Peripheral Insulin Edema and Pericardial Effusion in a 12-Year-Old Newly Diagnosed Girl with Type 1 Diabetes.

Introduction: Insulin induced edema (IIE) is a rare condition, usually found in newly diagnosed diabetes patients, either after insulin treatment initiation or after dose increment. It is a self-limited process, rarely associated with serosal effusions. Teenage girls with type 1 diabetes (T1DM) are most commonly affected. Patient and Methods: A 12-year-old girl was diagnosed with ketoacidosis (DKA). Seven days after initiation of the insulin treatment, at a stable total daily dose of insulin (TDDI) of 0.55 IU/kg, she came with two kilograms weight gain in only two days and edema of the feet and calves. Ultrasound of the heart found a 7 mm pericardial effusion. The diagnostic workout included clinical examination, biochemical, hormonal, allergen analyses and imaging which excluded other known causes of swelling. Conclusions: We describe an adolescent girl with newly diagnosed T1DM and a rare association of peripheral insulin-induced edema and pericardial effusion. Short-term diuretic treatment and salt restriction resolved this rare complication of insulin treatment.

Demographic, Clinical and Biochemical Characteristics of Pediatric Obesity: Interim Analysis of a Larger Prospective Study.

INTRODUCTION: Pediatric obesity is a common nutritional disorder that affects more than a third of the young population and predis-poses individuals to greater future morbidity and mortality. Materials and methods: Sixty-two children were recruited in the study. Demographic and clinical information regarding the pa-tients and their parents was collected. Data about the weight, height, systolic (SP) and diastolic (DP) blood pressure, lipid metabolic profile, thyroid hormone levels, glucose and insulin levels before and after oral glucose tolerance test (OGTT) of participants were also collected. Body mass index (BMI) was calculated and patients were classified into groups according to the International Obesity Task Force criteria. Descriptive, comparative parametric, non-parametric tests and Spearman's ranked correlations were used in the statistical analysis. Results: The study sample consisted of 34 males and 28 females aged 11.6 and 11.8 years, respectively (p=0.781). The mean BMI was 30.5 (SD 5.5): 8 of participant had normal weight (≤25 BMI), 22 were overweight (25-30 BMI), and 32 were obese (≥30 BMI). The chil-dren's BMIs were significantly associated with parental BMIs (r=0.395, p=0.004). Both SP and DP were significantly different between BMI subgroups (p=0.005 and p=0.001, respectively) with the obese group having the highest values (post-hoc Benjamini,  p=0.004). Obese children had lower average T4 levels when compared to the comparators (7.5 µg/dL vs. 9.9 µg/dL, p=0.021). Obese children had significantly lower baseline glucose levels and higher insulin levels when compared to the overweight/normal BMI children (73.8 mg/dL vs. 86.4 mg/dL, p.

Therapeutic challenges in a patient with the simple virilizing (SV) form of congenital adrenal hyperplasia (CAH) due to the P30L/I172N genotype.

Background Steroid 21-hydroxylase deficiency is an autosomal recessive disorder, present in 90-95% of all cases with congenital adrenal hyperplasia (CAH). The classical simple virilizing (SV) form of the disease causes virilization of the external genitalia in newborn females and pseudo-precocious puberty in both sexes, due to reactive androgen overproduction. Case presentation We describe a 3.5-year-old girl presenting with pubarche, P2 according to Tanner, advanced bone age of 6 years and 10 months, and high serum levels of 17-hydroxyprogesterone (17-OHP). Molecular analysis of the nine most common pseudogene-derived CYP21A2 point mutations was performed in the patient and her family members using the polymerase chain reaction/amplification-created restriction site (PCR/ACRS) method. We detected the P30L/I172N genotype in the patient. She had inherited a mild P30L mutation from her mother and a severe I172N mutation from her father. Conclusions Although the CAH phenotype is determined by the allele that produces most of the enzyme activity and the mild non-classical (NC) phenotype should be expected, the mild P30L known to be more virilizing probably induced the classical SV phenotype in our patient. A continuous regimen of hydrocortisone at a recommended dose failed to decrease the 17-OHP sufficiently. Careful tapering of the dose did not help, and her pubic hair advanced to P3 according to Tanner. Individually tailored treatment is warranted in this patient.

