ACAN 基因变异致家族性身材矮小一家系报告

目的分析家族性矮小家系的临床表型及基因变异特征。方法回顾1个采用靶向基因高通量测序结合Sanger测序技术确定致病基因的广西壮族地区家族遗传性矮小家系的临床资料。检索相关文献,总结ACAN基因变异患儿的临床表型与基因型的关系。结果患儿分别为9岁10个月和7岁的两兄弟,身材均矮小;其父母亲身高均为150 cm,非近亲婚配;叔叔和爷爷亦为矮小身材。基因测序证实两兄弟的ACAN基因12号外显子处均存在杂合变异c.6193 del C(p.Gln2065Serfs*27),均遗传自父亲。检索到英文文献11篇,包括本研究在内,在41个家系中发现33个存在ACAN基因致病性变异,包含4个来自中国患儿的变异,但未见中文文献报道。临床表现以特发性矮小最为多见,多为家族性遗传,也可散发。部分患儿还合并有骨关节炎、椎间盘突出或退化等症状。大部分患儿骨龄提前,但亦有部分正常甚至落后。予生长激素联合促性腺激素释放激素类似物推迟青春期治疗可有效改善身高。结论 ACAN基因杂合变异可导致儿童身材矮小,具显著的家系遗传特征,其临床特征与基因型不具备特征性联系。     

NPR2基因突变致Maroteaux型肢端肢中发育不全1例北大核心CSCD

对2018年11月天津医科大学总医院儿科诊治的1例Maroteaux型肢端肢中发育不全(AMDM)患儿的临床资料进行回顾性分析。患儿,女,3岁3个月,身高83 cm(-3.84 SD),表现为非匀称性矮小,前臂和小腿不成比例缩短,指趾粗短,基因检测显示 NPR2基因复合杂合突变c.1640T>A(p.Val547Asp)/c.682G>A(p.Gly228Ser),2个变异在人类基因突变数据库中未见报道,蛋白质功能预测有害,确诊为AMDM。患儿于门诊随诊至4岁8个月,身高90 cm(-4.35 SD),生长速率(GV)=4.9 cm/年,予重组人生长激素(rhGH)治疗并定期随诊,已使用rhGH 9个月,身高98.2 cm(-3.07 SD),GV=10.9 cm/年。该病例丰富了AMDM的基因突变谱。rhGH可有效改善患儿的身高,但长期疗效有待进一步随诊和观察。     

Crouzon 综合征合并生长激素缺乏症1 例报告及重组人生长激素治疗随诊

目的报告1例Crouzon综合征合并生长激素缺乏症(GHD)患儿及其重组人生长激素(rhGH)治疗结果。方法回顾分析患儿以rhGH治疗2年的临床资料。结果患儿女性,5岁4月龄时身高98.2 cm(P_3),有特殊面容(舟状头、突眼、反颌畸形等)。基因检测示FGFR2基因存在c.1061CG(p.Ser354Cys)杂合变异,源自母亲,为已知的致病变异,诊断为Crouzon综合征。同时相关检查提示患儿合并GHD。给予rhGH治疗2年,身高117 cm,平均生长速率为9.4 cm/a。治疗期间,头颅磁共振监测提示侧脑室及第三脑室略扩张等表现未进展,眼科随诊示左眼视盘水肿程度较前减轻,未发现不良反应。结论矮小可能是Crouzon综合征的表型,rhGH治疗可以改善Crouzon综合征合并GHD患儿的身高,且未引起患儿颅内压增高等不良反应。     

原因不明矮小症致病基因研究(附77例报告)

