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Through the use of genetic sequencing, molecular variants driving autoimmunity are increasingly identified in patients with chronic and refractory immune cytopenias. With the goal of discovering genetic variants that predispose to pediatric immune thrombocytopenia (ITP) or increase risk for chronic disease, we conducted a genome-wide association study in a large multi-institutional cohort of pediatric patients with ITP. Five-hundred ninety-one patients were genotyped using an Illumina Global Screening Array (GSA) BeadChip. Six variants met genome wide significance in comparison between children with ITP and a cohort of healthy children. One variant in NAV2 was inversely associated with ITP (aOR: 0.52, P=3.2x10-11). Two other variants in close proximity to NKD1 were also inversely associated with ITP (aOR: 0.43, P=8.86x10-15; aOR: 0.48, P=1.84x10-16). These genes have been linked to the canonical Wnt signaling pathway. No variants met genome-wide significance in comparison of those with ITP that self-resolved in less than 1 year versus those who developed chronic ITP. This study identifies genetic variants which may contribute to ITP risk and raises a novel pathway with a potential role in ITP pathogenesis.
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There are no agreed upon terminology to define "refractory" pediatric Immune Thrombocytopenia (ITP). Guidelines are therefore limited to arbitrary and outdated definitions. The Pediatric ITP Consortium of North America held a meeting in 2023 to define this entity. With 100% agreement, the faculty established that pediatric ITP that is refractory to emergent therapy could be defined as no platelet response after treatment with all eligible emergent pharmacotherapies. With 100% agreement, the working group established that pediatric patients with ITP that continue to demonstrate high disease burden and/or no platelet response despite treatment with multiple classes of disease modifying therapies represent a challenging subset of ITP. These patients are at higher risk of ongoing disease burden and merit additional investigation as well as consideration for clinical trials or novel therapies. Future efforts to define disease burden and disease response will be completed in collaboration with the ITP International Working Group.
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BACKGROUND: Patients with telomere biology disorders (TBD) develop hepatic disease, including hepatitis, cirrhosis, and hepatopulmonary syndrome. No specific treatment exists for TBD-related liver disease, and the role of liver transplantation (LT) remains controversial. Our study objectives were to describe the clinical characteristics, management, and outcomes in patients with TBD-related liver disease, and their LT outcomes. METHODS: Data from 83 patients with TBD-associated liver disease were obtained from 17 participating centers in the Clinical Care Consortium of Telomere-Associated Ailments and by self-report for our retrospective, multicenter, international cohort study. RESULTS: Group A ("Advanced") included 40 patients with advanced liver disease. Of these, 20 underwent LT (Group AT). Group M ("Mild") included 43 patients not warranting LT evaluation, none of whom were felt to be medically unfit for liver transplantation. Supplemental oxygen requirement, pulmonary arteriovenous malformation, hepatopulmonary syndrome, and higher bilirubin and international normalized ratio values were associated with Group A. Other demographics, clinical manifestations, and laboratory findings were similar between groups. Six group A patients were declined for LT; 3 died on the waitlist. Median follow-up post-LT was 2.9 years (range 0.6-13.2 y). One-year survival post-LT was 73%. Median survival post-LT has not been reached. Group AT patients had improved survival by age compared to all nontransplant patients (log-rank test p = 0.02). Of 14 patients with pretransplant hypoxemia, 8 (57%) had improved oxygenation after transplant. CONCLUSIONS: LT recipients with TBD do not exhibit excessive posttransplant mortality, and LT improved respiratory status in 57%. A TBD diagnosis should not exclude LT consideration.
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Trasplante de Hígado , Humanos , Femenino , Masculino , Estudios Retrospectivos , Adulto , Persona de Mediana Edad , Telómero , Adolescente , Hepatopatías/cirugía , Hepatopatías/genética , Adulto Joven , Niño , Resultado del Tratamiento , PreescolarRESUMEN
Severe aplastic anemia (SAA) is a rare potentially fatal hematologic disorder. Although overall outcomes with treatment are excellent, there are variations in management approach, including differences in treatment between adult and pediatric patients. Certain aspects of treatment are under active investigation in clinical trials. Because of the rarity of the disease, some pediatric hematologists may have relatively limited experience with the complex management of SAA. The following recommendations reflect an up-to-date evidence-based approach to the treatment of children with newly diagnosed SAA.
