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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.

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 Aktionsbündnis für 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.

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 be 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/m2) participated in a 12-week weight reduction program. After weight loss (T0), 143 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 (regainBMI) 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/m2 during the initial weight loss period. BMI maintained low in subjects of the intervention group until T12 (+0.07 ± 2.98 kg/m2; p = 0.58 compared to T0), while control subjects regained +0.98 ± 1.93 kg/m2 (p 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.

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. Treatment with setmelanotide, a new-generation MC4R agonist, provides durable weight loss in hyperphagic, leptin receptor–deficient patients, suggesting a pharmacological avenue to treat patients with various MC4R pathway defects.

Schilddrusenhormone regulieren eine Vielzahl physiologischer Prozesse und sind wesentlich fur die Entwicklung und das Wachstum von Kindern. Hierbei ist in ganz besonderer Weise die fruhe ZNS-Reifung von einer normalen Schilddrusenfunktion abhangig. Die zentrale Rolle der Schilddrusenhormone zeigt sich bei der klinischen Auspragung der unbehandelten angeborenen Hypothyreose. Hierbei sind der Kleinwuchs, die schwere motorische und kognitive Entwicklungsstorung, die Adipositas und die Depression eindruckliche Zeichen der physiologischen Bedeutung der Schilddrusenhormone. Tritt eine schwere Hypothyreose im Kindes- oder Adoleszentenalter auf – z. B. durch eine Hashimoto-Thyreoiditis – ist die weitere kognitive Entwicklung nicht beeintrachtigt; allerdings ist dann das somatische Wachstum verzogert, das ggf. auch bei adaquater Therapie zu einer geringeren Endgrose fuhrt.

Die haufigste 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 Fallen einer Hashimoto-Thyreoiditis initial zu einer Hyperthyreose kommen. Noch deutlich seltenere Sonderformen der Hyperthyreose sind autonome Adenome der Schilddruse, 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 Pubertat und die eher unspezifische klinische Symptomatik der Hyperthyreose ahnelt den Auffalligkeiten bzw. Beschwerden der pubertierenden Jugendlichen.

Angeborene Schilddrusenfunktionsstorungen fuhren unbehandelt zu erheblichen Entwicklungsdefekten der betroffenen Neugeborenen. Neben der haufigen angeborenen Hypothyreose, die unbehandelt zu einem Kretinismus fuhrt, konnen auch die selteneren angeborenen Hyperthyreosen unbehandelt zu kognitiven und somatischen Defekten der Kinder fuhren, z. B. einer Kraniosynostose. Eine angeborene Hypothyreose kann bei sehr schwerem Jodmangel auftreten. Diese Form der Hypothyreose, der endemische Kretinismus, ist nach Einfuhrung der Jodsupplementationsprogramme der WHO sehr selten. Genetisch vererbte und familiar gehauft auftretende Formen der angeborenen Hypothyreose treten durch autosomal-rezessiv vererbte Synthesedefekte der Schilddrusenhormone auf. Die haufigste Variante ist die Schilddrusendysgenesie, sie tritt mit einer Athyreose, Ektopie oder Hypoplasie auf. Die Ursache der Dysgenesien ist in den allermeisten Fallen noch immer unbekannt. Neben den primaren Formen der Hypothyreose, die mit einem Defekt der Schilddruse selbst einhergehen, sind wenige Kinder von einer sekundaren/zentralen Hypothyreose betroffen. Hierbei handelt es sich um Neugeborene, die durch eine fehlende Stimulation der Schilddruse durch einen Mangel an TSH eine z. T. auch schwere Hypothyreose aufweisen konnen. Die angeborene Hyperthyreose ist dagegen extrem selten. Dies gilt sowohl fur die autoimmun bedingten Falle bei Morbus Basedow der Mutter als auch fur die genetisch bedingten Falle 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 gefahrdet. Neben den hypo- und hyperthyreoten Defekten finden sich seltene, z. T. sehr komplexe Erkrankungen, die aus angeborenen Storungen des Schilddrusentransports und der Schilddrusenhormonwirkung resultieren und zusammen als „Schilddrusenhormonresistenzen“ zusammengefasst werden. Das folgende Kapitel beschreibt den heutigen Stand des Wissens zu diesen angeborenen Storungen der Schilddrusenhormonbildung und -wirkung.

Schilddrusenknoten sind im Kindesalter relativ haufig, Schilddrusenkarzinome dagegen sehr selten. Eine populationsbezogene Ultraschallscreening-Studie hat in Deutschland eine Pravalenz von Knoten > 1 cm von 0,6 in 100 Kindern und Jugendlichen ergeben. In neueren Studien aus Japan mit hochauflosenden Ultraschallgeraten wurde eine Knotenpravalenz 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 Malignitatsrate von nur 4 %. Die Malignitatsrate bei klinisch auffallenden Knoten, die im Mittel einen Durchmesser von 20 mm aufweisen, liegt dagegen bei 20–25 %. Bei haufigem Einsatz der Schilddrusensonografie werden aktuell sehr viele der gutartigen kleinen Schilddrusenknoten zufallig diagnostiziert (Schilddruseninzidentalome). Die richtige Beurteilung dieser Befunde mit der Notwendigkeit, differenzialdiagnostisch die haufigen gutartigen von den wenigen malignen Knoten abzugrenzen, stellt aktuell die groste Herausforderung auf dem Gebiet der Schilddrusenneoplasien – nicht nur im Kindesalter – dar.

