Semaglutide, A Long-Acting GLP-1 Analogue, for the Management of Early Onset Obesity due to MC4R defect - A Case Report.

INTRODUCTION: Childhood obesity is a global concern and has both nutritional and genetic causative factors. One of the most common monogenic causes of obesity is heterozygous mutations in the Melanocortin 4 receptor (MC4R), which are found in 5.7% to 8.6% of individuals with early-onset obesity. We report, the effect of Semaglutide, a long-acting Glucagon like peptide (GLP1) analogue, in the treatment of severe obesity in an adolescent boy with a heterozygous mutation in MC4R. CASE PRESENTATION: A 13-year-old boy with a history of excessive weight gain since infancy was referred to the specialised weight management team. He was born at full-term with a birth weight of 3.57kg (50th centile), but his weight consistently exceeded the 99.6th percentile after the age of one year. At the age of five years, he was diagnosed with autism spectrum disorder (ASD). Diagnostic investigations revealed insulin resistance, and dyslipidaemia, while genetic testing confirmed a heterozygous mutation in MC4R (E61K), inherited from his mother. Managing his condition was challenging due to his rapid weight gain, needle phobia, and behavioural difficulties. Despite intense multidisciplinary lifestyle interventions, he continued to gain weight, reaching a peak weight of 187.5kg [+16.65 standard deviation score (SDS)], body mass index (BMI) of 56.9kg/m2 (+4.19 SDS), body fat 63.9%] at the age of 13 years. Due to severe ASD and needle phobia, he was not keen on daily GLP-1 injections. He was commenced on Semaglutide subcutaneous injection at a dose of 0.25mg weekly, gradually increasing to the maximum dose of 1mg weekly. Over the course of 12 weeks, his BMI decreased to 52.2kg/m2 (+4.08SDS) and weight dropped to 176.8kg (+14.76SDS, body fat: 52.7%). At the 3-month and 12-month reviews post treatment, he achieved weight loss of 5.7% and 11% respectively. Quality of life questionnaire (QoL) showed improved scores from 35.95 to 60.36 at 12-month review indicating enhanced well-being. The CGM (continuous glucose monitor) demonstrated an improvement in TIR (time in range). CONCLUSION: Semaglutide, is approved by the FDA for weight management in adolescents aged 12 years and above in December 2022. A recent case series underscored the benefits of therapy with Liraglutide, a short-acting GLP-1 analogue, in rare genetic cases of early-onset obesity. To our knowledge, this is the first case report to highlight the efficacy and safety of Semaglutide in an adolescent with heterozygous MC4R mutation. Semaglutide could be a potential treatment option for monogenic obesity and will benefit from further research.

Burosumab Therapy in a Paediatric Patient with McCune-Albright Syndrome: A Case Report.

INTRODUCTION: McCune-Albright syndrome is characterized by the triad of fibrous dysplasia, café au lait skin pigmentation, and hyperfunctioning endocrinopathies. It is a sporadic condition caused by a missense mutation in the GNAS locus, located on chromosome 20q13.3, resulting in mosaic activation of the G protein alpha subunit. CASE PRESENTATION: We pre­sent a paediatric patient diagnosed with McCune-Albright syndrome at the age of 5 years. During the course of his condition, he was medically managed for a number of complications, such as peripheral precocious puberty and growth hormone excess, and monitored for hyperprolactinaemia. Due to fibroblast growth factor 23-mediated phosphate wasting, the patient was commenced on oral phosphate supplements and alfacalcidol. After 2 years of treatment, this therapy did not optimize his bone biochemistry (phosphate 0.96 mmol/L, alkaline phosphatase 1,172 IU/L, and parathyroid hormone 9.1 pmol/L), and the patient was started on two-weekly burosumab therapy via subcutaneous injection. His bone biochemistry soon normalized (phosphate 1.52 mmol/L, alkaline phosphatase 358 IU/L, and parathyroid hormone 6.9 pmol/L) following this, and he remains on burosumab without any adverse effects. DISCUSSION: This case shows the positive effect that a short-term course of burosumab has on bone health in a paediatric patient with McCune-Albright syndrome. Further research is required to assess long-term effects. Our patient also presented with precocious puberty and growth hormone excess, a coexistence that can be challenging to diagnose and is less common in males. He received medical management for both conditions, but due to the similar presentations, this case highlights the importance to investigate and diagnose associated complications as early as possible, so they can be managed in a timely manner.

