目的探讨1例KRAS基因变异致Noonan综合征3型的临床特征和基因变异情况,为该病诊断提供参考。方法选择2024年8月在东营市人民医院就诊的1例15岁2个月的Noonan综合征3型男性患者。采用回顾性研究方法,收集患者的相关临床资料,对患者及其...目的探讨1例KRAS基因变异致Noonan综合征3型的临床特征和基因变异情况,为该病诊断提供参考。方法选择2024年8月在东营市人民医院就诊的1例15岁2个月的Noonan综合征3型男性患者。采用回顾性研究方法,收集患者的相关临床资料,对患者及其父母外周血样进行全外显子测序,对候选变异进行Sanger测序验证和生物信息学分析。根据美国医学遗传学与基因学学会(American College of Medical Genetics and Genomic,ACMG)制定的《遗传变异分类标准与指南》,对该变异进行致病性评级。结果患者临床特征为身材矮小、生长发育迟缓、面部畸形、心电图异常等。全外显子测序显示KRAS基因为新发致病性点突变:NM_004985.4:c.40G>A(Val14Ile)。根据ACMG相关指南评判为致病变异(PS2_VeryStrong+PS3+PS4+PM1+PP2+PM2_Supporting)。结论KRAS基因新发变异考虑为Noonan综合征3型患者的遗传学病因。对身材矮小、生长发育迟缓、面部畸形、心电图异常的患者,应警惕Noonan综合征3型的可能,通过基因检测尽早明确诊断。本研究的发现亦扩展了KRAS基因的变异谱。展开更多
BACKGROUND Noonan syndrome is a relatively common autosomal dominant genetic disorder characterized by cardiovascular defects owing to functional abnormalities in key genes such as RAF1.Mutations in RAF1 are typically...BACKGROUND Noonan syndrome is a relatively common autosomal dominant genetic disorder characterized by cardiovascular defects owing to functional abnormalities in key genes such as RAF1.Mutations in RAF1 are typically associated with hypertrophic cardiomyopathy(HCM).However,in this case,the patient exhibited atrial and ventricular septal defects(VSDs).CASE SUMMARY This case report describes an 11-year-old boy diagnosed with Noonan syndrome,in whom genetic testing revealed a c.770C>T(p.Ser257 Leu)mutation in RAF1.The patient presented with intermittent chest discomfort and shortness of breath,symptoms that significantly worsened after physical activity.Clinical evaluation revealed marked growth retardation and multiple physical abnormalities.Electrocardiographic and echocardiographic assessments revealed VSDs,atrial septal defects,and left ventricular outflow tract obstruction.Following multidisciplinary consultation,the patient underwent cardiac surgical intervention,which led to clinical improvement;however,they subsequently developed a third-degree atrioventricular block,necessitating the implantation of a permanent pacemaker.During follow-up,echocardiographic findings demonstrated near-complete resolution of the shunt across the atrial and ventricular septa,significant improvement in left ventricular outflow tract obstruction,and notable reduction in ventricular septal thickness.A genetic mutation at the c.770C>T(p.Ser257 Leu)locus of RAF1 is typically associated with HCM and pulmonary hypertension.However,this patient’s clinical phenotype manifested as HCM,atrial septal defect,and VSD,suggesting that this mutation may involve a different pathophysiological mechanism.CONCLUSION This case confirms the genotype-phenotype heterogeneity of Noonan syndrome and highlights the complex management requirements of RAF1 mutation-associated cardiac pathologies.Early surgical intervention can ameliorate structural defects,but it must be integrated with genetic counseling and lifelong monitoring to optimize patient outcomes.展开更多