OBJECTIVES: Central hypothyroidism (CeH) is a rare form of hypothyroidism characterized by insufficient thyroid stimulation due to disturbed pituitary and/or hypothalamic functioning. Due to its origin and the whole clinical context, CeH represents a challenging condition in clinical practice as it is characterized by suboptimal accuracy of clinical and biochemical parameters for diagnosis and management. Since no expert consensus or guidance for this condition is currently available, a task force of experts received the commitment from the European Thyroid Association (ETA) to prepare this document based on the principles of clinical evidence. STUDY DESIGN: The task force started to work in February 2017 and after a careful selection of appropriate references (cohort studies, case reports, expert opinions), a preliminary presentation and live discussion during the 2017 ETA meeting, and several revision rounds, has prepared a list of recommendations to support the diagnosis and management of patients with CeH. RESULTS: Due to the particular challenges of this rare condition in the different ages, the target users of this guidance are pediatric and adult endocrinologists. Experts agreed on the need to recognize and treat overt CeH at all ages, whereas treatment of milder forms may be dispensable in the elderly (> 75 years). CONCLUSIONS: Despite the lack of randomized controlled clinical trials, the experts provide 34 recommendations supported by variable levels of strength that should improve the quality of life of the affected patients and reduce the metabolic and hormonal consequences of inadequate management.

Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte-stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopiomelanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist. The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2).

Naturally occurring thyrotropin (TSH) mutations are rare, which is also the case for the homologous heterodimeric glycoprotein hormones (GPHs) follitropin (FSH), lutropin (LH), and choriogonadotropin (CG). Patients with TSH-inactivating mutations present with central congenital hypothyroidism. Here, we summarize insights into the most frequent loss-of-function β-subunit of TSH mutation C105Vfs114X, which is associated with isolated TSH deficiency. This review will address the following question. What is currently known on the molecular background of this TSH variant on a protein level? It has not yet been clarified how C105Vfs114X causes early symptoms in affected patients, which are comparably severe to those observed in newborns lacking any functional thyroid tissue (athyreosis). To better understand the mechanisms of this mutant, we have summarized published reports and complemented this information with a structural perspective on GPHs. By including the ancestral TSH receptor agonist thyrostimulin and pathogenic mutations reported for FSH, LH, and choriogonadotropin in the analysis, insightful structure function and evolutionary restrictions become apparent. However, comparisons of immunogenicity and bioactivity of different GPH variants is hindered by a lack of consensus for functional analysis and the diversity of used GPH assays. Accordingly, relevant gaps of knowledge concerning details of GPH mutation-related effects are identified and highlighted in this review. These issues are of general importance as several previous and recent studies point towards the high impact of GPH variants in differential signaling regulation at GPH receptors (GPHRs), both endogenously and under diseased conditions. Further improvement in this area is of decisive importance for the development of novel targeted therapies.

(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.

Context The 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. Objective We report two unrelated boys presenting with a new combination of clinical findings that suggest both gain and loss of Gαs function. Design and Setting Clinical 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. Results Both 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. Conclusions The Gαs p.F376V mutation causes a previously unrecognized multisystem disorder.

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 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.

Context Early-onset obesity, characteristic for disorders affecting the leptin–melanocortin pathway, is also observed in pseudohypoparathyroidism type 1A (PHP1A), a disorder caused by maternal GNAS mutations that disrupt expression or function of the stimulatory G protein α-subunit (Gsα). Mutations and/or epigenetic abnormalities at the same genetic locus are also the cause of pseudohypoparathyroidism type 1B (PHP1B). However, although equivalent biochemical and radiographic findings can be encountered in these related disorders caused by GNAS abnormalities, they are considered distinct clinical entities. Objectives To further emphasize the overlapping features between both disorders, we report the cases of several children, initially brought to medical attention because of unexplained early-onset obesity, in whom PHP1B or PHP1A was eventually diagnosed. Patients and Methods Search for GNAS methylation changes or mutations in cohorts of patients with early-onset obesity. Results Severe obesity had been noted in five infants, with a later diagnosis of PHP1B due to STX16 deletions and/or abnormal GNAS methylation. These findings prompted analysis of 24 unselected obese patients, leading to the discovery of inherited STX16 deletions in 2 individuals. Similarly, impressive early weight gains were noted in five patients, who initially lacked additional Albright hereditary osteodystrophy features but in whom PHP1A due to GNAS mutations involving exons encoding Gsα was diagnosed. Conclusions Obesity during the first year of life can be the first clinical evidence for PHP1B, expanding the spectrum of phenotypic overlap between PHP1A and PHP1B. Importantly, GNAS methylation abnormalities escape detection by targeted or genome-wide sequencing strategies, raising the question of whether epigenetic GNAS analyses should be considered for unexplained obesity.

