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Die kongenitale Hypothyreose ist die h��ufigste angeborene endokrinologische Erkrankung. Die vorwiegende Ursache der CH ist eine strukturelle St��rung der Schilddr��senentwicklung, die Schilddr��sendysgenesie. In nur 5 % der F��lle einer Schilddr��sendysgenesie ist die genetische Ursache bekannt. Das NKX2-1-Gen ist unter anderem an der Schilddr��senentwicklung beteiligt, und mutationsbedingte St��rungen k��nnen Ursache der Schilddr��sendysgenesie sein. Es konnte gezeigt werden, dass Deletionen in einem nicht-kodierenden Bereich downstream von NKX2-1 zu einem NKX2-1 defizienten Ph��notyp f��hren. Auf dieser Grundlage wurde eine schilddr��senspezifische Enhancerfunktion in diesem nicht-kodierenden Bereich vermutet, deren genetische oder epigenetische St��rung Ursache der isolierten Schilddr��sendysgenesie sein k��nnte. F��r die Analyse der potenziellen Enhancer Region wurde eine der gr����ten Kohorten an Patienten mit Schilddr��sendysgenesie sowie sechs f��r die Schilddr��sendysgenesie diskordante monozygote Zwillingspaare verwendet. Zur vergleichenden Einordung wurden gesunde Kontrollen, Patienten mit Hyperthyreotropin��mie sowie Schilddr��sengewebe gesunder Personen in die Analyse mit einbezogen. In der genetischen Analyse konnte nur in Patienten mit isolierter Schilddr��sendysgenesie ein neuer Single Nucleotide Variant (SNV), sowie heterozygot seltene SNPs gefunden werden. Die epigenetische Methylierungsanalyse der potentiellen Enhancer Region (PER) zeigte eine gewebespezifische Hypomethylierung im Schilddr��sengewebe, die ein Hinweis f��r die postulierte schilddr��senspezifische regulative Funktion ist. Der Methylierungsvergleich der Kohorten im Blut ergab eine geringe signifikante Hypermethylierung der Patienten mit isolierter Schilddr��sendysgenesie, die sich in den diskordanten monozygoten Zwillingen nicht oder kaum reproduzieren lie��. Geschlechtsspezifisch zeigte sich eine signifikante Hypermethylierung der Frauen mit isolierter Schilddr��sendysgenesie, was mit der M��dchenwendigkeit der CH in Zusammenhang stehen k��nnte. Sowohl das Ergebnis der gewebespezifischen Hypomethylierung des Schilddr��sengewebes als auch die Hypermethylierung der Patienten mit isolierter Schilddr��sendysgenesie sind mit gewebespezifischer regulativer Funktion im Sinne eines schilddr��senspezifischen Enhancers vereinbar. Zur weiteren Einordnung und Interpretation der Daten ist eine Reproduktion der Ergebnisse in gr����eren und homogeneren Kohorten dringend erforderlich. Zusammenfassend zeigten sich sowohl in der genetischen Analyse als auch in der epigenetischen Methylierungsanalyse Hinweise f��r eine m��gliche Beteiligung der potentiellen Enhancer Region an der Pathogenese der Schilddr��sendysgenesie., Congenital hypothyroidism is the most frequent endocrine disorder in neonates.The most common cause is thyroid dysgenesis (TD), a structural disorder of thyroid development. Only in 5% of cases of TD, the genetic cause is known. The NKX2-1 gene is involved in thyroid development, and its mutation can cause TD. It could be shown that deletions in a non-coding region downstream of NKX2-1 cause an NKX2-1 deficient phenotype. On this basis, a thyroid-specific enhancer in this non-coding region was suspected, whose genetic or epigenetic disorder could cause isolated thyroid dysgenesis (ITD). To analyze this non-coding region downstream of NKX2-1, one of the largest cohorts of patients with ITD and six pairs of monozygotic twins that are discordant for ITD were used. To classify and interpret the results one cohort of patients with hyperthyrotropinaemia, one cohort with healthy controls and thyroid tissue of healthy controls were analyzed. In the genetic analysis, a new single nucleotide variant (SNV) an heterozygous rare SNPs were found only in patients with ITD. The epigenetic methylation analysis revealed tissue-specific hypomethylation of the non-coding region downstream of NKX2-1 in thyroid tissue, which is an indication of the postulated thyroid-specific regulatory function. The methylation comparison of the cohorts and the pairs of monozygotic twins revealed a small statistically significant hypermethylation in patients with ITD. This hypermethylation was hardly reproducable with monozygotic twins. A gender-specific analysis revealed statistically significant hypermethylation in women with ITD. This finding could be related to the girlish nature of the disease. Both the result of tissue-specific hypomethylation of thyroid tissue and the hypermethylation of patients with ITD are compatible with a tissue-specific regulatory function. A reproduction of of the results with larger and more homogenous cohorts is required for further evaluation and interpretation. In summary, both the genetic analysis and the epigenetic methylation analysis provided indications for a potential relevance of the analyzed non-coding region downstream of NKX2-1 for ITD.