BACKGROUND Noonan syndrome(NS)is an autosomal dominant,multisystem disorder with a prevalence of 1 in 1000-2500.Multiple etiologies have been proposed for short stature in NS,including resistance to growth hormone(GH)...BACKGROUND Noonan syndrome(NS)is an autosomal dominant,multisystem disorder with a prevalence of 1 in 1000-2500.Multiple etiologies have been proposed for short stature in NS,including resistance to growth hormone(GH)and GH deficiency(GHD).Irrespective of the presence of GHD,NS is a Food and Drug Administration-approved indication for recombinant-GH therapy.Few case reports of combined anterior pituitary hormone deficiency(CPHD)in NS have been reported.AIM To describe the clinico-biochemical characteristics of NS with CPHD and to assess the response to recombinant GH therapy.METHODS An ambispective case-control study was conducted to compare the clinicohormonal profile and response to recombinant-GH in pediatric patients with NS and CPHD and pediatric patients with NS but without CPHD.RESULTS Five children with NS and CPHD were compared to 6 patients with NS but without CPHD.The most common anterior pituitary hormone involvement in combination with GHD was adrenocorticotrophic hormone deficiency causing hypocortisolemia(n=3,60%),followed by hypogonadotropic hypogonadism and secondary hypothyroidism(n=1 each).Pituitary hypoplasia was seen in the magnetic resonance imaging of all patients with CPHD.Patients with NS and CPHD had lower standard deviation scores of height(-4.18 vs-2.52,P=0.009),bodyweight,and body mass index but a slightly better first year response to recombinant GH(9.2 vs 5.5,P=0.06).There were no differences in dysmorphisms and other anomalies between the two groups.Patients with NS and CPHD had a similar response to GH as patients with CPHD but without NS.One patient with NS and CPHD developed hypocortisolism after GH initiation.CONCLUSION Hypoplasia of the pituitary and GHD with involvement of other pituitary hormones may be seen in NS and may determine response to recombinant GH therapy.展开更多
BACKGROUND Protein-losing enteropathy(PLE)is a rare cause of hypoalbuminemia that can be attributed to intestinal lymphangiectasia.Patients with Noonan syndrome may present with disorder of lymph vessel formation.Howe...BACKGROUND Protein-losing enteropathy(PLE)is a rare cause of hypoalbuminemia that can be attributed to intestinal lymphangiectasia.Patients with Noonan syndrome may present with disorder of lymph vessel formation.However,PLE is rarely reported with Noonan syndrome.CASE SUMMARY A 15-year-old female was hospitalized multiple times for recurrent edema and diarrhea secondary to hypoalbuminemia.Additional manifestations included a ventricular septal defect at birth,intermuscular hemangioma,slightly wide interocular and intermammary distances,and absence of the distal phalanx of the left little finger since birth.Abdominal computed tomography revealed cavernous transformation of the portal vein,and liver biopsy indicated“porto-sinusoidal vascular disease”.Whole exome and Sanger sequencing revealed a heterozygous mutation(exon9:C.850C>T:P.R284C)in leucine zipper-like transcription regulator 1,suggesting Noonan syndrome type 10.Further examinations revealed thoracic duct dysplasia and intestinal lymphangiectasia causing PLE in this patient.A multidisciplinary team decided to address thoracic duct dysplasia with outlet obstruction.Approximately two years after the microsurgical relief of the thoracic duct outlet obstruction,the patient achieved persistent normal serum albumin level without edema or diarrhea.Furthermore,the relevant literatures on Noonan syndrome and PLE were reviewed.CONCLUSION Herein,we reported the first case of PLE associated with Noonan syndrome caused by a rare genetic mutation in leucine zipper-like transcription regulator 1(c.850C>T:P.R284C)with newly reported manifestations.This case presented the successful treatment of clinical hypoalbuminemia attributed to thoracic duct dysplasia,intestinal lymphangiectasia and PLE.展开更多