A new modular, outcome-based, interdisciplinary curriculum was introduced for undergraduate medical education at one of the largest European medical faculties. A key stated institutional goal was to systematically integrate sex and gender medicine and gender perspectives into the curriculum in order to foster adequate gender-related knowledge and skills for future doctors concerning the etiology, pathogenesis, clinical presentation, diagnosis, treatment, and research of diseases.A change agent was integrated directly into the curriculum development team to facilitate interactions with all key players of the curricular development process. The gender change agent established a supporting organizational framework of all stakeholders, and developed a 10-step approach including identification, selection, placing relevant sex and gender medicine-related issues in the curricular planning sessions, counseling of faculty members, and monitoring of the integration achieved.With this approach, quantitatively sex and gender medicine-related content was widely integrated throughout all teaching and learning formats and from early basic science to later clinical modules (94 lectures, 33 seminars, and 16 practical courses). Gender perspectives involve 5% of the learning objectives and represent an integral part of the assessment program. Qualitatively, the relevance of gender (sociocultural) differences was combined with sex (biological) differences in disease manifestation throughout the curriculum.The appointment of a change agent facilitates the development of systematic approaches that can be a key and serve as practice models to successfully integrate new overarching curricular perspectives and dimensions--in this case sex and gender medicine--into a new medical curriculum.

Mit den Fortschritten in der molekulargenetischen Diagnostik und den verbesserten Moglichkeiten einer Beweisfuhrung der sich daraus ergebenden Storungen z. B. im Modellorganismus ist es prinzipiell moglich, fur viele Erkrankungen, deren Ursache wir bis heute nicht kennen, eine Klarung herbeizufuhren und schlieslich darauf basierende Therapien zu entwickeln. Inzwischen sind mehr als 6000 unterschiedliche seltene Erkrankungen bekannt. Es werden stetig mehr, denn durch die Untersuchung des gesamten Genoms wird es moglich sein, Erkrankungen, die bislang nur unter beschreibenden Sammelbegriffen zusammengefasst werden, genauer zu definieren. Dies ist die Basis fur eine individualisierte Medizin, die besser als Prazisionsmedizin bezeichnet werden sollte, die eine Diagnose und die Therapie einer Vielzahl von angeborenen seltenen Erkrankungen moglich machen wird. Daher werden neue integrierte Versorgungs- und Forschungszentren benotigt, die eine rasche Umsetzung neuer Erkenntnisse in die Klinik ermoglichen und eine fur die seltenen Erkrankungen spezialisierte breite Expertise dauerhaft vorhalten. Im deutschen Nationalen Aktionsplan fur Menschen mit Seltenen Erkrankungen (NAMSE) wurde in einem breiten Konsens aller Beteiligten hierfur eine Strukturierung entwickelt. In diesem Beitrag wird das Berliner Centrum fur Seltene Erkrankungen (BCSE) als ein Beispiel vorgestellt, bei dessen Etablierung einige der im NAMSE vorgegebenen Kriterien bereits berucksichtigt wurden

Disorders/diversity of sex development (dsd) is an umbrella term for congenital conditions often diagnosed within childhood. As most parents are unprepared for this situation, psychological support (PsySupp) is recommended. The aim of this study was to analyse the extent to which parents express a need for PsySupp. Three hundred twenty-nine parents of children with dsd were included; 40.4 % of the parents indicated to have a need for PsySupp, only 50 % of this group received it adequately. The diagnoses partial gonadal dysgenesis, partial androgen insensitivity syndrome (pAIS) and disorders of androgen synthesis are associated with a high need for PsySupp in parents (54, 65, and 50 %). Sex assignment surgery neither reduced nor increased the need for PsySupp. Taking a picture, radiography, laparoscopy, gonadal biopsy, gonadectomy and hormonal puberty induction are associated with a high need for PsySupp. There was no association between the need for PsySupp and the parents' perception of the appearance of the genitalia.Having a child with dsd is associated with a high need for PsySupp in parents. In particular, parents of children with XY-dsd with androgen effects other than hypospadias expressed a high need of PsySupp. PsySupp for parents should be an obligatory part of interdisciplinary care to reduce fears and concerns. What is known • In parents, having a child with dsd provokes insecurities and fears. Hence, psychological support is recommended as part of the interdisciplinary care. What is new • This is the first study investigating the subjective need for psychological support in a large sample of parents of children with dsd in Germany. We present data on the subjective need for psychological support of the parents, related diagnoses and factors, which should be considered in psychological counselling.

The monocarboxylate transporter 8 (MCT8) is a member of the major facilitator superfamily (MFS). These membrane-spanning proteins facilitate translocation of a variety of substrates, MCT8 specifically transports iodothyronines. Mutations in MCT8 are the underlying cause of severe X-linked psychomotor retardation. At the molecular level, such mutations led to deficiencies in substrate translocation due to reduced cell-surface expression, impaired substrate binding, or decreased substrate translocation capabilities. However, the causal relationships between genotypes, molecular features of mutated MCT8, and patient characteristics have not yet been comprehensively deciphered. We investigated the relationship between pathogenic mutants of MCT8 and their capacity to form dimers (presumably oligomeric structures) as a potential regulatory parameter of the transport function of MCT8. Fourteen pathogenic variants of MCT8 were investigated in vitro with respect to their capacity to form oligomers. Particular mutations close to the substrate translocation channel (S194F, A224T, L434W, and R445C) were found to inhibit dimerization of MCT8. This finding is in contrast to those for other transporters or transmembrane proteins, in which substitutions predominantly at the outer-surface inhibit oligomerization. Moreover, specific mutations of MCT8 located in transmembrane helix 2 (del230F, V235M, and ins236V) increased the capacity of MCT8 variants to dimerize. We analyzed the localization of MCT8 dimers in a cellular context, demonstrating differences in MCT8 dimer formation and distribution. In summary, our results add a new link between the functions (substrate transport) and protein organization (dimerization) of MCT8, and might be of relevance for other members of the MFS. Finally, the findings are discussed in relationship to functional data combined with structural–mechanistical insights into MCT8.

