Volume 35, Issue 6

Background Investigation of monogenic obesity (MO), a rare condition caused by a single gene variant(s), especially in consanguineous populations, is a powerful approach for obtaining novel insights into the genetic alterations involved. Here, we present a systematic review of the genetics of MO in the 22 Arab countries and apply protein modeling in silico to the missense variants reported. Methods We searched four literature databases (PubMed, Web of Science, Science Direct and Scopus) from the time of their first creation until December 2020, utilizing broad search terms to capture all genetic studies related to MO in the Arab countries. Only articles published in peer-reviewed journals involving subjects from at least one of the 22 Arab countries and dealing with genetic variants related to MO were included. Protein modelling of the variants identified was performed using PyMOL. Results The 30 cases with severe early-onset obesity identified in 13 studies carried 14 variants in five genes ( LEP, LEPR, POMC, MC4R and CPE ). All of these variants were pathogenic, homozygous and carried by members of consanguineous families. Conclusion Despite the elevated presence of consanguinity in the Arab countries, the genetic origins of MO remain largely unexplained and require additional studies, both of a genetic and functional character.

Background Registries are considered valuable data sources for identification of pediatric conditions treated with growth hormone (GH), and their follow-up. Currently, there is no systematic literature review on the scope and characteristics of pediatric GH registries. Therefore, the purpose of this systematic review is to identify worldwide registries reported on pediatric GH treatment and to provide a summary of their main characteristics. Content Pediatric GH registries were identified through a systematic literature review. The search was performed on all related literature published up to January 30th, 2021. Basic information on pediatric GH registries, their type and scope, purpose, sources of data, target conditions, reported outcomes, and important variables were analyzed and presented. Summary Twenty two articles, reporting on 20 pediatric GH registries, were included in this review. Industrial funding was the most common funding source. The main target conditions included in the pediatric GH registries were: growth hormone deficiency, Turner syndrome, Prader Willi syndrome, small for gestational age, idiopathic short stature, and chronic renal insufficiency. The main objectives in establishing and running pediatric GH registries were assessing the safety and effectiveness of the treatment, describing the epidemiological aspects of target growth conditions and populations, serving public health surveillance, predicting and measuring treatment outcomes, exploring new and useful aspects of GH treatment, and improving the quality of patient care. Outlook This systematic review provides a global perspective on pediatric GH registries which can be used as a basis for the design and development of new GH registry systems at both national and international levels.

Overweight and obesity affect approximately 1/3 of children in the United States and are risk factors for prediabetes and type 2 diabetes. Progression from prediabetes to diabetes carries substantial long-term health burdens, culminating in decreased life-expectancy. Earlier development of type 2 diabetes is associated with poorer prognoses, and children lose glycemic control more rapidly than adults. Metformin is approved by the USFDA for the treatment of type 2 diabetes in children, has limited toxicity, and may help prevent the development of type 2 diabetes. The more rapid disease progression in children and the safety of metformin suggests that initiation of metformin treatment to children with prediabetes who have not effectively responded to lifestyle changes may help prevent short- and long-term health damage resulting from prediabetic and diabetic dysglycemia.

Objectives Prader–Willi syndrome (PWS) is a complex genetic disorder with severe hypotonia, failure to thrive, childhood obesity, hypogonadism/hypogenitalism and learning/behavioral problems with endocrine-related growth and other hormone deficiencies. The prevalence of central adrenal insufficiency (CAI) using dynamic testing ranges from rare to 60%. We compared routine morning plasma cortisol (MPC) and ACTH levels in large cohorts of PWS and control children to address CAI. Methods Retrospective analysis of MPC and ACTH levels was undertaken in 128 PWS growth hormone (GH)-treated children under medical care before considering dynamic testing for CAI and 128 non-syndromic control children with short stature evaluated for GH deficiency. Results The average MPC level in PWS was 9.7 ± 3.7 μg/dL with no difference in age, gender or PWS genetic subtype and 13.4 ± 5.7 μg/dL in the control group. MPC levels were significantly lower (p < 0.05) in PWS but in the normal range. The morning plasma ACTH level in the PWS group was 22.1  ±  8.0 pg/mL with one individual having an initial low plasma ACTH level (8 pg/mL), but normal upon repeat. Conclusions MPC levels in PWS are normal and comparable with control children, without evidence or increased risk of CAI. Lower but normal MPC levels were seen in PWS and suggestive of reduced local regeneration of cortisol from cortisone in adipose tissue by the GH-IGF-I system. Hence, MPC measures alone or in combination with ACTH should be considered for initial screening for CAI in PWS but prior to dynamic testing .

