Prevalence and factors associated with thyroid autoimmunity among children newly diagnosed with type 1 diabetes before and during the COVID-19 pandemic: Evidence from Kuwait.

AIMS: This study reports the prevalence and characteristics related to the development of thyroid autoimmunity among children newly diagnosed with type I diabetes (T1D) during the COVID-19 pandemic in Kuwait. MATERIALS AND METHODS: This is a prospective observational study of all children under age 14 years newly diagnosed with T1D in Kuwait. We define the duration of the COVID-19 pandemic from the official declaration of the first identified positive COVID-19 case on 24 February 2020 until 31 December 2022. For comparison, we use the time period directly before the COVID-19 pandemic, 1 January 2017 to 23 February 2020. RESULTS: One thousand twenty-four (1024) children newly diagnosed with T1D in Kuwait during the study period were included. Among newly diagnosed children, 20.3% tested positive for thyroid antibodies during the COVID-19 pandemic, compared with 14.5% during the pre-pandemic period (p = 0.015). Children with positive COVID-19 status were more likely to present with thyroid antibodies (p = 0.035). After adjusting for other characteristics, patients diagnosed with T1D during the COVID-19 pandemic had double the odds of testing positive for thyroid antibodies (Adjusted odds ratio = 2.173, 95%CI: 1.108, 4.261, p = 0.024). CONCLUSIONS: Incident cases of T1D during the COVID-19 pandemic may be different in aetiology or contextual factors leading to a higher risk of thyroid autoimmunity. Longitudinal studies are needed to understand the role of COVID-19 in the onset and progression of T1D and on thyroid autoimmunity and disease.

Ethnic Variations in the Levels of Bone Biomarkers (Osteoprostegerin, Receptor Activator of Nuclear Factor Kappa-Β Ligand and Glycoprotein Non-Metastatic Melanoma Protein B) in People with Type 2 Diabetes.

The global incidence of Type 2 diabetes (T2D) is on the rise, fueled by factors such as obesity, sedentary lifestyles, socio-economic factors, and ethnic backgrounds. T2D is a multifaceted condition often associated with various health complications, including adverse effects on bone health. This study aims to assess key biomarkers linked to bone health and remodeling-Osteoprotegerin (OPG), Receptor Activator of Nuclear Factor Kappa-Β Ligand (RANKL), and Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB)-among individuals with diabetes while exploring the impact of ethnicity on these biomarkers. A cross-sectional analysis was conducted on a cohort of 2083 individuals from diverse ethnic backgrounds residing in Kuwait. The results indicate significantly elevated levels of these markers in individuals with T2D compared to non-diabetic counterparts, with OPG at 826.47 (405.8) pg/mL, RANKL at 9.25 (17.3) pg/mL, and GPNMB at 21.44 (7) ng/mL versus 653.75 (231.7) pg/mL, 0.21 (9.94) pg/mL, and 18.65 (5) ng/mL in non-diabetic individuals, respectively. Notably, this elevation was consistent across Arab and Asian populations, except for lower levels of RANKL observed in Arabs with T2D. Furthermore, a positive and significant correlation between OPG and GPNMB was observed regardless of ethnicity or diabetes status, with the strongest correlation (r = 0.473, p < 0.001) found among Arab individuals with T2D. Similarly, a positive and significant correlation between GPNMB and RANKL was noted among Asian individuals with T2D (r = 0.401, p = 0.001). Interestingly, a significant inverse correlation was detected between OPG and RANKL in non-diabetic Arab individuals. These findings highlight dysregulation in bone remodeling markers among individuals with T2D and emphasize the importance of considering ethnic variations in T2D-related complications. The performance of further studies is warranted to understand the underlying mechanisms and develop interventions based on ethnicity for personalized treatment approaches.

Early autoantibody screening for type 1 diabetes: a Kuwaiti perspective on the advantages of multiplexing chemiluminescent assays.

