PDF(Pubmed)
Abstract：
We report the case of a 1-week-old male born full-term, who had two inconclusive severe combined immunodeficiency (SCID) newborn screens and developed scalp cellulitis and Escherichia coli bacteremia. He did not pass early confirmatory hearing screens. Initial blood counts and lymphocyte flow cytometry revealed profound neutropenia and lymphopenia with a T-/B-/NK- phenotype. Red blood cell adenosine deaminase 1 activity was within normal limits. A presumptive diagnosis of reticular dysgenesis was considered. Granulocyte colony-stimulating factor was started, but there was no improvement in neutrophil counts. Subsequent lymphocyte flow cytometry at around 4 weeks of age demonstrated an increase in T-, B- and NK-cell numbers, eliminating suspicion for SCID and raising concern for congenital neutropenia and bone marrow failure syndromes. Genetic testing revealed a novel variant in RAC2 [c.181C>A (p.Gln61Lys)] (Q61K). RAC2, a Ras-related GTPase, is the dominant RAC protein expressed in hematopoietic cells and is involved with various downstream immune-mediated responses. Pathogenic RAC2 variants show significant phenotypic heterogeneity (spanning from neutrophil defects to combined immunodeficiency) across dominant, constitutively activating, dominant activating, dominant negative, and autosomal recessive subtypes. Given the identification of a novel variant, functional testing was pursued to evaluate aberrant pathways described in other RAC2 pathogenic variants. In comparison to wild-type RAC2, the Q61K variant supported elevated superoxide production under both basal and PMA-stimulated conditions, increased PAK1 binding, and enhanced plasma membrane ruffling, consistent with other dominant, constitutively active mutations. This case highlights the diagnostic challenge associated with genetic variants identified via next-generation sequencing panels and the importance of functional assays to confirm variant pathogenicity.
摘要：
我们报告了一个1周大的男性足月出生的病例，有两次不确定的严重联合免疫缺陷（SCID）新生儿筛查，并发展为头皮蜂窝织炎和大肠杆菌菌血症。他没有通过早期确认的听力屏幕。初始血细胞计数和淋巴细胞流式细胞术显示严重的中性粒细胞减少症和淋巴细胞减少症，具有T-/B-/NK-表型。红细胞腺苷脱氨酶1活性在正常范围内。考虑了网状发育不全的推定诊断。启动粒细胞集落刺激因子，但中性粒细胞计数没有改善.随后在4周龄左右的淋巴细胞流式细胞术显示T增加，B细胞和NK细胞数量，消除对SCID的怀疑，并提高对先天性中性粒细胞减少症和骨髓衰竭综合征的关注。基因检测揭示了RAC2中的一种新变体[c.181C>A（p。Gln61Lys）]（Q61K）。RAC2，一种与Ras相关的GTPase，是在造血细胞中表达的显性RAC蛋白,并且与各种下游免疫介导的应答有关。致病性RAC2变异体显示显著的表型异质性（从中性粒细胞缺陷到联合免疫缺陷），组成型激活，显性激活，显性消极，和常染色体隐性亚型。鉴于新变体的鉴定，我们进行了功能测试,以评估其他RAC2致病变种中描述的异常途径.与野生型RAC2相比，Q61K变体在基础和PMA刺激条件下都支持超氧化物产量提高，PAK1结合增加，增强的质膜起皱，与其他占优势的，组成型活性突变。该病例强调了与通过下一代测序小组鉴定的遗传变异相关的诊断挑战，以及功能测定确认变异致病性的重要性。
