We report 24-month interim results of two multicenter phase III studies in previously untreated children with growth failure secondary to GH deficiency (GHD) that were paramount to the development of a new recombinant human GH (rhGH, somatropin), approved as the first ‘biosimilar’ in Europe. Study 1 consisted of 3 parts performed in 89 children. The objective was to compare efficacy and safety of the lyophilized formulation of the new somatropin [Somatropin Powder (Sandoz)] with a licensed reference rhGH preparation and the liquid formulation of the new somatropin [Somatropin Solution (Sandoz)] and to assess long-term efficacy and safety of this ready-to-use Somatropin Solution. Study 2 was performed in 51 children and designed to demonstrate efficacy and safety of Somatropin Powder and to confirm its low immunogenic potential; rhGH was given sc at a daily dose of 0.03 mg/kg. Primary [body height, height SD score (HSDS), height velocity, and height velocity (HV) SD score (HVSDS)] and secondary [IGF-I and IGF binding protein 3 (IGFBP-3)] efficacy end-points and safety parameters were assessed regularly. In study 1, all treatments showed comparable increases in growth. The baseline-adjusted difference between Somatropin Powder and the reference rhGH product in mean HV was −0.20 cm/yr (95% confidence interval (CI) [−1.34;0.94]) and in mean HVSDS was 0.76 (95% CI [−0.57;2.10]) after 9 months. These very small differences demonstrate comparable therapeutic efficacy between the two treatments. The results of study 2 were consistent with those seen in study 1. Equivalent therapeutic efficacy and clinical comparability in terms of safety and immunogenicity between Somatropin Powder and the reference rhGH product and between Somatropin Powder and Somatropin Solution was demonstrated. The safety and immunogenicity profiles were similar and as expected from experience with rhGH preparations.

DNA obtained from the blood cells of 88 adolescent patients with short stature, with low blood serum IGF-I concentrations, normal growth hormone (GH) secretion and normal GH receptor (GHR) structure, was analyzed in the promoter region for the IGF-I gene. A total of 24 genetic variants was detected in the DNA of 13 patients. An attempt was also made to analyze the impact of identified mutations on DNA-protein interactions using EMSA.

In Poland, where soil is deficient in iodine, supplementation of iodine was introduced in 1935, discontinued in 1980, and then re‐introduced in 1997. One of the effects of inadequate iodine intake, prior to 1997, was an increase in the prevalence of thyroid nodular disease (TND) in children. Chernobyl, located in the neighbouring country of Ukraine, suffered a catastrophic nuclear explosion in April 1986.

PROP1 gene mutations can be responsible for development of combined pituitary hormone deficiency. Fifteen ( 8-12 years old) patients with idiopathic growth hormone deficiency were studied.Genetic screening of exon 2 of PROM gene revealed homozygous 301_302AG deletion (c.301_302delAG) in two siblings. Their parents appeared to be heterozygous carriers of this alteration. These results indicate the necessity of early genetic analysis in young patients with apparent GHD.

Analysis of GHR and IGF-I coding sequences in 47 children with normal serum levels of GH, low IGF-I and growth disorders generally did not show mutation in the genes studied. Only one boy had a mutation located in the fifth exon of the GHR gene (C-->T in codon 88). This suggests that the growth disorders in this group of children might be due to a defect in a DNA region regulating expression of the GHR and IGF1 genes or genes involved in their regulation.

PURPOSE:The work concerns the substitution treatment with growth hormone (GH) in hypopituitary children, including cases that occurred in the course of tumor disease, craniopharyngioma (CP) and medulloblastoma (MB).MATERIAL AND METHODS:The studied population concerned 117 children who presented either somatotropic or polyhormonal pituitary insufficiency (the average age was 12.6 years for girls and 13.6 years for boys). The diagnosis of somatotropic pituitary insufficiency (SPI) was based on insulin and clonidin stimulation tests evaluating GH reserve of hypophysis. The computer tomography (CT) and nuclear magnetic resonance (NMR) examinations were carried out before GH substitution in all children. The tumors (four CP cases and one case of MB) were all found in boys and they were treated with surgery and/or radiotherapy. All studied children, including CP and MB operated patients were treated with human GH (hGH)--Genotropin 16 IU, administered in subcutaneous injections. The daily dose was calculated as 0.5 IU/kg/week.RESULTS:The annual increase of children height before GH therapy was about 3.2 cm. In the first year of GH therapy the difference in children growth between the CP/MB group as compared with the rest of patients was less than 1.0 cm: 9.4 and 10.2 cm/year, resp. During the second year of hormone substitution the growth became slower: average values were 8.2 cm and 7.4 cm/year, resp. In CP and MB patients the height increase calculated as SDS values was significant (2.7 and 1.0 resp.). Control NMR examination performed in CP/MB patients treated with surgery with subsequent hGH therapy did not demonstrate any recurrence of tumor.CONCLUSIONS:After two years of hGH therapy the final height of hypopituitary children, including CP patients, nearly reached the values observed in healthy children. GH therapy did not induce a recurrence of neoplasm in CP and MB patients.

