Glucocorticoid Sensitivity Among Young Survivors of Childhood Acute Lymphoblastic Leukemia: What Does It Matter?

The aim of the study was to assess glucocorticoid sensitivity in survivors of childhood acute lymphoblastic leukemia using in vivo and in vitro tests. Thirty leukemia survivors of both sexes aged ≥18 years participated in the study and at least two years after therapy withdrawal. In vivo tests comprised: a) a very low dose intravenous dexamethasone suppression test for measurement of serum cortisol before, after, and % suppression, compared with 32 age-matched controls; and b) 0.25 mg overnight oral dexamethasone suppression test for assessment of salivary cortisol before, after, and % suppression. In vitro methods comprised: c) glucocorticoid receptor polymorphisms: BcI1-NR3C1 and A3669G; and d) splicing variant of glucocorticoid receptor GR-α mRNA by real-time quantitative polymerase chain reaction, compared with 32 controls. There was a reduction in salivary cortisol, and 73.3% of leukemia survivors showed high sensitivity according to % suppression after oral dexamethasone (p<0.05). Serum cortisol at baseline, after the test, % suppression after intravenous dexamethasone, and the percentage of high sensitivity were reduced in the leukemia group (%F=36.7; p<0.05). The BcI1-NR3C1 and A3669G polymorphisms were present in 11/30 (36.7%) and 5/30 (16.7%) patients, respectively. GR-α mRNA levels were lower in the leukemia group than in the controls (p<0.05). Survivors of acute lymphoblastic leukemia presented with reduced glucocorticoid sensitivity. Glucocorticoid sensitivity allows individualized treatment to avoid adverse effects and may be involved in cardiovascular disease risk among this particular group of cancer survivors.

Trio-based whole exome sequencing in patients with ectopic posterior pituitary.

Introduction: Ectopic posterior pituitary (EPP) is a rare congenital abnormality, sometimes associated with other midline defects, such as pituitary stalk interruption syndrome (PSIS), in which thin or absent pituitary stalk and anterior pituitary hypoplasia are combined to EPP. Most cases are sporadic, with few reports of familial cases, and many congenital hypopituitarism (CH) cases remain unsolved. Objective: To search for candidate genes associated with this condition, we performed trio-based whole-exome sequencing (WES) on patients with EPP, including two familial cases. Methods: This study included subjects with EPP and PSIS diagnosed by a simple MRI protocol (FAST1.2). We performed two distinct analyses in the trio-based WES. We looked for previously described genes associated with pituitary development. Next, we investigated the whole exome for variants inherited in a pattern consistent with a monogenic etiology. Results: Ten families were evaluated; eight were composed of a child with EPP and healthy parents, one has two affected siblings, and one family has a son and mother with EPP. When analyzing the previously described candidate variants associated with pituitary development, we found variants in GLI2 and FGFR1 in three families. We also found six other variants of interest in three patients: KMT2A, GALR3, RTN4R, SEMA3A, NIPBL, and DSCAML1. Conclusion: The analysis allowed us to find previously reported and not reported GLI2 variants, all inherited from healthy parents, which reinforces the incomplete penetrance pattern of GLI2 variants in the development of EPP and draws attention to possible future functional studies of those variants that have a recurrent expression in CH. We also found novel FGFR1 and SEMA3A variants that suggest an oligogenic mechanism in PSIS and EPP, as seen in patients with hypogonadotropic hypogonadism. We report the first case of a patient with Wiedemann-Steiner syndrome and PSIS, suggesting that the KMT2A gene may be related to pituitary development. Furthermore, the trios' analysis allowed us to find five other variants of interest. Future investigations may clarify the roles of these variants in the etiology of EPP and PSIS.

