Venous thromboembolism in Cushing syndrome: results from an EuRRECa and Endo-ERN survey.

Background: Patients with Cushing syndrome (CS) are at increased risk of venous thromboembolism (VTE). Objective: The aim was to evaluate the current management of new cases of CS with a focus on VTE and thromboprophylaxis. Design and methods: A survey was conducted within those that report in the electronic reporting tool (e-REC) of the European Registries for Rare Endocrine Conditions (EuRRECa) and the involved main thematic groups (MTG's) of the European Reference Networks for Rare Endocrine Disorders (Endo-ERN) on new patients with CS from January 2021 to July 2022. Results: Of 222 patients (mean age 44 years, 165 females), 141 patients had Cushing disease (64%), 69 adrenal CS (31%), and 12 patients with ectopic CS (5.4%). The mean follow-up period post-CS diagnosis was 15 months (range 3-30). Cortisol-lowering medications were initiated in 38% of patients. One hundred fifty-four patients (69%) received thromboprophylaxis (including patients on chronic anticoagulant treatment), of which low-molecular-weight heparins were used in 96% of cases. VTE was reported in six patients (2.7%), of which one was fatal: two long before CS diagnosis, two between diagnosis and surgery, and two postoperatively. Three patients were using thromboprophylaxis at time of the VTE diagnosis. The incidence rate of VTE in patients after Cushing syndrome diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Conclusion: Thirty percent of patients with CS did not receive preoperative thromboprophylaxis during their active disease stage, and half of the VTE cases even occurred during this stage despite thromboprophylaxis. Prospective trials to establish the optimal thromboprophylaxis strategy in CS patients are highly needed. Significance statement: The incidence rate of venous thromboembolism in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Notably, this survey showed that there is great heterogeneity regarding time of initiation and duration of thromboprophylaxis in expert centers throughout Europe.

SRD5A2 gene mutations and polymorphisms in Spanish 46,XY patients with a disorder of sex differentiation.

One hundred and forty-six index patients with 46,XY DSD in whom gonads were confirmed as testes were consecutively studied for a molecular diagnosis during the period 2002-2010. AR gene was analysed in all patients as the first candidate gene, yielding a mutation in 42.5% of cases and SRD5A2 gene was analysed as the second candidate gene, resulting in the characterization of 10 different mutations (p.Y91D, p.G115D, p.Q126R, p.R171S, p.Y188CfsX9, p.N193S, p.A207D, p.F219SfsX60, p.R227Q and p.R246W) in nine index patients (6.2% of the total number of 46,XY DSD patients). One of the mutations (p.Y188CfsX9) has never been reported. In addition, we genotyped SRD5A2 gene p.V89L and c.281+15T>C polymorphisms in 46,XY DSD and in 156 normal adult males and found that patients with SRD5A2 mutations or without a known molecular diagnosis presented a higher frequency of homozygous p.L89, homozygous TT and combined CCTT genotypes compared with controls. This result suggests that 46,XY DSD patient phenotypes may be influenced by SRD5A2 polymorphism genotypes. SRD5A2 gene mutations may not be as infrequent as previously considered in 46,XY DSD patients with variable degrees of external genitalia virilization at birth and normal T production and appears to be the second aetiology in our series.

The exon 3-deleted/full-length growth hormone receptor polymorphism does not influence the effect of puberty or growth hormone therapy on glucose homeostasis in short non-growth hormone-deficient small-for-gestational-age children: results from a two-year controlled prospective study.

CONTEXT: The exon 3-deleted/full-length (d3/fl) GH receptor polymorphism (d3/fl-GHR) has been associated with responsiveness to GH therapy in short small-for-gestational-age (SGA) patients, although consensus is lacking. However, its influence on glucose homeostasis, at baseline or under GH therapy, has not been investigated. OBJECTIVE: Our objective was to evaluate whether the d3/fl-GHR genotypes influence insulin sensitivity in short SGA children before or after puberty onset or during GH therapy. DESIGN: We conducted a 2-yr prospective, controlled, randomized trial. SETTING: Thirty Spanish hospitals participated. Auxological, GH secretion, and glucose homeostasis evaluation was hospital based, whereas molecular analyses and data computation were centralized. PATIENTS: Patients included 219 short SGA children [body mass index sd score (SDS) < or = 2.0]; 159 were prepubertal (group 1), and 60 had entered puberty (group 2). INTERVENTION: Seventy-eight patients from group 1 were treated with GH (66 microg/kg.d) for 2 yr (group 3). MAIN OUTCOME MEASURES: Previous and 2-yr follow-up auxological and biochemical data were recorded, d3/fl-GHR genotypes determined, and data analyzed. RESULTS: In groups 1 and 2, fasting glucose, insulin, homeostasis model assessment (HOMA), and quantitative insulin sensitivity check index (QUICKI) were similar in each d3/fl-GHR genotype. Group 2 glucose, insulin, and HOMA were significantly higher and QUICKI lower than in group 1. In group 3 GH-treated patients, height SDS, growth velocity SDS, fasting glucose, insulin, and HOMA significantly increased as did body mass index SDS at the end of the second year, and QUICKI decreased during the first and second years, with no differences among the d3/fl-GHR genotypes. CONCLUSION: In short SGA patients, the d3/fl-GHR genotypes do not seem to influence prepubertal or pubertal insulin sensitivity indexes or their changes over 2 yr of GH therapy (66 mug/kg.d).

