46,XX male syndrome with mullerianosis of the urinary bladder: A new clinical entity.

Müllerianosis of the urinary bladder is a rare entity characterized by the presence of an admixture of at least two types of müllerian tissue in the muscularis propria of the bladder. We report the case of a 43-year-old male patient presented for urological evaluation due to episodes of total gross hematuria. Physical examination revealed ambiguous external genitalia. Abdomiopelvic CT scan revealed a tumor at the level of the bladder floor. Transurethral resection of the bladder lesions was done and histopathological studie confirmed the diagnosis of müllerianosis. Karyotype analysis showed a 46 XX male syndrome.

Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry.

OBJECTIVE: To evaluate genetic, demographic and clinical features in patients with cryopyrin-associated periodic syndrome (CAPS) from the Eurofever Registry, with a focus on genotype-phenotype correlations and predictive disease severity markers. METHODS: A web-based registry retrospectively collected data on patients with CAPS. Experts in the disease independently validated all cases. Patients carrying NLRP3 variants and germline-mutation-negative patients were included. RESULTS: 136 patients were analysed. The median age at disease onset was 9 months, and the median duration of follow-up was 15 years. Skin rash, musculoskeletal involvement and fever were the most prevalent features. Neurological involvement (including severe complications) was noted in 40% and 12% of the patients, respectively, with ophthalmological involvement in 71%, and neurosensory hearing loss in 42%. 133 patients carried a heterozygous, germline mutation, and 3 patients were mutation-negative (despite complete NLRP3 gene screening). Thirty-one different NLRP3 mutations were recorded; 7 accounted for 78% of the patients, whereas 24 rare variants were found in 27 cases. The latter were significantly associated with early disease onset, neurological complications (including severe complications) and severe musculoskeletal involvement. The T348M variant was associated with early disease onset, chronic course and hearing loss. Neurological involvement was less strongly associated with V198M, E311 K and A439 V alleles. Early onset was predictive of severe neurological complications and hearing loss. CONCLUSIONS: Patients carrying rare NLRP3 variants are at risk of severe CAPS; onset before the age of 6 months is associated with more severe neurological involvement and hearing loss. These findings may have an impact on treatment decisions.

Mode of inheritance in systemic lupus erythematosus in Saudi multiplex families.

Systemic lupus erythematosus (SLE) is a an autoimmune disease causing inflammation and injury of multiple organs like joints, skin, kidneys, eyes, central nervous system, heart. The etiology of SLE remains unknown. However; genetic component significantly contributes to the etiology of SLE. Familial SLE patients were defined as a family with more than one sibling diagnosed with SLE. The objective of the study is to describe the clinical features of the familial SLE and analyze the family pedigrees. Twenty-five individuals with SLE belonging to seven Saudi families were included. Three-generation pedigree was taken from the candidate families. The mean age at onset of the disease was 84.5 months (range: 18-144) while the mean age at diagnosis was 90.6 months (range: 24-144) and the mean duration of follow up was 48.5 months (range: 7-108). The proportion of girls was predominant (78%). Malar rash, arthritis and nephritis were the more frequent features. Sixteen patients had renal lesions, 10 of them had class VI nephritis according WHO classification. Five of the seven families are consanguineous reflecting the high percentage of consanguinity in our population. As many other autoimmune diseases, multifactorial is the most common form of inheritance. In the current study, the suggested mode of inheritance is autosomal recessive assuming Mendelian inheritance of single gene disorder.

Juvenile systemic lupus erythematosus in multicase families from Saudi Arabia: comparison of clinical and laboratory variables with sporadic cases.

The object of this study was to compare patients with familial versus sporadic systemic lupus erythematosus (SLE) with respect to clinical, laboratory variables and outcome. The familial SLE group comprised 12 patients while the comparative group comprised 24 patients selected by systemic sampling from our pediatric rheumatology clinic database. Those patients are listed according to the date of referral, which represents a sampling frame. The first patient was chosen randomly and subsequent patients were chosen at intervals of three. The two groups were compared with respect to: demographic information, age of onset of SLE, disease and follow up duration, clinical and laboratory variables and outcome. The patients from the familial group were younger and had an earlier age of onset of disease (P = 0.03, 0.001 respectively). Seven patients with familial SLE were from the eastern region of Saudi Arabia (P = 0.006). The two groups were comparable with respect to gender, disease duration and follow-up. At diagnosis, the discoid rash was more frequent in the familial group (P = 0.03) while other clinical and laboratory variables including disease activity as measured by SLEDAI did not show significant differences. The mean dose of steroid and use of other immunosuppressive therapy were similar in both groups. Three patients from the familial group died; two of them had unusual complications (one patient had transverse myelitis and pancreatic pseudocyst and the other one had extensive pyoderma gangrenosum). All patients from the sporadic group are alive in stable condition but one patient had severe central nervous system disease. Familial SLE patients tend to be younger and more likely to have discoid rash, in addition a marked difference in the origin of patients was noted. These differences may be helpful in identifying SLE patients with a stronger genetic predisposition. The mortality among familial SLE patients is more frequent which may reflect the disease severity.

