Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening systemic illness of abrupt onset and unknown cause. Proteolysis of the blood-clotting protein von Willebrand factor (VWF) observed in normal plasma is decreased in TTP patients. However, the identity of the responsible protease and its role in the pathophysiology of TTP remain unknown. We performed genome-wide linkage analysis in four pedigrees of humans with congenital TTP and mapped the responsible genetic locus to chromosome 9q34. A predicted gene in the identified interval corresponds to a segment of a much larger transcript, identifying a new member of the ADAMTS family of zinc metalloproteinase genes (ADAMTS13). Analysis of patients' genomic DNA identified 12 mutations in the ADAMTS13 gene, accounting for 14 of the 15 disease alleles studied. We show that deficiency of ADAMTS13 is the molecular mechanism responsible for TTP, and suggest that physiologic proteolysis of VWF and/or other ADAMTS13 substrates is required for normal vascular homeostasis.

Hepatic adenomatosis: rapid sequence MR imaging following gadolinium enhancement: a case report.

Hepatic adenomas are primary liver tumors usually associated with underlying metabolic disease or with anabolic steroid or oral contraceptive use. Hepatic adenomatosis (HA) is defined as the presence of more than four adenomas. Only 13 cases of HA have been reported in patients without glycogen storage disease or steroid use. We report a case of HA imaged by postcontrast T1-weighted images obtained during a breath-holding series. The lesions were most conspicuous 3-4 min after contrast administration; 4 of the 5 tumors were not identified on T2-weighted images. Unlike previous reports of HA in which the lesions remained hyperintense during sequential postcontrast imaging, the smaller lesions in this case demonstrated contrast washout, thereby distinguishing them from hemangiomata.

Hb Hammersmith [beta 42(CD1) Phe-->Ser]: occurrence as a de novo mutation in black monozygotic twins with multiple congenital anomalies.

PURPOSE: To present the occurrence of Hb Hammersmith as a de novo mutation in African-American twins with multiple congenital anomalies. METHODS: Standard hematologic methods were used. The presence of an unstable Hb variant was confirmed by brilliant cresyl blue staining and an isopropanol stability test. Hb Hammersmith was confirmed by the sequencing of polymerase chain reaction-amplified beta-globin gene. RESULTS: The presence of Hb Hammersmith was confirmed in female monozygotic twins of African-American origin with congenital Heinz body hemolytic anemia and multiple congenital anomalies. The variant occurred as a de novo mutation in the twins. CONCLUSION: This report describes the occurrence of Hb Hammersmith [B42(CD1)Phe-->Ser] in African-American twins. As with the other reported cases, both twins were female. In addition to Heinz body hemolytic anemia, a low arterial O2 saturation in the proposita was shown by pulse oximetry. Multiple congenital anomalies involving various systems were also found in both twins.

Primary chylous vaginal discharge in a 9-year-old girl: CT-lymphangiogram and MR appearance.

Chylous reflux is a manifestation of primary or secondary lymphatic obstruction. Primary lymphatic obstruction is defined as lymphangiectasia and incompetency of lymphatic valves without an underlying cause. Lymphangiectasia resulting from trauma, neoplasm, irradiation, or inflammation characterizes secondary lymphatic obstruction. Leakage of chyle into the uterus, vagina, bladder, or rectum can occur with either primary or secondary lymphatic obstruction. We report a patient with chylous vaginal discharge, a rare presentation of primary chylous reflux syndrome. CT-lymphangiography and magnetic resonance imaging clearly depicted this disorder. To our knowledge, only 20 cases of chylous vaginal discharge have been reported previously; chylous vaginal drainage occurred in the absence of chylous uterine reflux in only three. Although this is a rare anomaly, chylous reflux should be considered in a child with chronic vaginal discharge and lower extremity swelling.

Erythroleukemia of childhood and infancy: a report of two cases.

