naser ali mirhosseini

Neonatal diabetes mellitus (NDM) is a severe type of glucose metabolism disorder that appears in the first months of life and mostly presents with symptoms such as dehydration, inability to gain weight, and in extreme cases, ketoacidosis and coma. Strong evidence shows the benefits of early molecular tests that investigate variability in kATP channels such as KCNJ11, ABCC8, INS gene mutations, and 6q24 abnormalities. In the presence of these genomics changes, switching from Insulin treatment toward high-dose oral sulfonylurea can enhance the course of treatment, prognosis, and quality of life.

Case Report: 

In this study, we report four cases of neonatal diabetes with different symptoms who were referred to Shahid Sadoughi Medical Center in Yazd, Iran.

The diagnosis and treatment of NDM is a good model for implementing patient-centered and personalized medicine. For all patients with diabetes diagnosed before the 6th month of their age (even the 12th month), genetic testing should be considered.

Pyruvate carboxylase catalyzes the carboxylation of pyruvate to oxaloacetate, a crucial intermediate of the tricarboxylic acid (TCA) cycle and the initial step in converting pyruvate to glucose (gluconeogenesis). Pyruvate carboxylase deficiency is a rare metabolic disorder characterized by lactic acidosis, failure to thrive, development delay, and recurrent seizures at an early age in severely affected patients. The onset and severity of pyruvate carboxylase deficiency have been classified as severe neonatal (type B), usually fatal, less severe infantile (type A), compatible with survival but with impaired neurologic development, and milder, later onset (type C) with some residual impairment. Clinical manifestations include hypotonia, mixed hypertonia, ataxia, choreoathetosis, microcephaly, and other signs of impaired white matter development.

Case Report: 

A 7-day-old baby with a birth weight of 3kg, born to related parents, presented with clinical symptoms such as lethargy, poor feeding, and grunting since birth. Additionally, he experienced a drop in O2 saturation and cyanosis during his hospitalization. Test results revealed lactic acidosis and hyperammonemia. Furthermore, serum amino acids chromatography- HPLC indicated an increase in lysine and citrulline. The patient succumbed after 16 days due to multi-organ damage. Genetic analysis identified pyruvate carboxylase enzyme deficiency.

Pyruvate carboxylase deficiency is a rare inborn error of metabolism that can lead to developmental delay and failure to thrive, typically beginning in the neonatal or early infantile period. The possibility of pyruvate carboxylase deficiency should be considered in any child presenting with lactic acidosis and neurological abnormalities, particularly if associated with hypoglycemia, hyperammonemia, or ketosis.

Gaucher disease is the most common lysosomal storage disease. Defective activity of the acid β-glucosidose which is encoded by the GBA1 gene, leads to the accumulation of excess amounts of the glucosyl ceramide lipid. Gaucher disease is clinically classified into three variants based on the relative degree and progression of neurological involvement. Gaucher disease type 1 manifests markedly variable phenotypes ranging from asymptomatic individuals to children who have massive hepatosplenomegaly, pancytopenia, and severe skeletal abnormalities.

Case Report: 

We report a case series of four patients with Gaucher disease type 1 with variable clinical manifestations treated with enzyme replacement therapy (ERT). In follow-up, three patients showed visceral and hematological improvements, while one case did not respond to ERT and died due to liver failure.

Gaucher disease should be considered with differential diagnosis of patients with unexplained organomegaly, who bruise easily and have bone pain which can be treated with ERT.

Down syndrome and β-thalassemia are commonly prevalent genetic diseases worldwide. Predominantly, an extra copy of chromosome 21 or trisomy 21 predominantly causes Down syndrome (the most common genetic etiology of moderate intellectual disability). Down syndrome is associated with congenital anomalies and characteristic features. β-thalassemia major or transfusion- dependent Thalassemia refers to a severe expression of the disorder that requires early transfusion therapy.

Case Report: 

Here, we reported a male Down syndrome patient with a 47, xy, +21 karyotype who was diagnosed with β-thalassemia major at 6 months and treated with repeated transfusions every 20 days due to anemia.

The association between Down syndrome and major β-thalassemia is rare. The severity of the presentation of the child may be explained by the coincidence of these diseases.