Ziel: Das Ziel dieser Arbeit besteht darin, herauszufinden, ob ein Goldstandard bei der Detektion der Hypothyreose im Kindesalter vorliegt. Weiter sollen die zur Verfügung stehenden unterschiedlichen Untersuchungsmethoden sowie die Bedeutung der Schilddrüsenszintigraphie dargestellt werden. Methode: Zur Beantwortung der Forschungsfragen wurde eine ausführliche Literaturrecherche zu den Themen „Hypothyreose“, „Neugeborenen-Screening“, „Schilddrüsenszintigraphie im Kindesalter“, „Ultraschalluntersuchung“ und „Blutuntersuchung“ durchgeführt. Die Studien wurden von den wissenschaftlichen Datenbanken PubMed, SpringerLink und von der Bibliothek der Universität Wien bezogen. Weiter wurden zur Ergänzung der Literaturrecherche und Beantwortung der dritten Forschungsfrage vier Experteninterviews mit Nuklearmedizinern und in der pädiatrischen Endokrinologie tätigen Ärzt*innen durchgeführt. Ergebnisse: Das Neugeborenen-Screening zeigte sich als effektive Untersuchungsmethode zur Früherkennung einer kongenitalen Hypothyreose. Jedoch wurde von übersehenen Fällen berichtet, weshalb das Neugeborenen-Screening nicht als alleinige Untersuchung zur Bestätigung einer kongenitalen Hypothyreose ausreicht. Seit Einführung des Ultraschalls hat die Schilddrüsenszintigraphie deutlich an Bedeutung verloren. Jedoch wäre es sinnvoll, im Fall einer Schilddrüsenektopie das ektope Schilddrüsengewebe mittels Szintigraphie zu detektieren, um mögliche Neubildungen und Neoplasien rechtzeitig erkennen zu können. Diskussion: Um die Hypothyreose im Kindesalter zu diagnostizieren, werden in erster Linie strahlenfreie Untersuchungsmethoden wie Blut- und Ultraschalluntersuchungen angewendet. Dabei empfiehlt sich eine Kombination aus Ultraschall- und Blutuntersuchung, um aussagekräftige Ergebnisse zu bekommen. Der einzige Grund für eine Szintigraphie ist die Darstellung ektoper Schilddrüsengewebsanteile, die meistens auch mit Hilfe des Ultraschalls gut zu detektieren sind. Jedoch sind einige anatomische Besonderheiten nur mittels Szintigraphie zu lokalisieren. Aim: The aim of this study is to find out whether there is a gold standard for the detection of hypothyroidism in childhood. Furthermore, the available different examination methods and the importance of thyroid scintigraphy are to be presented and will be discussed. Method: To answer the research questions an extensive literature search was conducted on the topics of "hypothyroidism", "newborn screening", "thyroid scintigraphy in childhood", "ultrasound examination" and "blood examination". The studies were obtained from the scientific databases PubMed, SpringerLink and from the library of the University of Vienna. Furthermore to complement the literature review and answer the third research question four expert interviews were conducted with nuclear medicine doctors and doctors working in pediatric endocrinology. Results: Newborn screening was shown to be an effective investigation method for the early detection of congenital hypothyroidism, but overlooked cases have been reported, making newborn screening insufficient as a sole investigation to confirm congenital hypothyroidism. Since the introduction of ultrasound thyroid scintigraphy has lost it importance, but it would be useful to detect the ectopic thyroid tissue by scintigraphy in case of thyroid ectopy to detect possible neoplasms in time. Discussion: To diagnose hypothyroidism in childhood primarily examination methods are used - blood and ultrasound examinations - which can confirm the diagnosis of hypothyroidism without ionizing radiation. It is recommended that a combination of ultrasound and blood tests be performed to obtain conclusive results. The only reason to perform a scintigraphy is ectopic thyroid tissue, which can also be detected well with the help of ultrasound. But there are anatomical features that should be localized by scintigraphy.

