Expansion of the phenotype of Kosaki overgrowth syndrome

Abstract

Skeletal overgrowth is a characteristic of several genetic disorders that are linked to specific molecular signaling cascades. Recently, we established a novel overgrowth syndrome (Kosaki overgrowth syndrome, OMIM #616592) arising from a de novo mutation in PDGFRB, that is, c.1751C>G p.(Pro584Arg). Subsequently, other investigators provided in vitro molecular evidence that this specific mutation in the juxtamembrane domain of PDGFRB causes an overgrowth phenotype and is the first gain-of-function point mutation of PDGFRB to be reported in humans. Here, we report the identification of a mutation in PDGFRB, c.1696T>C p.(Trp566Arg), in two unrelated patients with skeletal overgrowth, further confirming the existence of PDGFRB-related overgrowth syndrome arising from mutations in the juxtamembrane domain of PDGFRB. A review of all four of these patients with an overgrowth phenotype and PDGFRB mutations revealed postnatal skeletal overgrowth, premature aging, cognitive impairment, neurodegeneration, and a prominent connective tissue component to this complex phenotype. From a functional standpoint, hypermorphic mutations in PDGFRB lead to Kosaki overgrowth syndrome, infantile myofibromatosis (OMIM #228550), and Penttinen syndrome (OMIM #601812), whereas hypomorphic mutations lead to idiopathic basal ganglia calcification (OMIM #615007). In conclusion, a specific class of mutations in PDGFRB causes a clinically recognizable syndromic form of skeletal overgrowth.

Phenotype expansion and development in Kosaki overgrowth syndrome

“…We note that the only patient in the present cohort without scoliosis is aged 3 years. 4 The earliest age of onset recorded however, is 4 years (this report…”

“…Two carry a de novo PDGFRB variant, c.1751C>G p.(Pro584Arg) and two carry the c.1696T>C p.(Trp566Arg) mutation in the same juxtamembrane domain of PDGFRB. 3,4 Now, in a first male, unrelated patient of Polish descent and fifth KOGS case reported, we identify 29/34 previously reported KOGS symptoms, and document a further 24 intrinsically new phenotypic features along a developmental timeline to establish an expanded phenotype, prognosis and diagnostic window. We propose a set of core symptoms for KOGS and define KOGS-diagnostic early childhood clinical symptomology.…”

“…Table 1). InTable 1we also compare the complete clinical data and natural history documented from birth for Patient 5, to the available clinical data for the four previously reported female KOGS cases to date 3,4. This reveals three subsets of symptoms.…”

Dysregulated mesenchymal PDGFR‐β drives kidney fibrosis

“…Conversely, increased PDGFR-b signaling resulting from activating mutations, gene translocation, or increased ligand abundance is involved in the pathogenesis of malignancies, atherosclerosis, and organ fibrosis (Bonner, 2004;Andrae et al, 2008;Demoulin & Essaghir, 2014;Klinkhammer et al, 2018). Activating mutations of PDGFR-b are also found in rare human genetic syndromes (Johnston et al, 2015;Takenouchi et al, 2015;Minatogawa et al, 2017) and in different malignancies (Cheung et al, 2013;Martignetti et al, 2013;Johnston et al, 2015;Arts et al, 2016). However, consequences of increased PDGFR-b activity for kidney development are currently unknown.…”

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.…”