MAMLD1 is suggested to play a role in the development of 46,XY disorders of sexual development (46,XY DSD). So far, mutations in this gene have been detected in several cases of hypospadias with normal testosterone levels at birth. From in vitro studies it was concluded that Mamld1 might transiently affect testosterone synthesis during genital development. We describe the first MAMLD1 mutation in a 46,XY patient with complete gonadal dysgenesis. The novel MAMLD1 missense mutation (p.P677L) results in a severely reduced transactivation in vitro of the promoter of the MAMLD1 target gene HES3/Hes3. However, as knowledge about the functional role of MAMLD1 in gonadal development is limited, we suggest that additional factors (digenic or oligogenic cause) play a role in the development of complete gonadal dysgenesis in this patient.

Context: Congenital hypothyroidism, the most frequent endocrine congenital disease, can occur either based on a thyroid hormone biosynthesis defect or can predominantly be due to thyroid dysgenesis. However, a genetic cause could so far only be identified in less than 10% of patients with a thyroid dysgenesis. Objectives: Exome sequencing was used for the first time to find additional genetic defects in thyroid dysgenesis. Patients and Methods: In a consanguineous family with thyroid dysgenesis, exome sequencing was applied, and findings were further validated by Sanger sequencing in a cohort of 94 patients with thyroid dysgenesis. Results: By exome sequencing we identified a homozygous missense mutation (p.Leu597Ser) in the SLC26A4 gene of a patient with hypoplastic thyroid tissue, who was otherwise healthy. In the cohort of patients with thyroid dysgenesis, we observed a second case with a homozygous missense mutation (p.Gln413Arg) in the SLC26A4 gene, who was additionally affected by severe hearing problems. Both mutations were previously described as loss-of-function mutations in patients with Pendred syndrome and nonsyndromic enlarged vestibular aqueduct. Conclusion: We unexpectedly identified SLC26A4 mutations that were hitherto diagnosed in thyroid dyshormonogenesis patients, now for the first time in patients with structural thyroid defects. This result resembles the historic description of thyroid atrophy in patients with the so-called myxedematous form of cretinism after severe iodine deficiency. Most likely the thyroid defect of the two homozygous SLC26A4 gene mutation carriers represents a kind of secondary thyroid atrophy, rather than a primary defect of thyroid development in the sense of thyroid agenesis. Our study extends the variable clinical spectrum of patients with SLC26A4 mutations and points out the necessity to analyze the SLC26A4 gene in patients with apparent thyroid dysgenesis in addition to the known candidate genes TSHR, PAX8, NKX2.1, NKX2.5, and FOXE1.

Obesity is one of the most challenging global health problems. One key player in energy homeostasis is the melanocortin-4 receptor (MC4R), which is a family A G-protein-coupled receptor (GPCR). It has recently been shown that MC4R has the capacity to form homo- or heterodimers. Dimerization of GPCRs is of great importance for signaling regulation, with major pharmacological implications. Unfortunately, not enough is yet known about the detailed structural properties of MC4R dimers or the functional consequences of receptor dimerization. Our goal, therefore, was to explore specific properties related to MC4R dimerization. First, we aimed to induce the dissociation of dimers to monomers and to compare the functional parameters of wild-type and MC4R variants. To inhibit homodimerization, we designed MC4R chimeras with the cannabinoid-1 receptor, a receptor that does not interact with MC4R. Indeed, we identified several substitutions in the intracellular loop 2 (ICL2) and adjacent regions of transmembrane helix 3 (TMH3) and TMH4 that lead to partial dimer dissociation. Interestingly, the capacity for signaling activity was generally increased in these MC4R variants, although receptor expression remained unchanged. This increase in activity for dissociated receptors might indicate a link between receptor dimerization and signaling capacity. Moreover, dimer dissociation was also observed in a naturally occurring activating MC4R mutation in ICL2. Taken together, this study provides new information on the structural prerequisites for MC4R dimerization and identifies an approach to induce the dissociation of MC4R dimers. This might be useful for further investigation of pharmacological properties.

