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Objetivos: A anemia falciforme (SCD) é uma doença hereditária causada pela polimerização de hemoglobina falciforme desoxigenada (HbS). Voxelotor é um inibidor de polimerização de HbS aprovado nos EUA e nos EAU para doentes com idade ≥4 anos, e na UE, Grã-Bretanha, Omã e Koweit, em doentes com idade ≥12 anos. O propósito deste estudo foi examinar os padrões de uso de voxelotor em pacientes de 9 instituições nos EUA como parte do Retrospective Real World Oxbryta Data Collection and Analysis Study (RETRO; NCT04930328). Materiais e metodologia: RETRO é um estudo de recolha e análise de dados retrospetivo, multicêntrico e posterior à colocação do produto no mercado. Os doentes elegíveis idade ≥12 anos, diagnosticados com SCD, tinham recebido voxelotor por ≥2 semanas consecutivas e tinham dados laboratoriais e clínicos disponíveis de 1 ano antes e até 1 ano após a primeira dose de voxelotor. Resultados: Foram recolhidos e analisados dados de 216 doentes. A média (SD) da idade dos doentes foi de 33,5 (14,2 anos) e 14,4% dos doentes tinham idade inferior a 18 anos. Um total de 120 doentes (55,6%) eram do sexo feminino, 189 (87,5%) eram afro-americanos ou negros e 199 (92,1%) tinham o genótipo HbSS. Sessenta por cento dos doentes foram tratados com voxelotor por ≥9 meses durante o período de estudo de 12 meses. A maioria dos doentes (86%) teve a prescrição de uma dose inicial de 1.500 mg uma vez ao dia, e 14% tiveram uma prescrição de uma dose inicial abaixo da recomendada na bula. Vinte e três por cento dos doentes tiveram uma modificação de dose iniciada pelo médico. A descontinuação do tratamento foi relatada por 21,8% dos doentes; os motivos incluíram acontecimentos adversos (8,3%) e “outros” (13,5%), que incluíram a perda de seguimento, decisão do médico e retirada do estudo. As análises preliminares de segurança sugerem que não houve evidência que a interrupção ou descontinuação do medicamento tenha levado ao início rápido de acontecimentos adversos (incluindo crises vaso-oclusivas (VOC)), conforme sugerido anteriormente para doentes com SCD grave (Nagalapuram V, Am J Hematol; 2022). Nos 45 doentes (20,8%) que apresentaram VOC após a interrupção ou descontinuação do medicamento, o tempo médio (percentil 25 a 75) para o início de uma VOC foi de 74 (29-138) dias. Dois doentes apresentaram uma VOC dentro de 1 semana após a interrupção ou descontinuação da dose; ambos os acontecimentos foram considerados como não relacionados com o voxelotor pelos investigadores. Discussão: Esses dados estão de acordo com os achados pré-clínicos do voxelotor na reologia eritrocitária após interrupção ou ou descontinuação do tratamento (Kanne CK et al, Front Physiol; 2021). Existem análises em curso para entender melhor os efeitos dos padrões de dosagem de voxelotor em termos de segurança e eficácia. Conclusões: RETRO é o maior estudo multicêntrico para e análise retrospetiva de dados no mundo real de doentes com SCD tratados com voxelotor. A maioria dos doentes não necessitou de modificação da dose ou de descontinuação do tratamento. A descontinuação e a interrupção da dose não foram relacionadas ao aparecimento subsequente de VOCs. Dados sobre padrões de uso de voxelotor no cenário do mundo real podem fornecer informações valiosas sobre práticas de prescrição e dosagem. Financiamento: Pfizer.

