Novel Overgrowth Syndrome Phenotype Due to Recurrent De Novo PDGFRB Mutation

A Point Mutation in PDGFRB Causes Autosomal-Dominant Penttinen Syndrome

“…We conclude that Penttinen syndrome is allelic to IBGC4, infantile myofibromatosis, and the syndrome described by Takenouchi et al 17 The four individuals described here had proptosis, a convex nasal bridge, underdeveloped cheekbones, delayed closure of the fontanels, delayed tooth eruption, progressive cutaneous atrophy and hypertrophic skin lesions, and skeletal changes, including acro-osteolysis (Table 1). It is striking to us that the hypertrophic skin changes in the four individuals described here are not myofibromas; that, although there are CNS findings in these individuals, they do not include basal ganglia calcifications; and that, whereas the individuals described by Takenouchi et al 17 were described as having thin and fragile skin, their facial features, skeletal changes, and cognitive-psychiatric features were distinct from the individuals described here. These four conditions show very little phenotypic overlap with each other, and we conclude that the disorder manifested in the four individuals described here is distinct and should be called Penttinen syndrome.…”

“…7,13,14 Predicted gain-of-function mutations have been associated with autosomal-dominant infantile myofibromatosis (MIM: 228550), 15,16 which has no overlapping features with IBGC4. Recently, Takenouchi et al 17 described two individuals with a distinctive phenotype of skeletal overgrowth, dysmorphic features, and neurobehavioral manifestations caused by a recurrent, apparently de novo c.1751C>G p.Pro584Arg variant in PDGFRB. We conclude that Penttinen syndrome is allelic to IBGC4, infantile myofibromatosis, and the syndrome described by Takenouchi et al 17 The four individuals described here had proptosis, a convex nasal bridge, underdeveloped cheekbones, delayed closure of the fontanels, delayed tooth eruption, progressive cutaneous atrophy and hypertrophic skin lesions, and skeletal changes, including acro-osteolysis (Table 1).…”

“…Recently, Takenouchi et al 17 described two individuals with a distinctive phenotype of skeletal overgrowth, dysmorphic features, and neurobehavioral manifestations caused by a recurrent, apparently de novo c.1751C>G p.Pro584Arg variant in PDGFRB. We conclude that Penttinen syndrome is allelic to IBGC4, infantile myofibromatosis, and the syndrome described by Takenouchi et al 17 The four individuals described here had proptosis, a convex nasal bridge, underdeveloped cheekbones, delayed closure of the fontanels, delayed tooth eruption, progressive cutaneous atrophy and hypertrophic skin lesions, and skeletal changes, including acro-osteolysis (Table 1). It is striking to us that the hypertrophic skin changes in the four individuals described here are not myofibromas; that, although there are CNS findings in these individuals, they do not include basal ganglia calcifications; and that, whereas the individuals described by Takenouchi et al 17 were described as having thin and fragile skin, their facial features, skeletal changes, and cognitive-psychiatric features were distinct from the individuals described here.…”

PDGFRβ regulates craniofacial development through homodimers and functional heterodimers with PDGFRα

“…Moreover, single-nucleotide polymorphisms in the PDGFC regulatory region that repress transcriptional activity of the promoter are associated with cleft lip and palate (Choi et al 2009). In the case of PDGFRB, heterozygous missense mutations that modify amino acids in the juxtamembrane and tyrosine kinase domains cause Kosaki overgrowth syndrome (OMIM 616592) and Penttinen syndrome (OMIM 601812), respectively, both of which are characterized by facial dysmorphism and fragile skin, among other defects (Johnston et al 2015;Takenouchi et al 2015). We now show that PDGFRβ also plays a role during craniofacial development in mice and that ablation of the gene encoding this RTK in the NCC lineage can lead to cartilage, bone, and skin phenotypes in mice that emulate those found in human patients with PDGFRB mutations.…”

A Clinical Review of Generalized Overgrowth Syndromes in the Era of Massively Parallel Sequencing

“…Facial features included sparse hair, prominent forehead, proptosis, downslanting palpebral fissures, wide nasal bridge, thin upper lip, and a pointed chin. Lipodystrophy and premature aging appearance was also noted [Takenouchi et al, 2015;Minatogawa et al, 2017]. The head circumferences of the patients were not included in the research article, and this condition may be better classified as a genetic syndrome associated with tall stature and postnatal bony overgrowth.…”