Patient with adrenal insufficiency due to a de novo mutation in the NR0B1 gene.

Objectives: Congenital X-linked adrenal hypoplasia is a rare disease with a known genetic basis characterized by adrenal insufficiency, hypogonadotropic hypogonadism, and a wide variety of clinical manifestations. Case presentation: We present the case of a 26-day old male newborn with symptoms consistent with adrenal insufficiency, hyponatremia, and hyperkalemia. Following NaCl and fludrocortisone supplementation, the patient remained clinically stable. 17-OH-progesterone testing excluded congenital adrenal hyperplasia. The rest of hormones were within normal limits, except for adrenocorticotropic hormone (ACTH), which was significantly elevated, and aldosterone, which was below the reference value. Further testing included very long chain fatty acids to exclude adrenoleukodystrophy, the CYP11B2 gene (aldosterone synthase), and an MRI to screen for other morphological abnormalities. All tests yielded normal results. Finally, after cortisol deficiency was detected, expanded genetic testing revealed a mutation in the NR0B1 gene, which led to a diagnosis of congenital adrenal hypoplasia. Conclusions: Diagnosis of congenital adrenal hypoplasia is challenging due to the heterogeneity of both clinical manifestations and laboratory abnormalities. As a result, diagnosis requires close monitoring and genetic testing.

Intralymphatic GAD-Alum (Diamyd®) Improves Glycemic Control in Type 1 Diabetes With HLA DR3-DQ2.

AIMS: Residual beta cell function in type 1 diabetes (T1D) is associated with lower risk of complications. Autoantigen therapy with GAD-alum (Diamyd) given in 3 intralymphatic injections with oral vitamin D has shown promising results in persons with T1D carrying the human leukocyte antigen (HLA) DR3-DQ2 haplotype in the phase 2b trial DIAGNODE-2. We aimed to explore the efficacy of intralymphatic GAD-alum on blood glucose recorded by continuous glucose monitoring (CGM). METHODS: DIAGNODE-2 (NCT03345004) was a multicenter, randomized, placebo-controlled, double-blind trial of 109 recent-onset T1D patients aged 12 to 24 years with GAD65 antibodies and fasting C-peptide > 0.12 nmol/L, which randomized patients to 3 intralymphatic injections of 4 µg GAD-alum and oral vitamin D, or placebo. We report results for exploratory endpoints assessed by 14-day CGM at months 0, 6, and 15. Treatment arms were compared by mixed-effects models for repeated measures adjusting for baseline values. RESULTS: We included 98 patients with CGM recordings of sufficient quality (DR3-DQ2-positive patients: 27 GAD-alum-treated and 15 placebo-treated). In DR3-DQ2-positive patients, percent of time in range (TIR, 3.9-10 mmol/L) declined less between baseline and month 15 in GAD-alum-treated compared with placebo-treated patients (-5.1% and -16.7%, respectively; P = 0.0075), with reduced time > 13.9 mmol/L (P = 0.0036), and significant benefits on the glucose management indicator (P = 0.0025). No differences were detected for hypoglycemia. GAD-alum compared to placebo lowered the increase in glycemic variability (standard deviation) observed in both groups (P = 0.0219). Change in C-peptide was correlated with the change in TIR. CONCLUSIONS: Intralymphatic GAD-alum improves glycemic control in recently diagnosed T1D patients carrying HLA DR3-DQ2.

Thyroid function in < 32 weeks gestation preterm infants.

INTRODUCTION: Preterm newborns (PN) have a higher risk of thyroid dysfunction than term newborns (TN). This condition may go unnoticed in neonatal screening due to a late elevation of thyrotropin (TSH) in these patients. OBJECTIVE: Evaluate thyroid function in the second week of life in PN of < 32 weeks gestation (WG), and to identify factors associated to its alteration. PATIENTS AND METHODS: A retrospective study was performed in neonates of < 32 weeks gestation (WG), in whom thyroid function was determined. An analysis was performed on thyroxine (T4L) and TSH levels, as well as their association with perinatal and neonatal outcomes. RESULTS: The study included a total of 358 patients with mean gestational age (GA) of 29.3 weeks, and mean birth weight (BW) 1127 grams. A linear correlation was found between T4L and BW (correlation coefficient (R) 0.356; p < 0.001) and GA (R = 0.442; p < 0.001). TSH values were associated with small for gestational age (SGA 5.3 mU/L [1.5-37]; non-SGA 2.89 mU/L [0.2-19.5]; p < 0.001), inotropic support (Yes 3.98 mU/L [0.6-22.9]; No 3.16 mU/L [0.2-37]; p = 0.019) and BW (R = -0.249; p < 0.001). Nine (2.5%) patients were treated with levothyroxine, of whom six were SGA. CONCLUSIONS: Thyroid function analysis in the second week of life helps to identify asymptomatic newborns with risk of thyroid dysfunction. SGA newborns are at higher risk of thyroid function alterations.

