Effects of Recombinant Human Growth Hormone Treatment, Depending on the Therapy Start in Different Nutritional Phases in Paediatric Patients with Prader-Willi Syndrome: A Polish Multicentre Study.

Recombinant human growth hormone (rhGH) treatment is an established management in patients with Prader-Willi syndrome (PWS), with growth promotion and improvement in body composition and possibly the metabolic state. We compared anthropometric characteristics, insulin-like growth factor 1 (IGF1) levels, metabolic parameters and the bone age/chronological age index (BA/CA) in 147 children with PWS, divided according to age of rhGH start into four groups, corresponding to nutritional phases in PWS. We analysed four time points: baseline, rhGH1 (1.21 ± 0.81 years), rhGH2 (3.77 ± 2.17 years) and rhGH3 (6.50 ± 2.92 years). There were no major differences regarding height SDS between the groups, with a higher growth velocity (GV) (p = 0.00) and lower body mass index (BMI) SDS (p < 0.05) between the first and older groups during almost the whole follow-up. IGF1 SDS values were lower in group 1 vs. other groups at rhGH1 and vs. groups 2 and 3 at rhGH2 (p < 0.05). Glucose metabolism parameters were favourable in groups 1 and 2, and the lipid profile was comparable in all groups. BA/CA was similar between the older groups. rhGH therapy was most effective in the youngest patients, before the nutritional phase of increased appetite. We did not observe worsening of metabolic parameters or BA/CA advancement in older patients during a comparable time of rhGH therapy.

Correlation of Genotype and Perinatal Period, Time of Diagnosis and Anthropometric Data before Commencement of Recombinant Human Growth Hormone Treatment in Polish Patients with Prader-Willi Syndrome.

Genotype-phenotype correlation in patients with Prader-Willi syndrome (PWS) has still not been fully described. We retrospectively analysed data of 147 patients and compared groups according to genetic diagnosis: paternal deletion of chromosome 15q11-q13 (DEL 15, n = 81), maternal uniparental disomy (UPD 15, n = 10), excluded DEL 15 (UPD 15 or imprinting centre defect, UPD/ID, n = 30). Group DEL 15 had an earlier genetic diagnosis and recombinant human growth hormone (rhGH) start (p = 0.00), with a higher insulin-like growth factor 1 (IGF1) level compared to group UPD/ID (p = 0.04). Among perinatal characteristics, there was only a tendency towards lower birth weight SDS in group UPD 15 (p = 0.06). We also compared data at rhGH start in relation to genetic diagnosis age-group 1: age ≤9 months, group 2: >9 months ≤ 2 years, group 3: > 2 years. Group 1 had the earliest rhGH start (p = 0.00), with lower body mass index (BMI) SDS (p = 0.00) and a tendency towards a higher IGF1 level compared to group 3 (p = 0.05). Genetic background in children with PWS is related to time of diagnosis and rhGH start, with a difference in IGF1 level before the therapy, but it seems to have little impact on perinatal data. Early genetic diagnosis leads to early rhGH treatment with favourable lower BMI SDS.

Cerebral salt wasting in a postoperative period.

Cerebral salt wasting syndrome (CSW-cerebral salt wasting) was first described in 1950 by Peters. This syndrome can occur in patients who have sustained damage to the central nervous system (e.g. patients with subarachnoid bleeding, bacterial meningitis or after neurosurgery). Patients present with excessive natriuresis and hyponatremic dehydration. Differentiating this syndrome with the syndrome of inappropriate antidiuretic hormone secretion (SIADH-syndrome of inappropriate antidiuretic hormone secretion), which may occur in the same group of patients, is necessary in order to administer the correct treatment which consists of fluid restriction and sodium replacement in SIADH and fluid and sodium replacement as well as occasional mineralocorticoid therapy in CSW.

The association of FGF23 levels in obese adolescents with insulin sensitivity.

