Elsevier

Autoimmunity Reviews

Volume 12, Issue 1, November 2012, Pages 44-51
Autoimmunity Reviews

Review
Blau syndrome, clinical and genetic aspects

https://doi.org/10.1016/j.autrev.2012.07.028Get rights and content

Abstract

Blau syndrome (BS) is a rare autosomal dominant, autoinflammatory syndrome characterized by the clinical triad of granulomatous recurrent uveitis, dermatitis and symmetric arthritis. The gene responsible for BS has been identified in the caspase recruitment domain gene CARD15/NOD2. In the majority of patients, the disease is characterized by early onset, usually before 3–4 years of age. The manifestations at disease onset are usually represented by articular and cutaneous involvement signs, generally followed later by ocular manifestations which are often the most relevant morbidity of BS. In some cases the presence of fever is also observed; atypical cases of BS have been reported with cardiovascular, neurological, renal, intestinal and other organ involvement. The rarity and the variations in the severity and evolution of its expressions do not permit sufficient data about optimal treatment for patients with BS. The first step of therapy is represented by the use of corticosteroids and successively, in case of unsatisfactory response, by additional treatment with immunosuppressive agents. The results with biologic anti-cytokine agents, such as anti-TNFα and anti-IL1β, are different, particularly with regard to ocular morbidity. Clinical and genetic aspects of the familial and the sporadic form of BS will be discussed and focused on. A description of a case study of an Italian family is also included.

Highlights

Blau syndrome is an autosomal dominantly inherited disorder. ► BS-associated NOD2 mutations occur in the NACHT domain. ► Cells expressing BS-mutated forms of NOD2 show increased NF-κB activation. ► Eye involvement is the most relevant morbidity of Blau syndrome. ► Atypical cases of Blau syndrome have been reported with visceral involvement.

Introduction

Blau syndrome is a rare autoinflammatory granulomatous disorder [1]. In 1985, the pediatrician Edward Blau described for the first time the disease as a dominantly inherited, chronic inflammatory syndrome characterized by the clinical triad of granulomatous dermatitis, symmetric arthritis and recurrent uveitis with onset below 4 years of age. The original description of Blau about the disorder, reported four generations with 11 members of the same family affected. Ten showed arthritis; two showed skin, eye and joint involvement; one showed skin and joint disease; and one manifested isolated ocular involvement with iritis [2]. Tromp et al. mapped the BS locus in 1996 by genotyping 72 of the 74-member pedigree with dinucleotide-repeat markers to the chromosomal region 16q12.1–13, which contain one of the susceptibility genes for Crohn's disease [3]. In 2001, Miceli-Richard et al. identified the gene that confers susceptibility for BS, discovering three missense mutations (R334Q, R334W and L469F) in the region encoding the nucleotide-binding domain (NBD) of the caspase recruitment domain gene (CARD15/NOD2) in four French and German BS affected families [4]. Hence, CARD15/NOD2 is involved in susceptibility to a second granulomatous disorder [5] in addition to Crohn's disease. Further reports of CARD15/NOD2 mutations were published in other families with BS, successively. Originally BS was considered a distinct entity from early onset sarcoidosis (EOS), in spite of the striking clinical similarities between them. Genetic analyses subsequently have shown that many patients with EOS have mutations in CARD15/NOD2. Thereafter, some authors proposed that BS and EOS are the familial and sporadic forms, respectively, of the same disease [6], [7]. Some others proposed the term ‘pediatric granulomatous arthritis’ due to the prevalence of the disease among infants. However this was inadequate to represent the systemic nature of this disease [8]. Thus, N. Milman, et al. proposed to classify these patients as sporadic BS due to de novo mutations, restricting the term EOS to patients with features of sarcoidosis and without mutations in CARD15/NOD2 [9].

This review will discuss the clinical and genetic aspects of BS, both in its familial and sporadic forms. In addition, we will describe an Italian family affected by BS who has been under our observation over the past 25 years [10]. We hope that this description of the characteristics and the evolution process of the disease over such a long time period may contribute to a better understanding of BS.

Section snippets

Clinical aspects

To our knowledge, BS has been observed until now in 193 persons belonging to 63 families (Table 1a).

The occurrence of BS is reported primarily among Caucasians although it has been also reported in Asians [6] as well as Afro-Americans [11]. No information is available regarding the extent to which the disease is spread. For most patients, the disease is characterized by early onset, typically at ages before 3–4 years [12]. Sometimes, however, symptoms appear only after 10 years of age [9]. Onset

Genetic and functional aspects

Blau syndrome (MIM# 186580) is an autosomal dominantly inherited disorder, due to mutations in the caspase recruitment domain gene CARD15/NOD2.

This gene, mapped on the chromosomal region 16q12.1–13 [3], has been firstly associated with Crohn's disease (MIM# 266600), a granulomatous inflammatory bowel disease [36], [37].

The identification of CARD15/NOD2 as the gene responsible for BS marked the major turning-point for BS studies [4]. Since 2001, several cohorts have been genotyped and different

An Italian family with BS

The proband, a 31-year-old Caucasian woman, was referred to our Unit in 1984, having arthritis of hands and feet and a papulonodular skin eruption. The patient reported that when she was 20 years old she had developed chronic, bilateral uveitis and glaucoma and then also cataracts a few years later. She underwent an iridectomy when she was 24 years old and 7 years later a cataract operation. Symmetrical arthritis involving fingers, wrists and feet, and skin manifestations, consisting of widespread

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