Band 29, Heft 9

Parathyroid carcinoma is a rare cause of primary hyperparathyroidism amongst children, with only nine previously reported cases. The objective of the study was to present the first pediatric case with a germline CDC73 (formerly known as HRPT2 ) mutation, and to review the literature. A 14-year-old girl presented with pathologic slipped capital femoral epiphysis (SCFE). The patient was noted to have an elevated calcium level of 3.4 mmol/L (13.4 mg/dL), a parathyroid hormone (PTH) level of 1013 ng/L (1013 pg/mL), and a 3-cm palpable neck mass. Ultrasound and 99m Tc-Sestamibi confirmed the suspicion of a parathyroid mass. Intraoperative findings and pathology confirmed the diagnosis of parathyroid carcinoma. Post-operative PTH decreased to 14 ng/L (14 pg/mL). Genetic testing showed a germline 70 G>T HRPT2 / CDC73 mutation. This is the first case documenting a germline 70 G>T HRPT2 / CDC73 gene mutation in a pediatric parathyroid carcinoma. Patients with sporadic parathyroid carcinoma may benefit from HRPT2 / CDC73 gene mutation screening.

Background: Type 1 diabetes mellitus (T1DM) is speculated to have an impaired immunological response to vaccines. This paper aimed to investigate the presence of specific antibodies against hepatitis B virus (HBV) and measles in diabetic children who had been immunized according to the standard national calendar of immunization. Methods: Two hundred and one diabetic children and 140 healthy controls were prospectively evaluated. Antibodies against hepatitis B (anti-HBs) and measles were detected in all individuals who completed the vaccination schedule. We noted onset of T1DM, duration of the disease, diabetes-related autoantibodies and mean HbA 1c levels. Results: Some 72.6% of diabetics and 82.1% of controls had anti-HBs (+) (p=0.04). We found a reduced efficacy of measles vaccination in anti-HBs (–) diabetic children (p=0.009), even though there was no significant difference between the study and control groups. Onset of the disease was earlier in anti-HBs (–) diabetics than in controls (p=0.038). No difference with respect to other parameters was found. Conclusions: Our data showed a reduced seroprotection rate for HBV vaccination in diabetic children and for measles with anti-HBs (–) diabetics. Larger studies should be encouraged to confirm the vaccine efficacy in diabetic children and to elucidate possible pathogenic mechanisms.

Background: The ISPAD guideline 2011/2014 advises annual podiatric screening to detect foot complications and identify other possible risk factors such as functional and structural foot abnormalities. The aim of this study was to assess the prevalence and awareness of neurovascular, functional and structural foot abnormalities in children and adolescents with type 1 diabetes mellitus (T1DM). Methods: All patients aged 0–18 years with T1DM were invited for a foot examination and structured questionnaire by a certified podiatrist. Results: Three of the examined patients (n=128) showed signs of possible long-term complications. Structural and functional foot problems were observed in 71.9% (n=92). Of all patients, 38.3% (n=49) required further treatment by a podiatrist. Conclusions: Functional and structural foot abnormalities are a frequent problem in children with T1DM in the southern part of the Netherlands. These abnormalities are an additional risk factor for developing long-term foot complications. Education in and implementation of the guideline are necessary.

Background: The World Health Organization (WHO) European Childhood Obesity Surveillance Initiative (COSI) is a public health program established in order to understand the progress of the obesity epidemic in young populations and gain inter-country comparisons within the European region, yet the data from a number of East European countries, including Serbia, were not available then. Therefore, the main aim of this cross-sectional study was to collect data about the prevalence of overweight and obesity among 6–9-year-old school children in Serbia according to the standardized protocol during the Fourth COSI Implementation Round. Methods: From September 2015 to November 2015, 5102 first- and second-grade primary-school children (age 7.7±0.6 years) were assessed for weight, height, and body mass index (BMI) in 14 Serbian school districts. Results: The prevalence rates of obesity, as calculated using the International Obesity Task Force (IOTF) cut-off points, vary across different age groups, with the lowest obesity rates reported in 7-year-old boys (6.2%), while the highest obesity prevalence rates were observed in 6-year-old boys (9.7%). In addition, being overweight was strongly associated with poor local community development and lower level of urbanization. The overall prevalence of overweight (23.1%, including obesity) and obesity (6.9%) in Serbian primary-school children seem to be comparable to rather high rates previously reported in other countries participating in the COSI program, indicating an obesity epidemic in Serbian children. Conclusions: This surveillance system should be regularly implemented throughout Europe, providing comparable data on rates of overweight/obesity in primary schools that might drive prudent actions to reverse the pandemic trend of childhood obesity.

