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9 Rare diseases
  1. E BASKIN,
  2. U SAATCI,
  3. A BAKKALOGLU,
  4. S OZEN,
  5. R TOPALOGLU,
  6. N BESBAS
  1. Hacettepe University, Department of Paediatric Nephrology and Rheumatology, Ankara, Turkey
    1. E BASKIN,
    2. U SAATÇI,
    3. S OZEN,
    4. R TOPALOGLU,
    5. A BAKKALOGLU,
    6. N BESBAS,
    7. O KALAYCI
    1. Hacettepe University Departments of Paediatric Nephrology, Rheumatology, and Immunology, Ankara, Turkey
      1. K DAVIES,
      2. ER STIEHM,
      3. P WOO,
      4. KJ MURRAY
      1. Department of Rheumatology, Great Ormond Street Hospital, London, UK
        1. R TOPALOGLU,
        2. E BASKIN,
        3. H OKUR,
        4. N BESBAS,
        5. U SAATCI,
        6. M TUNCER,
        7. A BAKKALOGLU
        1. Departments of Paediatric Nephrology and Haematology, Hacettepe University, Ankara, Turkey
          1. V VARGOVÁ,
          2. R VESELY
          1. Paediatric Department Medical Faculty UPJ and Faculty Hospital, Kosice, Slovakia
            1. R VESELY,
            2. V VARGOVÁ
            1. Paediatric Department Faculty Hospital, Medical Faculty UPJ_, Ko_ice, Slovakia
              1. A TOMMASINI,
              2. L LEPORE,
              3. E FRAGONAS,
              4. M LAZZERINI,
              5. V KIREN
              1. Department of Paediatrics, IRCCS Burlo Garofolo, University of Trieste, Italy
                1. E KOSKOVÁ,
                2. M KRUPA,
                3. V BOSÁK,
                4. KOPECKY,
                5. J LUKÁC,
                6. D MICEKOVÁ,
                7. J ROVENSKY
                1. Research Institute of Rheumatic Diseases, Pieslany, Slovak Republic
                  1. V PANAVIENE
                  1. Centre of Paediatrics Vilnius University, Lithuania
                    1. M JAKUTOVIC,
                    2. V PANAVIENE
                    1. Vilnius University Children's Hospital, Vilnius, Lithuania
                      1. C BROCHHAUSEN15-150,
                      2. B TRUTNAU15-150,
                      3. G KLAUS15-150,
                      4. L SCHWEIGERER15-151,
                      5. HW SEYBERTH15-150
                      1. Departments of Paediatrics, Universities of 15-150Marburg and 15-151Essen, Germany
                        1. I NIKISHINA,
                        2. N KUZMINA
                        1. Institute of Reumatology of RAMS, Moscow, Russia
                          1. R BRIK
                          1. Department of Paediatrics and Paediatric Rheumatology Service, Rambam Med Ctr, Haifa, Israel
                            1. P PICCO,
                            2. R MONTEVERDE,
                            3. A BUONCOMPAGNI M GATTORNO,
                            4. AM PRIEUR,
                            5. M DI ROCCO
                            1. Department of Rheumatology, G Gaslini Institute, Genoa Italy, Department of Rheumatology, Hospital des Enfantes Malades, Paris, France
                              1. A BUONCOMPAGNI M GATTORNO,
                              2. A BARABINO,
                              3. P GANDULLIA,
                              4. C MARINO,
                              5. P PICCO
                              1. Department of Rheumatology, Gastroenterology and Pathology, G Gaslini Institute Genoa Italy

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                                9.1 Urinary glycosaminoglycan in the course of FMF

