Jose Ignacio Labarta

Central Precocious Puberty in Children Living in Spain: Incidence, Prevalence, and Influence of Adoption and Immigration

CONTEXT No epidemiological data are available on central precocious puberty (CPP) in the general population or in adopted or immigrant children in Spain. OBJECTIVE We aimed to study the incidence and prevalence of CPP, assess the risk of developing this disorder among adopted and immigrant children, and analyze the predictive variables of CPP associated with intracranial pathology. DESIGN, SETTINGS, AND PATIENTS An observational study of children diagnosed with CPP in Spain was carried out between January 2008 and January 2010. A computer program was designed to process clinical and biological data and information on 250 patients treated in 34 pediatric endocrinology units throughout the country. RESULTS Of the patients registered, 226 were girls and 24 were boys. The global incidence rate of CPP was 5.66 cases per million person-years at risk, with an annual incidence ranging between 0.02 and 1.07 new cases per 100,000. The relative risk of CPP in domestic and internationally adopted children compared with those born in Spain was 27.82 (19.99-38.77), whereas the relative risk among immigrants was 1.55 (0.97-2.38). A logistic regression model developed for the study showed that the combined effect of four variables had a significant influence over the presence of organic disease: being male, having been adopted, age at diagnosis, and estimation of adult height. CONCLUSIONS CPP is a rare disease whose risk markedly increases with both national and international adoption but is not influenced by immigration. These results suggest a psychological influence on CPP.

Immunoblot studies of the acid‐labile subunit (ALS) in biological fluids, normal human serum and in children with GH deficiency and GH receptor deficiency before and after long‐term therapy with GH or IGF‐I respectively

The aims of this investigation were (a) to study the presence of immunoreactive forms of the acid‐labile subunit (ALS) in different human biological fluids, (b) to define the age dependence of serum ALS in normal children and adults and (c) to compare the regulation of ALS by GH or IGF‐I in children with GH deficiency (GHD) and GH receptor deficiency (GHRD) before and after 1 year of therapy with GH or IGF‐I, respectively.

Longitudinal Pubertal Growth According to Age at Pubertal Growth Spurt Onset: Data from a Spanish Study Including 458 Children (223 Boys and 235 Girls)

BACKGROUND Age at pubertal growth spurt (PGS) onset varies and is sex-dependent. We present anthropometric pubertal growth data for five 1-year interval age maturity groups: very early, early, intermediate, late and very late. METHODS Longitudinal growth study of 458 healthy children (223 boys, 235 girls). Ages at PGS onset and at adult height attainment, total pubertal growth (TPG), and peak height velocity (PHV) were evaluated. PGS begins between the ages of 10 and 15 in boys and 8 and 13 in girls; children were allocated to the corresponding 1-year interval age maturity group. RESULTS For each sex, the earlier the start of PGS onset, the higher were PHV and TPG gain. However, adult heights were similar among the five pubertal maturity groups. Height SDS values for mean values of the very early, early, late and very late maturity groups calculated according to data from the five pubertal maturity groups taken together as a single group differed from zero in both sexes, mainly during the pubertal years for the very early (> +1) and very late (> -1) maturers. These differences disappeared at adult height. CONCLUSIONS Our data might contribute to better clinical evaluation of pubertal growth according to individual pubertal maturity tempo.

Insulin-Like Growth Factors in Childhood-Onset Gaucher Disease

There is a high prevalence of growth retardation in children with type 1 Gaucher disease. The cause of this poor growth is not yet known; however, studies have shown acceleration of growth with enzyme replacement therapy (ERT). IGF are recognized as important determinants of somatic growth. It has been proven that chronic diseases with liver involvement might cause IGF deficiency. The aim of this study was to assess the IGF system in patients with childhood-onset Gaucher disease, before and after ERT, and its association with other clinical and analytical parameters. Twenty-two patients with type I Gaucher disease were included. The diagnosis was established before 14 y of age in all patients. Baseline determinations of total IGF-I, free IGF-I, and IGF binding protein 3 (IGFBP-3) were obtained in 19 patients before starting ERT at a mean age of 13.8 ± 11.2 y. A Spearman test was performed to establish the association with other clinical and analytical parameters. In a group of 13 patients receiving IGF, changes were evaluated during the initial 2 y of treatment. A Wilcoxon test was performed for the statistical analysis. Total IGF-I, free IGF-I, and IGFBP-3 were expressed as SD scores (SDS). We found low levels of IGF and its binding proteins before ERT. A significant association was found between the total IGF-I SDS before treatment and the age-adjusted severity score index:r = −0.62, p < 0.05. Total IGF-I and IGFBP-3 SDS correlated negatively with the presence of the L444P mutation (r = −0.53 and −0.5, respectively, p < 0.05). Height SDS correlated with total IGF-I and IGFBP-3 SDS in eight children (r = 0.84 and 0.78, respectively, p < 0.05). Total IGF-I SDS increased from −1.8 ± 0.8 to −0.8 ± 1.4 (p = 0.005) and free IGF-I increased from −1.2 ± 1 to 1.1 ± 2.1 after 12 ± 6.8 mo (p = 0.011) of ERT. IGFBP-3 SDS increased from −1.3 ± 0.6 to −0.2 ± 1.2 (p = 0.012) after 12 ± 4.5 mo of ERT. Type 1 Gaucher disease is associated with low levels of IGF and its binding proteins, which could be a consequence of liver involvement. Total IGF-I deficiency is associated with the severity of the illness. Growth retardation in pediatric patients with Gaucher disease is related to the alterations in IGF axis. Total IGF-I and IGFBP-3 are the two parameters that better correlate with height before treatment. ERT results in significant increase of total IGF-I, free IGF-I, and IGFBP-3 during the first year of treatment.

