It is over sixty years since the first administration of human growth hormone (GH) to children with GH deficiency, and over thirty years since recombinant human GH has been available for treatment of GH deficiency and a wider range of non-GH deficiency disorders. From a diagnostic perspective, genetic analysis, using single gene or Sanger sequencing and more recently next generation or whole exome sequencing, has brought advances in the diagnosis of specific causes of short stature, which has enabled therapy to be targeted more accurately. Genetic discoveries have ranged from defects of pituitary development and GH action to abnormalities in intracellular mechanisms, paracrine regulation and cartilage matrix formation. The strategy of GH therapy using standard doses has evolved to individualised GH dosing, depending on diagnosis and predictors of growth response. Evidence of efficacy of GH in GH deficiency, Turner syndrome and short children born small for gestational age is reviewed. The importance of critical assessment of growth response is discussed, together with the recognition and management of a poor or unsatisfactory growth response and the organisational issues related to prevention, detection and intervention regarding suboptimal adherence to GH therapy.

Objective: Non syndromic monogenic obesity is a rare cause of early onset severe obesity in the childhood period. This form may not be distinguishable from other forms of severe obesity without genetic analysis, particularly if patients do not exibit any physical abnormalities or developmental delay. The aim of this study was to screen 41 different obesity-related genes in children with non-syndromic early onset severe obesity.
Methods: Children with severe (body mass index-standard deviation score >3) and early onset (<7 years) obesity were screened by next-generation sequencing based, targeted DNA custom panel for 41 known-obesity-related genes and the results were confirmed by Sanger technique.
Results: Six novel variants were identified in five candidate genes in seven out of 105 children with severe obesity; two in SIM1 (p.W306C and p.Q36X), one in POMC (p.Y160H), one in PCSK1 (p.W130G fs Ter8), two in MC4R (p.D126E) and one in LEPR (p.Q4H). Additionally, two previously known variations in MC4R were identified in four patients (p.R165W in three, and p.V166I in one).
Conclusion: We identified six novel and four previously described variants in six obesity-related genes in 11 out of 105 childrens with early onset severe obesity. The prevalence of monogenic obesity was 10.4% in our cohort.

Objective: To evaluate glucose metabolism and insulin sensitivity in children with idiopathic growth hormone (GH) deficiency, treated with recombinant human GH (rhGH), and to identify possible risk factors for the development of glucose abnormalities in this population.
Methods: We retrospectively collected data from 101 patients (60 males, median age 10.4 years, 77 prepubertal), with confirmed GH deficiency, enrolled before starting rhGH and followed up during the first three years of treatment. Glucose metabolism was evaluated annually by oral glucose tolerance test (OGTT) and glycated hemoglobin A1c (HbA1c). OGTT was used to calculate insulin sensitivity (HOMA-S) and insulin resistance (HOMA-IR), defined as HOMA-IR >3.
Results: RhGH was effective in improving growth and dosages significantly reduced after the first year of therapy. No patient developed diabetes mellitus. After one year of therapy, a significant increase in HbA1c (p=0.0042) and insulin levels (fasting p<0.0001, 60 min p=0.0018, 120 min p=0.0003) was observed, with a higher prevalence of IR (p<0.05). These indices did not alter further during the follow-up and were not related to GH dose or to family history of diabetes. A significant correlation was found only for IR indices and pubertal status, weight and age (p<0.05).
Conclusion: In this retrospective study on a large GH deficient pediatric population, conventional use of replacement therapy resulted in an increase in HbA1c and IR after one year of therapy, regardless of rhGH dosage. These alterations did not worsen significantly in the following two years and were not associated with overt diabetes.

