Volume 30, Issue 8

Background: We aimed to describe the longitudinal changes in bone mineral content and influencing factors, in children with cystic fibrosis (CF). Methods: One hundred children (50 females) had dual X-ray absorptiometry (DXA) performed. Of these, 48 and 24 children had two to three scans, respectively over 10 years of follow-up. DXA data were expressed as lumbar spine bone mineral content standard deviation score (LSBMCSDS) adjusted for age, gender, ethnicity and bone area. Markers of disease, anthropometry and bone biochemistry were collected retrospectively. Results: Baseline LSBMCSDS was >0.5 SDS in 13% children, between −0.5; 0.5 SDS, in 50% and ≤−0.5 in the remainder. Seventy-eight percent of the children who had baseline LSBMCSDS >−0.5, and 35% of the children with poor baseline (LSBMCSDS<−0.5), showed decreasing values in subsequent assessments. However, mean LS BMC SDS did not show a significant decline in subsequent assessments (−0.51; −0.64; −0.56; p=0.178). Lower forced expiratory volume in 1 s percent (FEV1%) low body mass index standard deviation scores (BMI SDS) and vitamin D were associated with reduction in BMC. Conclusions: Bone mineral content as assessed by DXA is sub-optimal and decreases with time in most children with CF and this study has highlighted parameters that can be addressed to improve bone health.

Background: Impaired glucose metabolism and cystic fibrosis (CF)-related diabetes (CFRD) are associated with insufficient weight gain and impaired lung function in children and adolescents with CF. We have asked whether imminent CFRD may be a cause of poor growth in children and adolescents. Methods: A retrospective case control study including 32 patients with CF with or without diabetes was conducted. Sixteen pairs, matched according to age, gender and exocrine pancreatic insufficiency, were analysed. Standard deviation scores (SDS) of height, growth, weight, body mass index (BMI), forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and forced expiratory flow at 75% of expired FVC (FEF75) were recorded during a mean observation period of 13 years per patient. Results: SDS of height and weight were reduced in CF patients with diabetes compared to those without, not only at the point of diagnosis (both p<0.05) but years before the evidence of diabetes. Afterwards there was a significant decline in height (p<0.001) and weight (p<0.01) SDS in CFRD patients and an increasing difference between the height and weight of CF patients with or without diabetes. In contrast, no significant reduction of BMI-SDS was observed in CFRD patients. All analysed lung function parameters showed a marked decline in CFRD patients starting 1 year prior to the diagnosis of diabetes. Conclusions: Deteriorating growth, reduced weight and impaired lung function are related to the development of CFRD and are obvious several years before the actual diagnosis of diabetes.

Background: It is unclear whether the gold standard test for the detection of partial clinical remission (PCR) in new-onset type 1 diabetes (T1D), the insulin-dose adjusted Hemoglobin A 1c (IDAA 1c ) of ≤9, is superior to a new tool, total daily dose of insulin (TDD) of <0.3 units/kg/day. The aim of the study was to test the superiority of IDAA 1c over TDD of <0.3 units/kg/day for the detection of PCR. Methods: A retrospective analysis of 204 subjects of ages 2–14 years, mean age 7.9±3.2 years, (male 7.8±3.4 years, [n=98]; female 7.9±3.0 years, [n=106], p=0.816) with new-onset T1D. Anthropometric and biochemical data were collected for the first 36 months of disease. PCR was defined by both IDAA 1c ≤9 and TDD<0.3 units/kg/day. Results: There were 86 (42.2%) (age 9.1±3.0 years; male 57%) remitters by IDAA 1c ≤9 criterion, and 82 (40.2%) remitters (age 7.3±2.8 years) by TDD of <0.3 units/kg/day criterion (p=0.655). The duration of PCR was 10.0±6.1 months using TDD<0.3 units/kg/day, and 9.2±5.5 months using IDAA 1c (p=0.379). Subjects in PCR as denoted by TDD<0.3 units/kg/day had 1.44 times increased probability of entering PCR than those denoted by IDAA 1c of ≤9, after adjusting for BMI, bicarbonate, and HbA 1c :(OR=1.44, 95% CI [1.03–2.00], p=0.033). Peak prevalence for PCR was at 6–12 months by either definition; more subjects were in PCR at 6 months by IDAA 1c ≤9: 62/86 (72.1%) than by TDD<0.3 units/kg/day: 43/82 (52.4%), (p=0.011). Conclusions: There were no significant differences in the number of remitters, duration of PCR, or the time of peak remission defined by IDAA 1c of ≤9 or TDD of <0.3 units/kg/day.

