Assessment and management of children with growth failure has improved greatly over recent years. However, there remains a strong potential for further improvements by using novel digital techniques. A panel of experts discussed developments in digitalization of a number of important tools used by pediatric endocrinologists at the third 360° European Meeting on Growth and Endocrine Disorders, funded by Merck KGaA, Germany, and this review is based on those discussions. It was reported that electronic monitoring and new algorithms have been devised that are providing more sensitive referral for short stature. In addition, computer programs have improved ways in which diagnoses are coded for use by various groups including healthcare providers and government health systems. Innovative cranial imaging techniques have been devised that are considered safer than using gadolinium contrast agents and are also more sensitive and accurate. Deep-learning neural networks are changing the way that bone age and bone health are assessed, which are more objective than standard methodologies. Models for prediction of growth response to growth hormone (GH) treatment are being improved by applying novel artificial intelligence methods that can identify non-linear and linear factors that relate to response, providing more accurate predictions. Determination and interpretation of insulin-like growth factor-1 (IGF-1) levels are becoming more standardized and consistent, for evaluation across different patient groups, and computer-learning models indicate that baseline IGF-1 standard deviation score is among the most important indicators of GH therapy response. While physicians involved in child growth and treatment of disorders resulting in growth failure need to be aware of, and keep abreast of, these latest developments, treatment decisions and management should continue to be based on clinical decisions. New digital technologies and advancements in the field should be aimed at improving clinical decisions, making greater standardization of assessment and facilitating patient-centered approaches.

Objective: In small for gestational age (SGA) children, catch-up growth could be influenced by methylation of several genes involved in metabolism. Epigenetics may influence the development of metabolic diseases in adulthood. To compare the methylation of leptin (LEP), glucagon-like peptide-2 receptor (GLP2R), insulin receptor substrate-2 (IRS2) in SGA patients with and without catch-up growth.
Methods: Observational prospective study of SGA children. Demographical and clinical variables were collected from clinical records and parents’ questionnaire. Methylation status of LEP, IRS2, and GLP2R promoters was evaluated in DNA extracted from patient and one parent saliva samples.
Results: Forty-eight SGA patients were included. Twenty-six (54.2%) had catch-up growth phenotype and 22 (45.8%) did not. The median age was 5.2 years [RIC 4.1-6.8] without difference between groups (p=0.306). The catch-up group had increased appetite (42.3% vs 9.1%, p=0.008), family history of dyslipidemia (42.3% vs 27.3%) and diabetes (34.6% vs 22.7%) compared to non-catch-up group. Catch-up patients had significantly larger waist circumference compared to non-catch-up group (median 55 cm [RIC 52-58] versus median 49.5 cm [RIC46-52]; p<0.001). LEP and GLP2R were methylated in all samples. IRS2 was methylated in 60% of SGA patients without difference between groups (p=0.520).
Conclusion: There is no association between IRS2 methylation and catch-up growth among SGA patients. LEP and GLP2R were methylated in all SGA patients. Gene methylation may be implicated in metabolic disease later in life. More studies should be performed to confirm this hypothesis.

Objective: To investigate the incidence of pseudotumor cerebri syndrome (PTCS) in children treated with growth hormone (GH) in a paediatric hospital and to identify risk factors for this complication.
Methods: Prospective pilot study of paediatric patients treated with recombinant human GH, prescribed by the Paediatric Endocrinology Department, between February 2013 and September 2017. In all these patients, a fundus examination was performed before starting treatment and 3-4 months later.
Results: Two hundred and eighty-nine patients were included, of whom 244 (84.4%) had GH deficiency, 36 (12.5%) had short stature associated with small for gestational age, six (2.1%) had a mutation in the SHOX gene and three (1.0%) had Prader-Willi syndrome. Five (1.7%) developed papilledema, all were asymptomatic and had GH deficiency due to craniopharyngioma (n=1), polymalformative syndrome associated with hypothalamic-pituitary axis anomalies (n=2), a non-specified genetic disease with hippocampal inversion (n=1) and one with normal magnetic resonance imaging who had developed a primary PTCS years before.
Conclusion: GH treatment is a cause of PTCS. In our series, at risk patients had GH deficiency and hypothalamic-pituitary anatomic anomalies or genetic or chromosomal diseases. Fundus examination should be systematically screened in all patients in this at-risk group, irrespective of the presence or not of symptoms.