IGF1R Gene Alterations in Children Born Small for Gestitional Age (SGA).

BACKGROUND: Small for gestational age (SGA)-born children are a heterogeneous group with few genetic causes reported. Genetic alterations in the IGF1 receptor (IGF1R) are found in some SGA children. AIM: To investigate whether alterations in IGF1R gene are present in SGA born children. PATIENTS AND METHODS: We analysed 64 children born SGA who stayed short (mean -3.25 ± 0.9 SDS) within the first 4 years of age, and 36 SGA children who caught up growth (0.20 ± 1.1 SDS). PCR products of all coding IGF1R exons were screened by dHPLC followed by direct sequencing of conspicuous fragments to identify small nucleotide variants. The presence of IGF1R gene copy number alterations was determined by Multiplex Ligation-dependent Probe Amplification (MLPA). RESULTS: The cohort of short SGA born children revealed a heterozygous, synonymous variant c.3453C > T in one patient and a novel heterozygous 3 bp in-frame deletion (c.3234_3236delCAT) resulting in one amino acid deletion (p.Ile1078del) in another patient. The first patient had normal serum levels of IGF1. The second patient had unusually low IGF1 serum concentrations (-1.57 SD), which contrasts previously published data where IGF1 levels rarely are found below the age-adjusted mean. CONCLUSIONS: IGF1R gene alterations were present in 2 of 64 short SGA children. The patients did not have any dysmorphic features or developmental delay. It is remarkable that one of them had significantly decreased serum concentrations of IGF1. Growth response to GH treatment in one of the patients was favourable, while the second one discontinued the treatment, but with catch-up growth.

Favorable Growth Hormone Treatment Response in a Young Boy with Achondroplasia.

BACKGROUND: Achondroplasia is a skeletal dysplasia, the most common cause of rhizomelic dwarfism. CASE PRESENTATION: This is a ten year old boy who was first diagnosed prenatally. He had a mutation c1138G>A in the gene FGFR3 in a heterozygotic constellation. His IGF1 and IGFBP3 levels were normal. Two stimulation tests for growth hormone were performed with values within the reference range. His psychomotor development was adequate for his age except for speech difficulty. He started with recombinant hGH (r-hGH) at the age of 3.4 years in a dose of 0.06 mg/kg. His mean Height SDS (HtSDS) was -2.2. RESULTS: The growth increased to 10 cm/year in the first year of therapy (HtSDS -1.1). It decreased during the second year to 4 cm (HtSDS -1.7) and again increased during the third year to 8 cm/year (HtSDS-1.3). In the next years the growth was constant (6.5, 2.3, 3.5 cm / year). He is still growing in the 3(rd) percentile of the growth curve (HtSDS - 1.2) under GH treatment. The body disproportion remained the same. CONCLUSION: The growth response on GH treatment was satisfactory in the first 4 years of treatment, and the boy still continued to grow. The young age at the start of treatment was also of importance. Our other patients with achondroplasia who started treatment older had a poor response to growth hormone.

Mutational analysis of TAC and TACR3 in idiopathic central precocious puberty.

