Chaim Kaplinsky

Frequency and natural history of inherited bone marrow failure syndromes: the Israeli Inherited Bone Marrow Failure Registry

Background Inherited bone marrow failure syndromes are rare genetic disorders characterized by bone marrow failure, congenital anomalies, and cancer predisposition. Available single disease registries provide reliable information regarding natural history, efficacy and side effects of treatments, and contribute to the discovery of the causative genes. However, these registries could not shed light on the true incidence of the various syndromes. We, therefore, established an Israeli national registry in order to investigate the relative frequency of each of these syndromes and their complications. Design and Methods Patients were registered by their hematologists in all 16 medical centers in Israel. We included patients with Fanconi anemia, severe congenital neutropenia, Diamond-Blackfan anemia, congenital amegakaryocytic thrombocytopenia, dyskeratosis congenita, Shwachman-Diamond syndrome, and thrombocytopenia with absent radii. Results One hundred and twenty-seven patients diagnosed between 1966 and 2007 were registered. Fifty-two percent were found to have Fanconi anemia, 17% severe congenital neutropenia, 14% Diamond-Blackfan anemia, 6% congenital amegakaryocytic thrombocytopenia, 5% dyskeratosis congenita, 2% Shwachman-Diamond syndrome, and 2% thrombocytopenia with absent radii. No specific diagnosis was made in only 2 patients. Of the thirty patients (24%) developing severe bone marrow failure, 80% had Fanconi anemia. Seven of 9 patients with leukemia had Fanconi anemia, as did all 6 with solid tumors. Thirty-four patients died from their disease; 25 (74%) had Fanconi anemia and 6 (17%) had severe congenital neutropenia. Conclusions This is the first comprehensive population-based study evaluating the incidence and complications of the different inherited bone marrow failure syndromes. By far the most common disease was Fanconi anemia, followed by severe congenital neutropenia and Diamond-Blackfan anemia. Fanconi anemia carried the worst prognosis, with severe bone marrow failure and cancer susceptibility. Diamond-Blackfan anemia had the best prognosis. The data presented provide a rational basis for prevention programs and longitudinal surveillance of the complications of inherited bone marrow failure syndromes.

Chronic childhood idiopathic thrombocytopenia purpura : long-term follow-up

An understanding of the natural history of childhood chronic idiopathic thrombocytopenia purpura (ITP) could contribute to a rational therapeutic approach to its treatment, which remains controversial. In our retrospective study of 92 children with ITP, 22 had a chronic course and were followed for 3–14 years (median 8.6 years). Treatment, when indicated, was individualized: 4 patients (18.2%) did not receive any treatment, 14 (63.6%) received steroids only, while 4 (18.2%) were treated with steroids and one of the following: high‐dose gamma globulin (4 patients), splenectomy (2 patients) or immunosuppressive therapy (2 patients). During follow‐up, 14 patients (63.6%) achieved complete remission, 5 (22.7%) partial remission and only 3 (13.5%) remained severely thrombocytopenic, with minimal bleeding tendency. Eleven patients (50%) responded to the initial prednisone course (1–5mg/kg/day), but showed a marked decrease in platelet count when steroids were tapered off. In view of the high rates of complete and partial remission and the mild course of the few non‐responding patients, it is suggested that with adequate supportive therapy, follow‐up problems and fatalities can be kept to a minimum. We believe that aggressive therapy, such as splenectomy, should be reserved for the rare symptomatic and severely thrombocytopenic patient.

