Agammaglobulinemia associated with BCR⁻ B cells and enhanced expression of CD19.

Expression of a BCR is critical for B-cell development and survival. We have identified 4 patients with agammaglobulinemia and markedly reduced but detectable B cells in the peripheral circulation. These B cells have an unusual phenotype characterized by increased expression of CD19 but no BCR. The cells are positive for CD20, CD22, and CD38, but not for Annexin 5 or activation markers, including CD69, CD83, or CD86. EBV lines derived from these B cells lack functionally rearranged immunoglobulin heavy-chain transcripts, as shown by PCR-rapid amplification of cDNA ends (PCR-RACE). Analysis of BM from 2 of the patients showed a severe reduction in the number of pro-B cells as well as pre-B cells. Functionally rearranged heavy-chain transcripts were identified, indicating that machinery to rearrange immunoglobulin genes was intact. Flow cytometry of B-lineage cells suggested accelerated acquisition of maturation markers in early B-cell precursors and increased phosphorylation of signal transduction molecules. Further, expression of TdT, a molecule that is normally down-regulated by a functional pre-BCR complex, was decreased. We hypothesize that the accelerated maturation, increased expression of CD19, and lack of a BCR were due to the constitutive activation of the BCR signal transduction pathway in these patients.

Henoch-Schönlein purpura.

PURPOSE OF REVIEW: To provide an update on recent advances in the genetic susceptibility, pathogenesis and treatment of Henoch-Schönlein purpura. RECENT FINDINGS: Recent work has advanced our understanding of the genetic susceptibility and pathogenesis of Henoch-Schönlein purpura, but there are still significant gaps in our knowledge. Information concerning the most effective treatment of Henoch-Schönlein purpura has begun to emerge. Corticosteroid therapy reduces the duration and severity of abdominal and joint pain, but corticosteroids do not prevent the development of nephritis, or alter the natural history of Henoch-Schönlein purpura. The most effective treatment for severe nephritis remains unclear despite multiple, mostly retrospective reports investigating a variety of drugs. SUMMARY: Despite recent progress, our understanding of the genetic susceptibility, pathogenesis and treatment of Henoch-Schönlein purpura remains incomplete. Further research is necessary in order to clearly define the genetic susceptibility and the pathogenesis of Henoch-Schönlein purpura. Multicenter clinical trials are needed to determine the most effective treatment of Henoch-Schönlein purpura, particularly for patients with severe nephritis.

Mannose-binding lectin deficiency in a child with recurrent infections.

We describe an 11 month old girl with mannose-binding lectin deficiency who presented with recurrent infections. Her mother and brother also were affected. Mannose-binding deficiency is common, and we suggest that testing for it should be included in the evaluation of children with increased susceptibility to infection.

Incomplete penetrance of the NOD2 E383K substitution among members of a pediatric granulomatous arthritis pedigree.

Pediatric granulomatous arthritis (PGA) has been associated with 12 different substitutions in the NOD2 gene thus far. We report a case of PGA in a 6-year-old girl with the NOD2 E383K gene substitution. Genotype analysis of the patient's family members revealed that her affected paternal aunt, as well as her asymptomatic father and 3 younger siblings, were heterozygous for the E383K substitution. The patient's mother did not have a NOD2 mutation. This is the first report of a pedigree in which 4 asymptomatic members carry the E383K substitution in NOD2, as well as the first observation of an asymptomatic carrier state for any of the NOD2 "Blau mutations."

Henoch-Schönlein purpura associated with Helicobacter pylori infection in a child.

Henoch-Schönlein purpura is an acute leukocytoclastic vasculitis that primarily affects children. Henoch-Schönlein purpura is often associated with an infection, and a wide variety of infectious agents have been implicated in the pathogenesis. We report a child with Henoch-Schönlein purpura associated with Helicobacter pylori infection. Treatment of the Helicobacter pylori infection was accompanied by prompt resolution of the Henoch-Schönlein purpura.

Lyme arthritis presenting as transient synovitis of the hip.

Transient synovitis of the hip is a common cause of hip pain in children. The etiology of transient synovitis of the hip is unknown. Lyme arthritis is characterized by brief, often recurrent episodes of oligoarthritis. Lyme arthritis most often affects a single knee, but hip involvement is uncommon. This report describes 2 children with Lyme arthritis who presented with features of transient synovitis of the hip. Lyme arthritis should be considered in the differential diagnosis of transient synovitis of the hip in children.

Incomplete and atypical Kawasaki disease in a young infant: severe, recalcitrant disease responsive to infliximab.

