Band 29, Heft 2

Background: Obesity in children and adolescents is characterized by chronic sympathetic overdrive and reduced epinephrine-stimulated lipolysis. This resistance to catecholamines occurs during the dynamic phase of fat accumulation. This review will focus on the relationship between sympathetic-adrenal activity and lipid metabolism, thereby highlighting the role of catecholamine resistance in the development of childhood obesity. Results and conclusions: Catecholamine resistance causes lipid accumulation in adipose tissue by reducing lipolysis, increasing lipogenesis and impeding free fatty acid (FFA) transportation. Exercise improves catecholamine resistance, as evidenced by attenuated systemic sympathetic activity, reduced circulating catecholamine levels and enhanced β-adrenergic receptor signaling. Insulin resistance is mostly a casual result rather than a cause of childhood obesity. Therefore, catecholamine resistance in childhood obesity may promote insulin signaling in adipose tissue, thereby increasing lipogenesis. This review outlines a series of evidence for the role of catecholamine resistance as an upstream mechanism leading to childhood obesity.

The widespread use of supplemental vitamin D has dramatically reduced the incidence of rickets. While generally considered a safe practice, there is potential for toxicity in patients with idiopathic infantile hypercalcemia (IIH). Inadequate 24-hydroxylase-enzyme activity renders these individuals unable to degrade active vitamin D, resulting in hypercalcemia due to increased intestinal calcium absorption, decreased renal calcium excretion, and increased osteoclastic bone activity. Clinicians should be aware that even therapeutic doses of vitamin D can prove harmful for patients with CYP24A1 mutations. Studies have also demonstrated a link between inadequate 24-hydroxylase activity and nephrocalcinosis, renal insufficiency, and calcium containing kidney stones, further emphasizing the importance of early recognition of this disease and judicious use of vitamin D. We present a case with an interesting diagnostic algorithm used to diagnose IIH when given an incomplete history and subsequently review the existing literature on the subject.

Background: Congenital hypothyroidism (CH) is the most frequent endocrine disorder during the neonatal period, and a delay in diagnosis and treatment leads to irreversible complications. A high L-thyroxine (LT4) dose is recommended for treatment, while the optimal starting dose is still a matter of debate. The objective of this study was to determine the effects of various starting doses of LT4 on serum thyroid stimulating hormone (TSH) and thyroxine (fT4) at the end of the first month of treatment. Methods: A total of 71 patients (37 males, 52.1%) with CH were included in the study. The patients were designated into three sets of subgroups according to the following categorical variables: (i) initial LT4 doses : 6–9.9 μg/kg/day, 10–11.9 μg/kg/day and 12–17 μg/kg/day; (ii) initial TSH levels : 6–9.99 μIU/mL, 10–75 μIU/mL and >75 μIU/mL; and (iii) etiology : dyshormonogenesis and dysgenesis. A fT4 level >2.3 ng/dL±a TSH level <0.5 μIU/mL were considered as overtreatment. Results: The mean age of the study population was 22.3±13.2 days at diagnosis. At diagnosis, the mean fT4 was 0.84±0.32 ng/dL, and TSH was 39.3±30 μIU/mL. The mean initial dose of LT4 was 10.9±2.9 μg/kg/day. Overtreatment rates were significantly higher in the highest dose group (12–17 μg/kg/day) compared with the lowest dose group (6–9.9 μg/kg/day) (61.5% and 25%, respectively, p<0.05). None of the patients was undertreated. Conclusions: In this study, we found that the rate of overtreatment was significantly higher in patients who were given LT4 doses of 12–17 μg/kg/day. Thus, monitoring thyroid functions earlier than one month of treatment is necessary.

Background: To assess the effect of auditory guided imagery (AGI) on glucose levels, glycated hemoglobin (HbA 1c ), and quality of life (QOL) in type 1 diabetes mellitus children. Methods: A blinded randomized controlled study comparing the effect of AGI accompanied by background music and background music solely (BMS). The study included 13 children, (7–16 years). The participants were connected to continuous glucose monitoring system for 5 days (short phase), and the outcome measure was the change in mean interstitial glucose concentration (IGC). Participants listened to the recording twice a week for 12 weeks (long phase), and the outcome measures were changes in QOL and in HbA 1c . Results: Mean IGC decreased in both AGI and BMS groups while listening. HbA 1c decreased in both groups, but the decrease in the AGI group was significant. Conclusion: Listening to AGI is a potential approach for improving glycemic control and glucose levels in youth with T1DM, but further research is required.