Extra-pituitary midline structural abnormalities associated with ectopic posterior pituitary detected on a new rapid MRI protocol (FAST1.2)

ABSTRACT Objective: Test if the MRI FAST1.2 protocol can detect extra-pituitary midline structural brain abnormalities in patients with ectopic posterior pituitary (EPP), and highlighting their radiological-laboratory correlations. Subjects and methods: Cross-sectional study of patients with EPP and control group. All individuals were submitted to FAST1.2, which combines the FAST1 protocol developed by our group with 3D T2DRIVE imaging. Results: We evaluated 36 individuals with EPP and 78 as control group. Pituitary stalk (PS) was identified in 7/36 patients in EPP group by FAST1, and in 24/36 patients in FAST1.2 (p < 0.001). FAST1 failed to detect PS in one individual in the control group, while the FAST1.2 defined the PS in all individuals. In EPP group, eleven had interhypothalamic adhesion (IHA), three septo-optic dysplasia, and one cerebellar malformation. We didn't observe higher frequency of panhypopituitarism or developmental delay in patients with IHA. In control group, three had pars intermedia cysts, one hydrocephalus, and one hypothalamic hamartoma. Conclusions: FAST1.2 allows confident recognition of midline structural abnormalities, including the pituitary stalk and IHA, thereby making MRI acquisition faster and with no need for contrast administration. IHA could be associated with defects in neuronal migration, as occur in patients with EPP, with no clinical significance.

Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature.

Objective: Most children with short stature remain without an etiologic diagnosis after extensive clinical and laboratory evaluation and are classified as idiopathic short stature (ISS). This study aimed to determine the diagnostic yield of a multigene analysis in children classified as ISS. Design and methods: We selected 102 children with ISS and performed the genetic analysis as part of the initial investigation. We developed customized targeted panel sequencing, including all genes already implicated in the isolated short-stature phenotype. Rare and deleterious single nucleotide or copy number variants were assessed by bioinformatic tools. Results: We identified 20 heterozygous pathogenic (P) or likely pathogenic (LP) genetic variants in 17 of 102 patients (diagnostic yield = 16.7%). Three patients had more than one P/LP genetic alteration. Most of the findings were in genes associated with the growth plate differentiation: IHH (n = 4), SHOX (n = 3), FGFR3 (n = 2), NPR2 (n = 2), ACAN (n = 2), and COL2A1 (n = 1) or involved in the RAS/MAPK pathway: NF1 (n = 2), PTPN11 (n = 1), CBL (n = 1), and BRAF (n = 1). None of these patients had clinical findings to guide a candidate gene approach. The diagnostic yield was higher among children with severe short stature (35% vs 12.2% for height SDS ≤ or > -3; P = 0.034). The genetic diagnosis had an impact on clinical management for four children. Conclusion: A multigene sequencing approach can determine the genetic etiology of short stature in up to one in six children with ISS, removing the term idiopathic from their clinical classification.

Extra-pituitary midline structural abnormalities associated with ectopic posterior pituitary detected on a new rapid MRI protocol (FAST1.2).

Objective: Test if the MRI FAST1.2 protocol can detect extra-pituitary midline structural brain abnormalities in patients with ectopic posterior pituitary (EPP), and highlighting their radiological-laboratory correlations. Subjects and methods: Cross-sectional study of patients with EPP and control group. All individuals were submitted to FAST1.2, which combines the FAST1 protocol developed by our group with 3D T2DRIVE imaging. Results: We evaluated 36 individuals with EPP and 78 as control group. Pituitary stalk (PS) was identified in 7/36 patients in EPP group by FAST1, and in 24/36 patients in FAST1.2 (p < 0.001). FAST1 failed to detect PS in one individual in the control group, while the FAST1.2 defined the PS in all individuals. In EPP group, eleven had interhypothalamic adhesion (IHA), three septo-optic dysplasia, and one cerebellar malformation. We didn't observe higher frequency of panhypopituitarism or developmental delay in patients with IHA. In control group, three had pars intermedia cysts, one hydrocephalus, and one hypothalamic hamartoma. Conclusion: FAST1.2 allows confident recognition of midline structural abnormalities, including the pituitary stalk and IHA, thereby making MRI acquisition faster and with no need for contrast administration. IHA could be associated with defects in neuronal migration, as occur in patients with EPP, with no clinical significance.

Adding T2-Weighted Images to FAST1 Protocol to Evaluate the Anatomy of the Hypothalamic-Pituitary Region.

