Volume 34, Issue 4

Objectives Diagnostic process of mitochondrial disorders (MD) is challenging because of the clinical variability and genetic heterogeneity of these conditions. Next-Generation Sequencing (NGS) technology offers a high-throughput platform for nuclear MD. Methods We included 59 of 72 patients that undergone WES and targeted exome sequencing panel suspected to have potential PMDs. Patients who were included in the analysis considering the possible PMD were reviewed retrospectively and scored according to the Mitochondrial Disease Criteria Scale. Results Sixty-one percent of the patients were diagnosed with whole-exome sequencing (WES) (36/59) and 15% with targeted exome sequencing (TES) (9/59). Patients with MD-related gene defects were included in the mito group, patients without MD-related gene defects were included in the nonmito group, and patients in whom no etiological cause could be identified were included in the unknown etiology group. In 11 out of 36 patients diagnosed with WES, a TES panel was applied prior to WES. In 47 probands in 39 genes ( SURF1, SDHAF1, MTO1, FBXL4, SLC25A12, GLRX5, C19oRF12, NDUFAF6, DARS2, BOLA3, SLC19A3, SCO1, HIBCH, PDHA1, PDHAX, PC, ETFA, TRMU, TUFM, NDUFS6, WWOX, UBCD TREX1, ATL1, VAC14, GFAP, PLA2G6, TPRKB, ATP8A2, PEX13, IGHMBP2, LAMB2, LPIN1, GFPT1, CLN5, DOLK ) (20 mito group, 19 nonmito group) 59 variants (31 mito group, 18 nonmito group) were detected. Seven novel variants in the mito group ( SLC25A12, GLRX5, DARS2, SCO1, PC, ETFA, NDUFS6 ), nine novel variants in the nonmito group ( IVD, GCDH, COG4, VAC14, GFAP, PLA2G6, ATP8A2, PEX13, LPIN1 ) were detected. Conclusions We explored the feasibility of identifying pathogenic alleles using WES and TES in MD. Our results show that WES is the primary method of choice in the diagnosis of MD until at least all genes responsible for PMD are found and are highly effective in facilitating the diagnosis process.

Objectives Omnitrope ® (somatropin, Sandoz Inc.) is one of several recombinant human growth hormones (rhGH) approved in the United States (US) for use in pediatric indications, including growth hormone deficiency (GHD) and idiopathic short stature (ISS). We report data on the effectiveness and safety of Omnitrope ® in the US cohort of the PATRO Children (international, longitudinal, non-interventional) study. Methods All visits and assessments are carried out according to routine clinical practice, and doses of Omnitrope ® are given according to country-specific prescribing information. Results By September 2018, 294 US patients were recruited; the two largest groups were GHD (n=193) and ISS (n=62). Across all indications, HSDS improvement (ΔHSDS) from baseline at three years was +1.0 (rhGH-naïve, +1.2; pre-treated, +0.7). In pre-pubertal patients, ΔHSDS from baseline at three years was +0.94 (rhGH-naïve, +1.3; pre-treated, +0.7). Following three years of treatment, ΔHSDS from baseline was +1.3 in rhGH-naïve GHD patients and +1.1 in rhGH-naïve ISS patients. In pre-pubertal rhGH-naïve patients, ΔHSDS from baseline was +1.3 and +1.2 in GHD and ISS patients, respectively. Overall, 194 patients (66.0%) experienced adverse events (AEs; n=886 events); most were of mild-moderate intensity. Five patients (1.7%) had AEs that were suspected to be treatment-related (n=5 events). All reported neoplasms were benign, non-serious, and considered unrelated to rhGH therapy. No AEs of diabetes mellitus or hyperglycemia were reported. Conclusions Omnitrope ® appears to be well tolerated and effective in the majority of patients, without evidence of an increased risk of developing unexpected AEs, diabetes mellitus, or new malignancies during treatment.

