Volume 31, Issue 6

Background: Congenital hypothyroidism (CH) is the most common preventable cause of intellectual disability. The recommended starting dose of levothyroxine (LT4) is between 10 and 15 μg/kg, an extremely wide range. We hypothesized that a sizable proportion of newborns treated for CH at the higher end of the dosage range become biochemically hyperthyroid at a follow-up visit. Methods: This study is a retrospective chart review of infants with CH between 2002 and 2012. Results: Of the 104 patients included in this analysis, the average age at diagnosis was 11 days and the average starting dose of LT4 was 12±2.5 μg/kg. At follow-up, 36.5% required a dose reduction because of iatrogenic hyperthyroxinemia, 51% required no dose adjustment and 12.5% required a dose increase due to an elevated thyroid stimulating hormone (TSH). The starting doses of LT4 for those requiring a dose reduction, those not requiring an adjustment and those requiring an increase in the dose were 13.2±2.4, 11.5±2.1 and 10.3±2.6 μg/kg/day, respectively (p≤0.0001). Of the 34% of infants treated with an initial dose of >12.5 μg/day, 57.1% required a dose reduction at follow-up, compared to 26.1% of those whose initial starting dose was ≤12.5 μg/kg/day (p=0.007). Conclusions: Following the guidelines for initiating therapy for CH, 36.5% of the infants required a dose reduction for iatrogenic hyperthyroxinemia. These infants received a higher dose of LT4 than the infants who either required no adjustment or required an increase in the dose. A narrower range for initial dosing in CH may be appropriate.

Background: Congenital hypothyroidism (CH) is one of the most frequent, preventable causes of mental retardation. Little has been reported on the epidemiological characteristics of CH in China. We aimed to estimate the incidence of CH in China and investigate its geographical variation. Methods: We analyzed data from the nationwide newborn screening program for CH between 2013 and 2015. Poisson regression was used to generate the odds ratios (ORs) and 95% confidence intervals (CIs) between the rates of CH and selected demographic characteristics and assess the potential association between CH incidence and geographical locations. Results: A total of 18,666 patients with CH were identified from 45.2 million newborns, yielding an overall incidence rate of 4.13 per 10,000 live births. Compared with those in the remote area, regardless of infant sex, a higher incidence risk for CH was present in newborns in coastal areas and inland areas (females: OR=2.00, 95% CI: 1.86–2.16 and OR=1.74, 95% CI: 1.61–1.87, respectively; males: OR=1.70, 95% CI: 1.59–1.83 and OR=1.52, 95% CI: 1.42–1.63, respectively). Additionally, the highest risk of CH for thyroid-stimulating hormone (TSH) screening values <40 mU/L was observed among neonates in the coastal areas, while TSH screening values of 70–100 mU/L were observed among those in the inland areas. Conclusions: The overall incidence of CH is high in China. The significant geographical variations of CH incidence are presented in this study.

Background: Congenital hypothyroidism (CH) is one of the common causes of intellectual disability which can be prevented by early detection of an elevated thyroid stimulating hormone (TSH) level in the newborn and by treatment with thyroxine. In Thailand, neonatal TSH screening was implemented nationwide in 2005. The objective of the study was to determine the etiologies and the estimated incidences of CH in southern Thailand before and after the implementation of a neonatal TSH screening program in 2005. Methods: The medical records of pediatric patients who were diagnosed with primary CH at Songklanagarind Hospital during 1995–2013 were retrospectively reviewed. The study was divided into two time periods: study period 1 (SP1) (1995–2004) and study period 2 (SP2) (2005–2013), the time before and after TSH program implementation. Results: The most common form of CH during SP1 was overt permanent CH (66%), mostly caused by athyreosis or ectopic thyroid. In SP2, the most common form of CH was mild permanent CH (39%) (mostly due to dyshormonogenesis), followed by overt CH (32%) and transient CH (29%). The overall annual estimated incidence of CH per 10,000 live births in Songkhla Province was 1.69 (1:5021) in SP1, increasing to 4.77 (1:2238) in SP2; in all 14 provinces in southern Thailand, the estimated incidence was 1.24 (1:8094) in SP1 and 2.33 (1:4274) in SP2. Conclusions: Neonatal TSH screening has a significant impact on the increased detection of the mild form of permanent and transient CH cases, which may be important for the prevention of brain damage from less severe CH although this remains to be documented.