Objective: Voxelotor is a first-in-class sickle hemoglobin-polymerization inhibitor that was approved in 2019 by the US Food and Drug Administration for treatment of patients with sickle cell disease (SCD) aged ≥12 years; in 2021, the approval was extended to children with SCD aged 4 to 11 years. Additionally, both the Ministry of Health and Prevention for the United Arab Emirates and the European Commission granted marketing authorization for voxelotor in September 2021 and February 2022, respectively, for treatment of SCD in adults and pediatric patients aged ≥12 years. Thus, additional information on the patient experience with voxelotor would be useful for patients, caregivers, and healthcare professionals alike. The purpose of this study was to conduct semistructured interviews in an effort to understand the experiences and perspectives of voxelotor-treated patients with SCD., Methods: One-time semistructured interviews with adults, adolescents, and children with SCD and their primary caregivers were conducted in the United States. Twenty-three adults and adolescents were recruited across 4 clinical sites, and 10 children-caregiver dyads were recruited from a single site. The interview was designed to elicit patient perspectives on symptomatic changes with voxelotor and the impact of treatment on patients' perceived health-related quality of life. Individual interview transcripts were analyzed using a thematic analytic approach, and concept saturation was assessed in both cohorts., Results: Most patients reported improvements in their SCD symptoms with voxelotor treatment, specifically regarding pain crises, jaundice, and fatigue. Almost all patients experienced improvements in self-reported health-related quality of life with voxelotor treatment., Conclusions: This study provides patient and caregiver perspectives on the symptomatic benefits of voxelotor treatment. These findings not only highlight the benefits of voxelotor treatment in improving symptoms and increasing health-related quality of life across the entire SCD population but also can inform further research on SCD-specific patient-reported outcomes., Competing Interests: Clark Brown is an employee at Global Blood Therapeutics, Inc.; a consultant at Imara and Novo Nordisk; and a recipient of the research funding from Forma Therapeutics, Global Blood Therapeutics, Inc., Imara, and Novartis. Modupe Idowu is on the advisory board at Novartis; on the advisory board and a speaker at Global Blood Therapeutics, Inc.; and a recipient of the research funding from Pfizer Inc., Novartis, Global Blood Therapeutics, Inc., and Forma Therapeutics. Richard Drachtman is a consultant and speaker at Global Blood Therapeutics, Inc. and Agios; a speaker at Jazz Pharmaceuticals; and a consultant at Bluebird Bio. Anne Beaubrun is an employee at Global Blood Therapeutics, Inc. Irene Agodoa and Andy Nguyen are former employees at Global Blood Therapeutics, Inc. Kelly Lipman, Olga Moshkovich, Ryan Murphy, and M. Alex Bellenger are employees at ICON plc. Wally Smith is a consultant at Global Blood Therapeutics, Inc., Novartis, Pfizer Inc., GlycoMimetics, Ironwood, Novo Nordisk, Emmaus Pharmaceuticals, Fera Pharmaceuticals, and Agios Pharmaceuticals and a recipient of the research funding from Global Blood Therapeutics, Inc., NHLBI, PCORI, HRSA, Novartis, Forma Therapeutics, Imara, and Shire., (Copyright © 2023 Clark Brown et al.)

