Leg ulcers: A new symptom of Blau syndrome?

ARTICLE

Auteur(s) : Veerle Dhondt¹, Sarah Hofman¹, Karin Dahan², Hilde Beele¹

¹Department of Dermatology, University Hospital of Ghent, De Pintelaan 185, 9000 Ghent, Belgium
²Centre de génétique humaine, Université Catholique de Louvain, Av. E. Mounier, 1200 Bruxelles, Belgium

accepté le 30 Juillet 2008

A 63-year-old patient, with extreme deformation of the fingers (camptodactyly) (figure 1A), and suffering from poor vision for a number of years, presented with large and extremely painful ulcerations on both legs (figure 1B). The ulcers had already existed for several months and did not respond to conventional treatment modalities such as sugarpastes, wet wraps with potassium permanganate solution, povidon iodinegel in the wounds and topical betamethasonevalerate around the ulcers. Bacterial swabs had shown Escherichia coli and Proteus mirabilis, but only in small amounts. In his childhood, this patient had been diagnosed with Still’s disease. Further clinical examination revealed purpura on the knees (figure 1C) and a monomorph eruption of brown, non-itching, small papules on the abdomen and on the proximal extremities.

A biopsy of a lesion on the knee did not show any element to confirm the presumed diagnosis of vasculitis but revealed the presence of granulomas. A similar picture of granulomatous dermatosis was found in a biopsy of lesions on the abdomen. A biopsy taken from a wound on the lower leg also revealed granulomas (figures 2A and B). PAS, Giemsa and Ziehl-Nielsen staining were negative. The monomorph papules, the extreme deformation of the fingers, the uveitis, the absence of systemic features and the histological findings of granulomas are all typical for Blau syndrome.

To confirm our diagnosis, a genetic analysis was performed by direct sequencing which revealed a heterozygous C-to-T transition at nucleotide position 1036 in the CARD15 gene (c.1036C>T), resulting in an arginine to tryptophan amino acid change at codon 334 (p.R334W). The position of the mutated nucleotide corresponds to 1,000 counted from the first ATG (NM_022162) (figure 3A). This is 1 of the 4 mutations reported so far as responsible for Blau syndrome. As the family history of the patient was negative there could have been a variable expression of the phenotype or a new mutation in the family. Because he had no close relatives alive, we could not check the presence of the mutation in other family members.

A treatment with oral methylprednisolone 32 mg/d and topical betamethasonevalerate cream was started. With this treatment, there was a rapid amelioration of both pain and wound healing. Even with tapering of the corticoids, wound healing continued until complete closure of the wounds. The occurrence of granulomas in the leg ulcers and the successful treatment of the wounds with systemic corticoids, suggest that these ulcerations could be part of Blau syndrome in this patient.

Discussion

Micelli-Richard et al. have identified 3 missense mutations involving the residues 334 and 469 within the nucleotide-binding domain of CARD15 gene in four families with Blau syndrome: a leucine to a phenylalanine codon (L469F), an arginine to a glutamine codon (R334Q) and an arginine to a tryptophan codon (R334W) have been observed [5]. In 2005, a fourth missense mutation (E383K) was found by Van Duist et al. This mutation substitutes another strongly conserved amino acid of the protein CARD15 [6].

The CARD15 gene is a member of a family of apoptosis regulators (CED4/APAF1 family) and is located on chromosome 16q12 [5, 7]. It encodes a protein composed of two amino-terminal caspase recruitment domains (CARDs) linked to a nucleotide-binding oligomerization domain (NOD) and multiple carboxy-terminal leucine-rich repeats (LRR) [7-9]. This protein is involved in activation of the nuclear factor-κB inflammatory cascade and the regulation of apoptosis and is mainly expressed in monocytes, granulocytes and dendritic cells, which are the major cellular components of Blau syndrome granulomas [2, 3, 6]. It is known that the CARD15 gene also plays an important role in other granulomatous diseases such as Crohn’s disease (CD) and ‘early onset sarcoidosis’. In classical adult sarcoidosis no major role of CARD15 mutation has been detected [8, 10-12].

The association of NOD2/CARD15 mutations with CD and BS, and possibly also with early onset sarcoidosis, suggests a role for the gene in the development of granulomata. A granuloma is a collection of macrophages and other inflammatory cells that surround a tenacious agent. Granuloma formation usually constitutes a normal host response to certain intracellular infections. The inflammation gradually destroys the irritants and clears the debris. Granuloma formation is dependent on the activation of a T-helper 1 response and the subsequent production of cytokines (mainly IL-12, IFN-γ and TNF). A defect in the sensing by the NOD2/CARD15 receptor may lead to an inappropriate activation of the immune system with excessive granuloma formation [8, 9, 11]. Although Crohn’s disease and Blau syndrome are both associated with granulomatous inflammation, the mutations causing the disease are different. The CARD15 variants associated with Crohn’s disease are located within or near the C-terminal leucine-rich repeat domain; the CARD15 variants associated with Blau syndrome are located in the central nucleotide-binding oligomerization domain [8, 11].