                                Familial Mediterranean fever (FMF) is characterised by recurrent fever and serositis. The most important complication of the disease is amyloidosis, which is diagnosed by biopsy. Cheaper and non-invasive methods would be important in the early diagnosis of amyloidosis. We have attempted to study the role of urinary glycosaminoglycan (GAG) in the early diagnosis of amyloidosis. The study group included 123 patients with FMF without attack and 11 patients with FMF secondary amyloidosis. Patients with acute attack were excluded. Eight healthy children and 10 patients with primary nephrotic syndrome served as controls. Microalbumin was also measured in patients with FMF. In patients with amyloidosis, urinary GAG levels were lower than in patients with FMF, those with nephrotic syndrome, and controls. In 49 patients with FMF with a low GAG level, urinary GAG levels increased significantly with incremental increase in the colchicine dose (p<0.05). In some patients with low GAG levels, microalbuminuria was also detected. In these patients, microalbuminuria also decreased along with the increase in urinary GAG, when the colchicine dose was increased. These results suggest that in patients with FMF, monitoring urinary GAG and microalbumin levels may be important in the regulation of the colchicine dose and prevention of amyloidosis. We suggest that effective colchicine dose may be monitored by following urinary GAG levels.

                                9.2 Epithelial cell-derived neutrophil activator (ENA-78) levels in patients with FMF

                                The exact mechanism triggering acute attacks in familial Mediterranean fever (FMF) is unclear. Neutrophil is the effector cell of the inflammatory response at the serozal surface.

                                Epithelial cell-derived neutrophil activator (ENA-78) a recently discovered chemokine, is one of the most important chemotactic cytokines for neutrophil chemotaxis. We have examined plasma ENA-78 levels in 63 patients with FMF. Thirty one patients had acute attacks and 32 patients had remission. Mean (SD) ENA-78 levels were greater in patients with acute attacks than in attack-free patients (2186.45 (1046.37) v 1646.78 (774.93), p<0.05). The ENA-78 level correlated with erythrocyte sedimentation rate and fibrinogen levels. Our results suggest that ENA-78 may be an important factor in the pathogenesis and activity of FMF disease.

                                9.3 Five cases of juvenile idiopathic arthritis and the velocardiofacial (22q11) syndrome

                                Introduction—The association between juvenile idiopathic arthritis (JIA) and the velocardiofacial syndrome (VCFS) has recently been described by three separate groups in a total of eight cases. We report a further five cases, all of whom have deletions at the 22q11 locus.

                                Results—All five patients had a history of congenital heart disease (CHD) and velopharyngeal insufficiency (VPI). 4 have significant learning difficulties. None had a history of recurrent infections but two have a selective IgA deficiency and one has abnormal T cell function with a defective phytohaemagglutinin response. In all patients the arthritis is polyarticular onset or extended pauciarticular in nature, progressively requiring treatment with disease modifying agents and indistinguishable from true JIA. Three of our patients were diagnosed with VCFS in the first years of life as a result of the combination of CHD and VPI. In the other two the syndromic diagnosis was made at 17 and 21 years after rheumatology review. The immunological profiles of the 13 total cases of VCFS with JIA are reviewed: 5 are antinuclear antibody positive, 3 rheumatoid factor positive, 5 have T cell deficiencies, and 4 (2/5 of ours) have selective IgA deficiency. The increased incidence of both IgA deficiency and JIA in the 22q11 deletion syndrome provides further evidence for possible genetic factors in the pathogenesis of JIA. In addition, the presence of demonstrable T cell defects in 5/13 patients adds further weight to the hypothesis that JIA is a T cell related disease.

                                Conclusions—The severity of the arthritis in VCFS may reflect underrecognition of milder cases of joint disease in this syndrome and it is important for clinicians to be aware of the association. In addition, the possibility of VCFS should be considered in any patient with JIA in the presence of other features of the syndrome, such as CHD, speech problems, and learning difficulties.

