Publications by authors named "Raquel Corripio"

21 Publications

  • Page 1 of 1

Vaginal bleeding in a misdiagnosed Mayer-Rokitansky-Küster-Hauser syndrome.

BMJ Case Rep 2021 Apr 5;14(4). Epub 2021 Apr 5.

Department of Pediatric Endocrine, Parc Tauli Foundation-UAB University Institute, Sabadell, Catalunya, Spain

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, a spectrum of anomalies arising from incomplete development of the Müllerian ducts, is characterised by congenital aplasia of the uterus and upper part of the vagina, often in the absence of other phenotypical abnormalities. We report the case of a 13-year-old girl referred to our endocrinology unit after an incidental finding of uterine agenesis during laparoscopy to correct suspected ovarian torsion. Initial transabdominal ultrasonography found no uterus. Given her normal secondary sex characteristics, karyotype and hormone profile, MRKH syndrome was initially diagnosed. However, after vaginal bleeding compatible with menstruation, repeat transabdominal ultrasonography and MRI revealed a left-deviated unicornuate uterus.
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http://dx.doi.org/10.1136/bcr-2020-241387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8030473PMC
April 2021

NK Cell Subsets Changes in Partial Remission and Early Stages of Pediatric Type 1 Diabetes.

Front Immunol 2020 25;11:611522. Epub 2021 Jan 25.

Immunology Service, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.

Type 1 diabetes (T1D) is a chronic metabolic disease characterized by the autoimmune destruction of β-cells in the pancreatic islets. T1D is preceded by islet-specific inflammation led by several immune cells. Among them, natural killer (NK) cells are emerging as important players in T1D development. Human NK cells are characterized by CD56 and CD16 expression, which allows classifying NK cells into four subsets: 1) CD56CD16 or effector NK cells (NK); 2) CD56CD16 or regulatory NK cells (NK); 3) intermediate CD56CD16 NK cells; and 4) CD56CD16 NK cells, whose function is not well determined. Since many studies have shown that T1D progression is associated with changes in various immune cell types, we hypothesize that the kinetics of NK cell subsets in the blood could correlate with different stages of T1D. To that aim, pediatric patients newly diagnosed with T1D were recruited, and peripheral NK cell subsets were analyzed by flow cytometry at several disease checkpoints: disease onset, partial remission (PR), 8 months (for non-remitters), and 12 months of progression. Our results showed that total NK cells and their four subsets are altered at the early stages of T1D. A decrease in the counts and percentage of total NK cells and NK cells at the different disease stages was found when compared to controls. These results suggest the extravasation of these cells into the islets at disease onset, which is maintained throughout the follow-up. By contrast, NK cells increased during the early stages after T1D onset, and both intermediate NK cells and CD56CD16 NK cells diminished at the PR stage, which might reflect the immunoregulatory attempts and could be candidate biomarkers for this stage. Also, CD56CD16 NK cells increased during T1D progression. Finally, changes in CD16 expression were identified in the different T1D stages, highlighting a CD16 expression reduction in total NK cells and NK cells 1 year after diagnosis. That may reflect a state of exhaustion after multiple cell-to-cell interactions. Altogether, our preliminary data provide a longitudinal picture of peripheral NK cell subpopulations during the different T1D stages, which could be potential candidate biomarkers indicators of disease progression.
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http://dx.doi.org/10.3389/fimmu.2020.611522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869615PMC
June 2021

Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations.

J Clin Endocrinol Metab 2021 Mar;106(4):1041-1050

Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

Context: Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP).

Objective: To describe the clinical and hormonal features of a large cohort of patients with CPP due to MKRN3 mutations and compare the characteristics of different types of genetic defects.

Methods: Multiethnic cohort of 716 patients with familial or idiopathic CPP screened for MKRN3 mutations using Sanger sequencing. A group of 156 Brazilian girls with idiopathic CPP (ICPP) was used as control group.

Results: Seventy-one patients (45 girls and 26 boys from 36 families) had 18 different loss-of-function MKRN3 mutations. Eight mutations were classified as severe (70% of patients). Among the 71 patients, first pubertal signs occurred at 6.2 ± 1.2 years in girls and 7.1 ± 1.5 years in boys. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation and higher follicle-stimulating hormone levels than ICPP. Patients with severe MKRN3 mutations had a greater bone age advancement than patients with missense mutations (2.3 ± 1.6 vs 1.6 ± 1.4 years, P = .048), and had higher basal luteinizing hormone levels (2.2 ± 1.8 vs 1.1 ± 1.1 UI/L, P = .018) at the time of presentation. Computational protein modeling revealed that 60% of the missense mutations were predicted to cause protein destabilization.

Conclusion: Inherited premature activation of the reproductive axis caused by loss-of-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels.
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http://dx.doi.org/10.1210/clinem/dgaa955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993586PMC
March 2021

Effects of Subsp. (BPL1) Supplementation in Children and Adolescents with Prader-Willi Syndrome: A Randomized Crossover Trial.

