Natural history of Wolcott-Rallison syndrome: A systematic review and follow-up study.

BACKGROUND AND AIMS: To systematically review the literature for reports on Wolcott-Rallison syndrome, focusing on the spectrum and natural history, genotype-phenotype correlations, patient and native liver survival, and long-term outcomes. METHODS: PubMed, Livio, Google Scholar, Scopus and Web of Science databases were searched. Data on genotype, phenotype, therapy, cause of death and follow-up were extracted. Survival and correlation analyses were performed. RESULTS: Sixty-two studies with 159 patients met the inclusion criteria and additional 30 WRS individuals were collected by personal contact. The median age of presentation was 2.5 months (IQR 2) and of death was 36 months (IQR 50.75). The most frequent clinical feature was neonatal diabetes in all patients, followed by liver impairment in 73%, impaired growth in 72%, skeletal abnormalities in 59.8%, the nervous system in 37.6%, the kidney in 35.4%, insufficient haematopoiesis in 34.4%, hypothyroidism in 14.8% and exocrine pancreas insufficiency in 10.6%. Episodes of acute liver failure were frequently reported. Liver transplantation was performed in six, combined liver-pancreas in one and combined liver-pancreas-kidney transplantation in two individuals. Patient survival was significantly better in the transplant cohort (p = .0057). One-, five- and ten-year patient survival rates were 89.4%, 65.5% and 53.1%, respectively. Liver failure was reported as the leading cause of death in 17.9% of cases. Overall survival was better in individuals with missense mutations (p = .013). CONCLUSION: Wolcott-Rallison syndrome has variable clinical courses. Overall survival is better in individuals with missense mutations. Liver- or multi-organ transplantation is a feasible treatment option to improve survival.

A Specific CNOT1 Mutation Results in a Novel Syndrome of Pancreatic Agenesis and Holoprosencephaly through Impaired Pancreatic and Neurological Development.

We report a recurrent CNOT1 de novo missense mutation, GenBank: NM_016284.4; c.1603C>T (p.Arg535Cys), resulting in a syndrome of pancreatic agenesis and abnormal forebrain development in three individuals and a similar phenotype in mice. CNOT1 is a transcriptional repressor that has been suggested as being critical for maintaining embryonic stem cells in a pluripotent state. These findings suggest that CNOT1 plays a critical role in pancreatic and neurological development and describe a novel genetic syndrome of pancreatic agenesis and holoprosencephaly.

A randomized clinical trial of the efficacy and safety of sitagliptin as initial oral therapy in youth with type 2 diabetes.

OBJECTIVE: To assess the efficacy and safety of DPP-4 inhibition with sitagliptin in youth with type 2 diabetes (T2D). STUDY DESIGN: This was a 54-week, double-blind, randomized, controlled clinical trial evaluating the safety and efficacy of DPP-4 inhibition with sitagliptin 100 mg once daily as initial oral therapy in youth with T2D. The 190 participants, aged 10-17 years, had HbA1c 6.5%-10% (7.0%-10% if on insulin). All were negative for pancreatic autoantibodies and overweight/obese at screening or diagnosis. The trial was placebo controlled for the first 20 weeks, after which metformin replaced placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 20. RESULTS: Treatment groups were well balanced at baseline (mean ± SD HbA1c = 7.5% ± 1.0, BMI percentile = 97.1% ± 6.8, age = 14.0 years ± 2.0 [57.4% <15], 60.5% female). At Week 20, least squares mean changes from baseline in HbA1c were -0.01% (sitagliptin) and 0.18% (placebo); between-group difference (95% CI) = -0.19% (-0.68, 0.30), p = 0.448. At Week 54, the changes in HbA1c were 0.45% (sitagliptin) and -0.11 (placebo/metformin). There were no notable between-group differences in the adverse event profiles through Week 54. CONCLUSIONS: DPP-4 inhibition with sitagliptin did not provide significant improvement in glycemic control. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01485614; EudraCT: 2011-002528-42).

Efficacy and safety of the addition of sitagliptin to treatment of youth with type 2 diabetes and inadequate glycemic control on metformin without or with insulin.

