免疫骨骼发育不良伴神经发育异常2例并文献复习

doi:10.3877/cma.j.issn.1673-5250.2025.05.013

中华妇幼临床医学杂志(电子版) ›› 2025, Vol. 21 ›› Issue (05) : 598 -604. doi: 10.3877/cma.j.issn.1673-5250.2025.05.013

论著

免疫骨骼发育不良伴神经发育异常2例并文献复习

宋葳¹, 周文智¹^,^†(

), 唐立², 姜舟³, 杨柳²

¹电子科技大学医学院附属妇女儿童医院·　成都市妇女儿童中心医院康复科，成都　611731
²电子科技大学医学院附属妇女儿童医院·　成都市妇女儿童中心医院保健部，成都　611731
³电子科技大学医学院附属妇女儿童医院·　成都市妇女儿童中心医院新生儿疾病筛查科，成都　611731

收稿日期:2025-02-10 修回日期:2025-09-18 出版日期:2025-10-01
通信作者: 周文智

Immune skeletal dysplasia with neurodevelopmental abnormalities: two cases report and literature review

Wei Song¹, Wenzhi Zhou¹^,^†(), Li Tang², Zhou Jiang³, Liu Yang²

¹Department of Children Rehabilitation, Chengdu Women′s and Children′s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 611731, Sichuan Province, China
²Department of Healthcare, Chengdu Women′s and Children′s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 611731, Sichuan Province, China
³Department of Neonatal Screening, Chengdu Women′s and Children′s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 611731, Sichuan Province, China

Received:2025-02-10 Revised:2025-09-18 Published:2025-10-01
Corresponding author: Wenzhi Zhou

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引用本文：

宋葳, 周文智, 唐立, 姜舟, 杨柳. 免疫骨骼发育不良伴神经发育异常2例并文献复习[J/OL]. 中华妇幼临床医学杂志(电子版), 2025, 21(05): 598-604.

Wei Song, Wenzhi Zhou, Li Tang, Zhou Jiang, Liu Yang. Immune skeletal dysplasia with neurodevelopmental abnormalities: two cases report and literature review[J/OL]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2025, 21(05): 598-604.

目的

探讨免疫骨骼发育不良伴神经发育异常(ISDNA)患儿的临床特征及遗传学特点。

方法

选择2017年5月3日于成都市妇女儿童中心医院康复科门诊就诊的1例ISDNA患儿(先证者，患儿1)及其胞兄(患儿2)为研究对象。回顾性分析其临床资料，采用全基因组测序(WGS)检测其遗传学变异，并通过Sanger测序进行验证和家系共分离分析。以"免疫骨骼发育不良伴神经发育异常""骨骼发育不良""免疫缺陷和发育迟缓""immune skeletal dysplasia with neurodevelopmental abnormalities""ISDNA""EXTL3"为中、英文关键词，分别对中国知网、万方数据库、维普数据库、PubMed及Sci-Hub等数据库中，关于ISDNA患儿的研究文献，综合分析ISDNA患儿的临床特征及遗传学特点，检索时间设定为各数据库建库至2024年11月30日。本研究通过成都市妇女儿童中心医院医学伦理委员会批准[审批文号：科研伦审2021(41)号]，并取得患儿监护人知情同意。

结果

①先证者伴多发骨骼异常、肌张力低下及通贯掌，患儿2以癫痫、发育迟缓及免疫异常为主要表现，均合并不同程度的生长发育迟缓、神经发育异常及免疫功能异常。②WGS结果显示，先证者及患儿2的EXTL3基因(NM_001440.4)第3外显子和第7外显子各检测到1个杂合变异，分别为c.1849 A>G和c.2572 C>T。其中，c.1849A>G为错义变异，c.2572C>T为无义突变，分别来源于其母亲和父亲，符合复合杂合突变遗传模式；上述变异均为未报道的新变异，依据美国医学遗传学和基因组学学会(ACMG)指南评级为临床意义不明确(VUS)。③文献复习共检索到关于ISDNA患者研究相关文献为9篇，纳入20例ISDNA患者，加上本研究先证者及患儿2，共22例ISDNA患者被纳入ISDNA患者临床特征及遗传学特点综合分析。ISDNA患者最常见的临床表现为免疫系统功能异常(77.3%)、特殊面容(72.7%)及脊柱/骨盆发育异常和发育迟缓(68.2%)；共发现EXTL3基因11种不同变异位点，纯合突变占81.8%(18/22)，复合杂合突变占18.2%(4/22)。