Die primäre kongenitale Hypothyreose ist die häufigste angeborene endokrine Störung. Sie tritt weltweit mit einer Inzidenz von 1:4000 – 1:3000 auf. Die häufigste Ursache ist ein Entwicklungsdefekt der Schilddrüse, die sogenannte Schilddrüsendysgenesie. Genetische Ursachen für diese Erkrankung wurden bei weniger als 5% der Betroffenen gefunden. In der Regel sind von Schilddrüsendysgenesie betroffene monozygote Zwillinge hinsichtlich der Erkrankung diskordant. Da dies gegen eine klassische Mendelsche Vererbung spricht, wird angenommen, dass die Schilddrüsendysgenesie durch epigenetische Defekte verursacht wird. 2015 wurde erstmals eine kongenitale Hypothyreose mit den zu den epigenetischen Defekten gehörenden DNA-Methylierungsdefekten auf dem GNAS-Genlokus in Verbindung gebracht. GNAS codiert für die Gsα-Untereinheit des G-Proteins. G-Protein gekoppelte Rezeptoren vermitteln die Aktion zahlreicher Hormone, unter anderem die des Thyroidea-stimulierenden Hormons (TSH). Es wird angenommen, dass ein epigenetischer Defekt auf dem GNAS-Gen zu einer Fehlfunktion des TSH-Rezeptors und somit zu einer defekten Schilddrüsenentwicklung führt. Es wurden zwei Fragmente des GNAS-Genlokus zur Untersuchung ausgewählt. Das erste Fragment liegt in einer Region, in der bereits DNA-Methylierungen mit TSH-Resistenz in Verbindung gebracht werden konnten. Das zweite Fragment befindet sich in der Exon 1-Promoterregion des GNAS-Gens. Die dort lokalisierten DNA-Methylierungen wurden anschließend mittels Pyrosequenzierung bisulfitumgewandelter DNA von diskordanten monozygoten Zwillingen mit Schilddrüsendysgenesie analysiert. Eines der beiden Fragmente zeigte geringe DNA-Methylierungsdifferenzen zwischen den erkrankten und gesunden Zwillingen. Es ist unwahrscheinlich, dass diese Differenzen eine Ursache für die Erkrankung darstellen. Es werden jedoch weitere Studien benötigt, um herauszufinden, ob Methylierungsänderungen in GNAS eine Ursache für die Erkrankung sein könnten oder eher andere Mechanismen Einfluss darauf üben., The congenital hypothyroidism is the most common neonatal endocrine disorder with an incidence of 1:4000 – 1:3000 worldwide. The disease is primarly caused by a developmental defect called thyroid dysgenesis (TD). Genetic causes are known in less than 5% of patients with TD. In general monozygotic twins with the disorder have been reported as discordant. Therefore it is suggested that TD does not result from Mendelian inheritance but epigenetic defects. In 2015 a first epigenetic defect, a DNA-methylation defect, was found in the GNAS gene in a patient with congenital hypothyroidism. GNAS is encoding for the Gsα-subunit of the G-protein. G-protein linked mechanisms mediate the action of a number of hormones, including TSH (thyroid-stimulating hormone). It is supposed that an epigenetic defect in GNAS leads to a dysfunction of the TSH-receptor and therefore to a disrupted thyroid development. Two fragments of the GNAS locus were chosen to be analyzed. The first fragment is located in a region that is already known for DNA methylation defects in correlation to TSH resistance. The second fragment is located in the exon 1 promoter region of the GNAS-gene. DNA-methylation was analyzed by pyrosequencing of bisulfite treated DNA of discordant monozygotic twins with TD. One of the two fragments showed little DNA-methylation differences between the affected and the healthy twins. Although it is unlikely that this difference could be a cause for TD, further studies are needed to find out wether DNA-methylation defects in GNAS are a cause of the disease or other mechanisms are more relevant.

