PDGFRB – Infantile Myofibromatosis

Infantile myofibromatosis (IM) is an autosomal dominant disorder characterized by multifocal nodules in skin, muscle, bone and visceral organs often presenting in early infancy. Germline and somatic variants in PDGFRB disrupt the juxtamembrane and kinase domains, leading to constitutive receptor activation and aberrant proliferation of myofibroblasts. IM lesions may regress spontaneously but visceral involvement carries high morbidity and mortality, underscoring the need for precise genetic diagnosis and targeted therapy.

Case-level evidence includes 11 affected individuals in four families with the recurrent PDGFRB c.1681C>T (p.Arg561Cys) variant ([PMID:23731537]), eight additional families with either p.Arg561Cys or p.Pro660Thr variants ([PMID:23731542]), and a sporadic multicentric series with gain-of-function variants in 7/8 probands ([PMID:28334876]). Prenatal genetic diagnosis of c.1681C>T (p.Arg561Cys) predicted fetal demise in disseminated cases ([PMID:37568122]), and a late‐relapse case with c.1687G>A (p.Glu563Lys) highlights the role of PDGFRB testing in long-term follow-up ([PMID:39141797]).

Segregation of PDGFRB variants in multiplex kindreds with at least 19 additional affected relatives (siblings and multi‐generation transmission) provides compelling familial evidence, consistent with an autosomal dominant inheritance pattern. De novo and inherited cases, combined with reports of mosaic PDGFRB rearrangements, expand the mechanistic spectrum of pathogenic alleles.

The variant spectrum is dominated by missense changes within the kinase hinge (Arg561, Asn666, Glu563) and juxtamembrane regions, with the hotspot c.1681C>T (p.Arg561Cys) accounting for multiple familial cases. Somatic and germline mutations display variable allele fractions, and rare rearrangements disrupting the juxtamembrane domain have been shown to confer oncogenicity in cellular models.

Functional studies demonstrate ligand‐independent PDGFRB autophosphorylation, PDGF-independent proliferation of fibroblasts, and tumorigenic transformation in mouse embryo fibroblasts. Imatinib, sunitinib, dasatinib and ponatinib consistently inhibit mutant receptors in vitro, and clinical reports confirm durable responses to sunitinib ([PMID:28183292]) and imatinib ([PMID:26455322], [PMID:28726812]). These concordant data establish a gain-of-function mechanism amenable to targeted tyrosine kinase inhibition.

In conclusion, PDGFRB‐associated IM is a definitive gene–disease relationship underpinned by extensive case series, strong segregation, and robust functional concordance demonstrating constitutive kinase activation. Genetic testing for PDGFRB variants is critical for diagnosis, family counseling, and initiation of kinase inhibitor therapy. Key Take-home: Early identification of PDGFRB gain-of-function variants enables precision therapy with PDGFR inhibitors to improve outcomes in infantile myofibromatosis.

References

• American Journal of Human Genetics • 2013 • A recurrent PDGFRB mutation causes familial infantile myofibromatosis. PMID:23731537
• American Journal of Human Genetics • 2013 • Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis. PMID:23731542
• Human Molecular Genetics • 2017 • PDGFRB gain-of-function mutations in sporadic infantile myofibromatosis. PMID:28334876
• BMC Cancer • 2017 • Case report: rapid and durable response to PDGFR targeted therapy in a child with refractory multiple infantile myofibromatosis and a heterozygous germline mutation of the PDGFRB gene. PMID:28183292
• Cold Spring Harbor Molecular Case Studies • 2019 • Novel PDGFRB rearrangement in multifocal infantile myofibromatosis is tumorigenic and sensitive to imatinib. PMID:31645346
• Genetics in Medicine • 2018 • A patient with germ-line gain-of-function PDGFRB p.N666H mutation and marked clinical response to imatinib. PMID:28726812

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