Introduction: Testicular germ cell tumors, particularly nonseminomatous germ cell tumors (NSGCT), comprise the most common solid malignancy in male children and younger adults. While these patients experience excellent survival outcomes, few studies have characterized their survival by age. Thus, we aimed to characterize the relative survival of NSGCT by age, stratifying patients by stage group., Methods: Using the Surveillance Epidemiology and End Results (SEER) database, we divided patients with NSGCT into pediatric patients and adolescents (<19 years), young adults (19-30 years), and older adults (>30 years). Survival analysis, using Cox proportional hazards models and Kaplan Meier curves, described overall and cancer-specific survival (CSS) of each age category for Stage I-III NSGCT by stage group., Results: A total of 14,786 patients met inclusion criteria and comprised the age groups <19 years (N=1,287), 19 to 30 years (N=7,729), and >30 years (N=5,770). Stage group distribution at presentation was similar between each group. Survival analysis demonstrated no differences in cancer-specific survival (CSS) among Stage I or II NSGCT. However, among Stage III tumors, multivariable models noted worse CSS in patients >30 years (HR=3.35 (95%CI: 1.45-7.73), P=0.005) and those 19-30 years (HR=2.28 (95%CI: 0.99-5.21), P=0.053) compared to pediatric and adolescent patients., Conclusions: Younger NSGCT patients experience excellent oncologic outcomes compared to their older counterparts. These survival differences by age group are largely driven by differential survival among Stage III neoplasms. Furthermore, our report lends additional evidence that age is an important prognostic factor in advanced NSGCT, including pediatric and adolescent patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Advances in medical care have resulted in nearly 95% of all children with sickle cell disease (SCD) living to adulthood. There is a lack of effective transition programming, contributing to high rates of mortality and morbidity among adolescents and young adults (AYAs) during the transition from pediatric to adult healthcare. This nonrandomized study evaluated the feasibility, acceptability, and preliminary outcomes of a novel medical student mentor intervention to improve transition outcomes for AYA with SCD., Methods: Eligible participants were ages 18-25 years, either preparing for transition or had transferred to adult care within the past year. Twenty-four AYA with SCD (Mage = 20.3, SD = 2.6) enrolled in the program and were matched with a medical student mentor. Feasibility and acceptability of the intervention was assessed through enrollment rates, reasons for refusal, retention rates, engagement with the intervention, satisfaction, and reasons for drop-out. Dependent t-tests were used to evaluate the preliminary effects of the intervention on patient transition readiness, health-related quality of life, self-efficacy, SCD knowledge, medication adherence, and health literacy., Results: Participants (N = 24) demonstrated adequate retention (75.0%), adherence to the intervention (M = 5.3 of 6 sessions), and satisfaction with the intervention components. Participants demonstrated significant improvements in transition readiness (p = .001), self-efficacy (p = .002), medication adherence (p = .02), and health literacy (p = .05)., Conclusions: A medical student mentor intervention to facilitate transition from pediatric to adult care for AYA with SCD is both feasible and acceptable to patients and medical students. Preliminary results suggest benefits for patients, warranting a larger efficacy study., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The purpose of this study was to examine the factors associated with disparities in overall survival (OS) by race in pediatric diffuse large B-cell lymphoma (DLBCL) patients., Methods: We evaluated clinical features and survival among patients ≤21 years of age diagnosed with stage I-IV DLBCL from 2004 to 2014 from the National Cancer Database (NCDB) using a multivariable Cox proportional hazards model., Results: Among 1386 pediatric patients with DLBCL, 1023 patients met eligibility criteria. In unadjusted analysis, Black patients had a significantly higher overall death rate than White patients (HR Black vs. White 1.51; 95% CI: 1.02-2.23, p = 0.041). The survival disparity did not remain significant in adjusted analysis, though controlling for covariates had little effect on the magnitude of the disparity (HR 1.46; 95% CI 0.93-2.31, p = 0.103). In adjusted models, presence of B symptoms, receipt of chemotherapy, stage of disease, and Other insurance were significantly associated with OS. Specifically, patients with B symptoms and those with Other insurance were more likely to die than those without B symptoms or private insurance, respectively (HR 1.75; 95% CI 1.22-2.50, p = 0.002) and (HR 2.56; 95% CI, 1.39-4.73, p = 0.0027), patients who did not receive chemotherapy were three times more likely to die than those who received chemotherapy (HR 3.10; CI 1.80-5.35, p < 0.001), and patients who presented with earlier stage disease were less likely to die from their disease than those with stage IV disease (stages I-III HR 0.34, CI 0.18-0.64, p < 0.001; HR 0.50, CI 0.30-0.82, p = 0.006, HR 0.72, CI 0.43-1.13, p = 0.152, respectively)., Conclusions: Our results suggest that racial disparities in survival may be mediated by clinical and treatment parameters., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The purpose of this study was to examine factors associated with disparities in overall survival (OS) by race in pediatric Hodgkin Lymphoma (HL) patients. We evaluated clinical features and survival among patients ≤21 years of age diagnosed with stage I-IV HL from 2004 to 2015 from the National Cancer DataBase (NCDB) using a multivariable Cox proportional hazards model. Among 11,546 patients with pediatric HL, 9285 patients met eligibility criteria. Black patients experienced a 5-year OS of 91.5% vs 95.9% in White patients ( p  < .0001). After adjusting for confounders, Black race was associated with a significantly decreased OS (HR = 1.50; 95% CI: 1.12-1.99; p  < .01). In stratified analysis by ages ≤15 years, 16-18 years, and >18 years, Black race was associated with poorer OS among compared to Whites with rates of 95.4% vs 97.7%, 87.1% vs 96.1%, and 91.6% vs 94.6% respectively. Overall, Black pediatric HL patients had lower overall survival in this study.

