RESUMO
Rabson-Mendenhall syndrome (RMS) is a rare autosomal recessive disorder characterized by severe insulin resistance, resulting in early-onset diabetes mellitus. We report the first case of RMS in a Paraguayan patient. The patient is a 6-year-old girl who presented with hypertrichosis, acanthosis nigricans, nephrocalcinosis, and elevated levels of glucose and insulin that served as diagnostic indicators for RMS. Genetic testing by next-generation sequencing (NGS) revealed two pathogenic variants in exons 2 and 19 of the INSR gene: c.332G>T (p.Gly111Val) and c.3485C>T (p.Ala1162Val), in combined heterozygosis. The novel INSR c. 332G>T variant leads to the substitution of glycine to valine at position 111 in the protein, and multiple in silico software programs predicted it as pathogenic. The c.3485C>T variant leads to the substitution of alanine to valine at position 1162 in the protein previously described for insulin resistance and RMS. The management of RMS is particularly challenging in children, and the use of metformin is often limited by its side effects. The patient was managed with nutritional measures due to the early age of onset. This report expands the knowledge of RMS to the Paraguayan population and adds a novel pathogenic variant to the existing literature.
Assuntos
Síndrome de Donohue , Resistência à Insulina , Criança , Feminino , Humanos , Síndrome de Donohue/diagnóstico , Resistência à Insulina/genética , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Mutação , Valina/genética , Antígenos CD/genéticaRESUMO
OBJECTIVE: Pituitary adenomas (PA) are rare in young patients, and additional studies are needed to fully understand their pathogenesis in this population. We describe the clinical and genetic characteristics of apparently sporadic PA in a cohort of young patients. DESIGN: Clinical and molecular analysis of 235 patients (age ≤ 30 years) with PA. Clinicians from several Spanish and Chilean hospitals provided data. METHODS: Genetic screening was performed via next-generation sequencing and comparative genomic hybridization array. Clinical variables were compared among paediatric, adolescent (<19 years) and young adults' (≥19-30 years) cohorts and types of adenomas. Phenotype-genotype associations were examined. RESULTS: Among the total cohort, mean age was 17.3 years. Local mass effect symptoms were present in 22.0%, and prolactinomas were the most frequent (44.7%). Disease-causing germline variants were identified in 22 individuals (9.3%), more exactly in 13.1 and 4.7% of the populations aged between 0-19 and 19-30 years, respectively; genetically positive patients were younger at diagnosis and had larger tumour size. Healthy family carriers were also identified. CONCLUSIONS: Variants in genes associated with syndromic forms of PAs were detected in a large cohort of apparently sporadic pituitary tumours. We have identified novel variants in well-known genes and set the possibility of incomplete disease penetrance in carriers of MEN1 alterations or a limited clinical expression of the syndrome. Despite the low penetrance observed, screening of AIP and MEN1 variants in young patients and relatives is of clinical value.