This report describes a 7-week-old infant with incomplete and atypical Kawasaki disease, an acute vasculitis that predominantly affects infants and children. The patient was refractory to 2 doses of intravenous immunoglobulin and to high-dose intravenous methylprednisolone. He became afebrile only after 2 doses of infliximab. His prolonged, recalcitrant course was complicated by the development of peripheral gangrene and giant coronary artery aneurysms. Infants with incomplete and atypical Kawasaki disease are prone to intravenous immunoglobulin treatment failure and are at risk for the development of coronary artery aneurysms. In such patients, we suggest that consideration be given to early aggressive therapy with corticosteroids or infliximab added to intravenous immunoglobulin.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) associated with pemphigoid nodularis: a case report and review of the literature.

The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is a rare disorder caused by mutations of the FOXP3 gene. The FOXP3 gene encodes a DNA-binding protein of the forkhead/winged-helix family and is the central controller of the development of CD4+CD25+ regulatory T cells. CD4+CD25+ regulatory T cells help prevent autoimmune disease; a deficiency of these cells causes increased immunologic reactivity and autoimmunity. We describe a 14-year-old boy with IPEX syndrome confirmed by mutation analysis of the FOXP3 gene. The patient had chronic dermatitis and later developed bullous pemphigoid. He subsequently formed diffuse prurigo nodularis-like lesions resistant to multiple topical and systemic immunosuppressive medications. These lesions were confirmed by biopsy, direct immunofluorescence, and enzyme-linked immunosorbent assay of the 180 kd bullous pemphigoid antigen to be pemphigoid nodularis. He recently responded to rituximab, allowing discontinuation of his oral prednisone.

Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome.

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by lymphadenopathy, elevated numbers of T cells with alphabeta-T cell receptors but neither CD4 nor CD8 co-receptors, and impaired lymphocyte apoptosis in vitro. Defects in the Fas receptor are the most common cause of ALPS (ALPS Ia), but in rare cases other apoptosis proteins have been implicated, including caspase-10 (ALPS II). We investigated the role of variants of caspase-10 in ALPS. Of 32 unrelated probands with ALPS who did not have Fas defects, two were heterozygous for the caspase-10 missense mutation I406L. Like the previously reported ALPS II-associated mutation L285F, I406L impaired apoptosis when transfected alone and dominantly inhibited apoptosis mediated by wild type caspase-10 in a co-transfection assay. Other variants in caspase-10, V410I and Y446C, were found in 3.4 and 1.6% of chromosomes in Caucasians, and in 0.5 and <0.5% of African Americans, respectively. In contrast to L285F and I406L, these variants had no dominant negative effect in co-transfection assays into the H9 lymphocytic cell line. We found healthy individuals homozygous for V410I, challenging the earlier suggestion that homozygosity for V410I alone causes ALPS. Moreover, an association analysis suggested protection from severe disease by caspase-10 V410I in 63 families with ALPS Ia due to dominant Fas mutations (P<0.05). Thus, different genetic variations in caspase-10 can produce contrasting phenotypic effects.

Lyme arthritis in 20 children residing in a non-endemic area.

In non-endemic areas of the country, Lyme disease may not be considered in children who present with arthritis. This report details the clinical features of Lyme arthritis in 20 children residing in central Virginia. All patients presented with transient, often recurrent oligoarthritis of large joints, particularly the knee. Most patients were referred with a presumptive diagnosis of juvenile rheumatoid arthritis (JRA). This report reiterates the clinical presentation of Lyme arthritis in children and reminds physicians to consider the diagnosis of Lyme arthritis in children who present with acute arthritis even if they reside in a non-endemic area of the country. In addition, it differentiates the clinical presentation of Lyme arthritis from JRA.

Henoch-Schönlein purpura in a child with hyperimmunoglobulinemia D and periodic fever syndrome.

This report describes a 3-year-old girl with a long history of periodic fever who presented with Henoch-Schönlein purpura. She was diagnosed with hyperimmunoglobulinemia D and periodic fever syndrome by means of mutation analysis of the mevalonate kinase gene. The serum IgA concentration was markedly elevated, but the serum IgD concentration was normal. This report emphasizes that Henoch-Schönlein purpura may be an important clinical feature of hyperimmunoglobulinemia D and periodic fever syndrome. In addition, this syndrome should be considered in patients with Henoch-Schonlein purpura in whom there is a history of recurrent fevers, even when the serum IgD concentration is normal.

Tumor necrosis factor receptor-associated periodic syndrome in a young adult who had features of periodic fever, aphthous stomatitis, pharyngitis, and adenitis as a child.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) was diagnosed in a 22-year-old man after a 1-year history of periodic fever, myalgia, conjunctivitis, cervical lymphadenopathy, and oral ulcers. As a child he had signs and symptoms suggestive of periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome. This report indicates the importance of considering TRAPS as a cause of periodic fever in older children and adults and that TRAPS may present with signs and symptoms suggestive of periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome in young children.