45,X male - rare case of unbalanced translocation of Y chromosome to chromosome 2 presenting with developmental delay, learning difficulty and obesity.

Summary: A male phenotype accompanied by a 45,X karyotype is rare. It may occur due to Y chromosomal translocation or insertion to X/autosome. Clinical presentation may vary depending on the presence of the Y chromosomal locus and the degree of loss of autosome material. 45,X males can present with short stature and Turner syndrome phenotype due to haploinsufficiency of genes which are normally expressed in both X and Y chromosomes. The presence of the sex-determining region Y (SRY) gene leads to the differentiation of bipotential gonads to testis. Most individuals go through puberty normally, but some may need pubertal induction for delayed puberty. Rarely some can have a pubertal arrest. The risk of gonadoblastoma is minimal in these individuals due to functioning testicular tissue. The azoospermia factor (AZF) region is found on the long arm of the Yq chromosome and is needed for spermatogenesis. In a 45,X male with unbalanced translocation of Y chromosome, spermatogenesis can be affected due to the lack of AZF leading to Sertoli cell-only syndrome. This will have an implication on fertility in adult life. We present a 14-year-old boy with developmental delay, learning difficulties and subtle dysmorphic features who was diagnosed with 45,X,der(2)t(Y:2)(?:p25). Fluorescence in situ hybridisation analysis revealed translocation of SRY (Yp11.3) to the terminal part of the short arm of chromosome 2 resulting in the deletion of most of the Y chromosome (Yp11.2-q12) and part of chromosome 2(2p25.3). This is the first case where SRY translocation to chromosome 2 presents with the above clinical presentation. Learning points: 45,X karyotype is rare in male. It may occur due to SRY translocation or an insertion to X/autosome. SRY gene translocation to chromosome 2 has been not reported in the literature. Clinical presentation can be varied due to degree of loss of chromosomal material. Due to loss of AZF region found on the long arm of the Yq, spermatogenesis can be affected. Loss of 2p25 leads to learning difficulty and obesity.

Idiopathic intracranial hypertension in children with obesity.

AIM: Obesity is an under-recognised risk factor for raised intracranial pressure in the paediatric population. The pathophysiology remains unclear. The aim of our study was to investigate the association between idiopathic intracranial hypertension (IIH) and weight in children. METHODS: Patients diagnosed with IIH at a tertiary children's hospital were retrospectively identified between April 2017 and April 2019. Information regarding the patients' body mass index, presentation, investigation and treatment was collected and analysed. RESULTS: In total, 18 patients (M:F 7:11) were identified with a mean age of 11 years (±3.3SD; range: 6-15 years). The mean BMI was 30.3 kg/m2 and mean BMI SDS was +2.5. Twelve (66.6%) patients presented with both headaches and eye signs. Three patients were asymptomatic, with papilloedema noted on routine optician review. Of the 18 patients, 15 were treated medically, two had long-term neurosurgical interventions and one patient was managed conservatively. CONCLUSION: The results show that the majority of children with obesity who develop IIH were female. Awareness regarding IIH secondary to obesity needs to be highlighted to ensure detailed clinical evaluation takes place so that raised intracranial pressure can be diagnosed and managed earlier, to avoid more serious complications such as permanent visual loss.

Childhood obesity: A review of current and future management options.

