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Most of inborn errors of metabolism (IEMs) and rare endocrine-metabolic diseases (REMD) are rare diseases. According to the European Commission on Public Health, a rare disease is defined, based on its prevalence, as one affecting one in 2000 people. Many IEMs affect body stature, cause craniofacial abnormalities, and disturb the developmental process. Therefore, body proportion, dysmorphic characteristics, and morphological parameters must be assessed and closely monitored. This can be achieved only with the help of an anthropologist who has adequate tools. This is why the role of an anthropologist in collaboration with the physician in the diagnostic process is not to be underestimated. Clinical anthropologists contribute to assessing physical development and improve our understanding of the natural history of rare metabolic diseases. This paper presents anthropometric techniques and methods, such as analysis of demographic data, anthropometric parameters at birth, percentile charts, growth patterns, bioimpedance, somatometric profiles, craniofacial profiles, body proportion indices, and mathematical models of growth curves used in certain rare diseases. Contemporary anthropological methods play an important role in the diagnostic process of rare genetic diseases.

Background The study was done to assess high-density lipoprotein (HDL) functionality and to correlate this with paraoxonase 1 (PON1) activity in malnourished children. It aimed to find the effect of malnutrition on changes in PON1 activity, HDL functionality, lipid profile and lipid hydroperoxide formation. Methods This case control study included 30 malnourished children (up to age 5 years) and 30 healthy controls in the paediatric inpatient department of SRTR Government Medical College Ambajogai, India. Clinically diagnosed cases depending on anthropometric indices were selected. Serum PON1 activity by using phenyl acetate as a substrate, HDL functionality by haemin by its protection on H 2 O 2 and haemin induced LDL oxidation, lipid profile by routine enzymatic methods and lipid hydroperoxide using the FOX2 assay were measured. Results Malnourished children had significantly decreased PON1 activity (106.6 ± 12.74** vs. 132.23 ± 28.49 IU/L), HDL functionality (116.55 ± 8** vs. 132.29 ± 10.9%), total cholesterol (TC) (102.5 ± 16** vs. 116.4 ± 12.65 mg/dL), HDL-cholesterol (C) (33.41 ± 9.74** vs. 40.55 ± 5.85 mg/dL) and reduced total protein level (5.56 ± 0.91* vs. 6.06 ± 1.055) higher triglycerides (TG) (146.76 ± 34.97* vs. 125.96 ± 17.21 mg/dL) level and total hydroperoxide (TPX) levels (5.568 ± 1.70** vs. 3.22 ± 1.52 μM/L). *p < 0.05 **p < 0.001. PON1 activity (r 2  = 0.576) and TC (r 2  = 0.567) shows significant positive correlation with HDL functionality. PON1 activity, HDL-C, HDL functionality and TPX shows independent contribution towards malnutrition in children in multivariate and univariate logistic regression. TC lost its significance in multivariate regression. Conclusions Malnutrition leads to decrease in HDL functionality and increase in hydroperoxide levels with a decrease in PON1 activity.

Background There is limited information about cardiovascular complications among young adults (YA) with type 1 diabetes mellitus (T1DM) who are transitioning from pediatric to adult care. We aimed to study the prevalence and associated factors of dyslipidemia (DLD) and statin treatment in these patients. Methods We recruited 129 YA with T1DM aged 15–25 years. In a cross-sectional analysis, the prevalence of DLD (low-density lipoprotein cholesterol [LDL-C] ≥ 100 mg/dL, high-density lipoprotein cholesterol [HDL-C] <40 mg/dL [males] or <50 mg/dL [females], total cholesterol [TC] ≥200 mg/dL or triglycerides [TG] ≥150 mg/dL) was reported. Socioeconomic and clinical characteristics were compared between YA with and without DLD. We also assessed statin use among YA with DLD. Results DLD was found in 64% of YA, predominantly increased LDL-C (34.9%). Higher mean glycated hemoglobin (HbA 1c ) was associated with DLD (p < 0.043). Of all YA who met the criteria for statin therapy, only 42% had one prescribed. Conclusions The prevalence of DLD is high in YA with T1DM and is associated with poor glycemic control, and use of statin therapy in this high-risk population is low.

