Development of a pediatric differentiated thyroid carcinoma registry within the EuRRECa project: rationale and protocol.

Background: Although differentiated thyroid carcinoma (DTC) is the most frequent endocrine pediatric cancer, it is rare in childhood and adolescence. While tumor persistence and recurrence are not uncommon, mortality remains extremely low. Complications of treatment are however reported in up to 48% of the survivors. Due to the rarity of the disease, current treatment guidelines are predominantly based on the results of small observational retrospective studies and extrapolations from results in adult patients. In order to develop more personalized treatment and follow-up strategies (aiming to reduce complication rates), there is an unmet need for uniform international prospective data collection and clinical trials. Methods and analysis: The European pediatric thyroid carcinoma registry aims to collect clinical data for all patients ≤18 years of age with a confirmed diagnosis of DTC who have been diagnosed, assessed, or treated at a participating site. This registry will be a component of the wider European Registries for Rare Endocrine Conditions project which has close links to Endo-ERN, the European Reference Network for Rare Endocrine Conditions. A multidisciplinary expert working group was formed to develop a minimal dataset comprising information regarding demographic data, diagnosis, treatment, and outcome. We constructed an umbrella-type registry, with a detailed basic dataset. In the future, this may provide the opportunity for research teams to integrate clinical research questions. Ethics and dissemination: Written informed consent will be obtained from all participants and/or their parents/guardians. Summaries and descriptive analyses of the registry will be disseminated via conference presentations and peer-reviewed publications.

[Update of the S2k guidelines : Surgical treatment of benign thyroid diseases]. / Aktualisierung der S2k-Leitlinie : Operative Therapie benigner Schilddrüsenerkrankungen.

Thyroid resections represent one of the most common operations with 76,140 interventions in the year 2016 in Germany (source Destatis). These are predominantly benign thyroid gland diseases. Recommendations for the operative treatment of benign thyroid diseases were last published by the CAEK in 2010 as S2k guidelines (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V. [AWMF] 003/002) against the background of increasingly more radical resection procedures. Hemithyroidectomy and thyroidectomy are routinely performed for benign thyroid disease in practice. The operation-specific risks show a clear increase with the extent of the resection. Therefore, weighing-up of the risk-indications ratio between unilateral lobectomy or thyroidectomy necessitates an independent evaluation of the indications for both sides. This principle in particular has been used to update the guidelines. In addition, the previously published recommendations of the CAEK for correct execution and consequences of intraoperative neuromonitoring were included into the guidelines, which in particular serve the aim to avoid bilateral recurrent laryngeal nerve paralysis. Moreover, the recommendations for the treatment of postoperative complications, such as hypoparathyroidism and postoperative infections were revised. The updated guidelines therefore represent the current state of the science as well as the resulting surgical practice.

[Monogenic and syndromic symptoms of morbid obesity. Rare but important]. / Monogene und syndromale Krankheitsbilder bei morbider Adipositas. Selten aber wichtig.

BACKGROUND: Monogenic and syndromic obesity are rare diseases with variable manifestation. Therefore diagnosis is difficult and often delayed. OBJECTIVES: The purpose of this work was to develop a clinical diagnostic algorithm for earlier diagnosis. MATERIAL AND METHODS: Available publications for clinical symptoms and molecular defects of monogenic and syndromic obesity cases were evaluated. RESULTS: Monogenic and syndromic obesity can be expected in cases with early manifestation before the age of 5 years and a BMI above 40 or above the 99th percentile. Syndromic cases are mostly associated with a low IQ and dwarfism. Monogenic cases are associated with additional endocrine defects. Measurement of serum leptin proves the treatable leptin deficiency. Sequencing of the melanocortin-4 receptor gene (MC4R) allows diagnosis of the most frequent monogenic form of obesity. Treatment with a melanocyte-stimulating hormone (MSH) analog can be expected in the future. Early treatment of children with Prader-Willi syndrome can prevent severe obesity. CONCLUSION: Because in some cases treatment is available, monogenic and syndromic obesity should be diagnosed early. Based on the disease symptoms, serum leptin, and MC4R sequencing, a diagnostic algorithm is proposed, which can be used to diagnose cases of morbid obesity.