BACKGROUND: The genetic background of idiopathic central precocious puberty (ICPP) is not well understood, and is thought to arise from the effect of multiple genes. Familial ICPP have been reported suggesting the existence of monogenic causes of ICPP. The neurokinin B (NKB) system has recently been implicated in the regulation of the human reproductive axis. In humans, NKB and its receptor are encoded by the TAC3 and TACR3 genes, respectively. Mutations in these genes have been suggested to be causative for ICPP. METHODS: ICPP was defined by pubertal onset before 8 yrs of age in girls, and a pubertal LH response to GnRH testing. Twenty eight girls with ICPP were included in the study (age at diagnosis was 5.72±2.59; bone age, 6.12±2.81, height at the start of treatment, 0.90±1.48 SD). LHRH test was performed and was pubertal in all subjects (LH 20.35±32.37 mIU/ml; FSH 23.32±15.72 mIU/ml). The coding regions of TAC and TACR3 were sequenced. RESULTS: No rare variants were detected in TAC and TACR3 in the 28 subjects with ICPP. CONCLUSIONS: We confirmed that mutations in TAC and TACR3 are not a common cause for ICPP.

Mutational analysis of KISS1 and KISS1R in idiopathic central precocious puberty.

AIM: The genetic background of idiopathic central precocious puberty (ICPP) is not well understood. The genetic activation of pubertal onset is thought to arise from the effect of multiple genes. Familial ICPP has been reported suggesting the existence of monogenic causes of ICPP. Kisspeptin and its receptor are found to be involved in gonadotropin-releasing hormone (GnRH) secretion and puberty onset. Mutations in their genes, KISS1 and KISSR, have been suggested to be causative for ICPP. METHODS: ICPP was defined by pubertal onset before 8 years of age in girls, and a pubertal luteinizing hormone (LH) response to GnRH testing. Twenty-eight girls with ICPP were included in the study [age at diagnosis was 5.72±2.59, with a mean bone age advancement of 1.4 years (-0.1 to 2.8). Height at onset of therapy in SD score was 0.90±1.48 for age]. Luteinizing hormone-releasing hormone test was performed in all subjects, and all of them had a pubertal response (LH 20.35±32.37 mIU/mL; FSH 23.32±15.72 mIU/mL). The coding regions of KISS1 and KISS1R were sequenced. RESULTS: No rare variants were detected in KISS1 or KISS1R in the 28 subjects with ICPP. CONCLUSIONS: We confirmed that mutations in KISS1 and KISS1R are not a common cause for ICPP.

Childhood craniopharyngioma in Macedonia: incidence and outcome after subtotal resection and cranial irradiation.

BACKGROUND: craniopharyngioma is a frequent tumor in children with challenging surgical, endocrine, and visual consequences. We evaluated our experience in treating craniopharyngioma and its incidence in Macedonia. METHODS: Thirteen children (9 male and 4 female) with craniopharyngioma (age 9.55 ± 3.74 years; range 2.90-15.11) who had been treated between 1989 and 2008 in Macedonia were reviewed. RESULTS: initial signs were vision disturbances (10 children), seizures (1), growth retardation (13), and diabetes insipidus (DI) (2). All children were subjected to subtotal surgical removal. Cranial irradiation was performed in 12 of the 13 children, and intracystic bleomycin was given to one child. The patients were followed up for 6-229 months (mean ± SD: 107.00 ± 74.04 months). All children had multiple pituitary deficiencies after surgical removal of the tumor. Body mass index increased from 16.93 ± 6.34 standard deviation scores (SDS) at diagnosis to 26.33 ± 5.91 SDS (P>0.005) at the last follow-up. DI was permanent in 9 of the 13 children, and multiple pituitary deficiencies were seen in all children. Treatment with growth hormone resulted in normalization of adult height from -1.27 ± 1.52 SDS at the start of the treatment to -0.13 ± 1.39 SDS at the last followup. The final height was not significantly lower than the genetic target height (P>0.005). The permanent deficit was visual impairment: blindness in one or both eyes in 4 children, bitemporal hemianopsia in 4, and other defects in 2. Recurrence of the disease was ruled out in one child after 31 months. No mortality was observed in the observation period of 104.92 ± 76.11 months. CONCLUSIONS: the overall incidence of craniopharyngioma in the period of 1989-2008 in Macedonia was 1.43 per 1 000 000 person-years. Subtotal resection and systematic irradiation showed good life quality of survivors.

