Clinical application of ACMG-AMP guidelines in HNF1A and GCK variants in a cohort of MODY families.

Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. GCK -MODY and HNF1A -MODY are the prevalent subtypes. Currently, there is growing concern regarding the correct interpretation of molecular genetic findings. The American College of Medical Genetics and Genomics (ACMG) updated guidelines to interpret and classify molecular variants. This study aimed to determine the prevalence of MODY ( GCK / HNF1A ) in a large cohort of Brazilian families, to report variants related to phenotype, and to classify them according to ACMG guidelines. One hundred and nine probands were investigated, 45% with clinical suspicion of GCK -MODY and 55% with suspicion of HNF1A -MODY. Twenty-five different variants were identified in GCK gene (30 probands-61% of positivity), and 7 variants in HNF1A (10 probands-17% of positivity). Fourteen of them were novel (12- GCK /2- HNF1A ). ACMG guidelines were able to classify a large portion of variants as pathogenic (36%- GCK /86%- HNF1A ) and likely pathogenic (44%- GCK /14%- HNF1A ), with 16% (5/32) as uncertain significance. This allows us to determine the pathogenicity classification more efficiently, and also reinforces the suspected associations with the phenotype among novel variants.

[Diabetic ketoacidosis in children: review of pathophysiology and treatment with the use of the "two bags system"] / Cetoacidose diabética em crianças: revisão da fisiopatologia e tratamento com o uso do "método de duas soluções salinas"

OBJECTIVES: To review diabetic ketoacidosis, including the "two bags system", a method of administering liquids in order to provide a smoother correction of the hyperglycemic and ketotic states. METHODS: Review of recent publications (last 7 years) from a Medline search and chapters published in pediatric textbooks that discuss the etiology, therapy, and complications of diabetic ketoacidosis. The management approach incorporates the findings of these publications as well as the clinical experience at the Childrens Hospital of Philadelphia and Duke University Medical Center. RESULTS: The pathology of the type 1 Diabetes Mellitus involves the progressive destruction of the ss cells of the pancreas, causing insulin deficiency. Insulin is essential in the metabolism of carbohydrates, protein and fat. Insulin deficiency may lead to diabetic ketoacidosis which has three components: 1) hyperglycemia, which causes glycosuria and consequently dehydration; 2) lipolysis which, causes ketonemia/ketonuria; and 3) acidosis, that is caused by the dehydration and the high serum levels of ketones. Diabetic ketoacidosis is a serious condition and, if not treated appropriately, can cause coma and death. In children cerebral edema is the major complication of the therapy for diabetic ketoacidosis. Careful replacement of insulin, fluids, glucose and electrolytes is essential. CONCLUSIONS: The literature presents different ways to manage DKA in pediatrics, without a consensus on the cause of the most important complication (cerebral edema), and consequently without a consensus on the best approach. The use of the two saline bags in patients in DKA allows fast adjustments in the dextrose concentration of the infusion fluids, simplifying and reducing the costs of the treatment of diabetic ketoacidosis.

Insulin-like growth factor binding protein-1 levels in the diagnosis of hypoglycemia caused by hyperinsulinism.

The diagnosis of hypoglycemia caused by hyperinsulinism may be difficult because insulin levels are not uniformly elevated at the time of hypoglycemia. Insulin-like growth factor binding protein-1 (IGFBP-1) is a 28 kd protein whose secretion is acutely inhibited by insulin. We hypothesized that serum levels of IGFBP-1 would be a useful marker of hyperinsulinism. We measured IGFBP-1 levels during the course of standardized fasting studies in hospitalized children; 36 patients became hypoglycemic during the fasting studies, and samples obtained at the point of hypoglycemia were analyzed. On the basis of the currently used diagnostic criteria, 13 children had hyperinsulinism, 16 had ketotic hypoglycemia or no disorder, 3 had hypopituitarism or isolated growth hormone deficiency, 2 had glycogen storage disease type 1 and 2 had fatty acid oxidation disorders. In control subjects (children with ketotic hypoglycemia or no disorder), IGFBP-1 levels rose during fasting to a mean of 343.8 +/- 71.3 ng/ml in the sample drawn at the time of hypoglycemia. Mean IGFBP-1 levels at hypoglycemia for the entire group with hyperinsulinism were 52.4 +/- 11.5 ng/ml, significantly different from levels seen in control subjects (p < 0.0001). In children with moderately controlled hyperinsulinism (fasting tolerance > 4 hours), mean IGFBP-1 levels at the time of hypoglycemia were 71.5 +/- 16.9 ng/ml. IGFBP-1 levels in the children with poorly controlled hyperinsulinism (fasting tolerance < 4 hours) failed to rise during fasting, with a mean of 30.1 +/- 10.4 ng/ml in the final sample. IGFBP-1 levels were inversely correlated with serum insulin and C-peptide levels (r = -0.71 and -0.72, respectively; p < 0.0001). Patients with other endocrinologic or metabolic diseases that result in fasting hypoglycemia demonstrated a rise in IGFBP-1 levels similar to that seen in ketotic hypoglycemia. Low serum levels of IGFBP-1 at the time of hypoglycemia provide an additional marker of insulin action that might help to differentiate hyperinsulinism from other hypoglycemic disorders.