Amaia Vela

Panhypopituitarism : Genetic versus acquired etiological factors

OBJECTIVE Mutations in the genes encoding pituitary transcription factors (mainly PROP1, POUF1 and HESX1) are responsible for familial combined pituitary hormone deficiency (CPHD) and septo-optic dysplasia (SOD) while only a low percentage of mutations are the cause of sporadic forms. Indeed, it has been suggested that environmental rather than genetic factors could be important in the pathogenesis of CPHD. PATIENTS AND METHODS Thirty-six sporadic patients diagnosed with CPHD or SOD were included in the study. All coding exons and intron-exon boundary regions of PROP1, POUF1 and HESX1 were amplified by PCR and subsequently sequenced. RESULTS Two novel missense mutations in the HESX1 gene (Q117P, K176T) were identified in two patients. Polymorphisms in PIT1 and PROP1 were also detected. A higher percentage of breech delivery in male patients with CPHD versus females was observed. CONCLUSIONS The low percentage of mutations found in the most common transcription factors involved in CPHD show that a better characterization of hormonal and morphological phenotypes is necessary for patients with CPHD included in genetic studies, and other genetic or non-genetic factors have to be taken into account.

Urinary iodine and thyroid function in a population of healthy pregnant women in the North of Spain.

BACKGROUND Iodine is an essential trace element for the synthesis of thyroid hormones, which are keys in maternal metabolism during pregnancy as well as in neurological development during fetal and postnatal life. This was a prospective study on iodine status and thyroid function in women during pregnancy in the Basque country to assess whether there was any relationship among maternal urinary iodine, maternal thyroid function and thyrotropin (TSH) in newborns, and to explore any difference in women experiencing miscarriages. METHODS We analyzed TSH, free T(4) (FT(4)), free T(3) (FT(3)), thyroid peroxidase antibody (TPO-Ab) titers in serum and urinary iodine concentrations (UIC) in 2104 women in the first trimester of pregnancy and in 1322 of them in their second trimester. We obtained neonatal TSH levels in 1868 cases. RESULTS In the first (T1) and second trimesters (T2), the median UICs were 88.5 μg/L and 140 μg/L, respectively. No relationship was found between UIC and FT4, or maternal and neonatal TSH. In T1 and T2, 9.7% and 7.5% of women were TPO-Ab positive, respectively. The total miscarriage rate was 10%. The percentage of miscarriages in healthy women was 8.9%, lower than in women with overt hypothyroidism (21.2%; p < 0.001) and than in women with subclinical hypothyroidism (15.6%; p < 0.025). The miscarriage rate was not higher in TPO-Ab-positive women. CONCLUSIONS In this study most women had iodine deficiency during pregnancy. Neonatal TSH is not correlated with maternal UIC during pregnancy. Pregnant women with hypothyroidism have a higher rate of miscarriages.

Absence of diabetes mellitus type 2 in obese children and adolescents in the north of Spain.

Abstract Background: The worldwide epidemic of childhood obesity has been accompanied by an increase in the incidence of carbohydrate metabolism disorders. Objective: To determine the prevalence of type 2 diabetes mellitus (T2DM) and other carbohydrate metabolism disorders in obese young people in the Basque Country (Spain). Design: Prospective observational study. Patients: We studied 136 obese Caucasian children and adolescents (body mass index ≥2 SDS above the mean). Measurements: Their severity of obesity was classified as mild <3 SDS or moderate-to-severe ≥3 SDS. Data were collected on clinical and metabolic parameters; insulin resistance (IR) was calculated using the homeostasis model assessment, and an oral glucose tolerance test (OGTT) was carried out. Results: T2DM was not found. Impaired glucose tolerance (IGT) was found in 9.6% of patients being higher in moderate-to-severe obesity (12.8% vs. 2.4%; p=0.048) and in patients with acanthosis nigricans (27.8% vs. 6.8%; p=0.016). No differences were detected by sex or pubertal development in metabolic results as a function of OGTT’s response. IR (13.5%) was higher among those with moderate-to-severe obesity, in patients with acanthosis nigricans and was associated with other cardiovascular disease risk factors. Conclusions: We found no children with T2DM. The prevalence of IGT and IR was related to severity of obesity, to the association of acanthosis nigricans and was associated with cardiovascular risk.