Two rare de novo cases are presented of pediatric erythroleukemia (EL), AML-M6 in a four-month-old (patient A) and four-year-old (patient B) African-Americans who presented to the Medical College of Georgia from 1989 to 1995. The clinical, morphologic, immunophenotypic and cytogenetic features of both patients are reviewed. The purpose of this study is to correlate the bone marrow morphology with the immunophenotypes and the karyotypes of the neoplastic cells. The patients were both female, presented with flu-like symptoms, and were noted to have hepatosplenomegaly on physical examination. The peripheral blood examination was significant for anemia (Hb 54 (A), 84(B)g/L), and thrombocytopenia (86 (A), 70(B) x 10(9)/L). The bone marrow contained 75 percent (A) and 76.8 percent (B) erythroblasts and showed myelodysplastic changes in the erythroid cell line. Cytochemical analysis was performed, and greater than 10 erythroblasts per 100 cells were periodic acid-Schiff positive. Immunophenotypes of the pretreatment bone marrow showed glycophorin-A, CD71, and CD11b positivity. The karyotypes of both patients contained complex (> 3 per clone) cytogenetic abnormalities. Our data suggest that the initial presentation and course of disease are different in adults and children. However, once the adult form reaches the acute leukemia stage, the laboratory findings are similar to those at initial presentation in pediatric EL.

Childhood acute lymphoblastic leukemia: are routine end-of-therapy bone marrow and cerebrospinal fluid examinations necessary?

OBJECTIVE: To ascertain the usefulness of bone marrow and cerebrospinal fluid (CSF) examinations in identifying or predicting relapse in children with acute lymphoblastic leukemia (ALL) before discontinuation of chemotherapy. MATERIAL AND METHODS: We retrospectively reviewed the medical records of 113 children with ALL in first continuous complete remission who had undergone routine end-of-therapy bone marrow aspiration and CSF examinations. RESULTS: One patient had frank bone marrow relapse at the completion of therapy, which was evident by the presence of blasts in the peripheral blood. None of the other 112 patients had morphologic evidence of bone marrow relapse or positive CSF cytologic findings. The seven subsequent relapses could not have been predicted by the results of end-of-therapy bone marrow or CSF studies. CONCLUSION: Routine morphologic examination of the bone marrow and CSF at the completion of therapy for ALL has no diagnostic or prognostic value.

Recombinant human macrophage colony-stimulating factor in nonhuman primates: selective expansion of a CD16+ monocyte subset with phenotypic similarity to primate natural killer cells.

The CD16 receptor (Fc gamma R-III) is found on many tissue macrophages (M phi s), but its expression on circulating monocytes is restricted to a small, phenotypically distinct subset. The number of these CD16+ monocytes may be markedly increased in response to sepsis, human immunodeficiency virus infection, or metastatic malignancy. We have recently shown that the CD16+ monocyte population is selectively expanded by administration of recombinant human macrophage colony-stimulating factor (rhM-CSF). In the current study, we used the highly rhM-CSF-responsive cynomolgus primate model to further characterize this novel monocyte population. Animals treated with rhM-CSF underwent a progressive and essentially complete conversion to the CD16+ monocyte phenotype, with up to a 50-fold increase in the number of CD16+ cells. This increase was paralleled by the emergence of a population of circulating cells that morphologically resembled large granular lymphocytes (LGLs). However, quantitatively, this population corresponded closely to the number of CD16+ monocytes, and fluorescence-activated cell sorting (FACS) confirmed that they were the same. In addition to their LGL-like morphology, many rhM-CSF-induced CD16+ monocytes showed a pattern of size, granularity, and quantitative cell surface marker expression that closely resembled the pretreatment LGL/natural killer (NK) cell population but that did not resemble the pretreatment monocyte population. However, rhM-CSF-induced CD16+ monocytes could be distinguished from LGL/ NK cells by fact that they all expressed cell surface receptors for rhM-CSF, and many of them showed reduced but detectable phagocytic and respiratory burst activity. Studies of human subjects treated with rhM-CSF also showed an analogous population of "LGL-appearing" CD16+ mononuclear cells. Thus, our studies reveal a previously unsuspected ability of cells in the monocyte lineage to adopt a phenotype similar to that of LGL/NK cells. The extent of this phenotypic convergence suggests that the two lineages retain access to elements of a similar developmental pathway.

CD16+ monocytes in patients with cancer: spontaneous elevation and pharmacologic induction by recombinant human macrophage colony-stimulating factor.