Nutrients 2020 Oct 13;12(10). Epub 2020 Oct 13.

Institut de Recerca Sant Joan de Déu, 08950 Barcelona, Spain.

Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by a wide range of clinical manifestations, including obesity, hyperphagia, and behavioral problems. subsp. strain BPL1 has been shown to improve central adiposity in adults with simple obesity. To evaluate BPL1's effects in children with PWS, we performed a randomized crossover trial among 39 patients (mean age 10.4 years). Participants were randomized to placebo-BPL1 ( = 19) or BPL1-placebo ( = 20) sequences and underwent a 12-week period with placebo/BPL1 treatments, a 12-week washout period, and a 12-week period with the crossover treatment. Thirty-five subjects completed the study. The main outcome was changes in adiposity, measured by dual-energy X-ray absorptiometry. Secondary outcomes included lipid and glucose metabolism, hyperphagia, and mental health symptoms. Generalized linear modeling was applied to assess differences between treatments. While BPL1 did not modify total fat mass compared to placebo, BPL1 decreased abdominal adiposity in a subgroup of patients older than 4.5 years ( = 28). BPL1 improved fasting insulin concentration and insulin sensitivity. Furthermore, we observed modest improvements in some mental health symptoms. A follow-up trial with a longer treatment period is warranted to determine whether BPL1 supplementation can provide a long-term therapeutic approach for children with PWS (ClinicalTrials.gov NCT03548480).
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http://dx.doi.org/10.3390/nu12103123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650793PMC
October 2020

Novel Genetic and Biochemical Findings of DLK1 in Children with Central Precocious Puberty: A Brazilian-Spanish Study.

J Clin Endocrinol Metab 2020 10;105(10)

Department of Pediatrics, Universidad Autónoma de Madrid. Departments of Pediatrics and Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, IMDEA Food Institute. Madrid, Spain.

Background: Central precocious puberty (CPP) has been associated with loss-of-function mutations in 2 paternally expressed genes (MKRN3 and DLK1). Rare defects in the DLk1 were also associated with poor metabolic phenotype at adulthood.

Objective: Our aim was to investigate genetic and biochemical aspects of DLK1 in a Spanish cohort of children with CPP without MKRN3 mutations.

Patients: A large cohort of children with idiopathic CPP (Spanish PUBERE Registry) was studied. Genomic deoxyribonucleic acid was obtained from 444 individuals (168 index cases) with CPP and their close relatives. Automatic sequencing of MKRN3 and DLK1 genes were performed.

Results: Five rare heterozygous mutations of MKRN3 were initially excluded in girls with familial CPP. A rare allelic deletion (c.401_404 + 8del) in the splice site junction of DLK1 was identified in a Spanish girl with sporadic CPP. Pubertal signs started at 5.7 years. Her metabolic profile was normal. Familial segregation analysis showed that the DLK1 deletion was de novo in the affected child. Serum DLK1 levels were undetectable (<0.4 ng/mL), indicating that the deletion led to complete lack of DLK1 production. Three others rare allelic variants of DLK1 were also identified (p.Asn134=; g.-222 C>A and g.-223 G>A) in 2 girls with CPP. However, both had normal DLK1 serum levels.

Conclusion: Loss-of-function mutations of DLK1 represent a rare cause of CPP, reinforcing a significant role of this factor in human pubertal timing.
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http://dx.doi.org/10.1210/clinem/dgaa461DOI Listing
October 2020

Specific Dietary Components and Gut Microbiota Composition are Associated with Obesity in Children and Adolescents with Prader-Willi Syndrome.

Nutrients 2020 Apr 11;12(4). Epub 2020 Apr 11.

Institut de Recerca Sant Joan de Déu, 08950 Barcelona, Spain.

Prader-Willi syndrome is a rare genetic disorder associated with impaired body composition, hyperphagia, and excessive weight gain. Strict dietary restrictions from an early age is crucial to prevent or delay the early onset of obesity, which is the main driver of comorbidities in these patients. The aim of this study was to identify dietary and gut microbiota components closely linked to weight status of these patients. We studied a cohort of children and adolescents with genetic diagnosis of Prader-Willi syndrome ( = 31), in which we determined adiposity by Dual-energy X-ray absorptiometry (DXA) and dietary composition with 4-day food records. Furthermore, we obtained fecal samples to assess microbiota composition by 16S sequencing. Multivariate regression models showed that body mass index standard deviation score (BMI-SDS) and body fat mass were directly associated with saturated fat intake and meat consumption, and inversely associated with fruit consumption. Furthermore, the gut microbiome from normal weight patients was characterized by higher phylogenetic diversity compared to those overweight or obese, with differential abundance of several genera, including , , and . Notably, abundance was inversely correlated to adiposity, lipid and glucose homeostasis parameters, and meat intake. Our results suggest that limiting meat and increasing fruit intake might be beneficial for body weight management in children and adolescents with Prader-Willi syndrome.
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http://dx.doi.org/10.3390/nu12041063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230364PMC
April 2020

Measurement Properties of the Online EuroQol-5D-Youth Instrument in Children and Adolescents With Type 1 Diabetes Mellitus: Questionnaire Study.

