Alternative titles; symbols
SNOMEDCT: 720812002; ORPHA: 85199;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q13.2 | CDAGS syndrome | 603116 | Autosomal recessive | 3 | RNU12 | 620204 |
A number sign (#) is used with this entry because of evidence that CDAGS syndrome (CDAGS) is caused by compound heterozygous mutation in the RNU12 gene (620204) on chromosome 22q13.
CDAGS syndrome is characterized by craniosynostosis and clavicular hypoplasia, delayed closure of the fontanel, anal and genitourinary anomalies, and skin eruption of porokeratotic lesions (Mendoza-Londono et al., 2005).
Judge et al. (1990) reported a 13-month-old boy who at birth was noted to have craniosynostosis due to fusion of the coronal and sagittal sutures, as well as hypospadias, anteriorly placed rectum, and incurving of the fourth toes bilaterally. At 1 month of age he developed a rash on his face that spread to his extremities and perineum. Examination at 6 months of age showed a symmetric nonpruritic eruption of the face, limbs, and perineum, sparing the trunk. Lesions were well-demarcated erythematous hyperkeratotic plaques with raised brown hyperpigmented margins. Other features included hypotrichosis of the scalp and eyebrows and delayed primary dentition. Biopsies at age 7 and 9 months showed epidermal changes with parakeratosis, acanthosis, and several dyskeratotic cells; another biopsy at 13 months of age showed those changes as well as a cornoid lamella and focal vacuolar degeneration of the basal layer, characteristic of porokeratosis.
Flanagan et al. (1998) reported 2 brothers with CDAGS who were later found to have mutation in the RNU12 gene; 1 of the brothers was originally described by Judge et al. (1990). Both brothers had coronal craniosynostosis, anal anomalies, and porokeratosis. 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.
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, including the family with 2 affected brothers who were previously described by Judge et al. (1990) and Flanagan et al. (1998). 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.
Taylor et al. (2013) reported a 2-year-old girl with CDAGS who was later found to have mutation in the RNU12 gene. She was developmentally delayed and had imperforate anus noted at birth as well as craniosynostosis. Skin lesions suggestive of porokeratosis developed shortly after birth on the face and extremities. Family history revealed that she had 2 similarly affected cousins.
Pastrana-Ayala et al. (2017) reported a 2-year-old Mexican girl with CDAGS who was later found to have mutation in the RNU12 gene. She exhibited brachycephaly, cleft palate, anal malformation with rectovestibular fistula, and clinodactyly of the third toe overlapping the second. At age 4 months, she developed skin lesions that began on the lower limbs and spread to the upper limbs, head, and trunk, with palmoplantar sparing. The slightly pruritic lesions were erythematous scaly nummular plaques with well-defined elevated keratotic borders. Skin biopsy showed hyperkeratosis, parakeratosis, acanthosis, and perivascular inflammatory infiltration. Dental examination showed enamel dysplasia, and she had mild bilateral neurosensory hearing loss. She also exhibited sparse scalp hair and absent eyebrows and eyelashes.
Xing et al. (2021) reported a 2-year-old Caucasian boy with CDAGS and mutation in the RNU12 gene. He was born with bilateral coronal craniosynostosis requiring surgery in the first year of life. He developed an erythematous cutaneous eruption on the face and extremities at 3 to 6 months of age that was consistent with porokeratosis. He had 2 urethral openings, and x-rays showed a hypoplastic medial right clavicle with pseudoarthrosis. Other dysmorphic features included broad forehead with metopic depression, midface hypoplasia, bilateral epicanthal folds, flat nasal bridge, short anteverted nose, deep philtrum, tented upper lip, and short neck. His scalp hair was thin and sparse, and he had no eyebrows, lower eyelashes, or hair on his extremities.
The transmission pattern of CDAGS syndrome in the families reported by Mendoza-Londono et al. (2005) was consistent with autosomal recessive inheritance.
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.
