Giant platelet granules in a child with the Chediak-Higashi syndrome.

Previous ultrastructural investigation have not identified abnormal lysosomes in platelets obtained from humans or animals with the Chediak-Higashi Syndrome. We report here a patient whose megakaryocytes and platelets were found to contain giant granules when viewed by light and electron microscopy. The granules measured up to 1.5 micrometer in diameter, contained either homogeneous or heterogeneous material, were acid phosphatase positive, and were present in approximately 30% of bone marrow megakaryocytes and 5% of circulating platelets. A decrease was observed in serotonin containing dense granules, serotonin uptake and serotonin release as reported previously. Microtubules in platelets and megakaryocytes were intact and no other morphologic abnormalities were identified. No clinical evidence of bleeding was observed in this patient and platelet counts have been normal. The lack of giant platelet lysosomes in other reported cases of Chediak-Higashi Syndrome attests to significant heterogeneity in this disease with a spectrum of clinical and laboratory findings.

The cytosine arabinoside (Ara-C) syndrome.

Four patients with non-Hodgkin lymphoma and two with acute lymphocytic leukemia (ages 4 and 4 months to 16 years 6 months) exhibited a unique reaction to intravenously administered cytosine arabinoside (Ara-C) given alone as a part of the previously reported LSA2-L2 treatment protocol. The syndrome was characterized by fever, myalgia, bone pain, and occasionally by chest pain, maculopapular rash, and conjunctivitis. Each of the eleven episodes of this syndrome occurred within 6-12 hours of drug infusion and always abated after cessation of Ara-C. Prior to the reaction, patients had been on therapy for an average of 13.5 months during which they were exposed to 2298-5387 mg/m2 (mean of 3200 mg/m2) of Ara-C. The high incidence of this syndrome (50% of our patients on the LSA2-L2 regimen and 33% of those receiving Ara-C) has not been previously reported. Considering the prolonged exposure to Ara-C and our inability to document infections in the patients or pyrogens contaminating the drug lots, the most likely explanation for this syndrome is a hypersensitivity reaction to Ara-C. Prevention of these symptoms with corticosteroids supports this contention and provides a reasonable alternative to discontinuing Ara-C.

Hereditary pyropoikilocytosis and elliptocytosis: clinical, laboratory, and ultrastructural features in infants and children.

Clinical, biochemical and ultrastructural assessment of five Black children from four unrelated kindreds, who had morphologic and laboratory features of hereditary pyropoikilocytosis (HP) is described. In two of the unrelated propositi, both with relatives having elliptocytosis, the apparent HP gradually evolved into elliptocytosis. The mode of inheritance appeared to be autosomal dominant in one family and autosomal recessive in the other. None of the three children from two separate families with true HP had a parent with HP or elliptocytosis. A sixth Black child, whose mother also had elliptocytosis, demonstrated typical elliptocytosis from birth and never demonstrated the HP phenotype. Sequential quantitation of heat induced red cell fragmentation using histogram analyses revealed unchanged findings in three patients with true HP but progressive amelioration in the two patients with HP phenotype who eventually developed elliptocytic morphology. Previously unreported lesions in both true and apparent HP patients included endovesicle formation and submembrane particles, which were detected by electron microscopy, an increase in Heinz body formation, and elevation of oxidized glutathione levels. Our study demonstrates shared abnormalities present both in some neonates with elliptocytosis and in neonates with HP, which preclude the diagnosis of HP in infancy and provide further evidence of the heterogeneity of the elliptocytosis syndrome.

Anthracycline-induced cardiomyopathy in children: a report of six cases.

Although anthracycline antibiotics are among the most useful chemotherapy agents, the risk of producing cardiomyopathy and the absence of a reliable noninvasive technique to predict subclinical cardiomyopathy remain a major problem. We retrospectively reviewed our experience with anthracyclines over a 5-year period. Cardiomyopathy developed in 6 of 112 patients (5.3%) treated with anthracyclines and was fatal in 5 of the 6 patients. Our incidence and mortality rates are higher than those previously reported.

Management of localized thoracic neuroblastoma.

Thirteen children with localized (Evans stage I or II) thoracic primary neuroblastoma were divided into two groups according to the type of therapy administered, in order to compare the therapeutic efficacy and morbidity of excisional surgery followed by either irradiation alone or irradiation plus chemotherapy (group A) with similar surgery alone (group B). Group A consisted of 6 children (mean age 1 year, 2 months). Complete surgical excision was accomplished in 2 patients, while 4 had microscopic residual. All 6 patients are free of disease at 26--76 months (mean 47 months), including 2 who had recurrent tumor and received additional therapy. Two have developed congestive heart failure and one severe scoliosis secondary to irradiation. Of the 7 children in group B (mean age 2 years, 2 months), 3 had microscopic residual tumor and 2 had adjacent lymph node involvement. After 12--47 months (mean 23 months), no recurrence or surgery-related morbidity has been observed. From these limited data it appears that surgery alone may provide adequate therapy for localized thoracic neuroblastoma and obviate the morbidity associated with multimodal therapy.

