title: Characterization of a new syndrome that associates craniosynostosis, delayed fontanel closure, parietal foramina, imperforate anus, and skin eruption: CDAGS.
abstract: We describe the clinical characterization, molecular analyses, and genetic mapping of a distinct genetic condition characterized by craniosynostosis, delayed closure of the fontanel, cranial defects, clavicular hypoplasia, anal and genitourinary malformations, and skin eruption. We have identified seven patients with this phenotype in four families from different geographic regions and ethnic backgrounds. This is an autosomal recessive condition that brings together apparently opposing pathophysiologic and developmental processes, including accelerated suture closure and delayed ossification. Selected candidate genes--including RUNX2, CBFB, MSX2, ALX4, TWIST1, and RECQL4--were screened for mutations, by direct sequencing of their coding regions, and for microdeletions, by fluorescent in situ hybridization. No mutations or microdeletions were detected in any of the genes analyzed. A genomewide screen yielded the maximum estimated LOD score of +2.38 for markers D22S283 and D22S274 on chromosome 22q12-q13. We hypothesize that the gene defect in this condition causes novel context-dependent dysregulation of multiple signaling pathways, including RUNX2, during osteoblast differentiation and craniofacial morphogenesis.
authors.affiliation: Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030, USA. blee@bcm.tmc.edu
authors.forename: Roberto
authors.initials: R
authors.lastname: Mendoza-Londono
authors.forename: Edward
authors.initials: E
authors.lastname: Lammer
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Watson
authors.forename: John
authors.initials: J
authors.lastname: Harper
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hatamochi
authors.forename: Saori
authors.initials: S
authors.lastname: Hatamochi-Hayashi
authors.forename: Dobrawa
authors.initials: D
authors.lastname: Napierala
authors.forename: Pia
authors.initials: P
authors.lastname: Hermanns
authors.forename: Sinead
authors.initials: S
authors.lastname: Collins
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Roa
authors.forename: Madhuri R
authors.initials: MR
authors.lastname: Hedge
authors.forename: Keiko
authors.initials: K
authors.lastname: Wakui
authors.forename: Diep
authors.initials: D
authors.lastname: Nguyen
authors.forename: David W
authors.initials: DW
authors.lastname: Stockton
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D001006:Anus, Imperforate / Q000235:genetics; D002874:Chromosome Mapping; D003393:Cranial Sutures / Q000002:abnormalities; D003398:Craniosynostoses / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008126:Lod Score; D008297:Male; D010294:Parietal Bone / Q000002:abnormalities; D010375:Pedigree; D012873:Skin Diseases, Genetic / Q000235:genetics; D013577:Syndrome