Best Practice & Research Clinical Rheumatology 25 (2011) 703–714

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Best Practice & Research ClinicalRheumatology

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Blau syndrome

Leonardo Punzi, MD, PhD *, Alessandra Gava, PhD, Paola Galozzi, PhDStudent, Paolo Sfriso, MD, PhDRheumatology Unit, Department of Clinical and Experimental Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy

Keywords:Blau syndromeGranulomatous arthritisEarly-onset sarcoidosisAutoinflammatory syndromesAnti-IL1 therapy

* Corresponding author. Tel.: þ390498212190; fE-mail address: punzireu@unipd.it (L. Punzi).

1521-6942/$ – see front matter � 2011 Elsevier Ltdoi:10.1016/j.berh.2011.10.017

Blau syndrome (BS) is a rare dominantly inherited, inflammatorysyndrome characterised by the clinical triad of granulomatousdermatitis, symmetric arthritis and recurrent uveitis. The caspaserecruitment domain gene CARD15/NOD2 has been identified as thegene responsible for BS. In the majority of patients, the disease ischaracterised by early onset, usually before 3–4 years of age. Onsetis most often articular and cutaneous. Eye symptoms usually startlater; however, eye involvement is the most relevant morbidity ofBS. Atypical cases of BS have been reported with involvement oforgans other than skin, joint and eyes. Due to its rarity and thevariations in the severity and evolution of its expressions, therehave been no studies on the optimal treatment for patients withBS. If the therapeutic response to corticosteroids is unsatisfactory,additional treatment with immunosuppressive agents should betried. The results with biologic anti-cytokine agents, such asinfliximab and anakinra, are variable, particularly with regard toocular morbidity. This review will focus on the clinical andgenetics aspects of the familial and the sporadic form of BS.Further, we will describe an Italian family followed by us over thepast 25 years.

� 2011 Elsevier Ltd. All rights reserved.

Introduction

Blau syndrome (BS, MIM #186580) is a rare autosomal dominant granulomatous disorder [1]. Thediseasewas first described in 1985 by the paediatrician Edward Blau as a dominantly inherited, chronicinflammatory syndrome characterised by the clinical triad of granulomatous dermatitis, symmetricarthritis and recurrent uveitis with onset below 4 years of age. In his original description of the

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L. Punzi et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 703–714704

disorder, Blau reported four generations of a family with 11 members affected. Ten had arthritis; twohad skin, eye and joint involvement; one had skin and joint disease; and one had iritis only [1]. In 1996,the BS locus was mapped by Tromp et al. by genotyping 72 of the 74-member pedigree withdinucleotide-repeat markers to the chromosomal region 16q12.1–13, which also contains one of thesusceptibility genes for Crohn’s disease [2]. The gene responsible for BS was identified in 2001 byMiceli-Richard et al. The authors discovered three missense mutations (R334Q, R334W and L469F) inthe region encoding the nucleotide-binding domain (NBD) of the caspase recruitment domain gene(CARD15/NOD2) in four French and German families with BS [3]. Thus, in addition to Crohn’s disease,CARD15/NOD2 appears to be involved in susceptibility to a second granulomatous disorder [4]. Over thenext years, NOD2 mutations in additional families with BS were published. In spite of the strikingclinical similarities with BS, early onset sarcoidosis (EOS) was originally considered a distinct entity.Subsequent genetic analyses have shown that many patients with EOS have mutations in CARD15.Thus, some authors proposed that BS and EOS are the familial and sporadic forms, respectively, of thesame disease [5,6]. Due to common occurrence in infancy, some others proposed the term ‘paediatricgranulomatous arthritis’ which, however, was inadequate to represent the systemic nature of thisdisease [7].

Therefore, it was 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 [8].

This reviewwill focus on the clinical and genetics aspects of the familial and the sporadic form of BS.Further, we will describe an Italian family followed by us over the past 25 years. [9]. We hope thata description of its characteristics and the disease course over such a long time period may contributeto a better understanding of BS.

Clinical aspects

BS occurs predominantly among Caucasians but has been reported in both Asians [5] and Afro-Americans [10]. The prevalence is unknown. In the majority of patients, the disease is characterisedby early onset, usually before 3–4 years of age [11]. However, symptoms sometimes do not appearbefore 10 years of age [8]. Onset is most often articular and cutaneous [12�14] while eye symptomsusually start later, between 7 and 12 years of age [1,15].