Severe iodine deficiency during pregnancy seriously influences fetal brain development and in the worst case induces cretinism. Recent studies have shown that even a mild iodine deficiency during pregnancy and during the first years of life adversely affects brain development. The World Health Organisation (WHO) considers iodine deficiency as the most common preventable cause of early childhood mental deficiency. In this context, the insufficient production of the four iodine atoms containing thyroxine seems to play a causal role, i. e., due to the iodine substrate deficiency the neuronally particularly relevant free-thyroxine level falls. Due to the very limited iodine storage capacity, the infantile thyroid is eminently dependent on an adequate and steady iodine supply. In the first month of life, when milk is the only energy- and nutrient provider, infants fed a commercial formula regularly have a sufficient iodine supply. However, breastfed infants, who depend on maternal iodine status, frequently show an inadequate iodine intake. Furthermore, iodine intake is critical when complementary food (CF) is introduced. Especially homemade CF is poor in iodine, but also commercial CFs are only partly fortified. A simultaneous inadequate iodine supply of the breastfeeding mother and the preferential use of mostly iodine-poor organic milk cannot ensure an adequate iodine supply of the infant. In terms of an improvement of nutrient supply, especially concerning an unhindered brain development, the corresponding German reference value for iodine intake of infants until age 4 month should be raised from currently 40 microg/d to at least 60 microg/d (WHO-reference: 90 microg/d).

Since widespread screenings for hypothyreosis were started in 1981 in Germany, the numbers of mental and physical handicaps due to hypothyroidism are reduced markedly. The aim of this study is to evaluate the actual efficiency of the newborn screenings in Germany using in the federal state "Hessen".All children born between 1988 and 1992 with suspicions laboratory results in the screening examination were contacted personally and statements concerning the screening itself and the physical and mental development were gathered from their parents, doctors and teachers.99.1% of all hessian newborns born between 1988 and 1992 were included into the screening for hypothyreosis. The incidence of congenital hypothyreosis in general was 1:3 313. An etiological classification was possible in 77% of the patients which is divided as follows: 40% athyreosis, 24% hypoplasia of the thyroid, 8% dyshormonogenesis, 5% ektopia of the thyroid. In 67% of the cases hormone substitution was initiated during the first 14 days of life. In 23.9% it was started in the third week, in 6.8% in the fourth week and only in 2.3% of the patients treatment was started later on. The physical development of the children with congenital hypothyreosis can be regarded as widely normal. The school achievement was moderately retarded even when treatment was started in the early neonatal period.The screening for hypothyreosis is well established in Hessen concerning tracking, organisation and analysis. There are short comings concerning the follow ups of children with suspicions findings, which shall be overcome by creating a new position. The long-term-follow-up according to the guidelines of the "Arbeitsgemeinschaft Pädiatrische Endokrinologie" is of central interest. Furthermore compliance is improved by regular personal counselling with the parents.

The aim of neonatal screening programs for congenital hypothyroidism is to ensure early treatment in order to prevent brain dysfunction. There are several reasons why infants are missed in the screening program. We report on three patients with congenital hypothyroidism, who had a pathological screening result and initiation of therapy was delayed. The first patient had an increased TSH level, but she was missed because of mistakes in the confirmatory serum test. During the follow-up the patient showed typical symptoms of hypothyroidism and got a thyroxine supplementation not before the age of three years. The second patient did not get a therapy before the age of six months because of the noncompliance of the parents and physicians. The third patient had a central hypothyroidism. The neonatal screening-program revealed no measurable TSH activity. Although the child had clinical signs of a severe hypothyroidism diagnosis was not made before the age of 5.5 months. Although different reasons are known for screening errors, all these 3 patients were missed because of failures in the follow-up of a pathological screening result, indicating a poor quality in the follow-up procedure.

