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

La diabetes mellitus es una de las enfermedades crónicas más frecuentes en la infancia. Constituye un conjunto de enfermedades clínica y etiopatogénicamente heterogéneo, aunque más del 95% de los casos en nuestro entorno corresponden a diabetes tipo 1 autoinmune. Los avances ocurridos durante los últimos años han permitido la adscripción de un número cada vez mayor de pacientes a subtipos distintos. En esos casos, el diagnóstico correcto se ve facilitado por el hecho de que muchas de estas causas raras de diabetes se asocian con síndromes clínicos específicos o se manifiestan a una edad determinada. Muchas de ellas son, además, subsidiarias de diagnóstico molecular. El objetivo de esta revisión es poner al día los conocimientos actuales en este campo con objeto de facilitar la consecución de un diagnóstico preciso y entender las implicaciones del mismo sobre el tratamiento y el pronóstico de dichos pacientes(AU)

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(AU)

[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.

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

El hipoaldosteronismo congénito aislado es una enfermedad infrecuente que se manifiesta como un síndrome pierde sal durante la lactancia. La deficiencia de aldosterona sintetasa debida a mutaciones en el gen CYP11B2 es la causa subyacente más frecuente. Al margen de las anomalías electrolíticas clásicas (hiponatremia e hiperkaliemia), no se han descrito hasta el momento otras patologías extra-suprarrenales. Se describe un caso de hipoaldosteronismo congénito debido a una mutación sin sentido en homocigosis (Thr318Met) en CYP11B2. Además del cuadro clínico clásico, el paciente presentó una pérdida auditiva neurosensorial no filiada (AU)

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 (AU)

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.

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.

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.

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.

Diabetes mellitus en niños y adolescentes: complicaciones crónicas y enfermedades asociadas / Diabetes mellitus in children and adolescents: Chronic complications and associated diseases

La diabetes mellitus es una de las enfermedades crónicas más frecuentes. En la infancia y la adolescencia, la mayoría de los casos corresponden a diabetes mellitus tipo 1. La hiperglucemia crónica per se es responsable del desarrollo de numerosas complicaciones a largo plazo, tanto microvasculares (retinopatía, nefropatía, neuropatía) como macrovasculares (cardiopatía isquémica, enfermedad cerebrovascular, enfermedad vascular periférica). Por otro lado, la alteración inmune subyacente a la diabetes mellitus tipo 1 es responsable, además, de que los pacientes presenten una mayor incidencia de otras enfermedades autoinmunes. Esta revisión pretende actualizar los conocimientos más recientes en este campo con objeto de detectar precozmente las complicaciones crónicas y las enfermedades asociadas a la diabetes mellitus tipo 1 en la infancia, así como evitar su aparición o enlentecer su progresión mediante un control metabólico adecuado

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

Diabetes mellitus neonatal: complejidad clínica y heterogenidad genética / Neonatal diabetes mellitus: clinical complexity and genetic heterogeneity

La mayoría de los casos de diabetes mellitus (DM) que se diagnostican en niños prepuberales tiene una bese autoinmune. Sin embargo, en los últimos años se ha hecho cada vez más evidente que la DM neonatal, definida como la existencia de hiperglucemia en los primeros seis meses de vida en recién nacidos a término, tiene un origen radicalmente distinto. En este grupo de pacientes, las manifestaciones autoinmunes son excepcionales pero, en cambio, se han descrito numerosas formas de DM debidas a alteraciones genéticas involucradas en el desarrollo embrionario o la funcionalidad del páncreas, que pueden ser transitorias o permanentes. Su correcta identificación amplía las posibilidades etiológicas y explica algunos síndromes complejos y poco frecuentes. Por el momento, se han identificado 13 subtipos distintos de DM neonatal en el ser humano, secundarios a mutaciones en otros tantos genes: ZAC, IPF-1, PTF1A, HNF-1β, GLIS3, GCK, KCNJ11, ABCC8, SLC2A2, SLC19A2, EIF2AK3, FOXP3 e INSR. El estudio molecular de los pacientes con DM neonatal tiene una repercusión clínica inmediata, ya que puede ayudar a distinguir las formas de DM neonatal transitorias de las permanentes y en ocasiones, permite realizar cambios en la forma de tratamiento de algunos pacientes que conllevan una notable mejoría de su control metabólico y su calidad de vida (AU)