                                9.4 Effects of colchicine on neutrophil adhesion molecules in familial Mediterranean fever (FMF)

                                We aimed at elucidating the role of L-selectin (CD62) and β2 integrins (CD11b and CD18) and activated protein C (APC) in patients with FMF and determining the effect of colchicine treatment on these parameters. CD11b, CD18, and CD62 expression on lymphocytes and neutrophils was evaluated by immunofluorescence flow cytometry. Thirty one children with FMF during acute attack while receiving colchicine and 22 children during remission while receiving colchicine, together with 12 children with an acute attack who were not receiving colchicine were evaluated. The median level of neutrophil CD18 expression was significantly higher in patients with FMF in acute attack than in remission (p<0.05). Furthermore, patients with acute attack and receiving colchicine had a higher CD18 expression than those with acute attack but not receiving colchicine (p<0.05). No significant difference in CD62 and CD11 expression, both on neutrophils and lymphocytes, was seen between patients with acute attack and in remission and the patients not receiving colchicine. APC, which may upregulate the proinflammatory cytokines interleukin 6 (IL6) and IL8 in human endothelial cells, remained at normal levels both in patients with acute attack and those in remission. Our results suggest that as one of the neutrophil adhesion molecules CD18 appears to have an important role in the FMF attacks. Further studies are needed.

                                9.5 SAPHO syndrome and hemiparesis in a child

                                SAPHO syndrome is uncommon in children. It is sometimes associated with inflammatory bowel disease and ophthalmological conditions. We present the case of a child with acute transitory hemiparesis as presenting symptom of SAPHO.

                                An 8 year old boy was referred for a right flaccid hemiparesis and painful, warm, and erythematous mass over the right sternoclavicular joint. The past medical history included only primary enuresis. On admission, neurological examination showed decreased strength in the right upper and lower extremities, claudication but normal pain, thermal and light touch sensation. Laboratory tests showed erythrocyte sedimentation rate 47 mm/1st h, while C reactive protein, antinuclear antibody, rheumatoid factor, coagulation tests, and fungal, bacterial, and viral culture were normal. Standardx ray and computed tomography (CT) of the osteoarticular lesion were compatible with osteoperiostitis. Cerebral CT and magnetic resonance imaging (MRI) were negative; MRI of the spinal cord showed thoracic syringomyelic cavity between D5-D6 and D10-D11. An open biopsy of the sternoclavicular mass showed fibroinflammatory tissue with rare lymphocytes and plasma cells. On follow up the neurological problems completely recovered in a few weeks while the sternoclavicular lesion persisted with intermittent symptoms of pain and swelling.

                                The diagnosis of SAPHO syndrome is supported by the sternoclavicular involvement, the insidious clinical course, and the histological picture. Skin lesions in children can be absent at onset or appear later on during the course of the disease. A neuropathic arthropathy has been excluded on the basis of the level and entity of the syringomyelia, the preservation of pain, thermal sensation and cutaneous trophism, and the histology. However, the coincidence between the onset of SAPHO syndrome and acute transitory hemiparesis is peculiar and not previously reported.

                                9.6 Puzzling problems for the diagnosis of inflammatory diseases

                                The diagnosis of inflammatory disorders remains a challenge for the physicians. Indeed, each separate entity can mimic another one clinically and there are few biological tests to help the diagnosis. Moreover, a number of these diseases may aggregate in the same patient or in the same family.

                                Case 1—A 6 year old girl with periodic fever syndrome and ulcerative gastroenteritis and vascular purpura (HLA-B51−), one mutation of the gene responsible for FMF ((MEFV): M694V), mother: complete Behçet's syndrome (HLA-B51−), grandmother: ulcerative colitis (HLA-B51+).

                                Case 2—An 11 year old Algerian boy with prolonged fever, myalgia, purpuric rash, and orchitis (2 MEFV mutations M694I), final diagnosis: prolonged febrile myalgia syndrome showing FMF.

                                Case 3—A 3 year old boy with recurrent fever, oral ulcers, oedemas, rash, and sacroiliitis (MEFV: one L110P), 1 grandmother with Behçet's disease (BD) and 7 other family members with incomplete BD.

