Search

ZUSAMMENFASSUNGKinder mit vermeintlichen Wachstumsstörungen werden häufig in Kinderarztpraxen vorgestellt. Zur Diagnosefindung sind Anamnese, körperliche Untersuchung und Beurteilung des Wachstumsverlaufs unabdingbar. Neben physiologischen Wachstumsformen, die die biologische Varianz in der Bevölkerung widerspiegeln, kommen einige Pathologien infrage. Pathologische Wachstumsstörungen sind vor allem über eine veränderte Wachstumsgeschwindigkeit mit Abweichen von den ursprünglichen Perzentilen definiert. Hier seien unter anderem ein sekundärer Kleinwuchs bei chronischer Erkrankung, syndromaler Kleinwuchs, Kleinwuchs nach intrauteriner Wachstumsverzögerung und Wachstumshormonmangel genannt. Die Diagnosestellung ist häufig nicht einfach und erfordert einige Verlaufskontrollen und/oder endokrinologische Stimulationstests. Die Wachstumshormontherapie wird nicht nur bei Wachstumshormonmangel, sondern auch bei anderen Erkrankungen eingesetzt, verlangt jedoch eine gewissenhafte Indikationsstellung.

ZUSAMMENFASSUNGDer Mangel von Schilddrüsenhormonen hat starke Auswirkungen auf die Entwicklung von Kindern und Jugendlichen. Wachstumsretardierung, Gewichtszunahme, aber auch Depressionen gehören zu den typischen Symptomen. Die frühe Entwicklung des zentralen Nervensystems ist im Besonderen auf Schilddrüsenhormone angewiesen. Fehlen diese, kommt es zu einer schweren mentalen Retardierung, Kleinwuchs und Innenohrschwerhörigkeit, dem Bild eines Kretinismus. Je nach Manifestationsalter unterscheiden wir die angeborene von der erworbenen Hypothyreose. In Abhängigkeit der Ursachen können primäre und sekundäre Formen vorliegen. Beim Neugeborenen wird eine primäre Hypothyreose durch ein auffälliges Neugeborenenscreening erfasst. Eine zentrale angeborene Hypothyreose muss jedoch klinisch diagnostiziert werden. Eine erworbene Hypothyreose kann sich in jedem Lebensalter manifestieren, wobei die klinischen Zeichen häufig unspezifisch sind. Diese Übersicht soll helfen, betroffene Kinder durch Anamnese und Klinik besser identifizieren zu können und die Schilddrüsenparameter richtig zu interpretieren.

ZUSAMMENFASSUNGDie Beurteilung der Pubertätsentwicklung sowie Übergewicht und Adipositas sind tagtäglicher Bestandteil der pädiatrischen Praxis. Dabei beeinflussen sich Pubertätsentwicklung und Adipositas wechselseitig. Während Mädchen mit Adipositas häufig eine Pubertätsakzeleration aufweisen, sind die Daten bei Jungen weniger eindeutig. Möglicherweise verursacht Übergewicht hier eine Pubertätsbeschleunigung und Adipositas eine Pubertätsverzögerung. Leicht erhöhte Androgenspiegel bei Mädchen sowie leicht erhöhte Östrogenspiegel bei Jungen und eine präpubertäre Wachstumsakzeleration bei beiden Geschlechtern sind häufige Phänomene bei Kindern mit Adipositas. Die Ursachen sind multifaktoriell. Hierbei spielt das Fettgewebe eine entscheidende Rolle, sowohl durch die zentrale Aktivierung der Hypothalamus-Hypophysen-Gonadenachse über Leptin und Kisspeptin als auch durch periphere Effekte, wie beispielweise die Umwandlung von Androgenen zu Östrogen. Syndrome, welche sowohl Störungen der Pubertätsentwicklung als auch Adipositas umfassen, dürfen bei der klinischen Einschätzung nicht übersehen werden. Zur Einschätzung der altersgerechten Pubertätsentwicklung bei Kindern und Jugendlichen mit Adipositas kann in Kenntnis der typischen Veränderungen und Warnzeichen in den meisten Fällen jedoch auf weitere Diagnostik verzichtet und der Verlauf vorerst beobachtet werden.

ZUSAMMENFASSUNGVarianten der Geschlechtsentwicklung erfahren in der aktuellen Zeit einen immer größeren Interessenszuwachs, nicht zuletzt auch durch das große mediale Interesse der „LGBTQIA-Bewegung“ und dem daraus resultierenden offeneren Umgang mit Personen, die nicht in das klassische Bild einer Frau oder eines Mannes passen. Dies zeigt sich insbesondere durch den Wandel der Begrifflichkeiten von „intersexuell“ über „Störungen“ hin zu „Varianten der Geschlechtsentwicklung“ sowie auch durch die Einführung des 3. Geschlechts „divers“ im Jahr 2018. Die Tatsache, dass im Jahr 2021 weltweit jedoch lediglich 96 Personen als „divers“ registriert waren, macht die Diskrepanz zwischen großem Interesse auf der einen und Stigmatisierungsangst auf der anderen Seite deutlich. Eine ähnliche Berührungsangst erleben wir auch im klinischen Alltag. Ursächlich für diese Berührungsangst sind häufig eine ungenaue Vorstellung des Krankheitsbildes sowie die Sorge in der Diagnostik und Betreuung der Betroffenen und deren Familien, Fehler zu begehen. Diese Übersicht soll helfen, das Thema „Varianten der Geschlechtsentwicklung“ besser zu verstehen, die Unterschiede der einzelnen Formen aufzuzeigen, eine Orientierung in der Diagnostik zu bieten, sowie insbesondere die Besonderheiten in der Begleitung und einer potenziellen Therapie aufzuzeigen.

Skeletal dysplasias collectively affect a large number of patients worldwide. The majority of these disorders cause growth anomalies. Hence, assessing skeletal maturity via determining the bone age (BA) is one of the most valuable tools for their diagnoses. Moreover, consecutive BA assessments are crucial for monitoring the pediatric growth of patients with such disorders, especially for timing hormone treatments or orthopedic interventions. However, manual BA assessment is time-consuming and suffers from high intra-and inter-rater variability. This is further exacerbated by genetic disorders causing severe skeletal malformations. While numerous approaches to automatize BA assessment were proposed, few were validated for BA assessment on children with abnormal development. In this work, we present Deeplasia, an open-source prior-free deep-learning ensemble approach. After training on the public RSNA BA dataset, we achieve state-of-the-art performance with a mean absolute difference (MAD) of 3.87 months based on the average of six different reference ratings. Next, we demonstrate that Deeplasia generalizes to an unseen dataset of 568 X-ray images from 189 patients with molecularly confirmed diagnoses of seven different genetic bone disorders (including Achondroplasia and Hypochondroplasia) achieving a MAD of 5.84 months w.r.t. to the average of two references. Further, using longitudinal data from a subset of the cohort (149 images), we estimate the test-retest precision of our model ensemble to be at least at the human expert level (2.74 months). We conclude that Deeplasia suits assessing and monitoring the BA in patients with skeletal dysplasias.