Background Thiamine deficiency is commonly reported in patients with diabetes especially during diabetic ketoacidosis (DKA) that could attribute to myocardial dysfunction in those patients. However, there is limited data regarding its relation to myocardial function among those patients. This study aimed to explore the association between myocardial function and serum thiamine levels in children with type 1 diabetes mellitus (DM). Methods This cross-sectional comparative study included 25 patients with DKA. Clinical data assessment, echocardiographic examination and measurement of serum high-sensitive troponin T (hs-cTnT) and thiamine levels were done. We also assessed the association between troponin levels, echocardiographic ventricular systolic and diastolic function and serum thiamine. Results Twenty-four percent of children with DKA had thiamine deficiency. DKA children with thiamine deficiency had significant acidosis and higher serum troponin levels and significant impairment of diastolic function than those without thiamine deficiency. The serum thiamine level had a significant positive correlation with the echocardiographic indices of diastolic function but negative correlation with troponin levels. Conclusions Thiamine deficiency is a common finding during the treatment of children with DKA, and this deficiency may be associated with myocardial dysfunction.

Background The management options for Graves’ disease in children are limited and there is controversy regarding optimal treatment. Remission rate with anti-thyroid drug (ATD) treatment in children is said to be lower than in adults. Definitive treatments are effective, but they often result in permanent hypothyroidism. The objective of this study was to investigate the outcome of methimazole treatment, identify significant predictors of a remission and evaluate the adverse effects of methimazole in a pediatric population of GD patients. Methods Medical records of the patients who had been diagnosed with Graves’ disease were screened retrospectively. Diagnostic criteria included elevated free thyroxine (fT4) and total triiodothyronine (T3), suppressed thyroid-stimulating hormone (TSH) and either positive thyroid-stimulating immunoglobulin (TSI) or thyroid receptor antibodies (TRABs) or clinical signs suggestive of Graves’ disease, for example, exophthalmos. Remission was defined as maintenance of euthyroidism for more than 12 months after discontinuing methimazole treatment. Results Of the 48 patients, provisional remission was achieved in 21 patients. Of the 21 patients, 14 experienced a relapse (66.6%). Remission was achieved in seven (24.1%) of 29 patients who received methimazole treatment for more than 2 years. In patients who achieved long-term remission, the male sex ratio and fT4 levels at diagnosis were significantly lower than the relapsed and non-remission groups, whereas the free triiodothyronine (fT3)/fT4 ratio and duration of methimazole treatment were significantly higher than the relapse group. Conclusions Long-term methimazole treatment in pediatric Graves’ disease would be appropriate. High fT4 levels at the time of diagnosis and male sex were associated with a risk of relapse.

Background Neuroblastoma (NBL) is a child neoplasia affecting extracranial tissue of neuroectodermal origin. It accounts for 10% of solid malignancies in children and is characterized by a survival rate approaching 70%, confronting physicians with the emergence of an adult survivor population who have been previously exposed to surgery, cytotoxic drugs, radiation therapy or metaiodobenzylguanidine (MIBG) therapy. All these treatments potentially affect the endocrine system. Our study consists in a retrospective review of late endocrine effects arising in survivors treated for NBL during childhood. Methods The medical files of 47 patients (M/F = 26/21) treated for NBL were reviewed. Collected data consisted of age, height, weight and biological hormonal values at diagnosis and at the last follow-up consultation. The incidence of late effects in our sample was compared to the data from the literature. Results Patients were between 0 and 15.8 years of age at diagnosis (median: 1.16 years) and between 1 and 25 years of age at last follow-up (median: 16 years). Twenty-six patients were treated with chemotherapy (CT), 11 underwent CT and radiation therapy and five were treated with CT and MIBG therapy. Ten percent of the patients died before reaching the end of therapy. Late effects occurred in 54% of the patients. Thirty-six percent of patients had non-endocrine complications (musculoskeletal, neurological, hematological or hepatic chronic conditions). Endocrine complications (28%) affected mainly patients treated with CT and consisted of gonadal dysfunction (up to 42% patients of over 12 years of age at follow-up) and hypothyroidism (21%). Our analysis revealed that CT had a significant impact on final height (p < 0.05). Conclusions Treatment for childhood malignancies exposes children to late effects affecting the endocrine system. In children treated for NBL, hypothyroidism, gonadal failure and impaired growth appear to be the main endocrine complications. Close follow-up of survivors is thus appropriate.

