Band 32, Heft 3

Background We previously reported improved persistence and adherence to daily recombinant growth hormone (rGH) in children using jet transjection delivery compared to using needle-based devices. This study examines the relationship between improved adherence and medium-term growth outcomes in children receiving jet-delivered rGH (JrGH) at a single centre. Methods This was a retrospective longitudinal follow-up study of children (<16 years) treated with daily JrGH (somatropin; Ferring Pharmaceuticals) in the form of Zomacton ® with the Zomajet ® device. Delivery schedules of home distribution services were utilised to calculate adherence, quantified as the proportion of days covered (PDC) index (PDC > 0.8 adherent, PDC ≤ 0.8 less adherent). Demography, patient history, height standard deviation scores (HTSDS) and difference from mid-parental height SDS (MPHSDS − HTSDS) were extracted from hospital records for up to 3 years of treatment. Results Of 75 patients eligible for JrGH, 52 had PDC treatment and height data for at least 1 year and 22 for 3 years. A greater proportion of patients were classified as adherent in both 1- and 3-year treated cohorts (adherent 30 [57.7%] and 14 [63.6%], less adherent 22 [42.3%] and 8 [36.4%]). After 1 year of JrGH treatment, HTSDS was not significantly different in either adherence group. After 3 years, only adherent patients demonstrated sustained year-on-year increments in HTSDS and significant improvement in target HTSDS positions (by 1.32 SDS) compared to baseline (p = 0.0008). MPHSDS – HTSDS showed a similar significant improvement at 3 years in adherent patients only (p = 0.0043). Conclusions Patients adherent to JrGH demonstrate significant growth improvement compared to baseline over 3 years.

Background The Quality of Life in Short Stature Youth (QoLISSY) questionnaire is a condition-specific instrument for measuring the health-related quality of life (HRQoL) in short statured children/adolescents from patients’ and parents’ perspectives. The aim of this study was to investigate the psychometric properties of the Greek version of the QoLISSY questionnaire. Methods The original European QoLISSY scales were translated into Greek following the guidelines for linguistic validation and applied to 184 dyads of children 8–18 years old and their parents, as well as to 14 parents of children 4–7 years old in Greece. The field testing responses to the Greek version of QoLISSY were analyzed. Results The qualitative analysis of the Greek data provided results consistent with the European sample. The subsequent field test showed acceptable internal consistency (Cronbach α between 0.67–0.93) and high test-retest reliability (intraclass correlation coefficients [ICC] ≥0.70). Correlations with the generic KIDSCREEN questionnaire indicated good convergent validity. Confirmatory factor analysis (CFA) also yielded acceptable results. Higher HRQoL for taller children suggests that QoLISSY was able to detect significant height-related differences. Conclusions The Greek version of the QoLISSY questionnaire is psychometrically sound and its use is recommended in further clinical research to ascertain the impact of short stature (SS) and treatments in Greek children/adolescents and families.

Background Bartter syndrome is a group of rare autosomal-recessive renal disorders characterized by hypokalemic hypochloremic metabolic alkalosis associated with severe growth failure; the exact causes for growth retardation are unclear. GH deficiency (GHD) has been reported in a few cases of Bartter syndrome. The aim of our study was to determine the prevalence of GHD in children with antenatal Bartter syndrome and to assess their response to GH therapy. Methods Ten patients aged 1.5–14.5 years and diagnosed with antenatal Bartter syndrome were enrolled. Seven children with short stature underwent GH stimulation tests. Results Common presenting symptoms were failure to thrive and polyuria. The mean patient height at study entry was −2.7 standard deviation (SD) (range 0.89 to −5.95) and mean weight (SD) was −1.7 (range 1.89 to −4.11). A decline in height and weight (SD) was observed over the years. GHD was diagnosed in four children and GH therapy was started in all of them. Two patients responded very well and gained >1 SD in height, one patient stopped therapy due to non-adherence and one had a poor response. Conclusions In addition to other important causes for poor growth in antenatal Bartter syndrome, our findings suggest that GHD should also be considered as a cause of growth retardation and therefore, clinical assessment of the GH axis is recommended. GH therapy has a role in the treatment of growth failure in some individuals with Bartter syndrome.

