Blau syndrome

Blau syndrome (BS) is a rare dominantly inherited, inflammatory syndrome characterised by the clinical triad of granulomatous dermatitis, symmetric arthritis and recurrent uveitis. The caspase recruitment domain gene CARD15/NOD2 has been identified as the gene responsible for BS. In the majority of patients, the disease is characterised by early onset, usually before 3–4 years of age. Onset is most often articular and cutaneous. Eye symptoms usually start later; however, eye involvement is the most relevant morbidity of BS. Atypical cases of BS have been reported with involvement of organs other than skin, joint and eyes. Due to its rarity and the variations in the severity and evolution of its expressions, there have been no studies on the optimal treatment for patients with BS. If the therapeutic response to corticosteroids is unsatisfactory, additional treatment with immunosuppressive agents should be tried. The results with biologic anti-cytokine agents, such as infliximab and anakinra, are variable, particularly with regard to ocular morbidity. This review will 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.

Introduction

Blau syndrome (BS, MIM #186580) is a rare autosomal dominant granulomatous disorder . The disease was first described in 1985 by the paediatrician Edward Blau as a dominantly inherited, chronic inflammatory syndrome characterised by the clinical triad of granulomatous dermatitis, symmetric arthritis and recurrent uveitis with onset below 4 years of age. In his original description of the disorder, Blau reported four generations of a family with 11 members affected. Ten had arthritis; two had skin, eye and joint involvement; one had skin and joint disease; and one had iritis only . In 1996, the BS locus was mapped by Tromp et al. by genotyping 72 of the 74-member pedigree with dinucleotide-repeat markers to the chromosomal region 16q12.1–13, which also contains one of the susceptibility genes for Crohn’s disease . The gene responsible for BS was identified in 2001 by Miceli-Richard et al. The authors discovered 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 families with BS . Thus, in addition to Crohn’s disease, CARD15/NOD2 appears to be involved in susceptibility to a second granulomatous disorder . Over the next years, NOD2 mutations in additional families with BS were published. In spite of the striking clinical 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 the same disease . Due to common occurrence in infancy, some others proposed the term ‘paediatric granulomatous arthritis’ which, however, was inadequate to represent the systemic nature of this disease .

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 .

This review will 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. . We hope that a description of its characteristics and the disease course over such a long time period may contribute to a better understanding of BS.

Clinical aspects

BS occurs predominantly among Caucasians but has been reported in both Asians and Afro-Americans . The prevalence is unknown. In the majority of patients, the disease is characterised by early onset, usually before 3–4 years of age . However, symptoms sometimes do not appear before 10 years of age . Onset is most often articular and cutaneous while eye symptoms usually start later, between 7 and 12 years of age .

Arthritis is the most common manifestation of the disease, and it generally appears in the first decade of life . The initial presentation of arthritis in the absence of ocular or skin findings is often mistaken for juvenile rheumatoid arthritis (JRA).

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

Traditional X-rays show the typical deformities of periarticular swelling and, at times, joint space narrowing . Radiographic signs of erosive joint changes may be absent until later in the disease process. Progression to deforming arthritis may nonetheless occur leading to severe handicap caused by flexion contractures of fingers and toes (camptodactyly) and decreased motion of large joints.

Various skin manifestations have been described in BS but descriptions have not been uniformly consistent. Two main types of asymptomatic eruptions are usually reported: a papulonodular tender brownish rash and multiple, firm, subcutaneous plaques only apparent on palpation. The exanthema often presents as an erythema with maculopapular configuration. Pinhead-sized, lichenoid, yellow to brown papules are usually arranged in clusters and may become confluent. The appearance is variable, often symmetric, located on the trunk and/or extremities . Intermittent episodes of generalised exanthema with spontaneous resolution may occur during a period of years, eventually 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 . The histology of the lesions consistently demonstrates non-caseating granulomas with multinucleated giant cells ( Fig. 5 ). Electron microscopy may reveal ‘comma-shaped bodies’ in epithelioid cells , which seem to be a marker for BS ( Fig. 6 ).

Eye involvement is the most relevant morbidity of BS . From the perspective of quality of life, the ocular symptoms of BS require the closest attention. Recurrent anterior uveitis or panuveitis presenting with eye pain, photophobia and blurred vision are the most common presentations. Granulomatous uveitis, often bilateral, can evolve into a cataract and band keratopathy, frequently requiring surgery . Inflammation may afflict most ocular structures such as conjunctiva, lachrymal gland, retina and optic nerve. Other findings include vitritis, granulomatous disks and bilateral disseminated chorioretinal lesions that are surrounded by retinal haemorrhages and progressive subretinal fibrosis . Fundus modifications at times resemble those in sarcoid uveitis .

Typically, many patients require continuing follow-up and treatment for eye symptoms lifelong. Eye involvement is often complicated by chorioretinitis, cataract, glaucoma and retinal detachment, which may 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 , cerebral infarction and malignant hypertension .

Another family with BS was found to have ichthyosis vulgaris . There have also been reports of persistent or intermittent fever, granulomatous arteritis with central nervous system involvement including cranial neuropathies and corticosteroid-responsive hearing loss .

A patient with very large and painful ulcerations on both legs was recently described . where the 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 with BS .

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

A case of association between BS with chronic tubulointerstitial nephritis and renal clear cell carcinoma has been reported . Interestingly, histopathological examination showed giant cell granulomas in both the tumour and non-neoplastic renal tissue. Given the relation between chronic inflammation and 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 and interstitial pneumonitis has been reported . However, in contrast to sarcoidosis , involvement of the lungs has rarely been described in BS .

Due to its rarity and the variations in the severity and evolution of its expressions, there have been no studies on the optimal treatment for patients with BS. The major concern regards eye involvement, which may, at times, be severe . At the quiescent stage, low-dose glucocorticoids are generally satisfactory . High doses of glucocorticoids are, however, necessary in some acute stages. As disease onset is often during childhood, its long-term use especially at high doses, may be problematic. If the therapeutic response to corticosteroids is unsatisfactory, or a maintenance dose of prednisolone ≤10 mg day ⁻¹is needed for prolonged periods, additional treatment with immunosuppressive agents should be tried.

Biologic anti-cytokine agents such as infliximab, a tumour necrosis factor (TNF)-α inhibitor and anakinra, the IL-1 receptor antagonist, may represent promising therapeutic approaches in refractory cases . The results however are variable, particularly with regard to ocular morbidity. Furthermore, 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 is a promising agent for the reduction of granulomatous inflammation through its suppression of nuclear factor-κB (NF-κB) activation and interference with the proliferation and differentiation of monocytes .