Safety and Efficacy of Lonapegsomatropin in Children With Growth Hormone Deficiency: enliGHten Trial 2-Year Results.

PURPOSE: The objectives of the ongoing, Phase 3, open-label extension trial enliGHten are to assess the long-term safety and efficacy of weekly administered long-acting growth hormone lonapegsomatropin in children with growth hormone deficiency. METHODS: Eligible subjects completing a prior Phase 3 lonapegsomatropin parent trial (heiGHt or fliGHt) were invited to participate. All subjects were treated with lonapegsomatropin. Subjects in the United States switched to the TransCon hGH Auto-Injector when available. Endpoints were long-term safety, annualized height velocity, pharmacodynamics [insulin-like growth factor-1 SD score (SDS) values], and patient- and caregiver-reported assessments of convenience and tolerability. RESULTS: Lonapegsomatropin treatment during enliGHten was associated with continued improvements in height SDS through week 104 in treatment-naïve subjects from the heiGHt trial (-2.89 to -1.37 for the lonapegsomatropin group; -3.0 to -1.52 for the daily somatropin group). Height SDS also continued to improve among switch subjects from the fliGHt trial (-1.42 at fliGHt baseline to -0.69 at week 78). After 104 weeks, the average bone age/chronological age ratio for each treatment group was 0.8 (0.1), showing only minimal advancement of bone age relative to chronological age with continued lonapegsomatropin treatment among heiGHt subjects. Fewer local tolerability reactions were reported with the TransCon hGH Auto-Injector compared with syringe/needle. CONCLUSIONS: Treatment with lonapegsomatropin continued to be safe and well-tolerated, with no new safety signals identified. Children treated with once-weekly lonapegsomatropin showed continued improvement of height SDS through the second year of therapy without excess advancement of bone age.

Weekly Lonapegsomatropin in Treatment-Naïve Children With Growth Hormone Deficiency: The Phase 3 heiGHt Trial.

CONTEXT: For children with growth hormone deficiency (GHD), treatment burden with daily somatropin injections [human growth hormone (hGH)] is high, which may lead to poor adherence and suboptimal overall treatment outcomes. Lonapegsomatropin (TransCon hGH) is an investigational long-acting, once-weekly prodrug for the treatment of GHD. OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of once-weekly lonapegsomatropin vs daily somatropin. DESIGN: The heiGHt trial was a randomized, open-label, active-controlled, 52-week Phase 3 trial (NCT02781727). SETTING: This trial took place at 73 sites across 15 countries. PATIENTS: This trial enrolled and dosed 161 treatment-naïve, prepubertal patients with GHD. INTERVENTIONS: Patients were randomized 2:1 to receive lonapegsomatropin 0.24 mg hGH/kg/week or an equivalent weekly dose of somatropin delivered daily. MAIN OUTCOME MEASURE: The primary end point was annualized height velocity (AHV) at week 52. Secondary efficacy end points included change from baseline in height SD scores (SDS). RESULTS: Least squares (LS) mean (SE) AHV at 52 weeks was 11.2 (0.2) cm/year for lonapegsomatropin vs 10.3 (0.3) cm/year for daily somatropin (P = 0.009), with lonapegsomatropin demonstrating both noninferiority and superiority over daily somatropin. LS mean (SE) height SDS increased from baseline to week 52 by 1.10 (0.04) vs 0.96 (0.05) in the weekly lonapegsomatropin vs daily somatropin groups (P = 0.01). Bone age/chronological age ratio, adverse events, tolerability, and immunogenicity were similar between groups. CONCLUSIONS: The trial met its primary objective of noninferiority in AHV and further showed superiority of lonapegsomatropin compared to daily somatropin, with similar safety, in treatment-naïve children with GHD.

European multicentre study in children born small for gestational age with persistent short stature: comparison of continuous and discontinuous growth hormone treatment regimens.