INTRODUCTION: Ectopic posterior pituitary (EPP) is a malformation of the hypothalamic-pituitary region presented as a spectrum from isolated growth hormone deficiency (GHD) to multiple pituitary hormone deficiencies (MPHDs). Our goal was to establish whether the FAST1.2 protocol, which combines the FAST1 protocol with 3D-T2 DRIVE images, could identify the pituitary stalk (PS) and the regional anatomy more accurately. METHODS: A retrospective study of 36 individuals with EPP and hypopituitarism and a control group of 78 individuals with eutopic posterior pituitary was conducted. All individuals were submitted to FAST1.2. The position and size of the pituitary lobes were described, and the presence/absence of the PS was confirmed. RESULTS: FAST1 identified the PS in 19% of individuals with EPP, while FAST1.2 identified the PS in 67% (p < 0.001). In the FAST1.2 protocol, the PS was visible in all control individuals. All EPP patients with isolated GHD had visible PS in FAST1.2, while only 58.6% of MPHD cases had visible PS. The size of the anterior lobe and the anteroposterior length of the posterior pituitary were smaller in the EPP group versus controls (p < 0.001). We noticed a reduced anterior pituitary lobe in both diameters in MPHD patients (p < 0.05). Six patients acquired new pituitary hormone deficiencies not recognized at the time of MRI; in this group, only 1 patient had a PS not visible in FAST1.2. DISCUSSION/CONCLUSION: The FAST1.2 protocol could prevent the misdiagnosis of idiopathic GHD in patients with short stature and could also be important in the progression to MPHD. The PS could be considered a predictor of hypopituitarism, but its use as an isolated indicator for the progression to MPHD is not recommended. Our results reinforce the use of the size of the anterior lobe as a predictor of hypopituitarism and a possible predictor of the degree of pituitary insufficiency. The FAST1.2 protocol could be used as an alternative to gadolinium administration, as a cheaper and faster method, while eliminating the potential risks associated with the administration of contrast media.

The impact of COVID-19 in children and adolescents with obesity in Brazil.

Objective: The primary goal of the study was to evaluate weight gain in children and adolescents with obesity during the COVID-19 pandemic period, and compare it with the period before the pandemic. Methods: The sample comprised 68 children with obesity aged between 7 and 18 years, 30 (44.1%) boys and 38 (55.9%) girls, who were attended at the pediatric endocrinology clinic of the Irmandade da Santa Casa de Misericórdia de São Paulo, SP, Brazil. Weight gain in the sample in the pre-lockdown period (December 2, 2018 to March 11, 2020) was compared with that in the lockdown period (March 11, 2020 to February 21, 2021). Results: Approximately one year before the start of the pandemic period, the mean (SD) chronological age was 10.1 years old (± 2.4), and an average weight gain of 4.4 kg (± 4.8) was observed during the pre-lockdown period described. One year after the start of the pandemic, mean (SD) chronological age was 11.8 years old (± 2.4), and an average weight gain of 8.5 kg (± 7.6) was observed in the lockdown period described. When we compared the weight gain in the two periods, it was higher in the pandemic period, both in girls and boys (p = 0.013 and 0.035, respectively). Conclusion: The results of the study show that the period of social isolation adopted to mitigate the COVID-19 pandemic was associated with increased weight gain in the studied population, probably due to a reduction in physical activities and an increase in energy consumption.

The impact of COVID-19 in children and adolescents with obesity in Brazil

ABSTRACT Objective: The primary goal of the study was to evaluate weight gain in children and adolescents with obesity during the COVID-19 pandemic period, and compare it with the period before the pandemic. Subjects and methods: The sample comprised 68 children with obesity aged between 7 and 18 years, 30 (44.1%) boys and 38 (55.9%) girls, who were attended at the pediatric endocrinology clinic of the Irmandade da Santa Casa de Misericórdia de São Paulo, SP, Brazil. Weight gain in the sample in the pre-lockdown period (December 2, 2018 to March 11, 2020) was compared with that in the lockdown period (March 11, 2020 to February 21, 2021). Results: Approximately one year before the start of the pandemic period, the mean (SD) chronological age was 10.1 years old (± 2.4), and an average weight gain of 4.4 kg (± 4.8) was observed during the pre-lockdown period described. One year after the start of the pandemic, mean (SD) chronological age was 11.8 years old (± 2.4), and an average weight gain of 8.5 kg (± 7.6) was observed in the lockdown period described. When we compared the weight gain in the two periods, it was higher in the pandemic period, both in girls and boys (p = 0.013 and 0.035, respectively). Conclusion: The results of the study show that the period of social isolation adopted to mitigate the COVID-19 pandemic was associated with increased weight gain in the studied population, probably due to a reduction in physical activities and an increase in energy consumption.