The small subset of circulating monocytes that express the maturation-associated CD16 antigen has recently been reported to be elevated in patients with bacterial sepsis. We now show that this novel CD16+ monocyte population is also spontaneously expanded in patients with cancer. We studied 14 patients with metastatic gastrointestinal carcinoma enrolled ina clinical trial of recombinant human macrophage colony-stimulating factor (rhMCSF) plus monoclonal antibody D612. We found that before any cytokine treatment, 12 of 14 patients constitutively displayed significant elevations in both the percentage and the absolute number of CD16+ monocytes, as compared with both normal subjects and ill patients with elevated monocyte counts but without malignancy. CD16+ monocytes accounted for 46% +/- 22% of total monocytes in the patients with cancer versus 5% +/- 3% for controls (P < .01). The increase was not attributable to infection or intercurrent illness and appeared to be associated with the underlying malignancy itself. A similar spontaneous elevation of CD16+ monocytes was observed in 35 of 44 additional patients diagnosed with a variety of other solid tumors. When patients with gastrointestinal carcinoma were treated with rhMCSF, there was a marked further increase in the percentage of CD16+ monocytes (to 83% +/- 11%), as well as in the absolute number of CD16+ cells and the level of CD16 antigen expression. In every case, the patients with cancer showed a greater CD16+ monocyte response than the maximal response obtained in normal volunteer subjects treated witha similar regimen of rhMCSF (n = 5, P < .001), suggesting that the presence of malignancy primed patients for enhanced responsiveness to rhMCSF. We hypothesize that spontaneous expansion of the CD16+ monocyte population may represent a novel biologic marker for a widespread and previously unsuspected host immune response to malignancy.

Interferon-alpha-2a for the treatment of complex hemangiomas of infancy and childhood.

OBJECTIVE: The authors describe the use of interferon-alpha-2a (IFN-alpha-2a) in the treatment of complex hemangiomas and review the role of interferon (IFN) in this example of an angiogenic disease. SUMMARY BACKGROUND DATA: Hemangiomas are the most frequent tumors of infants and children. They grow rapidly for 6 to 8 months and then resolve over a period of years. Approximately 5% produce life-, sight-, or limb-threatening complications, with mortality rates between 20% and 50%. Aggressive therapy with steroids, arterial ligation or embolization, or surgery has been used in these situations with variable results and high morbidity. Recently, IFN-alpha was found to be effective treatment in these complex hemangiomas. METHODS: Four infants and one child were treated with IFN-alpha-2a at an initial subcutaneous dose of 1 million units/m2/day and a sustained dose of 3 million units/m2/day for 5 to 11 months. Appropriate laboratory values were monitored and adverse reactions and ultimate response to therapy were recorded. RESULTS: Two patients experienced minor complications that were managed easily. Three patients had total or near-total regression of the hemangioma, one had partial (50%) regression, and one had stabilization but no regression after an average of 7.1 months of IFN therapy. CONCLUSION: Interferon-alpha inhibits angiogenesis and endothelial cell migration and proliferation in vitro. The patients in this study add to the growing number who have benefited from IFN therapy. As such, IFN-alpha should be considered as a first-line agent in treating complex hemangiomas of infants and children.

Successful management of an infant with a giant hemangioma of the retroperitoneum and Kasabach-Merritt syndrome with alpha-interferon.

Giant vascular neoplasms in neonates generally require aggressive medical or surgical therapy for treatment of complications. Steroids, chemotherapy, embolization, radiation, and surgery have all been used with short-term beneficial and sometimes unknown long-term side effects. A new modality of treatment, alpha-interferon, has recently been described. The majority of hemangiomas in children involute by 8 years of age. Occasionally, hemangiomas can endanger vital structures and are associated with a consumption coagulopathy and thrombocytopenia (Kasabach-Merritt Syndrome). These hemangiomas occasionally do not respond to steroids, radiation therapy, cytotoxic drugs, or embolization. The mortality rates approach 50% in nonresponders. Alpha-interferon has been used in these children with life-threatening complications of hemangiomas with relief of symptoms. This case illustrates the potential use of alpha-interferon in the management of giant hemangiomas in children. This emerging form of biological therapy avoids the risks of radiation therapy, embolization, and surgery with only minimal side effects.