Background The objective of this study was to evaluate the physical growth and development characteristics of children with Williams syndrome (WS) aged 0–24 months, and provide help for early diagnosis of WS. Methods A total of 32 cases of children (17 males and 15 females) aged 0–24 months who were diagnosed with WS were enrolled between 2008 and 2017. These children were divided into four different groups: 1–6 months (six cases), 7–12 months (eight cases), 12–18 months (nine cases) and 19–24 months (nine cases). Meanwhile, a total of 32 healthy children (17 males and 15 females) were enrolled in the study from the Department of Health Care for physical examination in our hospital as the control group and matched with each divided group. Weight and height were measured, and meanwhile birth weight and height were also asked and recorded. Results There was no statistically significant difference in birth height between the two groups (p>0.05), and birth weight and the height and weight of the children with WS in the four groups were significantly lower than those of the children in the normal control (NC) group (p>0.05). When the corresponding age of WS children was compared to the Nine City Growth Curve Standards in China, 97% of cases were lagging behind in physical growth and development. Conclusions WS children often have the features of early slow physical growth, which provides certain help for the early diagnosis of WS. Therefore, for younger children, facial features combined with an accurate and objective physical growth assessment and ultrasonic cardiogram can greatly improve the screening rate.

Background Cardiorespiratory fitness (CRF) and pubertal stages have been related to many health outcomes, including obesity and adipocytokines. Thus, the present study aimed to analyze the moderator role of CRF and pubertal stage in the relationship between adiposity and adipocytokines in girls. Method This cross-sectional study was performed with 42 pre-pubertal girls aged from 7 to 11 years and 54 post-pubertal girls aged from 13 to 17 years. Blood samples were collected to determine the serum levels of leptin and adiponectin, and then the leptin/adiponectin ratio (L/A ratio) was calculated. CRF, anthropometric and body composition indicators were assessed. For statistical analysis, descriptive statistics and several linear regression models were used. The moderation analysis was tested using the PROCESS macro. Results An interaction between body mass index (BMI) and CRF (β: –0.70; confidence interval [CI]: –1.29, –0.12), as well as between BMI and pubertal stage (β: 0.79; CI: 0.28, 1.30) with leptin, was found. Regarding the L/A ratio, an interaction was found only in BMI × CRF (β: –0.56; CI: –1.06, –0.06). Using a combined interaction (CRF and pubertal stage), the results showed a positive association between BMI with leptin and L/A ratio only in low CRF, pre-pubertal and post-pubertal stages. Conclusion This study suggests a protective role of high levels of CRF in the relationship between BMI and adipocytokines. Despite the effect of pubertal stage, the results suggest that youth should be engaged in physical activity in order to improve CRF levels and consequently improve cardiometabolic health.

Background Obesity is an important cause of morbidity, and it has an increasing frequency in childhood. Studies have reported that 33% of adults and 20–27% of children and adolescents are obese. Recently, it has been shown that the prevalence of obesity in the childhood group is higher than the past years. Omentin-1 is an adipokine which is synthesized from the visceral fat tissue but not synthesized in the subcutaneous fat tissue. Omentin-1 has been shown to increase insulin-mediated glucose uptake, especially in the adipose tissue. Studies have shown that plasma omentin-1 levels, which play an important role in the pathogenesis of insulin resistance, are significantly lowered in obese, polycystic ovary syndrome (PCOS) and diabetic patients. The aim of this study was to investigate the relationship between obesity and omentin-1 levels in children. Methods The study included obese children with a body mass index (BMI) greater than the 95th percentile and healthy children with a BMI lower than the 85th percentile. Obese and healthy individuals had similar age and sex distributions. Glucose, insulin, lipid profiles, thyroid panels and metabolic markers were evaluated. Results The levels of omentin-1 in obese children were significantly lower than in the control group (p<0.05). Results of Spearman’s correlation analysis for all participants showed that omentin-1 levels were negatively related with triglycerides, total cholesterol, serum free thyroxine (FT4), insulin, homeostatic model assessment of insulin resistance (HOMA-IR), body weight, waist circumference (WC) and BMI percentile values. Conclusions Our findings indicate that serum omentin-1 levels are lower in obese children than in non-obese individuals. Omentin-1 can be used as a metabolic biomarker in children and adolescents.