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Anemia Aplásica , Humanos , Anemia Aplásica/terapia , Anemia Aplásica/diagnóstico , Niño , Medicina Basada en la Evidencia , Guías de Práctica Clínica como Asunto/normasRESUMEN
Severe aplastic anemia (SAA) is a rare potentially fatal hematologic disorder. Although overall outcomes with treatment are excellent, there are variations in management approach, including differences in treatment between adult and pediatric patients. Certain aspects of treatment are under active investigation in clinical trials. Because of the rarity of the disease, some pediatric hematologists may have relatively limited experience with the complex management of SAA. The following recommendations reflect an up-to-date evidence-based approach to the treatment of children with relapsed or refractory SAA.
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Anemia Aplásica , Humanos , Anemia Aplásica/terapia , Niño , Recurrencia , Medicina Basada en la Evidencia , Trasplante de Células Madre HematopoyéticasRESUMEN
BACKGROUND AND OBJECTIVES: Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare vascular tumors in children historically associated with significant morbidity and mortality. This study was conducted to determine first-line therapy in the absence of available prospective clinical trials. METHODS: Patients from 17 institutions diagnosed with KHE/TA between 2005 and 2020 with more than 6 months of follow-up were included. Response rates to sirolimus and vincristine were compared at 3 and 6 months. Durability of response and response to other treatment modalities were also evaluated. RESULTS: Of 159 unique KHE/TA subjects, Kasabach-Merritt phenomenon (KMP) was present in 64 (40.3%), and only two patients were deceased (1.3%). Over 60% (n = 96) demonstrated treatment response at 3 months, and more than 70% (n = 114) by 6 months (no significant difference across groups). The vincristine group had higher radiologic response at 3 months compared to sirolimus (72.7% vs. 20%, p = .03), but there were no differences between these groups at 6 months. There were no differences in rates of recurrent or progressive disease between vincristine and sirolimus. CONCLUSIONS: In this large, multicenter cohort of 159 patients with KHE/TA, rates of KMP were consistent with historical literature, but the mortality rate (1.3%) was much lower. Overall treatment response rates were high (>70%), and there was no significant difference in treatment response or durability of disease comparing sirolimus to vincristine. Our results support individualized treatment decision plans depending on clinical scenario and patient/physician preferences. Response criteria and response rates reported here will be useful for guiding future treatment protocols for vascular tumors.
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Hemangioendotelioma , Hemangioma , Síndrome de Kasabach-Merritt , Sarcoma de Kaposi , Neoplasias Cutáneas , Neoplasias Vasculares , Niño , Humanos , Síndrome de Kasabach-Merritt/tratamiento farmacológico , Síndrome de Kasabach-Merritt/patología , Vincristina , Estudios Prospectivos , Hemangioendotelioma/tratamiento farmacológico , Hemangioendotelioma/patología , Sarcoma de Kaposi/patología , Sirolimus/uso terapéuticoRESUMEN
Central conducting lymphatic anomaly (CCLA) due to congenital maldevelopment of the lymphatics can result in debilitating and life-threatening disease with limited treatment options. We identified 4 individuals with CCLA, lymphedema, and microcystic lymphatic malformation due to pathogenic, mosaic variants in KRAS. To determine the functional impact of these variants and identify a targeted therapy for these individuals, we used primary human dermal lymphatic endothelial cells (HDLECs) and zebrafish larvae to model the lymphatic dysplasia. Expression of the p.Gly12Asp and p.Gly13Asp variants in HDLECs in a 2dimensional (2D) model and 3D organoid model led to increased ERK phosphorylation, demonstrating these variants activate the RAS/MAPK pathway. Expression of activating KRAS variants in the venous and lymphatic endothelium in zebrafish resulted in lymphatic dysplasia and edema similar to the individuals in the study. Treatment with MEK inhibition significantly reduced the phenotypes in both the organoid and the zebrafish model systems. In conclusion, we present the molecular characterization of the observed lymphatic anomalies due to pathogenic, somatic, activating KRAS variants in humans. Our preclinical studies suggest that MEK inhibition should be studied in future clinical trials for CCLA due to activating KRAS pathogenic variants.