Discordant erythrocyte sedimentation rate and C-reactive protein in children with inflammatory bowel disease taking azathioprine or 6-mercaptopurine.

BACKGROUND: Inflammatory bowel disease (IBD) is characterized by periods of relapse and remission. Treatment is aimed at reducing symptoms during relapse and prolonging the duration of remissions. 6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are commonly used to prolong clinical remissions. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are two widely used laboratory markers of inflammation. The authors observed an unexplained discordance between ESR and CRP in children with asymptomatic IBD who were being treated with AZA or 6-MP. OBJECTIVE: To characterize children with IBD in remission treated with 6-MP or AZA who have persistently elevated ESR but normal CRP. METHODS: All patients seen in Pediatric Gastroenterology Clinic between January 1, 1995, and December 31, 2002, with Crohn disease or ulcerative colitis who received AZA or 6-MP continuously for at least 6 months were identified and their medical records reviewed. RESULTS: One hundred twenty patients met the eligibility criteria. Twelve had an ESR >18 mm/hour on at least three occasions during at least 12 consecutive months with a simultaneous CRP <0.8 mg/dL. Eleven of these 12 had no signs or symptoms of active disease and had Pediatric Crohn Disease Activity Index scores <10 for at least 12 consecutive months while the ESR was elevated. Disease duration was similar in the 11 children with asymptomatic disease and with discordant ESR and CRP and in 108 children with concordant ESR and CRP (69.2 + 22.5 months v 54.3 +/- 40.1 months, P = 0.0709). Duration of AZA or 6-MP therapy was greater in the 11 children with asymptomatic disease and discordant ESR and CRP than in those with or without symptoms and with concordant ESR and CRP (58.1 +/- 16.4 months v 36.6 +/- 24.1 months, P = 0.0043). There were no differences between the groups with respect to diagnosis, location of disease, or age at onset of symptoms. The mean corpuscular volume (MCV) was somewhat larger in the children with discordant ESR and CRP than in the children with concordant ESR and CRP (91.4 +/- 6.97 fL v 87.0 +/-7.07 fL, respectively, P = 0.0373); however, in both groups, the MCV was in the normal range. There were no significant differences in hematocrit, white blood cell count, serum albumin, total serum protein, or estimated serum globulin between the groups. CONCLUSIONS: The results suggest that among children treated with AZA or 6-MP, CRP may be a more reliable indirect indicator of inflammation than ESR. This report alerts clinicians that some children taking AZA or 6-MP may have persistent elevation of the ESR with a normal CRP and have no clinical evidence of active disease.

Pigmented villonodular synovitis of the knee in a 9-year-old child.

This report describes a 9-year-old girl with pigmented villonodular synovitis of the right knee. She presented with a chronic bloody effusion of the knee. The diagnosis of pigmented villonodular synovitis was suggested by the findings on magnetic resonance imaging and confirmed at the time of arthroscopic synovectomy. This report emphasizes the importance of considering pigmented villonodular synovitis in the differential diagnosis of chronic hemarthrosis in children.

Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes.

OBJECTIVE: To investigate the prevalence of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) among outpatients presenting with recurrent fevers and clinical features consistent with TRAPS. METHODS: Mutational screening was performed in affected members of 18 families in which multiple members had symptoms compatible with TRAPS and in 176 consecutive subjects with sporadic (nonfamilial) "TRAPS-like" symptoms. Plasma concentrations of soluble tumor necrosis factor receptor superfamily 1A (sTNFRSF1A) were measured, and fluorescence-activated cell sorter analysis was used to measure TNFRSF1A shedding from monocytes. RESULTS: Eight novel and 3 previously reported TNFRSF1A missense mutations were identified, including an amino acid deletion (Delta D42) in a Northern Irish family and a C70S mutation in a Japanese family, both reported for the first time. Only 3 TNFRSF1A variants were found in patients with sporadic TRAPS (4 of 176 patients). Evidence for nonallelic heterogeneity in TRAPS-like conditions was found: 3 members of the "prototype familial Hibernian fever" family did not possess C33Y, present in 9 other affected members. Plasma sTNFRSF1A levels were low in TRAPS patients in whom renal amyloidosis had not developed, but also in mutation-negative symptomatic subjects in 4 families, and in 14 patients (8%) with sporadic TRAPS. Reduced shedding of TNFRSF1A from monocytes was demonstrated in vitro in patients with the T50M and T50K variants, but not in those with other variants. CONCLUSION: The presence of TNFRSF1A shedding defects and low sTNFRSF1A levels in 3 families without a TNFRSF1A mutation indicates that the genetic basis among patients with "TRAPS-like" features is heterogeneous. TNFRSF1A mutations are not commonly associated with nonfamilial recurrent fevers of unknown etiology.