CYP21A2 Gene Analysis in Southern Iranian CAH Patients and a Brief Review of the Mutation Spectrum.

Background: CYP21A2 gene mutations are responsible for more than 95% of Congenital Adrenal Hyperplasia (CAH) disorders with autosomal recessive inheritance. Most of these pathogenic mutations originate from the CYP21A1P, a neighboring pseudogene with 98% homology, due to unequal crossing over or gene conversion events. Mutation identification of the gene could be beneficial for accurate diagnosis and outcome prediction. Methods: Twelve unrelated patients with CAH diagnosis were recruited for genetic counseling. To ensure distinct amplification of the CYP21A2 gene rather than its pseudogene, the complete sequence of the gene was amplified through two overlapping fragments by specific primers. The entire sequences were screened by direct Sanger sequencing using new sequencing primers. Results: Only two pathogenic point mutations were identified. The c.293-13C>G, also known as In2G, and the c.955C>T mutations were found in 37.5 and 33.3% of alleles, respectively. One patient showed homozygous gene deletion. We also reviewed recent reports on CYP21A2 gene mutations in Iran. Conclusion: Evaluating the ethnicity-specific gene mutation data is significant for populations with diverse ethnic groups including the Iranian population. Although several common mutations have been reported as causative mutations among CAH patients, identifying only two common point mutations in Fars province would help prioritize exon sequencing and reduce the cost and time of genotyping.

Adrenal insufficiency as a rare manifestation of secondary antiphospholipid syndrome: A pediatric case report and review of articles.

Key Clinical Message: Adrenal insufficiency is a rare, important manifestation of secondary antiphospholipid syndrome (APS) in pediatrics. In the presence of hematologic disorders such as thrombosis, we should consider APS. Abstract: Adrenal insufficiency can rarely occur in the context of vascular disorders and thrombosis in patients with antiphospholipid syndrome. There are few case reports in pediatrics. Here, we present a pediatric case-the first pediatric case report in Iran-and review articles in this age group.

Inborn Errors of Metabolism Associated With Autism Among Children: A Multicenter Study from Iran.

OBJECTIVE: This study aimed to find the common inborn errors of metabolism in Iranian patients with autism spectrum disorder. METHODS: In this cross-sectional multicenter study, 105 children and adolescents with autism spectrum disorder from six centers in different cities of Iran were enrolled between August, 2019 and October, 2020. Metabolic screening, including measuring plasma levels of amino acids, acylcarnitines, creatine, and guani-dinoacetate, and urinary levels of organic acids, purines, and pyrimidines was performed. Other data, including age, parental consanguinity, history of seizure, developmental mile-stones, and physical examination, were also recorded. RESULTS: An inborn error of metabolism was found in 13 (12.4%) patients. Five patients (4.8%) had cerebral creatine deficiency syndrome, 4 (3.8%) had arginine succinate aciduria, 2- methylbutyryl glycinuria, short-chain acyl-CoA dehydrogenase deficiency, and combined methylmalonic aciduria/malonic aciduria. There was a strong association between positive meta-bolic evaluation and parental consanguinity, history of seizures, microcephaly, and delayed development. CONCLUSIONS: Our results suggest that metabolic screening should be performed in the cases of autism associated with parental consanguinity, developmental delay, and a history of seizures. The assays to be considered as a screening panel include plasma or blood amino acids, acylcarnitines, creatine and guanidinoacetate, and urinary levels of organic acids.

Cohort Profile: Shiraz Pediatric Liver Cirrhosis Cohort (SPLCCS).

Liver diseases in children and adolescents are a significant and arising public health issue and should be surveyed from different dimensions (clinical and para-clinical, psychological, socio-economic) and in diverse populations. Shiraz Liver Transplant Center, Shiraz, Iran is the only center for pediatric liver transplantation and its pre-operative evaluations. This provides a unique and valuable situation for studying this vulnerable population. The Shiraz Pediatric Liver Cirrhosis Cohort Study (SPLCCS) was established to assess cirrhotic children, the course of their disease, and treatment over time. This cohort study aimed to prospectively evaluate the natural course and factors that contributed to complications and death of children with chronic liver disease in the region. SPLCCS was launched in September 2018 after obtaining ethical approval; until August 2022, 370 children with end-stage liver disease were enrolled and followed every six months. Here, the cohort's features, the included population's baseline characteristics, and primary outcomes are reported.

