Hashimoto Thyroiditis in Childhood -Review of the Epidemiology, Genetic Susceptibility and Clinical Aspects of the Disease

Abstract Chronic autoimmune thyroiditis or Hashimoto's thyroiditis (HT) is the most common cause of thyroid diseases in children and adolescents. It is also the most common cause of acquired hypothyroidism with or without goiter. The incidence of autoimmune thyroiditis has increased dramatically over the past few decades, affecting up to 5% of the general population in iodine sufficient areas. HT is caused by the complex interplay of genetic, environmental, and endogenous factors. Significant progress has been made in identifying and characterizing the genes involved in pathogenesis of the disease. The aim of this review is to analyze current opinions and options regarding the etiology, genetic contribution to the pathogenesis, evaluation, diagnosis, treatment, and prognosis of the HT in children

Genetics of Gland- in-situ or Hypoplastic Congenital Hypothyroidism in Macedonia

Neonatal screening in Macedonia detects congenital hypothyroidism (CH) with an incidence of 1 in 1,585, and more than 50% of cases exhibit a normally located gland-in-situ (GIS). Monogenic mutations causing dyshormonogenesis may underlie GIS CH; additionally, a small proportion of thyroid hypoplasia has a monogenic cause, such as TSHR and PAX8 defects. The genetic architecture of Macedonian CH cases has not previously been studied. We recruited screening-detected, non-syndromic GIS CH or thyroid hypoplasia cases (n = 40) exhibiting a spectrum of biochemical thyroid dysfunction ranging from severe permanent to mild transient CH and including 11 familial cases. Cases were born at term, with birth weight >3,000 g, and thyroid morphologies included goiter (n = 11), thyroid hypoplasia (n = 6), and apparently normal-sized thyroid. A comprehensive, phenotype-driven, Sanger sequencing approach was used to identify genetic mutations underlying CH, by sequentially screening known dyshormonogenesis-associated genes and TSHR in GIS cases and TSHR and PAX8 in cases with thyroid hypoplasia. Potentially pathogenic variants were identified in 14 cases, of which four were definitively causative; we also detected digenic variants in three cases. Seventeen variants (nine novel) were identified in TPO (n = 4), TG (n = 3), TSHR (n = 4), DUOX2 (n = 4), and PAX8 (n = 2). No mutations were detected in DUOXA2, NIS, IYD, and SLC26A7. The relatively low mutation frequency suggests that factors other than recognized monogenic causes (oligogenic variants, environmental factors, or novel genes) may contribute to GIS CH in this region. Future non–hypothesis-driven, next-generation sequencing studies are required to confirm these findings

The Association between Asthma and Obesity in Children – Inflammatory and Mechanical Factors

BACKGROUND: Association of asthma and obesity has been demonstrated in numerous epidemiological studies. However, the underlying mechanisms of the association are not well understood. Both conditions are characterised by chronic tissue inflammation, which includes numerous different inflammatory markers, and possible atopy. AIM: The study aimed to investigate the association between asthma and obesity in children and assess several of potential underlying mechanisms, including the parameters of systemic inflammation (CRP, fibrinogen) and the mechanical effect of obesity on the respiratory system through parameters of lung function. An additional aim was to examine the role of atopy in overweight children with asthma and to investigate the type of respiratory inflammation. MATERIAL AND METHODS: This prospective study included 72 patients in the age group of 7-15 years, including 38 with high body mass index (BMI), 16 with asthma and normal BMI, and 18 with asthma and high BMI for sex and age. Non-specific inflammatory markers (fibrinogen, CRP), eosinophilia, and total serum IgE were investigated. The patients underwent a skin prick test (SPT) with standard inhalant allergen extracts, measurement of fractional exhaled nitric oxide Fe (NO), and an assessment of lung function. RESULTS: In overweight groups of children we determined significantly higher values (p < 0.001) of both acute inflammatory reactants, CRP and fibrinogen, with no difference between children with and without asthma. There was a significant increase in eosinophilia, total IgE, and positive SPT in the asthmatic groups compared to the group of non-asthmatic patients (p < 0.001 for the three parameters). Compared to the group composed of overweight patients without asthma, the asthmatic patients had higher NO values (p < 0.001). No significant difference in the lung function parameters was found between the three groups (p > 0.05). CONCLUSION: A positive association between asthma and obesity with inflammation as an underlying mechanism, eosinophilic one in asthmatic patients and non-eosinophilic one in overweight patients, was determined. It seems that the lung function parameters did not differ between asthmatic patients and overweight patients. No influence of atopy in the association between asthma and obesity was verified. Further analyses of specific inflammatory markers, for an in-depth evaluation of the mechanisms leading to the association of obesity and asthma, are warranted