目的应用靶向捕获二代测序技术检测原因不明矮小症致病基因,并分析其与临床表型的相关性。方法收集2007年至2015年在上海交通大学医学院附属瑞金医院儿内科就诊的临床诊断为原因不明矮小症77例患儿的临床资料。制备包括与生长相关的187个基因编码区序列的基因panel,对77例患儿进行二代测序,根据美国医学遗传学与基因组学学会(ACMG)指南评判变异位点,筛选出致病基因,并通过Sanger测序验证,分析患儿基因型和临床表型相关性。结果检测到5例存在致病性变异;1例存在可能致病性变异;1例变异意义不明确。这7种变异均为杂合。1例ACAN基因存在致病性变异p.D2407fs,表现为矮小及骨龄偏大;3例发现PTPN11基因存在已知致病性变异,分别为p.A72G、p.I282V和p.P491S,确诊为Noonan综合征;1例COL2A1基因存在已知致病性变异p.R904C,确诊为Stickler综合征;1例COMP基因存在可能致病性变异p.D401N,可造成多发性骨骺发育不良;1例为家族性矮小患儿,发现GHSR基因新发杂合变异p.S289Y,其骨龄发育落后,基因型与临床表型一致,目前评判意义不明确。结论发现ACAN基因杂合缺陷与骨龄发育超前的特发性矮小相关。COMP基因p.D401N变异,可能与多发性骨骺发育不良有关。GHSR基因新发杂合变异p.S289Y,可能导致矮小,须进一步功能实验验证。     

EARS2 基因变异致新生儿丘脑脑干受累性脑白质病伴高乳酸血症1 例报告并文献复习

目的探讨丘脑脑干受累性脑白质病伴高乳酸血症的临床表型及基因型。方法回顾分析1例新生儿丘脑脑干受累性脑白质病伴高乳酸血症患儿的临床资料并复习相关文献。结果女性患儿,出生26小时,临床表现为反应差、抽搐及顽固性高乳酸血症。患儿于妊娠期时头颅MRI示胼胝体缺如。全外显子测序发现患儿EARS 2核基因第7号外显子c.1294C>T杂合无义变异和第5号外显子c.971G>T杂合错义变异,分别来自父亲和母亲;线粒体基因二代测序未发现患儿线粒体基因变异,但MLPA检测发现患儿及其母亲线粒体基因MTND 1-1*异质性缺失变异。结论发现导致丘脑脑干受累性脑白质病伴高乳酸血症新的EARS 2核基因外显子c.1294C>T无义变异和c.971G>T错义变异。     

婴儿神经轴索营养不良1 例临床和基因变异分析

目的探讨婴儿神经轴索营养不良(INAD)的临床特点和PLA2G6基因变异特征。方法回顾分析1例经基因检测确诊的INAD患儿的临床资料。结果患儿,女性,2岁。1岁7个月发病,临床表现为精神运动发育倒退、肌张力减低、病理征阳性。头颅磁共振成像(MRI)示双侧小脑萎缩;肌电图未见异常;2 h视频脑电图未见异常。基因检测示患儿PLA2G6基因两处变异c.150_153 del、c.799T>C,分别遗传自母亲和父亲,为复合杂合变异,均未在正常人群中检测到。c.150_153 del变异导致从第51号苏氨酸开始的氨基酸合成发生改变,并在改变后的第30个氨基酸终止(p.Pro51Thrfs*30),为移码变异;c.799T>C变异致第267号氨基酸由半胱氨酸变为精氨酸(p.Cys 267 Arg),为错义变异;Poly-Phen 2预测上述变异可导致蛋白质功能受到影响。结论二代测序技术可准确检测PLA2G6基因变异,扩大了中国INAD患者的基因变异谱。     

甲状腺球蛋白增高的先天性甲状腺功能减退症1 例报告并文献复习

目的探讨甲状腺球蛋白(TG)增高的先天性甲状腺功能减退症(CH)家系的临床特征及TG基因变异特征。方法回顾分析1个TG增高的CH家系的临床及TG基因检测结果,并复习相关国内外文献。结果先证者,女,45日龄,生后黄疸消褪延迟伴便秘。甲状腺功能检测提示为CH,同时发现TG水平增高。基因检测结果显示患儿TG基因存在c.2149 C>T和c.5401+113 A>G的复合杂合变异;Sanger测序验证c.2149 C>T来源于父亲,c.5401+113 A>G来源于母亲,其哥哥携带c.5401+113A>G杂合变异。患儿哥哥及父母表型正常。c.2149C>T及c.5401+113A>G变异尚未见文献报道,根据美国遗传变异分类标准与指南分别为疑似致病变异及临床意义未明变异。结论确诊TG基因变异引起CH患者TG水平增高,并发现2个新的TG基因变异位点。     