Background: We aimed at evaluating the urinary levels of kidney injury molecule-1 ( KIM-1) and neutrophil gelatinase associated lipocalin (NGAL), and the relationship between these markers and clinical and laboratory variables in normoalbuminuric children with type 1 diabetes (T1D). Methods: The study group consisted of 60 (F/M: 28/32) children with T1D with a median age of 13 (min: 7.1–max: 17.9) years and a mean HbA 1c of 8.6%. The average period of treatment was 6.8±2.2 years. The control group consisted of 60 healthy children [(F/M: 32/28); median age: 13.6 (min: 6.9–max: 17.9) years]. Results: Urinary KIM-1 and NGAL levels were significantly elevated in the diabetic group (KIM-1: 0.50±0.34 ng/mg-cr; NGAL: 33±31 ng/mg-cr) compared with the nondiabetic control subjects (KIM-1: 0.26±0.25 ng/mg-cr, NGAL 13.3±14.5 ng/mg-cr) (p<0.001). No significant associations were observed between NGAL or KIM-1 and the duration of diabetes and HbA 1c levels. NGAL was found to be weakly correlated with KIM-1 (p<0.005, r =0.289). Conclusions: NGAL and KIM are high in normoalbuminuric diabetic children before reduction in glomerular filtration rate. High NGAL and KIM-1 levels may indicate early diabetic kidney injury; however, we did not observe any relationship between these markers and diabetic indices. For clinical usefulness of these markers, long-term studies are required.

Background: Studies have suggested that triglyceride to HDL-cholesterol ratio (TRG/HDL) is a surrogate marker of insulin resistance (IR), but information regarding its use in pediatric patients is limited. This study investigated the ability of TRG/HDL ratio to assess IR in obese and overweight children. Methods: The sample consisted of de-identified electronic medical records of patients aged 10–17 years (n=223). Logistic regression was performed using TRG/HDL ratio as a predictor of hyperinsulinemia or IR defined using homeostasis model assessment score. Results: TRG/HDL ratio had limited ability to predict hyperinsulinemia (AUROC 0.71) or IR (AUROC 0.72). Although females had higher insulin levels, male patients were significantly more likely to have hypertriglyceridemia and impaired fasting glucose. Conclusions: TRG/HDL ratio was not adequate for predicting IR in this population. Gender differences in the development of obesity-related metabolic abnormalities may impact the choice of screening studies in pediatric patients.

Background: We aimed to evaluate the association between hyperlipidemia and carotid intima media thickness in obese children, compared to non-obese ones. Methods: Two hundred (110 girls, 90 boys) children aged between 6 and 15 years participated in this study. The obese group included 53 girls, 47 boys whose body mass indices (BMI) above 95th percentile, the control group included 57 girls, 43 boys who had normal weight. Fasting total cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) levels were measured. Carotid intima media thickness (cIMT) was performed with neck ultrasound. Results: The median thickness of right, left and mean carotis intima media were statistically higher in the study group, compared to the control group. The mean cholesterol, triglyceride, HDL-C, LDL-C levels of the study group were statistically higher, compared to the control group. There was no relationship between BMI and left carotis intima media thickness, but there was statistically significant relationship between BMI and right, mean cIMTs in the study group. There was no correlation between serum lipid levels and cIMTs in the study group. The mean atherogenic index of the study group was statistically higher, compared to the control group. There was no statistical correlation between atherogenic index and cIMTs in both of the groups. Conclusions: We observed that obese children had higher carotis intima media thicknesses. Carotis intima media thickness related to obesity can play an important role in future pre-atherosclerotic changes. Large population based studies are required to confirm this associaton.

