A genetic diagnosis of HNF1A diabetes alters treatment and improves glycaemic control in the majority of insulin-treated patients.

BACKGROUND AND AIMS: Hepatocyte nuclear factor-1 alpha (HNF1A) gene mutations are the commonest cause of monogenic diabetes, but patients are often misdiagnosed as having Type 1 diabetes and started on insulin treatment. Patients with HNF1A diabetes are particularly sensitive to the glucose-lowering effect of sulphonylureas, which are the pharmacological treatment of choice. We aimed to assess if patients do change from insulin to sulphonylurea treatment when HNF1A diabetes is confirmed and the impact of this treatment change on long-term glycaemic control. METHODS: We investigated the clinical course of 43 patients who were insulin treated from diagnosis for a median 4 years (range 1-14) before an HNF1A gene mutation was identified. RESULTS: Thirty-four patients (79%) stopped insulin following genetic testing and transferred to sulphonylureas. Twenty-four of them (71%) remained off insulin at a median 39 months (range 17-90) post-transfer. The 10 patients who recommenced insulin had a trend towards a longer duration of diabetes (18 vs. 7 years, P = 0.066) compared with those remaining on tablets. The median glycated haemoglobin (HbA(1c)) was good (6.9%; interquartile range 6.3-8.0%) in the patients who remained off insulin and 19/24 patients (79%) achieved HbA(1c) < 7.5% or improved their pre-genetic diagnosis HbA(1c) by > 1.0%. Transfer off insulin was not attempted in eight patients: one of these was planning pregnancy and two chose to remain on insulin. CONCLUSION: In this observational study we found that a molecular genetic diagnosis of HNF1A diabetes does alter treatment in clinical practice, with 79% attempting transfer to sulphonylureas. Transfer to sulphonylureas was successful in the majority of patients without deterioration in glycaemic control.

Testing for monogenic diabetes among children and adolescents with antibody-negative clinically defined Type 1 diabetes.

AIMS: Monogenic diabetes is frequently misdiagnosed as Type 1 diabetes. We aimed to screen for undiagnosed monogenic diabetes in a cohort of children who had a clinical diagnosis of Type 1 diabetes but were pancreatic autoantibody-negative. METHODS: We studied 252 patients diagnosed clinically with Type 1 diabetes between 6 months and 17 years of age. Pancreatic autoantibodies [islet cell autoantibodies (ICA), glutamic acid decarboxylase antibodies (GADA) and/or insulinoma-associated antigen-2 antibodies (IA2A)] were absent in 25 cases (9.9%). The most frequent genes involved in monogenic diabetes [KCNJ11 and INS for neonatal diabetes and HNF1A and HNF4A for maturity-onset diabetes of the young (MODY)] were directly sequenced. RESULTS: Two of the 25 (8%) antibody-negative patients had de novo heterozygous mutations in INS; c.94G>A (G32S) and c.265C>T (R89C). The two patients presented with non-ketotic hyperglycaemia at 8 and 11 months of age. In contrast, the four antibody-positive patients who presented at a similar age (6-12 months) had a more severe metabolic derangement, manifested as ketosis in all four cases, with ketoacidosis in two. At ages 15 and 5 years, both INS mutation patients were prescribed a replacement dose of insulin with good glycaemic control [glycated haemoglobin (HbA(1c)) 7.0 and 7.2%]. No mutations were found in KCNJ11, HNF1A or HNF4A. CONCLUSIONS: The identification of patients with monogenic diabetes from children with clinically defined Type 1 diabetes may be helped by clinical criteria including the absence of pancreatic autoantibodies.

Permanent neonatal diabetes caused by a homozygous nonsense mutation in the glucokinase gene.

Glucokinase deficiency is an unfrequent cause of permanent neonatal diabetes (PND), as only seven patients have been reported, either homozygous for a missense or frameshift mutation or compound heterozygous for both of them. We report here the first known case caused by a homozygous nonsense mutation (Y61X) in the glucokinase gene (GCK) that introduces a premature stop codon, generating a truncated protein that is predicted to be completely inactive as it lacks both the glucose- and the adenosine triphosphate-binding sites. The proband, born to consanguineous parents, was a full-term, intra-uterine growth-retarded male newborn who presented with a glycaemia of 129 mg/dL (7.16 mmol/L) on his second day of life, increasing thereafter up to 288 mg/dL (15.98 mmol/L) and 530 mg/dL (29.41 mmol/L) over the next 24 h, in the face of low serum insulin (<3 muIU/mL; <20.83 pmol/L). He was put on insulin on the third day of life. Insulin has never been discontinued since then. The patient was tested negative for anti-insulin and islet cell antibodies at age 5 months. His father had non-progressive, impaired fasting glucose for several years. The mother was found to be mildly hyperglycaemic only when her glucose was checked after the child was diagnosed. In conclusion, biallelic GCK loss should be considered as a potential cause of PND in children born to consanguineous parents, even if they are not known to be diabetic at the time of PND presentation.

[Diabetes mellitus in children and adolescents: chronic complications and associated diseases]. / Diabetes mellitus en niños y adolescentes: complicaciones crónicas y enfermedades asociadas.

Diabetes is one of the most common chronic diseases. Type 1, or autoimmune, diabetes accounts for more than 95 % of cases in children and adolescents. Chronic hyperglycemia per se is responsible for the development of several microvascular (retinopathy, nephropathy, neuropathy) and macrovascular complications (ischemic heart disease, cerebrovascular disease, and peripheral vascular disease). Other autoimmune diseases are also more frequent in type 1 diabetic patients. The present review aims to provide an update on some recent advances in this field to aid early detection of these complications and prevent or delay their progression through improved metabolic control.

