Deficiencia de hormona de crecimiento (GH) en la edad pediátrica / Growth hormone (GH) deficiency in the pediatric age

La deficiencia de hormona de crecimiento (DGH) provoca manifestaciones clínicas distintas, según su etiología y la etapa del desarrollo, pero siempre existe un denominador común: Las otras manifestaciones clínica dependerán d ela etiología (genética, adquirida o idiopática), de la intensidad de la deficienica y de si es la única hormona hipofisaria afectada o existe afectación de otras hormonas hipofisarias. Los avances de los últimos años han ampliado el conocimiento de sus bases moleculares y han caracterizado mejor las formas adquiridas. Sin embargo, la mayor parte de DGH no tienen una causa conocida y son catalogadas como idiopáticas. Mientras que los criterios clínicos y moleculares del diagnóstico de DGH están bien establecidos, los criterios hormonales continúan siendo un rompecabezas a esar de los esfuerzos realizados para armonizar las técnicas bioquímicas de análisis de GH y de IGF-1. Los diagnósticos basados en los estímulos secretores de GH han demostrado ser la escasa utilidad clínica para predecir la respueta terapéutica a la GH (AU)

Growth hormone (GH) deficiency manifests differently according to the individual´s developmental stage. During the paediatric period, one of the msot prominent clincial features is chronic skeletal growth retardation. Clinical signs also depend on the cause (genetic, acquired or idiopathic), deficiency intensity and whether GH is the only pituitary-affected hormone or is combined with that of other pituitary hormones. Growing knowledge of the genetic basis of GH deficiency continues to provide us with useful information to further characterise to provide us with useful information to further characterise mutation types and mechanisms for prevously-described and new candidate genes. Despite these advances, a high proportion of GH deficiencies with no recognisable acquired basis continue to be labelled as idiopathic. The hormonal diagnoses continue to be a conundrum despite efforts to harmonise biochemical assays for GH and IGF-1 analysis, and the diagnosis based on the so-called GH secretion stimulation tests with prove to be of limited usefulness for predicting response to GH therapy (AU)

Height gain at adult-height age in 184 short patients treated with growth hormone from prepubertal age to near adult-height age is not related to GH secretory status at GH therapy onset.

BACKGROUND: GH release after stimuli classifies short children as severe idiopathic isolated GH deficiency (IIGHD), mild IIGHD, dissociated GH release (DGHR) and normal GH release (NGHR) and anthropometric birth data as adequate for gestational age (AGA) or small for gestational age (SGA). GH release after stimuli classifies AGA patients as IIGHD or as idiopathic short stature (ISS). AIM: To compare height gain induced by GH therapy (31.8 ± 3.5 µg/kg/day, 7.7 ± 1.6 years) started at prepubertal age and stopped at near adult-height age. METHODS: A retrospective longitudinal multicenter study including 184 short patients classified as severe IIGHD n = 25, mild IIGHD n = 75, DGHR n = 55 and NGHR n = 29; or as IIGHD n = 78, ISS n = 57 and SGA n = 49. Height gain was evaluated throughout GH therapy and at adult-height age. RESULTS: Height-SDS gain at adult-height age was similar among severe IIGHD (1.8 ± 0.8 SDS), mild IIGHD (1.6 ± 0.6 SDS), DGHR (1.7 ± 0.7 SDS) and NGHR (1.6 ± 0.7 SDS), or among IIGHD (1.7 ± 0.7 SDS), ISS (1.7 ± 0.6 SDS) and SGA (1.6 ± 0.8 SD). CONCLUSION: GH-release stimuli are of little help for deciding on GH therapy in the clinical management of prepubertal children with IIGHD, ISS or SGA.

Growth hormone secretory status evaluated by growth hormone peak after two pharmacological growth hormone release stimuli did not significantly influence the two-year catch-up growth induced by growth hormone therapy in 318 prepubertal short children with idiopathic growth retardation.

BACKGROUND/AIMS: In prepubertal short children with idiopathic growth retardation, growth hormone (GH) peak after GH release stimuli classifies patients as growth hormone- deficient (GHD) or non-GHD. This study compared a 2-year growth response to GH therapy in 318 prepubertal short children. METHODS: Patients were classified as: severe GHD (GH peaks <5 ng/ml after 2 stimuli; n = 54), mild GHD (GH peaks <10 ng/ml, but one or two between 5 and 10 ng/ml; n = 140), dissociated GH release (GH peak ≥ 10 ng/ml after 1 stimulus and <10 ng/ml after the other; n = 89), and normal GH release (GH peaks ≥ 10 ng/ml after 2 stimuli; n = 35). RESULTS: Two-year height gain did not differ statistically among the 4 groups: 1.39 ± 0.51 SD, 16.4 ± 2.3 cm; 1.23 ± 0.56 SD, 15.8 ± 2.1 cm; 1.18 ± 0.53 SD, 15.3 ± 2.0 cm, and 1.14 ± 0.53 SD, 15.4 ± 2.0 cm, respectively, as was also the case for bone age gain: 2.5 ± 0.6, 2.4 ± 0.7, 2.6 ± 0.7 and 2.3 ± 0.5 years, respectively. CONCLUSIONS: Our results suggest that GH release stimuli are of little help for deciding on GH therapy in the clinical management of prepubertal short children with idiopathic growth retardation, while well-defined anthropometric and biochemical criteria may be useful.