ZUSAMMENFASSUNGEs wurde viel darüber spekuliert, ob durch Schulschließungen, eingeschränkte soziale Kontakte und den Wegfall sportlicher Aktivitäten während der Covid-19-Pandemie die Adipositasepidemie im Kindesalter verstärkt werden würde. Deshalb haben wir die BMI-Verläufe während der 15 Jahre vor und während der Covid-19-Pandemie untersucht. Der Trend der BMI-Veränderungen (als delta-BMI-SDS) und die Anteile der Kinder, die Gewicht zunahmen bzw. verloren, zwischen 2005 und 2019 sowie entsprechend Daten von 2019 vor der Pandemie und von 2020 nach dem Einsetzen der ersten Pandemiemaßnahmen wurden bei mehr als 150 000 Kindern (ca. 10 000 in der pandemischen Phase) verglichen. Während der Covid-19-Pandemie fand sich eine substanzielle Gewichtszunahme über alle Gewichtsklassen und Altersstufen hinweg. Die Änderung des mittleren BMI-SDS war wesentlich höher als in den Jahren zuvor. Ebenso stieg der Anteil der Kinder, die Gewicht zunahmen. Der Anteil der Kinder, die Gewicht über den Zeitraum verloren, nahm hingegen ab. Außerdem fanden wir ähnliche Trends, der zwar auf eine wesentlich schwächere, aber doch stetige Gewichtszunahme hinweisen, bereits seit 2005. Es ist alarmierend, dass sowohl der langfristige Trend als auch die kurzfristigen, pandemie-bezogenen Effekte bei Kindern, die bereits übergewichtig oder adipös waren, am größten waren.Die Trends, die wir in mehreren Parametern der Gewichtsveränderung über einen Zeitraum von mehr als 15 Jahren beobachten konnten, weisen auf eine Zunahme des BMI-SDS. Besonders bei adipösen Kindern ist diese Dynamik ausgeprägt. Covid-19-bezogene Maßnahmen verstärken die Effekte und könnten damit die Adipositasepidemie im Kindesalter weiter eskalieren.

Context Early initiation of growth hormone (GH) therapy is recommended for short children born small for gestational age (SGA); however, real-world data indicate that treatment is often delayed. Objective We aimed to assess the impact of patient age at GH therapy initiation on long-term growth outcomes and safety in short children born SGA. Methods Analysis of pooled data from NordiNet® International Outcome Study (NCT00960128; 469 European clinics) and the ANSWER Program (NCT01009905; 207 US clinics), two large, complementary observational studies. Patients received GH as prescribed by their treating physician. Enrolled patients born SGA were categorized into three groups based on their age at GH treatment initiation: 2 to Results The effectiveness analysis (treatment-naïve and prepubertal patients at GH initiation) included 3318 patients: 10.7% aged 2 to Conclusion Early initiation of GH therapy in short children born SGA may be an important contributor to height optimization. The data are reassuring regarding the long-term safety of GH therapy in this population.

ZUSAMMENFASSUNGHoloprosenzephalie (HPE) ist ein komplexes Krankheitsbild mit variabler genetischer und klinischer Ausprägung. Es existieren verschiedene Formen der HPE mit Unterschieden in der Schwere des Verlaufes. Die schwere Form der HPE stellen die lobare und alobare HPE dar, die mit Zyklopie (Vereinigung von beiden Augenanlagen in einer einzigen Orbita) einhergehen, wohingegen Minor-Formen/HPE-Spektrumerkrankungen eine Mikrozephalie und/oder Hypotelorismus oder eine Lippen-Kiefer-Gaumenspalte aufweisen. Die genetischen Mechanismen sind noch nicht abschließend geklärt. Es wurden autosomal-dominante, rezessive und digenetische Vererbungsmuster beschrieben. Wir ergänzen das Spektrum der HPE-Erkrankungen um eine Patientin mit compound heterozygoter DISP1-Mutation, die einen Panhypopituitarismus in Kombination mit Entwicklungverzögerung, Lippen-Kiefer-Gaumenspalte, persistierendem Ductus Arteriosus Botalli und Visusminderung aufweist.

Background/Objectives There is a concern that measures aiming to limit a further spread of COVID-19, e.g., school closures and social distancing, cause an aggravation of the childhood obesity epidemic. Therefore, we compared BMI trends during the 15 years before and during the COVID-19 pandemic. Subjects/Methods To assess the change in weight dynamics during the first months of COVID-19, we compared the trends of 3-month change in BMI-SDS (ΔBMI-SDS) and the proportions of children showing a high positive (HPC) or high negative (HNC) weight change between 2005 and 2019 and the respective changes from 2019 (pre-pandemic) to 2020 (after the onset of anti-pandemic measures) in more than 150,000 children (9689 during the pandemic period). The period of 3 months corresponds approximately to the first lockdown period in Germany. Results During the COVID-19 pandemic, we found a substantial weight gain across all weight and age groups, reflected by an increase in the 3-month change in BMI-SDS (β = 0.05, p p p β = 0.001 (p high_pos = 1.01 (p high_neg = 0.99 (p β = 0.02, ORhigh_pos = 1.14, and ORhigh_pos = 0.85 over the whole period 2005–2019. Alarmingly, both the long-term and the short-term effects were most pronounced in the obese subgroup. Conclusions There are positive dynamics in different measures of weight change, indicating a positive trend in weight gain patterns, especially within the group of children with obesity. These dynamics are likely to be escalated by COVID-19-related measures. Thus, they may lead to a significant further aggravation of the childhood obesity pandemic.

Context Prematurity carries a risk for impaired postnatal growth and long-term growth restriction. Especially children born SGA seem vulnerable for poor growth, as a persistent short stature can be observed in app 10-15% of these children. Objective In this study we aimed to recognize differences in growth patterns of children according to sex, maturity, and auxological status at birth facilitating earlier identification of small-for-gestational-age (SGA) children with adult short stature. Methods The growth data of 44 791 infants born between January 1, 1980, and December 30, 2012, among 2 pediatric cohorts with follow-up through December 31, 2020, were analyzed. A total of 5698 children with birth data had measurements at near final height (nfh) and at least 2 further points. Results Preterm children (gestational age Conclusion Final growth outcome was influenced by prematurity and auxological status at birth, but not by sex. Height/length SDS increments during year 1 are instrumental to discern SGA children with later normal or short stature. While observing CUG until year 2 and 3 can add specificity, discrimination thereafter becomes difficult.

