PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014, Oulu, Finland.
Department of Children and Adolescents, Oulu University Hospital, PO Box 23, 90029, Oulu, Finland.
Acta Neuropathol. 2018 May;135(5):727-742. doi: 10.1007/s00401-018-1817-z. Epub 2018 Feb 8.
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.
我们在两个非近亲家族的 3 位患者中发现了一种新的多器官疾病，该疾病在儿童早期致命。这些患儿出生时无症状，但在 2 个月大时出现进行性多器官症状，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、进行性生长发育不良、反复感染、慢性溶血性贫血和短暂肝功能障碍。在受影响的儿童中，神经病理学显示出增加的类血管瘤样软脑膜、皮质和浅层白质血管化和充血、空泡变性和白质髓鞘丢失以及神经元变性。肺部观察到间质纤维化和以前未描述的肉芽肿样病变。肝脏肿大、脂肪变性和胶原积累。对受影响儿童的两个无关家庭进行全外显子组测序显示 NHL 重复包含蛋白 2（NHLRC2）中存在两个杂合变体的传递；一个氨基酸取代 p.Asp148Tyr 和 2 个碱基的框移缺失 p.Arg201GlyfsTer6。NHLRC2 高度保守，在多个器官中表达，其功能未知。它包含一个硫氧还蛋白样结构域；然而，人类重组 NHLRC2 的胰岛素浊度测定显示没有硫氧还蛋白活性。在患者来源的成纤维细胞中，NHLRC2 水平较低，仅表达 p.Asp148Tyr。因此，具有框移缺失的等位基因可能无功能。Nhlrc2 基因敲除小鼠品系的发育在桑椹胚阶段停滞不前。斑马鱼胚胎中 nhlrc2 的 morpholino 敲低影响中脑区域细胞的完整性。这是对一种致命性、早发性疾病的首次描述；我们根据纤维化、神经退行性变和脑血管瘤样的病理特征将其命名为 FINCA 疾病。