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.

Spanish growth studies 2008. New anthropometric standards.

Cross-sectional and longitudinal growth studies have recently been conducted in Spain. These studies have allowed neonatal anthropometry in premature and term neonates and postnatal growth in children and adolescents to be evaluated. Moreover, a longitudinal study that allows pubertal growth to be evaluated for distinct groups according to maturation has also been published. Between 1999 and 2002, birth weight and vertex-heel length were evaluated in 9,362 newborns (4,884 boys and 4,478 girls), with a gestational age of 26-42 weeks. An increase in these values compared with previous Spanish studies (1987-1992) and sexual dimorphism were observed. Between 2000 and 2004, height, weight and body mass index (BMI) were evaluated in 32,064 individuals (16,607 males, 15,457 females) aged 0-24 years. An increasing secular trend was observed compared with data obtained 20 years previously. Increases in BMI exceeded those in height for BMI values above the 50th percentile. A longitudinal growth study of 458 healthy individuals (223 boys, 235 girls) born between 1978 and 1982 yielded pubertal growth and maturity standards for each of the five pubertal maturity groups. In addition, data on skinfolds, bone mass and intellectual development from birth to adulthood were also provided. Adult height in both studies was similar to that reported by European and American studies, but was lower than that reported for German, Swedish and Dutch populations. In males, BMI was higher than in other European populations and was close to that of the US population. In females, BMI was similar to that in European populations and was lower than that in the US population.

Successful use of cinacalcet to treat parathyroid-related hypercalcemia in two pediatric patients.

Two pediatric patients with different causes of hyperparathyroidism are reported. First patient is a 13-year-old male with severe hypercalcemia due to left upper parathyroid gland adenoma. After successful surgery, calcium and phosphate levels normalized, but parathormone levels remained elevated. Further studies revealed a second adenoma in the right gland. The second patient is a 13-year-old female with uncommon hypercalcemia symptoms. Presence of pathogenic calcium-sensing receptor gene (CASR) mutation was found, resulting in diagnosis of symptomatic familial hypocalciuric hypercalcemia. Cinacalcet, a calcium-sensing agent that increases the sensitivity of the CASR, was used in both patients with successful results. LEARNING POINTS: Hyperparathyroidism is a rare condition in pediatric patients. If not treated, it can cause serious morbidity.Genetic tests searching for CASR or MEN1 gene mutations in pediatric patients with primary hyperparathyroidism should be performed.Cinacalcet has been effective for treating different causes of hyperparathyroidism in our two pediatric patients.Treatment has been well tolerated and no side effects have been detected.

Osteoporosis and multiple fractures in an antiretroviral-naive, HIV-positive child.

As a result of the increased incidence of osteopenia and osteoporosis in HIV-infected patients, numerous publications have suggested that there may be a link between bone metabolism alterations and HIV infection. The early bone loss seen in these patients was initially attributed to the use of highly active antiretroviral treatment (HAART) that included protease inhibitors. Recent studies, however, have suggested that it may be a direct consequence of the viral infection on bone metabolism, persistent activation of pro-inflammatory cytokines (TNFa), or altered vitamin D metabolism secondary to the virus, combined with subsequent factors (e.g., antiretroviral treatment) that aggravate the bone demineralization. We present an antiretroviral-naive 6-year-old girl with vertically transmitted HIV infection who presented with severe osteoporosis and multiple pathological fractures of the vertebrae, ribs, and upper and lower limbs. The child was treated with HAART, appropriate nutritional support for her age, physiotherapy and rehabilitation, calcium and vitamin D supplements, and alendronate therapy. After 6 weeks of treatment, the intense pain and muscle atrophy had disappeared and she was able to walk unassisted. At 6 months, bone mass had increased by 72%. The interest of this case lies in the presence of severe osteoporosis and multiple pathological fractures in an HIVinfected naive child. To date, this condition has only been described in patients treated with antiretrovirals. Moreover, this is the first reported HIV-positive pediatric patient treated with bisphosphonates, which proved to be highly successful.

