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Study Question: What is the contribution of genetic defects in Portuguese patients with congenital hypogonadotropic hypogonadism (CHH)?, Summary Answer: Approximately one-third of patients with CHH were found to have a genetic cause for their disorder, with causal pathogenic and likely pathogenic germline variants distributed among 10 different genes; cases of oligogenic inheritance were also included., What Is Known Already: CHH is a rare and genetically heterogeneous disorder characterized by deficient production, secretion, or action of GnRH, LH, and FSH, resulting in delayed or absent puberty, and infertility., Study Design Size Duration: Genetic screening was performed on a cohort of 81 Portuguese patients with CHH (36 with Kallmann syndrome and 45 with normosmic hypogonadotropic hypogonadism) and 263 unaffected controls., Participants/materials Setting Methods: The genetic analysis was performed by whole-exome sequencing followed by the analysis of a virtual panel of 169 CHH-associated genes. The main outcome measures were non-synonymous rare sequence variants (population allele frequency <0.01) classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS)., Main Results and the Role of Chance: A genetic cause was identified in 29.6% of patients. Causal pathogenic and likely pathogenic variants were distributed among 10 of the analysed genes. The most frequently implicated genes were GNRHR , FGFR1 , ANOS1 , and CHD7 . Oligogenicity for pathogenic and likely pathogenic variants was observed in 6.2% of patients. VUS and oligogenicity for VUS variants were observed in 85.2% and 54.3% of patients, respectively, but were not significantly different from that observed in controls., Large Scale Data: N/A., Limitations Reasons for Caution: The identification of a large number of VUS presents challenges in interpretation and these may require reclassification as more evidence becomes available. Non-coding and copy number variants were not studied. Functional studies of the variants were not undertaken., Wider Implications of the Findings: This study highlights the genetic heterogeneity of CHH and identified several novel variants that expand the mutational spectrum of the disorder. A significant proportion of patients remained without a genetic diagnosis, suggesting the involvement of additional genetic, epigenetic, or environmental factors. The high frequency of VUS underscores the importance of cautious variant interpretation. These findings contribute to the understanding of the genetic architecture of CHH and emphasize the need for further studies to elucidate the underlying mechanisms and identify additional causes of CHH., Study Funding/competing Interests: This research was funded by the Portuguese Foundation for Science and Technology (grant numbers PTDC/SAU-GMG/098419/2008, UIDB/00709/2020, CEECINST/00016/2021/CP2828/CT0002, and 2020.04924.BD) and by Sidra Medicine-a member of the Qatar Foundation (grant number SDR400038). The authors declare no competing interests., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Introduction: Turner syndrome (TS), one of the most common chromosomal abnormalities in females, often results in adult cardiovascular and metabolic complications. Information on pediatric age is scarce. This study aimed to compare the presence of cardiometabolic risk factors in children with TS and healthy controls., Methods: This is a cross-sectional study comparing patients with TS to age-matched healthy controls, regarding cardiometabolic risk factors including lipid profile, fasting glucose, insulin resistance, body composition, body mass index, blood pressure, and carotid intima-media thickness (cIMT)., Results: We included nine TS patients and nine controls with a median age of 13 years (9-14 years). Three TS patients and three controls were prepubertal. All TS patients received growth hormone treatment (GHT), median treatment of six years (3-10 years); four patients underwent treatment with estradiol. No statistically significant differences were detected between TS patients and controls regarding body mass index (BMI), cholesterol levels, and insulin resistance. cIMT indexed to body surface area showed no significant differences between TS patients and controls (0.37 vs 0.35 mm/m 2 , respectively, p=0.605). TS patients had lower body fat levels (7.2% vs 34.9%, p=0.004). On the other hand, TS patients had higher levels of systolic (z-score 1.04 vs -0.08, p=0.001) and diastolic (z-score 1.08 vs 0.33, p=0.031) blood pressure (BP) and aspartate (AST) and alanine (ALT) aminotransferase levels (26 vs 20 U/L, p=0.008 and 19 vs 14 U/L, p=0.004, respectively)., Conclusion: Patients with TS, all submitted to GHT, had lower body fat levels compared with controls, despite similar BMI. Although we found no differences in cIMT between the two groups, young girls with TS had higher BP and transaminase levels. Early anthropometric, cardiovascular, and analytical monitoring of patients with TS is essential to detect abnormalities and prevent further complications., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Ethics Committee of Centro Hospitalar Universitário de São João/Faculdade de Medicina da Universidade do Porto issued approval #91/2023. This study complies with the World Medical Association Declaration of Helsinki regarding the ethical conduct of research involving human subjects. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Pais-Cunha et al.)