Objective: Obesity is known to affect thyroid function. Recently, waist-height ratio (WHtR) has been considered as a useful marker of subclinical hypothyroidism in obese cases, but its relation with thyroid autoimmunity still remains unclear. We evaluated the effect of body fat mass, WHtR, and metabolic parameters on thyroid autoantibody levels in children with obesity.
Methods: This was a cross-sectional study carried out with an obese [n=56, male/female (M/F): 29/26] and a healthy group (n=38, M/F: 19/19). All subjects underwent anthropometric measurements, laboratory investigations for thyroid function tests, thyroid peroxidase (TPO-ab) and thyroglobulin-antibodies (Tg-ab), transaminases, blood glucose, insulin levels, and lipids after overnight fasting; homeostatic model assessment for insulin resistance (HOMA-IR) was calculated for assessment of insulin resistance. Fat mass was estimated by multiple frequency bioimpedance analysis in the obese group, which was further divided into two subgroups according to the median of WHtR. All parameters were compared between the groups/subgroups.
Results: In the obese group, weight, height, body mass index (BMI), free triiodothyronine, thyrotropin, TPO-ab, insulin, low density lipoprotein-cholesterol, total cholesterol, alanine aminotransferase levels, and HOMA-IR were significantly higher than the controls group (p<0.05 for all). Median of WHtR was 0.6 in the obese group. In the “WHtR >0.6” subgroup (n=28), weight, BMI, fat mass, TPO-ab, Tg-ab, insulin and triglyceride levels were higher than WHtR ?0.6 subgroup (p<0.05). A positive correlation was obtained between Tg-ab and WHtR (rho=0.28, p=0.041).
Conclusion: Euthyroid children with obesity and a WHtR >0.6 are likely to have higher thyroid antibody levels, and Tg-ab levels have a positive correlation with WHtR, which reveals an association of central adiposity with thyroid autoantibody levels in these cases.

Objective: Characteristics of the glucose response during oral glucose tolerance test (OGTT) may reflect differences in insulin secretion and action. The aim was to examine whether timing of the glucose peak, shape of the glucose curve and their combination could be indicators of beta-cell dysfunction in obese/severely obese adolescents with normal glucose tolerance (NGT).
Methods: Data from 246 obese/severely obese adolescents who completed OGTT were reviewed. Out of 184 adolescents with NGT, 174 could be further classified into groups based on timing of the glucose peak (early/30 minutes vs late/?60 minutes) and shape of the glucose curve (monophasic vs biphasic). Groups were compared with respect to insulin sensitivity (whole body insulin sensitivity index - WBISI), early-phase insulin secretion (insulinogenic index - IGI) and beta-cell function relative to insulin sensitivity (oral disposition index - oDI).
Results: Late glucose peak (p=0.004) and monophasic glucose curve (p=0.001) were both associated with lower oDI after adjustment for age, sex, puberty stage and body mass index z-score. Among obese/severely obese adolescents with NGT, those with coexistent late glucose peak and monophasic glucose curve had lower oDI than those with early glucose peak and biphasic glucose curve (p=0.002). Moreover, a combination of late glucose peak and monophasic glucose curve was the most powerful predictor of the lowest oDI quartile [odds ratio (OR): 11.68, 95% confidence interval: 3.048-44.755, p<0.001].
Conclusion: Late timing of the glucose peak, monophasic shape of the glucose curve and, in particular, a combination of those characteristics during OGTT may indicate early beta-cell dysfunction in obese/severely obese adolescents with NGT.

Objective: As for other auto-immune processes, thyroiditis is monitored after vaccinations. The aim was to estimate the baseline incidence of thyroiditis among girls, before investigating papillomavirus vaccination as a potential risk factor.
Methods: Observational cohort study including girls aged 9-18 years and registered between 2002-2016 in the Spanish Primary Care Database for Pharmacoepidemiological Research. Girls were followed until a thyroiditis occurred, 19 years of age, left the cohort, died, or the study ended. Anonymized records were reviewed for diagnosis confirmation (endocrine discharge letter and/or free-text comments) in a random sample. Incidence rate (IR) per 105 person years (/105 py) was estimated.
Results: The cohort numbered 480,169 girls, of whom 641 had a record of thyroiditis: 346 autoimmune thyroiditis; 17 thyroiditis of other types; and 278 unspecified. Incidence of recorded thyroiditis increased with age, from 23.96 at age 9 years to 47.91 at age 14 years, and stabilized around 31.06-34.43 among girls aged 15-18 years. Of the 98 records reviewed, 60.2% were ‘confirmed’ cases, 32.7% ‘possible’ and 7.1% were discarded. After correction for discarded cases, IR=20.83 ‘confirmed’ cases, increasing to 32.12/105 py when ‘confirmed’ plus ‘possible’ cases were included. Between 2002-2005, incidences were lower (16.28 and 20.93 cases/105 py) than in the period 2007-2016 (21.17 and 33.78 cases/105 py) for ‘confirmed’ and ‘confirmed’ plus ‘possible’, respectively.
Conclusion: Two-thirds of the recorded thyroiditis included confirmatory evidence. The incidence of thyroiditis among girls increased with age and in the later period, and remained stable among girls aged 15-18 years.