[Thyroid dysfunction in pregnancy]. / Schilddrüsenfunktionsstörungen in der Schwangerschaft.

Thyroid dysfunction may impair fertility, course of pregnancy and fetal development. Physiological alterations of thyroid function parameters, that occur during pregnancy need to be distinguished from pathophysiological states of hypo- and hyperthyroidism. We performed a literature search (PubMed 1990-2013) and review relevant publications as well as consensus and practice guidelines of international thyroid/endocrine societies. Interpretation of thyroid function values in pregnancy must be based on trimester-specific TSH and T4 ranges. Alterations in thyroid function are present in up to 15% of pregnancies (0.4% overt hypothyroidism, 0.1-0.4% hyperthyroidism) and may lead to preventable complications in the pregnant woman and the fetus. Hypothyroidism is associated with an increased risk for abortion, premature delivery and stillbirth, besides impairment of neurocognitive development. The latter has also been shown in situations of grave iodine deficiency. In addition to new-born screening directed at early recognition of congenital hypothyroidism (incidence 0.03%), universal screening of all pregnant women should be implemented in health care guidelines. Newly diagnosed overt hypothyroidism in a pregnant woman requires immediate levothyroxine substitution at adequate doses. In subclinical hypothyroidism thyroid hormone replacement should be considered. Iodine supplementation is strongly recommended in all pregnant and breast-feeding women. Pregnancy causes a number of, that need to be of thyroid dysfunction. Both hypothyroidism and thyrotoxicosis may impair the course of pregnancy and may negatively affect the fetus. In particular, maternal hypothyroidism may lead to irreparable and detrimental deficits in the neurocognitive development of the fetus. Autoimmune thyroid disease is the most common cause of thyroid dysfunction in pregnancy. Hashimoto's thyroiditis is associated with impaired fertility and miscarriage, and may first manifest in pregnancy due to the increased thyroid hormone requirement. Graves' disease often shows a characteristic course in pregnancy with amelioration of thyrotoxicosis in the second half of pregnancy and exacerbation after delivery. In addition transplacental passage of maternal TSH receptor antibodies may lead to thyrotoxicosis in the fetus and/or newborn.

European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism

"OBJECTIVE: The aim was to formulate practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). EVIDENCE: A systematic literature search was conducted to identify key articles relating to the screening, diagnosis, and management of CH. The evidence-based guidelines were developed with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, describing both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. CONSENSUS PROCESS: Thirty-two participants drawn from the European Society for Paediatric Endocrinology and five other major scientific societies in the field of pediatric endocrinology were allocated to working groups with assigned topics and specific questions. Each group searched the literature, evaluated the evidence, and developed a draft document. These papers were debated and finalized by each group before presentation to the full assembly for further discussion and agreement. RECOMMENDATIONS: The recommendations include: worldwide neonatal screening, approaches to assess the cause (including genotyping) and the severity of the disorder, the immediate initiation of appropriate L-T4 supplementation and frequent monitoring to ensure dose adjustments to keep thyroid hormone levels in the target ranges, a trial of treatment in patients suspected of transient CH, regular assessments of developmental and neurosensory functions, consulting health professionals as appropriate, and education about CH. The harmonization of diagnosis, management, and routine health surveillance would not only optimize patient outcomes, but should also facilitate epidemiological studies of the disorder. Individuals with CH require monitoring throughout their lives, particularly during early childhood and pregnancy."

European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism

"OBJECTIVE: The aim was to formulate practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). EVIDENCE: A systematic literature search was conducted to identify key articles relating to the screening, diagnosis, and management of CH. The evidence-based guidelines were developed with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, describing both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. CONSENSUS PROCESS: Thirty-two participants drawn from the European Society for Paediatric Endocrinology and five other major scientific societies in the field of pediatric endocrinology were allocated to working groups with assigned topics and specific questions. Each group searched the literature, evaluated the evidence, and developed a draft document. These papers were debated and finalized by each group before presentation to the full assembly for further discussion and agreement. RECOMMENDATIONS: The recommendations include: worldwide neonatal screening, approaches to assess the cause (including genotyping) and the severity of the disorder, the immediate initiation of appropriate L-T4 supplementation and frequent monitoring to ensure dose adjustments to keep thyroid hormone levels in the target ranges, a trial of treatment in patients suspected of transient CH, regular assessments of developmental and neurosensory functions, consulting health professionals as appropriate, and education about CH. The harmonization of diagnosis, management, and routine health surveillance would not only optimize patient outcomes, but should also facilitate epidemiological studies of the disorder. Individuals with CH require monitoring throughout their lives, particularly during early childhood and pregnancy."

