Band 32, Heft 12

Context Preimplantation genetic diagnosis (PGD) is currently used for over 400 monogenic diseases. Some endocrine conditions that occur due to monogenic defects are either life-threatening or can cause severe morbidities; thus, PGD may be an option to avoid the occurrence of such diseases. Evidence acquisition An initial search in PubMed/Medline search was done to identify monogenic endocrine conditions using appropriate search terms. Eleven articles (1999–2018) reported 15 cases using PGD for monogenic endocrine diseases performed at major reproductive centers. Clinical and outcome data of these cases were reviewed with respect to the number of PGD cycles, successful pregnancy rates, live births and their genetic status. Evidence synthesis Fifteen couples underwent 32 PGD cycles (one to nine per couple), of which 17 resulted in a pregnancy. Seven couples underwent a single PGD cycle. Four couples had successful pregnancies each resulting in live births, one couple had an unsuccessful pregnancy, one needed medical termination of pregnancy and the outcome data were not reported in one. The remaining eight couples underwent multiple PGD cycles (two to nine per couple) and all had successful pregnancies in at least one cycle resulting in 16 live births. Of the total live births, 60% were genetically unaffected and 40% were carriers of the autosomal recessive gene mutation. Conclusions PGD may be a potential tool for preventing the inheritance of severe monogenic endocrine diseases in future generations. Currently, the use of PGD in endocrine disorders is rare but provides a promising option on a case-by-case basis, provided the optimal resources are available.

Background The genotype-phenotype relationship shows regional variability in 21-hydroxylase deficiency (21-OHD) caused by mutations in the CYP21A2 gene. This study focuses on the genotype-phenotype compatibility between patients and their siblings in a region where consanguineous marriage is common. Methods The most common mutations (I2G-P30L-I172N-V237E-M239K-V281L-Q318X-R356W-F306 + nt) were studied in 60 children with 21-OHD and 40 siblings (12 symptomatic and 28 asymptomatic; mean age 5.89 ± 4.63 and 8.34 ± 2.22 years, respectively). The allele number (patients; 93 siblings; 70 alleles) was counted for each case. Salt wasting (SW; n = 38), simple virilizing (SV; n = 11) and non-classical congenital adrenal hyperplasia (NCCAH; n = 11) types were compared with their genotypes classified into groups Null-AB-C-D-E based on enzyme impairment. Results Disease-causing mutations were identified in unrelated alleles: 80 out of 93 alleles (86%) in the patients: SW, 51/56 (91%); SV, 14/16 (87.4%) and NCCAH, 15/21 (71.4%). There were 43 out of 70 alleles (61.4%) in the siblings (asymptomatic, 25/50 [50%]; symptomatic, 18/20 [90%]). The most frequently detected mutations in the patients were: I2G (22%), Q318X-P30L-V281L (13% each). The distribution of the most common mutations by clinical types was: SW: I2G-Q318X (30.2%-19.6%), SV: I172NI2G (37.5%-18.7%), NCCAH: V281L-P30L (33.3%-28.5%). In patients and symptomatic siblings, the concordance percentages by genotype groups were: Null (100%-100%), A (85%-60%), B (100%-Not applicable), C (41.6%-50%). Eleven out of 28 asymptomatic siblings had disease-causing mutations (four, severe; one, moderate; six, mild). The distribution of genotypes by phenotypes were: SW: Null-A (88%), SV: B-A (50%-41.6%), NCCAH: C (100%). Conclusions This study showed that the most common alleles were IN2G-Q381X-R356W-P30L-V281L in the children with 21-OHD and asymptomatic siblings, and that the phenotype can be predicted from the genotype except for the P30L-V281L. This result suggests that the most common mutations in 21-OHD are similar to previous reports, but that the genotype-phenotype compatibility is good except for group C showing regional variability, and that genotyping of siblings discovered new patients.

Objective To evaluate whether 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD) should be routinely screened in newborns. Methods Dried blood spots (DBS) were collected and analyzed by tandem mass spectrometry (TMS). Blood samples were collected from infants with positive 3-MCCD results. Targeted sequencing was performed using the extended panel for inherited metabolic diseases to detect 306 genes. The sequencing libraries were quantified and used for massively parallel sequencing on the Illumina HiSeq 2500 platform. Results A total of 536,008 infants underwent newborn screening (NBS) and 14 cases of 3-MCCD were diagnosed. The incidence of 3-MCCD in Jiangsu province was 1:38,286. During the last 3 years of follow-up, none of the subjects with 3-MCCD exhibited obvious clinical symptoms. Only two children had mild feeding difficulties and vomiting. Eleven patients had complex variants of the MCCC1 gene, and three patients had mutations in MCCC2 . In total, 17 types of MCCC1 or MCCC2 variants were found, and c.639 + 2t > a was the most common mutation. Conclusions As far as the current results are concerned, 3-MCCD may be benign in Jiangsu province. However, additional investigations and a longer follow-up period are necessary to decide whether NBS of 3-MCCD is necessary or not.