SummaryObjective Rare congenital conditions with incongruence of chromosomal, gonadal and phenotypic sex have been classified as differences/disorders of sex development (DSD). Included in DSD are conditions with diverse genetic aetiology, varying levels of prenatal androgen effects, phenotypes and, subsequently, different medical treatments. Quality of life (QoL) and psychological well-being are indicators of successful psychosocial adaptation to the conditions. We sought to investigate the HRQoL and psychological well-being in this population. Design This multicentre clinical evaluation study was part of a German network related to DSD funded by the German Ministry of Science and Education (BMBF 2003 to 2007). Methods To assess health-related quality of life (HRQoL), we used the Short Form Health Survey (SF-36), and for psychological well-being, the Brief Symptom Inventory (BSI). Participants were classified into five groups: females with CAH, females with XY DSD conditions where there is a partial androgen effect (partial androgen insensitivity, mixed/partial gonadal dysgenesis, disorders of androgen biosynthesis), females with XY DSD without androgen effect (complete androgen insensitivity, complete gonadal dysgenesis), males with XY DSD, and individuals with DSD conditions and other gender. Results Participants included 110 adults with DSD (age range 17–62). We found a trend of lowered mental HRQoL and significant higher physical HRQoL for participants as compared to the norm. The high physical HRQoL especially applied to females with androgen effect and XY karyotype. Participants reported significant higher psychological distress compared to the norm. Forty-seven participants (42·7%) reported distress in a clinically relevant range on the BSI. Conclusions Although we did not find significant impairments in overall HRQoL, participants reported significant impaired psychological well-being. Specialized interdisciplinary care should focus in particular on psychological issues to ensure good overall health and well-being.

Aminoglycoside-mediated read-through of stop codons was recently demonstrated for a variety of diseases in vitro and in vivo. About 30 percent of human genetic diseases are the consequence of nonsense mutations. Nonsense mutations in obesity-associated genes like the melanocortin 4 receptor (MC4R), expressed in the hypothalamus, show the impact of premature stop codons on energy homeostasis. Therefore, the MC4R could be a potential pharmaceutical target for obesity treatment and targeting MC4R stop mutations could serve as proof of principle for nonsense mutations in genes expressed in the brain. We investigated four naturally occurring nonsense mutations in the MC4R (W16X, Y35X, E61X, Q307X) located at different positions in the receptor for aminoglycoside-mediated functional rescue in vitro. We determined localization and amount of full-length protein before and after aminoglycoside treatment by fluorescence microscopy, cell surface and total enzyme linked immunosorbent assay (ELISA). Signal transduction properties were analyzed by cyclic adenosine monophosphate (cAMP) assays after transient transfection of MC4R wild type and mutant receptors into COS-7 cells. Functional rescue of stop mutations in the MC4R is dependent on: (i) triplet sequence of the stop codon, (ii) surrounding sequence, (iii) location within the receptor, (iv) applied aminoglycoside and ligand. Functional rescue was possible for W16X, Y35X (N-terminus), less successful for Q307X (C-terminus) and barely feasible for E61X (first transmembrane domain). Restoration of full-length proteins by PTC124 could not be confirmed. Future pharmaceutical applications must consider the potency of aminoglycosides to restore receptor function as well as the ability to pass the blood-brain barrier.

Context: In this paper we report two new TSH receptor (TSHR) mutations. One mutation (Pro6396.50Leu) was identified in two siblings with congenital hypothyroidism, and a second mutation (Cys6366.47Arg) was found in a patient suffering from nonautoimmune hyperthyroidism. Both mutations are located in transmembrane helix (TMH) 6 at the conserved Cys6.47-Trp(Met)6.48-Leu(Ala)6.49-Pro6.50 motif of family A G protein-coupled receptors (GPCR). Objective: To study the pathogenic mechanisms, we tested patients' mutations and further side chain variations regarding their effects on TSHR signaling. Results: Substitution Pro639Leu fully inactivates the promiscuous TSHR for cAMP (Gs) and IP (Gq) signaling. In contrast, Cys636Arg leads to constitutive activation of Gs. Organization of TSHR in oligomers was not modified by mutations at position 636. Interestingly, it is known from crystal structures of GPCR that Pro6.50 is located at a TMH6 kink-distortion, which is a pivot during activation-related helical movements. However, the cell surface expressions of all mutants at position 639 were comparable to wild type, indicating a helical conformation like wild type. Conclusion: Until now, only naturally occurring constitutively activating mutations in TSHR TMH6 have been reported, but here we present the first pathogenic inactivating mutation (Pro639Leu). Our data are indicative of differentiated regulation of Gs and Gq signaling at particular TMH6 positions, but without any effects on TSHR oligomer constellation. Details of signaling modulation by each mutant at positions 6366.47 and 6396.50 help us to understand high conservation of these amino acids in family A GPCR. Described molecular (pathogenic) mechanisms are likely not unique for TSHR.

The worldwide obesity epidemic is increasing, yet at this time, no long-acting and specific pharmaceutical therapies are available. Peripheral hormonal signals communicate metabolic status to the hypothalamus by activating their corresponding receptors in the arcuate nucleus (ARC). In this brain region, a variety of G protein-coupled receptors (GPCRs) are expressed that are potentially involved in weight regulation, but so far, the detailed function of most hypothalamic GPCRs is only partially understood. An important and underappreciated feature of GPCRs is the capacity for regulation via di- and heterodimerization. Increasing evidence implicates that heterodimerization of GPCRs results in profound functional consequences. Recently, we could demonstrate that interaction of the melanocortin 3 receptor (MC3R) and the growth hormone secretagogue receptor (GHSR)-1a results in a modulation of function in both receptors. Although the physiological role of GPCR-GPCR interaction in the hypothalamus is yet to be elucidated, this concept promises new avenues for investigation and understanding of hypothalamic functions dependent on GPCR signaling. Since GPCRs are important targets for drugs to combat many diseases, identification of heterodimers may be a prerequisite for highly specific drugs. Therefore, a detailed understanding of the mechanisms and their involvement in weight regulation is necessary. Fundamental to this understanding is the interplay of GPCR-GPCR in the hypothalamic nuclei in energy metabolism. In this review, we summarize the current knowledge on melanocortin receptors and GHSR-1a in hypothalamic weight regulation, especially as they pertain to possible drug targets. Furthermore, we include available evidence for the participation and significance of GPCR dimerization.

