Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients who had undergone exome sequencing and were partially analyzed with next-generation phenotyping approaches. Molecular genetic diagnoses were established in 32% of the patients totaling 370 distinct molecular genetic causes, most with prevalence below 1:50,000. During the diagnostic process, 34 novel and 23 candidate genotype–phenotype associations were identified, mainly in individuals with neurodevelopmental disorders. Sequencing data of the subcohort that consented to computer-assisted analysis of their facial images with GestaltMatcher could be prioritized more efficiently compared with approaches based solely on clinical features and molecular scores. Our study demonstrates the synergy of using next-generation sequencing and phenotyping for diagnosing ultrarare diseases in routine healthcare and discovering novel etiologies by multidisciplinary teams.

Nearly 90 clinicians and researchers from around the world attended the first IMPROVE 2022 International Meeting on Pathway-Related Obesity. Delegates attended in person or online from across Europe, Argentina and Israel to hear the latest scientific and clinical developments in hyperphagia and severe, early-onset obesity, and set out a vision of excellence for the future for improving the diagnosis, treatment, and care of patients with melanocortin-4 receptor (MC4R) pathway-related obesity. The meeting co-chair Peter Kühnen, Charité Universitätsmedizin Berlin, Germany, indicated that change was needed with the rapidly increasing prevalence of obesity and the associated complications to improve the understanding of the underlying mechanisms and acknowledge that monogenic forms of obesity can play an important role, providing insights that can be applied to a wider group of patients with obesity. World-leading experts presented the latest research and led discussions on the underlying science of obesity, diagnosis (including clinical and genetic approaches such as the role of defective MC4R signalling), and emerging clinical data and research with targeted pharmacological approaches. The aim of the meeting was to agree on the questions that needed to be addressed in future research and to ensure that optimised diagnostic work-up was used with new genetic testing tools becoming available. This should aid the planning of new evidence-based treatment strategies for the future, as explained by co-chair Martin Wabitsch, Ulm University Medical Center, Germany.

