8例Blau综合征/早发型结节病临床表现、病理特征及基因突变的多样性分析

郑义; 贾韬; 延聪; 张欣悦; 杜雪珊; 周彤; 宋相瑾; 耿松梅

doi:10.12376/j.issn.2097-0501.2023.02.005

8例Blau综合征/早发型结节病临床表现、病理特征及基因突变的多样性分析

doi: 10.12376/j.issn.2097-0501.2023.02.005

西安交通大学第二附属医院皮肤病院，西安 710004

详细信息

通信作者:
耿松梅，E-mail：gsm312@yahoo.com

中图分类号: R725.9; R758.5
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出版历程
- 收稿日期: 2023-01-15
- 录用日期: 2023-02-04
- 网络出版日期: 2023-05-05

Analysis of 8 Cases of Blau Syndrome/Early-onset Sarcoidosis——Clinical Manifestations, Histopathology Features and Gene Mutation Diversity

Department of Dermatology, the Second Hospital Affiliated to Xi′an Jiaotong University, Xi′an 710004, China

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Corresponding author: GENG Songmei, E-mail: gsm312@yahoo.com

摘要

摘要: 目的总结Blau综合征/早发型结节病的临床表现、病理特征及基因突变多样性。方法收集2011年1月至2022年12月我院诊治的8例Blau综合征/早发型结节病患者一般资料及临床表现、辅助检查等结果，总结分析其特征及多样性。结果 8例患者中，男4例，女4例，发病年龄3~18月龄。7例(87.5%)患者以皮疹为首发症状。6例(75.0%)患者皮损表现为苔藓样丘疹，2例表现为红斑样皮损。有3例(37.5%)出现关节炎，2例(25.0%)出现葡萄膜炎等眼部炎症，4例(50.0%)出现间断性发热，3例(37.5%)出现神经系统、呼吸系统症状及高血压。8例患者皮肤组织病理均表现为非干酪样肉芽肿形成。血清学指标中，CRP和TNF-α在治疗前均显著升高，而经过糖皮质激素治疗，5例患者IL-6、IL-8、TNF-α及IL-2受体(IL-2R)显著下降。基因检测结果显示，7例患者中4例为p.R334W(c.1000C＞T)突变，1例为p.H313R(c.938A＞G)和p.R471C(c.1411C＞T)双突变，1例为p. 476_477del(c.1427_1429delcct)。结论 Blau综合征/早发型结节病在临床表现、组织病理及基因突变具有显著特征，但也具有多样性。
- Blau综合征 /
- 早发型结节病 /
- 临床表现 /
- 病理特征 /
- 基因突变多样性
Abstract: Objective To summarize the clinical manifestations, pathological features and gene mutation diversity of Blau syndrome/early-onset sarcoidosis. Methods We collected general data, clinical manifestations, and auxiliary examination results from 8 patients who were diagnosed of Blau syndrome/early-onset sarcoidosis and treated in our hospital from January 2011 to December 2022, and then summarized and analyzed their characteristics and diversity. Results Among the 8 patients, 4 were males and 4 were females. The onset age was 3 to 8 months old. Rash was the first symptom in 7 patients(87.5%). 6 patients(75.0%) had papules and erythema.3 cases(37.5%) had arthritis. 2 cases(25.0%) had uveitis and other eye inflammation. 4 cases (50.0%) also showed intermittent fever. 3 cases (37.5%) showed symptoms in nerve and respiratory system, and hypertension respectively. The skin histopathology of 8 patients showed non-caseous granuloma formation. In laboratory detection, CRP and TNF-α were significantly increased before treatment, while IL-6, IL-8, TNF-α and IL-2 receptor(IL-2R) were significantly decreased in 5 patients after glucocorticoid therapy. The results of genetic testing showed that 4 of the 7 patients had p.R334W(c.1000C > T) mutation, 1 had p.H313R(c.938A > G) and p.R471C(c.1411C > T)double mutation, and 1 had p.476_477del (c.1427_1429delcct). Conclusions Blau syndrome/early-onset sarcoidosis has significant features in clinical manifestations, histopathology and gene mutation, but it also has diversity.
- Blau syndrome /
- early-onset sarcoidosis /
- clinical manifestations /
- histopathology features /
- gene mutation diversity
注释:

