Band 29, Heft 10

Background: Risk of developing thyroid-associated ophthalmopathy (TAO) in children and adolescents is similar or may be even slightly higher than in adults. The aim of this article is to review and summarize current knowledge regarding diagnostic and therapeutic measures in pediatric TAO. Content: MEDLINE and EMBASE papers were searched using the terms ‘pediatric Graves’ ophthalmopathy’ ‘pediatric Graves’ orbitopathy’, ‘thyroid-associated ophthalmopathy in childhood and adolescence’ from the year 1970 to December 2015. Summary: TAO usually accompanies hyperthyreosis in Graves’ disease, but may also occur in patients with hypothyreosis due to chronic lymphocytic thyroiditis (Hashimoto’s disease) or in euthyroid patients. Current information regarding epidemiology, pathogenesis, symptoms and treatment of TAO in children and adolescents is presented. The course of the disease is usually mild, eye disturbances often regress after restoring euthyroidism and a ‘wait and see’ policy is appropriate in the majority of patients. In rare cases, sight-threatening complications [dysthyroid optic neuropathy (DON) or corneal breakdown] may develop and immediate surgical intervention might become necessary. Outlook: Close cooperation between pediatric endocrinologists and opthalmologists is extremely important to ensure best care and quality of life in patients with thyroid gland dysfunction. Further investigations on pathogenesis and course of TAO in children and adolescents should be performed for better management of this disease in this group of patients.

We conducted a systematic review and meta-analysis of the association between mumps and risk of type 1 diabetes mellitus (T1DM). Literature searches were conducted using Medline, EMBASE and Web of Science including studies published before February 2014. Crude and, where available, adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were extracted from the published reports of each included study. Combined OR estimates and tests of heterogeneity were obtained using meta-analysis techniques. The analysis was repeated in subgroups of studies on the basis of quality defined by the score on the Newcastle-Ottawa scale (NOS). In total, 18 articles met the eligibility criteria, and overall there was some evidence of a weak association between clinically diagnosed mumps and T1DM (OR=1.23, 95% CI 1.00–1.51; p=0.05) but marked heterogeneity between studies (I 2 =49%; p for heterogeneity=0.01). Restricting analyses to 13 high quality studies, there was little evidence of association between clinically diagnosed mumps and T1DM (OR=1.11, 95% CI 0.91–1.35; p=0.29) and there was much less heterogeneity (I 2 =26%; p for heterogeneity=0.18). Overall there was little evidence of any strong association between mumps infection and T1DM.

Background: Adolescents with type 1 diabetes (T1D) have increased risk of cardiovascular disease as well as elevations in biomarkers of systemic inflammation, plasma protein oxidation and vascular endothelial injury. It is unclear whether hyperglycemia itself, or variations in blood glucose are predictors of these abnormalities. Methods: This study was designed to determine the relationship of inflammatory (C-reactive protein, CRP), oxidative (total anti-oxidative capacity, TAOC) and endothelial injury (soluble intracellular adhesion molecule 1, sICAM1) markers to glycemic control measures from 3 days of continuous glucose monitoring (CGM) and to hemoglobin A 1c (HbA 1c ), and HbA 1c ×duration area under the curve (A1cDur). Results: Seventeen adolescents (8 F/9M; age, 13.1±1.6 years (mean±SD); duration, 4.8±3.8 years, BMI, 20.3±3.1 kg/m 2 ; A1c, 8.3±1.2%) were studied. Log CRP but was not related to age, duration, body mass index (BMI), HbA 1c , or A1cDUR. TAOC increased as logA1cDUR increased (n=13, r=0.61, p=0.028). CRP and sICAM were not related to CGM average glucose but log CRP increased as 3 day glucose standard deviation increased (r=0.66, p=0.006). TAOC increased as glucose standard deviation increased (r=0.63, p=0.028). Conclusions: Increased glucose variability is associated with increased inflammation in adolescents withT1D. Increased TAOC with increasing variability may be an effort to compensate for the ongoing oxidative stress.

