Advances in genetic sequencing have increased recognition of inborn errors of immunity (IEI), more than a quarter of which present with noninfectious features, including malignancy. Malignancy represents the initial presentation in 0.8-0.9% of cases in the U.S. and European IEI registries, most commonly in ataxia-telangiectasia, activated PI3K-delta syndrome, and DOCK8 deficiency. In addition, the incidence of cancer is 1.8-1.9 times higher in IEI patients at ages 40-50 years. The most common malignancies presenting or complicating IEI are of the lymphoreticular system: lymphomas, leukemias, malignant histiocytosis, and thymus tumors.
We retrospectively described IEI cases in which the diagnosis of IEI was established after malignancy diagnosis in the Pediatric Immunology Division IEI registry at Queen Rania Children’s Hospital in Jordan over a 10-year period (2015-2025).
Six patients (three males, three females) presented with malignancy at a median age (interquartile range) of 33 (35.5) months and were diagnosed with IEI at 113 (71.8) months, with a median diagnostic delay of 65 (78.5) months. These cases accounted for 1.86% of the 321 IEI patients diagnosed during the study period. Two patients had homozygous pathogenic DCLRE1C mutations and presented with lymphoma, including EBV-driven large B cell lymphoma. Other malignancies included hepatoblastoma in ataxia-telangiectasia, gallbladder adenocarcinoma in ARHGEF1 deficiency, Rosai–Dorfman disease in SLC29A3 deficiency, and Hodgkin lymphoma in RASGRP1 deficiency. IEI diagnosis was prompted by family history of DCLRE1C at the time of presentation, autoimmune cytopenias, EBV-driven lymphoproliferation, encephalopathy with elevated alpha-fetoprotein, while recurrent infections with bronchiectasis were reported in two patients (33%). Two patients (33%) died: the ataxia-telangiectasia and the H syndrome cases.
We have reported a higher rate of malignancy in IEI in Jordan than in the U.S. and European registries, with a diversity of malignancy types and IEI categories. Malignancy in the pediatric age group needs to be systematically evaluated for red flags of IEI, particularly noninfectious manifestations.