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.

Ezetimibe as monotherapy in the treatment of hypercholesterolemia in children and adolescents.

BACKGROUND: A prospective study was conducted to evaluate low-density lipoprotein-cholesterol (LDL-C) lowering efficacy and tolerability of ezetimibe as monotherapy in children and adolescents with polygenic hypercholesterolemia (PH) or familial hypercholesterolemia (FH). METHODS AND RESULTS: Children with PH (n=6) or FH (n=11) aged 5-15 years were consecutively enrolled to receive ezetimibe as monotherapy at 10 mg/day for 11.3 +/- 7.3 and 15.9 +/- 10.1 months, respectively. Plasma biochemical and lipid profiles were assessed before and after treatment. Ezetimibe significantly lowered total cholesterol (TC) and LDL-C in patients with PH and FH: TC from 260.5 +/- 12.4 to 180.0 +/- 21.6 mg/dl (p = 0.02) and from 315.3 +/- 41.8 to 233.3 +/- 36.8 mg/dl (p = 0.003), respectively, and LDL-C from 177.1 +/- 17.7 to 102.6 +/- 16.7 mg/dl (p = 0.02) and from 243.0 +/- 41.8 to 170.0 +/- 29.8 mg/dl (p = 0.003), respectively. However, high-density lipoprotein-cholesterol (HDL-C) only decreased significantly (from 58.1 +/- 10.0 to 49.3 +/- 9.1 mg/dl) (p < 0.01) in patients with FH and remained unaltered in patients with PH. Triglyceride levels remained unchanged in both groups. Biochemical profile (hemogram, transaminases, creatinine, calcium, phosphorus and liposoluble vitamins A and E) remained unchanged; no adverse effects were observed. CONCLUSIONS: Our data show that ezetimibe as monotherapy significantly lowered TC and LDL-C in children with PH and FH.

The exon 3-deleted/full-length growth hormone receptor polymorphism did not influence growth response to growth hormone therapy over two years in prepubertal short children born at term with adequate weight and length for gestational age.

CONTEXT: Consensus is lacking as to whether the exon 3-deleted (d3)/full-length (fl) GH receptor (GHR) polymorphism is associated with responsiveness to GH therapy. OBJECTIVE: Our objective was to evaluate, in short, prepubertal, appropriate-for-gestational age (AGA) patients, 2-yr growth response to GH therapy (31.7+/-3.5 microg/kg.d) according to exon 3-deleted/full-length GHR genotypes. DESIGN: We conducted a retrospective study. PATIENTS: We studied 106 short AGA children, 58 boys and 48 girls, 7.8+/-2.3 yr, (d3/d3 n=18, d3/fl n=42, and fl/fl n=46). The GH response to two provocative stimuli were under 10 ng/ml in 65 and one or both over 10 ng/ml in 41 patients. MAIN OUTCOME MEASURES: Patients were followed by a single clinical team and remained prepubertal during the study. The exon 3-deleted/full-length GHR genotypes were determined and analyzed in the same hospital. RESULTS: Growth velocity significantly (P<0.0001) increased during the first and second years of therapy, as did height sd score (SDS). These increases were similar in each exon 3-deleted/full-length GHR genotype. Total 2-yr height gain (SDS) did not differ statistically among genotypes: 15.5+/-2.2 cm and 1.2+/-0.5 SDS in d3/d3, 15.9+/-2.0 cm and 1.3+/-0.4 SDS in d3/fl, and 15.4+/-2.1 cm and 1.1+/-0.3 SDS in fl/fl. No significant differences among the three genotypes were found in both sexes or in patients with different GH peak response to provocative stimuli for these parameters. An analysis of previously published studies was also performed. CONCLUSIONS: These results confirm in AGA patients those previously found by us and others in small-for-gestational-age patients and suggest that neither sex nor GH peaks after provocative stimuli might influence significantly the responsiveness to GH therapy according to the exon 3-deleted/full-length GHR genotypes.

Diagnosis and treatment in utero of goiter with hypothyroidism caused by iodide overload.

A fetal goiter was detected by ultrasonography in a woman receiving potassium iodide. After this medication was discontinued at 29 weeks, a fetal hypothyroidism was confirmed by cordocentesis, and two doses of levothyroxine were administered by amniocentesis. At 34 weeks repeated cordocentesis showed fetal euthyroidism and ultrasonography shrinkage of the goiter. Growth and development normal at 1 year.

