Stankiewicz-Isidor综合征一例基因型及临床表型分析并文献复习

doi:10.16150/j.1671-2870.2023.01.009

摘要/Abstract

摘要：

目的: 分析1例Stankiewicz-Isidor综合征（Stankiewicz-Isidor syndrome，STISS）男童的临床特征及检查结果，并结合文献复习，为特殊类型矮小症的诊治提供参考。方法: 1例因“生长发育落后4年伴面部畸形和视力异常”就诊的4岁男童，对其进行详细的病史采集及体格检查，行生长激素激发试验、胰岛素样生长因子1、甲状腺功能等检测以及相关影像学检查。采用第二代目标区域捕获高通量测序技术对患儿及其父母进行全外显子检测，并对可疑基因变异位点进行Sanger测序验证。结合文献分析STISS患儿临床表型与基因型的特点。结果: 该例患儿存在生长发育迟缓、视力障碍，伴低耳位、下颌后缩和小颌畸形特殊面容；全外显子测序发现PSMD12基因1个杂合移码变异c.1118delinsCC:p.Ile373ThrfsTer15，而受检者父母均未携带该变异。根据美国医学遗传学与基因组学学会（American College of Medical Genetics and Genomics,ACMG）指南，评判该变异为致病性变异，且为新发变异，结合患儿基因型和临床表型诊断为STISS。检索数据库（中国知网、万方数据库、PubMed），获得46例STISS患者，加上本例患者共47例。分析发现，89.4%（42/47）存在生长发育障碍，85.1%（40/47）存在面部畸形，70.2%（33/47）存在智力障碍，但脑影像学异常以及皮肤表现异常则较少见。47例患者中，13例存在PSMD12基因缺失，34例存在单碱基位点变异。结论: 本文报道的STISS患儿为PSMD12基因变异导致，该变异为新发变异，且数据库内未见此类变异报道；该患儿存在生长发育障碍、面部畸形等常见临床表型，但不同基因型患者的临床表型存在异质性。

关键词: Stankiewicz-Isidor综合征, PSMD12基因, 基因型, 临床表型

Abstract:

Objective: To analyze the clinical characteristics and examination results of a child with Stankiewicz-Isidor syndrome (STISS), and to provide reference for the diagnosis and treatment of special types of short stature. Methods: A 4-year-old boy with “4 years of developmental delay with craniofacial abnomality and ophthalmological malformation” was recruited,and detailed medical history were collected. Physical examination, laboratory detection [growth hormone stimulation test, insulin-like growth factor 1( IGF-1), thyroid function and other tests] and imaging examinations were performed. Whole-exome sequencing(WES) was used to detect suspicious mutation sites in children and their parents with se-cond-generation target region capture high-throughput sequencing technology, and the findings were verified by Sanger sequencing. The phenotypes and genotype of the STISS children were analyzed in combination with cases reported in literature reported in PubMed, China National Knowledge Internet(CNKI) and WANFANG DATA. Results: The child presented growth retardation, visual impairment, low ear position, mandibular recession, and special facial features of micrognathia. WES revealed a novel heterozygous frameshift variant c.1118delinsCC:p.Ile373ThrfsTer15 in the PSMD12 gene. According to ACMG guidelines, this was a pathogenic variant, which led to STISS.A total of 46 patients with STISS reported pre-viously,and thus there were 47 cases to be analyzed. It indicated that 89.4%(42/47) had growth and development disorders, 85.1%（40/47） had facial deformities, 70.2%（33/47） had intellectual disabilities, while brain imaging abnormalities and skin manifestations were rare.In 47 patients, 13 cases had PSMD12 gene deletion and 34 cases carried single base site mutations in PSMD12 gene. Conclusions: The STISS reported in this article is caused by a novel variation in PSMD12 gene. The child has common clinical phenotypes such as growth and development disorders and facial deformities, but the clinical phenotypes in patients with different genotypes are heterogeneous.

Key words: Stankiewicz-Isidor syndrome, PSMD12 gene, Genotype, Clinical phenotype

中图分类号:

R596

张雪蕾, 何亲羽, 张习雯, 陈立芬, 董治亚. Stankiewicz-Isidor综合征一例基因型及临床表型分析并文献复习[J]. 诊断学理论与实践, 2023, 22(01): 58-63.

ZHANG Xuelei, HE Qinyu, ZHANG Xiwen, CHEN Lifen, DONG Zhiya. Genotype and clinical phenotype analysis of a case of Stankiewicz-Isidor syndrome and literature review[J]. Journal of Diagnostics Concepts & Practice, 2023, 22(01): 58-63.

