Melissa J. Rose

Congenital amegakaryocytic thrombocytopenia: The diagnostic importance of combining pathology with molecular genetics

Congenital Amegakaryocytic Thrombocytopenia (CAMT) is a rare bone marrow failure syndrome that presents with isolated thrombocytopenia within the first year of life. Classic diagnostic bone marrow findings reveal absent or significantly decreased megakaryocytes with otherwise normal marrow cellularity. We present a newborn with thrombocytopenia whose initial bone marrow aspirate showed an appropriate number of megakaryocytes. CAMT was subsequently diagnosed after molecular testing demonstrated a mutation in the thrombopoietin receptor. The presence of a normal number of megakaryocytes on an initial bone marrow aspirate should not exclude CAMT from the differential diagnosis of thrombocytopenia within the first year of life. Pediatr Blood Cancer 2008;50:1263–1265.

Bilateral Burkitt Lymphoma of the Ovaries: A Report of a Case in a Child with Williams Syndrome

A 10-year-old female with Williams Syndrome (WS) presented with a two-month history of fatigue, weight loss, and bilateral ovarian masses. Histologic, immunophenotypic, and cytogenetic studies confirmed the diagnosis of Burkitt lymphoma (BL). While there is no established association between the two disorders, this is the third case in the literature of Burkitt lymphoma in a patient with Williams Syndrome.

Clinical spectrum of pyruvate kinase deficiency: Data from the pyruvate kinase deficiency natural history study

An international, multicenter registry was established to collect retrospective and prospective clinical data on patients with pyruvate kinase (PK) deficiency, the most common glycolytic defect causing congenital nonspherocytic hemolytic anemia. Medical history and laboratory and radiologic data were retrospectively collected at enrollment for 254 patients with molecularly confirmed PK deficiency. Perinatal complications were common, including anemia that required transfusions, hyperbilirubinemia, hydrops, and prematurity. Nearly all newborns were treated with phototherapy (93%), and many were treated with exchange transfusions (46%). Children age 5 years and younger were often transfused until splenectomy. Splenectomy (150 [59%] of 254 patients) was associated with a median increase in hemoglobin of 1.6 g/dL and a decreased transfusion burden in 90% of patients. Predictors of a response to splenectomy included higher presplenectomy hemoglobin (P = .007), lower indirect bilirubin (P = .005), and missense PKLR mutations (P = .0017). Postsplenectomy thrombosis was reported in 11% of patients. The most frequent complications included iron overload (48%) and gallstones (45%), but other complications such as aplastic crises, osteopenia/bone fragility, extramedullary hematopoiesis, postsplenectomy sepsis, pulmonary hypertension, and leg ulcers were not uncommon. Overall, 87 (34%) of 254 patients had both a splenectomy and cholecystectomy. In those who had a splenectomy without simultaneous cholecystectomy, 48% later required a cholecystectomy. Although the risk of complications increases with severity of anemia and a genotype-phenotype relationship was observed, complications were common in all patients with PK deficiency. Diagnostic testing for PK deficiency should be considered in patients with apparent congenital hemolytic anemia and close monitoring for iron overload, gallstones, and other complications is needed regardless of baseline hemoglobin. This trial was registered at www.clinicaltrials.gov as #NCT02053480.

Physician decision making in selection of second-line treatments in immune thrombocytopenia in children

Immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder which presents with isolated thrombocytopenia and risk of hemorrhage. While most children with ITP promptly recover with or without drug therapy, ITP is persistent or chronic in others. When needed, how to select second‐line therapies is not clear. ICON1, conducted within the Pediatric ITP Consortium of North America (ICON), is a prospective, observational, longitudinal cohort study of 120 children from 21 centers starting second‐line treatments for ITP which examined treatment decisions. Treating physicians reported reasons for selecting therapies, ranking the top three. In a propensity weighted model, the most important factors were patient/parental preference (53%) and treatment‐related factors: side effect profile (58%), long‐term toxicity (54%), ease of administration (46%), possibility of remission (45%), and perceived efficacy (30%). Physician, health system, and clinical factors rarely influenced decision‐making. Patient/parent preferences were selected as reasons more often in chronic ITP (85.7%) than in newly diagnosed (0%) or persistent ITP (14.3%, P = .003). Splenectomy and rituximab were chosen for the possibility of inducing long‐term remission (P < .001). Oral agents, such as eltrombopag and immunosuppressants, were chosen for ease of administration and expected adherence (P < .001). Physicians chose rituximab in patients with lower expected adherence (P = .017). Treatment choice showed some physician and treatment center bias. This study illustrates the complexity and many factors involved in decision‐making in selecting second‐line ITP treatments, given the absence of comparative trials. It highlights shared decision‐making and the need for well‐conducted, comparative effectiveness studies to allow for informed discussion between patients and clinicians.

Hematopoietic cell transplantation for a child with OSTM1 osteopetrosis

HCT prior to onset of neurologic symptoms in children with OSTM1 osteopetrosis does not halt neurologic progression.

