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 ... 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).
In the patient with RIDDLE syndrome reported by Stewart et al. (2007), Stewart et al. (2009) identified compound heterozygosity for 2 truncating mutations in the RNF168 gene (612688.0001 and 612688.0002). The authors noted that the patient's father, who ... In the patient with RIDDLE syndrome reported by Stewart et al. (2007), Stewart et al. (2009) identified compound heterozygosity for 2 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.