Thirty eight children suffering from congenital primary permanent hypothyroidism were studied to determine the diagnostic impact of 123I scintigraphy in comparison to laboratory findings and ultrasonography.In all patients 123I scintigraphy was performed after intravenous administration of 3.7 MBq 123I. If accumulation of the radiotracer in thyroid tissue occurred a perchlorate discharge test was performed subsequently.Scintigraphy revealed athyrosis in 7 children. In 9 children a lingual thyroid was observed. Deficiency in iodine organification was diagnosed by a significant discharge of 123I in 15 patients. In four of these children the diagnosis of Pendred's syndrome could be established. Ectopic thyroid tissue could be demonstrated only by scintigraphy where clinical examination and sonography failed in the diagnosis in all cases. Hypoplasia of the thyroid gland as it was diagnosed in 2 cases by ultrasonography appeared to be unlikely because a normal 123I uptake was seen in these patients. In 2 patients with scintigraphic proven athyrosis an orthotopic gland had been falsely considered by ultrasound. In 44% of our patients the final diagnosis could only be established if 123I scintigraphy and perchlorate discharge test were performed.This findings suggest that scintigraphy is indispensible in the correct diagnostic work up of congenital hypothyroidism.

In Austria, neonatal screening for congenital hypothyreosis has been introduced since 1976 as a part of the national screening program for inborn errors of metabolism. Capillary blood spots are collected on filter paper from all newborns on day 3 to 5 and are subsequently investigated with a delayed fluorescence-immunoassay (DELFIA) for the determination of TSH. Since 1992 we have detected 105 patients with congenital hypothyreosis among 365,120 newborns. The recall rate of the primary TSH screening is about 0.35%. Only primary (thyroidal) hypothyreosis, but not secondary and tertiary (pituitary and hypothalamic) types of hypothyreosis are detected by the primary TSH newborn screening. As TSH is physiologically high during the first 2 days of life, the trend to early hospital discharge will result in a significant increase of the recall rate in future.

A 56 year old mentally disabled woman of short stature was admitted to our hospital because of severe chest pain and dyspnoea. An extended myocardial infarction in the anterior wall was clinically found and confirmed by autopsy. On admission cretinism with massive myxedema was diagnosed, which was confirmed by subsequent laboratory findings. Only at the base of the tongue thyroid tissue 3 mm in diameter was found. In the anterior lobe of the pituitary gland areas with nodular hyperplasia and microadenomas of TSH-producing cells were detected. Thyrotroph adenomas in long standing hypothyroidism are rare. There are only few reports on congenital hypothyroidism as primary underlying disease.

69 children with congenital hypothyroidism, who were detected by neonatal screening in Lower Saxony, were reevaluated 1-12 years after diagnosis. They had been treated either by regional children's hospitals, local pediatricians or general practitioners. Substitution of thyroid hormone had started for the majority between day 7 and 14, for 17%, however, only later. Symptoms suggestive of hypothyroidism at birth were observed in 35 children, but only 3 cases were correctly diagnosed before the result of the screening was known. Further diagnostic tests to elucidate the cause of congenital hypothyroidism had been performed in 33 children. In 36 cases the etiology remained undiagnosed at the evaluation. Hormone therapy had been administered continuously in all cases. The somatic development of all children was normal. Bone age at the time of diagnosis was retarded in more than 50%, later it became normal in most cases. The psychomotor and intellectual development was satisfactory as assessed by psychometric tests. The mean value of the Intelligence Quotients in the children older than six years was 96.3. 5 children of this age group had an IQ below 85 and only one child had an IQ of more than 115. In the younger group the results were similar, but children younger than 4 years showed deficiencies in speech development. In summary, the somatic development of the re-examined children with congenital hypothyroidism was normal, but the psychomotor and intellectual development was only subnormal in some cases. It is therefore suggested that children with congenital hypothyroidism should be closely followed by experienced pediatricians, especially in the early years of life.

The development of neonatal screening for congenital hypothyroidism in the GDR and particularly in Saxony after German reunification is described in this paper. The results of the studies and the experiences in respect of realisation and organisation of the screening for hypothyroidism in the screening centre of Leipzig are discussed. Measurement of TSH in the blood spot of about 65,000 newborn yielded an incidence rate of congenital hypothyroidism of 1:3,200. The onset of therapy within the first three weeks of life has been ensured until now since no children with congenital hypothyroidism were involved in cases of occasionally delayed blood sampling and/or postal delay. However, there has been some organisational disparity due to individually different handling of health insurance fund payments of screening fees for hypothyroidism in Saxony and also in the other federal states. The disadvantages of this lack of uniform regulations are explained. Neonatal screening for evidence of congenital adrenal hyperplasia by determining 17-alpha-hydroxyprogesterone, is under preparation.

