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

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.

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. (Pro584Arg). 7,8 Novel PDGFRB variants including p.(Asn666His), 9 p.
(Arg561_Tyr562delinsHis), 10 and p.(Asn666Ser) 11 have also been reported in patients with phenotypes overlapping these disorders. A schematic representation of the PDGFRB protein with the location of activating variants is shown in Figure 1. Loss-of-function variants are associated with idiopathic basal ganglia calcification (IBGC) syndrome (OMIM#615007; p.(Leu658Pro) and p.(Arg987Trp)). 12 Somatic activating mutations have been identified in tissue from fusiform cerebral aneurysms p.(Tyr562Cys). 13 Somatic rearrangements with a t (5;12) translocation leading to a ETV6-PDGFRB fusion gene are associated with myeloproliferative disorder with eosinophilia (OMIM#131440). 14 KOGS was first described in 2015 and to date, six patients have been reported with ages ranging from 3 to 19. 7,8,15,16  and feet, variable intellectual disability and neurological deterioration, scoliosis, hyperelastic thin and fragile skin, lipodystrophy, abnormalities on brain magnetic resonance imaging (MRI) including white matter lesions, ventricular enlargement/hydrocephalus and arachnoid cysts, and myofibromas in some individuals 7,8,[15][16][17] . Long-term outcome has not previously been reported and is of great interest given the apparently progressive course of this disorder.
Here, we report three new individuals with KOGS including the oldest patient at the age of 53 and expand the phenotype of this disorder. We describe a young adult with a novel variant in PDGFRB c.1477A > T p.(Ser493Cys), adding to our knowledge of the genotype-phenotype correlations in PDGFRB-related disorders. Importantly, we report cerebrovascular complications in both adults, highlighting the morbidity and mortality associated with this group of disorders. according to the manufacturer's recommendations for paired-end 76 bp reads. Raw data were processed as previously described (Thevenon, 2016). 18   Pterygia of the right eye at the age of 10 and the left eye at the age of 32 were treated with keratoplasty, but recurrence in both eyes resulted in visual impairment. Early osteoporosis was diagnosed at the age of 37, but the presence of plantar calcifications ruled out treatment with bisphosphonates. Scoliosis was rapidly progressive and not amenable to surgical intervention. At the age of 53, he presented with an ischaemic stroke caused by a basilar artery aneurysm thrombosis. Compassionate use of tyrosine kinase inhibitors was discussed but declined by the patient.

| Patient 2
Patient 2 ( Figure 4) was born at 37 weeks gestation weighing 3.7 kg (+1.9 SD) following induction of labour for prolonged rupture of the membranes and oligohydramnios. His parents were unrelated white British and his younger sibling and two elder maternal half siblings were healthy. At 48 hours of age, he had a bilateral orchidopexy for suspected testicular torsion and was noted to have cryptorchidism.

| Patient 3
Patient 3 ( Figure 5) was born to unrelated healthy parents and had two healthy elder sisters. His mother had hypertension from 34 weeks of pregnancy and labour was induced at term. Despite a normal birth weight of 3.26 kg, he appeared extremely thin with wrinkled skin. He also had extremely pale hair and irides and diastasis recti.
He had recurrent hypoglycaemic episodes between the ages of five months and three years. Extensive metabolic investigations were unremarkable and he was diagnosed with ketotic hypoglycaemia that resolved with age. Early developmental milestones were normal.

| DISCUSSION
KOGS is an ultra-rare disorder largely underdiagnosed with only six cases reported worldwide. Although a recognisable phenotype, the majority of cases have been diagnosed following a genotype-first approach, due to lack of knowledge of the disorder. A number of key features have been identified but each reported case has expanded the spectrum, leading to a heterogeneous phenotype with constant, occasional and rare features ( Figure 6). Characteristic facial features include wide spaced eyes, downslanting palpebral fissures, wide nasal bridge and nasal base, broad nasal tip, pointed chin, prominent supraorbital ridges, underdeveloped malae, cupid bow shaped and thin upper lip, proptosis and smooth philtrum. 15 Tall stature, MRI abnormalities including white matter lesions, arachnoid cysts, Dandy-Walker malformation and hydrocephalus, abnormal cranial shape, thin fragile hyperelastic skin, scoliosis, premature ageing, lipodystrophy, sparse hair, hypotonia in infancy, delayed speech and language, intellectual disability, neurological deterioration, and myofibroma are also recognised features. 15,16 Our cases confirm that several features previously reported in only a single individual with KOGS, including camptodactyly, progressive joint contractures, widely spaced teeth, and constriction rings 7,8,15 are part of the phenotypic spectrum. We also report novel features including craniosynostosis, ocular pterygia, anterior chamber cleavage syndrome, early osteoporosis, enlarged penis, diffuse erythrosis, increased pigmentation, recurrent haematomas, predisposition to cellulitis, nail dystrophy, carpal tunnel syndrome, recurrent hypoglycaemia in infancy, muscular build, joint dislocation, and splenomegaly (Table 1). In one of our patients visual impairment resulted from KOGS-related obstructive ventriculomegaly and mid brain cysts.   24 It has been established that the KOGS-specific pathogenic variants in PDGFRB are activating mutations that activate the PI3K-AKT pathway 16 and are responsive to imatinib 25 suggesting that individuals with KOGS might also be candidates for treatment with tyrosine kinase inhibitors.
In this report, we also extend the genotype-phenotype correla-