Objectives: Cushing's disease (CD) is a diagnostic and therapeutic challenge, especially in pediatric patients. CD, primarily caused by adrenocorticotropic hormone-secreting pituitary adenomas, manifests typically with growth retardation and weight gain. There are no published guidelines for pediatric patients., Case Presentation: We report three pediatric patients diagnosed with CD in a Portuguese tertiary hospital. All patients presented with hypercortisolism features. All patients underwent transsphenoidal pituitary surgery (TSS) as a first-choice treatment; however, it was unsuccessful in one patient and the other patients experienced recurrence. Patients were submitted to different approaches so basal serum cortisol levels could be achieved. Two of three patients achieved remission., Conclusions: TSS remains the first-line treatment yet challenging due to microadenomas and technical complexities. Medical therapy with agents like metyrapone or ketoconazole, pituitary radiotherapy, or bilateral adrenalectomy are, usually, second-line interventions, unless there is a contraindication to surgery. Our findings support the finding that a shorter hypothalamic-pituitary-adrenal axis recovery time increases the risk of recurrence of CD. Our cases illustrate the intricate management and variable outcomes of pediatric CD, underscoring the importance of multidisciplinary care and continuous surveillance., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Introduction: Craniopharyngiomas (CP) are tumors in the sellar region that, despite a high survival rate, are associated with significant morbidity, including hypothalamic, hormonal, and visual dysfunction. This study aimed to assess the quality of life (QoL) in pediatric patients with CP and to evaluate its relationship with various factors, with a focus on the impact of endocrine dysfunction., Methods: In this observational cross-sectional study, patients with CP aged between 0 and 18 years, currently followed up in a tertiary hospital by a multidisciplinary team, were included. QoL was assessed using the validated PEDS-QL4.0 questionnaire, which was administered to parents. This tool estimates Global QoL (QoL-G), further divided into Physical (QoL-P) and Psychosocial (QoL-PS) dimensions, including Emotional (QoL-Em), Social (QoL-S), and School (QoL-Sc) aspects. In Portugal, the estimated average QoL-G is 79.8, QoL-P is 83.5, and QoL-PS is 78.2. Variables studied included gender, current and diagnostic age, follow-up time, presence of hydrocephalus, hypothalamic involvement, type of resection (total or subtotal), radiotherapy, visual impairment, hormonal deficits, and therapy., Results: The study included 11 patients with a median age of 15.2 years (interquartile ratio (IQR), 9.7-17.9 years) and a mean age at diagnosis of 9.3±4.1 years. Of these patients, 54.5% were male, and 36.4% were obese. Subtotal resection was performed in 72.7% of cases. Hydrocephalus was present in 54.5% of the patients, hypothalamic involvement in 63.7%, radiotherapy was received by 81.8%, and visual impairment was noted in 54.5%. All patients presented with at least one hormonal deficit. The average QoL-G was 69.9±22.5, with QoL-P at 66.9±30.0 and QoL-PS at 70.9±21.4. A worse QoL-S was associated with female gender (p=0.030) and subtotal resection (p=0.048). Worse QoL-G, QoL-P, QoL-Em, and QoL-PS were linked to hypothalamic involvement (p values 0.008, 0.025, 0.015, and 0.009, respectively). Irradiated patients had worse QoL-G (p=0.006). Treatment with sexual hormones enhanced QoL-Global (p=0.035) and QoL-Emotional (p=0.020), while treatment for adrenal insufficiency and diabetes insipidus improved QoL-Emotional (p=0.021 and p=0.013). No significant associations with visual deficit or obesity were found., Conclusions: Pediatric patients with CP appear to have poorer QoL-G, QoL-P, and QoL-PS compared to the healthy Portuguese population. However, the small sample size limits statistically significant associations with many of these variables. Predictors of worse QoL include female gender, hypothalamic involvement, subtotal resection, and radiotherapy. The results may be biased due to the small sample size, questionnaire administration to parents, and possible inadequacy of the questionnaire for the studied population. There is a need for a more suitable tool to enable a more precise assessment of QoL in these patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Pereira Neto et al.)

Aim: The association between glycemic control and metabolic status is poorly defined in children and adolescents with T1D, besides being biologically plausible. We aimed to evaluate the association between glycemic control and body mass index (BMI), blood pressure (BP), and lipid profile in children and adolescents with T1D., Methods: Observational cross-sectional study including children and adolescents (5-18 years old) followed in our outpatient clinic with the diagnosis of T1D for at least a year. We used linear regression models (unadjusted and adjusted to sex and age) to evaluate the association between glycated hemoglobin (A1c) and time in range (TIR), several prespecified metabolic parameters, and prespecified demographic and clinical characteristics. We considered a p-value of <0.05 to be statistically significant., Results: A total of 144 patients were included, 51% of whom were female. The population had a mean age of 12.7±3.4 years old. We report a positive association between A1c and BMI, systolic and diastolic BP, total- and LDL-cholesterol and triglycerides. Females and patients diagnosed at a younger age presented with higher A1c values. There is a tendency for a negative association between TIR and the former parameters. Higher A1c levels and lower TIR were associated with higher glycemic variability and were treated with a higher basal insulin per Kg dose., Conclusion: Our results support an important association between worse glycemic control and an unhealthier metabolic profile in children and adolescents with T1D. We can hypothesize that a good glycemic profile is needed to achieve good metabolic control at a young age., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Canha et al.)