The intellectual development of 105 children with congenital hypothyroidism was assessed. In 70 children the assessment was repeated in several times. Correlations between development of intelligence and influence of biological and/or psychosocial risks were verified.

57 children with congenital, clinical diagnosed hypothyroidism were assessed with the Luria-Nebraska-Neuropsychological Battery-Children's Revision. The results of the psychomotor assessment were in conformity with the mental development. Univariate correlations between begin of therapy and mental development were not found in all groups.

Salt with 3.75 mg iodide per kg was introduced in Switzerland stepwise in the individual cantons between 1922 and 1952. The iodide content was raised to 7.5 mg in 1962 and to 15 mg per kg in 1980. 92% of retail salt and 78% of all salt for human consumption (including salt used in industrial food processing) was iodized in 1989. Under this measure, prevalence of grade 1b or larger goiter dropped continuously to a present value of 1.3% in school-children and 0.3% in male army recruits. Endemic cretinism has disappeared completely. Urinary iodine has reached the desired range of 150 +/- 77 (SD) micrograms per g creatinine. The following facts prove that iodization of salt (and not other changes of food habits) have corrected the iodine deficiency in Switzerland: 1. Urinary iodine is highly correlated with urinary sodium. Backward extrapolation yields a theoretical urinary iodine of 30 micrograms per g creatinine in the absence of iodized salt, a value typical of severe deficiency. 2. Goiter prevalence declined later in those cantons which introduced iodized salt last. 3. Surrounding countries without iodized salt (France, Italy, Federal Republic of Germany, Spain) suffer from considerable iodine deficiency with areas of high goiter prevalence and even endemic cretinism. The new data underscore the absolute and continued need for iodized salt in Switzerland.

6 cases of the primary empty sella syndrome, 5 boys and 1 girl aged from 1 to 22 years, are being treated. The patients became suspicious due to a deficiency of pituitary hormones, whereby a lack of growth hormone was most common. 5 patients were short of growth; in provocative tests all 6 children showed either a partial or a complete deficiency of growth hormone. 2 patients had secondary hypothyroidism, 2 hypogonadotropic hypogonadism. Sceletal maturation was retarded between 2/12 and 4 4/12 years in all cases. All patients underwent a skull roentgenogram. An enlargement of the sella turcica was found in the case of one boy only. The findings of the other 5 children were inconspicious. For all patients the diagnosis was testified by a cranial computer-tomography.

As far back as 1898 the Austrian Nobel price winner Wagner von Jauregg was the first to recommend iodination of salt as prophylaxis against endemic goitre (prevalence 48%) and cretinism (greater than 10%). In 1923 he achieved in a voluntary iodine supplementation of 5 mg KJ/kg table salt, which only lasted for a number of years. It was in 1963 when finally a mandatory iodized salt prophylaxis was introduced at the rate of 10 mg KJ/kg. In this study the effect of 25 years of iodine supplementation is investigated: Endemic cretinism, hypothyroidism, and goitre in newborns disappeared generally and endemic goitre in pupils was significantly reduced. However, due to epidemiological studies at elementary and secondary schools and army recruitment examinations we still found out endemic goitre grade I (according to WHO) mainly in female juveniles. Examinations were done by palpation, ultrasonography and urinary iodine excretion. In the above as well as in the urine of newborns and in mother's milk the iodine content was significantly lower than in iodine rich countries. Consequently a higher iodination of salt at the rate of 20 mg KJ/kg was recommended by the Austrian Society of Nuclear Medicine in 1985. This suggestion was taken up by the Austrian authorities and it will finally be instituted by law in May 1990 for the benefit of coming generations.

A 4-year-old girl with congenital dysgenesis of the thyroid gland is reported. The girl's appearance was that of hypothyroidism in childhood but the classical symptoms of constipation and cerebral retardation were missing. Thus it is assumed that relative insufficiency of the ectopic thyroid at the base of the tongue produced manifestations only a short time before diagnosis, having had no influence on cerebral maturity.

14,919 newborn infants were screened for congenital hypothyroidism within the last 5 years using a sensitive TSH method. 10 infants with congenital hypothyroidism were discovered thus presenting a frequency of 1:4500. Four of these infants showed abnormally high TSH levels and normal thyroxine levels. The determination of TSH in cord blood--or combined with the screening program for phenylketonuria--in eluate of dried filter paper specimens is the most sensitive test for primary hypothyroidism without false negative results and a low false positive recall rate of 0.16%. After initiation of therapy with thyroxine the TSH level falls unless therapy is delayed for longer. In the latter case TSH levels may remain elevated for several months despite therapy with thyroxine. We would suggest to start therapy with triiodothyronine for up to 14 days prior to initiation of the usual thyroxine therapy.