目的应用全外显子测序技术对疑似Noonan综合征(NS)的危重早产儿及其父母进行基因诊断,探讨基因型与临床表型之间的关系。方法收集患儿及其父母的外周血标本及临床资料,应用Agilent Sure Select Human All Exome V5试剂盒进行全基因组外...目的应用全外显子测序技术对疑似Noonan综合征(NS)的危重早产儿及其父母进行基因诊断,探讨基因型与临床表型之间的关系。方法收集患儿及其父母的外周血标本及临床资料,应用Agilent Sure Select Human All Exome V5试剂盒进行全基因组外显子捕获,Illumina 550测序仪进行双端高通量测序,Sanger测序验证家系成员以明确突变遗传方式。结果全外显子测序发现NS患儿RAF1基因杂合错义突变c. 770C>T,p. S257L、Sanger测序验证家系成员为新发突变。结合患儿特殊面容、双侧心房及右室增大、中度肺动脉高压(PAH)等临床症状诊断为Noonan综合征。结论应用全外显子测序技术能够快速发现Noonan综合征基因突变,对重症新生儿病例的明确诊断及临床遗传咨询具有重要意义。展开更多
文摘目的探讨1例KRAS基因变异致Noonan综合征3型的临床特征和基因变异情况,为该病诊断提供参考。方法选择2024年8月在东营市人民医院就诊的1例15岁2个月的Noonan综合征3型男性患者。采用回顾性研究方法,收集患者的相关临床资料,对患者及其父母外周血样进行全外显子测序,对候选变异进行Sanger测序验证和生物信息学分析。根据美国医学遗传学与基因学学会(American College of Medical Genetics and Genomic,ACMG)制定的《遗传变异分类标准与指南》,对该变异进行致病性评级。结果患者临床特征为身材矮小、生长发育迟缓、面部畸形、心电图异常等。全外显子测序显示KRAS基因为新发致病性点突变:NM_004985.4:c.40G>A(Val14Ile)。根据ACMG相关指南评判为致病变异(PS2_VeryStrong+PS3+PS4+PM1+PP2+PM2_Supporting)。结论KRAS基因新发变异考虑为Noonan综合征3型患者的遗传学病因。对身材矮小、生长发育迟缓、面部畸形、心电图异常的患者,应警惕Noonan综合征3型的可能,通过基因检测尽早明确诊断。本研究的发现亦扩展了KRAS基因的变异谱。
基金Supported by the Gansu Provincial Science and Technology Plan Project,No.24JRRA886 and No.23JRRA1287Gansu Provincial People’s Hospital:Excellent Doctoral Student Cultivation Program,No.22GSSYD-14.
文摘BACKGROUND Noonan syndrome is a relatively common autosomal dominant genetic disorder characterized by cardiovascular defects owing to functional abnormalities in key genes such as RAF1.Mutations in RAF1 are typically associated with hypertrophic cardiomyopathy(HCM).However,in this case,the patient exhibited atrial and ventricular septal defects(VSDs).CASE SUMMARY This case report describes an 11-year-old boy diagnosed with Noonan syndrome,in whom genetic testing revealed a c.770C>T(p.Ser257 Leu)mutation in RAF1.The patient presented with intermittent chest discomfort and shortness of breath,symptoms that significantly worsened after physical activity.Clinical evaluation revealed marked growth retardation and multiple physical abnormalities.Electrocardiographic and echocardiographic assessments revealed VSDs,atrial septal defects,and left ventricular outflow tract obstruction.Following multidisciplinary consultation,the patient underwent cardiac surgical intervention,which led to clinical improvement;however,they subsequently developed a third-degree atrioventricular block,necessitating the implantation of a permanent pacemaker.During follow-up,echocardiographic findings demonstrated near-complete resolution of the shunt across the atrial and ventricular septa,significant improvement in left ventricular outflow tract obstruction,and notable reduction in ventricular septal thickness.A genetic mutation at the c.770C>T(p.Ser257 Leu)locus of RAF1 is typically associated with HCM and pulmonary hypertension.However,this patient’s clinical phenotype manifested as HCM,atrial septal defect,and VSD,suggesting that this mutation may involve a different pathophysiological mechanism.CONCLUSION This case confirms the genotype-phenotype heterogeneity of Noonan syndrome and highlights the complex management requirements of RAF1 mutation-associated cardiac pathologies.Early surgical intervention can ameliorate structural defects,but it must be integrated with genetic counseling and lifelong monitoring to optimize patient outcomes.
