A novel multi-organ disease that is fatal in early childhood was identified in three patients from two non-consanguineous families. These children were born asymptomatic but at the age of 2 months they manifested progressive multi-organ symptoms resembling no previously known disease. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. In the affected children, neuropathology revealed increased angiomatosis-like leptomeningeal, cortical and superficial white matter vascularisation and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver. A whole-exome sequencing of the two unrelated families with the affected children revealed the transmission of two heterozygous variants in the NHL repeat-containing protein 2 (NHLRC2); an amino acid substitution p.Asp148Tyr and a frameshift 2-bp deletion p.Arg201GlyfsTer6. NHLRC2 is highly conserved and expressed in multiple organs and its function is unknown. It contains a thioredoxin-like domain; however, an insulin turbidity assay on human recombinant NHLRC2 showed no thioredoxin activity. In patient-derived fibroblasts, NHLRC2 levels were low, and only p.Asp148Tyr was expressed. Therefore, the allele with the frameshift deletion is likely non-functional. Development of the Nhlrc2 null mouse strain stalled before the morula stage. Morpholino knockdown of nhlrc2 in zebrafish embryos affected the integrity of cells in the midbrain region. This is the first description of a fatal, early-onset disease; we have named it FINCA disease based on the combination of pathological features that include fibrosis, neurodegeneration, and cerebral angiomatosis.

在来自两个非近亲家庭的三名患者中鉴定出了一种在儿童早期致命的新型多器官疾病。这些孩子出生时没有症状，但在2个月大时，他们表现出进行性多器官症状，类似于以前未知的疾病。主要临床特征包括进行性脑肺症状，吸收不良，进行性生长衰竭，反复感染，慢性溶血性贫血和短暂性肝功能障碍。在患病的儿童中，神经病理学检查显示血管瘤病样的软脑膜，皮质和浅表白质血管化和充血，液泡变性和白质中髓磷脂丢失以及神经元变性增加。在肺部观察到间质纤维化和先前未描述的肉芽肿样病变。肝肿大 在肝脏中检测到脂肪变性和胶原蛋白积聚。对与患病儿童有关的两个无关家庭的全外显子测序揭示了含有NHL重复序列的蛋白2（NHLRC2）中两个杂合变异体的传播。氨基酸取代p.Asp148Tyr和移码2 bp缺失p.Arg201GlyfsTer6。NHLRC2是高度保守的并在多个器官中表达，其功能尚不清楚。它含有硫氧还蛋白样结构域；但是，在人重组NHLRC2上进行的胰岛素浊度分析没有显示硫氧还蛋白的活性。在患者来源的成纤维细胞中，NHLRC2水平较低，仅表达p.Asp148Tyr。因此，具有移码缺失的等位基因可能是无功能的。的发展 对与患病儿童有关的两个无关家庭的全外显子测序揭示了含有NHL重复序列的蛋白2（NHLRC2）中两个杂合变异体的传播。氨基酸取代p.Asp148Tyr和移码2 bp缺失p.Arg201GlyfsTer6。NHLRC2是高度保守的并在多个器官中表达，其功能尚不清楚。它含有硫氧还蛋白样结构域；但是，在人重组NHLRC2上进行的胰岛素浊度分析没有显示硫氧还蛋白的活性。在患者来源的成纤维细胞中，NHLRC2水平较低，仅表达p.Asp148Tyr。因此，具有移码缺失的等位基因可能是无功能的。的发展 对与患病儿童有关的两个无关家庭的全外显子测序揭示了含有NHL重复序列的蛋白2（NHLRC2）中两个杂合变异体的传播。氨基酸取代p.Asp148Tyr和移码2 bp缺失p.Arg201GlyfsTer6。NHLRC2是高度保守的并在多个器官中表达，其功能尚不清楚。它含有硫氧还蛋白样结构域；但是，在人重组NHLRC2上进行的胰岛素浊度分析没有显示硫氧还蛋白的活性。在患者来源的成纤维细胞中，NHLRC2水平较低，仅表达p.Asp148Tyr。因此，具有移码缺失的等位基因可能是无功能的。的发展 Asp148Tyr和移码2 bp缺失p.Arg201GlyfsTer6。NHLRC2是高度保守的并在多个器官中表达，其功能尚不清楚。它含有硫氧还蛋白样结构域；但是，在人重组NHLRC2上进行的胰岛素浊度分析没有显示硫氧还蛋白的活性。在患者来源的成纤维细胞中，NHLRC2水平较低，仅表达p.Asp148Tyr。因此，具有移码缺失的等位基因可能是无功能的。的发展 Asp148Tyr和移码2 bp缺失p.Arg201GlyfsTer6。NHLRC2是高度保守的并在多个器官中表达，其功能尚不清楚。它含有硫氧还蛋白样结构域；但是，在人重组NHLRC2上进行的胰岛素浊度分析没有显示硫氧还蛋白的活性。在患者来源的成纤维细胞中，NHLRC2水平较低，仅表达p.Asp148Tyr。因此，具有移码缺失的等位基因可能是无功能的。的发展 具有移码缺失的等位基因可能是无功能的。的发展 具有移码缺失的等位基因可能是无功能的。的发展Nhlrc2空小鼠品系在桑ula期之前就停止了。斑马鱼胚胎中nhlrc2的吗啉敲低影响了中脑区域细胞的完整性。这是对致命的，早期发作的疾病的首次描述；我们根据包括纤维化，神经退行性变和脑血管瘤等病理特征的组合将其命名为FINCA疾病。