Función tiroidea en el recién nacido prematuro con edad gestacional igual o menor a 32 semanas / Thyroid function in < 32 weeks gestation preterm infants

Introducción: El recién nacido (RN) prematuro (RNPT) tiene mayor riesgo de disfunción tiroidea que el recién nacido a término (RNAT). Esta alteración puede pasar desapercibida en el cribado neonatal por una elevación tardía de tirotropina (TSH) en estos pacientes. Objetivo: Evaluar la función tiroidea en la segunda semana de vida en RNPT menores a 32 semanas de gestación (SG) e identificar factores asociados con la alteración de esta. Pacientes y métodos: Estudio restrospectivo que incluye RNPT de igual o menos de 32 SG, a los que se realizó función tiroidea. Se analizaron los valores de tiroxina (T4L) y TSH y su relación con variables perinatales y de evolución neonatal. Resultados: Se presentaron 358 pacientes con edad gestacional (EG) mediana de 29,3 semanas y peso al nacimiento (PN) de 1.127 gramos. Se encontró correlación lineal entre T4L y el PN (coeficiente de correlación (R) 0,356; p < 0,001) y la EG (R = 0,442; p < 0,001). Los valores de TSH se asociaron con ser pequeño para la edad gestacional (PEG 5,3 mU/L [1,5 a 37]; no PEG 2,89 mU/L [0,2 a 19,5]; p < 0,001), al soporte inotrópico (Sí 3,98 mU/L [0,6 a 22,9]; No 3,16 mU/L [0,2 a 37]; p = 0,019) y al PN (R = -0,249; p < 0,001). Recibieron tratamiento sustitutivo con levotiroxina nueve pacientes (2,5%), seis de los cuales fueron PEG. Conclusiones: El análisis de la función tiroidea en la segunda semana de vida permite identificar RNPT asintomáticos con riesgo de presentar alteración de la función tiroidea. Los RN PEG tienen un riesgo más elevado de disfunción tiroidea. (AU)

Introduction: Preterm newborns (PN) have a higher risk of thyroid dysfunction than term newborns (TN). This condition may go unnoticed in neonatal screening due to a late elevation of thyrotropin (TSH) in these patients. Objective: Evaluate thyroid function in the second week of life in PN of < 32 weeks gestation (WG), and to identify factors associated to its alteration. Patients and methods: A retrospective study was performed in neonates of < 32 weeks gestation (WG), in whom thyroid function was determined. An analysis was performed on thyroxine (T4L) and TSH levels, as well as their association with perinatal and neonatal outcomes. Results: The study included a total of 358 patients with mean gestational age (GA) of 29.3 weeks, and mean birth weight (BW) 1127 grams. A linear correlation was found between T4L and BW (correlation coefficient (R) 0.356; p < 0.001) and GA (R = 0.442; p < 0.001). TSH values were associated with small for gestational age (SGA 5.3 mU/L [1.5-37]; non-SGA 2.89 mU/L [0.2-19.5]; p < 0.001), inotropic support (Yes 3.98 mU/L [0.6-22.9]; No 3.16 mU/L [0.2-37]; p = 0.019) and BW (R = -0.249; p < 0.001). Nine (2.5%) patients were treated with levothyroxine, of whom six were SGA. Conclusions: Thyroid function analysis in the second week of life helps to identify asymptomatic newborns with risk of thyroid dysfunction. SGA newborns are at higher risk of thyroid function alterations. (AU)

Diabetis insípida associada a holoprosencefàlia / Diabetes insípida asociada a holoprosencefalia / Diabetes insipidus associated with holoprosencephaly

Introducció. L’holoprosencefàlia és una malformació congènita greu que compromet estructures cerebrals situades ala línia mitjana. Per la seva localització, l’hipotàlem i lahipòfisi són estructures afectades sovint en aquesta entitat. La seva disfunció pot provocar trastorns de l’homeòstasii endocrinopaties com l’adípsia i la diabetis insípida.Cas clínic. Es presenta el cas d’una nena de 6 anys diagnosticada d’holoprosencefàlia als 9 mesos de vida. Consulta per somnolència i febre de 48 hores d’evolució i enl’exploració presenta signes de deshidratació. La mare refereix que no reclama ingesta hídrica tot i trobar-se deshidratada. Analíticament destaca deshidratació hipernatrèmica greu amb disfunció renal. A les 72 hores d’ingrés,després d’haver corregit les diselectrolitèmies i amb lapacient normohidratada, reapareix la hipernatrèmia ambpoliúria i osmolalitat urinària disminuïda. Es fa un test dedesmopressina que confirma la sospita diagnòstica de dèficit d’hormona antidiürètica associat a adípsia. S’instauratractament amb desmopressina i restricció hídrica amb elqual s’assoleix un bon control hidroelectrolític que esmanté en controls posteriors.Comentaris. Els pacients amb holoprosencefàlia tenen riscde presentar endocrinopaties per disfunció hipotalamohipofisiària. Per aquest motiu cal buscar-les activament encas de presentar-se la clínica clàssica de poliúria, hipernatrèmia i hipoosmolalitat urinària. (AU)