J Med Internet Res 2019 11 12;21(11):e14947. Epub 2019 Nov 12.

Health Services Research Group, Hospital del Mar Medical Research Institute, Barcelona, Spain.

Background: The lack of continuity between health-related quality of life (HRQoL) instruments designed for children and adults hinders change analysis with a life course approach. To resolve this gap, EuroQol (EQ) developed the EQ-5D-Youth (EQ-5D-Y), derived from the EQ-5D for adults. Few studies have assessed the metric properties of EQ-5D-Y in children with specific chronic conditions, and none have done so for children with type I diabetes mellitus (T1DM).

Objective: This study aimed to evaluate the acceptability, validity, reliability, and responsiveness of the EQ-5D-Y in children and adolescents with T1DM, when administered online.

Methods: Participants with T1DM were consecutively recruited from July to December 2014, from a list of potential candidates aged 8-19 years, who attended outpatient pediatric endocrinology units. Before every quarterly routine visit, participants received an email/telephone reminder to complete the online version of two generic HRQoL questionnaires: EQ-5D-Y and KIDSCREEN-27. The EQ-5D-Y measures five dimensions, from which an equally weighted summary score was constructed (range: 0-100). Completion rate and distribution statistics were calculated. Construct validity was evaluated through known group comparisons based on general health, acute diabetic decompensations, mental health, family function, and a multitrait, multimethod matrix between EQ-5D-Y and KIDSCREEN by using Spearman correlations. Construct validity hypotheses were stated a priori. Reliability was assessed with the intraclass correlation coefficient and responsiveness by testing changes over time and calculating the effect size. Reliability and responsiveness were tested among the stable and improved subsamples defined by a KIDSCREEN-10 index change of <4.5 points or ≥4.5 points, respectively, from the first to the fourth visit.

Results: Of the 136 participants, 119 (87.5%) responded to the EQ-5D-Y at the last visit. The dimensions that showed higher percentages of participants with problems were "having pain/discomfort" (34.6%) and "worried/sad/unhappy" (28.7%). The mean (SD) of the EQ-5D-Y summary score was 8.5 (10.9), with ceiling and floor effects of 50.7% and 0%, respectively. Statistically significant HRQoL differences between groups defined by their general health (excellent/very good and good/regular/bad) and mental health (Strengths and Difficulties Questionnaire score ≤15 and >16, respectively) were found in three EQ-5D-Y dimensions ("doing usual activities," "having pain/discomfort," and "feeling worried/sad/unhappy"), summary score (effect size for general health and mental health groups=0.7 and 1.5, respectively), and KIDSCREEN-10 index (effect size for general health and mental health groups=0.6 and 0.9, respectively). Significant differences in the EQ-5D-Y dimensions were also found according to acute diabetic decompensations in "looking after myself" (P=.005) and according to family function in "having pain/discomfort" (P=.03). Results of the multitrait, multimethod matrix confirmed three of the four relationships hypothesized as substantial (0.21, 0.58, 0.50, and 0.46). The EQ-5D-Y summary score presented an intraclass correlation coefficient of 0.83. Statistically significant change between visits was observed in the improved subsample, with an effect size of 0.7 (P<.001).

Conclusions: These results support the use of the EQ-5D-Y administered online as an acceptable, valid, reliable, and responsive instrument for evaluating HRQoL in children and adolescents with T1DM.
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http://dx.doi.org/10.2196/14947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880238PMC
November 2019

Safety and effectiveness of growth hormone therapy in infants with Prader-Willi syndrome younger than 2 years: a prospective study.

J Pediatr Endocrinol Metab 2019 Aug;32(8):879-884

Service of Clinical Genetics, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autónoma de Barcelona, Sabadell, Barcelona, Spain.

Background There is little evidence of the effects of early treatment with growth hormone (GH) in infants with Prader-Willi syndrome (PWS). A prospective study was conducted to assess the safety of GH therapy in infants younger than 2 years of age with PWS. Methods A total of 14 patients with PWS started treatment with GH under the age of 2 years and were followed over a 2-year period. A deletion of chromosome 15 was present in nine infants (64.3%) and maternal uniparental disomy 15 in five infants (35.7%). The median age at start of GH treatment was 9.6 months (interquartile range [IQR] 9.0-18.3 months). Changes in height standard deviation score (SDS), body mass index (BMI) SDS and subcapsular and tricipital skinfolds in the follow-up period were evaluated with a mixed-model regression analysis using the Package R. Results There were no fatal adverse events. A significant decrease (p < 0.001) in tricipital and subcapsular skinfold thickness, with an upward trend of height SDS and a downward trend of BMI SDS, was observed. Infants who started GH before 15 months of age started walking at a median of 18.0 [17.0-19.5] months vs. 36.6 [36.3-37.8] months for those who began treatment with GH after 15 months of age (p = 0.024). Conclusions GH treatment in infants with PWS less than 2 years of age is safe and improved body composition. Infants who received GH before the age of 15 months started to walk earlier.
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http://dx.doi.org/10.1515/jpem-2018-0539DOI Listing
August 2019

Insulinoma: A Rare Cause of Hypoglycemia in Childhood.