Elevated CD9 expression as a potential biomarker for diagnosis of Bernard-Soulier syndrome.

Diagnosis of inherited platelet glycoprotein disorders is based on specific laboratory techniques such as aggregometry and flow cytometry. Flowcytometry is a powerful method, but equivocal results are produced in some cases. New cluster of differentiation markers could resolve the diagnostic dilemmas. Abnormal expression of CD9 in Bernard-Soulier syndrome (BSS) is recently reported. We aimed to determine the diagnostic significance of CD9 expression in a cohort of Iranian patients with inherited platelet glycoprotein defects. Twelve BSS, 21 Glanzmann thrombasthenia and 16 healthy controls were included in the present study. Flowcytometric diagnosis of BSS and Glanzmann thrombasthenia was made by analysis of CD41/61 and CD42a/42b CD markers. Moreover, phycoerythrin-labelled anti CD9 was examined in patients and healthy controls. The mean fluorescence intensity (MFI) of CD9 among the three groups was compared using suitable statistical methods and a P value of less than 0.05 considered statistically significant. Mean MFI of CD9 was 990.0 in BSS patients versus 421.2 and 317.3 in individuals with Glanzmann thrombasthenia and healthy controls, respectively (P < 0.05). Between the two-group comparison of means by the Mann-Whitney test revealed a P value of less than 0.001 for BSS group versus GT (2.4-fold) and BSS versus healthy controls (2.9-fold). CD9 molecule also expressed differently in patients with Glanzmann thrombasthenia in comparison with healthy controls (P < 0.001), although with a less magnitude (1.3-fold). According to our findings, CD9 is a potential biomarker for laboratory diagnosis of inherited glycoprotein defects, especially to elucidate the ambiguous results in BSS cases.

A case report: First presentation of diabetes mellitus type 1 with severe hyperosmolar hyperglycemic state in a 35-month-old girl.

Hyperglycemic hyperosmolar syndrome (HHS) is a rare complication of diabetes mellitus among pediatric patients. Since its treatment differs from diabetic ketoacidosis (DKA), hence, pediatricians should be aware of its diagnosis and management.

Optimal Frequency to Screen Celiac Disease amongst Patients with Type 1 Diabetes Mellitus: A Multicenter Study.

AIMS: Celiac disease (CD) is frequent amongst patients with type 1 diabetes mellitus (T1DM). Since there is a disagreement on the optimal interval and frequency to perform screening tests for CD among diabetic patients, this study aimed to evaluate these issues amongst patients with T1DM. METHODS: This retrospective cohort study was conducted in seven referral diabetic centers in different cities of Iran from January 2020 to January 2021. Data belonging to 106 patients who were affected by both T1DM and CD was collected. The time interval between CD diagnosis and diabetes (IBCD), the age of diabetes onset, and any associated diseases, symptoms, and family history of T1DM and CD were recorded and analyzed. RESULTS: Results show that 45% of the patients with CD were diagnosed during the first year of diabetes onset; furthermore, 18% and 16% of the patients with CD were diagnosed in the second or third year after being diagnosed with diabetes. In addition, another 18% of patients with CD were diagnosed during the fourth till the eighth year after diabetes onset. Moreover, there was a negative relationship between the age of T1DM diagnosis and IBCD. Most participants were asymptomatic at the time of CD diagnosis. CONCLUSIONS: Screening tests to detect CD amongst patients with T1DM should continue for at least eight years after the initial T1DM diagnosis, especially those affected at a younger age.

Role of Selenium Deficiency in Pediatrics with Acquired Hypothyroidism.

BACKGROUND: Although selenium is one of the nutrients that has an important role in the metabolism of thyroid hormones, it has been investigated in rare studies. This study aimed to evaluate role of selenium deficiency in children and adolescents with acquired hypothyroidism. METHODS: This case and control study was conducted on 60 acquired hypothyroidism and 60 healthy children who had been referred to the pediatrics endocrine clinic in Shiraz, Iran, from November 2018 to April 2019. Some information such as age, gender, weight, height, duration of disease, and level of plasma selenium were recorded. Plasma selenium level was measured by atomic absorption spectrophotometer. Data were analyzed using SPSS software 21.0. RESULTS: The mean of selenium level in the case and control groups were 93.77 ± 24.90 µg/dl and 85.96 ± 25.20 µg/dl, respectively. There was no significant difference between the two groups in the mean levels of selenium. Independent t-test showed no significant difference in the mean levels of selenium in male and female samples in the case group, but this difference was significant in the control group. CONCLUSION: Selenium deficiency may not have significant role as a cause of acquired hypothyroidism in pediatric and adolescent age group, in south of Iran. Thus, it does not seem necessary to routinely check the level of selenium for patients with thyroid dysfunction.