作者贡献：郑义、耿松梅负责课题设计及文章撰写；张欣悦、杜雪珊、周彤、宋相瑾负责临床资料收集；贾韬、延聪负责资料汇总及分析。

利益冲突：所有作者均声明不存在利益冲突。

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图 1 BS/EOS患者皮肤表现

A.早期苔藓样丘疹；B.晚期苔藓样丘疹；C.红斑基础上溃疡；D.水波纹样红斑及色素异常

Figure 1. Skin manifestations of BS/EOS patients

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图 2 BS/EOS患者皮肤病理表现

A~B.丘疹型皮疹处皮肤活检(HE, A标尺2 mm，B标尺600 μm)；C~D.溃疡处皮肤活检(HE, C标尺2 mm，D标尺600 μm)

Figure 2. Histopathological results of lesion from BS/EOS patients

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图 3 BS/EOS患者ESR、CRP、IL-6、IL-8、TNF-α及IL-2R水平及变化

A.治疗前患者ESR、CRP、IL-6、IL-8、TNF-α及IL-2R水平(红线为正常参考范围上限)；B.治疗前及随访过程中IL-6、IL-8、TNF-α及IL-2R的变化(灰色区域为正常范围)；IL-2R：人IL-2受体

Figure 3. ESR, CRP, IL-6, IL-8, TNF-α and IL-2R levels and changes of BS/EOS patients

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表 1 Blau综合征/早发型结节病(BS/EOS)患者临床表现

Table 1. Clinical characteristics of patients with Blau syndrome/early-onset sarcoidosis(BS/EOS)

患者序号	性别	发病年龄(月龄)	家族史	基因突变	皮疹	关节炎	葡萄膜炎	发热	其他系统表现
1	女	12	-	未检出	红斑^*	肩关节	-	间断性	中枢神经系统受累
2	男	8	父亲	p.H313R和p.R471C	红斑、溃疡	肩关节、指间关节^*	-	间断性	肺部结节
3	男	10	-	p.R334W	丘疹^*	-	葡萄膜炎	-	高血压，肾畸形
4	男	18	-	p.R334W	丘疹^*	-	虹膜睫状体炎、葡萄膜炎	-	-
5	女	3	-	p.R334W	丘疹^*	-	-	-	-
6	女	16	-	p. 476_477del	丘疹^*	膝关节、腕关节	-	间断性	-
7	男	12	-	-	丘疹^*	-	-	-	-
8	女	4	-	p.R334W	丘疹^*	-	-	间断性	-
^*表示首发症状; -表示无相关病史/症状

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表 2 BS/EOS多系统临床表现

Table 2. Multi-system clinical manifestations of BS/EOS

累及系统	临床表现	发生率
皮肤	丘疹	65%~90%^{[5, 13]}
	红色斑块伴鳞屑
	结节性红斑
	白细胞破裂性血管炎
	苔藓样糠疹
	皮肤溃疡
	皮肤异色
关节	多发关节炎	73%~90%^{[5, 13]}
	腱鞘炎
	指屈曲畸形
	腕关节发育不良
	桡骨双凹
	尺骨肥大
	第二掌骨畸形
眼部	葡萄膜炎	36%~80%^{[5, 13]}
	虹膜睫状体炎
	多灶性脉络膜炎
	带状角膜病变
	白内障
	青光眼
	黄斑水肿
	视网膜脱离
	视神经萎缩
呼吸	间质性肺病	15.28%^{[13, 15]}
泌尿	间质性肾炎	罕见^[16-17]
	急性肾小球肾炎
心血管	大血管炎	罕见^[18-24]
	主动脉炎
	高血压
	肺动脉高压
神经	面神经麻痹	罕见^{[22, 25-26]}
	发作性癫痫
其他	发热	27.78%^[13]
	全身性淋巴结病
	脾肿大	罕见^[8]
	肝肿大

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参考文献(38)