发-肝-肠综合征患儿SKIV2L基因变异分析1例

分析2021-01-24南京医科大学附属儿童医院消化科1例发-肝-肠综合征（tricho-hepato-enteric syndrome,THES）患儿临床特征及基因变异情况,采集患儿及其父母外周血提取基因组DNA,使用二代测序对患儿进行基因检测,对检出的可疑变异进行一代Sanger验证及生物信息学分析。患儿临床特征为肝功能损害、腹泻、头发蓬松易断、生长迟缓。头发光镜下见脆性结节。基因测序提示患儿SKIV2L基因存在复合杂合新变异c.29C>T(p.P10L)和c.321C>G(p.H107Q)。两种变异既往均未见报道,位点较为保守,多种生物信息学预测为有害。由此得到SKIV2L基因复合杂合变异c.29C>T/c.321C>G为患者的致病原因的结论。新变异位点的检出丰富了SKIV2L基因的变异谱,为该家系的遗传咨询提供了依据。     

NPHP 不同基因变异进展为终末期肾病的肾单位肾痨3 例

目的分析不同NPHP变异导致肾单位肾痨的临床特征。方法回顾分析3例NPHP变异致肾单位肾痨患儿的临床资料。结果 3例患儿均为女性,且均有贫血表现。例1存在内脏反位、肝功能异常等肾外表现;例2、例3的肾脏病理均示肾小球纤维化,肾小管基底膜完整性破坏,小管萎缩,肾脏间质炎症细胞浸润。例1、例2家族中有肾脏病史患者,例3弟弟有相同基因变异,暂无表现。基因检测显示3例患儿均存在NPHP基因变异。例1在NEK8/NPHP9基因存在c.388AC p.K130Q杂合变异以及c.1465GA,p.V489M杂合变异,均为新发现的变异;例2为NPHP1全基因缺失;例3的NPHP3基因存在c.3218TG,p.L1073*纯合变异,其弟弟存在相同的纯合变异位点。3例患儿均已行肾脏移植治疗,门诊随访中。结论肾单位肾痨是一类临床和遗传异质性疾病,临床表现无特异性,基因检测有助于诊断。肾移植是NPHP进展为终末期肾病的有效治疗手段。c.388AC p.K130Q杂合错义变异和c.1465GA,p.V489M杂合变异是新发现的NPHP基因变异。     

新生儿高苯丙氨酸血症筛查及PAH基因变异和缺失分析

目的 了解石家庄市新生儿高苯丙氨酸血症（HPA）的发病率、临床分型以及相关基因的变异特征。方法选择2017年3月至2021年5月在石家庄市新生儿疾病筛查中心进行HPA筛查的487 380名新生儿，经免疫荧光法检测其足跟血苯丙氨酸浓度，采用基因测序技术对可疑阳性患儿苯丙氨酸羟化酶（PAH）基因进行检测，患儿父母采用Sanger法进行目标基因变异验证，进一步将基因测序结果与正常人比对，找出片段缺失区域并进行分析。结果487 380名新生儿中筛查出阳性儿191例，确诊HPA 104例，均为PAH缺乏症，发病率为1/4686。104例患儿中共检测出62种基因变异，包括错义变异37种、剪接变异10种、无义变异7种、同义变异2种、整码变异1种以及杂合缺失5种。PAH基因常见的变异位点有c. 158 G>A(18.7%)、c. 728 G>A(10.5%)、c. 611 A>G(6.7%)、c. 331 C>T(4.8%)和c.721C>T(4.8%)，并发现未报道基因片段缺失（外显子6杂合缺失）及基因变异（c.630T>G、c.61-1G>A、c.912+...     

Treatment of cartilage–hair hypoplasia with recombinant human growth hormone

Cartilage–hair hypoplasia (CHH) is an autosomal recessive disorder characterized by short stature, hypoplastic hair and humoral immunity disorders. It is a mutation in the RMRP gene, located on chromosome 9p13.3, that leads to CHH. There is no special treatment for short stature in CHH. The efficacy and safety of recombinant human growth hormone (rhGH) therapy in CHH is still under discussion. The present study describes the case of a girl with CHH who was treated with rhGH. The rhGH treatment had a significant effect on the height gain: the height SD score was changed from ?4. to ?2.98 after 4 years 7 months of treatment. rhGH therapy should be considered as a treatment modality for CHH, and insulin‐like growth factor (IGF)‐1 and IGF‐binding protein 3 concentrations should be closely monitored, particularly because of the increased cancer risk that is a characteristic feature of CHH.     