Importance: To date, there is no well-defined standard of care for early-stage pediatric Hodgkin lymphoma (HL), which may include chemotherapy alone or combined modality therapy (CMT) with chemotherapy followed by radiotherapy. Although the use of radiotherapy in pediatric HL is decreasing, this strategy remains controversial., Objective: To examine the use of CMT in pediatric HL and its association with improved overall survival using data from a large cancer registry., Design, Setting, and Participants: This observational cohort study used data from the National Cancer Database to evaluate clinical features and survival outcomes among 5657 pediatric patients (age, 0.1-21 years) who received a diagnosis of stage I or II HL in the United States from January 1, 2004, to December 31, 2015. Statistical analysis was conducted from May 1 to November 1, 2018., Exposures: Patients received definitive treatment with chemotherapy or CMT, defined as chemotherapy followed by radiotherapy., Main Outcomes and Measures: Kaplan-Meier survival curves were used to examine overall survival. The association between CMT use, covariables, and overall survival was assessed in multivariable Cox proportional hazards regression models. Use of radiotherapy was assessed over time., Results: Among the 11 546 pediatric patients with HL in the National Cancer Database, 5657 patients (3004 females, 2596 males, and 57 missing information on sex; mean [SD] age, 17.1 [3.6] years) with stage I or II classic HL were analyzed. Of these patients, 2845 (50.3%) received CMT; use of CMT vs chemotherapy alone was associated with younger age (<16 years, 1102 of 2845 [38.7%] vs 856 of 2812 [30.4%]; P < .001), male sex (1369 of 2845 [48.1%] vs 1227 of 2812 [43.6%]; P < .001), stage II disease (2467 of 2845 [86.7%] vs 2376 of 2812 [84.5%]; P = .02), and private health insurance (2065 of 2845 [72.6%] vs 1949 of 2812 [69.3%]; P = .002). The 5-year overall survival was 94.5% (confidence limits, 93.8%, 95.8%) for patients who received chemotherapy alone and 97.3% (confidence limits, 96.4%, 97.9%) for those who received CMT, which remained significant in the intention-to-treat analysis and multivariate analysis (adjusted hazard ratio for CMT, 0.57; 95% CI, 0.42-0.78; P < .001). In the sensitivity analysis, the low-risk cohort (stage I-IIA) and adolescent and young adult patients had the greatest benefit from CMT (adjusted hazard ratio, 0.47; 95% CI, 0.40-0.56; P < .001). The use of CMT decreased by 24.8% from 2004 to 2015 (from 59.7% [271 of 454] to 34.9% [153 of 438])., Conclusions and Relevance: In this study, pediatric patients with early-stage HL receiving CMT experienced improved overall survival 5 years after treatment. There is a nationwide decrease in the use of CMT, perhaps reflecting the bias of ongoing clinical trials designed to avoid consolidation radiotherapy. This study represents the largest data set to date examining the role of CMT in pediatric HL.

Primary Ewing sarcoma of the kidney is an extremely rare and aggressive tumor affecting young adults. We present the case of a 22-year-old male with primary Ewing sarcoma/primitive neuroectodermal tumor (EWS/PNET) of the kidney who underwent right radical nephrectomy and adjuvant chemo-radiation.

Purpose: We examined national outcomes and patterns of care for pediatric patients with medulloblastoma (MB) in a large observational cohort., Methods and Materials: Using the National Cancer Database, we evaluated the clinical features and survival outcomes of patients diagnosed with MB. The association between intervention, covariables, and outcome was assessed in a multivariable Cox analysis and through logistic regression analysis. Survival was estimated using the Kaplan-Meier method., Results: Among the 4032 patients in the National Cancer Database with pediatric brain tumors, 1300 patients met the inclusion criteria of histologic diagnosis, receipt of chemotherapy and radiation, and age ≤18 years. The median age and follow-up were 8.4 years and 4.5 years, respectively. Five-year survival was 79.0%. In the univariate analysis, inferior outcome (overall survival) was associated with rural residence (hazard ratio [HR], 2.78; 95% confidence interval [CI],1.47-5.29; P  < .01) and histology (large cell; HR, 1.78; 95% CI,1.08-2.94; P  < .05). In multivariable analysis, both remained significant predictors of survival (large cell: HR, 1.68; P  < .05; rural residence: HR, 2.74; P  < .01). In 2013, the utilization rate of proton therapy (23% of patients) in the United States surpassed intensity modulate radiation therapy (16%), more frequently for patients with higher income ( P  < .05) or more favorable insurance status ( P  < .05)., Conclusions: As one of the largest data sets on pediatric MB, the observed variations in treatment intervention and survival outcomes may represent a target for further research.