BACKGROUND: The fibroblast growth factor 23 (FGF23) is the most important hormonal regulator of circulating phosphate levels. Apart from this essential role, it may also act as a 'hormone-like' factor involved in glucose and lipid metabolism. It is believed to have a potential role in the development of insulin resistance. AIM: The aim of the study was to compare FGF23 levels between two groups of obese adolescents: insulin resistant and non-insulin resistant. PATIENTS: The study included 36 obese, insulin-resistant adolescents (21 boys and 15 girls) of pubertal age (mean age, 13.95 years; Tanner stage IV or V). The control group consisted of 21 obese peers with normal HOMA-IR values. METHODS: FGF23 levels were measured in a fasting blood sample by Human Intact FGF-23 ELISA Kit (Immunotopics Inc., San Clemente, CA, USA). A standard oral glucose tolerance test was performed, which assessed fasting and 120 min postload plasma glucose and serum insulin levels; the insulin resistance index HOMA-IR was calculated. The definition of insulin resistance was based on a HOMA-IR threshold set for adolescents (> or = 3.16). RESULTS: There was a significant inverse correlation between FGF23 levels and HOMA-IR (R = -0.26, p < 0.05) in the study group. FGF23 levels were also significantly lower in the study group (9.8 vs. 11.9 pg/mL, p = 0.026). CONCLUSIONS: In adolescents with simple obesity and insulin resistance, FGF23 levels are lower compared with obese adolescents with normal HOMA-IR.

A decrease in fasting FGF19 levels is associated with the development of non-alcoholic fatty liver disease in obese adolescents.

AIM: Fibroblast growth factor 19 (FGF19) is a hormone released from the small intestine; recently, it has emerged as an endocrine regulator of glucose and lipid metabolism. The aim of this study was to investigate the role of FGF19 in the development of nonalcoholic fatty liver disease (NAFLD). PATIENTS: This study included 23 (17 boys) obese adolescents (mean age of 14.1 years) with NAFLD. The control group consisted of 34 (13 boys) obese peers with normal ultrasonographic imaging and normal liver function tests. METHODS: The definition of NAFLD was based on clinical criteria: elevated alanine aminotransferase (>35 U/L) and liver steatosis features on ultrasound imaging. Serum FGF19 levels were measured in a fasting blood sample. The definition of insulin resistance was based on the homeostasis model assessment (HOMA) threshold: >2.5. RESULTS: There was a significant difference between mean FGF19 levels in patients with NAFLD and controls (142.2 vs. 206 pg/mL, p=0.04). Mean fasting FGF19 levels were decreased in insulin-resistant patients in comparison with the non-insulin-resistant group (155.0 vs. 221.0 pg/mL, p=0.05). There was an inverse correlation between FGF19 and alanine aminotransferase levels (R=-0.3, p<0.05) and triglycerides (R=-0.27, p<0.05). CONCLUSION: A decrease in fasting FGF19 is associated with the development of NAFLD in obese adolescents. A decrease in fasting FGF19 levels may be a new important risk factor for NAFLD and the metabolic syndrome in adolescents. Further studies are needed to explain whether exogenous delivery of FGF19 might be therapeutically beneficial.

FGF23 contributes to insulin sensitivity in obese adolescents - preliminary results.

UNLABELLED: Fibroblast growth factor-23 (FGF23) is a hormonal regulator of circulating phosphate and vitamin D levels. Recent investigations revealed that besides a key role in the pathogenesis of calcium-phosphorus disorders, in some patients FGF23 may be an indicator of cardiovascular complications. As a 'hormone-like' factor, it may also be involved in some metabolic processes, especially in the metabolism of glucose and fat. Its potential contribution to metabolic syndrome (MS) development has not been confirmed yet. OBJECTIVE: The study was to examine the possible correlations between FGF23 serum levels and body composition, blood pressure and selected parameters of glucose, insulin and fat metabolism in adolescents with simple obesity. PATIENTS AND DESIGN: In 68 (35 female) adolescents (mean age 13·9 years) with simple obesity [mean BMI SDS 4·9 (95% CI 4·4-5·4)], the levels of FGF23, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides were measured. Standard oral glucose tolerance tests were performed with the assessment of fasting and after 120' postload glucose and insulin levels; the insulin resistance index HOMA-IR was calculated. RESULTS: Regardless of gender, there was a significant inverse correlation between FGF23 and fasting insulin level (r = -0·3), as well as HOMA-IR (r = -0·29). Multiple regression model showed the independent association between FGF23 and HOMA-IR. CONCLUSION: FGF23 seems to be a novel factor contributing to insulin sensitivity. Further investigations are needed to define its role in the development of MS.