Background: The aim of this study was to determine the feasibility of performing newborn screening (NBS) of inborn errors of metabolism (IEMs) using tandem mass spectrometry (TMS) and the impact on its detection rate in Malaysia. Methods: During the study period between June 2006 and December 2008, 30,247 newborns from 11 major public hospitals in Malaysia were screened for 27 inborn errors of amino acid, organic acid and fatty acid metabolism by TMS. Dried blood spot (DBS) samples were collected between 24 h and 7 days with parental consent. Samples with abnormal results were repeated and the babies were recalled to confirm the diagnosis with follow-up testing. Results: Cut-off values for amino acids and acylcarnitines were established. Eight newborns were confirmed to have IEM: two newborns with Maple syrup urine disease (MSUD), two with methylmalonic aciduria (MMA) one with ethylmalonic aciduria, two with argininosuccinic aciduria and one with isovaleric aciduria. Diagnosis was missed in two newborns. The detection rate of IEMs in this study was one in 2916 newborns. The sensitivity and specificity of TMS were 80% and 99%, respectively. Conclusions: IEMs are common in Malaysia. NBS of IEMs by TMS is a valuable preventive strategy by enabling the diagnosis and early treatment of IEM before the onset of symptoms aiming at prevention of mental retardation and physical handicap. A number of shortcomings warrant further solution so that in near future NBS for IEMs will become a standard of care for all babies in Malaysia in tandem with the developed world.

Background: It is known that the association with Down syndrome (DS) can affect the phenotypic expression of autoimmune thyroid diseases (AITDs), whilst is unknown whether the clustering of extra-thyroidal autoimmune diseases (ETADs) may also be atypical in DS children. Methods: The aim of this study was to investigate the clustering of ETADs in 832 children with AITDs divided in two groups with or without DS (A and B, respectively) and in four subgroups of patients aged either <6 or ≥6 years. Results: The rate of children with ETADs was significantly higher in Group A; in particular, alopecia areata (p=0.00001) and vitiligo (p=0.00001) were found more often in Group A irrespective of age, whilst the distribution of T1 diabetes mellitus was not different in the two groups. Celiac disease prevalence was significantly higher in DS patients only in the older subgroup. Conclusions: The association with DS may be able to modify the clustering of ETADs in the children with AITDs by favoring the aggregation of some specific diseases such as alopecia areata and vitiligo.

Background: Monogenic mutations, such as those in the potassium inwardly-rectifying channel, subfamily J, member 11 ( KCNJ11 ) and insulin ( INS ) genes, are identified in young patients with type 1B diabetes (non-autoimmune-mediated). We recently reported the results of a test for monogenic forms of diabetes in Japanese children who were diagnosed with type 1B diabetes at <5 years of age. In this study, we tested for monogenic forms of diabetes in Japanese children aged >5 to ≤15.1 years at the diagnosis of type 1B diabetes. Methods: Thirty-two Japanese children (eight males, 24 females) with type 1 diabetes negative for glutamate decarboxylase (GAD) 65 and/or IA-2A autoantibodies and who were aged >5 to 15.1 years at diagnosis were recruited from 16 independent hospitals participating in the Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT). We performed mutational analyses of genes with a high frequency of mutation [ INS , KCNJ11 , hepatocyte nuclear factor 1 alpha ( HNF1α ) and hepatocyte nuclear factor 4 alpha ( HNF4α )]. Results: We identified one missense mutation (G32S) in the INS gene and two mutations (R131Q and R203S) in the HNF1α gene that could be associated with diabetes. No missense change was found in the KCNJ11 gene. Conclusions: Our results suggest that although mutations in the INS gene can be detected in Japanese patients aged >5 years at diagnosis, the frequency of mutations decrease in older age groups. Conversely, the frequency of the mutation in the HNF1α gene increased in patients diagnosed at age 5 or older. Clinicians should consider the possibility of maturity onset diabetes of the young (MODY) in children diagnosed with type 1B diabetes.

Background: The aim of the study was to describe the referral pattern, baseline characteristics, and etiological profile of children referred with short stature in Kuwait. Methods: This is a cross-sectional retrospective review of children referred to the Endocrine Clinic with short stature. Short stature was defined as height or length below the 3rd centile or <–2 standard deviation score (SDS). Results: A total of 221 children were referred with no gender difference (p=0.346). Almost one fifth of these children had normal stature. Median (interquartile) age was 7.7 (4.7, 10.3) years and mean height SDS was –2.67 (0.68). The most common diagnoses were normal variants of growth, growth hormone deficiency (GHD). Conclusions: Our study highlights the need to improve the referral process in order to avoid unnecessary investigations and alleviate parental anxiety. There is no gender bias in short stature referrals in Kuwait. There is a need of further investigation of short stature in the region.

