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Coexistence of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency and Turner Syndrome (TS) is rare. We report a 6-year-old Portuguese girl with mosaic TS [45,XO(39)/47,XXX(21)] presented with premature pubarche at the age of 5 years. Laboratory findings showed elevated 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, androstenedione and total testosterone, and sex-determining region Y (SRY) was negative. CYP21A2 gene analysis revealed two mutations (c.[844G>T]; [CYP21A2del]), consistent with the non-classical form of CAH. Complete deletion of CYP21A2 allele occurred de novo. At 6 years and 4 months, she presented accelerated growth velocity and hydrocortisone at the dose of 5 mg/m2/day was initiated. This case highlights the need to perform global examinations looking for virilization signs in TS patients follow-up. It also supports the reported genetic combination of TS and CAH. Therefore, CAH should be kept in mind in TS patients with SRY negative and virilization signs, even in the absence of short stature.

While data on the efficacy and safety of continuous glucose monitoring (CGM) exist across a broad age spectrum, it is limited in very young children with type 1 diabetes (T1D). We aimed to assess real-world data in this high-risk population, focusing on glycemic variability and metrics beyond HbA1c. A 12-month multi-national, prospective, observational, registry-based cohort study in children with T1D aged 1-7 years compared glucose control using real-time CGM and using fingerstick blood glucose monitoring (BGM) alone. The prespecified primary endpoint was a difference in coefficient of variation (CV) between the CGM users and BGM-only cohort. Among 227 individuals using insulin pumps (42% female, age 5.3 years), 175 were CGM and 52 were BGM-only users. The median (IQR) CV was 39.1% (36.6-41.9) among CGM and 46.8% (42.3-51.2) among BGM-only users (P

Objectives Since the beginning of the COVID-19 pandemic, there has been a consistent decrease in the number of admissions to the emergency department, leading to a delay in the diagnosis of several pathologies. The time from onset of symptoms to the diagnosis of Type 1 diabetes is highly variable. This treatment delay can lead to the appearance of ketoacidosis. Methods Retrospective study of inaugural Type 1 diabetes cases, from March 2016 to March 2021. The pandemic group was considered between March 2020 to March 2021, and the remaining period was considered as pre-pandemic. Clinical variables were analysed: duration of symptoms, weight loss and value of ketonemia and glycated haemoglobin on admission. The mean differences were considered statistically significant at p Results 103 inaugural episodes of Type 1 diabetes were registered. The pandemic group had a lower mean age when compared to pre-pandemic group, and 51.7% of the episodes had ketoacidosis with a higher relative risk of ketoacidosis and severe ketoacidosis, when compared the pandemic with pre-pandemic group, there was a longer symptom evolution time (34 vs. 20 days), greater weight loss occurred (9.5% vs. 6.3%), the pH and HCO3 − values were lower (7.30 vs. 7.36 and 16.43 vs. 20.71 mmol/L respectively) and ketonemia was higher (5.9 vs. 2.3 mmol/L). Conclusions The COVID-19 pandemic caused a delay in the diagnosis of Type 1 diabetes, greater length of disease, greater weight loss, higher ketonemia and lower pH and HCO3 −. There was greater ketoacidosis relative risk in pandemic group when compared to pre-pandemic group.

Background Adrenal insufficiency (AI) is a life-threatening disease characterized by deficient production of glucocorticoids and/or mineralocorticoids. It is caused by primary or secondary/tertiary adrenal failure. Prompt diagnosis and management are essential and may even be life-saving. Methods We retrospectively collected clinical, laboratory and radiological data from AI patients observed over 34 years (1984–2017) in a pediatric endocrinology department of a tertiary care hospital. Results Seventy AI patients were identified: 59% with primary adrenal insufficiency (PAI) and 41% with central adrenal insufficiency (CAI). PAI patients were diagnosed at 1.5 ± 4.4 years and followed for 11.6 ± 6.2 years; 85% had classical congenital adrenal hyperplasia (CAH) and 7% had autoimmune PAI. At presentation, 73% had hyponatremia and more than half had mucocutaneous hyperpigmentation, asthenia, anorexia, weight loss, nausea and vomiting. All the patients were treated with hydrocortisone and 90% were also on fludrocortisone. Regarding CAI patients, they were diagnosed at 5.4 ± 5.0 years and they were followed for 9.6 ± 6.4 years; craniopharyngioma was present in 31% of the cases and 14% had pituitary hypoplasia. Besides corticotropin, thyrotropin (93%), growth hormone (63%) and antidiuretic hormone (52%) were the most common hormone insufficiencies. The most frequent manifestations were hypoglycemia (34.5%), nausea/vomiting (27.6%) and infectious diseases (27.6%); all the patients were treated with hydrocortisone. Conclusions Despite medical advances, the diagnosis and management of AI remains a challenge, particularly in the pediatric population. Raising awareness and knowledge in medical teams and population about the disease is of crucial importance to improve clinical outcomes and to reduce disease morbidity/mortality.