                                Case 4—A 20 year old woman with periodic fever, complete BD features and antiphospholipid syndrome (MEFV: one M694V).

                                This report suggests that a true genetic link may exist between inflammatory disorders. Inflammatory bowel diseases, PAN and BD have been reported in 1% of patients with FMF. We could document 2 MEFV mutations (true genetic FMF) in our case 2 (pseudo-PAN) that we consider as prolonged febrile myalgia syndrome. The presence of MEFV mutations in the other cases (without a true genetic FMF) suggests that the MEFV gene may be implicated in the accumulation of inflammatory diseases.

                                9.7 Hyper-IgD syndrome: case report

                                Hyper-IgD syndrome (HIDS) is characterised by attacks of spiking fever, which last for 1–7 days preceded by chills and rigors and accompanied by a number of symptoms—lymphadenopathy, abdominal distress, skin manifestation, arthritis, splenomegaly, etc. In 1999 the gene for mevalonate-kinase was discovered as the gene responsible for HIDS. Our patient is a girl who came to our department with recurrent fever at the age of 4 years and 7 months. Her fever appeared every week and lasted for 3 days. It was accompanied with cervical lymphadenopathy, abdominal pain, arthralgias, and raised inflammatory proteins and erythrocyte sedimentation rate. Infection and malignancy were excluded. Repeatedly, the IgD level was over 140 mg/l. The patient was treated with prednisone and the fever disappeared. After tapering of steroid treatment the fever appeared again and IgD reached its maximum—198 mg/l. The patient is now 9 years old, takes 2.5 mg prednisone daily, is without any symptoms, and her IgD concentration remains high. Currently, DNA analysis for MVK gene is being performed.

                                9.8 Chronic joint pain in tricho- rhino-phalangeal syndrome type I

                                Tricho-rhino-phalangeal syndrome type I (TRPS) is an autosomal dominantly inherited syndrome characterised by hypotrichosis of the scalp hair, bulbous tip of the nose and skeletal abnormalities including cone-shaped epiphyses of the phalanges and hip.

                                Our patient is a girl, the first child of three born to healthy parents. No consanguinity. Gross motor development was slightly delayed, but intellectual development has been normal. She was bald until the age of two. She developed a facial impression of TRPSI: the scalp hair was thin and sparse, protruding ears, a long broad philtrum, and a pear-shaped nose.

                                Since reaching school age she has had frequent and often daily complaints of pain in the neck, back, and peripheral joints, especially hands, fingers, knees, and ankles. She has pronounced hypermobility in both small and large joints and laxity of the skin. She has swelling of the proximal interphalangeal joints of both hands with bilateral ulnar deviations in the middle phalanges of the index fingers. Radiological examination of the hands has shown cone-shaped epiphyses of both second indices. Bone age development is retarded. There are no malformations in the hips.

                                Combined conventional cytogenic banding analysis and molecular cytogenetic analysis disclosed a pathogenic aberration showing a complex, apparently balanced, translocation t(7;13;8)(p21;q21;q24.1)del8(q24.1). The breaking point on chromosome 8 (8q24.1) has resulted in an interstitial deletion of at least 3 Mb covering most of the TRPSI gene region that has recently been cloned.1

                                References

                                1. 8-1.

                                9.9 X-linked lymphoproliferative syndrome with intracranial and pulmonary aneurysms

                                X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency to Epstein-Barr virus (EBV) infection that has been mapped to chromosome Xq25. The most common presentation is fulminant infectious mononucleosis (FIM), but more than 10% of boys have problems, usually infections or lymphoma without EBV infection. Our patient was born in 1985 as the second of three boys to healthy unrelated parents with negative family history. Both brothers died in early childhood after a short febrile condition resembling FIM. Our patient was well until 12 years when he started to have repeated respiratory symptoms and his x ray showed a strange picture of progressive fibrotic process of both lungs. In November 1999 he was admitted to our hospital and during hyperventilation at functional pulmonary test he suddenly developed massive cerebral bleeding. Subsequent careful imaging showed excessive aneurysms all over his cerebral and pulmonary arterial system. DNA analysis confirmed diagnosis of XLP (mutation of C163T in the second exon of the gene that causes an amino acid change in position 55—an Arg changes to a stop codon). This phenotype of XLP was never seen and we can only speculate about the vasculitic process causing multiple aneurysmatic changes. The patient is receiving corticosteroid treatment and recovering from the consequences of cerebral bleeding.

