Growth hormone signaling in fibroblasts from newborn boys and prepubertal boys.

BACKGROUND/AIM: Responsiveness to GH in target cells is mediated by its receptor, which activates the Janus kinase-2 (JAK2) and STAT5 (signal transducers and activators of transcription 5) leading to the expression of IGF-1 and IGFALS. The aim of this study was to compare the GH signaling pathway in newborns and prepubertal boys. SUBJECTS AND METHODS: We determined the GHR protein content and the effect of stimulation with recombinant human GH (rhGH; 200ng/mL) on JAK2 and STAT5 phosphorylation in skin fibroblast cultures obtained from newborns and prepubertal boys. The transcript levels of IGFALS and IGF-I, were also studied and compared after 16h or 24h of stimulation with GH in both study groups. RESULTS: Newborn infants showed less GHR protein than the prepubertal boys. After rhGH stimulation, JAK2 and STAT5 phosphorylation was absent in skin fibroblasts from newborns, but was clearly detectable in prepubertal boys. After 16h of treatment with rhGH, IGFALS and IGF-I transcript levels increased in the prepubertal boys when compared to baseline. In newborns, however, we did not observe a response after 16 and 24h of rhGH stimulation. CONCLUSION: The significant attenuation of the GH signaling pathway observed in fibroblasts from newborn boys appears to be related to a reduction in GHR content and lack of phosphorylation of JAK2 and STAT5 in response to rhGH. This might impair STAT5 dimer formation, leading to a reduction in the transcript levels of IGFALS and IGF-I during the newborn period.

Effects of thyroid hormone on the GH signal transduction pathway.

BACKGROUND/AIM: The importance of thyroid hormone on growth and development in children is well recognized. In addition, linear growth is highly dependent on the response of peripheral tissues to growth hormone, a process known as GH sensitivity, but little is known about the possible effects of T4 on this process. METHODS: We determined the effect of stimulation with recombinant human GH (rhGH; 200 ng/mL) alone or in combination with two different concentrations of T4 (250 nM and 500 nM for 24 h) on JAK2 and STAT5 activation in skin fibroblast cultures obtained from prepubertal boys with normal height. RESULTS: JAK2 and STAT5 were activated under co-incubation with T4 (at both concentrations) and rhGH in the non-nuclear fraction of the fibroblasts. In addition, after 24h of co-incubation with rhGH and T4 (500 nM), we observed an increase in phospho-STAT5 in the nuclear fraction, when compared to GH and T4 stimulation alone. This effect was not observed when the fibroblasts were co-incubated with GH and the lower concentration of T4 (250 nM). CONCLUSION: Combined stimulation with GH and T4 at a concentration of 500 nM increases synergistically nuclear phospho-STAT5 in skin fibroblasts, which may amplify tissue sensitivity to GH. These findings may help to explain the effect of T4 administration on growth velocity in some children with idiopathic short stature.

The IGF-I response to growth hormone is related to body mass index in short children with normal weight.

AIM: We investigated whether the insulin-like growth factor (IGF)-I response to growth hormone (GH) is regulated by body mass index (BMI) in short children with normal weight. METHODS: We studied 37 prepubertal children with idiopathic short stature (ISS), comparing children with high-normal BMI (standard deviation scores, SDS 1.23 +/- 0.11, n = 20) and low-normal BMI (SDS -0.93 +/- 0.12, n = 17). The IGF-I response to GH was determined with an abbreviated IGF-I generation test, by measuring serum IGF-I concentrations at baseline and 24 h after the administration of GH (0.033 mg/kg). RESULTS: Children with high- and low-normal BMI had similar age (8.5 +/- 0.7 vs. 8.7 +/- 0.7 years) and height (-2.0 +/- 0.1 vs. -2.2 +/- 0.2 SDS). However, children with high-normal BMI exhibited higher mean basal IGF-I (191 +/- 15 vs. 139 +/- 11 ng/ml, p < 0.05), higher mean IGF-I levels 24 h after GH administration (261 +/- 22 vs. 164 +/- 14 ng/ml, p < 0.05) and a higher IGF-I percent increase after GH administration (37 +/- 5 vs. 17 +/- 4%, p < 0.05) compared with children with normal-low BMI. CONCLUSION: BMI modulates the IGF-I response to GH, suggesting that GH sensitivity may be influenced by the nutritional status in children with ISS and normal body weight.