Causes and consequences of abandoning one-stage bilateral adrenalectomy recommended in primary pigmented nodular adrenocortical disease--case presentation.

We present a 7-year-old girl with a 2-year history of decelerated growth rate and cushingoidal obesity, upon admission presenting with fixed hypertension. Cyclic hypercortisolemia with inhibited baseline and post-CRH stimulation ACTH level pointed to primary adrenal hypercortisolemia. Ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) showed normal adrenal glands. 131J-labeled cholesterol scintiscan showed a weak but slightly more expressed tracer uptake in the left adrenal gland. Cushing syndrome concomitant with isolated primary pigmented nodular adrenocortical disease (PPNAD) was diagnosed. After hypotensive pretreatment, a left adrenalectomy was performed, resulting in normalization of corticoadrenal function, blood pressure, Cushing features and growth rate. Histopathology confirmed PPNAD. In the course of infection, corticoadrenal function showed absence of adrenal reserve, and adrenal crisis. Hydrocortisone (HC) therapy, followed by HC supplementation was introduced. Four years later, a contralateral adrenalectomy was performed and total HC supplementation was introduced. Causes and consequences of abandoning one-stage bilateral adrenalectomy recommended in PPNAD are reviewed.

[Long-term endocrine complications after brain tumor treatment--own experience]. / Odlegle powiklania endokrynologiczne po zakonczeniu leczenia guzów mózgu--doswiadczenia wlasne.

BACKGROUND: Long-term endocrine complications affect approximately 40% of childhood cancer survivors. THE AIM: The retrospective analysis of parameters of the endocrine system function up to 10 years after head radiotherapy (RT) and chemotherapy (CT) due to malignant solid tumor of the central nervous system. MATERIAL AND METHODS: The analysis included 30 patients (15 girls; 15 boys) followed in Endocrine Outpatient Department, University Children's Hospital of Krakow for 1-10 years (mean 5.8 years) after completion of cancer therapy. RESULTS: There was no endocrinopathy in 11 patients (34%), but only five of them were followed for longer than 5 years. A single endocrine disorder was seen in patients (28%), two independent disorders in six (20%), three in three children (10%), and four in two (6.7%). The most common endocrine disorder was growth hormone deficiency (GHD) (13 patients, 46.6%). Primary and secondary hypothyroidism were observed in seven (23%) and two patients (6.7%), respectively, secondary adrenal insufficiency in two (6.7%), hypogonadotropic or hypergonadotropic hypogonadism in seven (23%) and two patients (6.7%), respectively. Obesity without any hormone deficiency was present in five patients (16.6%) patients, in one case, the condition was complicated by glucose intolerance, in four children, by a high level of triglycerides and low HDL cholesterol. CONCLUSIONS: 1. Late endocrine complications after malignant brain tumor treatment affect 66% of patients followed for 1-10 years after completion of RT. That points to the necessity of long-term, regular followup of the patients after cancer treatment. 2. The most common endocrinopathy is GHD, followed by hypothyroidism, hypogonadism and adrenal insufficiency. 3. In patients after head RT and CT in childhood, there is noted secondary obesity, with complications typical for metabolic syndrome.

[Neurological disorders in patients with hypoparathyroidism]. / Zaburzenia neurologiczne u pacjentów z niedoczynnoscia przytarczyc.

