The germline p53 activation syndrome: A new patient further refines the clinical phenotype.

The tumor suppressor p53 has well known roles in cancer development and germline cancer predisposition disorders, but increasing evidence supports the role of activation of this transcription factor in the pathogenesis of inherited bone marrow failure and chromosomal instability disorders. Here we report a patient with red cell aplasia, which was steroid responsive, as well as intellectual disability, seizures, microcephaly, short stature, cellular radiosensitivity, and normal telomere lengths, who had a germline heterozygous C-terminal frameshift variant in TP53 similar to others that activate the transcription factor. This is the third reported individual with a germline p53 activation syndrome, with several unique features that refine the clinical disease associated with these variants.

Hospital Use and Mortality in Transition-Aged Patients With Sickle Cell Disease.

OBJECTIVES: Childhood mortality in sickle cell disease (SCD) has decreased, but the transition period is associated with poor outcomes and higher mortality rates. We analyzed recent US hospitalizations and mortality trends in the transition-aged population and evaluated for differences between patients with and without SCD. METHODS: Nationwide Inpatient Sample database was used to analyze hospitalizations among individuals aged 16 to 24 years from 2003 to 2017. Diagnoses were coded by using International Classification of Diseases, Ninth Revision, Clinical Modification and International Classification of Diseases, 10th Revision, Clinical Modification. We performed bivariate analyses to assess associations between sociodemographic characteristics and SCD hospitalizations, joinpoint regression analysis to describe mortality rate trends in SCD hospitalizations, and adjusted survey logistic regression to assess associations between patient characteristics and in-hospital mortality among transition-aged SCD and non-SCD-related hospitalizations. RESULTS: There were 37 344 532 hospital encounters of patients aged 16 to 24 years during 2003-2017; both SCD and non-SCD hospitalizations increased with age. Female patients accounted for 78% of non-SCD and 54.9% of SCD hospitalizations. Although there was a +3.2% average annual percent change in SCD hospitalizations, total SCD in-hospital mortality rates did not have a statistically significant increase in average annual percent change over the study period. Patients with SCD aged 19 to 21 and 22 to 24 were more likely to suffer in-hospital mortality than those aged 16 to 18 (odds ratio = 2.09 and 2.71, respectively); the increased odds in mortality by age were not seen in our non-SCD population. CONCLUSIONS: Transition-aged hospitalizations increase with age, but SCD hospitalizations have disparate age-related mortality rates. Hospital-based comprehensive care models are vital to address the persistent burden of early adulthood mortality in SCD.

Expansion of the clinical phenotype of GALE deficiency.

Congenital disorders of glycosylation are a group of rare monogenic inborn errors of metabolism caused by defective glycoprotein and glycolipid glycan synthesis and attachment. Here, we present a patient with galactose epimerase deficiency, also known as GALE deficiency, accompanied by pancytopenia and immune dysregulation. She was first identified by an abnormal newborn screen for galactosemia with subsequent genetic evaluation due to pancytopenia and immune dysregulation. The evaluation ultimately revealed that her known diagnosis of GALE deficiency was the cause of her hematologic and immune abnormalities. These findings further expand the clinical spectrum of disease of congenital disorders of glycosylation.

Barriers to and Facilitators of Iron Therapy in Children with Iron Deficiency Anemia.

OBJECTIVE: To characterize barriers to and facilitators of successful iron therapy in young children with iron deficiency anemia (IDA) from an in-depth parental perspective. STUDY DESIGN: Prospective, mixed methods study of children age 9 months to 4 years with a diagnosis of nutritional IDA by clinical history and laboratory criteria and their parents. Clinical data were obtained from the electronic health record. Semistructured interviews focused on knowledge of IDA, clinical effects, experience with iron therapies, and motivation were conducted with the parent who identified as the child's primary caregiver. RESULTS: Twenty patient-parent dyads completed the study; 80% (n = 16) identified as Hispanic/Latino (white). Patients' median age was 23 months (50% male); median initial hemoglobin concentration was 8.2 g/dL and duration of oral iron therapy was 3 months. Parents' median age was 29 years (85% female); 8 interviews (40%) were conducted in Spanish. Barriers included difficulty in administering oral iron owing to side effects and poor taste. Facilitators included provision of specific instructions; support from healthcare providers and additional caregivers at home; motivation to benefit child's health, which was strengthened by strong emotional reactions (ie, stress, anxiety) to therapy and follow-up; and an appreciation of child's improvement with successful completion of therapy. CONCLUSIONS: Our findings support the need for interventions designed to promote oral iron adherence in children with IDA. Rather than focusing on knowledge content related to IDA, interventions should aim to increase parental motivation by emphasizing the health benefits of adhering to iron therapy and avoiding more invasive interventions.

Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features.

Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (sbds) gene. Using trio whole-exome sequencing (WES) in an sbds-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in srp54 (encoding signal recognition particle 54 kDa). These 3 patients shared congenital neutropenia linked with various other SDS phenotypes. 3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was impaired. The level of SRP54 mRNA in the bone marrow was 3.6-fold lower in patients with SRP54-mutations than in healthy controls. Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype. In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond-like phenotype.

The genomic landscape of juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 or CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and could therefore be candidates for experimental therapies. In addition, few molecular pathways aside from the RAS-MAPK pathway have been identified that could serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia to expand knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, splicing, Polycomb repressive complex 2 (PRC2) and transcription. Notably, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome.

Antithrombin Concentrate Use in Children Receiving Unfractionated Heparin for Acute Thrombosis.

OBJECTIVE: To characterize features of antithrombin concentrate (ATC) use in children receiving unfractionated heparin (UFH) therapy for acute thrombosis. STUDY DESIGN: All pediatric patients at Texas Children's Hospital who received ATC in the context of UFH therapy for acute thrombosis during February 2011 to May 2013 were analyzed. RESULTS: Fifty-one children received ATC during UFH therapy for acute thrombosis. Median age was 3 months (IQR 1 to 18 months). Clinical indications included venous (53%), arterial (37%), venous and arterial (6%), and intracardiac (4%) thrombosis. Median baseline antithrombin (AT) level was 61% and UFH dose was 26 U/kg/h. The median dose of ATC was 49.9 IU/kg (IQR 32.6 to 50.0 IU/kg). Although most patients (86%) did not undergo a change in UFH dose, there was a significant increase in both AT and anti-factor Xa level after the first dose of ATC (P < .001 for both). There was no correlation between ATC dose or increment in AT level above baseline and the achievement of targeted anticoagulation by anti-factor X activity level. Adverse bleeding events occurred in 10% of patients. CONCLUSIONS: There was a significant change in AT and anti-factor Xa activity level after a single dose of ATC despite little to no change in dose of UFH. ATC appears to facilitate anticoagulation with UFH in some children with acute thrombosis but the degree of response is variable and dependent on factors identified in this study. Bleeding and other theoretical risks must be carefully considered.

Unrecognized hepatitis B in pre-screened children with hematologic and oncologic conditions.

BACKGROUND: This study evaluates the effectiveness and interpretation of hepatitis B (HBV) screening in an at-risk cohort of children with cancer or blood disorders. PROCEDURE: We conducted a retrospective epidemiologic analysis of children who screened positive for HBV (HBsAg, HbcAb) from 1999 to 2009 at a quaternary children's hospital, focusing on patients with hematologic and oncologic conditions. Descriptive statistics were generated for demographics and serologies. Follow-up of positive serologies and clinical outcomes were analyzed. RESULTS: A total of 12,754 children were screened for HBV. Of 391 that screened positive, 118 had a hematologic or oncologic diagnosis. Leukemia, anemia, and thrombocytopenia comprised 84% of diagnoses. The majority (98%) tested HBcAb positive but only 20% received confirmatory HBV DNA testing. Three patients (13% of those HBV DNA tested) were identified to have chronic disease. HBV was not a known pre-existing condition, and chemotherapy preceded HBV diagnosis in all cases. CONCLUSIONS: The majority of children with cancer or blood disorders who screened HBV positive did not receive follow-up DNA testing, exposing them to reactivation risk and delaying definitive therapy. HBcAb may be the only indicator of chronic HBV infection and DNA confirmation should be routine. Our findings suggest a significant number of additional patients eligible for HBV treatment may have been identified with reflexive DNA testing.

Staphylococcus aureus infections in pediatric oncology patients: high rates of antimicrobial resistance, antiseptic tolerance and complications.