Introduction: Omnitrope® was approved as a biosimilar recombinant human growth hormone (rhGH) in 2006. Objective: The purpose of this work was to evaluate the long-term safety and effectiveness of Omnitrope® in PATRO Children – an ongoing, international, longitudinal, non-interventional study in children who require rhGH treatment. Methods: The study population includes infants, children, and adolescents receiving Omnitrope®. Adverse events (AEs) are monitored for safety and rhGH effectiveness is evaluated by calculation of the height standard deviation score (HSDS), height velocity (HV), and HVSDS using height measurements and country-specific references. Results: As of November 2017, 6,009 patients from 298 centers across 14 countries were enrolled in PATRO Children. Overall, 57.7% of patients had growth hormone deficiency (GHD), 25.8% were born small for gestational age (SGA), and 4.8% had Turner syndrome (TS). In total, 84.1% were rhGH treatment naïve at study entry. The mean duration of Omnitrope® treatment in the study was 36.1 months (range 0–133.7). Overall, 10,360 AEs were reported in 2,750 patients (45.8%). Treatment-related AEs were reported in 396 patients (6.6%; 550 events), and serious AEs (SAE) in 636 patients (10.6%; 1,191 events); 50 SAEs in 37 patients (0.6%) were considered treatment related. Following 5 years of therapy in patients who were rhGH treatment naïve at study entry, improvement from baseline in mean HSDS was +1.85 in GHD, +1.76 in SGA, and +1.0 in TS patients. In total, 912 (17.9%) patients reached adult height (n = 577 GHD, n = 236 SGA, n = 62 TS). Conclusions: This analysis of PATRO Children indicates that biosimilar rhGH is well tolerated and effective in real-world clinical practice.

Assessment and management of children with growth failure has improved greatly over recent years. However, there remains a strong potential for further improvements by using novel digital techniques. A panel of experts discussed developments in digitalization of a number of important tools used by pediatric endocrinologists at the third 360 degrees European Meeting on Growth and Endocrine Disorders, funded by Merck KGaA, Germany, and this review is based on those discussions. It was reported that electronic monitoring and new algorithms have been devised that are providing more sensitive referral for short stature. In addition, computer programs have improved ways in which diagnoses are coded for use by various groups including healthcare providers and government health systems. Innovative cranial imaging techniques have been devised that are considered safer than using gadolinium contrast agents and are also more sensitive and accurate. Deep-learning neural networks are changing the way that bone age and bone health are assessed, which are more objective than standard methodologies. Models for prediction of growth response to growth hormone (GH) treatment are being improved by applying novel artificial intelligence methods that can identify non-linear and linear factors that relate to response, providing more accurate predictions. Determination and interpretation of insulin-like growth factor-1 (IGF-1) levels are becoming more standardized and consistent, for evaluation across different patient groups, and computer-learning models indicate that baseline IGF-1 standard deviation score is among the most important indicators of GH therapy response. While physicians involved in child growth and treatment of disorders resulting in growth failure need to be aware of, and keep abreast of, these latest developments, treatment decisions and management should continue to be based on clinical decisions. New digital technologies and advancements in the field should be aimed at improving clinical decisions, making greater standardization of assessment and facilitating patient-centered approaches.

ContextIGF1 receptor mutations (IGF1RM) are rare; however, patients exhibit pronounced growth retardation without catch-up. Although several case reports exist, a comprehensive statistical analysis investigating growth profile and benefit of recombinant human growth hormone (rhGH) treatment is still missing.Objective and methodsHere, we compared IGF1RM carriers (n = 23) retrospectively regarding birth parameters, growth response to rhGH therapy, near final height, and glucose/insulin homeostasis to treated children born small for gestational age (SGA) (n = 34). Additionally, health profiles of adult IGF1RM carriers were surveyed by a questionnaire.ResultsIGF1RM carriers were significantly smaller at rhGH initiation and had a diminished first-year response compared to SGA children (Δ height standard deviation score: 0.29 vs. 0.65), resulting in a lower growth response under therapy. Interestingly, the number of poor therapy responders was three times higher for IGF1RM carriers than for SGA patients (53 % vs. 17 %). However, most IGF1RM good responders showed catch-up growth to the levels of SGA patients. Moreover, we observed no differences in homeostasis model assessment of insulin resistance before treatment, but during treatment insulin resistance was significantly increased in IGF1RM carriers compared to SGA children. Analyses in adult mutation carriers indicated no increased occurrence of comorbidities later in life compared to SGA controls.ConclusionIn summary, IGF1RM carriers showed a more pronounced growth retardation and lower response to rhGH therapy compared to non-mutation carriers, with high individual variability. Therefore, a critical reevaluation of success should be performed periodically. In adulthood, we could not observe a significant influence of IGF1RM on metabolism and health of carriers.

Context There has been concern that GH treatment of children might increase meningioma risk. Results of published studies have been inconsistent and limited. Objective To examine meningioma risks in relation to GH treatment. Design Cohort study with follow-up via cancer registries and other registers. Setting Population-based. Patients A cohort of 10,403 patients treated in childhood with recombinant GH in five European countries since this treatment was first used in 1984. Expected rates from national cancer registration statistics. Main Outcome Measures Risk of meningioma incidence. Results During follow-up, 38 meningiomas occurred. Meningioma risk was greatly raised in the cohort overall [standardized incidence ratio (SIR) = 75.4; 95% CI: 54.9 to 103.6], as a consequence of high risk in subjects who had received radiotherapy for underlying malignancy (SIR = 658.4; 95% CI: 460.4 to 941.7). Risk was not significantly raised in patients who did not receive radiotherapy. Risk in radiotherapy-treated patients was not significantly related to mean daily dose of GH, duration of GH treatment, or cumulative dose of GH. Conclusions Our data add to evidence of very high risk of meningioma in patients treated in childhood with GH after cranial radiotherapy, but suggest that GH may not affect radiotherapy-related risk, and that there is no material raised risk of meningioma in GH-treated patients who did not receive radiotherapy., In a five-country cohort of 10,403 patients treated with recombinant growth hormone, meningioma risk was greatly raised in relation to radiotherapy, but not apparently related to growth hormone.