Background: Congenital hypothyroidism (CH) is a common cause of mental retardation; it has a worldwide incidence ranging from 1:3000 to 1:4500 live births. Predictably, an increase in the reported incidence of primary CH occurs when the cut-off levels of thyroid-stimulating hormone are lowered. We aimed to evaluate the results of a congenital hypothyroidism screening program and current status in this study. Methods: Analysis results of 1300 infants who were referred to the endocrinology polyclinic because of suspected CH within the scope of the Ministry of Health National Neonatal Screening Program were retrospectively evaluated. Results: The diagnosis of CH and initiation of treatment were both done in 223 (18.5%) and 10 (0.8%) infants as a result of the initial evaluation and follow-up, respectively. The mean capillary and venous thyroid-stimulating hormone (TSH) levels of 223 patients were 40.78 (5.5–100) μIU/mL and 67.26 (10.7–100) μIU/mL, respectively. These patients’ mean heel prick time was 8.65 (0–30, median: 7) days. The mean age of the 223 infants whose treatment was initiated as a result of the initial evaluation was 19.87 (4–51, median: 20) days, and the mean age of the infants whose treatment was started at follow-up was 43.71 (29–65) days. The duration between heel prick time and venous TSH time was 11.10 (2–28, median: 11) days and was longer than planned (3–5 days). Conclusions: Although the duration for the diagnosis and initiation of CH treatment were markedly reduced with the implementation of the screening program in Turkey compared to those before the implementation of the screening program, we have not yet achieved the ideal time (≤14 days).

Background: The objective of this study was to ascertain the risk of hypoglycemia among youth with type 2 diabetes (T2D) on insulin therapy. Methods: Twenty-two youth with T2D on insulin therapy (M=12, F=10, age=14.4±4.0 years) were enrolled from a single pediatric endocrine practice. They were followed-up for 3 months with weekly phone calls and monthly in-person visits to review blood glucose logs and document any signs or symptoms of hypoglycemia (defined as finger stick glucose of ≤70 mg/dL). Episodes of hypoglycemia were categorized into five categories: severe, documented symptomatic, asymptomatic, probable symptomatic and relative hypoglycemia. In addition to examining the risk of hypoglycemia, the degree to which hypoglycemia was associated with patient demographics (e.g. age, gender and body mass index [BMI]) or clinical factors (i.e. duration of diabetes, duration of insulin treatment, glycemic control or insulin dose and regimen) was determined. Results: Nine hypoglycemic events occurred during the study period in five patients with an incidence rate of nine events per 5.3 patient-years. Of the hypoglycemic events, five were symptomatic and four were asymptomatic. No severe hypoglycemic events occurred. Hypoglycemia was not associated with age, ethnicity, duration of insulin treatment, insulin dose or initial hemoglobin (HbA 1c ). However, a significant difference in BMI was noted, with T2D youth who experienced hypoglycemia having a lower BMI than those who did not experience hypoglycemia. Conclusions: The results of this study suggest that the risk of hypoglycemia in youth with T2D on insulin therapy is low.

Background: The incidence of pediatric metabolic syndrome (MS) has progressively increased. The incidence of type 1 diabetes mellitus (T1DM) has also increased. Thus, some children and adolescents with T1DM exhibit MS parameters. The aim of the study was to evaluate the presence of MS parameters in female adolescents with T1DM based on their nutritional status. Methods: We evaluated 44 adolescents with T1DM (consecutive non-randomized sample) aged between 14 and 18 years, who were on intensive therapy with insulin. Patients were subdivided according to their body mass index (BMI). Variables evaluated include: age, age at diagnosis, weight, height, BMI, abdominal circumference, blood pressure, glycated hemoglobin (HbA 1c ), abdominal and pelvic ultrasound and lipoprotein profile. Gynecological history data were also collected. Results: Lipid profile changes were identified in 32% of overweight or obese girls and in 23% of those with an adequate weight. Hypertension (HT) was observed in 19% of overweight or obese girls and in 14% of those with a BMI≥85th percentile (Pc). The only statistically significant difference between the groups was the presence of abdominal adiposity. All other features, including the presence of dyslipidemia, HT, abdominal adiposity, non-alcoholic steatohepatitis (NASH) and polycystic ovarian syndrome (PCOS), were present in both groups. Conclusions: Although being overweight and/or obese aggravates the risk of cardiovascular disease, MS is already present in many young adolescents with T1DM of normal weight. It is necessary that MS risk factors are routinely evaluated in all diabetic adolescents, including those with an adequate BMI.