This issue of Acta Paediatrica contains an exhaustive literature review on maternal autoimmune thyroiditis by Deligeorgopoulou et al.1 It provides a very valuable contribution to the controversial debate about whether this condition can lead to the manifestation of hypothyroidism in newborn infants even after a normal screening result. There is no doubt that maternal autoimmune thyroiditis can cause transient hypothyroidism in their unborn child due to the transplacental passage of antithyroid antibodies. The first case reports of familial transient congenital hypothyroidism in mothers with autoimmune thyroiditis were published as early as the 1970s2 with crude measurements of immunoglobulins. A better understanding of the pathomechanism was achieved when it became possible to measure the antibodies that had the capacity to block the thyroid-stimulating hormone (TSH) receptors (thyrotropin binding inhibiting immunoglobulins TBII).3 With the implementation of newborn screening programmes for congenital hypothyroidism newborn infants with transient hypothyroidism caused by maternal antithyroid antibodies were detected and it was estimated that the prevalence of transient congenital hypothyroidism (CH) was 2% of all newborns with CH.4 Newborn screening had been performed in earlier years at the age 5–7 days of life, but it shortened to 2–3 days of life about 15 years ago. Therefore, concern has been raised that some of these cases might be missed in by neonatal screening assays because of a delayed increase in TSH that can also occur in term infants.5 The timing of the TSH increase depends on the maturation of the hypothalamic–pituitary–thyroid axis as well as on the interference caused by maternal and neonatal treatment.6 Therefore, it was recommended that infants born to mothers with autoimmune thyroiditis should have their thyroid function investigated with serum TSH and free thyroxine in the first week of life. It should then be reinvestigated after 2–3 weeks, even if the newborn screening result was normal.7 The review by Deligeorgopoulou et al.1 includes the impressive number of 4400 infants of mothers with autoimmune thyroiditis and hypothyroidism. Of these infants, only 20 (0.5%) were diagnosed with hypothyroidism by newborn screening programmes. Another 16 infants were diagnosed but not detected by newborn screening. The authors carefully reviewed these cases and reported that only 11 of them—although with only mild hypothyroidism or hyperthyrotropinaemia—could be causally related to maternal autoimmune thyroiditis. However, thyroid antibodies were only reported in four of them. Thus, proof of causality was lacking in most of the patients. Hypothyroidism was transient in eight of the 11 children and their therapy was stopped after various time periods. The reason for continued therapy in the other three cases was not reported. In four infants, the underlying diagnosis was shown not to be related to maternal autoimmune thyroiditis. In these infants, hypothyroidism was caused by maternal hyperthyroidism, multiple pituitary hormone deficiencies and familial non-autoimmune hypothyroidism. Only one study included a newborn infant with severe congenital hypothyroidism, who was born to a mother with autoimmune thyroiditis and who has received thyroid hormone treatment. The infant was missed by neonatal screening and had a TSH of >200 mU/L and a significantly decreased serum-free thyroxine of 4.4 pmol/L at diagnosis. Thyroid antibodies were not detected and the thyroid gland was found to be in place. Therefore, this patient might have had dyshormogenesis, which, in some instances, is missed by newborn screening. For example, hypothyroidism due to Iodotyrosine dehalogenase mutations can be masked in newborn infants who are exposed to iodine during delivery or postnatally.8, 9 The authors quite rightly critically addressed the limitations of their review, which were unavoidably based on different screening procedures and significant variations in diagnostic evaluations. However, they concluded that the frequently performed and still recommended additional thyroid function tests did not seem to be justified. That seems more than fair. The prevalence of congenital hypothyroidism in newborn infants born to mothers with autoimmune thyroiditis is very low and the disturbed function is only mild and of transient nature. Therefore, the recommendations by the current European Society of Paediatric Endocrinology and American Academy of Paediatrics guidelines that the presumptive diagnosis of congenital hypothyroidism can be solely based on screening tests remain valid. Any medical procedure, which is not supported by scientific evidence should be critically addressed and abandoned if there is no significant benefit. This is not just because healthcare systems are under economic pressure. It protects patients from procedures that create uncertainty and anxiety and do not improve their quality of life. This is especially true during the postpartum period, which has been recognised as a very special phase for mothers and families, which is vulnerable with respect to maternal disease10 and the long-term effects on the children.11 With respect to the limitations, the authors recommend that worldwide studies should be conducted with the same inclusion criteria and thyroid function retesting timing. However, there are probably more significant questions that need to be answered in the context of newborn screening for congenital hypothyroidism. These relate more to patients with severe congenital hypothyroidism, for example, due to TSH deficiency missed by newborn screening than expanding the diagnostic procedures in women with thyroid peroxidase antibodies or thyroglobulin antibodies. Concerning maternal autoimmune disease mothers with a history of thyrotoxicosis, especially many years after thyroid ablation, have an increased risk of giving birth to children with thyrotoxicosis caused by unrecognised high titre thyrotropin receptor stimulating antibodies or their newborn infants can present with hypothyroidism due to unrecognised thyrotropin receptor blocking or antithyroid drug therapies.12, 13 The most effective way to reduce these risks is to vigorously establish maternal history during pregnancy and to investigate thyroid disorders during prenatal care. Therefore, systematic investigations of the thyroid function of newborn infants born to mothers with autoimmune thyroiditis should be discontinued if there is a normal newborn screening result. Additional tests are only warranted in newborn infants if their mothers have documented high titers of blocking or stimulating TSH-receptor antibodies. The availability of national health registries and electronic health records will be helpful in providing the basis for international studies in larger populations. None.

