Pharmacogenomics of insulin-like growth factor-I generation during GH treatment in children with GH deficiency or Turner syndrome.

Individual responses to growth hormone (GH) treatment are variable. Short-term generation of insulin-like growth factor-I (IGF-I) is recognized as a potential marker of sensitivity to GH treatment. This prospective, phase IV study used an integrated genomic analysis to identify markers associated with 1-month change in IGF-I (ΔIGF-I) following initiation of recombinant human (r-h)GH therapy in treatment-naïve children with GH deficiency (GHD) (n=166) or Turner syndrome (TS) (n=147). In both GHD and TS, polymorphisms in the cell-cycle regulator CDK4 were associated with 1-month ΔIGF-I (P<0.05). Baseline gene expression was also correlated with 1-month ΔIGF-I in both GHD and TS (r=0.3; P<0.01). In patients with low IGF-I responses, carriage of specific CDK4 alleles was associated with MAPK and glucocorticoid receptor signaling in GHD, and with p53 and Wnt signaling pathways in TS. Understanding the relationship between genomic markers and early changes in IGF-I may allow development of strategies to rapidly individualize r-hGH dose.

Sustained attention in school-age children with congenital hypothyroidism: Influence of episodes of overtreatment in the first three years of life. / Atención sostenida en niños con hipotiroidismo congénito en edad escolar. Influencia de los episodios de sobretratamiento en los primeros 3 años de vida.

INTRODUCTION: Children with congenital hypothyroidism (CH) are at risk of developing mild cognitive impairment despite normal overall intellectual performance. These deficits may be caused by disease-related and treatment-related factors. This study explores the impact of abnormal thyroid function during the first 3 years of life on attention performance at school age. METHODS: We included 49 children diagnosed with CH and receiving treatment for the condition: 14 boys (mean age 9.5±2.8 years) and 35 girls (9.6±2.6 years). The number of episodes of normal, under-, and overtreatment were estimated based on TSH levels during their first 3 years of life (at 12, 18, 24, 30, and 36 months). Children were assessed using a computerised version of a Sustained attention test. General linear models were calculated with the attention index as the dependent variable and sex, aetiology, and number of episodes of normal, under-, and overtreatment as independent variables. RESULTS: Higher numbers of episodes of overtreatment (low TSH level) were associated with poorer attention performance at school age (P=.005, r=-0.45). CONCLUSIONS: Children with CH should be monitored closely during the first 3 years of life in order to prevent not only hypothyroidism but also any adverse effects of overtreatment that may affect attentional function at school age.

[Autoimmune thyroid disease: autoimmune gastritis association's possibility]. / Enfermedad tiroidea autoinmunitaria: posibilidad de asociación a gastritis autoinmunitaria.

INTRODUCTION: A high prevalence of parietal cell antibodies (PCA) has been reported in children with autoimmune thyroid disease (AITD). The aim of this study was to determine the prevalence of autoimmune gastritis markers among children diagnosed as AITD. PATIENTS AND METHODS: We studied 26 patients with AITD. Basal samples were taken to determine: hemogram, vitamin B12 and folic acid plasmatic levels, gastrin plasmatic levels, and PCA's determination. Other autoimmune disease comorbidity were also studied. RESULTS: Free T4 and TSH values were normal, with hormonal substitutive treatment. Hb, MCV, HCM, vitamin B12, folic acid and gastrin were in normal range for all 26 patients. We reported 6 cases diabetes mellitus type 1 and 2 of celiac disease. A single patient was PCA positive. It was a 14-year-old hyperthyroid girl without any other autoimmune disease. CONCLUSIONS: AITD in childhood and adolescence is associated with other autoimmune diseases, specially DM1 and CD. PCA becomes an early and sensitive marker to detect autoimmune gastritis.

[Is immediate prophylactic thyroidectomy indispensable in familiar medullary thyroid carcinoma?]. / Es imprescindible la tiroidectomía profiláctica inmediata en el carcinoma medular de tiroides familiar?