Obesity is becoming increasingly prevalent in paediatric populations worldwide. In addition to increasing prevalence, the severity of obesity is also continuing to rise. Taken together, these findings demonstrate a worrying trend and highlight one of the most significant challenges to public health. Childhood obesity affects multiple organs in the body and is associated with both significant morbidity and ultimately premature mortality. The prevalence of complications associated with obesity, including dyslipidaemia, hypertension, fatty liver disease and psychosocial complications are becoming increasingly prevalent within the paediatric populations. Treatment guidelines currently focus on intervention with lifestyle and behavioural modifications, with pharmacotherapy and surgery reserved for patients who are refractory to such treatment. Research into adult obesity has established pharmacological novel therapies, which have been approved and established in clinical practice; however, the research and implementation of such therapies in paediatric populations have been lagging behind. Despite the relative lack of widespread research in comparison to the adult population, newer therapies are being trialled, which should allow a greater availability of treatment options for childhood obesity in the future. This review summarizes the current evidence for the management of obesity in terms of medical and surgical options. Both future therapeutic agents and those which cause weight loss but have an alternative indication are also included and discussed as part of the review. The review summarizes the most recent research for each intervention and demonstrates the potential efficacy and limitations of each treatment option.

Liraglutide combined with intense lifestyle modification in the management of obesity in adolescents.

OBJECTIVES: Childhood obesity is a public health concern worldwide, with rates continuing to rise, despite preventive measures. Lifestyle modification remains the mainstay in the treatment of patients with excessive weight, but unfortunately, this is not always successful. Options for medical management of obesity in the paediatric population are limited. METHODS: Seven adolescents (all girls, mean age 14.9 years) with a body mass index (BMI) above 98th percentile and serious complications secondary to obesity were offered an intense weight management programme. The participants were reviewed by a multidisciplinary team every two weeks for advice and support, and treated with daily subcutaneous injections of liraglutide (dose range 1.2-3.0 mg). Scores for anxiety and depression were evaluated using the Revised Child Anxiety and Depression Scale. RESULTS: The results showed a significant weight loss over the three months with an average reduction of 5.4 kg (4.2%; 95% CI 1.93-8.78; p=0.0087). The mean drop in BMI was 2.1 kg/m2, which is statistically significant (95% CI 0.973-3.199; p=0.0037). Resolution of complications (raised intracranial pressure and steatohepatitis) was noted following weight loss. Anxiety and depressive symptoms improved over the three-month intervention course, especially features of separation anxiety disorder. Liraglutide was well tolerated by all patients. CONCLUSIONS: Liraglutide medication, alongside a dedicated multidisciplinary team guided lifestyle therapy, is effective and safe in the treatment for excessive weight in adolescents, leading to the reversal of the complications related to obesity and improvement in the psychological symptoms.

Posaconazole-Induced Hypertension Masquerading as Congenital Adrenal Hyperplasia in a Child with Cystic Fibrosis.

BACKGROUND: Deficiency of 11ß-hydroxylase is the second most common cause of congenital adrenal hyperplasia (CAH), presenting with hypertension, hypokalaemia, precocious puberty, and adrenal insufficiency. We report the case of a 6-year-old boy with cystic fibrosis (CF) found to have hypertension and cortisol insufficiency, which were initially suspected to be due to CAH, but were subsequently identified as being secondary to posaconazole therapy. Case Presentation. A 6-year-old boy with CF was noted to have developed hypertension after administration of two doses of Orkambi™ (ivacaftor/lumacaftor), which was subsequently discontinued, but the hypertension persisted. Further investigations, including echocardiogram, abdominal Doppler, thyroid function, and urinary catecholamine levels, were normal. A urine steroid profile analysis raised the possibility of CAH due to 11ß-hydroxylase deficiency, and a standard short synacthen test (SST) revealed suboptimal cortisol response. Clinically, there were no features of androgen excess. Detailed evaluation of the medical history revealed exposure to posaconazole for more than 2 months, and the hypertension had been noted to develop two weeks after the initiation of posaconazole. Hence, posaconazole was discontinued, following which the blood pressure, cortisol response to the SST, and urine steroid profile were normalized. CONCLUSION: Posaconazole can induce a clinical and biochemical picture similar to CAH due to 11ß-hydroxylase deficiency, which is reversible. It is prudent to monitor patients on posaconazole for cortisol insufficiency, hypertension, and electrolyte abnormalities.

