TBX4 – Coxopodopatellar Syndrome

TBX4 encodes a T-box transcription factor essential for lower limb development and is associated with ischio-coxopodopatellar syndrome (coxopodopatellar syndrome) (MONDO:0007841). Affected individuals present with patellar aplasia or hypoplasia, pelvic anomalies, and foot malformations. Heterozygous TBX4 variants disrupt developmental pathways governing ossification of the ischia and inferior pubic rami.

Early genetic evidence derived from a landmark study identifying putative loss-of-function mutations in six unrelated families with small patella syndrome, including nonsense, frameshift, splice-site, and missense changes in the conserved T-box domain (6 families, >6 probands) (PMID:15106123). Segregation was confirmed in multiple kindreds with autosomal dominant inheritance and concordant limb phenotypes.

Subsequent case reports have expanded the variant spectrum. A novel heterozygous frameshift c.113dup (p.Leu39fs) was detected in a 19-year-old proband and her father with recurrent patellar dislocation and confirmed small patella syndrome (PMID:29854702). More recently, a family with variable severity harbored a frameshift c.735del (p.Phe245LeufsTer25) segregating in four additional affected relatives (PMID:39467966).

The overall variant spectrum in coxopodopatellar syndrome includes at least eight distinct loss-of-function alleles: six truncating, one splice-site, and one frameshift variant, all acting in a dominant negative or haploinsufficient manner. A representative allele is c.721G>T (p.Glu241Ter).

Functional studies support haploinsufficiency as the pathogenic mechanism. Mesenchymal stem cells overexpressing TBX4 mutants (including c.1241C>T (p.Pro414Leu)) exhibit reduced differentiation, decreased FGF10 expression, and diminished promoter binding in chromatin immunoprecipitation and luciferase assays, consistent with impaired TBX4 regulation of limb morphogenesis (PMID:35216193).

Integration of genetic and experimental data establishes a definitive gene-disease relationship. Autosomal dominant TBX4 haploinsufficiency causes coxopodopatellar syndrome with highly penetrant skeletal anomalies. No conflicting evidence has been reported. Key take-home: TBX4 variant testing enables early diagnosis of coxopodopatellar syndrome and guides orthopedic management.

References

• American journal of human genetics • 2004 • Mutations in the human TBX4 gene cause small patella syndrome. PMID:15106123
• Journal of orthopaedic case reports • 2018 • A Novel Heterozygous Mutation in the T-box Protein 4 Gene in an Adult Case of Small Patella Syndrome. PMID:29854702
• International journal of molecular sciences • 2022 • Identification and Functional Evaluation of a Novel TBX4 Mutation Underlies Small Patella Syndrome. PMID:35216193
• Genes & genomics • 2025 • A novel frameshift TBX4 variant in a family with ischio-coxo-podo-patellar syndrome and variable severity. PMID:39467966

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