常染色体显性遗传骨硬化症Ⅱ型的2例家系报道及文献复习

doi:10.6040/j.issn.1671-7554.0.2024.0064

摘要/Abstract

摘要： 目的分析两例常染色体显性骨硬化症(autosomal dominant osteopetrosis, ADO)患者的临床特点,对先证者及其家系的致病基因突变进行研究。方法收集两例骨硬化症患者的的临床特征及实验室检查资料进行总结分析,并复习相关文献对该病的诊治思路进行归纳总结。结果基因检测显示先证者1的氯离子通道蛋白7(chloride channel protein 7, CLCN7)基因第24外显子新的错义突变,即p.Gly765Cys,先证者2的CLCN7的第10外显子发现了一个已知的错义突变,即p.Arg286Trp,两位先证者均有骨量异常增高表现, 椎体呈“夹心饼”样改变,且两者均表现为血钙、磷和碱性磷酸酶水平正常,而乳酸脱氢酶和肌酸激酶水平升高。结论 ADO患者主要表现为骨密度异常增高、骨脆性增加及容易骨折等,目前该疾病多采取对症治疗,严重时可导致贫血、血小板减少伴出血、频发感染、肝脾肿大等,通过文献复习进一步总结ADO的临床表现和诊疗特点。

关键词: 常染色体显性遗传骨硬化症, 氯离子通道蛋白7, 错义突变, 骨折, 骨密度

Abstract: Objective To analyze the clinical features of two patients with autosomal dominant osteopetrosis(ADO), and to explore the mutations in the causative genes in the probands and their family lines. Methods The clinical characteristics and laboratory examination data of the two ADO cases were collected and analyzed, and relevant literature was reviewed to summarize the diagnosis and treatment of the disease. Results Genetic testing revealed a new missense mutation in exon 24 of the chloride channel protein 7(CLCN7)gene, p.Gly765Cys, in proband 1, and a known missense mutation, p.Arg286Trp, in exon 10 of the CLCN7 gene in proband 2. Both probands manifested abnormally high bone mass and "sandwich" vertebral body changes, but both had normal blood calcium, phosphorus and alkaline phosphatase levels and elevated lactate dehydrogenase and creatine kinase levels. Conclusion Patients with ADO mainly exhibit abnormally high bone density, increased bone fragility and susceptibility to fracture. Currently, the disease is mostly treated symptomatically. In severe cases, anemia, thrombocytopenia with hemorrhage, frequent infections, and liver and spleen enlargement may occur. Further literature review will better summarize the clinical presentation, diagnosis and therapeutic features of ADO.

Key words: Autosomal dominant osteopetrosis, Chloride channel protein 7, Missense mutation, Fracture, Bone mineral density

中图分类号:

R681

张迪,聂辰宇,刘继东,侯新国,陈丽. 常染色体显性遗传骨硬化症Ⅱ型的2例家系报道及文献复习[J]. 山东大学学报 (医学版), 2024, 62(6): 82-90.

ZHANG Di, NIE Chenyu, LIU Jidong, HOU Xinguo, CHEN Li. Two family reports and literature review of autosomal dominant osteopetrosis type II[J]. Journal of Shandong University (Health Sciences), 2024, 62(6): 82-90.