Background: Bone metabolism involves many complex pathways that are disturbed by several bone diseases. The literature shows some limitations concerning pediatric reference intervals to bone markers, mainly because of the low number of patients included in the studies, the heterogeneity of methods, beyond the fact that it is time-consuming and expensive. The aim of this study was to determine reference values for β-isomerized carboxy-terminal telopeptides collagen type I (β-CTX), a marker of bone resorption, for children and adolescents. Methods: Blood samples from 246 patients were collected and β-CTX was measured using an electrochemiluminescence immunoassay (ECLI). Results and conclusions: We propose reference ranges for β-CTX concentration from the 2.5 percentile and 97.5 percentile for each age group. The reference values obtained, concerning children and adolescents, might be useful in the evaluation of diseases such as osteosarcoma and anorexia in both childhood as adolescence.

Background: Brown adipose tissue (BAT) is present and functions to dissipate energy as heat in young adults and can be assessed using magnetic resonance imaging (MRI) to estimate the voxel fat fraction, i.e. proton density fat fraction (PDFF). It is hypothesized that subjects born preterm or small for gestational age (SGA) may exhibit disrupted BAT formation coupled to metabolic factors. Our purpose was to assess the presence of BAT in young adults born extremely preterm or SGA in comparison with controls. Methods: We studied 30 healthy subjects (median age, 21 years): 10 born extremely preterm, 10 full term but SGA and 10 full term with a normal birth weight (controls). We utilized an MRI technique combining multiple scans to enable smaller echo spacing and an advanced fat-water separation method applying graph cuts to estimate B 0 inhomogeneity. We measured supraclavicular/cervical PDFF, R2*, fat volume, insulin-like growth factor 1, glucagon, thyroid stimulating hormone and the BAT-associated hormones fibroblast growth factor 21 and irisin. Results: The groups did not significantly differ in supraclavicular/cervical PDFF, R2*, fat volume or hormone levels. The mean supraclavicular/cervical PDFF was equivalent between the groups (range 75–77%). Conclusions: Young adults born extremely preterm or SGA show BAT development similar to those born full term at a normal birth weight. Thus, the increased risk of cardiovascular and metabolic disorders in these groups is not due to the absence of BAT, although our results do not exclude possible BAT involvement in this scenario. Larger studies are needed to understand these relationships.

Background: The receptor for advanced glycation end products (RAGE) has a critical role in the pathogenesis of inflammation. In healthy children, its basal expression on the peripheral blood mononuclear cell (PBMC) and the basal circulating soluble RAGE (sRAGE) levels are unknown. The aim of this study was to describe both. Methods: This is a monocentric, observational and descriptive study of samples obtained from healthy children. The RAGE expression on PBMC was analyzed using flow cytometry. The sRAGE values were determined with a specific sandwich enzyme-linked immunosorbent assay (ELISA) kit, later the relation between cellular RAGE and sRAGE was described. Results: Forty-three children were included. The median sRAGE level was 849.0±579.0 pg/mL. The RAGE mean fluorescence intensity (MFI) was 1382±506 in monocytes and 792±506 in lymphocytes. There were no differences between genders. A negative correlation was found between sRAGE and RAGE MFI in lymphocytes (r=−0.3; p=0.04). Conclusions: We describe for the first time the RAGE surface levels on PBMC in children. It showed a negative correlation with sRAGE. The sRAGE circulating level is lower than the sRAGE level described in adult population or non-healthy children. Our findings should be confirmed in order to apply them as reference values for future investigations.

