Missense variants located to the "molecular brake" in the tyrosine kinase hinge region of platelet-derived growth factor receptor-β, encoded by PFGFRB, can cause Penttinen-type (Val665Ala) and Penttinen-like (Asn666His) premature ageing syndromes, as well as infantile myofibromatosis (Asn666Lys and Pro660Thr). We have found the same de novo PDGFRB c.1997A>G p.(Asn666Ser) variants in two patients with lipodystrophy, acro-osteolysis and severely reduced vision due to corneal neovascularisation, reminiscent of a severe form of Penttinen syndrome with more pronounced connective tissue destruction. In line with this phenotype, patient skin fibroblasts were prone to apoptosis. Both in patient fibroblasts and stably transduced HeLa and HEK293 cells, autophosphorylation of PDGFRβ was observed, as well as increased phosphorylation of downstream signalling proteins such as STAT1, PLCγ1, PTPN11/SHP2-Tyr580 and AKT. Phosphorylation of MAPK3 (ERK1) and PTPN11/SHP2-Tyr542 appeared unaffected. This suggests that this missense change not only weakens tyrosine kinase autoinhibition, but also influences substrate binding, as both PTPN11 tyrosines (Tyr542 and Tyr580) usually are phosphorylated upon PDGFR activation. Imatinib was a strong inhibitor of phosphorylation of all these targets, suggesting an option for precision medicine based treatment.

We have investigated a distinct disorder with progressive corneal neovascularization, keloid formation, chronic skin ulcers, wasting of subcutaneous tissue, flexion contractures of the fingers, and acro-osteolysis. In six affected individuals from four families, we found one of two recurrent variants in discoidin domain receptor tyrosine kinase 2 (DDR2): c.1829T>C (p.Leu610Pro) or c.2219A>G (p.Tyr740Cys). DDR2 encodes a collagen-responsive receptor tyrosine kinase that regulates connective-tissue formation. In three of the families, affected individuals comprise singleton adult individuals, and parental samples were not available for verification of the de novo occurrence of the DDR2 variants. In the fourth family, a mother and two of her children were affected, and the c.2219A>G missense variant was proven to be de novo in the mother. Phosphorylation of DDR2 was increased in fibroblasts from affected individuals, suggesting reduced receptor autoinhibition and ligand-independent kinase activation. Evidence for activation of other growthregulatory signaling pathways was not found. Finally, we found that the protein kinase inhibitor dasatinib prevented DDR2 autophosphorylation in fibroblasts, suggesting an approach to treatment. We propose this progressive, fibrotic condition should be designated as Warburg-Cinotti syndrome. Web ResourcesClinVar, https://www.ncbi.nlm.nih.gov/clinvar/ Exac Browser, http://exac.broadinstitute.org/ GnomAD Browser, http://gnomad.broadinstitute.org/ Online Mendelian Inheritance in Man, http://www.omim.org/

Purpose In 2006 Warburg et al. described a patient with blepharophimosis, corneal vascularization, retinal degeneration, deafness, loss of subcutanous tissue, flexion contractures of the fingers and acro‐osteolysis. Some years later Cinotti et al. reported a similar patient. In addition, we identified tree individuals from two different families with a similar clinical picture. In total, all six individuals from four different families were examined to identify the gene mutation associated with this disease Methods Exome sequencing was performed on affected individuals. Patient skin fibroblasts was obtained and examined using Elisa and Western blot analysis to determine levels of phosphorylated DDR2 and downstream effector proteins. Patient fibroblasts were also treated with Dasatabib, a protein kinase inhibitor affecting DDR2. Results We found two recurrent de novo mutations in DDR2, p.Leu610Pro or p.Tyr740Cys, to be associated with the condition. Increased phosphorylation of DDR2 was found suggesting reduced receptor autoinhibition and ligand‐independent activation of the kinase. Dasatinib prevented DDR2 autophosphorylation. No effect of the mutations were found on the examined downstream effector proteins of DRR2. Conclusion We found two recurrent, activating mutations in DDR2, p.Leu610Pro and p.Tyr740Cys, to be associated with this progressive fibrotic condition that we suggest to be called Warburgh‐Cinotti syndrome. In vitro dasatinib prevented autophosphorylation of DDR2 suggesting an approach to patient treatment. Reference