Background: Children born small for gestational age (SGA) are at risk for the metabolic syndrome (MetS) as adults. We examined whether indicators of MetS could be identified in pre-pubertal children born very preterm. Methods: Parameters associated with MetS were studied in 141 pre-pubertal schoolchildren with either very low birth weight (VLBW) or GA <32 weeks (SGA: n=43). Results: At 8.3±0.8 years, 36 children (SGA: n=15) were classified short. There were no differences between the SGA and appropriate for age (AGA) groups; nor were dissimilarities observed between short children and those with normal height for parameters such as body mass index (BMI), serum levels of hormones, HDL cholesterol, triglycerides, glucose, insulin, HOMA-IR, body composition, resting energy expenditure, grip strength and jump force. Conclusions: Neither SGA at birth nor short stature at follow-up (irrespective of size at birth), could be associated with parameters that indicate an increased risk for the MetS during childhood.

Background: X-linked partial androgen insensitivity syndrome (PAIS) causes under-virilization at all stages of development. In two thirds of males, this results in micropenis. Dihydrotestosterone (DHT) is a potent androgen that is critical for male genital development, which when applied topically, has been shown to increase penile length with micropenis of varying etiologies. We present the first case series using topical DHT gel to treat micropenis in 46,XY males with PAIS, before, during, and after puberty. Methods: Three related 46,XY males with confirmed p.L712F androgen receptor mutations exhibited varying degrees of micropenis post-surgical correction. They were of pre-pubertal, peri-pubertal and adult ages, respectively. Following baseline clinical and laboratory assessments all completed a 4-month course of daily DHT gel 2.5% (androstanolone) topically to penis (0.3 mg/kg body weight), with monitoring for adverse effects. Primary outcome was change in stretched penile length (SPL) following treatment. Results: Mixed results were obtained following topical DHT therapy. In the pre- and peri- pubertal patients, SPL changed from 2.5 cm to 3.5 cm (+40%), and 3.5 cm to 5.7 cm (+63%), respectively. In the adult patient with 1 year of prior high-dose weekly testosterone therapy, no additional change in SPL was seen. No adverse effects of topical DHT were reported or observed throughout the 4 months of treatment. Conclusions: Topical DHT treatment appears to be a safe and well-tolerated method of virilising micropenis both prior to and during puberty in children with PAIS. Questions remain about long-term outcomes into adulthood, and efficacy in adults with prior lengthy exposure to high-dose testosterone.

Background: Urinary myo- inositol (UMI) level is elevated in adult diabetic patients, and also increases after glucose loading. However, the relationship between UMI and plasma glucose levels in children is unknown. We aimed to assess whether UMI is a practical marker for glucose intolerance in children or not. Methods: In Study 1 (328 schoolchildren), fasting and postprandial UMI were measured, with ΔUMI defined as the difference between fasting and postprandial UMI levels. In Study 2, oral glucose tolerance tests and UMI measurements were conducted in 18 children with suspected having diabetes. Results: For Study 1, ΔUMI was observed [−0.65 (−3.9, 1.35) mg/g creatinine]. For Study 2, children with diabetes or impaired glucose tolerance had a significantly higher ΔUMI than children with normal glucose tolerance. Conclusions: These studies demonstrated the normal range of UMI in children and possibility of a novel biomarker for early detection of glucose intolerance in children.

Background: Delayed discussion about infertility with individuals affected by Turner syndrome (TS) has been found to result in psychological and social harm. The aim of this study was to identify barriers experienced when discussing infertility and determine resource types that may facilitate this conversation. Methods: An electronic survey, given to caregivers of girls with TS diagnosed at <5 years. Results and conclusions: Fifty percent of parents surveyed had spoken to their daughter about their possible infertility. Parents who had not yet discussed infertility with their daughter had younger daughters and reported more barriers in having the conversation. Although most individuals did not use resources to facilitate the conversation, they did express interest in additional resources.

