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Expansion of the phenotype of Kosaki overgrowth syndrome
Author(s) -
Minatogawa Mari,
Takenouchi Toshiki,
Tsuyusaki Yu,
Iwasaki Fuminori,
Uehara Tomoko,
Kurosawa Kenji,
Kosaki Kenjiro,
Curry Cynthia J.
Publication year - 2017
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.38310
Subject(s) - pdgfrb , phenotype , mutation , biology , genetics , cancer research , medicine , pathology , gene
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.