Objective: To retrospectively evaluate the follow-up data in patients with 46,XX congenital adrenal hyperplasia (CAH) who were raised male.
Methods: A national database was created. The data of patients were asked to be recorded in the data form.
Results: The median (range) age of diagnosis was three (0.1-18.3) years in 44 patients. Twenty nine cases were diagnosed after the age of two years. Most (95.4%) cases were stage 4-5 virilized. Hysterectomy and bilateral salpingoopherectomy, at a median age of 7.25 (2.4-25.3) years, was performed in 35 cases. Testicular prostheses were placed in 11 (25%) cases at a median age of 11.2 (2.8-17) years. The median final height was 149.2 (132.8-172) cms in 38 patients, including simple virilizing (n=18), salt-wasting (n=6), and 11-beta hydroxylase (n=12). Of the 16 patients above the age of eighteen, university education was completed in 25%.
Conclusion: It was seen that most (65.9%) of the 46,XX CAH cases raised male were diagnosed after two years of age. In these cases, hysterectomy and bilateral salpingoopherectomy, genital corrective surgeries and testicular prosthesis operations were performed in a very wide age rage.

Objective: Adiposity is associated with increased oxidative stress, leading to changed fat-soluble vitamin concentrations. The aim of this study was to determine whether weight loss alters fat-soluble vitamin status and whether these alterations are associated with dietary intake, anthropometric parameters and adipokines in obese children.
Methods: Vitamin A and E concentrations were measured using high-pressure liquid chromatography in 60 obese children before and after weight loss therapy. Retinol-binding protein 4 (RBP4), leptin, soluble leptin receptor (sOB-R), and high molecular weight adiponectin concentrations were determined by immunoenzymatic assays.
Results: The intake of vitamin E was lower in obese children with weight loss after therapy (p=0.038). In this group, an increase was found in the vitamin A/lipids (p=0.022) and the vitamin E/lipids (p=0.008) ratios but due to the reduction in triglyceride levels. In the obese group, changes in vitamin E level were positively correlated with changes in dietary vitamin E (p=0.017) and the leptin/sOB-R ratio (p=0.046). Changes in vitamin A level were positively correlated with changes in dietary vitamin A (p=0.001) and RBP4 concentration (p=0.023). Associations between changes in RBP4 level with the changes in body mass index (BMI) (p=0.011) and total cholesterol concentration (p=0.023) but not with changes in vitamin A concentration were found in the obese after therapy.
Conclusion: An increased risk of vitamin E deficiency may occur in children losing weight during lifestyle intervention. Changes in BMI value may influence changes in RBP4 concentrations and consequently the vitamin A status in obese children after therapy.

Objective: Pump-treated children with type 1 diabetes (T1DM) have widely differing basal insulin (BI) infusion profiles for specific periods of the day. The pattern of BI requirements depends on the timing and magnitude of cortisol and growth hormone secretion within each age group. In adolescents and young adults, a decreased insulin sensitivity is seen, particularly in the early morning (dawn phenomenon) and to a lesser extent, in the late afternoon (dusk phenomenon). Different approaches exist for the inititation of basal rates. However, there is a lack of evidence-based recommendation, especially in young children. Usually the basal rates are set equally throughout day and night or the day is divided into tertiles. The aim of this study was to analyze the change of the initial, equally distributed, BI rates over the first year of standard insulin pump therapy.
Methods: A total of 154 patients with T1DM, aged between 0 and <21 years at diagnosis, from a single center were documented. Patients were divided into five age groups according to age at pump initiation: group 1, <5 years (n=36); group 2, 5-8 years (n=20); group 3, 8-15 years (n=74); group 4, 15-18 years, (n=19); and group 5, >18 years, (n=5). Distribution of hourly basal rates at the initiation of the pump and at the end of first year were evaluated.
Results: Median (range) age and diabetes duration was 14.46 (1.91-26.15) and 7.89 (1.16-17.15) years, respectively. Forty-four percent were male, 56% were female. Mean total insulin dose/kg in the whole cohort at the initiation and after one year of pump therapy was 0.86±0.23 U/kg and 0.78±0.19 U/kg, respectively and differed significantly between each age group (p<0.001; p<0.001). Mean daily basal rate/kg showed significant differences between the five groups (p<0.001). Circadian distribution of BI differed markedly among the five age groups.
Conclusion: At the initiation of insulin pump therapy, circadian profiles by age group should be taken into account in pediatric patients to optimize basal rate faster and more easily.