OBJECTIVE: To assess the efficacy and safety of sitagliptin in youth with type 2 diabetes (T2D) inadequately controlled with metformin ± insulin. STUDY DESIGN: Data were pooled from two 54-week, double-blind, randomized, placebo-controlled studies of sitagliptin 100 mg daily or placebo added onto treatment of 10- to 17-year-old youth with T2D and inadequate glycemic control on metformin ± insulin. Participants (N = 220 randomized and treated) had HbA1c 6.5%-10% (7.0%-10% if on insulin), were overweight/obese at screening or diagnosis and negative for pancreatic autoantibodies. The primary endpoint was change from baseline in HbA1c at Week 20. RESULTS: Treatment groups were well balanced at baseline (mean HbA1c = 8.0%, BMI = 30.9 kg/m2 , age = 14.4 years [44.5% <15], 65.9% female). The dose of background metformin was >1500 mg/day for 71.8% of participants; 15.0% of participants were on insulin therapy. At Week 20, LS mean changes from baseline (95% CI) in HbA1c for sitagliptin/metformin and placebo/metformin were -0.58% (-0.94, -0.22) and -0.09% (-0.43, 0.26), respectively; difference = -0.49% (-0.90, -0.09), p = 0.018; at Week 54 the LS mean (95% CI) changes were 0.35% (-0.48, 1.19) and 0.73% (-0.08, 1.54), respectively. No meaningful differences between the adverse event profiles of the treatment groups emerged through Week 54. CONCLUSIONS: These results do not suggest that addition of sitagliptin to metformin provides durable improvement in glycemic control in youth with T2D. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01472367, NCT01760447; EudraCT: 2011-002529-23/2014-003583-20, 2012-004035-23).

Short stature with low insulin-like growth factor 1 availability due to pregnancy-associated plasma protein A2 deficiency in a Saudi family.

In 2016 a new syndrome with postnatal short stature and low IGF1 bioavailability caused by biallelic loss-of-function mutations in the gene encoding the metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) was described in two families. Here we report two siblings of a third family from Saudi Arabia with postnatal growth retardation and decreased IGF1 availability due to a new homozygous nonsense mutation (p.Glu886* in exon 7) in PAPPA2. The two affected males showed progressively severe short stature starting around 8 years of age, moderate microcephaly, decreased bone mineral density, and high circulating levels of total IGF1, IGFBP3, and the IGF acid-labile subunit (IGFALS), with decreased free IGF1 concentrations. Interestingly, circulating IGF2 and IGFBP5 were not increased. An increase in growth velocity and height was seen in the prepuberal patient in response to rhIGF1. These patients contribute to the confirmation of the clinical picture associated with PAPP-A2 deficiency and that the PAPPA2 gene should be studied in all patients with short stature with this characteristic phenotype. Hence, pediatric endocrinologists should measure circulating PAPP-A2 levels in the study of short stature as very low or undetectable levels of this protein can help to focus the diagnosis and treatment.

Glucose management for exercise using continuous glucose monitoring (CGM) and intermittently scanned CGM (isCGM) systems in type 1 diabetes: position statement of the European Association for the Study of Diabetes (EASD) and of the International Society for Pediatric and Adolescent Diabetes (ISPAD) endorsed by JDRF and supported by the American Diabetes Association (ADA).

Physical exercise is an important component in the management of type 1 diabetes across the lifespan. Yet, acute exercise increases the risk of dysglycaemia, and the direction of glycaemic excursions depends, to some extent, on the intensity and duration of the type of exercise. Understandably, fear of hypoglycaemia is one of the strongest barriers to incorporating exercise into daily life. Risk of hypoglycaemia during and after exercise can be lowered when insulin-dose adjustments are made and/or additional carbohydrates are consumed. Glycaemic management during exercise has been made easier with continuous glucose monitoring (CGM) and intermittently scanned continuous glucose monitoring (isCGM) systems; however, because of the complexity of CGM and isCGM systems, both individuals with type 1 diabetes and their healthcare professionals may struggle with the interpretation of given information to maximise the technological potential for effective use around exercise (i.e. before, during and after). This position statement highlights the recent advancements in CGM and isCGM technology, with a focus on the evidence base for their efficacy to sense glucose around exercise and adaptations in the use of these emerging tools, and updates the guidance for exercise in adults, children and adolescents with type 1 diabetes. Graphical abstract.

Glucose management for exercise using continuous glucose monitoring (CGM) and intermittently scanned CGM (isCGM) systems in type 1 diabetes: position statement of the European Association for the Study of Diabetes (EASD) and of the International Society for Pediatric and Adolescent Diabetes (ISPAD) endorsed by JDRF and supported by the American Diabetes Association (ADA).