BACKGROUND: The most effective growth hormone (GH) treatment regimen for increasing height in short children born small for gestational age (SGA) has not been well defined. METHODS: Short SGA children (n = 151, age 3-8 years, height less than -2.5 standard deviation scores) were randomised to receive low-dose GH for 2 years (0.033/0.033 mg/kg/day, n = 51), high-dose GH for 1 year and then no treatment for 1 year (0.100/0 mg/kg/day, n = 51) or were untreated for 1 year then received mid-dose GH for 1 year (0/0.067 mg/kg/day, n = 47). Height, bone age and adverse events were determined at check-ups every 3 months. RESULTS: The mean +/- SD additional height gain with GH after 1 year, relative to untreated controls, was higher with discontinuous high-dose than with continuous low-dose GH (6.5 +/- 0.2 vs. 3.3 +/- 0.2 cm). After 2 years, the additional height gain was similar between high- and low-dose GH groups (between-group treatment difference = 0.2, 95% CI = -0.8 to 1.2 cm, p = 0.702). Patients treated exclusively in the last year had a similar height gain to those in the other treatment groups (p = 0.604). CONCLUSIONS: In short SGA children, continuous low-dose and discontinuous high-dose GH regimens were associated with similar height gain. Treatment with mid-dose GH for 1 year also led to a similar improvement in growth.

Treatment of severe primary IGF-1 deficiency using rhIGF-1 preparation - first three years of Polish experience.

INTRODUCTION: The objective of this study was to analyse the effects of the first three years of treatment with recombinant human insulinlike growth factor 1 (rhIGF-1) in patients from the Polish population. MATERIAL AND METHODS: Twenty-seven children (22 boys and five girls) aged 2.8 to 16.0 years old were qualified for treatment with rhIGF-1 (mecasermin) in different treatment centres, according to Polish criteria: body height below -3.0 SD and IGF-1 concentration below percentile 2.5 with normal growth hormone (GH) levels. Mecasermin initial dose was 40 µg/kg bw twice a day and was subsequently increased to an average of 100 µg/kg bw twice a day. Body height, height velocity, weight, body mass index (BMI), and adverse events were measured. RESULTS: Mecasermin treatment resulted in a statistically significant increase in body height (1.45 ± 1.06 SD; p < 0.01) and height velocity in comparison with pre-treatment values. The biggest change in height velocity happened during the first year and diminished during subsequent years. Body weight and BMI also increased significantly after treatment (1.16 ± 0.76 SD and 0.86 ± 0.75 SD, respectively; p < 0.01). Eight patients reported adverse events. These were mild and temporary and did not require treatment modification except in two patients. CONCLUSIONS: Treatment with rhIGF-1 was effective and safe in Polish patients with primary IGF-1 deficiency. It had a clear beneficial effect on the height of the patients and significantly accelerated the height velocity, particularly in the first year of treatment.

Prevalence of thyroid hemiagenesis in an asymptomatic schoolchildren population.

BACKGROUND: Thyroid hemiagenesis is a rare congenital anomaly in which one lobe of thyroid gland fails to develop. Because variations of the prevalence of this anomaly have been reported, the aim of this study was to evaluate the prevalence rate of thyroid hemiagenesis in an apparently normal population from Northern Poland. METHODS: Ultrasound examination of the thyroid gland was performed in 4004 unselected 7-15-year-old school-children from the seaside zone of Northern Poland. RESULTS: Two cases of thyroid hemiagenesis were found, both being absence of the left lobe in two girls. Thyroid volumes, adjusted to body surface area, were within normal range; serum thyrotropin, free thyroxine, and free triiodothyronine were within normal limits. Physical examination, abdominal ultrasound, and echocardiography did not show extrathyroidal malformations. Thyroid ultrasound was normal in the girls, parents, and siblings. CONCLUSIONS: The study showed a 0.05% prevalence of thyroid hemiagenesis in asymptomatic schoolchildren population from iodine-sufficient area of Northern Poland.

[Evaluation of final height in patients with pituitary growth hormone deficiency who were treated with growth hormone replacement]. / Ocena wzrostu koncowego pacjentów z somatotropinowa niedoczynnoscia przysadki, leczonych hormonem wzrostu.