Arthritis is the most common manifestation of the disease, and it generally appears in the firstdecade of life [16]. The initial presentation of arthritis in the absence of ocular or skin findings is oftenmistaken for juvenile rheumatoid arthritis (JRA).

Joint manifestations usually present as symmetric polyarthritis, involving wrists, meta-carpophalangeal (MCP), 1st metatarsophalangeal (MTP) and proximal interphalangeal (PIP) joints ofhands and feet, ankles and rarely elbows. Arthritis is often accompanied by joint swelling due tosynovial thickening and effusion [12,13] with moderate redness, warmth and tenderness. In addition,granulomatous inflammation in the periarticular structures is frequent leading to marked periarticularswelling and tenosynovial cysts particularly affecting wrists and dorsa of the hands. Arthritis hasa chronic evolution in these patients and may lead to deformity of fingers and to wrist ankylosis. Jointinvolvement usually has a juvenile onset, presenting as painless cysts on the back of feet and wristswhich may evolve into mild ‘boutonnière finger deformities’ [17,18].

Traditional X-rays show the typical deformities of periarticular swelling and, at times, jointspace narrowing [17,18]. Radiographic signs of erosive joint changes may be absent until later in thedisease process. Progression to deforming arthritis may nonetheless occur leading to severehandicap caused by flexion contractures of fingers and toes (camptodactyly) and decreased motionof large joints.

Various skin manifestations have been described in BS but descriptions have not been uniformlyconsistent. Two main types of asymptomatic eruptions are usually reported: a papulonodular tenderbrownish rash and multiple, firm, subcutaneous plaques only apparent on palpation. The exanthemaoften presents as an erythema with maculopapular configuration. Pinhead-sized, lichenoid, yellow tobrown papules are usually arranged in clusters and may become confluent. The appearance is variable,often symmetric, located on the trunk and/or extremities [5,11,19,20]. Intermittent episodes ofgeneralised exanthema with spontaneous resolution may occur during a period of years, eventually

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leaving pitted scars at sites of previous papules. When the exanthema is mild, it can even go unnoticed.In some cases the eruptions are described as papular or plaque-like, maculopapular and tiny red dots;they have also been repeatedly described as erythematous, intermittent and generalized [21]. Thehistology of the lesions consistently demonstrates non-caseating granulomas with multinucleatedgiant cells [1,2,22�24] (Fig. 5). Electron microscopy may reveal ‘comma-shaped bodies’ in epithelioidcells [24], which seem to be a marker for BS [17,24] (Fig. 6).

Eye involvement is the most relevant morbidity of BS [1,25�27]. From the perspective of quality oflife, the ocular symptoms of BS require the closest attention. Recurrent anterior uveitis or panuveitispresenting with eye pain, photophobia and blurred vision are the most common presentations.Granulomatous uveitis, often bilateral, can evolve into a cataract and band keratopathy, frequentlyrequiring surgery [26]. Inflammation may afflict most ocular structures such as conjunctiva, lachrymalgland, retina and optic nerve. Other findings include vitritis, granulomatous disks and bilateraldisseminated chorioretinal lesions that are surrounded by retinal haemorrhages and progressivesubretinal fibrosis [1,2,26]. Fundus modifications at times resemble those in sarcoid uveitis [26].

Typically, many patients require continuing follow-up and treatment for eye symptoms lifelong. Eyeinvolvement is often complicated by chorioretinitis, cataract, glaucoma and retinal detachment, whichmay lead to significant visual impairment and even blindness.

Atypical cases of BS have been reported with involvement of organs other than skin, joint and eyes.There have been reports of BS in association with hepatic and renal granulomatous involvement

[28,29], cerebral infarction [30] and malignant hypertension [24].Another family with BS was found to have ichthyosis vulgaris [20]. There have also been reports of

persistent or intermittent fever, granulomatous arteritis with central nervous system involvementincluding cranial neuropathies [22] and corticosteroid-responsive hearing loss [22,31].

A patient with very large and painful ulcerations on both legs was recently described [32]. wherethe biopsy of the ulcers suggested that these are part of a granulomatous disease.

Granulomas in the lymph nodes, parotid glands and intestines were also reported in patients withBS [8].

There are very few data on the cardiovascular manifestations of BS. Recently, a case of sinus ofValsava aneurysm has been described, suggesting some form of auto-immune aortitis [33].