BACKGROUND: The term hypoparathyroidism refers to a group of disorders in which a relative or absolute deficiency of PTH leads to hypocalcemia and hyperphosphatemia. THE AIM OF THE STUDY: Was to evaluate clinical symptoms in patients with hypoparathyroidism during normocalcemic period and to try to establish its etiology (electrolyte imbalance, organic central nervous system lesions, coincidence of tetany and epilepsy). MATERIAL AND METHODS: The analysis included a group of 14 patients with hypoparathyroidism: 3 boys and 11 girls, aged from 12 months to 31 years (median 16.11 years), with duration of the disease 12 months to 26 years (median 10.9 years). In all the patients, the diagnosis was confirmed based on history, physical examination, results of biochemical and hormonal laboratory tests, radiological and neurological examinations. All the patients were followed by endocrinology specialists. Low phosphorus diet, calcium, magnesium, active vitamin D supplementation and management of other endocrine disorders were employed. RESULTS: In 9 patients, pseudo-hypoparathyrodism was diagnosed; of this number, in 8 children, type Ia Albright syndrome was confirmed. Five patients were diagnosed as true hypoparathyroidism, two girls in this group were found to have autoimmune hypoparathyroidism as a component of the autoimmune polyglandular syndrome type 1, 2 others were diagnosed in infancy as congenital hypoparathyroidism and 1 girl had true hypoparathyroidism as a component of Kearns-Sayre syndrome. Five patients were referred to neurological department with epilepsy suspicion. In the medical history, 9 patients had generalized epileptic seizures, moreover, 1 girl manifested absence attack and balance disturbances. In 3 patients, EEG demonstrated changes typical of generalized seizure activity. In 5 patients on anti-epileptic management, additional calcium and active vitamin D treatment was initiated, allowing for achieving seizure remission. CT of the head and pituitary gland showed calcification foci in the central nervous system in 9 patients. Five patients of the eight individuals with Albright syndrome showed mild or moderate mental retardation confirmed by psychological testing. CONCLUSIONS: 1. Hypoparathyroidism leads to functional and morphological CNS changes. 2. Restoring metabolic balance through administration of calcium and active vitamin D preparations may obliterate the need for anti-epileptic treatment. 3. Calcification foci in the central nervous system seem to be associated with the duration of hypoparathyroidism. 4. No correlation has been observed between the extent and location of calcification foci and neurological abnormalities. 5. Hypoparathyroid patients with calcification foci in CSN require long-term multidisciplinary medical management and neurophysiological, imaging and neuropsychological monitoring.

[Neurofibromatosis type I--the pediatric endocrinologist's point of view]. / Nerwiakowlókniakowatosc typu 1 z punktu widzenia endokrynologa dzieciecego.

AIM OF THE STUDY: A retrospective analysis of endocrine disorders in patients with neurofibromatosis type I consulted in the Children's University Hospital of Krakow in the period 2007-2010. MATERIAL AND METHODS: The analysis included 60 patients (33 girls, and 27 boys) aged 1.2-32 years, mean 11.6 years. The patients were followed up by many health care professionals: neurologists (EEG), neurosurgeons (CT, MRI), ophthalmologists, psychologists, ENT specialists, anthropologists (the assessment of body height and weight), geneticists, endocrinologists and gynecologists (the assessment of puberty according to Tanner scale, diagnostics of short stature, precocious puberty), and cardiologists (echo-cardiography). RESULTS: In the analyzed group of 60 patients, 46 were consulted by geneticists, 20 by endocrinologists, 19 by neurologists and cardiologists. The imaging of the central nervous system (CNS) was performed in 37 patients. Twenty-two patients presented with familial NF-I, 13 with sporadic NF-I, and in 25 patients, the family history was unavailable. Growth disorders were present in 27.7% of patients (13/47) that were referred to the anthropometric assessment. Short stature (height < or = (-) 2 SD) was recognized in 9/47 of children (19.1%). Tall stature (> (+) 2 SD) was recognized in 4/47 of patients (8.5%). All of the patients with tall stature presented with central precocious puberty (PD). Precocious puberty was also recognized in two children with normal stature. In all cases of PD, optic chiasm gliomas were recognized. Generally, organic CSN disorders were detected in 24 patients (63.2%). MRI revealed optic chiasm gliomas in 8 patients, 4 presented with gliomas of one or two optic nerves, 10 presented with hyperintensive areas on T2-weighted images, without enhancement after contrast injection, that may suggest the diagnosis of hamartoma of the CNS, and 2 with hydrocephaly. CONCLUSIONS: 1. The most common disorders of the somatic development revealed in NF-I patients are growth disorders: short stature and tall stature caused by central precocious puberty. 2. In view of the incidence of endocrine disorders in patients with NF-I, the authors suggest an endocrine consultation in each case of NF-I.