Infantile systemic hyalinosis: a fatal disorder commonly diagnosed among Arabs.

We retrospectively reviewed 19 patients (11 male, 8 female) with infantile systemic hyalinosis (ISH) seen at a tertiary care hospital. Fifteen patients (83.3%) presented in the neonatal period. The referral diagnosis was inaccurate in 14 patients (73.7%). Thirteen patients were products of first-degree cousin marriages (68%) and 5 families had more than one affected child. All patients had painful joint contractures and typical mucocutaneous changes (hyper-pigmented sclerodermatous skin over the knuckles and malleoli, gingival hyperplasia, subcutaneous and perianal fleshy nodules). Growth failure was noted in all of them and 39% had profuse diarrhea, 72% had low serum albumin. Radiological findings included osteopenia, periosteal reaction and osteolytic lesions. Tissue biopsy was consistent with the diagnosis in the 8 patients who had the biopsies. Despite aggressive management with physiotherapy and different medications (including NSAIDs, penicillamine and methotrexate), the disorder was progressive and none of them showed improvement. 16 patients died with a mean age of 11 months and only 3 are alive with a mean age of 20 months. This report represents the largest series of ISH. Our data suggests that ISH is a commonly diagnosed disorder in Saudi Arabia and among Arabs.

Pancreatic pseudocyst in paediatric systemic lupus erythematosus.

Pancreatitis is a rare complication of paediatric systemic lupus erythematosus (SLE). We describe a child with severe form of SLE who initially developed acute pancreatitis, subsequently complicated by extensive pancreatic pseudocyst. The treatment and outcome are discussed.

Cogan's syndrome in childhood.

We present a case of Cogan's syndrome in childhood presenting with arthralgia, myalgia, anorexia, uveitis, aortic regurgitation, and intermittent fever and who responded well to corticosteroid therapy and successful valvular replacement. The extensive diagnostic methods and a review of the literature are covered and intended to familiarize pediatricians with this rare but treatable disorder.

Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome.

The inherited osteolyses or 'vanishing bone' syndromes are a group of rare disorders of unknown etiology characterized by destruction and resorption of affected bones. The multicentric osteolyses are notable for interphalangeal joint erosions that mimic severe juvenile rheumatoid arthritis (OMIMs 166300, 259600, 259610 and 277950). We recently described an autosomal recessive form of multicentric osteolysis with carpal and tarsal resorption, crippling arthritic changes, marked osteoporosis, palmar and plantar subcutaneous nodules and distinctive facies in a number of consanguineous Saudi Arabian families. We localized the disease gene to 16q12-21 by using members of these families for a genome-wide search for homozygous-by-descent microsatellite markers. Haplotype analysis narrowed the critical region to a 1.2-cM region that spans the gene encoding MMP-2 (gelatinase A, collagenase type IV; (ref. 3). We detected no MMP2 enzymatic activity in the serum or fibroblasts of affected family members. We identified two family-specific homoallelic MMP2 mutations: R101H and Y244X. The nonsense mutation effects a deletion of the substrate-binding and catalytic sites and the fibronectin type II-like and hemopexin/TIMP2 binding domains. Based on molecular modeling, the missense mutation disrupts hydrogen bond formation within the highly conserved prodomain adjacent to the catalytic zinc ion.

Evaluation of parental knowledge of Pediatric Rheumatic Diseases.

OBJECTIVE: To investigate the parental knowledge of pediatric rheumatic diseases in general, and in particular information regarding their children's diseases. To focus on the important role of health education in understanding these chronic diseases, and formulate a future plan for establishing a general public education program. METHODS: One hundred sets of parents, of children with established rheumatic diseases with mean duration of illness, (4.1 +/- 2.83), a mean child age (9.9 +/- 3.15) years, were given a 20 multiple choice questionnaire during their routine visit to the Pediatric Rheumatology Clinic and Physiotherapy Department or to the pediatric ward at King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, over a 6-month period between December 1998 and June 1999. The questionnaire addressed 4 main areas: 1. parental awareness regarding their children's diagnosis and duration, 2. source of information and parental satisfaction, 3. general knowledge about rheumatic diseases and 4. knowledge about medical and physical therapy. The total possible score is 23. RESULTS: The overall mean score is 11.6. The mean total score is not affected by the parental education level. The majority of parents have wrong beliefs, regarding rheumatic diseases. The treating physician is the main source of parental information and in the majority of the parents, this information is satisfactory. CONCLUSION: The questionnaire is a simple and easy test to investigate parental knowledge regarding pediatric rheumatic diseases. The survey shows the need for health education programs and a future general public health education plan to improve awareness of pediatric rheumatic diseases and maybe other chronic illness.