                                9.10 CINCA (chronic, infantile, neurological, cutaneous, and articular) syndrome: report on three new cases

                                We describe 3 patients with CINCA syndrome, a rare multisystemic inflammatory disease of unknown cause. In all cases the typical rash was present at birth or within the first days of life; thereafter the disease progressively affected other organs.

                                In the first case the rash was associated with papilloedema, spiking fever, transient arthritis, and a diffuse and persistent lymphoadenomegaly, identified by biopsy as a reactive lymphoadenopathy with mixed hyperplasia.

                                The second case showed recurrent arthralgia and patellar hypertrophy. At direct immunofluorescence examination, the skin biopsy showed an urticaria-like vasculitis affecting the small and medium vessels of the dermis with IgM deposits in the dermis-epidermis junction.

                                The third case was characterised by transient arthritis, perceptive deafness, patellar overgrowth, papilloedema, morphological facial modifications, and spiking fever. Skin biopsy showed a leucocytoclastic vasculitis with IgM and complement deposits.

                                None of our cases had mental retardation (though described as a constant feature).

                                In all 3 cases laboratory findings showed leucocytosis, increased serum immunoglobulin levels, and raised C reactive protein and erythrocyte sedimentation rate.

                                In 2 cases the neutrophil activation markers were studied, CD11b and CD18 being greatly raised. These surface antigens have a role in the production of interleukin 8 and in the response to this cytokine. Chronic activation of both circulating and tissue neutrophils, suggesting a primitive defect of this cell line and of osteoclastic cells, which share the same staminal cells, may have an important role in the pathogenesis of CINCA.

                                9.11 Primary Sjögren's syndrome (pSS) in children and adolescents: clinical, imunological, and immunogenetic characteristics

                                We followed up five girls with average age 14.6 years (range 14–15). All patients had recurrent infections of upper airways, sustained fever, and fatigue. Clinical symptoms included arthralgia (5/5), Raynaud's Phenomenon (3/5), dental decay (3/5), hair loss (3/5), abdominal pain (3/5).Only two patients had sicca syndrome, detected by Schirmer's test and stimulated parotid secretion. Immunologically, we found polyclonal hypergamaglobulinaemia (4/5), positivity of rheumatoid factor (4/5), presence of antinuclear antibodies (3/5), anti-Ro/La antibodies positivity (3/5). Immunogenetic HLA typing showed that three of five patients had antigens B8/DR3, especially those with anti-Ro/La antibodies. The association HLA-B8/DR3 with pSS in adults and anti-Ro/La is typical for the Slovak population. All patients had sialographic changes typical for SS.

                                Diagnostic criteria for adult pSS are not fully applicable in children and adolescents, because laboratory autoantibody positivity in these patients precedes signs of sicca syndrome. Although anamnestic data, clinical symptoms, and immunological changes may suggest a diagnosis of pSS, sialography may be decisive for the diagnosis in childhood.

                                9.12 Primary juvenile Sjögren's syndrome: a rare disease in childhood

                                Primary Sjögren's syndrome is rare in childhood. The disease affects mainly older women and only a few cases of primary Sjögren's syndrome in children have been described.