Objectives Iodide transport defect (ITD) is one of the principal causes of congenital hypothyroidism (CH) and its primary molecular mechanism is a mutation of the sodium/iodide symporter (NIS) gene. This study aims to analyse the clinical characteristics and genetic mutations of ITD. Methods The participants were a pair of siblings diagnosed with congenital hypothyroidism. Inductively coupled plasma mass spectrometry was used to determine the concentration of salivary iodine and serum iodine and to calculate their ratio. At the same time, next-generation sequencing (NGS) was applied to detect all exons of congenital hypothyroidism-related genes. All suspicious variants were further validated in the patients and their parents by PCR and Sanger sequencing. Results Both patients were conclusively diagnosed with thyroid iodine transport defect (ITD). NGS identified two variants of the NIS gene in the siblings: c.1021G>A (p.Gly341Arg) with paternal origin and c.1330-2A>C with maternal origin. Both of these variants have not been reported to date. They are predicted to be pathogenic based on these clinical symptoms and comprehensive software analysis. Conclusions This is the first reported family study of congenital hypothyroidism with SLC5A5 mutation in China. Next-generation sequencing technology is an effective means of studying the genetics of congenital hypothyroidism. The therapeutic effect of potassium iodide needs to be further evaluated.

Objectives Differentiated thyroid cancers (DTCs) in the paediatric population differ from that of their adult counterparts in terms of clinicopathological characteristics and treatment outcomes. This systematic review and meta-analysis was conducted to comprehensively evaluate the prevalence of various genetic alterations underlying the pathogenesis of sporadic paediatric DTCs. Methods This study followed the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. Systematic searches were made on the PubMed and Embase databases using relevant keywords, and articles published until October 15, 2021 were selected. Data on the prevalence of various genetic alterations were extracted from the individual articles. Random-effects model was employed for meta-analysis to generate pooled estimates and their 95% confidence intervals (95% CIs). Results Thirty-three articles comprising 1,380 paediatric patients were included. RET rearrangement (pooled prevalence: 24.4%, 95% CI: 19.1–30.1) was observed to be the most common genetic alteration in sporadic paediatric DTCs, closely followed by BRAF point mutation (pooled prevalence: 21.2%, 95% CI: 17.2–25.5). Other common alterations included: NTRK rearrangement (pooled prevalence: 13.5%, 95% CI: 9.5–17.9) and DICER1 mutation (pooled prevalence: 12.5%, 95% CI: 3.6–25.7). RAS and TERT mutations were observed to be relatively uncommon (pooled prevalence: 5.7%, 95% CI: 2.9–9.3, and 2.2%, 95% CI: 0.4–5.5, respectively). There was no evidence of publication bias. Conclusions Fusion oncogenes are noted to be the major oncogenic drivers in sporadic paediatric DTCs and underlie their unique behaviour. However, despite the relatively lower frequency of BRAF point mutation compared to adults, it remains a major player in childhood DTCs.

Objectives Leptin resistance is one of the important causes of obesity in children. Besides known causes of leptin resistance like mutations in leptin and leptin receptor genes, overexpression of SOCS3 in arcuate nucleus is a potential cause of leptin resistance. We aimed to determine the effects of circulating miRNAs on leptin resistance in obese children by targeting SOCS3 pathway. Methods miRNAs potentially targeting SOCS3 were determined by using online target prediction databases. Polymorphisms in miRNA target sequences were determined by using online genome browsers. miRNA expression levels of obese (n=35) and non-obese (n=30) children were determined by qPCR method, genotyping were performed by real-time PCR method and serum leptin, leptin receptor and SOCS3 levels were measured by ELISA method. Results miRNA profiling have shown that serum miR-218-5p levels are significantly (p<0.05) increased in accordance with serum leptin levels in obese children. Conclusions In this study we used target prediction methods for evaluating potential miRNAs which may involve in development of leptin resistance. We have shown that miR-218-5p might be taking part in leptin resistance in obese children.