Most cases of diabetes mellitus (DM) diagnosed in prepubertal children have an autoinmune cause. However, evidence supports the hypothesis that neonatal DM, defined as the presence of hypothesis that neonatal DM, defined as the presence of hyperglycemia within the first six months of life in full-term newborns, has a completely different origin. Indeed, in this group of patients an autoimmune cause is exceptional. In contrast, multiple forms od DM are due to genetic abnormalities affecting either embryonic development or pancreatic function. In addition, neonatal DM can be transient or permanent. Molecular diagnosis is necessary and could help to explain some complex and rare syndromes. To date, 13 different subtypes of neonatal DM, secondary to the presence of mutations in 123 different genes, have been reported: ZAC, IPF-1, PTF1A, HNF-1β, GLIS3, GCK, KCNJ11, ABCC8, SLC2A2, SLC19A2, EIF2AK3, FOXP3 and INSR. The molecular study of patients with neonatal DM could help to distinguish between transient and permanent forms and sometimes this information can be used to modify therapy, improving the patient´s metabolic control and quality of life (AU)

Tratamiento con infusión subcutánea continua de insulina en pacientes pediátricos con diabetes mellitus tipo 1 / Treatment with continuous subcutaneous insulin infusion in pediatric patients with type 1 diabetes mellitus

No disponible

[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.

Síndrome de hiperinsulinismo-hiperamoniemia por mutación de novo en el exón 7 (G979A) del gen GLUD-1, con excelente respuesta a diazóxido / Hyperinsulism-hyperammonemia syndrome due to a de nove mutatuon in exon 7(G979A) del gen GLUD-1, con excelente respuesta a diazóxido

El síndrome de hiperinsulinismo-hiperamoniemia se caracteriza por hipoglucemias sintomáticas recurrentes en la infancia, secundarias a hiperinsulinismo, asociadas a un moderado y asintomático incremento de la amoniemia. Es debido a mutaciones en el gen de la glutamato deshidrogenasa (10q23.3), transmitidas de forma dominante, que alteran el control de la actividad enzimática y representa la segunda causa de hiperinsulinismo congénito de base conocida, siendo la primera enfermedad genética identificada debida a un aumento de la actividad de una enzima del metabolismo intermediario. Presentamos el caso de un niño de 16 meses con hipoglucemias sintomáticas recurrentes desde el final del primer año de vida, debidas a una mutación activadora de novo en el exón 7 (G979A) del gen de la GDH, con excelente respuesta terapéutica a diazóxido (AU)

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

Introducción El hipertiroidismo es poco frecuente en la infancia y aparece, en general, en el contexto de la enfermedad de Graves. La mejor forma de tratamiento continúa siendo objeto de debate. Pacientes y métodos: Se han revisado de forma retrospectiva las historias clínicas de 20 pacientes diagnosticados de enfermedad de Graves entre 1989 y 2003. Se ha analizado la sintomatología clínica inicial, la función tiroidea, los marcadores de autoinmunidad tiroidea, las pruebas de imagen tiroideas, el tratamiento de primera elección, las complicaciones de la enfermedad o del tratamiento, la necesidad de recurrir a tratamientos alternativos, así como su efecto sobre el paciente. Resultados: La edad en el momento del diagnóstico osciló entre 5 y 16 años, con un predominio del sexo femenino (3:1). El síntoma más frecuente fue el nerviosismo (58 por ciento). El signo más frecuente fue el bocio (79 por ciento). El 90 por ciento de los pacientes presentaron anticuerpos estimuladores del tiroides (TSI) al inicio de la enfermedad o durante la evolución. Todos los pacientes fueron inicialmente tratados con fármacos antitiroideos, pero la remisión de la enfermedad sólo se logró en 1 caso. En 3 casos hubo que recurrir a la tiroidectomía por falta de respuesta o aparición de complicaciones, y dos más recibieron radioyodo. Conclusión: Dado que la remisión de la enfermedad de Graves con el tratamiento médico es poco habitual, con frecuencia hay que recurrir a otro tipo de terapia (cirugía o radioyodo). Aunque los fármacos antitiroideos continúan siendo la primera opción terapéutica en nuestro medio, algunos autores abogan por el radioyodo como tratamiento de elección (AU)

[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.

Fisiología de la leptina y su papel en los trastornos nutricionales / Leptin physiology and its role in nutritional disturbances

Muchos de los avances más importantes de la investigación sobre la obesidad se han producido desde la identificación de una nueva hormona, denominada leptina, producida fundamentalmente en los adipocitos y cuya existencia era sospechada desde hacía 50 años. Sus funciones principales son, por un lado, regular el equilibrio energético indicando al hipotálamo, mediante la unión a receptores específicos, la cuantía de las reservas grasas del organismo, y por otro, permitir el desarrollo puberal adecuado y la capacidad de reproducción. Este doble papel sugiere que la leptina relaciona la función reproductora con el estado nutricional. Este artículo repasa los conocimientos actuales sobre el papel fisiológico de la leptina, los factores que regulan su secreción y las alteraciones que aparecen en los trastornos nutricionales más prevalentes en nuestro medio: la obesidad y la anorexia nerviosa (AU)