Maroufi Seyed F, Shaka Zoha, Mojtabavi Helia, Sadeghalvad Mona, Rayzan Elham, Sedighi Iraj, Shahkarami Sepideh, Najafi Mehri, Rohlfs Meino, Klein Christoph, Rezaei Nima
Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
Endocr Metab Immune Disord Drug Targets. 2021;21(9):1660-1668. doi: 10.2174/1871530321666210616110631.
Severe congenital neutropenia (SCN4) caused by mutations in glucose-6- phosphatase catalytic subunit 3 (G6PC3) is characterized by recurrent infections due to severe neutropenia, may be accompanied by other extra-hematopoietic manifestations; including structural heart defects, urogenital abnormalities, prominent superficial venous markings, growth retention, and inflammatory bowel diseases with rare incidence. The homozygous or compound heterozygous mutations of G6PC3 are responsible for most cases of autosomal recessive SCN4. Herein, we present two cases of SCN4 affected by novel mutations in the G6PC3, in addition to a summarized list of variants in G6PC3 gene that are reported as pathogenic and related to the SCN4 phenotype.
Herein, we present two cases of SCN4; the first case was a three-months old boy with severe neutropenia and prior history of hospitalization due to umbilical separation, umbilical herniation, omphalitis, and pyelonephritis; and the second case was an eight-year-old with a history of neutropenia, recurrent and severe episodes of intractable diarrhea, refractory rectovaginal and rectoperineal fistula, congenital inguinal hernia, and ASD type 2. Whole exome sequencing was performed for both cases, which revealed two novel homozygous missense mutations in G6PC3 that were predicted to be deleterious; c.337G>A, p. Gly113Arg in the first case and c.479C>T; P. Ser160Leu in the second case. To our knowledge, both of these two mutations have not been reported in the G6PDC3 gene.
In patients with severe neutropenia with varying extra hematopoietic syndrome, mutation of G6PC3 should be suspected after ruling out other mutations related to neutropenia. This study pointed toward novel G6PC3 mutations that should be considered in order to diagnose patients with severe congenital neutropenia.
由葡萄糖-6-磷酸酶催化亚基3（G6PC3）突变引起的严重先天性中性粒细胞减少症（SCN4）的特征是由于严重中性粒细胞减少导致反复感染，可能伴有其他造血外表现，包括结构性心脏缺陷、泌尿生殖系统异常、明显的浅表静脉纹、生长发育迟缓以及罕见的炎症性肠病。G6PC3的纯合或复合杂合突变是大多数常染色体隐性SCN4病例的病因。在此，我们报告两例受G6PC3新突变影响的SCN4病例，并总结了已报道的与SCN4表型相关的G6PC3基因致病性变体列表。
在此，我们报告两例SCN4病例；第一例是一名三个月大的男婴，患有严重中性粒细胞减少症，既往有因脐部分离、脐疝、脐炎和肾盂肾炎住院的病史；第二例是一名八岁儿童，有中性粒细胞减少症病史，反复出现严重的顽固性腹泻、难治性直肠阴道和直肠会阴瘘、先天性腹股沟疝以及2型房间隔缺损。对两例患者均进行了全外显子组测序，结果显示G6PC3中有两个新的纯合错义突变，预计具有有害性；第一例为c.337G>A，p.Gly113Arg，第二例为c.479C>T；P.Ser160Leu。据我们所知，这两个突变在G6PDC3基因中均未被报道。
对于患有不同造血外综合征的严重中性粒细胞减少症患者，在排除其他与中性粒细胞减少相关的突变后，应怀疑G6PC3突变。本研究指出了在诊断严重先天性中性粒细胞减少症患者时应考虑的新的G6PC3突变。
