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Heterozygous activating missense variants of PDGFRBare associated with the phenotype of Kosaki overgrowth syndrome (KOGS). Here, we present a family including a father and 2 siblings with a novel variant, c.2567A>T (p.Asn856Ile), localized in the cytoplasmic tyrosine kinase domain, exhibiting a KOGS phenotype. The coarsening of the facial features, enlargement of the hands/feet, and progressive scoliosis started to appear after an average age of 6. There were no signs of thin/fragile skin, premature aging appearance, myofibroma, white matter findings, and intellectual disability in any of them. Corneal pterygium and evidence of cerebral vasculopathy were only detected in the father. One sibling exhibited café-au-lait spots. Posterior fossa enlargement was revealed only in one sibling. KOGS is an extremely rare overgrowth syndrome. No familial cases of KOGS have been reported so far. Hereby, we demonstrated that the features of KOGS can show mild intrafamilial variability, and the risk of vascular complications may arise with age.

BackgroundPseudodiastrophic dysplasia (PDD) is a severe skeletal dysplasia associated with prenatal manifestation and early lethality. Clinically, PDD is classified as a ‘dysplasia with multiple joint dislocations’; however, the molecular aetiology of the disorder is currently unknown.MethodsWhole exome sequencing (WES) was performed on three patients from two unrelated families, clinically diagnosed with PDD, in order to identify the underlying genetic cause. The functional effects of the identified variants were characterised using primary cells and human cell-based overexpression assays.ResultsWES resulted in the identification of biallelic variants in the established skeletal dysplasia genes, B3GAT3(family 1) and CANT1(family 2). Mutations in these genes have previously been reported to cause ‘multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects’ (‘JDSCD’; B3GAT3) and Desbuquois dysplasia 1 (CANT1), disorders in the same nosological group as PDD. Follow-up of the B3GAT3variants demonstrated significantly reduced B3GAT3/GlcAT-I expression. Downstream in vitrofunctional analysis revealed abolished biosynthesis of glycosaminoglycan side chains on proteoglycans. Functional evaluation of the CANT1variant showed impaired nucleotidase activity, which results in inhibition of glycosaminoglycan synthesis through accumulation of uridine diphosphate.ConclusionFor the families described in this study, the PDD phenotype was caused by mutations in the known skeletal dysplasia genes B3GAT3and CANT1, demonstrating the advantage of genomic analyses in delineating the molecular diagnosis of skeletal dysplasias. This finding expands the phenotypic spectrum of B3GAT3-related and CANT1-related skeletal dysplasias to include PDD and highlights the significant phenotypic overlap of conditions within the proteoglycan biosynthesis pathway.

Primary systemic carnitine deficiency is caused by homozygous or compound heterozygous mutation in the SLC22A5 gene on chromosome 5q31. The most common presentations are in infancy and early childhood with either metabolic decompensation or cardiac and myopathic manifestations. We report a case of 9-year-old boy with dysmorphic appearance and hypertrophic cardiomyopathy. Tandem MS spectrometry analysis was compatible with carnitine uptake defect (CUD). His sister had died due to sudden infant death at 19 months. His second 4-year-old sister’s echocardiographic examination revealed hypertrophic cardiomyopathy, also suffering from easy fatigability. Her tandem MS spectrometry analyses resulted in CUD. We sequenced all the exons of the SLC22A5 gene encoding the high affinity carnitine transporter OCTN2 in the DNA. And one new mutation (c.1427T>G → p.Leu476Arg) was found in the boy and his sister in homozygous form, leading to the synthesis of an altered protein which causes CUD. The parent’s molecular diagnosis supported the carrier status. In order to explore the genetic background of the patient’s dysmorphic appearance, an array-CGH analysis was performed that revealed nine copy number variations only. Here we report a novel SLC22A5 mutation with the novel hallmark of its association with dysmorphologic feature.