Am J Case Rep 2018 Sep 21;19:1121-1125. Epub 2018 Sep 21.

Department of Pediatric Endocrinology, Parc Taulí Hospital Universitari, Research and Innovation Institute Parc Taulí I3PT, Autonomous University of Barcelona, Sabadell, Spain.

BACKGROUND Insulinomas are pancreatic neuroendocrine tumors that cause non-ketotic hypoglycemia due to hyperinsulinism; they are extremely rare, especially in children. CASE REPORT We present a case of a sporadic insulinoma in an 11-year-old boy who had episodes of self-limited drowsiness and behavior changes over a 3-month period, thought to be caused by psychological issues. Non-ketotic hypoglycemia was confirmed at our center. A fasting blood test found inappropriately elevated insulin levels during hypoglycemia, undetectable β-hydroxybutyrate, and increased C-peptide levels in line with insulin levels. Anti-insulin antibodies were negative and antidiabetic drugs untraceable. The glucagon-stimulation test was positive. Growth hormone, adrenocorticotropin hormone, and phosphorus and calcium metabolism were normal. Dual-phase computed tomography detected a lesion compatible with an insulinoma. Endoscopic ultrasound showed a homogenous lesion at the junction of the body and tail of the pancreas. Histologic analysis of a fine-needle aspiration biopsy was compatible with neuroendocrine neoplasia. Preoperatively, a fractional diet avoiding fast-absorbing carbohydrates maintained normal glucose blood levels. Enucleation was not possible, so the lesion was resected along with portions of the body and tail of the pancreas. The well-differentiated tumor measured 15 mm x 13 mm. Postoperative blood glucose levels were correct, allowing a normal diet. CONCLUSIONS In children with unspecific symptoms compatible with hypoglycemia, blood glucose must be evaluated to confirm low blood glucose levels. Determining blood ketone levels is important for the differential diagnosis. The diagnostic approach to pediatric insulinoma represents a challenge for multidisciplinary teamwork.
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http://dx.doi.org/10.12659/AJCR.910426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161565PMC
September 2018

Impact of monitoring health-related quality of life in clinical practice in children with type 1 diabetes mellitus.

Qual Life Res 2017 12 12;26(12):3267-3277. Epub 2017 Aug 12.

Health Services Research Unit, IMIM-Hospital del Mar Institute of Medical Research, Barcelona Biomedical Research Park (office 138.03), Dr Aiguader 88, 08003, Barcelona, Spain.

Purpose: To test whether the systematic monitoring of health-related quality of life (HRQOL) in clinical practice in Spanish pediatric patients with T1DM helps improve their daily life in a multicenter longitudinal study.

Methods: One hundred thirty-six patients participated, recruited from five centers in Barcelona, Spain (72 girls, mean age 13.4 years). Complete data were collected for 119 patients (85%). Pediatricians were randomly assigned to the HRQOL intervention (n = 70), or control group (n = 49). The intervention group discussed the results of HRQOL face to face with the physician, quarterly over a year. The control group received care as usual. HRQOL was assessed using KIDSCREEN-27 collected online. Standardized mean differences (effect size, ES) and generalized estimating equation (GEE) were computed to compare group differences between baseline and follow-up, taking into account sociodemographic and clinical variables.

Results: Statistically significant higher scores were seen in the intervention group at follow-up for the dimensions of Psychological well-being (ES = 0.56), School environment (ES = 0.56), and the KIDSCREEN-10 index (ES = 0.63). No differences were found in the control group. GEE analysis showed an improvement in HRQOL at follow-up with statistically significant association of the intervention on Psychological well-being (B = 4.32; p 0.03 for the interaction of group by follow-up) and School environment (B = 4.64; p 0.02 for the same interaction term).

Conclusions: Routine assessment and face-to-face patient-physician discussion of HRQOL results improved HRQOL scores after a year of follow-up, especially in Psychological well-being and school environment. The results support the routinary use of HRQOL assessment in clinical practice.
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http://dx.doi.org/10.1007/s11136-017-1682-6DOI Listing
December 2017

Gastric Dilatation and Abdominal Compartment Syndrome in a Child with Prader-Willi Syndrome.

Am J Case Rep 2017 Jun 7;18:637-640. Epub 2017 Jun 7.

Department of Paediatric Endocrinology, Parc Tauli Sabadell, Hospital Universitari, Universitat Autònoma de Barcelona, Sabadell, Spain.