参考文献

[1] Wang C, Zhang H, He JW, et al. The virulence gene and clinical phenotypes of osteopetrosis in the Chinese population: six novel mutations of the CLCN7 gene in twelve osteopetrosis families[J]. J Bone Miner Metab, 2012, 30(3): 338-348.
[2] 蒋洁, 徐潮, 赵家军. 骨硬化症的诊疗现状[J]. 国际内分泌代谢杂志, 2023, 43(4): 301-304. JIANG Jie, XU Chao, ZHAO Jiajun. Diagnosis and treatment of osteosclerosis[J]. International Journal of Endocrinology and Metabolism, 2023, 43(4): 301-304.
[3] Wu CC, Econs MJ, DiMeglio LA, et al. Diagnosis and management of osteopetrosis: consensus guidelines from the osteopetrosis working group[J]. J Clin Endocrinol Metab, 2017, 102(9): 3111-3123.
[4] Del Fattore A, Cappariello A, Teti A. Genetics, pathogenesis and complications of osteopetrosis[J]. Bone, 2008, 42(1): 19-29.
[5] Bug DS, Barkhatov IM, Gudozhnikova YV, et al. Identification and characterization of a novel CLCN7 variant associated with osteopetrosis[J]. Genes(Basel), 2020, 11(11): E1242.
[6] Cleiren E, Bénichou O, Van Hul E, et al. Albers-Schönberg disease(autosomal dominant osteopetrosis, type II)results from mutations in the ClCN7 chloride channel gene[J]. Hum Mol Genet, 2001, 10(25): 2861-2867.
[7] Li L, Lv SS, Wang C, et al. Novel CLCN7 mutations cause autosomal dominant osteopetrosis type II and intermediate autosomal recessive osteopetrosis[J]. Mol Med Rep, 2019, 19(6): 5030-5038.
[8] Ou M, Li C, Tang D, et al. Genotyping, generation and proteomic profiling of the first human autosomal dominant osteopetrosis type II-specific induced pluripotent stem cells[J]. Stem Cell Res Ther, 2019, 10(1): 251.
[9] Waguespack SG, Hui SL, DiMeglio LA, et al. Autosomal dominant osteopetrosis: clinical severity and natural history of 94 subjects with a chloride channel 7 gene mutation[J]. J Clin Endocrinol Metab, 2007, 92(3): 771-778.
[10] Palagano E, Menale C, Sobacchi C, et al. Genetics of osteopetrosis[J]. Curr Osteoporos Rep, 2018, 16(1): 13-25.
[11] Del Fattore A, Cappariello A, Teti A. Genetics, pathogenesis and complications of osteopetrosis[J]. Bone, 2008, 42(1): 19-29.
[12] Spinnato P, Pedrini E, Petrera MR, et al. Spectrum of skeletal imaging features in osteopetrosis: inheritance pattern and radiological associations[J]. Genes(Basel), 2022, 13(11): 1965.
[13] Bollerslev J, Henriksen K, Nielsen MF, et al. Autosomal dominant osteopetrosis revisited: lessons from recent studies[J]. Eur J Endocrinol, 2013, 169(2): R39-R57.
[14] Coudert AE, de Vernejoul MC, Muraca M, et al. Osteopetrosis and its relevance for the discovery of new functions associated with the skeleton[J]. Int J Endocrinol, 2015, 2015: 372156. doi:10.1155/2015/372156.
[15] Yuan P, Yue ZH, Sun LZ, et al. Novel mutation of TCIRG1 and clinical pictures of two infantile malignant osteopetrosis patients[J]. J Bone Miner Metab, 2011, 29(2): 251-256.
[16] Penna S, Villa A, Capo V. Autosomal recessive osteopetrosis: mechanisms and treatments[J]. Dis Model Mech, 2021, 14(5): dmm048940.
[17] Whyte MP. Carbonic anhydrase II deficiency[J]. Bone, 2023, 169: 116684. doi:10.1016/j.bone.2023.116684.
[18] Wang Z, Li X, Wang Y, et al. Natural history of type II autosomal dominant osteopetrosis: a single center retrospective study[J]. Front Endocrinol(Lausanne), 2022, 13: 819641. doi:10.3389/fendo.2022.819641.
[19] Bollerslev J, Henriksen K, Nielsen MF, et al. Autosomal dominant osteopetrosis revisited: lessons from recent studies[J]. Eur J Endocrinol, 2013, 169(2): R39-R57.
[20] Xue Y, Wang W, Mao T, et al. Report of two Chinese patients suffering from CLCN7-related osteopetrosis and root dysplasia[J]. J Craniomaxillofac Surg, 2012, 40(5): 416-420.
[21] Piret SE, Gorvin CM, Trinh A, et al. Autosomal dominant osteopetrosis associated with renal tubular acidosis is due to a CLCN7 mutation[J]. Am J Med Genet A, 2016, 170(11): 2988-2992.
[22] Whyte MP, Chines A, Silva DP, et al. Creatine kinase brain isoenzyme(BB-CK)presence in serum distinguishes steopetrosis among the sclerosing bone disorders[J]. J Bone Miner Res, 1996, 11(10): 1438-1443.
[23] Waguespack SG, Hui SL, White KE, et al. Measurement of tartrate-resistant acid phosphatase and the brain isoenzyme of creatine kinase accurately diagnoses type II autosomal dominant osteopetrosis but does not identify gene carriers[J]. J Clin Endocrinol Metab, 2002, 87(5): 2212-2217.
[24] Alatalo SL, Ivaska KK, Waguespack SG, et al. Osteoclast-derived serum tartrate-resistant acid phosphatase 5b in albers-schoönberg disease(type II autosomal dominant osteopetrosis)[J]. Clin Chem, 2004, 50(5): 883-890.
[25] Whyte MP, Kempa LG, McAlister WH, et al. Elevated serum lactate dehydrogenase isoenzymes and aspartate transaminase distinguish Albers-Schönberg disease(Chloride Channel 7 Deficiency Osteopetrosis)among the sclerosing bone disorders[J]. J Bone Miner Res, 2010, 25(11): 2515-2526.
[26] Chu K, Koller DL, Snyder R, et al. Analysis of variation in expression of autosomal dominant osteopetrosis type 2: searching for modifier genes[J]. Bone, 2005, 37(5): 655-661.
[27] Pang Q, Chi Y, Zhao Z, et al. Novel mutations of CLCN7 cause autosomal dominant osteopetrosis type II(ADO-II)and intermediate autosomal recessive osteopetrosis(IARO)in Chinese patients[J]. Osteoporos Int, 2016, 27(3): 1047-1055.
[28] Bénichou O, Cleiren E, Gram J, et al. Mapping of autosomal dominant osteopetrosis type II(Albers-Schönberg disease)to chromosome 16p13.3[J]. Am J Hum Genet, 2001, 69(3): 647-654.
[29] Kim SY, Lee Y, Kang YE, et al. Genetic analysis of CLCN7 in an old female patient with type II autosomal dominant osteopetrosis[J]. Endocrinol Metab(Seoul), 2018, 33(3): 380-386.
[30] Frattini A, Pangrazio A, Susani L, et al. Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis[J]. J Bone Miner Res, 2003, 18(10): 1740-1747.
[31] Leisle L, Ludwig CF, Wagner FA, et al. ClC-7 is a slowly voltage-gated 2Cl(-)/1H(+)-exchanger and requires Ostm1 for transport activity[J]. EMBO J, 2011, 30(11): 2140-2152.
[32] Alkhayal Z, Shinwari Z, Gaafar A, et al. Carbonic anhydrase II activators in osteopetrosis treatment: a review[J]. Curr Issues Mol Biol, 2023, 45(2): 1373-1386.
[33] Key LL, Ries WL, Rodriguiz RM, et al. Recombinant human interferon gamma therapy for osteopetrosis[J]. J Pediatr, 1992, 121(1): 119-124.
[34] Polgreen LE, Imel EA, Econs MJ. Autosomal dominant osteopetrosis[J]. Bone, 2023, 170: 116723. doi:10.1016/j.bone.2023.116723.
[35] Teti A, Econs MJ. Osteopetroses, emphasizing potential approaches to treatment[J]. Bone, 2017, 102: 50-59. doi:10.1016/j.bone.2017.02.002.

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