Problems typical for patients with hypopituitarism - a case presentation

The authors present a 20-year follow-up of a typical case of hypopituitarism resulting from the Prop-1 gene mutation and diagnosed when the patient was 8 years of age based on growth deficit (-4 SD), delayed bone age (3.5 years), as well as proven deficit of GH and TSH, as well as LH and FSH detected in the peripubertal period. Following 8-year rhGH substitution treatment (0.75 IU (0.25) mg/kg/week and therapy with the levorotatory form of thyroxine and estrogens, the patient achieved an appropriate height (168 cm) and - after a 2-year preliminary period of treatment with a metabolic rhGH dose (0.5 IU/kg/week) - normalization of bone mineral density (z score -1.1 vs. -2.1 for lumbar spine) and improved quality of life. In both treatment periods the authors also observed normalization of the lipid profile without any detrimental effect on glucose and insulin concentration levels, what indicates a necessity for employing rhGH supplementation also after growth completion. The lack of progression in size of a Prop-1 mutation-dependent hypopituitary tumor (10x12x13 mm) demonstrated over the 20 years of follow-up emphasizes the importance of conservative management in such special cases.     

Third-generation Aromatase Inhibitor Improved Adult Height in a Japanese Boy with Testotoxicosis

In this study, we report a Japanese boy with testotoxicosis due to a heterozygous mutation [p. A572V] in the LH/CGR gene, who was the first boy treated with a third-generation aromatase inhibitor (AI) and reached his adult height in Japan. He showed accelerated growth and rapid penile growth from 3 yr of age and was diagnosed as having testotoxicosis. Combined treatment with anastrozole and spironolactone was started when he was 7 yr old and 145.8 cm (+4.45 SD) tall, at which point his bone age (BA) was 13.5 yr. His predicted adult height (PAH) was estimated to be 158.3 cm. The combined treatment was continued until he was 13 yr old and 166.5 cm tall, with his BA being 15.5 yr. He reached his adult height of 166.9 cm at 15 yr of age. Combined treatment with anastrozole and spironolactone successfully decelerated BA advancement, prolonged pubertal period and improved adult height.     

重组人生长激素治疗颅咽管瘤术后生长激素缺乏症

目的探讨低剂量基因重组人生长激素(rhGH)治疗颅咽管瘤术后生长激素缺乏症(GHD)患儿的疗效和安全性。方法回顾性分析2008年4月-2011年4月在北京三博脑科医院内分泌门诊治疗的12例7～15岁术后病理确诊为颅咽管瘤且继发生长迟滞患儿的病例资料及随访资料。患儿均给予rhGH治疗(每晚睡前皮下注射0.1 IU.kg-1,每周5次注射),疗程3～36个月。定期检测肝功能、肾功能、激素水平等指标,并比较患儿治疗前后身高、体质量、生长速度、身高标准差计数、胰岛素样生长因子1(IGF-1)、骨龄等生长指标的改变。结果在rhGH治疗期间,12例患儿在治疗第1年生长速率增加显著,由(2.2±1.3)cm.a-1增加到(6.63±4.97)cm.a-1(P<0.01),身高标准差计数由治疗前-3.3±2.3增加到-3.2±2.8,血IGF-1治疗前为(38±64)μg.L-1,治疗后为(173±167)μg.L-1(患儿治疗后血清IGF-1水平达到正常范围),差异均有统计学意义(Pa<0.01)。治疗期间,患儿肝肾功能等均保持在正常值范围,骨龄无明显变化,随访时尚无患儿肿瘤复发。结论低剂量rhGH治疗儿童颅咽管瘤术后继发GHD是经济、有效的,在充分评估及严密监控下开展GH替代治疗是安全的。     