BACKGROUND: Growth hormone (GH) therapy has been used for children with pituitary GH deficiency. It resulted in improving their height velocity and achieving an adult height in the normal range for the general population. OBJECTIVES: To evaluate the final height in childhood-onset growth hormone deficiency patients who had already completed treatment and were still GH deficient in adult life. MATERIAL AND METHODS: 21 children (12 boys and 9 girls) diagnosed as GH deficiency and treated with growth hormone to final height at doses of 0.17 mg/kg/week (0.5 IU/kg/week) subcutaneously for 7 days. There were 7 patients with isolated GHD and 14 with multiple pituitary hormone deficiencies. RESULTS: At the diagnosis peak serum GH concentrations were 2.8+/-2.8 mU/l in insulin tolerance test and 3.3+/-2.2 mU/l in clonidine test. Reconfirmation of the GH deficiency diagnosis after growth hormone treatment revealed a peak serum GH 1.77+/-1.2 mU/l in insulin tolerance test. Mean chronological age of the patients at the beginning of treatment was 10.29+/-3.57 years and was significantly higher in boys. Patients had completed a course of treatment in the chronological age of 17.85+/-1.97 years. Children began treatment with mean bone age 7.24+/-3.57 years and ended with 15+/-0.97 years. After the treatment a significant improvement in height was shown. Height SDS at the beginning of the treatment was -4.03+/-0.91 and -0.69+/-1.01 after the treatment. There was no difference between final height and target height (-0.54+/-0.93 SDS) in our patients. CONCLUSIONS: Children with pituitary growth hormone deficiency who were treated with growth hormone replacement achieve a final height in the normal range for the general population and their target height.

[Cardiovascular malformations in Turner syndrome]. / Wady ukladu sercowo-naczyniowego w zespole Turnera.

BACKGROUND: A literature review indicates that the prevalence of cardiovascular malformations in patients with Turner syndrome ranges from 17 to 47 percent. OBJECTIVES: The aim of the study was to evaluate the cardiovascular system in patients with Turner syndrome, controlled by the Pediatric Endocrinology Clinic of the Medical University of Gdansk. MATERIAL AND METHODS: The study included 55 females with Turner syndrome aged 3-20 years (mean age 9.6 years). The procedure included an interview, subject examination, chest X-rays and echocardiography. The echocardiography included M-mode measurements, two-dimensional evaluations from all standard planes, pulsed and continuous wave Doppler as well as color flow mapping. In selected cases, cardiologic examination embraced also cardiac catheterization, cineangiography and continuous 24-hour blood pressure measurement. RESULTS: Cardiovascular malformations were found in 18 out of 55 females (32.7%). Aortic coarctation was detected in 9 out of 18 patients (50%), bicuspid aortic valve in 33%, and aortic insufficiency in 22% of them. 78% of Turner subjects with cardiovascular malformations had monosomy (45,X). All females, except one, with aortic coarctation, had a 45,X karyotype. One aortic coarctation was diagnosed during prenatal examination. Before the last medical examination, 9 females had undergone a surgical treatment. In one case, the surgical treatment was preceded by a balloon angioplasty. Due to a recoarctation, one female was submitted to an additional balloon angioplasty. One female died during the post surgical period suffering from aortic wall injury. In four cases, despite successful surgeries, there still remains an arterial hypertension requiring pharmacological treatment. In 4 out of 18 cases (22%) isolated aortic valves defects were diagnosed, however, at present time they do not require any surgical treatment. In three cases, echocardiographic examination indicated a persistent left superior vena cava and aneurysm atrial septal defect with an intact septum. CONCLUSIONS: Due to a high prevalence of cardiovascular malformations, girls with Turner syndrome should be monitored by a pediatric cardiologist. In each case, female with Turner syndrome should be submitted to echocardiography. Also a careful control of the blood pressure is indicated.

[Endocrinologic problems in children with Down syndrome]. / Problemy endokrynologiczne u dzieci z zespolem Downa.

This "Endocrinologic health care guide" was prepared for individuals with Down syndrome. We hope this will serve as a reference for primary care physicians. We presented clinical characteristics, laboratory issues and treatment of children with Down syndrome and endocrinologic problems: abnormalities of thyroid function, obesity, diabetes mellitus, obesity, fertility control.

[Endocrinology complications of Langerhans cell histiocytosis]. / Endokrynologiczne powiklania histiocytozy.

The aim of presentation is an unusual case report of a 17 year old boy with short statured (SD (-)4), absent puberty and thyroid enlargement. Endocrine tests demonstrated a growth hormone and gonadotropin deficiency with diabetes insipidus. Magnetic resonance imaging showed a small pituitary gland and an absence of the posterior bright signal. Fine needle aspiration cytology of the focus localized in the left lobe of thyroid gland and nearest enlarged lymph nodes revealed diffuse infiltrate by the large histiocytosis confirming Langerhans cell histiocytosis like in the skin histological specimen biopsy. After chemotherapy we observed a regretion of focal changes in the thyroid.