Analysis of the Wilms' tumor suppressor gene (WT1) in patients 46,XY disorders of sex development.

CONTEXT: The Wilms' tumor suppressor gene (WT1) is one of the major regulators of early gonadal and kidney development. WT1 mutations have been identified in 46,XY disorders of sex development (DSD) with associated kidney disease and in few isolated forms of 46,XY DSD. OBJECTIVE: The objective of the study was the evaluation of WT1 mutations in different phenotypes of isolated 46,XY DSD and clinical consequences. DESIGN: The design of the study was: 1) sequencing of the WT1 gene in 210 patients with 46,XY DSD from the German DSD network, consisting of 150 males with severe hypospadias (70 without cryptorchidism, 80 with at least one cryptorchid testis), 10 males with vanishing testes syndrome, and 50 raised females with partial to complete 46,XY gonadal dysgenesis; and 2) genotype-phenotype correlation of our and all published patients with 46,XY DSD and WT1 mutations. RESULTS: We have detected WT1 mutations in six of 80 patients with severe hypospadias (7.5%) and at least one cryptorchid testis and in one of 10 patients with vanishing testes syndrome (10%). All patients except one developed Wilms' tumor and/or nephropathy in childhood or adolescence. CONCLUSION: WT1 analysis should be performed in newborns with complex hypospadias with at least one cryptorchid testis and in isolated 46,XY partial to complete gonadal dysgenesis. Kidney disease might not develop until later life in these cases. WT1 analysis is mandatory in all 46,XY DSD with associated kidney disease. WT1 analysis is not indicated in newborns with isolated hypospadias without cryptorchidism. Patients with WT1 mutations should be followed up closely because the risk of developing a Wilms' tumor, nephropathy, and/or gonadal tumor is very high.

Ethnicity and comorbidities in an overweight and obese multiethnic childhood cohort in Berlin.

AIM: This study aims to analyse the association between ethnicity, elevated metabolic parameters and metabolic syndrome (MS) in a multiethnic cohort of overweight to obese children and adolescents. METHODS: For 1053 patients, standard deviation of body mass index (BMI-SDS) was calculated and metabolic parameters (fasting blood glucose, fasting insulin, homeostasis model assessment-IR, lipids, blood pressure) were measured. MS was defined by WHO criteria. Bivariate and multivariate analyses were performed. Adjusted differences in BMI-SDS and metabolic parameters between different migration groups were assessed with linear regression models. The risk for MS was calculated with multiple logistic regression models. RESULTS: Forty-eight per cent of the children were German, 25% Turkish and 27% had another ethnicity. Concerning weight status, 23% are overweight, 31% obese and 46% extremely obese with higher rates among the immigrant population. Multivariable models indicate significant associations between elevated metabolic parameters and higher BMI-SDS values. Overall prevalence of MS was 32.3%. MS was detected significantly more often among Turkish patients (40.4%) compared to Germans (27.3%; p=0.02). Logistic regression analysis showed a greater risk for MS with older age (OR=1.09; p=0.003) and Turkish ethnicity (OR=1.62; p=0.02). CONCLUSION: Nearly all patients had symptoms of MS, and 40% had MS showing that this highly health-threatening condition is quite common. Therefore, effective therapy and prevention efforts must be developed for this high risk group. More migration-specific research regarding insulin resistance, MS and Type 2 DM is needed.

Screening chromosomal aberrations by array comparative genomic hybridization in 80 patients with congenital hypothyroidism and thyroid dysgenesis.

