Effect of recombinant growth hormone on leptin, adiponectin, resistin, interleukin-6, tumor necrosis factor-α and ghrelin levels in growth hormone-deficient children.

BACKGROUND: Treatment with GH promotes linear growth and decreases body fat in patients with isolated GH deficiency (GHD). However, few studies have analyzed how GH replacement modifies ghrelin levels and the adipokine profile and the relationship of these modifications with the metabolic changes. AIMS: To analyze the eventual differences between serum levels of leptin, leptin soluble receptor (sOBR), resistin, adiponectin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), total (TG) and acylated ghrelin (AG) and lipid and glycemic profiles in children with GHD, as well as to determine the effect of GH replacement on these parameters during the first year of therapy. SUBJECTS AND METHODS: Thirty pre-pubertal (Tanner stage I) GHD children and 30 matched controls were enrolled. Children with GHD were studied before and after 6 and 12 months of GH treatment. Weight, height, BMI, fasting glucose, insulin, lipid profile and serum levels of adipokines and ghrelin were studied at every visit. Adi - pokines, insulin and ghrelin levels were determined by using commercial radio- and enzymoimmunoassays. RESULTS: At baseline children with GHD had significantly higher sOBR (p<0.01) and adiponectin (p<0.01) levels than controls. Treatment with GH resulted in a decline in leptin (p<0.05) and TG (p<0.001) levels, an increase of homeostasis model assessment index and restored IGF-I levels (p<0.001). CONCLUSIONS: These data indicate that GH replacement has a negative effect on leptin levels and may also produce a slight unfavorable effect on carbohydrate metabolism. In addition, the changes observed in the adipokine profile appear to be independent of body mass index.

Novel (60%) and recurrent (40%) androgen receptor gene mutations in a series of 59 patients with a 46,XY disorder of sex development.

BACKGROUND: Androgen receptor (AR) gene mutations are the most frequent cause of 46,XY disorders of sex development (DSD) and are associated with a variety of phenotypes, ranging from phenotypic women [complete androgen insensitivity syndrome (CAIS)] to milder degrees of undervirilization (partial form or PAIS) or men with only infertility (mild form or MAIS). OBJECTIVE: The aim of the study was to characterize the contribution of the AR gene to the molecular cause of 46,XY DSD in a series of Spanish patients. SETTING: We studied a series of 133 index patients with 46,XY DSD in whom gonads were differentiated as testes, with phenotypes including varying degrees of undervirilization, and in whom the AR gene was the first candidate for a molecular analysis. METHODS: The AR gene was sequenced (exons 1 to 8 with intronic flanking regions) in all patients and in family members of 61% of AR-mutated gene patients. RESULTS: AR gene mutations were found in 59 individuals (44.4% of index patients), of whom 46 (78%) were CAIS and 13 (22%) PAIS. Fifty-seven different mutations were found: 21.0% located in exon 1, 15.8% in exons 2 and 3, 57.9% in exons 4-8, and 5.3% intronic. Twenty-three mutations (40.4%) had been previously described and 34 (59.6%) were novel. CONCLUSIONS: AR gene mutation is the most frequent cause of 46,XY DSD, with a clearly higher frequency in the complete phenotype. Mutations spread along the whole coding sequence, including exon 1. This series shows that 60% of mutations detected during the period 2002-2009 were novel.

[SOS1 mutation: a new cause of Noonan syndrome]. / Mutación en el gen SOS1 como nueva causa de síndrome de Noonan.

Noonan syndrome, characterized by short stature, facial anomalies, heart disease and cryptorchidism in males, is an autosomal dominant, genetically heterogeneous disease. Approximately 50 % of Noonan syndrome cases are caused by gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase (SHP2) and 5 % are caused by KRAS mutations. Recently, a new mutation in SOS1 gene has been identified in approximately 20 % of cases of Noonan syndrome without PTPN11 mutation. That difference in genotype has a relationship with phenotype that we must investigate. We report a case of Noonan syndrome due to an SOS1 mutation; we describe his phenotype and subsequent outcome.

