Semaglutide as a potential therapeutic alternative for HNF1B-MODY: a case study.

Maturity-onset diabetes of the young (MODY) is a grouping of monogenic disorders. It is characterized by dominantly inherited, non-insulin-dependent diabetes. MODY is relatively rare, encompassing up to 3.5% in those diagnosed under 30 years of age. Specific types are most commonly treated with sulfonylurea, particularly those identified as HNF4A-MODY and HNF1A-MODY. HNF1B-MODY is another type that is most frequently managed with insulin therapy but lacks a defined precision treatment. We present an 18-year-old, non-obese female patient diagnosed with HNF1B-MODY. She displays complete gene deletion, a renal cyst, and hypomagnesemia. Her treatment plan includes both long- and short-acting insulin, though she frequently encountered hypoglycemia and hyperglycemia. Semaglutide, a GLP-1RA, was administered weekly over 4 months. The patient's glucose level was continuously tracked using Dexcom's Continuous Glucose Monitoring system. The data suggested a notable improvement in her condition: time-in-range (TIR) increased from 70% to 88%, with some days achieving 100%, and the frequency of hypoglycemic episodes, indicated by time-below-range values, fell from 5% to 1%. The time-above-range values also dropped from 25% to 10%, and her HbA1c levels declined from 7% to 5.6%. During the semaglutide therapy, we were able to discontinue her insulin treatment. Additionally, her body mass index (BMI) was reduced from 24.1 to 20.1 kg/m2. However, the semaglutide treatment was halted after 4 months due to side effects such as nausea, vomiting, and reduced appetite. Other contributing factors included exam stress and a COVID-19 infection, which forced a switch back to insulin. Her last recorded HbA1c level under exclusive insulin therapy rose to 7.1%, and her BMI increased to 24.9 kg/m2. In conclusion, semaglutide could potentially replace insulin to improve glucose variability, TIR, and HbA1c in patients with HNF1B-MODY. However, more extensive studies are required to confirm its long-term safety and efficacy.

Modern approaches to the management of homozygous familial hypercholesterolemia in the Middle East and North Africa.

Homozygous familial hypercholesterolaemia (HoFH) is a severe form of FH in which inheritance of two defective or null mutations in genes associated with metabolism of low-density lipoprotein cholesterol (LDL-C) results in extremely high LDL-C, premature atherosclerotic cardiovascular disease (ASCVD) and mortality. Treatment of HoFH comprises a multi-modal approach of statins, ezetimibe, lipoprotein apheresis; and inhibitors of proprotein convertase subtilisin/kexin type, angiopoietin-like protein 3 (ANGPTL3) and microsomal triglyceride transfer protein. These treatments are generally costly, and patients also often require treatment for ASCVD consequent to HoFH. Therefore, in the interests of both economics and preservation of life, disease prevention via genetic screening and counselling is rapidly becoming a key element in the overall management of HoFH. Guidelines are available to assist diagnosis and treatment of HoFH; however, while advancements have been made in the management of the disease, there has been little systematic attention paid to prevention. Additionally, the Middle East/North Africa (MENA) region has a higher prevalence of HoFH than most other regions - chiefly due to consanguinity. This has led to the establishment of regional lipid clinics and awareness programs that have thrown education and awareness of HoFH into sharp focus. Incorporation of principles of prevention, education, awareness, and data from real-world use of existing therapeutics will significantly enhance the effectiveness of future guidelines for the management of HoFH, particularly in the MENA region.

Isolated Pancreatic Agenesis Secondary to PTF1A Gene Mutation: A Case Series and Literature Review.

Background Neonatal diabetes mellitus is a rare form of monogenic diabetes which is diagnosed in the first six months of life. It is often related to genetic mutations; hence, genetic testing is warranted. Here, we present six cases of pancreatic agenesis resulting in neonatal diabetes with PTF1A gene mutation. Methodology This retrospective case series study included six pediatric cases of neonatal diabetes mellitus who are currently following at pediatric endocrinology clinics at King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Results The study reported six patients with a mean age of eight years who presented with pancreatic agenesis resulting in neonatal diabetes with PTF1A gene mutation. In four patients, there was no evidence of cerebellar agenesis. Conclusions Neonatal diabetes is a challenging disease that must be diagnosed early to prevent subsequent metabolic complications. Genetic testing is recommended in neonates who present with prolonged duration of hyperglycemia. Insulin replacement is the treatment of choice.