Physical exercise is an important component in the management of type 1 diabetes across the lifespan. Yet, acute exercise increases the risk of dysglycaemia, and the direction of glycaemic excursions depends, to some extent, on the intensity and duration of the type of exercise. Understandably, fear of hypoglycaemia is one of the strongest barriers to incorporating exercise into daily life. Risk of hypoglycaemia during and after exercise can be lowered when insulin-dose adjustments are made and/or additional carbohydrates are consumed. Glycaemic management during exercise has been made easier with continuous glucose monitoring (CGM) and intermittently scanned continuous glucose monitoring (isCGM) systems; however, because of the complexity of CGM and isCGM systems, both individuals with type 1 diabetes and their healthcare professionals may struggle with the interpretation of given information to maximise the technological potential for effective use around exercise (ie, before, during and after). This position statement highlights the recent advancements in CGM and isCGM technology, with a focus on the evidence base for their efficacy to sense glucose around exercise and adaptations in the use of these emerging tools, and updates the guidance for exercise in adults, children and adolescents with type 1 diabetes.

Acidosis and Deafness in Patients with Recessive Mutations in FOXI1.

Maintenance of the composition of inner ear fluid and regulation of electrolytes and acid-base homeostasis in the collecting duct system of the kidney require an overlapping set of membrane transport proteins regulated by the forkhead transcription factor FOXI1. In two unrelated consanguineous families, we identified three patients with novel homozygous missense mutations in FOXI1 (p.L146F and p.R213P) predicted to affect the highly conserved DNA binding domain. Patients presented with early-onset sensorineural deafness and distal renal tubular acidosis. In cultured cells, the mutations reduced the DNA binding affinity of FOXI1, which hence, failed to adequately activate genes crucial for normal inner ear function and acid-base regulation in the kidney. A substantial proportion of patients with a clinical diagnosis of inherited distal renal tubular acidosis has no identified causative mutations in currently known disease genes. Our data suggest that recessive mutations in FOXI1 can explain the disease in a subset of these patients.

Ramadan fasting in children.

Fasting during Ramadan is obligatory for all able bodiedadult Muslims. Though children are exempt from fasting, many children (and their parents) do observe the Ramadan fast. Responsible diabetes care professionals are expected to offer appropriate and pragmatic advice to children in their care. This communication describes the physiology of fasting in children, and assists physicians in sharing medically accurate information with them. Counselling regarding fasting must be made an integral part of diabetes care in Ramadan-observing families.

Paediatric insulin injection technique: The softer side.

This communication highlights the unique features of insulin injection technique in the paediatric age group. It describes the anatomical, neurodevelopmental and psychosocial characteristics of children and adolescents of various age groups. These are correlated to highlight 'best practices' or 'injection manner' which diabetes care providers and care givers should observe, in order to achieve a 'happy' and healthy insulin injection experience for the child. The softer side of paediatric insulin injection technique adds to existing guidelines on insulin delivery. It encourages research on the special needs and challenges of children and adolescents living with diabetes.

Genetic characteristics, clinical spectrum, and incidence of neonatal diabetes in the Emirate of AbuDhabi, United Arab Emirates.

Neonatal diabetes mellitus (NDM) can be transient (TNDM) or permanent (PNDM). Data on NDM from the Gulf region are limited to few studies on PNDM.The objective of this study was to describe the genetic and clinical spectrum of NDM and estimate its incidence in AbuDhabi, capital of the United Arab Emirate (UAE). Patients were identified from the pediatric diabetes clinics and sequencing of known NDM genes was conducted in all families. Twenty-five patients were identified. Incidence during 1985-2013 was 1:29,241 Live births. Twenty-three out of twenty-five had PNDM (incidence 1:31,900) and 2/25 had TNDM (incidence 1:350,903). Eleven out of twenty-five had extra-pancreatic features and three had pancreatic aplasia. The genetic cause was detected in 21/25 (84%). Of the PNDM patients, nine had recessive EIF2AK3 mutations, six had homozygous INS mutations, two with deletion of the PTF1A enhancer, one was heterozygous for KCNJ11 mutation, one harboured a novel ABCC8 variant, and 4/21 without mutations in all known PNDM genes. One TNDM patient had a 6q24 methylation defect and another was homozygous for the INS c-331C>G mutation. This mutation also caused permanent diabetes with variable age of onset from birth to 18 years. The parents of a child with Wolcott-Rallison syndrome had a healthy girl following pre-implantation genetic diagnosis. The child with KCNJ11 mutation was successfully switched from insulin to oral sulphonylurea. The incidence of PNDM in Abu Dhabi is among the highest in the world and its spectrum is different from Europe and USA. In our cohort, genetic testing has significant implications for the clinical management.

