Cdags Syndrome

Clinical Features

Mendoza-Londono et al. (2005) described the clinical characterization, molecular analysis, and genetic mapping of a distinct genetic disorder, designated by the acronym CDAGS, which summarizes its most prominent features: 'C' stands for craniosynostosis and clavicular hypoplasia; 'D' stands for delayed closure of the fontanel, cranial defects, and, in some patients, deafness; 'A' stands for anal anomalies, including anterior placement of the anus and imperforate anus; 'G' stands for genitourinary malformations; and 'S' stands for skin eruption, which, in some patients, had been classified as porokeratosis. They identified the CDAGS phenotype in 4 families from different geographic regions and ethnic backgrounds. The families displayed an autosomal recessive pattern of inheritance. The craniofacial component of CDAGS overlapped with some of the features seen in cleidocranial dysplasia (CCD; 119600), an autosomal dominant disorder characterized by hypoplastic or absent clavicles, delayed closure of the cranial sutures and fontanels, dental anomalies, and delayed skeletal development.

One of the families studied by Mendoza-Londono et al. (2005) had been described by Flanagan et al. (1998), who reported coronal craniosynostosis, anal anomalies, and porokeratosis in 2 male sibs. One of the brothers had anterior imperforate anus, and the other had anterior placement of the anus. A third male sib and the parents were phenotypically normal. Flanagan et al. (1998) used the acronym CAP to designate the constellation of findings and suggested autosomal recessive inheritance, although X-linked inheritance or gonadal mosaicism could not be excluded.

Mapping

Mendoza-Londono et al. (2005) isolated DNA from all affected individuals and first-degree relatives and performed a genomewide screen with 400 markers. Analysis of the genotype data yielded a maximum estimated lod score of 2.38 for markers D22S283 and D22S274 on 22q12-q13. Haplotype analysis narrowed the region of interest to a 34-cM interval between D22S1163 and D22S1170.

Molecular Genetics

In affected members of the family originally reported by them, Flanagan et al. (1998) analyzed the FGFR1 (136350), FGFR2 (176943), FGFR3 (134934), and TWIST1 (601622) genes for mutations associated with craniosynostosis; no abnormalities were found.

To identify the molecular basis of the CDAGS phenotype, Mendoza-Londono et al. (2005) initially undertook a candidate gene approach. Because CDAGS shares multiple features with CCD, the authors considered RUNX2 (600211) and its coactivator CBFB (121360) as attractive candidates. They examined these and several other candidate genes, screening for mutations by direct sequencing of the coding regions and for microdeletions by fluorescence in situ hybridization, with negative results. Mendoza-Londono et al. (2005) hypothesized that the gene defect in CDAGS causes novel context-dependent dysregulation of multiple signaling pathways, including that of RUNX2, during osteoblast differentiation and craniofacial morphogenesis.