BACKGROUND Prader-Willi syndrome (PWS) is a genetic disorder characterized by initial muscular hypotonia and feeding difficulties, and later an insatiable appetite, hyperphagia and obesity along with mild to moderate intellectual impairment. Affected individuals' food-seeking behavior and suspected delayed gastric emptying can lead to gastric dilatation with subsequent necrosis and perforation. CASE REPORT We present the case of a 5-year-old boy diagnosed with Prader-Willi syndrome at neonatal age due to muscular hypotonia, who started growth hormone therapy at 20 months. He presented with two episodes of a rapidly progressing gastric dilatation that led to abdominal hypertension and secondary shock at the age of 2 and 5. No large amount of food was eaten before any of the episodes, and he had abdominal pain and vomiting on both occasions. On arrival at the emergency room, a nasogastric tube was placed and aspiration of food material was performed. Abdominal X-ray and CT scan revealed massive gastric dilatation. He was admitted at the Pediatric Intensive Care Unit and after a variable period of fasting, tolerated oral intake and could be discharged. CONCLUSIONS Gastric dilatation due to gastroparesis in PWS is a rare complication. However, it is a life-threatening situation and physicians should therefore maintain a high level of suspicion for gastric dilatation when patients present with warning symptoms such as abdominal pain or discomfort and vomiting.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469321PMC
http://dx.doi.org/10.12659/ajcr.903608DOI Listing
June 2017

Health-related quality of life (HRQOL) and its associated factors in children with Type 1 Diabetes Mellitus (T1DM).

BMC Pediatr 2017 01 13;17(1):16. Epub 2017 Jan 13.

Catalan Agency for Health Quality and Assessment, Roc Boronat 81-95, 08005, Barcelona, Spain.

Background: The objective of the study was to describe the baseline health-related quality of life (HRQOL) in a cohort of children and adolescents with type 1 diabetes mellitus (T1DM), and analyze its associated clinical and sociodemographic factors, assessing HRQOL through internet.

Methods: This was a descriptive study of 136 patients with T1DM from 5 hospitals in Catalonia, Spain (72 girls, mean age 13.4 years (range 8-19). Inclusion criteria were more than 6 months from diagnosis, more than 8 years old and without cognitive problems. Sociodemographic (age, sex, family level of education, type of family and origin) and clinical variables (type of insulin therapy, duration of disease, adherence to treatment, body mass index and HbA1c) were collected. HRQOL was assessed using the EuroQol-5D (EQ-5D-Y) and KIDSCREEN, collected via web. Mental health status was assessed using the Strengths and Difficulties Questionnaire. Multiple linear regression models were adjusted.

Results: Physical-well-being mean scores were lower (worse) than the European average (<50) and especially in girls, older children (>11 years old), those from single-parent families, and those with low adherence. Older children and patients with poor metabolic control (HbA1c >7,5% [58 mmol/mol]) showed worse scores in the KIDSCREEN-10 index. Similar results were observed with the EQ-5D-Y. Multivariate models showed that age, single-parent families, adherence and mental health were the most influential factors.

Conclusions: Diabetic patients report similar HRQOL than the population of the same age with slightly worse physical well-being. The study shows some factors to be taken into account to improve HRQOL, and also the feasibility of using web to collect information in clinical practice.
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http://dx.doi.org/10.1186/s12887-017-0788-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237211PMC
January 2017

Changes in Body Mass Index in Girls with Idiopathic Central Precocious Puberty under Gonadotropin-Releasing Hormone Analogue Therapy: The Spanish Registry.

Horm Res Paediatr 2016 13;86(3):154-160. Epub 2016 Aug 13.

Pediatric Endocrine Department, Corporació Parc Taulí, Sabadell Hospital, Institut Universitari Parc Taulí, Universitat Autònoma de Barcelona (UAB), Cerdanyola del Vallès, Spain.

Background: The influence of gonadotropin-releasing hormone analogue (GnRHa) treatment on body mass index (BMI) evolution in girls with idiopathic central precocious puberty (CPP) is unclear. Hence, we aimed to evaluate the effect of GnRHa treatment on BMI-standard deviation score (SDS) from diagnosis of idiopathic CPP until adult height.

Methods: An observational study of girls diagnosed with CPP in Spain was carried out between January 2008 and December 2014. A computer program was designed to process clinical and biological data from patients treated in 55 departments of pediatric endocrinology throughout the country. The inclusion criteria were (1) girls diagnosed with CPP before 8 years of age; (2) born after 1992; (3) with a difference between bone and chronological age of at least 1 year, and (4) with a luteinizing hormone peak >7 U/l during luteinizing hormone-releasing hormone testing. The influence of GnRHa treatment on BMI-SDS evolution was analyzed.

Results: Data from 333 girls (22.2% adopted) were evaluated. We report follow-up data at 6, 12, 24, 36, 48 and 60 months and adult height from 269, 232, 198, 153, 105, 56 and 49 girls, respectively. During treatment, there was an increase in BMI-SDS of 0.43 ± 1.17 (95% CI: 0.20-0.64). At adult height (n = 49), BMI-SDS was 1.51 ± 1.38, which was 0.60 ± 1.09 higher than at diagnosis (95% CI: 0.43-0.75).

