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Abstract：
Mulibrey nanism (MUL) is a rare disorder caused by TRIM37 gene variants characterized by growth failure, dysmorphic features, congestive heart failure (CHF), and an increased risk of Wilms\' tumor. Although immune system impairment has been documented in MUL, the underlying mechanisms remain poorly understood.
We present a case of MUL with progressive lymphopenia and review similar cases from the literature.
Our patient presented with prenatal onset growth restriction, characteristic dysmorphic features, and Wilms\' tumor. She developed progressive lymphopenia starting at 10 years of age, leading to the initiation of intravenous immunoglobulin (IVIG) replacement therapy and infection prophylaxis. Genetic analysis detected a likely pathogenic variant on the maternal allele and copy number loss on the paternal allele in TRIM37. Subsequently a cardiac magnetic resonance imaging was conducted revealing signs of pericardial constriction raising concerns for intestinal lymphatic losses. The cessation of IVIG therapy did not coincide with any increase in the rate of infections. The patient exhibited a distinct immunological profile, characterized by hypogammaglobulinemia, impaired antibody responses, and skewed T-cell subsets with an altered CD4+/CD8+ ratio, consistent with previous reports. Normal thymocyte development assessed by artificial thymic organoid platform ruled out an early hematopoietic intrinsic defect of T-cell development.
The immunological profile of MUL patients reported so far shares similarities with that described in protein-losing enteropathy secondary to CHF in Fontan circulation and primary intestinal lymphangiectasia. These similarities include hypogammaglobulinemia, significant T-cell deficiency with decreased CD4+ and CD8+ counts, altered CD4+/CD8+ ratios, and significantly modified CD4+ and CD8+ T-cell phenotypes toward effector and terminal differentiated T cells, accompanied by a loss of naïve CD45RA+ T lymphocytes. In MUL, CHF is a cardinal feature, occurring in a significant proportion of patients and influencing prognosis. Signs of CHF or constrictive pericarditis have been evident in the case reported here and in all cases of MUL with documented immune dysfunction reported so far. These observations raise intriguing connections between these conditions. However, further investigation is warranted to in-depth define the immunological defect, providing valuable insights into the pathophysiology and treatment strategies for this condition.
We present a case of MUL with progressive lymphopenia and review similar cases from the literature.
Our patient presented with prenatal onset growth restriction, characteristic dysmorphic features, and Wilms\' tumor. She developed progressive lymphopenia starting at 10 years of age, leading to the initiation of intravenous immunoglobulin (IVIG) replacement therapy and infection prophylaxis. Genetic analysis detected a likely pathogenic variant on the maternal allele and copy number loss on the paternal allele in TRIM37. Subsequently a cardiac magnetic resonance imaging was conducted revealing signs of pericardial constriction raising concerns for intestinal lymphatic losses. The cessation of IVIG therapy did not coincide with any increase in the rate of infections. The patient exhibited a distinct immunological profile, characterized by hypogammaglobulinemia, impaired antibody responses, and skewed T-cell subsets with an altered CD4+/CD8+ ratio, consistent with previous reports. Normal thymocyte development assessed by artificial thymic organoid platform ruled out an early hematopoietic intrinsic defect of T-cell development.
The immunological profile of MUL patients reported so far shares similarities with that described in protein-losing enteropathy secondary to CHF in Fontan circulation and primary intestinal lymphangiectasia. These similarities include hypogammaglobulinemia, significant T-cell deficiency with decreased CD4+ and CD8+ counts, altered CD4+/CD8+ ratios, and significantly modified CD4+ and CD8+ T-cell phenotypes toward effector and terminal differentiated T cells, accompanied by a loss of naïve CD45RA+ T lymphocytes. In MUL, CHF is a cardinal feature, occurring in a significant proportion of patients and influencing prognosis. Signs of CHF or constrictive pericarditis have been evident in the case reported here and in all cases of MUL with documented immune dysfunction reported so far. These observations raise intriguing connections between these conditions. However, further investigation is warranted to in-depth define the immunological defect, providing valuable insights into the pathophysiology and treatment strategies for this condition.
