Expansion of the phenotype of Kosaki overgrowth syndrome
2017
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 mutationin
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
PDGFRBcauses an overgrowth phenotype and is the first gain-of-
function pointmutation of
PDGFRBto 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 syndromearising from mutations in the juxtamembrane domain of
PDGFRB. A review of all four of these patients with an overgrowth phenotype and
PDGFRBmutations 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
PDGFRBlead 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
PDGFRBcauses a clinically recognizable syndromic form of skeletal overgrowth.
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