Introduction Bone age (BA) is a quantitative determination of skeletal maturation. The role of puberty in variations in BA is poorly understood as hypothalamic-pituitary-gonadal (HPG) axis maturation and skeletal maturation are regulated in parallel but independently by multiple different factors. In countries like India where there is rapid nutrition transition and increase in prevalence of obesity, their impact on height and BA is not well understood. Objectives To study if in 2–17 year old healthy children, the difference between chronological age (CA), height age (HA) and BA is less than 1 year on either side of the chronological age and to assess relationship of BA with height, weight and BMI with special reference to gender and puberty. Methods This cross-sectional study included 804 preschool/school-going Indian children. Anthropometric measurements and pubertal assessments were performed using standard protocols and were converted to age and sex standardized z-scores using Indian references while BA was estimated by Tanner-Whitehouse (TW3) method. p<0.05 was considered statistically significant. Results The mean age and gender standardized z-scores for height, weight, body mass index (BMI) and BA were −0.3 ± 0.7, −0.7 ± 0.8, −0.1 ± 1.0, and −0.2 ± 0.9 respectively. HA was more delayed in girls while BA was more delayed in boys. The mean BA z-score increased with increasing BMI. After the onset of puberty, there was higher increment in BA in girls and HA in boys (p<0.05). Conclusions HA, BA and CA were tightly correlated in healthy Indian children with a significant role of nutritional status and puberty in causing variation in the same.

Objectives Congenital adrenal hyperplasia (CAH) remains one of the most challenging endocrine disorders to diagnose, manage, and treat, especially in Africa where there is lack of neonatal screening program, and limited access to care. Data on biomolecular anomaly are sparse, therefore type of mutations are unknown, increasing management challenges and genetic counseling. The present study aims to describe clinical, biomolecular aspects of a group of Cameroonian patients. Methods We did an observational retrospective study at the pediatric endocrinology unit of the Mother and Child Centre of the Chantal Biya Foundation in Yaounde from May 2013 to December 2019, including all patients diagnosed with CAH. Results We consecutively included 31 patients aged less than 21 years, diagnosed CAH. Median age at diagnosis was 1.71 years (IQR 0.08–2.57 years). Abnormal genitalia was the main complain in 48.4%(n=15). The most prevalent genetic anomaly found in our study population (n=24) was on CYP11, found in 16 patients (66.6%) followed by CYP21A2 mutation found in 8 patients. Homozygous mutation of p.Q356X was found in half of patients with 11 hydroxylase deficiency. This mutation was mostly found in people from semi-Bantu tribes, declared non consanguineous. Conclusions 11 hydroxylase deficiency is the most prevalent form of CAH found in this group of Cameroonian children.

Objectives There is a paucity of information regarding the profile of entire paediatric endocrine clinics and how they are changing. This study aimed to analyse the clinic profile of the Western Australian tertiary paediatric endocrine outpatient service over 10 years and compare to national and international data. Methods Retrospective analysis of the Western Australian Paediatric Endocrine Database (WAPED) between 2007 and 2017 looking at the frequency, proportion and longitudinal change of diagnosis categories, specific diagnoses, and gender breakdown. Results In total, 2,791 endocrine diagnoses were recorded for 2,312 patients. The most frequent reason for referral (22.1% of patients), was for evaluation of abnormalities in thyroid function. The most common diagnosis being hypothyroidism (76.7%). Evaluation of short stature was the reason for referral in 19.2% of patients, 14.6% of whom were diagnosed with growth hormone deficiency. Evaluation of puberty disorders, syndromes with endocrine features and disorders of calcium and phosphate metabolism were other common reasons for clinic referral, seen in 11.3, 9.8 and 8.2% of patients respectively. Between 2007 and 2017, the odds ratio of a thyroid diagnosis increased by 1.07 per year (95% CI: 1.02–1.12), whilst the odds ratio of a short stature diagnosis decreased by 0.91 per year (95% CI: 0.87–0.95). Conclusions The profile of the WAPED is similar to previously published national and international data. The analysis of the profile of diagnoses and its longitudinal change over a ten-year period offer a unique opportunity to guide clinic planning, resource allocation and future research.