Background: The aim of this study was to investigate the prevalence of, and traditional and emerging risk factors associated with, retinopathy in a hospital-based population of Australian children and adolescents with type 1 diabetes. Methods: This was a cross-sectional study of 483 children and adolescents with type 1 diabetes. Medical files were audited to collect all relevant clinical data. Diabetic retinopathy was assessed from colour retinal images by an ophthalmologist. Results: Diabetic retinopathy was observed in 11 (2.3%) participants. Logistic regression revealed that the principal components analysis derived risk profile of: higher serum creatinine, older age, higher systolic blood pressures, higher body mass index, abnormal estimated glomerular filtration rate (eGFR) (<59 mL/min), lower high density lipoproteins (HDL) cholesterol, higher serum sodium, longer duration of diabetes and narrower retinal arteriolar calibre was associated with diabetic retinopathy (ExpB=2.60, 95% CI 1.36/4.96, p=0.004). Conclusions: These results support the concept that the pathogenesis of diabetic retinopathy is likely due to the combined influence of various risk factors, many already identified.

Background: This study sought to investigate the effects of omega (ω)-3 polyunsaturated fatty acid (PUFA) supplementation on the lipid profiles and glucose (GLU) levels of overweight (OW) schoolchildren with metabolic syndrome (MS). Methods: Thirty-nine OW schoolchildren with MS, including 19 girls and 20 boys, received 1-month of dietary supplementation with gel capsules containing ω-3 fatty acids. Fasting lipid profiles and GLU levels were measured before and after supplementation. Results: Both sexes of OW schoolchildren with MS who received daily supplementation with 2.4 g of ω-3 fatty acids for 1 month displayed improved lipid profiles, reduced fasting GLU levels and reduced blood pressure (BP). Conclusions: These findings support the addition of omega-3 fatty acid supplementation to programs aiming to improve the metabolic status of OW children with MS, although additional research on the longer-term safety and efficacy of this treatment in this population is required.

Background: Hereditary tyrosinemia type 1 (HT1) is a rare, inborn error of tyrosine metabolism. It is a fatal disorder without treatment. Early treatment may prevent acute liver failure, renal dysfunction, liver cirrhosis, hepatocellular carcinoma (HCC) and improves survival. The aim of the present study is to describe the clinical, biochemical, imaging and follow-up of seven patients with HT1 and to define the consequences of the late and interrupted treatment. Methods: A retrospective study was carried out with seven HT1 patients. Results: The median age at onset of clinical symptoms was 11.2 months (range, 3–28 months) and the median age at diagnosis was 22 months (range, 6–58 months). Liver enzymes and coagulation parameters were back to normal in all symptomatic patients in about 2 weeks. Alfa-fetoprotein (AFP) levels were normalized within the first year of therapy. Hypoechoic nodule formation was detected in two of the seven patients despite drug treatment without an increase of AFP and any dysplastic changes in the biopsies. One patient died due to metastatic HCC because of the late diagnosis and the poor compliance of the follow-up. Conclusions: This study showed once again that adherence to the treatment and a follow-up schedule of the patients are very important. Also it should not be forgotten that nodule formation can occur despite nitisinone treatment without an increase of AFP. Despite nitisinone treatment, HT1 patients still carry the risk of HCC. HCC must be detected before metastasis to other organs otherwise, patients may lose the chance for liver transplantation.