Introduction: PATRO Children is an international, observational, postmarketing surveillance study for a biosimilar recombinant human growth hormone (rhGH; somatropin, Omnitrope®; Sandoz), approved by the European Medicines Agency in 2006. We report safety and effectiveness data for patients with Turner syndrome (TS). Methods: The study population included infants, children, and adolescents with TS who received Omnitrope® treatment according to standard clinical practice. Adverse events (AEs) were monitored for safety evaluation, and height velocity (HV), height standard deviation score (HSDS), and HVSDS were calculated to evaluate treatment effectiveness. Results: As of August 2019, 348 TS patients were enrolled from 130 centers. At baseline, 314 patients (90.2%) were prepubertal and 284 patients (81.6%) were rhGH treatment naïve. The mean (range) age at baseline was 9.0 (0.7–18.5) years, and mean (SD) treatment duration in the study was 38.5 (26.8) months. Overall, 170 patients (48.9%) reported AEs, which were considered treatment related in 25 patients (7.2%). One treatment-related serious AE was reported (intracranial hypertension). Mean ΔHSDS after 3 years of therapy was +1.17 in treatment-naïve prepubertal patients and +0.1 in pretreated prepubertal patients. In total, 51 patients (31.1%) reached adult height (AH), 35 of whom were rhGH treatment naïve; in these patients, mean (SD) HSDS was −2.97 (1.03) at the start of Omnitrope® treatment, and they achieved a mean (SD) AHSDS of −2.02 (0.9). Conclusion: These data suggest that biosimilar rhGH is well tolerated and effective in TS patients managed in real-life clinical practice. Optimization of rhGH dose may contribute to a higher AH.

Zusammenfassung Hintergrund Es gibt viele Ursachen für einen Kleinwuchs. Kleinwuchs in Kombination mit einer intrauterinen Wachstumsretardierung (IUGR), einer Entwicklungsverzögerung und/oder ungewöhnlichen Stigmata sollte immer auch an eine syndromale Ursache denken lassen. Fragestellung Diese Arbeit soll für Kleinwuchssyndrome sensibilisieren, deren Diagnose aufgrund der potenziell lebensbedrohlichen Folgen möglichst frühzeitig gestellt werden sollte. Material und Methoden Die vorliegende Arbeit wurde auf Basis klinikinterner Fallberichte vor dem Hintergrund der aktuellen Literatur erstellt. Ergebnisse Das PTEN-Hamartom-Tumor-Syndrom (PHTS), das Bloom-Syndrom (BS), der mikrozephale osteodysplastische primordiale Kleinwuchs Typ II (MOPD-II-Syndrom) sowie das Ligase-IV-Syndrom (Lig4-Syndrom) sind seltene Kleinwuchssyndrome mit potenziell letalem Ausgang. Gemeinsame Merkmale liegen in einer Abweichung des Kopfumfangs (KU) und einer Entwicklungsverzögerung. Die Verdachtsdiagnose wird molekulargenetisch gesichert. Die Behandlung erfolgt in erster Linie symptomorientiert, für das PHTS und das Ligase-IV-Syndrom existieren darüber hinaus bereits kausale Therapieansätze. Für alle Syndrome gibt es Empfehlungen im Hinblick auf gezielte Vorsorgeuntersuchungen. Schlussfolgerung Bei entsprechenden Hinweisen auf einen syndromalen Kleinwuchs sollte zügig eine molekulargenetisch gestützte Diagnostik erfolgen, um rechtzeitig geeignete Therapieoptionen und Vorsorgeprogramme initiieren zu können.

Isolated growth hormone deficiency (GHD) is defined by growth failure in combination with retarded bone age, low serum insulin-like growth factor-1, and insufficient GH peaks in two independent GH stimulation tests. Congenital GHD can present at any age and can be associated with significant malformations of the pituitary-hypothalamic region or the midline of the brain. In rare instances, genetic analysis reveals germline mutations of transcription factors involved in embryogenesis of the pituitary gland and the hypothalamus. Acquired GHD is caused by radiation, inflammation, or tumor growth. In contrast to organic GHD, idiopathic forms are more frequent and remain unexplained. There is a risk of progression from isolated GHD to combined pituitary hormone deficiency (> 5% for the total group), which is clearly increased in children with organic GHD, especially with significant malformation of the pituitary gland. Therefore, it is prudent to exclude additional pituitary hormone deficiencies in the follow-up of children with isolated GHD by clinical and radiological observations and endocrine baseline tests. In contrast to primary disorders of endocrine glands, secondary deficiency is frequently milder in its clinical manifestation. The pituitary hormone deficiencies can develop over time from mild insufficiency to severe deficiency. This review summarizes the current knowledge on diagnostics and therapy of additional pituitary hormone deficits occurring during rhGH treatment in children initially diagnosed with isolated GHD. Although risk factors are known, there are no absolute criteria enabling exclusion of children without any risk of progress to combined pituitary hormone deficiency. Lifelong monitoring of the endocrine function of the pituitary gland is recommended in humans with organic GHD. This paper is the essence of a workshop of pediatric endocrinologists who screened the literature for evidence with respect to evolving pituitary deficits in initially isolated GHD, their diagnosis and treatment.

In this chapter, we want to give an overview on what we have learned from more than 30 years ago on the use of recombinant human growth hormone (rhGH) and later recombinant human IGF-1 which was introduced for the treatment of short children and what are the safety issues concerned with this treatment. However, rhGH is used not solely in conditions where short stature is the consequence of GH deficiency but also in various disorders without a proven GH deficiency. In clinical studies, growth responses to various forms of rhGH therapy were analyzed, adding to our concept about the physiology of growth. Most patients under rhGH treatment show a considerable short-term effect; however, the long-term gain of height in a child obtained by a year-long treatment until final height remains controversial in some of the growth disorders that have been treated with rhGH or IGF-1. Today the first studies on the long-term safety of rhGH treatment have been published and raising some questions whether this treatment is similarly safe for all the patient groups treated with rhGH. Although there is a long-standing safety record for these hormone replacement therapies, in the face of the considerable costs involved, the discussion about the risk to benefit ratio is continuing. Newer developments of rhGH treatment include long-term preparations, which have only to be injected once a week. Although some of these drugs already have proven their non-inferiority to conventional rhGH treatment, we have to await further results to see whether they show improvements in treatment adherence of the patients and prove their long-term safety.