Objectives Endocrinopathy can occur as a postoperative sequel in children treated for supratentorial tumors (STTs). We assessed prediction of a residual hypothalamic/pituitary insufficiency (HPI) in these patients and factors associated with prolonged length of hospital stay (LOS). Methods This is a retrospective cohort study of children who had surgery for STTs in two tertiary centers in Saudi Arabia (2009–2019). We assessed PICU postoperative management and risk of HPI. Data were analyzed using SPSS V24.0 and a logistic regression model for a prediction of a prolonged LOS. Results Data included 55 children (1–18 years, mean 9.5 ± 4.9 years) who required STT surgeries, 32 (54%) females. Craniopharyngioma (27.3%) was the commonest STTs and 20% of patients had initial symptoms of HPI. PICU management included the use of different types of intravenous fluids (IVFs) and medications such as steroids and desmopressin (DDAVP). An early postoperative DI was reported in 21.8% (n=12/55). Residual HPI included 24 (43.6%) presumed cortisol deficient and 18 (32.7%) central DI patients. Risk factors for postoperative HPI were female gender, age <6 years, headache and preoperative pituitary symptoms. LOS (Median=25.5 ± 12.2 days) was significantly prolonged in patients who required two or more doses of DDAVP [B=13; 95% CI= (1.7–24.3) days] and reduced in patients who had suspected preoperative HPI [B=−19.6; 95% CI= (−31.1, −8.2) days]. Conclusions Prediction of postoperative HPI in pediatric STTs enhances an early initiation of treatment in PICU and reduces LOS. A meticulous use of IVF and medications supervised by a multidisciplinary team is essential for a favorable outcome.

Objectives To investigate if digital approaches can ameliorate the known consequences of social-distancing restrictions in the context of the global COVID-19 pandemic for adolescent participants originally registered for a face-to-face outpatient weight regulation program and whether video-based multiprofessional outpatient obesity therapy is successful for a group of adolescents with preexisting obesity. Methods The certified KiCK outpatient training program for children and adolescents with overweight and obesity was remodeled as a consequence of the lockdown traditional face-to-face program to a completely digital and video-based format on short notice. The virtual approach was compared with the results of the conventional program regarding metabolic parameters, body mass index standard deviation score (BMI SDS), well-being, and physical fitness. Results Sixty-nine of 77 enrolled participants for KiCK (age 8 to 17 years, BMI z score >2.0) were able and willing to participate virtually. After the first lockdown significant improvements of BMI SDS (mean 0.18; p=0.02), homeostasis model assessment (HOMA) index (mean 1.4; p=0.016), triglycerides (mean 0.18 mmol/dL; p=0.021), 6 minute-walk-test (mean 97.0 m; p=0.030, and well-being according to the World Health Organization 5 (WHO-5) questionnaire (mean 2.5; p=0.002) were found after the virtual intervention, which was comparable to the results observed previously in matched pairs data from the program during the pre-COVID period. After the end of the second lockdown weight SDS, BMI SDS, HOMA INDEX, and cholesterol were also measured reduced compared to baseline parameters measured before program initiation. Walking distance in the 6 MWT and improvement in general well-being in the WHO-5 questionnaire also persisted. Conclusions These results indicate good acceptance and efficacy of the video-intervention for youth with overweight and obesity during the lockdown, supporting the use of virtual modules in future programs after the pandemic.

Objectives Glycemic control is an important parameter that can predict long-term complications of diabetes mellitus. It can be affected by many factors. Hence, identifying those factors for improving disease outcomes is essential. The purpose of this study was to assess glycemic control in children who were treated with a conventional insulin regimen and to identify its associated factors. Methods A retrospective cohort study was conducted among children with type one diabetes mellitus (T1DM) who had follow-up from November 2015 to November 2020 at the pediatric endocrinology clinic of St. Paul’s Hospital Millennium Medical College in Addis Ababa, Ethiopia. Glycemic control was assessed by measuring glycosylated hemoglobin (HbA 1C ) and children who had HbA 1C within three to six months of the data collection were recruited. Results A total of 106 children with TIDM who were on conventional insulin therapy were included in this study. Their median age at diagnosis was nine years, 47.2% were females, and 57.5% were from urban areas. The average HbA 1c of the children was 9.7%. The majority (85.2%) of the children had poor glycemic control (>7.5%). Younger age, longer disease duration, and urban residence were found to be significant predictors of good glycemic control. Conclusions A significant majority of children with T1DM had poor glycemic control. This calls for the need to create access to intensive diabetes care by health authorities and stakeholders to prevent the long-term complications of T1DM.

