title: Large fontanelles are a shared feature of haploinsufficiency of RUNX2 and its co-activator CBFB.
abstract: CBFB at 16q22 heterodimerizes with either RUNX2 (also known as CBFA1) or RUNX1 (CBFA2) to activate the transcription of downstream molecules. RUNX2 regulates osteoblast differentiation and chondrocyte maturation and its haploinsufficiency leads to cleidocranial dysplasia, characterized large fontanelles, hypoplasia or aplasia of the clavicles, hypoplasia of the distal phalanges, and a wide pubic symphysis. Complete loss of Runx1 or Cbfb in mice is lethal because of the absence of fetal liver hematopoiesis. Fetal rescue in Cbfb(-/-) mice by providing the Cbfb functions in the hematopoietic progenitors leads to wide fontanelle and delayed chondrocyte maturation, presumably resulting from the incomplete function of the transcriptional pathway mediated by the Cbfb-Runx2 heterodimer. The present report describes a patient with a small deletion of chromosome 16q22.1 encompassing CBFB. Skeletal abnormalities included a widely open fontanelle, multiple wormian bones along the sagittal suture, hypoplasia of the distal phalanges, and mildly shortened clavicles. G-banding analysis revealed a shortening of the 16q22.1 band. A fluorescence in situ hybridization analysis, using the BAC probe spanning the CBFB locus at 16q22.1, revealed that the CBFB probe hybridized to only one of the two homologous chromosome 16 regions. Array-comparative genomic hybridization analysis revealed that the deletion spans 1.2 megabases. In reviewing eight previously reported cases of 16q interstitial deletions involving band q22, large cranial sutures were noted in all but one case. Considering the phenotypic similarity of the 16q22 deletion case and Cbfb(-/-) mice rescued for hematopoiesis and the consistency of the phenotype among 16q22 deletion cases, we suggest that the common phenotypic feature of the 16q22 deletion, large fontanelles, can be attributed to a haploinsufficiency of CBFB.
authors.affiliation: Department of Neurology, Tokyo Metropolitan Kiyose Children's Hospital, Tokyo, Japan.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Goto
authors.forename: Michihiko
authors.initials: M
authors.lastname: Aramaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshihashi
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Takao
authors.initials: T
authors.lastname: Takahashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishii
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Fukushima
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kosaki
mesh_terms: D000818:Animals; D002871:Chromosome Banding; D002872:Chromosome Deletion; D002885:Chromosomes, Human, Pair 16; D050659:Core Binding Factor Alpha 1 Subunit; D050658:Core Binding Factor beta Subunit; D003388:Cranial Fossa, Posterior / Q000002:abnormalities* / Q000000981:diagnostic imaging; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D007621:Karyotyping; D008297:Male; D051379:Mice; D011859:Radiography; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C493692:CBFB protein, human; C493693:Cbfb protein, mouse; D050659:Core Binding Factor Alpha 1 Subunit; D050658:Core Binding Factor beta Subunit; D004268:DNA-Binding Proteins; C493709:RUNX2 protein, human; C493716:Runx2 protein, mouse; D050656:Transcription Factor AP-2; D014157:Transcription Factors