低磷酸酯酶症的口腔表现及基因分析

Orodental phenotype and genotype findings in 8 Chinese children with hypophosphatasia

目的分析低磷酸酯酶症(HPP)患儿口腔临床表型、基因变异类型,并探讨其口腔表现与基因变异类型的关系,为口腔临床提供参考。方法收集2008年1月至2023年1月就诊于浙江大学医学院附属儿童医院口腔科的8例HPP患儿,其中5例进行致病基因测序,对8例患儿的口腔表现、实验室检查及基因变异类型特点进行回顾性分析。结果8例HPP患儿中男性3例、女性5例,主诉均为乳牙过早脱落。3例为牙型,5例为儿童型(2例同胞姐弟初诊时为牙型,5岁时修改诊断为儿童型)。第一颗乳牙脱落的年龄为9~18个月,诊断年龄为20~104个月。牙型仅表现为乳前牙过早脱落,儿童型波及多颗乳磨牙并伴随不同程度的全身症状。全口曲面体层X线片显示乳恒牙牙髓腔宽大、髓角高耸,根管壁较薄,部分病例伴牙釉质发育不良、牙根短小,乳磨牙牙根吸收,牙槽骨吸收。所有患儿血清碱性磷酸酶(ALP)值(30~107 U/L)均低于健康同龄人,1~3岁女童ALP值儿童型(30~33 U/L)与牙型(61~107 U/L)差异无统计学意义(P>0.05)。5例患儿及家系检测到8个肝-骨-肾-ALP基因(ALPL)变异位点,均为错义变异,其中c.1334C>G(p.Ser445Cys)和c.1259G>T(p.Gly420Val),为新的变异型;1例杂合变异,符合常染色体显性遗传,其余4例为复合杂合变异,符合常染色体隐性遗传。结论儿童型和牙型HPP常于儿童口腔科最先发现,轻型HPP常被延迟诊断,HPP病情严重程度与血清ALP值和ALPL基因变异位点有关。

Objective To analyze the oral phenotype and gene variation of children with hypophosphatasia(HPP),and explore the genotype-phenotype correlations.Methods Eight children diagnosed with HPP from January 2008 to January 2023 in The Children′s Hospital,Zhejiang University School of Medicine were recruited in this study.The pathogenic genes of 5 of them were sequentially analyzed and all of their oral manifestations,laboratory tests and genetic variation types were retrospectively analyzed.Results A total of 8 children were recruited in the study,3 males and 5 females,aged from 20 to 104 months,whose main complaints were premature deciduous tooth loss.Among them,3 children were diagnosed with odonto HPP,and the other 5 children were diagnosed with childhood HPP,including 2 children was odonto HPP at the first diagnosis and modified as childhood HPP at the age of 5.The age range of first deciduous tooth loss is 9 to 18 months,and the age range of diagnosis was 20 to 104 months.The patients of odonto HPP only showed premature loss of deciduous anterior tooth,while the patients with childhood HPP also showed premature loss of multiple deciduous molars.Panoramic radiographic film revealed enlarged pulp chambers and radicular canals in some primary and permanent teeth.The enamel hypoplasia,hypoplastic short roots,and alveolar resorption of deciduous molar were observed in some cases.The serum alkaline phosphatase(ALP)(30-107 U/L)levels of all the patients were lower than that in the normal children of same age and gender,and the ALP value of the 1-3 years old girls with childhood HPP(30-33 U/L)was lower than that of the three children with odonto HPP(61-107 U/L),but there was no significant difference in statistical analysis.There were 8 variation sites of ALP liver/bone/kidney(ALPL)gene detected in 5 children and their families,all of which were missense variation,including the new variants in the mutations of c.1334C>G(p.Ser445Cys)and c.1259G>T(p.Gly420Val)that were not reported in the literature.One case was autosomal dominant inheritance and other 4 cases were complex heterozygous variation with autosomal recessive inheritance.Conclusions Pediatric stomatologists are often the first doctors to detect childhood and odonto HPP.Diagnosis of mild HPP is often delayed.The severity of HPP is related to serum ALP level and ALPL gene mutation sites.