A case of association between BS with chronic tubulointerstitial nephritis and renal clear cell carci-nomahas been reported [34]. Interestingly, histopathological examination showed giant cell granulomasin both the tumour and non-neoplastic renal tissue. Given the relation between chronic inflammationand cancer, the authors suggest that patients with BS should be monitored for malignancies.

An atypical case of BS with an R334Q mutation associated with granulomatous lymphadenitis andinterstitial pneumonitis has been reported [35]. However, in contrast to sarcoidosis [18], involvementof the lungs has rarely been described in BS [11,19].

Due to its rarity and the variations in the severity and evolution of its expressions, there have beenno studies on the optimal treatment for patients with BS. The major concern regards eye involvement,which may, at times, be severe [1,9,26]. At the quiescent stage, low-dose glucocorticoids are generallysatisfactory [25]. High doses of glucocorticoids are, however, necessary in some acute stages. As diseaseonset is often during childhood, its long-term use especially at high doses, may be problematic. If thetherapeutic response to corticosteroids is unsatisfactory, or a maintenance dose of prednisolone�10 mg day�1 is needed for prolonged periods, additional treatment with immunosuppressive agentsshould be tried.

Biologic anti-cytokine agents such as infliximab, a tumour necrosis factor (TNF)-a inhibitor andanakinra, the IL-1 receptor antagonist, may represent promising therapeutic approaches in refractorycases [13,19]. The results however are variable, particularly with regard to ocular morbidity. Further-more, a recent in vitro study suggests that in contrast to related IL-1 beta-dependent auto-inflammatory cryopyrinopathies, BS is not mediated by excess IL-1 beta or other IL-1 activity.

Finally, the results of a pilot study on two sporadic BS patients suggest that thalidomide isa promising agent for the reduction of granulomatous inflammation through its suppression ofnuclear factor-kB (NF-kB) activation and interference with the proliferation and differentiation ofmonocytes [36].

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Genetic aspects

In 1996, a linkage analysis of a large pedigree allowed Tromp and colleagues to identify the BSsusceptibility locus on the chromosomal region 16q12.1–13 [2].

The caspase recruitment domain gene CARD15/NOD2, originally reported as NOD2, has been map-ped in that region and its variants have been firstly associated with Crohn’s disease (MIM 266600), aninflammatory bowel disease with epithelioid granulomas [37,38].

The identification of CARD15/NOD2 as the gene responsible for BS was the major breakthrough forBS research [38]. Up to date, 10 Blau-associated genetic mutations have been identified within thisgene, almost in heterozygous state. Two of these mutations (R334Q and R334W) account for more than50% of the mutated alleles [39,40], making codon 334 a genetic hot spot for mutations (Table 1;Fig. 1(a)).

CARD15/NOD2 mutations have been described by two independent groups in patients with EOS,confirming earlier suspicions that EOS and BS have a common genetic aetiology [6,41]. Interestingly,recent evidence demonstrated that CARD15/NOD2 polymorphisms could also influence outcome aftertransplantation [42].

CARD15/NOD2 encodes a multidomain cytosolic protein of 1040 amino acids, namely NOD2, and isa member of the CATERPILLER group (CARD, transcription enhancer, R (purine)-binding pyrin, lots ofLRRs), also known as NLR, and is involved in pathogen recognition in both plants and animals.

As shown in Fig. 1(b), NOD2 has a characteristic three-domain structure consisting of an N-terminaleffector region with two adjacent caspase recruitment domains (CARD), responsible for signalling,a central nucleotide binding and oligomerisation domain (NACHT) and a C-terminal region with nineleucine-rich repeat domains (LRRs) [43]. NOD2 is an intracellular sensor for small peptides derivedfrom the bacterial cell wall components and the LRRs have an important function in recognition ofpathogen-associated molecular patterns (PAMPs) such as MurNAc-L-Ala-D-isoGln, called MDP formuramyl dipeptide, a peptidoglycan constituent of Gram-positive and Gram-negative bacteria [44].

The protein is expressed mainly in the cytosol of myelomonocytic cells (monocytes/macrophagesand granulocytes) and dendritic cells, which are major components of Blau granulomas [45]. Further,the subcellular distribution of NOD2 has been investigated and NOD2 has been found also associatedwith the plasma membrane on intestinal epithelial cells [46�48].

Table 1Mutations in NOD2.