Estrogen receptor mRNA determined by Quantitative Real-Time PCR in the nasal mucosa of women taking oral contraceptives / Receptor ARNm de estrógeno determinado por PCR Cuantitativa en Tiempo Real en la mucosa nasal de mujeres tratadas con anticonceptivos orales

SUMMARY: Estrogen receptors (ER) have been identified in human nasal mucosa, but its physiologic and pathologic impacts are not totally established. ER have been demonstrated in nasal mucosa by several authors, mainly by immunohistochemical method in nasal mucosa samples surgically removed. The present study aimed to quantify ERα and ERβ mRNA concentration by using an absolute quantitative real-time PCR in cells from nasal mucosa smear of women under oral contraceptive therapy. Nasal epithelium smear samples were collected from 110 patients divided in two groups: 55 women who present regular menstrual cycle without using contraceptives and 55 women who present regular menstrual cycle and have been using oral contraceptives for more than 3 months. All the patients answered a rhinitis symptoms questionnaire. The current study showed the potential usefulness of nasal turbinate mucosa cell sourcing, collected through swab, for extracting useful RNA for gene expression. We have identified the predominant expression of ERα isoform in a ratio 10-15 times higher compared to ERβ isoform. There is a tendency for positive correlation between the ERb isoform and the rhinitis severity score.

RESUMEN: Se han identificado receptores de estrógeno (RE) en la mucosa nasal humana, sin embargo sus impactos fisiológicos y patológicos aún no están totalmente establecidos. Varios autores han demostrado RE en la mucosa nasal, principalmente por método inmunohistoquímico en muestras obtenidas quirúrgicamente. El presente estudio tuvo como objetivo cuantificar la concentración de ARNm de REa y REb mediante el uso de una PCR cuantitativa absoluta en tiempo real en células de frotis de mucosa nasal de mujeres bajo terapia anticonceptiva oral. Se recolectaron muestras de frotis de epitelio nasal de 110 pacientes divididas en dos grupos: 55 mujeres que presentan ciclo menstrual regular sin uso de anticonceptivos y 55 mujeres que presentan ciclo menstrual regular con uso de anticonceptivos orales durante más de 3 meses. Todas las pacientes respondieron un cuestionario de síntomas de rinitis. El estudio actual mostró la utilidad de la obtención de células de la mucosa de la concha nasal, recolectadas a través de un hisopo, para extraer ARN para la expresión génica. Hemos identificado la expresión predominante de la isoforma REμ en una proporción de 10 a 15 veces mayor en comparación con la isoforma REß. Hemos identificado la expresión predominante de la isoforma REα en una proporción de 10 a 15 veces mayor en comparación con la isoforma REß. Existe una tendencia a una correlación positiva entre la isoforma REß y la puntuación de gravedad de la rinitis.

Androgens by immunoassay and mass spectrometry in children with 46,XY disorder of sex development.

