Alternative titles; symbols
SNOMEDCT: 783099001; ORPHA: 420741; DO: 0090113;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q29 | RIDDLE syndrome | 611943 | Autosomal recessive | 3 | RNF168 | 612688 |
A number sign (#) is used with this entry because of evidence that RIDDLE syndrome (RIDL) is caused by homozygous or compound heterozygous mutation in the RNF168 gene (612688) on chromosome 3q29.
RIDDLE is an acronym for the major features of this syndrome: radiosensitivity, immunodeficiency, dysmorphic facies, and learning difficulties (Stewart et al., 2007).
Stewart et al. (2007) described a male Caucasian patient with a novel syndrome of increased radiosensitivity, immunodeficiency, mild motor control and learning difficulties, facial dysmorphism, and short stature. They termed the disorder RIDDLE syndrome. The patient's parents were nonconsanguineous, and there was no family history of immunodeficiency. At age 1 year, the patient's IgG and IgM levels were below normal limits. His B cells produced no detectable IgG in vitro. The patient was treated with intramuscular IgG from age 3 years, and he was switched to subcutaneous Ig at age 22 years. The patient's cells lacked the ability to recruit TP53BP1 (605230) to sites of DNA double-strand breaks, resulting in hypersensitivity to ionizing radiation, cell cycle checkpoint abnormalities, and impaired end joining in the recombined switch regions. No mutations were identified in TP53BP1 or other genes that regulate ionizing radiation-induced TP53BP1 foci formation. Stewart et al. (2007) concluded that a double-strand break repair protein exists upstream of TP53BP1 that contributes to normal development of the immune system. Stewart et al. (2009) noted the pathologic similarities to the ataxia-telangiectasia syndrome (AT; 208900).
Devgan et al. (2011) reported a Turkish man, born of unrelated parents, who presented with short stature and mild ataxia at age 16 years. He had microcephaly but displayed displayed normal intelligence. Other features included conjunctival telangiectasia, recurrent sinus infections, decreased serum IgA, and increased alpha-fetoprotein. At age 29 years, the patient presented with progressive pulmonary failure that resulted in death at age 30. Pulmonary work-up revealed restrictive lung disease with interstitial thickening, bronchial telangiectasia, and possible pulmonary fibrosis. Patient cells were radiosensitive and showed defects in the repair of DNA double-strand breakage.
The transmission pattern of RIDL in the family reported by Stewart et al. (2009) was consistent with autosomal recessive inheritance.
In the patient with RIDDLE syndrome reported by Stewart et al. (2007), Stewart et al. (2009) identified compound heterozygosity for truncating mutations in the RNF168 gene (612688.0001 and 612688.0002). The authors noted that the patient's father, who was heterozygous for 1 of the mutations, had developed chronic B-cell leukemia, suggesting that RNF168 may also act as a tumor suppressor gene.
In a Turkish man with a phenotype consistent with RIDDLE syndrome, Devgan et al. (2011) identified a homozygous truncating mutation in the RNF168 gene (612688.0003). Ectopic expression of RNF168 in patient cells restored the DNA repair defect. Devgan et al. (2011) noted some phenotypic similarities to chromosome 3q29 deletion syndrome (609425).
Devgan, S. S., Sanal, O., Doil, C., Nakamura, K., Nahas, S. A., Pettijohn, K., Bartek, J., Lukas, C., Lukas, J., Gatti, R. A. Homozygous deficiency of ubiquitin-ligase ring-finger protein RNF168 mimics the radiosensitivity syndrome of ataxia-telangiectasia. Cell Death Diff. 18: 1500-1506, 2011. [PubMed: 21394101] [Full Text: https://doi.org/10.1038/cdd.2011.18]
Stewart, G. S., Panier, S., Townsend, K., Al-Hakim, A. K., Kolas, N. K., Miller, E. S., Nakada, S., Ylanko, J., Olivarius, S., Mendez, M., Oldreive, C., Wildenhain, J., Tagliaferro, A., Pelletier, L., Taubenheim, N., Durandy, A., Byrd, P. J., Stankovic, T., Taylor, A. M. R., Durocher, D. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell 136: 420-434, 2009. [PubMed: 19203578] [Full Text: https://doi.org/10.1016/j.cell.2008.12.042]
Stewart, G. S., Stankovic, T., Byrd, P. J., Wechsler, T., Miller, E. S., Huissoon, A., Drayson, M. T., West, S. C., Elledge, S. J., Taylor, A. M. R. RIDDLE immunodeficiency syndrome is linked to defects in 53BP1-mediated DNA damage signaling. Proc. Nat. Acad. Sci. 104: 16910-16915, 2007. [PubMed: 17940005] [Full Text: https://doi.org/10.1073/pnas.0708408104]