National growth charts for United Arab Emirates children with Down syndrome from birth to 15 years of age.

BACKGROUND: Specific centile growth charts for children with Down syndrome (DS) have been produced in many countries and are known to differ from those of normal children. Since growth assessment depends on the growth pattern characteristic for these conditions, disorder-specific charts are desirable for various ethnic groups. AIMS: To provide cross-sectional weight, height, and head circumference (HC) references for healthy United Arab Emirates (UAE) children with DS. METHODS: A retrospective and cross-sectional growth study of Emirati children with DS, aged 0 to 18 years old, was conducted. Height, weight, and HC were measured in each child. Cole's LMS statistical method was applied to estimate age-specific percentiles, and measurements were compared to UAE reference values for normal children. RESULTS: Incidence of DS in the UAE population is 1 in 374 live births (267 in 10 000 live births). We analyzed 1263 growth examinations of 182 children with DS born between 1994 and 2012. The male-to-female ratio was 1.6:1. Height, weight, and HC centile charts were constructed for ages 0 to 13 years. The prevalence of overweight and obesity in DS children aged 10 to 13 years of age was 32% and 19%, respectively. The DS children were significantly shorter and heavier than normal children in the UAE. CONCLUSIONS: Weight, height, and HC growth charts were created for children with DS. These can be used as a reference standard for the UAE children with DS. Overweight and obesity are quite common in DS children ≥ 10 years of age, as DS children tend to be shorter and heavier than non-DS children.

Neonatal diabetes mellitus around the world: Update 2024.

Neonatal diabetes mellitus (NDM), defined as diabetes with an onset during the first 6 months of life, is a rare form of monogenic diabetes. The initial publications on this condition began appearing in the second half of the 1990s and quite surprisingly, the search for new NDM genes is still ongoing with great vigor. Between 2018 and early 2024, six brand new NDM-genes have been discovered (CNOT1, FICD, ONECUT1, PDIA6, YIPF5, ZNF808) and three genes known to cause different diseases were identified as NDM-genes (EIF2B1, NARS2, KCNMA1). In addition, NDM cases carrying mutations in three other genes known to give rise to diabetes during childhood have been also identified (AGPAT2, BSCL2, PIK3R1). As a consequence, the list of NDM genes now exceeds 40. This genetic heterogeneity translates into many different mechanism(s) of disease that are being investigated with state-of-the-art methodologies, such as induced pluripotent stem cells (iPSC) and human embryonic stem cells (hESC) manipulated with the CRISPR technique of genome editing. This diversity in genetic causes and the pathophysiology of diabetes dictate the need for a variety of therapeutic approaches. The aim of this paper is to provide an overview on recent achievements in all aspects of this area of research.

The clinical and genetic diversity of thyroid hormone resistance: four clinical vignettes.

INTRODUCTION: Resistance to thyroid hormones (RTH) is a rare but an important genetic cause of decreased peripheral tissue responses to the actions of thyroxine. Most RTH cases are caused by mutations in thyroid hormone receptor ß (TRß, THRB), while a few are caused by mutations in thyroid hormone receptor α (TRα, THRA). RTH is clinically heterogeneous, and the biochemical features are often confusing, resulting in misdiagnoses, mismanagement, and life-long consequences for affected individuals. An awareness of the clinical and genetic spectrum of RTH is therefore essential to avoid misdiagnosis and to ensure timely referral for definitive management. CASE PRESENTATION: Here we present four clinical vignettes describing three children and one adult with RTH encountered in our "real-world" tertiary pediatric endocrinology practice. We describe a novel THRA (NM_199334.3:c.-298+5G>A) missense mutation in the first intron in the 5' untranslated region (UTR) of THRA, with causal variant prediction with CADD placing the mutation in the top 1% most deleterious variants (scaled C-score 21.7). We speculate that this mutation causes an exon skipping event affecting the 5'UTR and protein-coding region, thereby resulting in abnormal or absent TRα1, although supporting clinical, genetic, and/or functional analyses are required to upgrade the pathogenicity classification from uncertain significance to pathogenic/likely pathogenic. The three cases describing "classical" RTH caused by THRB mutations showcase the consequences of misdiagnosis, with two patients prescribed medications that could exacerbate symptoms and one child presenting with behavioral problems that might benefit from tailored management with hormone therapies. CONCLUSION: This report not only highlights the importance of a high index of suspicion for RTH to prompt the genetic diagnosis but also contributes to a growing appreciation of the pathogenic role of non-coding variants in rare diseases.