Background: Iodine is a part of thyroid hormones and has been reported to act directly as an antioxidant or induce indirectly antioxidant enzymes. This study aimed to assess the urinary iodine concentration and its relationship between the antioxidant and oxidative stress capacity in healthy school-aged children. Methods: In total, 196 students from five primary schools, randomly selected between 9 and 12 years (mean age: 10.2±1.2 years), were enrolled in the study. Urinary iodine levels were measured by spectrophotometry with the Sandell-Kolthoff reaction. Total antioxidant status (TAS) and total oxidant status (TOS) were analysed from urine samples. The ratio of TOS to TAS was regarded as an oxidative stress index (OSI), an indicator of the degree of oxidative status. Results: Fifty-four percentage (107) of the children had iodine deficiency (ID) and the majority of them (30%) had mild ID. There was no severe-ID child in the population (<20 μg/L). Urine TAS levels were significantly lower in the moderate-ID group than in the mild-ID group (6.5±4.1 vs. 11.3±4.1 mmol, p<0.001) and the iodine-sufficient group (11.0±5.3 μmol, p<0.001). TOS levels and OSI were found higher in the moderate-ID group than in the mild-ID group (4.8±2.1 vs. 3.7±2.1 μmol, p<0.001) and the iodine-sufficient group (4.8±2.1 vs. 3.4±2.5 mmol, p<0.001). In the moderate-ID group, low urine iodine levels exhibited significant negative correlations with OSI (r=−0.660) and TOS (r=−0.248) and a positive correlation with TAS (r=0.475). Conclusions: We found that children with moderate ID were exposed to more oxidative burden than children with mild ID or iodine sufficiency. Increased systemic oxidative stress induced by moderate ID could cause development of ID-related complications and diseases. Iodine supplementation could have a beneficial role in the prevention of oxidative stress.

Background: Vitamin D deficiency is commonly seen among African American adolescents. Lipid levels during childhood are excellent predictors of adult dyslipidemia and atherosclerosis. There is a paucity of data on the relationship between 25 hydroxy vitamin D [25(OH)D] levels and lipids among African American adolescents. The objective of this study was to determine if there is an association between 25(OH)D levels and circulating lipids in African American adolescents residing in midwestern United States. Methods: African American adolescents residing in Rochester, MN (latitude 44°N), USA, underwent measurements of 25(OH)D and lipids following overnight fast. Pearson’s correlation test, linear regression model and scatter plots were used to explore the association between 25(OH)D levels and lipids. Results: 25(OH)D levels <30 ng/mL were seen in 21/24 (87%) of the subjects. 25(OH)D levels were inversely correlated with total cholesterol (r=–0.42; p=0.040) and with non-high-density lipoprotein (non-HDL) cholesterol (r=–0.42; p=0.040 ). These associations remained statistically significant after adjustment for age, gender and adiposity. In the multivariate linear regression model, and after adjusting for BMI Z-score, each 1 ng/mL increase in 25(OH)D was associated with a decrease in total cholesterol of 1.38 mg/dL (95% CI: –2.63, –0.14, p=0.030) and with a decrease in non-HDL cholesterol of 1.14 mg/dL (95% CI: –2.09, –0.18, p=0.020). Conclusions: 25(OH)D levels were inversely correlated with total cholesterol and non-HDL cholesterol levels in African American adolescents residing in midwestern United States. Further studies with larger sample sizes are needed to determine if low vitamin D status in African American adolescents is a potential modifiable risk factor for cardiovascular disease.

Background: The aim of this study was to investigate the early signs of atherosclerosis and to evaluate serum endoglin and obestatin levels as predictors of subclinical atherosclerosis in obese children. Methods: A total of 95 children (60 obese and 35 controls) aged 10–18 years were included in the study. Their endoglin and obestatin levels and biochemical parameters were measured. The carotid intima media thickness (cIMT) and brachial artery flow-mediated dilatation (FMD) responses were evaluated. Results: The cIMT values were higher (p < 0.001) and FMD responses were lower (p = 0.003) in the obese group than in the control group. A logistic regression multivariate analysis revealed that cIMT was independently associated with the body mass index (BMI) Z-score (β = 0.323, p = 0.003) and low density lipoprotein (LDL) (β = 0.29, p = 0.008), while FMD % was independently associated with waist circumference (β = −0.36, p = 0.002). The obese and control groups were similar in endoglin (p = 0.67) and obestatin levels (p = 0.70). The endoglin level was inversely correlated with the cholesterol and LDL levels (r = −0.23, p = 0.032; rho = −0.25, p = 0.019). Conclusions: The cIMT and brachial artery FMD response in obese children are significantly different compared to healthy controls. Circulating endoglin and obestatin levels are not predictive markers for subclinical atherosclerosis in obese children aged 10–18 years old.