This study aimed to examine the health-related quality of life (HrQoL), coping, height-related beliefs, and social support of children/adolescents with short stature, the sociodemographic, clinical, and psychosocial variables associated with HrQoL, and the moderating role of sociodemographic and clinical variables on the associations between psychosocial variables and HrQoL. 114 Portuguese children/adolescents with short stature, aged 8-18 years old, completed the Quality of Life in Short Stature Youth questionnaire and the Satisfaction with Social Support Scale. Regression analyses explained 54% of the variance of HrQoL, with significant main effects of current height deviation and height-related beliefs, and a significant interaction effect between beliefs and diagnosis. Results suggest that a multidisciplinary therapeutic approach, not only focused on hormone treatment to boost physical growth, but also including psychosocial interventions focused on the modification of height-related beliefs, may contribute to improve the HrQoL of pediatric patients with short stature., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: CYP21A2 mutation heterozygote carriers seem to have an increased risk of hyperandrogenism. However, the clinical relevance of the heterozygote carrier status and the reliability of hormonal testing in discriminating a carrier from a non-carrier are puzzling questions. We aimed to characterize a population of Portuguese females suspected of having non-classic congenital adrenal hyperplasia (NC-CAH) due to clinical and biochemical criteria and who have undergone CYP21A2 molecular analysis., Methods: Retrospectively, we have analyzed the clinical records of 131 females (32 girls aged 3-9 and 99 adolescents and premenopausal women aged 13-49) who underwent complete CYP21A2 molecular analysis due to suspicion of NC-CAH. We divided included participants into three groups according to the CYP21A2 molecular analysis: NC-CAH females (46), heterozygous carriers (49), and wild type (36). We then compared clinical signs and symptoms as well as biochemical and molecular data between carriers and NC-CAH individuals and between carriers and wild type females. We measured 17OHP by electrochemiluminescence immunoassay., Results: Clinical features were similar between groups. Heterozygous carriers presented higher basal and post-cosyntropin 17-hydroxyprogesterone (17OHP) than wild type individuals (p < 0.05) and lower basal and stimulated 17OHP levels than NC-CAH patients (p < 0.05). We discovered a considerable overlap between 17OHP levels among groups. The most common pathogenic variant we identified was p.Val282Leu., Conclusion: In this population of hyperandrogenic women and children, heterozygous carriers showed higher basal and stimulated 17OHP than non-carriers although normal basal and stimulated 17OHP responses do not exclude heterozygosity for CYP21A2 pathogenic variants. In this study, only the molecular analysis presented good sensitivity in identifying heterozygotes.

Introduction Recombinant human growth hormone (rhGH) replacement therapy might be able to induce hypothyroidism, but this is a controversial issue. Previous studies evaluated the effects of rhGH replacement therapy on thyroid function, but little information is available in the subset of children with isolated idiopathic growth hormone deficiency (GHD). Our aim was to assess the effects of rhGH replacement therapy on thyroid function in children with isolated idiopathic GHD. Methods Retrospective analysis of the medical files of 64 children with confirmed GHD treated with rhGH. After review, 56 children with isolated idiopathic GHD and treated with rhGH for at least one year were included. Auxological (weight standard deviation score [SDS], height SDS, growth velocity [GV] SDS) and biochemical (free thyroxine [FT4], thyroid-stimulating hormone [TSH], and insulin-like growth factor 1 [IGF-1]) parameters were recorded before, during, and after treatment with rhGH. Results FT4 and TSH levels decreased significantly during rhGH therapy in children with isolated idiopathic GHD. Twenty-one percent (n=12) of the children developed hypothyroidism, on average 47 months after initiation of rhGH. Higher baseline FT4 levels were protective against the need for levothyroxine (LT4) (OR=0.8, CI 0.592-0.983; p=0.036). Hypothyroidism was reversed after interruption of rhGH, except in one patient; FT4 levels returned to baseline in the first year after completing the treatment. Final height SDS of the children who developed hypothyroidism was not different from their counterparts without hypothyroidism (-1.24 [-1.52 to -1.10] vs -1.13 [-1.78 to -0.74], p=1.000). Predicted adult height (PAH) SDS in patients who completed rhGH treatment was similar in both LT4 supplemented (n=7; final Ht SDS -1.16 [-1.31 to -1.10] vs PAH -1.00 [-1.42 to -0.48]; p=0.398) and not supplemented patients (n=25; final Ht SDS -1.46 [-1.83 to -0.78] vs PAH SDS -0.88 [-1.35 to -0.56]; p=0.074). Conclusions Our results show that patients with isolated idiopathic GHD may transiently need LT4 during GH treatment. Properly supplemented patients achieved PAH., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Salazar et al.)

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Background Non-classical congenital adrenal hyperplasia (NC-CAH) is a chronic disease characterised by   excessive androgen production that may negatively affect the quality of life (QoL) of affected patients. Pediatric Quality of Life Inventory 4.0 (PedsQL™) is a validated tool to assess health-related QoL (HRQoL). Methods A cross-sectional study including 19 patients with NC-CAH was carried out in the pediatric endocrinology department. NC-CAH patients who agreed to participate were included. Anthropometric data   was collected. PedsQL™ was applied to the patients and their parents. Patients were divided into four groups according to age: 2-4, 5-7, 8-12, and 13-18 years old. The control group consisted of healthy individuals from the instrument's validation studies for the Portuguese population and the standard control population used in the PedsQL™ validation study. Results The only difference found concerns the parents' score results for children aged 8-12, which showed physical health and emotional dimension scores significantly higher (86.16±9.86 vs.68.90±23.02 p=0.004, 69.17±14.14 vs. 65.82±19.24 p=0.004), while psychosocial health's score and total scale score were significantly lower than the control group (59.99±9.90 vs. 69.34±14.07 p=0.047, 73.11±4.65 vs.78.86±16.61 p=0.017). Conclusion HRQoL scores are not negatively affected by NC-CAH in most group ages, with the exception of the parents' reports on HRQoL for children aged 8-12. Further studies with a greater number of patients are needed to determine the impact of this chronic disease on the HRQoL of children., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Ferreira et al.)