Type 1 diabetes (T1D) incidence has increased globally over the last decades, alongside other autoimmune diseases. Early screening of individuals at risk of developing T1D is vital to facilitate appropriate interventions and improve patient outcomes. This is particularly important to avoid life-threatening diabetic ketoacidosis and hospitalization associated with T1D diagnosis. Additionally, considering that new therapies have been developed for T1D, screening the population and individuals at high risk would be of great benefit. However, adopting such screening approaches may not be feasible due to limitations, such as cost, adaptation of such programs, and sample processing. In this perspective, we explore and highlight the use of multiplexing chemiluminescent assays for T1D screening and emphasize on their advantages in detecting multiple autoantibodies simultaneously, maximizing efficiency, and minimizing sample volume requirements. These assays could be extremely valuable for pediatric populations and large-scale screening initiatives, providing a cost-efficient solution with increased diagnostic accuracy and deeper insights into T1D pathogenesis. Eventually, the adoption of such screening methods can help transform T1D diagnosis, especially in countries with high T1D prevalence, such as Kuwait, which will contribute to the development of novel therapeutic interventions, positively impacting the lives of those affected by T1D and other autoimmune diseases.

Mutational analysis of rare subtypes of congenital adrenal hyperplasia in a highly inbred population.

CONTEXT: Apart from 21 Hydroxylase deficiency, other subtypes of congenital adrenal hyperplasia (CAH) are rare. We studied the clinical features and molecular genetics of a relatively large series of patients with CYP17A1, HSD3ß2 and StAR deficiencies. PATIENTS AND METHODS: We studied 21 patients including 7 patients with CYP17A1, 10 patients with HSD3ß2 and 4 patients with StAR deficiencies. For mutation detection, we isolated DNA from peripheral leucocytes, amplified genes of interest using polymerase chain reaction and directly sequenced the amplicons using Dideoxy Chain Termination method. RESULTS: Regardless of their karyotype, patients with CYP17A1 deficiency presented with normally looking external female genitalia and were raised as females. Hypertension and hypokalemia were prominent features in 4 of 7 patients. Two missense (p.R416H, p.R239Q) and 2 non-sense (p.Y329X, p.Y329X) mutations were found in these 7 cases. In 3 unrelated families with 10 affected siblings with HSD3ß2 mutations, two non-sense mutations were found (p.Q334X, p.R335X). 46XY patients with HSD3ß2 deficiency presented with ambiguous genitalia while 46XX patients presented with normal female external genitalia. Adrenal crisis was common in patients with both karyotypes. In the 4 patients with StAR deficiency, both genetic male and female patients presented with normally looking female external genitalia and adrenal crisis. One previously reported missense mutation (p.R182H) was found in 3 unrelated patients and a novel non-sense mutation (p.Q264X) in the fourth patient. CONCLUSIONS: These cases of rare subtypes of CAH illustrate the heterogeneous phenotypic and genetic features of these subtypes and add unique novel mutations to the previously known ones.

A high rate of novel CYP11B1 mutations in Saudi Arabia.

Despite ethnic variation, 11 ß-hydroxylase deficiency (11ß-OHD) has generally been considered the second most common subtype of congenital adrenal hyperplasia (CAH). We report a high rate of novel mutations in this gene (CYP11B1) in patients from Saudi Arabia. We studied 16 patients with 11ß-OHD from 8 unrelated families. DNA was isolated from peripheral blood. The 9 exons and exon-intron boundaries of CYP11B1 were PCR-amplified and directly sequenced. The novel mutations were functionally characterized using subcloning, in vitro mutagenesis, cell transfection and 11-deoxycortisol: cortisol conversion assays. Six mutations were found in these 8 unrelated families. Three of these mutations are completely novel and two have just been recently described as novel mutations from the same population. These include a single nucleotide insertion mutation in codon 18 (c.53_54insT) leading to frameshift and truncation in 4 siblings, a novel mutation (c.1343G>C, p.R448P) in 3 unrelated families, a novel mutation (c.1394A>T, p.H465L) in 2 siblings, a novel mutation (c.617G>T, p.G206V) in 1 patient, and a recently described non-sense novel mutation (c.780G>A, p.W260X) in another patient. Out of the 6 mutations described in this report, only one mutation (p.Q356X) was reported previously. In vitro functional testing of the 3 missense and nonsense novel mutations revealed complete loss of the 11 hydroxylase activity. We conclude that 11 ß-OHD in Saudi Arabia has a unique genotype with a high rate of novel mutations. The novel p. R448P mutation is the most common mutation in this highly inbred population.