Mutation Sequence variant Protein variant dbSNPb Functionalstudyc

Reference

R334Wa c.1000C > T p.Arg334Trp rs104895462 Yes [3]R334Qa c.1001G > A p.Arg334Gln rs104895461 Yes [3]D382E c.1146C > G p.Asp382Glu rs104895476 Yes [5]E383Ka c.1147G > A p.Glu383Lys rs104895477 Yes [9]E383Ga c.1148A > G p.Glu383Gly rs104895493 Yes [14]G464Wa c.1390G > T p.Gly464Trp rs104895492 No Khubchandani RP et al.

Personal communicationL469Fa c.1405C > T p.Leu469Phe rs104895460 Yes [3]G481D c.1442G > A p.Gly481Asp rs104895494 Yes [57]W490La c.1469G > T p.Trp490Leu rs104895480 Unknown Van Duist M et al.

Personal communicationC495Y c.1484G > A p.Cys495Tyr rs104895478 No [12]H496L c.1487A > T p.His496Leu rs104895472 Yes [5]M513T c.1538T > C p.Met513Thr rs104895473 Yes [5]M513Ra c.1538T > G p.Met513Arg – No [58]R587Ca c.1759C > T p.Arg587Cys rs104895479 No [12]T605Na c.1814C > A p.Thr605Asn – No [8]T605P c.1813A > C p.Thr605Pro rs104895474 Yes [5]N670K c.2010C > A p.Asn670Lys rs104895475 Yes [5]

a These mutations are strictly associated with Blau syndrome.b These data were obtained from http://www.ncbi.nlm.nih.gov/snp.c These data were obtained from http://fmf.igh.cnrs.fr/infevers.

Fig. 1. Localization of the positions of mutations associated with Blau syndrome, both in nucleotide and amino acids sequences.A) Schematic presentation of CARD15/NOD2 gene. Exons are represented by boxes whereas horizontal lines stand for introns.B) CARD15 protein representation to scale in more detail. The numbers under the diagram are the first and last amino acids of eachstructural domain or motif (data are obtained from http://www.uniprot.org/uniprot/Q9HC29).

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Recently, Brooks and colleagues have demonstrated that NOD2 messenger RNA (mRNA) andprotein expression increase as monocytes differentiate into macrophages, suggesting a particularrole for NOD2 in human macrophages as an intracellular receptor that regulates the host responseto infections [49].

In resting cells, NOD2 resides in the cytoplasm in an autoinhibited conformation due to theintramolecular interactions of its LRR and CARD domains: in response to bacterial components (MDP),a conformational change occurs in the molecule resulting in activation of NOD2, downstreamengagement of receptor interacting protein-2 (RIP2) and subsequent activation of NF-kB [50] (Fig. 2).

RIP2 is an adaptor protein and is a CARD-containing serine/threonine kinase that physically asso-ciates with the CARD(s) of NOD2: these homotypic CARD–CARD interactions are important for theactivation of NF-kB, although it has been shown that NOD2 might need also the interaction withanother intracellular molecule, GRIM19 (gene-associated with retinoid–IFN–induced mortality 19), foran optimal activation of NF-kB [51].

NF-kB is present in the cytoplasm as an inactive form bonded with inhibitory proteins (inhibitor ofkBs (IkBa)): in response to different stimuli, the NOD2/RIP2 complex is able to induce NF-kB activationthrough the phosphorylation and degradation of IkBa. Then the active NF-kB translocates to thenucleus where it initiates the transcriptional activation of target genes, such as pro-IL-1b.

Recent results proved the essential role of RIP2 in the modulation of both innate and adaptiveimmunity triggered by NOD2 ligands [52] and, in RIP2-deficient mice, it was established that RIP2played a critical role not only in NF-kB, but also in mitogen-activated protein kinase signalling (MAPK),in macrophages stimulated with NOD ligands [53]. However, Nod-dependent but RIP2-independentsignalling also exists: Travassos and colleagues demonstrated that in RIP2-deficient cells a NOD-dependent induction of autophagy occurs, and this involves the direct recruitment of the autophagyprotein ATG16L1 to the activated NOD complex [54].

Two distinct groups of functional alterations of NOD2/CARD15 are involved in the two granulo-matous diseases (Crohn’s disease and BS): Crohn’s disease-associated NOD2 variants predominantlyreside in the LRRs, while BS-associated NOD2 mutations occur in the NACHT domain.