Mutación en el gen SOS1 como nueva causa de síndrome de Noonan / SOS1 mutation: a new cause of Noonan syndrome

El síndrome de Noonan, caracterizado generalmente por talla baja, dismorfia facial, defectos cardíacos y criptorquidia en varones, es una enfermedad autosómica dominante, genéticamente heterogénea. Su origen se encuentra en el 50 % en mutaciones en el gen PTPN11, que codifica la proteína tirosinfosfatasa (SHP2) y da lugar a un aumento de su función y en el 5 % a mutaciones del gen KRAS. Recientemente, se ha identificado una nueva mutación en el gen SOS1, que se relaciona aproximadamente con el 20 % de los síndromes de Noonan sin mutación en el gen PTPN11. Esta diferencia en el genotipo produce diferencias fenotípicas que debemos conocer. Presentamos un caso de síndrome de Noonan por una mutación en el gen SOS1 en el que se describe su fenotipo y evolución a lo largo de la infancia y la pubertad (AU)

Noonan syndrome, characterized by short stature, facial anomalies, heart disease and cryptorchidism in males, is an autosomal dominant, genetically heterogeneous disease. Approximately 50 % of Noonan syndrome cases are caused by gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase (SHP2) and 5 % are caused by KRAS mutations. Recently, a new mutation in SOS1 gene has been identified in approximately 20 % of cases of Noonan syndrome without PTPN11 mutation. That difference in genotype has a relationship with phenotype that we must investigate. We report a case of Noonan syndrome due to an SOS1 mutation; we describe his phenotype and subsequent outcome (AU)

[Male pseudohermaphroditism]. / Seudohermafroditismo masculino.

Diagnosis of ambiguous genitalia in a newborn is an emergency that can be difficult to manage, not only because salt wasting entities must be ruled out, but also due to the importance of gender assignment before psychological gender is established. We report two cases of male pseudohermaphroditism, a true hermaphroditism and a 5-alfa-reductase deficiency. The physiology of sexual differentiation and diagnosis, as well as the management of these infants, are discussed.

Seudohermafroditismo masculino / Male pseudohermaphroditism

El abordaje de un recién nacido (RN) con genitales ambiguos es una urgencia de difícil manejo, no sólo urge el diagnóstico de entidades que podrían implicar una pérdida salina, sino también la asignación del sexo al RN antes de que éste fije su sexo psicológico. Presentamos 2 casos de seudohermafroditismo masculino, uno de ellos del tipo hermafroditismo verdadero y el otro secundario a un déficit de 5alfa-reductasa. Se analiza la fisiología de la diferenciación sexual, las entidades diagnósticas y el protocolo que hay que seguir

Diagnosis of ambiguous genitalia in a newborn is an emergency that can be difficult to manage, not only because salt wasting entities must be ruled out, but also due to the importance of gender assignment before psychological gender is established. We report two cases of male pseudohermaphroditism, a true hermaphroditism and a 5-alfa-reductase deficiency. The physiology of sexual differentiation and diagnosis, as well as the management of these infants, are discussed

The majority of cases of neonatal diabetes in Spain can be explained by known genetic abnormalities.

BACKGROUND: Neonatal diabetes is a rare disease characterized by hyperglycaemia within the first 3 months of life and requiring insulin treatment; it can either be transient (TNDM) or permanent (PNDM). Alterations at band 6q24 and heterozygous activating mutations in KCNJ11, the gene encoding the pore-forming subunit of the KATP channel, can cause neonatal diabetes. Aims We screened the 6q24 region, KCNJ11, GCK, FOXP3 and IPF1 genes for mutations in families with PNDM or TNDM to establish a phenotype-genotype correlation. METHODS: Twenty-two patients with neonatal diabetes were recruited. Inclusion criteria were insulin-treated diabetes diagnosed within the first 3 months and insulin treatment for at least 15 days. Clinical data were recorded in a questionnaire. RESULTS: We identified 17 genetic alterations in our patients: six alterations at the 6q24 band associated with TNDM and nine mutations in KCNJ11, five of which were novel. The analysis for a phenotype-genotype correlation showed that patients with 6q24 alterations had a lower birth weight and were diagnosed earlier than patients with KCNJ11 mutations. At follow-up of the TNDM patients with genetic alterations, 43% developed diabetes or impaired glucose tolerance in later life (one with 6q24 duplication and two with N48D and E227K mutations at KCNJ11 gene). Furthermore, half the first-degree relatives who carried a genetic alteration but who had not suffered from neonatal diabetes were diagnosed with diabetes or impaired glucose tolerance before the age of 30 years. CONCLUSIONS: KCNJ11 mutations are common in both TNDM and PNDM and are associated with a higher birth weight compared with patients with 6q24 abnormalities. Patients with TNDM should be screened for abnormalities in glucose metabolism in adult life.