Introducción. La holoprosencefalia es una malformación congénitagrave que compromete estructuras cerebrales situadas en la líneamedia. Por su localización, el hipotálamo y la hipófisis son estructuras frecuentemente afectadas en esta entidad. Su disfunciónpuede generar trastornos de la homeostasis y endocrinopatíascomo la adipsia y la diabetes insípida.Caso clínico. Se presenta el caso de una niña de 6 años diagnosticada de holoprosencefalia a los 9 meses de vida. Consulta por somnolencia y fiebre de 48 horas de evolución y en la exploración físicadestacan signos de deshidratación. La madre refiere que no reclama ingesta hídrica pese a encontrarse deshidratada. Analíticamente destaca deshidratación hipernatrémica grave y disfunciónrenal. A las 72 horas de ingreso, corregidas las diselectrolitemias yencontrándose la paciente normohidratada, reaparece hipernatremia asociando poliuria e hipoosmolalidad urinaria. Se realiza untest de desmopresina que confirma la sospecha diagnóstica de déficit de hormona antidiurética asociado a adipsia. Se instaura tratamiento con desmopresina y restricción hídrica, alcanzando un buencontrol hidroelectrolítico que mantiene en controles posteriores.Comentarios. Los pacientes con holoprosencefalia tienen riesgo depresentar endocrinopatías por disfunción hipotálamo-hipofisaria.Por ese motivo es necesario buscarlas activamente en caso depresentarse la clínica clásica de poliuria, hipernatremia e hipoosmolalidad urinaria. (AU)

Introduction. Holoprosencephaly is a severe developmental defectthat compromise midline brain structures. Due to their location,the hypothalamus and the hypophysis are frequently involvedin this illness. Their dysfunction can lead to homeostatic andendocrine disorders such as thirst disturbances and diabetesinsipidus.Case report. Herein we report the case of a 6-year-old girl who wasdiagnosed with holoprosencephaly at 9 months old. She presentedwith a 48-hours history of somnolence and fever with signs of dehydration on examination. Her mother stated that despite beingdehydrated, she did not demand water intake. Laboratory evaluation revealed a severe hypernatremic dehydration with renal impairment. Seventy-two hours after admission, having successfullyattained fluid and electrolyte correction, she presented hypernatremia with polyuria and urine hypoosmolality. A desmopressin testwas performed confirming the suspected diagnosis of antidiuretichormone deficiency and adipsia. She responded well to desmopressin treatment and fluid restriction with restoration of serumelectrolytes, which remained within acceptable limits at follow-up.Discussion. Children with holoprosencephaly are at risk for endocrine disorders related to hypothalamic-pituitary dysfunction. It isimportant to rule out these disturbances if they present with theclassic triad of hypernatremia, polyuria and urine hypoosmolality. (AU)

Seventy eight children born small for gestational age without catch-up growth treated with growth hormone from the prepubertal stage until adult height age. An evaluation of puberty and changes in the metabolic profile.

A wide variation in height gain rate is observed in children small for gestational age (SGA) treated with growth hormone (GH). The aim of this study was to evaluate prepubertal and pubertal growth, height gain attained at adult age and to assess potential predictive factors in catch-up growth. Changes in metabolic profile were also analyzed. PATIENTS AND METHODS: Seventy-eight children born SGA were treated with a GH median dose of 33.0±2.8mcg/kg/day at a mean age of 7.3±2.0 (boys) and 6.0±1.8 (girls). RESULTS: Mean height (SDS) at GH onset was -3.31±0.7 for boys and -3.48±0.7 for girls. According to age at pubertal growth spurt onset patients were classified in their pubertal maturity group. Adult height attained expressed in SDS was -1.75±0.7 for boys and -1.69±1.0 for girls, both below the range of their mid-parental height. The greatest height gain occurred during the prepubertal period. Patients with greater height gain were lighter (p<0.001), shorter (p=0.005), and younger (p=0.02) at the start of GH, and also showed a greater increase in growth velocity during the first year on GH (p<0.001). SGA children started puberty at the same age and with the same distribution into pubertal maturity group as the reference population. No relevant GH-related adverse events were reported, including in the insulin resistance parameters evaluated. Differences were found in fasting plasma glucose values, but were without clinical relevance. IGF-I plasma values remained within the safety range. CONCLUSIONS: GH therapy is safe and beneficial for SGA children. The response to GH therapy is widely heterogeneous, suggesting that GH should be started at a young age and the GH dose prescribed should be individualized. SGA children started puberty at the same age as the reference population. The only factor that predicts greater adult height is growth velocity during the first year of therapy.

Ultrasound criteria (EU-TIRADS) to identify thyroid nodule malignancy risk in adolescents. Correlation with cyto-histological findings.