PURPOSE: To emphasize the importance of genetic studies in family members and early prophylactic thyroidectomy in oncogene mutation carriers in the management of familiar medullary thyroid carcinoma. METHODS: A retrospective review of families with familiar medullary thyroid carcinoma treated at our center in the last 7 years was performed. We identified a total of 7 families who has isolated prevalences with thyroid malignancies. Forty members of the 7 families were screened for gene RET mutations. Prophylactic total thyroidectomy was performed in every RET mutation gene carriers. RESULTS: In all families the index case were patients with medullary thyroid carcinoma presenting at a mean age of 37.25 years (range 23-42). The RET oncogen mutation was in codon 634 in exon 11 (multiple endocrine neoplasia type 2A) in all these patients. Fourteen gene carriers were identified with a mean age of 20 years (range 7-37), eleven of whom had medullary thyroid carcinoma at the time of surgery. Five of the gene carriers were children, with a mean age of 11 years (range 7-16), four of whom had microcarcinoma and one had metastatic carcinoma at the time of surgery. After surgery no hypoparathyroidism or recurrent nerve paralysis were documented. No pediatric patient has presented with phaeochromocytoma or hypoparathyroidism to date Four of the five children have normal calcitonin levels (< 2 pg/ml) and they are free of disease. The one who presented metastatic carcinoma has recurrent disease and is awaiting surgical treatment. CONCLUSIONS: Genetic studies of family members related to patients with familiar medullary thyroid carcinoma and RET mutations is indispensable. The RET mutation in codon 634 exon 11 was found to be the most frequent association. Prophylactic thyroidectomy is the only curative treatment and has minimal complications when performed by expert surgeons. Early thyroidectomy is recommended since distant metastatic spread can occur at early age.

Multiple endocrine neoplasia: paediatric perspective.

Neuroendocrine tumours constitute a heterogeneous association of neoplasms, originated from a common precursor cell population. They include endocrine glands, such as the pituitary, the parathyroids, the cells of the neuroendocrine adrenals, endocrine islets within glandular tissue (thyroid, pancreas) and dispersed cells (diffuse endocrine system). Neuroendocrine tumours can occur sporadically or in a familial context, such as multiple endocrine neoplasia (MEN) syndromes. These are inherited autosomal dominant cancer syndromes, transmitted with 100% penetrance. They are categorized into MEN type 1 and type 2. The dream of each physician who treats cancer is to develop a strategy that will have a significantly favourable impact on morbidity and mortality associated with malignant tumours. This has been achieved as a result of improved screening and early treatment strategies in MEN. MEN 2 and medullary thyroid carcinoma (MTC) are of special relevance in childhood, because they require urgent and early diagnosis and treatment. The explication of the genetic basis of MTC has revolutionised management of the familial forms of this tumour.

Molecular analysis in familial neurohypophyseal diabetes insipidus: early diagnosis of an asymptomatic carrier.

Familial neurohypophyseal diabetes insipidus (FNDI) is an inherited deficiency of the hormone arginine vasopressin (AVP) and is transmitted as an autosomal dominant trait. In the present study we have analyzed the AVP-neurophysin II (AVP-NPII) gene in a Spanish kindred. Studies were performed on seven members (four clinically affected) of the family. Patients were diagnosed at the Hospital Universitario Gregorio Marañón (Madrid, Spain). The entire coding region of the AVP-NPII gene of all family members was amplified by PCR and sequenced. All affected individuals presented a missense mutation (G1757-->A) that replaces glycine at position 23 with arginine within the NPII domain. The substitution was confirmed by restriction endonuclease analysis and was present in heterozygosis. Additionally, one of the asymptomatic relatives (a girl 8 months old at the time of study) was identified as carrier of the same mutation and developed the disease 3 months later. The alteration found in the second exon of the gene in this family seems to be responsible for the disease, as all individuals harboring the mutation had been previously diagnosed or have eventually developed FNDI. Identification of the molecular defect underlying FNDI in affected families is a powerful tool for early asymptomatic diagnosis in infants.

Exaggerated circadian variation in basal thyrotropin (TSH) and in the dopaminergic inhibition of TSH release in pathological hyperprolactinemia: evidence against a hypothalamic dopaminergic defect.

In order to delineate more accurately the dopaminergic control of anterior pituitary function in normal subjects and in patients with pathological hyperprolactinemia, we investigated the nature of the circadian variation in the dopaminergic inhibition of TSH release in such subjects. Ten euthyroid women with hyperprolactinemia due to presumed PRL-secreting microadenomas (aged 18-60 yr) were compared with 11 normal, euthyroid women (aged 18-32 yr). Each received the dopamine receptor blocking drug domperidone (10 mg, iv) at 1100 and 2300 h (tests randomized and separated by at least 1 week). Blood was sampled 10, 20, 30, 45, and 60 min after drug administration. Normal women had a greater TSH response to domperidone and, hence, greater dopaminergic inhibition of TSH release at 2300 than at 1100 h (sum of TSH increments; mU/liter mean +/- SE, 8.5 +/- 1.3 vs. 4.8 +/- 0.5, P less than 0.01), whereas there was no difference in the dopaminergic inhibition of PRL release at each time of day. Hyperprolactinemic women also had a significantly greater TSH response to domperidone at 2300 than at 1100 h (42.0 +/- 10.2 vs. 19.1 +/- 2.8, P less than 0.001). The hyperprolactinemic women had a greater TSH response to domperidone than normal women at each time of day studied (1100 h, 19.1 +/- 2.8 vs. 4.8 +/- 0.5, P less than 0.001; 2300 h, 42.0 +/- 10.2 vs. 8.5 +/- 1.3, P less than 0.001). The incremental PRL responses to domperidone were significantly less in hyperprolactinemic than in normal women and did not differ at each time of day. In conclusion, the circadian change in the dopaminergic inhibition of TSH secretion is specific for TSH and not PRL. This indicates that the dopaminergic control of TSH and PRL secretion can be dissociated in normal subjects. Second, hyperprolactinemic women with presumed PRL-secreting microadenomas had qualitatively normal but quantitatively exaggerated circadian pattern of dopaminergic inhibition of TSH release. These data argue against a hypothalamic dopaminergic defect in hyperprolactinemia and support the view that the established dopaminergic defect in the inhibition of PRL release is related specifically to PRL control and may well be at the anterior pituitary level.