Most individuals with rare diseases initially consult their primary care physician. For a subset of rare diseases, efficient diagnostic pathways are available. However, ultra-rare diseases often require both expert clinical knowledge and comprehensive genetic diagnostics, which poses structural challenges for public healthcare systems. To address these challenges within Germany, a novel structured diagnostic concept, based on multidisciplinary expertise at established university hospital centers for rare diseases (CRDs), was evaluated in the three year prospective study TRANSLATE NAMSE. A key goal of TRANSLATE NAMSE was to assess the clinical value of exome sequencing (ES) in the ultra-rare disease population. The aims of the present study were to perform a systematic investigation of the phenotypic and molecular genetic data of TRANSLATE NAMSE patients who had undergone ES in order to determine the yield of both ultra-rare diagnoses and novel gene-disease associations; and determine whether the complementary use of machine learning and artificial intelligence (AI) tools improved diagnostic effectiveness and efficiency. ES was performed for 1,577 patients (268 adult and 1,309 pediatric). Molecular genetic diagnoses were established in 499 patients (74 adult and 425 pediatric). A total of 370 distinct molecular genetic causes were established. The majority of these concerned known disorders, most of which were ultra-rare. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were delineated, mainly in individuals with neurodevelopmental disorders. To determine the likelihood that ES will lead to a molecular diagnosis in a given patient, based on the respective clinical features only, we developed a statistical framework called YieldPred. The genetic data of a subcohort of 224 individuals that also gave consent to the computer-assisted analysis of their facial images were processed with the AI tool Prioritization of Exome Data by Image Analysis (PEDIA) and showed superior performance in variant prioritization. The present analyses demonstrated that the novel structured diagnostic concept facilitated the identification of ultra-rare genetic disorders and novel gene-disease associations on a national level and that the machine learning and AI tools improved diagnostic effectiveness and efficiency for ultra-rare genetic disorders.

PurposeThe transition process from paediatric/adolescent to adult medical care settings is of utmost importance for the future health of adolescents with chronic diseases and poses even more difficulties in the context of rare diseases (RDs). Paediatric care teams are challenged to deliver adolescent-appropriate information and structures. Here we present a structured transition pathway which is patient-focused and adoptable for different RDs.MethodsThe transition pathway for adolescents 16 years and older was developed and implemented as part of a multi-centre study in 10 university hospitals in Germany. Key elements of the pathway included: assessment of patients' disease-related knowledge and needs, training/educational and counselling sessions, a structured epicrisis and a transfer appointment jointly with the paediatric and adult specialist. Specific care coordinators from the participating university hospitals were in charge of organization and coordination of the transition process.ResultsOf a total of 292 patients, 286 completed the pathway. Deficits in disease-specific knowledge were present in more than 90% of participants. A need for genetic or socio-legal counselling was indicated by > 60%. A mean of 2.1 training sessions per patient were provided over a period of almost 1 year, followed by the transfer to adult care in 267 cases. Twelve patients remained in paediatric care as no adult health care specialist could be identified. Targeted training and counselling resulted in improved disease-specific knowledge and contributed to empowering of patients.ConclusionThe described transition pathway succeeds to improve health literacy in adolescents with RDs and can be implemented by paediatric care teams in any RD specialty. Patient empowerment was mainly achieved by individualized training and counselling.

The successful organization and management of the transition and transfer of adolescents and young adults with a chronic rare disease from pediatric to adult care is an important but complex task in the decentralized German healthcare system. The structured transition pathway of the consortium TRANSLATE-NAMSE, funded by the innovation fund of the Federal Joint Committee (G-BA, funding number 01NVF16024 TRANSLATE-NAMSE) is a program that has meanwhile been tested in practice. The main principle of the transition in this program is the quality-assured transfer of information from the pediatric treatment team to the adolescent patient as well as to the healthcare provider(s) of the adult care facility. Based on a structured assessment and documentation of the individual need for information, the transition training is carried out by the pediatric treatment team for adolescent patients aged 16 years and older. In addition, transfer clinics, with the representatives of the previous pediatric and the future adult healthcare providers and the transfer of all necessary medical documentation to the patient and to the new health care provider are part of the program. A final evaluation of the project is expected in late 2020.

