MRH is a systemic non-Langerhans cell histiocytosis first described in 1937 by Weber and Freudenthal [1]. Later, Goltz and Laymon coined the term multicentric reticulohistiocytosis [1]. About 200 cases have been reported since first described, but only about 10 of these cases had onset in childhood. Of these, the youngest case described is that of a 6 year old child [2].
MRH is predominantly a condition of the adult population, and it is more common in females with a ratio of about 1.85 females per 1 male [1]. MRH is characterized by severe destructive bilateral and symmetric arthritis, mainly affecting the interphalangeal joints, shoulders, wrists, and hips. Characteristic skin findings are described as cutaneous nodules or papules that are usually localized in the periungual region, pinnae of the ears, nasal folds, and scalp. The pathognomonic "coral bead sign", which our patient demonstrated, is present in about 26% of the cases [1]. Systemic findings such us fever and anemia are absent in most. An association with malignancy has been reported, but no single neoplastic disorder is directly associated with MRH. The co-occurrence of malignancy is about 15 to 25%. The reported malignancies associated with this condition include melanoma, lymphoma, breast cancer, and ovarian cancer [3, 4]. MRH has also been associated with autoimmune diseases [3].
Histologic evaluation usually demonstrates multinucleated giant cells with a fine, ground-glass appearance, and in some cases, foamy or vacuolated histiocytes, as in our patient's case and that of a 14 year old girl [5, 6]. Some authors report that early in the disease there are more eosinophils, lymphocytes and histiocytes with fewer number of multinucleated giant cells which increase as the disease progresses, which could explain why there were no giant cells present on our patient's biopsy [7]. There is an associated lymphocytic infiltrate. Immunohistochemistry is variable, but in most cases, staining is positive for CD68, CD4, CD45, HLA-DR, and lysozyme, but negative for S100, CD20, and factor XIIIa [7]. While the clinical presentation and course of our patient is consistent with MRH, the histopathology and age of our patient are atypical for this disorder. The biopsy was positive for CD68 and lysozyme but did not demonstrate typical MRH cells. Radiologic findings of MRH may be similar to rheumatoid arthritis, psoriatic arthritis, and osteoarthritis, but subtle differences may help to differentiate them. Radiographically, MRH presents as periarticular soft tissue swelling and juxta-articular erosions of the joints of the hands symmetrically. The erosions spread centrally and cause separation of the bony areas [8]. Osteoporosis has not been described, but osteopenia was found in our patient and was reported in a 14 year old African American girl [9]. There can be compromise of the atlantoaxial joint causing subluxation and instability. The disease can progress to arthritis mutilans [8].
The differential diagnosis of xanthomas and arthritis is short but includes familial hypercholesterolemia type II and sitosterolemia. Familial Hypercholesterolemia type II is a common, autosomal dominant genetic disorder caused by a mutation in the LDL receptor gene that may present with xanthomatous lesions and oligoarthritis. Sitosterolemia is a rare, autosomal recessive lipid disorder characterized by extremely elevated plasma plant sterol levels. It is clinically characterized by tuberous skin and tendon xanthomatous lesions, arthritis, and premature vascular disease. Our patient had normal lipid levels and sterol screening which ruled out these diagnoses.
Other disorders like Von Gierke glycogen storage disease and Farber's disease can present with xanthomas and joint complaints. The lack of systemic involvement and progressive course did not support these diagnoses in our patient. The lack of osteocondrodystrophy, ocular findings, and family history in our patient excluded familial histiocytic dermatoarthritis and dermochondrocorneal dystrophy as possible diagnoses. Xanthoma disseminatum, also part of the non-Langerhans histiocytic disorder spectrum, typically occurs in teenagers and young adults. The skin lesions are described as yellow to brown growths forming plaques and nodules that can present anywhere on the skin but most commonly in flexural areas of the extremities, the eyelids, and mucosae; visceral involvement has been described. Case reports of skeletal involvement presenting with limb pain caused by bone infiltration of xanthomas exist, but no cases of joint infiltration or associated arthritis have been published. Other non- LCH disorders such as juvenile xanthogranuloma (JXG) and generalized eruptive histiocytomas (GEH) can present with xanthomatous lesions. Skin biopsy of these lesions shows a characteristic vacuolated histiocytic infiltrate which contains Touton giant cells in 85% of the cases and a characteristic positivity of the lesions to factor XIIIa, CD68, CD163, fascin, and CD14 but negative S100 and CD1 on immunohistochemistry [10]. The histologic findings of JXG and GEH are different from those of our patient. Moreover, these entities are not known to be associated with arthritis.