Background Zinc transporter 8 autoantibodies (ZnT8Abs) together with glutamic acid decarboxylase autoantibodies (GADAbs), insulinoma antigen 2 autoantibodies (IA-2Abs) and insulin autoantibodies (IAbs) are markers of type 1 diabetes mellitus (T1DM). We studied the prevalence of ZnT8Ab in children with autoimmune thyroid diseases (AITDs) to assess the association of AITDs and T1DM at the serological level. Methods The study groups consisted of 44 children with Graves’ disease (GD), 65 children with Hashimoto’s thyroiditis (HT), 199 children with T1DM with or without AITDs and 58 control children. ZnT8Ab, GADAb, IA-2Ab, IAb, 21-hydroxylase autoantibodies (21-OHAbs) and acetylcholine receptor autoantibodies (AChRAbs) were measured. Results ZnT8Abs were found in 4/44 (9.1%) patients with GD, and 4/44 (9.1%) patients with GD were positive for GADAb. Of the 65 HT patients, six (9.2%) were positive for ZnT8Ab, while four (6.2%) were positive for GADAb. In the T1DM group, 128/199 (64%) of the patients were positive for ZnT8Ab, 133/199 (67%) for GADAb and 109/199 (55%) for IA-2Ab. One GD patient and one HT patient were positive for all the four diabetes-associated autoantibodies. Two HT patients were positive for three diabetes autoantibodies. Two GD (4.5%) and five HT (7.7%) patients were positive for 21-OHAb only. None of the patients had AChRAb. In the control group, 2/58 (3.4%) were positive for GADAb and 2/58 (3.4%) were positive for ZnT8Ab. Conclusions Diabetes-associated autoantibodies including ZnT8Ab were found in children and adolescents with GD and HT.

Background There is limited data on adrenal function in the early days after birth in extremely premature infants. The relationship between plasma adrenocorticotrophic (ACTH) and cortisol hormone is central to the integrity of the hypothalamic-pituitary-adrenal (HPA) axis yet there are no studies examining this relationship in prematurity. Methods The aim of this study was to examine the relationship between early morning plasma cortisol and ACTH concentrations during the first 5 days after birth in infants born at less than 28 weeks’ gestation and to identify any independent factors that determine plasma cortisol levels in these infants during extreme prematurity. We prospectively studied early morning plasma ACTH and cortisol concentrations in infants born below 28 weeks’ gestation during the first 5 days of birth. Plasma cortisol was measured without extraction, using DPC Immulite ® 2000 using a solid phase 2 site chemiluminescent immunometric assay. ACTH was measured using a radioimmunoassay. Spearman’s correlation was used to examine the relationship between cortisol and ACTH. Multiple regression analysis was used to examine the relationship between plasma cortisol and clinical risk index for babies (CRIB) score, antenatal dexamethasone, mode of delivery and gestation. Results There were 95 infants (53 males) of mean gestation 25.3 ± 1.3 standard deviation (SD) (range 23–27 + 6) weeks. The mean birth weight was 809 ± 17.0 g. The mean plasma cortisol was 400.5 ± 42.6 nmol/L and the mean plasma ACTH was 4.5 ± 0.9 pmol/L. Early morning plasma cortisol correlated significantly with gestation (R = 0.4, p = 0.005). Early morning plasma ACTH did not correlate with early morning plasma cortisol (R = −0.12, p = 0.7). Multiple regression analysis showed that gestation was the only independent determinant of early morning plasma cortisol concentration (beta coefficient = −0.4, p = 0.04). Conclusions The relationship between early morning plasma ACTH and plasma cortisol is either not established or is impaired in infants of less than 28 weeks’ gestation in the first 5 days after birth. The plasma cortisol level is mainly determined by gestation and is not directly related to illness severity, antenatal steroids or plasma ACTH in these infants in the first 5 days after birth.

Background Testicular tumours are uncommon in children, accounting for only 1% of all childhood tumours. Prepubertal Leydig cell tumours actively secrete testosterone and as a result, patients typically present with isosexual precocious pseudopuberty, this being the first cause of consultation. We present three cases of Leydig cell tumours in prepubertal patients with an atypical presentation. Methods We studied three cases of Leydig cell tumours in prepubertal boys, who either consulted for testicular asymmetry or were incidentally found to have the tumour in the absence of systemic signs of systemic hyperandrogenism or precocious puberty. In all cases, a well-circumscribed testicular mass was found by testicular ultrasound. The diagnosis was confirmed by histology. In all three cases, testicular enucleation was performed with satisfactory follow-up. Results Following the surgical procedure, during the follow-up, all patients showed a normal testicular volume in comparison with the contralateral testis. No complications were seen during follow-up. Conclusions A testicular ultrasound in children developing asymptomatic testicular asymmetry might be recommended due to its possible hormonal action locally. An early testicular ultrasound, testicular swelling discrepancies, tumour size and androgen production are key factors in the prognosis and management of this type of tumour.