Dopaminergic modulation of circadian thyrotropin rhythms and thyroid hormone levels in euthyroid subjects.

Basal TSH levels are known to rise during the evening, but the mechanism by which this rise occurs is poorly understood. The rise in TSH in response to dopamine (DA) receptor blockade with metoclopramide in the morning in normal subjects and hypothyroid patients has provided evidence for a tonic inhibitory role for DA in the control of TSH secretion. We have tested the hypothesis in normal, euthyroid volunteers (14 females, aged 20--40 yr; 12 males, aged 22--45 yr) that the nocturnal elevation of serum TSH levels might result from a reduction in DA action on the thyrotroph, in which case a reduced TSH response to metoclopramide would be expected. We found, however, that the TSH response to DA receptor blockade with metoclopramide (10 mg, iv) was significantly greater at 2300 h than at 1100 h [net incremental response over 120 min, 14.9 +/- 2.5 vs. 6.7 +/- 1.6 mU/liter (mean +/- SE); P < 0.001], indicating greater DA inhibition of TSH release at night. Thus, the nocturnal elevation of TSH is not due to decreased DA action on the thyrotroph; rather, increased DA tone is present and may limit the TSH response to other as yet unknown factors. Thyroid hormone levels also rose significantly after metoclopramide at both 1100 and 2300 h compared with control values after placebo [incremental difference (in nanomoles per liter) between 0 and 120 min values (mean +/- SE): 1100 h, T3, 0.24 +/- 0.09 vs. -0.05 +/- 0.08 (P < 0.02); T4, 19.4 +/- 6.1 vs. -1.8 +/- 2.5 (P < 0.01); 2300 h, T3 +/- 0.53 +/-0.07 vs. 0.04 +/- 0.07 (P < 0.01); T4 20.9 +/- 5.6 vs. 2.8 +/- 3.2 (P < 0.01)]. Incremental thyroid hormone and TSH responses to metoclopramide were directly related (T3 vs. TSH, r = 0.59 and P < 0.001; T4 vs. TSH, r = 0.41 and P < 0.01), suggesting that the thyroid hormone responses were mediated by TSH and illustrating the sensitivity of the thyroid gland to even small increases in endogenous TSH levels.

Growth hormone responses to growth hormone-releasing factor (1-29) in euthyroid, hypothyroid and hyperthyroid rats.

In order to investigate whether the impaired GH secretion associated with hypothyroidism and hyperthyroidism is due to a hypothalamic or a pituitary disorder, we have studied plasma GH responses to GH-releasing factor (1-29) (GRF) in euthyroid, hypothyroid and hyperthyroid rats. Hypothyroid rats showed a significant (P less than 0.001) reduction in GH responses to GRF (5 micrograms/kg) at 5 min (350 +/- 35 vs 1950 +/- 260 micrograms/l), 10 min (366 +/- 66 vs 2320 +/- 270 micrograms/l) and 15 min after GRF injection (395 +/- 72 vs 1420 +/- 183 micrograms/l; mean +/- S.E.M.) compared with euthyroid rats. Hyperthyroid rats showed a significant (P less than 0.05) decrease in GH responses to 5 micrograms GRF/kg after 30 min (200 +/- 14 vs 325 +/- 35 micrograms/l) but not at other time-points, or after the administration of 1 microgram GRF/kg. These data indicate that in hypothyroidism and perhaps hyperthyroidism there is an alteration in the responsiveness of the somatotroph to GRF administration.

Undetectable levels of tumor necrosis factor-alpha, nitric oxide and inadequate expression of inducible nitric oxide synthase in congenital hypothyroidism.

