Volume 31, Issue 1

Background: Allergic and non-allergic skin reactions to recombinant human growth hormone (rhGH) are uncommon and infrequently reported. However, physicians should be aware of these potential side effects to determine whether the reactions constitute true allergies and how to proceed with growth hormone therapy. To review allergic and non-allergic skin reactions caused by rhGH and subsequent diagnostic workup and management options. Case presentation: We report the case of a 12-year-old healthy male presenting with idiopathic short stature. He developed an itchy skin rash over the chest and abdomen, 15 min after administration of the first dose of rhGH, leading us to review allergic and non-allergic skin reactions to rhGH. In our patient, an immediate skin reaction after administration of rhGH prompted a concern about a type I hypersensitivity reaction (HS) and the discontinuation of rhGH. However, after a dermatologic evaluation and observed administration of rhGH without subsequent rash, the initial eruption was likely an exacerbation of his underlying atopic dermatitis and a type I HS was felt to be unlikely. The rhGH was resumed and he has been on rhGH for the past 1 year with no recurrence of rash and with improvement in growth velocity. Conclusions: Though rare, allergic and non-allergic skin reactions are known to occur with rhGH. It is important to know if the allergic reaction was due to the growth hormone molecule or one of the preservatives. It is also important to consider a non-allergic reaction due to flare up of underlying skin disorders as in our patient.

Background: One of the main concerns in chronic diseases such as growth hormone (GH) deficiency is adherence to the treatment, which significantly affects treatment outcomes. Methods: This cross-sectional study was conducted among 169 GH recipient children (2–12 years) and teens (13–19 years) referred to a GH distributing teaching pharmacy. The eight-item Morisky Medication Adherence Scale (MMAS) and auto-compliance method were used for the assessment of patients’ adherence to GH. The potential barriers to GH therapy adherence and medication persistence were also explored. Results: Based on the MMAS method, 56.7% of the children and 57.9% of the adolescent groups were adherent to GH therapy. Conversely, according to the auto-compliance method almost all the patients were adherent in the children (95.2%) and adolescent (95.5%) groups. Forgetting to take the injection or refill the prescription, being away from home, exhaustion from long-term injection, drug shortage and inaccessibility to the pharmacy were barriers found to be significantly associated with a low adherence in the children group. While in the adolescent group, forgetting to take the injection, painful injection, concern about long-term complications and exhaustion from long-term injection revealed a significant association with low adherence. Persistence with GH therapy was reported in 75.3% and 67% of children and adolescent patients, respectively. Conclusions: The current study revealed that overall adherence of the study population is low. Considering the barriers with significant association with adherence, different strategies can be incorporated to enhance adherence to GH therapy, i.e. providing early patient and parent education and support, medication reminder systems and longer duration of GH prescriptions.

Background: Despite the fact that priming with sex steroids in prepubertal children before growth hormone (GH) provocative tests is recommended, there is an ongoing controversial discussion about the appropriate age of the children, the drug used for priming, the dose and the period between priming and the GH test. Interestingly, there is no discussion on the safety of this procedure. To date, only little data have been available on the possible side effects of priming with testosterone. Methods: We analyzed the outcome in 188 short-statured prepubertal boys who had been primed with testosterone enanthate (n=136: 50 mg; n=51: 125 mg, and accidentally one boy with 250 mg) 7 days prior to the GH test. Serum testosterone levels were measured on the day of the GH test in 99 boys. Results: Overall, only five boys developed adverse side effects. Two boys (dose 125 mg) showed severe low-flow priapism and had to undergo decompression of the corpora cavernosa. One boy suffered from self-limiting priapism and testicular pain (dose 50 mg). Two patients reported testicular pain (each dose 50 mg). The single patient with 250 mg testosterone did not show any adverse effects. The total side effect rate was 2.7%. The serum testosterone levels of the boys with side effects were not different from the testosterone levels of the boys without any side effects. Conclusions: Parents and patients should be informed about the possible side effects of priming with testosterone such as priapism and testicular pain. However, the overall side effect rate is low. We found no correlation between the outcome and the testosterone dose used and/or the level of serum testosterone.