© 2021 Thieme. All rights reserved., Background: Elucidating mechanisms of brain damage in cerebral venous thrombosis (CVT) would be instrumental to develop targeted therapies and improve prognosis prediction. Matrix metalloproteinase-9 (MMP-9), a gelatinase that degrades major components of the basal lamina, has been associated to blood-brain barrier disruption. We aimed to assess, in patients with CVT, the temporal change in serum concentrations of MMP-9 and its association with key imaging and clinical outcomes. Methods: Pathophysiology of Venous Infarction-PRediction of InfarctiOn and RecanalIzaTion in CVT (PRIORITy-CVT) was a multicenter prospective cohort study of patients with newly diagnosed CVT. Serial collection of peripheral blood samples performed on day 1, 3, and 8, and standardized magnetic resonance imaging on day 1, 8, and 90. MMP-9 was quantified using enzyme-linked immunosorbent assay in 59 patients and 22 healthy controls. Primary outcomes were parenchymal brain lesion, early evolution of brain lesion, early recanalization, and functional outcome on day 90. Results: CVT patients with parenchymal brain lesion had higher baseline concentrations of MMP-9 compared with controls (adjusted p = 0.001). The area under receiver operating characteristic curve value for MMP-9 for predicting brain lesion was 0.71 (95% confidence interval [CI]: 0.57-0.85, p = 0.009). Patients with venous recanalization showed early decline of circulating MMP-9 and significantly lower levels on day 8 (p = 0.021). Higher MMP-9 on day 8 was associated with persistent venous occlusion (odds ratio: 1.20 [per 20 ng/mL], 95% CI: 1.02-1.43, p = 0.030). Conclusion: We report a novel relationship among MMP-9, parenchymal brain damage, and early venous recanalization, suggesting that circulating MMP-9 is a dynamic marker of brain tissue damage in patients with CVT., This study was supported by 11° Bolsa de Investigação Fundação AstraZeneca - Faculdade de Medicina Universidade de Lisboa, D. Manuel de Mello grant, and Fundação Amélia de Mello. D.A.S. was supported by a doctoral grant SFRH/SINTD/92677/2013 from Fundação para Ciência e Tecnologia.

Copyright © 2020 European Academy of Neurology, Background and purpose: Experimental studies suggest inflammation can contribute to blood barrier disruption and brain injury in cerebral venous thrombosis (CVT). We aimed to determine whether blood biomarkers of inflammation were associated with the evolution of brain lesions, persistent venous occlusion or functional outcome in patients with CVT. Methods: Pathophysiology of Venous Infarction-Prediction of Infarction and Recanalization in CVT (PRIORITy-CVT) was a multicenter prospective cohort study of patients with newly diagnosed CVT. Evaluation of neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) concentrations in peripheral blood samples was performed at admission in 62 patients. Additional quantification of interleukin (IL)-6 was performed at day 1, 3 and 8 in 35 patients and 22 healthy controls. Standardized magnetic resonance imaging was performed at day 1, 8 and 90. Primary outcomes were early evolution of brain lesion, early recanalization and functional outcome at 90 days. Results: Interleukin-6 levels were increased in patients with CVT with a peak at baseline. IL-6, NLR and CRP levels were not related with brain lesion outcomes or early recanalization but had a significant association with unfavourable functional outcome at 90 days (IL-6: OR = 1.28, 95% CI: 1.05-1.56, P = 0.046; NLR: OR = 1.39, 95% CI: 1.4-1.87, P = 0.014; CRP: OR = 1.756, 95% CI: 1.010-3.051, P = 0.029). Baseline IL-6 had the best discriminative capacity, with an area under the receiver operating characteristic curve to predict unfavourable functional outcome of 0.74 (P = 0.031). Conclusions: Increased baseline levels of NLR, CRP and IL-6 may serve as new predictive markers of worse functional prognosis at 90 days in patients with CVT. No association was found between inflammatory markers and early evolution of brain lesion or venous recanalization., This work was supported by 11° Bolsa de Investigação Fundação AstraZeneca, Faculdade de Medicina Universidade de Lisboa, D. Manuel de Mello grant, Fundação Amélia de Mello. D.A.d.S. was supported by a doctoral grant SFRH/SINTD/92677/2013 from Fundação para a Ciência e a Tecnologia.

