Elsevier

Autoimmunity Reviews

Volume 8, Issue 3, January 2009, Pages 228-232
Autoimmunity Reviews

Clinical and genetic aspects of Blau syndrome: A 25-year follow-up of one family and a literature review

https://doi.org/10.1016/j.autrev.2008.07.034Get rights and content

Abstract

Blau syndrome (BS) is a rare familial disease transmitted as an autosomal dominant trait, characterized by arthritis, uveitis, skin rash and granulomatous inflammation. Until now BS has been observed in 136 persons belonging to 28 families as well as in 4 sporadic cases. The gene responsible for BS has recently been identified in the nucleotide-binding domain (NBD) of caspase recruitment domain (CARD15/NOD2), also involved in the pathogenesis of Crohn's disease. In addition to three missense mutations (R334Q, R334W and L469F) previously identified, a new CARD 15 mutation (E383K) has recently been described in a family followed by us for the past 25 years. The characteristics of this family which, to our knowledge, is the only one affected with BS in Italy, are the object of this manuscript. Both the proband and her daughter were originally affected with a papulonodular skin eruption and then with mild arthritis of the hands and feet. The proband, but not the daughter, complained of severe chronic bilateral uveitis, followed by glaucoma and, a few years later, by cataracts. Histological examination of skin biopsies from both subjects and a joint biopsy (daughter only), showed non-caseating granulomas with multinucleated giant cells which, at electron microscopy, revealed “comma-shaped bodies” in epithelioid cells, thought to be a marker for BS. The disease is presently well controlled with low doses of prednisone for the mother and non-steroidal anti-inflammatory drugs (NSAIDs) plus low doses of prednisone, when necessary, for the daughter. As in Crohn's disease, CARD15/NOD2 mutation is believed to be responsible for the granulomatous autoinflammatory reactions probably triggered by microorganisms in BS.

Introduction

Blau syndrome (BS) is a rare familial disease characterized by arthritis, uveitis, skin rash and granulomatous inflammation [1]. In 1985 Blau described 4 generations of a family with eleven members affected with granulomatous disease of the skin, eyes, and joints. Ten had arthritis; two had skin, eye, and joint involvement; one had skin and joint disease, and one had iritis only [1]. Observing that the disease was transmitted as an autosomal dominant trait and only partially resembling sarcoidosis, he considered it a new syndrome. Eleven years later 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 several inflammatory bowel disease susceptibility loci [2]. Significant progress was further made when Miceli-Richard et al. observed that the gene responsible for BS was in the caspase recruitment domain (CARD15), also called NOD2 [3]. Three missense mutations (R334Q, R334W and L469F) were identified by these investigators in the nucleotide-binding domain (NBD) of CARD15/NOD2 in four French and German families with Blau syndrome. Thus, in addition to Crohn's disease, CARD15/NOD2 appears to be involved in susceptibility to a second granulomatous disorder [4]. A new CARD 15 mutation (E383K) has recently been identified in a family followed by us over the past 25 years [5]. As this, to our knowledge, is the only diagnosed family in Italy, we hope that a description of its characteristics and the disease course over such a long time period may contribute to better understanding of BS.

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

The patient presented with asymptomatic, diffuse, miliary brownish papule and firm subcutaneous nodules, varying in size from 5 to 30 mm in diameter, on the dorsa of hands and feet and on the extensor leg surfaces. Arthritis was evident on the bilateral metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints. Neither red nor hot, the joints were only slightly tender and swollen. The bilateral 1st and the 2nd metatarsophalangeals (MTP) of the feet were similarly involved. Camptodactylia (flexion contractures of the fingers and toes) was not present. Radiographs of hands and feet revealed only a slight periosteal enlargement of the bone and a chest X-ray was negative. Results of all laboratory tests including inflammatory indices were normal. Human leukocyte antigen (HLA) typing revealed A2, A3; B8, B21; DR3, DR7. Skin biopsy specimens of the forearms were processed for light and electron microscopy examination. The specimens were fixed in formalin for histologic assessment, embedded in paraffin and thin sections were obtained with hematoxylin–eosin, PAS, PAS-diastase and Weigert–van Gieson. Small fragments 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 toluidine blue and observed with a light microscope and ultrathin sections were stained with uranyl acetate and observed with a transmission electron microscope.