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Proteínas Proto-Oncogénicas p21(ras) , Pez Cebra , Animales , Humanos , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Células Endoteliales/metabolismo , Fosforilación , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
The MECOM gene encodes multiple protein isoforms that are essential for hematopoietic stem cell self-renewal and maintenance. Germline MECOM variants have been associated with congenital thrombocytopenia, radioulnar synostosis and bone marrow failure; however, the phenotypic spectrum of MECOM-associated syndromes continues to expand and novel pathogenic variants continue to be identified. We describe eight unrelated patients who add to the previously known phenotypes and genetic defects of MECOM-associated syndromes. As each subject presented with unique MECOM variants, the series failed to demonstrate clear genotype-to-phenotype correlation but may suggest a role for additional modifiers that affect gene expression and subsequent phenotype. Recognition of the expanded hematologic and non-hematologic clinical features allows for rapid molecular diagnosis, early identification of life-threatening complications, and improved genetic counseling for families. A centralized international publicly accessible database to share annotated MECOM variants would advance their clinical interpretation and provide a foundation to perform functional MECOM studies.
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Enfermedades de la Médula Ósea , Enfermedades Hematológicas , Pancitopenia , Humanos , Enfermedades de la Médula Ósea/diagnóstico , Enfermedades de la Médula Ósea/genética , Síndrome , Trastornos de Fallo de la Médula Ósea , Factores de Transcripción/genética , Fenotipo , Proteína del Locus del Complejo MDS1 y EV11/genéticaRESUMEN
Acquired aplastic anemia (AA) is caused by autoreactive T cell-mediated destruction of early hematopoietic cells. Somatic loss of human leukocyte antigen (HLA) class I alleles was identified as a mechanism of immune escape in surviving hematopoietic cells of some patients with AA. However, pathogenicity, structural characteristics, and clinical impact of specific HLA alleles in AA remain poorly understood. Here, we evaluated somatic HLA loss in 505 patients with AA from 2 multi-institutional cohorts. Using a combination of HLA mutation frequencies, peptide-binding structures, and association with AA in an independent cohort of 6,323 patients from the National Marrow Donor Program, we identified 19 AA risk alleles and 12 non-risk alleles and established a potentially novel AA HLA pathogenicity stratification. Our results define pathogenicity for the majority of common HLA-A/B alleles across diverse populations. Our study demonstrates that HLA alleles confer different risks of developing AA, but once AA develops, specific alleles are not associated with response to immunosuppression or transplant outcomes. However, higher pathogenicity alleles, particularly HLA-B*14:02, are associated with higher rates of clonal evolution in adult patients with AA. Our study provides insights into the immune pathogenesis of AA, opening the door to future autoantigen identification and improved understanding of clonal evolution in AA.
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Anemia Aplásica , Adulto , Humanos , Anemia Aplásica/genética , Anemia Aplásica/patología , Alelos , Antígenos de Histocompatibilidad Clase I/genética , Antígenos HLA-B/genética , Antígenos HLA/genéticaRESUMEN
Congenital lymphatic leak may develop in patients with maldeveloped lymphatics and result in life-threatening fluid and electrolyte imbalance, protein deficiency, and immunodeficiency. Rapid diagnosis and therapy are necessary to prevent these complications; however, the field lacks clinical trials to support standardized diagnostic treatment guidelines. We present our current multidisciplinary approach to the diagnosis and management of congenital lymphatic leak including chylous pleural effusions and ascites. Depending on the rate of lymphatic leak, therapy can range from observation with nutritional modifications to surgical and interventional procedures aimed to reduce lymphatic drainage. Modalities to image central and peripheral lymphatics have advanced considerably. Genetic variants and subsequent targets that drive lymphatic maldevelopment have expanded the repertoire of possible pharmacotherapeutic options.
