Skeletal findings in the first 12 months following initiation of glucocorticoid therapy for pediatric nephrotic syndrome.

UNLABELLED: Incident vertebral fractures and lumbar spine bone mineral density (BMD) were assessed in the 12 months following glucocorticoid initiation in 65 children with nephrotic syndrome. The incidence of vertebral fractures was low at 12 months (6 %) and most patients demonstrated recovery in BMD Z-scores by this time point. INTRODUCTION: Vertebral fracture (VF) incidence following glucocorticoid (GC) initiation has not been previously reported in pediatric nephrotic syndrome. METHODS: VF was assessed on radiographs (Genant method); lumbar spine bone mineral density (LS BMD) was evaluated by dual-energy X-ray absorptiometry. RESULTS: Sixty-five children were followed to 12 months post-GC initiation (median age, 5.4 years; range, 2.3-17.9). Three of 54 children with radiographs (6 %; 95 % confidence interval (CI), 2-15 %) had incident VF at 1 year. The mean LS BMD Z-score was below the healthy average at baseline (mean ± standard deviation (SD), -0.5 ± 1.1; p = 0.001) and at 3 months (-0.6 ± 1.1; p < 0.001), but not at 6 months (-0.3 ± 1.3; p = 0.066) or 12 months (-0.3 ± 1.2; p = 0.066). Mixed effect modeling showed a significant increase in LS BMD Z-scores between 3 and 12 months (0.22 SD; 95 % CI, 0.08 to 0.36; p = 0.003). A subgroup (N = 16; 25 %) had LS BMD Z-scores that were ≤-1.0 at 12 months. In these children, each additional 1,000 mg/m(2) of GC received in the first 3 months was associated with a decrease in LS BMD Z-score by 0.39 at 12 months (95 % CI, -0.71 to -0.07; p = 0.017). CONCLUSIONS: The incidence of VF at 1 year was low and LS BMD Z-scores improved by 12 months in the majority. Twenty-five percent of children had LS BMD Z-scores ≤-1.0 at 12 months. In these children, LS BMD Z-scores were inversely associated with early GC exposure, despite similar GC exposure compared to the rest of the cohort.

The development of bone mineral lateralization in the arms.

UNLABELLED: Bone mineral content (BMC) is known to be greater in the dominant arm after the age of 8 years. We studied a group of children and found that BMC sidedness gradually increased up to the age of 6 years and then remained stable into late adolescence. INTRODUCTION: Bone mineral content (BMC) exhibits sidedness in the arms after the age of 8 years, but it is not known whether BMC is greater in the dominant arm from birth or whether lateralization develops in early childhood. To address this, we examined bone mineral status in relation to handedness and age. METHODS: Subjects (N = 158) were children recently initiating glucocorticoids for underlying disease (leukemia 43 %, rheumatic conditions 39 %, nephrotic syndrome 18 %). Handedness was determined by questionnaire and BMC by dual-energy X-ray absorptiometry. RESULTS: Median age was 7.2 years (range, 1.5 to 17.0 years), 49 % was male, and the spine BMD Z-score was -0.9 (SD, 1.3). By linear regression, BMC sidedness in the arms was significantly related to age (r = 0.294, p = 0.0005). Breakpoint analysis revealed two lines with a knot at 6.0 years (95 % CI, 4.5-7.5 years). The formula for the first line was: dominant:nondominant arm BMC ratio = 0.029 × age [in years] + 0.850 (r = 0.323, p = 0.017). The slope of the second line was not different from 0 (p = 0.332), while the slopes for the two lines were significantly different (p = 0.027). CONCLUSIONS: These results show that arm BMC sidedness in this patient group develops up to age 6 years and then remains stable into late adolescence. This temporal profile is consistent with mechanical stimulation of the skeleton in response to asymmetrical muscle use as handedness becomes manifest.

Prevalent vertebral fractures among children initiating glucocorticoid therapy for the treatment of rheumatic disorders.

OBJECTIVE: Vertebral fractures are an under-recognized problem in children with inflammatory disorders. We studied spine health among 134 children (87 girls) with rheumatic conditions (median age 10 years) within 30 days of initiating glucocorticoid therapy. METHODS: Children were categorized as follows: juvenile dermatomyositis (n = 30), juvenile idiopathic arthritis (n = 28), systemic lupus erythematosus and related conditions (n = 26), systemic arthritis (n = 22), systemic vasculitis (n = 16), and other conditions (n = 12). Thoracolumbar spine radiograph and dual x-ray absorptiometry for lumbar spine (L-spine) areal bone mineral density (BMD) were performed within 30 days of glucocorticoid initiation. Genant semiquantitative grading was used for vertebral morphometry. Second metacarpal morphometry was carried out on a hand radiograph. Clinical factors including disease and physical activity, calcium and vitamin D intake, cumulative glucocorticoid dose, underlying diagnosis, L-spine BMD Z score, and back pain were analyzed for association with vertebral fracture. RESULTS: Thirteen vertebral fractures were noted in 9 children (7%). Of these, 6 patients had a single vertebral fracture and 3 had 2-3 fractures. Fractures were clustered in the mid-thoracic region (69%). Three vertebral fractures (23%) were moderate (grade 2); the others were mild (grade 1). For the entire cohort, mean +/- SD L-spine BMD Z score was significantly different from zero (-0.55 +/- 1.2, P < 0.001) despite a mean height Z score that was similar to the healthy average (0.02 +/- 1.0, P = 0.825). Back pain was highly associated with increased odds for fracture (odds ratio 10.6 [95% confidence interval 2.1-53.8], P = 0.004). CONCLUSION: In pediatric rheumatic conditions, vertebral fractures can be present prior to prolonged glucocorticoid exposure.

