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浙江大学学报(医学版)  2022, Vol. 51 Issue (3): 314-320    DOI: 10.3724/zdxbyxb-2022-0213
专题报道     
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
谢婷1,谭敏沂1,蒋翔1,冯瑜妤1,陈倩瑜1,梅慧芬2,蔡雁英1,邹红梅3,*(),黄永兰1,*()
1.广州市妇女儿童医疗中心 广州市新生儿筛查中心 广东省儿童健康与疾病临床医学研究中心,广东 广州 510623
2.广州市妇女儿童医疗中心遗传与内分泌科 广东省儿童健康与疾病临床医学研究中心,广东 广州 510623
3.广州市妇女儿童医疗中心新生儿科 广东省儿童健康与疾病临床医学研究中心,广东 广州 510623
Clinical features and outcomes of 31 children with congenital hypothyroidism missed by neonatal screening
XIE Ting1,TAN Minyi1,JIANG Xiang1,FENG Yuyu1,CHEN Qianyu1,MEI Huifen2,CAI Yanying1,ZOU Hongmei3,*(),HUANG Yonglan1,*()
1. Guangzhou Women and Children’s Medical Center, Guangzhou Newborn Screening Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, China;
2. Department of Pediatric Endocrinology and Genetic Metabolism, Guangzhou Women and Children’s Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, China;
3. Department of Neonatology, Guangzhou Women and Children’s Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, China
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摘要:

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。

关键词: 先天性甲状腺功能减退症新生儿筛查假阴性DUOX2基因预后    
Abstract:

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.

Key words: Congenital hypothyroidism    Neonatal screening    False negative    DUOX2 gene    Prognosis
收稿日期: 2022-04-29 出版日期: 2022-09-21
CLC:  R72  
基金资助: 广州市科技计划项目(201510010010)
通讯作者: 邹红梅,黄永兰     E-mail: xxhuang321@163.com
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谢婷
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引用本文:

谢婷,谭敏沂,蒋翔,冯瑜妤,陈倩瑜,梅慧芬,蔡雁英,邹红梅,黄永兰. 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[J]. 浙江大学学报(医学版), 2022, 51(3): 314-320.

XIE Ting,TAN Minyi,JIANG Xiang,FENG Yuyu,CHEN Qianyu,MEI Huifen,CAI Yanying,ZOU Hongmei,HUANG Yonglan. Clinical features and outcomes of 31 children with congenital hypothyroidism missed by neonatal screening. J Zhejiang Univ (Med Sci), 2022, 51(3): 314-320.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2022-0213        https://www.zjujournals.com/med/CN/Y2022/V51/I3/314

例序

性别

胎龄

(周)

出生体重(kg)

bsTSH

(mU/L)

诊断年龄

sTSH

(mU/L)

FT4

(pmol/L)

TG

(μg/L)

甲状腺超声检查

药物维持剂量(μg/d)

转归

DUOX2基因

1

28

0.75

2.70

27?d

>150.0

5.5

正常

12.5

6月龄夭折

2

28

0.65

1.60

29?d

15.1

14.8

正常

12.5

暂时性CH

3

34

2.35

2.90

10?d

75.0

7.5

59.0

增大

12.5

暂时性CH

p.Ser199TrpfsX122/p.Arg683Leu

4

34

2.40

1.67

13?d

85.0

6.8

73.2

增大

12.5

暂时性CH

p.Ser199TrpfsX122/p.Arg683Leu

5

28

1.31

0.34

12?d

89.4

5.4

101.3

10.0

暂时性CH

6

34

1.35

5.90

20?d

28.0

8.7

增大

12.5

暂时性CH

7

36

2.15

5.27

43?d

10.1

14.9

82.0

增大

12.5

永久性CH

p.Ile1130Phe#

8

36

2.25

6.82

18?d

51.6

11.2

369.3

增大

25.0

暂时性CH

9

38

3.10

4.31

19?d

36.4

14.9

118.0

增大

12.5

暂时性CH

10

26

0.80

2.69

31?d

61.8

6.9

正常

12.5

2月龄夭折

11

26

1.01

2.65

21?d

18.8

13.3

正常

6.3

暂时性CH

12

27

1.18

3.12

15?d

127.3

4.3

12.5

治疗中

13

30

1.40

2.91

24?d

31.3

12.4

81.7

正常

12.5

暂时性CH

p.Tyr1450His/ p.Gly702del

14

32

2.12

4.05

14?d

>150.0

5.7

25.0

治疗中

15

32

1.85

3.29

33?d

90.9

18.9

135.0

增大

10.0

暂时性CH

未见异常

16

34

2.58

5.05

7?d

16.5

14.5

正常

25.0

暂时性CH

未见异常

17

34

3.38

3.65

18?d

>150.0

6.3

37.5

50?d夭折

18

35

2.48

3.46

27?d

56.5

10.6

66.1

正常

12.5

暂时性CH

未见异常

19

36

2.30

7.50

60?d

34.2

11.9

107.0

正常

25.0

永久性CH

20*

36

2.70

6.83

15?d

>150.0

8.5

67.0

增大

17.0

暂时性CH

p.Lys530X/p.Ala649Glu

21

38

2.07

7.05

9?d

37.0

15.9

62.7

增大

25.0

暂时性CH

未见异常

22*

38

2.24

8.97

9?d

33.6

14.9

24.5

正常

12.5

治疗中

p.Arg434X

23

38

3.25

8.72

15?d

86.0

7.0

9.3

正常

12.5

治疗中

未见异常

24

39

3.20

4.07

22?d

23.0

13.1

67.7

正常

12.5

治疗中

p.Lys530X/p.Arg885Leu

25

39

3.70

5.54

27?d

51.8

10.3

增大

12.5

治疗中

p.Ser1349Cys

26

39

2.48

5.25

15?d

41.8

13.7

639.0

正常

37.5

永久性CH

未见异常

27

39

2.90

4.18

2岁半

37.0

8.8

增大

37.5

永久性CH

28

40

3.29

8.27

13?d

31.6

14.4

34.2

正常

12.5

暂时性CH

29

40

2.85

4.02

21?d

89.3

9.4

999.4

正常

17.0

暂时性CH

p.Glu879Lys

30*

40

3.18

8.79

60?d

9.7

11.1

增大

25.0

暂时性CH

p.Arg683Leu/p.Lys530X

31*

39

3.20

8.86

4岁

15.4

17.3

17.0

正常

37.5

永久性CH

未见异常

表 1  31例新生儿筛查阴性的CH患儿临床特征及外显子测序结果

组  别

n

bsTSH(mU/L)

sTSH(mU/L)

FT4(pmol/L)

DUOX2突变组

10

4.67(1.67~8.97)

42.7(9.6~150.0)

10.7(6.8~14.9)

双位点突变

6

3.49(1.67~8.79)

53.2(9.6~150.0)

9.8(6.8~13.1)

单位点突变

4

5.41(4.02~8.97)

42.7(10.1~89.3)

12.6(9.4~14.9)

DUOX2突变组

7

5.25(3.29~8.86)

41.8(15.4~90.9)

14.5(7.0~18.9)

表 2  有无携带突变的先天性甲状腺功能减退症患儿生化指标检测结果比较
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