Background Cystinosis is a rare autosomal-recessive disorder caused by a defective transport of cystine across the lysosomal membrane. Previous studies have mapped cystinosis to the CTNS gene which is located on chromosome 17p13, and various CTNS mutations have been identified to correlate them with this disease. Methods We analyzed six patients from five unrelated families who were diagnosed with cystinosis in our hospital. We described the diagnostic procedures for all the patients and proposed alternative therapies for cystinosis patients instead of using cysteamine, an orphan drug which was commercially unavailable in China. Moreover, genetic analysis of all patients’ samples was carried out to identify novel CTNS gene mutations. Results and conclusions The patients in this study were followed up from 1 to more than 10 years to monitor their growth and development, which indicated that the alternative therapies we used were helpful to ameliorate the complications of the cystinosis patients without cysteamine. Furthermore, by sequencing the patients’ genome, we identified novel mutations in the CTNS gene including: c.477C > G (p.S159R), c.274C > T (p.Q92X) and c.680A > T (p.E227V); these mutations were only observed in cystinosis patients and had never been reported in any other populations, suggesting they might be specific to Chinese cystinosis patients.

Background The aim of this study was to compare the validity of various approaches to pediatric continuous metabolic syndrome (cMetS) scores including siMS scores (2 waist/height + fasting blood glucose [FBG]/5.6 + triglycerides [TG]/1.7 + systolic blood pressure [BP]/130 + high-density lipoprotein [HDL]/1.02), Z-scores, principal component analysis (PCA) and confirmatory factor analysis (CFA) for predicting metabolic syndrome (MetS). Methods This nationwide cross-sectional study was conducted on 4200 Iranian children and adolescents aged 7–18 years. The cMetS was computed using data on HDL, cholesterol, TGs, FBG, mean arterial pressure (MAP) and waist circumference (WC). The areas under the receiver operating characteristic curves (AUCs) were used to compare the performances of different cMetS scores. Results Data of 3843 participants (52.4% boys) were available for the current study. The mean (standard deviation [SD]) age was 12.6 (3) and 12.3 (3.1) years for boys and girls, respectively. The differences in AUC values of cMetS scores were significant based on the Delong method. The AUCs (95% confidence interval [CI]) were for Z-scores, 0.94 (0.93, 0.95); first PCA, 0.91 (0.89, 0.93); sum PCA, 0.90 (0.88, 0.92), CFA, 0.79 (0.76, 0.3) and also for siMS scores 1 to 3 as 0.93 (0.91, 0.94), 0.92 (0.90, 0.93), and 0.91 (0.90, 0.93), respectively. Conclusions The results of our study indicated that the validity of all approaches for cMetS scores for predicting MetS was high. Given that the siMS scores are simple and practical, it might be used in clinical and research practice.

Background Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Cushing’s syndrome (CS) in childhood. We describe a case series of patients presenting at our centre along with a review of the literature. Methods A retrospective analysis of six index cases and one family were done for demographic features, hormonal profile, imaging findings, genetic mutation status, histopathologic findings and follow-up details. Diagnosis was based on biochemistry and confirmed with histopathology and or genetic mutation. All patients had suppressed 8 am adrenocorticotropic hormone (ACTH) (<10 pg/mL) despite evidence of hypercortisolism. Results The mean age in our cohort was 8.2 years (range 15 months to 20 years). All patients presented with overt CS, including one patient with cyclic Cushing’s. Three patients had additional features of Carney complex (CNC). Imaging did not reveal any obvious mass lesions on computed tomography (CT), the classical beaded appearance was present in only two of the patients. Mutation analysis was positive in three patients. Five patients underwent bilateral adrenalectomy and had features of PPNAD on histopathology. Conclusions PPNAD is a rare cause of ACTH-independent CS in childhood and may signal underlying CNC. Patients with younger age of onset with overt CS may still have a mutation in the PRKAR1A gene and warrant genetic testing.

Very recently, it was reported that a patient with classical galactosemia and a very high intelligence quotient (IQ) score obtained a university degree. In the present study, two siblings with classical galactosemia (homozygous for Q188R mutation) received upper normal IQ scores when tested with psychometric tools. Additionally, the same IQ scores were determined in their healthy brother when tested at the same age. It was concluded that patients could achieve upper normal IQ scores when on diet and followed up closely. Family and especially maternal care may ameliorate the psychomotor development.