Medical and Pediatric OncologyVolume 38, Issue 4 p. 290-291 Brief Report Thyroid carcinoma in a fourteen-year-old boy with Graves disease Marek Niedziela MD, PhD, Corresponding Author Marek Niedziela MD, PhD nie[email protected] or [email protected] Department of Pediatric Endocrinology and Diabetes, Karol Marcinkowski University of Medical Sciences, Poznan, PolandDepartment of Pediatric Endocrinology and Diabetes, Karol Marcinkowski University of Medical Sciences in Poznan, Szpitalna Street 27/33, 60-572 Poznan, Poland.Search for more papers by this authorEugeniusz Korman MD, PhD, Eugeniusz Korman MD, PhD Department of Pediatric Endocrinology and Diabetes, Karol Marcinkowski University of Medical Sciences, Poznan, PolandSearch for more papers by this author Marek Niedziela MD, PhD, Corresponding Author Marek Niedziela MD, PhD nie[email protected] or [email protected] Department of Pediatric Endocrinology and Diabetes, Karol Marcinkowski University of Medical Sciences, Poznan, PolandDepartment of Pediatric Endocrinology and Diabetes, Karol Marcinkowski University of Medical Sciences in Poznan, Szpitalna Street 27/33, 60-572 Poznan, Poland.Search for more papers by this authorEugeniusz Korman MD, PhD, Eugeniusz Korman MD, PhD Department of Pediatric Endocrinology and Diabetes, Karol Marcinkowski University of Medical Sciences, Poznan, PolandSearch for more papers by this author First published: 12 March 2002 https://doi.org/10.1002/mpo.1330Citations: 8AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. REFERENCES 1 Shapiro SJ, Friedmann NB, Pezik SL, Catz B. Incidence of thyroid carcinoma in Graves disease. Cancer 1970; 26: 1261–1270. 2 Nikiforov YE, Fagin JA. Risk factors for thyroid cancer. Trends Endocrinol Metab 1997; 8: 20–25. 3 Pellegriti G, Belfiore A, Giuffrida D, et al. Outcome of differentiated thyroid cancer in Graves patients. J Clin Endocrinol Metab 1998; 83: 2805–2809. 4 Loh K-C, Greenspan FS, Dong F, et al. Influence of lymphocytic thyroiditis on the prognostic outcome of patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 1999; 84: 458–463. 5 Williams D. Childhood thyroid cancer and Chernobyl. Topical Endocrinol 1996; 2: 10–12. 6 McClellan DR, Francis GL. Thyroid cancer in children, pregnant women and patients with Graves disease. Endocrinol Metab Clin North Am 1996; 25: 27–48. 7 Cantalamessa L, Baldini M, Orsatti A, et al. Thyroid nodules in Graves disease and the risk of thyroid carcinoma. Arch Intern Med 1999; 159: 1705–1708. Citing Literature Volume38, Issue4April 2002Pages 290-291 ReferencesRelatedInformation