Concentraciones basales de ACTH y cortisol en niños infectados por el virus de la inmunodeficiencia humana / Basal levels of Acth and cortisol in human immunodeficiency virus infected children

Objetivos. Determinar las concentraciones plasmáticas basales de ACTH y cortisol en niños infectados por el virus de la inmunodeficiencia humana (VIH). Comparar estas concentraciones en las distintas categorías de progresión de la enfermedad. Pacientes y métodos. Se estudió a 31 pacientes (14 varones) de edades entre 2 y 15 años diagnosticados de infección por el VIH. Se distribuyeron en las categorías de los CDC (Centers for Disease Control). El grupo control lo constituyeron 36 niños sanos (17 varones) de edades entre 2 y 15 años. Se determinaron las concentraciones plasmáticas basales matinales de ACTH y cortisol. Resultados. Las concentraciones hormonales medias fueron significativamente más altas en los pacientes infectados que en los controles sanos: ACTH, 33,2 frente a 21,3 pg/ml, y cortisol, 187,7 frente a 145,6 ng/ml. En las categorías de los CDC, las concentraciones basales de cortisol fueron significativamente más altas en la "C" (269,6 ng/ml). La cortisolemia se correlacionó con la elevación de la velocidad de sedimentación (r = +0,36) y de la inmunoglobulina A (r = +0,44) y con la disminución del porcentaje de linfocitos T CD4 (r = -0,45). Conclusiones. Los niños con infección por el VIH presentan unas concentraciones basales de ACTH y cortisol elevadas en comparación con los niños sanos. La concentración basal de cortisol es mayor en la categoría "C" de los CDC (AU)

The auditory threshold in a school-age population is related to iodine intake and thyroid function.

The aim of this study was to determine the relationship between auditory capacity and urinary iodine, taking into account thyroid volume and function, in a population of school-age children. Audiometry was carried out in 150 children (ages 6-14 years), together with measurements of thyroid volume, thyrotropin (TSH), free T3, free T4, thyroglobulin, antiperoxidase and anti-TSH receptor antibodies, as well as iodine in a casual urine sample. Children with a TSH >5 microU/mL were excluded from the study. In the children with palpable goiter, there was an inverse relation between the auditory threshold at all frequencies and ioduria. Children with thyroglobulin values >10 ng/mL had a higher auditory threshold at all frequencies. In the children with palpable goiter and ioduria <100 microg/L, the levels of thyroglobulin and ioduria and the age accounted for 75% of the decibel (dB) variance at 2000 (Hertz), with similar results at other frequencies. The children with a thyroid sized at the >95th percentile had an odds ratio of 3.86 (95% confidence interval: 2.59-5.10) of having a threshold >20 dB. The results warn that iodine prophylaxis is needed to prevent not only goiter but also other iodine-deficiency disorders, such as involvement of the auditory threshold in school-age children.

[Excessive growth and growth hormone deficiency after treatment for craniopharyngioma]. / Hipercrecimiento y déficit de hormona del crecimiento tras tratamiento para el craneofaringioma.

Some children grow normally or excessively after extirpation of a craniopharyngioma, despite growth hormone deficiency. We report a 4-year-old girl with suprasellar craniopharyngioma. Removal of the tumor resulted in panhypopituitarism. For the next 5 years growth continued at a rate of 8.4-10.6 cm/year and then decreased progressively to 1.2 cm/year. Administration of growth hormone increased growth rate to 9.3 cm/year.