[1]	Matsuda T, Kambe N, Ueki Y, et al. Clinical character-istics and treatment of 50 cases of Blau syndrome in Japan confirmed by genetic analysis of the NOD2 mutation[J]. Ann Rheum Dis, 2020, 79(11): 1492-1499. doi: 10.1136/annrheumdis-2020-217320
[2]	Caso F, Galozzi P, Costa L, et al. Autoinflammatory granulomatous diseases: from Blau syndrome and early-onset sarcoidosis to NOD2-mediated disease and Crohn's disease[J]. RMD Open, 2015, 1(1): e000097. doi: 10.1136/rmdopen-2015-000097
[3]	Jindal AK, Pilania RK, Suri D, et al. A young female with early onset arthritis, uveitis, hepatic, and renal granulomas: a clinical tryst with Blau syndrome over 20 years and case-based review[J]. Rheumatol Int, 2021, 41(1): 173-181. doi: 10.1007/s00296-019-04316-6
[4]	Rosé CD, Doyle TM, McIlvain-Simpson G, et al. Blau syndrome mutation of CARD15/NOD2 in sporadic early onset granulomatous arthritis[J]. J Rheumatol, 2005, 32(2): 373-375.
[5]	Kaufman KP, Becker ML. Distinguishing Blau syndrome from systemic sarcoidosis[J]. Curr Allergy Asthma Rep, 2021, 21(2): 10. doi: 10.1007/s11882-021-00991-3
[6]	Poline J, Fogel O, Pajot C, et al. Early-onset granuloma-tous arthritis, uveitis and skin rash: characterization of skin involvement in Blau syndrome[J]. J Eur Acad Dermatol Venereol, 2020, 34(2): 340-348. doi: 10.1111/jdv.15963
[7]	Aróstegui JI, Arnal C, Merino R, et al. NOD2 gene-associated pediatric granulomatous arthritis: clinical diversity, novel and recurrent mutations, and evidence of clinical improvement with interleukin-1 blockade in a Spanish cohort[J]. Arthritis Rheum, 2007, 56 (11): 3805-3813. doi: 10.1002/art.22966
[8]	Saini SK, Rose CD. Liver involvement in familial granulomatous arthritis (Blau syndrome)[J]. J Rheumatol, 1996, 23(2): 396-399.
[9]	Inoue Y, Kawaguchi Y, Shimojo N, et al. A case of infantile Takayasu arteritis with a p. D382E NOD2 mutation: an unusual phenotype of Blau syndrome/early-onset sarcoidosis?[J]. Mod Rheumatol, 2013, 23(4): 837-839. doi: 10.3109/s10165-012-0720-z
[10]	Yotsumoto S, Takahashi Y, Takei S, et al. Early onset sarcoidosis masquerading as juvenile rheumatoid arthritis[J]. J Am Acad Dermatol, 2000, 43(5 Pt 2): 969-971.
[11]	Rosenstiel P, Fantini M, Bräutigam K, et al. TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells[J]. Gastroenterology, 2003, 124(4): 1001-1009. doi: 10.1053/gast.2003.50157
[12]	Wouters CH, Maes A, Foley KP, et al. Blau syndrome, the prototypic auto-inflammatory granulomatous disease[J]. Pediatr Rheumatol Online J, 2014, 12: 33. doi: 10.1186/1546-0096-12-33
[13]	张俊梅, 赵晓珍, 唐雪梅, 等. 中国儿童Blau综合征临床特点和治疗分析-全国多中心研究[J]. 罕见病研究, 2022, 1(3): 252-258. doi: 10.12376/j.issn.2097-0501.2022.03.005
[14]	Suresh S, Tsui E. Ocular manifestations of Blau syndrome[J]. Curr Opin Ophthalmol, 2020, 31(6): 532-537. doi: 10.1097/ICU.0000000000000705
[15]	Becker ML, Martin TM, Doyle TM, et al. Interstitial pneumonitis in Blau syndrome with documented mutation in CARD15[J]. Arthritis Rheum, 2007, 56(4): 1292-1294. doi: 10.1002/art.22509
[16]	Meiorin SM, Espada G, Costa CE, et al. Granulomatous nephritis associated with R334Q mutation in NOD2[J]. J Rheumatol, 2007, 34(9): 1945-1947.
[17]	Ting SS, Ziegler J, Fischer E. Familial granulomatous arthritis(Blau syndrome)with granulomatous renal lesions[J]. J Pediatr, 1998, 133(3): 450-452. doi: 10.1016/S0022-3476(98)70286-0
[18]	Rosé CD, Aróstegui JI, Martin TM, et al. NOD2-associated pediatric granulomatous arthritis, an expanding phenotype: study of an international registry and a national cohort in Spain[J]. Arthritis Rheum, 2009, 60(6): 1797-1803. doi: 10.1002/art.24533
[19]	Gross KR, Malleson PN, Culham G, et al. Vasculopathy with renal artery stenosis in a child with sarcoidosis[J]. J Pediatr, 1986, 108(5 Pt 1): 724-726.