SUMMARY Purpose: Febrile seizures (FS) are the most common type of convulsive events in children. FS are suggested to result from a combination of genetic and environmental factors. However, the pathophysiologic mechanisms underlying FS remain unclear. Using an animal model of experimental FS, it was demonstrated that hyperthermia causes respiratory alkalosis with consequent brain alkalosis and seizures. Here we examine the acid–base status of children who were admitted to the hospital for FS. Children who were admitted because of gastroenteritis (GE), a condition known to promote acidosis, were examined to investigate a possible protective effect of acidosis against FS. Methods: We enrolled 433 age-matched children with similar levels of fever from two groups presented to the emergency department. One group was admitted for FS (n = 213) and the other for GE (n = 220). In the FS group, the etiology of fever was respiratory tract infection (74.2%), otitis media (7%), GE (7%), tonsillitis (4.2%), scarlet fever (2.3%) chickenpox (1.4%), urinary tract infection (1.4%), postvaccination reaction (0.9%), or unidentified (1.4%). In all patients, capillary pH and blood Pco2 were measured immediately on admission to the hospital. Key Findings: Respiratory alkalosis was found in children with FS (pH 7.46 ± 0.04, [mean ± standard deviation] Pco2 29.5 ± 5.5 mmHg), whereas a metabolic acidosis was seen in all children admitted for GE (pH 7.31 ± 0.03, Pco2 37.7 ± 4.3 mmHg; p < 0.001 for both parameters). No FS were observed in the latter group. A subgroup (n = 15; 7%) of the patients with FS had GE and, notably, their blood pH was more alkaline (pH 7.44 ± 0.04) than in the GE-admitted group. During the enrollment period, eight of the patients were admitted on separate occasions because of FS or GE. Consistent with the view that generation of FS requires a genetic susceptibility in addition to acute seizure triggering factors, each of these patients had an alkalotic blood pH when admitted because of FS, whereas they had an acidotic pH (and no FS) when admitted because of GE (pH 7.47 ± 0.05 vs. pH 7.33 ± 0.03, p < 0.005). Significance: The results show that FS are associated with a systemic respiratory alkalosis, irrespective of the severity of the underlying infection as indicated by the level of fever. The lack of FS in GE patients is attributable to low pH, which also explains the fact that children with a susceptibility to FS do not have seizures when they have GE-induced fever that is associated with acidosis. The present demonstration of a close link between FS and respiratory alkalosis may pave the way for further clinical studies and attempts to design novel therapies for the treatment of FS by controlling the systemic acid–base status.

ObjectiveTo study whether metformin reduces obesity, homeostasis model assessment for insulin resistance index (HOMA-IR), and the metabolic syndrome (MtS) in obese European adolescents in addition to previous unsuccessful lifestyle intervention.Design and methodsAfter 6 months of multiprofessional lifestyle intervention, 70 out of 86 adolescents without improvement in body mass index (BMI) and HOMA-IR were randomized into either the placebo (n=34) or the metformin group (2×500 mg/day,n=36) in addition to ongoing lifestyle intervention for another 6 months.ResultsAge was 13.8 years, BMI was 33.1 kg/m2, 65% were female, and 89% were Caucasians. During lifestyle intervention alone, BMI and HOMA-IR deteriorated significantly. In the subsequent medication period, HOMA-IR and fasting insulin improved similarly in the placebo and metformin groups (HOMA-IR decreased 73 vs 54% respectively in metformin versus placebo;P=0.048), but BMI remained unchanged. The insulin sensitivity index, however, only improved in the metformin group. High fasting insulin is correlated with a subsequent BMI increase irrespective of the medication. MtS remained unchanged.ConclusionsObese European adolescents' insulin sensitivity improved without weight change during placebo or metformin intervention in addition to lifestyle intervention. Most differences did not reach statistical significance, probably due to improved compliance with lifestyle intervention as a placebo effect. In addition, the metformin dose may be too low.