Background This study aimed to investigate the completing endogenous RNA (ceRNA) network involved in childhood obesity. Methods The microarray dataset GSE9624 was downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed long non-coding RNAs (lncRNAs) (DELs) and messenger RNAs (DEMs) were isolated between the childhood obesity and non-obesity tissue samples. Then, Gene Ontology (GO) functional and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of isolated DEMs were performed. DELs and DEMs targeted miRNAs were predicted to construct a ceRNA regulatory network. Finally, critical lncRNAs were validated in another dataset. Results A total of 1257 differentially expressed RNAs were screened, including 28 lncRNAs and 1229 mRNAs. In addition, these RNAs were mainly involved in defense response, cell cycle, mitogen-activated protein kinase (MAPK) signaling pathway, apoptosis, etc. Three lncRNAs (human leukocyte antigen complex 5 [HCP5], long intergenic non-protein coding RNA 839 [LINC00839] and receptor activity modifying protein 2 [RAMP2-AS1]) and two related miRNAs (hsa-miR-17-5p and hsa-miR-27a/b-3p) were identified as key RNAs in childhood obesity. Specifically, lncRNA HCP5 interacted with miR-17-5p and miR-27a/b to regulate nemo-like kinase (NLK) and Ras-related protein 2 (RRAS2) via the MAPK signaling pathway. Finally, four genes ( RRAS2 , NLK , bcl2/adenovirus E1B protein-interacting protein 3 [ BNIP3 ] and phorbol-12-myristate-13-acetate-induced protein 1 [ PMAIP1 ]) targeted by miRNAs were predicted as critical genes and might be novel diagnostic biomarkers of childhood obesity. Conclusions lncRNA HCP5 could serve as a ceRNA sponging miR-17-5p and miR-27a/b to regulate the pathogenesis of childhood obesity via NLK and RRAS2 in the MAPK signaling pathway.

Background Previous studies investigating the beneficial effects of exercise in type 1 diabetes mellitus (T1DM) are relatively insufficient compared to studies on type 2 diabetes mellitus (T2DM), due to the fear of hypoglycemia. Recently, several researchers have reported that combined aerobic and resistance exercise prevents hypoglycemia during and after exercise. Furthermore, exercise has been shown to have beneficial effects on the psychological status of patients with various diseases. The aim of this study was to evaluate the effect of combined aerobic and resistance exercise in adolescents with T1DM. Methods Thirty-five type 1 diabetic patients were enrolled, and subjects were divided into either an exercise group or a control group. Thirty patients (20 patients in the exercise group, 10 patients in the control group) completed the study. The exercise program was performed for 1 h at a time, once a week, for 12 weeks. Study parameters were evaluated at baseline and 3 months after baseline evaluation. Results Combined aerobic and resistance exercise better controlled the body mass index (BMI), and also improved maximum muscular strength and maximum exercise intensity. On psychological tests, subjects’ attention and quality of life showed improving tendency, while their stress and behavioral problems diminished. The number of exercise events increased in the training group, while the daily total insulin dose and glycated hemoglobin (HbA 1c ) level showed no significant changes. Conclusions A 12-week structured exercise program consisting of aerobic and resistance exercises improves cardiovascular, neurocognitive and psychobehavioral functions, and positively helps lifestyle modification in patients with T1DM.