[Anthropometric patterns in non-Caucasian full-term neonates of African, Moroccan and South American origin born in Catalonia (Spain)]. / Patrones antropométricos de los recién nacidos a término de grupos étnicos de raza no caucásica procedentes de Africa subsahariana, Marruecos y Sudamérica nacidos en Cataluña.

INTRODUCTION: The rise in immigration to Spain in recent decades has increased the number of non-Caucasian newborns in our environment. The aims of this study were to establish normal intrauterine development values for weight, length and head circumference in a population of non-Caucasian full-term newborns (FTN). PATIENTS AND METHODS: We studied 2,444 healthy full-term singleton newborns (37-42 weeks' gestational age; 1,230 boys, 1,214 girls) with the following ethnic origins: black (n =1,257; 622 boys, 635 girls), Moroccan (n =520; 297 boys, 223 girls) and South-American (n =667; 356 boys, 311 girls). Mean values and standard deviations were estimated for each week of gestation for sex and race and these values were compared with those of a Spanish population of the same gestational age and sex. RESULTS: Anthropometric values in black FTN were similar to those of the Catalan population. By contrast, these values were higher in Moroccans and South-American FTN than in the native population. Statistically-significant differences were observed in all the parameters evaluated from the 38th week of gestation in full-term Moroccan newborns compared with the reference population. Statistically significant differences were observed in full-term South-American newborns from the 38th week of gestation in girls and from the 40th week in boys. The presence of sexual dimorphism in the anthropometric patterns evaluated was not constant at all the gestational ages evaluated. CONCLUSIONS: Anthropometric patterns of the Spanish Caucasian FTN population are not extrapolable to FTN of other ethnicities.

Spontaneous, but not induced, puberty permits adequate bone mass acquisition in adolescent Turner syndrome patients.

Lumbar L2-L4 bone mineral density (BMD) values were measured in 37 adolescent and young adult Turner syndrome patients. Nine had developed spontaneous puberty and had had regular menses since menarche (12.55 years +/- 1.17 years) to the time of BMD evaluation (14.96 years +/- 1.26 years). In the other 28, puberty was induced with increasing doses of oral ethinyl estradiol (2.5-10.0 microg/day, for 2 years) and later administration of estrogen/gestagen therapy up to the time of BMD evaluation. In 18, the adolescent group, menarche appeared at 14.68 years +/- 0.63 years and BMD was evaluated at 17.77 years +/- 0.70 years, and in the other 10, the young adult group, menarche appeared at 14.47 years +/- 0.53 years and BMD was evaluated at 20.90 years +/- 0.68 year. BMD values were in the normal range in those who had developed spontaneous puberty (Z score values, -0.24 +/- 0.22) and in the osteopenia range in those in whom puberty was induced (Z score values, -2.09 +/- 0.79 and -2.18 +/- 0.32 for the adolescent and young adult groups, respectively) p < 0.0001. Height Z score values were similar in all three groups (-3.45 +/- 0.77, -3.15 +/- 0.83, and -3.08 +/- 0.33, respectively). No significant differences in calcium intake or physical activity were found among groups. Neither the karyotype distribution nor growth hormone (GH) therapy (five in the spontaneous puberty and six in the induced puberty groups had been treated for a 3.5- to 4.4-year period) explained the differences in BMD values. Because the main difference between groups was the availability of estrogens to bone tissue from infancy to menarche and of estrogens/gestagens from then on up to the time of BMD evaluation, our results suggest that normal gonadal function from infancy to adulthood may be required for adequate bone mass peaking. Early detection of osteopenia and improvement in general measures for adequate bone mass peaking (calcium intake and physical activity) should be considered mandatory in the health care of these patients.

[Anomalous origin of the right pulmonary artery from the ascending aorta. Its echo-Doppler diagnosis]. / Origen anómalo de la arteria pulmonar derecha desde la aorta ascendente. Diagnóstico eco-Doppler.

The anomalous origin of the right pulmonary artery from the ascending aorta is a rare malformation. Its diagnosis and early surgical treatment are necessary to avoid its fatal outcome. We present the pulsed and color echo-Doppler findings in a patient with this pathology.