Patients with rare diseases often undergo a diagnostic odyssey that can last many years until the diagnosis is definitively established. To improve the diagnosis and treatment of these patients, the German National Task Force for Patients With Rare Diseases (Nationales Aktionsbündnis für Menschen mit Seltenen Erkrankungen, NAMSE) has recommended the creation of Rare Disease Centers (RDCs).As part of the joint Translate-NAMSE project, sponsored by the G-BA Innovation Fund (G-BA, German Federal Joint Committee), we investigated the performance of RDCs in establishing the diagnosis of patients suspected to have a rare disease. The results of interdisciplinary case conferences and of exome diagnostic tests were analyzed in a prospective, multicenter observational study.A total of 5652 patients (of whom 3619 were under 18 years old, and 2033 were at least 18 years old) from 10 RDCs who did not yet have a definitive diagnosis of a rare disease were included in the study. On average, those who were under 18 years old had been symptomatic for 4.5 years without receiving a diagnosis in a standard care setting; the analogous figure for adult patients was 8.2 years. Over the course of this project (2017-2021), 1682 patients (30%) received a definitive diagnosis. 193 had a common disease, 88 had a psychosomatic disease (only in patients who were at least 18 years old), and 1401 had a rare disease. 14 850 case conferences were conducted. 1599 exome analyses led to 506 definitive genetic diagnoses (32%).A diagnostic evaluation with the aid of interdisciplinary case conferences and the opportunity for exome analysis can be of benefit to people with rare diseases who have not received a definitive diagnosis in a standard care setting. Further improvement of the diagnosis rate can come from whole-genome analysis and from the introduction of an international registry.

Background: Patients with rare diseases often undergo a diagnostic odyssey that can last many years until the diagnosis is definitively established. To improve the diagnosis and treatment of these patients, the German National Task Force for Patients With Rare Diseases (Nationales Aktionsbundnis fur Menschen mit Seltenen Erkrankungen, NAMSE) has recommended the creation of Rare Disease Centers (RDCs). Methods: As part of the joint Translate-NAMSE project, sponsored by the G-BA Innovation Fund (G-BA, German Federal Joint Committee), we investigated the performance of RDCs in establishing the diagnosis of patients suspected to have a rare disease. The results of interdisciplinary case conferences and of exome diagnostic tests were analyzed in a prospective, multicenter observational study. Results: A total of 5652 patients (of whom 3619 were under 18 years old, and 2033 were at least 18 years old) from 10 RDCs who did not yet have a definitive diagnosis of a rare disease were included in the study. On average, those who were under 18 years old had been symptomatic for 4.5 years without receiving a diagnosis in a standard care setting; the analogous figure for adult patients was 8.2 years. Over the course of this project (2017-2021), 1682 patients (30%) received a definitive diagnosis. 193 had a common disease, 88 had a psychosomatic disease (only in patients who were at least 18 years old), and 1401 had a rare disease. 14 850 case conferences were conducted. 1599 exome analyses led to 506 definitive genetic diagnoses (32%). Conclusion: A diagnostic evaluation with the aid of interdisciplinary case conferences and the opportunity for exome analysis can be of benefit to people with rare diseases who have not received a definitive diagnosis in a standard care setting. Further improvement of the diagnosis rate can come from whole-genome analysis and from the introduction of an international registry.

ZusammenfassungDie erfolgreiche Organisation und Umsetzung des Übergangs von Jugendlichen und jungen Erwachsenen mit einer chronischen seltenen Erkrankung aus der Pädiatrie in eine Versorgungsform (Transition) und Versorgungsstruktur (Transfer) der Erwachsenenmedizin ist eine wichtige Aufgabe im dezentral aufgebauten deutschen Gesundheitssystem. Ein mittlerweile in der Praxis erprobtes Programm stellt der strukturierte Versorgungspfad des vom Innovationsfonds des gemeinsamen Bundesausschuss (G‑BA) geförderten Konsortiums TRANSLATE-NAMSE dar (Förderkennzeichen 01NVF16024 TRANSLATE-NAMSE). Grundlage des Übergangs in diesem Programm ist der qualitätsgesicherte Informations- und Kompetenztransfer vom pädiatrischen Behandlungsteam zum adoleszenten Patienten, sowie zur neuen Versorgungseinrichtung. Basierend auf einer strukturierten Epikrise und Erhebung des individuellen Beratungsbedarfs erfolgt, ab dem Alter von 16 Jahren, die strukturierte Transitionsschulung des Patienten durch den Pädiater. Nach erfolgreich absolvierten Transfersprechstunden, gemeinsam mit Vertretern der bisherigen pädiatrischen und der zukünftigen erwachsenenmedizinischen Versorgungseinrichtungen, mündet der Prozess in die Übergabe aller notwendigen medizinischen Unterlagen an den Patienten und den Weiterbehandler sowie den Wechsel des Patienten in die neue Versorgungseinrichtung. Eine abschließende Evaluation des Projekts ist für Herbst 2020 geplant.