Background A provisionary screening programme for 21-hydroxylase deficiency (21-OHD) was initiated in Beijing in 2014. The aim of this study was to investigate the incidence and the associated clinical characteristics of neonatal congenital adrenal hyperplasia (CAH) in Beijing and to provide evidence-based guidance for its application in CAH screening. Methods Live birth newborns (n=44,360) were screened for CAH in Beijing from July 2014 to April 2018. The levels of 17-hydroxyprogesterone (17-OHP) in the blood were estimated using the time-resolved fluoroimmunoassay. Neonates with a positive result and a level >30 nmol/L of 17-OHP were called for a retest. CAH was diagnosed based on further laboratory findings combined with clinical signs, such as weight loss, feeding difficulties, skin pigmentation, and atypical genitalia. Through a review of medical records, the clinical findings including molecular data were reported. Results Of the 44,360 neonates screened, 280 cases were deemed positive. Of these, 203 neonates were recalled for further tests and six patients (three boys and three girls) were diagnosed with CAH. Five cases of classic salt-wasting and one case of simple virilising 21-OHD were identified. The incidence of CAH in Beijing was 1:7393. The most frequent 21-OHD mutation was c.293-13C/A>G. Conclusions The incidence of CAH in Beijing was higher than the national average. The results support the need for neonatal CAH screening in Beijing. This pilot study demonstrates the clinical characteristics of 21-OHD through newborn screening. Early detection and treatment through neonatal screening may reduce mortality rates and optimise developmental outcomes.

Background 11β-hydroxylase deficiency (11βOHD) is a rare disease representing the second most common cause of congenital adrenal hyperplasia (CAH) (5–8%) with an incidence of about 1:100,000. In contrast to 21-hydroxylase deficiency (21OHD), 11βOHD is not included in neonatal screening programmes. The objective of this study was to demonstrate the typical features of male patients with 11βOHD. Methods Clinical, biochemical and radiological data of patients with 11βOHD were analysed in this retrospective single-centre analysis. Results Six male patients of four unrelated families with 11βOHD were identified (0.1–13.5 years of chronological age [CA] at diagnosis). The predominant symptoms were arterial hypertension, tall stature and precocious pseudopuberty. Bone ages (BAs) were remarkably advanced at diagnosis in four index patients (median difference BA–CA: 5.5 years, range 1.5–9.2 years). Homozygous mutations were identified in exon 7 (c.1179_1180dupGA [p.Asn394Argfs*37]) and exon 8 (c.1398+2T>C) of the CYP11B1 gene leading both to a complete loss of function. The latter mutation has not yet been described in databases. 11βOHD was identified by the measurement of 11-deoxycortisol in a newborn screening card of one patient retrospectively. Testicular adrenal rest tumours (TARTs) were detected in three patients at 3.7 years, 11 years and 14.4 years. Conclusion The diagnosis of CAH due to 11βOHD is delayed and should be suspected in children with arterial hypertension, tall stature and precocious pseudopuberty. Patients may develop TARTs as early as infancy. 11βOHD should be included in newborn screening programmes, at least in newborns of index families, to allow early diagnosis and the start of treatment to reduce morbidity.

Background Oxidative stress may be one of the causes responsible for mental retardation in phenylketonuria (PKU) patients. Phenylalanine (Phe) reduces antioxidant defense and promotes oxidative stress by causing increase in reactive oxygen-nitrogen species. Our study aimed to investigate the effect of different treatments (amino acid mixture/large neutral amino acid [LNAA] supplements) on oxidative stress which are applied to late-diagnosed patients. To the best of our knowledge, this is the first study to investigate the effect of LNAA supplements on oxidative stress. Methods Twenty late-diagnosed classic PKU patients were included in this study. Patients were classified into two groups: patients under Phe-restricted diet and using Phe-free amino acid mixtures (Group I) (mean age: 13.8 ± 2.8), and patients taking LNAA supplements (Group II) (mean age: 14.8 ± 3.8). Healthy controls (mean age: 13.6 ± 4.8) with ages consistent with the ages of the patients in the experimental groups were included. Results Glutathione peroxidase is lower in patients of taking LNAA supplements than the control group (p = 0.022). Coenzyme Q10 is lower in patients of using Phe-free amino acid mixtures than the control group and it is significantly higher in Group II than Group I (p = 0.0001, p = 0.028, respectively). No significant differences were detected in total antioxidant status, total oxidant status, oxidative stress index, paraoxonase 1 and L-carnitine levels. Conclusions Different treatments affect oxidative stress parameters in PKU patients. In this study, although patients were followed up with classic PKU, patient-specific adjuvant antioxidant therapies should be implemented in response to oxidative stress.