Objective: Adequate glycemic control in children with type 1 diabetes reduces the risk of future complications. Identifying factors affecting haemoglobin A1c (HbA1c) is crucial to management of metabolic control. We aimed to identify possible socioeconomic predictors of poor metabolic control this patient group in Jordan, a developing country with limited resources.
Methods: Medical charts of children with type 1 diabetes attending the pediatric endocrine clinics in two major diabetes centers were reviewed. HbA1c ?7.5% (58 mmol/mol) was considered to reflect poor metabolic control. Logistic regression analysis was performed to identify predictors of poor glycemic control. The association between socioeconomic characteristics and metabolic control was evaluated using multiple correspondence analysis (MCA).
Results: Two hundred and fifty-nine children were enrolled in the study. One fifth of the patients (20.5%) achieved HbA1c <7.5%. Patients with dietary non-compliance [odds ratio (OR): 3.533, confidence interval (CI): 1.803 - 6.926; p<0.001], and those who were overweight (OR: 3.869, CI: 1.218 - 12.294; p=0.022) were more likely to have poor metabolic control. Children whose mothers had a bachelor’s degree or higher were less likely to have poor metabolic control compared to children whose mothers had only elementary education (OR: 0.241, CI: 0.079 - 0.734; p=0.012). MCA revealed an association between low socioeconomic status and poor metabolic control. Children with deceased mothers had significantly higher HbA1c of 10.6±1.86% compared to an average of 8.7±1.45% for the rest of participants (p=0.005).
Conclusion: Low socioeconomic status, lower levels of maternal education and maternal death were associated with poor metabolic control. Identifying children with these risk factors might play an important role in optimizing metabolic control and provide better diabetes care.

Objective: Tri-ponderal mass index (TMI) has been reported to estimate body fat more accurately than body mass index (BMI). This study aimed to compare the efficacy of TMI and BMI in predicting insulin resistance (IR), hyperlipidemia, impaired liver enzymes or thyroid hormone function, and vitamin D concentration.
Methods: One hundred and forty-three overweight or obese children, based on BMI-standard deviation (SD) scoring (BMI-SDS) were studied retrospectively. TMI thresholds for overweight status were 16.0 kg/m3 for boys and 16.8 kg/m3 for girls and 18.8 kg/m3 for boys and 19.7 kg/m3 for girls for obese status.
Results: Twenty-two overweight and eight obese children by BMI-SDS were classified as normal by TMI. Of the overweight children 22 (22.7%) had IR and IR was detected in 2 of 8 obese children with normal TMI. There was no increase in liver enzymes in any of the children with normal TMI. Forty-four obese children were overweight according to TMI and IR was detected in 40.9%. Thyroid stimulating hormone levels were significantly higher in BMI-based obese children. Vitamin D levels were similar in all groups of both classifications.
Conclusion: When TMI was used there may be a risk of overlooking IR. However, if it is assumed that liver enzymes are elevated as a result of visceral adiposity, TMI can be used as an auxiliary parameter to show visceral effects of adiposity. Normal TMI may indicate that visceral organ functions have not deteriorated yet. More studies are needed to evaluate TMI as a clinical tool.

Objective: Neuron-specific enolase (NSE) and S100 calcium-binding protein B (S100B) are markers of different neurological disorders. The aim was to investigate the relationship between NSE and S100B serum concentrations and the severity of diabetic ketoacidosis (DKA) in diabetic children.
Methods: Eighty children with DKA, 40 with type 1 diabetes mellitus (T1DM) without DKA and 40 healthy controls were enrolled. Severity of DKA was assessed according to blood pH and bicarbonate concentration. Serum NSE and S100B were measured in all participants. In the DKA group serum NSE and S100B were measured at three time points, at admission and at 12 hours and 24 hours after starting treatment.
Results: Children with DKA showed significantly higher serum levels of NSE at all time points compared to children with T1DM without DKA and controls (p<0.01), while serum S100B concentrations did not differ between the three cohorts. Children with T1DM but without DKA also had significantly higher serum levels of NSE (p<0.01) compared to healthy controls. Patients with low Glasgow Coma Scale score (GCSS) and those with moderate and severe DKA had significantly higher levels of NSE at all time points (p<0.01 for each) compared to patients with normal GCSS and those with mild DKA. No significant differences were found in serum S100B levels according to the severity of DKA and GCS (p>0.05). Younger age, lower GCSS, higher glucose and HbA1c, lower pH and lower serum bicarbonate were the risk factors associated with elevated NSE.
Conclusion: Serum NSE is elevated in all patients with type 1 DM and, in patients with DKA, correlates with severity of DKA. However, serum S100B concentration did not differ between T1DM with or without DKA and healthy controls.