BACKGROUND: : Patients with malignancies represent a population at high risk for drug-resistant infections. We sought to determine the clinical spectrum and molecular epidemiology of Staphylococcus aureus infections in pediatric oncology patients followed at Texas Children's Hospital (Houston, TX). Furthermore, we determined the prevalence of the chlorhexidine resistance gene qacA/B from isolates in this unique population. METHODS: : Patients with a history of malignancy and a culture-proven S. aureus infection were identified from 2001 to 2011. Antibiotic susceptibility, pulsed-field gel electrophoresis and detection of qacA/B by polymerase chain reaction were performed on all isolates. Medical records for all patients were reviewed. RESULTS: : During the study period, 213 isolates were identified from 179 patients with malignancies. Thirty-one percent of the isolates were methicillin-resistant S. aureus. The most common infectious diagnosis was bacteremia (85/213 [39.9%], with 72/85 [84.7%] being catheter-associated). Thirteen patients with bacteremia were found to have pulmonary nodules at the time of presentation; only S. aureus was found in tissue in 5 of the 6 patients who underwent lung biopsy. After 2007, 18.2% of isolates were qacA/B positive with a steady increase in prevalence every year (χ for trend P = 0.04). CONCLUSIONS: : S. aureus is a significant cause of morbidity and mortality in pediatric oncology patients at Texas Children's Hospital. In addition to the more well-known clinical manifestations, this pathogen can also be associated with pulmonary nodules. Furthermore, the prevalence of S. aureus isolates carrying antiseptic resistance genes increased in this population. Additional clinical and molecular studies and surveillance among pediatric oncology patients are warranted to further explore these findings.

Successful treatment of congenital TTP with a novel approach using plasma-derived factor VIII.

We describe a 19-year-old boy who was diagnosed with congenital thrombotic thrombocytopenic purpura (cTTP) at 7 months of age. He was subsequently treated with fresh frozen plasma infusions every 3 to 4 weeks for the next 15 years at which point he developed significant hypersensitivity reactions to fresh frozen plasma. He required immunosuppressive therapy with systemic desensitization in the intensive care unit but did not tolerate this regimen and suffered debilitating adverse effects. On the basis of the observations from United Kingdom, he was started on a trial with Koate, a plasma-derived factor VIII concentrate with ADAMTS-13 activity that is commercially available in the United States. He tolerated Koate without any complications and attained a target platelet count of>100,000/µL. He has now been in remission for 36 months and responds to exacerbations of cTTP with additional doses of Koate. For patients with cTTP who are intolerant to plasma infusions, therapy with select plasma-derived factor concentrates with ADAMTS-13 activity may represent a reasonable alternative therapy.

An analysis of outcomes and treatment costs for children undergoing splenectomy for chronic immune thrombocytopenia purpura.

PURPOSE: Indications and timing for splenectomy in pediatric chronic immune thrombocytopenic purpura (cITP) are controversial because of high spontaneous remission rates and concern for overwhelming postsplenectomy infection. The objective of this study was to assess the risks, costs, and benefits of medical and surgical intervention for children with cITP. METHODS: After receiving institutional review board approval, medical records for all children with cITP who underwent splenectomy from 2002 through 2009 were retrospectively reviewed (n = 22). Preoperative and postoperative data were collected. Medical and surgical costs were calculated based on pharmacy charges per dose and hospital charges, respectively. RESULTS: The median age at diagnosis was 11 years (range, 3-16 years). Medical management included steroids (n = 21), intravenous gamma globulin (n = 19), anti-D antibody (n = 19), or a combination of these therapies (n = 22). Nineteen patients (86%) reported side effects from medical therapy. Median age at splenectomy was 13 years (range, 6-18 years), and time to surgery was 23 months from diagnosis (range, 6-104 months). Splenectomy increased platelet counts in all children from a median of 25,500 to 380,000 postoperatively (P < .0001). One child experienced overwhelming postsplenectomy infection after a dog bite (n = 1). At the last follow-up (15 months; range, 1-79 months), 19 patients (86%) were asymptomatic with platelet counts greater than 50,000. Of the 3 children with persistent thrombocytopenia, 2 were diagnosed with secondary cITP. Median cost of splenectomy was significantly less than the cost of medical therapy ($20,803 vs $146,284; P < .0002). CONCLUSION: Earlier surgical consultation for children with cITP may be justified given the high success rate and low morbidity, particularly given the significant complication rate and cost of continued medical treatment.

Plasma methotrexate, red blood cell methotrexate, and red blood cell folate values and outcome in children with precursor B-acute lymphoblastic leukemia: a report from the Children's Oncology Group.