Conclusions: During treatment with GnRHa, girls experience a significant increase in BMI-SDS that persists after therapy is stopped and adult height has been reached. © 2016 S. Karger AG, Basel.
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http://dx.doi.org/10.1159/000448552DOI Listing
April 2017

Lack of Postprandial Peak in Brain-Derived Neurotrophic Factor in Adults with Prader-Willi Syndrome.

PLoS One 2016;11(9):e0163468. Epub 2016 Sep 29.

Department of Endocrinology and Nutrition, Sabadell University Hospital, Corporació Sanitària Parc Taulí, Sabadell, Spain, Autonomous University of Barcelona, Bellaterra, Spain.

Context: Prader-Willi syndrome (PWS) is characterized by severe hyperphagia. Brain-derived neurotrophic factor (BDNF) and leptin are reciprocally involved in energy homeostasis.

Objectives: To analyze the role of BDNF and leptin in satiety in genetic subtypes of PWS.

Design: Experimental study.

Setting: University hospital.

Subjects: 90 adults: 30 PWS patients; 30 age-sex-BMI-matched obese controls; and 30 age-sex-matched lean controls.

Interventions: Subjects ingested a liquid meal after fasting ≥10 hours.

Main Outcome Measures: Leptin and BDNF levels in plasma extracted before ingestion and 30', 60', and 120' after ingestion. Hunger, measured on a 100-point visual analogue scale before ingestion and 60' and 120' after ingestion.

Results: Fasting BDNF levels were lower in PWS than in controls (p = 0.05). Postprandially, PWS patients showed only a truncated early peak in BDNF, and their BDNF levels at 60' and 120' were lower compared with lean controls (p<0.05). Leptin was higher in PWS patients than in controls at all time points (p<0.001). PWS patients were hungrier than controls before and after eating. The probability of being hungry was associated with baseline BDNF levels: every 50-unit increment in BDNF decreased the odds of being hungry by 22% (OR: 0.78, 95%CI: 0.65-0.94). In uniparental disomy, the odds of being hungry decreased by 66% (OR: 0.34, 90%CI: 0.13-0.9). Postprandial leptin patterns did no differ among genetic subtypes.

Conclusions: Low baseline BDNF levels and lack of postprandial peak may contribute to persistent hunger after meals. Uniparental disomy is the genetic subtype of PWS least affected by these factors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163468PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042477PMC
September 2016

Human MAMLD1 Gene Variations Seem Not Sufficient to Explain a 46,XY DSD Phenotype.

PLoS One 2015 16;10(11):e0142831. Epub 2015 Nov 16.

Pediatric Endocrinology and Diabetology, Department of Clinical Research, University Children's Hospital Bern, Bern, Switzerland.

MAMLD1 is thought to cause disordered sex development in 46,XY patients. But its role is controversial because some MAMLD1 variants are also detected in normal individuals, several MAMLD1 mutations have wild-type activity in functional tests, and the male Mamld1-knockout mouse has normal genitalia and reproduction. Our aim was to search for MAMLD1 variations in 108 46,XY patients with disordered sex development, and to test them functionally. We detected MAMDL1 variations and compared SNP frequencies in controls and patients. We tested MAMLD1 transcriptional activity on promoters involved in sex development and assessed the effect of MAMLD1 on androgen production. MAMLD1 expression in normal steroid-producing tissues and mutant MAMLD1 protein expression were also assessed. Nine MAMLD1 mutations (7 novel) were characterized. In vitro, most MAMLD1 variants acted similarly to wild type. Only the L210X mutation showed loss of function in all tests. We detected no effect of wild-type or MAMLD1 variants on CYP17A1 enzyme activity in our cell experiments, and Western blots revealed no significant differences for MAMLD1 protein expression. MAMLD1 was expressed in human adult testes and adrenals. In conclusion, our data support the notion that MAMLD1 sequence variations may not suffice to explain the phenotype in carriers and that MAMLD1 may also have a role in adult life.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142831PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646284PMC
June 2016

A follow-up study to monitor adult height among Spanish children with growth hormone deficiency who received biosimilar human recombinant growth hormone (Omnitrope®) during a phase III clinical trial.

Adv Ther 2015 Feb 11;32(2):148-56. Epub 2015 Feb 11.

Hospital General de Granollers, Barcelona, Spain.

Introduction: An initial Phase III clinical trial has evaluated the efficacy and safety of biosimilar recombinant human growth hormone (rhGH; Omnitrope(®), Sandoz) in Spanish children with growth hormone deficiency (GHD). At the end of the study, those patients still growing were offered to remain on treatment (as in usual clinical practice), and continued to be monitored. The aim of this study was to determine the adult height achieved by the Spanish children who participated in the initial Phase III clinical trial, and to evaluate the long-term safety of rhGH treatment.

Methods: This study was a multicenter, observational, retrospective follow-up study of patients who participated in the Phase III clinical trial (70 patients recruited). Auxological parameters [including height, height velocity, and their associated height standard deviation scores (HSDS)] were obtained from 39 patients. Safety was assessed by recording any adverse events (AEs).