Copyright © Ordem dos Médicos 2019, Children with DiGeorge syndrome/chromosome 22q11.2 deletion syndrome might have a variable degree of immunodeficiency, which may limit the use of live vaccines. The aim of this study was to review the adverse effects of live vaccines and possible relation with immune status in patients with DiGeorge Syndrome/partial 22q11.2 deletion syndrome.Material e Métodos: Foi realizado um estudo retrospetivo por revisão dos processos clínicos das crianças com deleção do cromossoma 22q11.2 e fenótipo de síndrome de DiGeorge, seguidos num centro de referência de imunodeficiências primárias. Foi realizada colheita de dados, incluindo: características demográficas; história médica; historial de vacinação com vacinas vivas; contagem de linfócitos T-CD4+ e respostas proliferativas linfocitárias a antigénios e mitogénios; reações adversas; falências vacinais. Resultados: Foram incluídas 23 crianças com síndrome de DiGeorge/deleção 22q11.2, 65,2% do sexo masculino e idade média de diagnóstico de 11,3 meses. Destas, 18 crianças (78%) receberam a vacina bacillus Calmette-Guérin: todas com evidência de atividade tímica; três apresentaram linfopénia T-CD4+ moderada e respostas proliferativas linfocitárias anormais; uma com respostas proliferativas linfocitárias anormais para mitogénios, quatro para derivado de proteína purificada e uma para toxóide tetânico. A vacina tríplice contra o sarampo, parotidite e rubéola foi administrada a 15 crianças, três com imunossupressão moderada e respostas proliferativas linfocitárias anormais. A vacina viva atenuada contra poliomielite foi administrada a quatro crianças sem imunossupressão e a vacina contra o rotavírus a três crianças, uma com imunossupressão moderada. Não foram reportadas reações adversas. Discussão: Estes dados estão de acordo com as conclusões de outros estudos internacionais. Conclusão: Na nossa amostra, as vacinas vivas atenuadas foram bem toleradas, incluindo em crianças com linfopénia T-CD4+ moderada e com respostas proliferativas linfocitárias a antigénios/mitogénios anormais., Introduction: Children with DiGeorge syndrome/chromosome 22q11.2 deletion syndrome might have a variable degree of immunodeficiency, which may limit the use of live vaccines. The aim of this study was to review the adverse effects of live vaccines and possible relation with immune status in patients with DiGeorge Syndrome/partial 22q11.2 deletion syndrome. Material and Methods: Retrospective study with analysis of the clinical records of children with chromosome 22q11.2 deletion syndrome and DiGeorge syndrome phenotype, followed in a Primary Immunodeficiency center. Data were collected on: demographic characteristics; medical and vaccination history with live vaccines; T-CD4+ lymphocyte counts and lymphocyte proliferative responses to antigens and mitogens; adverse reactions; vaccine failure. Results: Twenty three children with DiGeorge syndrome/22q11.2 deletion syndrome were included, 65.2% male, with average age at diagnosis of 11.3 months. Eighteen children (78%) received bacillus Calmette-Guérin vaccine: all with evidence of thymic activity; three presented moderate T-CD4+ lymphopenia and abnormal lymphocyte proliferative responses; one had abnormal lymphocyte proliferative responses for mitogens, four for purified protein derivative and one for tetanus toxoid. Measles, mumps and rubella vaccine was administered to 15 children, three of them with moderate immunosuppression and abnormal lymphocyte proliferative responses. Live attenuated polio vaccine was administered to 4 children without immunosuppression and the rotavirus vaccine to three children, one with moderate immunosuppression. No significant adverse reactions were reported. Discussion: These data are in line with the findings of other international studies. Conclusion: In our sample, live vaccines were well-tolerated, even in children with moderate T-CD4+ lymphopenia and abnormal lymphocyte proliferative responses to antigens/mitogens.

