Anne-Marie Prieur

CARD15 mutations in Blau syndrome.

We have identified three missense mutations in the nucleotide-binding domain (NBD) of CARD15/NOD2 in four French and German families with Blau syndrome. Our findings indicate that, in addition to Crohn disease, CARD15 is involved in the susceptibility to a second granulomatous disorder.

Chronic Infantile Neurological Cutaneous and Articular Syndrome Is Caused by Mutations in CIAS1, a Gene Highly Expressed in Polymorphonuclear Cells and Chondrocytes

Chronic infantile neurological cutaneous and articular (CINCA) syndrome is a severe chronic inflammatory disease of early onset, characterized by cutaneous symptoms, central-nervous-system involvement, and arthropathy. In the present study, we report, in seven unrelated patients with CINCA syndrome, distinct missense mutations within the nucleotide-binding site of CIAS1, a gene encoding cryopyrin and previously shown to cause Muckle-Wells syndrome and familial cold urticaria. Because of the severe cartilage overgrowth observed in some patients with CINCA syndrome and the implications of polymorphonuclear cell infiltration in the cutaneous and neurological manifestations of this syndrome, the tissue-specific expression of CIAS1 was evaluated. A high level of expression of CIAS1 was found to be restricted to polymorphonuclear cells and chondrocytes. These findings demonstrate that CIAS1 missense mutations can result in distinct phenotypes with only a few overlapping symptoms and suggest that this gene may function as a potential inducer of apoptosis.

Efficacy of cyclosporine A in the treatment of macrophage activation syndrome in juvenile arthritis: Report of five cases

OBJECTIVES To evaluate the efficacy of cyclosporine A in the treatment of macrophage activation syndrome (MAS) occurring in children with juvenile arthritis. STUDY DESIGN MAS developed in two boys and three girls with systemic juvenile arthritis (four) and polyarticular juvenile arthritis (one). In three children whose condition was life-threatening, increased parenteral administration of corticosteroids failed to improve their condition; therefore cyclosporine A (2 to 5 mg/kg per day) was added. In two other patients with less severe clinical manifestations, cyclosporine A alone (2 to 8 mg/kg per day) was given. RESULTS After the introduction of cyclosporine A, rapid improvement was obtained in all patients and apyrexia occurred within 24 to 48 hours. The biologic abnormalities disappeared more slowly (up to 5 weeks for liver enzymes). CONCLUSIONS These observations underline the usefulness of cyclosporine A in this complication. The use of this drug may circumvent the need for increased doses of corticosteroids in some patients. The mechanism of action of cyclosporine A remains speculative, but these results indicate indirectly that T-helper lymphocytes may play a role in the pathogenesis of MAS.

Cryopyrinopathies: update on pathogenesis and treatment

Cryopyrinopathies are a group of rare autoinflammatory diseases that includes familial cold autoinflammatory syndrome, Muckle–Wells syndrome and chronic infantile neurologic cutaneous articular syndrome (also termed neonatal-onset multisystemic inflammatory disease). These syndromes were initially considered to be distinct disease entities despite some clinical similarities; however, mutations of the same gene have since been found in all three cryopyrinopathies. These diseases, therefore, are not separate but represent a continuum of subphenotypes. The gene in question, CIAS1 (now renamed NLRP3) encodes NALP3 (also known as cryopyrin). NALP3 is an important mediator of inflammation and interleukin 1β processing. New therapies based on biologic agents that specifically target interleukin 1β are currently being developed. These new agents have provided very encouraging results for patients with these long-lasting inflammatory conditions—which used to be considered refractory to treatment. The development of therapeutic options for these cryopyrinopathies illustrates effective translation of basic science to clinical practice and the convergence of human genetics and targeted therapies.

Mevalonate Kinase Deficiency: A Survey of 50 Patients

OBJECTIVE: The goal of this study was to describe the spectrum of clinical signs of mevalonate kinase deficiency (MKD). METHODS: This was a retrospective French and Belgian study of patients identified on the basis of MKD gene mutations. RESULTS: Fifty patients from 38 different families were identified, including 1 asymptomatic patient. Symptoms began during the first 6 months of life in 30 patients (60%) and before the age of 5 years in 46 patients (92%). Symptoms consisted of febrile diarrhea and/or rash in 23 of 35 patients (66%). Febrile attacks were mostly associated with lymphadenopathy (71%), diarrhea (69%), joint pain (67%), skin lesions (67%), abdominal pain (63%), and splenomegaly (63%). In addition to febrile attacks, 27 patients presented with inflammatory bowel disease, erosive polyarthritis, Sjögren syndrome, and other chronic neurologic, renal, pulmonary, endocrine, cutaneous, hematologic, or ocular symptoms. Recurrent and/or severe infections were observed in 13 patients, hypogammaglobulinemia in 3 patients, and renal angiomyolipoma in 3 patients. Twenty-nine genomic mutations were identified; the p.Val377Ile mutation was the most frequently found (29 of 38 families). Three patients died of causes related to MKD. The disease remained highly active in 17 of the 31 surviving symptomatic patients followed up for >5 years, whereas disease activity decreased over time in the other 14 patients. Interleukin 1 antagonists were the most effective biological agents tested, leading to complete or partial remission in 9 of 11 patients. CONCLUSION: MKD is not only an autoinflammatory syndrome but also a multisystemic inflammatory disorder, a possible immunodeficiency disorder, and a condition that predisposes patients to the development of renal angiomyolipoma.

