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.

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.

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.

[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.

[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.

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.