OBJECTIVE: Steroid measurement is a challenge in pediatric endocrinology. Currently, liquid chromatography with tandem mass spectrometry (LC-MS/MS) is considered a gold standard for this purpose. The aim of this study was to compare both LC-MS/MS and immunoassay (IA) for androgens before and after human recombinant chorionic gonadotropin (rhCG) stimulus in children with 46,XY disorders of sex development (DSD). METHODS: Nineteen patients with 46,XY DSD were evaluated; all of them were prepubertal and non-gonadectomized. Testosterone, dihydrotestosterone (DHT), DHEA and androstenedione were measured by IA and LC-MS/MS before and 7 days after rhCG injection. The correlation between IA and LC-MS/MS was analyzed by the intraclass correlation coefficient (ICC) and Spearman's rank correlation coefficient (SCC). For concordance analysis the Passing and Bablok (PB) regression and the Bland and Altman (BA) method were used. RESULTS: Testosterone showed excellent correlation (ICC = 0.960 and SCC = 0.964); DHT showed insignificant and moderate correlations as indicated by ICC (0.222) and SCC (0.631), respectively; DHEA showed moderate correlation (ICC = 0.585 and SCC = 0.716); and androstenedione had poor and moderate correlations in ICC (0.363) and SCC (0.735), respectively. Using the PB method, all hormones showed a linear correlation, but proportional and systematic concordance errors were detected for androstenedione, systematic errors for testosterone and no errors for DHEA and DHT. By the BA method, there was a trend of IA to overestimate testosterone and androstenedione and underestimate DHEA and DHT when compared to LC-MS/MS. CONCLUSION: Traditional IA should be replaced by LC-MS/MS for the androgens measurement in prepubertal children whenever is possible.

Association between SNPs and Loss of Methylation Site on the CpG island of the Promoter Region of the Smoothened Gene, Potential Molecular Markers for Susceptibility to the Development of Basal Cell Carcinoma in the Brazilian Population.

OBJECTIVE: Perform genotyping of SNPs in the promoter region of the SMO gene in BCC samples from patients from northeastern Brazil, and to determine if there is an association of these SNPs of the gene in question with the susceptibility to the development of the BCC. METHODS: 100 samples of paraffined tissue from patients with histopathological diagnosis of BCC and 100 control samples were analyzed for each polymorphism by a newly developed genotyping method, the Dideoxy Single Allele Specific - PCR. The software Bioestat - version 5.3 and Haploview 4.2 were used for the statistical analysis. For all tests a P-value.

Elastography for the evaluation of thyroid nodules in pediatric patients.

OBJECTIVE: To evaluate the usefulness of elastography (using manual compression) as an additional diagnostic tool for children and adolescents with thyroid nodules. MATERIALS AND METHODS: This was a prospective study conducted between September 2012 and August 2013 at a hospital in Brazil. We performed elastography, ultrasound, and fine-needle aspiration biopsy in 32 patients between 6 and 18 years of age who had, in total, 38 thyroid nodules. RESULTS: The elastography findings correlated with the histopathological diagnosis in 78.5% of cases. In three patients, an unnecessary thyroidectomy could have been avoided if the elastography results had been prioritized. Only one malignant thyroid nodule was found to show high elasticity. CONCLUSION: Our results suggest that high elasticity of a nodule on elastography is associated with a low risk of thyroid cancer. If further confirmed in other studies, elastography may prove useful as a complementary test for screening thyroid nodules in children.

OBJETIVO: Avaliar a utilidade da elastografia (usando compressão manual) como uma ferramenta adicional de diagnóstico em crianças e adolescentes com nódulos da tireoide. MATERIAIS E MÉTODOS: Este foi um estudo prospectivo realizado entre setembro de 2012 e agosto de 2013 em um hospital no Brasil. Realizamos elastografia, ultrassonografia e biópsia por aspiração com agulha fina em 32 pacientes com idade entre 6 e 18 anos que tinham, no total, 38 nódulos tireoidianos. RESULTADOS: Os achados da elastografia em relação ao histopatológico foram corretos em 78,5% dos casos. A elastografia poderia ter evitado a tireoidectomia desnecessária de três pacientes. Apenas um nódulo maligno da tireoide foi classificado como E1. CONCLUSÃO: Nossos resultados sugeriram que a alta elasticidade de um nódulo na elastografia está associada a um baixo risco de câncer de tireoide. Caso se confirme em outros estudos, a elastografia pode ser útil como teste de triagem complementar de nódulos tireoidianos em crianças.