结论

ISDNA是罕见的常染色体隐性遗传性疾病，ISDNA患儿临床表现多样，并且存在异质性，易被临床漏诊及误诊，患者预后较差，可因严重免疫缺陷致死，或有严重残疾。本研究先证者EXTL3基因(NM_001440.4)第3外显子c.1849A>G错义变异＋第7外显子c.2572C>T无义变异，患儿2携带的EXTL3基因(NM_001440.4)第7外显子c.2572C>T无义变异，均为未报道的新变异，本研究丰富了ISDNA患者的EXTL3基因变异谱。分子遗传学诊断是目前ISDNA患儿的唯一确诊方法。

关键词: 免疫骨骼发育不良伴神经发育异常, EXTL3基因, 全基因组测序, 突变, 骨骼发育不良, 神经发育障碍, 儿童

Objective

To investigate the clinical and genetic characteristics of children with immunoskeletal dysplasia with neurodevelopmental abnormalities (ISDNA).

Methods

Two siblings with ISDNA who were evaluated at the Department of Rehabilitation Medicine, Chengdu Women′s and Children′s Central Hospital on May 3, 2017, including the proband (Patient 1) and his brother (Patient 2), were enrolled. Their clinical data were retrospectively reviewed. Whole-genome sequencing (WGS) was performed to identify genetic variants, which were subsequently validated by Sanger sequencing and segregation analysis. A literature search was conducted using the keywords " immunoskeletal dysplasia with neurodevelopmental abnormalities" " ISDNA" " skeletal dysplasia" " immunodeficiency and developmental delay" and " EXTL3" in both Chinese and English in the CNKI, Wanfang, VIP, PubMed, and Sci-Hub databases from inception of each database to November 30, 2024, to summarize the clinical and genetic features of ISDNA. The study was approved by the Ethics Committee of Chengdu Women′s and Children′s Central Hospital [Approval No. 2021(41)], and informed consent was obtained from the guardians.

Results

① Both patients presented with varying degrees of growth retardation, neurodevelopmental abnormalities, and immune dysfunction. The proband (Patient 1) additionally exhibited multiple skeletal anomalies, hypotonia, and a single transverse palmar crease, whereas his brother (Patient 2) mainly manifested with epilepsy, developmental delay, and immune abnormalities. ② WGS revealed two heterozygous variants in the EXTL3 gene (NM_001440.4) of the proband and Patient 2: a missense variant c. 1849A>G in exon 3 and a nonsense variant c. 2572C>T in exon 7, inherited from the mother and father, respectively, consistent with a compound heterozygous pattern. Both variants were novel and were classified as variants of uncertain significance (VUS) according to the ACMG guidelines. ③The literature review identified 9 publications involving 20 patients with ISDNA; together with the present 2 cases, a total of 22 patients were analyzed. The most common clinical features were immune abnormalities (77.3%), characteristic facial features (72.7%), and spinal/pelvic abnormalities and developmental delay (68.2%). Eleven distinct EXTL3 variants were identified, of which homozygous variants accounted for 81.8% (18/22) and compound heterozygous variants for 18.2% (4/22).

Conclusions

ISDNA is a rare autosomal recessive disorder characterized by heterogeneous clinical manifestations and a poor prognosis. Patients may die from severe immunodeficiency or suffer from significant disability. Molecular genetic testing currently represents the only definitive method for confirming the diagnosis.