OBJECTIVE: Congenital hypothyroidism occurs in 1:3500 live births and is therefore the most common congenital endocrine disorder. A spectrum of defective thyroid morphology, termed thyroid dysgenesis (TD), represents 80% of permanent congenital hypothyroidism cases. Although several candidate genes have been implicated in thyroid development, comprehensive screens failed to detect mutation carriers in a significant number of patients with nonsyndromic TD. Due to the sporadic occurrence of TD, de novo chromosomal rearrangements are conceivably representing one of the molecular mechanisms participating in its etiology. METHODS: The introduction of array comparative genomic hybridization (CGH) has provided the ability to map DNA copy number variations (CNVs) genome wide with high resolution. We performed an array CGH screen of 80 TD patients to determine the role of CNVs in the etiology of the disease. RESULTS: We identified novel CNVs that have not been described as frequent variations in the healthy population in 8.75% of all patients. These CNVs exclusively affected patients with athyreosis or thyroid hypoplasia and were nonrecurrent, and the regions flanking the CNVs were not enriched for segmental duplications. CONCLUSIONS: The high rate of chromosomal changes in TD argues for an involvement of CNVs in the etiology of this disease. Yet the lack of recurrent aberrations suggests that the genetic causes of TD are heterogenous and not restricted to specific genomic hot spots. Thus, future studies may have to shift the focus from singling out specific genes to the identification of deregulated pathways as the underlying cause of the disease.

No correlation between androgen receptor CAG and GGN repeat length and the degree of genital virilization in females with 21-hydroxylase deficiency.

CONTEXT: In 21-hydroxylase (CYP21A2) deficiency (21OHD), the level of in vitro enzymatic function allows for classification of mutation groups (null, A, B, C) and prediction of disease severity. However, genital virilization in affected females correlates only weakly with CYP21A2 mutation groups, suggesting the influence of genetic modifiers. OBJECTIVE: The objective of the study was to investigate the influence of the polymorphic CAG and GGn repeats of the androgen receptor (AR) gene on the degree of genital virilization in 21OHD females. DESIGN AND PATIENTS: Design of the study was the determination of CYP21A2 genotype, degree of genital virilization (Prader stage), and X-weighted biallelic mean of AR CAG and GGn repeat length in 205 females with 21OHD. OUTCOME MEASUREMENTS: Correlation of AR CAG and GGn repeat lengths with Prader stages using nested stepwise logistic regression analysis was measured. RESULTS: CYP21A2 mutation groups null and A showed significantly higher levels of genital virilization than groups B and C (P < 0.01). However, Prader stages varied considerably within mutation groups: null, Prader I-V (median IV); A, Prader I-V (median IV); B, Prader I-V (median III); C, 0-III (median I). Mean GGn repeat length of patients was not significantly associated with Prader stages, classified as low (0-I), intermediate (II-III), or severe (IV-V) (odds ratio per repeat: 0.98, 95% confidence interval 0.71-1.35). In contrast, patients with Prader 0-I showed a trend toward longer CAG repeats without reaching statistical significance (P = 0.07, odds ratio per repeat: 0.82, 95% confidence interval 0.65-1.02). CONCLUSION: Neither CAG nor GGn repeat lengths are statistically significant modifiers of genital virilization in females with 21OHD.

Two puzzling cases of thyroid dysgenesis.

BACKGROUND: In the last couple of years, different genes that play major roles in embryonic thyroid development have been identified. Several mutations, e.g., NKX2.1, FOXE1 and PAX8, were identified in patients with congenital hypothyroidism due to thyroid dysgenesis. However, the pathophysiology of most cases of thyroid dysgenesis remains unknown. Due to the sporadic occurrence and discordance observed in monozygotic twins, a classic genetic hypothesis for thyroid dysgenesis is improbable. CASE REPORT: We present two pairs of monozygotic twins discordant for thyroid dysgenesis that exemplify these conceptual difficulties. CONCLUSIONS: Identification of the epigenetic differences observed in monozygotic twins discordant for thyroid dysgenesis may be crucial in discovering the pathogenesis of thyroid dysgenesis.

Is there a further acceleration in the age at onset of menarche? A cross-sectional study in 1840 school children focusing on age and bodyweight at the onset of menarche.

OBJECTIVE: More 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. DESIGN: A 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. METHODS: Median 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. RESULTS: Nine 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). CONCLUSIONS: Age 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.

Impaired glucose tolerance and type 2 diabetes mellitus: a new field for pediatrics in Europe.