Plasma steady state methotrexate (MTX) level and red blood cell (RBC) MTX and folate concentrations were evaluated in 1124 children with newly diagnosed acute lymphoblastic leukemia enrolled in the Pediatric Oncology Group studies 9005 (lower risk; Regimens A and C) and 9006 (higher risk; Regimen A). These regimens included intermediate-dose MTX (1 g/m) given as a 24 hours infusion every other week for 12 doses during intensification. Plasma MTX level was evaluated at the end of MTX infusions. RBC MTX and folate concentrations were measured at the end of intensification. The 5 year continuous complete remission was 76±1.4% versus 85±3.0% for those patients with steady state MTX levels less than or equal to and greater than 14 µM, respectively (P=0.0125). Hispanic children had significantly reduced median steady state MTX levels, 8.7 µM, compared with non-Hispanic children, 9.95 µM (P=0.0015), but this did not correlate with a difference in outcome. Neither RBC MTX, RBC folate, nor the RBC MTX:folate ratio identified children at increased risk of failure.

Leadership: "They never taught me this in medical school".

SUMMARY: Pediatric hematologist/oncologists lead in a variety of roles and settings: at the bedside, in private or academic practice, in the laboratory, and in wider society. Whether their leadership is the result of innate ability, technical expertise, or educational experience, patients, colleagues, academic centers, and communities turn to physicians for leadership. But where do these physicians learn this complex skill? Physicians do acquire leadership skills, but mainly through interaction with role models and in a hit or miss fashion. This article provides a theoretical framework for medical leadership education and describes a leadership-focused educational seminar that has been offered to pediatric hematology-oncology fellows at Texas Children's Cancer Center since 1995. Retrospective pre/post evaluations by fellows indicated significant improvement in self-rated ability for all 24 dimensions assessed, including a variety of items drawn from the roster of the Accreditation Council for Graduate Medical Education Core Competencies. In this article we extend the concept of physician leadership from its roots in practice and present a comprehensive model that prepares pediatric hematologist/oncologists for leadership in clinical, research, and educational arenas.

Assessment of cardiac iron by MRI susceptometry and R2* in patients with thalassemia.

A magnetic resonance imaging cardiac magnetic susceptometry (MRI-CS) technique for assessing cardiac tissue iron concentration based on phase mapping was developed. Normal control subjects (n=9) and thalassemia patients (n=13) receiving long-term blood transfusion therapy underwent MRI-CS and MRI measurements of the cardiac relaxation rate R2*. Using MRI-CS, subepicardium and subendocardium iron concentrations were quantified exploiting the hemosiderin/ferritin iron specific magnetic susceptibility. The average of subepicardium and subendocardium iron concentrations and R2* of the septum were found to be strongly correlated (r=0.96, P<.0001), and linear regression analysis yielded CIC (microg Fe/g(wet tissue))=(6.4+/-0.4).R2* (septum) (s(-1)) - (120+/-40). The results demonstrated that septal R2* indeed measures cardiac iron level.

Oral iron chelation and the treatment of iron overload in a pediatric hematology center.

BACKGROUND: Recent advances have led to the development of oral iron chelators, which have changed clinical practice. The objective of this study was to descriptively assess the use of one such agent, deferasirox, as standard of care treatment in a large pediatric hematology center. PROCEDURE: We retrospectively studied all patients at the Texas Children's Hematology Center who were previously or currently treated with deferasirox. We gathered data on demographics, clinical diagnoses, length of time on chronic transfusions, previous use of deferoxamine, adherence to therapy, and reasons for discontinuation. We also assessed changes in serum ferritin, liver function tests, and creatinine for those on deferasirox for a minimum of 12 months. RESULTS: Fifty-nine patients were studied. Eighty-one percent of patients treated with deferasirox had a diagnosis of sickle cell disease. The mean baseline ferritin level for our study population was 2,117 ng/ml (range 754-7,211). Fifty-three percent of patients had been previously treated with deferoxamine. Adherence to oral therapy was documented in 76% of patients. For those on deferasirox for a minimum of 12 months, serum ferritin decreased in 30% of patients (44% of compliant patients, 11% of poorly compliant patients). Changes in creatinine and liver function tests were mild and did not result in long-term discontinuation of deferasirox in any cases. CONCLUSIONS: Outside of controlled clinical trials, deferasirox can be utilized safely as an oral iron chelator in children although adherence to therapy and the complex interaction of factors that contribute to iron overload still present challenges for clinicians.