INTRODUCTION: Thyroid nodule (TN) harbouring a thyroid carcinoma are more common in paediatric than adult patients. In paediatric population, the evaluation of a TN should require specific paediatric tools for its diagnostic and therapeutic management. High-resolution ultrasonography and cytological evaluation after fine-needle aspiration biopsy (FNAB) remain the cornerstones of evaluation of TN. OBJECTIVES: To evaluate in paediatric TN for the first time the usefulness and precision of the ultrasound criteria defined by the "Thyroid Imaging Reporting and Data System (EU-TIRADS) 2017 in adults" to establish the ultrasound indication for the practice of FNAB and stratify the risk of malignancy. PATIENTS AND METHODS: 24 paediatric patients under age 18 years with thyroid nodules were attended in the last 15 years, 24 of them (31 nodules; age: 15.2 ±â€¯2.2 years; 18 women) met the inclusion criteria: FNAB with Bethesda classification and ultrasound with EU-TIRADS score. EU-TIRADS score were evaluated retrospectively. Fourteen patients underwent surgery and the definitive histological diagnosis was obtained, this allowed the calculations of sensitivity, specificity and positive and negative predictive values of the EU-TIRADS and Bethesda classification. Data on the largest diameters of the nodules were collected. RESULTS: Of the overall 31 nodules, the distribution by EU-TIRADS (T) category was: T1 (3.2%), T2: 2 (6.4%), T3: 7 (22.6%), T4: 16 (51.6%) and T5: 5 (16.1%). All malignant nodules were included in EU-TIRADS category 4 or 5. By the other hand, 13 of the 25 benign nodules were also included in the EU-TIRADS 4 category, and one in the 5. The distribution by categories of Bethesda's classification (B): BI: 6 (19.4%), BII: 14 (45.2%), BIII: 5 (16.1%), BIV: 2 (6.5%), BV: 0 and BVI: 4 (12.9%). The pathological diagnosis of the 14 patients who underwent surgery was: 6 papillary carcinomas and 8 with benign lesions: 6 nodular hyperplasia and 2 follicular adenoma. The percentage of malignancy was 42%. The sensitivity of the EU-TIRADS classification to detect malignant nodules was 100%, the specificity was 25%, PPV 44% and NPV 100%. The sensitivity of the Bethesda classification to detect malignant nodules was 86%, the specificity was 75%, PPV 67% and NPV 90%. The analysis of the largest diameter of the nodules did not show statistically significant differences between benign and malignant lesions. CONCLUSIONS: EU-TIRADS for ultrasonographic criteria classification in combination with the clinical history is an adequate and reproducible method to estimate suspicion of malignancy of paediatric TN. It is also a reliable diagnostic tool to decide which nodules will be candidates for FNAB.

Seventy eight children born small for gestational age without catch-up growth treated with growth hormone from the prepubertal stage until adult height age. An evaluation of puberty and changes in the metabolic profile.

A wide variation in height gain rate is observed in children small for gestational age (SGA) treated with growth hormone (GH). The aim of this study was to evaluate prepubertal and pubertal growth, height gain attained at adult age and to assess potential predictive factors in catch-up growth. Changes in metabolic profile were also analyzed. PATIENTS AND METHODS: Seventy-eight children born SGA were treated with a GH median dose of 33.0±2.8mcg/kg/day at a mean age of 7.3±2.0 (boys) and 6.0±1.8 (girls). RESULTS: Mean height (SDS) at GH onset was -3.31±0.7 for boys and -3.48±0.7 for girls. According to age at pubertal growth spurt onset patients were classified in their pubertal maturity group. Adult height attained expressed in SDS was -1.75±0.7 for boys and -1.69±1.0 for girls, both below the range of their mid-parental height. The greatest height gain occurred during the prepubertal period. Patients with greater height gain were lighter (p<0.001), shorter (p=0.005), and younger (p=0.02) at the start of GH, and also showed a greater increase in growth velocity during the first year on GH (p<0.001). SGA children started puberty at the same age and with the same distribution into pubertal maturity group as the reference population. No relevant GH-related adverse events were reported, including in the insulin resistance parameters evaluated. Differences were found in fasting plasma glucose values, but were without clinical relevance. IGF-I plasma values remained within the safety range. CONCLUSIONS: GH therapy is safe and beneficial for SGA children. The response to GH therapy is widely heterogeneous, suggesting that GH should be started at a young age and the GH dose prescribed should be individualized. SGA children started puberty at the same age as the reference population. The only factor that predicts greater adult height is growth velocity during the first year of therapy.

Intralymphatic Glutamic Acid Decarboxylase With Vitamin D Supplementation in Recent-Onset Type 1 Diabetes: A Double-Blind, Randomized, Placebo-Controlled Phase IIb Trial.

OBJECTIVE: To evaluate the efficacy of aluminum-formulated intralymphatic glutamic acid decarboxylase (GAD-alum) therapy combined with vitamin D supplementation in preserving endogenous insulin secretion in all patients with type 1 diabetes (T1D) or in a genetically prespecified subgroup. RESEARCH DESIGN AND METHODS: In a multicenter, randomized, placebo-controlled, double-blind trial, 109 patients aged 12-24 years (mean ± SD 16.4 ± 4.1) with a diabetes duration of 7-193 days (88.8 ± 51.4), elevated serum GAD65 autoantibodies, and a fasting serum C-peptide >0.12 nmol/L were recruited. Participants were randomized to receive either three intralymphatic injections (1 month apart) with 4 µg GAD-alum and oral vitamin D (2,000 IE daily for 120 days) or placebo. The primary outcome was the change in stimulated serum C-peptide (mean area under the curve [AUC] after a mixed-meal tolerance test) between baseline and 15 months. RESULTS: Primary end point was not met in the full analysis set (treatment effect ratio 1.091 [CI 0.845-1.408]; P = 0.5009). However, GAD-alum-treated patients carrying HLA DR3-DQ2 (n = 29; defined as DRB1*03, DQB1*02:01) showed greater preservation of C-peptide AUC (treatment effect ratio 1.557 [CI 1.126-2.153]; P = 0.0078) after 15 months compared with individuals receiving placebo with the same genotype (n = 17). Several secondary end points showed supporting trends, and a positive effect was seen in partial remission (insulin dose-adjusted HbA1c ≤9; P = 0.0310). Minor transient injection site reactions were reported. CONCLUSION: Intralymphatic administration of GAD-alum is a simple, well-tolerated treatment that together with vitamin D supplementation seems to preserve C-peptide in patients with recent-onset T1D carrying HLA DR3-DQ2. This constitutes a disease-modifying treatment for T1D with a precision medicine approach.