Screening for Wiskott-Aldrich syndrome by flow cytometry

Quantifying WAS protein predicts WAS mutations with 89% sensitivity and 100% specificity, but correlated poorly with disease severity. Absent WAS protein confirms WAS mutation but the presence of WAS protein must be corroborated by sequencing.

Prevalence and management of iron overload in pyruvate kinase deficiency: report from the Pyruvate Kinase Deficiency Natural History Study

Pyruvate kinase (PK) deficiency is the most common red cell glycolytic enzyme defect causing hereditary non-spherocytic hemolytic anemia. Current treatments are mainly supportive and include red cell transfusions and splenectomy.[1][1] Regular red cell transfusions are known to result in iron

Matched unrelated donor transplantation in glycogen storage disease type 1b patient corrects severe neutropenia and recurrent infections

Glycogen storage disease type 1b (GSD-1b) (OMIM 232220) is an autosomal recessive disorder that was first distinguished as a separate entity in 1978 [1]. GSD-1b is caused by a mutation in the glucose-6-phosphate transporter 1 gene (G6PT1) located on chromosome 11q23 [2, 3]. This transporter is important in translocating the glucose-6phosphate (G6P) from the cytoplasm across the endoplasmic reticulum (ER) where distinctive enzymes, depending on the cell type, hydrolyze this compound [4]. Glucose-6-phosphatase-α (G6Pase-α) that is strictly expressed and embedded in the ER of the liver, kidney, and intestines hydrolyzes G6P to glucose, an essential component of glucose homeostasis between meals [4]. Its deficiency leads to GSD type 1a [5]. Glucose-6-phosphatase-β (G6Pase-β) is another enzyme that is expressed ubiquitously in cells with increased glucose demands including neutrophils [6, 7]. Failure to meet these demands results in stressed ER and ultimately apoptosis of neutrophils [8]. Therefore, G6PT1 mutation results in defective translocation of G6P in all of the above-mentioned cell types and in addition to the GSD-1a phenotype, the majority of patients with GSD-1b develop neutropenia, neutrophil dysfunction, recurrent infections, and inflammatory bowel disease (IBD) [9, 10]. Dietary modifications, granulocytes colonystimulating factor (G-CSF), and liver transplant are the main management strategies [11]. While G-CSF has been used successfully to improve neutrophil counts and decrease recurrent infections, it has not been shown to decrease apoptosis or improve chemotaxis [8, 12]. Besides, G-CSF has its own risks including splenomegaly with hypersplenism, osteoporosis/osteopenia, and leukemic transformation [13, 14]. Liver transplant can restore glucose homeostasis for GSD-1a but cannot resolve the neutropenia component in GSD-1b. Hematopoietic cell transplant (HCT) from a matched related donor has been reported in one patient for extremely poor quality of life despite maximal therapy as evidenced by frequent hospital stays and life-threatening complications caused by impaired bone marrow function [15]. Post-transplant course in that patient was notable for improved neutrophil counts, decreased infections, improved metabolic control, and the original plan for liver transplant was postponed indefinitely [15]. Our patient is a 5-year-old Hispanic male born to consanguineous parents, who presented at 4 months of age with abdominal distension and vomiting. He had hepatosplenomegaly, mild neutropenia >1 × 10/L, blood glucose of 20 mg/dL, transaminitis, lactic acidosis, and hypertriglyceridemia. Gastrostomy tube (G-tube) was placed and continuous feeds were initiated after initial unsuccessful attempts at daytime bolus feeding. Liver biopsy showed glycogenosis with micro and macro-vesicular steatosis. GSD in the liver was significant for low G6P activity (Table 1). Analysis of the G6PT1 gene, SLC37A4 sequence, revealed a novel homozygous mutation at c.170C>A (p.S57X) predicted to result in a stop codon and thus, a deleterious mutation, consistent with GSD-1b. His neutropenia gradually worsened and he eventually developed severe neutropenia. * Lubna S. Mehyar Lubna.mehyar@nationwidechildrens.org

Hemolytic Anemia in a 5-Year-Old Child

1. Dark urine and fever; markedly reduced RBC count, hemoglobin level, and hematocrit; reticulocytosis on hospital day 1 that resolved by hospital day 3 following transfusion of 5 doses of packed RBCs on day 1 (3 doses) and days 2 (1 dose) and 4 (1 dose); markedly elevated ESR, LD, and bilirubin (total, direct, and indirect) levels; a reduced haptoglobin level; a red and hazy urine containing detectable amounts of protein, ketones, urobilinogen, and a large amount of occult blood, along with microscopic findings of a large number of RBCs/hpf; positive antibody findings for Epstein-Barr virus viral capsid antigen IgG antibody (EBV VCA IgG Ab) and EBV nuclear antigen (NA) IgG antibodies; and positive direct antiglobulin test (DAT), using anti-C3 antiserum only, and strongly positive 3cell antibody screen findings at 4°C (Table 1).