Objectives Current treatment protocols in acute lymphoblastic leukemia (ALL) are associated with high remission rates and long life expectancy, enhancing the importance of quality of life and prevention of treatment-related complications in patient care. As osteoporosis is a frequent complication in patients under chemotherapy, we investigated the effect of vitamin K2 (100 mcg menaquinone-7) and vitamin D3 (10 mcg calcitriol) on bone metabolism in children with ALL. Methods Twenty-nine consecutive patients recently diagnosed with B precursor ALL (B-ALL) and treated according to the Turkish Acute Lymphoblastic Leukemia Berlin Frankfurt Münster 2000 protocol were randomly assigned into study and control groups. The study group (n=15, M/F: 8/7, age 1–14.5 years, mean 6.5 years) received vitamin K2 and vitamin D3 with their chemotherapy, while the control group (n=14, M/F 9/5, age 2–17 years, mean 7.1 years) received chemotherapy only. Serum calcium, phosphorus, magnesium, alkaline phosphatase, bone-specific alkaline phosphatase, uncarboxylated osteocalcin (ucOC), tartrate resistant acid phosphatase 5b, carboxyl terminal procollagen propeptide (PICP), osteoprotegerin (OPG), and receptor activator nuclear kappa B ligand (RANKL) were measured and bone mineral density (BMD) was determined at baseline and first, second, third and sixth months. Results The study group had higher serum OPG/RANKL ratio and lower ucOC levels compared to the control group at the first month; PICP levels were higher in the study group at second and third months. Conclusions These results suggest an early beneficial effect of the combination of vitamin K2 and vitamin D3 on BMD in ALL patients especially during the period of intensive steroid therapy in the first months.

Objectives The Bethesda system for reporting cytopathology (TBSRTC) has been widely adopted in the management of thyroid nodules. Based on the limited pediatric data available, the implied malignancy risk for each of the categories may be significantly different in pediatrics vs. adults, especially in the indeterminate categories (Bethesda Class III or IV). We report the diagnostic utility of fine needle aspiration (FNA) biopsy at our institution based on the Bethesda system and the risk of malignancy in each category. Methods We retrospectively reviewed all patients who underwent a thyroid FNA at our tertiary pediatric hospital from 12/1/2002 to 11/30/2018. FNA results were classified according to TBSRTC. Patient demographics, cytology, histopathology, radiological and clinical follow-ups were examined. Results A total of 171 patients were included with 203 cytological samples. Average age at initial FNA was 14.7 years (range 6.9–18.6 years). The numbers of nodules reported for Bethesda categories I–VI were 29, 106, 22, 14, 6 and 26, respectively, and the rate of malignancy was: 13.8, 4.7, 22.7, 35.7, 83.3 and 100%, respectively. Use of ultrasound guidance reduced the non-diagnostic rate from 38.1 to 11.5%. Introduction of on-site adequacy testing further reduced the non-diagnostic rate to 6.5% since 2014. Conclusions The risk of malignancy for thyroid nodules in this pediatric cohort is higher than reported in adults. However, rates described here are much closer to adult ranges than previously published pediatric cohorts. The addition of adequacy testing improved the non-diagnostic rate of FNA procedures performed with ultrasound guidance.

Objectives Accurate diagnosis and follow-up of pediatric patients with thyroid disorders, depends on the availability of appropriate data for normal thyroid volume (TV). The aim of this study was to determine the TV by ultrasonography (US) in subjects from the newborn period up to 18 years of age from the Aegean region of Turkey. Methods We measured the thyroid volumes in 513 children using US and compared them with the children’s age, gender, standard deviation score (SDS) of body height (BH-SDS), body weight (BW-SDS), body mass index (BMI-SDS), and body surface area (BSA-SDS). The 3rd, 50th, and 97th percentiles of the age-dependent distribution of the TV were calculated and compared with national and international references. Results The BH, BW, BMI, and BSA of all the participants were within the normal ranges for Turkish children. The TV was significantly positively correlated with age, gender, BH-SDS, BW-SDS, BMI-SDS, and BSA-SDS in all subjects (r=0.748, r=0.267, r=0.730, r=0.735, r=0.664 and r=0.735, respectively; p<0.0001 for all). The most important predictors for TV were age and BW-SDS, followed by BSA-SDS and BH-SDS. In multivariate regression, age and BW-SDS were the only significant independent predictors for TV. Our results were nearly similar to the corresponding data reported by the World Health Organisation in 2004. Conclusions The present study provides updated values for TV that can serve as a potential tool in differentiating the normal from the abnormal size of the thyroid gland in children aged 0–18 years from the Aegean region of Turkey.