Uncommon TERT Promoter Mutations in Pediatric Thyroid Cancer.

PURPOSE: The aim of this study was to determine the rate and significance of TERT promoter mutations that have been recently described in adult thyroid cancer (TC) but not yet in the uncommonly occurring pediatric TC. Furthermore, the role of the BRAF(V600E) mutation in the clinical outcome of pediatric TC is unknown. METHOD: The study included 55 pediatric (median age 16 years, range 9-18 years; 46 females) and 210 adult TC patients (median age 40 years, range 20-75 years; 155 females) seen during the same time period. DNA was isolated from TC tissues and subjected to direct sequencing. Genetic-clinicopathological correlations were analyzed. RESULTS: Only one case of pediatric TC was found to harbor the C228T TERT promoter mutation (1.8%). The C250T mutation was not detected in any of the 55 pediatric TC. In contrast, there was a significantly higher rate of TERT promoter mutations in the adult patients (15.7%, 33/210) compared with the pediatric patients (p = 0.003). In addition, persistent/recurrent TC was seen in 8/12 (66.7%) pediatric patients harboring the BRAF(V600E) mutation versus 14/41 (34.1%) patients harboring the wild type BRAF (p = 0.05), and when only conventional papillary TC was examined, in 7/9 (77.8%) cases harboring BRAF(V600E) mutation versus 11/33 (33.3%) cases harboring wild type BRAF (p = 0.025). CONCLUSIONS: This is the first study on TERT promoter mutations in pediatric TC, which revealed an exceedingly low prevalence, suggesting a limited role of these mutations in pediatric TC. This study also for the first time demonstrates an association of the BRAF(V600E) mutation with TC recurrence in pediatric patients.

Coexistence of endocrinopathies in children with rheumatic diseases.

BACKGROUND AND OBJECTIVES: To examine the frequency of endocrinopathies in children with systemic lupus erythematosus (SLE) and juvenile idiopathic arthritis (JIA). DESIGN AND SETTING: A cross-sectional study. PATIENTS AND METHODS: A study was conducted in Saudi children with SLE and JIA who were seen at King Faisal Specialist Hospital and Research Centre, Riyadh, between September 2013 and April 2015. All enrolled patients completed the clinical evaluation, which included information about family history of autoimmune disease, growth parameters and tanner stage, as well as the following assessments: vitamin D profile (parathyroid hormone and 25-OH vitamin D levels), TSH, FT4 and total T3, thyroglobulin antibodies, thyroperoxidase antibodies, random blood sugar, HbA1C, IGF1, IGFBP-3, LH, and FSH. RESULTS: A total of 42 patients, 22 with JIA and 20 with SLE, were included in the study. The mean participant age was 12.2 ± 5.3 years with a mean disease duration of 3.2 ± 3.4 years. Female gender was predominant (17 SLE, 13 JIA) in the patient population. Fifteen patients (35.7%) presented with a family history of autoimmune disease. The most frequently detected endocrinopathies were vitamin D insufficiency (35%) and thyroid disease (31%). Eight JIA patients and 7 SLE patients exhibited low vitamin D levels; 10 patients presented with hyperparathyroidism. Thyroid dysfunction was observed in 13 patients (8 SLE, 5 JIA), and 2 patients were found to be euthyroid (normal TSH, FT4) with positive thyroid autoantibodies. Furthermore, 7 patients presented with subclinical hypothyroidism (high TSH, normal FT4), and 4 patients presented with overt hypothyroidism (high TSH, low FT4). Seven patients (4 SLE and 3 JIA) presented with short stature due to growth hormone insufficiency (low IGF1, IGFBP-3). Two patients exhibited delayed puberty accompanied by low LH levels. Diabetes mellitus was more frequently observed in patients with JIA (4 patients) than in patients with SLE (1 patient). CONCLUSION: Our findings demonstrated that coexistence of endocrinopathies is not uncommon in children diagnosed with JIA and SLE. Abnormal thyroid function occurs frequently and at a similar rate in children diagnosed with SLE and JIA. Thus, screening for endocrinopathies, namely thyroid disease, during the assessment of childhood SLE and JIA is worth consideration.