Funding: E.B. was supported by a grant from the Junta de Castilla y Leon (Fondo Social Europeo, ORDEN EDU/346/2013, Valladolid, Spain). This work was supported by the CB16/ 12/00400 and CB/16/12/00233 grants (CIBERONC, Instituto de Salud Carlos III, Ministerio de Economıa y Competitividad, Madrid, Spain, and FONDOS FEDER), the FIS PI12/00905-FEDER grant (Fondo de Investigacion Sanitaria of Instituto de Salud Carlos III, Madrid, Spain) and a grant from Fundacion Mutua Madrile~na (Madrid, Spain). The coordination and innovation processes of this study were supported by the EuroFlow Consortium. Background: Predominantly antibody deficiencies (PADs) are the most prevalent primary immunodeficiencies, but their B-cell defects and underlying genetic alterations remain largely unknown. Objective: We investigated patients with PADs for the distribution of 41 blood B-cell and plasma cell (PC) subsets, including subsets defined by expression of distinct immunoglobulin heavy chain subclasses. Methods: Blood samples from 139 patients with PADs, 61 patients with common variable immunodeficiency (CVID), 68 patients with selective IgA deficiency (IgAdef), 10 patients with IgG subclass deficiency with IgA deficiency, and 223 age-matched control subjects were studied by using flow cytometry with EuroFlow immunoglobulin isotype staining. Patients were classified according to their B-cell and PC immune profile, and the obtained patient clusters were correlated with clinical manifestations of PADs. Results: Decreased counts of blood PCs, memory B cells (MBCs), or both expressing distinct IgA and IgG subclasses were identified in all patients with PADs. In patients with IgAdef, B-cell defects were mainly restricted to surface membrane (sm)IgA + PCs and MBCs, with 2 clear subgroups showing strongly decreased numbers of smIgA + PCs with mild versus severe smIgA + MBC defects and higher frequencies of nonrespiratory tract infections, autoimmunity, and affected family members. Patients with IgG subclass deficiency with IgA deficiency and those with CVID showed defects in both smIgA + and smIgG + MBCs and PCs. Reduced numbers of switched PCs were systematically found in patients with CVID (absent in 98%), with 6 different defective MBC (and clinical) profiles: (1) profound decrease in MBC numbers; (2) defective CD27 + MBCs with almost normal IgG 3 + MBCs; (3) absence of switched MBCs; and (4) presence of both unswitched and switched MBCs without and; (5) with IgG 2 + MBCs; and (6) with IgA 1 + MBCs. Conclusion: Distinct PAD defective B-cell patterns were identified that are associated with unique clinical profiles. publishersversion published

Introduction: Hypoparathyroidism is characterized by low or inappropriately normal PTH production, hypocalcemia and hyperphosphatemia. Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of this, caused by heterozygous activating mutations in the CASR gene. Some individuals fail to meet treatment goals despite standard therapy. Clinical Case: A 13-year-old male patient was admitted in the emergency department due to syncope during physical activity. There was no reference to seizures or other complaints. Standard screening for metabolic diseases revealed no changes at the 7th day of life and family history was unremarkable. There was a history of febrile seizures up to 5 years of age with several hospitalizations for diagnosis investigation that were inconclusive. Physical examination showed a positive Chvostek signal, without other changes. A basic workup revealed hypocalcemia 1.67mmol/L (NR: 2.19-2.66), hyperphosphatemia 3.06mmol/L (NR: 0.95-1.75), hypomagnesemia 0.62mmol/L (NR: 0.7-1.0), low 25Hydroxyvitamin D 8.7ng/mL (NR: >30ng/mL) and inappropriately low PTH 4.0pg/mL (NR: 16.0-87.0). Cranial computed tomography scan showed bilateral calcifications of the basal ganglia. Dual-energy x-ray absorptiometry revealed bone mineral density z-scores increased 15% in spine lumbar and decreased 7% in left femur. Cardiac ultrasound and electrocardiography were normal. The patient started therapy with intravenous calcium gluconate. During this treatment, he developed significant calcification of the peripheral veins at the site of administration, leading to intravenous therapy suspension. The dose of oral calcium, calcitriol and magnesium was gradually increased and sevelamer started to control hyperphosphatemia. Despite the optimization, the patient maintained hypocalcemia refractory to standard therapy. As a last resource strategy in therapeutic optimization, the patient started on rhPTH (1-34). Ever since, the patient has been clinically asymptomatic with biochemical stability and with a reasonable quality of life. At age 18, renal ultrasound revealed diffuse medullary nephrocalcinosis. The genetic testing revealed a novel variant c.368T>C p.(Leu123Ser) likely pathogenic in heterozygosity in the CASR gene, suggesting the diagnosis of ADH type 1. The patient′s mother did not give her consent for genetic study and patient’s father had already died with a diagnosis of acute leukemia. Conclusion: This case can be explained by the presence of a likely pathogenic variant in heterozygosity in the CASR gene that has been described in the medical literature that has not been identified in gnomAD population database, suggesting the diagnosis of ADH type 1. rhPTH (1-34) may be a treatment option for those individuals who are not well controlled on standard therapy, but long-term follow-up studies are needed to reinforce its safety.

