Hematologic abnormalities in Shwachman Diamond syndrome: lack of genotype-phenotype relationship
Hematologic abnormalities in Shwachman Diamond syndrome: lack of genotype-phenotype relationship
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DOI：
10.1182/blood-2004-11-4371
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发表时间：
2005-07-01
期刊：
影响因子：
20.3
通讯作者：
Hennekam, RCM
中科院分区：
文献类型：
--
作者：
Kuijpers, TW;Alders, M;Hennekam, RCM
Shwachman-Diamond综合征（SIDS）是一种常染色体隐性遗传疾病，以身材矮小、胰腺外分泌功能不全和血液学缺陷为特征。对23例临床SIDS患者中的20例进行了致病SBDS基因测序。在75%的患者中发现SBDS基因突变，其中11例患者相同。随时间推移测定所有3种谱系的血液学参数，如中性粒细胞绝对计数（ANC）、粒细胞功能以及来自造血祖细胞的红系和髓系集落形成（红系爆发形成单位[BFU-E]和粒细胞-单核细胞集落形成单位[CFU-GM]）、胎儿血红蛋白（HbF）百分比和血小板计数。在没有细胞凋亡的情况下，43%的患者出现持续性中性粒细胞减少，与趋化性缺陷（65%）或感染率无关。无论体内ANC如何，在所有检测的SIDS患者中均观察到CFU-GM异常（14/14），而BFU-E较少受影响（9/14）。在19例无骨髓增生异常的患者中，5例发生细胞遗传学畸变。1例患儿在异基因骨髓移植过程中死亡。总之，中性粒细胞减少和趋化性缺陷不会导致SDS中的严重临床感染。所有受试患者的CFU-GM均受损。从SBDS序列数据中，我们得出结论，在遗传学证实的SDS患者中，SDS的基因型-表型关系在临床和血液学方面不存在。
Shwachman-Diamond syndrome (SIDS) is an autosomal-recessive disorder characterized by short stature, exocrine pancreatic insufficiency, and hematologic defects. The causative SBDS gene was sequenced in 20 of 23 unrelated patients with clinical SIDS. Mutations in the SBDS gene were found in 75 %, being identical in 11 patients. Hematologic parameters for all 3 lineages were determined over time such as absolute neutrophil counts (ANCs), granulocyte functions, and erythroid and myeloid colony formation (erythroid burst-forming unit [BFU-E] and granulocyte-monocyte colony-forming unit [CFU-GM]) from hematopoietic progenitor cells, percentage of fetal hemoglobin (HbF), and platelet counts. Persistent neutropenia was present in 43 % in the absence of apoptosis and unrelated to chemotaxis defects (in 65 %) or infection rate. Irrespective of the ANC in vivo, abnormal CFU-GM was observed in all patients with SIDS tested (14 of 14), whereas BFU-E was less often affected (9 of 14). Cytogenetic aberrations occurred in 5 of 19 patients in the absence of myelodysplasia. One child died during allogeneic bone marrow transplantation. In conclusion, neutropenia and defective chemotaxis did not result in severe clinical infection in SDS. CFU-GMs were impaired in all patients tested. From the SBDS sequence data, we conclude that in patients with genetically proven SDS a genotype-phenotype relationship in SDS does not exist in clinical and hematologic terms.