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.

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.

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.

Chronic Pneumocystis carinii pneumonia associated with extensive pneumatocele formation in a child with human immunodeficiency virus infection.

We describe a 12-year-old boy with Pneumocystis carinii pneumonia complicated by extensive pneumatocele formation as the presenting manifestation of human immunodeficiency virus infection. This report emphasizes the importance of considering Pneumocystis carinii infection in the differential diagnosis of pneumonia associated with pneumatocele formation in children.

Comparison of high-dose and low-dose aspirin plus intravenous immunoglobulin in the treatment of Kawasaki syndrome.

The efficacy of intravenous immunoglobulin (IVIG) in the treatment of Kawasaki syndrome (KS) has been unequivocally established, but questions remain concerning the proper dose of adjunctive aspirin therapy in the treatment of KS. The medical records of 72 children with KS were reviewed. All patients were treated with IVIG; 21 received 400 mg/kg/dose on 4 consecutive days and 51 received 2 g/kg as a single infusion. Seventy patients also received aspirin. Twenty-four of the 70 patients were started on high-dose aspirin (80-100 mg/kg/day) at the time of diagnosis. High-dose aspirin was given for a mean (+/- SE) duration of 6.1+/-0.9 days, then switched to low-dose aspirin (3-5 mg/kg/day). Forty-six of the 70 patients were started on low-dose aspirin at the time of diagnosis and remained on low-dose aspirin for the duration of treatment. Coronary artery abnormalities were present at the time of diagnosis in 12 of 72 patients (17%), including 6 of 6 of patients (100%) with atypical KS and 6 of 66 patients (9%) with typical KS. None of the remaining 60 patients developed coronary artery abnormalities after treatment with IVIG and aspirin. The mean duration of fever after initiation of therapy was 44+/-6 hours in patients treated with IVIG 400 mg/kg/dose on 4 consecutive days and 35+/-5 hours in patients treated with 2 g/kg as a single infusion (p=0.3). The mean duration of fever after the initiation of therapy was 47+/-8 hours in patients treated with high-dose aspirin compared to 34+/-5 hours in patients treated with low-dose aspirin (p=0.13). These preliminary results indicate there is no benefit to high-dose aspirin compared to low-dose aspirin in the treatment of children with KS.

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."

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.

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.

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.

Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) in a child with normal serum IgD, but increased serum IgA concentration.

This report describes a boy with hyperimmunoglobulinemia D and periodic fever syndrome (HIDS). The serum IgD level was normal, but the serum IgA concentration was markedly elevated. In addition, he had a history of orchitis on two occasions, a previously unreported manifestation of HIDS. This report expands the clinical and laboratory features associated with HIDS and serves to emphasize that a normal serum IgD level does not exclude the diagnosis of HIDS.