                                We report the case of a five year old girl, whose initial manifestation of disease was Raynaud's phenomenon. After 6 months, arthralgia and peripheral polyarthritis developed. Two years later recurrent swelling of the parotid glands (mainly right sided), dry cough, and vasculitis were additionally seen, dental caries progressed. Raised erythrocyte sedimentation rate, positive rheumatoid factor test, positive antinuclear antibody test, pulmonitis shown by a chestx ray, osteolysis of distal phalanges in a hand x ray were found. An ophthalmologist showed conjunctivitis with lachrymal hypersecretion. In a biopsy of the salivary glands plasmic cell infiltration in the glands and in hypertrophied epithelium of ductuli, paracolagenic amyloid concentration around canaliculi was found. A diagnosis of Sjögren's syndrome with secondary amyloidosis was made. Corticosteroid treatment and basic treatment with Leukeran (chlorambucil) improved the general status of the patient. After 6 months of treatment no signs of inflammation, were found, but disorder of the peripheral blood circulation and acrocyanosis was present. Typical dry mouth and eyes syndromes and symptoms of other systemic autoimmune disease did not develop during the period of the observation.

                                This clinical case report suggests, that primary juvenile Sjögren's syndrome can manifest without sicca features, typical in adults. Early diagnosis and treatment relieves the course of the disease and, probably, protects dysfunction of the exocrine glands.

                                9.13 Thrombosis associated with antiphospholipid antibody in paediatric systemic lupus erythematosus

                                Antiphospholipid syndrome is a disorder of recurrent arterial or venous thromboses, thrombocytopenia, and the presence of circulating antiphospholipid antibodies. Recurrent fetal loss is a common manifestation of the syndrome and frequently occurs in women with no history of thrombosis. Thrombocytopenia occurring during the course of the antiphospholipid syndrome is usually mild. If the clinical syndrome occurs in a patient with systemic lupus erythematosus, or less commonly in other disorders, such as systemic sclerosis, rheumatoid arthritis, or Behçet's syndrome, antiphospholipid syndrome is regarded as secondary. In primary antiphospholipid syndrome there is no evidence of other underlying disease.

                                We report the case of a 14 year old boy, whose initial manifestation of disease was arterial occlusions of major vessels of the legs with claudication and gangrene of digits. After several months, transient ischaemic attacks, due to thrombosis of intracerebral arteries, developed. The patient conformed to the American Rheumatism Association criteria for the classification of systemic lupus erythematosus with the presence of antiphospholipid antibodies in serum. Good results were achieved with long term treatment.

                                This clinical case report suggests that the presence of antiphospholipid antibodies must be ruled out in the case of young patients with thrombotic events and cerebral ischaemia. Because any artery or vein may be affected, the spectrum of clinical manifestations of antiphospholipid syndrome is so wide that it includes virtually all medical specialties.

                                9.14 Remission of haemophagocytosis upon treatment with an anti-TNFα antibody

                                Haemophagocytosis is a severe disease characterised by inappropriate macrophage activation resulting in pancytopenia and excessive inflammation; it can occur as a familial inherited form or in association with diseases such as juvenile idiopathic arthritis.

                                At the age of 1 month, a girl presented at our hospital with a first episode of haemophagocytosis. Remission was induced by using intravenous immunoglobulins (IVIG), cyclosporin A (CSA), and steroids. Haemophagocytosis was reactivated at the age of 7 months. The patient was treated with IVIG, increased doses of steroids, and intravenous CSA. However, the patient deteriorated further and had to be transferred to the intensive care unit.

                                In diseases such as rheumatoid arthritis and Crohn's disease, characterised also by an exaggerated secretion of an array of proinflammatory mediators, application of anti-tumour necrosis factor α (anti-TNFα) antibodies has proved beneficial. This led us to treat our patient with a monoclonal anti-TNFα antibody (infliximab), rather than using more toxic drugs such as antithymocyte globulins or etoposide. Other treatments (steroids, CSA) remained unchanged. The patient started to recover, temperature, pancytopenia, and hepatosplenomegaly improved and serum levels of interferon γ normalised. The patient was discharged from the hospital in good general condition 4 weeks after the first dose of anti-TNFα.