Ultrasound criteria (EU-TIRADS) to identify thyroid nodule malignancy risk in adolescents. Correlation with cyto-histological findings. / Criterios ecográficos (EU-TIRADS) para identificar el riesgo de malignidad de los nódulos tiroideos en adolescentes. Correlación con los hallazgos cito-histológicos.

INTRODUCTION: Thyroid nodule (TN) harboring a thyroid carcinoma are more common in pediatric than adult patients. In pediatric population, the evaluation of a TN should require specific pediatric tools for its diagnostic and therapeutic management. High-resolution ultrasonography and cytological evaluation after fine-needle aspiration biopsy (FNAB) remain the cornerstones of evaluation of TN. OBJECTIVES: To evaluate in pediatric TN for the first time the usefulness and precision of the ultrasound criteria defined by the"Thyroid Imaging Reporting and Data System (EU-TIRADS) 2017 in adults" to establish the ultrasound indication for the practice of FNAB and stratify the risk of malignancy. PATIENTS AND METHODS: 24 pediatric patients under age 18 years with thyroid nodules were attended in the last 15 years, 24 of them (31 nodules; age: 15.2 ± 2.2 years; 18 women) met the inclusion criteria: FNAB with Bethesda classification and ultrasound with EU-TIRADS score. EU-TIRADS score were evaluated retrospectively. Fourteen patients underwent surgery and the definitive histological diagnosis was obtained, this allowed the calculations of sensitivity, specificity and positive and negative predictive values of the EU-TIRADS and Bethesda classification. Data on the largest diameters of the nodules were collected. RESULTS: Of the overall 31 nodules, the distribution by EU-TIRADS (T) category was: T1 (3.2%), T2: 2 (6.4%), T3: 7 (22.6%), T4: 16 (51.6%) and T5: 5 (16.1%). All malignant nodules were included in EU-TIRADS category 4 or 5. By the other hand, 13 of the 25 benign nodules were also included in the EU-TIRADS 4 category, and one in the 5. The distribution by categories of Bethesda's classification (B): BI: 6 (19.4%), BII: 14 (45.2%), BIII: 5 (16.1%), BIV: 2 (6.5%), BV: 0 and BVI: 4 (12.9%). The pathological diagnosis of the 14 patients who underwent surgery was: 6 papillary carcinomas and 8 with benign lesions: 6 nodular hyperplasia and 2 follicular adenoma. The percentage of malignancy was 42%. The sensitivity of the EU-TIRADS classification to detect malignant nodules was 100%, the specificity was 25%, PPV 44% and NPV 100%. The sensitivity of the Bethesda classification to detect malignant nodules was 86%, the specificity was 75%, PPV 67% and NPV 90%. The analysis of the largest diameter of the nodules did not show statistically significant differences between benign and malignant lesions. CONCLUSIONS: EU-TIRADS for ultrasonographic criteria classification in combination with the clinical history is an adequate and reproducible method to estimate suspicion of malignancy of pediatric TN. It is also a reliable diagnostic tool to decide which nodules will be candidates for FNAB.

[50 years of the Neonatal Screening Program in Catalonia.] / 50 años del Programa de Cribado Neonatal en Cataluña.

The Catalonian Newborn Screening Program (CNSP) began in 1969, in Barcelona. It was promoted by Dr. Juan Sabater Tobella and supported by Barcelona Provincial Council and Juan March Foundation. That is how the Institute of Clinical Biochemistry was born, whose aims were diagnosis, research and teaching, along with the spirit of contributing to the prevention of mental retardation. The CNSP began with the detection of phenylketonuria (PKU), and, in 1982, the Program was expanded with the inclusion of congenital hypothyroidism detection. Towards 1990, the Program covered almost 100% of all newborns (NB) in Catalonia. In 1999, the CNSP was expanded with the incorporation of cystic fibrosis. It took fourteen years, until 2013, to make the largest expansion so far, with the incorporation of 19 metabolic diseases to the screening panel. The detection of sickle cell disease began in 2015 and in 2017 the detection of severe combined immunodeficiency was included. Currently, the CNSP includes 24 diseases in its main panel. Since 1969, 2,787,807 NBs have been screened, of whom 1,724 have been diagnosed with any of these diseases, and 252 of other disorders by differential diagnosis with those included in the main panel. The global prevalence is 1: 1,617 NBs affected by any of the diseases included in the CNSP and 1: 1,140 NBs if incidental findings diagnosed through the CNSP are included.

El Programa de Cribado Neonatal de Cataluña (PCNC) se inició en el año 1969, en Barcelona, impulsado por el Dr. Juan Sabater Tobella y apoyado por la Diputación de Barcelona y la Fundación Juan March. Así nació el Instituto de Bioquímica Clínica para acometer funciones asistenciales, de investigación y docencia, con el espíritu de contribuir a la prevención del retraso mental. El PCNC se inició con la detección de la fenilcetonuria (PKU) y en el año 1982 se amplió con la detección del hipotiroidismo congénito. Hacia el año 1990 la cobertura territorial llegó casi al 100% de todos los recién nacidos en Cataluña. En 1999 se amplió el PCNC con la incorporación de la fibrosis quística y tras catorce años, en 2013, se realizó la ampliación más numerosa hasta ahora, con la incorporación de la detección de 19 enfermedades metabólicas hereditarias. En el año 2015 comenzó la detección de la enfermedad de células falciformes y en el 2017 la detección de la inmunodeficiencia combinada grave. Actualmente, el PCNC incluye la detección de 24 enfermedades. Desde su inicio en el año 1969, se han cribado 2.787.807 recién nacidos, de los cuales 1.724 han sido diagnosticados de alguna de las 24 enfermedades que componen nuestro panel principal y 252 por diagnóstico diferencial de las primeras. En total la prevalencia global es de 1:1.617 RN afectos de alguna de las enfermedades incluidas en el PCNC y de 1:1.140 RN si se incluyen los hallazgos incidentales encontrados.

