Deniskin Roman, Sasa Ghadir S, Nandiwada Sarada L, Rider Nicholas L
Department of Pediatrics (Pediatrician Scientist Training and Development Program), Houston, TX, United States.
Section of Hematology and Oncology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, United States.
Front Pediatr. 2019 Jan 18;6:390. doi: 10.3389/fped.2018.00390. eCollection 2018.
Fanconi anemia (FA) is an inherited bone marrow failure and cancer predisposition disorder due to mutations in DNA repair pathways proteins (FANC). The dysfunctional proteins are unable to repair DNA breaks and cause genomic instability. Mutations in many of the 19 genes are well characterized biochemically and clinically. Little is known about the gene which acts downstream of the FA-core proteins. Here we report a 11-year-old female previously diagnosed with FA and bone marrow failure. Gene sequencing demonstrated deletion of exons 2-18 and a pathologic missense mutation (c. 2444G>A, p. Arg815Gln) in (Chr3). Her medical history is significant for an episode of pneumococcal sepsis despite adequate vaccination. Repeated blood samples and immunophenotyping demonstrated severe lymphopenia. There were markedly low CD4 T-cell counts with a low CD4:CD8 ratio. Changes in the composition of the B-cell population included significantly diminished absolute total B-cells, and decreased mature cells. There was no immunogenic response to vaccination against . The NK-cell count was unaffected and demonstrated normal spontaneous and stimulated cytotoxic response. Bone marrow analysis demonstrated hypocellularity without dysplasia. The clinical and laboratory features are suggestive of combined immune deficiency. FANCD2 may be involved in the transition of immature B and T cells to mature cells, a process that requires substantial DNA recombination not observed in NK cells. Additional genetic and biochemical evaluation is needed to further characterize the novel genetic and clinical findings.
范可尼贫血（FA）是一种由于DNA修复途径蛋白（FANC）突变导致的遗传性骨髓衰竭和癌症易感性疾病。功能失调的蛋白无法修复DNA断裂并导致基因组不稳定。19个基因中的许多基因的突变在生化和临床方面都有很好的特征描述。对于在FA核心蛋白下游起作用的基因了解甚少。在此，我们报告一名先前被诊断为FA和骨髓衰竭的11岁女性。基因测序显示第3号染色体上的基因外显子2 - 18缺失以及一个病理性错义突变（c. 2444G>A，p. Arg815Gln）。尽管接种了足够的疫苗，但她有肺炎球菌败血症发作的病史。重复的血液样本和免疫表型分析显示严重淋巴细胞减少。CD4 T细胞计数显著降低，CD4:CD8比值低。B细胞群体组成的变化包括绝对总B细胞显著减少以及成熟细胞减少。针对[疫苗名称未给出]的疫苗接种没有免疫原性反应。NK细胞计数未受影响，并且显示出正常的自发和刺激细胞毒性反应。骨髓分析显示细胞减少但无发育异常。临床和实验室特征提示存在联合免疫缺陷。FANCD2可能参与未成熟B细胞和T细胞向成熟细胞转变的过程，这一过程需要大量DNA重组，而NK细胞中未观察到这种重组。需要进一步的基因和生化评估来进一步明确这些新的基因和临床发现。