OBJECTIVE: To analyse the production of TNF-alpha and NO in euthyroid and hypothyroid newborns. PATIENTS: A cross-sectional study was conducted involving 10 newborns diagnosed with primary congenital hypothyroidism (CH; group A) and 10 euthyroid children (group B). RESULTS: There were undetectable plasma levels of TNF-alpha and NO in the hypothyroid children, however plasma levels of TNF-alpha (5.5 0.5 pg/ml) and NO (5.6 1.7 microM) were detected at normal levels in all euthyroid children. Moreover, expression of iNOS mRNA in PBMC, determined by RT-PCR, was negative in both groups of infants. CONCLUSION: TNF-alpha and NO production are both impaired in hypothyroid newborns. We report for the first time evidence of undetectable levels of TNF-alpha and NO in infants with CH.

[Prenatal molecular genetic diagnosis and treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency]. / Diagnóstico genético molecular y tratamiento prenatal de la hiperplasia adrenal congénita por déficit de la enzima 21-hidroxilasa.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OH), in its severe forms, produces virilization of the external genitalia of the affected female fetus. Early treatment with dexamethasone of the pregnant mother at risk of a fetus with 21-OH deficiency avoids the masculinization of the affected female fetus. We present a pregnant mother, where the prenatal diagnosis was established by DNA analysis of a chorionic villous sample obtained in the 9th week of gestation. Molecular analysis showed the female fetus to be affected of 21-OH deficiency. Maternal treatment with dexamethasone started on the 6th week of gestation has prevented the virilization of the affected baby. No significant side effects have been encountered. Prenatal diagnosis and treatment for 21-OH deficiency is effective and safe, as is described in the literature. This is the first case in Spain where both prenatal molecular diagnosis and treatment for 21-OH deficiency have been reported.

[Relations between Sheehan's syndrome and empty sella turcica. A functional study apropos of 6 cases]. / Relación entre síndrome de Sheehan y silla turca vacía. Estudio funcional a propósito de 6 casos.

We evaluated six patients in whom a diagnosis of Sheehan's syndrome had been made. The plasma levels of the following hormones were measured: basal thyroxine (T4), estradiol and cortisol; and also follicle-stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH), thyrotropin (TSH), prolactin (PRL) and adrenocorticotropic hormone (ACTH), basally and after acute challenge with LH releasing hormone (LHRH), GRF (1-29)NH2 or insulin hypoglycemia, TSH releasing hormone (TRH) and lysine-8-vasopressin, respectively. Two patients underwent chronic LHRH stimulation by pulsatile subcutaneous administration with infusion pump. In 4 cases, computed tomography (CT) was performed although cranial X-ray study was normal. A severe and generalized pituitary involvement was found in all patients, 3 of whom had diabetes mellitus. Probably, more insidious cases go unnoticed. The presence of asymptomatic partial empty sella (ES) in all the CTs that were carried out raises the possibility that it is another evolutive feature of SS.

[Addison's disease: forms of presentation in paediatrics]. / Enfermedad de Addison. Formas de presentación en pediatría.

Addison's disease or primary adrenal insufficiency is a rare disease in children. The signs and symptoms at diagnosis are frequently non-specific and insidious. Since adrenal crisis represents an emergency, it is important to be aware and to have a high degree of suspicion of the disorder in order to achieve an early diagnosis and treatment. We present a retrospective study describing the epidemiological, clinical and etiological data at diagnosis of five patients with Addison's disease followed up in our hospital. Dehydration, hyponatremia and skin hyperpigmentation were the most prevalent signs and symptoms at onset of the disease. The patients had low serum cortisol levels and positive adrenal antibodies. One patient with negative antibodies presented with a polyglandular syndrome.

Episodes of overtreatment during the first six months in children with congenital hypothyroidism and their relationships with sustained attention and inhibitory control at school age.

BACKGROUND/AIMS: Contradictory results regarding the optimal initial dose of levothyroxine in children with congenital hypothyroidism (CH) hamper the clinical management of these children during their early infancy. We explore the relationships between the initial dose of levothyroxine and endocrine control during the first 6 months and cognition at school age. SUBJECTS AND METHODS: Fifty children with CH, 14 boys (10+/-3.1 years) and 36 girls (9.7+/-2.6 years), at the Pediatric Endocrine Unit of the Hospital Gregorio Marañón in Madrid were studied. Neurocognitive evaluation was carried out exploring alertness and inhibitory control. The number of episodes of overtreatment during the first 6 months, the initial dose of levothyroxine, etiology and sex were the predictor variables. RESULTS: Inhibitory control was significantly lower in children with CH than in controls. An interaction with gender and etiology was obtained. Alertness had an inverse relationship with the number of episodes of overtreatment with no interaction with gender or etiology. CONCLUSION: Episodes of overtreatment and not the initial dose of levothyroxine are a risk factor for deficit in alertness whereas subtle inhibitory control deficit seems to be a permanent problem with the current therapeutic approach.