New clinical aspects of immune dysregulation in atypical severe combined immunodeficiency due to mutations in IL2RG and RAG1

Abstract

Abstract Purpose The mild form of severe combined immunodeficiency disease (SCID) is called atypical SCID resulting from hypomorphic mutations in SCID-causing genes. We characterize the new clinical aspects in four atypical SCID children. Methods Four pediatric patients diagnosed with atypical SCID between March 2014 and March 2022 in Beijing Children’s Hospital were retrospectively analyzed. Results The onset of age was 1 ~ 6.5 years old. Interstitial lung disease (ILD) was present in three patients, and it was the leading presentation in one of them. Diffuse alveolar hemorrhage (DAH) was a leading and single manifestation in one patient with mutation in RAG1. Atypical membranous nephropathy (AMN) was detected in one patient with RAG1 mutations and with congenital adrenal hyperplasia due to CYP21A2 mutations. Other clinical manifestations included chronic eczema, colitis, thrombocytopenia, bilateral renal calculi, and respiratory infections and bronchiectasis. Two boys had hemizygous mutations in IL2RG; instead of the typical lymphocytic changes of T−B+NKlow, one had the TlowBlowNK+ phenotype with higher serum IgE, and the other had the TlowB+NK+ phenotype with higher serum immunoglobulins. Two patients had compound heterozygous mutations in RAG1, instead of the typical lymphocytic changes of T−B−NK+, one had the TlowBlowNKlow phenotype, and the other had the TlowBlowNK+ phenotype with lower serum IgA. Conclusions The clinical manifestations are highly variable in atypical SCID, being a challenge of early diagnosis and appropriate treatment to clinicians. We report here the new clinical aspects of ILD and DAH as the leading manifestations, and an atypical SCID patient with AMN and proteinuria.