Despite the clinical picture being consistent with MRH, the histologic examination of the skin lesions and the synovium were consistent with a diagnosis of papular xanthoma (PX). This entity, a normo-lipemic, non-Langerhans cell histiocytosis, is also a very rare disease in childhood. The cases reported in children have been characterized clinically by the presence of generalized yellow to brown papules and papulonodules on the face, trunk and limbs and a distinctive resolution in 1 to 5 years leaving anatoderma like scars in 60% of the case [11]. Histologic examination of the lesions shows similar characteristics as the ones seen in our patient: a dermal infiltrate of foamy histiocytes; however, our patient did not have Touton giant cells that are commonly be seen in PX. In popular xanthoma, histiocytes are CD68, KiM1p, and HAM 56 positive but negative for XVIIIa, S-100, lysozyme and CD56 [11]. Usually, these patients have no systemic involvement, and there is no report in the literature of an association with arthritis.
Multiple treatment options have been utilized in patients with MRH including NSAIDs, cyclophosphamide, azathioprine, methotrexate, hydroxychloroquine, corticosteroids and, recently, biologics with no definitive treatment regimen that can control the disease in all cases [12–14]. Several case reports in children have described acceptable results with NSAIDs or methotrexate alone [2, 6]. For severe cases, more aggressive therapy is warranted. Systemic steroids can be effective for the arthritis, serositis, and xanthomatous skin lesions as was seen in our patient, but this is not a good long term treatment option given the toxicity.
The tumor necrosis factor (TNF) antagonists are a logical consideration given the evidence of increased TNF-α in patients with MRH [15]. Etanercept, an α-TNF receptor fusion protein, has been reported efficacious in some adult patients with difficult to treat MRH, but has not been successful in other reports [16]; the use of etanercept has not been reported in children with MRH. Etanercept did not completely control the synovitis in our patient. Infliximab, a monoclonal antibody against human-TNF-α, has been used in combination with methotrexate and prednisolone, with success in two case reports [12, 17]; however, no benefit was achieved with infliximab in combination with methotrexate in another patient [13]. Adalimumab, a recombinant human IgG1 monoclonal antibody against TNF-α, has also been reported to be useful in the treatment of MRH [14].
There have also been reports of improved disease control when bisphosphonates are either added to or used as monotherapy to the treatment regimen in MRH [18]. Multinucleated cells from cutaneous nodules in MRH have been found to stain strongly with osteoclast markers, suggesting osteoclast differentiation [18]. In MRH, RANKL and macrophage colony stimulating factor stimulate synovial fluid macrophages to differentiate into osteoclasts [18]. Bisphosphonate therapy can decrease RANKL levels and promote osteoclast apoptosis. Therefore, bisphosphonates could be a promising treatment option for children with MRH, but more studies need to be conducted.
Preventing erosive joint destruction, particularly blocking the progression of MRH to arthritis mutilans, is the ultimate goal in treatment, and the search for an ideal treatment regimen continues. Corticosteroids seem to be very effective, but side effects limit its long term use especially in growing children. TNF inhibitors may be of benefit to some, although they were not very effective in our patient in that the effects were not sustained, and the use of TNF inhibitors did not have a steroid sparing effect. Combination regimens of several different immunosuppressive drugs seem to be the most effective way to control the disease. Bisphosphonates are another unexplored treatment option to consider in children with MRH.