Head, neck, and maxillofacial childhood Burkitt's lymphoma : A retrospective analysis of 31 patients

Thirty-one children with Burkitts lymphoma of the head, neck, and maxillofacial region diagnosed between 1976 and 1988 were reviewed. The age range was 2 to 17 years (median, 7.2 years), and 77.4% were males. The most common presenting symptoms were detectable masses, floating and/or painful teeth, enlarged cervical lymph nodes, sore throat, and neurologic signs. The predominant primary tumor sites were the jaws and tonsils. All patients were staged by a clinical staging system, 17 of them having stage I-II, and 14 stage III-IV. Levels of lactate dehydrogenase and ferritin were the only significant laboratory parameters correlating with initial staging and disease-free survival. Radiologic features in the jaws were poorly circumscribed destructive lytic lesions with migration and crypt destruction of unerupted teeth buds. Complete disappearance of these findings was noted after successful chemotherapy and clinical regression of the tumor. Eighteen (58.1%) patients attained complete remission with a follow-up of 5 to 100 months. Stage was the most significant variable affecting outcome, with 90.2% disease-free survival of stage I patients, 72.4% of stage II, and 18.2% of stage III-IV. Based on these results, it is concluded that localized (stage I and II) Burkitts lymphoma is responsive to chemotherapy and thus has a favorable prognosis.

Biologic and cytogenetic characteristics of leukemia in infants

Clinical features, leukemic cell characterization, chromosomal findings, and treatment outcome were analyzed in a retrospective study of 30 cases with acute leukemia of infancy, 24 infants with acute lymphoblastic leukemia (ALL), and six cases with acute nonlymphoblastic leukemia (ANLL). Extensive bulky disease with organomegaly, central nervous system (CNS), and skin involvement were prominent features at diagnosis with a higher frequency in ANLL as compared to ALL. Four of six ANLL patients were classified as monocytic or myelomonocytic. In the ALL group nine of 24 (36%) were non‐L1 morphology and six of 17 (33%) were common ALL antigen (CALLA) negative, the majority of them (five of six) were included in the non‐L1 group. Immunophenotyping revealed four cases with early B‐cell (three patients: Ia+B4+, and one patient: Ia+) and two cases with T‐cell. Mixed lineage leukemia was found in five infants. Heavy chain immunoglobulin gene rearrangement was present in six cases tested, two CALLA+, two with Ia+B4+, and two were undifferentiated mixed lineage leukemia. Chromosomal aberrations were detected in ten of 18 patients, mostly in ANLL and CALLA negative ALL. Translocations were detected in six patients, involving 4q21‐23 and 11q23 in three and two cases, respectively. The probability of five‐year DFS was 27% for the whole group. The worst prognosis was observed in infants younger than 6 months of age, in whom the leukemia cell characteristics was compatible with stem cell: ANLL, very early pre‐B, or undifferentiated mixed type. The chromosomal aberrations found in all cases included translocation with the seemingly nonrandom breakpoints at 4q21 and 11q23, and breakpoints that corresponded to known fragile sites. This finding may be suggestive of an underlying genetic predisposition associated with the poor prognosis of leukemia of infancy.

Neuroblastoma : evaluation with contrast enhanced MR imaging

The use of GD-DTPA was introduced recently for MR imaging of the body. This paper presents our experience with GD-DTPA enhanced MRI in the evaluation of neuroblastoma in children. The characteristics of the tumor-enhancement are described, its contribution to the diagnosis and the follow-up of this disease are discussed.

Association between hyperflexibility of the thumb and an unexplained bleeding tendency: is it a rule of thumb?

A bleeding tendency manifested by petechiae and ecchymoses is one of the most common causes for referral of patients to haematology clinics. Vessel wall pathology is not usually considered to be a cause for deranged haemostasis, although coexistence of increased capillary fragility and joint hypermobility have been reported.