Objectives Short stature and thyroid autoimmunity are common comorbidities in Turner syndrome (TS). Recombinant human growth hormone (rhGH) significantly improves height growth in TS individuals. This study aims to investigate the association of thyroid autoimmunity and the response to rhGH treatment in TS patients. Methods Medical records of 494 patients with TS were reviewed. Among 126 patients who regularly tested for thyroid autoantibodies, 108 patients had received rhGH treatment. Clinical characteristics, including karyotype and the presence of autoimmune thyroid diseases, as well as rhGH treatment records were analyzed. Height velocity (HV) of patients with or without thyroid autoimmunity was compared to assess the response to rhGH treatment. For patients who developed thyroid autoantibodies during rhGH treatment, HV before and after antibody presence were compared. Results 45XO monosomy presented in 36% (176/496) of patients. 42.1% of patients (53/126) had elevated circulating anti-thyroid peroxidase antibody and anti-thyroglobulin antibody. In 108 patients who received rhGH treatment, HVs were significantly correlated to age, height, weight and BMI at the initiation of treatment. For patients who developed thyroid autoantibodies during rhGH treatment, HVs after thyroid autoantibody presence significantly decreased compared with HVs before thyroid autoantibody detection (n=44, p=0.0017). Conclusions Our data suggested that in TS patients who developed thyroid autoantibodies during rhGH treatment, the response to rhGH is negatively associated with the development of thyroid autoimmunity.

Background A Turner Syndrome (TS) Transition clinic, Royal Hospital for Children Glasgow (RHCG), with paediatric and adult endocrinology/gynaecology teams was established in 1998 with an aim of improving health outcomes in TS throughout the lifespan. Objective To evaluate the success of our TS transition service, focussing on evaluating established follow-up after transfer to adult services. Methods Girls attending the TS Transition clinic at Royal Hospital for Children Glasgow, 1998–2017, were identified. Attendance data were obtained from patient records and an electronic appointment system. We assessed good and late early attendance in our cohort of TS patients as well as established endocrine follow-up, defined as those still attending adult endocrine services 3 years after transfer. Success of TS transition was determined by the proportion of girls in established endocrine follow-up. Results Forty-six girls (median age 18.3 yrs) were identified. Thirty-six, 36/46 girls transferred prior to 2015 and 26 of those (72%) were in established follow-up at 3 years, 22/36 girls had met with an Adult specialist prior to transfer and 14/36 had not met with an adult specialist prior to transfer. Twenty-one (80.7%) were good early attenders (p = 0.10). In the early attenders’ cohort, there was no significant difference between those that had and had not met an adult specialist prior to transfer. Conclusion A significant proportion of girls with TS are currently lost to endocrine follow-up following transfer to adult clinics. Early attendance at an adult clinic appears to predict established long-term follow-up. Strategies to improve early attendance and long-term endocrine follow-up are needed to ensure lifelong health needs are addressed.

Objectives To determine appetite-regulating hormone levels in girls with central precocious puberty (CPP) before and after 20 weeks of gonadotropin-releasing hormone analogue (GnRH-A) treatment. Methods Eighteen newly diagnosed CPP girls were enrolled. Body composition measured by bioelectrical impedance analysis and GnRH-A test were performed with fasting serum leptin, ghrelin and peptide YY (PYY) measurements at baseline (before) and after 20 weeks of GnRH-A treatment. Results Following GnRH-A treatment, all patients had prepubertal gonadotropin and estradiol levels. Mean (SD) fat mass index (FMI) was significantly increased from 4.5 (1.7) to 5.0 (1.8) kg/m 2 after treatment. Also, median (IQR) serum leptin level was significantly increased from 6.9 (4.2–8.6) to 7.4 (5.3–13.1) ng/mL. FMI had a positive correlation with serum leptin level (r=0.64, p=0.004). In contrast, no significant changes of serum ghrelin and PYY levels were observed. Conclusions Decreased estrogen following short-term GnRH-A treatment in CPP girls may cause an increase in appetite and consequently an elevation of FMI. Increased serum leptin may be a result of having increased FMI secondary to an increase in appetite.

Objectives The early and late complications after hematopoietic stem cell transplantation (HSCT) determine the patients’ prognosis and life quality. We aim to determine the metabolic syndrome development frequency after HSCT in children to find out the risk factors and compare them with healthy adolescents. Methods Thirty-six children who underwent HSCT at least two years ago were analyzed prospectively and cross-sectionally. Our study included 18 healthy children between the ages of 11 and 17 as a control group. All of the cases were assessed in terms of metabolic syndrome (MS) through the use of Modified WHO Criteria. Results The patients’ median age was 10.6 (5.1–17) years, the median time of follow-up after HCST was 4.1 (2–13.5) years and 70% were male. Two cases were diagnosed with MS (5.6%). When considered in terms of the sub-components of MS, 2 cases (5.6%) were found to have obesity, 17 cases (47%) abnormal glucose tolerance, 11 cases (30.7%) dyslipidemia, and 3 cases (8.6%) hypertension. The MS rate was not different when compared with the 11–17 year-old healthy control group (0 vs. 11%, p=0.48). Myeloablative conditioning regimen (65 vs. 20%) and the increased age at which HSCT was performed were considered to be risk factors in terms of insulin resistance (p=0.025 and 0.002). Conclusions Age and conditioning regimens were found to be the risk factors for insulin resistance development. The long-term follow-up of the cases who had undergone HSCT in childhood in terms of MS and its sub-components is important in order to increase life quality.