Ultrasound image of the thyroid gland in obese children.

Obesity as a disease of affluence also affects younger children. Numerous observations suggest a link between excessive body weight and thyroid function disorders. Subclinical hypothyroidism has been diagnosed increasingly frequently in patients with obesity. A growing number of papers also point to morphological changes of the thyroid gland in the ultrasound examination in obese children. These reports mainly concern changes in echogenicity. The present paper discusses the most important aspects of this topic on the basis of the literature as well as containing a brief analysis based on own experiences.

[Sudden death caused by myocarditis in a 14-year old boy with type I diabetes]. / Nagly zgon z powodu zapalenia miesnia serca u 14-letniego chlopca z cukrzyca typu I.

We report a case of diabetic ketoacidosis complicated by acute myocarditis which was confirmed by necroscopy. A 14 year boy was hospitalised with severe ketoacidosis. The patient levels of creatinine, transaminases were elevated, symptoms of hearth disease were complicated by dehydration and high temperature. An episode of upper respiratory viral infection before the onset of acute diabetes suggested that the patient died from viral myocarditis.

[Growth velocity in children after chemo- and radiotherapy]. / Przebieg wzrastania dzieci dotknietych choroba nowotworowa.

UNLABELLED: The increasing number of childhood cancer survivors has resulted in growing interest in the late effects of chemo- and radiotherapy including growth also. THE AIM OF STUDY: The aim of study was to evaluate growth in children treated for acute lymphoblastic leukaemia (ALL) and Wilms' tumour who achieved complete continuous first remission following treatment. PATIENTS AND METHODS: 52 children included in this study: 30 treated for ALL - group I and 22 with Wilms' tumour - group II since 1986 to 1996. Group I- all children received prophylactic cranial irradiation at the total dose 12 and 18 Gy and chemotherapy according to therapeutic course BFM 83 and BFM 90. Group II - all children received abdomen irradiation with total dose 15-35 Gy, chemotherapy according to therapeutic course SIOP 9 and SIOP 92. We analysed growth velocity from the time of diagnosis to the time of examination. Results were reported as standard deviation score (SDS) to allow for comparison of patients of different age and sex. RESULTS: We observed significant growth deceleration in the first year of treatment and catch-up after 12 months from completion of therapy in both groups. The greatest reduction in yearly decrements in height SDS occurred in the first year after diagnosis. Patients of group I treated with prophylactic cranial irradiation with total dose 12 Gy presented significantly higher catch-up growth than treated with dose 18 Gy one year from completion of cancer therapy (p=0.001). Growth hormone deficiency in children of both groups was not observed. Bone age deceleration was retarded one year or more in both groups (group I p=0.025, group II p=0.001). CONCLUSIONS: 1) The chemotherapy and radiotherapy contribute to growth retardation in the first year of treatment in both groups 2) It seems that prophylactic cranial irradiation in children with ALL with total doses 12 and 18 Gy does not contribute to retardation of growth velocity after cancer treatment 3) Endocrine follow-up should be introduced in order to detect and treat complications as early as possible.

[Thyroid autoantibodies in children with recently diagnosed insulin-dependent diabetes mellitus]. / Przeciwciala przeciwtarczycowe u dzieci ze swiezo rozpoznana cukrzyca typu 1.

UNLABELLED: 119 newly diagnosed insulin dependent diabetes mellitus (IDDM) children - 59 girls and 60 boys aged 2-16 years were examined for the presence of thyroid autoantibodies (TA), T3, T4 and TSH levels. Estimate was repeated after 2 years with sonography of thyroid in children with the presence of TA. At onset of IDDM positive TA were found in 38 (32%) diabetic children - in 20 boys and 18 girls. The highest frequency of TA was stated in children aged 10-13 years. One boy with high TA was identified to have primary hypothyroidism caused by Hashimoto thyroiditis. In the remaining of children T3, T4 and TSH were in normal ranges and there was no significant difference between TA positive and TA negative group. In the examination after 2 years TA were found in 24% of children who were positive at onset. There were significant differences in T3 and T4 levels between children with positive TA at onset of IDDM and after 2 years. Thyroid volume by ultrasound was significantly higher in AT positive children (10.79+/-4.1 ml) than in ones who were TA negative 2 years later (7.99+/-4.3 ml). In half of TA positive children ultrasound changes were observed. CONCLUSIONS: High frequency of TA at onset of IDDM in children was observed. Careful follow-up examinations of thyroid function and ultrasound in that group are advised.