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Quilotórax , Ascitis Quilosa , Trastornos Respiratorios , Ascitis/diagnóstico , Ascitis/etiología , Ascitis/terapia , Niño , Quilotórax/diagnóstico , Quilotórax/terapia , Ascitis Quilosa/diagnóstico , Ascitis Quilosa/etiología , Ascitis Quilosa/terapia , Drenaje , HumanosRESUMEN
Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 drives inv(3)/t(3;3) myeloid leukemias via structural rearrangement of an enhancer that upregulates transcription of EVI1. Here, we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 that is frequently present in inv(3)/t(3;3) acute myeloid leukemia (AML) and directly contributes to leukemic transformation. This EVI1 isoform is generated by oncogenic mutations in the core RNA splicing factor SF3B1, which is mutated in >30% of inv(3)/t(3;3) myeloid neoplasm patients and thereby represents the single most commonly cooccurring genomic alteration in inv(3)/t(3;3) patients. SF3B1 mutations are statistically uniquely enriched in inv(3)/t(3;3) myeloid neoplasm patients and patient-derived cell lines compared with other forms of AML and promote mis-splicing of EVI1 generating an in-frame insertion of 6 amino acids at the 3' end of the second zinc finger domain of EVI1. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells, and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21q26) allele resulted in generation of this novel EVI1 isoform in mice and hastened leukemogenesis in vivo. The mutant SF3B1 spliceosome depends upon an exonic splicing enhancer within EVI1 exon 13 to promote usage of a cryptic branch point and aberrant 3' splice site within intron 12 resulting in the generation of this isoform. These data provide a mechanistic basis for the frequent cooccurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).
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Leucemia Mieloide Aguda , Proto-Oncogenes , Animales , Inversión Cromosómica , Cromosomas Humanos Par 3/metabolismo , Proteínas de Unión al ADN/metabolismo , Humanos , Leucemia Mieloide Aguda/patología , Proteína del Locus del Complejo MDS1 y EV11/genética , Ratones , Proto-Oncogenes/genética , Factores de Transcripción/metabolismoRESUMEN
OBJECTIVE: To evaluate the effect of the RAS-MAPK pathway inhibitor trametinib on medically refractory chylous effusions in 3 hospitalized patients with Noonan syndrome. STUDY DESIGN: Pharmacologic MEK1/2 inhibition has been used to treat conditions associated with Noonan syndrome, given that activation of RAS-MAPK pathway variants leads to downstream MEK activation. We describe our experience with 3 patients with Noonan syndrome (owing to variants in 3 distinct genes) and refractory chylous effusions treated successfully with MEK inhibition. A monitoring protocol was established to standardize medication dosing and monitoring of outcome measures. RESULTS: Subjects demonstrated improvement in lymphatic leak with additional findings of improved growth and normalization of cardiac and hematologic measurements. Trametinib was administered safely, with only moderate skin irritation in 1 subject. CONCLUSIONS: Improvements in a variety of quantifiable measurements highlight the potential utility of MEK1/2 inhibition in patients with Noonan syndrome and life-threatening lymphatic disease. Larger, prospective studies are needed to confirm efficacy and assess long-term safety.
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Antineoplásicos , Síndrome de Noonan , Niño , Humanos , Quinasas de Proteína Quinasa Activadas por Mitógenos , Síndrome de Noonan/complicaciones , Síndrome de Noonan/tratamiento farmacológico , Síndrome de Noonan/genética , Piridonas/uso terapéutico , Pirimidinonas/uso terapéuticoRESUMEN
Fanconi anemia (FA), a genetic DNA repair disorder characterized by marrow failure and cancer susceptibility. In FA mice, metformin improves blood counts and delays tumor development. We conducted a single institution study of metformin in nondiabetic patients with FA to determine feasibility and tolerability of metformin treatment and to assess for improvement in blood counts. Fourteen of 15 patients with at least 1 cytopenia (hemoglobin < 10 g/dL; platelet count < 100 000 cells/µL; or an absolute neutrophil count < 1000 cells/µL) were eligible to receive metformin for 6 months. Median patient age was 9.4 years (range 6.0-26.5 ). Thirteen of 14 subjects (93%) tolerated maximal dosing for age; 1 subject had dose reduction for grade 2 gastrointestinal symptoms. No subjects developed hypoglycemia or metabolic acidosis. No subjects had dose interruptions caused by toxicity, and no grade 3 or higher adverse events attributed to metformin were observed. Hematologic response based on modified Myelodysplastic Syndrome International Working Group criteria was observed in 4 of 13 evaluable patients (30.8%; 90% confidence interval, 11.3-57.3). Median time to response was 84.5 days (range 71-128 days). Responses were noted in neutrophils (n = 3), platelets (n = 1), and red blood cells (n = 1). No subjects met criteria for disease progression or relapse during treatment. Correlative studies explored potential mechanisms of metformin activity in FA. Plasma proteomics showed reduction in inflammatory pathways with metformin. Metformin is safe and tolerable in nondiabetic patients with FA and may provide therapeutic benefit. This trial was registered at as #NCT03398824.