Die Hypophyse ist das zentrale Organ bei der hormonellen Steuerung. Sie integriert eine Vielzahl von lebenswichtigen hormonellen Regelkreisen. So sezerniert die Hypophyse Peptide und Proteohormone, welche Wasserhaushalt (Hypophysenhinterlappen), Stressantwort des Organismus (Nebennierenachse), Fortpflanzung (Gonadenachse), Wachstum (Wachstumshormonachse) und Energiehaushalt (Schilddrusenachse) steuern.

The dynamics of body-mass index (BMI) in children from birth to adolescence are unclear, and whether susceptibility for the development of sustained obesity occurs at a specific age in children is important to determine.To assess the age at onset of obesity, we performed prospective and retrospective analyses of the course of BMI over time in a population-based sample of 51,505 children for whom sequential anthropometric data were available during childhood (0 to 14 years of age) and adolescence (15 to 18 years of age). In addition, we assessed the dynamics of annual BMI increments, defined as the change in BMI standard-deviation score per year, during childhood in 34,196 children.In retrospective analyses, we found that most of the adolescents with normal weight had always had a normal weight throughout childhood. Approximately half (53%) of the obese adolescents had been overweight or obese from 5 years of age onward, and the BMI standard-deviation score further increased with age. In prospective analyses, we found that almost 90% of the children who were obese at 3 years of age were overweight or obese in adolescence. Among the adolescents who were obese, the greatest acceleration in annual BMI increments had occurred between 2 and 6 years of age, with a further rise in BMI percentile thereafter. High acceleration in annual BMI increments during the preschool years (but not during the school years) was associated with a risk of overweight or obesity in adolescence that was 1.4 times as high as the risk among children who had had stable BMI. The rate of overweight or obesity in adolescence was higher among children who had been large for gestational age at birth (43.7%) than among those who had been at an appropriate weight for gestational age (28.4%) or small for gestational age (27.2%), which corresponded to a risk of adolescent obesity that was 1.55 times as high among those who had been large for gestational age as among the other groups.Among obese adolescents, the most rapid weight gain had occurred between 2 and 6 years of age; most children who were obese at that age were obese in adolescence. (Funded by the German Research Council for the Clinical Research Center "Obesity Mechanisms" and others; ClinicalTrials.gov number, NCT03072537 .).

CrescNet ist ein Projekt der Leipziger Universitatsklinik fur Kinder- und Jugendmedizin, das niedergelassene Kinder- und Jugendarzte und spezialisierte Behandlungszentren mittels einer IT-Plattform miteinander verknupft. Denn die Messung von Korpergrose, Korpergewicht und Kopfumfang soll nicht nur ein fester Bestandteil jeder kinderarztlichen Untersuchung sein, ihr Entwicklungsverlauf und dessen Beurteilung soll aktiv fur die Fruherkennung und die Aktualisierung von Referenzwerten angewendet werden.

Combined pituitary hormone deficiency (CPHD) is characterized by a malformed or underdeveloped pituitary gland resulting in an impaired pituitary hormone secretion. Several transcription factors have been described in its etiology, but defects in known genes account for only a small proportion of cases. To identify novel genetic causes for congenital hypopituitarism, we performed exome-sequencing studies on 10 patients with CPHD and their unaffected parents. Two candidate genes were sequenced in further 200 patients. Genotype data of known hypopituitary genes are reviewed. We discovered 51 likely damaging variants in 38 genes; 12 of the 51 variants represent de novo events (24%); 11 of the 38 genes (29%) were present in the E12.5/E14.5 pituitary transcriptome. Targeted sequencing of two candidate genes, SLC20A1 and SLC15A4, of the solute carrier membrane transport protein family in 200 additional patients demonstrated two further variants predicted as damaging. We also found combinations of de novo (SLC20A1/SLC15A4) and transmitted variants (GLI2/LHX3) in the same individuals, leading to the full-blown CPHD phenotype. These data expand the pituitary target genes repertoire for diagnostics and further functional studies. Exome sequencing has identified a combination of rare variants in different genes that might explain incomplete penetrance in CPHD.

Growth hormone (GH) insensitivity syndrome (GHIS) is a rare clinical condition in which production of insulin-like growth factor 1 is blunted and, consequently, postnatal growth impaired. Autosomal-recessive mutations in signal transducer and activator of transcription (STAT5B), the key signal transducer for GH, cause severe GHIS with additional characteristics of immune and, often fatal, pulmonary complications. Here we report dominant-negative, inactivating STAT5B germline mutations in patients with growth failure, eczema, and elevated IgE but without severe immune and pulmonary problems. These STAT5B missense mutants are robustly tyrosine phosphorylated upon stimulation, but are unable to nuclear localize, or fail to bind canonical STAT5B DNA response elements. Importantly, each variant retains the ability to dimerize with wild-type STAT5B, disrupting the normal transcriptional functions of wild-type STAT5B. We conclude that these STAT5B variants exert dominant-negative effects through distinct pathomechanisms, manifesting in milder clinical GHIS with general sparing of the immune system., Severe growth hormone insensitivity syndrome (GHIS) with immunodeficiency is caused by autosomal recessive mutations in STAT5B. Here the authors report heterozygous STAT5B mutations with dominant-negative effects, causing mild GHIS without immune defects.

Acrodysostosis is a very rare congenital multisystem condition characterized by skeletal dysplasia with severe brachydactyly, midfacial hypoplasia, and short stature, varying degrees of intellectual disability, and possible resistance to multiple G protein-coupled receptor signalling hormones. Two distinct subtypes are differentiated: acrodysostosis type 1 resulting from defects in protein kinase type 1-α regulatory subunit and acrodysostosis type 2 caused by mutations in phosphodiesterase 4D (PDE4D). Most cases are sporadic. We report on a rare multigenerational familial case of acrodysostosis type 2 due to a novel autosomal dominantly inherited PDE4D mutation. A 3.5-year-old boy presented with short stature, midfacial hypoplasia, severe brachydactyly, developmental delay, and behavioural problems. Laboratory investigations revealed mild thyrotropin resistance. His mother shared some characteristic features, such as midfacial hypoplasia and severe brachydactyly, but did not show short stature, intellectual disability or hormonal resistance. Genetic analysis identified the identical, novel heterozygous missense mutation of the PDE4D gene c.569C>T (p.Ser190Phe) in both patients. This case illustrates the significant phenotypic variability of acrodysostosis even within one family with identical mutations. Hence, a specific clinical diagnosis of acrodysostosis remains challenging because of great interindividual variability and a substantial overlap of the two subtypes as well as with other related Gsα-cAMP-signalling-linked disorders.