OBJECTIVE:The aim of this study was to find out if infants after cardiopulmonary bypass develop non-thyroidal illness and if illness severity after cardiopulmonary bypass depends on hormone concentration in ultrafiltrate. METHODS:Thyroid hormone status was assessed in 20 infants with congenital heart defects undergoing cardiac surgery (age range 7 days-11 months). Blood samples were collected preoperatively, during cardiopulmonary bypass, after cardiopulmonary bypass, and also postoperatively in 1, 2, 3, and 8 day after cardiac surgery. Plasma thyrotropin, thyroxine, free thyroxine, triiodothyronine, free triiodothyronine and reverse triiodothyronine were measured in blood samples and also in ultrafiltrate. RESULTS:All patients had reduction in serum thyrotropin, thyroxine, free thyroxine, triiodothyronine, free triiodothyronine, and elevation of reverse triiodothyronine after cardiac surgery. In all patients we performed ultrafiltration. Patients were divided in to two groups. (with and without prolonged recovery). In the group of patients with prolonged recovery we noticed significantly higher amount of triiodothyronine per kilogram body weight. One of these patients died. The average level of total thyroxine decreased from the level 126 nmol/l before bypass to the minimal level 73 nmol/l after bypass, free thyroxine from the level 18 pmol/l before bypass to the minimal level 12 pmol/l after bypass. The average level of total triiodothyronine decreased from the level 1.54 nmol/l before bypass to the minimal level 0.42 nmol/l after bypass, free triiodothyronine from the level 6.12 pmol/l before bypass to the minimal level 3.21 pmol/l after bypass. The average level of TSH decreased from the level 4.31 mU/l before bypass to the level 0.64 mU/l after bypass. The average level of reverse-triiodothyronine increase from the level 0.83 nmol/l before bypass to the maximal level 1.94 nmol/l after bypass. CONCLUSIONS:We conclude that non-thyroidal illness occurs in all infants after cardiopulmonary bypass. The amount of free triiodothyronine that is filtrated during cardiopulmonary bypass may influence postoperative recovery.

Current methods of research into thyroid nodular disease (TND) based on the polymerase chain reaction (PCR) and reverse-transcription (RT) permit the detection of some markers, even in poorly cellular biological material. The findings from fine-needle aspiration biopsy (FNAB), the most commonly used procedure in TND, do not always correlate with the postoperative histopathological diagnosis, sometimes giving a false negative result. The aim of this present study was to improve the classical cytological evaluation of the material obtained with ultrasound-guided biopsy with a RT-PCR based technique in order to detect carcinoma even in a minimally invasive form. Aspirate from the 30 patients included in the study was smeared for conventional cytology (H+E and MGG staining) and the leftover material in the needle was frozen for subsequent PCR analysis. Fine-needle aspiration specimens were evaluated for the presence of galectin-3 (GAL-3), the most promising molecular marker of malignancy. As a positive control for cells of follicular origin, thyroglobulin (Tg) gene expression was performed. RT-PCR was performed on extracted RNA and with specific primers for the screened genes, based on a one-step reaction with a Biometra PCR machine. Tg expression was observed in 23 aspirates, among which 10 were positive for the expression of GAL-3 [3 cases of PTC, 1 an oxyphilic variant of FTC, 1 an oxyphilic variant of follicular adenoma (FA), 1 a foetal variant of FA, 2 of Hashimoto thyroiditis (HT) and 2 of HT with coexisting FA]. Our results are the first evidence that GAL-3 expression, previously documented in thyroid carcinoma of follicular origin, is also present in Hashimoto thyroiditis. This study reveals some limitations in nodule or multiple nodules of benign character. If the diagnosis of HT is excluded, then the usefulness of the method in the diagnosis of malignancy may still be very high.

In an iodine deficient area, a high incidence of hot thyroid nodules was observed in children after the introduction of iodine supplementation in 1997. Thirty-one children (28 girls, 3 boys) were identified with hot nodules between the years 1996-2000 (3 patients in 1996, 4 in 1997, 10 in 1998, 7 in 1999, and 7 in 2000). The incidence ratio of hot nodules in this study population increased significantly from 0.23 in 1996 to 0.80 in 1998. In 17 children, radionuclide uptake was confined exclusively to areas corresponding to the nodules. Cancer was detected in one child in post-operative histological examination. In the other 14 children, the predominant uptake was in nodules, but it was also registered within extranodular tissue. In the latter group, eight tumors were eventually diagnosed as cancer and six as benign tumors. The majority of tumors in the entire group was located in the right lobe (19/31) and was accompanied by reduced TSH levels (23/31), but only 14 of the 31 patients had signs of hyperthyroidism. The years 1996-2000, in which the increase in the incidence of "hot" nodules in children with nodular goiter was observed, correspond to a period of enforced salt iodinization. The existence of cancer within hot nodules is rare, ranging from 2-5% of all nodules. By contrast, the risk of cancer in hot nodules in the cohort of this study was significantly higher (9/31; 29.0%), especially in cases of hot nodules with a rudimentary radionuclide uptake in the extranodular area. We conclude that, in geographical regions affected with iodine deficiency, the therapeutic protocol for children with hot nodules should be based primarily on surgery rather than on radioiodine.