Incidence of childhood-onset type 1 diabetes in Biscay, Spain, 1990-2013.

To identify the incidence rate (IR) and epidemiologic trends of childhood type 1 diabetes mellitus (T1DM) in children aged 0 to 14‐yr‐old from 1990 to 2013, in the north of Spain (Biscay).

Normal intellectual development in children born from women with hypothyroxinemia during their pregnancy.

Proper maternal thyroid function is known to be essential for neural differentiation and migration in the fetus during the first half of pregnancy. The objectives of this study were to assess the relationship between thyroxin levels, in pregnant women with no thyroid disease and the intellectual development of their offspring in a non-iodine-deficient area, and to know specifically whether or not isolated hypothyroxinemia during pregnancy was associated with a lower intelligence in the offspring. Previously we had publicated values TSH, FT4, free T3 (FT3), anti-thyroid peroxidase antibodies (TPO Abs) and urinary iodine concentration (UIC) in 1322 pregnant women in our hospital area. Now we presented results of intelligence quotient in children born from these pregnancies. We assessed 455 children at one year of age using Brunet-Lezine scale. Of these, 289 children were evaluated again at 6-8 years of age using the WISC-IV. From the total group of children recruited, we established as control subgroup, children born of rigorously normal pregnancies (women with UIC > 150 μg/L, FT4>10th percentile and TPO-Ab negative in both trimesters). The remaining children were divided into two subgroups: those born to mothers with FT4 below the 10th percentile and the rest. No correlation was found between FT4 maternal levels, in either of trimesters studied, and the intellectual scores of offspring. No differences were found in intellectual scores comparing children born to mothers with hypothyroxinemia and those whose mothers were euthyroxinemic in both trimesters, or with the control subgroup. As conclusions we did not find any association between the levels of maternal FT4 during pregnancy and the subsequent intellectual development the offspring from these pregnancies. We attribute this result to the fact that all the pregnant women included had normal thyroid function.

Heterozygous glucokinase mutations and birth weight in Spanish children.

August 2009 (results I and III, Table 1). Bleicher first described diabetic ketoalkalosis in 1967 [1], with few published cases since [2–7]. The mechanisms for the development of alkalosis despite diabetic ketosis include the loss of hydrogen ions (H+) as a result of vomiting, and hypovolaemia (from poor oral intake and hyperglycaemiainduced osmotic diuresis) with subsequent development of fluid volume contraction alkalosis—where the extracellular fluid contracts around a fixed bicarbonate concentration [8]. This is worsened by renal H+ loss and bicarbonate reabsorption as a result of hypovolaemia-driven activation of the renin– angiotensin–aldosterone system, an effect augmented in the setting of hypokalaemia [8]. Hyponatraemia further worsens this, with exchange of sodium for H+ in the distal tubules [4]. These electrolyte changes were all present in our patient, as well as in nine patients with DKA and coexistent metabolic alkalosis described byMoses et al. [9]. In the other published cases, further contributing factors identified were: self-medication with alkali [3], diuretic therapy worsening the dehydration and electrolyte loss [4,6], hypercortisolism because of ectopic adrenocorticotropic hormone (ACTH) [5], gastroparesis [7] and concomitant respiratory alkalosis from hyperventilation [4]. The latter two factors likely contributed in our patient, as he had known severe gastroparesis, and a lower than expected PaCO2. Acute renal failure may have contributed to his raised anion gap, and alcoholic ketoacidosis could also have played a role, but our patient denied drinking alcohol prior to admission. In summary, our patient had a triple acid-base disturbance with metabolic acidosis from DKA and acute renal failure; metabolic alkalosis from hypovolaemia and vomiting, exacerbated by gastroparesis; and a mild superimposed respiratory alkalosis. We hope that this case of recurrent diabetic ketoalkalosis can serve as a reminder that ketosis does not always equal acidosis. It is important to recognize this condition in order to avoid being falsely reassured by a normal or elevated pH and potentially under treat a patient who may be severely dehydrated and ketotic.

Familial hyperinsulinism-hyperammonemia syndrome in a family with seizures: case report.