[Thyroid function in < 32 weeks gestation preterm infants]. / Función tiroidea en el recién nacido prematuro con edad gestacional igual o menor a 32 semanas.

INTRODUCTION: Preterm newborns (PN) have a higher risk of thyroid dysfunction than term newborns (TN). This condition may go unnoticed in neonatal screening due to a late elevation of thyrotropin (TSH) in these patients. OBJECTIVE: Evaluate thyroid function in the second week of life in PN of < 32 weeks gestation (WG), and to identify factors associated to its alteration. PATIENTS AND METHODS: A retrospective study was performed in neonates of < 32 weeks gestation (WG), in whom thyroid function was determined. An analysis was performed on thyroxine (T4L) and TSH levels, as well as their association with perinatal and neonatal outcomes. RESULTS: The study included a total of 358 patients with mean gestational age (GA) of 29.3 weeks, and mean birth weight (BW) 1127 grams. A linear correlation was found between T4L and BW (correlation coefficient (R) 0.356; p < 0.001) and GA (R = 0.442; p < 0.001). TSH values were associated with small for gestational age (SGA 5.3 mU/L [1.5-37]; non-SGA 2.89 mU/L [0.2-19.5]; p < 0.001), inotropic support (Yes 3.98 mU/L [0.6-22.9]; No 3.16 mU/L [0.2-37]; p = 0.019) and BW (R = -0.249; p < 0.001). Nine (2.5%) patients were treated with levothyroxine, of whom six were SGA. CONCLUSIONS: Thyroid function analysis in the second week of life helps to identify asymptomatic newborns with risk of thyroid dysfunction. SGA newborns are at higher risk of thyroid function alterations.

Enfermedad de Graves con autoanticuerpos contra el receptor de la TSH negativos: a propósito de 5 casos / Graves disease with negative TSH receptor antibodies: A presentation of 5 cases

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Pubertat precoç com a síndrome paraneoplàstica / Pubertad precoz como síndrome paraneoplásico / Precocious puberty as paraneoplastic syndrome

INTRODUCCIÓ: L'hepatoblastoma és un tumor hepàtic maligne que destaca per la capacitat de secreció hormonal. Aquestes hormones s'utilitzen en el seguiment (alfa-fetoproteïna) o poden provocar complicacions paraneoplàstiques mimetitzant la funció d'altres hormones. Es presenta un cas clínic d'un nen de 18 mesos amb pubertat precoç. CAS CLÍNIC: Pacient diagnosticat d'hepatoblastoma en tractament quimioteràpic segons el protocol SIOPEL-6, que en la valoració clínica prequirúrgica presenta un estadi de Tanner G3 P2 I un volum testicular de 12 cc bilateral. A nivell analític destaca una elevació de la testosterona I de la gonadotrofina coriònica humana (hCG), sense elevació de la hormona luteoestimulant (LH) ni de la hormona estimulant del fol·licle (FSH), compatible amb una pubertat precoç perifèrica. Després de la resecció tumoral es demostra un descens de la testosterona, de l'hCG I de l'alfa-fetoproteïna, I s'orienta com a síndrome paraneoplàstica del tumor. COMENTARIS: Dins del diagnòstic diferencial de la pubertat precoç, cal distingir entre pubertat precoç central (activació de l'eix hipotàlem-hipofític-gonadal) I perifèrica (producció externa d'hormones sexuals independentment de l'activació central). En el cas descrit s'orienta com a pubertat precoç perifèrica a causa de la secreció d'hCG per l'hepatoblastoma. L'hCG presenta una estructura molecular similar a l'LH I en concentracions elevades promou la secreció de testosterona per les cèl·lules de Leydig. En canvi, l'augment de volum testicular depèn directament de l'FSH, de manera que es planteja la hipòtesi que la producció d'esteroides gonadals en una pubertat precoç perifèrica acabaria sensibilitzant I estimulant l'eix hipotàlem-hipofític

INTRODUCCIÓN: El hepatoblastoma es un tumor hepático maligno que destaca por su capacidad de secreción hormonal. Estas hormonas se utilizan en el seguimiento (alfafetoproteína) o pueden provocar complicaciones paraneoplásicas simulando la función de otras hormonas. Se presenta un caso clínico de un niño de 18 meses con pubertad precoz. CASO CLÍNICO: Paciente diagnosticado de hepatoblastoma en tratamiento quimioterápico según protocolo SIOPEL-6, que en la valoración clínica prequirúrgica presenta un estadio de Tanner G3 P2 y un volumen testicular de 12 cc bilateral. A nivel analítico destaca una elevación de testosterona y gonadotrofina coriónica humana (hCG) sin elevación de la hormona luteinizante (LH) ni de la hormona estimulante del folículo (FSH), compatible con una pubertad precoz periférica. Tras la resección tumoral se demuestra el descenso de testosterona y hCG, orientándose como síndrome paraneoplásico del tumor. COMENTARIOS: Dentro del diagnóstico diferencial de la pubertad precoz, hay que distinguir entre pubertad precoz central (activación del eje hipotálamo-hipofisario-gonadal) y periférica (producción externa de hormonas sexuales independientemente de la activación central). En el caso descrito se orienta como pubertad precoz periférica, debido a la secreción de hCG por el hepatoblastoma. La hCG presenta una estructura molecular similar a la LH y en elevadas concentraciones promueve la secreción de testosterona por las células de Leydig. Dado que el aumento del volumen testicular depende directamente de la FSH, se plantea la hipótesis de que la producción de esteroides gonadales en la pubertad precoz periférica acabaría sensibilizando y estimulando el eje hipotálamo-hipofisario