Background The association between thyroid-stimulating hormone (TSH) concentrations and blood pressure is well described in adults, but only studied to a limited extent in children and adolescents and almost entirely in population-based cohorts. The present study investigates the association between TSH and blood pressure, and the influence of leptin and adiponectin, in a cohort of children and adolescents enrolled in obesity treatment compared with a population-based cohort. Methods We studied 4154 children and adolescents aged 6–18 years from an obesity clinic cohort and a population-based cohort from The Danish Childhood Obesity Data- and Biobank. Anthropometrics, blood pressure and biochemical markers, including TSH, leptin and adiponectin concentrations, were collected. Adjusted correlation and interaction analyses were performed. Results Patients from the obesity clinic cohort exhibited higher concentrations of TSH and higher blood pressure than participants from the population-based cohort. TSH standard deviation scores (SDS) were significantly associated with all blood pressure-related variables in the population-based cohort, but only with systolic blood pressure SDS and hypertension in the obesity clinic cohort. The interaction between TSH SDS and adiponectin was found to be independently associated with systolic blood pressure and hypertension in the population-based cohort only. Conclusions The significant associations between TSH, adiponectin and blood pressure, observed in children and adolescents from a population-based cohort, are attenuated or absent in children and adolescents with overweight or obesity, suggesting that childhood obesity distorts the healthy interplay between the thyroid axis, thyroid-adipokine interaction and blood pressure.

Aims A decrease in health-related quality of life (HRQOL) measures among obese (OB) and overweight (OW) children has been shown in several studies, but knowledge about the variables affecting HRQOL impairments is missing. The aim of this study was to evaluate the relationship between HRQOL and sociodemographic characteristics, anthropometric measurements, metabolic parameters, mental symptoms and parental attitudes in a sample of OB/OW children. Methods Eighty-six OB/OW children, aged between 9 and 17 years, participated in the study. We performed sociodemographic questioning, anthropometric examinations and laboratory evaluations of the participants. HRQOL was assessed using the Pediatric Quality-of-Life Inventory (PedsQL), and levels of anxiety and depressive symptoms were measured using the Screen for Child Anxiety-Related Disorders (SCARED) questionnaire and the Children’s Depression Inventory (CDI), respectively. Parental attitudes were assessed with the Parental Attitude Research Instrument (PARI) questionnaire. Results A statistically significant relationship was found between total scores of CDI and SCARED answered by children and the total and subscale scores of PedsQL. Scores of total quality of life subscale, physical functionality and emotional functionality subscales were significantly lower in children with a family history of mental illness. No relationship was found between PedsQL subscales, anthropometric and metabolic parameters. Conclusions Emotional problems and parental psychological distress are important factors in models of HRQOL in the OB/OW pediatric population.

Background The standard treatment of central precocious puberty (CPP) is gonadotropin-releasing hormone analogues (GnRHa). It is a concern that children treated with GnRHa are at risk of developing obesity which could impair the treatment outcomes. This study aimed to investigate the effect of GnRHa on body mass index (BMI) standard deviation score (SDS), and the influence of BMI status on treatment outcomes in children with idiopathic CPP (iCPP). Methods A retrospective cohort study in children with iCPP who completed GnRHa treatment and had attained near final adult height (NFAH) was conducted. Children with a history of disease or drug ingestion which could affect their BMI were excluded. BMI, BMI SDS, height (Ht), Ht SDS, predicted adult height (PAH), and NFAH were compared at baseline, 1 and 2 years during treatment, and at NFAH according to the baseline BMI status; normal weight and overweight/obesity. Results Fifty-eight children with iCPP treated with GnRHa were enrolled. The BMI SDS was significantly increased at 1 and 2 years during treatment in the overweight/obese group and at 1 year during treatment in the normal-weight group. However, at NFAH (2 years after treatment discontinuation), the BMI SDS was not statistically different from baseline in both groups. Ht gain, change in Ht SDS and BMI SDS were not statistically different from the baseline in both groups. Conclusions GnRHa results in a transient increase in BMI SDS during treatment and returned to baseline after treatment cessation. The benefit of GnRHa treatment on final Ht improvement is similar between overweight/obese and normal-weight patients.

Background Anorexia nervosa (AN) is a serious eating disorder that is associated with decreased bone mineral density (BMD) and greater lifetime risk for fractures. The aim of this study was to determine the correlation between BMD and genetic polymorphisms in AN. Methods This case-control study analyzed vitamin D receptor (VDR) (VDRBsml, VDRFokl) and estrogen receptor (ESR) (ESR1Xbal, ESR1Pvull) polymorphisms in 45 adolescents diagnosed with AN and 46 age-matched healthy controls. BMD values of the AN group were classified as low or normal, and polymorphisms were compared between cases and controls. The effects of body mass index (BMI), duration of disease and amenorrhea on BMD were also evaluated. Results In girls with AN, a positive effect of the bb genotype of VDRBsmI polymorphism on femur Z-scores (p = 0.103) and of the Ff genotype of VDRFokI polymorphism on vertebra Z-scores (p = 0.097) was observed. In boys with AN, a positive effect of the Ff genotype of VDRFokI polymorphism on vertebra BMD (g/cm 2 ) was detected (p = 0.061). No association was detected between ESR polymorphisms. An inverse relationship was observed between BMD and duration of illness and amenorrhea. A direct relationship was detected between BMD and BMI. Conclusions Specific VDR gene polymorphism genotypes may have positive effects on BMD in patients with AN. Additionally, the lack of association between ESR gene polymorphisms on BMD could be attributed to the low estrogen status of the patient.

