A novel mutation of Beta-ketothiolase deficiency: The first report from Iran and review of literature

Background:Beta-ketothiolase deficiency is a rare autosomal recessive disorder characterized by an inborn error of isoleucine catabolism and affecting ketone body metabolism. Clinical features characterized by intermittent keto acidotic episodes associated with clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients, with an onset during infancy or toddler-hood.Case presentation: A two months old girl presented with acute episode of fever and toxic encephalopathy with attack of vomiting, hypotonia, lethargy, tonic clonic seizures and then a day in coma, few days after vaccination .After then similar episodes happened until 7 months age.  . Biochemical tests that suggested diagnose of beta ketothiolase deficiency were attacks of ketoacidosis with urinary exertion of 2-methyl-3-hydroxybutric acid 2-methyl aceto acetic acid tiglylglycine. In genetic assessment we detected a novel homozygous mutation c.664A> C (p. Ser 222 Arg) in ACAT gene. This is a first report of beta ketothiolase deficiency confirmed by molecular analysis from Iran.Conclusion: we report on a homozygous variant in the ACAT1 gene that is the first time we detect this variant and is a novel mutation. According to the obtained result and patient’s phenotype, we recommended carrier testing for all informative family members to recognize mutations in asymptomatic family members

Peripheral Neuropathy in Children and Adolescents with Insulin-dependent Diabetes Mellitus

Introduction: Type 1 diabetes mellitus(T1DM) is a chronic immune-mediated disease. Diabetic peripheral neuropathy (DPN) is an important micro vascular complication of T1DM. One of the most important risk factors for the development of DPN is poor glycemic control. The aim of this study was to evaluate the prevalence of DPN among T1DM patients and to determine the association between DPN and glycated hemoglobin(HbA1c) level.Methods: The subjects were recruited prospectively upon initial evaluation at a tertiary hospital. Patients with T1DM were selected based on the inclusion criteria (i.e., age of 6≤years and absence of other co-morbidities). DPN was assessed through electro diagnostic studies and neurological examinations, while diabetes control was evaluated by measuring the HbA1c level.Results: In total, 50 patients with T1DM were enrolled in this study. The mean diabetes duration of patients was 8.38±3.79 years (mean age16.68±6.68 years). The mean HbA1c level was 8.6±2.1% in patients without DPN and 10.5±3 in those with DPN (P=0.016). Overall, 24% of the subjects were presented with DPN according to nerve conduction velocity(NCV) findings. A positive correlation was found between NCV and clinical symptoms with signs (P<0.001, r=0.45 and P<0.001, r=0.644, respectively). Sensitivity and specificity of neurological examination for DPN diagnosis were 91.7% and 63.2%, respectively. Our findings revealed that, poor diabetes control is associated with DPN. Also, HbA1c level was used as an index for glycemic control over the past six months.Conclusion: It seems that rigid blood glucose control and periodic neurological examinations were the best strategies to prevent DPN. Introduction: Type 1 diabetes mellitus(T1DM) is a chronic immune-mediated disease. Diabetic peripheral neuropathy (DPN) is an important micro vascular complication of T1DM. One of the most important risk factors for the development of DPN is poor glycemic control. The aim of this study was to evaluate the prevalence of DPN among T1DM patients and to determine the association between DPN and glycated hemoglobin(HbA1c) level.Methods: The subjects were recruited prospectively upon initial evaluation at a tertiary hospital. Patients with T1DM were selected based on the inclusion criteria (i.e., age of 6≤years and absence of other co-morbidities). DPN was assessed through electro diagnostic studies and neurological examinations, while diabetes control was evaluated by measuring the HbA1c level.Results: In total, 50 patients with T1DM were enrolled in this study. The mean diabetes duration of patients was 8.38±3.79 years (mean age16.68±6.68 years). The mean HbA1c level was 8.6±2.1% in patients without DPN and 10.5±3 in those with DPN (P=0.016). Overall, 24% of the subjects were presented with DPN according to nerve conduction velocity(NCV) findings. A positive correlation was found between NCV and clinical symptoms with signs (P<0.001, r=0.45 and P<0.001, r=0.644, respectively). Sensitivity and specificity of neurological examination for DPN diagnosis were 91.7% and 63.2%, respectively. Our findings revealed that, poor diabetes control is associated with DPN. Also, HbA1c level was used as an index for glycemic control over the past six months.Conclusion: It seems that rigid blood glucose control and periodic neurological examinations were the best strategies to prevent DPN.