Anemia in the adolescent athlete.

Anemia is a common disorder among adolescents regardless of level of physical activity. The major cause of anemia in adolescents is nutritional iron deficiency. Iron metabolism may be altered in some athletes training and competing in endurance sports. The dilutional "sports anemia" that can occur in the more elite adolescent athlete may be an adaptation to aerobic conditioning. Screening for anemia in adolescent athletes is warranted because anemia may contribute to morbidity and diminished exercise performance. Current concepts and controversies regarding anemia in adolescent athletes are addressed, and application of this information to preparticipation physical examinations is examined.

Nonlymphoblastic lymphoma in children--histology and stage-related response to therapy: a Pediatric Oncology Group study.

From May 1979 to March 1983, 93 eligible patients with nonlymphoblastic lymphoma (NLBL) were treated by members of the Pediatric Oncology Group (POG) with Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), vincristine, prednisone, cyclophosphamide, and mercaptopurine (ACOP+); CNS prophylaxis with intrathecal (IT) methotrexate, hydrocortisone, and cranial irradiation (2,400 rads), and radiation therapy to the primary disease were administered in stages I and II, and to residual disease in stages III and IV. Duration of treatment was 2 years for stages I, II, and III and 3 years for stage IV disease. Of the 93 patients entered onto the study, 47 had diffuse small noncleaved-cell lymphoma (DSNCL), 38 had diffuse large-cell lymphoma (DLCL), and eight had other histologies. Localized disease (stages I and II) was present in 51 patients, and 42 had advanced (stages III and IV) disease. The study confirmed previously reported importance of stage with a 4-year event-free survival (EFS) of 78% (SE +/- 7%) for patients with localized disease as compared with 44% (SE +/- 9%) in patients with advanced disease (P less than or equal to .001). In localized disease, seven of 11 adverse events occurred in patients who were off therapy and more than 30 months after the initial diagnosis (relapse, three; second malignancy, two; death in remission, two). Large-cell histology proved to be an important prognostic factor in patients with stages III and IV disease with EFS at 4 years of 67% (SE +/- 11%) for DLCL versus 17% (SE +/- 11%) for DSNCL (P less than or equal to .001). We conclude that it is important to distinguish histologically between small noncleaved-cell and large-cell types of NLBL as a basis for further controlled clinical trials.

Clinical and biological heterogeneity of childhood B cell acute lymphocytic leukemia: implications for clinical trials.

Thirty-two children or adolescents had B cell acute lymphocytic leukemia (ALL) diagnosed by demonstration of surface immunoglobulin expression on greater than 10% of their bone marrow blasts. All patients had greater than 25% bone marrow lymphoblasts. Only five of 32 patients (16%) presented with an abdominal mass; however, 24 cases (75%) had FAB L3 morphology. By comparison with findings in common ALL, these 32 children were older (median age, 8 years) and had a higher incidence of central nervous system disease at presentation (22%); all but one were white, and 24 were males. Blast cells from individual cases expressed mu kappa (n = 13), mu lambda (n = 9), gamma kappa (n = 1), alpha kappa (n = 1), or mu with an undetermined light chain (n = 8). The most frequently identified cytogenetic abnormality was the classic B cell-associated t(8;14)(q23;q24) (n = 4); the t(1;19)(q23;p13.3), t(9;22)(q23;q11), and t(1;22) were observed in single cases. Twenty patients were treated uniformly on a single protocol designed for children with advanced B cell malignancy; therapy for the other 12 children varied. Nine children (28%) are surviving event-free; all but one for 3 years or more. We conclude that approximately 25% of children with B cell ALL are curable with intensive multiagent chemotherapy and that classification by immunophenotyping is superior to use of clinical and/or lymphoblast morphologic features.

Gallium 67 uptake in thymic rebound.

We have reported a case of localized thymic enlargement and uptake of gallium 67 in a child who had received antineoplastic chemotherapy. The enlarged thymus showed normal histology, a picture consistent with thymic rebound after nonspecific stress. This case further demonstrates the need to consider thymic rebound as a cause of gallium 67 uptake in children with neoplastic diseases.