[Adult height, pattern of growth and pubertal development in patients with congenital adrenal hyperplasia, salt losing form]. / Talla adulta, patrón de crecimiento y desarrollo puberal en pacientes con hiperplasia suprarrenal congénita, forma perdedora de sal.

BACKGROUND: The height growth pattern in 24 patients with the salt-wasting from of congenital adrenal hyperplasia was retrospectively evaluated from the neonatal period to attainment of adult height. PATIENTS AND METHODS: All patients were on mineralcorticoid therapy and received hydrocortisone (mg/m2 body surface and day. Mean +/- SD): 34.53 +/- 8.2 during the first year of life, 22.83 +/- 4.1 from then to the puberty onset and 21.83 +/- 3.6 during puberty. Height was measured every 3-4 months and compared with that of the normal age- and sex-matched controls. RESULTS: Height differences with respect to reference population (M +/- SD) were: +0.38 +/- 0.82 in the neonatal period; -2.21 +/- 1.1 at one year of age; -0.76 +/- 1.25 at three years of age; -0.45 +/- 0.99 at the onset of puberty and -1.34 +/- 0.79 at attainment of adult height. Adult height differed significantly (p < 0.01) from control values and in girls from those of their mothers (p < 0.05). Hyperandrogenism, evaluated through urinary 17-ketosteroids, testosterone, delta 4 androstenedione and DA-S, was not documented during prepuberty and puberty. CONCLUSIONS: Our patients showed a lower growth rate than those of the control population during the two periods of higher growth potentiality: the first year of life and puberty, and this results in adult height impairment.

Natural history of premature pubarche: an auxological study.

The natural history of girls with premature pubarche is reported to be normal, but the effects on puberty and on final height are not well documented. We assessed the outcome of a group of girls with premature pubarche from two Latin populations in whom 21-hydroxylase deficiency had been ruled out by an ACTH test. Patients comprised 127 girls (70 Northern-Italian and 57 Northern-Spanish), of whom 69 had entered puberty and 38 had attained adult height. Height, bone age, onset and progression of puberty, height prognosis, adult height, and baseline plasma androgen levels were evaluated. Advanced skeletal maturation and tall stature were constant features during the first years of follow-up and subsequently declined. Puberty began at 9.7 +/- 0.9 yr, and age at menarche (12.0 +/- 1.0 yr) was comparable to maternal and population menarcheal ages. The appearance and chronology of pubertal milestones in both populations were very similar. Adult heights correlated with the height prognosis at diagnosis and at onset of puberty, and were above midparental heights. Premature pubarche produces a transient acceleration in growth and bone maturation with no negative effects on the onset and progression of puberty and final height.

[Fistula of the pyriform sinus. Report of 2 cases]. / Fístula del sinus piriforme. A propósito de dos casos.

The authors present two patients of 8 and 11 years of age that presented a left sided piriform sinus fistula diagnosed by esophagram and surgically treated in our centre. One had been operated previously with a diagnosis of relapsing thyroglossal quist on five occasions. The piriform sinus fistula is a recently recognised entity as cause of thyroiditis and suppurative cervical infections in the pediatric age. Communicated for the first time in the literature in 1957 by Japanese authors, it was not until 1973 that Tucker published for the first time in English a case of recurrent cervical abscess caused by a fistula initiated in the piriform sinus. Until now very few cases have been published. The majority of authors consider it to be an embryological residue of the third or fourth pharyngeal pouch. The key to diagnosis is to bear it in mind whenever a patient presents suppurative thyroiditis or repetitive cervical infections, principally of the left side. An esophagram is necessary to demonstrate the course of the fistula. In cases of thyroiditis a thyroidal gammagraphy will allow vision of a cold zone in the upper third of the affected lobe. Treatment consists of total extirpation of the fistula and affected portion of the thyroidal lobe, once the infection has been solutioned. Before intervention it is important to collocate a tube in the fistula's course by means of a direct microlaryngoscopy which will serve as guide and allow the injection of methylene blue.

Insulin treatment in adolescence.

Treatment of the adolescent diabetic continues to be a challenge for the physician. Ninety-five diabetic patients aged from 12-18 years were treated according to several therapeutic regimens. Principally the Spanish school time-table and, in some cases, life-style or brittle diabetes, determined the adoption of one of five proposed routines. The degree of control achieved assessed by the mean levels of HbA1 (10.6-10.3%), and the frequency and severity of hypoglycaemic accidents ("mild" variety in 25-30% of patients) were similar in all groups with total pancreatic insufficiency. The switch to a four-daily injection regimen (routine 5) with a pen-injector failed to improve metabolic control but patients had more flexibility in meal size and timing. These results suggest that even in teenagers diabetes can be acceptably treated.