Background Growth hormone (GH) treatment in children with short stature homeobox-containing gene ( SHOX ) deficiency is recognized to increase height velocity (HV) and adult height. Prediction of growth response continues to be a challenge. A comparatively accurate method is the Cologne prediction model developed in children with GH deficiency. The aim was to investigate whether this model also applies to patients with SHOX deficiency. Methods Included were 48 patients with SHOX deficiency confirmed by DNA analysis and treated with 0.05 mg/kg/day of somatropin. Prediction by the Cologne model uses the following variables: relative bone age (BA) retardation, baseline insulin-like growth factor-I (IGF-I), urinary deoxypyridinoline (DPD) cross-links at 4 weeks and HV at 3 months. Results HV and height standard deviation scores (SDS) increased significantly during the first year of treatment. Predicted and observed HV (cm/year) showed a Pearson correlation coefficient of 0.50 (p<0.001; root-mean-square error=1.63) and for first-year change in height SDS a Pearson correlation coefficient of 0.751 (p<0.001; root-mean-square error=0.32). Poor response could be adequately predicted using SDS change, with sensitivity and specificity both above 70% for certain thresholds. Conclusions: The results demonstrate that the Cologne model can be used to predict growth response in patients with SHOX deficiency with reasonable precision in the first treatment year, comparable to prediction in patients with GH deficiency.

Background: It is unclear whether the World Health Organization (WHO) 2006 Child Growth Standards are applicable to East Asian populations. We investigated the applicability of the WHO standards of length/height and weight to a cohort representing middle-class children in Japan. Methods: A cohort of children aged 0–5 years (3430 boys, 3025 girls) in the Tokyo Child Care Center Survey consecutively recruited from 2007 to 2013 were studied. Age- and sex-specific z-scores of length/height, weight and weight for length/height were calculated relative to either the WHO standards or the Japanese 2000 Growth References (nationally representative cross sectional survey data). Results: Compared with the WHO standards, Japanese children at birth, 1, 3, 5 years were shorter (length/height standard deviation score [SDS] −0.26, −0.82, −0.81, −0.63 for boys, and −0.15, −0.67, −0.84, −0.62 for girls, respectively) and lighter (weight SDS −0.62, −0.36, −0.34, −0.42 for boys and −0.60, −0.17, −0.29, −0.43 for girls, respectively). Weight for length/height showed smaller differences at various length/height points (SDS −0.05 to 0.15 for boys, 0.01 to 0.29 for girls, respectively). Conclusions: Adoption of the WHO standards would substantially alter the prevalence of short stature, underweight and overweight in Japanese children 0–5 years of age. These findings advocate the use of the national references in Japan.

Background: This study was designed to determine the effects of diabetes type and gender on depression risk determined by a highly sensitive screening questionnaire in adolescents. Glycemic control and counseling affect were also studied. Methods: A retrospective chart review of patients seen between 2013 and 2015 was performed. Five hundred and thirty adolescents with type 1 (T1DM) or 2 (T2DM) diabetes mellitus completed the Patient Health Questionnaire-9 (PHQ-9) to identify depressive symptoms. Hemoglobin A 1c (HbA 1c ) was measured when the PHQ-9 was given, and at 1 year. Patients with increased depression risk were referred for counseling and comparisons were made between those who did and did not attend. Results: Females with T2DM, but not males, had increased depression compared to T1DM. Females had increased depression compared to males in T1DM (p = 0.046) and a near significant increase in T2DM (p = 0.069). In T1DM, but not T2DM, HbA 1c levels were increased in high and moderate, compared to low, risk depression risk groups (p = 0.007). Follow-up HbA 1c was unchanged 1 year later and there were no differences between those involved in counseling and those who refused to attend. Sex and type of diabetes had no effect on response to counseling. Conclusions: These results demonstrate increased depression in adolescents with T2DM compared to T1DM and in females compared to controls. Glycemic control did not change in adolescents who reported moderate to severe symptoms of depression and received counseling intervention compared to adolescents who declined counseling.

Background: Recent findings have supposed that the underlying association between the increased prevalence of both asthma and obesity may be insulin resistance (IR). Methods: Insulin and glucose serum levels were analyzed to calculate the homeostatic model assessment of insulin resistance (HOMA-IR) for IR in 98 pre-pubertal children. Lung function and allergy status evaluation were performed. The study population was divided into four groups: (1) obese asthmatic children (ObA); (2) normal-weight asthmatic children (NwA); (3) normal-weight non-asthmatic children (Nw) and (4) obese non-asthmatic children (Ob). Results: Forced expiratory volume in 1 s (FEV 1 ) was slightly lower in obese subjects compared with normal-weight subjects and forced vital capacity (FVC) appeared lower in asthmatics, whereas between non-asthmatics subjects, it was lower in the obese group than in the normal-weight one. The post hoc analysis revealed a statistically significant reduction in FEV 1 , peak expiratory flow (PEF), forced expiratory flows (FEF) between 50% and 25% of the FVC (FEF 50 and FEF 25 ) between ObA and Nw and in FEV 1 , FVC, PEF, FEF 50 and FEF 25 between NwA and Nw, but no statistically significant differences of lung function parameters were observed between ObA and NwA. We found an inverse relationship between HOMA-IR and all spirometric parameters, although without any statistical significance. We also observed a significantly lower FVC in insulin-resistant children (HOMA-IR>95th percentile) (p=0.03). Conclusions: This study suggests that lung function could be early altered in obese children, already in pre-pubertal age. Although IR should not manifest its effects on lungs in pre-pubertal obese children, the prevention or treatment of obesity in the pre-pubertal period may prevent definitive negative effects on lungs.