Background: Children with central precocious puberty (CPP) are treated with gonadotropin-releasing hormone agonists (GnRHa) to suppress puberty. Optimizing treatment outcomes continues to be studied. The relationships between growth, rate of bone maturation (bone age/chronological age [ΔBA/ΔCA]), luteinizing hormone (LH), predicted adult stature (PAS), as well as variables influencing these outcomes, were studied in children treated with depot leuprolide (LA Depot) Methods: Subjects (64 girls, seven boys) with CPP received LA Depot every 3 months for up to 42 months. Multivariate regression analyses were conducted to examine the predictors affecting ΔBA/ΔCA, PAS and growth rate. Results: Ninety percent of subjects (18 of 20) were suppressed (LH levels <4 IU/L) at 42 months. Over 42 months, the mean growth rate declined 2 cm/year, the mean BA/CA ratio decreased 0.21 and PAS increased 8.90 cm for girls (n=64). PAS improved to mid-parental height (MPH) in 46.2% of children by 30 months of treatment. Regression analysis showed that only the Body Mass Index Standardized Score (BMI SDS) was significantly associated (β+0.378 and +0.367, p≤0.05) with growth rate. For PAS, significant correlations were with MPH (β+0.808 and +0.791, p<0.001) and ΔBA/ΔCA (β+0.808 and +0.791, p<0.001). For ΔBA/ΔCA, a significant association was found only with BA at onset of treatment (β−0.098 and −0.103, p≤0.05). Peak-stimulated or basal LH showed no significant influence on growth rate, ΔBA/ΔCA or PAS. Conclusions: Growth rate and bone maturation rate normalized on treatment with LA Depot. LH levels were not significantly correlated with growth rate, ΔBA/ΔCA or PAS, suggesting that suppression was adequate and variations in gonadotropin levels were below the threshold affecting outcomes.

Background: The objective of the study was to identify national trends in the utilization of histrelin acetate implants among transgender children in the United States. Methods: We analyzed demographic, diagnostic and treatment data from 2004 to 2016 on the use of histrelin acetate reported to the Pediatric Health Information System (PHIS) to determine the temporal trends in its use for transgender-related billing diagnoses, e.g. “gender identity disorder”. Demographic and payer status data on this patient population were also collected. Results: Between 2004 and 2016, the annual number of implants placed for a transgender-related diagnosis increased from 0 to 63. The average age for placement was 14 years. Compared to natal females, natal males were more likely to receive implants (57 vs. 46) and more likely to have implants placed at an older age (62% of natal males vs. 50% of natal females were ≥;13 years; p<0.04). The majority of children were White non-Hispanic (White: 60, minority: 21). When compared to the distribution of patients treated for precocious puberty (White: 1428, minority: 1421), White non-Hispanic patients were more likely to be treated with a histrelin acetate implant for a transgender-related diagnosis than minority patients (p<0.001). This disparity was present even among minority patients with commercial insurance (p<0.001). Conclusions: Utilization of histrelin acetate implants among transgender children has increased dramatically. Compared to natal females, natal males are more likely to receive implants and also more likely to receive implants at an older age. Treated transgender patients are more likely to be White when compared to the larger cohort of patients being treated with histrelin acetate for central precocious puberty (CPP), thus identifying a potential racial disparity in access to medically appropriate transgender care.

Background: The objective of this study was to investigate the initial presenting features of children with classical congenital adrenal hyperplasia (CAH). Methods: This is a descriptive retrospective study over a period of 5 years. Data analysis was performed using Statistical Package for Social Science. Results: Ambiguous genitalia (AG) was the commonest initial presentation marking 50.7% of the patients. On the other hand, 33.3% presented with a salt-losing crisis, 4.1% of whom presented with shock, while 14.5% had a combined presentation of both AG and a salt-losing crisis. Conclusions: CAH should be highly suspected in all females born with AG. Contrarily, affected male newborns more frequently present with a salt-losing crisis, and considering the recent institution of newborn screening in Saudi Arabia, earlier detection in these children is anticipated.