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Anemia de Fanconi , Metformina , Niño , Anemia de Fanconi/tratamiento farmacológico , Anemia de Fanconi/genética , Humanos , Metformina/uso terapéutico , Adulto JovenRESUMEN
Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome with leukemia predisposition. An understanding of the hematologic complications of SDS with age could guide clinical management, but data are limited for this rare disease. We conducted a cohort study of 153 subjects from 143 families with confirmed biallelic SBDS mutations enrolled on the North American Shwachman Diamond Registry or Bone Marrow Failure Registry. The SBDS c.258 + 2T>C variant was present in all but 1 patient. To evaluate the association between blood counts and age, 2146 blood counts were analyzed for 119 subjects. Absolute neutrophil counts were positively associated with age (P < .0001). Hemoglobin was also positively associated with age up to 18 years (P < .0001), but the association was negative thereafter (P = .0079). Platelet counts and marrow cellularity were negatively associated with age (P < .0001). Marrow cellularity did not correlate with blood counts. Severe marrow failure necessitating transplant developed in 8 subjects at a median age of 1.7 years (range, 0.4-39.5), with 7 of 8 requiring transplant prior to age 8 years. Twenty-six subjects (17%) developed a myeloid malignancy (16 myelodysplasia and 10 acute myeloid leukemia) at a median age of 12.3 years (range, 0.5-45.0) and 28.4 years (range, 14.4-47.3), respectively. A lymphoid malignancy developed in 1 patient at the age of 16.9 years. Hematologic complications were the major cause of mortality (17/20 deaths; 85%). These data inform surveillance of hematologic complications in SDS.
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Enfermedades de la Médula Ósea , Insuficiencia Pancreática Exocrina , Enfermedades Hematológicas , Adolescente , Adulto , Enfermedades de la Médula Ósea/complicaciones , Enfermedades de la Médula Ósea/genética , Enfermedades de la Médula Ósea/patología , Niño , Preescolar , Estudios de Cohortes , Insuficiencia Pancreática Exocrina/complicaciones , Insuficiencia Pancreática Exocrina/genética , Enfermedades Hematológicas/complicaciones , Humanos , Lactante , Persona de Mediana Edad , Síndrome de Shwachman-Diamond , Adulto JovenRESUMEN
The timely identification of germline genetic causes of pediatric bone marrow failure (BMF) impacts medical screening practices, family counseling, therapeutic decision-making, and risk of progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). At diagnosis, treatment decisions need to be made quickly to mitigate risks associated with profound cytopenias. As genetic testing options are rapidly evolving, an efficient multi-disciplinary approach and algorithm, including early involvement of a genetics team, is needed to expedite diagnosis and therapeutic decision-making. This process aids in the identification of appropriate candidates for molecular genetic testing. We present our single center experience reviewing the implementation of genetic counseling and a diagnostic and therapeutic algorithm used to guide genetic evaluation of pediatric BMF. Disease-specific next-generation sequencing (NGS) panels were most often pursued in patients who presented with a clinical phenotype consistent with a known inherited BMF syndrome and when trying to reduce incidental or uninformative results. Broader BMF NGS panels were most often utilized when unable to narrow the suspected etiology to a single disorder. Whole exome sequencing helped with optimizing treatment decision-making in higher risk children with BMF who required expedited hematopoietic stem cell transplantation. The experience has led to improvements to our process for evaluating patients with BMF.