Human endogenous retrovirus with a high genomic sequence homology with IDDMK(1,2)22 is not specific for Type I (insulin-dependent) diabetic patients but ubiquitous.

AIMS/HYPOTHESIS: It has been reported recently that a novel human endogenous retroviral gene, insulin-dependent diabetes mellitus (IDDM)K(1,2)22, was expressed in the plasma of Type I diabetic patients but not in that of nondiabetic control subjects. This investigation was initiated to determine the specificity of the selective expression of IDDMK(1,2)22 in diabetic patients. METHODS: We isolated the total RNA from the plasma and lymphocytes of 13 new onset Type I diabetic patients and 10 normal control subjects and amplified it by reverse transcriptase polymerase chain reaction. We then determined the presence of IDDMK(1,2)22 with a specific primer set, U3/R-poly(A), used in a recent report and the 5 'SAg/3 'SAg primer set recognizing the putative superantigen encoding the region of the IDDMK(1,2)22 envelope (env) gene. In addition, we carried out nested PCR of the U3/R-poly(A) polymerase chain reaction product using U3N/R primers. RESULTS: We found no difference in the presence of the polymerase chain reaction products between diabetic patients and all nondiabetic subjects tested. Sequencing of the U3/R-poly(A) polymerase chain reaction products showed that the exact sequence of IDDMK(1,2)22 was not present in any of the samples tested, neither in the plasma of diabetic patients nor in that of nondiabetic control subjects. Endogenous retroviral sequences with 90-93% sequence homology to IDDMK(1,2)22 were, however, equally present in both the diabetic and nondiabetic subjects. CONCLUSION/INTERPRETATION: We conclude that a human endogenous retroviral gene with high sequence homology with IDDMK(1,2)22 is not specific for diabetic patients but, rather, is ubiquitous.

Use of immunoglobulin A-antiendomysial antibody to screen for celiac disease in North American children with type 1 diabetes.

OBJECTIVE: Our objective was to determine if a serological marker, the immunoglobulin A antiendomysial antibody (IgA-EMA), can be used to screen for celiac disease in North American children with type 1 diabetes. RESEARCH DESIGN AND METHODS: Subjects included 236 diabetes clinic patients and 56 gastrointestinal clinic patients who underwent intestinal biopsy for suspected malabsorption. Total IgA and IgA-EMA assays were performed. Diabetic patients who were positive for IgA-EMA were asked to undergo biopsy. RESULTS: Of 236 diabetic patients tested, none were IgA deficient and 19 were positive for IgA-EMA (8%). Of 17 patients biopsied, 12 had celiac disease and 3 were symptomatic. The estimated prevalence of celiac disease was 5.1%, consistent with data from European diabetic clinics. Of the 56 gastrointestinal clinic patients, the 3 who were IgA-EMA positive had biopsies diagnostic of celiac disease. Three were found to be IgA deficient, one of whom had celiac disease. Of the 50 IgA-sufficient and IgA-EMA-negative patients, 1 had celiac disease and 49 did not. The IgA-EMA test had a sensitivity of 94% and a specificity of 91% for IgA-sufficient biopsied patients. CONCLUSIONS: IgA-EMA is an appropriate tool for demonstrating an increased prevalence of celiac disease in a North American pediatric diabetic population. Positive testing should be confirmed by intestinal biopsy, and false-positive results require serial follow-up. Symptomatic children require biopsy regardless of their IgA-EMA status.

National Cooperative Growth Study substudy VIII: a new look at the natural history of short stature.

National Cooperative Growth Study (NCGS) substudy VIII was designed to determine the characteristics of children who are referred to pediatric endocrinologists for evaluation of short stature but are not treated with growth hormone (GH). No specific course of treatment is required to enter the study. Data on the subjects' characteristics at enrollment, the diagnostic procedures used by the investigators, and the occurrences of various medical conditions and intercurrent illnesses will be collected prospectively and will be compared with the corresponding data on children in the NCGS who are treated with GH.