In 2 unrelated families with CDAGS, 1 of which (family 2) had been previously studied by Taylor et al. (2013), Xing et al. (2021) performed whole-exome sequencing and identified compound heterozygosity for mutations in the RNU12 gene in both probands (620204.0002-620204.0004). Sanger sequencing of the RNU12 gene in 2 more families with CDAGS, including 2 brothers (family 3) originally described by Judge et al. (1990) and Flanagan et al. (1998) and a 2-year-old Mexican girl (family 4) previously reported by Pastrana-Ayala et al. (2017), also revealed compound heterozygous mutations (620204.0002, 620204.0005, and 620204.0006). All 5 patients shared the same rare mutation in the precursor 3-prime extension of RNU12 (620204.0002) as well as another point mutation, and the mutations segregated fully with disease in each family.
Exclusion Studies
In 2 brothers with CDAGS, one of whom was originally described by Judge et al. (1990), Flanagan et al. (1998) analyzed the FGFR1 (136350), FGFR2 (176943), FGFR3 (134934), and TWIST1 (601622) genes for mutations associated with craniosynostosis, but identified no abnormalities.
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.
Flanagan, N., Boyadjiev, S. A., Harper, J., Kyne, L., Earley, M., Watson, R., Jabs, E. W., Geraghty, M. T. Familial craniosynostosis, anal anomalies, and porokeratosis: CAP syndrome. J. Med. Genet. 35: 763-766, 1998. [PubMed: 9733036] [Full Text: https://doi.org/10.1136/jmg.35.9.763]
Judge, M. R., Michaels, M., Sams, V. R., David, T. J., Harper, J. I. Disseminated porokeratosis in an infant with craniosynostosis. Brit. J. Derm. 123: 249-254, 1990. [PubMed: 2400728] [Full Text: https://doi.org/10.1111/j.1365-2133.1990.tb01855.x]
Mendoza-Londono, R., Lammer, E., Watson, R., Harper, J., Hatamochi, A., Hatamochi-Hayashi, S., Napierala, D., Hermanns, P., Collins, S., Roa, B. B., Hedge, M. R., Wakui, K., Nguyen, D., Stockton, D. W., Lee, B. Characterization of a new syndrome that associates craniosynostosis, delayed fontanel closure, parietal foramina, imperforate anus, and skin eruption: CDAGS. Am. J. Hum. Genet. 77: 161-168, 2005. [PubMed: 15924278] [Full Text: https://doi.org/10.1086/431654]
Pastrana-Ayala, R., Pena-Castro, G. L., Valencia-Herrera, A. M., Mena-Cedillos, C. A., Toussaint-Caire, S., Akaki-Carreno, Y. I., Garcia-Delgado, C., Moran-Barroso, V. F., Toledo-Bahena, M. Craniosynostosis, delayed closure of the fontanelle, anal, genitourinary, and skin abnormalities (CDAGS syndrome): first report in a Mexican patient and review of the literature. Int. J. Derm. 56: 435-439, 2017. [PubMed: 28217872] [Full Text: https://doi.org/10.1111/ijd.13504]
Taylor, A., Nguyen, R. H., Glass, D. A., II, Agim, N. G. JAAD grand rounds: annular plaques and craniosynostosis. J. Am. Acad. Derm. 68: 881-884, 2013. [PubMed: 23602181] [Full Text: https://doi.org/10.1016/j.jaad.2011.12.005]
Xing, C., Kanchwala, M., Rios, J. J., Hyatt, T., Wang, R. C., Tran, A., Dougherty, I., Tovar-Garza, A., Purnadi, C., Kumar, M. G., Berk, D., Shinawi, M., Irvine, A. D., Toledo-Bahena, M., Agim, N. G., Glass, D. A., II. Biallelic variants in RNU12 cause CDAGS syndrome. Hum. Mutat. 42: 1042-1052, 2021. [PubMed: 34085356] [Full Text: https://doi.org/10.1002/humu.24239]