Although bacteria’s role in its pathogenesis has not been demonstrated, BS has been found to beassociated with a distinctive mutation in CARD15/NOD2.

For BS, the observed gain-of-function mutations of NOD2/CARD15 explain dominant inheritanceand exhibit increased basal NF-kB activity, with enhanced response to bacterial components [55]. Thisis in contrast to NOD2 loss-of-function polymorphisms associated with Crohn’s disease that displaydefective recognition of MDP. The consequence of these aberrant responses could facilitate bacterialpersistence and lead to the chronic inflammatory response that characterises Crohn’s disease [56].

Fig. 2. MDP activates cytosolic NOD2 (nucleotide-binding oligomerisation-domain protein 2) through direct interaction with theleucine-rich repeat (LRR) region. Binding leads to the oligomerisation of NOD2 and recruitment of the kinase RIP2 throughhomotypic CARD–CARD interactions. RIP2 then activates the IKK complex through IKK/NEMO. This results in phosphorylation,ubiquitination and degradation of IkappaB, and downstream activation of associated NF-kB (Nuclear factor-kappaB).

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However, it remains unknown how these gain-of-function mutations in NOD2 affect the patho-genesis of BS and whether a genotype–phenotype correlation exists between the clinical manifes-tations and NOD2 mutations. Recent studies [40] suggest the possibility that an elevated basal NF-kBactivity may affect disease progression rather than disease onset as they found that patients withmutated NOD2 and low NF-kB activity tended to experience complications (i.e., arthritis and uveitis)at a later age.

An Italian family with BS

The proband, a 31-year-old Caucasian womanwith arthritis of hands and feet and a papulonodularskin eruption was referred to our Unit in 1984. The patient reported that she had developed chronic,bilateral uveitis and glaucoma when she was 20 years old and cataracts a few years later. She under-went an iridectomy when she was 24 years old and a cataract operation 7 years later. Symmetricalarthritis involving fingers, wrists and feet, and skin manifestations, consisting of widespread papulesand firm subcutaneous nodules on the extremities, made their appearance during adolescence andintermittently thereafter althoughwell-controlled by non-steroidal anti-inflammatory drugs (NSAIDs).

The patient presented with asymptomatic, diffuse, miliary brownish papule and firm subcutaneousnodules, varying in size from 5 to 30 mm in diameter, on the dorsa of hands and feet and on theextensor leg surfaces (Fig. 3). Arthritis was evident on the bilateral MCP and PIP joints. Neither red norhot, the joints were only slightly tender and swollen. The bilateral 1st and the 2nd MTPs of the feetwere similarly involved.

Camptodactylia (flexion contractures of the fingers and toes) was not present. Radiographs of handsand feet revealed only a slight periosteal enlargement of the bone (Fig. 4) and a chest X-ray wasnegative. Results of all laboratory tests including inflammatory indices were normal. Human leucocyteantigen (HLA) typing revealed A2 and A3; B8 and B21; DR3 and DR7. Skin biopsy specimens of theforearms were processed for light and electron microscopy examination. The specimens were fixed informalin for histologic assessment, embedded in paraffin and thin sections were obtained with hae-matoxylin–eosin, periodic acid Schiff (PAS), PAS-diastase and Weigert–van Gieson stains. Small frag-ments were fixed in glutaraldehyde for ultrastructural examination, post-fixed in osmium tetroxide,dehydrated in ethanol solution and embedded in epon. Semithin sections were stained with toluidineblue and observed with a light microscope and ultrathin sections were stained with uranyl acetate andobserved with a transmission electron microscope.

Fig. 3. Proband. Asymptomatic diffuse brownish papulae of some mm of diameter, firm subcutaneous nodules, varying in size from5 to 30 mm of diameter, on the extensor surfaces of the legs.

Fig. 4. Proband. Radiographs of hands revealed only a slight periosteal enlargement of the bone.

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Histology revealed non-caseating granulomas, containing several histiocytes and multinucleatedgiant cells with strong PAS positivity and rare lymphocytes and eosinophils (Fig. 5).

Transmission electron microscopy showed polyploid histiocytes with abundant cytoplasm con-taining a well-developed Golgi complex and endoplasmic reticulum, profuse mitochondria, lysosomesand glycogen granules, probably determining PAS positivity (Fig. 6). Pleomorphic cytoplasmaticinclusions were found in a few cells. Some collagen fibres were in close apposition to cellularmembranes, often surrounded by a cytoplasmatic process of histiocytes, but without clear evidence ofphagocytosis. Capillary vessels with swollen endothelial cells due to cellular infiltrates were found. Dueto the limited efficacy of NSAIDs, low doses of steroids (methylprednisolone 4 mg day�1) wereintroduced and are continued even now with satisfactory control of all disease manifestations.

