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From 1971 to 2001, 188 fine-needle aspiration biopsies (FNAB) of the thyroid gland were performed in 169 children and adolescents with thyroid nodules. In 65.4% the results of FNAB were classified as benign. In 13.8% FNAB was considered insufficient for diagnosis, due to the absence or small number of cells. The results of FNAB were classified as suspicious or malignant in 17.6% (n = 33). Surgery was performed in 118 patients (69.8%) and the results of cytological evaluation and histopathology were compared. The accuracy of FNAB was 77.2%, specificity 63.6%, and sensitivity 78.9%, which is less than reported for adults. Histopathological evaluation showed 13 malignant tumors. In two of the 13 malignancies, FNAB was inadequate because of a lack of thyroid cells. Of the remaining 11 malignancies, seven were detected by FNAB but four of these were classified as benign. Because of the lower accuracy of FNAB, we suggest a more aggressive diagnostic and therapeutic approach in children and adolescents than for adults.

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BACKGROUND: The iodine supply of the population in Berlin has normalized during the last 5 Years. Therefore autoimmune thyroiditis has become the most important differential diagnosis in children and adolescents with goiter. OBJECTIVE: The aim of the present study was to define the prevalence of anti-thyroid peroxidase (TPO) antibodies and autoimmune thyroiditis in children and adolescents with a normalized iodine intake. DESIGN: To enable the measurement of antibodies to thyroid peroxidase (anti-TPO-Ab) in a large cohort, a method to determine anti-TPO-Ab in dried filter paper blood spots was established. In co-operation with pediatricians the antibody prevalence was assessed and data regarding thyroid size, echostructure and the medical history concerning iodine intake and familial thyroid diseases were collected. METHODS: 660 children and adolescents participated in the study; urinary iodine, TSH and TPO-Ab were measured and an ultrasound of the thyroid gland was performed. RESULTS: The sensitivity of the newly established filter paper assay was 91.8% and specificity was 100%. The results confirmed the improved iodine supply, with a median urinary iodine concentration of 139 microg iodine/g creatinine. The prevalence of anti-TPO-Ab was 3.4% with a female to male ratio of 2.7:1. CONCLUSION: The prevalence of anti-TPO-Ab is lower or equal to data reported from other iodine sufficient areas. Data from a moderate iodine deficiency in schoolchildren range from 0.0 to 7.3%. Using the new filter paper method field studies can be implemented to monitor the effect of changes in iodine nutrition on thyroid autoimmunity. Furthermore, this study on the prevalence of anti-TPO-Ab in a cohort of healthy children and adolescents in an iodine replete area can serve as reference data for future investigations and for the comparison with other groups of patients with increased risks for thyroid autoimmunity.

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BACKGROUND/AIMS: Wilson disease is caused by a large number of different mutations in the ATP7B gene. Wilson disease patients from a homogeneous ethnical background (Saxonia) were studied for distribution and phenotypes of ATP7B mutations. METHODS: Eighty-two patients were analyzed. The H1069Q mutation was assayed by a polymerase chain reaction-based restriction fragment length polymorphism test. Exons 8 and 15 were sequenced in all, and the entire gene in 30, non-H1069Q-homozygotes. RESULTS: Four novel and 12 known mutations were found. Thirty-two (39%) Wilson disease patients were homozygous and 39 (48%) heterozygous for the H1069Q mutation (allele frequency 63%). Together with sequence analysis of exons 8 and 15 mutations in both alleles were identified in 65% of patients. Only one patient had both mutations at other locations. In H1069Q homozygotes symptoms started later (21.3+/-7.2 years) than in H1069Q compound heterozygotes (14.6+/-5.8, P<0.001) or H1069Q negatives (10+/-4.4, P<0.001), and they had more frequently neurologic symptoms (93 vs. 47%, P<0.001) and Kayser-Fleischer rings (82 vs. 51%, P<0.001). Mutation status did not correlate with liver biopsy findings, serum ceruloplasmin levels or (64)Cu-assay results. CONCLUSIONS: In spite of many known ATP7B mutations, only few occur in this homogeneous population. Limited genetic testing is useful to confirm Wilson disease in this population.