Assigning single clinical features to their disease-locus in large deletions: the example of chromosome 1q23-25 deletion syndrome

Aim: Assigning a disease-locus within the shortest regions of overlap (SRO) shared by deleted/duplicated subjects presenting this disease is a robust mapping approach, although the presence of different malformation traits and their attendance only in a part of the affected subjects can hinder the interpretation. To overcome the problem of incomplete penetrance, we developed an algorithm that we applied to the deletion region 1q23.3-q25, which contains three SROs, each contributing to the abnormal phenotype without clearly distinguishing between the different malformations. We describe six new subjects, including a healthy father and his daughter, with 1q23.3-q25 deletion of different sizes. The aim of this study was to correlate specific abnormal traits to the haploinsufficiency of specific gene/putative regulatory elements. Methods: Merging cases with those in the literature, we considered four traits, namely intellectual disability (ID), microcephaly, short-hands/feet, and brachydactyly, and conceived a mathematical model to predict with what probability the haploinsufficiency of a specific portion of the deletion region is associated with one of the four malformations. Results: The haploinsufficiency of PBX1 is strongly associated with ID. DNM3 and LHX4 are confirmed as responsible for growth retardation, whereas ATPIB1 was identified as a new candidate gene for microcephaly, short-hands/feet, and brachydactyly. Conclusion: Although our model is hampered by long-term position effects of regulatory elements, synergistic cooperation of several genes, and incomplete clinical assessment, it can be useful for contiguous gene syndromes showing a complex pattern of clinical characteristics. Obviously, functional approaches are needed to warrant its reliability

Chimerism after Liver Transplantation for Type IV Glycogen Storage Disease and Type 1 Gaucher's Disease

Background: Liver transplantation for type IV glycogen storage disease (branching-enzyme deficiency) results in the resorption of extrahepatic deposits of amylopectin, but the mechanism of resorption is not known. Methods: We studied two patients with type IV glycogen storage disease 37 and 91 months after liver transplantation and a third patient with lysosomal glucocerebrosidase deficiency (type 1 Gaucher's disease), in whom tissue glucocerebroside deposition had decreased 26 months after liver replacement, to determine whether the migration of cells from the allograft (microchimerism) could explain the improved metabolism of enzyme-deficient tissues in the recipient. Samples of blood and biopsy specimens of the skin, lymph nodes, heart, bone marrow, or intestine were examined immunocytochemically with the use of donor-specific monoclonal anti-HLA antibodies and the polymerase chain reaction, with preliminary amplification specific to donor alleles of the gene for the beta chain of HLA-DR molecules, followed by hybridization with allele-specific oligonucleotide probes. Results: Histopathological examination revealed that the cardiac deposits of amylopectin in the patients with glycogen storage disease and the lymph-node deposits of glucocerebroside in the patient with Gaucher's disease were dramatically reduced after transplantation. Immunocytochemical analysis showed cells containing the HLA phenotypes of the donor in the heart and skin of the patients with glycogen storage disease and in the lymph nodes, but not the skin, of the patient with Gaucher's disease. Polymerase-chain-reaction analysis demonstrated donor HLA-DR DNA in the heart of both patients with glycogen storage disease, in the skin of one of them, and in the skin, intestine, blood, and bone marrow of the patient with Gaucher's disease. Conclusions: Systemic microchimerism occurs after liver allotransplantation and can ameliorate pancellular enzyme deficiencies., In patients with type IV glycogen storage disease, deficiency of the branching enzyme α-1,4-glucan:α-1,4-glucan 6-glucosyltransferase is responsible for the accumulation in the liver and elsewhere of an insoluble and irritating amylopectin-like polysaccharide1. We recently described the absorption of this amylopectin from the extrahepatic tissues after liver transplantation,2 leading Howell to predict that an explanation of the benefit would “clearly teach us a great deal about transplantation”3. That prediction has been shown to be accurate by our observation in this study that patients with type IV glycogen storage disease in whom liver transplantation was successful became chimeras: the cells… © 1993, Massachusetts Medical Society. All rights reserved

ВажноÑÑ‚ на 6 минутниот теÑÑ‚ на одење во дијагноÑтика на ретка метаболна миопатија – приказ на Ñлучај на карнитин палмитоил транÑфераза 2 дефицит

