Long-term effectiveness of growth hormone therapy in children born small for gestational age: An analysis of LG growth study data.

PURPOSE: Growth hormone (GH) treatment has been used to improve growth in short children who were born small for gestational age (SGA). The aim of this study was to investigate the long-term efficacy of GH treatment in these children. METHODS: Data from a multicenter observational clinical trial (ClinicalTrials.gov NCT01604395, LG growth study) were analyzed for growth outcome and prediction model in response to GH treatment. One hundred fifty-two children born SGA were included. RESULTS: The mean age of patients born SGA was 7.13 ± 2.59 years. Height standard deviation score (SDS) in patients born SGA increased from -2.55 ± 0.49 before starting treatment to -1.13 ± 0.76 after 3 years of GH treatment. Of the 152 patients with SGA, 48 who remained prepubertal during treatment used model development. The equation describing the predicted height velocity during 1st year of GH treatment is as follows: the predictive height velocity (cm) = 10.95 + [1.12 x Height SDS at initial treatment (score)] + [0.03 x GH dose (ug/kg/day)] + [0.30 x TH SDS at initial treatment (score)] + [0.05 x age (year)] + [0.15 x Weight SDS at initial treatment (score)] ± 1.51 cm. CONCLUSIONS: GH treatment improved growth outcome in short children born SGA. We also developed a prediction model that is potentially useful in determining the optimal growth outcome for each child born SGA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01604395.

Comparison of the clinical characteristics and outcomes of pediatric patients with and without diabetic ketoacidosis at the time of type 1 diabetes diagnosis.

PURPOSE: We investigated the possible effects of diabetic ketoacidosis (DKA) at the initial diagnosis of type 1 diabetes mellitus (T1DM) on the clinical outcomes of pediatric patients. METHODS: Medical records of children and adolescents with newly diagnosed T1DM seen in the Ajou University Hospital from January 2008 to August 2020 were reviewed and analyzed. RESULTS: Among 129 diagnosed T1DM patients, 40.3% presented with DKA. Although demographic and basic characteristics did not differ between DKA and non-DKA patients, DKA patients needed a significantly higher insulin dosage than non-DKA patients for 2 years after diagnosis. However, control of glycated hemoglobin was not different between the DKA and non-DKA groups during the observation period. In the biochemical analysis, C-peptide, insulin-like growth factor-1, and insulin-like growth factor binding protein 3, high-density lipoprotein cholesterol, free T4, and T3 values were lower, but thyroid-stimulating hormone, initial serum glucose, uric acid, total cholesterol, triglyceride, and low-density lipoprotein cholesterol values were higher in DKA patients than non-DKA patients at the diagnosis of T1DM; however, these differences were temporarily present and disappeared with insulin treatment. Other clinical outcomes, such as height, thyroid function, and urine microalbumin level, did not vary significantly between the DKA and non-DKA groups during 5 years of follow-up. CONCLUSION: DKA at initial presentation reflects the severity of disease progression, and the deleterious effects of DKA seem to impact insulin secretion. Although no difference in long-term prognosis was found, early detection of T1DM should help to reduce DKA-related islet damage and the socioeconomic burden of T1DM.

Long-term outcomes of Graves' disease in children and adolescents receiving antithyroid drugs.

PURPOSE: Antithyroid drugs (ATDs) are primarily used as an initial treatment in pediatric patients with Graves' disease (GD). We aimed to investigate the long-term outcomes in pediatric GD patients receiving ATDs. METHODS: Retrospective data from a single center were collected from April 2003 to July 2020. A total of 98 children and adolescents aged 2-16 years diagnosed with GD and receiving ATDs was enrolled. We investigated the factors correlated with remission by comparing children who achieved remission after 5 years and those with persistent disease. RESULTS: The study included 76 girls (77.6%) and 22 boys (22.4%). During the 5-year follow-up period, 18 children (18.3%) maintained remission, ATDs could not be discontinued in 74 patients (75.5%), and relapse occurred in 6 patients (6.2%). The remission group had significantly lower thyroid-stimulating hormone-binding inhibitory immunoglobulin (TBII) level at diagnosis (P=0.002) and 3 months (P=0.002), 1 year (P=0.002), 2 years (P≤0.001), 3 years (P≤0.001), 4 years (P≤0.001), and 5 years (P≤0.001) after ATD treatment than did the nonremission group. The remission group also had a shorter time for TBII normalization after ATD treatment (P≤0.001). Multiple logistic regression analysis showed that the time to TBII normalization (cutoff time=2.35 years) was related to GD remission (odds ratio, 0.596; 95% confidence interval, 0.374-0.951). CONCLUSION: TBII level and time to TBII normalization after ATD treatment can be used to predict remission in pediatric GD patients.

Factors influencing growth hormone therapy effect during the prepubertal period in small for gestational age children without catch-up growth.