[Newborn mass screening for congenital hypothyroidism in Gdansk region]. / Badania przesiewowe noworodków w kierunku wrodzonej niedoczynnosci tarczycy w regionie gdanskim.

Newborn mass screening for congenital hypothyroidism was introduced in the Gdansk region in 1993. During the period 1993-2001 180708 newborns were screened. The prevalence of congenital hypothyroidism was 1:4203. The prevalence of transient hyperthyrotropinemia before implementation of the program of universal salt iodization was 0.016%, after that 0.003%.The request rate for repeated samples was 0.47% before and 0.24% after salt iodization.

[Effect of three years obligatory iodine prophylaxis on the incidence of goiter in school children fron the seaside region of Poland]. / Wplyw trzyletniej obowiazkowej profilaktyki jodowej na czestosc wystepowania wola u dzieci szkolnych w regionie nadmorskim Polski.

UNLABELLED: In 1993 a mild iodine deficiency in the seaside region of Poland was revealed. In 1997 a mandatory iodine prophylaxis was introduced. The aim of the study was to determine the prevalence of goiter in schoolchildren aged 12-15 years from the seaside area after 3 years of obligatory iodine prophylaxis. The study comprised 628 children (291 boys and 337 girls). Thyroid size was estimated by palpation and by ultrasonography. Analysis of iodine excretion (Uroiod-Test Merck) was performed in 147 children. The goiter was found in 9% of children by palpation. The mean thyroid volume in 12 years old group was 9.3 +/- 5.1 ml, in 13 years old group 10.6 +/- 4.2 ml, 14 years old group 11.7 +/- 3.9 ml, 15 years 13.8 +/- 4.3 ml. The thyroid volume in girls was larger than that in boys. Thyroid volume above 97th percentile was assessed by ultrasound in 16% children (all of them from rural area). No goiter was found by palpation or ultrasound in children living in Gdansk Thyroid volume is closely correlated with iodine excretion, age and height. Urinary iodine excretion above 100 micrograms/l was stated in 68% children. CONCLUSIONS: Model of obligatory iodised salt prophylaxis is highly effective and is able to increase urinary iodine excretion and decrease of goiter prevalence. Ultrasound is especially recommended for the evaluation of thyroid volume in children from previously mild iodine deficiency areas.

[Difficulties in the diagnosis of thyroid cancer in 8-year-old boy]. / Trudnosci w rozpoznaniu raka gruczolu tarczowego u 8-letniego chlopca.

The 8-year-old boy with 13 months history of enlargement of right cervical lymph nodes is described in this paper. Infectious lymphadenopathy was initially diagnosed. He was treated with antibiotics without success. Fine-needle aspiration biopsy in one of the enlarged lymph nodes showed the cells of normal thyroid gland without any signs of atypical growth. USG and scintigraphy revealed normal thyroid gland without nodules; no extra thyroid glands were detected. In 13th month of the disease two enlarged (about 5 ml each), painful, rather hard cervical nodules were present. The thyroid gland was no enlarged and without any palpable nodules. Chest X-ray and second thyroid scintigraphy were normal. Ultrasound imaging of thyroid gland revealed hypoechogenic lesion 11 x 9 x 12 in diameter in the upper part of right thyroid lobe. The morphological findings of removed nodules allowed to make a diagnosis of carcinoma papillare psammomatosum glandulae thyroideae. Total thyroidectomy with removal of cervical ipsilateral lymph nodes was performed. The operation is to be followed by radioactive iodine ablation and thyroid hormone suppression. The authors analyzed the causes and difficulties in diagnosis.

Graves' disease, Celiac disease and liver function abnormalities in a patient--clinical manifestation and diagnostic difficulties.

Autoimmune diseases due to probable common pathogenesis tend to coexist in some patients. Complex clinical presentation with diverse timing of particular symptoms and sophisticated treatment with numerous side effects, may cause diagnostic difficulties, especially in children. The paper presents diagnostic difficulties and pitfalls in a child with Graves' disease, celiac disease and liver function abnormalities.