Objectives Polycystic Ovary Syndrome (PCOS) is a common female endocrine disorder presenting as early as adolescence. Recent data suggest that Asians may be at increased risk. This study examines PCOS prevalence by race/ethnicity in a large, diverse population of adolescent females. Methods This retrospective study included 244,642 females (ages 13–17) with well-child visits during 2012–2018 in a Northern California healthcare system. Race/ethnicity and Asian ethnicity were classified using self-reported data. Body mass index was classified as healthy, overweight, and moderate/severe obesity. PCOS was determined by clinical diagnosis within one year of the visit. Results The overall prevalence of PCOS was 0.7% and increased substantially with weight. Among those with obesity, PCOS prevalence was 4.2, 2.9, 2.4, 2.1% in Asian/Pacific Islander (PI), Hispanic/Latina, Non-Hispanic White, Black adolescents and 7.8, 6.7, 5.7, 3.4% in South Asian, Chinese, Filipina, Native Hawaiian/PI adolescents, respectively. Compared to White adolescents, Asian/PIs had two-fold higher risk of PCOS, and Hispanic/Latinas had 1.3-fold higher risk. Compared to Chinese adolescents, South Asians had 1.7-fold higher risk, while Native Hawaiian/PIs had half the risk. Conclusions The increased burden of diagnosed PCOS in Asian/PI and Hispanic/Latina adolescents, especially those with obesity, calls for further examination and clinical surveillance of at-risk populations.

Objectives Feminizing adrenal tumors are rare in childhood. We present a case of a special category of adrenal tumor, an oncocytoma, causing isosexual peripheral precocity. Case presentation A 4-year old girl presented with breast development and menstrual bleeding over a period of 3–4 months. Her SMR staging was breast stage 4, pubic hair stage 3. Her bone age was advanced (6 year 10 months), stimulated LH 0.7 IU/L, estradiol 206 pmol/L and DHEAS >27.1 micromol/L. CT scan revealed a right adrenal mass with features of atypical adrenal adenoma. Laparoscopic adrenalectomy was done and histopathology revealed oncocytoma. Lin–Weiss–Bisceglia criteria classified it as likely benign, borne out till a 2 year follow up. Conclusions Adrenal oncocytoma can be a cause of isosexual peripheral precocity in a young girl. Recognition and correct classification of this histological variant, which is more often benign, is important for prognostication and choice of therapy after surgery.

Objectives The normal development of the pituitary gland requires multiple induction signals and transcription factors encoded by more than 30 genes, including OTX2 . OTX2 mutations have been described with eye abnormalities and variable congenital hypopituitarism, but rarely with hypopituitarism without ocular manifestations. Case presentation We report a girl with hypopituitarism associated with pituitary hypoplasia and pituitary stalk atrophy, without ocular manifestations. NGS revealed a novel heterozygous mutation in OTX2 c.426dupC:p.(Ser143Leufs*2). Conclusions Mutations in the transcription factor OTX2 have been associated with ocular, craniofacial, and pituitary development anomalies. Here we describe a novel mutation in OTX2 associated with hypopituitarism without an ocular phenotype.

Objectives Wilm’s Tumor (WT) is the most common pediatric kidney cancer. Whereas most WTs are isolated, approximately 5% are associated with syndromes such as Denys-Drash (DDS), characterized by early onset nephropathy, disorders of sex development and predisposition to WT. Case presentation A 46,XY patient presenting with bilateral WT and genital ambiguity without nephropathy was heterozygous for the novel c.851_854dup variant in WT1 gene sequence. This variant affects the protein generating the frameshift p.(Ser285Argfs*14) that disrupts a nuclear localization signal (NLS) region. Conclusions This molecular finding is compatible with the severe scenario regarding the Wilm’s tumor presented by the patient even though nephropathy was absent.

Objectives Arthrogryposis multiplex congenita-5 (AMC5) is an autosomal recessive disease caused by homozygous or compound heterozygous mutations in the TOR1A gene on chromosome 9q34. Congenital multiple joint contractures with microcephaly, typical facial dysmorphism, developmental delay, strabismus, tremor, and increased tone are the main characteristics defined in seven patients thus far. One third of the individuals with monoallelic mutations of the gene develop isolated early-onset dystonia (DYT1 dystonia), which is inherited in an autosomal dominant fashion, with variable expressivity and incomplete penetrance. We believe that different inheritance patterns of the same gene resulting in different phenotypes will provide an opportunity to understand other similar disease groups and different aspects of gene functions. Case presentation We present a case with severe arthrogryposis multiplex congenita, respiratory failure, and feeding difficulties, with additional hitherto unreported symptoms, such as spontaneous bone fracture, sliding esophageal hernia, and uterine prolapse. The patient carried a novel homozygous variant (c.835delA, p.Lys275Asnfs*3) in the TOR1A gene (NM_000113.2). Conclusions We want to contribute to the phenotypic and genotypic spectra of this extremely rare disease.