Results: In total, 27 men and 12 women provided auxological data. At the start of the follow-up study, the mean age of the patients was 12.5 ± 2.7 years, mean height was 144.8 ± 13.9 cm and mean HSDS was -1.16 ± 0.63. By the end of the follow-up period, mean height had increased to 163.1 ± 7.6 cm (n = 36; men 165.5 ± 7.8 cm, women 157.6 ± 3.2 cm) and mean HSDS also increased to -1.01 ± 0.59 (n = 36; men -1.07 ± 0.52, women -0.86 ± 0.72). In terms of safety, no treatment-related AEs were reported during the study.

Conclusion: This cohort of Spanish patients with GHD showed a positive response to rhGH treatment, achieving adult height within the local normal ranges. In addition, rhGH treatment was well tolerated, with no new or additional safety concerns.
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http://dx.doi.org/10.1007/s12325-015-0181-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349959PMC
February 2015

Disorder of sex development as a diagnostic clue in the first Spanish known newborn with P450 oxidoreductase deficiency.

BMJ Case Rep 2013 Jul 22;2013. Epub 2013 Jul 22.

Department of Paediatric Endocrine, Hospital de Sabadell, Corporació Sanitària Parc Taulí, Sabadell, Institut Universitari Parc Taulí-UAB, Universitat Autònoma de Barcelona, Campus d'Excelència Internacional, Sabadell, Spain.

We report the first known case of p450 oxidoreductase deficiency (PORD) in a Spanish boy who presented ambiguous genitalia at birth as a unique feature. He had palpable gonads in the inguinal canal and a normal 46,XY karyotype. Blood tests showed increased lanosterol and androgen precursors (17-OH-pregnenolone and 17-OH-progesterone) and low adrenal androgens (dehydroepiandrosterone and its sulfate). Blood pressure and serum electrolytes were normal. As he had low-testosterone response to human chorionic gonadotropin stimulation but responded to exogenous testosterone with phallic growth, male sex was assigned. Testosterone/dihydrotestosterone ratio and inhibin B were normal. Adrenal insufficiency was detected by corticotropin test. Hydrocortisone replacement treatment was administered. Congenital adrenal hyperplasia was ruled out and molecular analysis of POR gene showed the missense mutation p.Gly539Arg in compound heterozygosity located at splice acceptor site of intron 2 and the coding variant p.Gly80Arg. Surgery for cryptorchidism and hypospadias was performed.
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http://dx.doi.org/10.1136/bcr-2013-010251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736265PMC
July 2013

Pseudohypoaldosteronism without nephropathy masking salt-wasting congenital adrenal hyperplasia genetically confirmed.

BMJ Case Rep 2013 Jan 30;2013. Epub 2013 Jan 30.

Department of Pediatrics, Hospital de Sabadell, Corporació Sanitària Parc Taulí. Sabadell, Institut Universitari Parc Taulí-UAB, Universitat Autònoma de Barcelona, Campus d'Excel.lència Internacional, Sabadell, Spain.

Salt-losing crisis with hypoglycaemia and shock are the main manifestations of congenital adrenal hyperplasia (CAH) during the first weeks of life, while hyponatremia and hyperpotassemia alone are seen on mineralocorticoid deficiency or resistance. During the neonatal period, high blood levels of adrenal steroids may lead to confusing laboratory tests not being able to identify the real level of each hormone. A 33-day-old male baby was admitted at the emergency department with severe salt-losing crisis (Na(+) 99 mEq/l and K(+) 9.4 mEq/l) and mild acidosis. No hypoglycaemia or hypotension was seen. Urinary tract infection was excluded. Despite treatment with hydrocortisone and fludrocortisone, hyperpotassemia was hard to control. Laboratory tests could not differentiate between pseudohypoaldosteronism and CAH as both the aldosterone (2454 pg/ml) and 17-OH-progesterone (656.6 ng/ml) levels were high. Diagnosis was made, thanks to the genetic study that proved classical mutations in both alleles of the 21-hydroxylase gene.
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http://dx.doi.org/10.1136/bcr-2012-008281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3603811PMC
January 2013

Plasma brain-derived neurotrophic factor in prepubertal obese children: results from a 2-year lifestyle intervention programme.

Clin Endocrinol (Oxf) 2012 Nov;77(5):715-20

Department of Paediatric Endocrine, Sabadell Hospital, Parc Tauli Corporation, University Autonomous of Barcelona, Sabadell, Spain.

Context: Brain-derived neurotrophic factor (BDNF) is a neurotrophin potentially involved in the pathophysiology of obesity and metabolic syndrome in adults. In children, it has scarcely been studied.

Objective: To analyse plasma BDNF and its relationship with metabolic syndrome components before and after 2 years of a lifestyle intervention programme in a prepubertal obese cohort.

Design And Setting: Case-control study with a 2-year prospective follow-up in a referral paediatric endocrine outpatient centre.