Key words: Immunoskeletal dysplasia with neurodevelopmental abnormalities, EXTL3 gene, Whole-genome sequencing, Mutation, Skeletal dysplasia, Neurodevelopmental disorder, Child

图1 本研究先证者(男性，8岁)0~1岁时生长曲线图(图1A：身高曲线图；图1B：体重曲线图)注：先证者为免疫骨骼发育不良伴神经发育异常患儿

图2 先证者(男性，8岁)及患儿2(男性，11岁)与其父母EXTL3基因Sanger测序图[图2A、2B：先证者及其母亲EXTL3基因第3外显子c.1849A>G杂合突变(红色方框所示)；图2C：先证者父亲该位点未见突变(红色方框所示)；图2D：患儿2该位点亦可见该突变(红色方框所示)]注：先证者及患儿2均为免疫骨骼发育不良伴神经发育异常患儿

图3 先证者(男性，8岁)及患儿2(男性，11岁)与其父母EXTL3基因Sanger测序图[图3A、3C、3D：分别为先证者及患儿2与其父亲EXTL3基因第7外显子c.2572C>T杂合突变(红色方框所示)；图3B：先证者母亲该位点未见突变(红色方框所示)]注：先证者及患儿2均为免疫骨骼发育不良伴神经发育异常患儿

表1 本研究22例ISDNA患者的临床特征及基因检测结果比较

患儿编号	文献(第1作者，发表年)	性别/年龄	脊柱和骨盆异常	四肢骨短	发育迟缓	肌张力异常	癫痫	免疫系统异常	特殊面容	肝囊肿	皮疹	基因检测结果
1	本研究	男/8岁	－	＋	＋	＋↓	－	±^b	－	－	－	c.1849 A>G，c.2572 C>T
2	本研究	男/11岁	－	－	＋	＋↓	＋	＋	－	－	＋	c.1849 A>G，c.2572 C>T
3	Akçahan^[1]，2021	男/15岁	＋	－	＋	＋↓	＋	±^c	/^a	＋	－	c.953 C>T
4	Volpi^[2]，2017	男/11个月龄	＋	＋	＋	－	＋	＋	－	－	＋	c.1015C>T
5	Volpi^[2]，2017	女/7个月龄	＋	＋	＋	－	＋	＋	－	＋	＋	c.1015C>T
6	Volpi^[2]，2017	女/2岁	＋	＋	＋	＋↓	－	＋	＋	－	－	c.1382 C>T
7	Bajaj^[3]，2022	女/15个月龄	＋	＋	＋	＋↓	－	－	＋	－	－	c.953 C>T
8	Oud^[4]，2017	女/7周龄	＋	＋	/^a	/^a	－	＋	＋	＋	－	c.1537C>T
9	Oud^[4]，2017	女/未报道	－	＋	＋	/^a	－	＋	＋	－	＋	c.2008 T>G
10	Oud^[4]，2017	男/未报道	－	＋	＋	/^a	－	＋	＋	－	＋	c.2008 T>G
11	Oud^[4]，2017	女/未报道	＋	－	＋	/^a	－	－	＋	－	－	c.1382 C>T
12	Oud^[4]，2017	男/30岁	＋	＋	＋	/^a	－	－	＋	－	－	c.1382 C>T
13	Oud^[4]，2017	女/未报道	＋	＋	－	/^a	－	－	＋	－	－	c.1382 C>T
14	Oud^[4]，2017	女/未报道	＋	＋	－	/^a	－	－	＋	－	－	c.1382 C>T
15	Oud^[4]，2017	男/6个月龄	＋	－	/^a	/^a	－	＋	＋	＋	＋	c.1970 A>G
16	Oud^[4]，2017	男/10个月龄	＋	－	/^a	/^a	－	＋	＋	＋	＋	c.1970 A>G
17	Guo^[5]，2017	女/2岁	＋	＋	＋	＋↓	－	＋	＋	＋	－	c.953 C>T
18	Guo^[5]，2017	女/未报道	＋	＋	＋	/^a	－	±^d	＋	＋	－	c.953 C>T
19	Demir^[6]，2023	女/未报道	/^a	/^a	/^a	＋↓	－	＋	＋	＋	－	c.1537 C>T
20	Tian^[7], 2023	女/17个月龄	/^a	/^a	＋	＋↑	－	＋	＋	－	＋	c.2015 G>A
21	林晴晴^[8]，2024	男/4个月龄	＋	/^a	/^a	＋↓	－	＋	＋	－	＋	c.1970A>G，c.1262G>A
22	Mehta^[9]，2024	男/1岁	－	－	＋	/^a	－	＋	－	＋	－	c.1537C>G，c.2305G>C