(1) Background: Central congenital hypothyroidism (CCH) is a rare endocrine disorder that can be caused by mutations in the β-subunit of thyrotropin (TSHB). The TSHB mutation C105Vfs114X leads to isolated thyroid-stimulating-hormone-(TSH)-deficiency and results in a severe phenotype. The aim of this study was to gain more insight into the underlying molecular mechanism and the functional effects of this mutation based on two assumptions: a) the three-dimensional (3D) structure of TSH should be modified with the C105V substitution, and/or b) whether the C-terminal modifications lead to signaling differences. (2) Methods: wild-type (WT) and different mutants of hTSH were generated in human embryonic kidney 293 cells (HEK293 cells) and TSH preparations were used to stimulate thyrotropin receptor (TSHR) stably transfected into follicular thyroid cancer cells (FTC133-TSHR cells) and transiently transfected into HEK293 cells. Functional characterization was performed by determination of Gs, mitogen activated protein kinase (MAPK) and Gq/11 activation. (3) Results: The patient mutation C105Vfs114X and further designed TSH mutants diminished cyclic adenosine monophosphate (cAMP) signaling activity. Surprisingly, MAPK signaling for all mutants was comparable to WT, while none of the mutants induced PLC activation. (4) Conclusion: We characterized the patient mutation C105Vfs114X concerning different signaling pathways. We identified a strong decrease of cAMP signaling induction and speculate that this could, in combination with diverse signaling regarding the other pathways, accounting for the patient’s severe phenotype.

CONTEXTThe α subunit of the stimulatory G protein (Gαs) links numerous receptors to adenylyl cyclase. Gαs, encoded by GNAS, is expressed predominantly from the maternal allele in certain tissues. Thus, maternal heterozygous loss-of-function mutations cause hormonal resistance, as in pseudohypoparathyroidism type Ia, whereas somatic gain-of-function mutations cause hormone-independent endocrine stimulation, as in McCune-Albright syndrome.OBJECTIVEWe report two unrelated boys presenting with a new combination of clinical findings that suggest both gain and loss of Gαs function.DESIGN AND SETTINGClinical features were studied and sequencing of GNAS was performed. Signaling capacities of wild-type and mutant Gαs were determined in the presence of different G protein-coupled receptors (GPCRs) under basal and agonist-stimulated conditions.RESULTSBoth unrelated patients presented with unexplained hyponatremia in infancy, followed by severe early onset gonadotrophin-independent precocious puberty and skeletal abnormalities. An identical heterozygous de novo variant (c.1136T>G; p.F376V) was found on the maternal GNAS allele in both patients; this resulted in a clinical phenotype that differed from known Gαs-related diseases and suggested gain of function at the vasopressin 2 receptor (V2R) and lutropin/choriogonadotropin receptor (LHCGR), yet increased serum PTH concentrations indicative of impaired proximal tubular PTH1 receptor (PTH1R) function. In vitro studies demonstrated that Gαs-F376V enhanced ligand-independent signaling at the PTH1R, LHCGR, and V2R and, at the same time, blunted ligand-dependent responses. Structural homology modeling suggested mutation-induced modifications at the C-terminal α5 helix of Gαs that are relevant for interaction with GPCRs and signal transduction.CONCLUSIONSThe Gαs p.F376V mutation causes a previously unrecognized multisystem disorder.

