Joanne Yacobovich

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.

Acquired proximal renal tubular dysfunction in β-thalassemia patients treated with deferasirox.

Deferasirox is a recently approved oral iron chelator for treatment of patients with transfusion-related iron overload. Although renal function disturbances were recognized, proximal renal tubulopathy was not addressed in published safety reports for deferasirox. Although subclinical proximal tubulopathy was described in β-thalassemia homozygotes, overt Fanconi kidney is not an established disease complication. We describe 4 cases out of 50 children and adults with transfusion-dependent β-thalassemia, treated with deferasirox for iron overload, who developed clinically significant Fanconi syndrome. Three had concomitant infectious events; the fourth case was entirely spontaneous. In addition, all 4 patients were moderately to well chelated. Cessation of deferasirox resulted in prompt recovery. We propose the necessity for diligent monitoring for proximal tubule nephropathy, possibly related to infectious events, during treatment with deferasirox.

Analysis of health-related quality of life in children with immune thrombocytopenia and their parents using the kids' ITP tools.

The diagnosis, treatment, and prognosis of immune trombocytopenic purpura (ITP) have been extensively studied, but data on its effect on health-related quality of life in children remain sparse. To shed more light on this issue, we administered the Kids’ ITP Tools (KIT) questionnaire to 17 children with ITP attending a tertiary pediatric medical center and their parents (n=34). The mean KIT score was significantly lower in the parents’ group than in the children’s group (P=0.000). The main domains of concern for the parents were disease side effects and their child’s future; the children were mostly concerned about the need to restrict physical activities. The presence of acute versus chronic disease had no impact on the KIT score in either group. These findings stress the need to develop different interventional programs for children with ITP and their parents to provide appropriate support to each.

Characterization of Two Unique α-Globin Gene Cluster Deletions Causing α-Thalassemia in Israeli Arabs

Abstract The molecular basis of α-thalassemia (α-thal) is complex. The use of multiplex ligation-dependent probe amplification (MLPA) has offered the possibility of identifying more gene deletions causing α-thal. Our objective was to determine the molecular basis of two patients with Hb H (β4) disease. By using MLPA in combination with comparative genomic hybridization (CGH) we identified two novel α-globin gene cluster deletions: a 30 kb deletion (patient 1) we refer to as – –JAL and a large 216 kb deletion (patient 2) we refer to as – –LOD. Patient 1 was a compound heterozygote for – –JAL and –α3.7 (rightward deletion). Twelve family members of patient 1 carrying the – –JAL deletion were available for evaluation: five with – –JAL/–α3.7, four with – –JAL/αHph Iα and three with – –JAL/αα. Their clinical picture of compound heterozygosity was compatible with moderate Hb H disease. In patient 2 (– –LOD/–α3.7), no additional symptoms were present despite the heterozygous deletion of seven known genes, three non coding RNAs (ncRNAs), four unknown genes and two pseudo genes. Further analysis of more patients with α-thal deletions will have implications for genetic counseling and appropriate therapy.

Steroid therapy may be effective in augmenting hemoglobin levels during hemolytic crises in children with hereditary spherocytosis

The course of hereditary spherocytosis (HS) may be subject to hemolytic episodes, sometimes requiring blood transfusion. The aim of this study was to evaluate the efficacy of a short course of steroid therapy in elevating hemoglobin levels during hemolytic crisis.

Diamond Blackfan Anemia: A Nonclassical Patient With Diagnosis Assisted by Genomic Analysis.

Diamond Blackfan anemia (DBA) is an inherited syndrome usually presenting with severe macrocytic anemia in infancy, paucity of erythroid precursors in the bone marrow, and congenital anomalies. We describe a child with mild, transfusion independent normocytic anemia whose diagnosis of DBA was established by identification of a novel de novo mutation disrupting normal splicing of the ribosomal protein RPL5. The diagnosis of DBA was confirmed by elevated erythrocyte adenosine deaminase levels and an abnormal ribosomal RNA profile. This case demonstrates the usefulness of genomic analysis in establishing the diagnosis of DBA in patients with a nonclassical presentation of the disease.

Thalassemia Major and Sickle Cell Disease in Adolescents and Young Adults

The increased longevity of patients with thalassemia and sickle cell disease (SCD) introduces new clinical challenges due to the accumulation of disease-related morbidity, psychosocial issues and health care adjustments. Patients with thalassemia major now live into adulthood without suffering heart failure but must confront delayed puberty, impaired fertility and progressive bone disease. The increased survival in SCD brings to the front previously unrecognized complications including pulmonary hypertension, silent cerebral infarcts and also reproductive dysfunction. Adolescents and young adults (AYAs) have age-related psychosocial needs in their transition from the pediatric health care environment to the adult system. In this review we present the uniquely age-related medical issues facing the AYA thalassemia and SCD cohort in their transition into adulthood.

MPL Baltimore mutation and thrombocytosis: case report and literature review.

Thrombocytosis is a common finding and is a frequent cause of referral for further investigation. The MPL Baltimore (Lys39Asn) mutation has been reported as a cause of thrombocytosis in 7% of African Americans. We describe an 11-month-old Ethiopian Jewish boy referred for evaluation of thrombocytosis who was found to be homozygous for MPL Baltimore. So far, there is no indication whether patients with thrombocytosis who have this mutation, particularly homozygotes, are at increased risk of thrombotic or hemorrhagic complications. Nevertheless, this entity should be considered in the differential diagnosis of every patient with thrombocytosis, particularly those of African origin.

Molecular diagnosis of α-thalassemia in a multiethnic population

α‐Thalassemia, one of the most common genetic diseases, is caused by deletions or point mutations affecting one to four α‐globin genes. Molecular diagnosis is important to prevent the most severe forms of the disease. However, the diagnosis of α‐thalassemia is complex due to a high variability of the genetic defects involved, with over 250 described mutations. We summarize herein the findings of genetic analyses of DNA samples referred to our laboratory for the molecular diagnosis of α‐thalassemia, along with a detailed clinical description.

From blood smear to lipid disorder: a case report.

Neutral lipid storage disease (Chanarin-Dorfman syndrome) is a rare autosomal recessive disorder of lipid metabolism, characterized by systemic accumulation of neutral lipids in multiple tissues. We report a case of a 14-year-old girl with generalized ichthyosis, liver cirrhosis, and a hearing impairment. A peripheral blood smear demonstrated marked cytoplasmatic vacuoles in most polymorphonuclear cells (Jordan’s anomaly). Bone marrow examination revealed vacuoles in myeloid precursors. Genetic analysis showed that the patient was homozygous for the p.Arg312Ter mutation in the CGI-58 gene, a key enzyme in lipid metabolism. The peripheral blood smear is diagnostic, and should be performed in any patient with ichthyosis.