Objective: Gynecomastia is defined as a benign proliferation of male breast glandular tissue. Its prevalence during puberty varies between 50-60% and is also common in neonatal and elderly males. It develops mainly due to the disequilibrium between estrogen and androgen activity in breast tissue, where estradiol (E2) binds to estrogen receptors and stimulates ductal and glandular cells. The aim of this work was to investigate the relationship between sex hormone alterations and the natural history of gynecomastia.
Methods: Participants in this study were young males referred to an outpatient clinic, between January 2011 and February 2016, with breast enlargement. Thyroid function, liver function, hormone concentrations and tumor markers were measured and anthropometric assessment was conducted.
Results: Subjects comprised 93 males, aged 9 to 18 (mean±standard deviation age 13.8±2.6) years. In 63 of 93 (67.7%) the gynecomastia was confirmed and 28 were followed-up for a median period of three months. None of the boys showed any reduction in breast size during follow-up. There was no correlation between body mass index Z-score and breast size. Breast enlargement progressed in nine boys (32.1%). A positive correlation between estrogen to testosterone (E2/TTE) ratio and Tanner B stage (r=0.47; p=0.034) was observed.
Conclusion: The E2/TTE ratio may be a helpful tool in diagnosing gynecomastia. Altered E2/TTE ratio might be responsible for a proportion of cases described previously as idiopathic. Additionally, weight loss does not imply reduction of breast size in boys. Nonetheless it should be the first step in the management of prolonged gynecomastia.

Objective: Elevated liver function tests (LFTs) are common in adult Turner syndrome (TS) patients. Data regarding children and adolescents are lacking. To investigate the prevalence of abnormal LFTs in children and adolescents with TS during several years of observation; to evaluate the potential impact of increased body mass index (BMI) and sex hormone replacement therapy (HRT) on LFTs.
Methods: The analysis included 100 girls with TS, aged 4-16 years, all of whom were receiving recombinant human growth hormone therapy. A longitudinal study was conducted which included 81 patients.
Results: Mean BMI-standard deviation (SD) score of the subjects was 0.63 (SD: 1.53). Forty-four were being treated with HRT. Elevated LFTs were found in 34% of the patients overall (32% not receiving HRT vs 36% on HRT). The relative risk of increased LFTs was not higher in obese vs normal weight [odds ratio (OR): 0.2; 95% confidence interval (CI): 0.1-0.36, p=0.38 vs OR: 0.16; 95% CI: 0.08-0.3, p=0.1]. HRT did not increase the risk of abnormal LFTs activity (OR: 0.8; 95% CI: 0.5-1.2, p=0.37 vs OR: 0.7; 95% CI: 0.4-1.1, p=0.27). During the follow-up period (mean±SD=4.31±0.82 years), no patient developed overt liver disease. There was no significant increase nor decrease of abnormal LFT frequency in the subsequent years of follow up.
Conclusion: Constantly elevated LFTs in TS are common in children and adolescents with TS. However the causes and clinical significance remain unclear. This study suggests that obesity and HRT do not increase the risk of elevated LFTs.

Objective: To explore the clinical presentation and molecular genetic characteristics of a cohort of congenital hyperinsulinism (CHI) patients from southern China and also to explore the most appropriate therapeutic approaches.
Methods: We retrospectively reviewed a cohort of 65 children with CHI. Mutational analysis was performed for KCNJ11 and ABCC8 genes. The GLUD1 gene was sequenced in patients with hyperammonaemia. GCK gene sequencing was performed in those patients with no mutation identified in the ABCC8, KCNJ11 or GLUD1 genes.
Results: ABCC8 mutations were identified in 16 (25%) of the cohort, GLUD1 mutations were identified in five children, and no KCNJ11 or GCK mutations were identified. Moreover, some unique features of ABCC8 gene mutations in southern Chinese CHI patients were found in this study. The most common mutation was a deletion/insertion mutation p.Thr1042GlnfsX75 was found in five unrelated patients, which possibly represents a relatively common mutation in southern China. Five novel ABCC8 mutations were detected. The mutations were p.Phe5SerfsX72, p.Gln273ArgfsX85, p.Leu724del, p.Asp1447Gly and IVS 25-1G>T. Five compound heterozygous mutations of ABCC8 gene were identified in this study, and three of these patients were diazoxide-responsive. Forty patients were diazoxide-responsive, 13 patients were diazoxide-unresponsive and 12 patients received dietary treatment only. A pancreatectomy was performed in 10 patients who were unresponsive to medical treatment.
Conclusion: To the best of our knowledge, this is the first study of CHI in south China. Mutations in ABCC8 are the most common causes of CHI in this cohort. Diazoxide and dietary treatment were effective in most patients. Multicentre studies are necessary to obtain the long-term follow-up characteristics of such patients at a national level.

