31例新生儿筛查阴性的先天性甲状腺功能减退症患儿临床特点及转归

Clinical features and outcomes of 31 children with congenital hypothyroidism missed by neonatal screening

目的:探讨新生儿筛查阴性的先天性甲状腺功能减退症(CH)患儿的临床特点及转归。方法:回顾性分析2015年2月至2022年2月广州市妇女儿童医疗中心确诊的31例筛查阴性CH患儿的临床、实验室资料,其中17例进行了全外显子组高通量测序基因分析。结果:31例CH患儿中,早产儿19例(61.3%),足月儿12例(38.7%),胎龄36(26~40)周,出生体重2.35(0.75~3.70)kg,诊断年龄20 d(7 d~4岁),初筛干血斑促甲状腺素4.18(0.34~8.97)mU/L。同性别双胎儿9例(29.0%),有甲状腺功能减退家族史4例(12.9%)。首发症状为体重增长缓慢11例(35.5%),黄疸消退延迟7例(22.6%),矮小症、腹胀伴脐疝、胎儿水肿、甲状腺肿各1例(3.2%)。17例患儿全外显子组测序结果显示,10例检出DUOX2基因突变(携带双位点突变6例,携带单位点突变4例),其中3例伴甲状腺功能减退家族史。22例进行了诊断再评估,其中17例(77.3%)为暂时性CH,5例(22.7%)为永久性CH。10例DUOX2基因突变患儿中,6例为暂时性CH,1例为永久性CH,3例(均为3岁以下)仍在治疗中。结论:CH筛查假阴性多见于早产、低出生体重、同性别双胎、有甲状腺功能减退家族史患儿,DUOX2基因突变是常见的分子生物学发病基础,多数患儿为暂时性CH。对不明原因生长缓慢、黄疸消退延迟患儿应及时进行甲状腺功能评估,以便早期诊断。

Objective:To investigate the clinical features and outcomes of children with congenital hypothyroidism(CH)missed by neonatal screening.Methods:The clinical and laboratory date of 31 children with CH missed by neonatal screening from February 2015 to February 2022 in Guangzhou Women and Children’s Medical Center were retrospectively analyzed.Whole-exome high-throughput sequencing analysis was performed in 17 patients.Results:Among the 31 patients,19 cases(61.3%)were preterm,12 cases(38.7%)were term neonates.The median value of gestation age was 36(26-40)weeks,birth weight was 2.35(0.75-3.70)kg,diagnosed age was 20 d(7 d-4 years),dry blood spot thyrotropin was 4.18(0.34-8.97)mU/L.Nine cases(29.0%)were same-sex twins and 4 cases(12.9%)had a family history of hypothyroidism.The initial clinical symptoms were growth retardation in 11 cases(35.5%),prolonged jaundice in 7 cases(22.6%),short stature,abdominal distension,fetal edema and goiter in 1 case(3.2%),respectively.Genetic analysis of the 17 children showed that DUOX2 gene mutations were detected in 10 cases(6 cases with biallelic mutations and 4 cases with monoallelic mutations),of whom 3 had a family history of hypothyroidism.A total of 22 patients were reevaluated at the age of 2-3 years,of whom 17 cases(77.3%)were transient CH and 5 cases(22.7%)were permanent CH.Among the 10 cases with DUOX2 gene mutations,6 cases were transient CH,1 case was permanent CH,and 3 cases(<3 years old)were still under treatment with L-thyroxine.Conclusions:False negative results on neonatal screening for CH often occurs in preterm birth,low birth weight,same-sex twins,family history of hypothyroidism,and DUOX2 defects are the common molecular pathogenesis,most of whom are transient CH.Thyroid function should be evaluated in time for children with unexplained slow growth and delayed jaundice regression.