OBJECTIVE: Several studies have shown that obese children and adolescence seem to have an increased risk to develop a disturbed glucose metabolism as already known for obese adults. This might result in the same disastrous outcomes of cardiovascular diseases as it has been shown for adult obese patients. The most sensitive measurement for detecting changes in glucose metabolism in obese children seems to be an oral glucose tolerance test (OGGT) which is not practical for all daily outpatient clinics. DESIGN: Cross-sectional study. SUBJECTS AND MEASUREMENTS: We therefore made a preselection from a cohort of 491 subjects according to the American Diabetes Association (ADA) criteria for the diagnosis of diabetes. In the selected high-risk subgroup (n = 102) of obese pediatric subjects, we measured the prevalence of impaired glucose tolerance (IGT) by OGTT. RESULTS: We diagnosed six patients with type 2 diabetes and 37 patients with impaired glucose tolerance. In addition, we found a close correlation of IGT to disturbances of triglyceride and cholesterol parameters. This prevalence was comparable to a similar study group that was screened without preselection. CONCLUSIONS: These prevalence data further underline the need to diagnose children with obesity-associated risk factors in terms of an insulin resistance syndrome. The preselection of a high-risk subgroup by ADA criteria might be a practical approach.

[Who needs what? New approaches to multidisciplinary diagnostics and therapy for adipose children and youths in a multiethnic city]. / Wer braucht was? Neue Ansätze der multidisziplinären Diagnostik und Therapie adipöser Kinder und Jugendlicher in einer multiethnischen Grossstadt.

Over the past two decades, obesity in children has been increasing worldwide, leading to serious complications. The treatment for childhood obesity remains largely ineffective; therefore preventive measures are crucial. The prevalence of obesity depends on the BMI-percentiles used. Recent BMI-percentiles may underestimate the problem. Currently, the only representative cross-sectional BMI-data are obtained at the school entry examination. These data reveal certain risk groups (migrants, low socioeconomic status). More representative longitudinal data are needed to study the progression of obesity during childhood. Our obesity clinic provides multidisciplinary therapy programs (group or individual) and is also focused on the diagnosis and treatment of comorbidity, especially of the metabolic syndrome. Almost 60% of our severely obese patients are already affected. The molecular diagnosis of rare monogenetic or syndromal forms of obesity may be helpful in providing additional support for these patients. In general, most obesity programs are successful only in families without severe psychosocial problems and with motivation for lifestyle changes. This can be expected in only 3% of our families. Therefore, a substantial societal effort is needed to facilitate prevention for all children, and effective therapies have to be tailored depending on biological and psychosocial risk factors.

The use of L-T4 as liquid solution improves the practicability and individualized dosage in newborns and infants with congenital hypothyroidism.

UNLABELLED: Dosage recommendations for the initial therapy of congenital hypothyroidism (CH) in newborns vary between 8 microg/kg/d and 10-15 microg/kg/d. AIM: To evaluate the practicability of LT4 in liquid form and to define the initial dosage for optimal treatment. METHODS: Liquid LT4 solution was administered to 28 consecutive newborns with primary CH. We measured TSH, T3, T4, free T3 and free T4 before therapy and during follow-up up to 2 years. After 2 years a standardized developmental test (Griffith) was performed. RESULTS: The median dosage at start of therapy was 12.3 microg LT4/kg/d and decreased to about 5 microg LT4/kg/d after 9 months. The median time of normalization of TSH (< or =6 mU/l) was 2 weeks. In 21 patients, who received a median starting dosage of 12.7 microg LT4/kg (range 9.8-17.1 microg/kg), TSH levels normalized within a median of 1 week. Seven patients receiving only 10.1 microg LT4/kg normalized their TSH only after a median of 2 months. CONCLUSIONS: Newborns with CH should normalize their TSH within 1-2 weeks. The initial dose necessary to normalize TSH is not lower when a liquid solution is used. The higher dose used in tablets is not due to inefficient absorption, but rather reflects the increased demand for thyroid hormone in the first weeks of life.

[Hypothyroidism in dizygotic premature twins due to excessive prepartal vaginal iodine application]. / Hypothyreose bei zweieiigen frühgeborenen Zwillingen durch exzessive präpartale vaginale Jodapplikation an die Mutter.