[The impact of the 4-year human recombinant growth hormone treatment on growth, body composition and bone mineral density in patients with isolated growth hormone deficiency and multihormonal pituitary insufficiency]. / Wplyw 4-letniego leczenia ludzkim rekombinowanym hormonem wzrostu na wzrastanie, sklad ciala oraz gestosc mineralna koscca u dzieci z izolowana somatotropinowa niedoczynnoscia przysadki i wielohormonalna niedoczynnoscia przysadki.

BACKGROUND: In addition to stimulating bone growth in length, human recombinant growth hormone (rhGH) significantly affects in a direct and IGF-I-mediated manner body composition (body fat/lean body mass ratio) and skeletal maturation in vitro and in vivo. The direct role of rhGH on bone mineralization and its effect on bone mineral density is controversial. AIM: To compare growth and body composition, bone mineral density (BMD) and bone mineral content (BMC) in prepubertal children with isolated growth hormone deficiency (GHD) and congenital multihormonal pituitary deficiency (MPD), including MPD resulting from the PROP-1 gene mutation. MATERIAL AND METHODS: The study included 53 children (36 boys and 17 girls) aged 8.4 +/- 3.2 years with diagnosed GH deficiency. The subjects were divided into three groups. Group 1 consisted of patients with MPD resulting from the PROP-1 gene mutation: 14 children (8 girls and 6 boys) aged 6.4 +/- 2.1 years, Group 2 included children with MPD resulting from causes other than the PROP-1 gene mutation: 21 patients (5 girls and 16 boys) aged 9.6 +/- 3.9 years, while Group 3 represented children with GHD: 18 subjects (4 girls and 14 boys) aged 8.6 +/- 2.5 years. All the children were clinically and biochemically euthyreotic. The patients were assessed auxologically every three months. Their bone age was evaluated every year. Puberty stages were determined according to Tanner. BMI was calculated in keeping with the equation: kg/m2. Bone densitometry and body composition were determined by DEXA (DPX-IQ Lunar) prior to initiation of rhGH substitution and at yearly intervals in the course of rhGH treatment. RESULTS: Prior to commencement of rhGH substitution, the height of the PROP [+] patients was the lowest of all groups, with statistical significance demonstrated when comparing the above children to the GHD group (PROP [+]: -3.3 SD; PROP [-]: -2.8; GHD: -2.7 SD). Growth analysis in the three groups of patients showed a statistically significant improvement in each group, with the strongest effect in the PROP [+] group; the respective height increase in particular groups was: PROP [+]: 2.8 SD; PROP [-] 1.6 SD; GHD 1.9 SD. After 4-year rhGH substitution, patients with MPD PROP [+] and PROP [-] demonstrated an increase of BMC by 585.9 g and 350.2 g, respectively; no significant increase was observed in the GHD group. Prior to treatment, all the groups showed a comparable decrease of lumbar spine BMD (BMD LS): Z-score PROP [+] (-) 2.5 SDS; PROP [-] (-2.8) SDS; GHD (-) 2.0 SDS. In subsequent years of treatment, the BMD LS values were within normal range, i.e. above (-) 2.0 SD. A statistically significant increase of BMD LS by (+) 1.1 SD was noted in the PROP [-] patients. In all the groups, the mean total BMD values were within normal range, i.e. above (-) 2.0 SD prior to initiation of rhGH substitution and in subsequent years of follow-up. Prior to commencement of rhGH substitution vBMDLS SDS of the PROP [+] patients was the lowest of all groups, with statistical significance demonstrated when comparing the above children to the GHD group (PROP [+]:(-)2,8 +/- 1,6; PROP [-]:(-)1,9 +/- 1,8; GHD: (-)1,9 +/- 2,3 SD. After 4-year rhGH substitution lowest values of vBMDLS SDS were found also in PROP[+]: (-)1,6 +/- 1,3 SD, ans subsequently PROP[-]: (-)0,9 +/- 1,0 and SNP: (-)0,7 +/- 1,8 SD. Body fat percentage prior to rhGH substitution was the highest in the PROP [+] patients and the lowest in the GHD group: PROP [+]: 28%, PROP [-]: 26%, GHD: 20%, with the difference between PROP [+] and GHD being statistically significant. During all study period all children remained prepubertal. CONCLUSIONS: 1) Patients with MPD and the PROP1 gene mutation are characterized by a shorter stature, lower BMD and lower lean body mass as compared to MPD patients without PROP1 mutation and to GHD patients. 2) In comparison to children with GHD, rhGH substitution in patients with MPD exerted a more favorable effect on their growth, BMD and body composition.