摘要：
■Mulibreynanism（MUL）是由TRIM37基因变异引起的一种罕见疾病，其特征是生长失败，变形特征，充血性心力衰竭（CHF），和Wilms\'肿瘤的风险增加。尽管MUL已经记录了免疫系统损伤，潜在的机制仍然知之甚少。
■我们介绍一例MUL伴进行性淋巴细胞减少的病例，并从文献中回顾类似病例。
■我们的患者出现产前生长受限，特征性的异形特征，和威尔姆斯肿瘤。她从10岁开始出现进行性淋巴细胞减少症，导致开始静脉注射免疫球蛋白（IVIG）替代疗法和感染预防。遗传分析在TRIM37中检测到母系等位基因上可能的致病变异和父系等位基因上的拷贝数丢失。随后进行了心脏磁共振成像，发现心包收缩的迹象引起了对肠道淋巴丢失的担忧。IVIG治疗的停止与感染率的任何增加都不一致。患者表现出明显的免疫学特征，以低丙种球蛋白血症为特征，受损的抗体反应，和扭曲的T细胞亚群与改变的CD4+/CD8+比率，与以前的报告一致。通过人工胸腺类器官平台评估的正常胸腺细胞发育排除了T细胞发育的早期造血内在缺陷。
■迄今为止报道的MUL患者的免疫学特征与Fontan循环中CHF继发的蛋白质丢失性肠病和原发性肠淋巴管扩张症相似。这些相似之处包括低丙种球蛋白血症，显著的T细胞缺乏与减少的CD4+和CD8+计数，CD4+/CD8+比值改变，和显著修饰的CD4+和CD8+T细胞表型对效应和终末分化的T细胞，伴有幼稚CD45RA+T淋巴细胞的损失。在MUL,CHF是一个主要特征，发生在相当比例的患者中并影响预后。在本文报道的病例中以及迄今为止报道的所有MUL病例中，CHF或缩窄性心包炎的体征都很明显。这些观察结果在这些条件之间引起了有趣的联系。然而,进一步的调查是必要的，以深入界定免疫缺陷，为这种疾病的病理生理学和治疗策略提供有价值的见解。
■我们介绍一例MUL伴进行性淋巴细胞减少的病例，并从文献中回顾类似病例。
■我们的患者出现产前生长受限，特征性的异形特征，和威尔姆斯肿瘤。她从10岁开始出现进行性淋巴细胞减少症，导致开始静脉注射免疫球蛋白（IVIG）替代疗法和感染预防。遗传分析在TRIM37中检测到母系等位基因上可能的致病变异和父系等位基因上的拷贝数丢失。随后进行了心脏磁共振成像，发现心包收缩的迹象引起了对肠道淋巴丢失的担忧。IVIG治疗的停止与感染率的任何增加都不一致。患者表现出明显的免疫学特征，以低丙种球蛋白血症为特征，受损的抗体反应，和扭曲的T细胞亚群与改变的CD4+/CD8+比率，与以前的报告一致。通过人工胸腺类器官平台评估的正常胸腺细胞发育排除了T细胞发育的早期造血内在缺陷。
■迄今为止报道的MUL患者的免疫学特征与Fontan循环中CHF继发的蛋白质丢失性肠病和原发性肠淋巴管扩张症相似。这些相似之处包括低丙种球蛋白血症，显著的T细胞缺乏与减少的CD4+和CD8+计数，CD4+/CD8+比值改变，和显著修饰的CD4+和CD8+T细胞表型对效应和终末分化的T细胞，伴有幼稚CD45RA+T淋巴细胞的损失。在MUL,CHF是一个主要特征，发生在相当比例的患者中并影响预后。在本文报道的病例中以及迄今为止报道的所有MUL病例中，CHF或缩窄性心包炎的体征都很明显。这些观察结果在这些条件之间引起了有趣的联系。然而,进一步的调查是必要的，以深入界定免疫缺陷，为这种疾病的病理生理学和治疗策略提供有价值的见解。