McCune-Albright syndrome (MAS): early and extensive bone fibrous dysplasia involvement and "mistaken identity" oophorectomy.

BACKGROUND: McCune-Albright syndrome (MAS) is a triad of gonadotropin-independent precocious puberty (GIPP), café-au-lait spots (CALS) and fibrous dysplasia (FD) of bone. The extent of the abnormalities is variable. PATIENT AND RESULTS: We report a 3 year old girl with CALS since infancy, FD diagnosed at age of 2.5 years, and at the age of 3 years vaginal bleeding. The ultrasound revealed a cystic mass of the ovary, surgical pathology found ovarian cyst. LHRH stimulation demonstrated GIPP (LH 9.8 mIU/ml and FSH 8.9 mIU/ml; normal LH 1.8-10, FSH 9-26 mIU/ml). Radiographs and bone scans demonstrated FD in multiple bones. Peripheral leucocytes and the ovary were negative for GNAS gene mutations. Treatment with Letrasole interrupted the pubertal development. CONCLUSIONS: We conclude that the clinical signs of MAS are telling and that timely MAS diagnosis prevents unnecessary oophorectomy. A close follow up is recommended regarding development of endocrine disorders and spreading of FD.

Autoimmune thyroiditis and diabetes mellitus type 1 after long-term gonadotropin-releasing hormone agonist treatment for central precocious puberty: evolution or coincidence?

Very few abnormalities in endocrine function have been reported during long term gonadotropin-releasing hormone agonist (GnRHa) treatment in girls. Most authors agree that this therapy is safe and effective. We present an unusual outcome of long term GnRHa therapy in two girls with central precocious puberty(CPP) of idiopathic or organic origin. They have received monthly depot injections of triptorelin acetate for a time period of 8 years. Thyroid function was examined by measuring serum levels of thyrotropin (TSH), thyroxine (T4), thyroid antibodies, and ultrasound of the thyroid gland. One of the girls was at the age of 8.5 years, having elevated thyroid antibodies, mild goitier and an abnormal ultrasound of the thyroid gland, suggesting autoimmune thyroiditis. Another girl with a hypothalamic hamartoma developed diabetes mellitus at the age of 9 years. Both of these girls were early diagnosed for CPP, at 6 months and 8 months respectively, and given GnRHa treatment. So far, it is not known whether these autoimmune diseases are related to the GnRHa treatment or are simply a coincidence. However, we suggest a closer monitoring of girls with CPP who have had a long period of treatment.

Weight, height and puberty in a cohort of Macedonian girls.

Obesity is becoming a growing problem in developed and developing countries. Many studies report an increasing incidence of obesity in the last decade. The aim of our transversal epidemiological study was to evaluate the prevalence of overweight children, auxological characteristics and pubertal stage in healthy girls from first (200 girls), third (209), fifth (290) and seventh (223) grade of school. In this study 928 girls were evaluated through systematic school examinations in the ambulance of municipality of Karposh, Skopje. The Rome and Turkish nationality, as well as Serbian were present in a small percentage, while detailed analysis was performed in the Macedonian and Albanian population of girls. The initiation of puberty (stage M2 or P2 by Tanner) was present in Macedonian girls: 4.3% of children in first grade, 23% in third grade, and 51.7% in fifth grade. In Albanians, in first grade M2 is present in 2.7%, in third grade 5.2%, and in fifth grade 46.9%. Body mass index (BMI SDS) was +3.5 +/- 1.5 in 35% of Macedonian girls and only 5% of Albanian girls. The Macedonian girls were also significantly higher (p < 0.01) and more obese than the Albanian girls. The pubertal stage was also more advanced in Macedonian girls. Most of the obese children who were included in the study reported increased consumption of fast food. Although in the past years obesity was not a problem in our country, it is becoming more severe with every year.