ObjectiveRecently several industrialized countries reported a stabilization or even a decrease in childhood overweight and obesity prevalence rates. In Germany, this trend started in 2004. The present study therefore aimed to evaluate whether this trend has continued or even leads in a clear direction.Design/Setting/SubjectsBMI (>90th percentile (overweight), >97th percentile (obesity)) from the CrescNet database was analysed in 326 834 children and adolescents according to three age groups (4–7·99, 8–11·99 and 12–16 years), gender and between time points (2005–2015).ResultsTrend analysis from 2005 to 2010 demonstrated that the prevalence of overweight and obesity decreased significantly in boys and girls in the entire group (4–16 years) and in 4–7·99-year-olds. From 2010 to 2015 there was a significant decrease in boys for overweight and obesity in the entire group and for overweight among 8–11·99-year-olds. Within the cross-sectional analysis, prevalence rates for overweight decreased significantly for both genders in the age groups of 4–7·99 and 8–11·99 years (2005 v. 2015). For obesity, prevalence rates showed a significant decrease for boys (2005 v. 2015) and girls (2005 v. 2010) in 4–7·99-year-olds.ConclusionsWe observed a further stabilization of overweight and obesity prevalence rates for all age groups and even a decrease in the rates for the younger ages (4–7·99 years, 8–11·99 years). As other industrialized countries have also reported similar trends, it seems that the epidemic of childhood overweight and obesity is reaching a turning point in the industrial part of the world.

ZusammenfassungGeschlechtsdysphorie (GD) im Kindes- und Jugendalter ist geprägt von einem anhaltenden, klinisch relevanten Unbehagen gegenüber dem eigenen biologischen Geschlecht. Studien, die die Prävalenz der GD in Deutschland beschreiben, gibt es bisher noch nicht. An-hand einiger europäischer Studien kann aber davon ausgegangen werden, dass sie ungefähr bei 0,2–0,6 % liegt. Jungen sind häufiger betroffen als Mädchen, wobei nach neuester Studienlage anzunehmen ist, dass sich das Geschlechterverhältnis allmählich angleicht. Da die anhaltende Geschlechtsdysphorie im Kindes- und Jugendalter häufig mit sozialer Ausgrenzung und psychiatrischen Komorbiditäten wie Depressionen sowie selbstverletzendem und suizidalem Verhalten einhergeht, ist eine adäquate Betreuung der Betroffenen ausgesprochen wichtig. Neben der psychologischen oder psychiatrischen Therapie der Begleiterkrankungen können Jugendliche den internationalen Empfehlungen entsprechend ab dem 12. Lebensjahr bzw. dem Pubertätsstadium 2–3 nach Tanner mit GnRH-Analoga therapiert werden, um ein Voranschreiten der Pubertät zu verhindern und damit den wachsenden Stress zu verringern. Ab dem Alter von 16 Jahren können Jugendliche mit gegengeschlechtli-chen Hormonen therapiert werden. Eine chirurgische Geschlechtsangleichung ist ab einem Alter von 18 Jahren möglich, die Mastektomie wird häufig sogar schon früher durchgeführt. Die Behandlungsmöglichkeiten sind nicht unumstritten. Aufgrund fehlender Langzeitdaten und der geringen Rate an persistierenden GD wird besonders der Einsatz von GnRH-Analoga zur Unterdrückung der Pubertät kontrovers diskutiert. Ungeklärt sind bislang auch die Ursa-chen der Geschlechtsdysphorie im Kindes- und Jugendalter, weshalb weitere Forschung auf diesem Gebiet erforderlich ist.

ZusammenfassungSchwere mentale und körperliche Retardierung sind bekannte Folgen einer nicht behandelten primären Hypothyreose. Seit Einführung des erweiterten Neugeborenenscreenings in Deutschland sehen wir das gesamte Ausmaß dieser Folgeerscheinungen erfreulicherweise kaum noch. Wir berichten hier über ein Mädchen, welches trotz gestellter Diagnose im Neugeborenenscreening und umgehend eingeleiteter Behandlung mit initialer Normalisierung der Serumparameter unter extremem Kleinwuchs sowie weiteren Auswirkungen einer manifesten Hypothyreose litt.

Introduction Beta-propeller protein-associated neurodegeneration (BPAN) is a very rare, X-linked dominant (XLD) inherited member of the neurodegeneration with brain iron accumulation (NBIA) disease family. Case report We present a female case of BPAN with infantile spasms in the first year, Rett-like symptomatology, focal epilepsy, and loss of motor skills in childhood. Menarche occurred at the age of 9, after precocious pubarche and puberty.Dystonia-parkinsonism as extrapyramidal sign at the age of 10 years resulted in radiological and genetic work-up. Results Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS) measured 66/120 points in body part-related dystonia symptoms. Cerebrospinal fluid examination showed dopamine depletion.T2 and B0 sequences of the diffusion-weighted magnetic resonance imaging showed susceptibility artifacts with NBIA-typical hypointense globus pallidus (GP) and substantia nigra (SN). Next-generation sequencing revealed a BPAN-causing pathogenic variant in WDR45 (WD repeat-containing protein 45) gene (c.830 + 1G > A, XLD, heterozygous, de novo). Skewed X-inactivation was measured (2:98). Conclusions Autophagy-related X-linked BPAN disease might still be underdiagnosed in female cases of infantile spasms.Skewed X-inactivation will have mainly influenced the uncommon, very early childhood neurodegenerative symptomatology in the present BPAN case. Oral levodopa substitution led to improvement in sleep disorder, hypersalivation, and swallowing.Reduced white matter and hypointense signals in SN and GP on susceptibility sequences in magnetic resonance imaging are characteristic radiological findings of advanced disease in NBIA. No BPAN-typical halo sign in T1-weighted scan at midbrain level was seen at the age of 11 years. NBIA panel is recommended for early diagnosis.

The second 360° European Meeting on Growth Hormone Disorders, held in Barcelona, Spain, in June 2017, included a session entitled Pragmatism vs. Curiosity in Genetic Diagnosis of Growth Disorders, which examined current concepts of genetics and growth in the clinical setting, in terms of both growth failure and overgrowth. For patients with short stature, multiple genes have been identified that result in GH deficiency, which may be isolated or associated with additional pituitary hormone deficiencies, or in growth hormone resistance, primary insulin-like growth factor (IGF) acid-labile subunit deficiency, IGF-I deficiency, IGF-II deficiency, IGF-I resistance, and primary PAPP-A2 deficiency. While genetic causes of short stature were previously thought to primarily be associated with the GH-IGF-I axis, it is now established that multiple genetic anomalies not associated with the GH-IGF-I axis can result in short stature. A number of genetic anomalies have also been shown to be associated with overgrowth, some of which involve the GH-IGF-I axis. In patients with overgrowth in combination with an intellectual disability, two predominant gene families, the epigenetic regulator genes, and PI3K/AKT pathway genes, have now been identified. Specific processes should be followed for decisions on which patients require genetic testing and which genes should be examined for anomalies. The decision to carry out genetic testing should be directed by the clinical process, not merely for research purposes. The intention of genetic testing should be to direct the clinical options for management of the growth disorder.