Involvement of 11p15 and 3q21q26 in therapy-related myeloid leukemia (t-ML) in children: Case reports and review of the literature☆

The cytogenetic findings of therapy-related myeloid leukemia (t-ML) in three children are presented. These included one male patient with acute lymphoblastic leukemia (ALL) who underwent bone marrow transplantation and developed therapy-related myeloproliferative disease (t-MPD) in the female-donor hematopoietic cells 2.5 years after receiving radiation and epipodophyllotoxin therapy for ALL testicular relapse. Bone marrow leukemic cell karyotype revealed 46,XX,add (11)(p15) and a normal female karyotype in the peripheral blood lymphocytes. The other two children, one with ALL and one with ganglioneuroblastoma, developed fatal t-MPD and therapy-related acute myeloblastic leukemia (t-AML) preceded by myelodysplastic syndrome (t-MDS), respectively, 5 years after diagnosis, following administration of alkylating agents and irradiation. Monosomy 7 was present in both, and was combined with inv(3)(q21q26) in the second patient. Our review of the cytogenetic findings in 91 previously reported pediatric patients with t-ML suggested that the involvement of 11p15 and 3q21-->23, 3q24-q26 with or without a combination of translocation 11q23 and -7/7q-, respectively, are nonrandom aberrations of t-ML in children. Comparison of the chromosomal changes in t-ML between the pediatric and an adult series revealed some differences which may result from differences in treatment modalities and which, in addition, may indicate a possible role of genetic and/or age-dependent factors in the pathogenesis of therapy-related leukemogenesis in children.

Hemostasis and Thrombosis in Critically Ill Children

Patients in the pediatric intensive care unit (PICU) often suffer from a variety of pathophysiologic conditions that are associated with abnormal hemostasis. Bleeding is a major complication of any surgery or trauma, thus patients with inherited or acquired coagulopathies or those experiencing massive trauma or undergoing major (especially cardiac) operations present a special challenge to the ICU experts as well as to the hematologist. Awareness of thromboembolic events in the pediatric population has been increasing in the past few years mainly due to improvement in diagnostic tools, advances in new therapy and procedures, together with an increased index of suspicion. Young infants are at greater risk for either bleeding or thromboembolic events, due to lower concentration of vitamin K-dependent procoagulant clotting factors, reduced thrombin potential, and altered fibrinolytic pathway with low levels of the coagulation inhibitors. The combination of infection, hypotension, acidosis, and release of activated substances, such as tumor necrosis factor, is common after severe trauma or in seriously ill ICU patients and often leads to disseminated intravascular coagulation, which may be complicated either by bleeding or thrombosis. The conditions, risk factors, and therapeutic options available for critically ill PICU patients are discussed in this review.

Spontaneous regression of congenital leukaemia with an 8;16 translocation

Congenital leukaemia (CL) is a rare disorder that presents with extramedullary infiltrates and a myeloid phenotype. CL can progress rapidly without adequate treatment, but, paradoxically, may also remit spontaneously. Because of the significant toxicity involved in delivering chemotherapy to newborns, it is important to identify those newborns who may not require treatment. We describe an infant who presented at 1 week of age with congenital myeloid leukaemia. Cytogenetic analysis revealed a t(8;16)(q11;p13) translocation. The infants leukaemia underwent a spontaneous regression. This case further confirms the possibility of spontaneous remission in congenital leukaemia. Moreover, it suggests that the presence of a clonal cytogenetic aberration does not preclude the possibility of a spontaneous regression in CL.

Dactinomycin Potentiation of Radiation Pneumonitis: a Forgotten Interaction

No mention of dactinomycin potentiation of pulmonary radiation was found in a review of the literature of the past 12 years. Before that, this complication was well described and investigators had calculated that dactinomycin increased the toxic effect of lung radiation by a factor of 1.3 and reduced the radiation tolerance of the lung by at least 20%. An example of such a toxic effect is described in the treatment of a 7-year-old girl with lung metastases from Ewings sarcoma. The chemotherapy protocol followed contained cyclophosphamide, vincristine, dactinomycin, adriamycin, cisplatinum, VP16, and radiotherapy. The treatment was associated with fatal pulmonary fibrosis following the reintroduction of dactinomycin after radiotherapy. Our experience suggests that there is clinical significance to this complication in sarcoma therapy when dactinomycin-containing protocols are used with radiation in the treatment of pulmonary metastases.