ObjectiveHypospadias is a frequent congenital anomaly but in most cases an underlying cause is not found. Steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) is a key regulator of human sex development and an increasing number of SF-1 (NR5A1) mutations are reported in 46,XY disorders of sex development (DSD). We hypothesized that NR5A1 mutations could be identified in boys with hypospadias.Design and methodsMutational analysis of NR5A1 in 60 individuals with varying degrees of hypospadias from the German DSD network.ResultsHeterozygous NR5A1 mutations were found in three out of 60 cases. These three individuals represented the most severe end of the spectrum studied as they presented with penoscrotal hypospadias, variable androgenization of the phallus and undescended testes (three out of 20 cases (15%) with this phenotype). Testosterone was low in all three patients and inhibin B/anti-Müllerian hormone (AMH) were low in two patients. Two patients had a clear male gender assignment. Gender re-assignment to male occurred in the third case. Two patients harbored heterozygous nonsense mutations (p.Q107X/WT, p.E11X/WT). One patient had a heterozygous splice site mutation in intron 2 (c.103-3A/WT) predicted to disrupt the main DNA-binding motif. Functional studies of the nonsense mutants showed impaired transcriptional activation of an SF-1-responsive promoter (Cyp11a). To date, adrenal insufficiency has not occurred in any of the patients.ConclusionsSF-1 (NR5A1) mutations should be considered in 46,XY individuals with severe (penoscrotal) hypospadias, especially if undescended testes, low testosterone, or low inhibin B/AMH levels are present. SF-1 mutations in milder forms of idiopathic hypospadias are unlikely to be common.

Thyroid hormone transport into cells requires plasma membrane transport proteins. Mutations in one of these, monocarboxylate transporter 8 (MCT8), have been identified as underlying cause for the Allan–Herndon–Dudley syndrome, an X-linked mental retardation in which the patients also present with abnormally high 3′,3,5-triiodothyronine (T3) plasma levels. Mice deficient inMct8replicate the thyroid hormone abnormalities observed in the human condition. However, no neurological deficits have been described in mice lackingMct8. Therefore, we subjectedMct8-deficient mice to a comprehensive immunohistochemical, neurological, and behavioral screen. Several behavioral abnormalities were found in the mutants. Interestingly, some of these behavioral changes are compatible with hypothyroidism, whereas others rather indicate hyperthyroidism. We thus hypothesized that neurons exclusively dependent onMct8are in a hypothyroid state, whereas neurons expressing other T3transporters become hyperthyroid, if they are exposed directly to the high plasma T3. The majority of T3uptake in primary cortical neurons is mediated by Mct8, but pharmacological inhibition suggested functional expression of additional T3transporter classes. mRNAs encoding six T3transporters, including L-type amino acid transporters (LATs), were coexpressed withMct8in isolated neurons. We then demonstratedLat2expression in cultured neurons and throughout murine brain development. In contrast,LAT2is expressed in microglia in the developing human brain during gestation, but not in neurons. We suggest that lack of functional complementation by alternative thyroid hormone transporters in developing human neurons precipitates the devastating neurodevelopmental phenotype inMCT8-deficient patients, whereasMct8-deficient mouse neurons are functionally complemented by other transporters, for possiblyLat2.

The challenge to eradicate iodine deficiency disorders (IDD) by the year 2000 worldwide will have positive consequences for more than 20 million people suffering from IDD. This is the main and common goal for the developing but also for a lot the developed countries. Sensitive tools like neonatal thyroid screening (NTS) can be used in order to make changes in iodine supplementation more transparent and to have a dynamic target oriented approach. The comparison between six districts in Bulgaria and Berlin revealed despite of some positive changes after the fortification of the iodine supplementation program still existing iodine deficiency in Bulgaria which is more profound than in Berlin in 1990. The shift to higher TSH-values in the Black-Sea region, classified by goitre-prevalence in 1956 as non-endemic for iodine deficiency, needs further investigation. Besides of iodine deficiency an influence of iodine-containing disinfectants and/or goitrogens is possible.

Screening for congenital hypothyroidism for all newborns of the former western parts of the city of Berlin was instituted in 1978 by determination of the TSH levels in dried filter paper blood spots of the 3rd to 5th day of life. Since 1991 the newborns of the former eastern parts have been also included in the same screening program. From 1978 to 1995 a total number of 104 newborns with permanent congenital hypothyroidism have been detected resulting in a prevalence of congenital hypothyroidism of 1:3800. The etiological diagnosis of hypothyroidism was made by imaging studies (ultrasonography or 99mTc scintigraphy) and assessment of serum thyroglobulin and thyroid hormone levels. Using this approach in 37 children (30 female, 7 male) the diagnosis of athyrosis, in 20 children (15 female, 5 male) the diagnosis of ectopy and in 21 children (18 female, 3 male) the diagnosis of thyroid hypoplasia was made, 16 children (8 female, 8 male) had a normally sized gland and 4 (1 female, 3 male) had congenital goiter. In 86% of all patients the age at onset of thyroxine (L-T4) replacement therapy was 8 or 9 days of life (3-42 days) and the median initial L-T4 dose was 14 micrograms/kg/day (10-16 micrograms/kg/day). The intellectual outcome of 77 children (2-16 years) was studied and normal scores for the intelligence (IQ) and developmental (DQ) quotients were found in 71 (92%). Outcome was not correlated to the age at onset of treatment, the initial dose and the severity of hypothyroidism, but there was a positive correlation of the socioeconomic status of the family and the IQ of the patients. The results of the screening program in Berlin document that an early and efficient thyroxine replacement can normalize the intellectual outcome of patients with congenital hypothyroidism independent of the severity of the disease as assessed by the residual thyroid function detectable at diagnosis.

