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.

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.

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.

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.

[Pathological daytime sleepiness in an 11-year old girl receiving growth hormone treatment previously cured from craniopharyngioma]. / Napady patologicznej sennosci dziennej u 11-letniej dziewczynki leczonej ludzkim rekombinowanym hormonem wzrostu po zakonczonym leczeniu z powodu czaszkogardlaka.

UNLABELLED: An 11-year old girl with multihormonal pituitary deficiency previously cured from craniopharyngioma was admitted to the endocrinology Department because of pathological daytime sleepiness. At the age of 7 she had undergone brain tumor surgery with adjuvant radiotherapy (complete dose of 5400 cGy). She had been given replacement therapy of thyroid hormone, cortisol and adiuretin. At the age of 10 years she had started growth hormone (rGH) treatment. After a period of four months of rGH replacement therapy the girl's mother had observed symptoms of excessive daytime sleepiness with a tendency to escalation. MRI of the brain had been performed; no progression has been shown. After 10 months from the start of rGH replacement therapy was referred to the endocrinology department. On the basis of laboratory findings electrolyte and hormonal abnormalities were excluded. On physical examination, the girl manifested massive tonsillar hypertrophy. It was disclosed that she developed obstructive sleep apnea with the drop of oxygen saturation to 60%. The patient was qualified to adenotonsillectomy. There was a spectacular postoperative improvement observed with no future episodes of night apnea and daytime sleepiness. In our opinion, the rGH treatment in our patient induced hypertrophy of the tonsils and adenoid, which led to obstructive sleep apnea syndrome with compensatory daytime sleepiness. CONCLUSIONS: Obstructive sleep apnea syndrome with compensatory daytime sleepiness may occur in children on rGH replacement therapy. During rGH therapy children should be regularly examined by a laryngologist.

[The evaluation of the influence of growth hormone therapy on growing process and metabolic functions in patients after treatment of craniopharyngioma]. / Ocena wplywu terapii hormonem wzrostu na przebieg wzrastania i funkcje metaboliczne u pacjentów po leczeniu craniopharyngioma.

INTRODUCTION: Craniopharyngioma (CP) is a tumor, which damages pituitary function because of its localization. Panhypopituitarism (PHP) and excessive weight gain with lipid dysfunction are frequently observed. The growth hormone therapy (rGH) profits in the increase of growth rate and also may have metabolic effects like body weight reduction. AIM OF THE STUDY: The evaluation of benefits from rGH therapy in patients cured from CP. MATERIAL AND METHODS: 12 patients (7 boys and 5 girls) treated for CP with surgery; 3 of them also underwent radiotherapy. The mean age at examination time was 11.7 yrs; remission time 2.96 yrs; rGH therapy started on average 3.69 yrs after the surgery. Height (hSDS), weight, BMI were measured after the surgery, before and after 1 yr of rGH treatment. Height velocity (HV) was evaluated before and after 1 yr of rGH therapy. Pituitary GH-function was assessed. In addition, measurements of TSH, ACTH, LH, FSH. Cholesterol, LDL, HDL, triglycerides and HbA1c were estimated before and after one year of rGH therapy. RESULTS: All patients presented PHP. The GH-peak average 1.53 mIU/l; IGF-1 39.37 ng/ml; TSH 0.1 U/l; ACTH 17.48 pg/ml; LH 0.13 U/l; FSH 0.41 mIU/ml. HSDS after oncological treatment (OT) average -1.66 SD and decreased significantly until rGH therapy; weight after OT average 28.45 kg and until rGH therapy increased significantly; BMI after OT average 19.26 and increased significantly until rGH therapy as well. HV was on average 3.34 cm/yr until rGH started. After one year of rGH therapy hSDS and HV increased significantly; they average -1.65SD and 10.21 cm/yr respectively. BMI, HbA1c and LDL decreased significantly. During rGH therapy neither tumor recurrence nor severe side effects were observed. CONCLUSIONS: rGH therapy of patients cured from CP influences profitably not only growth rate, but also BMI reduction and the decrease in cholesterol LDL and HbA1c.

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.

[Trends in age and height at diagnosis of childhood growth hormone deficiency during the period 1995-2004]. / Jak zmienial sie wiek i wysokosc ciala dzieci z somatotropinowa niedoczynnoscia przysadki kwalifikowanych do leczenia hormonem wzrostu na przestrzeni lat 1995-2004?

THE AIM OF THE STUDY: was to evaluate age and height at the diagnosis of childhood growth hormone deficiency in the group of children who were qualified to growth hormone (GH) treatment in pediatric endocrinology department at Medical University of Gdansk in period 1994-2004. MATERIAL AND METHODS: The analysis comprised 170 GH-deficient children (111 boys) in whom GH treatment was indicated in our department in the period 1995-2004 yr. RESULTS: At diagnosis the mean age was 11,1+/-3,2 yr., mean height -3,6+/-1,0 SDS. Mean age in males was significantly higher, than in females, but there was no statistically significant difference between them. 25% of patients were pubertal. 44% of children lived in rural area, 56% in urban area and the age of diagnosis was similar in both groups. Children from rural area were, however, significantly shorter than those from urban area. 25.3% of patients started with GH treatment in the period 1995-2000 yr. and 74.7% after year 2000. Children who started with GH treatment before year 2000 were younger (9,6+/-3,6 yr.) than those after year 2000 (11.6+/-2.9 yr.). They were also significantly shorter (-4.2+/-1.1 SDS) than patients diagnosed after year 2000 (-3.4+/-0.9 SDS). Height in 67% of patients diagnosed before year 2000 and 36% diagnosed after year 2000 was below -3.5 SDS. CONCLUSIONS: Children with GH deficiency were referred to our department relatively late and the age of the diagnosis did not decrease during the period 1995-2004. The deep height deficiency observed in children at the diagnosis of GH deficiency decreased after year 2000 but it is still a problem in patients from rural area. General practitioners should earlier identify children with height deficiency and refer them to pediatric endocrinologists.