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The mean age at which the diagnosis of growth disorders such as Turner's syndrome, growth hormone (GH) deficiency or true GH-dependent gigantism is established is still rather late in many countries around the world. In addition, the question of secular trends in a given population and the rate at which childhood obesity is increasing in industrialized countries make it mandatory to establish a time-adapted system to develop percentiles for body height, weight and body mass index (BMI) and also to develop a screening system for growth disorders. In 1998 we established a network, now involving more than 160 paediatric practices in Germany and seven paediatric endocrinology departments. Paediatricians record heights, weights and growth velocities of all children in their care and systematically feed the data into the database at our centre usually by mailing formatted, structured data tickets. Data are then continuously analysed at the centre and the paediatricians in the network are informed immediately about their individual patients' growth situations via phone or E-mail (feedback system). Regular annual conferences including structured reports, scientific presentations and discussion groups are organized for all participants at our centre. By May 2001, the data of 83,721 children and adolescents had been analysed. The mean values for height were 1-1.5 cm higher than the mean values in the German Synthetic Growth Curve, which serves as an internal standard. However, and most importantly, in comparison with the internal standard and historical normative data from Germany and Switzerland, there is a continuous increase in the 97th percentile for weight and BMI, while the third percentile remains unchanged. In addition, many children with short stature and tall stature due to a variety of endocrine disorders and genetic diseases which had not been diagnosed previously are now being identified. In conclusion, the databank allows for a continuous adaptation of normative curves based on a large number of children in a given population, i.e. eastern Germany. Secondly, the system allows for detection of pathological growth curves and is already serving to diagnose growth disorders in a defined population in a systematic way.

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This retrospective multicenter study was designed to survey the management of childhood and adolescent hyperthyroidism in six pediatric endocrinological units in Germany. Fifty-six patients aged between 1.1 and 17.0 yr (median 10.5 yr) were enrolled. Data were collected retrospectively from the patients' records by a trained pediatric endocrinologist using standardized questionnaires. After the diagnosis of hyperthyroidism was established on the basis of clinical and biological findings, treatment with antithyroid drugs (carbimazole, methimazole, thiamazole, propylthiouracil) was started in all patients. In 55/56 of the patients treated with antithyroid drugs, euthyroidism was achieved (98%). However, 26 patients (47%) were still hyperthyroid after discontinuation of the medication. Eight children with continued hyperthyroidism ultimately underwent subtotal thyroidectomy 13-136 (median 28) months after the initial diagnosis. Management principles of the participating centers were heterogeneous. As a consequence, prospective multicenter studies are urgently needed to establish clear standards for the diagnosis and therapy of childhood hyperthyroidism.

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Iodine deficiency is the most important etiological factor for euthyroid endemic goiter. However, family and twin pair studies also indicate a genetic predisposition for euthyroid simple goiter. In hypothyroid goiters several molecular defects in the thyroglobulin (TG), thyroperoxidase (TPO), and Na+/I- symporter (NIS) genes have been identified. The TSH receptor with its central role for thyroid function and growth is also a strong candidate gene. Therefore, we investigated a proposita with a relapsing euthyroid goiter and her family, in which several members underwent thyroidectomy for euthyroid goiter. Sequence analysis of the complementary DNA (cDNA) of the TPO and TSH receptor genes revealed several previously reported polymorphisms. As it is not possible to exclude a functional relevance for all polymorphisms, we opted for linkage analysis with microsatellite markers to investigate whether the candidate genes are involved in the pathogenesis of euthyroid goiter. The markers for the genes TG, TPO, and NIS gave two-point and multipoint logarithm of odds score analysis scores that were negative or below 1 for all assumed recombination fractions. As no significant evidence of linkage was found, we conclude that these candidate genes can be excluded as a major cause of the euthyroid goiters in this family. In contrast, we have found evidence for linkage of familial euthyroid goiter to the recently identified locus for familial multinodular nontoxic goiter (MNG-1) on chromosome 14q. The haplotype cosegregates clearly with familial euthyroid goiter. Our results provide the first confirmation for MNG-1 as a locus for nontoxic goiter.

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Constitutively activating thyrotropin-receptor (TSHR) germline mutations have been identified as a molecular cause of hereditary nonautoimmune hyperthyroidism. To date, seven cases of familial and six cases of sporadic nonautoimmune hyperthyroidism have been described associated with 13 different TSHR germline mutations, with a variable clinical course. We report the case of a 12.3-year-old girl with a history of thyrotoxicosis since the age of 11 months who developed diffuse thyroid hyperplasia at the age of 4.5 years. The patient has required continuous moderate-dose antithyroid medication, to maintain euthyroidism. There were no clinical signs of autoimmune thyroid disease and autoantibodies were negative. An activating germline mutation in the TSHR gene was suspected and was found in TSHR exon 10 (Ser505Asn) but was absent in the girl's mother. This same mutation, was first reported in a patient with severe intrauterine hyperthyroidism with early and progressive goiter development. Our patient had a significantly less severe clinical course with later onset compared to the original patient with the same TSHR germline mutation.