Hipercrecimiento y déficit de hormona del crecimiento tras tratamiento para el craneofaringioma / Excessive growth and growth hormone deficiency after treatment for craniopharyngioma

Algunos niños continúan creciendo bien o experimentan crecimiento excesivo tras la extirpación de un craneofaringioma, a pesar de tener deficiencias de hormona del crecimiento. Presentamos el caso de una niña diagnosticada a los 4 años de craneofaringioma con extensión supraselar. Tras la intervención presentó hipopituitarismo múltiple. En los 5 años siguientes creció entre 8,4 y 10,6 cm/año. Después la velocidad de crecimiento disminuyó progresivamente hasta 1,2 cm/año, incrementándose de nuevo a 9,3 cm/año tras instaurar tratamiento con hormona del crecimiento (AU)

Adult height in children with idiopathic short stature treated with growth hormone.

Idiopathic short stature (ISS) includes a heterogeneous group of patients with common characteristics to those of familial short stature and constitutional delay. Some authors state that these children can often respond to GH treatment, thus increasing their adult height. The aims of this study were to determine the effect of GH treatment (0.5-0.7 IU/kg/week) and the influence of some initial variables on adult height in patients with ISS. It was a non-randomized, observational study of 30 boys with ISS and a historical control group of 42 patients. The patients were followed until achieving their adult height. The mean height gain of the treated group attributable to GH was 4.5 cm. A stepwise regression model considering predicted adult height and target height as independent variables and final height as dependent variable gave an R2 coefficient of 0.38. We conclude that GH significantly increases final height in boys with ISS.

[Spontaneous development of idiopathic short stature. Analysis of a group of 42 children followed to their final body height]. / Evolución espontánea de la talla baja idiopática. Análisis de un grupo de 42 niños hasta talla final.

UNLABELLED: Idiopathic short stature is a common pediatric problem that has a heterogeneous nature and an unknown outcome concerning adult height (AH). OBJECTIVE: The main objective of this study was to assess the spontaneous adult height and the influence of several pre and post pubertal predictors over AH. The secondary objective was to create an historical control group to compare these patients with others that had been treated with growth-promoting therapies. PATIENTS AND METHODS: A prospective observational study was made with prepubertal male patients who consulted for short stature before 1986 until they reached AH. They did not receive any treatment. The data are shown as mean and standard deviation. Student's paired t test was used for comparison of groups. Predictive and descriptive models over final height were performed with multivariant analysis. A "p" value of less than 0.05 was considered statistically significant. RESULTS: Data of 42 children was analyzed. Mean age was 10.8 (2.2) years. The standard deviation score (SDS) for adult height spontaneously increased in 0.37 +/- 0.24 (p < 0.05), but it was under target height by 0.59 +/- 0.26 (p = 0.05). Main predictors of AH were: initial height, prognosis of AH and initial age (R2 = 0.58). Final height was no different between children with familial or non-familial short stature. CONCLUSIONS: This group of children had a mean loss of 4 cms below their target height. These children may be considered as an historical control group to evaluate the treatment with growth-promoting therapies.

Treatment with growth hormone. What do children know and how do they accept it?

Treatment with growth hormone in children is a very effective promotor of growth. The psychosocial environment of children may influence the results of this treatment. It has been shown that there is a clear relationship between the knowledge and understanding a child has of the treatment and the degree of compliance and acceptance. We have studied 90 children treated with growth hormone who filled in a questionnaire in order to know the knowledge and acceptance of their treatment. The scores for acceptance were significantly higher than for knowledge (p < 0.00001), without correlations between the two variables. The higher marks were achieved by children who had attended an educational camp. A serious lack of knowledge about the aspects directly related with the injection system was noted. We advise to design a suitable educational program for these patients.

[Incidence of IDDM in children (age 0-14 yrs) in Málaga 1982-1988]. / Incidencia de IDDM en niños (0-14 a.) en Málaga, 1982-1988.

The annual incidence of diabetes mellitus in children 0 to 14 years of age in the province of Malaga (Spain) between 1982 and 1988 was 11.4 cases per 100,000 inhabitants (range = 9.7-13.1). There was an inverse relationship with seasonal temperature; the onset of the disease occurred more frequently during the colder months. The highest incidence was found among children between 5 and 9 years of age, with 13.88 cases per 100,000. The male/female ratio was 1.3 in children between 0 and 5 years and in children between 5 and 9 years of age and 0.97 in children between 10-14 years. The onset of the disease as ketoacidosis remained constant at 25% and was independent of age. When compared with other European epidemiological studies, we found a higher incidence of diabetes mellitus than that in Central European or Mediterranean Countries.