Background: Menarche is the last stage of pubertal development, which coincides, with the completion of longitudinal growth. Our aim was to evaluate, post-menarcheal growth and clinical variables proposed to be associated with this growth. Methods: In a prospective fashion, 106 healthy girls attending five different socioeconomic status (SES) schools of Santiago were randomly recruited. A pediatric endocrinologist obtained anthropometrics and registration of date at menarche every 6 months. The evolution of the girls’ heights was assessed through mixed models adjusted to the SESes, parental height and body mass index (BMI). Results: Sixty-three girls from a high socioeconomic status (HSS) and 50 from a low socioeconomic status (LSS) were followed. Four years post menarche, the girls reached a growth plateau and the average height gain was 5.2±2.5 cm. This gain was not associated with SES, BMI, nor with parental height (p=0.744). The only variable that modulated this gain was age at menarche (r=−0.1997, p=0.0332). There was an inverse correlation between height at the moment of menarche and the height reached after 4 years of follow-up adjusted to parental height (r=−0302, p=0.0011). Conclusions: Post-menarcheal growth ends 4 years post-event and is inversely correlated with the age at menarche and with the height at the moment of menarche independent of BMI, parental height and SES.

Background: The aim of the study was to provide the age- and sex-specific percentile values of anthropometric measures for Iranian children and adolescents. Methods: This cross-sectional nationwide survey was conducted on a representative sample of 14,880 school students, selected by multistage random cluster sampling from urban and rural areas of 30 provinces in Iran. Anthropometric measures including body mass index (BMI), waist circumference (WC), hip circumference (HC), and wrist circumference were measured under standard protocols by using calibrated instruments. Age- and gender-specific reference values were developed for anthropometric measures by the maximum penalized likelihood approach [Cole’s least mean square (LMS) method]. Results: In the present study, 13,486 out of the 14,880 invited subjects completed all the required data of the study (participation rate: 90.6%). Participants consisted of 6640 girls (49.2%) and 75.6% urban residents; their mean and standard deviation (SD) age was 12.47±3.36 years. The BMI percentile curves of girls had a sharp increase from 14 to 18 years, and then began to plateau, but among boys, these curves had a consistent increase until the age of 18 years. In addition, the higher percentiles were higher in adolescent boys than girls. The HC percentile curves of both sexes had a persistent increase and the percentiles for HC were higher in adolescent girls than in boys. WC had a sharp increase from 7 to 18 years of age for boys, whereas for girls, these curves had a less sharp increase with age. In all ages, the percentiles for wrist circumference were higher in adolescent boys than girls. Conclusions: The findings of this study highlight the necessity of paying special attention to developing age- and gender-specific percentiles of anthropometric measures in children and adolescents.

Background: The aim of this study was to analyze thyroid hormones and antibodies, ferritin, vitamins B12 and D, adrenal and gonadal steroid levels, and celiac antibodies in children diagnosed with attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Methods: Between February 2014 and July 2014, a total of 77 children and adolescents (31 girls, 46 boys) who were admitted to the Van Training and Research Hospital were included in the study. The study population was divided into three groups including ADHD (n=34), ASD (n=16), and age- and sex-matched healthy controls (n=27). The diagnosis of ADHD was made on the basis of Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition (DSM-5) and DSM-4 Turkish version with the diagnostic interview and Disruptive Behavior Disorder Rating Scale (DBDRS). The diagnosis of ASD was based on the DSM-4 and DSM-5 Turkish version with the diagnostic interview and the Childhood Autism Rating Scale (CARS). The blood samples were obtained between 8:00 and 9:00 A.M. Results: There was a statistically significant difference in vitamin B12 and D levels and ferritin values among the three groups. The ASD group had the highest ferritin and the lowest vitamins B12 and D levels. Vitamin D levels of the ADHD group were significantly lower compared to the healthy controls. Conclusions: Our study results highlight the importance of supplementation of vitamins B12 and D in the ASD and ADHD patients.