Background Autosomal recessive axonal neuropathy with neuromyotonia is a recently described entity associated to the HINT1 gene, encoding histidine triad nucleotide-binding protein 1. Patient The authors report a Portuguese 16-year-old girl of Roma ethnicity, descendant of consanguineous parents, with progressive distal muscular atrophy and weakness, beginning at age 6. After several years of extensive investigation with inconclusive results, clinical myotonia was identified. Electrophysiologic studies revealed neuromyotonia associated with a severe chronic predominantly motor axonal neuropathy and homozygous mutation (c.334 C > A, p.H112 N) in HINT1 was detected. Conclusion This report emphasizes the late onset of clinical myotonia essential to the diagnosis.

Limbic encephalitis is a rare neurological disorder that may be difficult to recognize. Clinical features include memory impairment, temporal lobe seizures and affective disturbance. We report the case of a 10-year-old girl with type 1 diabetes mellitus that presented with seizures, depressed mood and memory changes. The diagnosis of glutamic acid decarboxylase 65 (GAD65) mediated limbic encephalitis relied on cerebral magnetic resonance imaging lesions and high serological and cerebrospinal fluid GAD65-antibodies titers. High-dose steroidal therapy was started with clinical improvement. Relapse led to a second high-dose steroid treatment followed by rituximab with remission. A correlation between serum GAD65-antibodies levels and symptoms was found, demonstrating GAD65-antibodies titers may be useful for clinical follow-up and immunotherapy guidance. This report raises awareness of this serious neurological condition that may be associated with type 1 diabetes, underlining the importance of an early diagnosis and prompt treatment for a better prognosis.

Summary Alternating between hyper- and hypo-thyroidism may be explained by the simultaneous presence of both types of TSH receptor autoantibodies (TRAbs) – thyroid stimulating autoantibodies (TSAbs) and TSH blocking autoantibodies (TBAbs). It is a very rare condition, particulary in the pediatric age. The clinical state of these patients is determined by the balance between TSAbs and TBAbs and can change over time. Many mechanisms may be involved in fluctuating thyroid function: hormonal supplementation, antithyroid drugs and levels of TSAbs and TBAbs. Frequent dose adjustments are needed in order to achieve euthyroidism. A definitive therapy may be necessary to avoid switches in thyroid function and frequent need of therapeutic changes. We describe an immune-mediated case of oscillating thyroid function in a 13-year-old adolescent. After a short period of levothyroxine treatment, the patient switched to a hyperthyroid state that was only controlled by adding an antithyroid drug. Learning points Autoimmune alternating hypo- and hyper-thyroidism is a highly uncommon condition in the pediatric age. It may be due to the simultaneous presence of both TSAbs and TBAbs, whose activity may be estimated in vitro through bioassays. The clinical state of these patients is determined by the balance between TSAbs and TBAbs and can change over time. The management of this condition is challenging, and three therapeutic options could be considered: I-131 ablation, thyroidectomy or pharmacological treatment (single or double therapy). Therapeutic decisions should be taken according to clinical manifestations and thyroid function tests, independent of the bioassays results. A definitive treatment might be considered due to the frequent switches in thyroid function and the need for close monitoring of pharmacological treatment. A definitive treatment might be considered due to the frequent switches in thyroid function and the need for close monitoring of pharmacological treatment.

Naïve FoxP3-expressing regulatory T-cells (Tregs) are essential to control immune responses via continuous replenishment of the activated-Treg pool with thymus-committed suppressor cells. The mechanisms underlying naïve-Treg maintenance throughout life in face of the age-associated thymic involution remain unclear. We found that in adults thymectomized early in infancy the naïve-Treg pool is remarkably well preserved, in contrast to conventional naïve CD4 T-cells. Naïve-Tregs featured high levels of cycling and pro-survival markers, even in healthy individuals, and contrasted with other circulating naïve/memory CD4 T-cell subsets in terms of their strong γc-cytokine-dependent signaling, particularly in response to IL-7. Accordingly, ex-vivo stimulation of naïve-Tregs with IL-7 induced robust cytokine-dependent signaling, Bcl-2 expression, and phosphatidylinositol 3-kinase (PI3K)-dependent proliferation, whilst preserving naïve phenotype and suppressive capacity. Altogether, our data strongly implicate IL-7 in the thymus-independent long-term survival of functional naïve-Tregs, and highlight the potential of targeting the IL-7 pathway to modulate Tregs in different clinical settings., This work was supported by Fundação para a Ciência e Tecnologia (FCT; POCI2010/IC/83068/2007 to RMMV; PTDC/SAU-MIC/109786/2009 to AES), and Gulbenkian Foundation (96526/2009 to JF; P132532/2013 to AES). SLS, ASA, RBF, ARP, PM and SMF received FCT scholarships.