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.

Clinico-pathological conference: a preterm infant with multiple congenital anomalies.

A preterm female infant (28 weeks; 880 g) presented with bilateral ectrodactyly of the feet, small cleft palate, esophageal atresia and T-E fistula, multivalvular dysplasia and VSD, thrombocytopenia, and other minor anomalies. Cytogenetic analysis showed trisomy 18.

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.

Hematopoietic elements in cerebrospinal fluid in children.

Immature hematopoietic elements have been identified in eight Wright-stained cytocentrifuge preparations of lumbar puncture-derived cerebrospinal fluid (CSF) from infants and children. These immature hematopoietic elements probably represent contamination from vertebral bone marrow. Recognition that the nucleated cells in the CSF are a contaminant and not indicative of infection or leukemia is important to the immediate care of the child. The only adverse clinical sequela of this contamination identified has been a transient headache. Bone marrow contaminants are one of several abnormalities of CSF found in childhood diseases and may or may not elevate the CSF white blood cell count. This supports the need for pathologist review of all CSF cytocentrifuge preparations from children.

Isolation of parainfluenza virus type 3 from cerebrospinal fluid associated with aseptic meningitis.

Parainfluenza virus type 3 has been isolated from the cerebral spinal fluid (CSF) from six individuals--four children and two adults--over a 10-year period. All had fever, and four had signs of meningitis. All recovered uneventfully, including one child undergoing chemotherapy for medulloblastoma. The clinical presentation of this child who developed parainfluenza virus type 3 meningitis is described, and the cases of five other individuals with parainfluenza virus type 3 isolated from the CSF are briefly reviewed. The paramyxovirus parainfluenza type 3, in addition to mumps virus, may be considered capable of infecting the central nervous system.

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.

Necrotizing funisitis.

Necrotizing funisitis is an umbilical cord lesion characterized by perivascular bands of necrotic Wharton jelly containing inflammatory cells in various stages of degeneration. Sixty cases were reviewed histologically. Clinical information was available in 45. Forty-five age-matched infants with acute (nonspecific) funisitis only were used as controls. Infants with necrotizing funisitis had more stillbirths, birth weights below the tenth percentile (small for gestational age [SGA]), infectious complications, and necrotizing enterocolitis. No consistent infectious agents or predisposing maternal factors were found. Cord neovascularization correlated with SGA infants. Necrotizing funisitis occurred in 0.1% of deliveries greater than 20 weeks' gestation. The perivascular bands, likened to the pattern of an Ouchterlony diffusion plate, suggest the presence of a diffusible toxin in the amniotic fluid. The stillbirths and SGA infants may represent the toxin's effect on the fetus. The lack of perivascular necrotic bands around vessels on the placental surface suggests neutralization or more effective clearing of the agent in this region, for reasons as yet undetermined. The factors underlying the cord lesion may contribute to superimposed acute nonspecific vasculitis and chorioamnionitis.

Trisomy 8 in alveolar soft part sarcoma.

Cytogenetic studies were performed on an alveolar soft part sarcoma of a 6-year-old boy. An extra chromosome 8 was present in 26 of 28 metaphases analyzed.

Dermatofibrosarcoma protuberans with 46,XY,t(X;7) abnormality in a child.

A 9-year-old child with dermatofibrosarcoma protuberans demonstrated a balanced translocation, 46,XX,t(X;7)(q21l2;q11.2), in the untreated tumor, an abnormality not previously reported. Unlike seven of eight other reports of dermatofibrosarcoma protuberans, no ring chromosomes were present.

Aggressive giant cell fibroblastoma with a balanced 17;22 translocation.

Cytogenetic analysis of an aggressive giant cell fibroblastoma in a 15-month-old male revealed the following balanced translocation: t(17;22)(q21.33;q13.1). This is the first cytogenetic report on this early childhood tumor.

Familial dystonia and choreoathetosis in three generations associated with bilateral striatal necrosis.

Nine cases of dystonia and choreoathetosis (six females and three males) have developed in three generations of a single family. There has been one death. Neuropathologic examination disclosed bilateral striatal necrosis. In this family, the neurologic disorder has evolved gradually or in association with a febrile illness. There has been no neurologic recovery. The disease is worse in females, has been transmitted only through females, and shows incomplete penetrance and anticipation. The maternal inheritance pattern suggests either an autosomal dominant trait also affecting male reproductive ability or a defect involving the mitochondrial genome.

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.

Delicate longitudinal nuclear grooves in childhood ependymomas.

Nuclei of ependymal tumor cells have a pattern of delicate uniform, linear, longitudinal, excentric grooves or clefts, usually single, involving the nuclear membrane and extending at least half the nuclear diameter, producing a notched mitten-shaped nuclear outline, forming a pattern not seen in other neural tumors. Histologically, 13 of 14 childhood ependymal tumors had nuclear clefts. Using these clefts with other histologic criteria, ependymal tumors were identified at the time of surgery 11 of 11 times, with no false-positive results. Cytologically, eight of 10 ependymal and seven of 32 other brain tumors had clefts. These seven other tumors had either additional nonuniform convolutions or folds (n = 5) or had only rare clefts (n = 2). This uniform pattern of nuclear clefts may help identify poorly differentiated ependymal tumors on permanent sections and may help recognize ependymal tumors at surgery, guiding the surgeons' resection.

Lipid peroxidation and pulmonary hyaline membranes of the newborn: a histochemical, fluorescent microscopic and ultrastructural study.

Representative portions of lung from 17 newborn infants with hyaline membrane disease were studied. The consistent findings in the hyaline membranes of Schiff's positivity requiring periodic acid pretreatment, their autofluorescence between 350 and 400 nm, and the granular ultrastructure of the membrane matrix provided morphologic evidence for lipid peroxidation's having occurred in association with the genesis of pulmonary hyaline membranes of the newborn.

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.

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.

Laboratory evaluation of pediatric bone and soft-tissue tumors.

This article discusses how specimens are approached and handled by the laboratory. Basic histology is reviewed. Contributions by electron microscopy and immunoperoxidase staining are briefly discussed. Current uses of DNA indices, cytogenetic analysis, and new molecular diagnostic advances are highlighted. Proper communication between the pathologist and the orthopedist is the cornerstone for optimal use of laboratory resources.

Cure of hypoglycemic hyperinsulinism by enucleation of a focal islet cell adenomatous hyperplasia.

During pancreatectomy for refractory neonatal hyperinsulinemic hypoglycemia, a well-delineated focal adenomatous hyperplasia was enucleated. Intraoperative glucose levels returned to normal and pancreatectomy was averted. Seven months later the child is euglycemic. This experience suggests that during surgery for neonatal refractory hypoglycemia, a focal lesion should be sought, and if found, enucleated, and blood glucose monitored. If the glucose rises to euglycemic levels or above, the child should be monitored clinically. If sustained elevation is not maintained, a search for an additional focal lesion or pancreatectomy should be performed. Saving the pancreas may prevent future development of diabetes mellitus.

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.

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.