Background: Involved field radiotherapy (IFRT) after cytotoxic chemotherapy has become the standard of care in treating pediatric patients with Hodgkin lymphoma. However, recent interest in shrinking the treatment volume to involved node radiotherapy (INRT) may allow lower doses to critical organ structures. We dosimetrically compared IFRT and INRT treatment approaches., Methods: INRT treatment plans were retrospectively constructed from 17 consecutively treated pediatric patients identified with Hodgkin lymphoma who had been previously treated with conventional IFRT. The radiation doses delivered to organs-at-risk (OARs) with virtual INRT treatment plans based on INRT field design were then compared to the original IFRT treatment plans. Metrics for comparison included mean doses to organs and volumes of organ receiving at least 50% of the original prescription dose (V50%). A one-tailed, paired t-test was then performed to verify statistical significance at an alpha level of 0.05., Results: All organs at risk compared in this investigation (kidneys, heart, thyroid, parotids, and lungs) had significantly lower doses of radiation with INRT when compared to IFRT (p<0.05). Furthermore, the volume of the breast receiving at least 50% of the initial prescription dose was statistically lower in the INRT plans., Conclusions: Utilizing the concept of INRT results in a reduction of radiation dose to critical organ structures in pediatric patients with Hodgkin lymphoma when compared to the more traditional method of IFRT., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Germline von Hippel-Lindau (VHL) gene mutations underlie dominantly inherited familial VHL tumor syndrome comprising a predisposition for renal cell carcinoma, pheochromocytoma/paraganglioma, cerebral hemangioblastoma, and endolymphatic sac tumors. However, recessively inherited congenital polycythemia, exemplified by Chuvash polycythemia, has been associated with 2 separate 3' VHL gene mutations in exon 3. It was proposed that different positions of loss-of-function VHL mutations are associated with VHL syndrome cancer predisposition and only C-terminal domain-encoding VHL mutations would cause polycythemia. However, now we describe a new homozygous VHL exon 2 mutation of the VHL gene:(c.413C>T):P138L, which is associated in the affected homozygote with congenital polycythemia but not in her, or her-heterozygous relatives, with cancer or other VHL syndrome tumors. We show that VHL(P138L) has perturbed interaction with hypoxia-inducible transcription factor (HIF)1α. Further, VHL(P138L) protein has decreased stability in vitro. Similarly to what was reported in Chuvash polycythemia and some other instances of HIFs upregulation, VHL(P138L) erythroid progenitors are hypersensitive to erythropoietin. Interestingly, the level of RUNX1/AML1 and NF-E2 transcripts that are specifically upregulated in acquired polycythemia vera were also upregulated in VHL(P138L) granulocytes.

A retrospective chart review of 40 patients with sickle cell anemia (SCA) between the ages of 5-19 years who were seen within a 1-year period was performed to determine clinical and laboratory correlates for microalbuminuria and proteinuria. Age, sex, height, body mass index (BMI), serum creatinine [and estimated glomerular filtration rate (eGFR) by Schwartz and MDRD formulas], type of SCA, hemoglobin (Hb) level [total Hb and hemoglobin F percentage (HbF%)], lactate dehydrogenase (LDH) level, reticulocyte count, blood pressure, history of splenectomy, history of hydroxyurea use, and history of transfusions were correlated with microalbuminuria and proteinuria by univariate and multivariate regression analysis. The prevalence of microalbuminuria and proteinuria among these patients was 15 and 5%, respectively. Univariate analyses revealed a significant correlation between LDH level and microalbuminuria (Pearson r=0.47, p=0.04) and between LDH level and proteinuria (Pearson r=0.48, p=0.035). Multivariate analysis revealed a significant correlation between microalbuminuria and LDH level (p = 0.04) when controlled for age, sex, eGFR, Hb level, HbF%, type of SCA, BMI, history of transfusions, and reticulocyte count. In this pediatric SCA population, LDH was found to correlate with the presence of microalbuminuria and proteinuria. Further studies are needed to confirm LDH as an early marker for the risk of kidney involvement among SCA patients.

Thyroid carcinomas are an uncommon entity in childhood. We report a case of papillary thyroid cancer presenting as Horner syndrome in a 14 year-old child, which is the only reported such case in the pediatric population., (Copyright 2010 Wiley-Liss, Inc.)