The most frequent type of thyroid malignancy in children is papillary thyroid carcinoma (PTC), which usually presents as a thyroid nodule, but may also present as a diffuse infiltration with microcalcifications. Herein, we report the case of an uncommon presentation of a PTC in a 7-year-old boy. The child was referred for a goiter with cervical lymphadenopathies. Ultrasonography showed a hypervascularised goiter without microcalcifications but with numerous bilateral cervical nodular formations. A lymph node biopsy revealed metastatic thyroid cancer, hence a total thyroidectomy and complete neck dissection were performed. Histopathology confirmed a PTC. Ablative 131 I, 30 mCi was performed 4 months postsurgery. At the end of this treatment, a metastatic lung nodule was identified. Since then, another three ablative 131 I treatments have been administered. Thyroid cancers presenting as a diffuse infiltration without microcalcifications are rare. In the presence of lymphadenopathies, thyroid cancer needs to be suspected, even without microcalcifications., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

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Introduction: Wolfram syndrome (WFS) is a neurological and endocrinological degenerative disorder, also known as DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, progressive Optic Atrophy, and Deafness) syndrome. It is an autosomal recessive disorder, mostly involving the Wolfram syndrome 1 gene (WFS1). The phenotypic pleiomorphism, rarity, and molecular complexity complicate the follow-up of these patients., Material and Methods: We aimed to describe the clinical characteristics and the follow-up of 11 patients with this disorder. We retrospectively analysed all WFS patients diagnosed between 1990 and 2020 in the Centro Hospitalar São João, a tertiary hospital in Northern Portugal., Results: Eleven patients were included. Four patients had all 4 components of DIDMOAD. The presentation was diabetes mellitus (DM) in 9 patients, optic atrophy (OA) in another patient, and diabetes insipidus (DI) in another one. The median age of DM and OA diagnosis was 6 and 14 years, respectively. Nine patients had diabetes mellitus, and the other 2 patients had impaired glucose tolerance. All patients had OA. Four patients presented DI, all of them diagnosed in adolescence. Four patients had hearing impairment, 5 had urological abnormalities, 5 had neurological disorders, and 8 had psychiatry disorders. Eight patients had a broad spectrum of recessive mutations in WFS1., Conclusion: The information obtained in this study can facilitate further research in an attempt to improve prevention strategies for this devastating disease.

CHARGE syndrome is a complex disorder involving multiple congenital anomalies and is caused by heterozygous mutations in the CHD7 gene. Growth retardation is a characteristic finding and about 10% of cases present growth hormone (GH) deficiency. GH treatment of short stature in CHARGE syndrome has shown some benefit, but normal height is rarely attained. We report a girl with CHARGE syndrome due to a de novo frameshift mutation in the CHD7 gene (c.2509&#95;2512delCATT), in whom recurrent hypoglycaemia led to the diagnosis of GH deficiency in the second month of life. Early initiation of treatment with recombinant GH resulted in normal growth over ten years of follow-up. This case is the youngest reported CHARGE patient to be diagnosed and treated for GH deficiency and demonstrates that GH deficiency in CHARGE syndrome may manifest early in life through hypoglycaemia, before growth retardation is noted, and can be successfully treated with recombinant GH.

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Deficient anterior pituitary with variable immune deficiency (DAVID) syndrome is a rare condition characterized by symptomatic ACTH deficiency and primary hypogammaglobulinemia, caused by pathogenic variants of the nuclear factor kappa-B subunit 2 ( NF-κB2 ) gene. We report the case of a 9-yr-old boy diagnosed with common variable immunodeficiency at the age of 3, who is under monthly intravenous immunoglobulin. The patient was admitted twice to the pediatric emergency service at the age of 9 due to symptomatic hypoglycemic events. During the hypoglycemic crisis, serum cortisol was low (< 0.1 μg/dL), ACTH level was inappropriately low (4.4 ng/L) and the ACTH stimulation test failed to raise the blood cortisol level. Pituitary magnetic resonance imaging showed a hypoplastic pituitary. Other pituitary deficiencies, primary hyperinsulinism and other metabolic diseases were excluded. He started hydrocortisone replacement treatment while maintaining immunoglobulin substitution and he remains asymptomatic. Molecular analysis revealed the heterozygous nonsense pathogenic variant, c.2557C>T (Arg853Ter) in the NF-κB2 gene. Thus, symptomatic hypoglycemia in a child with primary immunodeficiency should raise the suspicion of DAVID syndrome, prompting NF-κB2 molecular analysis, to allow timely and appropriated therapy and genetic counseling., (2020©The Japanese Society for Pediatric Endocrinology.)

An individual's sexual phenotype is usually determined by the presence or absence of the Y chromosome in the embryo's karyotype, however, due to abnormal X/Y terminal exchange through male meiosis, a few individuals develop male genitalia in the absence of the Y chromosome. This case report presents an adolescent referred to the Pediatric Endocrinology Unit due to bilateral gynecomastia. A diagnosis of hypergonadotropic hypogonadism was established and chromosomal analysis disclosed 46,XX karyotype, with the SRY gene locus found on one of his X chromosomes. A multidisciplinary approach, including psychological support and genetic counseling, is ideal for the management of these patients. Neoplastic transformation of the dysgenetic gonads has been described in several cases, and hence self-examinations and regular ultrasounds are commonly advised., (2020©The Japanese Society for Pediatric Endocrinology.)

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Objectives: To investigate in a large population the proportion of daily basal insulin dose (BD) to daily total insulin dose (TD) (BD/TD) and its association with glycated hemoglobin A1c (HbA1c), body mass index (BMI)- SDS, and treatment modality in children with type 1 diabetes., Study Design: Cross-sectional study in subjects with type 1 diabetes, age ≤18 years, and ≥2 years of diabetes duration, registered in the international multicenter Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference registry in March 2018. Variables included region, sex, age, diabetes duration, treatment modality (multiple daily injections [MDI] or continuous subcutaneous insulin infusion [CSII]), self-monitoring blood glucose, HbA1c, BD/TD, and BMI-SDS. BMI was converted to BMI-SDS using World Health Organization charts as reference. Hierarchic linear regression models were applied with adjustment for age, sex, and diabetes duration., Results: A total of 19 687 children with type 1 diabetes (49% female, 49% CSII users) with median age 14.8 (11.5; 17.2) years and diabetes duration 6.0 (3.9; 9.0) years were included. HbA1c was 63 (55; 74) mmol/mol (7.9 [7.2; 8.9]%), and BMI-SDS 0.55 (-0.13; 1.21). Unadjusted, a lower BD/TD was associated with lower HbA1c, male sex, younger age, shorter diabetes duration, lower BMI-SDS, higher numbers of self-monitoring blood glucose and CSII (all P < .01). After adjustment for confounders, lower BD/TD was associated with lower HbA1c (P < .01) and lower BMI-SDS (P < .01) in children on CSII, but not on MDI., Conclusions: Lower BD/TD is positively associated with lower HbA1c and lower BMI-SDS in children with type 1 diabetes on CSII. It remains to be investigated in a prospective study whether reducing BD/TD insulin will improve metabolic control and normalize body weight in children with type 1 diabetes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background Permanent primary congenital hypothyroidism (CH) can be caused by thyroid dysgenesis or dyshormonogenesis. A molecular genetic study is recommended in dyshormonogenesis, in syndromic hypothyroidism and when there is a family history of CH. The aim of this study was to identify a monogenic etiology for CH in selected individuals from a cohort of primary permanent CH. Methods From an initial cohort of 79 patients with permanent CH (3-19 years), 11 patients were selected for molecular analyses. Nine patients with dyshormonogenesis (normal in-situ gland or goiter) were screened for causative variants, by next-generation sequencing (NGS), in 28 genes known to be responsible for CH. One patient with a family history of CH was screened for the paired-box gene 8 (PAX8) gene and another patient with a syndromic CH was screened for the NKX2-1 gene. Results We found a monogenic basis of disease in eight patients, involving the thyroid peroxidase (TPO) gene (four patients), the thyroglobulin (TG) gene (two patients), and the PAX8 and NKX2-1 genes (one patient each). Two patients were heterozygotes, one harboring a variant in the TG gene and the other in the SLC5A5 gene. In one patient, we found no potential causative variants in any of the 28 genes screened. We described five novel variants: three in the TG gene, one in the NKX2-1 and one in the SLC5A5 gene, all of them classified as pathogenic. Conclusions In eight of the 11 screened patients, a monogenic disease was found. These results highlight the advantage of using an NGS panel and provide further data regarding the molecular basis of CH.

Background Premature adrenarche (PA) is defined as the appearance of clinical signs of androgen action associated with levels of dehydroepiandrosterone sulfate (DHEAS) ≥40 μg/dL, before age 8 years in girls and 9 years in boys, without breast or testicular enlargement. The aim of this study was to characterize a population of prepubertal Caucasian children with PA and to compare them with regard to gender and body mass index (BMI) (normal BMI vs. overweight/obesity). Methods We performed a cross-sectional study of Portuguese Caucasian prepubertal children followed, due to PA, in pediatric endocrinology clinics of a university hospital. Results Eighty-two girls and 15 boys were included (mean age at evaluation: 7.4 ± 1.3 years). The mean birth weight was 2990 ± 689 g; only two children were small for gestational age. Girls presented premature pubarche at a younger age (median [interquartile range (IQR)] 6 (5-6) years vs. 7 (7-8) years in boys; p < 0.001). No gender differences were found for gestational age, birth weight, maternal age at menarche, anthropometry, bone age advancement or androgen levels. The majority of the subjects were overweight or obese (59%). Overweight/obese PA children were taller and had a more advanced bone age than normal-BMI PA children. Overweight/obese children presented higher levels of DHEAS and androstenedione. Bone age advancement and DHEAS were correlated (r = 0.449; p = 0.05). Conclusions We found no evidence of reduced fetal growth. Girls presented premature pubarche at a younger age. No major gender differences in androgen levels were found in prepuberty. Obese and overweight PA children tend to be taller, have a more advanced bone age and higher levels of androgens than normal-BMI PA children.

