BACKGROUND The features of Shwachman-Diamond syndrome (SDS) include exocrine pancreatic insufficiency, skeletal abnormalities and bone marrow dysfunction;an often overlooked feature is hepatic involvement. CASE SUMMAR...BACKGROUND The features of Shwachman-Diamond syndrome (SDS) include exocrine pancreatic insufficiency, skeletal abnormalities and bone marrow dysfunction;an often overlooked feature is hepatic involvement. CASE SUMMARY We report a child who initially presented with failure to thrive and mildly elevated transaminase levels and was determined to have pancreatic insufficiency due to SDS. During follow-up he had persistently elevated transaminase levels and developed hepatosplenomegaly. An investigation was performed to determine the etiology of ongoing liver injury, including a liver biopsy which revealed hepatic cirrhosis. CONCLUSION Cirrhosis has rarely been reported with SDS. While many of the hepatic disorders associated with SDS improve with age, there are rare exceptions with serious implications for long-term outcome.展开更多
Shwachman-Diamond syndrome （SDS） is a multi-system disorder characterized by bone marrow failure, pancreatic insufficiency, skeletal abnormalities, and increased risk of leukemic transformation. Most patients with S...Shwachman-Diamond syndrome （SDS） is a multi-system disorder characterized by bone marrow failure, pancreatic insufficiency, skeletal abnormalities, and increased risk of leukemic transformation. Most patients with SDS contain mutations in the Shwachman- Bodian-Diamond syndrome gene （SBDS）, encoding a highly conserved protein that has been implicated in ribosome biogenesis. Emerging evidence also suggests a distinct role of SBDS beyond protein translation. Using the yeast model of SDS, we examined the underlying mechanisms that cause cells lacking Sdolp, the yeast SBDS ortholog, to exhibit reduced tolerance to various stress conditions. Our analysis indicates that the environmental stress response （ESR）, heat shock response （HSR）, and endoplasmic reticulum unfolded protein response （UPR） of sdolA cells are functional and that defects in these pathways do not produce the phenotypes observed in sdolh yeast. Depletion of mitochondlial DNA （mtDNA） was observed in sdolh cells, and this is a probable cause of the mitochondrial insufficiency in SDS. Prior disruption of POR1, encoding the mitochondrial voltage dependent anion channel （VDAC）, abrogated the effects of SD01 deletion and substantially restored resistance to environmental stressors and protected against damage to mtDNA. Conversely, wild-type cells over-expressing POR1 exhibited growth impairment and increased stress sensitivity similar to that seen in sdolA cells. Overall, our results suggest that specific VDAC inhibitors may have therapeutic benefits for SDS patients.展开更多
目的探索我国儿童Shwachman-Diamond综合征(SDS)的临床表型及基因型特征,以供早期诊断参考。方法以"Shwachman-Diamond综合征""SDS""SBDS基因""遗传性骨髓衰竭"等为关键词,设定检索年限为2002...目的探索我国儿童Shwachman-Diamond综合征(SDS)的临床表型及基因型特征,以供早期诊断参考。方法以"Shwachman-Diamond综合征""SDS""SBDS基因""遗传性骨髓衰竭"等为关键词,设定检索年限为2002年1月至2022年10月,检索在万方数据和中国知网数据库相关文献。同时以"Shwachman-Diamond syndrome"为关键词,检索2002年1月至2022年10月内Web of Science和美国医学文摘数据库(PubMed)的文献报道病例,包含上海市同济医院治疗的1例SDS患儿,共计44例作为研究对象。参照《国际SDS诊断标准》作为诊断标准,应用χ2检验和t检验统计学分析,以系统回顾的方式进行循证研究,对资料完整的44例临床数据进行病例系列研究,归纳我国儿童SDS流行病学、临床特征和早期诊断要点,并与国际病例资料进行对比。结果中国儿童SDS主要特征归纳如下:(1)男女比例大约为1.3∶1,起病中位年龄为3个月,诊断中位年龄为14个月,相对起病年龄滞后。(2)常见首发症状为胰腺消化酶缺乏(31.8%)和中性粒细胞减少伴感染(31.8%)。国际共识所示SDS三类主要病变发生率分别为血细胞减少(95.4%),胰腺病变(72.7%)和骨骼异常(40.9%)。(3)SDS常见致病SBDS基因变异位点为c.258+2T>C和c.183184TA>CT,其表型与临床表现无明显相关性(P>0.05)。(4)与国际报道比较,中国儿童SDS三系减少的发生率与部分亚洲国家及北美地区均存在一定差异(P<0.05),基因变异也存在一定种族差异。结论儿童SDS起病年龄早,个体差异明显。需加强病例报道和资料汇总,以提高临床对于SDS的认识和早期诊断率,以利及时实施有效临床干预措施。展开更多
文摘BACKGROUND The features of Shwachman-Diamond syndrome (SDS) include exocrine pancreatic insufficiency, skeletal abnormalities and bone marrow dysfunction;an often overlooked feature is hepatic involvement. CASE SUMMARY We report a child who initially presented with failure to thrive and mildly elevated transaminase levels and was determined to have pancreatic insufficiency due to SDS. During follow-up he had persistently elevated transaminase levels and developed hepatosplenomegaly. An investigation was performed to determine the etiology of ongoing liver injury, including a liver biopsy which revealed hepatic cirrhosis. CONCLUSION Cirrhosis has rarely been reported with SDS. While many of the hepatic disorders associated with SDS improve with age, there are rare exceptions with serious implications for long-term outcome.