Diagnosis of rare inherited neuromuscular disorders is sometimes delayed due to variations in time of onset, different clinical appearance and limited diagnostic possibilities. The management of patients  starts  with neurological examination, followed by  specific laboratory tests  and neurophysiologic assessment. In the  era of molecular medicine, molecular biology tools are useful in avoiding some of the invasive investigations such as muscle biopsy. We present a boy with a mild form of metabolic myopathy due to carnitine  palmitoyltransferase  2 deficiency diagnosed upon timed functional assessment. A child had delayed developmental milestones, associated with fatigue and muscle pain during exercising and longer walks. There were no episodes of myoglobinuiria during exercise or during febrile illnesses. Neurological examination reveled proximal muscle weakness. Serum creatine kinase (CK) and serum lactate were above normal limits. Serum acylcarnitine profile was normal. Short timed functional tests such as 10 meters  walk/run test  showed normal results. Nord Star Ambulatory Assessment showed difficulties in balance and jumping. Diagnosis of myopathy was suspected after performance of 6-minute walk test, when the passed distance was 327 meters with slowing and fatigue. EMG and echocardiography were within normal range. Diagnosis was established by sequencing  of the CPT II gene which revealed   c.338C>T (p.Ser113Leu) mutation in homozygous form as characteristic CPT II deficiency profile.Дијагнозата на ретките невромуÑкулни заболувања е понекогаш пролонгирана заради различното вре- ме на почеток на Ñимптомите, различната клиничка Ñлика и ограничените дијагноÑтички можноÑти. Обработката на пациентот започнува Ñо невролошки преглед, по што Ñледат Ñпецифични лаборато- риÑки теÑтови и неврофизиолошки иÑпитувања. Во ера на молекуларната медицина, генетÑката анали- за овозможува да Ñе избегнат некои од инвазивните иÑпитувања, како на пример муÑкулната биопÑија. Прикажуваме момче Ñо блага форма на метаболичка миопатија Ñо карнитин палмитоил транÑфераза 2 (CPT II) дефицит, која е дијагноÑтицирана врз оÑнова на временÑка функционална проценка. Детето имало забавен моторен развој, Ñо замор и муÑкулна болка во тек на вежбање или подолго одење. Ðема- ло епизоди на миоглобинурија во тек на вежбање или во тек на фебрилни болеÑти. Ðевролошкиот пре- глед покажа прокÑимална муÑкулна ÑлабоÑÑ‚. СерумÑката креатин киназа и ÑерумÑкото ниво на лакта- ти беа над нормалните граници. СерумÑкиот профил на ацил карнитини беше нормален. Кратките функционални теÑтови како 10 метри одење/трчање покажаа уредни резултати. Nord Star Ambulatory Assessment  – теÑтирањето покажа потешкотии во рамнотежата и при Ñкокање. Сомнение за вродена миопатија Ñе поÑтави по изведување на подолготраен функционален теÑÑ‚ – 6-минутниот теÑÑ‚ на одење кога поминатата  Ð´Ð¸Ñтанца беше 327 метри Ñо уÑпорување и замор. Електроневромиографијата и ехо- кардиографијата кај детето покажаа нормални наоди. Дијагнозата беше потврдена Ñо Ñеквенциони- рање на CPT II генот Ñо региÑтрирање на c.338C>T (p.Ser113Leu) мутација  Ð²Ð¾ хомозиготна форма која е карактериÑтична за CPT II дефицит

Neonatal Screening in Europe Revisited: An ISNS Perspective on the Current State and Developments Since 2010

Neonatal screening (NBS) was initiated in Europe during the 1960s with the screening for phenylketonuria. The panel of screened disorders (“conditions”) then gradually expanded, with a boost in the late 1990s with the introduction of tandem mass spectrometry (MS/MS), making it possible to screen for 40–50 conditions using a single blood spot. The most recent additions to screening programmes (screening for cystic fibrosis, severe combined immunodeficiency and spinal muscular atrophy) were assisted by or realised through the introduction of molecular technologies. For this survey, we collected data from 51 European countries. We report the developments between 2010 and 2020 and highlight the achievements reached with the progress made in this period. We also identify areas where further progress can be made, mainly by exchanging knowledge and learning from experiences in neighbouring countries. Between 2010 and 2020, most NBS programmes in geographical Europe matured considerably, both in terms of methodology (modernised) and with regard to the panel of conditions screened (expanded). These developments indicate that more collaboration in Europe through European organisations is gaining momentum. We can only accomplish the timely detection of newborn infants potentially suffering from one of the many rare diseases and take appropriate action by working together

Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies

Peer reviewe