Objectives Recent studies have shown a potential link between chronic exposure to Bisphenol A (BPA) and exogenous obesity, the prevalence of which has been increasing dramatically in all age groups and particularly among children in the last decades. In this study, we aimed at comparing BPA exposure levels between controls and otherwise healthy, drug-naive, pre-pubertal children having exogenous obesity with/without metabolic syndrome. Methods A total of 63 pre-pubertal children with exogenous obesity whom 27 of them having metabolic syndrome attending Hacettepe University Ihsan Dogramaci Children’s Hospital were included in this study. The control group consisted of 34 age- and sex-matched healthy children with no significant underlying medical conditions. Urinary BPA levels were measured using LC-MS/MS (high-performance liquid chromatography coupled with tandem mass spectrometry) methodology. Results Urinary BPA levels among obese children were significantly higher than those of the control group (median: 22.9 μg/g-creatinine and 6.9 μg/g-creatinine, respectively; p=0.0001). When adjusted with generalized linear models for age, gender and z scores of body mass index, obese children having metabolic syndrome had significantly higher urinary BPA levels than obese children without metabolic syndrome and both obese groups had considerably elevated levels of urinary BPA than the controls (estimated marginal mean ± standard error: 42.3 ± 7.4 μg/g-creatinine, 22.6 ± 3.5 μg/g-creatinine and 12.1 ± 2.5 μg/g-creatinine, respectively, p=0.0001) Conclusions This study shows much higher BPA exposure among obese children with metabolic syndrome during the prepubertal period.

Objective Insulin-induced lipodystrophy is of two types, lipohypertrophy and lipoatrophy. Lipodystrophy often leads to worsening of glycemic control in type 1 diabetes mellitus. Our objective was to identify the clinical, immunological, and other factor(s) associated with the development of lipodystrophy. Methods In this observational cross-sectional hospital-based study, 95 children, adolescents, and young adults with type 1 diabetes mellitus were observed for the development of lipodystrophy. Injection technique, insulin dose, and glycemic parameters were noted. Serum TNF-α, IL-1β, and anti-insulin antibody levels were measured. Histopathological examination of the lipodystrophic area was done in a small number of people. Results Among the participants, 45.2% of participants had lipohypertrophy and 4.2% had lipoatrophy exclusively; 3.1% of participants had coexisting lipohypertrophy and lipoatrophy. Improper injection site rotation technique was more common in participants with lipohypertrophy in comparison to those without lipodystrophy. The age of onset of diabetes, duration of insulin use, and the number of times of needle reuse were not significantly different between the lipohypertrophy and nonlipodystrophy groups. Serum TNF-α, IL-1β, and anti-insulin antibody levels; HbA 1c ; rate of hypoglycemia; and body weight-adjusted dose requirement were higher among the participants with lipohypertrophy. On histopathology, scant, or no inflammatory infiltrate was found in lipoatrophic and lipohypertrophic areas, respectively. Conclusion Improper insulin injection technique and higher levels of proinflammatory cytokines and anti-insulin antibody are associated with lipodystrophy in type 1 diabetes mellitus. HbA 1c and rate of hypoglycemia are higher in people with lipodystrophy.

Objectives Bangladesh has limited information regarding incidence of type 1 diabetes (T1D) and type 2 diabetes (T2D) in young people. The objective of this study was to measure minimum incidence of T1D and T2D, and record other types of new-onset diabetes in children and adolescents <20 years (y), in Dhaka District, Bangladesh, from 2011–2018. Methods Retrospective study using clinical records from Diabetic Association of Bangladesh clinics. Cases were classified by clinical evaluation. Results 725 cases were diagnosed. 482 (66.5%) had T1D, 205 (28.3%) T2D, 14 (1.9%) fibrocalculous pancreatic diabetes, and 24 (3.3%) other types. Male:female ratios for T1D/T2D were 1:1.6 (p<0.0001) (T1D) and 1:1.4 (p<0.01) respectively. T1D cases by age-group were 7.3% (0–4 y), 19.9% (5–9 y), 43.6% (10–14 y) and 29.3% (15–19 y). Mean ± SD ages of onset were 12.3 ± 4.2 y (T1D) and 13.1 ± 2.4 y (T2D). Annual T1D mean incidences/100,000 were 1.22 [95%CI: 0.85–1.58] (<15 y) and 1.25 [0.94–1.57] (<20 y), and for T2D 0.52 [0.33–0.73] (<20 y). T1D incidence <15 y was 1.04 [0.69–1.39] in 2011 and 1.42 [1.04–1.80] in 2018 (p=0.08). T2D incidence rose from 0.22 [0.80–0.36] (2011) to 0.57 [0.36–0.77] (2018), an annualized increase of 12% [8–22%] (p=0.001). Ascertainment was estimated as 95%. Conclusions T1D was most common, but T2D, FCPD and other forms also occur. T2D incidence increased during the study period.