Background It is known that iron deficiency anemia effects appetite and growth negatively. The aim of this study was to investigate the effect of iron therapy on appetite, growth and plasma ghrelin and leptin levels in children aged between 12 and 24 months with isolated nutritional iron deficiency anemia. Methods Iron deficiency anemia was diagnosed by clinic and laboratory findings. All 19 cases were given 5 mg/kg/day iron therapy for 3 months. Results The mean plasma ghrelin level was 936.7±428.8 pg/mL before therapy and it increased to 1284.7±533.3 pg/mL (p<0.001) while the mean plasma leptin level decreased from 3.4±1.6 ng/mL to 1.9±1.0 ng/mL (p<0.01) after therapy. The amount of daily caloric intake, carbohydrate and protein intake were significantly increased after therapy (p<0.001). Δ body weight was correlated with plasma ghrelin levels before and after therapy significantly. Conclusions In conclusion, the findings of this study indicate that plasma ghrelin level increases and leptin level decreases and growth accelerates because of an increase in appetite and daily calories, carbohydrate and protein amount in children with nutritional iron deficiency anemia after iron therapy. The increase in appetite and acceleration on growth in iron deficiency anemia might result from decreased leptin and increased plasma ghrelin levels. The most important finding of this study is significantly increased plasma ghrelin levels after iron therapy, and this finding might be related to both the improved appetite and catch-up growth.

Background Phenylketonuria (PKU) is an inherited metabolic disorder characterized by high levels of phenylalanine in the blood and brain, resulting in mental retardation, etc. Dietary treatment with low phenylalanine is the common treatment for this disease. Patients with other metabolic disorders, such as diabetes mellitus, were reported to have a higher percentage of quality-of-life damage (QLD) and social discriminations (SDs). Methods To evaluate the degree (%) of maternal QLD and SD in relation to their educational status and place of living during the participation of their PKU children in public events, 110 mothers of PKU children with an average age of 25.7 years took part in this study. We evaluated their QLD and SD according to their educational status (primary school, high school and university) and place of living (small town ≤300,000, city >300,000 inhabitants). A control group was not needed. Special questions (checklist) were created to evaluate the QLD and SD of the mothers of children under dietary control. Cronbach’s α test was used for the measurement of the function of the items in the checklists. Results The covariance between the item pairs and the variance of the total score were calculated. Mothers who had completed primary school and lived in a city with a population >300,000 experienced the highest degree of QLD. In contrast, mothers with a university degree experienced the lowest SD. Overall, the highest SD was observed in mothers who lived in a small town. The affected group of mothers should be psychologically supported.

Background During pubertal development in healthy boys, increased levels of different sex steroids occur which are responsible for sexual maturation and physical changes. However, relationships between various sex hormones and pubertal development stages have not been sufficiently studied. Methods The investigation included 165 normal boys (mean age 12.7±2.8 years, mean body mass index [BMI] 19.6±4.2 kg/m 2 ). Pubic hair (PH) stages were stratified by Tanner and testicular volume (TV) by means of the Prader orchidometer and assigned to the prepubertal, pubertal and postpubertal development phase. Four different sex steroids (testosterone [TE], dehydroepiandrosterone [DHEA]/dehydroepiandrosterone-sulfate [DHEAS], androstenedione (AE), 17-hydroxyprogesterone [17-OHP]) were measured in saliva by enzyme-linked immunosorbent assay (ELISA) and as serum total steroids by different assays (radioimmunoassay [RIA], chemiluminescence immunoassay [CLIA], electrochemiluminescence immunoassay [ECLIA]). Validation of saliva-based ELISA tests included data related to inter- and intra-assay coefficients of variation (CVs), recovery and linearity. Results Using Spearman rank correlation, salivary steroids significantly correlated (p<0.001) with pubertal development: TE (TV r=0.74 and PH stages r=0.72), DHEA (r=0.58 and 0.62), AE (r=0.38 and 0.45) and 17-OHP (r=0.42 and 0.43). Correlations between salivary and serum concentrations of steroids were also statistically significant (p<0.001). Binomial logistic regression analysis revealed significant correlations between salivary TE and pubertal maturation during the development phases of prepuberty-puberty and puberty-postpuberty. Inclusion of further salivary steroids did not improve analysis results. Conclusions Salivary TE permits a good non-invasive characterization of pubertal maturation stages. The consideration of further salivary sex steroids did not improve diagnostic accuracy.

