RESUMEN
FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans. The functions of FRYL in mammals are largely unknown, and variants in FRYL have not previously been associated with a Mendelian disease. Here, we report fourteen individuals with heterozygous variants in FRYL who present with developmental delay, intellectual disability, dysmorphic features, and other congenital anomalies in multiple systems. The variants are confirmed de novo in all individuals except one. Human genetic data suggest that FRYL is intolerant to loss of function (LoF). We find that the fly FRYL ortholog, furry (fry), is expressed in multiple tissues, including the central nervous system where it is present in neurons but not in glia. Homozygous fry LoF mutation is lethal at various developmental stages, and loss of fry in mutant clones causes defects in wings and compound eyes. We next modeled four out of the five missense variants found in affected individuals using fry knockin alleles. One variant behaves as a severe LoF variant, whereas two others behave as partial LoF variants. One variant does not cause any observable defect in flies, and the corresponding human variant is not confirmed to be de novo, suggesting that this is a variant of uncertain significance. In summary, our findings support that fry is required for proper development in flies and that the LoF variants in FRYL cause a dominant disorder with developmental and neurological symptoms due to haploinsufficiency.
Asunto(s)
Discapacidad Intelectual , Anomalías Musculoesqueléticas , Animales , Niño , Humanos , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/diagnóstico , Discapacidad Intelectual/genética , Mamíferos , Anomalías Musculoesqueléticas/genética , Mutación Missense , Factores de Transcripción/genética , DrosophilaRESUMEN
The mRNA COVID-19 vaccine and COVID-19 infection caused by the SARS-CoV-2 virus may be immunologic triggers for the development of thrombotic thrombocytopenic purpura (TTP). There is not yet literature that discusses TTP induced by COVID-19 vaccination or infection in pediatric or adolescent patients. We describe three adolescents presenting with TTP (both de novo and relapsed disease) following administration of the Pfizer COVID-19 vaccine or after COVID-19 infection. Our observations demonstrate that the Pfizer-BioNTech mRNA vaccine and COVID-19 infection can act as triggers for the development/relapse of both congenital and acquired TTP.
Asunto(s)
COVID-19 , Púrpura Trombocitopénica Trombótica , Adolescente , Vacuna BNT162 , COVID-19/complicaciones , Vacunas contra la COVID-19/efectos adversos , Niño , Humanos , Púrpura Trombocitopénica Trombótica/genética , ARN Mensajero/genética , SARS-CoV-2 , Vacunas Sintéticas , Vacunas de ARNmRESUMEN
Evans syndrome is a rare but challenging disorder in children; and despite rapidly growing evidence for targetable systemic immune dysregulation driving these "idiopathic" autoimmune cytopenias, precision diagnosis and management remains sub-optimal among these patients. We analyzed retrospective clinical data for 60 pediatric ES patients followed at 3 large tertiary referral centers in the United States over a recent 6-year period and found that definable underlying systemic immune dysregulation was identified in only 42% of these patients throughout the course of clinical care. Median time from ES diagnosis to identification of the underlying systemic immune dysregulation disorder was 1.3 years (<1 month for rheumatologic disease, 2.3 years for CVID, 3.4 years for ALPS, and 7.4 years for monogenic disorders of immune regulation). Notably, a significantly higher percentage of patients in whom a definitive immune dysregulation disorder was ultimately identified required ≥3 cytopenia-directed therapies (92%) and also second- and third-line immunomodulatory agents (84%), vs those in whom no unifying immune dysregulation was diagnosed (65%, and 35%, respectively)-indicating that autoimmune cytopenias as a manifestation of systemic immune dysregulation are more treatment-refractory and severe. These data underline the importance of identifying the underlying systemic immune dysregulation and providing targeted therapy in pediatric ES.
Asunto(s)
Anemia Hemolítica Autoinmune , Enfermedades Autoinmunes , Trombocitopenia , Adolescente , Adulto , Anemia Hemolítica Autoinmune/diagnóstico , Anemia Hemolítica Autoinmune/inmunología , Anemia Hemolítica Autoinmune/terapia , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Estudios Retrospectivos , Trombocitopenia/diagnóstico , Trombocitopenia/inmunología , Trombocitopenia/terapiaRESUMEN
A transient pancytopenic phase has been described in pediatric leukemia. The characteristic complete recovery of peripheral counts can obscure a clinician's suspicion for malignancy and may impact subsequent follow-up care. The authors describe 4 pediatric patients that had transient pancytopenia with an initial abnormal marrow finding. These patients were subsequently diagnosed with acute leukemia within 5 months of presentation. Awareness of this phenomenon by the provider and education of families may help with the appropriate and timely diagnosis of subsequent leukemia.