Background Arterial stiffness is a consequence of aging, but there are several diseases that contribute to this process. The evaluation of pulse wave velocity (PWV) allows a dynamic evaluation of vascular distensibility and the detection of atherosclerosis at an early stage. It was intended to evaluate the PWV in children and adolescents with type 1 diabetes mellitus (T1DM) and to compare their outcome according to the type of treatment used. Methods Forty-eight patients were randomly selected. Inclusion criteria: T1DM, under intensive insulin therapy (multiple daily insulin administrations [MDI] or continuous insulin infusion system [CIIS]). Exclusion criteria: existence of another chronic pathology or microvascular complications. Echocardiography was performed and three measurements of PWV were done, with their mean calculated. Results Most of the children and adolescents presented a PWV ≥ the 75th centile. There was a statistically significant difference for hemoglobin A1c (HbA1c) (7.8 in CIIS vs. 9 in MDI, p < 0.05). There were not statistically significant differences in the PWV between the two groups. This can be attributed to the fact that children with CIIS are those who previously presented greater glycemic instability. There was a significant correlation between PWV and disease duration (Pearson's correlation coefficient [r] = 0.314, p = 0.036). Conclusions This study showed that in children and adolescents with T1DM, there is an important prevalence of arterial stiffness, translated by an increase in PWV. This increase in PWV appears to exist even in very young children with little disease evolution time.

Chiari Malformation Type 1 is a congenital, condition characterized by abnormally shaped cerebellar tonsils that are displaced below the level of the foramen magnum. NKX2-1 gene encodes a transcription factor expressed during early development of thyroid, lung, and forebrain, and germline NKX2-1 mutations can lead to dysfunction in any of these three organs, resulting in brain-lung-thyroid syndrome. There have been few reports of structural brain anomalies in patients with an NKX2-1 -related disorder. We report the first case of a girl with a genetically identified mutation in NKX2-1 that presents with a Chiari Malformation Type 1, eventually expanding the phenotypic spectrum of NKX2-1 -related disorders while also highlighting a novel heterozygous pathogenic variant at exon 3 that disrupts the reading framework, originating an NKX2-1 protein with a different C-terminal., Competing Interests: There are no conflicts of interest., (Copyright: © 2019 Journal of Pediatric Neurosciences.)

Purpose: Guidelines on pituitary incidentalomas evaluation and management are limited to adults since there are no data on this matter in the paediatric population. We aim to analyse the morphologic characteristics, hormonal profile and follow-up of these lesions in children., Methods: We have searched for pituitary incidentalomas in the neuroimaging reports and electronic medical records of the Paediatric Endocrinology Clinic of our centre. Patients with 18 years-old or less were included., Results: Forty-one incidentalomas were identified, 25 of them (62.4%) in females. The mean age at diagnosis was 12.0 ± 4.96 years-old. Headaches were the main reason that led to image acquisition (51.2%) and MRI was the imaging method that detected the majority of the incidentalomas (70.7%). The most prevalent lesion was pituitary hypertrophy (29.3%), which was mainly diagnosed in female adolescents (91.7%), followed by arachnoid cysts (17.1%), pituitary adenomas (14.6%) and Rathke's cleft cysts (12.2%). Most patients (90.2%) did not present clinical or laboratorial findings of hypopituitarism or hormonal hypersecretion. Four patients presented endocrine dysfunction: three had growth hormone deficiency and one had a central precocious puberty. Twenty-three patients (56.1%) underwent imagiological revaluation during a median follow-up time of 24.6 months (interquartile range 5.07). None of them presented dimensional progression., Conclusions: To the best of our knowledge, this is the first series of pituitary incidentalomas in pediatric age. Comparing our series with those conducted in adults, we have observed a higher preponderance of pituitary hypertrophy over adenomas, a lower prevalence of hormonal hyper/hyposecretion and lower risk of dimensional progression during follow-up.

Background Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Cushing's syndrome (CS). It may occur sporadically or as part of a familial syndrome called Carney complex (CC). It is a rare entity, with fewer than 750 cases reported. Case presentation We describe the case of a 16-year-old otherwise healthy female referred to our endocrinology department for progressive weight gain. During investigation, an adrenocorticotropic hormone (ACTH) independent CS was identified and the possibility of an adrenocortical tumor was suggested. The histological exam of the left adrenal gland was compatible with PPNAD. Genetic study identified a novel pathogenic variant in the PRKAR1A gene. Her family history was then reviewed and her father had died prematurely due to a cardiac myxoma. Besides abnormal skin pigmentation, the girl presented no other features of CC. Conclusions Careful follow-up of these patients is important to detect other manifestations of CC and to prevent life-threatening comorbidities, like cardiac myxomas or malignant diseases. Genetic counseling of the patients and their siblings is also very important.