Subclinical Neuropathy in Children With Type I Diabetes Mellitus: Tertiary Care Centre Experience.

INTRODUCTION: Diabetic peripheral neuropathy is a common complication of diabetes mellitus (DM) type 1. However, it can occur without evidence of symptoms or clinical signs of neuropathy labeled as subclinical neuropathy, which neurophysiological studies can best detect. PURPOSE: To evaluate the prevalence of subclinical neuropathy among children with DM type 1, determine the association with blood sugar control, and evaluate the pattern of nerve involvement in neurophysiological studies. METHODS: This cross-sectional study evaluated 100 children with DM type 1, aged five to 15 years, at least one year after the diagnosis. Subclinical neuropathy was evaluated using nerve conduction study. Glycemic control was assessed using hemoglobin A1c (HbA1c). RESULTS: The mean age of subjects was 11.5 ± 0.25 years. The average age at the onset of the disease was 5.95 ± 0.25 years. There were 64 patients who had electrophysiological evidence of peripheral neuropathy. The most observed electrophysiological changes were distal latency abnormalities in the left and right peroneal nerves in 39 and 33 patients, respectively. Sensory nerve amplitude, peak latency, and conduction velocity were normal in all patients (100%). HbA1c level did not show a statistically significant association with the incidence of subclinical neuropathy. CONCLUSION: Subclinical neuropathy was prevalent in children with DM type 1. Poor glucose control was only associated with an increased odds ratio of subclinical neuropathy.

Puberty Induction in Adolescent Males: Current Practice.

Puberty is a developmental stage characterized by the appearance of secondary sexual characteristics which leads to complete physical, psychosocial, and sexual maturation. The current practice of hormonal therapy to induce puberty in adolescent males is based on published consensus and expert opinion. Evidence-based guidelines on optimal timing and regimen in puberty induction in males are lacking, and this reflects some discrepancies in practice among endocrinologists. It is worth mentioning that the availability of various hormonal products in markets, their different routes of administration, and patients/parents' preference also have an impact on clinical decisions. This review outlines the current clinical approach to delayed puberty in boys with an emphasis on puberty induction.

Case Report: Homozygous DNAJC3 Mutation Causes Monogenic Diabetes Mellitus Associated With Pancreatic Atrophy.

Introduction: DNAJC3, abundant in the pancreatic cells, attenuates endoplasmic reticulum stress. Homozygous DNAJC3 mutations have been reported to cause non-immune juvenile-onset diabetes, neurodegeneration, hearing loss, short stature, and hypothyroidism. Case Description: We report a case of homozygous DNAJC3 mutation in two siblings of a consanguineous family. A 3-year-old boy presented with short stature and a thyroid nodule. Laboratory findings confirmed hypothyroidism. Subsequently, levothyroxine was administered. Growth hormone (GH) stimulation test results were within the normal limits. His stature was exceedingly short (80.5 cm) (-3.79 SDS). The patient developed sensorineural hearing loss at age 6 years; his intellectual functioning was impaired. Recombinant Human Growth Hormine (rhGH) treatment was postponed until the age of 6.9 years due to a strong family history of diabetes. At age 9 years, he developed an ataxic gait. Brain magnetic resonance imaging (MRI) revealed neurodegeneration. The patient developed diabetes at the age of 11 years-5 years after the initiation of rhGH treatment. Tests for markers of autoimmune diabetes were negative. Lifestyle modification was introduced, but insulin therapy was eventually required. Whole-exome-sequencing (WES) revealed a homozygous DNAJC3 mutation, which explained his clinical presentation. MRI revealed a small, atrophic pancreas. At the age of 17, his final adult height was 143 cm (-4.7 SDS). His elder brother, who had the same mutation, had a similar history, except that he had milder ataxia and normal brain MRI finding at the age of 28 years. Conclusion: We propose that DNAJC3 mutation can be considered as a cause of maturity onset diabetes of the young. Patients with DNAJC3 mutations may possess a small atrophic pancreas.

Prevalence and special clinical and biochemical characteristics of familial type 1 (insulin dependent) diabetes mellitus in pediatric patients in a tertiary care setting.