CARD15 mutations in Crohn’s disease result in defective recognition of muramyl-dipeptide (MDP), a component of bacterial cell wall peptidoglycan, resulting in a reduced cytokine response and decreased NF-κB activation [8, 9, 11]. Impairment in this defense process may lead to a persistent triggering of alternate stress routes, subsequently leading to abundant local secretion of proinflammatory cytokines (e.g. TNFα, IL12,IL6,IL1) [3, 11, 13]. This may provide a possible mechanism of granuloma formation in septic sites in Crohn’s disease. In metastatic Crohn’s disease sterile granulomatous skin lesions arise at sites remote from the gastrointestinal tract [14]. The pathogenesis of granulomas in these distant lesions remains unknown. It has been suggested that they result from an immune mechanism with circulating immune complexes or from a type IV hypersensitivity reaction [14].

In contrast, CARD15 mutations associated with Blau syndrome are gain-of-function mutations and promote MDP independent NF-κB activation which provides a possible explanation for granuloma formation in aseptic sites in Blau syndrome. In Blau syndrome, there is an increase in the basal activity of NF-κB, compared with the wild type allele. This indicates a constitutive NF-κB CARD15 activity and suggests that such mutations of conserved amino acid in the NOD motif can trigger a highly penetrant uncontrolled inflammatory signalling, resulting in early onset dominant inflammatory diseases [7, 12, 13].

Controversy exists about the distinction between Blau syndrome (BS) and ‘Early onset sarcoidosis’(EOS). ‘Early onset sarcoidosis’ presents with the same triad of arthritis, uveitis and cutaneous eruption as in Blau syndrome [3]. Blau syndrome can be distinguished by the autosomal dominant inheritance pattern [3, 15, 16]. As our patient has no children and his familial history is negative, the distinction between Blau syndrome and ‘Early onset sarcoidosis’ in this case remains uncertain.

It has been suggested renaming BS/EOS as ‘pediatric granulomatous arthritis’. Schaffer et al. disagreed with this suggestion because the term does not encompass the full disease spectrum. Secondly, they also argue that arthritis is absent in half of patients at the time of initial presentation, and in approximately 10% of the affected individuals it never develops. They propose the term ‘juvenile systemic granulomatosis’ after Miller, who suggested in 1986 that BS and ‘EOS’ might represent a single disease entity and proposed the term ‘juvenile systemic granulomatosis, sporadic or familial’ [17]. The observations of Kanazawa of a sporadic case of systemic granulomatosis with a CARD15 mutation (7) and of Rosé of a sporadic case with granulomatous arthritis, carrying the same CARD15 gene mutation as observed in BS [16], confirm the phenotypic overlap. These observations, corroborated by others, illustrate that most cases of BS and early onset sarcoidosis might arise from a common genetic event in the CARD15 gene [16, 18].

Ulcerations have been described in a number of cutaneous granulomatous diseases. We could identify a small number of case reports of ulcerative lesions in sarcoidosis. It has been suggested that an underlying vasculitis may be an aetiological factor. Granulomatous vasculitis has been described in pulmonary sarcoidosis but only rarely in cutaneous sarcoidosis. Poonawalla et al. describe an ulcerative sarcoidosis in which they believe an extrapulmonary vasculitis involved the cutaneous vasculature of the legs [19, 20]. Only three other cases of sarcoidosis with leg ulcers that were histologically consistent with cutaneous granulomatous vasculitis, have been previously reported [21-23]. In the biopsy of our patient, we could not find any arguments to support the hypothesis of vasculitis.

In metastatic Crohn’s disease the overlying epidermis may ulcerate, probably due to a vascular involvement. The lymphocytic infiltration is superficial and deep, approximating the normal anatomy of the superficial and deep vascular plexus, though frank vasculitis is rather exceptional and is not always associated with epidermal ulceration [14].We assume that such a mechanism, as occurring in metastatic Crohn’s disease, might also have caused ulcerations overlying the granulomata in our patient.

In conclusion, we want to recall the clinical picture of our patient presenting with very large and very painful ulcerations on both legs. The presence of non-caseating granulomata in the biopsy of the ulcers and the knowledge that granulomatous lesions may ulcerate, suggest that these are part of a granulomatous disease. Genetic analysis in our patient confirmed the diagnosis of BS, although EOS could not be excluded completely. To our knowledge, this is the first description of leg ulcers being a manifestation of Blau syndrome or early onset sarcoidosis.

Acknowledgments

References

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