Histology revealed non-caseating granulomas, containing several histiocytes and multinucleated giant cells with strong PAS positivity and rare lymphocytes and eosinophils (Fig. 1a). Transmission electron microscopy showed polypoid histiocytes with abundant cytoplasm containing a well-developed Golgi complex and endoplasmic reticulum, profuse mitochondria, lysosomes and glycogen granules, probably determining PAS positivity (Fig. 1b). Pleomorphic cytoplasmatic inclusions were found in a few cells. Some collagen fibers were in close apposition to cellular membranes, often surrounded by a cytoplasmatic process of histiocytes, but without clear evidence of phagocytosis. Capillary vessels with swollen endothelial cells due cellular infiltrates were found. Due to the limited efficacy of NSAIDs, low doses of steroids (methylprednisolone 4 mg/day) were introduced 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 five-year-old daughter who had recently developed skin manifestations similar, although less severe, to her own. No therapy was prescribed at that time as the entity of the disturbances was negligible. Four years later, however, she developed arthritis with slight swelling of all fingers of both hands and moderate pain. As there was a simultaneous worsening of dermatitis, she was admitted to the Dermatological Department of the University of Padova. All routine laboratory investigations, including serum lipids, rheumatoid factor and antinuclear antibodies, were within normal limits. A skin biopsy, of the right forearm, revealed some granulomas, prevalently composed of PAS positive histiocytes and multinucleated 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 be taken when necessary for a few days time for pain control.

The daughter was admitted to our Rheumatological Unit when she was 12 because of painful arthritis. At the physical examination she presented asymptomatic erythematous papules on the extremities, in particular on the extensor leg surfaces, symmetric arthritis involving PIP and MCP of the hands (|Fig. 2) and 1st MTP of the feet, which were swollen, tender and slightly warm. Radiographs revealed periarticular swelling and slight space narrowing of the PIP and of the first right MTP of the hands. Laboratory investigation showed a slightly elevated erythrocyte sedimentation rate (ESR) 26 mm 1st h (NV < 20 mm) and policlonal hypergammaglobulinemia 22.5 % (total proteins 7.7 mg/dl). Rheumatoid factor and antinuclear antibodies (ANA) 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 abdominal ultrasound were negative. An ophthalmologic examination was, curiously, negative. Synovial biopsy specimens, of the third left PIP, were similar to the skin biopsies previously taken, in particular with regards to the non-caseous granulomas. The diagnosis of BS was confirmed but steroids were not prescribed because of the patient's age and NSAIDs were begun. One year later, when the patient was 13, she presented bilateral anterior uveitis, successfully treated with topical drugs. However, some weeks later, since arthritis and skin lesions were worsening, low doses of oral steroids were introduced for one–two week cycles, obtaining a good response. Continuing with the same therapeutic regimen (mean weeks/year on steroids are 4 even now), the disease is under control without relevant impairment of the quality of life.

All the members of the proband's family underwent genetic investigation two years ago. No one in her family, composed of two sisters and brother, her husband, and her other daughter, showed symptoms of BS. A new CARD15 E383K mutation was found only in the patients described here.

Section snippets

Clinical aspects

To our knowledge, BS has been observed until now in 154 persons belonging to 41 families (Table 1) [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [32], [33], [34] and in 4 sporadic cases [21], [22], [23]. Joint discomfort is the most frequently reported symptom, followed by skin and eye disturbances. Camptodactyly, considered a common finding in BS by Blau [1], and subsequently described in some cases, was not a symptom in our

Take-home messages

  • Blau syndrome is a prototype of autoinflammatory syndrome without fever and detectable acute phase reaction, which may be useful to better understand mechanisms and role of non-caseating granuloma in inflammation.

  • The expanding clinical heterogeneity of the pediatric granulomatous diseases syndromes and the high prevalence of sporadic cases should alert clinicians to the possible genetic basis of the condition and support the inclusion of DNA analysis as a diagnostic test.

References (35)

  • Y. Ogura et al.

    Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kB

    J Biol Chem

    (2001)
  • G. Tromp et al.

    Genetic linkage of familial granulomatous inflammatory arthritis, skin rash, and uveitis to chromosome 16

    Am J Hum Genet

    (1996)
  • C. Miceli-Richard et al.

    CARD15 mutations in Blau syndrome

    Nat Genet

    (2001)
  • J. Cavanaugh

    NOD2: ethnic and geographic differences

    World J Gastroenterol

    (2006)
  • M.M. Van Duist et al.

    A new CARD 15 mutation in Blau syndrome

    Eur J Hum Gen

    (2005)
  • R. Hafner et al.

    Sarcoidosis of early onset. A challenge for the pediatric rheumatologist

    Clin Exp Rheumatol

    (1993)
  • I. Moraillon et al.

    Blau syndrome or familial form of sarcoidosis with onset during infancy

    Ann Dermatol Venereol

    (1996)
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