PDGFRB – Kosaki overgrowth syndrome

Kosaki overgrowth syndrome is an autosomal dominant disorder characterized by skeletal overgrowth, craniofacial dysmorphism, hyperelastic skin, and white matter lesions. Heterozygous activating variants in the platelet-derived growth factor receptor beta gene (PDGFRB) underlie this condition through constitutive kinase activation and downstream PI3K-AKT pathway signaling anomalies.

Multiple unrelated probands have been reported with de novo missense PDGFRB variants, including c.1751C>G (p.Pro584Arg), c.1696T>C (p.Trp566Arg), and c.1477A>T (p.Ser493Cys), totaling over 13 cases to date (PMID:28639748, PMID:30941910, PMID:29226947, PMID:32291752).

Segregation analysis in a multigenerational family harboring the novel c.2567A>T (p.Asn856Ile) variant demonstrated co-segregation in three affected relatives, including two siblings and their heterozygous father (PMID:35221873).

The variant spectrum in Kosaki overgrowth syndrome is predominantly missense and clustered in the juxtamembrane and kinase domains. Recurrent or founder alleles are not established, but c.1696T>C (p.Trp566Arg) recurs in unrelated patients. Deep-intronic and structural variants have not been described.

Functional assays, including patient‐derived cellular studies and heterologous expression, show that disease-associated PDGFRB mutants exhibit ligand-independent autophosphorylation, enhanced MAPK/ERK and PI3K-AKT activation, and oncogenic transformation capacity. The p.Pro584Arg mutant transforms NIH3T3 and Ba/F3 cells and is sensitive to imatinib and other TKIs (PMID:26455322). Rescue of aberrant signaling by tyrosine kinase inhibitors supports a gain-of-function mechanism.

In summary, strong genetic and functional evidence links heterozygous PDGFRB gain-of-function variants to Kosaki overgrowth syndrome. Baseline cardiovascular imaging is recommended due to aneurysm risk, and targeted TKI therapy may offer clinical benefit. Key take-home: PDGFRB testing should be pursued in individuals with early overgrowth and connective tissue findings to enable diagnosis, surveillance, and potential targeted therapy.

References

• American journal of medical genetics. Part A • 2019 • Constitutive activation of the PI3K-AKT pathway and cardiovascular abnormalities in an individual with Kosaki overgrowth syndrome. PMID:30941910
• Clinical genetics • 2020 • Kosaki overgrowth syndrome: A novel pathogenic variant in PDGFRB and expansion of the phenotype including cerebrovascular complications. PMID:32291752
• Clinical genetics • 2018 • Phenotype expansion and development in Kosaki overgrowth syndrome. PMID:29226947
• American journal of medical genetics. Part A • 2017 • Expansion of the phenotype of Kosaki overgrowth syndrome. PMID:28639748
• Molecular syndromology • 2022 • Kosaki Overgrowth Syndrome: Report of a Family with a Novel PDGFRB Variant. PMID:35221873
• Oncogene • 2016 • PDGFRB mutants found in patients with familial infantile myofibromatosis or overgrowth syndrome are oncogenic and sensitive to imatinib. PMID:26455322

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