Background: The objective of the study was to assess the effect of atorvastatin on inflammation markers and low-density lipoprotein (LDL) subfractions. Methods: In a prospective, randomized, double-blind pilot study involving 28 adolescents with type 1 diabetes (T1D), lipoprotein-associated phospholipase A 2 (Lp-PLA2) activity, high-sensitivity C-reactive protein (hsCRP), and subfractions of LDL were measured at baseline, after 1 year and 2 years of treatment with atorvastatin (10 mg/day) vs. placebo. Results: For the atorvastatin group, we found posttreatment reductions of Lp-PLA2 activity (p<0.001), LDL cholesterol (p=0.001), non-small dense LDL cholesterol (p<0.001), total cholesterol (p<0.001), and apolipoprotein B (apo B) (p<0.001), whereas small dense LDL cholesterol and hsCRP did not change significantly. Conclusions: In adolescents with T1D, long-term treatment with atorvastatin is safe and may reduce cardiovascular risk by significant decreases of Lp-PLA2 activity and LDL cholesterol.

Background: Congenital hyperinsulinism (CHI) is a rare disease with an estimated incidence of 1:40,000 live births. Here, we characterize 11 patients treated at Munich Children’s Hospital Schwabing. Methods: We analyzed data on birth, treatment and laboratory results including genetic testing and evaluated the long-term course with a follow-up visit. Results: All patients had severe, diazoxide-(DZX)-resistant hypoglycemia, beginning immediately after birth. Two patients were treated by medical therapy, eight underwent subtotal pancreatectomy and one had a partial resection. Both patients who had medical therapy still suffer from occasional hypoglycemia. Six patients with subtotal pancreatectomy were affected by mild hypoglycemia. Seventy-five percent of patients who had surgical treatment developed diabetes mellitus (DM) at a median age of 10.5 (8–13) years. In 89% of patients with available genetic testing, mutations of the ABCC8 gene were detected. Conclusions: The majority of CHI-patients not responding to DZX underwent surgery. After subtotal pancreatectomy, patients typically developed diabetes around early puberty.

Background: The objective of the study was to describe the pituitary volume (PV) in pediatric patients with isolated growth hormone deficiency (IGHD), idiopathic short stature (ISS) and normal controls. Methods: Sixty-nine patients (57 male, 12 female), with a mean age of 11.9 (±2.0), were determined to have IGHD. ISS was identified in 29 patients (20 male, 9 female), with a mean age of 12.7 (±3.7). Sixty-six controls (28 female, 38 male), mean age 9.8 (±4.7) were also included. Three-dimensional (3D) magnetic resonance images with contrast were obtained to accurately measure PV. Results: There was a significant difference in the mean PV among the three groups. The IGHD patients had a mean PV 230.8 (±89.6), for ISS patients it was 286.8 (±108.2) and for controls it was 343.7 (±145.9) (p<0.001). There was a normal increase in PV with age in the ISS patients and controls, but a minimal increase in the IGHD patients. Conclusions: Those patients with isolated GHD have the greatest reduction in PV compared to controls and the patients with ISS fall in between. We speculate that a possible cause for the slowed growth in some ISS patients might be related to diminished chronic secretion of growth hormone over time, albeit having adequate pituitary reserves to respond acutely to GH stimulation. Thus, what was called neurosecretory GHD in the past, might, in some patients, be relative pituitary hypoplasia and resultant diminished growth hormone secretion. Thus, PV determinations by magnetic resonance imaging (MRI) could assist in the diagnostic evaluation of the slowly growing child.

Insulin receptor mutations cause extreme insulin resistance resulting in acanthosis nigricans and hyperandrogenism. We report a pre-menarchal adolescent female with normal weight, with severe acanthosis nigricans, acne, and hirsutism. Initial investigation revealed elevated fasting and post-prandial insulin and high testosterone and androstenedione levels. Her father had frequent complaints of hypoglycemia. Coding sequence and splice junction analysis of the INSR gene, in our patient and her father, revealed a heterozygous missense mutation in the β subunit of the insulin receptor (Arg1131Trp), resulting in receptor loss of function. Metformin therapy and carbohydrate control improved acanthosis and menarche ensued within 3 months. Our case highlights the importance of distinguishing insulin resistance commonly associated with obesity from monogenic defects. Although, there is no consensus on treatment of children with monogenic forms of insulin resistance due to its rarity, dietary and lifestyle modifications and insulin-sensitizing agents play a key role in management.