BACKGROUND AND OBJECTIVES: The hereditable nature of type 1 diabetes mellitus (T1DM) makes it a condition that is in some cases shared among siblings. Studies that focus on the epidemiology of T1DM among siblings are scarce. The primary focus of the study is to estimate the prevalence of familial T1DM among siblings and the secondary focus is to identify the presence of any special clinical or biochemical characteristics specific to this entity. METHODS: In a retrospective cross-sectional study, the charts of 308 children (>1 year) diagnosed with type 1 diabetes mellitus in a Saudi tertiary care setting were reviewed. The patients who have one sibling or more with T1DM were included. The prevalence of familial T1DM among siblings was calculated, and specific clinical and biochemical characteristics were investigated. Data were analyzed using Statistical Package for the Social Sciences software version 22 (IBM SPSS Statistics for Windows). The control group includes all patients with type I DM who were excluded for sibling with DM. RESULTS: The prevalence of familial T1DM among siblings was estimated at 15.9%. Seventy-four percent of the patients with a positive family history of diabetes mellitus had one affected sibling only. The clinical presentation showed no significant differences relative to the age of presentation, gender, parental consanguinity, diabetic ketoacidosis at presentation, and its number of episodes. For the biochemical characteristics, autoantibody tests revealed no statistically significant difference, but the mean initial HbA1c levels were lower in patients who had diabetic siblings. CONCLUSION: The prevalence of familial T1DM was found to be higher than that reported in other studies. No specific clinical or biochemical features were found to characterize familial T1DM among siblings.

Cord blood versus heel-stick sampling for measuring thyroid stimulating hormone for newborn screening of congenital hypothyroidism.

BACKGROUND: Screening for congenital hypothyroidism (CH) using cord blood or heel-stick samples is considered essential for the prevention of long-term complications CH, which include intellectual disability and slow growth. OBJECTIVE: Compare the sensitivity and specificity of cord blood and heel-stick samples for determining thyroid-stimulating hormone (TSH) levels for the detection of CH. DESIGN: Comparative diagnostic accuracy. SETTINGS: Tertiary care center in Riyadh. PATIENTS AND METHODS: The study included all infants who were delivered during the period from May 2011 to May 2013. As part of routine newborn screening, both cord blood and heel-stick samples were collected from each newborn for CH screening by measuring TSH levels. A cord TSH level was considered positive if the concentration of TSH was more than 60 mIU/L and negative if less than 30 mIU/L. Any cord TSH level between 30-60 mIU/L was considered borderline, and free T4 was measured from the same cord sample. The result was considered positive if the free T4 level was below 9 pmol/L. Heel-stick TSH levels more than 20 µU/L were considered positive. All newborns with positive results were recalled and a peripheral venous sample was taken for TSH and free T4 for confirmation. MAIN OUTCOME MEASURES: Sensitivity and specificity, positive and negative predictive values and recall rates. SAMPLE SIZE: 17 729 screened babies. RESULTS: Of 17 729 neonates screened, 7 were diagnosed as having primary CH. All confirmed cases were detected by both cord and heel-stick TSH levels: 88 cord results were positive (sensitivity 100%, specificity 99.6%, with a recall rate of 0.04%) and 305 heel-stick results were positive (sensitivity 100%, specificity 98.3%, with a recall rate of 1.68%). CONCLUSION: Both cord and heel-stick TSH testing detected all cases of CH. Cord testing was superior to heel-stick testing as the recall rate was lower. We think cord TSH testing is preferable when heel-stick is difficult or early discharge is the practice. LIMITATIONS: Retrospective; the timing of newborn screening for TSH sampling was premature. CONFLICT OF INTEREST: None.

Diagnosis and management of growth disorders in Gulf Cooperation Council (GCC) countries: Current procedures and key recommendations for best practice.