A commercial immunoradiometric assay (IRMA) for thyroid stimulating hormone (TSH) was modified to be used with dried blood on filter paper of our neonatal screening programme. Sensitivity and precision were as good as with the conventional radioimmunoassay (RIA), but the IRMA was faster. In addition the IRMA was extremely cheap, because all kit reagents could be prediluted 1:4. Our screening procedure for congenital hypothyroidism now combines a determination of TSH with the IRMA technic and a determination of free thyroxin (FT4) by radioimmunoassay. The kit for FT4 can be diluted 1:3, as described earlier. The combination of TSH-IRMA und FT4-RIA to our knowledge is not only much faster but also considerably cheaper than measuring one parameter with consecutive retesting of suspicious samples, which is the procedure in some countries. As the combination gives two independent results it is also of greater clinical value than measuring TSH in dublicates, which is still officially recommended in the Federal Republic of Germany.

Meteorism in a newborn may be a symptom of different diseases including hypothyroidism. It is caused by a disturbed peristalsis of the gut. Since in rare cases - as demonstrated in one infant - obligatory screening for hypothyroidism may be missed, meteorism should be considered a serious symptom and should lead to the right diagnosis before too much time is lost.

A premature infant was born with goiter and hypothyroidism 3 weeks after amniography. The correlation between excessive iodide exposure and thyroid function of discussed. The danger of using of idodine containing contrast media for amniography are emphasized.

Cerebellar ataxia was diagnosed in a 62-year-old woman, its signs regressing almost completely within six weeks during treatment with thyroxine and triiodothyronine. The cause of cerebellar ataxia in association with hypothyroidism remains unknown. No typical morphological changes in the cerebellum have been described. It is assumed that a thyrogenic, specific metabolic factor is responsible which aggravates already existing non-specific cerebellar changes. The prognosis is very good. On the other hand, cerebellar ataxia resulting from congenital hypothyroidism has typical histological cerebellar changes and prognosis is very poor unless thyroid treatment is started soon after birth.

According to more recent knowledge L-thyroxine alone is recommended for thyroid hormone replacement therapy, no longer the combination of L-thyroxine and triiodothyronin, since L-thyroxine is converted to triiodothyronine in the periphery of the body. Additional application of triiodothyronine causes unphysiological elevations of blood levels of triiodothyronine. When changing from the combined thyroid hormone therapy to treatment with L-thyroxine alone it is enough in most cases to replace the previous amount of L-thyroxine only; previous recommendations for the dosage of thyroid hormone were rather high. Average requirements of adults for L-thyroxine are around 170 mug per day. Children need about 90--100 mug per m2 body surface per day. -- When hypothyroidism is suspected in newborns or infants no protracted diagnostic procedures are justified with respect to brain development and its requirement of thyroid hormone during this period of life. Replacement therapy should be started within 1--2 days. The exact diagnosis can be established later, for instance during the third day of life when a temporary interuption of treatment for diagnostic purposes has no longer such negative effect on normal brain development. As long as physiological doses of L-thyroxine are used no side effects are to be expected for patients who later turn out to be euthyroid. -- Following exclusion of hyperthyroidism goitres in children and adolescents equally need thyroid hormone replacement therapy to reduce the size or prevent further enlargement or even the development of nodules within the gland. The dosage for this is about half to three quarters of the full replacement dose. The nature of thyroid nodules should be investigated, even surgically, since malignancies can develop in children and juveniles as well as in adults.

A dried-blood screening test for demonstration of congenital hypothyroidism was developed using materials of a commercially available radioimmunoassay for estimation of thyroxin (T4) in serum. The method is characterised by simple performance and satisfactory precision (coefficient of variation 7.8-12.4%). Performance of the test parallel to single determination of thyrotropin (TSH) instead of the usual TSH double determination is considered. Diagnostic advantages of both methods can thus be combined. Screening is not burdened by additional cost. However, an increase of the number of follow-up investigations may be expected.