The arthritis of inflammatory childhood myositis syndromes.

OBJECTIVE: Arthritis has been an associated finding in juvenile dermatomyositis (JDM), but its prevalence, course, and response to therapy has not been well described. We investigated the frequency, course, and clinical and radiographic features in a large cohort of patients with JDM. METHODS: The charts of 94 patients with idiopathic myositis (1984-99) were reviewed: 80 JDM, 3 juvenile polymyositis (JPM), 5 amyopathic JDM, and 6 overlap myositis syndromes. Compiled data included demographics, clinical features, a detailed description of the arthritis, investigations (radiographs, autoantibodies), course, and response to therapy. All radiographs were independently reviewed by a single radiologist. RESULTS: Sixty-one percent (95% CI 50-72%) of patients with JDM had arthritis. The arthritis was reported a median 4.5 mo (range -73.6 to 76.6 mo) after the JDM onset. When compared to patients with no arthritis, the occurrence of arthritis was not significantly related to sex, race, positive antinuclear antibody or rheumatoid factor, calcinosis, nodules, vasculitis, or Raynaud's phenomenon. The initial involvement was pauciarticular in 67% and polyarticular in 33%. In the pauci group, asymptomatic knee effusions were the predominant finding (n = 19, 58%), and in 18 patients may have been the result of steroid therapy. Two patients evolved from a pauci onset to a polyarticular course. All responded to therapy (corticosteroids; 47 were taking other medications) with remission of the arthritis within a median of 2.0 mo (range 0.1-64.5 mo). However, the arthritis recurred in 39% as the corticosteroids were tapered. Four patients with JDM eventually required corticosteroid wrist injections, with resolution of the arthritis. The arthritis was nonerosive in all cases. No patient with JPM had arthritis. Three of 5 patients with amyopathic JDM and 4 of 6 with overlap myositis syndrome had a nonerosive polyarthritis. CONCLUSION: Nonerosive arthritis involving the knees, wrists, elbows, and fingers is a frequent manifestation of JDM and other idiopathic childhood myositis. The arthritis is seen early in the course of JDM and often responds to treatment. However, the arthritis may recur with tapering of corticosteroids despite remission of the JDM. In a significant proportion of JDM cases, arthritis is the major sequela and may warrant further medical therapy or intraarticular corticosteroid injections.

Infections associated with juvenile systemic lupus erythematosus.

OBJECTIVE: To determine the rate and nature of infection in a cohort of children with SLE. METHODS: Records of 70 children with SLE were reviewed for documentation of infections. All patients with infection seen between 1990 and 1998 were included. Data extracted comprised demographics and clinical features including the disease activity index (SLEDAI), detailed descriptions of therapy, and response to antibiotic therapy. Infections were identified and catagorized as class I (minor) or class II (major). RESULTS: A total of 29 patients (41%) had infections; 73% had class I and 27% had class II infections. The most common cause of class II infection was bacteremia (45%), while urinary tract infection was more frequent (38%) in class I infections. There was no association between the severity of infection and various potential risk factors. CONCLUSION: Our data confirm that infection is common among children with SLE. There were no deaths directly related to infection.

Coexistent linear scleroderma and juvenile systemic lupus erythematosus.

We describe a girl who initially presented with linear scleroderma. Five and a half years later she developed systemic lupus erythematosus (SLE). Previous descriptions of the coexistence of linear scleroderma and SLE in childhood are reviewed.

Intravenous immunoglobulin therapy for juvenile dermatomyositis: efficacy and safety.

OBJECTIVE: To assess the efficacy of intravenous immunoglobulin (IVIG) for the treatment of juvenile dermatomyositis (JDM) in patients who were unresponsive to corticosteroids (steroid resistant or steroid dependent) or showed unacceptable toxicity. METHODS: A retrospective chart review of the course of all patients with JDM treated with IVIG who attended the Dermatomyositis Clinic at The Hospital for Sick Children, Toronto, Canada, from August 1986 to December 1996. RESULTS: Eighteen patients with JDM were treated with IVIG. Ten patients were taking additional 2nd line treatments, methotrexate, azathioprine, cyclosporine, and cyclophosphamide. The main indication for starting IVIG was the failure of steroid therapy to induce remission of JDM. Twelve patients showed clinical improvement with IVIG. In these patients, the corticosteroid dose was reduced by > 50% for > 3 months without clinical or biochemical flare. Nine of these 12 patients had IVIG alone as a 2nd line agent, whereas 3 patients were treated with additional agents. Six patients remained steroid dependent; they subsequently required multiple agents to induce remission of JDM. CONCLUSION: Most steroid dependent or steroid resistant patients in our clinic were able to markedly reduce their dose of corticosteroid with the addition of IVIG. Given the retrospective nature of our data and the fact that multiple agents were sometimes used together, it will be important to confirm these findings in a controlled trial.