Background: Recent data indicates that adults with Down syndrome (DS) are at increased risk for cardiovascular disease (CVD) that significantly contributes to their morbidity and mortality. Although identification of cardiometabolic risk factors during childhood is desirable to design preventive interventions, the data on such risk factors in children with DS is scarce. The aim of this study was to study the cardiometabolic risk factors such as insulin resistance (IR), leptin and adiponectin concentrations, lipid abnormalities and leptin resistance in non-obese children with DS. Methods: This cross-sectional case control study included karyotype confirmed trisomy-21 DS children aged 2–12 years and their matched healthy controls. After detailed anthropometry, weight, height and body mass index (BMI) standard deviation scores (SDSs) were calculated with reference data. Laboratory evaluation included determination of fasting lipid parameters, insulin, glucose, leptin and adiponectin concentrations. The homeostasis model assessment method (HOMA-IR) was used to assess IR and the ratio of leptin to BMI was used as an index of leptin resistance. Results: Seventy-seven children (39 with DS and 38 controls) comprised the study cohort. The anthropometric parameters were similar in the two groups. Children with DS showed significantly higher mean leptin concentrations (2.098±1.68 ng/mL vs. 1.44±0.52 ng/mL, p-value: 0.00) and higher indices of leptin resistance (0.127±0.085 vs. 0.09±0.03, p-value: 0.001) as compared to controls. Fasting adiponectin concentrations were lower (20.64±19.87 ng/mL vs. 32.58±34.25 ng/mL, p-value: 0.21) and fasting glucose higher (89.25±8.12 mg/dL vs. 85.71±5.52 mg/dL, p-value: 0.06) in the DS group as compared to the controls but the differences did not reach statistical significance. The concentrations of insulin, various lipid parameters and calculated HOMA-IR values were similar in the two groups. In the DS group, five children were identified to have high (>75th centile) leptin levels and four as impaired fasting glucose as compared to none in the controls. Conclusions: Alterations of several cardiometabolic risk factors, in particular, leptin concentrations and leptin resistance are present in children with DS. The presence of hyperleptinemia without hyperinsulinemia suggests a probable inherent genetic basis for increased leptin resistance in patients with DS. There is a need for larger studies to further understand increased leptin resistance in DS that may contribute to increased CVD related morbidity and mortality in these patients.

Background: Eating habits formed during childhood may contribute to the increasing prevalence of cardiometabolic disorders. Assessing nutritional risk in young children may help to prevent later cardiometabolic disease. The objective of this study was to determine whether parent-reported nutritional risk in preschool-aged children was associated with laboratory indices of cardiometabolic risk, namely leptin and insulin. Methods: In this cross-sectional study, the relationship between nutritional risk as determined by the parent-completed NutriSTEP ® questionnaire was assessed and compared to the serum leptin and insulin concentrations, hormones involved in regulation of food intake and biomarkers of adiposity and cardiometabolic risk. The community-based primary care research network for children in Toronto, Canada (TARGet Kids!) was used. The participants were children aged 3–5 years recruited from TARGet Kids! A total of 1856 children were recruited from seven primary care practices. Of these, 1086 children completed laboratory testing. Laboratory data for leptin and insulin were available for 714 and 1054 of those individuals, respectively. Results: The total NutriSTEP ® score was significantly associated with serum leptin concentrations (p=0.003); for each unit increase in the total NutriSTEP ® score, there was an increase of 0.01 ng/mL (95% confidence interval [CI] 0.004–0.018) in serum leptin concentrations after adjusting for potential confounders. The total NutriSTEP ® score was not significantly associated with serum insulin concentration. Conclusions: Parent reported nutritional risk is associated with serum leptin, but not insulin, concentrations in preschool-aged children. The NutriSTEP ® questionnaire may be an effective tool for predicting future cardiometabolic risk in preschool-aged children.