One month after her first examination in our Division, the proband consulted us about her 5-year-old daughter who had recently developed skinmanifestations similar, although less severe, to her own.No therapy was prescribed at that time, as the entity of the disturbances was negligible. Four yearslater, however, she developed arthritis with slight swelling of all fingers of both hands and moderatepain. As there was a simultaneous worsening of dermatitis, she was admitted to the DermatologicalDepartment of the University of Padova. All routine laboratory investigations, including serum lipids,rheumatoid factor and antinuclear antibodies (ANAs), were within normal limits. A skin biopsy of theright forearm revealed some granulomas, prevalently composed of PAS-positive histiocytes andmultinucleated giant cells without intracellular lipids, similar to those observed in the proband.

BS was diagnosed, but no specific treatment was prescribed except for NSAIDs, which were to betaken when necessary for a few days’ time for pain control.

The daughter was admitted to our Rheumatological Unit when she was 12 years old because ofpainful arthritis. At the physical examination, she presented asymptomatic erythematous papules on

Fig. 5. Proband. Skin biopsy from the right forearm. Non-caseating granulomas, containing several histiocytes and multinucleatedgiant cells with strong PAS positivity and rare lymphocytes and eosinophils.

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the extremities, in particular on the extensor leg surfaces, symmetric arthritis involving PIP andMCP ofthe hands (Fig. 7) and 1st MTP of the feet, which were swollen, tender and slightly warm. Radiographsrevealed periarticular swelling and slight space narrowing of the PIP and of the first right MTP of thehands. Laboratory investigation showed a slightly elevated erythrocyte sedimentation rate (ESR)26 mm 1st h (NVb 20 mm) and polyclonal hypergammaglobulinaemia 22.5% (total proteins7.7 mg dl�1). Rheumatoid factor and ANAs were absent. HLA typing revealed A23, A24, B18, B51, Bw4,DR11, DRw52 and DQw7. An electrocardiogram was normal and chest X-ray as well as abdominalultrasound were negative. An ophthalmologic examination was, curiously, negative. Synovial biopsyspecimens, of the third left PIP, were similar to the skin biopsies previously taken, in particular withregard to the non-caseous granulomas. The diagnosis of BS was confirmed but steroids were notprescribed because of the patient’s age and NSAIDs were begun. One year later, when the patient was13 years old, she presented bilateral anterior uveitis, successfully treated with topical drugs. However,some weeks later, as arthritis and skin lesions were worsening, low doses of oral steroids wereintroduced for 1–2 week cycles, obtaining a good response.

Continuing with the same therapeutic regimen (mean weeks/year on steroids are 4 even now), thedisease is under control without relevant impairment of the quality of life.

Fig. 6. Proband. Skin biopsy from the right forearm. Electron microscopy showing (a) polipoid hystiocytes with abundant cytoplasmcontaining lysosomes and glycogen granules and (b) the characteristics pleiomorphic cytoplasmic bodies called “comma-shapedbodies”.

Fig. 7. Daughter. Hands with symmetrical enlargement of interphalangeal joints.

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All the members of the proband’s family underwent genetic investigation 2 years ago. None in herfamily, composed of two sisters and a brother, her husband, and her other daughter, showed symptomsof BS. A new CARD15/NOD2 E383K mutation was found only in the patients described here.

Practice points

� The initial presentation of arthritis in the absence of ocular or skin findings is often mistakenfor juvenile rheumatoid arthritis.

� Eye involvement is the most relevant morbidity of BS and require the closest attention.� Atypical cases of BS have been reported with involvement of organs other than skin, joint andeyes.

� Biologic anti-cytokine agents may represent promising therapeutic approaches in refractorycases

Research agenda

� Assessment of risk factors for severe eye involvement.� Multicentre studies to define patient monitoring guidelines and disease activity criteria.� Studies to evaluate various treatment strategies for severe eye involvement.� Development of new therapies specifically targeted to the underlying disease mechanism.� Studies of the genotype–phenotype correlation between the clinical manifestations andNOD2 mutations.

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