 Conversion of glucose-6-phosphate to glucose is the final step in both glycogenolysis and gluconeogenesis. In glycogen storage disease type Ia (GSD type Ia), decreased activity of the enzyme glucose-6-phosphatase leads to an increased concentration of glucose-6-phosphate within the hepatocytes and shunting into alternative pathway with the following consequences: hyperlactatemia, hyperuricemia and hypertriglyceridemia. Patients develop hypoglycemia within 3 to 4 hours after a meal.

Case Report:

 We reported four patients with GSD type Ia with different clinical manifestations such as hypoglycemia, hepatomegaly, lactic acidosis, hyperchylomicronemia, and hyperuricemia and also described their prognosis.

 Previously, many children with GSD Ia died in infancy or early childhood. Recurrent severe hypoglycemia can cause brain damage, but the prognosis has improved dramatically with early diagnosis and long term maintenance of optimal metabolic control.

 Turner syndrome (TS) is the most common genetic disorder affecting only females. The criteria for diagnosis include the complete or partial absence of the second sex (x) chromosome (with or without cell line mosaicism) plus short stature and primary ovarian failure with or without the presence of other phenotypic TS features. The genotype in TS, as tested in peripheral blood, is most commonly 45xo. β-thalassemia major or transfusion-dependent thalassemia refers to severe β-thalassemia that requires early transfusion therapy. The association between Turner syndrome and thalassemia major is rare, which may result from transcription factor gene mutation.

Case Report: 

We report a girl with thalassemia major who was treated by recurring monthly transfusions since the age of six months. Short stature, triangular face, low set ear, hypertelorism, webbed neck, lordosis and genu valgum were observed in the examination. The patient was diagnosed with Turner syndrome, and her karyotype also was defined as 45xo.

 In the case of Turner syndrome and β-thalassemia major association, a mutation in the transcription factor gene is proposed, which can be confirmed by genetic testing.

Deficiency of hepatic fructose 1,6 bisphosphatase (FBPase), a key enzyme in gluconeogenesis, impairs the formation of glucose from all gluconeogenic precursors including dietary fructose. Patients present with life threatening metabolic acidosis, fasting hypoglycemia, hepatomegaly, hyperketosis, elevated lactate and uric acid level. Glycerol and glycerol-3 phosphate have been found in the urine. The diagnosis of FBPase deficiency is confirmed via DNA molecular analysis from peripheral leukocytes. The acute life threatening episodes are treated with IV glucose at high rate and bicarbonate to control hypoglycemia and acidosis.

Here we report a girl referred with anorexia, lethargy, recurrent vomiting, progressive respiratory distress, and hepatomegaly following respiratory viral infection. She also had a history of twice similar attacks but milder than previous episodes. The test results showed hypoglycemia and severe metabolic acidosis. Despite proper treatment, the patient died of pulmonary edema following a respiratory viral infection.

Once FBPase deficiency has been diagnosed and adequate management introduced, its course is usually benign. Growth both psychomotor and intellectual development are unimpaired and tolerance to fasting improves with age.

Hereditary hyperphosphatasia is a congenital and rare disease with high bone turn over. The disease is defined with extremely elevated alkaline phosphatase levels. Neonates with hyperphosphatasia are normal at birth but develop progressive long bone deformities, fracture, vertebral collapse, skull enlargement due to massively thickened calvarium, and deafness.

Here, we described a male patient with progressive deformity in limbs and pain during walking that onset of symptoms was from age of two. The patient admitted to the Shahid Sadoughi Hospital, Yazd, was born from a non-consanguineous marriage. He was treated with pamidronate until halt of the disease progression and followed up for 18 months.

Bisphosphonate is the treatment of choice for hyperphosphatasia because it can normalize bone turnover, improve growth rates, and skeletal quality.

Carnitine palmitoyltransferase 1A deficiency is a rare genetic disorder with autosomal recessive inheritance pattern of fatty acid metabolism secondary to CPT1A mutation. Several dozen infants and children have been described with a deficiency of the liver and kidney CPT1 isoenzyme (CPT1-A). Clinical manifestation includes fasting-induced hypoketotic hypoglycemia, occasionally with extremely abnormal liver function test (LFT) and rarely with renal tubular acidosis. Acyl carnitine analysis has been the main method for the diagnosis of CPT1A deficiency.  Prompt treatment of hypoglycemia includes intravenous fluid containing 10% dextrose. To prevent hypoglycemia, infants should eat frequently during the day and have cornstarch continuously at night. Fasting should not last more than 12 hours during illness, surgery, or medical procedures.