Background Familial hypokalemic periodi9c paralysis (hypoKPP) is a rare autosomal dominant disorder characterized by episodic paralytic attacks caused by fall in blood potassium. CACNA1S , SCN4A or KCNJ2 variants can cause hypoKPP. Case presentation We investigated a Pakistani family affected with autosomal dominant familial hypoKPP through whole exome sequencing (WES). A heterozygous KCNJ2 missense variant c.919A > G was found segregating with the disease phenotype in the family. Conclusions The KCNJ2 missense variant is the likely cause of the disorder in the affected family. The finding should help improve antenatal screening and genetic counselling of this family.

Background Diabetic ketoacidosis (DKA) is a common complication of type 1 diabetes mellitus (T1DM). Infants and children with new-onset T1DM may present with DKA, and the risk of cerebral edema is high in infantile DKA. What is new? Neurological deterioration during an episode of DKA is usually attributed to cerebral edema and cerebrovascular accidents. However, cerebral infarction is a very rare complication in infantile DKA. Case presentation We describe a rare case of infantile cerebral infarction caused by severe DKA in a patient with new-onset T1DM. Conclusions Cerebral infarction is an important intracranial complication in infantile DKA. Careful observation and treatment for DKA during the first 24 h of therapy are necessary in infants with new-onset T1DM because the risk of cerebral infarction is highest during this timeframe.

Background Cholesterol metabolism has dramatically changed under hyperthyroid status. However, a combination of hyperthyroidism and cholecystolithiasis is very rare. Case presentation We report a case of cholelithiasis accompanied by hyperthyroidism in a 13-year-old girl who had recently lost 13 kg of weight (from 53 to 40 kg) in 1 month without loss of appetite. Ultrasonography showed multiple hyperechoic areas with acoustic shadowing in the gallbladder. Thyroid function tests showed that her serum free triiodothyronine (T3) and thyroxine (T4) levels were elevated and the thyroid-stimulating hormone level was decreased. In addition, serum thyrotropin receptor antibody and thyroid-stimulating antibody were detected. The final diagnosis was cholelithiasis with Graves’ disease. Thiamazole ingestion was started immediately after the diagnosis, and laparoscopic cholecystectomy was performed 33 days after hospitalization. Conclusions Massive and sudden weight loss could be a risk factor for gallstone formation in children. In addition, hyperthyroidism has the potential to promote cholelithiasis via cholesterol metabolism.

Background Mucolipidosis II α/β (ML II) is an autosomal recessive disease associated with the abnormality of lysosomal enzyme trafficking. Case presentation We present an unusual patient with: (a) marked skeletal anomalies with secondary hyperparathyroidism; (b) serum intact parathyroid hormone level normalized by 7 weeks but abnormally elevated serum alkaline phosphate persisted; and (c) two mutations identified in the GNPTAB gene. One mutation, c.3503_3504delTC, is the most common mutation in ML II. However, the second mutation, c.2896delA, is a rare mutation for which clinical presentation has not been described previously.

Malignancy-induced hypercalcemia is a very rare condition in children whereas it is more common among adult patients with malignancy. The mechanisms of malignancy-induced hypercalcemia include the over-secretion of parathyroid hormone-related protein (PTHrP), osteolytic metastases and the over-production of 1,25-dihydroxyvitamin D (calcitriol). Although hypercalcemia due to PTHrP secretion has been published before, overproduction of calcitriol has not been reported yet in pediatric squamous cell skin carcinoma cases. Herein, we report calcitriol-mediated severe hypercalcemia in a 5-year-old boy with squamous cell skin carcinoma arising in the background of xeroderma pigmentosum (XP) which responded well to zoledronate treatment. To the best of our knowledge, this is the first pediatric case of malignancy-induced hypercalcemia which is mediated by calcitriol in squamous cell skin carcinoma.