Asunto(s)
Leucemia Mieloide Aguda/diagnóstico , Pancitopenia/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Niño , Preescolar , Femenino , Humanos , Leucemia Mieloide Aguda/complicaciones , Masculino , Pancitopenia/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicacionesRESUMEN
BACKGROUND: Autoimmune neutropenia (AIN) is a common cause of chronic neutropenia in childhood. Despite an expected benign clinical course, many patients undergo extensive evaluation. Data on healthcare utilization and rates of bloodstream infections in young patients with AIN are limited. METHODS: All patients with a diagnosis code of leukopenia, neutropenia, or AIN followed within the outpatient hematology clinic of a single institution from 2014 to 2016 were identified. Patients aged ≤5 years with absolute neutrophil count (ANC) ≤500/µL persisting for ≥3 months, a clinical diagnosis of AIN, and documented resolution of neutropenia were included. Data on clinical management, including infectious outcomes and emergency center (EC) encounters, were collected. RESULTS: Forty-three patients with AIN (18 male [42%], median age at diagnosis 12 months) met eligibility criteria. Children were followed by hematology for a median duration of 18 (range, 2-85) months. Diagnostic evaluations were variable. Thirty patients (70%) had ≥ 1 EC encounters for evaluation of isolated fever with a total of 113 EC encounters for the overall cohort. Patients with ANC < 500/µL and isolated fever were admitted for observation, which resulted in 24 hospitalizations in 16 patients. Of 138 blood cultures drawn, two were positive, both later determined to be contaminants. CONCLUSION: At a large tertiary care center, no bloodstream infections were identified in a cohort of 43 children with AIN presenting to the EC for assessment of fever. A less-intensive, more cost-effective management paradigm, which continues to prioritize patient safety, among young children with AIN is needed.
Asunto(s)
Enfermedades Autoinmunes/complicaciones , Bacteriemia/prevención & control , Infecciones/diagnóstico , Neutropenia/complicaciones , Aceptación de la Atención de Salud/estadística & datos numéricos , Bacteriemia/diagnóstico , Bacteriemia/etiología , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Infecciones/economía , Infecciones/etiología , Masculino , Pronóstico , Estudios RetrospectivosAsunto(s)
Anemia Ferropénica/tratamiento farmacológico , Compuestos Férricos/efectos adversos , Hipofosfatemia/inducido químicamente , Maltosa/análogos & derivados , Fósforo/sangre , Adolescente , Factores de Edad , Anemia Ferropénica/sangre , Niño , Preescolar , Femenino , Compuestos Férricos/administración & dosificación , Humanos , Hipofosfatemia/epidemiología , Lactante , Infusiones Intravenosas , Masculino , Maltosa/administración & dosificación , Maltosa/efectos adversos , Estudios Retrospectivos , Adulto JovenRESUMEN
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.
RESUMEN
Newborn screening (NBS) provides early diagnosis of sickle hemoglobinopathies. After Hb S [ß6(A3)GluâVal, GAG>GTG], Hb C [ß6(A3)GluâLys, GAG>AAG] is the most common hemoglobin (Hb) abnormality identified in the United States (1,2). Published data regarding children with Hb C disease are limited. This study was conducted to summarize a single institution's clinical and laboratory data for patients with Hb C disease, specifically homozygous Hb CC and its variants over a 10-year period. Forty-seven patients, whose mean age at diagnosis was 2.9 years (range 0.04 to 23 years), were identified. Twenty-nine had Hb CC and the remainder had compound heterozygous variants [10 Hb C/ß(+)-thalassemia (ß(+)-thal), four Hb C/ß(0)-thal, and one each with Hb C/Hb Hope or ß136(H14)GlyâAsp (GGT>GAT), Hb C/Hb Lepore (a hybrid δß-globin gene), Hb C/HPFH (hereditary persistence of fetal Hb) [probably a (G)γ HPFH-2 (the Ghanaian type)], and Hb C/Osu-Christiansborg or ß52(D3)AspâAsn (GAT>AAT)]. All patients had mild microcytic anemia with reticulocytosis and frequent target cells on peripheral smear. Splenomegaly or cholelithiasis occurred in 2.6% of patients <8 years of age, however, these symptoms were more common (71.0%) in patients >8 years of age. No patient had serious infections or painful events resembling vasoocclusion. Accurate diagnosis and understanding of Hb C-related disorders helped to avoid confusion with sickle hemoglobinopathies and aided in proper clinical management.
