Raphael S A, Blau E B, Zhang W H, Hsu S H
Department of Pediatrics, Temple University School of Medicine, Philadelphia, PA.
Am J Dis Child. 1993 Aug;147(8):842-8. doi: 10.1001/archpedi.1993.02160320044017.
To determine whether HLA and autoimmunity contribute to the pathogenesis of Blau syndrome (familial granulomatous arthritis, uveitis, and rash) and evaluate whether this condition is related to sarcoidosis.
Large family survey.
General community, Green Bay, Wis, and two tertiary care medical centers in Philadelphia, Pa.
Thirty-six family members and spouses from a large kindred with Blau syndrome.
Volunteer and convenience sample.
None.
Ten affected and many unaffected subjects were personally examined. Medical records and previous biopsy reports and specimens, when available, were reviewed. Two affected subjects had skin biopsies performed and three affected adult subjects were tested with Kveim skin-test reagent. Serologic and genomic class I and class II HLA typing was performed on 27 affected and unaffected subjects. All 13 living affected subjects and the one obligate carrier had the following assays performed; antinuclear antibody titer, rheumatoid factor, serum angiotensin converting enzyme level, quantitative immunoglobulins of the IgG, IgM, and IgA classes, and clinical chemistry profiles. Several had complete blood cell counts and erythrocyte sedimentation rates performed. Four affected subjects, one possibly affected subject, and one obligate carrier were newly identified. Flexion contractures of the fingers and toes (camptodactyly) were found, for the first time, to be a phenotype characteristic. Earlier onset and worsening of symptoms in succeeding generations (anticipation) were observed. Sixteen HLA haplotypes were identified. No conclusive evidence for linkage between these haplotypes and phenotype expression could be demonstrated. All 13 affected subjects, however, carried the DR2 (DR beta 11501) and/or DR4 (DR beta 10401) allele. There was no evidence of hypercalcemia, hypergammaglobulinemia M, rheumatoid factor production, or abnormal blood cell counts. Two affected subjects had low-titer antinuclear antibody screening tests, five had mild to moderately elevated IgG and/or IgA levels, two had raised serum angiotensin converting enzyme levels, and three had mild elevation of the erythrocyte sedimentation rate. All three subjects tested with Kveim skin-test reagent showed no reactivity by visual inspection. Both subjects who had had skin biopsies performed had evidence of granulomatous inflammation.
This family's illness is distinct from both classic and early-onset sarcoidosis. There is minimal evidence for autoimmunity and systemic inflammation. Camptodactyly should be added to the list of syndrome-defining characteristics. Although HLA haplotypes do not appear to segregate with affected subjects, HLA-DR2 and HLA-DR4 subtypes may play a permissive role in phenotype expression. This family represents a unique opportunity to define the molecular mechanisms involved in the initiation of arthritis and uveitis in humans. Genetic linkage studies to determine the chromosomal location of the Blau syndrome gene are in progress.
确定人类白细胞抗原（HLA）和自身免疫是否在布劳综合征（家族性肉芽肿性关节炎、葡萄膜炎和皮疹）的发病机制中起作用，并评估这种疾病是否与结节病相关。
大型家系调查。
威斯康星州格林湾的普通社区以及宾夕法尼亚州费城的两个三级医疗中心。
来自一个患有布劳综合征的大家系的36名家庭成员及其配偶。
志愿者和便利样本。
无。
对10名患病和多名未患病的受试者进行了亲自检查。如有可用的病历、既往活检报告和标本，均进行了查阅。对2名患病受试者进行了皮肤活检，并对3名成年患病受试者进行了克维姆皮肤试验试剂检测。对27名患病和未患病受试者进行了血清学及基因组I类和II类HLA分型。对所有13名在世的患病受试者和1名肯定携带者进行了以下检测：抗核抗体滴度、类风湿因子、血清血管紧张素转换酶水平、IgG、IgM和IgA类定量免疫球蛋白以及临床化学指标。数名受试者进行了全血细胞计数和红细胞沉降率检测。新发现了4名患病受试者、1名可能患病的受试者和1名肯定携带者。首次发现手指和脚趾的屈曲挛缩（屈曲指）是该综合征的一种表型特征。观察到后代症状出现更早且病情加重（遗传早现）。鉴定出16种HLA单倍型。无法证明这些单倍型与表型表达之间存在明确的连锁关系。然而，所有13名患病受试者均携带DR2（DRβ11501）和/或DR4（DRβ10401）等位基因。没有高钙血症、高丙种球蛋白血症M、类风湿因子产生或血细胞计数异常的证据。2名患病受试者抗核抗体筛查试验滴度较低，5名受试者IgG和/或IgA水平轻度至中度升高，2名受试者血清血管紧张素转换酶水平升高，3名受试者红细胞沉降率轻度升高。所有3名接受克维姆皮肤试验试剂检测的受试者经肉眼检查均无反应。2名进行了皮肤活检的受试者均有肉芽肿性炎症的证据。
这个家族的疾病既不同于经典结节病，也不同于早发型结节病。自身免疫和全身炎症的证据极少。屈曲指应被添加到该综合征的定义特征列表中。尽管HLA单倍型似乎与患病受试者不连锁，但HLA - DR2和HLA - DR4亚型可能在表型表达中起允许作用。这个家族为确定人类关节炎和葡萄膜炎发病起始所涉及的分子机制提供了一个独特的机会。正在进行基因连锁研究以确定布劳综合征基因的染色体位置。