Context Germ cell tumours (GCTs) secreting β-human chorionic gonadotropin (β-HCG) are a rare cause of gonadotropin-independent precocious puberty (GIPP). Case description A 5.7-year-old boy presented with GIPP. Investigations to elucidate the underlying cause revealed elevated serum β-HCG. Ultrasound of the abdomen and testes, urine steroid profile, bone isotope scan, and sequencing of the luteinizing hormone receptor gene ( LHCGR ) were normal. Despite paired serum and cerebrospinal fluid β-HCG measurement suggesting local (brain) β-HCG production, repeated magnetic resonance imaging (MRI) of the brain as well as MRI of the mediastinum did not identify a tumour source of persistently elevated serum β-HCG. Treatment with cyproterone acetate and spironolactone was unsuccessful. Increase in testicular volumes prompted the addition of a gonadotropin releasing hormone (GnRH) analogue. Due to progressing virilisation and skeletal maturation, treatment was changed to a combination of anastrozole and bicalutamide at the age of 7 years. One year later, serum β-HCG and testosterone concentrations spontaneously normalised followed by reductions in the height velocity, skeletal maturation and virilisation. The proband achieved his genetic height potential. No medication side effects were observed. The patient subsequently presented with non-secreting pineal GCT at 14 years, 8½ years after his initial presentation with GIPP. Conclusions Our case highlights that GIPP with no definite underlying aetiology at diagnosis should be considered as a prodrome for GCTs, and regular radiological surveillance for earlier tumour identification is warranted. To the best of our knowledge, our case is the first reported case of the use of anastrozole and bicalutamide in the setting of idiopathic GIPP. The good height outcome in our case warrants the trial of anastrozole and bicalutamide in similar cases.

Background Obesity has become one of the greatest health risks worldwide. Recently, there was an explosion of information regarding the role of the central nervous system (CNS) in the development of monogenic and syndromic obesity. Case presentation Over the last decade, terminal and interstitial submicroscopic deletions of copy number variants (CNVs) in 2p25.3 and single nucleotide variants (SNVs) in myelin transcription factor 1 like ( MYT1L ) were detected by genome-wide array analysis and whole exome sequencing (WES) in patients with a nonspecific clinical phenotype that commonly includes intellectual disability (ID), early onset of obesity and speech delay. Here, we report the first Saudi female patient with mild to moderate ID, early onset of obesity and speech delay associated with a de novo pathogenic SNV in the MYT1L gene (c. 1585G>A [Gly529Arg]), which causes an amino acid change from Gly to Arg at position 529 that leads to mental retardation, autosomal dominant 39.

Background Monoallelic mutations of GHR have been described in idiopathic short stature (ISS), although the significance of these remain unclear. We report a case of ISS with novel monoallelic S219L mutation of GHR and discuss the possible significance of monoallelic GHR mutation in ISS. Case presentation The proband, a 13.9-year-old Japanese boy, had severe short stature (−3.8 standard deviation [SD]). Serum insulin-like growth factor (IGF)-I level and growth hormone (GH) secretion was normal. His parents were nonconsanguineous and had normal stature. Genetic analyses revealed a novel monoallelic missense variation in exon 7 of GHR (S219L). The proband’s mother had the same variation. S219L might be the novel mutation judging from there being no registration of it as a single-nucleotide polymorphism (SNP) in any database, evolutional conservation of Ser 219 , in silico analyses, and computational molecular visualization analysis. Furthermore, a review of the literature showed that the median height of missense mutation carriers of GHR was relatively low. Conclusions We propose the possibility that monoallelic mutation of GHR increases the susceptibility to short stature.

Background Insulin autoimmune syndrome (IAS) is a rare cause of hyperinsulinemic hypoglycemia (HH) not addressed as a potential differential diagnosis in current pediatric guidelines. We present a case of IAS in a child with no previous history of autoimmune disease, no previous intake of triggering medications and absence of genetic predisposition. Case presentation A 6-year-old boy presented with recurrent HH (blood glucose of 26 mg/dL [1.4 mmol/L] and insulin of 686 μU/mL). Abdominal imaging was normal. After multiple therapeutic failures, we hypothesized misuse of exogenous insulin and factitious hypoglycemia. Council of Guardianship had the child separated from his mother, but insulin levels remained high. A chromatography test was then performed which showed high titers of endogenous insulin autoantibody (IAA) with early dissociation from the insulin molecule. The human leukocyte antigen (HLA) test showed a DRB1 *13:01/*08:02 genotype. The patient was advised to control food intake and physical activity routines. During a 5-year follow-up, hypoglycemic episodes were sparse, despite high insulin levels. Conclusions Misdiagnosis of IAS with factitious hypoglycemia may happen if IAS is not considered as a differential diagnosis, leading to potential traumatic consequences. Further efforts should be made to increase awareness of IAS as a differential diagnosis of hypoglycemia and to include it in pediatric guidelines.