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

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

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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