Background: The incidence of pediatric metabolic syndrome (MS) has progressively increased. The incidence of type 1 diabetes mellitus (T1DM) has also increased. Thus, some children and adolescents with T1DM exhibit MS parameters. The aim of the study was to evaluate the presence of MS parameters in female adolescents with T1DM based on their nutritional status., Methods: We evaluated 44 adolescents with T1DM (consecutive non-randomized sample) aged between 14 and 18 years, who were on intensive therapy with insulin. Patients were subdivided according to their body mass index (BMI). Variables evaluated include: age, age at diagnosis, weight, height, BMI, abdominal circumference, blood pressure, glycated hemoglobin (HbA1c), abdominal and pelvic ultrasound and lipoprotein profile. Gynecological history data were also collected., Results: Lipid profile changes were identified in 32% of overweight or obese girls and in 23% of those with an adequate weight. Hypertension (HT) was observed in 19% of overweight or obese girls and in 14% of those with a BMI≥85th percentile (Pc). The only statistically significant difference between the groups was the presence of abdominal adiposity. All other features, including the presence of dyslipidemia, HT, abdominal adiposity, non-alcoholic steatohepatitis (NASH) and polycystic ovarian syndrome (PCOS), were present in both groups., Conclusions: Although being overweight and/or obese aggravates the risk of cardiovascular disease, MS is already present in many young adolescents with T1DM of normal weight. It is necessary that MS risk factors are routinely evaluated in all diabetic adolescents, including those with an adequate BMI.

Phthalates are a group of chemical compounds used as plasticizers in the manufacture of plastic materials. They can be present in many commonly used products. There seems to be a relationship between exposure to phthalates and the occurrence of metabolic dysfunctions, such as a decrease in glucose tolerance, oxidative stress, loss of beta cells, and a decrease in insulin synthesis. As beta cells play a key role in the onset of type 1 diabetes mellitus (T1DM), we sought to investigate the relationship between exposure to phthalates and the diagnosis of T1DM in prepubertal children. Design concentrations of phthalate metabolites were compared in the urine of a population of prepubertal children with new-onset diabetes, patients with T1DM diagnosed more than 6 months previously, and healthy control children. Although the concentrations of DBP and DiBP metabolites were statistically identical in the new-onset diabetes, diabetes, and control groups, there was a clear trend for higher levels of DiBP metabolites in the children with new-onset diabetes. In our sample, there was a trend for higher levels of DiBP metabolites in children with new-onset diabetes.

Background: Type 1 diabetes mellitus (T1DM) is an autoimmune disease with beta-cell destruction, resulting in insulin deficiency. It is now clear that environmental factors also play a role in disease development. The prevalence of type 1 diabetes in children and young people in Portugal is 0.16% between 0 and 19 years of age. The main cause of death in T1DM is cardiovascular disease, and early endothelial dysfunction is its pathophysiologycal precursor. Hyperglycemia is associated with increased production of free radicals and increased oxidative stress. The aim of this study was to analyze the antioxidant status in a pediatric portuguese diabetic population., Methods: The study was conducted to characterize and compare the antioxidant status in children aged 2 - 10 years old, with type 1 diabetes and healthy children. Plasmatic profile of total phenolic content (TPC), ferric reducing antioxidant power (FRAP), Trolox equivalent antioxidant capacity (TEAC) in children with diabetes and controls, pre-pubescent, and with BMI < 85th centile were evaluated., Results: FRAP values were significantly lower in diabetic children compared with healthy controls (P < 0.001). There was not any statistical significant difference in the TPC and the TEAC determinations., Conclusions: Young Portuguese diabetic children have a lower antioxidant status than healthy children.

Introduction: Hyponatremia is a common electrolyte alteration which has the potential for significant morbidity and mortality. Endocrine disorders, such as primary hypothyroidism and adrenal insufficiency are uncommon causes of hyponatremia. We present the case of a teenager with symptomatic hyponatremia caused by a rare disorder., Case: A 17-year-old boy was admitted to the emergency department with abdominal pain, nausea and vomiting, asthenia, and weight loss. He was in poor general condition, hypotensive, and he had dry mucous membranes and skin as well as mucosa hyperpigmentation. The laboratory findings showed severe hyponatremia, hyperkalemia, and renal dysfunction. The patient started inotropic support and antibiotics. Plasma cortisol and corticotropin levels allowed the diagnosis of primary adrenal insufficiency. He began replacement therapy with hydrocortisone and fludrocortisone, with gradual symptom resolution. An abdominal computed tomography scan showed adrenal hypoplasia. Findings for antiadrenal and antithyroid antibodies were positive, allowing the diagnosis of autoimmune polyglandular syndrome type II., Discussion: Adrenal insufficiency is a rare disease, especially in children, and its clinical manifestations are due to glucocorticoid and mineralocorticoid deficiency. In most of the cases, symptoms are nonspecific, requiring a high index of clinical suspicion. If the diagnosis and treatment are delayed, acute adrenal insufficiency carries a high morbidity and mortality.