Objective: A consensus on how to monitor girls with central precocious puberty (CPP) during gonadotropin-releasing hormone agonist (GnRHa) treatment is lacking. Increased, unstimulated basal luteinizing hormone (LH) concentrations have been suggested to indicate lack of suppression. The aim was to evaluate pre-injection basal LH concentrations during GnRHa (leuprorelin 3.75 mg) treatment every four weeks in girls with CPP.
Methods: Medical records were reviewed for girls with CPP treated at a single center from 2014-2019. Clinical characteristics and laboratory findings during treatment were systematically recorded.
Results: A total of 587 GnRHa pre-injection basal LH concentrations were analyzed in 74 girls. Basal LH was pubertal (?0.3 IU/L) in 53.5% of blood samples and 87.8% of all girls had a pubertal basal LH concentration at least once. A GnRH test (n=29) was repeated in 23 girls due to suspicion of clinical progression, elevated basal LH or recordable estradiol concentrations. None had a stimulated LH >3.1 IU/L. The predictability of treatment suppression (specificity) of basal LH concentrations was 12.0% when compared to repeated GnRH stimulation tests. Despite shortening the GnRHa injection interval to three weeks, basal LH concentrations remained pubertal in 85.7% girls. A significant reduction in height standard deviation score (p<0.001) and bone age advance (p<0.001) was observed during treatment.
Conclusion: Pre-injection basal LH remains at pubertal concentrations during treatment with leuprorelin 3.75 mg in girls with CPP. Clinical monitoring of pubertal progression is preferable to routine basal LH concentrations. Repeat GnRH stimulation testing should be regarded as the gold standard.

Adrenoleukodystrophy (ALD) is an X-linked, metabolic disorder caused by deficiency of peroxisomal ALD protein resulting in accumulation of very-long chain fatty acids (VLCFA), primarily in the adrenal cortex and central nervous system. Approximately 35-40% of boys with ALD develop cerebral ALD (CALD), which causes rapidly progressive cerebral demyelination, loss of neurologic function, and death. Approximately 70-80% of boys with ALD have impaired adrenal function prior to the onset of neurologic symptoms. We present a boy who had recurrent episodes of hypoglycaemia from age two years and was diagnosed with adrenal insufficiency without adrenal antibodies at age 5.5 years. Following initial normal VLCFA levels, subsequent VLCFA analysis demonstrated elevated C26 fatty acids consistent with peroxisomal dysfunction and suggestive of ALD, which was confirmed via molecular genetic analysis of the ABCD1 gene. Brain imaging at age 7 suggested cerebral involvement and the child underwent successful allogeneic hematopoietic stem cell transplantation. At last assessment (11.5 years old), he was performing as expected for age. This case highlights the importance of pursuing a diagnosis when clinical suspicion remains, and the significance of VLCFA analysis for patients with adrenal insufficiency without adrenal antibodies in securing an ALD diagnosis. Subsequent brain imaging surveillance can detect early, pre-symptomatic cerebral disease, allowing for timely treatment and successful arrest of cerebral disease progression.