INTRODUCTION: Hepatoblastoma is a malignant liver tumour characterized by its hormonal secretion. The secreted hormones are used in the follow-up (alpha-fetoprotein) or can cause paraneoplastic complications simulating the function of other hormones. We present a clinical case of an 18-month-old boy with precocious puberty. CASE REPORT: Patient with diagnosis of hepatoblastoma undergoing chemotherapy treatment according to SIOPEL-6 protocol, which presents Tanner G3 P2 stage and testicular volume of 12cc bilateral in the presurgical clinical assessment. In the blood test, there is an elevation of testosterone and human chorionic gonadotropin (hCG) without elevation of luteinising hormone (LH) and follicle-stimulating hormone (FSH), compatible with peripheral precocious puberty. After tumour resection, decrease in testosterone and hCG blood levels are demonstrated, pointing itself as a paraneoplastic tumour syndrome. COMMENTS: In the differential diagnosis of precocious puberty, one must distinguish between central precocious puberty (activation of hypothalamic-pituitary-gonadal axis) and peripheral precocious puberty (external production of sex hormones independently of central activation). The case is an example of peripheral precocious puberty, due to the secretion of hCG by hepatoblastoma. HCG has a molecular structure similar to LH and in high concentrations promotes secretion of testosterone by Leydig cells. However, the increase in testicular volume depends directly on FSH and one hypothesis would be that the production of gonadal steroids in peripheral precocious puberty would end up sensitizing and stimulating the hypothalamic-pituitary axis

50 años del Programa de Cribado Neonatal en Cataluña / 50 years of the Neonatal Screening Program in Catalonia

El Programa de Cribado Neonatal de Cataluña (PCNC) se inició en el año 1969, en Barcelona, impulsado por el Dr. Juan Sabater Tobella y apoyado por la Diputación de Barcelona y la Fundación Juan March. Así nació el Instituto de Bioquímica Clínica para acometer funciones asistenciales, de investigación y docencia, con el espíritu de contribuir a la prevención del retraso mental. El PCNC se inició con la detección de la fenilcetonuria (PKU) y en el año 1982 se amplió con la detección del hipotiroidismo congénito. Hacia el año 1990 la cobertura territorial llegó casi al 100% de todos los recién nacidos en Cataluña. En 1999 se amplió el PCNC con la incorporación de la fibrosis quística y tras catorce años, en 2013, se realizó la ampliación más numerosa hasta ahora, con la incorporación de la detección de 19 enfermedades metabólicas hereditarias. En el año 2015 comenzó la detección de la enfermedad de células falciformes y en el 2017 la detección de la inmunodeficiencia combinada grave. Actualmente, el PCNC incluye la detección de 24 enfermedades. Desde su inicio en el año 1969, se han cribado 2.787.807 recién nacidos, de los cuales 1.724 han sido diagnosticados de alguna de las 24 enfermedades que componen nuestro panel principal y 252 por diagnóstico diferencial de las primeras. En total la prevalencia global es de 1:1.617 RN afectos de alguna de las enfermedades incluidas en el PCNC y de 1:1.140 RN si se incluyen los hallazgos incidentales encontrados

The Catalonian Newborn Screening Program (CNSP) began in 1969, in Barcelona. It was promoted by Dr. Juan Sabater Tobella and supported by Barcelona Provincial Council and Juan March Foundation. That is how the Institute of Clinical Biochemistry was born, whose aims were diagnosis, research and teaching, along with the spirit of contributing to the prevention of mental retardation. The CNSP began with the detection of phenylketonuria (PKU), and, in 1982, the Program was expanded with the inclusion of congenital hypothyroidism detection. Towards 1990, the Program covered almost 100% of all newborns (NB) in Catalonia. In 1999, the CNSP was expanded with the incorporation of cystic fibrosis. It took fourteen years, until 2013, to make the largest expansion so far, with the incorporation of 19 metabolic diseases to the screening panel. The detection of sickle cell disease began in 2015 and in 2017 the detection of severe combined immunodeficiency was included. Currently, the CNSP includes 24 diseases in its main panel. Since 1969, 2,787,807 NBs have been screened, of whom 1,724 have been diagnosed with any of these diseases, and 252 of other disorders by differential diagnosis with those included in the main panel. The global prevalence is 1: 1,617 NBs affected by any of the diseases included in the CNSP and 1: 1,140 NBs if incidental findings diagnosed through the CNSP are included

Oral glucose tolerance test and continuous glucose monitoring to assess diabetes development in cystic fibrosis patients / Test de tolerancia oral a la glucosa y monitorización continua de glucosa para evaluar el desarrollo de diabetes en pacientes con fibrosis quística

