Kosaki overgrowth syndrome: A novel pathogenic variant in PDGFRB and expansion of the phenotype including cerebrovascular complications.

Abstract

Heterozygous activating variants in platelet-derived growth factor, beta (PDGFRB) are associated with phenotypes including Kosaki overgrowth syndrome (KOGS), Penttinen syndrome and infantile myofibromatosis (IM). Here, we present three new cases of KOGS, including a patient with a novel de novo variant c.1477A > T p.(Ser493Cys), and the oldest known individual age 53 years. The KOGS phenotype includes characteristic facial features, tall stature, scoliosis, hyperelastic thin skin, lipodystrophy, variable intellectual and neurological deterioration, and abnormalities on brain imaging. Long-term outcome is unknown. Our cases confirm the phenotypic spectrum includes progressive flexion contractures, camptodactyly, widely spaced teeth, and constriction rings. We also propose novel occasional features including craniosynostosis, ocular pterygia, anterior chamber cleavage syndrome, early osteoporosis, increased pigmentation, recurrent haematomas, predisposition to cellulitis, nail dystrophy, carpal tunnel syndrome, recurrent hypoglycaemia in infancy, joint dislocation, and splenomegaly. Importantly, we report fusiform aneurysm of the basilar artery in two patients. Complications include thrombosis and stroke in the oldest reported patient and fatal rupture at the age of 21 in the patient with the novel variant. We conclude that cerebrovascular complications are part of the phenotypic spectrum of KOGS and KOGS-like disorders and suggest vascular imaging is indicated in these patients.

• Authors: Alison Foster, Basile Chalot, Thalia Antoniadi, Elise Schaefer, Rebecca Keelagher, Gavin Ryan, Quentin Thomas, Christophe Philippe, Ange-Line Bruel, Arthur Sorlin, Christel Thauvin-Robinet, Marc Bardou, Maxime Luu, Veronique Quenardelle, Valerie Wolff, Jessica Woodley, Pierre Vabres, Derek Lim, Rebecca Igbokwe, Annie Joseph, Harriet Walker, Andrea Jester, Jonathan Ellenbogen, Diana Johnson, Bethanie Rooke, Celia Moss, Trevor Cole, Laurence Faivre
• Journal: Clinical genetics (Clin Genet) Vol. 98 Issue 1 Pg. 19-31 (07 2020) ISSN: 1399-0004 [Electronic] Denmark
• PMID: 32291752 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.

Chemical References

• PDGFRB protein, human
• Receptor, Platelet-Derived Growth Factor beta

Topics

• Adult
• Cerebrovascular Disorders (etiology, genetics)
• Genetic Variation (genetics)
• Growth Disorders (complications, genetics)
• Humans
• Male
• Middle Aged
• Phenotype
• Receptor, Platelet-Derived Growth Factor beta (genetics)