CEDIE   05498
CENTRO DE INVESTIGACIONES ENDOCRINOLOGICAS "DR. CESAR BERGADA"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Identification of a Novel Insulin Receptor Gene Mutation in Patient with Type A Insulin Resistance Syndrome
Autor/es:
GRYNGARTEN M; GUTIÉRREZ M; NATALE MI; ROPELATO MG; SCAGLIA P; SUAREZ L; FREIRE A; VALINOTTO LE; ARCARI A; REY R; BALLERINI MG; BERGADA I
Lugar:
Washington
Reunión:
Congreso; 10th International Meeting of Pediatric Endocrinology; 2017
Institución organizadora:
The global community of pediatric endocrinology
Resumen:
Objectives: INTRODUCTION: Hyperandrogenism, acanthosis nigricans (AN) and severe insulin resistance in the absence of obesity clinically define Type A IR syndrome. Most cases of this syndrome are due to mutations in the insulin receptor gene (INSR) or its signaling pathway.Methods: CASE REPORT: A 14 year-old girl presented with hirsutism, AN and absence of menarche. The physical exam revealed normal height (50th centile), BMI 14.3 kg/m2 (-1.3 SD), F&G score 32 and clitoral hypertrophy, biochemical hyperandrogenism (Testosterone 128 ng/dL, RV:10-50; Androstenodione: 995 ng/dL, RV: 80-280). OGTT showed fasting glucose level of 73 mg/dL and 136 mg/dL at 120 min, with severe hyperinsulinemia (47.7 and 600 μUI/mL, respectively). Pelvic ultrasound showed enlarged, polycystic ovariesResults: Exome analysis was performed using the Illumina TrueSight One assay in a NextSeq500 system. NGS results were analyzed taking into account mutation impact (high or moderate), population frequency (INSR: NM_000208.3 (INSR): c.3449T>C (p.Leu1150Pro). Sanger sequencing confirmed the finding in the patient and revealed that her mother was heterozygous for the same variant. According to ACMG guidelines, this variant, which is located in the tyrosine kinase domain, is classified as likely pathogenic. Variant p.Leu1150Pro was not reported in publicly available 1000G, ExAC, EVS and NCBI dbSNP databases and was predicted to be pathogenic by 5 in silico bioinformatics tools. Based upon these findings, the variant p.Leu1150Pro could be responsible for the patient´s phenotype. Therefore, treatment with metformin at 1700 mg/day was initiated.Conclusions: By using a NGS approach, we identified a novel heterozygous mutation in the Insulin Receptor gene in an adolescent with Type A insulin resistant syndrome. It was an objective way of confirming the genetic diagnosis, thus orientating a targeted treatment and taking proactive actions related to the disease clinical course. Moreover, extending genetic diagnosis to other family members might explain the phenotypic variability.