Desafio no diagnóstico genético de paciente com Nefrocalcinose, Hiperparatireoidismo e Amelogenesis imperfecta

• Ano de defesa: 2019
• Autor(a) principal: Radonsky, Vanessa [UNIFESP]
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Hyperparathyroidism; Nephrocalcinosis; Nefrocalcinose; Hiperparatireoidismo; Amelogenesis Imperfecta
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=7895741; https://repositorio.unifesp.br/handle/11600/59396

This paper describes the challenges of genetic diagnosis of a 6-year-old boy referred to the outpatient clinic of endocrinology for hyperparathyroidism associated with nephrocalcinosis. He had a history of recurrent urinary infections, polydipsia and polyuria, and serum laboratory tests showed normal calcium and phosphorus concentrations, high PTH and discreetly reduced magnesium, and an increase in urinary calcium. Nephrocalcinosis was seen on computed tomography of the kidney. In order to optimize the etiological diagnosis considering several candidate genes, we chose the use of the complete exome sequencing technique (WES), which identified 105,390 variants between mutations and polymorphisms, which did not justify the phenotype. The main diagnostic hypothesis would be a mutation in the CLDN16 gene, responsible for Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHNNC), initially not identified by the WES. However, when the BAM (binary alignment) file was evaluated to verify the reading coverage, we observed the absence of exons 2 to 5 of the CLDN16 gene, and the hypothesis of large gene deletion was confirmed by the PCR and MLPA techniques. This paper will present a review of the literature on the subject, in addition to describing FHHNC in more detail. FHHNC is caused by the mutation of genes encoding the Claudine 16 or Claudine 19 proteins, which are para-cellular adhesion proteins located in the ascending portion of the Henle loop. These molecules undergo heterodimerization, forming a para-cellular barrier that regulates the absorption of calcium and magnesium. In addition to hypomagnesemia, hypercalciuria and nephrocalcinosis, which progresses to chronic renal failure, it is usually associated with secondary hyperparathyroidism. Recently, the presence of Amelogenesis imperfecta associated with the syndrome, also observed in this patient, has been described. The WES technique has brought great advances in the diagnosis of point mutations, but still presents limitations in the detection of large deletions or duplications. This work provided a great learning and accumulation of knowledge on the interpretation of molecular biology methodologies in the diagnosis of endocrine diseases.