Objective: Thyroid hormones have an important role in the regulation of the cardiovascular system. The aim of this study was to investigate the presence of subclinical myocardial dysfunction in children with euthyroid Hashimoto’s thyroiditis (eHT) without evident heart disease using tissue doppler imaging (TDI) and speckle tracking echocardiography (STE) methods.
Methods: TDI and STE were peformed in 50 children with eHT and in 35 healthy children. To assess myocardial velocities and time intervals, including peak systolic velocity (Sm), peak early diastolic velocity (Em), peak late diastolic velocity (Am), isovolumetric contraction time (IVCT), isovolumetric relaxation time (IVRT) and ejection time (ET), TDI was performed at the base of the interventricular septum (IVS) and in the left and right ventricles (LV and RV, respectively). Analysis of myocardial deformation by STE including strain (S) and strain rate (SR) was performed globally in two planes, longitudinal (L) and mid-circumferential (C) in LV [LV global longitudinal strain (LVGLS), LV global longitudinal strain rate (LVGLSR), LV global circumferential strain (LVGCS), LV global circumferential strain rate (LVGCSR)] and RV [(RV global longitudinal strain (RVGLS), RV global longitudinal strain rate (RVGLSR)].
Results: Among TDI parameters, ET at LV and IVS were significantly lower, IVRT and myocardial performance index at LV and IVS were significantly higher in the eHT group compared to controls (p=0.001). There were no significant differences in Sm, Em, Am and IVCT values between patients and controls. LVGLS, LVGLSR, LVGCS and LVGCSR values were significantly lower in patients than controls (p=0.01). There was a negative correlation between thyroid antibody levels and LV global longitudinal and circumferential strain and strain rate values (TPO-Ab and Tg-Ab between LVGLS, LVGLSR, LVGCS and LVGCSR; r=-411, p<0.001; r=-541, p<0.001; r=-430, p<.0.001; r=-502, r<0.01 and r=-397, p<0.001; r=-473, p<0.001; r=-519, p<0.001; r=-421, p<0.00, respectively).
Conclusion: The results show that myocardial function in children with eHT is impaired in the absence of any clinical symptoms and that conventional echocardiography is inadequate to determine these changes.

Borjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked disease caused by PHF6 mutations. Classic BFLS has been associated with intellectual disability (ID), developmental delay (DD), obesity, epilepsy, typical facial features and anomalies of fingers and toes. Endocrinological phenotypes and outcome of treatment in this condition remain to be delineated. Here we report a patient who exhibited complete growth hormone deficiency who responded to hormonal treatment but with adverse effects. Horseshoe kidney was present in this patient, which is also atypical in BFLS. A heterozygous nonsense mutation c.673C>T (p.R225X) of PHF6 gene was identified in the patient, inherited from her unaffected mother. Both the patient and her mother showed highly skewed X-inactivation. We reviewed the phenotypes of all reported BFLS cases, and summarized their endocrine presentations. This first report of an Asian patient with BFLS further delineated the genetic and phenotypic spectrum of the syndrome. The adverse effect experienced by the patient suggests caution in the use of growth hormone treatment in this condition.

