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Abstract
Introducción: El retraso del neurodesarrollo es relativamente frecuente en niños. Las causas genéticas contribuyen de manera significativa a esta enfermedad, pudiendo ser solo una de las manifestaciones que conforman un síndrome genético, por lo que debe estudiarse mediante pruebas genéticas. El síndrome de Sotos es un trastorno genético poco frecuente caracterizado por discapacidad intelectual, sobrecrecimiento y apariencia facial típica que debe considerarse como una posibilidad diagnóstica.
Objetivo: Describir el caso de un paciente pediátrico con retraso del neurodesarrollo, déficit cognitivo, deterioro conductual, epilepsia, hipotiroidismo, sobrecrecimiento y hallazgos dismórficos, sin antecedentes familiares relacionados, con sospecha de un síndrome genético, a quien se realizó array CGH.
Métodos y resultados: Se realizó un aCGH de 180.000 sondas (180K). Se realizó la hibridación mediante el array Agilent® 4x180K SurePrint G3 Human ICGH. Se realizó el escaneo de los datos mediante SureScan®. La toma de datos, el análisis de calidad y el análisis de los resultados se llevaron a cabo con el software Agilent CytoGenomics v5®.
Se detectó una deleción subtelomérica heterocigótica patogénica en la región cromosómica 5q35.2q35.3 con coordenadas genómicas chr5:176517339_179570928. Esta representa una CNV de 3,05 Mb, que involucra 49 genes codificadores de proteínas, 12 de ellos, patogénicos. El Síndrome de Sotos corresponde a una variante en el gen NSD1, localizado en el cromosoma 5q35.2-q35.3.
Conclusiones: El retraso del desarrollo es una condición frecuente en niños, con heterogeneidad clínica y genética, permitiendo sospechar un síndrome genético asociado. El síndrome de Sotos es un trastorno genético poco frecuente caracterizado por sobrecrecimiento, rasgos dismorfológicos y discapacidad intelectual. El Array CGH es la prueba genética que ha demostrado superioridad, con una mayor tasa de diagnóstico y detección de variantes en pacientes con diferentes fenotipos asociados a retraso del neurodesarrollo, permitiéndonos tener un diagnóstico específico para establecer terapéuticas personalizadas, acercándonos a la medicina de precisión.
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References
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References
. C. Cokyaman, M. Erdogan, M. K. Ceylan, and A. Yildiz, “Diagnostic utility of array comparative genomic hybridization in children with neurological diseases,” Fetal Pediatr. Pathol., vol. 41, no. 1, pp. 68–76, 2022, doi: 10.1080/15513815.2020.1764683.
. G. Conteduca et al., “Identification of alternative transcripts of NSD1 gene in Sotos Syndrome patients and healthy subjects,” Gene, vol. 851, p. 146970, 2023, doi: 10.1016/j.gene.2022.146970.
. N. Gupta, “Deciphering intellectual disability,” Indian J. Pediatr., vol. 90, no. 2, pp. 160–167, 2023.
. T. Hiraide et al., “Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing,” Clin. Genet., vol. 100, no. 1, pp. 40–50, 2021, doi: 10.1111/cge.13951.
. K. Hung et al., “Genetic diagnosis in children with developmental delay,” Children, vol. 11, no. 6, p. 669, 2024, doi: 10.3390/children11060669.
. M. Juneja et al., “Diagnosis and management of global development delay: Consensus guidelines of growth, development and behavioral pediatrics chapter, neurology chapter and neurodevelopment pediatrics chapter of the Indian Academy of Pediatrics,” Indian Pediatr., vol. 401, 2022.
. S. Karim et al., “Identification of extremely rare pathogenic CNVs by array CGH in Saudi children with developmental delay, congenital malformations, and intellectual disability,” Children, vol. 10, no. 4, p. 40662, 2023, doi: 10.3390/children10040662.
. C. Lee et al., “Array-CGH increased the diagnostic rate of developmental delay or intellectual disability in Taiwan,” Pediatr. Neonatol., vol. 60, no. 4, pp. 453–460, 2019, doi: 10.1016/j.pedneo.2018.11.006.
. S. Lesinskiene et al., “Neuropsychiatric aspects of Sotos Syndrome: Explorative review building multidisciplinary bridges in clinical practice,” J. Clin. Med., vol. 13, no. 8, 2024, doi: 10.3390/jcm13082204.
. V. Lourdes et al., “Beyond the known phenotype of Sotos Syndrome: A 31-individual cohort study,” Front. Pediatr., vol. 11, 2023, doi: 10.3389/fped.2023.1184529.
. E. Lundberg et al., “Hyperinsulinemia in Sotos Syndrome with a de novo NSD1 deletion,” J. Clin. Res. Pediatr. Endocrinol., 2024, doi: 10.4274/jcrpe.galenos.2024.2023-5-15.
. K. Manickam et al., “Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: An evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG),” Genet. Med., vol. 23, no. 11, pp. 2029–2037, 2021, doi: 10.1038/s41436-021-01242-6.
. A. Masri, “Global developmental delay and intellectual disability in the era of genomics: Diagnosis and challenges in resource-limited areas,” Clin. Neurol. Neurosurg., 2023.
. R. Mishra, “Genetic counseling for global developmental delay/intellectual disability (GDD/ID) - Changing landscapes and persisting challenges,” Indian Pediatr., vol. 60, no. 1, pp. 142–145, 2023.
. N. Nouri, “Clinical and genetic profile of children with unexplained intellectual disability/developmental delay and epilepsy,” Epilepsy Res., vol. 177, p. 106782, 2021, doi: 10.1016/j.eplepsyres.2021.106782.
. M. Pinheiro et al., “Array-CGH: Importance in the study of developmental delays in pediatrics,” Rev. Neurol., vol. 71, no. 5, pp. 171–176, 2020.
. Z. Ren et al., “Identification of novel NSD1 variations in four pediatric cases with Sotos Syndrome,” BMC Med. Genomics, vol. 17, no. 1, 2024, doi: 10.1186/s12920-024-01889-5.
. A. Sharma et al., “The etiological profile of global developmental delay at a tertiary care hospital in India: An observational study,” Cureus, 2023, doi: 10.7759/cureus.41066.
. M. Siracusano et al., “Cognitive, adaptive and behavioral profile in Sotos Syndrome children with 5q35 microdeletion or intragenic variants,” Am. J. Med. Genet. A, vol. 191, no. 7, pp. 1836–1848, 2023.
. B. Testa et al., “Molecular analysis and reclassification of NSD1 gene variants in a cohort of patients with clinical suspicion of Sotos Syndrome,” Genes, vol. 14, no. 2, 2023, doi: 10.3390/genes14020295.
. UCSC Genome Browser on Human (GRCh38/hg38), "HgTracks: Human Genome GRCh38/hg38," [Online]. Available: https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38. [Accessed: Oct. 2023].
. A. Verma et al., “Sotos Syndrome with a novel mutation in the NSD1 gene associated with congenital hypothyroidism,” Int. J. Pediatr. Adolesc. Med., vol. 8, no. 3, pp. 191–194, 2021, doi: 10.1016/j.ijpam.2020.06.001.