Treatment of familial hypercholesterolemia in children and adolescents: effect of lovastatin. Canadian Lovastatin in Children Study Group.

OBJECTIVE: Familial hypercholesterolemia (FH), an inherited autosomal dominant disorder of lipoprotein metabolism, is associated with premature atherosclerosis. The recommended pediatric therapy consists of dietary intervention and, when necessary, treatment with bile acid-binding resins. However, compliance has been poor in many children. Therefore, our objectives were to determine the efficacy, safety, and tolerance of the short-term use of lovastatin, a 3-hydroxy 3-methylglutaryl coenzyme A reductase inhibitor, in the control of severe FH in a male pediatric population and to evaluate the dose-response relationship. METHODS: Sixty-nine male patients with FH 12.9 +/- 2.4 years of age (mean +/- SD) participated in this multicenter, randomized, double-blind trial. After a 4-week placebo period, the patients were allocated to four treatment groups (lovastatin 10, 20, 30, 40 mg/d) for 8 weeks. Plasma lipid and apolipoprotein (Apo) concentrations were measured every 2 weeks. Clinical and laboratory evidence of adverse events was monitored periodically throughout the study. RESULTS: All lovastatin doses reduced total cholesterol (-17% to -29%), low density lipoprotein cholesterol (-21% to -36%), and ApoB (-19% to -28%) concentrations. A dose-response relationship was seen, and between-group comparisons showed that results were significantly improved up to a dose of 30 mg/d. We observed a 7% increase in high-density lipoprotein cholesterol and a 4% increase in ApoA1 concentrations. The medication was well tolerated by all patients. No serious clinical adverse experience was reported. Lovastatin increased aspartate aminotransferase concentrations, but there was no evidence of a dose-response relationship, and no value exceeded two times the upper limit of normal. No significant change in alanine aminotransferase was observed. Three patients had marked (more than three times the upper limit of normal) asymptomatic elevations in their creatine kinase values, which returned spontaneously to normal, and no action was required regarding the drug.

Hyperglycemia in diarrhea-associated hemolytic-uremic syndrome.

Hyperglycemia is a recognized complication of diarrhea-associated hemolytic-uremic syndrome (D + HUS). Hyperglycemia developed in 8 (6.6%) of 121 patients with D + HUS. A literature review revealed a further 11 patients with D + HUS who developed hyperglycemia. The mortality rate in this group of patients is high. Hyperglycemia is more common in patients with D + HUS uremic syndrome who are female, who have an elevated white blood cell count on admission, and who develop anuria or a central nervous system complication.

Interaction between T cell receptor beta chain and immunoglobulin heavy chain region genes in susceptibility to insulin-dependent diabetes mellitus.

Despite some reports of an association between insulin-dependent diabetes mellitus (IDDM) and a BglII RFLP in the T cell receptor beta chain (TCRB) constant region, results of several recent studies, including our own, have failed to support such an association. However, we here report evidence for an IDDM-TCRB relationship which is dependent on immunoglobulin heavy-chain-region genes. We analyzed 198 unrelated diabetics and 84 normal siblings (maximum one sibling per diabetic) typed for the BglII TCRB RFLP and Gm immunoglobulin allotypes Glm(1), Glm(2), G2m(23), and G3m(5), which identify the four common Gm haplotypes. The BglIII TCRB genotype frequencies were significantly different between diabetics positive and negative for G2m(23) (P = .017) and G3m(5) (P = .021) but were not different between normal siblings positive and negative for those allotypes (P = .94 and P = .77, respectively). Thus, there were significant interactions between TCRB, Gm, and IDDM for two of the four immunoglobulin allotypes examined. We have previously reported interactions between HLA, Gm (particularly G2m(23)), and IDDM and postulate that the TCRB-Gm-IDDM and HLA-Gm-IDDM interaction effects may be functionally related.

Probable autoimmune thyroid disease and combined immunodeficiency disease.

An 8-year-old girl with combined immunodeficiency secondary to adenosine deaminase deficiency developed thyroid failure of probable autoimmune origin manifested by linear growth deceleration, marked bone-age delay, and myxedema. To our knowledge, this association has not been previously reported. Immunologic abnormalities included absolute T-cell lymphopenia and markedly reduced in vitro lymphocyte responses to phytohemagglutinin and to alloantigen in the mixed lymphocyte reaction. The diagnosis of autoimmune thyroid disease was suggested by the presence of antithyroglobulin antibodies in the serum and by decreased, patchy uptake of iodine 123 on a thyroid scan. Autoimmune thyroid disease may have developed because the immunodeficient state, with its greater deficiency of suppressor/cytotoxic T cells, allowed expression of a clone of helper T lymphocytes specific for thyroidal antigens. Thus, autoimmune disease may be more common in immunodeficient states and appropriate surveillance should be instituted.