Isolated growth hormone (GH) deficiency (IGHD) type 2 is a rare autosomal dominant disorder characterized by severe short stature with low GH level. Timely diagnosis is important for optimal results of recombinant human GH (rhGH) treatment and detection of additional pituitary deficiencies in affected relatives. A male child presented at the age of one year with severe, proportionate short stature [-4.9 standard deviation score (SDS)] and with a normal body mass index (-1.1 SDS). Physical examination revealed frontal bossing, midfacial hypoplasia, normal external genitalia and no dysmorphic features. Paternal and maternal heights were -6.1 and -1.9 SDS. Serum insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 were undetectable and the peak GH concentration by clonidine stimulation test was extremely low (0.18 ng/mL). Brain magnetic resonance imaging showed anterior pituitary hypoplasia. Genetic analysis identified a novel heterozygous mutation (c.291+2T>G) expected to lead to splicing out exon 3 of GH1. rhGH from age 2.4 years led to appropriate catch-up. In conclusion, we identified a novel GH1 gene mutation in an infant with classical IGHD type 2 presentation.

Acid-labile subunit (ALS) forms ternary complexes with insulin like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) and is essential for normal circulating IGF-1 levels. The IGFALS gene encodes the ALS and mutations in IGFALS cause ALS deficiency. We describe a patient with ALS deficiency with a novel homozygous frameshift mutation in IGFALS presenting with short stature and delayed puberty but ultimately achieving an adult height (AH) comparable to his target height (TH). A 15.25 year old boy presented with short stature (149.9 cm, -3.04 standard deviation score). The patient had a low circulating IGF-1 concentration, extremely low IGFBP-3 concentration, insulin resistance and osteopenia. The peak growth hormone (GH) response to GH stimulation test was high (31.6 ng/mL). Sequencing of IGFALS revealed a novel, homozygous, frameshift mutation (p.Ser555Thrfs.19). His mother and elder sister were heterozygous carriers. Although he had delayed puberty and short stature at the onset of puberty, he reached his TH and an AH similar to those of his heterozygous mother and sister. The heterozygous carriers had normal or low IGF-1 concentrations and low IGFBP-3 concentrations but not as markedly low as that of the patient. They had normally timed puberty, insulin metabolism and bone mineral density (BMD). The phenotype of ALS deficiency is quite variable. Despite short stature and delayed puberty, patients can achieve normal pubertal growth and AH. ALS deficiency may cause osteopenia and hyperinsulinemia. Heterozygous carriers may have normal prenatal growth, puberty, insulin metabolism and BMD.

Osteopetrosis is a rare genetic disease characterized by increased bone density and bone fractures due to defective osteoclast function. Autosomal dominant osteopetrosis type 2 (ADO-2), Albers-Schonberg disease, is characterized by the sclerosis of bones, predominantly involving the spine, pelvis and the base of the skull. Here, we report a typical case of osteopetrosis in a 17.7-year-old male who carries a heterozygous c.746C>T mutation in exon 9 in the chloride voltage-gated channel 7 (CLCN7) gene. The patient’s spine showed multiple sclerotic changes including sandwich vertebra. His father had the same mutation but his skeletal radiographs were normal. This is the first reported case of ADO-2, confirmed by genetic testing in a Korean patient.

Idiopathic hypogonadotropic hypogonadism (IHH) is a rare disease caused by defects in the secretion of gonadotropin releasing hormone (GnRH) or the action of GnRH on the pituitary gonadotrophes. KISS1R is one of the genes which, when mutated, cause IHH and mutations of this gene are responsible for about 2-5% of patients with normosmic IHH (NIHH). In this report, we present three siblings with NIHH due to a compound heterozygous KISS1R mutation. Genetic studies were carried out in the 14 year old index case with IHH and three siblings, two of whom were prepubertal. Genomic DNA was extracted from peripheral leukocytes and KISS1R gene was sequenced by using standard polymerase chain reaction amplification procedures. In molecular analysis of the index case, a compound heterozygous mutation was determined in KISS1R gene c.969C>A (p.Y323X) (known pathogenic) and c.170T>C (p.L57P) (novel). Mutation c.170T>C (p.L57P) was inherited from the mother while c.969C>A (p.Y323X) was inherited from the father. The same genotype was also found in two of the three siblings. A compound heterozygous mutation of the KISS1 gene, including one novel mutation, was found to cause NIHH and also incomplete puberty in a non-consanguineous family.