HNF1B-maturity-onset diabetes of the young is caused by abnormalities in the HNF1B gene encoding the transcription factor HNF-1beta. We aimed to investigate detailed clinical features and the type of HNF1B gene anomaly in five pediatric cases with HNF1B-MODY.From a cohort of 995 children and adolescents with diabetes, we analyzed the most frequent maturity-onset diabetes of the young genes (GCK, HNF1A, HNF4A) including HNF1B sequencing and deletion analysis by quantitative Multiplex-PCR of Short Fluorescent Fragments (QMPSF) if patients were islet autoantibody-negative and had one parent with diabetes or associated extrapancreatic features or detectable C-peptide outside honeymoon phase. Presence and size of disease-causing chromosomal rearrangements detected by QMPSF were further analyzed by array comparative genomic hybridization.Overall, five patients had a heterozygous HNF1B deletion, presenting renal disease, elevated liver enzymes, and diabetes. Diabetes was characterized by insulin resistance and adolescent onset of hyperglycemia. Additionally, clinical features in some patients were pancreas dysplasia and exocrine insufficiency (two of five patients), genital defects (three of five), mental retardation (two of five), and eye abnormalities (coloboma, cataract in two of five). One case also had severe growth deficit combined with congenital cholestasis, and another case had common variable immune deficiency. All patients reported here had monoallelic loss of the entire HNF1B gene. Whole genome array comparative genomic hybridization confirmed a precurrent genomic deletion of approximately 1.3-1.7 Mb in size.The clinical data of our cases enlarge the wide spectrum of patients with HNF1B anomaly. The underlying molecular defect in all cases was a 1.3- to 1.7-Mb deletion, and paired, segmental duplications along with breakpoints were most likely involved in this recurrent chromosomal microdeletion.

ObjectiveMore than 30 years ago Frisch and Revelle proposed a body weight threshold for the onset of menarche. Based on this hypothesis, a further acceleration of age at menarche can be expected in times of childhood obesity.DesignA cross-sectional study of 1840 healthy school girls (Berlin school children's cohort, BSCOC) within the age groups 10–15 years was conducted in 2006–2007.MethodsMedian age of menarche was calculated by Kaplan–Meier survival analysis. Bi- and multivariate analyses were performed to analyze the associations between menarche age and weight status. A locally weighted regression was used to analyze the relationship respectively between height, weight, and body mass index (BMI)–SDS and age stratified by menarche status.ResultsNine hundred and thirty six (50.9%) girls had already experienced menarche at a median age of 12.8 years. Two hundred and thirty six of these girls reached their menarche recently. Obese/overweight girls reached menarche significantly earlier (12.5 years), than normal weight (12.9 years), and underweight girls (13.7 years). The mean total body weight was similar in all girls at menarche irrespective of age (mean 51.1 kg,s.d.8.1) and height. BMI–SDS remained the only significant factor for onset of menarche within a multiple regression model for early menarche (OR 2.1, 95% confidence interval 1.3–3.3,P=0.002).ConclusionsAge at onset of menarche did not accelerate even in a childhood population with more than 10% obesity prevalence. Nevertheless, a negative correlation of BMI–SDS with age at onset of menarche exists.

DEHAL1 has been identified as the gene encoding iodotyrosine deiodinase in the thyroid, where it controls the reuse of iodide for thyroid hormone synthesis. We screened patients with hypothyroidism who had features suggestive of an iodotyrosine deiodinase defect for mutations in DEHAL1. Two missense mutations and a deletion of three base pairs were identified in four patients from three unrelated families; all the patients had a dramatic reduction of in vitro activity of iodotyrosine deiodinase. Patients had severe goitrous hypothyroidism, which was evident in infancy and childhood. Two patients had cognitive deficits due to late diagnosis and treatment. Thus, mutations in DEHAL1 led to a deficiency in iodotyrosine deiodinase in these patients. Because infants with DEHAL1 defects may have normal thyroid function at birth, they may be missed by neonatal screening programs for congenital hypothyroidism.

History and clinical findings Dizygotic twin sisters were born to a woman who, shortly before becoming pregnant, had developed Graves' disease with markedly elevated triiodothyronine (T3) levels and highly positive TSH receptor antibody titres (TRAb: 169 mU/ml). From the second week of life onwards they had a goitre and hyperexcitability, tachycardia and failure to thrive were noted. In addition, twin I had mild exophthalmos. As thyrostatic treatment of the mother was very difficult, intrauterine hypothyroidism or transitory hyperthyroidism had presumably occurred in the twins. Investigations Twin I had maximal thyroxine (T4) concentration of 26.2 micrograms/dl, while it was 24.7 micrograms/dl in twin II with suppressed TSH. Both twins had high concentrations of TRAb and antibodies against thyroid peroxidase. Diagnosis, treatment and course With the diagnosis of neonatal Graves' disease established, both twins were treated with propranolol (2 mg/kg.d) and phenobarbitone (2-4 mg/kg.d). Twin I, whose symptoms were more severe, also received propylthiouracil (5 mg/kg.d) until euthyroidism had been achieved. Although twin II became euthyroid spontaneously, she gained weight only slowly and microcephaly developed together with definite motor and mental retardation. It remains unclear whether these were consequences of intrauterine hypothyroidism or post-partum hyperthyroidism. Conclusion Graves' disease during pregnancy demands interdisciplinary collaboration between gynaecologist, physician and paediatrician to prevent severe sequelae in the children. Early risk assessment is possible by measuring the TSH receptor antibody titre in umbilical blood.