Osteogenesis imperfecta (OI) is characterized by fractures and progressive bone deformities. Fracture rates peak during the toddler and adolescent years and decline during adulthood but do not stop entirely. We describe a kindred, the affected members of which were the mother and two sons, who presented with an apparently unique phenotype of OI. Our patients demonstrated a pattern of prenatal bone deformities followed by multiple, nontraumatic long bone fractures within the first two years of life and then an absence of nontraumatic fractures thereafter. No extra-skeletal manifestations have been noted to date. The mother did not receive bisphosphonate therapy but had no nontraumatic fractures after the age of five months. Intravenous bisphosphonate therapy was started for both sons within two months of birth, with the most recent infusions at age 18 months and 28 months in Patients 2 and 3, respectively. Two patients harbored a variant of uncertain significance in the COL1A1 gene. This heterozygous variant, c.3548C>T; p.(Pro1183Leu), is listed in the OI Variant Database as affecting only one other individual with osteopenia. We describe three family members with a unique presenting phenotype of OI, characterized by cessation of nontraumatic fractures after the first two years of life.

Most cases of malignancies appear to be sporadic, but some syndromes are associated with malignancies with germline variants. Herein, a child with an unusual association of oncocytic variant adrenocortical carcinoma (ACC) and rhabdomyosarcoma (RMS) was presented. An 18-month-old-boy was admitted with virilization of the genital area, penis enlargement and erection, which had begun six months earlier. Serum total testosterone (457 ng/dL; NR <10), androstenedione (3.35 ng/mL; NR <0.5) and dehydroepiandrosterone- SO4 (206 mcg/dL; NR<35) were above the normal ranges. Right adrenal mass was detected. After adrenalectomy, histopathological examination revealed an oncocytic variant ACC. Three-month after surgery, he then presented with 6x8 cm sized swelling of the left leg. Histopathological examination revealed embryonal RMS. Testing for tumor protein (TP53) variant by DNA sequence analysis was positive; however; fluorescence in situ hybridization analysis was negative. After chemotherapy and local radiotherapy, the patient is in good condition without tumor recurrence. Only about one-third of these tumors have a variant of TP53. This status also applies to other genetic variants related to cancer. However, a significant association of malignancies strongly suggests a problem in tumor suppressor genes or new variants. Another as yet unidentified suppressor gene may also be present and effective in this locus. The occurrence of ACC as a part of a syndrome and positive family history of malignancies in patients are clinically important. These patients and their families should be scanned for genetic abnormalities. The patient with ACC should be followed-up carefully for other tumors to detect malignancy early.

Corticosterone methyloxidase deficiency type 2 is an autosomal recessive disorder presenting with salt loss and failure to thrive in early childhood and is caused by inactivating mutations of the CYP11B2 gene. Herein, we describe four Turkish patients from two families who had clinical and hormonal features compatible with corticosterone methyloxidase deficiency and all had inherited novel CYP11B2 variants. All of the patients presented with vomiting, failure to thrive and severe dehydration, except one patient with only failure to thrive. Biochemical studies showed hyponatremia, hyperkalemia and acidosis. All patients had normal cortisol response to adrenocorticotropic hormone stimulation test and had elevated plasma renin activity with low aldosterone levels. Three patients from the same family were found to harbor a novel homozygous variant c.1175T>C (p.Leu392Pro) and a known homozygous variant c.788T>A (p.Ile263Asn) in the CYP11B2 gene. The fourth patient had a novel homozygous variant c.666_667delCT (p.Phe223ProfsTer35) in the CYP11B2 gene which caused a frame shift, forming a stop codon. Corticosterone methyloxidase deficiency should be considered as a differential diagnosis in patients presenting with hyponatremia, hyperkalemia and growth retardation, and it should not be forgotten that this condition is life-threatening if untreated. Genetic analyses are helpful in diagnosis of the patients and their relatives. Family screening is important for an early diagnosis and treatment. In our cases, previously unreported novel variants were identified which are likely to be associated with the disease

Familial male-limited precocious puberty (FMPP), also known as testotoxicosis, is a rare cause of precocious puberty in males. It is caused by a mutation in the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) gene, resulting in the receptor being constitutively activated. This causes excessive production of testosterone, leading to precocious puberty in males. Generally, boys present with signs of puberty, such as pubic hair growth, acne, and increased height velocity around the age of 2-4 years old. Like any other cause of precocious puberty, the goal of treatment is to prevent virilization and also delay closure of the epiphyseal plates to maintain adult height potential. Treatment, therefore, is aimed at decreasing the effects of testosterone, as well as stopping the conversion of testosterone to estrogen. Little is known about the long-term effects of treatment because the disorder is so rare. However, studies using bicalutamide and anastrozole have been promising. In this report, we present a boy with FMPP with a novel mutation in the LHCGR gene, who has been responding well to therapy using both drugs.