Comparison of three doses of leuprolide acetate in the treatment of central precocious puberty: preliminary results.

OBJECTIVE: Depot luteinizing-hormone releasing hormone (LHRH) agonist have been widely used for the treatment of central precocious puberty (CPP), but the optimal doses to obtain hormonal suppression are still unknown, especially in patients with higher weights. The goal of our study was to compare the efficacy of three leuprolide acetate (LA) preparations, suppressing gonadotropin secretion in patients with CPP. DESIGN: In an open 12-month protocol, we evaluated LA 7.5 mg/month, 11.25 and 22.5 every 3 months. PATIENTS: Fourteen girls with CPP and weights over 30 kg. MEASUREMENTS: Clinical, radiological and laboratory follow-up: GnRH test plus LH, FSH 40 min post analogue was performed periodically. RESULTS: Pretreatment basal and LHRH stimulated LH levels between groups were not different. Basal and LHRH stimulated LH levels decreased significantly between baseline and from 3 up to 12 months of therapy in all groups (P = 0.001). GnRH stimulated LH peak <2 IU/l, the main efficacy criterion was met in 80, 75 and 100% of the children at 6 months in the 7.5, 11.25, 22.5 mg doses respectively. By 12 months, 100% of patients had LH suppressed to <2 IU/l. CONCLUSIONS: These results affirm that 3-month injections may be a satisfactory alternative for the therapy of children with CPP to avoid monthly injections. In addition, suppression of LH occurs sooner in the 3-month 22.5 mg LA dose compared to the 3-month 11.5 mg; therefore, adequate dosing may be important for optimal outcome. Further investigation is needed in more patients over 30 kg, with longer treatment duration, and ultimately final height consideration.

Familial tumoral calcinosis caused by a novel FGF23 mutation: response to induction of tubular renal acidosis with acetazolamide and the non-calcium phosphate binder sevelamer.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is an uncommon disease characterized by periarticular calcifications produced by the deposition of amorphous extraosseous calcifications of hydroxyapatite. It is associated with hyperphosphatemia due to increased tubular phosphate reabsorption, despite normal renal function and normal plasma PTH levels. The disease can be caused by inactivating mutations in either the fibroblast growth factor 23 (FGF23) gene, the UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) gene or in human KLOTHO (KL) gene. Herein, we describe a Caucasian 3-year-old girl with tumoral calcinosis who presented with elevated serum phosphorus levels and a large calcified mass at her left elbow which led to ulceration of the skin. Treatment with the phosphate binder sevelamer and the carbonic anhydrase inhibitor acetazolamide successfully reduced the serum phosphate levels and led to a reduction of the calcified mass. This medical management has not been described previously. Her 7-month-old sister also had elevated serum phosphate levels, but did not have ectopic calcifications. Sequencing analysis revealed a novel homozygous FGF23 missense mutation (c.367G>T, p.Gly123Trp) in both siblings while the parents were carriers of the mutation.

[Congenital hypopituitarism: report of 23 cases]. / Hipopituitarismo congénito: Experiencia en 23 casos.

BACKGROUND: Congenital hypopituitarism is an uncommon cause of hypophyseal insufficiency It is less common than growth hormone deficiency which has an incidence of 1:4.000 to 1:8.000 live newborns. Early diagnosis of this condition is important to prevent impairment of cognitive function, poor growth and alterations in metabolic profile in these patients. AIM: To report 23 patients diagnosed with congenital hypopituitarism. MATERIAL AND METHODS: Retrospective review of clinical records of 23 patients (12 males) with congenital hypopituitarism, diagnosed during a 21 years period. In a group of 16 patients a molecular study was performed searching for mutations in HESX1, PROP-1 or POUF-1. RESULTS: Short stature was the most frequent sign at the first evaluation, followed by neonatal hypoglycemia and presence of nystagmus, strabismus, atrophic optic nerve or malformations in the middle line showed in CNS imaging, suggesting septo-optic-dysplasia. All male patients diagnosed during neonatal period, exhibited micropenis. CNS images showed isolated hypophyseal hypoplasia or associated to an ectopic neurohypophysis in most patients. No patient in the subgroup subjected to molecular analysis had any of the mutations in the searched genes. CONCLUSIONS: The diagnosis of hypopituitarism must be based on clinical grounds, especially when hypoglycemia, prolonged jaundice, micropenis or midline alterations are found in the neonatal period.