Lessons learned from the real-world diagnosis and management of hereditary hypophosphatemic rickets.

Hypophosphatemic rickets, which is often hereditary, is still under- or misdiagnosed in both children and adults, denying these individuals access to optimal management and genetic counseling. There have been recent calls to compile real-world data and share best practice on these rare conditions to guide clinical decision-making. Here we present eight clinical vignettes of patients with hypophosphatemic rickets encountered in our tertiary pediatric endocrinology practice. We describe the clinical features, genetics, and management of four cases of X-linked hypophosphatemia (PHEX mutations), one each of autosomal recessive hypophosphatemic rickets (DMP1 mutation) and autosomal recessive vitamin D-dependent rickets type 1A (CYP27B1 mutation), and two cases of distal renal tubular acidosis with FOXI1 mutation-associated hypophosphatemic rickets. Our cases prompt consideration of the (i) frequent misdiagnosis of hypophosphatemic rickets in clinical practice and the importance of comprehensive genetic testing; (ii) variable expressivity of the causative mutations; and (iii) a lack of responsiveness and/or compliance to conventional therapy and the value of burosumab in modern management, provided access is equitable. These cases highlight common real-world themes and challenges to managing patients presenting with these diverse conditions, especially the burden of disease hidden by misdiagnosis. In sharing these cases, we hope to raise awareness of these conditions, promote best practice in genetic diagnosis and management, and further advocate for reimbursement equity for the best available therapies.

Dental caries in children and adolescents with poorly-controlled diabetes: a case-control study.

The relationship between diabetes and dental caries remains uncertain. The main objective of this study was to quantify dental caries in children and adolescents with and without poorly-controlled diabetes to examine whether poorly-controlled diabetes influences caries prevalence and severity. This was a case-control study of children and adolescents with poorly-controlled diabetes and age-matched controls attending paediatric clinics at Sheikh Shakhbout Medical City, Abu Dhabi, UAE in August 2022. Dental caries was diagnosed by visual examination and dental probing to derive total number of decayed, missing, and filled tooth or surface (DMFT/DMFS) indices. Differences in caries metrics between subjects with diabetes and controls were assessed using chi-squared or Mann Whitney U-tests. Fifty-seven children and adolescents without diabetes and 42 with poorly-controlled (HbA1c ≥ 7.5) diabetes were recruited. The median (interquartile range, IQR) DMFT index was 4 (5) and the DMFS index was 4 (11). There were no significant differences in DMFT % [14.0 (21.5) vs.13.0 (20.0); p = 0.602], DMFT index [4 (5) vs. 3 (6); p = 0.749], nor DMFS index [5 (12) vs. 4 (11); p = 0.484] between patients and controls. Diabetes either has no effect on caries risk or its effect is so small that it is masked by dominant risk factors such as diet and obesity that require addressing through robust public health measures. While poor glycaemic control does not appear to influence caries risk, diet and obesity remain serious and addressable risk factors affecting oral health.

Characteristics of adolescents referred for bariatric surgery in Abu Dhabi, United Arab Emirates.

About a third of children and adolescents are overweight or obese in the United Arab Emirates, and referrals for metabolic and bariatric surgery (MBS) are now common. Despite excellent evidence that MBS should be considered in adolescents with severe obesity, it remains a management approach of last resort in many cases. Baseline, real-world data on adolescent patients living with obesity referred for surgery, their characteristics, and how these relate to current and future referral policy are important to ensure best practice. Here we examined the demographic, anthropometric, and clinical characteristics of adolescents referred for MBS over a three-year period to Sheikh Shakhbout Medical City (SSMC), Abu Dhabi, UAE. Ninety-two adolescents living with obesity were recruited: 54.3% were female, the average age was 16.3 ± 2.4 years, and 88.0% of patients had a first-degree relative with a history of obesity and 62% a family history of bariatric surgery. The average BMI was 47.7 ± 10.5, and the average percentage of the 95th percentile BMI was 169.5 ± 38.8%. Complications of obesity (hypertension, type 2 diabetes and prediabetes, dyslipidemia, and liver function abnormalities) were common. Our analysis highlights that there exists a mismatch between the profiles of patients referred for MBS, local guidelines, and international best practice in decision-making for referral to MBS services. While many adolescents in the UAE seem to enjoy family support and experience in the surgical management of obesity, local guidelines need updating to reflect changes in the definitions of obesity, thresholds for referral, and to remove unnecessary developmental stage barriers to increase the window for personalized surgical management.