基金supported by the Faculty of Science,Mahidol University(ANJ)
文摘Shwachman-Diamond syndrome （SDS） is a multi-system disorder characterized by bone marrow failure, pancreatic insufficiency, skeletal abnormalities, and increased risk of leukemic transformation. Most patients with SDS contain mutations in the Shwachman- Bodian-Diamond syndrome gene （SBDS）, encoding a highly conserved protein that has been implicated in ribosome biogenesis. Emerging evidence also suggests a distinct role of SBDS beyond protein translation. Using the yeast model of SDS, we examined the underlying mechanisms that cause cells lacking Sdolp, the yeast SBDS ortholog, to exhibit reduced tolerance to various stress conditions. Our analysis indicates that the environmental stress response （ESR）, heat shock response （HSR）, and endoplasmic reticulum unfolded protein response （UPR） of sdolA cells are functional and that defects in these pathways do not produce the phenotypes observed in sdolh yeast. Depletion of mitochondlial DNA （mtDNA） was observed in sdolh cells, and this is a probable cause of the mitochondrial insufficiency in SDS. Prior disruption of POR1, encoding the mitochondrial voltage dependent anion channel （VDAC）, abrogated the effects of SD01 deletion and substantially restored resistance to environmental stressors and protected against damage to mtDNA. Conversely, wild-type cells over-expressing POR1 exhibited growth impairment and increased stress sensitivity similar to that seen in sdolA cells. Overall, our results suggest that specific VDAC inhibitors may have therapeutic benefits for SDS patients.
文摘目的探索我国儿童Shwachman-Diamond综合征(SDS)的临床表型及基因型特征,以供早期诊断参考。方法以"Shwachman-Diamond综合征""SDS""SBDS基因""遗传性骨髓衰竭"等为关键词,设定检索年限为2002年1月至2022年10月,检索在万方数据和中国知网数据库相关文献。同时以"Shwachman-Diamond syndrome"为关键词,检索2002年1月至2022年10月内Web of Science和美国医学文摘数据库(PubMed)的文献报道病例,包含上海市同济医院治疗的1例SDS患儿,共计44例作为研究对象。参照《国际SDS诊断标准》作为诊断标准,应用χ2检验和t检验统计学分析,以系统回顾的方式进行循证研究,对资料完整的44例临床数据进行病例系列研究,归纳我国儿童SDS流行病学、临床特征和早期诊断要点,并与国际病例资料进行对比。结果中国儿童SDS主要特征归纳如下:(1)男女比例大约为1.3∶1,起病中位年龄为3个月,诊断中位年龄为14个月,相对起病年龄滞后。(2)常见首发症状为胰腺消化酶缺乏(31.8%)和中性粒细胞减少伴感染(31.8%)。国际共识所示SDS三类主要病变发生率分别为血细胞减少(95.4%),胰腺病变(72.7%)和骨骼异常(40.9%)。(3)SDS常见致病SBDS基因变异位点为c.258+2T>C和c.183184TA>CT,其表型与临床表现无明显相关性(P>0.05)。(4)与国际报道比较,中国儿童SDS三系减少的发生率与部分亚洲国家及北美地区均存在一定差异(P<0.05),基因变异也存在一定种族差异。结论儿童SDS起病年龄早,个体差异明显。需加强病例报道和资料汇总,以提高临床对于SDS的认识和早期诊断率,以利及时实施有效临床干预措施。