Unlabelled: The development of male internal and external genitalia in an XY fetus requires a complex interplay of many critical genes, enzymes, and cofactors. The enzyme 17β-hydroxysteroid-dehydrogenase type 3 (17βHSD3) is present almost exclusively in the testicles and converts Delta 4-androstenodione (Δ4) to testosterone. A deficiency in this enzyme is rare and is a frequently misdiagnosed autosomal recessive cause of 46,XY, disorder of sex development. The case report is of a 15-year-old adolescent, who was raised according to female gender. At puberty, the adolescent had a severe virilization and primary amenorrhea. The physical examination showed a male phenotype with micropenis and blind vagina. The Tanner stage was A3B1P4, nonpalpable gonads. The karyotype revealed 46,XY. The endocrinology study revealed: testosterone=2.38 ng/ml, Δ4>10.00 ng/ml, and low testosterone/Δ4 ratio=0.23. Magnetic resonance imaging of the abdominal-pelvic showed the presence of testicles in inguinal canal, seminal vesicle, prostate, micropenis, and absence of uterus and vagina. The genetic study confirmed the mutation p.Glu215Asp on HSD17B3 gene in homozygosity. The dilemma of sex reassignment was seriously considered when the diagnosis was made. During all procedures the patient was accompanied by a child psychiatrist/psychologist. The teenager desired to continue being a female, so gonadectomy was performed. Estrogen therapy and surgical procedure to change external genitalia was carried out. In this case, there was a severe virilization at puberty. It is speculated to be due to a partial activity of 17βHSD3 in the testicles and/or extratesticular ability to convert Δ4 to testosterone by 17βHSD5. Prenatal exposure of the brain to androgens has increasingly been put forward as a critical factor in gender identity development, but in this case the social factor was more important for the gender assignment., Learning Points: In this case, we highlight the late diagnosis, probably because the patient belongs to a poor family without proper primary medical care.We emphasize the psychological and social aspects in the sex assignment decision.

Objective: To describe clinical presentation, preoperative study, intervention, histology, surgical complications and follow-up characteristics, and survival in patients with thyroid carcinoma (TC) with less than 18 years at presentation., Material and Methods: retrospective analysis of clinical data of all children and adolescents followed in S. João Hospital from January 1, 2000 to March 31, 2010 with histologic diagnosis of TC., Results: Twenty-three patients were identified, 19 girls, and 4 boys. Median age at presentation was 17.0 years. Annual incidence was 2.3 cases/year. The main presenting symptom was a solitary thyroid nodule (60.8%). Three (13%) patients had risk factors for TC, 2 of the 3 had previous cervical irradiation. The other was a smoker. Total thyroidectomy was performed in 16 (69.6%), and 10 patients underwent a second surgical procedure. Four (17.4%) patients had postoperative complications. Histologic examination revealed differentiated TC in all, papillary thyroid carcinoma (PTC) in 86.9%, follicular carcinoma in the remaining. All patients received thyroxine suppressive therapy and 20 underwent therapeutic radioactive iodine (131I). During follow-up (7.1 years), 7 out of the 23 patients presented new metastases and needed new treatment. All patients are currently alive., Conclusions: TC is a reality in pediatric population, thyroid routine examination should take part in all clinical examination in children and adolescents., (Copyright © 2011 SEEN. Published by Elsevier Espana. All rights reserved.)

Background: Growth hormone (GH) deficiency is one of the most frequent endocrine problems occurring in cancer survivors, particularly when there is a previous history of central nervous system (CNS) tumour and submission to radiotherapy (RT)., Material and Methods: We retrospectively assessed pediatric cancer survivors with GH deficiency, submitted to GH treatment from 1988 to 2010 in a tertiary level hospital. We analised the following data: sex, age, oncologic diagnosis, oncologic treatment, auxology, Tanner puberty stage, final height, target height and other associated endocrine problems. We determined the height z-score difference between the beginning and the end of GH treatment (for patients who ended treatment), and between the beginning of GH treatment and the last observation (for patients who are currently on treatment), which was defined as the dependent variable. SPSS® version 17.0 was used for statistical analysis., Results: A sample of 18 patients was obtained, 12 male, with a median age of cancer diagnosis of six years old. The diagnostics were CNS tumors (n=15) and hematologic neoplasia (n=3). Cancer treatment modalities were craniospinal RT (n=9), cranial RT (n=4), chemotherapy (n=14) and CNS surgery (n=15). The median of time between cancer treatment and beginning of GH treatment was 4 years and 8 months. Height z-score difference was positive in 12 patients. Statistical significant differences between medians and centiles of height z-score difference occurred in patients submitted to craniospinal RT (-0.08), cranial RT (0.59) and no RT (1.56) (p=0.003, IC 95%). The biggest differences between final height and target height (-10 and -11.5 cm) occurred in two patients submitted to craniospinal RT, with associated precocious puberty., Conclusions: Our results are consistent with previous studies, which point to a lesser efficacy of GH treatment when there is a past history of RT, namely craniospinal RT, and in association with precocious puberty.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases in women of reproductive age. PCOS typically develops during adolescence and is a heterogeneous syndrome classically characterized by features of anovulation combined with signs of androgen excess (hirsutism, acne). Increasing obesity in adolescents probably exacerbates signs of PCOS, contributing to its earlier recognition. Recognizing the features of this syndrome can be very challenging in adolescence. Although adolescents' concerns are often cosmetic, if left untreated these girls are at risk for diabetes, metabolic syndrome, and infertility as they mature. Efforts should be made to diagnose and treat PCOS to minimize the development of symptoms and prevent the onset of cardiovascular and metabolic disturbances., (Copyright 2009 SEEN. Published by Elsevier Espana. All rights reserved.)