Background: The molecular basis underlying the development of thyroid dysgenesis remains largely unknown. The objective of this study was to analyze the PAX8 gene in 32 children with congenital hypothyroidism due to thyroid dysgenesis for mutations, and to characterize the functional consequences of the mutations. Methods: The 5′-untranslated region and the entire coding region of the PAX8 gene were analyzed in 32 children. Functional analyses with a reporter gene assay were performed in transfected PCCL3 and TSA cells. Results: Thirty children did not have any sequence alterations. Two individuals had a previously identified monoallelic cytosine to thymine transition at position -983 in the promoter (-983C>T; mutant P. A of the ATG of the initiator codon is designated as +1), and a novel guanine to cytosine transversion in the non-coding exon 1 (-465G>C; mutant E). Functional analysis revealed that the basal transcriptional activity of the mutants is decreased compared to the wild type. Gel mobility shift assays indicated that mutant P does not interact with a transacting factor whose nature remains to be elucidated. The DNA binding property of mutant E were similar compared to the wild type. Conclusions: These results suggest that mutations in PAX8 are most likely a very rare cause of thyroid dysgenesis. The observed sequence alterations result in diminished transcriptional activity and, in conjunction with other genetic and non-genetic modifiers, they may contribute to the pathogenesis of thyroid hypoplasia and hypothyroidism.

Background: Growth hormone deficiency (GHD) and small for gestational age (SGA) status are associated with cardiovascular risks. We therefore, investigated antiatherogenic effects of growth hormone (GH). Methods: Subfractions of low-density lipoprotein (LDL) and high-density lipoprotein (HDL), lipoprotein-associated phospholipase A 2 (Lp-PLA2), and high-sensitivity C-reactive protein (hsCRP) were measured at baseline, after 8 and 52 weeks of GH treatment in 51 short children born SGA (n=33) or with GHD (n=18). Results: The overall group showed post-treatment reductions of LDL cholesterol (LDL-C) (p=0.016), small-dense LDL cholesterol (sdLDL-C, p<0.001), Lp-PLA2 (p<0.001), and hsCRP (p=0.005), but increase of HDL2a cholesterol (HDL2a-C, p=0.025). SGA children revealed significant correlations between Lp-PLA2 and LDL-C and sdLDL-C both before and after GH, significant reductions of sdLDL-C, Lp-PLA2, hsCRP, and an increase of HDL2a-C. GHD children showed the same lipid responses, though not significantly. Conclusions: Children with GHD or born SGA may benefit from GH by growth acceleration and reduction of cardiovascular long-term risks.

Background: Reninoma is an extremely rare renal tumor characterized by excessive renin secretion causing secondary hypertension and hypokalemia. Reninoma is a benign and highly manageable lesion if it is discovered early and removed surgically. Methods: We report six cases of reninoma and provide a literature review on this rare disease, highlighting the diagnostic evaluation and follow-up of each patient. Results and conclusions: Reninoma should be considered in young adults with elevated renin activity and refractory hypertension. Imaging studies and selective venous catheterization are often helpful in identifying the lesion. In most cases of reninoma presenting with renin-mediated hypertension, conservative surgical treatment should be considered to remove the small, superficial lesion.

Rhabdomiomas are rare mesenchymal benign tumors of striated muscle origin. Setting aside the cardiac (most atrial) rhabdomiomas typically associated to neurocutaneous syndromes (tuberous sclerosis), extracardiac rhabdomyomas appear clinically as a subcutaneous nodule or as a submucosal polypoid lesion. Among them, three main histologic subtypes can be differentiated on the basis of the degree of tumor differentiation: 1) fetal rhabdomioma, usually diagnosed during childhood and almost exclusively located in the in the head and neck region with rare reports in other locations; 2) adult rhabdomioma; and 3) genital rhabdomioma, reported to occur in the lower genital tract of young and middle-aged women and, exceptionally, in children (5).