ABSTRACT Hyperinsulinism-hyperammonemia (HI/ HA) syndrome is the second most frequent cause of congenital hyperinsulinism (CHI) and it is characterized by recurrent symptomatic hypoglycemia and persistent hyperammonemia. We describe the familial case of a 2-year-old child and her 32-year-old mother who, having suffered from tonic-clonic seizures since infancy, had both been diagnosed with epilepsy and treated with sodium valproate. Hypoglycemia was identified in the child in routine analysis. Six days after admission, a complete study of hypoglycemia showed test results compatible with hyperinsulinemic hypoglycemia and hyperammonemia. A mutation in the GDH gene (Arg269His) confirmed the diagnosis in both the mother and the child. An important peculiarity of this case is the diagnosis of a 32-year-old woman, previously diagnosed with epilepsy through her daughters diagnosis at a Pediatric Endocrinology Department and subsequently treated ineffectively with sodium valproate. We conclude that, as hypoglycemia may be subtle, the diagnosis of HI/HA should be considered in children or adults with seizures/epilepsy and hyperammonemia, serum ammonia being a simple screening test for the disease.

Heterogeneity in phenotype of hyperinsulinism caused by activating glucokinase mutations: a novel mutation and its functional characterization.

Mutations in the GCK gene lead to different forms of glucokinase (GCK)‐disease, activating mutations cause hyperinsulinaemic hypoglycaemia while inactivating mutations cause monogenic diabetes. Hyperinsulinism (HI) is a heterogeneous condition with a significant genetic component. The major causes are channelopathies, the other forms are rare and being caused by mutations in genes such as GCK.

Clinical and genetic characterization of congenital hyperinsulinism in Spain

CONTEXT Congenital hyperinsulinism (CHI) is a clinically and genetically heterogeneous disease characterized by severe hypoglycemia caused by inappropriate insulin secretion by pancreatic β-cells. OBJECTIVE To characterize clinically and genetically CHI patients in Spain. DESIGN AND METHODS We included 50 patients with CHI from Spain. Clinical information was provided by the referring clinicians. Mutational analysis was carried out for KCNJ11, ABCC8, and GCK genes. The GLUD1, HNF4A, HNF1A, UCP2, and HADH genes were sequenced depending on the clinical phenotype. RESULTS We identified the genetic etiology in 28 of the 50 CHI patients tested: 21 had a mutation in KATP channel genes (42%), three in GLUD1 (6%), and four in GCK (8%). Most mutations were found in ABCC8 (20/50). Half of these patients (10/20) were homozygous or compound heterozygous, with nine being unresponsive to diazoxide treatment. The other half had heterozygous mutations in ABCC8, six of them being unresponsive to diazoxide treatment and four being responsive to diazoxide treatment. We identified 22 different mutations in the KATP channel genes, of which ten were novel. Notably, patients with ABCC8 mutations were diagnosed earlier, with lower blood glucose levels and required higher doses of diazoxide than those without a genetic diagnosis. CONCLUSIONS Genetic analysis revealed mutations in 56% of the CHI patients. ABCC8 mutations are the most frequent cause of CHI in Spain. We found ten novel mutations in the KATP channel genes. The genetic diagnosis is more likely to be achieved in patients with onset within the first week of life and in those who fail to respond to diazoxide treatment.

Clinical evaluation and health care in childhood and adolescent obesity

In recent years research on the causes and development of obesity has risen dramatically, linked to the high rise in its prevalence, particularly in Western countries. Several studies show that obesity follows this trend in Spain, both in frequency and in the increase in the proportion of severe cases. This increase is particularly important among children and adolescents, a group in which 13.8% of patients between 2 and 24 are obese. This value represents 6% increase compared to 1980. Although growing research in the field has brought about interesting results, due to a deeper knowledge of the mechanisms of weight increase and maintenance (the interactive role of several hormones, as well as genetic variations), these have not been transferred to clinical practice in an efficient manner. For instance, there was an atmosphere of great expectation when trying to establish leptin alterations as a possible cause of many cases of severe obesity, but it was not proven due to its extreme infrequency. Because of this, there have been few changes from the point of view of adequate clinical evaluation and treatment of childhood and adolescent obesity, and consequently the results of treatments are very poor for a great number of patients.