文摘BACKGROUND Noonan syndrome(NS)is an autosomal dominant,multisystem disorder with a prevalence of 1 in 1000-2500.Multiple etiologies have been proposed for short stature in NS,including resistance to growth hormone(GH)and GH deficiency(GHD).Irrespective of the presence of GHD,NS is a Food and Drug Administration-approved indication for recombinant-GH therapy.Few case reports of combined anterior pituitary hormone deficiency(CPHD)in NS have been reported.AIM To describe the clinico-biochemical characteristics of NS with CPHD and to assess the response to recombinant GH therapy.METHODS An ambispective case-control study was conducted to compare the clinicohormonal profile and response to recombinant-GH in pediatric patients with NS and CPHD and pediatric patients with NS but without CPHD.RESULTS Five children with NS and CPHD were compared to 6 patients with NS but without CPHD.The most common anterior pituitary hormone involvement in combination with GHD was adrenocorticotrophic hormone deficiency causing hypocortisolemia(n=3,60%),followed by hypogonadotropic hypogonadism and secondary hypothyroidism(n=1 each).Pituitary hypoplasia was seen in the magnetic resonance imaging of all patients with CPHD.Patients with NS and CPHD had lower standard deviation scores of height(-4.18 vs-2.52,P=0.009),bodyweight,and body mass index but a slightly better first year response to recombinant GH(9.2 vs 5.5,P=0.06).There were no differences in dysmorphisms and other anomalies between the two groups.Patients with NS and CPHD had a similar response to GH as patients with CPHD but without NS.One patient with NS and CPHD developed hypocortisolism after GH initiation.CONCLUSION Hypoplasia of the pituitary and GHD with involvement of other pituitary hormones may be seen in NS and may determine response to recombinant GH therapy.
基金Supported by the Shandong Provincial Natural Science Foundation of China,No.ZR2023QH015Qingdao Municipal Natural Science Foundation of China,No.23-2-1-134-zyyd-jch.
文摘BACKGROUND Protein-losing enteropathy(PLE)is a rare cause of hypoalbuminemia that can be attributed to intestinal lymphangiectasia.Patients with Noonan syndrome may present with disorder of lymph vessel formation.However,PLE is rarely reported with Noonan syndrome.CASE SUMMARY A 15-year-old female was hospitalized multiple times for recurrent edema and diarrhea secondary to hypoalbuminemia.Additional manifestations included a ventricular septal defect at birth,intermuscular hemangioma,slightly wide interocular and intermammary distances,and absence of the distal phalanx of the left little finger since birth.Abdominal computed tomography revealed cavernous transformation of the portal vein,and liver biopsy indicated“porto-sinusoidal vascular disease”.Whole exome and Sanger sequencing revealed a heterozygous mutation(exon9:C.850C>T:P.R284C)in leucine zipper-like transcription regulator 1,suggesting Noonan syndrome type 10.Further examinations revealed thoracic duct dysplasia and intestinal lymphangiectasia causing PLE in this patient.A multidisciplinary team decided to address thoracic duct dysplasia with outlet obstruction.Approximately two years after the microsurgical relief of the thoracic duct outlet obstruction,the patient achieved persistent normal serum albumin level without edema or diarrhea.Furthermore,the relevant literatures on Noonan syndrome and PLE were reviewed.CONCLUSION Herein,we reported the first case of PLE associated with Noonan syndrome caused by a rare genetic mutation in leucine zipper-like transcription regulator 1(c.850C>T:P.R284C)with newly reported manifestations.This case presented the successful treatment of clinical hypoalbuminemia attributed to thoracic duct dysplasia,intestinal lymphangiectasia and PLE.
文摘目的应用全外显子测序技术对疑似Noonan综合征(NS)的危重早产儿及其父母进行基因诊断,探讨基因型与临床表型之间的关系。方法收集患儿及其父母的外周血标本及临床资料,应用Agilent Sure Select Human All Exome V5试剂盒进行全基因组外显子捕获,Illumina 550测序仪进行双端高通量测序,Sanger测序验证家系成员以明确突变遗传方式。结果全外显子测序发现NS患儿RAF1基因杂合错义突变c. 770C>T,p. S257L、Sanger测序验证家系成员为新发突变。结合患儿特殊面容、双侧心房及右室增大、中度肺动脉高压(PAH)等临床症状诊断为Noonan综合征。结论应用全外显子测序技术能够快速发现Noonan综合征基因突变,对重症新生儿病例的明确诊断及临床遗传咨询具有重要意义。