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.

The effect of growth hormone treatment on serum bone alkaline phosphatase in growth hormone deficient children.

INTRODUCTION: Growth hormone (GH) promotes longitudinal growth in children with growth hormone deficiency. Serum bone alkaline phosphatase (BALP) has been considered to be a good marker of bone formation with narrow circadian variation. The aim of the study was to determine the effect of GH treatment on serum BALP levels in children with idiopathic GH deficiency. MATERIAL AND METHODS: A total of 26 prepubertal children (10 girls) with GH deficiency in mean age 9.06+/-1.24 yrs were enrolled in the study. They were treated with daily sc injections of GH (0.5 IU/kg/week). Serum BALP levels were measured using enzyme immunoassay (Alkaphase-B kit, Metra Biosystems) at baseline, 3 and 6 months of GH treatment. RESULTS: A significant increase in serum BALP levels after 3 months of GH treatment was observed. No significant differences between BALP levels after 3 and 6 months of GH therapy were stated. Baseline serum BALP levels correlated positively with the height velocity during the 3 months period before the GH treatment initiation (r=0.63, p<0.05). The BALP increase after 3 months of treatment correlated with height velocity in that period (r=0.69, p<0.05). The change in BALP after 3 months of GH treatment correlated with the improvement in the height after 3 and 6 months (r=0.76, p<0.05) as well as after 12 months of GH treatment (r=0.77, p<0.05). CONCLUSIONS: We conclude that serum BALP appears to be a good early predictor of the growth responses to GH therapy in GH-deficient children.

[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.

[Influence of surgery and radiotherapy on growth and pubertal development in children treated for brain tumour]. / Wplyw zabiegu operacyjnego i radioterapii na tempo wzrastania i rozwoju dzieci z guzami osrodkowego ukladu nerwowego.

INTRODUCTION: The increasing number of childhood cancer survivors has resulted in a growing interest in the late effects, which depend on type of treatment. Frequently, a brain tumour and its therapy in children are endocrinologically devastating. AIM OF STUDY: The aim of study was to compare growth and pubertal development in children after brain tumour therapy treated or not treated with recombinant growth hormone (rGH). MATERIAL AND METHODS: 18 children were included in this study. Group I - (12/18) not treated with rGH, after total resection of brain tumour: craniopharyngeoma (8/12), astrocytoma (2/12) ependymoma (1/12), germinoma (1/12). Mean time of remission was 5,0yrs (+/- 0,9). Group II - (6/12) treated with rGH, after subtotal resection of craniopharyngeoma (4/6), ependymoma (1/6), medulloblastoma (1/6) and cranial irradiation with mean total doses 46,5 Gy (+/- 5,65). Children were qualified for rGH replacement according to deceleration of growth and lower growth hormone secretion (< 10 ng/ml) in stimulating tests. Mean time of remission was 6,5 yrs (+/- 2,41). Growth, height in centimeters converted to standard deviation score--SDS, body mass index (BMI), pubertal status and hormonal tests, were also evaluated. RESULTS: All patients were treated with surgery with no cranial irradiation in prepubertal age. 100% children of group I needed substitution because of secondary hypothyreosis, 83% due to secondary adrenal insufficiency and 53% of diabetes insipidus. Mean height after brain tumour surgical treatment in group I was - 1,24 SDS (+/- 0,85) and did not significantly change in the time of observation. Two girls needed hormonal substitution for hypogonadotropic hypogonadism. Mean BMI after total resection of brain tumour was 18,09 (+/- 4,20) and significantly increased to 23,73 (+/- 2,82). In group II - all children presented multihormonal pituitary insufficiency. Mean deviation score of height before rGH treatment was - 3,84 SDS (+/- 2,87) and after mean time of rGH therapy of 1,5 yrs (+/- 1,2) decreased to 2,6 (+/- 1,06). Mean BMI before treatment with rGH 18, 06 (+/- 4,4) increased to 22,41 (+ 0,74) in the time of observation and decreased to 18,5 (+/- 2,87) after 1,5 years (+/- 1,2) of rGH treatment. CONCLUSIONS: 1. Children treated with surgery for brain tumour need substitution for secondary hypothyroidism, part of then need treatment for secondary adrenal and gonadal insufficiency and diabetes incipidus. 2. Children who were treated with surgery and/or cranial irradiation developed multihormonal pituitary insufficiency, growth failure and replacement rGh therapy was needed. 3. Total resection of brain tumour without chemo- and radiotherapy did not impair growth in first years after surgery.

[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.

[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.