PURPOSE: Because small for gestational age (SGA) children who fail to experience catch-up growth have an increased risk of short stature in adulthood, growth hormone (GH) treatment is recommended for effective growth. In this study, we evaluated the effect of GH treatment during the prepubertal period and analyzed for correlation between GH treatment response and clinical factors in SGA children. METHODS: A retrospective, single-center study was conducted from 2014 to 2020. A total of 34 prepubertal children of short stature up to 4 years of age and born as SGA were enrolled. We recorded clinical data including birth data, age, weight, height, bone age (BA), and insulin-like growth factor 1 (IGF-1) levels. RESULTS: The mean gestational age and birth weight were 37.50±2.51 weeks and 2,200.00±546.79 g. At the start of GH treatment, the mean chronological age and BA were 5.54±1.73 years and 4.52±1.85 years, respectively. The height standard deviation score (SDS) (-2.47±0.45) and IGF-1 SDS (0.16±1.57) were calculated. Height velocity was 9.43±1.40 cm during the first GH treatment year and 7.63±1.16 cm during the second year (P<0.05). The treatment growth response was positively correlated with young age (P=0.047) and lower BA (P=0.049) at the start of treatment. In multiple regression analysis, IGF-1 SDS change had a significantly positive association with GH treatment response (P=0.045). CONCLUSION: GH treatment is effective for short stature SGA children who do not experience catch-up growth. Early initiation of GH treatment improved growth outcomes. As IGF-1 SDS is positively correlated with height SDS, IGF-1 monitoring is important during GH treatment of SGA prepubertal children.

Low Bone Mineral Density at Initial Diagnosis in Children and Adolescents with Graves' Disease.

Previous studies have reported reduced bone mineral density (BMD) in patients with hyperthyroidism. We assessed the association of BMD in children and adolescents with Graves' disease (GD) after correcting for potential confounders affecting BMD such as age, sex, and pubertal status. Forty-four children and adolescents with GD and 172 age- and sex-matched healthy controls were enrolled in this study. We analyzed auxological features, BMD, and levels of thyroid hormone, thyroid-stimulating hormone, and thyroid autoantibodies. We measured BMD by dual-energy X-ray absorptiometry at the time of diagnosis in all patients. The mean age of all patients with GD (9 boys and 32 girls) was 12.1 ± 2.2 years (range, 7.0-16.0). Their initial mean free T4 and thyroid-stimulating hormone levels were 3.51 ± 1.56 ng/dL and 0.04 ± 0.03 IU/L, respectively. The mean BMD Z-scores of the lumbar spine (LS), femoral neck, and total body less head of patients with GD were significantly lower than those of control subjects. Eleven patients (26.8%) had low bone density (LS BMD Z-scores < -2.0). To identify correlations of patient characteristics with BMD Z-scores at each site, alkaline phosphatase had a significant negative correlation with BMD Z-scores at LS and femoral neck, but not total body less head (r = -0.441; p = 0.004 and r = -0.351; p = 0.025, respectively). Children and adolescents with newly diagnosed GD had lower bone mass than their healthy peers. These results suggest that BMD measurement at initial evaluation may be necessary in this population.

Effectiveness of growth hormone therapy in children with Noonan syndrome.

PURPOSE: Recombinant human growth hormone (rhGH) has been used to improve growth in children with Noonan syndrome (NS). This study aimed to investigate the efficacy of rhGH therapy in Korean children with NS. METHODS: Seventeen prepubertal children (10 boys, 7 girls) with NS who received rhGH therapy for at least 3 years between 2008 and 2017 were included. To compare the response, age- and sex-matched children with GH deficiency (GHD; n=31) were included. Height and growth velocity before and during treatment were analyzed. RESULTS: The mean age of NS patients was 6.34±2.32 years. After treatment, the height standard deviation score (SDS) increased from -2.93±0.81 to -1.51±1.00 in patients with NS and from -2.45±0.42 to -1.09±0.47 in patients with GHD. There were no significant differences in growth velocity or change in height SDS between patients with NS and GHD. Growth velocity in the first year of treatment was higher in patients with PTPN11 mutations than those without PTPN11 mutations, but the change in height SDS was not significantly different between those 2 groups. CONCLUSION: rhGH therapy can increase linear growth in prepubertal children with NS. The growth response between patients with NS and patients with GHD was not significantly different. Furthermore, we observed that lower doses of growth hormone have a similar effect on height compared to previous studies in patients with NS. Our study indicates that rhGH treatment is useful for growth promotion.

Identification of rare missense mutations in NOTCH2 and HERC2 associated with familial central precocious puberty via whole-exome sequencing.

Objective: Genetic factors play a critical role in pubertal progression; however, mutations associated with central precocious puberty (CPP) have been reported only in four genes: KISS1, KISS1R, DLK1, and MKRN3. This study aimed to identify novel, potentially pathogenic variants in patients with familial CPP via whole-exome sequencing (WES).Methods: WES analysis was applied in 28 patients (25 girls and three boys) belonging to 14 families, wherein all siblings were diagnosed with CPP. Data analysis aimed to select only very rare variants (minor allele frequency <1%). Nonsense, splice-site, and frameshift variants were considered the most ideal candidate variants. Additionally, non-synonymous missense variants predicted as being deleterious using in silico analysis tools were further considered.Results: The analysis of exome sequencing data resulted in the identification of rare mutations in two promising candidate genes (NOTCH2 and HERC2) in a family. Siblings with CPP exhibited two heterozygous missense mutations (p. Leu15Phe in NOTCH2 and p. Arg4081His in HERC2). Moreover, their parents without history of CPP had a missense variant in either NOTCH2 or HERC2.Conclusions: We identified new candidate genes with potential roles in pubertal development. Digenic inheritance of the two genetic mutations associated with the Notch signaling pathway may have a synergistic effect resulting in CPP.