Xiong Linyan, Zhao Qin, Zhao Qian, Zhang Zhiyong, An Yunfei, Tang Xuemei, Kanegane Hirokazu, Yang Xi, Zhao Xiaodong
Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China.
National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
Front Immunol. 2025 Aug 18;16:1628507. doi: 10.3389/fimmu.2025.1628507. eCollection 2025.
UNC13D deficiency is the most common form of familial hemophagocytic lymphohistiocytosis (FHL) in Asia. Hypogammaglobulinemia is a rare phenotype observed in both patients with FHL3 and sporadic hemophagocytic lymphohistiocytosis (HLH). Our observations suggest that UNC13D deficiency with hypogammaglobulinemia presents a distinct clinical phenotype compared to other HLH patients. This finding provides valuable clinical insights and may contribute to a more comprehensive understanding of the disease, highlighting the need for further investigation into its genetic and clinical characteristics.
We retrospectively analyzed the clinical features of five patients with UNC13D deficiency with hypogammaglobulinemia at our center, along with a literature review. The clinical findings were then compared with those of sporadic HLH patients presenting with hypogammaglobulinemia.
All patients experienced respiratory infections, with two patients showing recurrent episodes. Seizures were observed in 75% of the patients. HLH-related biomarkers were present in all patients. The four patients who did not undergo allogeneic hematopoietic stem cell transplantation (HSCT), all died. Eight variant sites were identified, with 25% located in exon 9 and another 25% in exon 20. The majority (66.67%) of the variants were found in the region responsible for interaction with RAB27α. UNC13D deficiency with hypogammaglobulinemia was associated with a higher frequency of respiratory manifestations, neurological involvement, and an increased mortality rate.
Our study presents the first comprehensive description of the clinical features of UNC13D deficiency with hypogammaglobulinemia. Patients with this condition tend to exhibit more severe clinical manifestations and a poorer prognosis. Allogeneic HSCT may help mitigate immune dysregulation.
UNC13D缺乏是亚洲家族性噬血细胞性淋巴组织细胞增生症（FHL）最常见的形式。低丙种球蛋白血症是在FHL3患者和散发性噬血细胞性淋巴组织细胞增生症（HLH）患者中均观察到的罕见表型。我们的观察结果表明，伴有低丙种球蛋白血症的UNC13D缺乏与其他HLH患者相比呈现出独特的临床表型。这一发现提供了有价值的临床见解，可能有助于更全面地了解该疾病，凸显了对其遗传和临床特征进行进一步研究的必要性。
我们回顾性分析了本中心5例伴有低丙种球蛋白血症的UNC13D缺乏患者的临床特征，并进行了文献综述。然后将临床发现与伴有低丙种球蛋白血症的散发性HLH患者的临床发现进行比较。
所有患者均经历过呼吸道感染，其中2例患者有反复发作。75%的患者出现过癫痫发作。所有患者均存在HLH相关生物标志物。4例未接受异基因造血干细胞移植（HSCT）的患者均死亡。共鉴定出8个变异位点，其中25%位于外显子9，另外25%位于外显子20。大多数变异（66.67%）位于与RAB27α相互作用的区域。伴有低丙种球蛋白血症的UNC13D缺乏与更高频率的呼吸道表现、神经受累及死亡率增加相关。
我们的研究首次全面描述了伴有低丙种球蛋白血症的UNC13D缺乏的临床特征。患有这种疾病的患者往往表现出更严重的临床表现和更差的预后。异基因HSCT可能有助于减轻免疫失调。
