ReviewBlau syndrome, clinical and genetic aspects
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
References (77)
- et al.
Miscellaneous non-inflammatory musculoskeletal conditions. Blau syndrome
Best Pract Res Clin Rheumatol
(2011) Familial granulomatous arthritis, iritis, and rash
J Pediatr
(1985)- et al.
Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome
Blood
(2005) - et al.
Blau syndrome: a new kindred
J Am Acad Dermatol
(2003) - et al.
Familial granulomatous synovitis, uveitis, and cranial neuropathies
Am J Med
(1985) - et al.
Multifocal choroiditis in patients with familial juvenile systemic granulomatosis
Am J Ophthalmol
(2002) - et al.
Ocular manifestations in Blau syndrome associated with a CARD15/Nod2 mutation
Ophthalmology
(2003) - et al.
Blau syndrome associated with a CARD15/NOD2 mutation
Am J Ophthalmol
(2006) - et al.
Familial granulomatous arthritis (Blau syndrome) with granulomatous renal lesions
J Pediatr
(1998) - et al.
Presence of a sporadic case of systemic granulomatosis syndrome with a CARD15 mutation
J Invest Dermatol
(2004)
Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB
J Biol Chem
TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells
Gastroenterology
Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease
J Biol Chem
Nucleotide-binding oligomerization domain proteins are innate immune receptors for internalized Streptococcus pneumoniae
J Biol Chem
Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection
J Biol Chem
GRIM-19 interacts with nucleotide oligomerization domain 2 and serves as downstream effector of anti-bacterial function in intestinal epithelial cells
J Biol Chem
Autosomal dominant granulomatous arthritis, uveitis, skin rash, and synovial cysts
J Pediatr
Uveitis in Blau syndrome from a de novo mutation of the NOD2/CARD15 gene
J AAPOS
Genetic linkage of familial granulomatous inflammatory arthritis, skin rash, and uveitis to chromosome 16
Am J Hum Genet
CARD15 mutations in Blau syndrome
Nat Genet
NOD2: ethnic and geographic differences
World J Gastroenterol
Blau syndrome mutation of CARD15/NOD2 in sporadic early onset granulomatous arthritis
J Rheumatol
Blau syndrome revisited
Curr Opin Rheumatol
A novel mutation in the NOD2 gene associated with Blau syndrome: a Norwegian family with four affected members
Scand J Rheumatol
A new CARD15 mutation in Blau syndrome
Eur J Hum Genet
The Blau syndrome gene is not a major risk factor for sarcoidosis
Sarcoidosis Vasc Diffuse Lung Dis
Blau syndrome and related genetic disorders causing childhood arthritis
Curr Rheumatol Rep
Pediatric granulomatous arthritis: an international registry
Arthritis Rheum
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
Arthritis Rheum
Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early-onset sarcoidosis
Arthritis Rheum
CARD15 mutations in familial granulomatosis syndromes: a study of the original Blau syndrome kindred and other families with large-vessel arteritis and cranial neuropathy
Arthritis Rheum
Diagnosis and management of autoinflammatory diseases in childhood
J Clin Immunol
Blau syndrome of granulomatous arthritis, iritis, and skin rash: a new family and review of the literature
Am J Med Genet
Analysis of a large kindred with Blau syndrome for HLA, autoimmunity, and sarcoidosis
Am J Dis Child
Blau syndrome presenting with ichthyosis
Australas J Dermatol
Favourable effect of TNF-alpha inhibitor (infliximab) on Blau syndrome in monozygotic twins with a de novo CARD15 mutation
APMIS
Sarcoidosis of early onset. A challenge for the pediatric rheumatologist
Clin Exp Rheumatol
Liver involvement in familial granulomatous arthritis (Blau syndrome)
J Rheumatol
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