Effect of Growth Hormone treatment on Height Velocity of Children with Pycnodysotosis.

OBJECTIVE: Pycnodysostosis is a rare autosomal recessive osteochondrodysplasia resulting from osteoclast dysfunction. Growth hormone (GH) secretion impairment and low insulin growth factor 1 (IGF-I) concentrations have been reported in these patients. The present study aims to describe GH effect on linear growth of eight children with pycnodysostosis. METHODS: This study was conducted on 8 children suffering from pycnodysostosis. After evaluating systemic diseases, adrenal insufficiency, and hypothyroidism, bone age, height standard deviation score (HtSDS), body mass index (BMI), and some demographical characteristics were measured. To measure the serum GH, we performed two clonidine tests in two different days with an interval of 24 hours. With initiation of the trial, human GH was injected subcutaneously once a day 6 days a week for a period of 1.5 years. The patients were followed up every 3 months to document their height and BMI until 6 months after the end of the treatment. FINDINGS: All of the patients had growth hormone deficiency. HtSDS at the first visit continued to decrease during the 6 months before starting the treatment; however, HtSDS started to increase after beginning of GH administration. This value again declined after discontinuing the GH. Overall, the mean of linear growth was improved after GH administration in the patients. CONCLUSION: The present clinical study revealed that GH administration had a positive impact on the linear growth of the children suffering from pycnodysostosis.

Changing the Treatment of Permanent Neonatal Diabetes Mellitus from Insulin to Glibenclamide in a 4-Month-Old Infant with KCNJ11 Activating Mutation.

Permanent neonatal diabetes mellitus (PNDM) is a rare type of diabetes and KCNJ11 gene activating mutation is one of its prevalent causes. We introduced a 4-month-old male infant with poor feeding, restlessness, tachypnea, hyperglycemia, metabolic acidosis, and ketonemia. He was discharged with insulin and after 2 months, KCNJ11 gene mutation was found and treatment was switched from subcutaneous insulin to oral glibenclamide. Now, he is 1 year old with desirable glycemic control; therefore, genetic study is recommended for KCNJ11 gene mutation in such patients because if the mutation is found, treatment can be switched from insulin to sulfonylurea.

Cardiovascular involvement in children with osteogenesis imperfecta.

OBJECTIVE: Osteogenesis imperfecta is a hereditary disease resulting from mutation in type I procollagen genes. One of the extra skeletal manifestations of this disease is cardiac involvement. The prevalence of cardiac involvement is still unknown in the children with osteogenesis imperfecta. The present study aimed to investigate the prevalence of cardiovascular abnormalities in these patients. METHODS: 24 children with osteogenesis imperfecta and 24 normal children who were matched with the patients regarding sex and age were studied. In both groups, standard echocardiography was performed, and heart valves were investigated. Dimensions of left ventricle, aorta annulus, sinotubular junction, ascending and descending aorta were measured and compared between the two groups. FINDINGS: The results revealed no significant difference between the two groups regarding age, sex, ejection fraction, shortening fraction, mean of aorta annulus, sinotubular junction, ascending and descending aorta, but after correction based on the body surface area, dimensions of aorta annulus, sinotubular junction, ascending and descending aorta in the patients were significantly higher than those in the control group (P<0.05). Two (8.3%) patients had aortic insufficiency and five (20%) patients had tricuspid regurgitation, three of whom had gradient >25 mmHg and one patient had pulmonary insufficiency with indirect evidence of pulmonary hypertension. According to Z scores of aorta annulus, sinotubular junction and ascending aorta, 5, 3, and 1 out of 24 patients had Z scores >2 respectively. CONCLUSION: The prevalence of valvular heart diseases and aortic root dilation was higher in children with osteogenesis imperfecta. In conclusion, cardiovascular investigation is recommended in these children.