                                This is the first, promising observation in one single patient treated with anti-TNFα. Further use of this drug in selected patients is warranted to assess whether the observed clinical benefit is causally related to its use.

                                9.15 Successful treatment of vasculitis associated deep cutaneous ulcers with prostaglandin E1 (PGE1) in a patient with CINCA syndrome

                                Introduction—The cause of the chronic infantile neurological articular syndrome (CINCA) is unknown. Clinical findings, raised C reactive protein, erythrocyte sedimentation rate, white blood count, and granulomatous inflammatory processes on histology point to an important role for chronic vasculitis in the pathogenesis of CINCA syndrome.

                                Case report—A 14 year old girl with CINCA presented with large skin ulcers of the legs resistant to conventional local treatment. On biopsy a vasculopathy affecting all layers of the dermis was found, implicating a secondary obstruction of the blood vessels, which in turn may have caused the necrosis. We suggested that stimulation of angiogenesis might be valuable in healing of the lesions. In view of the known ability of PGE1 to stimulate angiogenesis in animal experiments, the patient was treated with continuous PGE1 infusion of 6 μg/kg/24 h for 5 days. This was followed by markedly improved blood perfusion of the lesions and wound repair, which persisted for 3 weeks. After this period, the skin defects deteriorated and a second course of PGE1 infusion was performed, again showing improvement in wound healing. After 1 year of spaced PGE1 courses (4 weeks), permanent closure of the skin defects was seen. Side effects of treatment were pain and erythema on PGE1 infusion.

                                Conclusion—In this girl with CINCA syndrome severe skin necrosis developed, which might be a consequence of the vasculopathy. The effect of intermittent PGE1 on healing of the skin lesions may include inhibition of platelet aggregation, vasodilatation, and/or angiogenesis.

                                9.16 Mistakes of, and obstacles to, recognition of neoplastic and haematological disorders mimicking juvenile chronic arthritis

                                The present paper is the summary of our observations on neoplastic and haematological disorders of both malignant and benign origin that developed with pronounced rheumatological manifestations and were not identified on early stages.

                                The most rare case of Askin's tumour (from PNET group malignancies) in a 6 year old girl was presented as systemic juvenile rheumatoid arthritis (JRA) (so-called subsepsis allergica) followed by vasculitis-like disease, suspected to be Wegener's granulomatosis. Askin's tumour was diagnosed after death by histological and immunohistochemical analysis, though oncological examination was done repeatedly during the course of disease with negative results. We also dealt with a case of non-Hodgkin's lymphoma (Ki-1), presenting as a vasculitis-like syndrome with asymmetrical polyarthritis in an 11 year old girl. We observed a series of different neoplastic and haematological disorders mimicking juvenile spondyloarthropathies (JSA) owing to the localisation of peripheral arthritis, the presence of enthesitis, sacroiliitis and axial disease (1 melanoma, 1 mediastinal neuroblastoma, 1 Ewing's sarcoma, 2 acute leukaemia, and 2 patients with heritable spherocytic anaemia). One more case of JSA mimicking was found in a teenage boy who had back pain due to exostosis of the lumbar spine (not detected previously by x ray) and talalgia accompanied by ankle arthralgia due to an orthopaedic problem. We also observed 3 cases of secondary knee monarthritis due to atypical localisation of osteoid osteomas, exostosis, and haemangioma.

                                In all reported cases the mistaken diagnosis was caused by (a) pronounced rheumatological manifestations; (b) erroneous unification of different disorders under a single title; (c) an overestimate of the negative results of the previous diagnostic procedures. Our experience proves that in all doubtful cases differential diagnostic research should be continued.