Asunto(s)
Hemoglobina C/genética , Hemoglobinopatías/genética , Hemoglobinopatías/patología , Adolescente , Niño , Preescolar , Índices de Eritrocitos , Eritrocitos/metabolismo , Eritrocitos/patología , Femenino , Hemoglobinas Anormales/genética , Heterocigoto , Homocigoto , Humanos , Lactante , Masculino , Mutación Puntual , Adulto Joven , Talasemia beta/genética , Talasemia beta/patologíaRESUMEN
Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially life-threatening hematologic disease, presenting a myriad of diagnostic and management challenges in children. Here, we provide a review of this disorder and discuss 2 exemplary cases of TTP occurring in adolescents, emphasizing the need for consideration of late-onset congenital TTP (cTTP). We demonstrate the importance of early confirmation of ADAMTS13 enzyme deficiency and the presence or absence of ADAMTS13 inhibitor in order to rapidly initiate the appropriate life-saving therapies. Ultimately, molecular testing is paramount to distinguishing between congenital and acquired immune-mediated TTP.
Asunto(s)
Púrpura Trombocitopénica Trombótica , Adolescente , Niño , Humanos , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/genética , Púrpura Trombocitopénica Trombótica/terapiaRESUMEN
OBJECTIVE: To investigate the relation between arterial resistance and placental growth hormone (hGH-V) levels in the maternal circulation. STUDY DESIGN: Sixty-seven women with normal pregnancy, 13 with preeclampsia (PE) and 11 with intrauterine fetal growth restriction (IUGR) underwent Doppler sonography of the placental and nonplacental uterine and cubital artery and blood sampling. hGH-V was measured with a highly sensitive sandwich-type immunofluorometric assay and pituitary growth hormone (hGH-N) and insulinlike growth factor I (IGF-I) with a chemiluminescence assay. A p value of < 0.05 was considered significant. RESULTS: During normal pregnancy the arterial pulsatility index (PI) decreased (p < 0.001), serum levels of hGH-V and IGF-I increased (p < 0.0001), and hGH-N decreased (p < 0.0001). Pathologic pregnancies (PE, IUGR) showed a significant higher PI in all arteries, but hGH-V and the IGF-I were decreased. CONCLUSION: Our data demonstrate a strong correlation between decreasing uterine and peripheral arterial resistance and increasing hGH-V during normal pregnancies with impaired uterine blood flow there were lowered serum levels of hGH-V, hGH-N and IGF-I. Lower levels of hGH-V and hGH-N might contribute to impaired uteroplacental circulation.
Asunto(s)
Retardo del Crecimiento Fetal/sangre , Hormona del Crecimiento/fisiología , Placenta/irrigación sanguínea , Hormonas Placentarias/fisiología , Preeclampsia/sangre , Embarazo/sangre , Útero/irrigación sanguínea , Resistencia Vascular , Adulto , Arterias , Estudios de Casos y Controles , Femenino , Retardo del Crecimiento Fetal/fisiopatología , Hormona del Crecimiento/sangre , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Circulación Placentaria , Preeclampsia/fisiopatología , Flujo Sanguíneo Regional , Ultrasonografía Doppler de Pulso/métodosRESUMEN
Gestational primary hyperparathyroidism (GPHPT) is a rare condition with fewer than 200 cases reported. We present the case of a 21-year-old woman who presented at 10 weeks' gestation with severe hypercalcemia. Laboratory investigation was consistent with primary hyperparathyroidism. Neck ultrasound did not reveal any parathyroid enlargement. Due to the persistence of severe hypercalcemia, she was treated with 4 weeks of cinacalcet therapy, which was poorly tolerated due to nausea and vomiting. At 14 weeks' gestation, she underwent neck exploration with right lower, left upper, and partial right upper parathyroid gland excision. Intra- and postoperative parathyroid hormone (PTH) and calcium levels remained elevated. After a thorough discussion of risks/benefits, the patient requested further treatment. A parathyroid sestamibi scan (PSS) revealed an ectopic adenoma in the left mediastinum. The adenoma was removed via video-assisted thorascopic parathyroidectomy with intraoperative PTH declining to nearly undetectable levels. She ultimately delivered a physically and developmentally normal infant at 37 weeks' gestation. Appropriate treatment of severe GPHPT may prevent the maternal and fetal complications of hypercalcemia. This case, in which cinacalcet therapy and PSS were used, adds to the body of literature regarding treatment of severe GPHPT.