表1 本研究22例ISDNA患者的临床特征及基因检测结果比较

患儿编号	文献(第1作者，发表年)	性别/年龄	脊柱和骨盆异常	四肢骨短	发育迟缓	肌张力异常	癫痫	免疫系统异常	特殊面容	肝囊肿	皮疹	基因检测结果
1	本研究	男/8岁	－	＋	＋	＋↓	－	±^b	－	－	－	c.1849 A>G，c.2572 C>T
2	本研究	男/11岁	－	－	＋	＋↓	＋	＋	－	－	＋	c.1849 A>G，c.2572 C>T
3	Akçahan^[1]，2021	男/15岁	＋	－	＋	＋↓	＋	±^c	/^a	＋	－	c.953 C>T
4	Volpi^[2]，2017	男/11个月龄	＋	＋	＋	－	＋	＋	－	－	＋	c.1015C>T
5	Volpi^[2]，2017	女/7个月龄	＋	＋	＋	－	＋	＋	－	＋	＋	c.1015C>T
6	Volpi^[2]，2017	女/2岁	＋	＋	＋	＋↓	－	＋	＋	－	－	c.1382 C>T
7	Bajaj^[3]，2022	女/15个月龄	＋	＋	＋	＋↓	－	－	＋	－	－	c.953 C>T
8	Oud^[4]，2017	女/7周龄	＋	＋	/^a	/^a	－	＋	＋	＋	－	c.1537C>T
9	Oud^[4]，2017	女/未报道	－	＋	＋	/^a	－	＋	＋	－	＋	c.2008 T>G
10	Oud^[4]，2017	男/未报道	－	＋	＋	/^a	－	＋	＋	－	＋	c.2008 T>G
11	Oud^[4]，2017	女/未报道	＋	－	＋	/^a	－	－	＋	－	－	c.1382 C>T
12	Oud^[4]，2017	男/30岁	＋	＋	＋	/^a	－	－	＋	－	－	c.1382 C>T
13	Oud^[4]，2017	女/未报道	＋	＋	－	/^a	－	－	＋	－	－	c.1382 C>T
14	Oud^[4]，2017	女/未报道	＋	＋	－	/^a	－	－	＋	－	－	c.1382 C>T
15	Oud^[4]，2017	男/6个月龄	＋	－	/^a	/^a	－	＋	＋	＋	＋	c.1970 A>G
16	Oud^[4]，2017	男/10个月龄	＋	－	/^a	/^a	－	＋	＋	＋	＋	c.1970 A>G
17	Guo^[5]，2017	女/2岁	＋	＋	＋	＋↓	－	＋	＋	＋	－	c.953 C>T
18	Guo^[5]，2017	女/未报道	＋	＋	＋	/^a	－	±^d	＋	＋	－	c.953 C>T
19	Demir^[6]，2023	女/未报道	/^a	/^a	/^a	＋↓	－	＋	＋	＋	－	c.1537 C>T
20	Tian^[7], 2023	女/17个月龄	/^a	/^a	＋	＋↑	－	＋	＋	－	＋	c.2015 G>A
21	林晴晴^[8]，2024	男/4个月龄	＋	/^a	/^a	＋↓	－	＋	＋	－	＋	c.1970A>G，c.1262G>A
22	Mehta^[9]，2024	男/1岁	－	－	＋	/^a	－	＋	－	＋	－	c.1537C>G，c.2305G>C

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Immune skeletal dysplasia with neurodevelopmental abnormalities: two cases report and literature review

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Immune skeletal dysplasia with neurodevelopmental abnormalities: two cases report and literature review