BackgroundDeciphering the monogenetic causes of neurodevelopmental disorders (NDD) is an important milestone to offer personalized care. But the plausibility of reported candidate genes in exome studies often remains unclear, which slows down progress in the field.MethodsWe performed exome sequencing (ES) in 198 cases of NDD. Cases that remained unresolved (n=135) were re-investigated in a research setting. We established a candidate scoring system (CaSc) based on 12 different parameters reflecting variant and gene attributes as well as current literature to rank and prioritize candidate genes.ResultsIn this cohort, we identified 158 candidate variants in 148 genes with CaSc ranging from 2 to 11.7. Only considering the top 15% of candidates, 14 genes were already published or funneled into promising validation studies.ConclusionsWe promote that in an approach of case by case re-evaluation of primarily negative ES, systematic and standardized scoring of candidate genes can and should be applied. This simple framework enables better comparison, prioritization, and communication of candidate genes within the scientific community. This would represent an enormous benefit if applied to the tens of thousands of negative ES performed in routine diagnostics worldwide and speed up deciphering the monogenetic causes of NDD.

Introduction: Almost 20 years after the first international guidelines on the diagnosis and treatment of GHD have been published, clinical practice varies significantly. The low accuracy of endocrine tests for GHD and the burden caused by ineffective treatment of individual patients were strong motives for national endocrine societies to set up national guidelines regarding how to diagnose GHD in childhood. This audit aims to review the current state and identify common changes, which may improve the diagnostic procedure. Methods: A group of eight German pediatric endocrinologists contacted eight pediatric endocrinologists from Spain, France, Poland, the UK, the Netherlands, Denmark, Italy, and the US. Each colleague responded as a representative for the own country to a detailed questionnaire containing 22 open questions about national rules, guidelines, and practice with respect to GHD diagnostics and GH prescription. The results were presented and discussed in a workshop and then documented in this study which was reviewed by all participants. Results: National guidelines are available in 7 of 9 countries. GH is prescribed by pediatric endocrinologists in most countries. Some countries have established boards that review and monitor prescriptions. Preferred GH stimulation tests and chosen cutoffs vary substantially. Overall, a trend to lowering the GH cutoff was identified. Priming is becoming more popular and now recommended in 5 out of 9 countries; however, with different protocols. The definition of pretest-conditions that qualify the patient to undergo GH testing varies substantially in content and strictness. The most frequently used clinical sign is low height velocity, but definition varies. Height, IGF-1, and bone age are additional parameters recommended in some countries. Conclusions: GHD diagnostics varies substantially in eight European countries and in the US. It seems appropriate to undertake further efforts to harmonize endocrine diagnostics in Europe and the US based on available scientific evidence.

In this chapter, we want to give an overview on what we have learned from more than 30 years ago on the use of recombinant human growth hormone (rhGH) and later recombinant human IGF-1 which was introduced for the treatment of short children and what are the safety issues concerned with this treatment. However, rhGH is used not solely in conditions where short stature is the consequence of GH deficiency but also in various disorders without a proven GH deficiency. In clinical studies, growth responses to various forms of rhGH therapy were analyzed, adding to our concept about the physiology of growth. Most patients under rhGH treatment show a considerable short-term effect; however, the long-term gain of height in a child obtained by a year-long treatment until final height remains controversial in some of the growth disorders that have been treated with rhGH or IGF-1. Today the first studies on the long-term safety of rhGH treatment have been published and raising some questions whether this treatment is similarly safe for all the patient groups treated with rhGH. Although there is a long-standing safety record for these hormone replacement therapies, in the face of the considerable costs involved, the discussion about the risk to benefit ratio is continuing. Newer developments of rhGH treatment include long-term preparations, which have only to be injected once a week. Although some of these drugs already have proven their non-inferiority to conventional rhGH treatment, we have to await further results to see whether they show improvements in treatment adherence of the patients and prove their long-term safety.

Background: Obesity can affect growth and development of children but there is uncertainty regarding the dynamics and potential causes. We assessed the growth dynamics of children with obesity from infancy to adolescence and evaluated associated endocrine and metabolic changes. Methods: In the population-based LIFE Child and the obesity-enriched Leipzig Obesity Childhood Cohorts encompassing 7,961 children (35,134 measurements), we compared (parental-height-corrected) height, growth velocities and serum hormone levels between normal-weight and children with obesity aged 0 to 20 years. Findings: Children with obesity were significantly taller than normal-weight children, independently of parental height, reaching a maximum difference of 7·6 cm at age 6-7 years. Already at birth, children with obesity were up to 0·5 cm taller and had slightly increased growth velocities of up to 0·9 cm/y (+1·1 SDS) in early childhood. During puberty, children with obesity showed a catch-down in height, with an almost blunted growth spurt particularly in boys. The reduction in pubertal growth velocity by 30% coincided with a decrease in levels of insulin-like growth factor-1 (IGF-1) (by 17%) and testosterone (by 61%) in boys, as well as with reductions in estradiol (by 44%) in girls with obesity. Interpretation: Children with obesity are taller in early childhood with catch-down growth in puberty. The blunted pubertal growth spurt is paralleled by reduced serum levels of IGF-1 and sex hormones. Funding: German Research Foundation, European Union, European Regional Development Fund, Free State of Saxony, German Federal Ministry of Education and Research, and European Society for Pediatric Endocrinology. Declaration of Interest: The authors have nothing to declare. Ethical Approval: The study was approved by the ethics committee of the University of Leipzig (NCT02550236, NCT02208141, NCT01605123).