We reported three patients with CPT1A deficiency presented with hypoglycemia and Reye like syndrome in early childhood that with early diagnosis and treatment they are well in follow-up.

Prognosis of this genetic disorder will be good with appropriate treatment.

Inborn errors of metabolism can cause a number of morbidities and mortality in pediatric population. Glutaric aciduria II (GAII) or multiple acyl-CoA dehydrogenase deficiency (MADD) is an ultra-rare (i.e. <1:50 000) disorder of mitochondrial fatty acid oxidation (FAO) and amino acid metabolism. It is inherited in an autosomal recessive manner. Congenital deficiency of electron transfer flavoproteins and ETF dehydrogenase genes cause an illness that combines the features of impaired fatty acid oxidation and impaired oxidation of several aminoacides. Newborn screening (NBS) using tandem mass spectrometry (MS/MS) permits detection of neonates with glutaricaciduria-Type II.

We reported a five-year-old boy with muscle weakness of lower limb and inability to walk (myopathy), seizure due to hypoglycemia (as a result of prolonged fasting), hepatomegaly and rhabdomyolysis that treated with high dose riboflavin and he is well in follow up.

Early diagnosis of mild cases and treatment with high dose riboflavin may have better prognosis.

Diabetes insipidus is a syndrome that begins with polyuria and is often associated with polydipsia. Three significant differential diagnosis are important to consider in evaluating the causes of polyuria, including primary polydipsia, diabetes mellitus, and diabetes insipidus. In diabetes incipidus, ADH hormone is not synthesized and secreted in central DI or the hormone has lost its function in the renal tubules in nephrogenic DI type.

The present case was about 5.5 year-old-boy with polyurea and polydipsia from the beginning of the infancy. The patient had the serum osmolality of 277 mOsm/kg with the 24 hours urine volume of 4500 cc and urine osmolality of 200 mOsm/kg. The patient underwent water deprivation test for 12 hours. After administration of 20 μg of desmopressin spray, the urine osmolality increased to 720 mOsm/kg. Central diabetes insipidus was diagnosed. There was posterior hypophyseal agenesis in the brain MRI.

The above patient seemed to be one of the rare cases of autosomal recessive central DI that became symptomatic with polyuria and polydipsia from the early days of life. This rare and interesting case had isolated posterior pituitary agenesis. Desmopressin treatment resolved the patient's complaints. The patient was asymptomatic, and had normal growth in one year follow up.

Methylmalonic acidemia (MMA) is a congenital disorder due to the defects in the propionate pathway. It results from a deficiency in methylmalonyl coenzyme A mutase or one of the steps of the synthesis of the cobalamin (B12) cofactors for the enzyme. There is deficiency of methylmalonyl coA mutase (MCM) in the classic MMA.It presents with severe metabolic acidosis in the first month of life, progressive failure to thrive, feeding problems, recurrent vomiting, dehydration, hepatomegaly, lethargy, seizures, and developmental delay. Quantitative analysis of urinary organic acid patterns by GC-MS is used in MMA diagnosis. Treatment with large doses of hydroxocobalamin is helpful in some cases of MMA.

We Reported 6 patients with MMA with a variety of clinical manifestations and outcomes.

The overall prognosis of classic MMA remains doubtful, whereas vitamin B12 responsive MMA has a reasonable outcome.

Farber disease is a very rare autosomal recessive disease of lipid metabolism caused by deficient activity of lysosomal acid ceramidase. Symptoms can begin in the first year of life by a triad of painful and swollen joints and subcutaneous nodules, progressive hoarseness and variable central nervous system involvement.

A5 monthsold girl with subcutaneous nodules in limbs, pain and swelling in her fingers, Knees, elbow and hoarseness was referredto our clinic. She had neurodevelopment delay in walking and talking. Genetic analysiswas reported homozygosity for a c.830C>A mutation in exon 11 of N-Acylsphingosine Amidohydrolase 1 (ASAH1)gene. She diagnosed with Farber disease and treated with bone marrow transplantation. After that her signs and symptoms were improved and she could to walk.

Farber disease is associated with characteristics including swollen joints, subcutaneous nodules, progressive hoarseness and variable CNS involvement. Moreover, bone marrow transplantation improved these symptoms.