Schilddrüsenknoten sind im Kindesalter relativ häufig, Schilddrüsenkarzinome dagegen sehr selten. Eine populationsbezogene Ultraschallscreening-Studie hat in Deutschland eine Prävalenz von Knoten > 1 cm von 0,6 in 100 Kindern und Jugendlichen ergeben. In neueren Studien aus Japan mit hochauflösenden Ultraschallgeräten wurde eine Knotenprävalenz von 1 in 100 beschrieben. Nur ein Bruchteil dieser Knoten ist maligne. In der japanischen Studie, in der Knoten per Ultraschall und Feinnadelbiopsie nachuntersucht wurden, fand sich eine Malignitätsrate von nur 4 %. Die Malignitätsrate bei klinisch auffallenden Knoten, die im Mittel einen Durchmesser von 20 mm aufweisen, liegt dagegen bei 20–25 %. Bei häufigem Einsatz der Schilddrüsensonografie werden aktuell sehr viele der gutartigen kleinen Schilddrüsenknoten zufällig diagnostiziert (Schilddrüseninzidentalome). Die richtige Beurteilung dieser Befunde mit der Notwendigkeit, differenzialdiagnostisch die häufigen gutartigen von den wenigen malignen Knoten abzugrenzen, stellt aktuell die größte Herausforderung auf dem Gebiet der Schilddrüsenneoplasien – nicht nur im Kindesalter – dar.

Context:The optimal levothyroxine (LT4) dose to treat congenital hypothyroidism (CH) remains unclear, with debate over whether higher starting doses (>10 µg/kg) are necessary and safe for a normal intelligence quotient (IQ).Objective:To examine psychomotor, metabolic, and quality of life (QoL) outcomes in patients with CH treated with a mean high initial LT4 dose.Design, settings, participants:A cross-sectional cohort study of patients with CH identified in the Berlin newborn screening program from 1979 to 2003; 76 patients with CH (mean age, 18 years; mean initial LT4 dose, 13.5 µg/kg) and 40 siblings completed the study.Main outcome measures:Psychomotor (Wechsler Intelligence Test, CNS Vital Signs), QoL (short form-36 Health Survey), anthropometric (body mass index, height), and metabolic (intima media thickness, laboratory parameters) outcomes were compared with those of healthy siblings. Mean values and percentage of episodes of elevated thyroxine (T4) and tri-jod-thyronin (T3) and suppressed thyrotropin (TSH) before age 2 years were analyzed. A meta-analysis of CH treatment studies was performed.Results:There were no significant differences in IQ, QoL, or other outcome measures in patients with CH compared with controls. Most T4 levels were high before age 2 years and during subsequent testing, but mean T3 and TSH levels remained normal. The meta-analysis showed a significant IQ difference in severe vs mild CH cases only when treatment started with an LT4 dose <10 µg/kg.Conclusions:High initial LT4 dosing was effective and safely achieved optimal cognitive development in patients with CH, including those severely affected. Supranormal T4 values during infancy were not associated with impaired IQ in adolescence.

Background: Lifestyle based weight loss interventions are hampered by long-term inefficacy. Prediction of individuals successfully reducing body weight would be highly desirable. Although sympathetic activity is known to contribute to energy homeostasis, its predictive role in body weight maintenance has not yet been addressed. Objectives: We investigated, whether weight regain could he modified by a weight maintenance intervention and analyzed the predictive role of weight loss-induced changes of the sympathetic system on long-term weight regain. Design: 156 subjects (age > 18; BMI >= 27 kg/m(2)) participated in a 12-week weight reduction program. After weight loss (T0), 43 subjects (weight loss > 8%) were randomized to a 12-month lifestyle intervention or a control group. After 12 months (T12) no further intervention was performed until month 18 (T18). Weight regain at T18 (regains(BMI)) was the primary outcome. Evaluation of systemic and tissue specific estimates of sympathetic system was a pre-defined secondary outcome. Results: BMI was reduced by 4.67 +/- 1.47 kg/m(2) during the initial weight loss period. BMI maintained low in subjects of the intervention group until T12 (+0.07 +/- 2.98 kg/m(2); p=0.58 compared to T0), while control subjects regained +0.98 +/- 1.93 kg/m(2) (p<0.001 compared to T0). The intervention group regained more weight than controls after ceasing the intervention (1.17 +/- 1.34 vs. 0.57 +/- 0.93 kg/m(2)) until T18. Consequently, BMI was not different at T18 (33.49 (32.64; 34.33) vs. 34.18 (33.61; 34.75) kg/m(2); p=0.17). Weight loss-induced modification of urinary metanephrine excretion independently predicted regain(BMI) (R-2 = 0.138; p<0.05). The lifestyle intervention did not modify the course of urinary metanephrines after initial weight loss. Conclusions: Our lifestyle intervention successfully maintained body weight during the intervention period. However, no long-term effect could be observed beyond the intervention period. Predictive sympathetic activity was not persistently modified by the intervention, which may partially explain the lack of long-term success of such interventions. (C) 2018 Elsevier Inc. All rights reserved.