                                9.17 Familial Mediterranean fever (FMF) presenting with unusual musculoskeletal manifestations

                                FMF is characterised by recurrent episodes of peritonitis, pleuritis, and synovitis. Although the most common musculoskeletal manifestation of the disease is acute recurrent monarthritis other manifestations have been described, including chronic joint disease, spondyloarthropathy, myopathy, and the “febrile myalgia syndrome”. The diversity and non-specificity of these clinical features are often an obstacle to the diagnosis of FMF. We describe a group of patients who displayed a variety of non-specific musculoskeletal symptoms and in whom genetic screening showed homozygosity for the FMF gene.

                                Ten patients were Sephardic Jews and 3 were Israeli Arabs. Nine were homozygous for the M694V mutation and the rest were homozygous or compound heterozygous for one of the other 4 mutations (V726A, M680I, M694I, E148Q). Six patients had the “febrile myalgia syndrome”, 2 had recurrent episodes of calf pain and pretibial swelling, 2 had non-specific myopathy, 1 had recurrent episodes of thigh swelling, 1 had chronic knee arthritis without any other features of FMF, and 1 had spondyloarthropathy.

                                Conclusions—Our observations indicate that genetic screening for FMF should be included in an investigation of recurrent or unexplained episodes of musculoskletal symptoms among children of Mediterranean extraction.

                                9.18 Treatment of hyper-IgD syndrome: a question unanswered

                                A long term follow up of a child affected with hyper-IgD syndrome (3 years) is reported, with particular emphasis on the treatment of this disease. A male child, born on March 1996 from unrelated, healthy parents, developed recurrent fever spikes associated with chills, severe malaise, short term diarrhoea from December 1996. Between disease flare ups, he was well. Three months later, a widespread enlargement of mesenteric lymph nodes and a thickening of colonic walls were shown. In the following months we noted (a) high IgA plasma concentration (9.45 g/l); (b) increased mevalonate urinary excretion; (c) strongly reduced activity of mevalonate kinase (5.4 v 347 pmol/min/mg). Familial Mediterranean fever was ruled out by genetic analysis. On this basis, we suggested the diagnosis of hyper-IgD syndrome. The patient was treated with colchicine (1 mg/day continuously), prednisone (0.5 mg/kg), and naproxene (15 mg/kg) only at the beginning of flare up. Table 18-1 shows the results obtained.

                                Table 18-1

                                Although our one case does not permit statistical analysis, our data seem to suggest that colchicine gives better disease control, reducing fever flare ups, whereas prednisone and naproxene sharply stop the fever attack at the beginning.

                                9.19 Joint involvement in eosinophilic gastroenteropathy in childhood

                                Eosinophilic gastroenteropathy (GE) is an uncommon disease characterised by eosinophilic infiltration of the gut wall. The disease may have different clinical presentations. Joint involvement is likely an underestimated complication of GE.

                                We report on 13 patients seen during the period 1992–99. Their mean age at the presentation of the disease was 8 months (range 1–4). All patients underwent gut endoscopy with multiple biopsies. We considered the gold standard to be villous containing >20 eosinophils infiltrating the epithelium.

                                The heralding symptoms were severe iron deficiency anaemia in 5 patients, which was associated with oedema due to loss of protein through diarrhoea in a further 5 patients; and haematochezia in 5 patients. Two patients presented severe bloody diarrhoea. The remaining patient came to us because of exudative ascites.

                                Four patients developed non-erosive arthritis in both the knee (2) and at the tibiotarsal joints. This symptom occurred after 12–19 months from the diagnosis. Arthritis was treated with sodium naproxene in 2 patients and intra-articular steroid infiltration in 1 patient. Interestingly, 1 patient developed a good response to an exclusive monomeric diet; when this schedule was modified arthritis flared up. No patient needed steroids or immunosuppressive drugs for the control of arthritis.

                                Our experience suggests that (a) arthritis is a relatively common complication of GE; (b) the feeding treatment using monomeric dietary schedule may be effective in the treatment of GE related arthritis.

                                View Abstract

                                Footnotes

                                • We thank RA Wanders for the mevalonate-kinase assay.

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