儿童原发性甲状旁腺功能减退症临床表型与基因型分析

Clinical and genetic characteristics of primary hypoparathyroidism in children

目的分析儿童原发性甲状旁腺功能减退症的临床特点及遗传学特征。方法收集13例2017年5月至2019年12月在首都儿科研究所附属儿童医院确诊的原发性甲状旁腺功能减退症患儿的年龄、症状、实验室检查结果及头颅CT等临床资料,并收集患儿及父母的外周血进行全外显子测序和(或)染色体拷贝数变异检测。结果13例原发性甲状旁腺功能减退症患儿中男7例、女6例,起病年龄3岁(1日龄~12岁),发病至诊断用时2个月(2 d^10年)。临床表现为惊厥9例,手足搐搦2例,肌肉疼痛1例,精神发育迟滞5例,耳聋1例,病初误诊癫痫5例。辅助检查示血钙(1.7±0.3)mmol/L,血磷(2.8±0.4)mmol/L,甲状旁腺激素8.2(3.9~28.7)ng/L,头颅CT见异位钙化7例。基因检测结果示基因异常7例,其中染色体22q11.2部分区域杂合缺失最多见,共5例,仅1例具有典型DiGeorge综合征表现。CaSR基因c.2495T>G(p.F832C)新生杂合变异导致常染色体显性遗传性低钙血症1型1例。GATA3基因c.708dupC(p.S237Qfs*66)新生杂合变异导致甲状旁腺功能减退-耳聋-肾发育不良综合征1例。结论儿童原发性甲状旁腺功能减退症的临床表现主要为低钙血症,并因遗传学病因不同而伴随相应的症状;除二代测序检测单基因病外,应重视大片段缺失的检测以排除22q11.2缺失综合征。

Objective To analyze the clinical and genetic characteristics of primary hypoparathyroidism in children.Methods The clinical data including age,symptoms,laboratory examination and cranial CT of 13 children with primary hypoparathyroidism diagnosed in the Capital Institute of Pediatrics from May 2017 to December 2019 were collected and analyzed retrospectively.These children and their parents also had gene detected by whole exome sequencing and(or)copy number variation sequencing.Results Among the 13 patients,7 were male and 6 female.The onset age was 3 years(1 day-12 years)old.The time from onset to confirmed diagnosis was 2 months(2 days-10 years).The clinical manifestations included convulsion(9 cases),tetany(2 cases),muscle pain(1 case),mental retardation(5 cases),deafness(1 case),and initially misdiagnosed epilepsy(5 cases).The lab examination showed average blood calcium level of(1.7±0.3)mmol/L,blood phosphorus of(2.8±0.4)mmol/L,and parathyroid hormone of 8.2(3.9-28.7)ng/L.Head CT found 7 cases of ectopic calcification.Among the 7 cases who had genetic abnormalities according to the gene detection,5 had heterozygous deletion of 22q11.2 region,and only one of whom was diagnosed with typical DiGeorge syndrome.As for the rest 2 cases,one had autosomal dominant hypocalcemia caused by novel heterozygous variation of CaSR gene c.2495T>G(p.F832C),and the other was hypoparathyroidism-deafness-renal dysplasia syndrome caused by GATA3 c.708dupC(p.S237Qfs*66)novel heterozygous variation.Conclusions Primary hypoparathyroidism in children is mainly characterized by hypocalcemia and usually accompanied with diverse symptoms which may indicate genetic disorders.The detection of large fragment deletion should be considered to exclude 22q11.2 deletion syndrome.