59 Context: The alpha-subunit of the stimulatory G-protein (Gαs) links numerous receptors to adenylyl 60 cyclase. Gαs, encoded by GNAS, is expressed predominantly from the maternal allele in certain tissues. 61 Thus, maternal heterozygous loss-of-function mutations cause hormonal resistance, as in 62 pseudohypoparathyroidism type Ia, while somatic gain-of-function mutations cause hormone63 independent endocrine stimulation, as in McCune-Albright Syndrome. 64 Objective: We here report two unrelated boys presenting with a new combination of clinical findings 65 that suggest both gain and loss of Gαs function. 66 Design, Setting: Clinical features were studied and sequencing of GNAS was performed. Signaling 67 capacities of wild-type and mutant-Gαs were determined in the presence of different G protein-coupled 68 receptors (GPCRs) under basal and agonist-stimulated conditions. 69 Results: Both unrelated patients presented with unexplained hyponatremia in infancy, followed by 70 severe early-onset gonadotrophin-independent precocious puberty and skeletal abnormalities. An 71 identical heterozygous de novo variant (c.1136T>G; p.F376V) was found on the maternal GNAS allele, 72 in both patients; this resulted in a clinical phenotype that differ from known Gαs-related diseases and 73 suggested gain-of-function at the receptors for vasopressin (V2R) and lutropin (LHCGR), yet increased 74 serum parathyroid hormone (PTH) concentrations indicative of impaired proximal tubular PTH1 75 receptor (PTH1R) function. In vitro studies demonstrated that Gαs-F376V enhanced ligand-independent 76 signaling at the PTH1R, LHCGR and V2R and, at the same time, blunted ligand-dependent responses. 77 Structural homology modeling suggested mutation-induced modifications at the C-terminal α5-helix of 78 Gαs that are relevant for interaction with GPCRs and signal transduction. 79 Conclusions: The Gαs p.F376V mutation causes a previously unrecognized multi-system disorder. 80

Schilddrüsenhormone regulieren eine Vielzahl physiologischer Prozesse und sind wesentlich für die Entwicklung und das Wachstum von Kindern. Hierbei ist in ganz besonderer Weise die frühe ZNS-Reifung von einer normalen Schilddrüsenfunktion abhängig. Die zentrale Rolle der Schilddrüsenhormone zeigt sich bei der klinischen Ausprägung der unbehandelten angeborenen Hypothyreose. Hierbei sind der Kleinwuchs, die schwere motorische und kognitive Entwicklungsstörung, die Adipositas und die Depression eindrückliche Zeichen der physiologischen Bedeutung der Schilddrüsenhormone. Tritt eine schwere Hypothyreose im Kindes- oder Adoleszentenalter auf – z. B. durch eine Hashimoto-Thyreoiditis – ist die weitere kognitive Entwicklung nicht beeinträchtigt; allerdings ist dann das somatische Wachstum verzögert, das ggf. auch bei adäquater Therapie zu einer geringeren Endgröße führt.

Eine erworbene Hypothyreose ist im Kindes- und Jugendalter eher selten. Im Kleinkindalter tritt eine Hypothyreose fast nie auf. Die Hauptmanifestation findet sich im Pubertätsalter, vor allem bei Mädchen. Als Ursache einer erworbenen Hypothyreose ist fast ausschließlich die Hashimoto-Thyreoiditis zu nennen. Lediglich ein kleiner Anteil an betroffenen Patienten mit Hashimoto-Thyreoiditis entwickelt allerdings eine manifeste Hypothyreose. Neben den Fällen der erworbenen Hypothyreose bei Hashimoto-Thyreoiditis müssen die iatrogenen Fälle nach Thyreoidektomie – bei Morbus Basedow und Schilddrüsentumoren – und nach Behandlung einer malignen Erkrankung mit Bestrahlung der Halsregion (dann primäre Hypothyreose) oder nach Therapie eines hypophysären Tumors (dann sekundäre Hypothyreose) abgegrenzt werden; diese sind ebenfalls sehr selten. Für die Diagnose einer manifesten Hypothyreose ist der Nachweis erniedrigter T4- oder T3-Werte obligat; für die alleinige Erhöhung des TSH, die als Hyperthyreotropinämie bezeichnet wird, konnten im Kindes- und Jugendalter bisher keine Krankheitskorrelate beschrieben werden.

Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of 45–61 weeks. Compared to formerly developed and tested MC4R agonists, setmelanotide has the unique capability of activating nuclear factor of activated T cell (NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants. Our data demonstrate the potency of setmelanotide in treatment of individuals with diverse MC4R-related pathway deficiencies.

Angeborene Schilddrüsenfunktionsstörungen führen unbehandelt zu erheblichen Entwicklungsdefekten der betroffenen Neugeborenen. Neben der häufigen angeborenen Hypothyreose, die unbehandelt zu einem Kretinismus führt, können auch die selteneren angeborenen Hyperthyreosen unbehandelt zu kognitiven und somatischen Defekten der Kinder führen, z. B. einer Kraniosynostose. Eine angeborene Hypothyreose kann bei sehr schwerem Jodmangel auftreten. Diese Form der Hypothyreose, der endemische Kretinismus, ist nach Einführung der Jodsupplementationsprogramme der WHO sehr selten. Genetisch vererbte und familiär gehäuft auftretende Formen der angeborenen Hypothyreose treten durch autosomal-rezessiv vererbte Synthesedefekte der Schilddrüsenhormone auf. Die häufigste Variante ist die Schilddrüsendysgenesie, sie tritt mit einer Athyreose, Ektopie oder Hypoplasie auf. Die Ursache der Dysgenesien ist in den allermeisten Fällen noch immer unbekannt. Neben den primären Formen der Hypothyreose, die mit einem Defekt der Schilddrüse selbst einhergehen, sind wenige Kinder von einer sekundären/zentralen Hypothyreose betroffen. Hierbei handelt es sich um Neugeborene, die durch eine fehlende Stimulation der Schilddrüse durch einen Mangel an TSH eine z. T. auch schwere Hypothyreose aufweisen können. Die angeborene Hyperthyreose ist dagegen extrem selten. Dies gilt sowohl für die autoimmun bedingten Fälle bei Morbus Basedow der Mutter als auch für die genetisch bedingten Fälle mit aktivierender Mutation des TSH-Rezeptors. Die Diagnose sollte ebenso wie bei der Hypothyreose rasch gestellt werden, da die unbehandelte Hyperthyreose ebenfalls die Entwicklung der Kinder gefährdet. Neben den hypo- und hyperthyreoten Defekten finden sich seltene, z. T. sehr komplexe Erkrankungen, die aus angeborenen Störungen des Schilddrüsentransports und der Schilddrüsenhormonwirkung resultieren und zusammen als „Schilddrüsenhormonresistenzen“ zusammengefasst werden. Das folgende Kapitel beschreibt den heutigen Stand des Wissens zu diesen angeborenen Störungen der Schilddrüsenhormonbildung und -wirkung.

Die häufigste Ursache einer Hyperthyreose im Kindes- und Jugendalter ist der Morbus Basedow. Er tritt mit einer Inzidenz von 1 in 100.000 auf. Daneben kann es in wenigen Fällen einer Hashimoto-Thyreoiditis initial zu einer Hyperthyreose kommen. Noch deutlich seltenere Sonderformen der Hyperthyreose sind autonome Adenome der Schilddrüse, aktivierende Mutationen des TSH-Rezeptors und TSH-produzierende Adenome der Hypophyse. Die Diagnose einer Hyperthyreose ist im Kindes- und Jugendalter schwierig zu stellen. Die Manifestation der Autoimmunthyreoiditiden findet sich meist im Rahmen der Pubertät und die eher unspezifische klinische Symptomatik der Hyperthyreose ähnelt den Auffälligkeiten bzw. Beschwerden der pubertierenden Jugendlichen.