Division of Immunology and the Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation Brno and Medical Faculty, Masaryk University, Brno, Czechia.
J Allergy Clin Immunol. 2024 Nov;154(5):1313-1324.e7. doi: 10.1016/j.jaci.2024.08.002. Epub 2024 Aug 13.
Agammaglobulinemia due to variants in IGLL1 has traditionally been considered an exceedingly rare form of severe B-cell deficiency, with only 8 documented cases in the literature. Surprisingly, the first agammaglobulinemic patient identified by newborn screening (NBS) through quantification of kappa-deleting recombination excision circles harbored variants in IGLL1.
We comprehensively reviewed clinical and immunologic findings of patients with B-cell deficiency attributed to variants in IGLL1.
NBS programs reporting the use of kappa-deleting recombination excision circle assays, the European Society for Immunodeficiencies Registry, and authors of published reports featuring patients with B-cell deficiency linked to IGLL1 variants were contacted. Only patients with (likely) pathogenic variants, reduced CD19 counts, and no alternative diagnosis were included.
The study included 13 patients identified through NBS, 2 clinically diagnosed patients, and 2 asymptomatic siblings. All had severely reduced CD19 B cells (< 0.1 × 10/L) at first evaluation, yet subsequent follow-up assessments indicated residual immunoglobulin production. Specific antibody responses to vaccine antigens varied, with a predominant reduction observed during infancy. Clinical outcomes were favorable with IgG substitution. Two patients successfully discontinued substitution therapy without developing susceptibility to infections and while maintaining immunoglobulin levels. The pooled incidence of homozygous or compound heterozygous pathogenic IGLL1 variants identified by NBS in Austria, Czechia, and Switzerland was 1.3:100,000, almost double of X-linked agammaglobulinemia.
B-cell deficiency resulting from IGLL1 variants appears to be more prevalent than initially believed. Despite markedly low B-cell counts, the clinical course in some patients may be milder than reported in the literature so far.
由于 IGLL1 变异导致的无丙种球蛋白血症传统上被认为是一种极其罕见的严重 B 细胞缺陷形式，文献中仅记载了 8 例确诊病例。令人惊讶的是，通过对 κ 缺失重组切除环进行定量分析，首次通过新生儿筛查（NBS）发现的无丙种球蛋白血症患者携带 IGLL1 变异。
我们全面回顾了归因于 IGLL1 变异的 B 细胞缺陷患者的临床和免疫学发现。
我们联系了报告使用 κ 缺失重组切除环检测法的 NBS 项目、欧洲免疫缺陷学会注册处，以及发表的与 IGLL1 变异相关的 B 细胞缺陷患者报道的作者。仅纳入存在（可能）致病性变异、CD19 计数减少且无其他诊断的患者。
本研究纳入了通过 NBS 发现的 13 例患者、2 例临床诊断患者和 2 例无症状的同胞。所有患者初次评估时 CD19 B 细胞严重减少（<0.1×10/L），但随后的随访评估表明存在免疫球蛋白产生。针对疫苗抗原的特异性抗体反应存在差异，在婴儿期观察到主要减少。使用 IgG 替代疗法的临床结局良好。2 例患者成功停止替代治疗，而未发生感染易感性，同时维持免疫球蛋白水平。在奥地利、捷克和瑞士，通过 NBS 发现的纯合或复合杂合致病性 IGLL1 变异的总发生率为 1.3:100000，几乎是 X 连锁无丙种球蛋白血症的两倍。
由 IGLL1 变异引起的 B 细胞缺陷似乎比最初认为的更为普遍。尽管 B 细胞计数明显较低，但某些患者的临床过程可能比迄今为止文献报道的更为轻微。