Hyperinsulinism-hyperammonemia (HI/HA) syndrome is a rare autosomal dominant disease characterized by recurrent hypoglycemia and persistent mild elevation of plasma ammonia. HI/HA syndrome is one of the more common forms of congenital hyperinsulinism (CHI), caused by activating mutations within the GLUD1 gene that encodes the mitochondrial enzyme glutamate dehydrogenase (GDH). We report here on monozygotic twin girls presented with fasting- and protein-induced hypoglycemia and mild persistent hyperammonemia. Genetic analysis revealed that both girls were heterozygous for a novel missense mutation within exon 11 [c.1499A>T, p.(R443W)] of the GLUD1 gene. Despite early treatment with diazoxide and a low protein diet, they both developed non-hypoglycemic seizures in early childhood followed by cognitive impairment. In addition to their clinical course, a review of the literature on HI/HA syndrome is provided.

Permanent neonatal diabetes (PNDM) is a rare genetic condition characterized by hyperglycemia, insulinopenia, and failure to thrive beginning in the first 6 months of life. Recessive mutations in INS lead to decreased production of insulin via a variety of mechanisms. We present a case of two brothers, born to consanguineous parents, with a novel homozygous intronic variant in the INS gene. Each patient presented with intrauterine growth restriction (IUGR) and significant hyperglycemia within the first 24 h of life. All the grandparents have a diagnosis of diabetes, one of them requiring insulin treatment and the parents currently deny personal histories of diabetes. Although this mutation has not previously been described, given the segregation of the mutation, absence of heterozygosity (AOH) in the genomic region encompassing the INS locus, documented insulinopenia, and high neonatal insulin requirements, we suspect that this variant is pathogenic. Possible implications for personalized treatment of the underlying molecular etiology for an individual’s diabetes are discussed.

Mauriac syndrome is characterized by growth impairment, Cushingoid features, and hepatomegaly in patients with poorly controlled type 1 diabetes mellitus (T1DM). We report a novel presentation of Mauriac syndrome in a 9-year-old girl who was diagnosed with neonatal diabetes at 3 months of age due to the p.R201C mutation in KCNJ11 . She was initially treated successfully with glipizide at a dose of 0.85 mg/kg/day but after being lost to follow-up and having improper adjustment in dose over many years, the recent dose of 0.6 mg/kg/day appears to have been insufficient for glycemic control but enough to maintain a low level of C-peptide and prevent diabetic ketoacidosis. With proper insulin administration, all presenting clinical characteristics were resolved within 1 month. A review of the literature relating to clinical manifestations of Mauriac syndrome in children with diabetes was performed and included in this report for comparison with our patient. While Mauriac syndrome has been traditionally associated with T1DM, the presence of Mauriac syndrome should not be excluded in other types of diabetes mellitus.

The calcium sensing receptor (CASR) is expressed most abundantly in the parathyroid glands and the kidney. CASR regulates calcium homeostasis through its ability to modulate parathormone secretion and renal calcium reabsorption. Inactivating mutations in the CASR gene may result in disorders of calcium homeostasis manifesting as familial benign hypocalciuric hypercalcemia (FBHH) and neonatal severe hyperparathyroidsm (NSHPT). Two cases were referred with severe hypercalcemia in the neonatal period. Laboratory evaluation revealed severe hypercalcemia and elevated PTH. The parents also had mild hypercalcemia. The serum calcium level did not normalize with conventional hypercalcemia treatment and there was also no response to cinacalcet in case 1. Total parathyroidectomy was performed when the patient was 70 days old. Genetic analysis revealed a novel homozygous p.Arg544* mutation in the CASR gene. Case 2 underwent total parathyroidectomy and autoimplantation when she was 97 days old, but the parathyroid gland implanted into the forearm was removed 27 days later because the hypercalcemia continued. Genetic evaluation revealed a novel homozygous p.Pro682Leu mutation with normal anthropometric measurements. The neurological development is consistent with age in both cases while case 2 has mild mental retardation. No bone deformity or fracture is present in either case and normocalcemia is ensured with calcitriol in both cases.

Aarskog-Scott syndrome (ASS) is a rare X-linked recessive genetic disorder caused by FGD1 mutations. FGD1 regulates the actin cytoskeleton and regulates cell growth and differentiation by activating the c-Jun N-terminal kinase signaling cascade. ASS is characterized by craniofacial dysmorphism, short stature, interdigital webbing and shawl scrotum. However, there is a wide phenotypic heterogeneity because of the additional clinical features. ASS and some syndromes including the autosomal dominant inherited form of Robinow syndrome, Noonan syndrome, pseudohypoparathyroidism, Silver-Russel and SHORT syndrome have some overlapping phenotypic features. Herein, we report a patient with ASS and a large anterior fontanel who was initially diagnosed as Robinow syndrome. He was found to have a novel c.1340+2 T>A splice site mutation on the FGD1 gene.