Background: Multinodular goiter (MG) is very common in adults. MG may occur in children in some exceptional circumstances. The objective of this study was to examine two cases of MG in children who relapsed soon after surgery and to discuss the treatment options in pediatric ages. Methods: Two girls consulted for euthyroid colloid goiter, uninodular goiter and bilateral MG. They were intervened by hemithyroidectomy and total thyroidectomy, respectively, due to the existence of local symptoms. Results: Goiters reappeared 3 years after intervention in both cases. They already appeared as bilaterally MG, and patients underwent a total thyroidectomy, in one case after 1 year of treatment with levothyroxine (LT4). Conclusions: MG treatment remains controversial. There is an increasing trend to a more radical surgery decreasing recurrence risk. Treatment with LT4 may be tested but it is rarely effective. Regardless of the therapeutic option, these children should be followed up and they should know about the possibility of goiter regeneration and the need for reintervention.

Background: Increased thyroid stimulating hormone (TSH) serum concentration can be a marker of subclinical hypothyroidism (SCH) or transient hyperthyrotropinemia. The aim of our study was to evaluate whether high serum TSH concentrations in allergic children could represent true SCH or isolated and transient hyperthyrotropinemia. Methods: We enrolled 620 allergic children (1.11–12.8 years) consecutively attending to our department. They were classified as atopics and non-atopics on the basis of the atopy work-up and, at baseline, they were investigated for thyroid function and low-grade inflammation state. Further, TSH was evaluated after 6 (T1) and 12 (T2) months. Results: Both atopics and non-atopics showed higher SCH prevalence compared to controls (p=0.0055 and p=0.02, respectively), and a significant association between atopy and SCH (OR 10.11, 95% CI 1.36–75.12) was found. Both at T1 and T2, atopics had a significant risk of developing severe SCH compared to non-atopics (RR 1.8, 95% CI 1.39–2.34 and 1.61, 95% CI 1.21–2.14; respectively). Conclusions: Our data may suggest that hyperthyrotropinemia in atopic children could be used as a marker of true SCH.

Background: The embryonic development of the thyroid gland is regulated by the expression of several candidate genes which are related to congenital hypothyroidism. These genes include the numerous critical thyroid transcription factors such as NKX2.1, NKX2.5, FOXE1, and PAX8. The molecular analysis of these loci will be essential to the explanation of the participation of these transcription activators in the etiology of hypothyroidism. Among them, the role of NKX2.5 is important during the early thyroid morphogenesis and in controlling thyroidal cell differentiation and migration. Importantly, NKX2.5 change nucleotides are recognized to be central to the genesis of congenital hypothyroidism. Methods: A case-control study was conducted in 65 unrelated patients, diagnosed with primary congenital hypothyroidism and all of them were diagnosed according to the clinical presentations of thyroid hypoplasia and without cardiovascular defects. Mutational screening of the entire NKX2–5 coding sequence was performed in a cohort of pediatric patients by PCR-SSCP and direct sequencing. Results: We identified two known variations 73C>T (R25C) and 63A>G (E21E) in patients with thyroid hypothyroidism. Both of them are located in conserved region of the gene and previously reported in cases with thyroid dysgenesis and congenital heart defects. There was a significance association between 63A>G variation with primary hypothyroidism (p=0.003). Conclusions: These SNPs are probably related to thyroid hypoplasia because the allele frequency of the 63A>G polymorphism was significantly different in patients and controls and also R25C variation not observed in healthy cases.