Background X-linked adrenoleukodystrophy (ALD) affects up to 25% of boys diagnosed with adrenal insufficiency in childhood. Because early identification of these individuals can be lifesaving, all boys with new-onset primary adrenal insufficiency should be tested for ALD with a plasma very long-chain fatty acid (VLCFA) level. While plasma VLCFA is a diagnostic test with high sensitivity and specificity, false-positive results have been reported in individuals on a ketogenic diet. Case presentation We present a case of an 11-year-old boy with new-onset primary adrenal insufficiency due to autoimmune adrenalitis who was initially found to have elevated VLCFA levels, suggestive of ALD, that normalized on repeat testing. Conclusions As advances in gene therapy and newborn screening for ALD expand, VLCFA testing may increase, and clinicians should be aware that testing during the initial presentation of primary adrenal insufficiency may lead to false-positive results and associated psychosocial distress.

Objective We present a case of an unusual cause of prepubertal gynecomastia. Case Presentation Enlargement of breast tissue in males, or gynecomastia, is a rare condition in prepubescent boys. We describe an 8-year-old male who developed unilateral gynecomastia secondary to marked dietary soy consumption. While the majority of cases are idiopathic, soy products, particularly those consumed by our patient, can contain high levels of phytoestrogens, which have been documented in limited case studies to contribute to abnormal development of breast tissue in adolescent and adult males. To our knowledge, this is the first documented case of gynecomastia occurring in a prepubescent patient resulting from excessive intake of dietary soy. Importantly, we also report a complete resolution of gynecomastia upon exclusion of dietary products containing significant amounts of soy. Conclusion While soybeans and soy-derived products can be an important source of nutrition for some, those with abnormal sensitivity to phytoestrogens may benefit from limiting dietary soy consumption to avoid potential adverse effects, including gynecomastia.

Objectives Congenital Hyperinsulinism (CHI) is the most common cause of persistent hypoketotic hypoglycaemia in neonates and infants. It is a genetic disorder with both familial and sporadic forms. Case Presentation In this study, we examined two unrelated infants of diabetic mothers (IDMs) presented with HH. DNA sequencing (Sanger and NGS panel) identified pathogenic variants of the Hepatocyte Nuclear Factor 4A ( HNF4A ) gene in both families. Pathogenic variants of HNF4A gene are reported to cause HH in the newborn period and Maturity Onset Diabetes of the Young (MODY) later in life. The diagnosis of MODY was made in retrospect for the two mothers, thus improving the management of their diabetes. Conclusion Genetic testing for CHI is strongly recommended if neonatal hypoglycemia persists . A family history of MODY or presumed type II diabetes can support that the affected gene is HNF4A .

We present an unusual case of SHOX deficiency associated with Léri-Weill dyschondrosteosis (LWD), Hashimoto’s thyroiditis and pseudohypoparathyroidism 1B in a young woman. To our knowledge, this is the first ever report of these disorders coexisting. At the age of nine years, the proband was diagnosed of hypothyroidism due to Hashimoto’s thyroiditis, and developed biochemical abnormalities consistent with hyperphosphatemia, mild hypocalcemia and elevated parathyroid hormone without any clinical symptoms except short stature. Replacement therapy with levothyroxine, calcium and alphacalcidol was initiated. The diagnosis of pseudohypoparathyroidism 1B was confirmed at the age of 17.5 years with the demonstration of methylation alteration at the GNAS locus. At the age of 16 years, 3.5 years after her menarche, she presented clear features of LWD. A large deletion of the SHOX gene was confirmed. Family genetic tests were not doable since she was adopted. We discuss the diagnostic challenges of these coexisting rare endocrinopathies.