Papillary Carcinoma Thyroid in a Nine-year-old Child: A Case Report

Thyroid enlargement and nodules are very rare in children, but when they occur, the chance of malignancy among these nodules is very high. Thyroid carcinoma is rare in childhood, but in the last two decades, its incidence has increased two-fold. A painless nodule in the neck is the most common presentation of the disease. Dysphagia, hoarseness, cervical lymphadenopathy, weight loss, and fatigue are other presentations. Surgical resection is the primary therapy for thyroid cancer. Levothyroxine and Iodine-131 (I131) are usually used as adjunctive therapy. This article presents the case of a 9-year-old girl who referred to our center with the chief complaint of a neck mass. Her symptoms had begun 6 months earlier

Mccune-Albright Syndrome: A Case Report Associated with Pamidronate Therapy and Literature Review

McCune-Albright Syndrome (MAS) is a rare sporadic disease characterized by bone fibrous dysplasia, Café au lait spots and a variable association of hyperfunction endocrine disorders. There is not any certain treatment available for this syndrome, and both physical and emotional disability in these patients is still a major concern for physicians. In present report we have described a 10- year-old girl, presented with precocious puberty, multiple Café au lait  macules and fibrous dysplasia, successfully treated with pamidronate in a four-year follow-up period

Primordial Dwarfism: A Case Series From North East of Iran and Literature Review

Introduction: Primordial dwarfism is a rare class of genetic disorders, characterized by intrauterine growth retardation, short stature at birth and growth deficiency that persist throughout life. This disorder is caused by various mechanisms such as chromosomal abnormalities, molecular changes and mutation of genes that result in developmental defects, facial dysmorphism and skeletal abnormalities in fetus. Primordial dwarfism includes 5 specific subtypes that their descriptions vary from one type to another. This study aimed to report 7 cases of primordial dwarfism as the first case series study and literature review of this disorder in Iran.  Case Presentations: This study presented primordial dwarfism patients and summarized clinical findings of 7 cases who referred to Pediatric endocrine wards in Imam Reza Hospital, from June 2016 to September 2017. The cases suffered from severe growth retardation and clinical features of this disorder that were not explained by other disorders. We also conducted a literature review about primordial dwarfism on Google Scholar, Medline, and PubMed to compare our results with other reports. Seven patients (5 females and 2 males) aged between 18 months and 12 years were identified, during the study. The most prevalent referring symptoms were growth retardation, presenting in all cases. Other clinical signs and symptoms included intrauterine growth retardation, low birth weight, specific clinical features such as microcephaly, narrow face, high pitch voice, prominent nose, etc. Biochemical and imaging studies were performed to rule out other diseases that can cause growth retardation. The diagnosis of primordial dwarfism was made based o clinical presentation. Conclusions: This review will provide an overview of the clinical aspects and different subtypes of primordial dwarfism disorder and draw the attention of clinicians for diagnose and further evaluations of this disorder

Efficacy of zinc sulfate in reducing unconjugated hyperbilirubinemia in neonates

Hyperbilirubinemia is a common disease and unconjugated hyperbilirubinemia has been seen mainly in neonates. Severe form of unconjugated hyperbilirubinemia may cause kernicterus and even death. Conventional treatment for severe unconjugated hyperbilirubinemia consists of phototherapy and exchange transfusion that have several known disadvantages; specially exchange transfusion is associated with a significant morbidity and even mortality. These harmful effects indicate the need to develop alternative pharmacological treatment strategies for unconjugated hyperbilirubinemia. One of these pharmacological agents is zinc salts. Zinc has been shown to lower the bilirubin levels by inhibition of the enterohepatic cycling of unconjugated bilirubin. Oral zinc has been shown to reduce serum unconjugated bilirubin in animals, adolescents and low birth weight neonates. However, studies in healthy term neonates given oral zinc showed no reduction in hyperbilirubinemia based on daily measurement. In order to improve the accuracy, hyperbilirubinemia may be determined based on measurements every hour. More studies are needed to know the effect of zinc in neonatal jaundice

The Therapeutic Effect of Zinc Sulfate on Neonatal Hyperbilirubinemia

Background: Approximately 60% of term neonates and 80% of preterm ones suffer from hyperbilirubinemia in theirfirst week of life. This study sought to characterize the therapeutic effect of oral zinc sulfate on neonatalhyperbilirubinemia.Methods: In this randomized, double-blind, placebo-controlled clinical trial, 70 term neonates with total serumbilirubin (TSB) level ≥ 20 mg/dl were enrolled. Thirty-four cases were treated with phototherapy and zinc (10 mg/day,single dose) as case, while the remainder received phototherapy plus placebo. TSB level was measured at the onset ofthe intervention, as well as 12, 24 and 48 h after the intervention and compared with each other.Results: The mean TSB levels were significantly lower in the zinc group after 12, 24 and 48 h (P=0.038, 0.005, 0.001,respectively). The mean durations of phototherapy in the case and control groups were 2.03±0.174 and 2.33±0.478days, respectively, being significantly less in the case group (P=0.002).Conclusion: This study revealed that oral zinc sulfate at a single dose of 10 mg/day diminished TSB level and durationof phototherapy