Diabetic ketoacidosis (DKA) is one of the precipitating factors that can evoke a thyroid storm. Thyroid storm may cause cerebral ischemia in Moyamoya disease, which can coexist in patients with Graves’ disease. A 16-year-old girl complaining of dizziness and palpitations visited the emergency department and was diagnosed with DKA combined with hyperthyroidism. A thyroid storm occurred 6 h after the start of DKA management. Her Burch and Wartofsky score was 65 points. Right hemiplegia developed during the thyroid storm, and brain magnetic resonance (MR) diffusion-weighted images revealed multiple acute infarcts in both hemispheres. MR angiography showed stenosis of both distal internal carotid arteries and both M1 portions of the middle cerebral arteries, consistent with Moyamoya disease. After acute management for the thyroid storm with methimazole, Lugol solution and hydrocortisone, the patient’s neurological symptoms completely resolved within 1 month, and free T4 level normalized within 2 months. Thyroid storm may trigger cerebral ischemia in Moyamoya disease and lead to rapid progression of cerebrovascular occlusive disease. As a simultaneous occurrence of DKA, thyroid storm and cerebrovascular accident in Moyamoya disease highly elevates morbidity and mortality, prompt recognition and management are critical to save the patient’s life.

Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare and severe neurometabolic disease. We present two siblings with BVVLS with a novel homozygous mutation in SLC52A3 (formerly C20orf54 ) gene. The first sibling was admitted with respiratory insufficiency and required mechanical ventilation. After administration of a high dose of riboflavin, all his clinical symptoms were resolved, which also strongly suggested the diagnosis of BVVLS. The second sibling was also found to have the same genetic mutation as her brother. Although she was symptom-free, riboflavin was initiated empirically. On follow-up, she developed no neurologic or metabolic problems with entirely normal growth and development. BVVLS should be considered in the differential diagnosis of unexplained neurologic symptoms such as polyneuropathy and respiratory insufficiency, as BVVLS and multiple acyl-CoA dehydrogenation defect have broadly overlapping symptoms. Furthermore, our cases once again suggest that with proper diagnosis and early high-dose riboflavin treatment, complete reversal of neurologic deficits in BVVLS is possible.

We report the case of a 46,XX infant referred at 3 months of age for evaluation of ambiguous genitalia with no palpable gonads. The phallus was replaced by a homogeneous peduncular structure covered by skin, and a second peduncular structure covered by mucosa was located between the labia minora above the urethral meatus and the vaginal opening. There were no associated anomalies, and she had normal growth and neuromotor development. During surgery to remove these structures, a bifid clitoris was detected and cystoscopy and vaginoscopy revealed normal female urethra and vagina. The structure located on the phallic region was a superficial lipomatous nevus, and the other mass was a congenital urethral caruncle with ectopic migration/differentiation of colonic epithelium into ventral and anterior part of the urogenital sinus. Both genital lipomas and congenital caruncles of the female urethra are very rare and their etiology is unknown. There is no previous report of coincidence of these two rare findings in an otherwise healthy girl.

Thyrotropinomas (TSHomas) are rare pituitary adenomas, particularly in childhood. We present here the case of an 11-year-old boy with type 1 autoimmune polyglandular syndrome (APS1) and TSHoma which was diagnosed by elevated thyroid – stimulating hormone and thyroid hormones levels without evident clinical signs of hyperthyroidism. He was underwent partial resection of the tumor via transsphenoidal approach and subsequently radiation therapy. Consequently, 1 year after radiotherapy, the patient developed growth hormone deficiency, three and half years after radiation became euthyroid, and five and half years after treatment – hypothyroid. This is the first case of the coexistence of these two rare endocrine diseases in one patient.

3-M syndrome (OMIM #273750, #612921, and #614205) is a rare autosomal recessive growth disorder that is characterized by pre- and postnatal growth retardation, normal intelligence, and characteristic faces. This syndrome also has characteristic radiological features, such as slender long bones and tall vertebral bodies. Three genes, cullin 7 ( CUL7 ), coiled-coil domain containing 8, and obscurin-like 1 are genetic candidates of 3-M syndrome. Patients with 3-M syndrome have a characteristic facial appearance, including a triangular face, frontal bossing, an anteverted nose, dolichocephaly, and a long philtrum. However, information on adult 3-M syndrome patients, including facial appearance, is scarce. We report an adult female with 3-M syndrome that was caused by novel compound heterozygous mutations (c.4023-1 G>A in splice acceptor site of exon 22 and c.4359_4363dupGGCTG in exon 23) in the CUL7 gene. We also report the growth chart and changes in facial appearance of this patient from the neonate to adult.