Background: Treatment with growth hormone (GH) is standard clinical practice in children with GH deficiency (GHD) or Turner syndrome (TS). Hitherto, no long-term data on auxological outcome and safety of Zomacton® have been published. Data comparing needle-free administration (NF) and needle injection (NI) of GH are very sparse. Aims: To analyse longitudinal auxological outcome and safety data of GH treatment-naïve patients diagnosed with GHD or TS and to compare NF and NI in a real-life setting. Methods: Pooled auxological data and safety information from three consecutive prospective observational Zomacton® studies covering 22 years of treatment were analysed and NF was compared to NI. Results: The safety cohort comprised 1,595 patients who received at least one GH dose. The auxological outcome cohort comprised 856 treatment-naïve patients with follow-up data ≥12 months. Height-SDS and height velocity improved significantly during the first 3 years of treatment. Documented choice of device was available for 658 patients (NF 69.1%, NI 30.9%). NF administration was non-inferior to NI. No previously unknown safety signals occurred. Conclusion: Real-life data show that treatment with Zomacton® improves auxological outcome parameters without new safety concerns. NF administration of GH represents a useful alternative to NI in children with growth disorders.

BACKGROUND: Small for gestational age (SGA)-born children are a heterogeneous group with few genetic causes reported. Genetic alterations in the IGF1 receptor (IGF1R) are found in some SGA children. AIM: To investigate whether alterations in IGF1R gene are present in SGA born children. PATIENTS AND METHODS: We analysed 64 children born SGA who stayed short (mean -3.25 ± 0.9 SDS) within the first 4 years of age, and 36 SGA children who caught up growth (0.20 ± 1.1 SDS). PCR products of all coding IGF1R exons were screened by dHPLC followed by direct sequencing of conspicuous fragments to identify small nucleotide variants. The presence of IGF1R gene copy number alterations was determined by Multiplex Ligation-dependent Probe Amplification (MLPA). RESULTS: The cohort of short SGA born children revealed a heterozygous, synonymous variant c.3453C > T in one patient and a novel heterozygous 3 bp in-frame deletion (c.3234_3236delCAT) resulting in one amino acid deletion (p.Ile1078del) in another patient. The first patient had normal serum levels of IGF1. The second patient had unusually low IGF1 serum concentrations (-1.57 SD), which contrasts previously published data where IGF1 levels rarely are found below the age-adjusted mean. CONCLUSIONS: IGF1R gene alterations were present in 2 of 64 short SGA children. The patients did not have any dysmorphic features or developmental delay. It is remarkable that one of them had significantly decreased serum concentrations of IGF1. Growth response to GH treatment in one of the patients was favourable, while the second one discontinued the treatment, but with catch-up growth.

Background: Pituitary development and GH secretion are orchestrated by multiple genes including GH1, GHRHR, GLI2, HESX1, LHX3, LHX4, PROP1, POU1F1, and SOX3. We aimed to assess their mutation frequency and clinical relevance in children with severe GH deficiency (GHD). Methods:The Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) was a prospective, open-label, observational research program for pediatric patients receiving GH treatment, conducted in 30 countries between 1999 and 2015. The study included a sub-study to investigate mutations in the genes listed above. PCR products from genomic blood cell DNA were analyzed by Sanger sequencing. DNA variants were classified as pathogenic according to the recommendations of the American College of Medical Genetics and Genomics. Demographic, auxologic, and endocrine data at baseline and during GH treatment were documented and related to the genotyping results. Findings: The analysis comprised 917 patients. In 92 patients (10%) 33 mutations were found, 16 previously described and 17 novel (52%). Mutation carriers were significantly younger, shorter, and more slowly growing than non-carriers. In general, their peak values in GH stimulation tests were very low; however, in 15/77 (20%) patients with GH1, PROP1, and SOX3 mutations they were only moderately diminished (3- 6µg/L). Two patients with a GH1 mutation developed TSH deficiency and one ADH deficiency. Using logistic multi-regression analysis, significant indicators of a mutation were combined pituitary hormone deficiency, greater patient-parent height difference (SDS), low GH peak, and young age. Final height SDS gain in mutation carriers (mean±SD 3.4±1.4) was greater than in non-carriers (2.0±1.4; P

Objective The IGF/IGF1R axis is involved in the regulation of human growth. Both IGF1 and IGF2 can bind to the IGF1R in order to promote growth via the downstream PI3K/AKT pathway. Pathogenic mutations in IGF1 and IGF1R determine intrauterine growth restriction and affect postnatal body growth. However, to date, there are only few reports of pathogenic IGF2 mutations causing severe prenatal, as well as postnatal growth retardation. Results Here we describe a de novo c.195delC IGF2 variant (NM_000612, p.(Ile66Serfs*93)) in a 4-year-old patient with severe pre- and post-natal growth retardation in combination with dystrophy, facial dimorphism, finger deformities, as well as a patent ductus. Cloning and sequencing of a long-range PCR product harboring the deletion and a SNP informative site chr11:2153634 (rs680, NC_000011.9:g.2153634T>C) demonstrated that the variant resided on the paternal allele. This finding is consistent with the known maternal imprinting of IGF2. 3D protein structure prediction and overexpression studies demonstrated that the p.(Ile66Serfs*93) IGF2 gene variation resulted in an altered protein structure that impaired ligand/receptor binding and thus prevents IGF1R activation. Conclusion The severity of the phenotype in combination with the dominant mode of transmission provides further evidence for the involvement of IGF2 in growth disorders.

Amiodarone-induced hyperthyroidism is a known side effect of amiodarone treatment. In the pediatric population, long-term amiodarone treatment is rarely indicated because of its severe side effects including thyroid function impairment. Treatment is therefore restricted to therapy-resistant arrhythmias. In the literature, scarce data are available on the management and therapy of amiodarone-induced thyroid dysfunction at a young age. We present three adolescent patients developing amiodarone-induced thyrotoxicosis in the months after amiodarone therapy. A latency period for thyroid dysfunction has been described in adulthood but was not previously reported in pediatric patients. The gap between amiodarone treatment and the development of symptoms and the diagnosis of hyperthyroidism was between 3 and 10 months. In two patients, hyperthyroidism was transient and resolved without treatment. These two patients, one boy and on girl, were almost asymptomatic. In contrast, in one male patient overt and severe hyperthyroidism developed. We began treatment with thiamazole without benefit. Control of hyperthyroidism was achieved under prednisone treatment, which was continued for 9 months. Clinical evaluation proved an amiodarone-induced destructive thyroiditis in this patient. Amiodarone-induced thyroid dysfunction is frequent also in pediatric patients with long-term amiodarone treatment. Patients and clinicians should be aware of the impact of amiodarone on thyroid function during and also in the months and maybe years after treatment. Careful follow-up is needed, as symptoms might be associated with the underlying cardiac disease in these patients. Amiodarone-induced thyrotoxicosis often resolves without treatment but can be challenging in some cases.