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.

True radial artery aneurysm in a patient with somatic mosaicism for a mutation in platelet-derived growth factor receptor β gene

“…16 PDGFRB is expressed in pericytes and vascular smooth muscle cells, and is essential for the regulation of vascular smooth cell proliferation during vascular growth. 9 PDGFRB mutations have been associated with primary familial brain calcification 10 , idiopathic basal ganglia calcification 11 , Kosaki overgrowth syndrome 12 , infantile myofibromatosis 13 , dermatofibrosarcoma protuberans 14 , and Penttinen premature aging syndrome. 15 The patient's phenotype most closely resembles the rare syndrome PWS, caused by mutations in the RASA1, and characterized by limb overgrowth, port-wine stains due to capillary malformations and diffuse AVM.…”

Segmental overgrowth and aneurysms due to mosaic PDGFRB p.(Tyr562Cys)

“…We specifically reviewed all reports for vascular aneurysms in patients with PDGFRB variants, overgrowth syndrome, premature aging, or IM. A total of eight patients were identified with aneurysms (Brasseur et al, 2010; Foster et al, 2020; Frezin et al, 2015; Karasozen et al, 2019; Wright et al, 2004; Zarate et al, 2019; Zufferey et al, 2013) and their clinical characteristics are provided in Table 1 (Numbered 1–8). The variants in reported cases were detected in blood (Cases 5, 7, and 8) or in tissues (Case 6 and our Patient 1).…”

Progressive cerebral and coronary aneurysms in the original two patients with Kosaki overgrowth syndrome

“…Subsequently, a similar phenotype of skeletal overgrowth, thin skin, premature aging appearance, and cerebral periventricular white matter abnormalities were observed in patients who carried a de novo heterozygous mutation in PDGFRB , that is, p.Trp566Arg (Minatogawa et al, 2017). The newly identified condition was eponymized as Kosaki overgrowth syndrome (KOGS) (OMIM #616592) by Johnston et al (Johnston et al, 2015) and has been referred to as KOGS by multiple authors (Foster et al, 2020; Gawlinski et al, 2018; Minatogawa et al, 2017; Takenouchi et al, 2019). So far, the known neurological phenotype of KOGS includes various degrees of intellectual disability, and the neuroimaging phenotype includes cerebral periventricular white matter abnormalities and conspicuous arachnoid cysts in the posterior fossa (Gawlinski et al, 2018; Takenouchi et al, 2019).…”

“…Through international efforts to delineate full phenotypic features of KOGS, aneurysms and cerebral and coronary arterial tortuosity have been newly recognized as complications of patients with activating germline mutations in PDGFRB , that is, p.Trp566Arg (Zarate et al, 2019), and p.Pro584Arg and p.Ser493Cys (Foster et al, 2020). The patient ages at the time of the identification of the vascular lesions ranged from 13 to 53 years old.…”

“…Moreover, a somatic activating variant in PDGFRB , that is, p.Tyr562Cys, was reported to cause a fusiform cerebral aneurysm (Karasozen et al, 2019). Recently, two adult KOGS patients (at 53 and 21 years of age) were found to have basilar artery aneurysms (Foster et al, 2020). One patient had a basilar artery aneurysm thrombosis with subsequent dissection of the aneurysm and subarachnoid hemorrhage at 21 years old.…”