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Anemia Aplásica , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Anemia Aplásica/diagnóstico , Anemia Aplásica/genética , Anemia Aplásica/terapia , Trastornos de Fallo de la Médula Ósea , Niño , Asesoramiento Genético , Humanos , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapiaRESUMEN
The North American Pediatric Aplastic Anemia Consortium (NAPAAC) is a group of pediatric hematologist-oncologists, hematopathologists, and bone marrow transplant physicians from 46 institutions in North America with interest and expertise in aplastic anemia, inherited bone marrow failure syndromes, and myelodysplastic syndromes. The NAPAAC Bone Marrow Failure Diagnosis and Care Guidelines Working Group was established with the charge of harmonizing the approach to the diagnostic workup of aplastic anemia in an effort to standardize best practices in the field. This document outlines the rationale for initial evaluations in pediatric patients presenting with signs and symptoms concerning for severe aplastic anemia.
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Anemia Aplásica/diagnóstico , Anemia Aplásica/patología , Médula Ósea/patología , Niño , Diagnóstico Diferencial , Hemoglobina Fetal/análisis , Antígenos HLA/análisis , Humanos , América del Norte , Índice de Severidad de la EnfermedadRESUMEN
To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.
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Hematopoyesis Clonal/genética , Hematopoyesis Clonal/fisiología , Síndrome de Shwachman-Diamond/genética , Síndrome de Shwachman-Diamond/metabolismo , Adolescente , Adulto , Enfermedades de la Médula Ósea/genética , Enfermedades de la Médula Ósea/metabolismo , Niño , Preescolar , Factores Eucarióticos de Iniciación/genética , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación , Ribosomas/genética , Proteína p53 Supresora de Tumor/genética , Adulto JovenRESUMEN
OBJECTIVES: Hepatitis-associated aplastic anemia (HAAA) is a potentially life-threatening diagnosis without clear treatment guidelines. The goal of the study was to characterize the presentation, evaluation, histopathology, and outcomes of therapy in children with HAAA to guide future research and to develop standardized care guidelines for this rare disease. METHODS: Retrospective chart review of 4 patients with HAAA who presented to Children's Hospital Colorado between 2016 and 2019 was conducted. Patient presentation, evaluation, bone marrow and liver pathology, interventions, and clinical course were collected. Immunohistochemistry of liver biopsies was performed. RESULTS: We treated 4 patients with HAAA without liver failure. All had evidence of systemic hyperinflammation and CD8+ T cell predominant liver tissue infiltration. One had a genetic mutation predisposing him to immune-mediated disease, but all other genetic testing was negative. In 3 of the 4 patients, hepatitis was poorly responsive to standard therapy with steroids, azathioprine, or tacrolimus; however, sustained biochemical remission of hepatitis was induced after more aggressive immunosuppressive therapies including Anti-Thymocyte Globulin (ATG) at standard immunosuppressive therapy (IST) dosing for severe Aplastic Anemia (sAA). Two patients underwent hematopoietic stem cell transplant (HSCT); 1 as first line therapy and 1 for refractory sAA. CONCLUSIONS: We found that ATG-based IST induced remission of hepatitis in patients with steroid-refractory HAAA. This is also an appropriate initial treatment for severe Aplastic Anemia, though may not prevent the need for HSCT. We propose that equine ATG based IST at standard dosing regimen for sAA is a therapy that in select cases can be considered early on in the treatment course and could lead to a sustained remission of both hepatitis and sAA. This should be considered in collaboration with a pediatric hematologist.
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Anemia Aplásica , Hepatitis , Anemia Aplásica/complicaciones , Anemia Aplásica/terapia , Animales , Niño , Colorado , Hepatitis/complicaciones , Hepatitis/diagnóstico , Caballos , Humanos , Inmunosupresores/uso terapéutico , Masculino , Estudios Retrospectivos , Tacrolimus , Resultado del TratamientoRESUMEN
The field of vascular anomalies has grown tremendously in the last few decades with the identification of key molecular pathways and genetic mutations that drive the formation and progression of vascular anomalies. Understanding these pathways is critical for the classification of vascular anomalies, patient care, and development of novel therapeutics. The goal of this review is to provide a basic understanding of the classification of vascular anomalies and knowledge of their underlying molecular pathways. Here we provide an organizational framework for phenotype/genotype correlation and subsequent development of a diagnostic and treatment roadmap. With the increasing importance of genetics in the diagnosis and treatment of vascular anomalies, we highlight the importance of clinical geneticists as part of a comprehensive multidisciplinary vascular anomalies team.