儿童X连锁显性遗传性低磷血症性佝偻病临床及基因分析

Genetic and clinical analysis of X-linked hypophosphatemic rickets

目的了解X连锁显性遗传性低磷血症性佝偻病(XLH)患儿的临床特征、PHEX基因变异特点及治疗情况。方法回顾性收集2010年1月至2020年1月首都医科大学附属北京儿童医院内分泌遗传代谢科诊治的25例XLH患儿的临床资料,总结临床特点、PHEX基因变异特点及临床转归。根据PHEX基因变异位置将患儿分为N端变异组和C端变异组,根据变异是否位于重要的锌离子结合域17或19号外显子分为17或19号外显子变异组和非17或19号外显子变异组,分别分析各组发病年龄、治疗前的身高标准差积分(HtSDS)、膝间距或踝间距、血磷及治疗后的HtSDS、膝间距或踝间距。组间比较使用秩和检验或t检验。结果25例XLH患儿中男8例、女17例,发病年龄为1.2(1.0,1.8)岁,确诊年龄2.5(1.5,4.3)岁。初诊时主要临床表现为双下肢弯曲[24例(96%)]、步态异常[17例(68%)]。HtSDS为-2.0(-3.2,-0.8),膝间距或踝间距为4.5(3.0,6.0)cm。空腹血磷0.8(0.7,0.9)mmol/L,血钙(2.5±0.1)mmol/L,碱性磷酸酶(721±42)U/L,有3例(12%)甲状旁腺激素水平高于正常值。25例(100%)患儿骨骼X线片均提示有活动性佝偻病改变。2例(9%)双肾髓质内少量钙质沉着。25例患儿检测出24种PHEX基因变异,11例(44%)为未报道过的变异,未发现热点变异。N端变异组21例、C端变异组4例;17或19号外显子组4例、非17或19号外显子变异组21例。N端变异、C端变异组和17或19号外显子变异、非17或19号外显子变异组患儿的发病年龄、HtSDS、膝间距或踝间距、血磷及治疗后的HtSDS、膝间距或踝间距差异均无统计学意义(均P>0.05)。25例患儿随访2.7(1.6,5.0)年,24例(96%)患儿规律口服磷酸盐制剂及活性维生素D,96%(24/25)症状得到缓解。HtSDS治疗前后差异无统计学意义[-2.0(-3.2,-0.8)比-2.0(-2.8,-1.1),Z=-0.156,P>0.05]。治疗后膝间距或踝间距较治疗前明显减小,差异有统计学意义[4.5(3.0,6.0)比1.5(0,3.3)cm,Z=-3.043,P<0.05]。经治疗17例患儿复查骨骼X线片佝偻病改变均有所修复。18例患儿合并了继发性甲状旁腺功能亢进症,7例出现了肾脏钙质沉着症。结论XLH患儿以步态异常、双下肢弯曲及身材矮小为主要临床表现。发现PHEX基因未报道的变异高发,未发现热点变异,也未发现基因型与表型的相关性。经规律磷酸盐制剂和活性维生素D治疗后除身高外症状均可明显改善,但继发性甲状旁腺功能亢进症和肾脏钙质沉着症的不良反应发生率高。

Objective To investigate the clinical and genetic features,and treatment of X-linked hypophosphatemic rickets(XLH).Methods In this retrospective study,we reviewed the medical records of 25 pediatric patients with XLH who were admitted to Department of Endocrinology Genetics and Metabolism,Beijing Children′s Hospital from January 2010 to January 2020.The clinical characteristics,PHEX gene variants,as well as clinical outcome of the patients were summarized.To analyze the correlation between genotype and phenotype,the patients were divided into different subgroups according to the location of the variants,including N-terminal-located vs.C-terminal-located variant,and Zn-binding domain exon 17 or 19 variant vs.non-exon 17 or 19 variant.The age at onset,height standard deviation score(HtSDS),intercondylar or intermalleolar distance,fasting serum phosphorus,and HtSDS and intercondylar or intermalleolar distance at the final follow-up were compared by rank sum test or t text.Results Among the 25 children with XLH,8 were boys and 17 were girls.The median age of onset was 1.2(1.0,1.8)years,and the median age of diagnosis was 2.5(1.5,4.3)years.The main clinical manifestations were abnormal gait and lower limb deformity.The HtSDS was-2.0(-3.2,-0.8),and the intercondylar or intermalleolar distance was 4.5(3.0,6.0)cm.The fasting serum phosphorus level was 0.8(0.7,0.9)mmol/L,while the serum alkaline phosphatase level was(721±41)U/L and the serum calcium level was(2.5±0.1)mmol/L.Three patients(12%)had parathyroid hormone levels above the upper limit of the normal range.Twenty-five patients(100%)showed radiographic changes of active rickets.Nephrocalcinosis was found in 2 cases(9%).Twenty-four different PHEX variations were detected in 25 patients,among whom 11(44%)had not been reported previously.No hot spot variation was found.No statistical differences(all P>0.05)were identified in clinical features and outcomes either in comparing patients with N-terminal(21 cases)and C-terminal(4 cases)variants,or in comparing patients with variant located in exon 17 or 19(4 cases)or not(21 cases).Twenty-four cases(96%)were treated regularly with phosphate supplements and active vitamin D.After 2.7(1.6,5.0)years of follow-up,clinical symptoms were relieved in 96%(24/25)of the patients.The HtSDS after treatment had no significant difference compared to that before treatment(-2.0(-3.2,-0.8)vs.-2.0(-2.8,-1.1),Z=-0.156,P>0.05),while the intercondylar or intermalleolar distance after treatment was significantly reduced compared to that before treatment(4.5(3.0,6.0)vs.1.5(0,3.3)cm,Z=-3.043,P<0.05).Bone X-rays were reexamined in 17 cases after treatment,and radiographic signs of rickets were improved.Eighteen cases had secondary hyperparathyroidism and 7 cases had nephrocalcinosis.Conclusions The main clinical manifestations of XLH are abnormal gait,lower limb deformity and short stature.A high proportion of novel variations of PHEX gene but no hot spot variation neither genotype-phenotype correlation are found.Regular treatment with phosphate supplements and active vitamin D can significantly improve the symptoms except for the height.However,the rate of adverse events including secondary hyperparathyroidism and nephrocalcinosis seems to be high.