Primary hyperparathyroidism, typically a disease of the middle aged and the old, is less commonly seen in children. In children the disease has a bimodal age distribution with calcium sensing receptor mutation presenting in infancy as hypercalcemic crises and parathyroid adenoma or hyperplasia presenting later in childhood with bone disease. The childhood parathyroid adenomas are often familial with multiglandular disease and manifest with severe bone disease unlike adults. We report a series of four male patients with juvenile primary hyperparathyroidism, three of whom presented with bone disease masquerading as rickets-osteomalacia. One patient had asymptomatic hypercalcemia with short stature. Parathyroid adenoma was detected in all the four cases and all of them underwent resection of parathyroid adenomas confirmed on histopathology. Post-surgery all the cases had initial hypocalcaemia followed by normocalcemia. One case developed pancreatitis after surgery even after achieving normocalcemia. We conclude that parathyroid adenomas, although uncommon in children, are an important cause of skeletal disease that may initially be confused with hypovitaminosis D.

Most inborn errors of metabolism (IEMs) are inherited in an autosomal recessive manner. IEMs are one of the major concerns in Iran due to its extensive consanguineous marriages. Herein, we report two patients with two co-existent IEMs: a girl affected by classic phenylketonuria (PKU) and maple syrup urine disease (MSUD) and a male patient affected with Sandhoff disease and PKU, where Sandhoff disease was suspected due to the presence of a cherry-red spot in the eyes at 6 months which is unrelated to PKU. Sequencing of candidate genes in the first patient revealed one novel and three recurrent compound heterozygous mutations of p.Ser231Pro and p.Ala300Ser in the PAH gene and p.Glu330Lys and p.Arg170Cys mutations in the BCKDHB gene. Genetic testing results in the second patient showed previously reported homozygous mutations of p.Arg261Gln in the PAH and p.Arg533Cys mutation in the HEXB gene. Genetic testing confirmed the clinical diagnosis of both diseases in both patients. To the best of our knowledge; this is the first report of the co-existence of two distinct genetic disorders in two individuals from Iran. Co-existent different IEMs in patients complicated the clinical diagnosis and management of the diseases.

Triple A syndrome, formerly known as Allgrove syndrome (AS), is characterized by achalasia, alacrima and adrenal insufficiency. Here we report an adolescent male with adrenal insufficiency who developed severe malnutrition secondary to a delayed diagnosis of achalasia. The severe malnutrition in our patient led to superior mesenteric artery (SMA) obstruction syndrome. Severe malnutrition to the point of SMA syndrome has not been previously described in the literature in Triple A syndrome.

While being well known that the diagnosis of many genetic disorders relies on a combination of clinical suspicion and confirmatory genetic testing, not rarely, however, genetic testing needs much perseverance and cunning strategies to identify the causative mutation(s). Here we present a case of a thorny molecular diagnosis of mucolipidosis type III alpha/beta, which is an autosomal recessive lysosomal storage disorder, caused by a defect in the GNPTAB gene that codes for the α/β-subunits of the GlcNAc-1-phosphotransferase. We used both cDNA and gDNA analyses to characterize a mucolipidosis type III alpha/beta patient whose clinical diagnosis was already confirmed biochemically. In a first stage only one causal mutation was identified in heterozygosity, the already described missense mutation c.1196C>T(p.S399F), both at cDNA and gDNA levels. Only after conducting inhibition of nonsense-mediated mRNA decay (NMD) assays and after the utilization of another pair of primers the second mutation, the c.3503_3504delTC deletion, was identified. Our findings illustrate that allelic dropout due to the presence of polymorphisms and/or of mutations that trigger the NMD pathway can cause difficulties in current molecular diagnosis tests.