Hipopituitarismo congénito: experiencia en 23 casos / Congenital hypopituitarism: report of 23 cases

Background: Congenital hypopituitarism is an uncommon cause of hypophyseal insufficiency It is less common than growth hormone deficiency which has an incidence of 1:4.000 to 1:8.000 Uve newborns. Early diagnosis ofthis condition is important to prevent impairment of cognitive function, poor growth and alterations in metabolic profile in these patients. Aim: To report 23 patients diagnosed with congenital hypopituitarism. Material and methods: Retrospective review of clinical records of 23 patients (12 males) with congenital hypopituitarism, diagnosed during a 21 years period. In a group of 16 patients a molecular study was performed searching for mutations in HESX1, PROP-1 or POUF-1. Results: Short stature was the most frequent sign at the first evaluation, followed by neonatal hypoglycemia and presence of nistagmus, strabismus, atrophic optic nerve or malformations in the middle Une showed in CNS imaging, suggesting septo-optic-dysplasia. All male patients diagnosed during neonatal period, exhibited micropenis. CNS images showed isolated hypophyseal hypoplasia or associated to an ectopic neurohypophysis in most patients. No patient in the subgroup subjected to molecular analysis had any of the mutations in the searched genes. Conclusions: The diagnosis of hypopituitarism must be based on clinical grounds, speciaUy when hypoglycemia, prolonged jaundice, micropenis or midline alterations are found in the neonatal period.

Densitometría mineral ósea en pacientes pediátricos: interpretación de resultados e indicaciones / Indications and interpretation of results of pediatric bone densitometry

There is a growing interest in the evaluation of bone mass in children, to support the adequate management of several diseases in this age group. This interest was boosted by the improvement in bone mass measuring techniques and by the increase in the incidence of osteoporosis during childhood, due to the longer lifespan of children with congenital or acquired diseases. Other reason to measure bone mass is that an adequate bone accretion in children will prevent osteoporosis during adulthood. The extensive use of bone densitometry in children requires an adequate knowledge about its indications and interpretation. The morphology, size and constitution of the skeleton of child changes constantly, therefore densitometry results cannot be interpreted as those of a small adult. We review the advances in pediatric bone densitometry, specially its indications and the interpretation of results.

Diabetes mellitus neonatal transitoria por duplicación paterna 6q24 / Transient neonatal mellitus diabetes due to paternal duplication 6q24

Neonatal diabetes mellitus is defined as severe hyperglycemia beginning during the first six months of life, lasting at least one month and needing insulin as a treatment. The incidence is about 1 in 200.000 born alive. We report a preterm female newborn, small for gestational age, whose actual age is 19 months. At the third day of life she became severely ill, with serious shock, losing 20 percent of her weight at birth. Laboratory work-up showed a blood glucose level of 633 mg/dl, hypernatremia, metabolic acidosis and renal failure. During the initial 4 months she was treated with insulin infusions that were tapered and finally discontinued at four months of age. The molecular study of this patient showed abnormal maternal methylation at chromosome 6 and the novo paternal duplication of 6q24.

Guía de manejo en niños con diálisis peritoneal

La diálisis peritoneal, es un procedimiento que se utiliza en niños con lesión reanl grave, en algunas intoxicaciones y en alteraciones electrolíticas a metabólicas diversas. Realiza una depuración sanguínea intracorporal y extrarenal utilizando como membrana dializante el peritoneo, entre la sangre que circula por los capilares y una solución infundida a la cavidad peritoneal.