Background: Laron syndrome (LS), which can be defined as primary growth hormone resistance or insensitivity, is a rare genetic disease inherited by an autosomal recessive trait. Although it is undistinguishable from growth hormone deficiency, LS has high levels of growth hormone, but insulin-like growth factor (IGF-1) cannot be synthesized. Mecasermin treatment is the only option for the patients who suffer from LS. This study aims to research cardiac findings of children with LS, who receive treatment with mecasermin. Methods: The study enrolled five children four males and one female, 4 M/1 F with LS, two of whom were siblings with a mean age of 6.3±2.1 years, a body weight of 13.36±4.74 kg, a height of 88±8.7 cm, and a body mass index (BMI) of 16.47±3.35. Their demographic data were obtained from their family and files. The children received mecasermin via subcutaneous injection at 0.04–0.12 μg/kg doses twice per day. The duration of mecasermin treatment was 8–53 months. All of them were examined clinically by electrocardiogram and echocardiogram. Results: Their cardiac examinations were normal, except for one case, who had systolic murmur at cardiac auscultation. Arrhythmia was not observed on their electrocardiograms. The echocardiograms did not show a significant congenital cardiac anomaly. Their cardiac measure and functions were within normal ranges. The echocardiogram of the child with the murmur showed mitral and tricuspid insufficiency. The Doppler images showed pulmonary hypertension findings. These findings were proven by angiography. The vasoreactivity test results of that patient were negative. No reason could be found for the observed pulmonary hypertension. We diagnosed this finding as a primary pulmonary hypertension and Bosentan therapy was started. Conclusions: In this study, we showed that cardiac findings were consistent with previous studies. To the best of our knowledge, the observed pulmonary hypertension in children with LS, who received treatment with or without mecasermin, is reported for first time in the literature.

Background: Alström syndrome is a rare autosomal recessive inherited disorder caused by mutations in the ALMS1 gene. Methods: We describe the clinical and five novel mutational screening findings in six patients with Alström syndrome from five families in a single center with distinct clinical presentations of this condition. Results: Five novel mutations in ALMS1 in exon 8 and intron 17 were identified, one of them was a compound heterozygous: c.2259_2260insT, p.Glu754*; c.2035C>T p.Arg679*; c.2259_2260insT, p.Glu754*; c.5969C>G, p.Ser1990*; c.6541C>T, p. Gln2181*/c.11666-2A>G, splicing. One patient had gallstones, this association, to our knowledge, has not been reported in Alström syndrome previously. Conclusions: Early diagnosis of Alström syndrome is often difficult in children and adolescents, because many of the clinical features develop over time. Early diagnosis can initiate an effective managemen of this condition, and it will help to reduce future damage.

Background: Mucormycosis is a potentially fatal complication of diabetes. The rhino-orbito-cerebral form is the most common presentation, however, rarely other types can also be seen. Case presentation: We describe the case of a 4½ -year-old boy not previously known to be a diabetic who presented to the plastic surgery department for gangrene of the left middle finger with surrounding erythema and induration. After the diagnosis of diabetes and initial treatment, pus from the wound showed broad aseptate hyphae suggestive of mucormycosis which was further confirmed on culture. Aggressive surgical debridement including amputation, antifungal treatment and glycemic control achieved a complete cure. Conclusions: Cutaneous mucormycosis is a rare complication of type 1 diabetes mellitus and can even be seen at the onset of diabetes. High index of suspicion, timely antifungal treatment and aggressive surgical debridement usually lead to recovery in the localized form of the disease.

Background: In this case report, we present a preterm newborn with persistent lactic acidosis who received total parenteral nutrition (TPN) that lacked thiamine. Case presentation: A 28-week-old, 750 g female infant was born with an Apgar score of 8 at the 5th minute. Umbilical cord blood gas levels, including lactate level, were normal, and she was admitted to our neonatal intensive care unit (NICU). Achieving full enteral feeding was not possible due to gastric residues and abdominal distention, making the patient dependent on TPN during the first 2 weeks of life. An insidious increase in lactic acid levels and uncompensated metabolic acidosis were apparent from the 23rd day of life. Severe metabolic acidosis was persistent despite massive doses of bicarbonate. The acidosis resolved dramatically within 6 h when the patient was administered with thiamine. Conclusions: Although TPN is life saving in the NICU, meticulous attention must be paid to provide all essential macro- and micro-nutrients.

Background: Carbonic anhydrase 12 (CA12) deficiency, a newly recognized rare disorder, has been described among Israeli Bedouin kindred as an autosomal recessive form of isolated salt wasting in sweat, which leads to severe infantile hyponatremic dehydration, visible salt precipitation after sweating, poor feeding and slow weight gain in infancy. Case presentation: We present two adolescents diagnosed with CA12 deficiency who developed severe rhabdomyolysis as a result of physical activity in a hot climate. Conclusions: This presentation highlights a previously unreported but significant clinical complication of this disorder and emphasizes the persistent risk of excessive salt loss via sweat and a need for certain precautions, such as increased salt intake and avoidance of prolonged and/or strenuous exercise.