Background The mutations of thiamine pyrophosphokinase-1 ( TPK1 ) gene have been frequently studied in some patients with thiamine metabolism dysfunction syndrome-5 (THMD5), while TPK1 mutations in Chinese patients have been investigated by only homozygous. A search of the literature on the mutations in the Chinese population currently published revealed that no reports of compound heterozygous mutations were reported. Here, we report a Chinese patient with compound heterozygous TPK1 mutations who underwent magnetic resonance imaging (MRI), whole exome sequencing (WES), molecular diagnosis, bioinformatics analysis, and three-dimensional (3D) protein structure analysis. Case presentation A Chinese boy was born after an uneventful pregnancy to non-consanguineous and healthy parents. On the sixth day after his birth, the lactate level of the patient was between 8.6 mmol/L and 14.59 mmol/L in plasma (the normal level is in the range of 0.5–2.2 mmol/L). Lactate was reduced to the normal level after rehydration, acid correction, expansion, and other treatments. After 4 months, the patient presented with an acute, 3-h-long, non-induced convulsions, and was admitted to our hospital for weakness, decreased oral intake, and lethargy. Results achieved by electroencephalography (EEG), cerebrospinal fluid, and other biochemical findings were normal. A visible hemorrhagic lesion was also observed in the brain. Seizures increased significantly during infection, which was accompanied by higher lactic acid levels. MRI of the brain showed an obvious signal shadow, in which bilateral frontal and temporal parietal subarachnoid cavities were widened, and more abnormal signals were observed; therefore, further consideration of hypoxic-ischemic encephalopathy and genetic metabolic disease was taken into account. Conclusions The results of WES revealed that the patient was associated with compound heterozygous mutations NM_022445.3:c.[263G>A]; [226A>G] of TPK1. His parents were non-consanguineous; while his father was found to be a heterozygous carrier with the mutation c.[263G>A], his mother was identified as a heterozygous carrier with the mutation c.[226A>G]. The results indicated that the patient had a compound heterozygous TPK1 mutation, and this is the first reported case in China.

Background Congenital hyperinsulinism (CHI) occurs due to an unregulated insulin secretion from the pancreatic β-cells resulting in hypoglycaemia. Causative mutations in multiple genes have been reported. Phenotypic variability exists both within and between different genetic subgroups. Case presentation A male infant born at 35+6 weeks’ gestation with a birth weight of 4.3 kg [+3.6 standard deviation score (SDS)] had recurrent hypoglycaemic episodes from birth. Biochemical investigations confirmed a diagnosis of CHI. Diazoxide was started and the dose was progressively increased to maintain euglycaemia. His father was slim and had been diagnosed with type 2 diabetes in his 30s. Sequence analysis identified a heterozygous hepatocyte nuclear factor 4 alpha ( HNF4A ) mutation (p.Arg245Pro, c.734G>C) and compound heterozygous ABCC8 mutations (p.Gly92Ser, c.274G>A and p.Ala1185Val, c.3554C>T) in the patient. The p.Ala1185Val ABCC8 mutation was inherited from his unaffected mother and the p.Arg245Pro HNF4A and p.Gly92Ser ABCC8 mutations from his father. All three mutations were predicted to be pathogenic. Identification of the HNF4A mutation in the father established a diagnosis of maturity-onset diabetes of the young (MODY), which enabled medication change resulting in improved glycaemic control. Conclusions We report a rare patient with CHI due to dual genetic aetiology. Although he is currently responsive to the maximum dose of diazoxide, the long-term prognosis remains unclear.

Background Neonatal severe hyperparathyroidism (NSHPT) is commonly treated with either parathyroidectomy or pharmacologic agents with varying efficacy and numerous side effects. Reports of using cinacalcet for NSHPT have increased, however, the effective dose for pediatric patients from the onset of symptoms through infancy has not been established. Case presentation We describe the clinical course of a newborn with a de novo R185Q mutation in the calcium-sensing receptor ( CASR ) gene, causing NSHPT. The infant received cinacalcet from the first days of life until 1 year of age. Conclusions Cinacalcet therapy effectively controlled the patient’s serum calcium, phosphorus, and parathyroid hormone (PTH) levels without side effects.