Clinical Efficacy Evaluation of Sirolimus in Congenital Hyperinsulinism

Background. Congenital hyperinsulinism (CHI) is a rare and life-threatening genetic disorder. Sirolimus as a mammalian target of rapamycin inhibitor may be helpful in patients with CHI who do not respond well to other treatments including diazoxide and octreotide. However, the safety and efficacy of this therapy are still unclear. This study aimed to evaluate the potential therapeutic effects of sirolimus in CHI patients with mutations in the ABCC8 and KCNJ11 genes. Methods. During the period of this follow-up study, every child with a confirmed diagnosis of unresponsive CHI underwent genetic evaluation. Among those who had positive genetic testing, six families agreed to participate in this study. The participants were evaluated for ABCC8, KCNJ11, or HNF4α gene mutations by polymerase chain reaction (PCR) sequencing. The participants who were unresponsive to diazoxide and octreotide therapy received 0.5 mg/m2/d of sirolimus, and the dose was gradually increased until a serum concentration of 5–15 ng/ml was achieved. Then, the participants were followed up for any possible complications. Results. Among the study participants, only one neonate was completely free of hypoglycemia after one year of follow-up, whereas three others experienced a partial reduction in hypoglycemic episodes over six months. One neonate underwent pancreatectomy despite receiving sirolimus. The oldest participant with a mutation in the ABCC8 gene responded well to sirolimus therapy after surgery and remained asymptomatic for 18 months. Conclusion. This study suggested that sirolimus therapy needs further evaluation to determine which patients will benefit the most. The genetic basis of CHI may have possible implications for determining the patient’s response

Genotyping of ABCC8, KCNJ11, and HADH in Iranian Infants with Congenital Hyperinsulinism

Background. Congenital hyperinsulinism (CHI) is a heterogeneous disease with various underlying genetic causes. Among different genes considered effective in the development of CHI, ABCC8, KCNJ11, and HADH genes are among the important genes, especially in a population with a considerable rate of consanguineous marriage. Mutational analysis of these genes guides clinicians to better treatment and prediction of prognosis for this rare disease. The present study aimed to evaluate genetic variants in ABCC8, KCNJ11, and HADH genes as causative genes for CHI in the Iranian population. Methods. The present case series took place in Mashhad, Iran, within 11 years. Every child who had a clinical phenotype and confirmatory biochemical tests of CHI enrolled in this study. Variants in ABCC8, KCNJ11, and HADH genes were analyzed by the polymerase chain reaction and sequencing in our patients. Results. Among 20 pediatric patients, 16 of them had variants in ABCC8, KCNJ11, and HADH genes. The mean age of genetic diagnosis was 18.6 days. A homozygous missense (c.2041-21G > A) mutation in the ABCC8 gene was seen in three infants. Other common variants were frameshift variants (c.3438dup) in the ABCC8 gene and a missense variant (c.287-288delinsTG) in the KCNJ11 gene. Most of the variants in our population were still categorized as variants of unknown significance and only 7 pathogenic variants were present. Conclusion. Most variants were located in the ABCC8 gene in our population. Because most of the variants in our population are not previously reported, performing further functional studies is warranted

Niemann-Pick Diseases; largest Iranian cohort with genetic analysis

Background: Niemann-Pick diseases (NPD) is an autosomal recessive inherited lysosomal lipid storage disorder which occurs due to a defect in cellular cholesterol trafficking, leading to excess lipid accumulation in multiple organ systems such as the brain, lungs, spleen and liver. SPMD1-associated disease includes classic infantile and visceral NPD type A and B respectively. Type C NPD is subacute or juvenile.Methods: Sanger sequencing of the candidate genes for NPD were performed followed by bioinformatic analysis to confirm the types of NPD and to identify novel mutations. All patients underwent full clinical assessment.Results: In this case series, we present two cases with NPD type A, six cases with NPD type B, and 11 cases with type C with various enzymatic defects identified in these cases. Within these 19 patients we present seven previously reported mutations and 10 novel mutations causing NPD.Conclusion: Our report demonstrates that NPD has a variable age of onset and can present early in life. In this study, we investigated the clinical and genetic manifestations of a large Iranian cohort. Understanding the variable presentation of NPD will allow for clinicians to have a high index of suspicion for the disease