Autoimmune thyroiditis, the most frequent cause of acquired hypothyroidism in childhood and adolescents, is characterized by raised levels of the specific antibodies to thyroperoxidase (TPOAb) and thyroglobulin (TgAb). We report a girl aged 10 years and 9 months who presented with arrested growth and breast development (thelarche). She also exhibited myxedema of the face and legs, prominent striae on the thighs, dry, cold skin, and hypertrichosis on her back. There was no goiter, no history of thyroid pain and no family history of thyroid disease. She complained occasionally of a transient headache. The patient's height was below the 3rd percentile, while her body weight was at the 50th percentile and bone age was normal. Laboratory tests proved severe hypothyroidism (fT4 0 ng/dl, fT3 0.99 pg/ml, TSH >100 microIU/ml plus an increased titer of TPOAb). Thyroid ultrasound supported the diagnosis of thyroiditis. Pituitary PRL and FSH levels and peripheral estradiol were all elevated. L-Thyroxine therapy, instituted following diagnosis, improved the growth velocity to 11 cm/year and the FSH and E2 levels were normalized to prepubertal values. Complete regression of the breast development was observed within 4 months. However, 4 months later a true (central), isosexual LHRH-dependent puberty started. The pubertal features at the time of the original diagnosis might be explained by: 1. the direct action of elevated TRH on gonadotropes to stimulate gonadotropin secretion and on lactotrophes to stimulate PRL secretion, and 2. TSH action on LH and mostly FSH receptors (homologous to TSH receptors) in the ovary, stimulating the secretion of estradiol.

There are clinical similarities between anorexia nervosa (AN) and hypothyroidism. Previous reports have shown decreasing fT3, increasing rT3, sporadically decreasing fT4 and normal levels of serum TSH. To asses thyroid function in 36 patients with AN (4 boys, 32 girls, the subjects ages ranged from 12 to 18 years) serum levels of fT4, fT3, rT3, TSH were measured. We examined activation of the hypothalamic - pituitary- thyroid axis by using TRH test (TRH i.v. 0,2 mg, measured TSH at 0', 30', 60', 90') in 30 patients out of this group. 67% (24) patients of the examined group resulted in low level of fT4 (0,75-0,97 ng/dcl), but low decreasing fT3 (=0,67 pg/ml) was only found with 1. The level of rT3 were normal. The level of TSH were low (0,87-0,97 micro IU/ml) in 25% (9) of patients, but 6 of them also manifested low decreasing fT4 (0,87-0,97 ng/dcl). A hyporesponse of TSH to TRH was noted in 17% (5) of patients, a delayed TSH response to TRH was seen only in 1. Thyroidal dysfunction in AN was basically expressed by low decreasing fT4, and also by the disturbances of the TRH-TSH secretion.

The increase in diabetes type 1 incidence observed in various centers in Poland and the need for a centralized study covering large population have resulted in the construction of a standardized registry of type 1 diabetes in 1998 within the Polish Multicenter Study in Diabetes Epidemiology. The aim of the study was to present the incidence rates of type 1 diabetes in the age group 0-14 in 7 distinct regions of Poland (Krakow, Wroclaw, Warsaw, Bialystok, Poznan, Rzeszow and Olsztyn centers) with over 30% of the Polish population at risk in 1998 and 1999. The data for the standardized registry were obtained prospectively from paediatric hospital wards and diabetes outpatient units. The incidence rates calculated in 1998 showed the highest value of 14.6 and 14.5/100,000 for Olsztyn and Warsaw, and the lowest (8.4/100,000) for Poznan center. In 1999 the highest value of 14.7/100,000 was noted in Krakow and the lowest (9.3/100,000) in Poznan center. The differences in diabetes type 1 incidence rates between age groups 0-4, 5-9 and 10-14 were found to be significant (p < 0.0005) and were also significant when incidence rates were compared between males and females in these age groups in the whole study area in 1998-1999 (p = 0.002 and p = 0.015 respectively).

The last two decades have been characterized by a remarkable improvement of the methods used for the determination of thyroid hormones concentration as well as by mass screening of congenital hypothyroidism. This has resulted in an expanded knowledge on the development of the hypothalamus-hypophysis-thyroid function in the fetus and in newborn. The paper presents the latest advancements in this field. The following thyroid dysfunction syndromes in premature infants are discussed: transient hypothyroxinemia, transient primary hypothyroidism, transient idiopathic hyperthyrotropinemia, low T3 - syndrome. All these conditions should be taken into consideration while determining the thyroid function in premature infants, particularly while screening newborns with congenital hypothyroidism.