RESUMEN
This study aimed to determine whether absolute sex hormone concentrations predict the magnitude of knee joint laxity changes across the menstrual cycle. Twenty-two females (18-30 years, body mass index Asunto(s)
Estradiol/sangre
, Inestabilidad de la Articulación/diagnóstico
, Articulación de la Rodilla/fisiología
, Ciclo Menstrual/fisiología
, Progesterona/sangre
, Testosterona/sangre
, Adolescente
, Adulto
, Femenino
, Predicción
, Humanos
, Ciclo Menstrual/sangre
, Rango del Movimiento Articular/fisiología
RESUMEN
INTRODUCTION: In adolescent thromboembolism (TE), multiple risk factors (RFs) and co-morbidities (CMs) are reported, though overall prevalence has not been evaluated. We hypothesized that the spectrum of RFs/CMs in adolescent TE differs from children overall and sought to review Texas Children's Hospital's experience. PATIENTS/METHODS: Medical records of adolescents aged 12-21years, diagnosed with arterial or venous TE (AT/DVT) from 2004 to 2014, were retrospectively reviewed and analyzed with IRB approval. RESULTS: Sixty-four adolescents (median age 16, range 12-20years) met study criteria. Fifty-seven (89%) had DVT and six (9%) had AT. Associated RFs/CMs included obesity (47%), CVC (27%), infection (27%), surgery (27%), autoimmune disease (19%), immobility (22%), anatomical abnormality (20%), cancer (8%), estrogen therapy (6%), tobacco use (6%), trauma (3%), inherited thrombophilia (19%), and other medical conditions (11%). Fifty-two (81%) had ≥2 RFs/CMs. Therapy included anticoagulants, antiplatelet agents, and interventional therapy. Of those with follow-up imaging, 49 had complete or partial resolution, 5 had no change and 4 had progression. Fourteen (22%) had recurrent TE. The majority with recurrent TE (79%) had ≥2 RFs at initial diagnosis. Mean time to recurrence was 4.80years; time to recurrence was shorter for occlusive TE (p=0.026). CONCLUSION: Adolescent TE is often multi-factorial with the majority having ≥2 RFs at diagnosis, suggesting the need for detailed evaluation for RFs in this population, which may enable optimal management including thromboprophylaxis, and institution of RF-modifying strategies to prevent occurrence/recurrence.
Asunto(s)
Tromboembolia/epidemiología , Adolescente , Adulto , Factores de Edad , Anticoagulantes/uso terapéutico , Niño , Comorbilidad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Estudios Retrospectivos , Factores de Riesgo , Tromboembolia/diagnóstico , Tromboembolia/tratamiento farmacológico , Adulto JovenRESUMEN
Human placental GH (hGH-V) is a variant of pituitary hGH (hGH-N) synthesized and secreted by syncytiotrophoblasts during pregnancy. It differs from hGH-V by only 13 amino acid residues, which makes difficult a specific measurement of hGH-V without interference from hGH-N. To overcome the analytical difficulties, we produced new high affinity monoclonal antibodies specific for hGH-V. Precise screening and epitope mapping allowed identification of a pair of monoclonal antibodies suitable to establish a highly sensitive assay for hGH-V measurement. In a prospective, longitudinal study involving 84 normal pregnancies, we measured maternal concentrations of hGH-V, leptin, IGF-I, and cord blood IGF-I. hGH-V was detectable as early as gestational week (GW) 7. Mean concentrations of hGH-V increased from 0.9 +/- 0.5 microg/liter (GW 7-13) to 2.8 +/- 0.9 microg/liter (GW 18-22), 7.3 +/- 2.6 microg/liter (GW 28-32), and 13.0 +/- 9.6 (GW 37-41). A negative correlation was found between prepregnancy body mass index and hGH-V concentrations from GW 28 onward. Peak hGH-V levels occurred at wk 36.5 +/- 2.6 and were significantly lower in obese (P = 0.029) and higher in underweight (P = 0.035) mothers compared with those in mothers of normal weight. The increase in hGH-V between GW 18-22 and GW 28-32 was negatively correlated to the increase in maternal leptin during this period (P = 0.027). Maternal IGF-I concentrations were correlated to those of hGH-V from GW 18 onward (P = 0.039). The strongest correlation was found at GW 28-32 (P = 0.001). Furthermore, maternal hGH-V concentrations in late pregnancy correlated with cord blood IGF-I (P = 0.025) and size of the newborn (P = 0.017). These results, obtained by a new, highly sensitive hGH-V-specific immunoassay, highlight the importance of maternal hGH-V in the regulation of maternal and fetal IGF-I. In addition, the results indicate that maternal weight has a major impact on circulating concentrations of hGH-V.