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Autosomal dominant nonautoimmune hyperthyroidism is a hereditary form of hyperthyroidism caused by constitutively activating germline mutations in the TSH-receptor gene. Clinical features comprise familial prevalence of thyroid autonomy in more than 2 generations and conditions of persisting neonatal hyperthyroidism or nonautoimmune hyperthyroidism of childhood onset with frequent relapses of hyperthyroidism under thyrostatic therapy and after thyroid surgery. Once clinically suspected the diagnosis can be confirmed by mutation analysis of genomic DNA extracted from a routinely obtainable EDTA blood sample. In patients with hereditary nonautoimmune hyperthyroidism a near total thyroidectomy is recommended as the first line treatment to avoid relapses from residual thyroid tissue with the activating TSHR mutation. Furthermore, genetic counselling of the affected patients is advised.

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Catch-up growth was analyzed in 20 prepubertal children with primary hypothyroidism (PH) starting treatment at an age of 4.4 (1.2-10.1) years and a height (HT) SD score (HT SDS) of -3.1 (+/-0.8). All patients were followed for at least 3 prepubertal years. HT velocity was 12.3 +/- 2.3, 9.0 +/- 1.8 and 7.5 +/- 2.2 cm/year, and change in HT SDS was 1.60 +/- 0.56, 0.57 +/- 0.33 and 0.28 +/- 0.38 during the 1st, 2nd and 3rd year, respectively. The 11 children followed to adult height reached a HT SDS of -0.11 +/- 1.1, all within their target HT range. HT gain (DeltaHT SDS) during the 1st year was correlated with the degree of catch-up growth (r2 = 0.78, p < 0.001). While catch-up growth in childhood-onset PH is complete, this is not the case in GH deficiency (GHD). Based on the auxological characteristics of the patients with PH, HT velocities during the first 2 years were predicted applying prediction models devised for prepubertal children with idiopathic GHD. The modalities of GH treatment observed in the models were used to calculate predicted HT velocities of the PH patients. Observed HT velocities in PH were higher than predicted HT velocities during the 1st (10.67 +/- 1.37 cm/year, p < 0.01) and 2nd (8.35 +/- 0.86 cm/year, p = 0.128) year. The data show that catch-up potential in idiopathic GHD of childhood onset is reduced compared to PH. Since early catch-up as well as total HT recovery in children with GHD are often not reached by present treatment modalities, catch-up growth in PH may serve as a model towards optimizing GH treatment. The data suggest that initial GH doses of 1.0 IU/kg/week, rather than the presently recommended 0. 6 IU/kg/week, need to be given in GHD in order to achieve the degree of early catch-up observed in PH and to consequently improve the final outcome.

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Constitutively activating germline mutations in the TSH receptor (TSHR) gene have been identified as a cause of autosomal dominant nonautoimmune hyperthyroidism and sporadic congenital hyperthyroidism. We report a 10-yr-old boy and his 31-yr-old mother, both presenting with a history of recurring toxic thyroid hyperplasia and no evidence for autoimmune thyroid disease. In the boy, onset of hyperthyroidism and goiter was neonatal. In the mother, onset of thyroid disease dates back to early childhood. There was no history of thyroid disease in the rest of the family. Screening for germline mutations in exon 10 of the TSHR was performed by direct sequencing of genomic DNA extracted from peripheral blood leukocytes of both patients. In the boy and his mother, an identical heterozygous TSHR mutation was identified, exchanging leucine for phenylalanine at residue 629 of the TSHR (TTG-->TTT). Transient expression of the mutated TSHR construct in COS-7 cells confirmed the constitutive activity of the new TSHR germline mutation. This is the second family displaying congenital manifestation of hyperthyroidism in familial nonautoimmune hyperthyroidism.

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Resistance to thyroid hormone (RTH) is an inherited defect manifesting as variable tissue hyporesponsiveness to thyroid hormone, usually caused by mutations in the thyroid hormone receptor beta (TR beta) gene. Up to now 78 mutations in this gene have been identified, mostly clustered in two regions located in exon 9 and 10. We describe a new point mutation replacing the normal thymidine-1274 with a cytosine that results in the substitution of the normal leucine-330 with a serine (L330S) in the receptor protein. This mutation was identified in an 11-year-old boy who presented with symptoms and signs suggestive of both hyperthyroidism and hypothyroidism. Interestingly a mutation in the same codon (L330F) has been previously described in a patient who presented with stigmata suggestive of thyrotoxicosis.