[20]	Rose CD, Eichenfield AH, Goldsmith DP, et al. Early onset sarcoidosis with aortitis——'juvenile systemic granulomatosis?'[J]. J Rheumatol, 1990, 17(1): 102-106.
[21]	Rotenstein D, Gibbas DL, Majmudar B, et al. Familial granulomatous arteritis with polyarthritis of juvenile onset[J]. N Engl J Med, 1982, 306(2): 86-90. doi: 10.1056/NEJM198201143060208
[22]	Wang X, Kuivaniemi H, Bonavita G, et al. CARD15 mutations in familial granulomatosis syndromes: a study of the original Blau syndrome kindred and other families with large-vessel arteritis and cranial neuropathy[J]. Arthritis Rheum, 2002, 46(11): 3041-3045. doi: 10.1002/art.10618
[23]	Mourad F, Tang A. Sinus of valsalva aneurysm in Blau's syndrome[J]. J Cardiothorac Surg, 2010, 5: 16. doi: 10.1186/1749-8090-5-16
[24]	Khubchandani RP, Hasija R, Touitou I, et al. Blau arteritis resembling Takayasu disease with a novel NOD2 mutation[J]. J Rheumatol, 2012, 39(9): 1888-1892. doi: 10.3899/jrheum.120156
[25]	Jabs DA, Houk JL, Bias WB, et al. Familial granulo-matous synovitis, uveitis, and cranial neuropathies[J]. Am J Med, 1985, 78(5): 801-804. doi: 10.1016/0002-9343(85)90286-4
[26]	Emaminia A, Nabavi M, Mousavi Nasab M, et al. Central nervous system involvement in Blau syndrome: a new feature of the syndrome?[J]. J Rheumatol, 2007, 34 (12): 2504-2505.
[27]	Pepys MB, Hirschfield GM. C-reactive protein: a critical update[J]. J Clin Invest, 2003, 111(12): 1805-1812. doi: 10.1172/JCI200318921
[28]	Li HX, Liu ZM, Zhao SJ, et al. Measuring both procalcitonin and C-reactive protein for a diagnosis of sepsis in critically ill patients[J]. J Int Med Res, 2014, 42(4): 1050-1059. doi: 10.1177/0300060514528483
[29]	Nagakura T, Wakiguchi H, Kubota T, et al. Tumor necrosis factor inhibitors provide longterm clinical benefits in pediatric and young adult patients with Blau syndrome[J]. J Rheumatol, 2017, 44(4): 536-538.
[30]	Lu L, Shen M, Jiang D, et al. Blau syndrome with good reponses to tocilizumab: a case report and focused literature review[J]. Semin Arthritis Rheum, 2018, 47(5): 727-731. doi: 10.1016/j.semarthrit.2017.09.010
[31]	Kanazawa N, Okafuji I, Kambe N, et al. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome[J]. Blood, 2005, 105(3): 1195-1197.
[32]	Kumar TD, Kumar US, Laeeque NAS, et al. Computa-tional model to analyze and characterize the functional mutations of NOD2 protein causing inflam-matory disorder-Blau syndrome[J]. Adv Protein Chem Struct Biol, 2020, 120: 379-408.
[33]	Saulsbury FT, Wouters CH, Martin TM, et al. Incomplete penetrance of the NOD2 E383K substitution among members of a pediatric granulomatous arthritis pedigree[J]. Arthritis Rheum, 2009, 60(6): 1804-1806. doi: 10.1002/art.24532
[34]	Sarens IL, Casteels I, Anton J, et al. Blau syndrome-associated uveitis: preliminary results from an international prospective interventional case series[J]. Am J Ophthalmol, 2018, 187: 158-166. doi: 10.1016/j.ajo.2017.08.017
[35]	Rosé CD, Pans S, Casteels I, et al. Blau syndrome: cross-sectional data from a multicentre study of clinical, radiological and functional outcomes[J]. Rheumatology (Oxford), 2015, 54(6): 1008-1016. doi: 10.1093/rheumatology/keu437
[36]	Simonini G, Xu Z, Caputo R, et al. Clinical and transcriptional response to the long-acting interleukin-1 blocker canakinumab in Blau syndrome-related uveitis[J]. Arthritis Rheum, 2013, 65(2): 513-518. doi: 10.1002/art.37776
[37]	Paç Kisaarslan A, Sözeri B, Şahin N, et al. Blau syndrome and early-onset sarcoidosis: a six case series and review of the literature[J]. Arch Rheumatol, 2019, 35 (1): 117-127.
[38]	Zhang S, Cai Z, Mo X, et al. Tofacitinib effectiveness in Blau syndrome: a case series of Chinese paediatric patients[J]. Pediatr Rheumatol Online J, 2021, 19 (1): 160. doi: 10.1186/s12969-021-00634-x