In dizygotic premature twins delivered by Caesarean section after prolonged efforts to effect premature birth we found markedly enhanced thyroid stimulating hormone levels. The mother had been subjected to local polyvidone iodine therapy for seven weeks with PVP suppositories to prevent vaginal infections. Control checks revealed persistently elevated TSH levels, whereas T3/T4 levels were always reduced. Greatly pronounced iodine excretion was seen in the urine of both the babies. This raised the suspicion of iodine-induced hypothyroidism in both children. Substitution with 1-thyroxine was initiated and a withdrawal trial performed after 12 weeks. The patients remained euthyroid after the treatment had been discontinued. Due to possible transfer of iodide to the fetus associated with the risk of iodine-induced hypothyroidism, it is recommended to abstain from vaginal application of iodine during pregnancy.

[Gene, fast food and no motion. Causes of childhood obesity]. / Gene, Fast Food und No Motion. Ursachen der kindlichen Adipositas.

Obesity in children and adolescents should be seen as a chronic disorder and not merely as a biological variant. One aspect of the pathological significance of obesity in childhood and adolescence is determined by functional and individual limitation and psychosocial impairment. Another is the fact that these children and adolescents have a higher comorbidity, and appreciably increased morbidity and mortality rates in adulthood. The major causes of the condition are lifestyle related, in particular excessive intake of energy- and fat-rich foods together with increasingly inadequate exercise. In addition, however, there also appears to be a genetic predisposition that manifests as early and massive obesity in young years. Considerable importance attaches to the recording of height and weight development during regular examinations in the doctor's office. In addition, in particular the children of overweight parents, together with their families, should be instructed and advised on the need for a healthy and appropriate diet and regular exercise. In the case of extremely overweight children, a genetic investigation would be worthwhile.

Constitutively activating TSH-receptor mutations as a molecular cause of non-autoimmune hyperthyroidism in childhood.

BACKGROUND: The glycoprotein hormone TSH (thyroid-stimulating hormone) and its receptor, the TSH-receptor (TSHR), play a crucial role in thyroid growth and function. Constitutively activating germline mutations within the TSHR gene were identified in patients with sporadic or familial non-autoimmune hyperthyroidism. Inheritance of these mutations is autosomal dominant. PATIENTS AND METHODS: We investigated two patients with neonatal onset of non-autoimmune hyperthyroidism and two families in whom the child and one parent are affected. RESULTS: Hyperthyroidism was difficult to treat in all of these patients and was complicated by premature craniosynostosis. Sequencing of all exons of the TSHR gene in one family with hyperthyroidism revealed a mutation in exon 10 (T6321), which was first identified in toxic adenomas and found to constitutively activate the TSHR. In the other family, we identified a new mutation in the first membrane spanning segment (G431S). In both patients with sporadic hyperthyroidism, a heterozygous mutation in exon 9 (S281N) was detected. The functional characterization of S281N and G431S demonstrated that both mutants were constitutively active. Therefore, these mutations are the molecular cause of non-autoimmune hyperthyroidism in the patients. CONCLUSIONS: For patients suffering from non-autoimmune hyperthyroidism, screening for mutations and their functional characterization is recommended. In case of an ineffective hyperthyroidism treatment, thyroidectomy should be performed to prevent lengthy anti-thyroid drug treatment and complications like premature craniosynostosis.

Molecular pathogenesis of neonatal hypothyroidism.

In patients with congenital hypothyroidism (CH), the autosomal recessive inheritance of mutations of thyroid peroxidase, thyroglobulin and the NIS and pendrin genes encoding for sodium iodide transporters has been identified. CH due to thyroid dysgenesis was considered to be a sporadic disease, but recently, inheritable defects of thyroid development have been described. The autosomal recessive inheritance of mutations of the thyroid-stimulating hormone receptor gene was recognized in patients with CH and thyroid hypoplasia, while autosomal dominant mutations of the Pax-8 gene were described in patients with thyroid dysgenesis. In addition, analysis of mutations of the beta-thyrotropin gene has resulted in a new understanding of the pathogenesis of central CH. Molecular genetic studies in patients with CH detected by newborn screening will provide the information necessary for genetic counselling and may help to explain the less favourable outcome present in 5-10% of the patients.