Background: The aim of the study was to assess health-related quality of life (HR-QoL) in children with Turner syndrome in comparison with controls. Methods: We prospectively recruited 16 female girls with Turner syndrome (mean age 15.2±2.6 years) and 78 female controls (mean age 12.7±2.8 years) in randomly selected schools. We used the PedsQL, a generic HR-QoL questionnaire (self and parents’ versions). Results: Global HR-QoL scores in Turner syndrome were lower than controls for self-reports (respectively, 74.3±3.0 vs. 82.8±1.3, p=0.01) and parents’ reports (62.7±3.8 vs. 80.1±1.7, p<0.0001). In Turner syndrome, self-reported HR-QoL was impaired in school functioning (70.6±4.0 vs. 80.71±1.7, p=0.02), social functioning (78.2±4.0 vs. 90.4±1.8, p<0.01) and physical functioning (78.5±3.2 vs. 87.1±1.4, p=0.02), but not in emotional functioning. Parents’ reported HR-QoL was impaired in all four dimensions. Conclusions: HR-QoL was impaired in this cohort of young females with Turner syndrome, as in previously reported adult studies. In addition to medical treatment and routine clinical follow-up, female girls and teenagers with Turner syndrome should also be supported psychologically by social, educational and psychotherapeutic interventions that aim to address their self-esteem and emotional difficulties.

Background: Survivors of acute lymphoblastic leukemia (ALL) may experience endocrine dysfunction. This study evaluated growth and pubertal patterns in survivors of childhood ALL. Methods: Longitudinal assessment of anthropometric measurements and pubertal status was performed in a retrospective cohort of survivors (n=183). Median age at last endocrine visit was 16.1 years (range 8.2–27.6); median follow-up time was 8.7 years (range 3–21.4). Results: Treatment with chemotherapy+prophylactic cranial radiation (pCRT, n=29) was associated with lower mean height standard deviation score (SDS) than chemotherapy alone (n=154) (p=0.001) and higher prevalence of adult short stature (13% vs. 2.2%). Mean age at pubertal onset was normal (girls: 10.3±1.3 years; boys: 12.0±1.3 years). Precocious puberty, diagnosed in 8.7% of patients, was more prevalent in pCRT-treated girls. Rates of overweight and obesity were 22.9% and 9.3%, respectively. Predictors of endocrine disorders were pCRT (p=0.031) and female gender (p=0.041); of obesity, higher body mass index (BMI)-SDS at diagnosis (p=0.001); and of short stature, lower height-SDS at diagnosis (p=0.038). Conclusions: Most childhood ALL survivors given chemotherapy alone attain normal adult height and puberty. Childhood ALL survivors are at increased risk of overweight, especially those with increased BMI at diagnosis. Clinicians should screen for overweight early in survivorship and introduce early interventions.

Background: The objective of the study was to investigate clinical and gene mutation characteristics of primary carnitine deficiency (PCD) patients identified by newborn screening using tandem mass spectrometry (MS/MS). Methods: Tandem mass spectrometry (MS/MS) was applied to screen inherited metabolic disease and seven patients with PCD were diagnosed among 62,568 samples. The SLC22A5 gene was detected by using diagnosis panel of genetic and metabolic diseases based on Ion Torrent Semiconductor Sequencing Technology. Results: The initial free carnitine (C0) concentrations of the patients were 6.43±1.36 μmol/L, and the recall screening concentrations were 5.59±0.89 μmol/L. The patients were treated with oral carnitine, so the levels after treatment were 20.24±3.88 μmol/L. All patients had two pathogenic mutation alleles. Conclusions: The combined application of MS/MS and a next generation sequencing panel could be used for the accurate diagnosis of PCD. The results of genetic diagnosis can guide the assisted reproductive treatment. The prognosis of PCD patients is good after early treatment.