Introduction: Patients with cystic fibrosis (CF) undergo a slow and progressive process toward diabetes. Oral glucose tolerance test (OGTT) is recommended to diagnose impaired glucose levels in these patients. Continuous glucose monitoring (CGM) measures glucose profiles under real-life conditions. Objective: To compare OGTT and CGM results in CF patients. Methods: Paired OGTT and 6-day CGM profiles (146.2±9.1h/patient) were performed in 30 CF patients aged 10-18 years. Results: According to OGTT, 14 patients had normal glucose tolerance (NGT), 14 abnormal glucose tolerance (AGT), and two cystic fibrosis-related diabetes (CFRD). In 27 patients (13 NGT, 13 AGT, 1 CFRD), CGM showed glucose values ranging from 140 to 200mg/dL during similar monitoring times (2%-14% with NGT, 1%-16.9% with AGT, and 3% with CFRD). Glucose peak levels ≥200mg/dL were seen in seven patients (3 NGT, 3 AGT, 1 CFRD). According to CGM, two patients had all glucose values under 140mg/dL (1 NGT, 1 AGT). Seventeen patients had glucose levels ranging from 140 to 200mg/dL (10 NGT, 6 AGT, 1 CFRD). Ten patients (3 NGT, 7 AGT) had glucose values ≥200mg/dL for ≤1% of the monitoring time and one (CFRD) for >1% of the monitoring time. Conclusions: OGTT results did not agree with those of the CGM. CGM allows for diagnosis of glucose changes not detected by OGTT. Such changes may contribute to optimize pre-diabetes management in CF patients (AU)

Introducción: Los pacientes con fibrosis quística (FQ) evolucionan lenta y progresivamente hacia la diabetes, siendo el test de tolerancia oral a la glucosa (TTOG) el método utilizado para diagnosticar sus alteraciones glucémicas. La monitorización continua de glucosa (MCG) proporciona perfiles de glucosa en condiciones de vida habituales del paciente. Objetivo: Comparar los resultados del TTOG y de la MCG en pacientes con FQ. Métodos: TTOG seguido de MCG (146,2±9,1h/paciente) en 30 pacientes con FQ (10-18 años de edad). Resultados: Según el TTOG, 14 pacientes presentaron tolerancia normal a la glucosa (TNG), 14 tolerancia anormal a la glucosa (TAG) y 2 diabetes relacionada con la fibrosis quística (DRFQ). En 27 pacientes (13 con TNG, 13 con TAG, uno con DRFQ) la MCG mostró valores de glucosa 140-200mg/dL durante periodos similares de tiempo (2-14%, 1-16,9% y 3%, respectivamente). Picos de glucosa ≥200mg/dL se observaron en 7 pacientes (3 con TNG, 3 con TAG y uno con DRFQ). Según la MCG, 2 pacientes tuvieron todos los valores de glucosa <140mg/dL (uno con TNG y otro con TAG); 17 pacientes entre 140-200mg/dL (10 con TNG, 6 con TAG y uno con DRFQ); 10 pacientes ≥200mg/dL durante ≤1% del tiempo valorado (3 con NGT, 7 con TAG) y uno ≥200mg/dL durante >1% del tiempo valorado (con DRFQ). Conclusiones: Los resultados del TTOG no concuerdan con los de la MCG. La MCG permite el diagnóstico de anomalías de la glucosa no detectadas mediante el TTOG y sus resultados podrían contribuir a optimizar el tratamiento de la prediabetes en estos pacientes (AU)

Oral glucose tolerance test and continuous glucose monitoring to assess diabetes development in cystic fibrosis patients.

INTRODUCTION: Patients with cystic fibrosis (CF) undergo a slow and progressive process toward diabetes. Oral glucose tolerance test (OGTT) is recommended to diagnose impaired glucose levels in these patients. Continuous glucose monitoring (CGM) measures glucose profiles under real-life conditions. OBJECTIVE: To compare OGTT and CGM results in CF patients. METHODS: Paired OGTT and 6-day CGM profiles (146.2±9.1h/patient) were performed in 30 CF patients aged 10-18 years. RESULTS: According to OGTT, 14 patients had normal glucose tolerance (NGT), 14 abnormal glucose tolerance (AGT), and two cystic fibrosis-related diabetes (CFRD). In 27 patients (13 NGT, 13 AGT, 1 CFRD), CGM showed glucose values ranging from 140 to 200mg/dL during similar monitoring times (2%-14% with NGT, 1%-16.9% with AGT, and 3% with CFRD). Glucose peak levels ≥200mg/dL were seen in seven patients (3 NGT, 3 AGT, 1 CFRD). According to CGM, two patients had all glucose values under 140mg/dL (1 NGT, 1 AGT). Seventeen patients had glucose levels ranging from 140 to 200mg/dL (10 NGT, 6 AGT, 1 CFRD). Ten patients (3 NGT, 7 AGT) had glucose values ≥200mg/dL for ≤1% of the monitoring time and one (CFRD) for >1% of the monitoring time. CONCLUSIONS: OGTT results did not agree with those of the CGM. CGM allows for diagnosis of glucose changes not detected by OGTT. Such changes may contribute to optimize pre-diabetes management in CF patients.

Hipoglucèmia / No disponible

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