Background: Sufficient serum concentrations of vitamin D are required to maintain bone health during growth. The aims of this study were to determine whether vitamin D deficiency is more prevalent among children and adolescents with obesity compared to their normal weight peers and to identify clinical and biochemical variables associated with vitamin D deficiency. Methods: One thousand four hundred and eighty-four children and adolescents with overweight/obesity and 2143 population-based controls were recruited from the Danish Childhood Obesity Biobank. Anthropometric variables and fasting concentrations of serum 25-hydroxy vitamin D (25-OH-D), plasma parathyroid hormone (PTH), calcium and phosphate were assessed at baseline. Vitamin D deficiency was defined as serum 25-OH-D concentrations <30 nmol/L. Linear and logistic regressions were used to identify variables associated with vitamin D deficiency. Results: A total of 16.5% of the children and adolescents with obesity (body mass index [BMI] standard deviation score [SDS]>2.33) exhibited vitamin D deficiency, with an odds ratio (OR) 3.41 (confidence interval [CI]: 2.27–5.71; p<0.0001) for being vitamin D deficient compared to their normal weight peers. BMI-SDS was independently and inversely associated with serum 25-OH-D concentrations. Other independent risk factors for vitamin D deficiency were being older than 14 years (OR: 2.39; CI: 1.28–4.48; p=0.006), more than 4 daily hours of screen time (OR: 4.56; CI: 2.59–8.05; p<0.0001) and blood sample assessment during winter-spring (OR: 6.44; CI: 4.47–9.26; p<0.0001). Conclusions: Vitamin D deficiency was common among Danish children and adolescents with obesity. The degree of obesity was independently associated with lower serum 25-OH-D concentrations.

Background: This study aimed to investigate the relationship between daily sitting time and the risk of metabolic syndrome in Korean adolescents. Methods: Data from 486 adolescents aged 12–18 years were obtained from national surveys. Daily sitting time was measured using questionnaires and divided into three intervals: <8 h; 8–12 h; and ≥12 h. Results: The mean daily sitting time and prevalence of positive metabolic components were 620.9±9.9 min/day and 45.5±2.7%, respectively. In a multivariate logistic regression analysis, adolescents who sat longer were more likely to have metabolic components (p<0.05), independent of age, sex, area of residence, sleeping time and body mass index. Conclusions: Longer daily sitting time appears to be associated with an increased risk of metabolic syndrome in adolescents. These findings highlight the need to focus on reducing sitting time for all adolescents, not just for those at risk of obesity.

Background: Classic galactosemia is an autosomal recessive disorder of galactose metabolism caused by severely decreased activity of galactose-1-phosphate uridylyltransferase (GALT) due to pathogenic mutations in the GALT gene. To date more than 330 mutations have been described, with p.Q188R and p.K285N being the most common in Caucasian populations. Although acute manifestations can be fully avoided by a galactose-restricted diet, chronic complications, such as neurological ones, cannot be prevented in a significant number of patients despite compliance with the dietary treatment. Methods: A cohort of 16 galactosemic Croatian patients, including one pair of siblings, was studied. Molecular characterization was performed by direct sequence analysis of the GALT gene. Results: Sixteen patients were analyzed and only four different mutations were detected. As expected, p.Q188R and p.K285N were common, accounting for 40% and 37% of unrelated alleles, respectively. The third mutation accounting for 20% of mutant alleles was p.R123X causing a premature stop codon, is thus considered to be severe, which is in accordance with the phenotype presented by the homozygous patient described here. The fourth mutation p.E271D was found in a single allele. More than half of our patients manifested some chronic neurological complications. Conclusions: This is the first report on mutational and phenotypic spectra of classic galactosemia in Croatia that expands the knowledge on the mutational map of the GALT gene across Europe and reveals the genetic homogeneity of the Croatian population.

