DDR2 – Warburg-Cinotti Syndrome

Warburg-Cinotti Syndrome is a rare autosomal dominant connective tissue disorder characterized by progressive corneal neovascularization, keloid formation, chronic skin ulceration, subcutaneous tissue wasting, flexion contractures of the fingers (HP:0012785), and osteolytic defects of the phalanges of the hand (HP:0009771). The syndrome arises from activating variants in the collagen receptor tyrosine kinase DDR2, which lead to ligand-independent receptor autophosphorylation and fibrotic tissue remodeling. Molecular diagnosis of this condition enables early intervention and guides consideration of targeted kinase inhibitors.

Initial genetic evidence was provided by a multi-patient study in which six affected individuals from four families harbored one of two heterozygous missense variants in DDR2: c.1829T>C (p.Leu610Pro) or c.2219A>G (p.Tyr740Cys) (PMID:30449416). In three families these were presumed de novo singleton cases, and in a fourth family the c.2219A>G variant arose de novo in the mother and segregated with disease in two offspring (2 additional affected relatives) (PMID:30449416).

A subsequent case report detailed a seven-year-old boy presenting with recurrent gelatinous conjunctival masses that invaded the cornea; whole-exome sequencing confirmed the c.2219A>G (p.Tyr740Cys) variant in hemizygosity consistent with an autosomal dominant mode of inheritance (PMID:39095787). These seven unrelated probands establish the recurrent nature of DDR2 missense activation in Warburg-Cinotti Syndrome.

Functional assays in patient-derived fibroblasts demonstrate that both p.Leu610Pro and p.Tyr740Cys variants increase DDR2 autophosphorylation, indicating reduced receptor autoinhibition and sustained kinase activation. Treatment with the tyrosine kinase inhibitor dasatinib abolishes aberrant phosphorylation, supporting a gain-of-function mechanism and providing a pharmacologic rescue approach (PMID:30449416).

No conflicting reports have been described, and the concordant genetic and experimental data firmly support a pathogenic role for dominant activating DDR2 variants in this fibrotic connective tissue disorder.

Key Take-home: Activating DDR2 missense variants cause Warburg-Cinotti Syndrome via gain-of-function kinase activity, enabling molecular diagnosis and potential dasatinib therapy.

References

• American Journal of Human Genetics • 2018 • Recurrent, Activating Variants in the Receptor Tyrosine Kinase DDR2 Cause Warburg-Cinotti Syndrome. PMID:30449416
• BMC Ophthalmology • 2024 • Progressive conjunctival invasion of cornea in a child with Warburg-Cinotti Syndrome: a case report. PMID:39095787

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