Vaginal Bleeding in Pre-pubertal Females.

STUDY OBJECTIVE: Puberty is a normal process for adolescents, and the first signs may include change in body odor, breast development, or pubic hair growth. This is then followed by menarche approximately 2 years later. Vaginal bleeding in pre-pubertal female individuals is rare. The aim of this study was to investigate causes of pre-pubertal bleeding in a group of patients. DESIGN, SETTING, METHOD, AND MAIN OUTCOME MEASURES: Seventeen patients who presented with pre-pubertal recurrent vaginal bleeding with no other signs of precocious puberty were investigated, to determine the cause of this symptom. RESULTS: The mean age for the onset of vaginal bleeding was 7.4 years, ranging from 4 to 9.67 years. Gonadotrophin-releasing hormone (GnRH) stimulation tests showed a pre-pubertal response in all cases. Pelvic ultrasound scans showed a pre-pubertal uterus in all patients. Two patients were found to have foreign bodies identified during a genital examination under anesthetic, and in both cases removal of the foreign bodies terminated the vaginal bleeding. CONCLUSION: In conclusion, recurrent vaginal bleeding was not associated with GnRH response, raised estradiol levels, or abnormal pelvic ultrasound findings. In cases of recurrent vaginal bleeding with normal hormonal investigations in pre-pubertal girls, it is recommended that a genital examination under anesthetic be undertaken to rule out undiagnosed causes of the presenting symptom.

Effect of Growth Hormone Therapy in Patients with Noonan Syndrome: A Retrospective Study.

BACKGROUND: Noonan syndrome is an autosomal dominant condition with an incidence of 1:1000 to 1:2500. The disorder is associated with distinct dysmorphic features, cardiac anomalies, developmental delay and delayed puberty. Short stature is a recognised feature of Noonan syndrome. OBJECTIVES: The aim of this study is to assess the effect of growth hormone treatment in patients with Noonan syndrome. METHODS: Retrospective data was collected from patients with Noonan syndrome treated with growth hormone. The results were analysed with variables expressed as mean values and standard deviation scores. RESULTS: Twelve Noonan syndrome patients (M: F = 10:2) treated with growth hormone were identified. The mean age of starting growth hormone was 8 years, with baseline height standard deviation score of -2.96 (range: -1.64 to -5.54). The height standard deviation score significantly improved to -2.50 (P = 0.0035) and then -2.22 (P = 0.0025), following one and two years of treatment, respectively. The average height velocity for the patients prior to starting treatment was 5.16cm/year (range: 2.4 - 8.2 cm/year), which significantly improved to 7.76cm/year (ranging from 4.1 to 12.8 cm/year) after one year of growth hormone treatment (P = 0.020) and to 6.51cm/year at the end of two years. CONCLUSIONS: Our study has shown that growth hormone treatment significantly improves the height standard deviation score of patients with Noonan syndrome over a two-year course of growth hormone therapy without any side effects. Further research is required to analyse the long-term effect of growth hormone therapy in patients with Noonan syndrome, including the impact on final adult height.

A rare case of congenital hyperinsulinism (CHI) due to dual genetic aetiology involving HNF4A and ABCC8.

Background Congenital hyperinsulinism (CHI) occurs due to an unregulated insulin secretion from the pancreatic ß-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.

Increased insulin requirement may contribute to risk of obesity in children and young people with Type 1 Diabetes Mellitus.