Diagnosis and management of growth disorders comprises an important area of pediatric practice. Current procedures in the different stages of the identification, referral, investigation, and treatment of growth disorders in the Gulf Cooperation Council (GCC) countries have been summarized. Evidence-based procedures, relating specifically to height screening for identification of short stature, auxological criteria for patient referral from primary to secondary pediatric care, and general and endocrine investigations and diagnosis have been discussed and outlined. The management issues related to key disorders that are licensed for growth hormone (hGH) therapy, namely GH deficiency, Turner syndrome, short stature related to birth size small for gestational age (SGA), and idiopathic short stature are discussed with recommendations described for best practice. Finally, two key components of short stature management, namely transitional care for the transfer of patients from pediatric to adult endocrinology services and adherence to recommended therapy with hGH, have been addressed with current practice outlines and recommendations presented.

Is type 1 diabetes mellitus a cause for subtle hearing loss in pediatric patients?

The objective of this study is to investigate the effects of IDDM on the function of the auditory pathway from the cochlea to the auditory cortex in child patients. Totally, 140 ears of 70 children with IDDM and 60 ears of 30 age and gender-matched healthy controls were included in the study. The ages of patients and controls ranged from 4 to 14 years. Audiological assessment including pure-tone audiometry, otoacoustic emission testing (OAE) and auditory brainstem response testing (ABR) has been performed to all participants. There was no significant difference between the patients and controls regarding pure-tone thresholds on audiometry (p > 0.05). The latencies of waves I, III and V on ABR were not significantly different between the patients and controls (p > 0.05). The amplitudes on DPOAE testing obtained from both groups were not significantly different at the frequencies of 2,000 and 4,000 Hz (p > 0.05). However, the DPOAE amplitudes of the patients at 1,000 Hz were significantly lower than those of controls at the same frequency (p = 0.03). There was no difference between the patients who had chronic disease (>5 years) and healthy controls regarding pure-tone audiometry, ABR and DPOAE testing results (p > 0.05). In the light of the findings obtained with pure-tone audiometry, and OAE and ABR testing, it seems that auditory system is spared in children with IDDM at clinical level. Diabetes control and chronicity of the disease do not impact on the auditory system except for a subclinical involvement in the apical portion of the cochlea.

ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies.

We describe a previously unreported syndrome characterized by secondary (post-natal) microcephaly with fronto-temporal lobe hypoplasia, multiple pituitary hormone deficiency, seizures, severe visual impairment and abnormalities of the kidneys and urinary tract in a highly consanguineous family with six affected children. Homozygosity mapping and exome sequencing revealed a novel homozygous frameshift mutation in the basic helix-loop-helix transcription factor gene ARNT2 (c.1373_1374dupTC) in affected individuals. This mutation results in absence of detectable levels of ARNT2 transcript and protein from patient fibroblasts compared with controls, consistent with nonsense-mediated decay of the mutant transcript and loss of ARNT2 function. We also show expression of ARNT2 within the central nervous system, including the hypothalamus, as well as the renal tract during human embryonic development. The progressive neurological abnormalities, congenital hypopituitarism and post-retinal visual pathway dysfunction in affected individuals demonstrates for the first time the essential role of ARNT2 in the development of the hypothalamo-pituitary axis, post-natal brain growth, and visual and renal function in humans.

Age- and gender-specific reference intervals for serum lipid levels (measured with an Advia 1650 analyzer) in school children.

BACKGROUND: Due to the lack of country-specific norms in Saudi Arabia, age- and gender-specific lipid reference intervals are needed to be established for Saudi children. METHODS: Blood samples were collected from 1168 children aged 6-16 years: 500 boys (43%) and 668 girls (57%), and were analyzed for cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL). Reference intervals were established by calculating the mean and the 2.5th and 97.5th percentiles. RESULTS: There were significant differences between boys at each Tanner stage with respect to cholesterol (P < 0.001); and HDL (P < 0.0001) but not LDL (P < 0.06) among girls. There were significant differences between boys and girls during puberty with respect to cholesterol (P < 0.0001), HDL (P < 0.0001), and LDL (P < 0.001). There was a significant positive correlation between total cholesterol levels, LDL and HDL levels at all Tanner stages in both genders. In girls, the only significant inverse correlation was at stage I (r=-0.243, P= 0.001); there was no significant correlation at other stages. CONCLUSIONS: Unlike children in other developing countries, Saudi children do not have lower serum cholesterol than their Western counterparts. These findings reflect changing dietary habits and increasing affluence in Saudi Arabia. These reference intervals may be used to aid in the early assessment of cardiovascular risk in Saudi pediatric populations.