Elastography for the evaluation of thyroid nodules in pediatric patients / A elastografia na avaliação de nódulos tireoidianos em pacientes pediátricos

Abstract Objective: To evaluate the usefulness of elastography (using manual compression) as an additional diagnostic tool for children and adolescents with thyroid nodules. Materials and Methods: This was a prospective study conducted between September 2012 and August 2013 at a hospital in Brazil. We performed elastography, ultrasound, and fine-needle aspiration biopsy in 32 patients between 6 and 18 years of age who had, in total, 38 thyroid nodules. Results: The elastography findings correlated with the histopathological diagnosis in 78.5% of cases. In three patients, an unnecessary thyroidectomy could have been avoided if the elastography results had been prioritized. Only one malignant thyroid nodule was found to show high elasticity. Conclusion: Our results suggest that high elasticity of a nodule on elastography is associated with a low risk of thyroid cancer. If further confirmed in other studies, elastography may prove useful as a complementary test for screening thyroid nodules in children.

Resumo Objetivo: Avaliar a utilidade da elastografia (usando compressão manual) como uma ferramenta adicional de diagnóstico em crianças e adolescentes com nódulos da tireoide. Materiais e Métodos: Este foi um estudo prospectivo realizado entre setembro de 2012 e agosto de 2013 em um hospital no Brasil. Realizamos elastografia, ultrassonografia e biópsia por aspiração com agulha fina em 32 pacientes com idade entre 6 e 18 anos que tinham, no total, 38 nódulos tireoidianos. Resultados: Os achados da elastografia em relação ao histopatológico foram corretos em 78,5% dos casos. A elastografia poderia ter evitado a tireoidectomia desnecessária de três pacientes. Apenas um nódulo maligno da tireoide foi classificado como E1. Conclusão: Nossos resultados sugeriram que a alta elasticidade de um nódulo na elastografia está associada a um baixo risco de câncer de tireoide. Caso se confirme em outros estudos, a elastografia pode ser útil como teste de triagem complementar de nódulos tireoidianos em crianças.

AGK-BRAF is associated with distant metastasis and younger age in pediatric papillary thyroid carcinoma.

BACKGROUND: The incidence of thyroid carcinoma has increased in most populations, including pediatric patients. The increase is almost exclusively due to an increase in the incidence of papillary thyroid carcinoma (PTC). Genetic alterations leading to mitogen-activated protein kinase (MAPK) pathway activation are highly prevalent in PTC, with BRAF V600E mutation being the most common event in adult PTC. Although a lower prevalence of BRAF V600E had been reported among pediatric patients, a higher prevalence of BRAF fusion has been identified in both radiation-exposed and sporadic pediatric PTC. However, little is known about the prognostic implications of BRAF fusions in pediatric PTC. PROCEDURE: In this study, we investigated the prevalence of BRAF alterations (AGK-BRAF fusion and BRAF V600E mutation) in a large set of predominantly sporadic pediatric PTC cases and correlate with clinicopathological features. Somatic AGK-BRAF fusion was investigated by RT-PCR and confirmed by FISH break-apart. The BRAF V600E mutation was screened using Sanger sequencing. RESULTS: AGK-BRAF fusion, found in 19% of pediatric PTC patients, was associated with distant metastasis and younger age. Conversely, the BRAF V600E, found in 15% of pediatric PTC patients, was correlated with older age and larger tumor size. CONCLUSION: Collectively, our results advance knowledge concerning genetic bases of pediatric thyroid carcinoma, with potential implications for diagnosis, prognosis, and therapeutic approaches.

Single-Nucleotide Polymorphisms of the MSH2 and MLH1 Genes, Potential Molecular Markers for Susceptibility to the Development of Basal Cell Carcinoma in the Brazilian Population.

