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.

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.

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)

Osteoporosis juvenil idiopática / Idiopathic juvenile osteoporosis

No disponible

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.

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

La obesidad es el trastorno nutricional más frecuente durante la infancia y adolescencia. El incremento de su prevalencia y de la intensidad del exceso ponderal han puesto de manifiesto las numerosas e importantes comorbilidades asociadas a la misma. La hiperinsulinemia y la resistencia a la insulina son el eje central del desarrollo posterior de estados de intolerancia a la glucosa, diabetes tipo 2 y/o síndrome metabólico. El depósito de grasa en el espacio visceral abdominal y en el espacio miocelular, y no la obesidad per se, es el principal factor independiente de riesgo para desarrollar resistencia a la insulina y el síndrome metabólico. Otros elementos del síndrome metabólico, como la dislipemia y la hipertensión pueden también estar ya presentes en los niños y adolescentes obesos y están estrechamente relacionados con el grado de adiposidad y con la presencia de resistencia a la insulina. En el transcurso de los últimos años se ha comprobado que la persistencia de la obesidad y de sus alteraciones metabólicas en la edad adulta incrementa de forma significativa el riesgo de presentar enfermedad cardiovascular degenerativa precoz y determina una menor esperanza de vida (AU)

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 (AU)

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.

[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.

Aceleración secular de peso, talla e IMC. Estudios españoles transversales y longitudinales de crecimiento 2008 / Secular acceleration of weight, height and BMI. Cross-sectional and longitudinal Spanish studies on growth 2008

En España recientemente han finalizado estudios de crecimiento transversales que permiten evaluar la antropometría neonatal de recién nacidos prematuros y a término, y el crecimiento postnatal de niños y adolescentes. Además, disonemos de estudios longitudinales que permiten evaluar el crecimiento puberal diferenciado para cada grupo madurador. El peso y longitud al nacer fueron evaluados (1999-2002) en 9.362 recién nacidos, 26-42 semanas de edad gestacional, observándose dimorfismo sexual y un incremento en ambos parámetros respecto a estudios previos (1987-1992) particularmente en el grupo de recién nacidos pretérmino. El peso, talla e IMC fueron evaluados (2000-2004) en 32.064 niños y adolescentes (16.607 varones y 15.457 mujeres) de 0-24 años de edad, observándose aceleración secular en los tres parámetros respecto a estudios realizados hace 20 años. El incremento ponderal fue excesivo respecto al de talla, para los valores del IMC superiores al percentil 50. El estudio longitudinal (458 sujetos: 223 varones,235 mujeres, nacidos entre 1978 y 1982) permitió obtener patrones de crecimiento y de maduración puberal diferenciados para cada uno de los cinco grupos maduradores. La talla adulta en ambos estudios, es similar a la reportada en estudios europeos y americanos, aunque inferior a la alemana, sueca y holandesa. En varones el IMC fue superior al observado en países europeos y próximos al reportado en EE.UU. En mujeres el IMC fue similar al de países europeos e inferior al reportado en EE.UU (AU)

Cross-sectional and longitudinal growth studies have recently been conducted in Spain. Between 1999 and 2002, weight and vertex-heel length were evaluated in 9,362 new-borns (4,884 males, 4,478 females), 26-42 weeks of gestational age. Age increase in these values compared with previous Spanish studies (1987-1992) and sexual dimorphism were observed. Between 2000 and 204, height, weight and body mass index were evaluated in 32,064 subjects 816,607 males, 15,457 females) from birth to adulthood. A secular trend of growth was observed compared to data obtained 20 years ago, with a higher increase in BMI values above the 50 th percentile. A longitudinal growth study of 458 healthy subjects (223 boys, 235 girls) born between 1978 and 1982 yielded pubertal growth and maturity standards for each of the five pubertal maturity groups. Adult height was similar to that reported by European and American studies, but lower than that reported for German, Swedish and Netherlands populations. In males, BMI was higher than in other European population and near to the USA population. In females, BMI was similar to European populations and lower than in the USA population (AU)

Estudios españoles de crecimiento 2008. Nuevos patrones antropométricos / Spanish growth studies 2008. New anthropometric standards

En España, recientemente han finalizado estudios de crecimiento transversales que permiten evaluar la antropometría neonatal de prematuros y a término, y el crecimiento posnatal y de niños y adolescentes. Además, disponemos de un estudio longitudinal que permite evaluar el crecimiento puberal diferenciado para cada grupo madurador. El peso y la longitud al nacer fueron evaluados (1999-2002)en 9.362 recién nacidos (4.884 niños, 4.478 niñas), 26-42 semanas de edad estacional, y se observó dimorfismo sexual y un incremento en ambos parámetros respecto a estudios previos (1987-1992). El peso, la talla y el índice de masa corporal (IMC) fueron evaluados (2000-2004) en 32.064niños y adolescentes (16.607 varones y 15.457 mujeres) de 0-24 años de edad, y se observó aceleración secular en los 3 parámetros respecto a estudios realizados hace 20 años. El incremento ponderal fue excesivo respecto al de talla, para los valores del IMC superiores al percentil 50. El estudio longitudinal (458 sujetos: 223 varones, 235 mujeres, nacidos en1978-1982) permitió obtener patrones de crecimiento y de maduración puberal diferenciados para cada uno de los 5 grupos maduradores y datos de pliegues cutáneos, masa ósea y desarrollo intelectual desde el nacimiento a la edad adulta. La talla adulta, en ambos estudios, es similara la comunicada en estudios europeos y americanos, aunque inferior a la alemana, la sueca y la holandesa. En varones el IMC fue mayor que el observado en países europeos y próximo al de Estados Unidos. En mujeres el IMC fue similar al de países europeos e inferior al comunicado en Estados Unidos (AU)

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 of26-42 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 (16,607males, 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 the50th percentile. A longitudinal growth study of 458 healthy individuals (223 boys,235 girls) born between 1978 and 1982yielded 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 population sand 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 (AU)

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).

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.

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.

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.