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1.
Am J Hum Genet ; 108(10): 1964-1980, 2021 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-34547244

RESUMEN

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.


Asunto(s)
Proteasas ATP-Dependientes/genética , Proteasas ATP-Dependientes/fisiología , Anomalías Craneofaciales/genética , Variaciones en el Número de Copia de ADN , Anomalías del Ojo/genética , Trastornos del Crecimiento/genética , Hernias Diafragmáticas Congénitas/genética , Luxación Congénita de la Cadera/genética , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/fisiología , Mutación Missense , Osteocondrodisplasias/genética , Anomalías Dentarias/genética , Animales , Estudios de Casos y Controles , Estudios de Cohortes , Anomalías Craneofaciales/patología , Anomalías del Ojo/patología , Femenino , Trastornos del Crecimiento/patología , Hernias Diafragmáticas Congénitas/patología , Luxación Congénita de la Cadera/patología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Osteocondrodisplasias/patología , Linaje , Anomalías Dentarias/patología
2.
J Pediatr Hematol Oncol ; 44(3): e770-e774, 2022 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-34862354

RESUMEN

A 6-year-old female presenting with an abdominal mass was found to have an unresectable undifferentiated sarcoma. The tumor did not respond to multiagent chemotherapy. However, molecular testing identified an NTRK3-fusion, and treatment was changed to larotrectinib monotherapy. Following 6 months of therapy, the patient achieved a very good partial response with 96% reduction in tumor size. She underwent proton beam radiation therapy with continued larotrectinib therapy and achieved a complete response. This case report shows that an NTRK fusion positive undifferentiated sarcoma can be safely treated with larotrectinib and radiation therapy and highlights the importance of early molecular testing.


Asunto(s)
Neuroblastoma , Sarcoma , Neoplasias de los Tejidos Blandos , Niño , Femenino , Humanos , Neuroblastoma/tratamiento farmacológico , Proteínas de Fusión Oncogénica/genética , Protones , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Sarcoma/tratamiento farmacológico , Sarcoma/genética , Sarcoma/radioterapia , Neoplasias de los Tejidos Blandos/patología
3.
Pediatr Radiol ; 40(2): 200-5, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20020117

RESUMEN

Since the World Health Organization declared a global pandemic of novel influenza A H1N1 in June 2009, there has been a sustained rise in the number of cases of this strain of influenza. Although most cases are mild with complete and uneventful recovery, multiple cases of severe infection with complications including death have been reported. To the best of our knowledge, the majority of fatal outcomes in the United States have been related to pulmonary complications. We report a 12-year-old girl infected with influenza A H1N1 whose clinical course was complicated by rapid progressive neurologic deterioration and striking CT and MRI findings consistent with acute necrotizing encephalopathy (ANE). To our knowledge this has not been reported in the pediatric radiology literature. We hope this case will alert radiologists to this complication and familiarize radiologists with imaging findings that herald ANE.


Asunto(s)
Encefalitis Viral/complicaciones , Encefalitis Viral/diagnóstico , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana/complicaciones , Gripe Humana/diagnóstico , Leucoencefalitis Hemorrágica Aguda/complicaciones , Leucoencefalitis Hemorrágica Aguda/diagnóstico , Encéfalo/patología , Niño , Femenino , Humanos , Imagen por Resonancia Magnética
5.
Pediatr Cardiol ; 30(3): 389-90, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19225826

RESUMEN

We present three-dimensional reconstructed images of the vascular ring of a 4-day-old extremely premature neonate which were obtained utilizing multidetector computer tomography. This is a unique case of early detection of Kommerell's diverticulum and vascular ring in an extremely low-birth-weight infant using this noninvasive technology.


Asunto(s)
Anomalías Múltiples , Aorta Torácica/anomalías , Conducto Arterioso Permeable/diagnóstico por imagen , Recién Nacido de muy Bajo Peso , Arteria Subclavia/anomalías , Malformaciones Vasculares/diagnóstico por imagen , Angiografía , Aorta Torácica/diagnóstico por imagen , Aorta Torácica/cirugía , Procedimientos Quirúrgicos Cardíacos/métodos , Diagnóstico Diferencial , Conducto Arterioso Permeable/cirugía , Humanos , Recién Nacido , Arteria Subclavia/diagnóstico por imagen , Tomografía Computarizada por Rayos X
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