重组人生长激素治疗特发性矮小12个月疗效评估

目的 分析重组人生长激素(rhGH)对特发性矮小（ISS）患儿的治疗效果和影响因素,为寻求优化治疗效果的途径提供参考依据。 方法 回顾性分析2003年2月至2011年7月在首都儿科研究所生长发育门诊确诊为ISS患儿的临床资料,依据是否予rhGH治疗分为rhGH组和对照组。以身高标准差变化（ΔHtSDS）和生长速度（GV）作为评估指标进行疗效和影响因素分析。分析治疗期间骨龄、身高年龄及胰岛素样生长因子(IGF-1)水平的变化。 结果 rhGH组35例,对照组33例进入分析。①rhGH组治疗前、治疗后12个月HtSDS呈增长趋势(P<0.05);对照组均未见升高趋势。治疗后0～3个月的ΔHtSDS水平为(0.22±0.13),治疗后~6、~9和~12个月分别为(0.20±0.10)、(0.12±0.14)和(0.14±0.15),呈降低趋势,但差异无统计学意义。治疗后0～3个月GV为(10.78±2.70) cm·year-1,治疗后~6、~9和~12个月分别为(10.52±2.44)、(8.31±2.78)和(8.50±2.29) cm·year-1,呈降低趋势,但差异无统计学意义。治疗后0~6个月ΔHtSDS和GV水平均显著高于～12个月［ΔHtSDS :(0.43±0.20) vs (0.27±0.24), GV: (10.48±2.17) vs (8.48±2.39) cm·year-1］。②治疗后12个月的ΔHtSDS水平与治疗开始时的年龄呈负相关,与治疗后0～3个月的ΔHtSDS呈正相关;治疗后12个月的GV水平与治疗前的GH峰值和治疗后3个月的GV水平呈负相关。③治疗后1年青春期前、青春早中期和青春后期ΔHtSDS差异总体上有统计学意义（P=0.016）,其中青春期前显著高于青春早中期和青春后期;GV差异无统计学意义。④rhGH组治疗后12个月的骨龄变化差异无统计学意义,身高年龄显著高于对照组。⑤rhGH组IGF-1水平在治疗后1个月升高较明显,之后升高趋势减缓。 结论 rhGH用于ISS患儿的治疗应尽量选择青春期前;治疗后3个月的效果可作为第1年治疗效果的预测因素;rhGH治疗不会使ISS患儿骨龄明显提前。     

ACAN基因突变致家族性矮身材7例临床特点及基因分析

目的　研究聚集蛋白聚糖（aggrecan，ACAN）基因突变致家族性矮身材的临床特点及遗传学特征，并进行文献复习，以提高对该病的认识及诊断的准确性。方法　回顾性分析2017年3月至2020年12月湖南省人民医院﹑中南大学湘雅二医院及柳州市妇幼保健院诊断的ACAN基因突变致家族性矮身材7例患儿的临床资料及基因检测结果。结果　所有患儿均进行了全外显子测序（WES）检测，结果显示他们都具有ACAN基因的杂合突变。7例患儿分别来自4个家系，其中男性5例，女性2例，患儿均因身高增长缓慢就诊且有身材矮小家族史，病史中均无关节疼痛、关节活动受限及肿大等骨关节炎表现。其中2例有特殊面容，表现为眼距宽、鼻梁低、鼻脊塌陷、前额突出及面中部发育不良；3例有特殊体征，表现为短颈、脚趾宽大；2例有明显的骨龄提前；行脊柱全长片检查除1例有骶椎隐裂外均无异常。结论　ACAN基因杂合变异可导致儿童身材矮小，且具显著的家系遗传特征，由于变异的差异部分患儿可能会伴有骨龄提前的情况及特殊的外貌和体征。     