Basal cell carcinoma - BCC is considered a multifactorial neoplasm involving genetic, epigenetic and environmental factors. Where UVB radiation is considered the main physical agent involved in BCC carcinogenesis. The Brazil and state of Paraíba are exposed to high levels of UVB rays. The mismatch repair - MMR is important DNA repair mechanisms to maintain replication fidelity. Therefore, single nucleotide polymorphisms (SNPs) in genes encoding proteins involved in MMR may be potential molecular markers of susceptibility to BCC. The objective of this study was to evaluate and describe for the first time the SNPs rs560246973, rs2303425 and rs565410865 and risk of developing BCC. The present study analyzed 100 samples of paraffin-embedded tissue from patients with histopathological diagnosis of BCC and 100 control samples. The results were obtained by genotyping method, Dideoxy Unique Allele Specific - PCR (DSASP). The SNPs rs2303425 were not associated with Basal Cell Carcinoma. However, the SNPs rs560246973 and rs565410865 was shown to be associated with the development of BCC when compared to control samples (P < 0.0001). The SNPs rs565410865 was also statistical significance between the genotypes of and the age group (p = 0.0027) and tumor location (p = 0,0191). The result suggests that SNPs rs2303425 and rs565410865 are associated with susceptibility to the development of BCC in the Brazilian population and may be considered as potential molecular markers for BCC.

Height Increment and Laboratory Profile of Boys Treated With Aromatase Inhibitors With or Without Growth Hormone.

Aromatase inhibitors (AIs) have been used to recover height loss due to their capacity to delay growth plate closure. Long-term studies describing final heights are needed to determine the efficacy and safety profiles of these drugs for the treatment of impaired growth. This study aims to identify the therapeutic efficiency of AIs in improve growth and to describe potential adverse effects during treatment. Retrospective data analysis of 96 adolescents, among which 22 patients already attained near-final height, were followed at outpatient clinics of two referral centers. Patients were all in puberty and present idiopathic decrease in predicted adult height. Patients were treated with Anastrozole (ANZ: 1 mg/day) or Letrozole (LTZ: 2.5 mg/day) with/without recombinant human growth hormone (0.05 mg/kg/day) for 1.0 to 3.5 years (2.1±1.2 years). Height gain, body mass index, lipid, liver enzyme, gonadotropins and testosterone levels were described before and at the end of treatment. Predicted adult height (PAH) and NF height were compared with the TH. The height SDS (adjusted to bone age) significantly increased (p<0.05) in all groups [0.8±0.7 (ANZ), 0.7±0.7 (ANZ+GH), 0.3±0.5 (LTZ), and 1.2±0.8 (LTZ+GH)]; the latter group exhibited the highest increment of PAH and growth recovery to the TH (p<0.004). No significant side effects were observed. AI treatment, especially when used in association with GH was able to improve growth and the attainment of familial target height.

Distinct inflammatory gene expression in extraocular muscle and fat from patients with Graves' orbitopathy.

OBJECTIVE: This study sought to compare patients with thyroid eye disease (TED) and normal controls with respect to the expression of the NR3C1, CHUK, IKBKB, FOS, NFKB and HSD11B1 genes in orbital fat (OF) and extraocular muscle (EOM). DESIGN AND METHODS: A prospective study design was used to evaluate 34 TED patients and 38 healthy controls. OF was harvested from 33 TED patients and 27 controls. EOM biopsies were obtained from 32 TED patients and 18 controls. Samples were examined by real-time PCR and evaluated using appropriate statistical analyses with a significance cut-off of P < 0.05. RESULTS: NR3C1 mRNA levels were higher in TED EOM (median 213 (96-376)) than those in control EOM (78 (34-138)) (P < 0.001), and NFKB expression was elevated in TED muscle (223 (31-520)) relative to that in control muscle (8 (6-31)) (P < 0.001). HSD11B1 expression was higher in TED EOM (0.78 (0.47-2.01)) than that in control EOM (0.22 (0.09-0.51)) (P < 0.001). Levels of CHUK, IKBKB, and FOS were higher in TED EOM (115 (20-223), 111 (54-299) and 0.11 (0.03-0.19), respectively) than those in control EOM (5.8 (2-13), 21 (5-52) and 0.05 (0.001-0.03) respectively) (P < 0.001). CONCLUSION: Tissues involved in GO exhibited different mRNA levels of NR3C1, CHUK, IKBKB, FOS, NFKB and HSD11B1. Gene expression in OF was similar for TED patients and controls. CHUK, IKBKB, FOS, NFKB, and HSD11B1 mRNA levels were higher in TED EOM than those in control EOM. NFKB was disproportionally elevated compared with NR3C1; this finding was indicative of a local proinflammatory profile.