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In the former East Germany (GDR) like in the former West Germany (FRG) iodine deficiency and endemic goiter have been described since more than 2 decades. After a program of salt iodization which was started in East Germany in 1985 the urinary iodine excretion of the population increased significantly. The thyroid gland of the newborn is much more sensible to changes of the iodine supply than the thyroid of older children. A total of 1732 subjects was enrolled in the study. After the implementation of the mandatory salt iodization the goiter prevalence in newborns decreased markedly to less than 1%. After the reunification of Germany in 1990 the mandatory prophylaxis was stopped and the urinary iodine excretion in newborns, school-children, adolescents and adults diminished markedly. So in newborns the renal iodine excretion decreased to 2.82 micrograms I/dl in 1992. Since 1994 a reasonable improvement of the iodine supply is observed in the region of Leipzig. In school-children, adolescents and adults the mean value of the urinary iodine excretion is now above 10.0 micrograms I/dl. This value may be considered as an indicator for a normal iodine supply. In a small cohort (n = 28) of newborns infants we found a renal iodine excretion of 18.74 micrograms/dl in 1997. That value also means a significant increase since 1992 and a normal iodine supply in the fetal period. The present results from the region of Leipzig/Saxonia are not representative for the whole of East Germany. To provide an optimal iodine nutrition the use of iodized salt for food manufacturing must be significantly increased.

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Iodine deficiency is the major cause of an increase in thyroid gland volume in infants and children. In this field study we monitored the iodine supply and its effect on the thyroid gland volume in prepubertal and pubertal children in the eastern and western parts of the city of Berlin, so far considered as an area with borderline iodine deficiency. The thyroid gland volume was determined by ultrasound in 1080 (f = 552, m = 528) children aged 3-15 years, and was correlated to age, body-surface area and iodine excretion, which was measured in a first-morning spot urine. The mean iodine concentration was 115.8 micrograms iodine/g creatinine (12.2 micrograms iodine/dl urine), with no significant differences between eastern parts with 114.5 micrograms iodine/g creatinine (12.3 micrograms iodine/dl urine) vs 116.7 micrograms iodine/g creatinine (12.0 micrograms iodine/dl urine) in the western parts of the city. This good iodine supply of the children was surprising compared to former studies in children and adults. Moreover this normalization of the iodine excretion was reflected by smaller thyroid gland volumes in the children. The volume was found to increase with age and was 2.4 +/- 1.1 ml in prepubertal (Prader and Largo: f < or = 10.9 ys, m < or = 11.5 ys) children, compared to 4.3 +/- 1.7 ml in pubertal children. The goiter prevalence, calculated on this data was below 5%. Among all children there were only 11 (aged 8-13 ys) with abnormal findings of the thyroid gland on ultrasound: 6 with small nodules, 1 girl with a thyroid-cyst, 2 girls had an inhomogenous echo structure and 2 girls presented with a hemithyroidea. This study shows that the iodine supply of the children in Berlin has improved, resulting in smaller sized thyroid glands, compared to those which have been previously published for Germany (Müller-Leisse 1988; Klingmüller, 1991; Menken, 1992), but they correspond well to volumes described in countries with sufficient iodine supply.

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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.

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The effect of a mammalian-cell-derived recombinant human growth hormone (rhGH) on nitrogen and whole-body protein metabolism was assessed in 12 children with complete growth hormone (GH) deficiency. All the patients received single oral doses of 15N-glycine (95 atom % 15N), 20 mg/kg body weight, prior to and following 7 days of treatment with rhGH, 1.7 IU/m2 body surface area (BSA) per day, administered subcutaneously. Prior to rhGH, mean urinary 15N-nitrogen excretion was 42.8 +/- 8% of the administered dose, which fell significantly to 22.8 +/- 7% during rhGH administration (p < 0.0001). Stimulation of protein metabolism by rhGH resulted in a protein net gain rate of 1.1 +/- 0.4 g/kg/day, which was significantly higher than the 0.6 +/- 0.5 g/kg/day rate seen prior to rhGH (p < 0.001). In patients subsequently placed on daily subcutaneous injections of rhGH 1.7 IU/m2 BSA, mean height velocity standard deviation score (HV SDS) for chronological age significantly increased from -3.8 +/- 2.6 to +8.5 +/- 3.1 and +3.3 +/- 2.2, during the 1st and 2nd years of treatment, respectively. However, there was no correlation between the long-term response to rhGH treatment and the short-term changes in nitrogen or protein metabolism in GH-deficient children.

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