Phenotype expansion and development in Kosaki overgrowth syndrome

Abstract

We expand the Kosaki overgrowth syndrome (KOGS) phenotype by over 70% to include 24 unreported KOGS symptoms, in a first male patient, the third overall associated with the PDGFRB c.1751C>G p.(Pro584Arg) mutation. Eighteen of these symptoms are unique to our patient, the remaining six are shared with other patients. Of the 24 unreported features overall, 6 show marked phenotype evolution and varying time of onset. The triangular face detected at 14 months and long palpebral fissures with lateral ectropion at 4 years are present in other members of the cohort. The remaining 4 are unique to Patient 5: pronounced macrocephaly from birth, increasingly triangular anterior skull from 14 months, camptodactyly, emerging at 4 years and worsening joint contractures from 6 years. Compilation of all new symptoms reported here with published clinical data further identifies at least 18 clinical parameters common to all cases to date, encompassing both known KOGS‐associated PDGFRB mutations. We therefore propose a set of 18 core KOGS symptoms, with 16 present in early childhood. These results should also impact diagnostic/prognostic scope, intervention and outcome potential for KOGS patients, particularly for developmentally progressive conditions such as scoliosis and myofibroma.

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

“…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).…”

“…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 .…”

Constitutive activation of the PI3K‐AKT pathway and cardiovascular abnormalities in an individual with Kosaki overgrowth syndrome

“…In humans, germline activating heterozygous PDGFRB mutations are known to cause different phenotypes: infantile myofibromatosis (MIM 228550), premature aging syndrome, Penttinen type (MIM 601812), and Kosaki overgrowth syndrome (KOGS, MIM 616592; Arts et al, ). Two different point substitutions (p.Pro584Arg and p.Trp566Arg) located in the juxtamembrane domain of PDGFRB have been found in the five previously reported cases of KOGS, a recently described overgrowth syndrome characterized by distinctive facial features, brain white matter lesions, and developmental delay (Gawlinski et al, ; Minatogawa et al, ; Takenouchi et al, ). Of interest, other findings such as hyperextensible and fragile skin, abnormal scarring, and a constellation of musculoskeletal features have been reported indicating an overlap with other connective tissue disorders.…”

A tyrosine kinase-activating variant Asn666Ser in PDGFRB causes a progeria-like condition in the severe end of Penttinen syndrome

“…So far, PDGFRB is the only of the two PDGF receptors where variants have been linked to congenital disease. Missense variants in PDGFRB have been associated with idiopathic basal ganglia calcifications (OMIM#615007; Leu658Pro and Arg987Trp) [6], infantile myofibromatosis (OMIM#228550; Arg561Cys, Pro660Thr and Asn666Lys) [7][8][9], Penttinen-type premature aging syndrome (OMIM#601812; Val665Ala) [10][11][12], Kosaki overgrowth syndrome (OMIM#616592; Pro584Arg and Trp566Arg) [13][14][15], and was recently found (Asn666His) in a single patient with Penttinen-overlapping features (hemangioma, craniosynostosis, intracranial cysts, gingival hypertrophy, acro-osteolysis, contractures and carpal tunnel syndrome) [16]. PDGFR targeted tyrosine kinase inhibitor treatment has been effective in two patients with germline activating PDGFRB variants; one a Penttinen-syndrome like patient with Asn666His [16], the other a child with infantile myofibromatosis and germline Arg681Cys [17].…”