Gonadal response after a single-dose stimulation test with recombinant human chorionic gonadotropin (rhCG) in patients with isolated prepubertal cryptorchidism.

BACKGROUND: The evaluation of prepubertal gonadal Leydig cells secretion requires gonadotropin stimulation. Urinary hCG (human chorionic gonadotropin) is currently unavailable in many countries, however, recombinant hCG (rhCG) can be used. Our aim was to evaluate rhCG-stimulated testicular hormones in a group of patients with cryptorchidism. METHODS: We evaluated 31 prepubertal boys (age range, 0.75-9.0 years) presenting with unilateral (n = 24) or bilateral (n = 7) cryptorchidism. Patients with other genital abnormalities, previous use of hCG or testosterone or previous surgeries were excluded. Blood samples were obtained at baseline and 7 days after a single subcutaneous dose of rhCG (Ovidrel® 250 mcg) to measure the testosterone, DHT (dihydrotestosterone), AMH (anti-Mullerian hormone), and inhibin B levels. RESULTS: rhCG stimulation significantly increased testosterone levels from 10 ng/dl to 247.8 ± 135.8 ng/dl, increased DHT levels from 4.6 ± 0.8 to 32.3 ± 18.0 ng/dl, and increased the T/DHT ratio from 2.2 ± 0.4 to 8.0 ± 3.5. There was also a significant increase in inhibin B (from 105.8 ± 65.2 to 132.4 ± 56.1 pg/ml; p < 0.05) and AMH levels (from 109.4 ± 52.6 to 152.9 ± 65.2 ng/ml; p < 0.01) after the rhCG stimulation. CONCLUSIONS: In this cohort, hormonal responses can be elicited after the rhCG stimulation test, suggesting that rhCG is a promising stimulation test to replace the urinary hCG test during the evaluation of gonadal Leydig cells function. The clinical applicability and adequate performance of rhCG testing must be investigated in future studies.

CONTEXTE: L'évaluation de la sécrétion des cellules gonadiques de Leydig prépubères nécessite une stimulation par les gonadotrophines. La gonadotrophine chorionique humaine (hCG) urinaire est actuellement indisponible dans de nombreux pays; toutefois, l'hCG recombinante (rhCG) peut être utilisée. Notre objectif était d'évaluer les hormones testiculaires sous stimulation par rhCG dans un groupe de patients qui présentaient une cryptorchidie. MÉTHODES: Nous avons évalué 31 garçons prépubères (âgés de 0,75 à 9 ans) qui présentaient une cryptorchidie uni (n=24) ou bilatérale (n=7). Ont été exclus les patients avec d'autres anomalies génitales, ceux qui avaient été traités auparavant par hCG ou testostérone ou par chirurgie. Des échantillons sanguins ont été prélevés au départ et à 7 jours après une unique dose sous cutanée de rhCG (Ovidrel® 250 mcg) pour les mesures des taux de testostérone, dihydrotestostérone (DHT), hormone antimüllérienne (AMH) et inhibine B. RÉSULTATS: La stimulation par rhCG augmente de façon significative les taux de testostérone de 10 ng/dl à 247.8±135.8 ng/dl, de DHT de 4.6±0.8 à 32.3±18.0 ng/dl, et le ratio T/DHT de 2.2±0.4 à 8.0±3.5. Les taux d'inhibine B (de 105.8±65.2 à 132.4±56.1 pg/ml; p< 0.05) et d'AMH (de 109.4±52.6 to 152.9±65.2 ng/ml; p< 0.01) ont aussi été significativement augmentés après stimulation par rhCG. CONCLUSION: Dans cette cohorte, des réponses hormonales ont été obtenues après le test de stimulation par rhCG; ceci suggère que rhCG est un test de stimulation prometteur pour remplacer le test par l'hCG urinaire lors de l'évaluation de la fonction gonadique des cellules de Leydig. L'applicabilité clinique et l'évaluation adéquate de la performance du test par rhCG doivent être étudiées dans de futures études.