[Bone mass in patients with cystic fibrosis of the pancreas. Relationship with anthropometric parameters and genotype]. / Masa ósea en pacientes con fibrosis quística de páncreas. Relación con parámetros antropométricos y genotipo.

BACKGROUND: Cross-sectional study of bone mineral density (BMD) in children and adolescents with cystic fibrosis of the pancreas. The relationship of BMD values with nutritional status, respiratory function and the cystic transmembrane regulator genotype was also evaluated. PATIENTS AND METHODS: BMD expressed as grams of hydroxyapatite/cm2 was measured by dual-energy X-ray absorptiometry in the lumbar spine (L2-L4) in 41 patients (21 males and 20 women; age range: 4-21 years) with cystic fibrosis of the pancreas and compared with that of 471 normal controls (256 males and 215 women; age range: 1-20 years). Twenty patients were prepubertal, 9 pubertal and 12 young adults. RESULTS: Clinical repercussion of the disease evaluated by clinical and anthropometric data (weight, height and body mass index) and respiratory function was considered moderate. Height z score (mean [MSE]) was -0.53 (0.28), weight -0.81 (0.21) and body mass index -0.82 (0.12) BMD z score values (mean [MSE]) were -1.14 (0.17) and differed significantly (p < 0.001) from those of normal age- and sex-matched controls. No significant differences were observed between males and women or among prepubertal, pubertal and young adult patients. BMD z score values less than-1 z score were found in 53% and under -2 z score in 8%. Cystic transmembrane regulator genotype was studied in 36 patients (17 were F508/-, 10 F508/F508, 5 G542X/- and 4 diverse) and did not predict bone mineral status. A statistically significant correlation was found between BMD z score values and height z score, weight z score, body mass index z score and clinical assessment according to Shwachman criteria. A negative and statistically significant correlation was observed between BMD z score and functional score. CONCLUSIONS: The decrease in BMD values in CF patients begins early in life and appears to be related to the degree of clinical expression of the disease.

[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.

[Anthropometric growth patterns of preterm and full-term newborns (24-42 weeks' gestational age) at the Hospital Materno-Infantil Vall d'Hebron (Barcelona)(1997-2002]. / Patrones antropométricos de los recién nacidos pretérmino y a término (24-42 semanas de edad gestacional) en el Hospital Materno-Infantil Vall d'Hebron (Barcelona) (1997-2002).

BACKGROUND AND OBJECTIVE: Gestational age and neonatal anthropometric parameters are significant predictive factors of neonatal and adult morbidity. Our objective was to evaluate these parameters in a population of preterm and full-term newborns. SUBJECTS AND METHOD: We retrospectively analyzed neonatal anthropometric parameters (weight, vertex-heel length and head circumference) in 1470 live preterm neonates born at 24-36 weeks' gestation between 1997 and 2002. The same parameters were prospectively analyzed in 1786 live newborns born at 37-42 weeks after uncomplicated pregnancies between 2001 and 2002. All preterm and full-term neonates were the result of single pregnancies and were born at the Hospital Materno-Infantil Vall d'Hebron in Barcelona. Only Caucasian neonates whose parents were born in Spain were included. In the group of full-term neonates all measurements were made by the same researcher. RESULTS: The mean and standard deviation and percentile distribution values of weight, length and head circumference according to sex and gestational age are presented. These parameters progressively increased with gestational age and sexual dimorphism from the 30th week of gestation onwards, with statistically significant differences (p < 0.05) for all parameters at 38-42 weeks' gestational age. The mean gains in male full-term newborns compared with female full-term newborns were: 129.1 g of weight, 0.68 cm of length and 0.45 cm of head circumference (P < 0.05). In our population, 10th percentile values for weight and length were higher than those in other Spanish populations reported in 1988 and 1996. CONCLUSIONS: Sexual dimorphism was found in intrauterine anthropometric growth parameters. These parameters change over time and should be updated periodically.

[Considerations regarding the treatment of non-aganglionic congenital intestinal neuropathies]. / Consideraciones al tratamiento de las neuropatías intestinales congénitas no agangliónicas.

Hyperganglionosis or neuronal intestinal dysplasias (NID) and hypoganglionosis (HO) are intestinal diseases of difficult diagnosis and treatment and diverse evolution, despite identical histologic findings. The aim of this study was to discuss the therapeutic problems derived from the patients differing clinical course. Retrospective review of 14 patients with regard to diagnosis, manometry and histology (hematoxylin-eosin, acetylcholinesterase activity, immunohistochemistry and Smith's silver stain) was done. Six patients presented intestinal occlusion or sub-occlusion from the first months of life with impeded oral feeding. Ileostomy was performed in 5 and total colectomy with anastomosis in 1. All patients required parenteral nutrition; cisapride was added in 2. Three died from sepsis (3 NID). Of the 3 survivors, 2 have ileostomies (2 NID) and the other ileo-rectal anastomosis (NID). Of the remaining patients, two presented aganglionism and the finding of proximal hyperganglionism occurred post-surgery. Surgery was repeated in one patient. The remaining 6 (1 HO, 5 NID) were diagnosed between 3 and 10 years of age because of constipation. Four are under treatment with cisapride and 2 required partial colic resection. No relationship can be established between histologic findings and clinical manifestations. In chronic clinical courses, treatment with cisapride and cleaning enemas should be tried first. Acute clinical pictures (occlusion-sub occlusion) should be treated by decompressive ileostomy. Partial colic resection may lead to new intestinal failure.

[Acute gastric volvulus in a patient with asplenic syndrome]. / Vólvulo gástrico agudo en un paciente con síndrome de asplenia.

A 18 month-old boy with asplenic syndrome was admitted to our hospital with a twelve hours history of mucous vomiting, abdominal pain and a round epigastric mass. It was diagnosed as having a gastric volvulus and an emergency laparotomy was performed. The stomach was situated at the right side and a mesenterioaxial volvulus was found, with cyanosis of the antrum. The gastrophrenic and gastrosplenic ligaments were absent. The clinical and radiological characteristics of asplenic syndrome are reviewed. The pediatric surgeons must be aware of the digestive malformations of the asplenic syndrome, because some of that like malfixation of the stomach could be the cause of an acute abdomen.

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.

[Obesity-related metabolic disorders in childhood and adolescence]. / Complicaciones metabólicas de la obesidad infantil.

Obesity is the most frequent nutritional disorder in childhood and adolescence. The rise in its prevalence and severity has underlined the numerous and significant obesity-related metabolic disorders. Altered glucose metabolism, manifested as impaired glucose tolerance, appears early in severely obese children and adolescents. Obese young people with glucose intolerance are characterized by marked peripheral insulin resistance and relative beta-cell failure. Lipid deposition in muscle and the visceral compartment, and not only obesity per se, is related to increased peripheral insulin resistance, the triggering factor of the metabolic syndrome. Other elements of the metabolic syndrome, such as dyslipidaemia, and hypertension, are already present in obese youngsters and worsen with the degree of obesity. The long-term impact of obesity-related insulin resistance on cardiovascular morbidity in these patients is expected to emerge as these youngsters become young adults.

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.

Retinol-binding protein 4 levels in obese children and adolescents with glucose intolerance.

BACKGROUND: Retinol-binding protein 4 (RBP4) is known to be involved in obesity-associated insulin resistance. AIMS: To study the relationships between the degree of adiposity, insulin resistance indices, plasma lipids, inflammatory parameters, glucose intolerance (GI) status and plasma RBP4 levels in obese children and adolescents. PATIENTS AND METHODS: Prospective study comprising 199 obese patients (95 boys) aged 8-16 years (11.8 +/- 1.9). Fifty-three subjects (23 boys) of similar mean age, 11.3 +/- 2.1 years, served as controls. BMI, waist and hip circumferences, plasma lipids, and inflammatory parameters were measured and patients underwent an oral glucose tolerance test. Plasma RBP4 levels were determined by nephelometry. RESULTS: Plasma RBP4 levels (pg/ml) in obese patients with GI (n = 15) were higher (45.0 +/- 14.1) compared with those of obese patients without GI (35.9 +/- 11.7, p = 0.02; n = 184) and controls (31.5 +/- 12.3, p = 0.04) in a generalized linear model adjusted for age, sex, BMI and pubertal status. A negative correlation was found between the skeletal muscle insulin resistance index and RBP4; positive correlations were found between the RBP4 and BMI Z-score (r = 0.213, p < 0.001), waist circumferences (r = 0.135, p < 0.05), plasma triglycerides (r = 0.187, p = 0.005) and apolipoprotein B (0.187, p = 0.007). CONCLUSIONS: Our results suggest a direct relationship between circulating insulin and RBP4 levels, which indicates that this protein might contribute to the development of muscle insulin resistance.

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.