A Case Report: Treatment, follow-up, and literature review of type A insulin resistance syndrome caused by a De Novo INSR c.3328G>C mutation.

BACKGROUND: Type A insulin resistance syndrome (TAIRS) is a rare inherited disorder caused by mutations in the insulin receptor (INSR) gene. It is characterized by severe insulin resistance, hyperandrogenism, and acanthosis nigricans. Its clinical manifestations overlap with those of polycystic ovary syndrome (PCOS), making it prone to misdiagnosis, particularly in adolescent females. Currently, the diagnosis of TAIRS relies on clinical evaluation and genetic confirmation, while long-term management strategies remain limited and challenging.

CASE PRESENTATION: We report a 12-year-old female proband who presented with severe hyperinsulinemia, hyperandrogenism (hirsutism), acanthosis nigricans, and polycystic ovarian changes despite a non-obese phenotype. Whole-exome sequencing identified a de novo heterozygous variant in the INSR gene (NM_000208.4:c.3328G>C, p.Asp1110His). This variant was absent from the ClinVar and gnomAD databases and was predicted to be deleterious by in silico analyses. Family segregation analysis demonstrated that neither parent nor the proband's brother carried the variant, consistent with a de novo event. According to ACMG guidelines, this variant was classified as "likely pathogenic," providing a molecular basis for the diagnosis of TAIRS.

CONCLUSIONS: This case is attributed to a de novo p.Asp1110His variant in INSR. The diagnostic process highlights the importance of genetic testing in adolescents presenting with atypical PCOS features, particularly severe hyperinsulinemia and non-obesity. This report expands the known pathogenic variant spectrum of the INSR gene and reviews TAIRS cases reported since 2010. It further emphasizes that long-term management of TAIRS requires individualized, multidisciplinary strategies, including pharmacological and medical nutrition therapy in addition to lifestyle interventions. Type A insulin resistance syndrome (TAIRS) is a rare genetic disorder resulting from mutations in the insulin receptor (INSR) gene and may be inherited in either an autosomal dominant or autosomal recessive manner. The disorder is primarily characterized by severe insulin resistance, accompanied by clinical features such as hyperandrogenism, hirsutism, and acanthosis nigricans. In female patients, polycystic ovary syndrome (PCOS) is a common associated condition. Early diagnosis and intervention are crucial, as they can delay the onset of precocious puberty and reduce the risk of metabolic and endocrine complications, as well as related neoplasms. This article reports a TAIRS proband carrying a novel mutation, with the aim of providing a reference for the clinical diagnosis and management of this rare condition.