Treatment of Growth Failure in Juvenile Chronic Arthritis

We retrospectively assessed linear growth and final height in a group of 24 patients suffering from juvenile idiopathic arthritis (JIA) during childhood, receiving steroid therapy. In these patients, a significant loss of height (–2.7 ± 1.5 SDS) occurred in the first years of the disease which was positively correlated with prednisone therapy duration. After remission of the disease and prednisone discontinuation, most of the patients (70%) had catch-up growth but 30% had a persistent loss of height. Their mean final height was strongly correlated with their mean height at the end of steroid therapy and was significantly different between the group of patients with catch-up growth (–1.5 ± 1.6 SDS) and the group without catch-up growth (–3.6 ± 1.2 SDS). This pattern of growth observed in JIA patients should help us to define strategies of GH treatment in these patients in order to improve their final height. We have previously reported the beneficial effects on growth and body composition of a 1-year GH treatment in a group of 14 growth-retarded patients suffering from juvenile idiopathic arthritis, receiving glucocorticoid therapy. These patients (n = 13) were treated again with GH at the same dosage (0.46 mg/kg/week) for another 3-year period. GH treatment markedly increased growth velocity in these patients, but had a minor effect on SDS height suggesting that these children will remain short at adult age. Using GH earlier in these patients during the course of their disease may prevent growth deterioration and metabolic complications induced by chronic inflammation and long-term steroid therapy.

Molecular Basis of a Selective C1s Deficiency Associated with Early Onset Multiple Autoimmune Diseases

We have investigated the molecular basis of selective and complete C1s deficiency in 2-year-old girl with complex autoimmune diseases including lupus-like syndrome, Hashimoto’s thyroiditis, and autoimmune hepatitis. This patient’s complement profile was characterized by the absence of CH50 activity, C1 functional activity <10%, and undetectable levels of C1s Ag associated with normal levels of C1r and C1q Ags. Exon-specific amplification of genomic DNA by PCR followed by direct sequence analysis revealed a homozygous nonsense mutation in the C1s gene exon XII at codon 534, caused by a nucleotide substitution from C (CGA for arginine) to T (TGA for stop codon). Both parents were heterozygous for this mutation. We used the new restriction site for endonuclease Fok-1 created by the mutation to detect this mutation in the genomic DNA of seven healthy family members. Four additional heterozygotes for the mutation were identified in two generations. Our data characterize for the first time the genetic defect of a selective and complete C1s deficiency in a Caucasian patient.

Clostridium difficile-associated reactive arthritis in two children.

In adults, reactive arthritis (ReA) following Clostridium difficile-enterocolitis has been documented. In children, only one case of C. difficile-associated ReA has been reported. We now describe two other cases of ReA associated with C. difficile in children. The characteristics of ReA due to C. difficile appear to be similar in adults and children. Both children show polyarthritis after an episode of diarrhoea with positive stool cultures for C. difficile. Arthritis is asymmetrical with a self-limiting course. Nonsteroidal antiinflammatory drug (NSAID) therapy is sufficient. One case is remarkable because of its prolonged course of ReA despite NSAID therapy, and its association with the presence of HLA-B27 antigen.

Clinical variability and genetic homogeneity of the camptodactyly-arthropathy-coxa vara-pericarditis syndrome

The camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is an autosomal recessive condition characterized by the association of congenital or early onset camptodactyly and noninflammatory arthropathy with synovial hyperplasia. Progressive coxa vara deformity and/or noninflammatory pericardial or pleural effusions have been observed in some patients. Recently, the disease gene has been assigned to human chromosome region 1q25-q31, and truncating mutations have been identified in the megakaryocyte stimulating factor gene. Studying 12 patients from 8 unrelated families, we emphasized hip and spine involvement, particularly in the course of the disease as shown in a 58-year-old patient. Despite clinical variability, linkage studies support genetic homogeneity of the disease.

Cataract surgery with primary intraocular lens implantation in children with uveitis: Long-term outcomes

PURPOSE: To report long‐term outcomes of cataract surgery with primary posterior chamber intraocular lens (IOL) implantation in children with chronic uveitis. SETTING: Department of Ophthalmology, Pitié‐Salpêtrière Hospital, Paris, France. DESIGN: Case series. METHODS: This case series comprised patients younger than 16 years with chronic uveitis who underwent phacoemulsification with primary implantation of a heparin surface‐modified poly(methyl methacrylate) posterior chamber IOL in the capsular bag. The intraocular inflammation was fully controlled for at least 3 consecutive months before surgery in all cases. The main outcome measures were final corrected distance visual acuity (CDVA), postoperative inflammation, complications, and level of immunosuppressive treatment. RESULTS: Twenty‐two eyes of 16 children (7 girls, 9 boys; median age at surgery 9.5 years old) were included. Underlying uveitic entities were juvenile idiopathic arthritis in 9 patients; idiopathic uveitis in 4; and Behçet disease, sarcoidosis, and varicella zoster‐associated uveitis in 1 patient each. The final CDVA was 0.3 logMAR or better in all cases. Postoperative complications included posterior capsule opacification requiring laser capsulotomy in 2 eyes, glaucoma in 4 eyes, and cystoid macular edema/macular dysfunction in 3 eyes. The mean dose of oral prednisone was 29.5 mg/day preoperatively and 8.13 mg/day at the last follow‐up. The median follow‐up was 6 years (range 5 to 19 years). CONCLUSION: The results indicate that uveitis is not a formal contraindication to primary IOL implantation in the management of pediatric cataract surgery in cases with full control of intraocular inflammation. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned.