Parathyroid hyperplasia: an unusual cause of neonatal hypercalcemia.

Primary hyperparathyroidism (PHPT) in infants is caused by parathyroid chief cell hyperplasia. Patients present with symptoms of chronic hypercalcemia, such as failure to thrive, irritability, abdominal pain, and anorexia. Medical therapy is inadequate, often resulting in chronic hypercalcemia or death. Partial or total surgical removal of the parathyroid gland is the preferred treatment. We describe a case of a 7-month-old infant with PHPT secondary to hyperplasia successfully treated with a subtotal parathyroidectomy.

Hodgkin lymphoma in a renal transplant recipient associated with low peripheral blood Epstein-Barr virus genome copies.

Posttransplant lymphoproliferative disorders are often accompanied by >500 Epstein-Barr virus (EBV) genome copies/10(5) lymphocytes, and they occur shortly after transplantation. Hodgkin lymphoma occurs rarely after transplantation, appearing a mean of 4.2 years posttransplant, and although Hodgkin lymphoma has strong associations with EBV, no quantitative analysis of peripheral blood EBV genome copies has been reported. A mixed cellularity Hodgkin lymphoma developed in a 17-year-old boy 4 years after a renal transplant. Serial EBV genome copy numbers from blood by competitive polymerase chain reaction had been obtained to assess for lymphoproliferative disease. Epstein-Barr virus genome copy numbers peaked at 500 copies/10(5) lymphocytes 8 months prior to Hodgkin lymphoma diagnosis but fell to 8 copies/10(5) lymphocytes at diagnosis. Reliance on EBV levels greater than 500 copies may result in delay of biopsy and diagnosis of Hodgkin disease in the posttransplant setting.

Malignant teratoma of the thyroid with primitive neuroepithelial and mesenchymal sarcomatous components.

A 15-year-old black girl had a near total resection of a malignant thyroid teratoma with bilateral nodal involvement and mediastinal extension. A predominant neuroepithelial pattern had ependymal rosettes and mitoses, stained for neuron-specific enolase, neuron-specific B tubulin, and synaptophysin. A malignant spindle cell component stained for smooth-muscle actin, muscle actin, and to a lesser extent S-100. Loose myxoid tissue resembled primitive cartilage. Epithelial membrane antigen and cytokeratin identified epithelial foci. Chromogranin A, MIC2, glial fibrillary acidic protein, and thyroid stimulating hormone receptor stains were negative. There was focal anaplasia. DNA ploidy by laser scanning cytometry was 1.2. The tumor from the left and right thyroid lobes exhibited trisomy 8, the right also had hyperdiploid cell lines. She was treated with aggressive combination chemotherapy and radiation. Presently there is no residual disease 16 months after diagnosis. Malignant thyroid teratoma is an aggressive tumor, with 15 of 27 reported patients dying 2 weeks to 3 years after diagnosis. Survivors have been treated with total or subtotal resection, combination chemotherapy with agents effective in the treatment of germ cell tumors as well as sarcomas, and radiation for either recurrent or residual disease. The heterologous elements, lacking MIC2 staining and t(11;22), support the diagnosis of malignant teratoma rather than a neuroepithelial tumor. Trisomy 8 is the first cytogenetic abnormality described in malignant thyroid teratoma. Therapy should be tailored to the management of all transformed histologies.

Renal involvement in juvenile rheumatoid arthritis: report of two cases.

Renal involvement is a rare occurrence in juvenile rheumatoid arthritis (JRA). We report on two JRA patients with kidney disease. The first was a 14-year-old African-American female with a 12-month history of polyarthritis. On presentation she was found to have an ESR of 127 mm/h and a positive ANA, rheumatoid factor (RF), perinuclear antineutrophil cytoplasmic antibodies (pANCA), haematuria, proteinuria with normal BUN and creatinine. Renal biopsy showed focal segmental glomerulosclerosis. Her renal function deteriorated to end-stage renal failure requiring dialysis within a few months, despite aggressive treatment with steorids and monthly i.v. pulses of cyclophosphamide. The second patient presented with a 6-week history of polyarthritis and intermittent fever, and had a salmon-coloured evanescent rash. On presentation his laboratory evaluation was significant for elevated ESR and negative ANA, RF and ANCA tests. Within 8 months the patient had developed a persistent microscopic haematuria. Renal biopsy showed mild mesangial glomerulonephritis. On low-dose methotrexate therapy his JRA went into remission and his renal function remained normal. The haematuria persisted for 1 year and then resolved spontaneously. This is the first time that focal segmental glomerulosclerosis and mesangial glomerulonephritis have been described in JRA. Although the association may be just coincidental, further studies are needed to define the role of JRA in these renal conditions. In patients with JRA, urinalysis and renal function should be routinely monitored.

Immunotactoid glomerulopathy in sickle cell anemia.

A 12-year-old African American male with homozygous sickle cell disease (SCD) was admitted with insidious onset of periorbital and scrotal edema. The initial evaluation failed to reveal any underlying monoclonal gammopathy, or cryoglobulinemia, or other systemic causes for the renal disease. A percutaneous renal biopsy was consistent with immunotactoid glomerulopathy (ITG), which is rare in children and is characterized histologically by fibrillar deposits in the glomeruli. Children can present with symptoms of nephrotic syndrome and progress to end stage renal disease. Our patient was treated with an ACE inhibitor and is currently free of edema and with normal renal function on follow-up at 1 year. Immunotactoid glomerulopathy should be considered in the differential diagnosis of nephrotic syndrome in children with sickle cell disease. Renal biopsy is indicated in children with sickle cell disease and nephrotic syndrome and ITG should be considered as potential cause. Although there is no effective treatment for this condition, ACE inhibitors can decrease the protein-uria and possibly delay the progression to end stage renal disease. The side effects related to the use of ACE inhibitors should be monitored. These include renal impairment, hyperkalemia, anemia, neutropenia, and angioedema. Since we have a short follow-up in our patient, the role and safety of ACE inhibitors in the management of ITG need further evaluation.

Separation of hemoglobin variants with similar charge by capillary isoelectric focusing: value of isoelectric point for identification of common and uncommon hemoglobin variants.

Clinical assays for the primary evaluation of congenital hemoglobin (Hb) disorders must detect and identify a variety of Hb variants. We analyzed hemolysates containing Hb variants with similar charge to evaluate the diagnostic sensitivity and specificity of automated capillary isoelectric focusing (CIEF). Peak separation was observed for each variant in samples containing Hb S, D, and G. The calculated isoelectric points (pI) of these variants were significantly different such that each could be identified in a single run with pI as the sole criterion of identification. The pI of Hb C was significantly different from that of Hb E, C-Harlem, and O-Arab. Hb E, C-Harlem, and O-Arab had similar pI and were not readily differentiated. Hb Koln, M-Saskatoon, Aida, and S/Aida hybrid were readily separated from common Hb variants and detected by CIEF. We conclude that CIEF exhibits both diagnostic sensitivity and specificity, and that pI is an objective and specific criterion of Hb variant identification.

Detection of interferon regulatory factor-1 in lamina propria mononuclear cells in Crohn's disease.

BACKGROUND: The transcription factor, interferon regulatory factor (IRF)-1, is stimulated by interferon-gamma and regulates the expression of several genes implicated in the pathogenesis of inflammatory bowel disease, including interleukin-6, major histocompatibility complex class II molecules, and inducible nitric oxide synthase. Interferon regulatory factor-1 also stimulates naive CD4+ T-cells to differentiate into T-helper-1 cells, the T-cell subset that appears to be upregulated in Crohn's disease. The purpose of this study was to examine the expression of IRF-1 in the nuclei of lamina propria mononuclear cells in situ in colonoscopic biopsy specimens from pediatric patients with Crohn's disease, in patients with ulcerative colitis, and in control patients with no histopathologic abnormalities. METHODS: Archival paraffin-embedded tissue sections were obtained from 25 pediatric patients with Crohn's disease, 6 patients with ulcerative colitis, and 12 control patients who had undergone colonoscopy. Tissue sections were stained with polyclonal rabbit anti-human antisera to IRF-1 and horseradish-peroxidase-conjugated, biotinylated, goat anti-rabbit secondary antibody. Slides were scored and scores compared among patient groups using analysis of variance. RESULTS: Patients with Crohn's disease had significantly higher IRF-1 scores (95% confidence interval [CI], 1.70-2.04) than patients with ulcerative colitis (95% CI, 0.92-1.23) or control subjects (95% CI, 1.11-1.52). CONCLUSIONS: Increased expression of IRF-1 in lamina propria mononuclear cells from patients with Crohn's disease may be relevant to the pathogenesis of Crohn's disease.

Delayed diagnosis of fatal medium-chain acyl-CoA dehydrogenase deficiency in a child.

A 5-year-old white female presented with coma and died unexpectedly. She had a history of recurrent episodes of febrile illnesses associated with lethargy and coma. Postmortem investigation revealed a fatty liver, leading to a suspicion of inborn error of fatty acid oxidation. The diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency was suggested by abnormal acylcarnitine profile with increased octanoylcarnitine in the blood, and confirmed by fatty acid oxidation studies and mutation analysis in skin fibroblast cultures. This case emphasizes the need to consider fatty acid oxidation disorders in all children who present with hypoglycemia with absent or mild ketones in the urine and high anion gap metabolic acidosis.

Desmoplastic infantile ganglioglioma.

We present the clinical, anatomic, and laboratory findings in a 4-month-old child with desmosplastic infantile ganglioglioma. Microtubule-associated protein-2 (AP18) and neuron-specific B-tubulin (TUJ-1) were more sensitive in detecting immature neural elements than synaptophysin. Despite the immature neuroblastic component, focal intermediate proliferation indices, microinvasion, presence of secondary features (extension into Virchow Robin spaces, perineuronal satellitosis), and subtotal resection, the child has done well, with striking improvement of the magnetic resonance imaging (MRI) image, head size improvement, no tumor recurrence, and minimal neurological deficits.

Membranous nephropathy associated with childhood sarcoidosis.

Sarcoidosis is a chronic multisystemic granulomatous disease of unknown etiology. It is relatively rare in children. Renal involvement in sarcoidosis is described less commonly than other organ involvement such as pulmonary, eye, musculoskeletal, and skin. We report a 13-year-old girl with sarcoidosis and nephrotic syndrome. Renal biopsy showed findings of membranous nephropathy. She received intravenous pulse methylprednisolone and oral cyclophosphamide with resolution of the symptoms of fever and edema, and improvement of the proteinuria. Her condition is stable with no progression of her renal disease. To the best of our knowledge, this is the first report of membranous nephropathy associated with childhood sarcoidosis.

Laboratory diagnosis of structural hemoglobinopathies and thalassemias by capillary isoelectric focusing.

Structural hemoglobinopathies and thalassemias are congenital hemoglobin (Hb) disorders that cause anemia, morbidity, and mortality resulting from abnormal Hb function. Structurally different normal Hb variants include HbA(2), HbF (fetal hemoglobin), and HbA (adult hemoglobin). Each is a protein tetramer consisting of two α-globins, and either two δ-, γ-, or ß-globins, respectively. Fetal Hb (α(2)γ(2)) predominates in neonates (60-95% of total Hb), but declines to <1% in older children and adults. HbA(2) (α(2)δ(2)) is a minor constituent with apparently normal function that is not detected in neonates, but increases to about 2-3% of HbA (α(2)ß(2)) in older children and adults. Mutations in the genes that regulate the structure and synthesis of α-, ß-, γ- and δ-globins produce abnormal and often dysfunctional Hb variants (structural hemoglobinopathy), or cause decreased synthesis of normal Hb variants (thalassemia) (1,2). DNA mutations that cause structural hemoglobinopathies are most commonly diagnosed by indirect assays that identify abnormal gene products (i.e., Hb variants) rather than abnormal genes. Over 600 abnormal structural Hb variants have been reported (3), most of which (95%) differ from normal HbA by replacement of a single amino acid (2). Although some structural mutations are benign, many (50% of ß-variants and 20% of α-variants) alter Hb solubility, stability, or oxygen affinity in ways that adversely affect Hb function. In contrast, thalassemia syndromes are caused either by deletions of entire genes or by mutations that affect the production or processing of normal globin mRNAs.

Dipstick only urinalysis screen for the pediatric emergency room.

To determine if microscopic urinalysis is needed in all pediatric emergency room patients screened for urinary tract infections (UTI), we compared the dipstick urinalysis and complete urinalysis (dipstick and microscopy) with urine cultures in 236 children, aged 3 weeks to 21 years. The ability to detect UTI by dipstick only and by complete urinalysis was the same, however microscopic evaluation added many false-positive results without detecting additional UTIs. Because the ability to detect UTI (sensitivity) is maintained, we now offer a dipstick only urinalysis to our emergency room for children 2 years of age or older, with a microscopic analysis performed automatically if dipstick results are positive. If no microscopic urinalysis is required, testing turn-around time is reduced by 12.3 min/test and the hospital charge is reduced from U.S. $32 to U.S. $12.

Florid reactive periostitis.

An 11-year-old boy developed florid reactive periostitis several years after minor trauma. The symptoms responded initially to antibiotics, but after cessation, rapidly recurred and progressed, requiring a ray amputation to relieve the pain and to achieve a functional hand. The reactive periostitis affected the volar aspect of two adjacent phalanges with sparing of the intervening joint, confirming that this is a reactive process rather than a benign neoplasm.

Analysis of hemoglobin variants by capillary isoelectric focusing.

Clinical laboratory evaluation of congenital hemoglobin disorders requires both the accurate identification of major and minor hemoglobin variants, and precise quantitation of these variants over a wide range of concentrations. Capillary isoelectric focusing is an automated, microanalytical technique that produces diagnostic information comparable to that obtained from multiple conventional assays now used by most hospital laboratories. This report describes the advantages of capillary isoelectric focusing for the routine primary assessment of hemoglobinopathies and thalassemias. The use of capillary isoelectric focusing for the identification of unusual hemoglobinopathies, including an extremely rare doubly heterozygous disorder (hemoglobin C/E disease), is described. Application of the technique for rapid (< 4 minutes) neonatal hemoglobinopathy screening, and for the analysis of Hb A1c to monitor glycemic control in diabetic subjects is also discussed. In an increasingly competitive and cost-conscious clinical diagnostic market, capillary isoelectric focusing is a rapid, specific, precise, and low-cost method for comprehensive primary analysis of hemoglobin variants.

Hemoglobin A2 levels in healthy persons, sickle cell disease, sickle cell trait, and beta-thalassemia by capillary isoelectric focusing.

Simultaneously measuring major and minor hemoglobin (Hb) variants by capillary isoelective focusing, we obtained HbA2 intervals in healthy volunteers (n = 412) (reference value) and patients with HbS or beta-thalassemia. We classified normal HbA2 reference intervals into three age groups: 5 months or younger (1.2% +/- 1.5%), 6 months to 1 year (2.2% +/- 0.9%), and 1 year or older (2.4% +/- 0.9%). These intervals were comparable to those used with other methods. Patients 1 year of age or older with HbS had significantly higher HbA2 levels (sickle cell trait, 2.9% +/- 0.9%; sickle cell anemia, 2.8% +/- 1.0%; P < .05). Although reference HbA2 intervals overlapped those in patients with HbS, no overlap in HbA2 levels was noted between these groups and patients with beta-thalassemia (observed range, 4.3% to 7.5%). The higher than normal HbA2 interval in patients with HbS must be considered before a diagnosis of sickle cell trait or sickle cell disease with beta-thalassemia is made.

Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma.

Dermatofibrosarcoma protuberans (DP), an infiltrative skin tumour of intermediate malignancy, presents specific features such as reciprocal translocations t(17;22)(q22;q13) and supernumerary ring chromosomes derived from the t(17;22). In this report, the breakpoints from translocations and rings in DP and its juvenile form, giant cell fibroblastoma (GCF), were characterised on the genomic and RNA level. These rearrangements fuse the platelet-derived growth factor B-chain (PDGFB, c-sis proto-oncogene) and the collagen type I alpha 1 (COL1A1) genes. PDGFB has transforming activity and is a potent mitogen for a number of cell types, but its role in oncogenic processes is not fully understood. COL1A1 is a major constituent of the connective tissue matrix. Neither PDGFB nor COL1A1 have so far been implicated in any tumour translocations. These gene fusions delete exon 1 of PDGFB, and release this growth factor from its normal regulation.