Familial short stature and intrauterine growth retardation associated with a novel mutation in the IGF-I receptor (IGF1R) gene

IGF‐I is essential for normal human growth and mediates its effects through the IGF1R. IGF1R mutations have been associated with varying degrees of intrauterine and postnatal growth retardation.

Short stature diagnosis and referral

The “360° GH in Europe” meeting, which examined various aspects of GH diseases, was held in Lisbon, Portugal, in June 2016. The Merck KGaA (Germany) funded meeting comprised three sessions entitled “Short Stature Diagnosis and Referral,” “Optimizing Patient Management,” and “Managing Transition.” Each session had three speaker presentations, followed by a discussion period, and is reported as a manuscript, authored by the speakers. The first session examined current processes of diagnosis and referral by endocrine specialists for pediatric patients with short stature. Requirements for referral vary widely, by country and by patient characteristics such as age. A balance must be made to ensure eligible patients get referred while healthcare systems are not over-burdened by excessive referrals. Late referral and diagnosis of non-GH deficiency conditions can result in increased morbidity and mortality. The consequent delays in making a diagnosis may compromise the effectiveness of GH treatment. Algorithms for growth monitoring and evaluation of skeletal disproportions can improve identification of non-GH deficiency conditions. Performance and validation of guidelines for diagnosis of GH deficiency have not been sufficiently tested. Provocative tests for investigation of GH deficiency remain equivocal, with insufficient information on variations due to patient characteristics, and cutoff values for definition differ not only by country but also by the assay used. When referring and diagnosing causes of short stature in pediatric patients, clinicians need to rely on many factors, but the most essential is clinical experience.

Serum Insulin-Like Growth Factor (IGF)-I, IGF-II and IGF Binding Protein -3 Are Not Correlated With Weight of Fetal Rabbits † 907

Serum Insulin-Like Growth Factor (IGF)-I, IGF-II and IGF Binding Protein -3 Are Not Correlated With Weight of Fetal Rabbits † 907

DISTRIBUTION OF INSULIN-LIKE GROWTH FACTORS AND IGF BINDING PROTEINS DURING PREGNANCY IN THE RABBIT. † 1326

We have previously demonstrated a 16,000-fold increase in maternal insulin-like growth factor (IGF)-II with parallel changes in IGF binding proteins (IGFBPs) by mid-late gestation in the rabbit. The purpose of the present study was to characterize the distribution of the IGF-I, -II and IGFBPs and to identify the site(s) of production of these peptides in pregnant rabbits. In serum from nonpregnant rabbits and from does up to 24 days of gestation (term = 31-32 days), total circulating IGF was predominately associated with the 150 kDA ternary complex by neutral size-exclusion chromatography, but at day 30 both IGFs were carried by the smaller IGFBPs. The distribution of serum IGFBPs at day 24 revealed a substantial increase in the IGFBP-3 doublet and a broad 30kDa IGFBP eluting in fractions of the 150 kDa region, yet at day 30, all IGFBPs were substantially decreased. Although there was no IGFBP-3 proteolytic activity detected at day 24, but there was significant proteolytic activity at day 30, possible explaining the decreased IGFBPs. Northern blot analysis demonstrated that IGF-II and IGFBP-3 are produced by the placenta, while maternal liver is the source of IGFBP-1. These data suggest that the placenta is the key modulator of the IGF axis in the pregnant rabbit. (Supported by NIH CA-58110 and HL-44941, Dr. Labarta received scholarship 94/5373 from Fondo de Investigation Sanitaria, Spain).

SERUM INSULIN-LIKE GROWTH FACTOR (IGF)-I, -II AND IGF BINDING PROTEIN-3 DO NOT CORRELATE WITH FETAL SIZE IN THE RABBIT. 526

SERUM INSULIN-LIKE GROWTH FACTOR (IGF)-I, -II AND IGF BINDING PROTEIN-3 DO NOT CORRELATE WITH FETAL SIZE IN THE RABBIT. 526