Characterization of a new syndrome that associates craniosynostosis, delayed fontanel closure, parietal foramina, imperforate anus, and skin eruption: CDAGS.
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.
Mendoza-Londono
Roberto
R
Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030, USA. blee@bcm.tmc.edu
Lammer
Edward
E
Watson
Rosemarie
R
Harper
John
J
Hatamochi
Atsushi
A
Hatamochi-Hayashi
Saori
S
Napierala
Dobrawa
D
Hermanns
Pia
P
Collins
Sinead
S
Roa
Benjamin B
BB
Hedge
Madhuri R
MR
Wakui
Keiko
K
Nguyen
Diep
D
Stockton
David W
DW
Lee
Brendan
B
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