INTRODUCTION: Type 1 diabetes mellitus (T1DM) is an autoimmune disorder that interferes with the function of the beta cells in the pancreas. Reports show that the incidence of T1DM is increasing throughout England and Wales, along with the Body Mass Index (BMI) of this patient group. The association between type 2 diabetes mellitus (T2DM) and obesity is recognised, but literature describing the association between T1DM and high BMI is more limited. The aim of this paper is to identify factors affecting BMI and the impact that this increasing trend has on children and young people with T1DM. METHODS: Information was obtained from the medical records of patients with T1DM at the local paediatric centre. BMI standard deviation scores (SDS) were calculated and compared to other factors, which include insulin requirement, HbA1c, pubertal status and age at diagnosis. RESULTS: This study involved 102 patients (43 male and 59 female). The mean age at diagnosis was 7.79 years (range from 0.16 to 16.91 years). Our results showed a significant association between insulin requirement and BMI SDS (r = 0.23, p = 0.02) and a significant association between insulin requirement and mean HbA1c (r = 0.59, p=<0.01). A multivariable regression analysis of factors affecting BMI SDS showed that insulin requirement was an independent factor affecting BMI SDS. CONCLUSION: There were significant associations between increased insulin requirement, high BMI SDS and poorer glycaemic control. Further research is required to fully understand the risk factors that may contribute to obesity in T1DM.

Mode of clinical presentation and delayed diagnosis of Turner syndrome: a single Centre UK study.

BACKGROUND: Early diagnosis of girls with Turner syndrome (TS) is essential to provide timely intervention and support. The screening guidelines for TS suggest karyotype evaluation in patients presenting with short stature, webbed neck, lymphoedema, coarctation of aorta or ≥ two dysmorphic features. The aim of the study was to determine the age and clinical features at the time of presentation and to identify potential delays in diagnosis of TS. METHODS: Retrospective data on age at diagnosis, reason for karyotype analysis and presenting clinical features was collected from the medical records of 67 girls with TS. RESULTS: The mean age of diagnosis was 5.89 (±5.3) years ranging from pre-natal to 17.9 years (median 4.6 years). 10% were diagnosed antenatally, 16% in infancy, 54% in childhood (1-12 years) and 20% in adolescence (12-18 years). Lymphoedema (27.3%) and dysmorphic features (27.3%) were the main signs that triggered screening in infancy. Short stature was the commonest presenting feature in both childhood (52.8%) and adolescent (38.5%) years. At least 12% of girls fulfilled the criteria for earlier screening but were diagnosed only at a later age (mean age = 8.78 years). 13.4% of patients had classical 45XO karyotype and 52.3% of girls had a variant karyotype. CONCLUSION: Majority of girls with TS were diagnosed only after the age of 5 years. Short stature triggered evaluation for most patients diagnosed in childhood and adolescence. Lack of dedicated community height-screening programme to identify children with short stature and lack of awareness could have led to potential delays in diagnosing TS. New strategies for earlier detection of TS are needed.

Socioeconomic Deprivation, Household Education, and Employment are Associated With Increased Hospital Admissions and Poor Glycemic Control in Children With Type 1 Diabetes Mellitus.

BACKGROUND: Socioeconomic deprivation, obesity, and emotional discomfort are important determinants of health inequalities and poor glycemic control in children and young people with type 1 diabetes mellitus (T1D). OBJECTIVES: The aims of this study were to evaluate the incidence of hospital admissions of T1D children in relation to socioeconomic deprivation, and to determine the effects of social deprivation, body mass index (BMI), and patient-reported emotional well-being on glycemic control. METHODS: All hospital admissions of T1D patients aged 1-18 years were identified during 2007 and 2012. Admission cause and glycemic control were related to social deprivation, BMI, and psychological, emotional well-being. Indices of Multiple Deprivation (IMD) 2010 were applied to the United Kingdom data. The associations were calculated using the Spearman's rank correlation coefficient. RESULTS: A significant correlation was found between hospital admission rates and overall deprivation scores (r = -0.18, p = 0.04). Patients living in deprived areas were more likely to selfpresent to the accident and emergency department (r = -0.24, p = 0.02). Poor glycemic control (n = 124) was significantly associated with lower levels of education (r = -0.22, p = 0.02) and unemployment (r = -0.19, p = 0.04). Significance was not reached for level of income (r = -0.16, p = 0.07) and overall deprivation (r = -0.17, p = 0.06). Glycemic control was not found to be associated with BMI, standard deviation scores (SDS), or emotional well-being. CONCLUSION: Early intervention and education from primary care and specialist diabetes teams within the community in deprived areas may be effective in reducing hospital admissions for diabetes-related problems and improving glycemic control.