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参考文献 21

[1]	KÜRY S, BESNARD T, EBSTEIN F, et al. De novo disruption of the proteasome regulatory subunit PSMD12 causes a syndromic neurodevelopmental disorder[J]. Am J Hum Genet, 2017, 100(4):689. doi: S0002-9297(17)30106-4 pmid: 28388435
[2]	KHALIL R, KENNY C, HILL R S, et al. PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features[J]. Am J Med Genet B Neuropsychiatr Genet, 2018, 177(8):736-745. doi: 10.1002/ajmg.v117.8 URL
[3]	PALUMBO P, PALUMBO O, ESTER D M, et al. Expan-ding the clinical and molecular spectrum of PSMD12-related neurodevelopmental syndrome:an additional patient and review[J]. Arch Clin Med Case Rep, 2019; 3(5):250-260.
[4]	ISIDOR B, EBSTEIN F, HURST A, et al. Stankiewicz-Isidor syndrome: expanding the clinical and molecular phenotype[J]. Genet Med, 2022, 24(1):179-191. doi: 10.1016/j.gim.2021.09.005 URL
[5]	YAN K, ZHANG J, LEE P Y, et al. Haploinsufficiency of PSMD12 Causes Proteasome Dysfunction and Subclinical Autoinflammation[J]. Arthritis Rheumatol, 2022, 74(6):1083-1090. doi: 10.1002/art.v74.6 URL
[6]	TAVTIGIAN S V, HARRISON S M, BOUCHER K M, et al. Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines[J]. Hum Mutat, 2020, 41(10):1734-1737. doi: 10.1002/humu.v41.10 URL
[7]	HAN B, LUO J, JIANG P, et al. Inhibition of embryonic HSP 90 function promotes variation of cold tolerance in zebrafish[J]. Front Genet, 2020, 11:541944. doi: 10.3389/fgene.2020.541944 URL
[8]	FÖRSTER F, UNVERDORBEN P, SLEDŹ P, et al. Unveiling the long-held secrets of the 26S proteasome[J]. Structure, 2013, 21(9):1551-1562. doi: 10.1016/j.str.2013.08.010 pmid: 24010714
[9]	HANCAROVA M, MALIKOVA M, KOTROVA M, et al. Association of 17q24.2-q24.3 deletions with recognizable phenotype and short telomeres[J]. Am J Med Genet A, 2018, 176(6):1438-1442. doi: 10.1002/ajmg.a.38711 pmid: 29696806
[10]	STANKIEWICZ P, KHAN T N, SZAFRANSKI P, et al. Haploinsufficiency of the chromatin remodeler BPTF causes syndromic developmental and speech delay, postnatal microcephaly, and dysmorphic features[J]. Am J Hum Genet, 2017, 101(4):503-515. doi: S0002-9297(17)30336-1 pmid: 28942966
[11]	ROSENFELD J A, PATEL A. Chromosomal microarrays: understanding genetics of neurodevelopmental disorders and congenital anomalies[J]. J Pediatr Genet, 2017, 6(1):42-50. doi: 10.1055/s-0036-1584306 pmid: 28180026
[12]	RICE G I, MELKI I, FRÉMOND M L, et al. Assessment of type I interferon signaling in pediatric inflammatory disease[J]. J Clin Immunol, 2017, 37(2):123-132. doi: 10.1007/s10875-016-0359-1 pmid: 27943079
[13]	ZHANG N, OSBORN M, GITSHAM P, et al. Using yeast to place human genes in functional categories[J]. Gene, 2003, 303:121-129. pmid: 12559573
[14]	GAMBIN T, YUAN B, BI W, et al. Identification of novel candidate disease genes from de novo exonic copy number variants[J]. Genome Med, 2017, 9(1):83. doi: 10.1186/s13073-017-0472-7 pmid: 28934986
[15]	DAMBACHER C M, WORDEN E J, HERZIK M A, et al. Atomic structure of the 26S proteasome lid reveals the mechanism of deubiquitinase inhibition[J]. Elife, 2016, 5:e13027. doi: 10.7554/eLife.13027 URL
[16]	SAEZ I, KOYUNCU S, GUTIERREZ G R, et al. Insights into the ubiquitin-proteasome system of human embryonic stem cells[J]. Sci Rep, 2018, 8(1):4092. doi: 10.1038/s41598-018-22384-9 pmid: 29511261
[17]	SAXTON R A, SABATINI D M. MTOR signaling in growth,metabolism,and disease[J]. Cell, 2017, 168(6):960-976. doi: 10.1016/j.cell.2017.02.004 URL
[18]	TĂRLUNGEANU D C, NOVARINO G. Genomics in neurodevelopmental disorders: an avenue to personalized medicine[J]. Exp Mol Med, 2018, 50(8):1-7.
[19]	ISIDOR B, KÜRY S, ROSENFELD J A, et al. De novo truncating mutations in the kinetochore-microtubules attachment gene CHAMP1 cause syndromic intellectual disability[J]. Hum Mutat, 2016, 37(4):354-358. doi: 10.1002/humu.22952 pmid: 26751395
[20]	NAUD M E, TOSCA L, MARTINOVIC J, et al. Prenatal diagnosis of a 2.5 Mb De Novo 17q24.1q24.2 Deletion encompassing KPNA2 and PSMD 12 Genes in a fetus with craniofacial dysmorphism, equinovarus feet, and syndactyly[J]. Case Rep Genet, 2017; 2017:7803136.
[21]	SARRABAY G, MÉCHIN D, SALHI A, et al. PSMB10, the last immunoproteasome gene missing for PRAAS[J]. J Allergy Clin Immunol, 2020, 145(3):1015-1017. doi: S0091-6749(19)31607-0 pmid: 31783057

Indice	Results	Reference range
GH peak/（ng·mL^-1）	23.96	>10.0
IGF-1/(ng·mL^-1)	55	49~289
HbA1c/%	5.4	4.7~6.4
Thyroid function	Normal range	-
Bone age/y	2.5	-
Imaging examination	Normal	-

Clinical phenotypes	Clinical phenotypes reported（46 cases）	Clinical phenotype of the child
Gender	Male（25/46），Female（21/46）	Male
Age at assessment	1 d~42 years	4 years
Growth retantation	41/46	+
Craniofacial abnomalities	39/46	+
Intellectual disability	33/46	-
Delay motor	17/46	-
Delay speech	33/46	-
Seizures	6/46	-
Autism	5/46	-
Ophthalmological malformations	24/46	+
Deafness	23/46	-
Hypotonia	8/46	+
Feeding difficulties	17/46	+
Brain MRI	6/46	-
Chilblains resembling signs	2/46	-
Urticaria	2/46	-