Background: Rhizomelic chondrodysplasia punctata (RCDP) is a rare peroxisomal disease characterised by punctate calcifications of non-ossified cartilage epiphyseal centres. The main biochemical marker of all RCDP types is a decrease in the levels of plasmalogens. Additionally, the accumulation of phytanic acid can be used as a differential marker between types of RDCP. Due to the biochemical overlap between types 1 and 5 RCDP, a genetic analysis of these genes should be performed in patients to identify the type. Case presentation: A 2-month-19-day-old male child presented with symptoms of limited movement and discomfort with movement in the extremities. His sister, who had similar clinical findings, was diagnosed with tetralogy of Fallot and died at 6 months of age. A physical examination revealed an atypical facial appearance, bilateral cataracts, sensitivity to touch in the extremities, shortness in the proximal segments of the long bones, limited movement in both knees and elbows and axial hypotonicity. Laboratory analyses revealed normal ammonia, lactate, plasma and urine amino acids, long chain fatty acids and phytanic acid levels. Rhizomelia, significant metaphyseal expansion, irregularities in the cortex, loss of ossification, fragmented appearance and punctate calcifications in both elbows, both knees and in the femoral epiphysis were seen on the skeletal survey. A homozygote p.L70W (c.209T>G) mutation was found in the PEX7 gene. Conclusions: Plasma phytanic acid levels can be normal in a patient with type 1 RCDP that develops as a result of a PEX7 gene mutation, as in our case. A molecular genetic analysis and/or fibroblast culture must be conducted in clinically suspicious cases. While no cardiac pathology was found in our case, tetralogy of Fallot was present in his sister with similar clinical findings. The presence of different cardiological phenotypes in the sibling suggested that the genotype-phenotype correlation may not be complete in this disorder.

Background: Severe hypertriglyceridemia (HTG) as well as diabetic ketoacidosis (DKA) are complications of type 1 diabetes (T1DM). HTG is an exceedingly rare complication in the pediatric population and herein we report a case of HTG at new-onset T1DM in DKA and discuss management and potential complications. Case presentation: An 11-year-old previously well patient with a history of fatigue and weight loss presented with: glucose >600 mg/dL, venous blood gas: pH 7.26, pCO 2 20 mmHg, PO 2 101 mmHg and base deficit 13 with triglyceride level 3573 mg/dL. An insulin drip was continued past criteria for discontinuation to facilitate lipoprotein lipase-based triglyceride metabolism. Conclusions: Lipemia secondary to severe HTG, though exceedingly rare, may exist in new onset T1DM with DKA. Complicating the diagnosis is the possibility of an analytical error from lipemia causing incongruence in diagnostic criteria. Clinicians should rely on clinical criteria for management and should consider HTG if laboratory data is inconsistent with the clinical picture.

Background: The 45,X/46,XY karyotype has been associated with mixed gonadal dysgenesis (MGD) and ovotesticular disorder of sex development (DSD). Our aim was to revise the diagnosis of ovotesticular DSD in two patients in the context of a retrospective study of 45,X/46,XY subjects with genital ambiguity. Case presentation: Patient 1 had a left streak gonad; the right one was considered an ovotestis. Patient 2 had a right testis; the left gonad was considered an ovary. Revision of the histological sections was performed. Both the “ovarian” part of the right gonad of patient 1 and the left “ovary” of patient 2 contained ovarian-type stroma with clusters of sex-cordlike structures and rare germ cells, compatible with undifferentiated gonadal tissue (UGT). Misdiagnosis of ovarian tissue in patients with 45,X/46,XY mosaicism or its variants could also be found in six published case reports. Conclusions: A distinction between 45,X/46,XY ovotesticular DSD and MGD should be made on past and future cases keeping in mind that UGT may be mistaken as ovarian tissue.

Background: Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is the most common genetic disorder of fatty acid oxidation, which presents before the age of 2 with the onset of acute hypoketotic hypoglycemia, and is typically precipitated by stress. Case presentation: We report serial brain magnetic resonance imaging (MRI) changes, including MR spectroscopy (MRS) and diffusion weighted imaging (DWI), in a patient with a classical MCAD presentation, compared with five healthy controls. Conclusions: Through this unique case we analyze the evolution of radiological findings during the first month of illness and we highlight the pivotal role of MRI, especially DWI, in the early diagnosis of the decompensated state of the disease.