重组人生长激素对38例特纳综合征的疗效观察

目的探讨重组人生长激素(rhGH)治疗特纳综合征(TS)的疗效及影响疗效的因素。方法选取确诊为TS的患儿38例为研究对象,每晚均接受rhGH治疗,剂量0.11～0.21 IU.kg-1.d-1,疗程6～36个月。定期随访,观察生长速率(GV)、胰岛素样生长因子-1(IGF-1)和甲状腺功能、肝功能、糖化血红蛋白等。按照rhGH用药剂量将患儿分为2组,≤0.15 IU.kg-1.d-1组和>0.15 IU.kg-1.d-1组,分析不同剂量与疗效的关系。按照治疗初始年龄将患儿分成≤10岁组及>10岁组,分析治疗年龄与疗效的关系。按照治疗前生长激素(GH)峰值将患儿分成GH≥10μg.L-1组及<10μg.L-1组,观察疗效与治疗前GH峰值的关系。结果 TS患儿用药前及用药0.5 a后GV[(2.47±0.42)cm.a-1vs(9.37±2.68)cm.a-1]比较差异有统计学意义(P=0.001)。IGF-1由用药前(186.73±73.32)μg.L-1增至用药后0.5 a(433.93±163.91)μg.L-1,二者比较差异有统计学意义(P<0.001)。rhGH剂量与GV无显著相关。治疗初始年龄与第1年GV无关。治疗前GH峰值与GV无显著相关。结论 rhGH治疗TS可以明确改善身高。较以往常用剂量更小的剂量也可以达到很好的疗效。用药前患儿GH峰值与疗效关系不大,可以不用常规做GH激发试验。患儿治疗的初始年龄与GV无明显相关性。IGF-1是治疗过程中的重要检测指标。     

Growth hormone and body composition in children younger than 2 years with Prader-Willi syndrome

OBJECTIVES: To assess body composition of infants with Prader-Willi syndrome (PWS) by using deuterium dilution and investigating the efficacy of early institution of growth hormone (GH) therapy in increasing lean mass (LM) and preventing massive obesity. STUDY DESIGN: One group of 11 children with PWS <2 years before and during 30-month GH therapy (GH group) was compared with 6 infants administered only coenzyme Q(10) for 1 year (Q10 group). LM adjusted for height (LM(Ht)) and relative fat mass (%FM(Age)) standard deviation scores (SDS) were calculated from data of 95 healthy children. RESULTS: Initially, LM(Ht) of all patients was below the normal average. LM(Ht) decreased by -0.46 +/- 0.3 SD (P=.03) per year in the Q10 group but rose by 0.25 +/- 0.3 SD (P=.02) per year during GH therapy, normalizing after 30 months (-0.70 +/- 1.0 SD). Despite low to normal weight for height (WfH), %FM(Age) was above the normal average (GH group, 31.0% +/- 4.5%, Q10 group, 32.4% +/- 9.5%). In the Q10 infants, %FM(Age) increased by 0.71 +/- 0.7 SD per year, whereas in the GH group, %FM(Age) remained more stable up to 30 months. CONCLUSIONS: Diminished LM(Ht) found in infants with PWS further declines during the early years. Early institution of GH therapy lifts LM(Ht) into the normal range and delays fat tissue accumulation.     

Recombinant growth hormone treatment in short patients with thalassemia major: results after 24 and 36 months

Treatment with recombinant growth hormone (rhGH), 0.6 IU/kg/week s.c., previously successfully conducted for one year, was continued in 15 (Group A) and 8 (Group B) short thalassemia major patients with reduced GH reserve, for two and three years, respectively. In Group A, height for chronological age (Ht SDSCA) increased significantly (p = 0.021) from the start of treatment, but the positive effect was only apparent because of the concomitant slight worsening of height for bone age (Ht SDSBA). Median deltaHt SDSCA/deltaHt SDSBA was <1.0 with respect to both the start (0.87) and the end of the first year of rhGH therapy (0.89). IGF-I levels increased significantly (p = 0.043) compared with values both at the start and at the end of the first year of rhGH therapy. In Group B neither Ht SDSCA nor Ht SDSBA differed statistically from starting values, the former having a positive trend and the latter a negative one. Median deltaHt SDSCA/deltaHt SDSBA was 0.92 with respect to the start, and 0.94 with respect to the end of the second year. IGF-I levels increased significantly (p = 0.043) with respect to starting values. Our data show that the encouraging results described from the first year of rhGH treatment did not persist during the second and third years, and we conclude that this is because increase in bone age with continued treatment is equal to, or slightly greater than the height age increase. We propose that patients with thalassemia major with short stature should receive rhGH treatment for only one year, and that more prolonged treatment should be reserved for selected adolescents who have psychological problems due to shortness; for these patients growth acceleration could represent the main goal, even if this leads to a substantially unchanged or slightly decreased final height.