Patients And Methods: Seventy-three prepubertal obese children, 8·03 ± 1·08 years old, and 47 age- and gender-matched lean controls were studied. Anthropometric parameters, blood pressure, platelet count (PLT), oral glucose tolerance test, homoeostatic model assessment for insulin resistance (HOMA-IR), lipid profile, BDNF, diet and physical activity were evaluated. Weight loss was considered if z-score body mass index (BMI) decreased at least 0·5 SD.

Results: At baseline, BDNF tended to be lower in prepubertal obese children compared with lean controls (P = 0·076). BDNF did not correlate with any metabolic syndrome component. After 2 years, obese patients showed an increase in BDNF. Regression model analysis adjusted by age, sex, puberty, BMI, PLT and HOMA-IR showed that BDNF increased in subjects who lost weight (P = 0·036), practiced sports (P = 0·008) and had an adequate carbohydrate intake (P = 0·032).

Conclusions: Plasma BDNF tends to be lower in obese prepubertal children than in lean controls, is not related to any other metabolic syndrome component and increases after a lifestyle intervention programme.
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http://dx.doi.org/10.1111/j.1365-2265.2012.04431.xDOI Listing
November 2012

Weight loss in prepubertal obese children is associated with a decrease in adipocyte fatty-acid-binding protein without changes in lipocalin-2: a 2-year longitudinal study.

Eur J Endocrinol 2010 Dec 24;163(6):887-93. Epub 2010 Sep 24.

Department of Pediatric Endocrinology, Hospital de Sabadell, Institut Universitari Parc Taulí, Universitat Autònoma de Barcelona (UAB), C/Parc Taulí SN, 08208 Sabadell, Spain.

Context: Lipocalin-2 and adipocyte fatty-acid-binding protein (A-FABP or FABP4) are adipokines potentially involved in the pathophysiology of obesity and metabolic syndrome in adults. In children, they have been scarcely studied.

Objective: To analyze lipocalin-2 and A-FABP circulating levels before and after 2 years of a dieting and lifestyle intervention in a prepubertal obese cohort.

Design And Setting: Case-control study with a prospective follow-up of cases for 2 years in our referral pediatric endocrine outpatient center.

Patients And Methods: Seventy-three prepubertal obese children, 8.03 ± 1.08-years old, and 47 age- and gender-matched lean controls were studied. Anthropometric parameters, blood pressure, fasting oral glucose tolerance test, homeostatic model insulin resistance index (HOMA-IR), lipid profile, lipocalin-2, and A-FABP were evaluated. Weight loss was considered if z-score body mass index (BMI) decreased at least 0.5 s.d.

Results: At baseline, lipocalin-2 and A-FABP were higher in prepubertal obese children than those in lean controls (P<0.001). A-FABP showed a gradual increase, according to the obesity degree (r(2)=0.632; P<0.001). After 2 years, obese patients who lost weight showed a decrease in A-FABP (a mean 2% reduction in BMI was associated with a mean 29% decrease in A-FABP (P<0.001)) without changes in lipocalin-2 levels. Regression model analysis adjusted by age, sex, BMI, and HOMA showed that A-FABP was lower in males (β=-5.77 (CI 95%: -9.7; -1.84)) and was modified by BMI (β=2.7 (CI 95%: 1.77-3.62), r(2)=0.659). Lipocalin-2 was not modified by any of these variables.

Conclusions: Prepubertal obese children show high plasma lipocalin-2 and A-FABP levels, but only A-FABP is influenced by weight loss.
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http://dx.doi.org/10.1530/EJE-10-0408DOI Listing
December 2010

Central precocious puberty in children living in Spain: incidence, prevalence, and influence of adoption and immigration.

J Clin Endocrinol Metab 2010 Sep 16;95(9):4305-13. Epub 2010 Jun 16.

Pediatric Endocrinology Unit, Institute of Biomedical Research-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, E-28049 Madrid, Spain.

Context: No epidemiological data are available on central precocious puberty (CPP) in the general population or in adopted or immigrant children in Spain.

Objective: We aimed to study the incidence and prevalence of CPP, assess the risk of developing this disorder among adopted and immigrant children, and analyze the predictive variables of CPP associated with intracranial pathology.

Design, Settings, And Patients: An observational study of children diagnosed with CPP in Spain was carried out between January 2008 and January 2010. A computer program was designed to process clinical and biological data and information on 250 patients treated in 34 pediatric endocrinology units throughout the country.

Results: Of the patients registered, 226 were girls and 24 were boys. The global incidence rate of CPP was 5.66 cases per million person-years at risk, with an annual incidence ranging between 0.02 and 1.07 new cases per 100,000. The relative risk of CPP in domestic and internationally adopted children compared with those born in Spain was 27.82 (19.99-38.77), whereas the relative risk among immigrants was 1.55 (0.97-2.38). A logistic regression model developed for the study showed that the combined effect of four variables had a significant influence over the presence of organic disease: being male, having been adopted, age at diagnosis, and estimation of adult height.

Conclusions: CPP is a rare disease whose risk markedly increases with both national and international adoption but is not influenced by immigration. These results suggest a psychological influence on CPP.
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http://dx.doi.org/10.1210/jc.2010-1025DOI Listing
September 2010