A Chinese adolescent girl with Fechtner-like syndrome

We describe a 15-y-old girl with Fechtner-like syndrome, who is the first Chinese reported to have this rare syndrome. She presented with left homonymous hemianopia and neuroimaging revealed haemorrhage in both parietal and occipital lobes. Peripheral blood smear showed macrothrombocytopenia and intracytoplasmic inclusion bodies inside leucocytes. Thrombocytopenia and proteinuria responded to intravenous immunoglobulin and pulsed methylprednisolone. This case illustrates that life-threatening haemorrhage can occur in patients with Fechtner syndrome. Although there was no effective treatment reported in the literature, high dose steroid and immunoglobulin seemed to be useful in our patient. Our patient also had nephritic-nephrotic syndrome with renal insufficiency, which is unusual in adolescent female patients.     

Fechtner综合征异常家系的临床与分子缺陷

  目的  分析一先天性血小板减少症家系的临床、实验室特点, 并探讨其分子发病机制。  方法  收集该家系成员的临床资料, 采集先证者及其家系成员的静脉血, 分别进行全自动及人工血小板计数; 显微镜下观察血小板形态; 流式细胞术分析血小板膜蛋白; 透射电镜观察中性粒细胞胞浆包涵体。聚合酶链反应扩增非肌性肌球蛋白重链9基因(non-muscle myosin heavy chain9gene, MYH9)的40个外显子, 分析PCR产物的核苷酸序列, 并直接测序确定突变位点。  结果  镜下观察外周血涂片巨大血小板占90%以上, 血小板膜糖蛋白(CD41、CD61、CD42a、CD42b)均在正常范围内, 血小板功能正常; 中性粒细胞胞浆透射电镜可见无包膜分隔的包涵体, MYH9基因38号外显子第5521位核苷酸存在G→A杂合突变(GAG→AAG), 从而导致其编码的非肌性肌球蛋白重链A(NMMHC2A)第1841位谷氨酸变为赖氨酸, 正常对照及该家系正常者未见此突变。  结论  MYH9基因点突变并伴有血小板减少及巨大血小板是Fechtner综合征的主要特征。     

End-stage renal disease in two pediatric patients with Fechtner syndrome

Fechtner syndrome, a disease in the spectrum of the hereditary nephridites, is a macrothrombocytopenia associated with sensorineural hearing loss, cataracts, nephritis, and characteristic leukocyte inclusions. Renal biopsy findings are consistent with those of Alport syndrome, and the associated renal disease is said to be unusual before mid to late adulthood. Here, we review the available literature on this disease and report two African-American pediatric patients with Fechtner syndrome who rapidly progressed to end-stage renal disease during adolescence. We conclude that chronic renal failure can occur at a young age in patients with Fechtner syndrome, with a possible relation to race/ethnicity. Fechtner syndrome, or other variants of Alport syndrome, need to be considered in patients presenting with proteinuria and thrombocytopenia. Received: 13 July 1998 / Revised: 2 June 1999 / Accepted: 3 June 1999     

Fechtner综合征肾脏病理特点及机制探讨

目的 研究Fechtner综合征先证者肾脏病改变特点并探讨其发病机制。 方法 采用HE染色、免疫组化、免疫荧光和电镜等方法对Fechtner综合征患者的肾活检组织进行研究。 结果 免疫组化结果显示在足细胞和远曲小管上皮，非肌性肌球蛋白重链IIA（NMMHC-IIA）有高表达，近曲小管刷状缘有微弱表达。与正常肾组织相比，患者NMMHC-IIA在硬化的肾小球足细胞的表达减少。免疫荧光结果提示患者肾小球有明显的NMMHC-IIA沉积；足细胞特异性抗体标记结果显示NMMHC-IIA主要沉积在患者的足细胞；电镜显示足突部分融合并伴微绒毛形成。 结论 突变的NMMHC-IIA沉积在肾小球足细胞，足突部分融合伴微绒毛形成影响了足细胞的功能,导致了Fechtner综合征肾脏病变的发生。     

Identification of six novel MYH9 mutations and genotype–phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions

The autosomal dominant macrothrombocytopenia with leukocyte inclusions, May-Hegglin anomaly (MHA), Sebastian syndrome (SBS), and Fechtner syndrome (FTNS), are rare platelet disorders characterized by a triad of giant platelets, thrombocytopenia, and characteristic Döhle body-like leukocyte inclusions. The locus for these disorders was previously mapped on chromosome 22q12.3–q13.2 and the disease gene was recently identified as MYH9, the gene encoding the nonmuscle myosin heavy chain-A. To elucidate the spectrum of MYH9 mutations responsible for the disorders and to investigate genotype–phenotype correlation, we examined MYH9 mutations in an additional 11 families and 3 sporadic patients with the disorders from Japan, Korea, and China. All 14 patients had heterozygous MYH9 mutations, including three known mutations and six novel mutations (three missense and three deletion mutations). Two cases had Alport manifestations including deafness, nephritis, and cataracts and had R1165C and E1841K mutations, respectively. However, taken together with three previous reports, including ours, the data do not show clear phenotype–genotype relationships. Thus, MHA, SBS, and FTNS appear to represent a class of allelic disorders with variable phenotypic diversity.     

一种非肌性肌球蛋白重链9基因突变相关疾病——Fechtner综合征一例报告并文献复习

目的 提高对Fechtner综合征(FTNS)的认识.方法 报告1例FTNS患者的临床和实验室检查资料及其家系调查,包括外周血和骨髓涂片的细胞形态学检查(瑞特-姬姆萨染色).结果 患者外周血涂片和骨髓穿刺涂片中均发现巨大血小板、血小板减少和粒细胞内存在包涵体(D(o)hle样小体).同时患者还有肾脏损害、感音性失聪以及玻璃体病变.经家系调查发现此病例有家族遗传倾向.结论 该病例具有巨大血小板、血小板减少、粒细胞内包涵体和FTNS的典型临床表现,综合各种检查结果和临床表现,FTNS的诊断成立.

Abstract：

Objective To improve the recognition of Fechtner syndrome. Methods The clinical and laboratory data and family survey of a patient with Fechtner' s syndrom was reported. Results and conclusion Giant platelets, thrombocytopenia and characteristic granulocyte inclusion bodies (D(o)hle-like bodies) were found in both peripheral blood and bonemarrow smears of the patient. Clinically the patient had renal damage, nervous deafness, and vitreous lesions. There was a family genetic tendency on family survey the diagnosis of Fechtner syndrome is established.     

Fechtner综合征的非肌性肌球蛋白重链ⅡA的表达与功能研究

本研究探讨对非肌性肌球蛋白ⅡA的表达和功能，以阐明MYH9综合征肾脏病变和中性粒细胞包涵体形成的机制。采用半定量Westem—blot检测中性粒细胞非肌性肌球蛋白ⅡA的表达；以胚肾细胞（HEK-293）为研究对象对ⅡA、ⅡB之间的相互作用进行了探讨；RT-PCR法检测HEK-293细胞中非肌性肌球蛋白ⅡA、ⅡB的表达，并对其进行了免疫共沉淀的研究。结果显示：先证者中性粒细胞ⅡA／β-actin比值为（0.35±0．12），较正常对照中性粒细胞ⅡA／β-actin的比值（0．87±0．18）明显减少（P〈0．01）。非肌性肌球蛋白ⅡA、非肌性肌球蛋白ⅡB在HEK-293细胞中均有较高的表达；免疫共沉淀分析表明，非肌性肌球蛋白ⅡA和非肌性肌球蛋白ⅡB均有表达，而阴性对照两者均无表达。结论：非肌性肌球蛋白ⅡA的负显性效应导致了中性粒细胞包涵体的产生。ⅡA和ⅡB有明显的相互作用，ⅡB至少是部分补偿了Fechtner综合征突变的ⅡA蛋白的作用并延缓了组织的功能障碍。     

一例Fechtner综合征临床与分子缺陷研究——附文献复习

目的对1例Fechtner综合征先证者及其家系进行临床与实验室研究并检测非肌性肌球蛋白重链9基因（MYH9）突变。方法采用瑞特染色观察先证者及其家系患者的外周血涂片血小板和中性粒细胞的特殊形态；透射电镜观察先证者血小板及中性粒细胞的超微结构。从先证者及其家系成员外周血白细胞中提取基因组DNA，PCR扩增MYH9的40个外显子及侧翼内含子序列，检测其基因突变。结果该家系中Fechtner综合征患者表现为血小板减少、巨大血小板、中性粒细胞包涵体，伴或不伴遗传性肾炎。先证者及其家系患病成员的MYH9改变为外显子40第5981位核苷酸C-T杂合改变，使第1933位密码子CGA（编码Arg）突变为终止密码TGA。结论国内首次报道Fechtner综合征家系。MYH9（外显子40）R1933X杂合改变是导致Fechtner综合征的原因。