associated with structural or chromosomal abnormalities) 1
Among complex cases, only 7.1% had chromosomal abnormalities and 26.2% had associated structural anomalies 1
Bilateral vs. Unilateral Presentation
Bilateral presentation does NOT indicate syndromic etiology—in prenatal diagnosis studies, 70.7% of clubfoot cases were bilateral and 29.3% were unilateral, but bilateral presentation was unrelated to the presence of associated anomalies (p = 0.40) 1
Patients with the recurrent FLNB deletion variant were more likely to have bilateral clubfoot, but most still presented with isolated clubfoot without syndromic features 3
When to Suspect Syndromic Clubfoot
High-Risk Genetic Syndromes
22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome): Clubfoot is reported as one of the musculoskeletal manifestations requiring surgical intervention in some cases 4
Osteogenesis imperfecta: Bilateral clubfoot identified in the first trimester via fetal ultrasound may be an early presentation of severe OI, particularly when associated with multiple fractures in the second trimester 5
Williams syndrome: Associated with chromosome deletion in band 7q11.23, clubfoot can occur alongside supravalvular aortic stenosis and developmental disorders 4
Clinical Red Flags for Syndromic Cases
Presence of other structural anomalies on prenatal ultrasound or physical examination suggests complex clubfoot requiring genetic evaluation 1
Family history with incomplete penetrance may indicate genetic variants in FLNB or other genes, though most affected individuals still have isolated clubfoot 3
First-trimester detection with subsequent identification of multiple fractures should prompt evaluation for osteogenesis imperfecta with COL1A1/COL1A2 genetic testing 5
Genetic Evaluation Recommendations
Universal genetic testing and genetic counseling should be offered to all children with bilateral Wilms tumors (not clubfoot specifically), but this principle does not extend to isolated bilateral clubfoot 4
For clubfoot specifically, genetic testing is indicated when syndromic features are present or when there is a positive family history with multiple affected individuals 3, 2
Recurrent FLNB E1792 deletion is identified in only 0.43% of isolated clubfoot patients, making it among the most common known genetic causes but still representing a small minority of cases 3
Critical Clinical Pitfalls
Do not assume bilateral clubfoot indicates syndromic etiology—the majority of bilateral cases are still isolated 1
Do not delay orthopedic treatment while pursuing genetic workup unless there are specific concerns for bone fragility (as in osteogenesis imperfecta) that would alter surgical approach 6
Screen for associated anomalies systematically: In 22q11.2 deletion syndrome, look for cardiac defects, immune deficiency, hypocalcemia, and developmental delays in addition to musculoskeletal findings 4
Consider environmental factors in genetic counseling: Even in cases with genetic predisposition (such as maternal OI), environmental factors like bisphosphonate therapy and amniocentesis may contribute to clubfoot development 6