Efficacy of recombinant human growth hormone in children with juvenile rheumatoid arthritis and growth failure.

Ten patients with juvenile rheumatoid arthritis (JRA) and growth failure were treated with recombinant human growth hormone (GH) for 1 to 3 years at a dosage of 0.57 IU/kg/wk. All the patients had been on prednisone at a mean dosage of 4.12 mg p.o. daily. GH was low in one patient, two patients had a borderline level and seven patients had adequate response to provocative tests or post-sleep measurement. Serum IGF-I was found to be low in five of six patients. Mean growth velocity increased from 2.45 cm/yr to 4.79 cm/yr after 1 year's treatment with GH (P<0.004). Six patients continued on GH treatment for a second year and continued to have a better growth velocity, with a mean of 5.43 cm/yr (P<0.014). Two patients entered puberty during the second year of GH treatment. This study demonstrates the potential beneficial effect of GH treatment in patients with JRA with growth failure of systemic onset or polyarticular onset who are on prednisone. Further study is needed to determine the long-term effect of GH treatment on ultimate height.

New form of idiopathic osteolysis: nodulosis, arthropathy and osteolysis (NAO) syndrome.

We describe 10 patients (6 females and 4 males) from 6 unrelated families with an autosomal recessive disease characterized by simultaneous presentation of nodulosis, arthropathy and osteolysis. They were followed up regularly at King Faisal Specialist Hospital and Research Center in Saudi Arabia for clinical evaluation, serial blood work-up, and evaluating radiological changes. Nodulosis and arthropathy were the clinical criteria for inclusion in this study, and the ten patients fulfilled these criteria. All patients had nodulosis and distal arthropathy. Eight patients (80%) presented with deformed hands and four (40%) with painful hands. All patients had parents who were first cousins and three families had more than one affected child, the finding suggesting autosomal recessive inheritance. Osteopenia and undertubulation of bones distally more than proximally, and upper limbs affected more often than lower limbs, were found in all patients. Osteolysis was seen in carpal and tarsal bones. Other common findings were sclerotic cranial sutures, brachycephaly, and broad medial clavicles. This novel phenotype should be considered in the differential diagnosis of chronic arthritis. Familial arthropathies are more often seen in communities where interfamilial marriage is common. Such a collection of patients is ideal for homozygosity mapping of the disease locus.

Hemophagocytosis complicating Kawasaki disease.

A 6-year-old boy developed hemophagocytic syndrome during the recurrent course of Kawasaki disease. Despite the appropriate treatment modalities for Kawasaki disease, he developed pancytopenia, marked hepatosplenomegaly, high-grade fever, hyperferritinemia, hypertriglyceremia, and evidence of hemophagocytosis in the liver biopsy. Although the course was stormy, he responded well to a combination therapy of corticosteroids, etoposide VP16, and granulocyte colony-stimulating factor G-CSF. The clinical course and the treatment given were compared with the previous reported cases.

Efficacy of early treatment of severe juvenile dermatomyositis with intravenous methylprednisolone and methotrexate.

A pilot study was conducted to assess the efficacy of early treatment of severe juvenile dermatomyositis (JDMS) patients with intravenous methylprednisolone (IVMP) and methotrexate (MTX). Twelve children diagnosed with severe JDMS were treated with IVMP and MTX. Six patients were treated early (within 6 weeks of the diagnosis) while in the other six patients, MTX was started 5-72 months after the diagnosis was made. The clinical responses of the patients to treatment, including alterations in muscle strength, muscle enzyme levels and corticosteroid dosage as well as the development of side-effects, were recorded. The indications for starting the treatment were defined and documented. The primary measures of response were resolution of the clinical indications for treatment, decreased activity of the disease manifestations and tapering of the corticosteroids to the minimal dose or discontinuation without clinical or biochemical flare. The main indications for starting IVMP and MTX were dysphagia and severe cutaneous vasculitis. All the patients received MTX orally for at least 8 months, as well as IVMP (30 mg/kg/dose), but none of the patients was on additional second-line treatments. The six patients who were treated early with MTX showed a significant clinical improvement. In five out of the six, the corticosteroid dosage was eventually reduced to <5 mg/day. None of them developed calcinosis. In contrast, two of the six patients who were treated late with MTX developed calcinosis. This study suggests that MTX and IVMP are a useful combination in the early treatment of severe JDMS. Given the fact that our sample was small, further studies in a controlled trial are necessary to confirm these findings.