Stroke is a well-known complication of sickle cell disease (SCD). It is estimated to occur in approximately 11% of patients with SCD by the age of 20. The most frequent cause of cerebrovascular accident (CVA) is blockage of the intracranial internal carotid and middle cerebral arteries. Hemorrhagic stroke is less common, occurring in approximately 3% of children by age 20. Transcranial Doppler (TCD) is the standard test for prediction of stroke risk in children with sickle cell anemia. The authors present a case of a 12-year-old female with SCD transferred to their institution after suffering a catastrophic intracranial hemorrhage. Her most recent TCD was normal 6 months prior to her admission.

Background: Patients with metastatic osteosarcoma have a poor prognosis. The objectives of the study were to determine the antitumor activity and toxicity of topotecan (daily x5) in newly diagnosed patients with metastatic osteosarcoma followed by chemotherapy (ifosfamide, carboplatin, etoposide [ICE], alternating with cisplatin and doxorubicin [CD])., Methods: Newly diagnosed patients (< or =30 years of age) with extensive metastatic disease (primary and > or =5 pulmonary nodules and/or bone metastases) with normal hepatic, renal, and cardiac function were eligible. Patients were eligible to receive further topotecan after standard chemotherapy if they exhibited a response. Twenty-eight patients were enrolled. Seventeen had metastases to the lung only and 11 had metastases to the bone or multiple sites. Of 28 patients enrolled, 27 could be evaluated for response. A limited dose escalation was incorporated., Results: No responses were seen in the 11 patients treated at 3 mg/m(2)/day. One partial response (PR) and 1 clinical response (CLR) were reported among 15 patients who received topotecan at 3.5 mg/m(2)/day. No dose-limiting toxicity was observed. Principal nondose-limiting toxicities were hematologic and gastrointestinal. The 2- and 5-year event-free survival rates were low, 7% and 4%, respectively, but the 2- and 5-year overall survival rates were 44% and 22%, respectively., Conclusions: Topotecan at dose of 3.5 mg/m(2)/day can be safely administered upfront to newly diagnosed patients without excessive toxicity. Insufficient activity was seen with topotecan in this schedule to warrant further studies in osteosarcoma. The combination of ICE and CD was tolerable when delivered after initial topotecan therapy.

Dextromethorphan (DM) is a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, which is widely used as an antitussive agent. DM also prevents neuronal damage and modulates pain sensation via noncompetitive antagonism of excitatory amino acids (EAAs). DM has been found to be useful in the treatment of pain in cancer patients and in the treatment of methotrexate-induced neurotoxicity. Clinical studies with DM in cancer patients are reviewed in this article.

Cerebrovascular disease is a common cause of morbidity in sickle cell anemia (HbSS): approximately 10% of patients have a clinical stroke before 20 years of age, and another 22% have silent infarction on magnetic resonance imaging. The phenotypic variation among patients with HbSS suggests a role for modifier genes and/or environmental influences. To assess the familial component of clinical stroke in HbSS, we estimated the prevalence of clinical stroke among all patients and among HbSS sibling pairs at 9 pediatric centers. The sample included 3425 patients with sickle cell disease who were younger than 21 years, including 2353 patients with HbSS. The stroke prevalence was 4.9% for all genotypes; 7.1% for patients with HbSS; 1.1% for patients with HbSbeta(o) thalassemia; 0.6% for patients with Sbeta(+) thalassemia; and 0% for patients with HbSC. In 207 sibships, more than 1 child had HbSS. There were 42 sibships in which at least 1 sibling had a stroke, and in 10 of the 42, 2 siblings had a stroke. A permutation test indicated that the number of families in which 2 children had strokes was larger than the number expected if strokes were randomly distributed among children in sibships (P =.0012). There was no difference in stroke prevalence based on sex, nor was the mean age at stroke presentation significantly different between singletons and sibships with stroke. We conclude that there is a familial predisposition to stroke in HbSS. Attempts to identify genetic modifiers should be initiated with family-based studies.

Two siblings with congenital neurologic structural anomalies and delayed-onset selective bone marrow hypoplasia in a previously undescribed constellation of symptoms are presented. Differences between these cases and other well known syndromes are discussed. The importance of this association is the implication that children with congenital neurologic abnormalities may be at increased risk for the development of hypoplastic hematopoietic conditions.