[Graves' disease in children: management and review of 20 patients]. / Enfermedad de Graves: estado actual y revisión de 20 casos.

INTRODUCTION: Hyperthyroidism is a rare condition among children and the most common cause is Graves' disease. The best therapy for these patients continues to be debated. PATIENTS AND METHODS: The medical records of 20 patients with Graves' hyperthyroidism who were treated between 1989 and 2003 were reviewed. Clinical symptoms, thyroid function, thyroid autoantibodies, thyroid imaging tests, first line therapy, disease or treatment-induced complications and the need for a secondary treatment option, as well as outcomes, were analyzed. RESULTS: Age at diagnosis ranged from 5 to 16 years and there were more girls than boys (3:1). The most frequent symptom was hyperactivity (58 %). The most frequent sign was goiter (79 %). Thyroid-stimulating immunoglobulin antibodies were found in 90 % of the patients, at the beginning or during the course of the disease. All of the patients received antithyroid medication as first line therapy, but remission was achieved in just one patient. Surgical thyroidectomy was required in three patients, and two patients were treated with radioiodine. CONCLUSION: Because few children achieve remission with medical therapy, other types of treatment (surgery or radioiodine) are often required. Although antithyroid drugs are considered the first choice for treatment in Europe, some authors advocate radioiodine as the treatment of choice.

[Hyperinsulinism-hyperammonemia syndrome due to a de novo mutation in exon 7 (G979A) of the glutamate dehydrogenase gene with excellent response to diazoxide]. / Síndrome de hiperinsulinismo-hiperamoniemia por mutación de novo en el exón 7 (G979A) del gen GLUD-1, con excelente respuesta a diazóxido.

Hyperinsulinism-hyperammonemia syndrome is characterized by recurrent and symptomatic hypoglycemias in childhood, secondary to hyperinsulinism associated with mild and asymptomatic hyperammonemia. This syndrome is caused by dominantly expressed mutations of the glutamate dehydrogenase gene (10q23.3). These mutations modify control of enzyme activity and represent the second cause of congenital hyperinsulinism of known genetic etiology. Moreover, this syndrome is the first genetic disorder due to an increase of function in an enzyme of intermediary metabolism to have been identified. We present the case of a 16-month-old boy with symptomatic recurrent hypoglycemias from the end of the first year of life, caused by a de novo mutation in exon 7 (G979A) of the GDH gene, with excellent outcome after diazoxide treatment.

[Diabetes mellitus: clinical presentation and differential diagnosis of hyperglycemia in childhood and adolescence]. / Diabetes mellitus: formas de presentación clínica y diagnóstico diferencial de la hiperglucemia en la infancia y adolescencia.

Diabetes mellitus is one of the most common chronic diseases in childhood. Despite being a clinical and etiopathogenically heterogeneous disorder, type 1 autoimmune diabetes accounts for more than 95% of cases in children. Recent advances have meant that a growing number of patients have been assigned to other subtypes of diabetes. In such cases, the correct diagnosis is facilitated by the fact that many of these rare causes of diabetes are associated with specific clinical syndromes or may present at a certain age. Many of them are also subsidiaries of molecular diagnosis. The aim of this review is to update the current knowledge in this field of pediatric diabetes, in an attempt to determine the most accurate diagnosis and its implications on appropriate treatment and prognosis.

[Primary hypoaldosteronism and moderate bilateral deafness in a child with a homozygous missense mutation (Thr318Met) in the CYP11B2 gene]. / Hipoaldosteronismo primario e hipoacusia bilateral moderada en un niño con una mutación sin sentido en homocigosis (Thr318Met) en el gen CYP11B2.

Isolated congenital hypoaldosteronism is a rare disorder that presents as chronic salt-wasting syndrome during infancy. Aldosterone synthase deficiency due to mutations in CYP11B2 is the underlying cause in most cases. Apart from the classical electrolyte disturbances (hyponatremia and hyperkalemia), no other extra-adrenal features have been described to date. We report a male child with congenital hypoaldosteronism due to a homozygous missense mutation (Thr318Met) in CYP11B2 who also presented with unexplained sensorineural hearing loss.

Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations.

OBJECTIVE: The phenotype associated with heterozygous HNF4A gene mutations has recently been extended to include diazoxide responsive neonatal hypoglycemia in addition to maturity-onset diabetes of the young (MODY). To date, mutation screening has been limited to patients with a family history consistent with MODY. In this study, we investigated the prevalence of HNF4A mutations in a large cohort of patients with diazoxide responsive hyperinsulinemic hypoglycemia (HH). SUBJECTS AND METHODS: We sequenced the ABCC8, KCNJ11, GCK, GLUD1, and/or HNF4A genes in 220 patients with HH responsive to diazoxide. The order of genetic testing was dependent upon the clinical phenotype. RESULTS: A genetic diagnosis was possible for 59/220 (27%) patients. K(ATP) channel mutations were most common (15%) followed by GLUD1 mutations causing hyperinsulinism with hyperammonemia (5.9%), and HNF4A mutations (5%). Seven of the 11 probands with a heterozygous HNF4A mutation did not have a parent affected with diabetes, and four de novo mutations were confirmed. These patients were diagnosed with HI within the first week of life (median age 1 day), and they had increased birth weight (median +2.4 SDS). The duration of diazoxide treatment ranged from 3 months to ongoing at 8 years. CONCLUSIONS: In this large series, HNF4A mutations are the third most common cause of diazoxide responsive HH. We recommend that HNF4A sequencing is considered in all patients with diazoxide responsive HH diagnosed in the first week of life irrespective of a family history of diabetes, once K(ATP) channel mutations have been excluded.