Background: Congenital generalized lipodystrophy (CGL) produces clinical features with severe metabolic consequences. Research has focused on measuring the response to the drugs. Nevertheless, there are no studies on the response to dietary therapy. The aim of this study was to show the clinical response to early nutritional intervention to modify or reverse metabolic effects in pediatric patients with CGL. Methods: A retrospective study was conducted on patients with CGL followed up between January 2003 and June 2017. After diagnosis, patients were indicated a diet with a total calorie intake according to the reference daily intake (RDI), without fast sugars. Clinical feature and laboratory tests (insulin, glucose, A 1C , lipid panel, liver and kidney function tests), and complementary studies (abdominal ultrasonography, echocardiogram), at the first visit and during follow-up were recorded. Statistics, version 10, was used for analysis. Results: Eight patients were included. The median age at the first visit was 1.1 years (range, 0.28–9.9 years) and the median time of follow-up was 3.9 years (range, 0.4–9.47 years). The median initial triglyceride level was 516 mg/dL (range, 327–3590 mg/dL) p=0.014; median low-density lipoprotein (LDL) was 157 mg/dL (range, 94–370 mg/dL) p=0.03; median glycemia was 84 mg/dL (range, 63–126 mg/dL) p=0.02; median insulin was 28.84 µUI/mL (range, 3.9–116); median homeostatic model assessment-insulin resistance (HOMA-IR) was 5.3 (range, 1.21–23.2). After 3–6 months of diet, the median percentage of triglyceride decrease was 79.5% (range, 47–97%), LDL 44% (range, 20.5–59%), glycemia 8.8% (range, 0–53.1%), insulin 67.8% (range, 0–92.8%) p=0.02 and HOMA-IR was 81.5% (range, 50–98%) p=0.05. As of the last follow-up visit, in none of the patients, liver ultrasonography or echocardiogram had deteriorated. Conclusions: In these pediatric patients with CGL, a diet adjusted to RDI with restriction of fast sugars led to a marked improvement in metabolic parameters.

Background: Congenital hyperinsulinism results in refractory hypoglycemia. If a therapy with diazoxide has been unresponsive this has been treated by subtotal pancreatectomy in the past. This therapeutic option poses an increased risk of developing diabetes at a later stage. There have been a few case reports on the use of sirolimus in such situations in the recent past. Case presentation: Our patient was started on sirolimus very early, on day 29 of life and at the age of 14 months is doing well on sirolimus therapy. His growth and development have been good and he has not had any major complications so far. Genetic testing showed a novel KCNJ11 homozygous mutation on next generation sequencing and the parents were heterozygous carriers. Conclusions: We report the successful use of sirolimus in the management of diazoxide unresponsive congenital hyperinsulinism with diffuse pancreatic involvement. We believe this is the youngest patient to be initiated on sirolimus so far.

Background: Iodine deficiency is the most common cause of acquired hypothyroidism worldwide. Although uncommon in the Western world, the incidence of iodine deficiency may be rising due to the increased use of restrictive diets. Case presentation: We present a 23-month-old boy diagnosed with iodine deficiency hypothyroidism, induced by a vegan diet. Conclusions: This case highlights the risk for iodine deficiency in children on a vegan diet after discontinuation of breast/formula feeding that could lead to acquired hypothyroidism.

Background: Bannayan Riley Ruvalcaba syndrome (BRRS) is exceedingly rare, with only about 50 reported cases to date. Case presentation: We report a patient with hypoglycemia, precocious puberty and diffuse testicular microlithiasis accompanying BRRS, and think that this case is important in the light of a newly identified mutation in the PTEN gene. Conclusions: Close attention must be paid in terms of PTEN mutations in cases of macrocephaly and accompanying neurological and dermatological findings.

Background: Polyglandular autoimmune syndrome (PGA) and eosinophilic granulomatosis with polyangiitis (EGPA) do not seem to represent a coincidental association. Case presentation: A case of a 15-year-old boy is reported who presented with severe systemic inflammation, perimyocarditis and cardiogenic shock, in whom EGPA was initially suspected and later diagnosed with autoimmune adrenalitis with PGA. Conclusions: The severity of the systemic inflammation and perimyocarditis suggests a more widespread autoimmune-mediated process. Autoimmune adrenal insufficiency should be considered in all cases of pericarditis and perimyocarditis, especially when the severity of clinical manifestations exceeds the expected for the severity of the cardiac findings, as timely identification and prompt treatment may be life-saving.