[Disorders of lipid metabolism in adolescents with simple obesity]. / Zaburzenia metabolizmu lipidów u mlodziezy z otyloscia prosta.

BACKGROUND: Obesity affects approximately 45 millions of children worldwide. Some of them present with secondary dyslipidemia that leads to premature atherosclerosis. AIM OF THE STUDY: 1) Assessment of the frequency and type of dyslipidemia in obese adolescents. 2) An attempt at defining risk factors of atherogenic lipid profile in obese adolescents. MATERIAL AND METHODS: In 146 (84 girls/62 boys) obese (mean BMI SDS 4.95, 95% CI 4.62-5.29) adolescents (age 10-18, mean 14.7 years), the levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc) and triglicerydes (TG) were measured. Atherogenic dyslipidemia was defined as a high TG level with a concomitant low HDLc level. Standard oral glucose tolerance test was performed with the assessment of fasting and after 120' post-load of 75 g of glucose and insulin levels; the insulin resistance index HOMA-IR was calculated. RESULTS: The mean values of the lipid fractions were in normal ranges: TC 4.64 mmol/L (95% CI 4.48-4.8), LDLc 2.86 mmol/L (95% CI 2.73-2.99), TG 1.4 mmol/L (95% CI 1.3-1.5), and HDLc 1.16 (95% CI 1.1-1.2). However, in 50.69% of the patients (45.24% girls and 58.06% boys), elevated levels of TC, LDLc, and TG were observed respectively in 23.29%, 17.81% and 37.67%, and low HDLc in 15.07% of patients. A total of 10.96% of the patients presented with coexistence of a low HDLc and a high TG. In 26.7%, dyslipidemia was followed by arterial hypertension. There was a reverse correlation between a low HDLc value and BMI SDS [R (-) 0.22, p < 0.05] and not with TC, LDLc, and TG. The relative risk of abnormal lipid profile occurrence was higher in obese patients with insulin resistance (OR 1.72; 95% CI 0.8-3.4; p = 0.12), being significant only for boys (OR 3.67; 95% CI 1.1-12.1; p = 0.03). There was a reverse correlation between fasting insulin level, HOMA-IR and HDLc [R (-) 0.2; p < 0.05; R (-) 0.2; p < 0.05) respectively], as well as TG (R 0.26 ; p < 0.05; R 0.26; p < 0.05, respectively), and between post-load insulin level and TG (R 0.24; p < 0.05). CONCLUSIONS: 1) Lipid disorders occur in about one-half of obese adolescents, of which 10% presents with atherogenic lipid profile. 2) One of the most important risk factors of atherogenic lipid profile occurrence is insulin resistance, especially in boys. The severity of the obesity (BMI-SDS) is of lesser importance.