Dysgranulopoietic neutropenia and abnormal monocytes in childhood vitamin B12 deficiency.

Neutropenia and/or leukopenia (associated with elevated serum lysozyme levels) in three children with vitamin B12 deficiency were evaluated using soft agar culture and ultrastructural and cytochemical techniques. In two patients a marked increase in peripheral myeloid colony forming cells (CFC) was observed; whereas a marginal increase in CFC was present in the third, less symptomatic, patient. Marrow CFC was normal or slightly increased. Serum colony stimulating activity (CSA) was normal but elaboration of CSA by white blood cells was low. Normal maturation of the progenitors was present in vitro and serum inhibitors of myelopoiesis were absent. Megaloblastic neutrophils and monocytes with nuclear-cytoplasmic asynchrony were observed ultrastructurally in directly sampled marrow specimens. These cells contained autophagic and/or heterophagic vacuoles and an increase in cytoplasmic granules. Both monocytes and neutrophils also contained enlarged-disrupted centrioles. Many marrow macrophages contained phagocytic vacuoles, which enclosed disrupted neutrophils and cellular debris.

Phagocytosis of neutrophils by marrow macrophages in childhood chronic benign neutropenia.

Chronic benign neutropenia of childhood is a heterogeneous disorder. This study describes two severely neutropenic children with a benign clinical course and the unique bone marrow finding of macrophage engulfment of band and segmented neutrophils. Phagocytic vacuoles in the majority of macrophages contained neutrophils in various stages of digestion at both the light and electron microscope level (with as many as four neutrophils observed in single macrophages). Ultrastructural studies demonstrated that the neutrophils were morphologically normal, and apparently viable at the time of phagocytosis. This type of neutrophil phagocytosis was not observed in five other consecutively studied children with CBN. All of these children with CBN had ultrastructurally normal neutrophils, lacked demonstrable antineutrophil antibodies or serum inhibitors to in vitro myelopoiesis, and had normal colony-forming cells and colony-stimulating activity in vitro. Thus despite many similar clinical and laboratory features in children with CBN, only a unique subgroup of these patients demonstrates abnormal neutrophil-macrophage interaction.

Wiskott-Aldrich syndrome: cellular impairments and their implication for carrier detection.

A family in which two male siblings were affected with Wiskott-Aldrich syndrome (WAS) was studied using G-6-PD isoenzymes as an X-linked marker in order to investigate the nature of cellular abnormalities. Isolated peripheral blood cell types from the doubly heterozygous mother of the affected males seemingly failed to express the G-6-PD allele in cis position with the WAS allele while her cultured skin fibroblasts expressed both G-6-PD alleles. Additionally, a histogram analysis of platelet size revealed a single population of abnormally small platelets in the affected propositus, whereas the heterozygous mother had no appreciable small platelet subpopulation. In vitro culture of hemopoietic progenitor cells of the heterozygous mother showed that the majority of progenitor cells did not express the WAS allele. However, a small number of cells expressing the G-6-PD type linked with the WAS allele were detected. The proportion of the latter progenitors was significantly higher among more primitive progenitors (those giving rise to later appearing colonies). This observation suggests that selection against cells expressing the Wiskott-Aldrich defect takes place in the hemopoietic system of the heterozygous female and offers a possible means of carrier detection in some women. Linkage studies in this family revealed one example of probable recombination between the loci for WAS and G-6-PD among three informative subjects, suggesting that these two loci may not be closely linked on the X-chromosome.

Congenital dysgranulopoietic neutropenia: clinical, serologic, ultrastructural, and in vitro proliferative characteristics.

Six children with severe congenital neutropenia and repeated life-threatening infections were investigated by examining clinical features and myeloid cell ultrastructure, cytochemistry, and in vitro proliferation. Despite the presence of neutropenia, normal numbers of colony-forming cells (CFC) were present in blood and marrow specimens, and colony-stimulating activities (CSA) from blood cells and serum were normal or slightly increased in all patients. In vitro maturation of the progenitors to neutrophils was also uniformly present in the colonies. No patients had demonstrable antineutrophil antibodies or serum inhibitors of myelopoiesis. Serum lysozyme levels were normal. Ultrastructural and cytochemical studies of directly sampled marrow cells revealed several abnormalities in most neutrophilic myeloid cells from each of the patients consistent with an intrinsic myeloid precursor cell defect. These included (1) the defective synthesis or degeneration of primary granules, (2) an absence or marked decrease of secondary granules in the few late neutrophils observed in the bone marrow, and (3) the presence of autophagy. Phagocytosis of intact myeloid cells with subsequent degeneration was not observed; however, neutrophil debris was evident in phagocytic vacuoles of marrow macrophages. Our demonstration of ultrastructurally dysmorphic neutrophilic granulocytes, intramedullary cell lysis, normal stem cell numbers, and negative serology is comparable to similar observations of erythroid cells from patients with congenital dyserythropoietic anemia. We therefore hypothesize that the dysgranulopoiesis in these children results in neutropenia and propose the descriptive name congenital dysgranulopoietic neutropenia.