Neonatal diabetes mellitus due to a new KCNJ11 mutation - 10 years of the patient`s follow-up.

BACKGROUND: Mutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the ATP-sensitive potassium channel, often result in neonatal diabetes. CASE: In this report, we describe a 10-year-old girl who is heterozygous for a new missense mutation in the KCNJ11 gene and whose treatment was successfully switched from insulin to sulfonylurea (glibenclamide) therapy when she was one month old. 10-year data on a low-dose of glibenclamide monotherapy showed excellent glycaemic control with no reports of severe hypoglycaemia and microvascular complications. CONCLUSION: An early genetic diagnosis of neonatal diabetes mellitus is highly beneficial because early switch from insulin to sulfonylurea is safe, avoids unnecessary insulin therapy and promotes sustained improvement of glycaemic control on long-term follow-up.

Redox properties of transitional milk from mothers of preterm infants.

AIM: There is a discrepancy between the amount of transitional milk produced by mothers of preterm infants and the low capacity of premature infants to consume it. This milk can be used in milk banks, but previous studies found that there are large variations in the level of host-defence proteins in individual samples of milk from mothers of premature infants, which implies that large individual variations in antioxidative defence composition are also possible. METHODS: Milk samples were collected from 20 healthy mothers of preterm infants. We determined the values for non-enzymatic antioxidative capacity parameters (oxygen radical absorbance capacity (ORAC)), static oxidation-reduction potential (ORP), activities of antioxidant defence enzymes and the amount of vitamin C in whole milk, skim and whey fractions of transitional milk. RESULTS: The main low-molecular-weight antioxidant in transitional milk is vitamin C and most of it is contained in whey. ORAC is higher in whole transitional milk than in skim milk and whey, and ORP is lower in whole transitional milk than that in skim milk and whey. Antioxidative enzyme activities are similar in all individual samples of transitional milk from mothers of preterm infants. CONCLUSIONS: Our results indicate that transitional milk of mothers of preterm infants shows slow individual variations in antioxidative defence composition; therefore, it can be used in human milk banks.

Metabolically based liver damage pathophysiology in patients with urea cycle disorders - A new hypothesis.

The underlying pathophysiology of liver dysfunction in urea cycle disorders (UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle (UC) intermediates are toxic for hepatocyte mitochondria. It is possible that liver injury is directly caused by the toxicity of ammonia. The rarity of UCDs, the lack of checking of iron level in these patients, superficial knowledge of UC and an underestimation of the metabolic role of fumaric acid, are the main reasons that are responsible for the incomprehension of the mechanism of liver injury in patients suffering from UCDs. Owing to our routine clinical practice to screen for iron overload in severely ill neonates, with the focus on the newborns suffering from acute liver failure, we report a case of citrullinemia with neonatal liver failure and high blood parameters of iron overload. We hypothesize that the key is in the decreased-deficient fumaric acid production in the course of UC in UCDs that causes several sequentially intertwined metabolic disturbances with final result of liver iron overload. The presented hypothesis could be easily tested by examining the patients suffering from UCDs, for liver iron overload. This could be easily performed in countries with a high population and comprehensive national register for inborn errors of metabolism. CONCLUSION: Providing the hypothesis is correct, neonatal liver damage in patients having UCD can be prevented by the supplementation of pregnant women with fumaric or succinic acid, prepared in the form of iron supplementation pills. After birth, liver damage in patients having UCDs can be prevented by supplementation of these patients with zinc fumarate or zinc succinylate, as well.

Lipids on the Second Day in Ischemic and Normoxemic Term Neonates.

INTRODUCTION: In hypoxic newborns requiring oxygen, lipid peroxidation affects the peripheral blood lipids. OBJECTIVES: Determine the influence of perinatal oxygen therapy for hypoxia on serum lipid concentrations on the second day of life. MATERIALS AND METHODS: Our study included 50 newborns with perinatal hypoxia requiring oxygen and 50 healthy newborns without oxygen therapy. Arterialized capillary blood was taken for categorization of hypoxia (pO2) after birth in both groups. Lipid concentrations: total cholesterol (TC), high density lipoproteins (HDL), low density lipoproteins (LDL), and triglycerides (TG) were measured on day 2 in both groups. RESULTS: TC, LDL, HDL, TG, HC03 levels were statistically lower in the study group compared to the control one, while pCO2 and BE levels were statistically higher in newborns with perinatal hypoxia. CONCLUSION: Lower lipid levels in hypoxic newborns may suggest that circulating lipids are oxidized, peroxidized, and removed from the peripheral circulation.

Early onset of abdominal venous thrombosis in a newborn with homozygous type II heparin-binding site antithrombin deficiency.

: The overall incidence of thromboembolic events in the neonatal period is 5 per 100 000 births, wherein more than 40% of all such manifestations are symptomatic renal vein thromboses. We describe the case of a newborn female who developed extensive thrombosis, which filled the inferior vena cava and renal vein and was diagnosed in the first weeks of life. A homozygous type II heparin-binding site antithrombin deficiency (c. 391C>T, p. Leu131Phe) was detected in the background. Despite the timely diagnosis and appropriate treatment, clinical signs of renal insufficiency, because of left kidney atrophy and arterial hypertension, were observed. Our case demonstrates the seriousness of the consequences arising after early onset of venous thrombosis caused by homozygous type II heparin-binding site antithrombin deficiency. In addition to prompt diagnosis, of huge importance is the determination of inherited thrombophilia, as it significantly affects therapeutic treatment and indicates that long-term follow-up is mandatory.

Problems in diabetes managment in school setting in children and adolescents with type 1 diabetes in Serbia.

RESULTS: The obtained results show that not all children test blood glucose levels at school (50% of children in the 6-10-year-old age group and 67.3% in the age group over 11 years) and that not all children receive insulin at school (81.1% vs. 18.9%, and 57.7% vs. 42.3%, respectively). The frequency of severe hypoglycemia was 2.7% in children and 3.3% in adolescents. A high proportion of teachers did not have diabetes training. CONCLUSION: This brief report about problems in children and adolescents with type 1 diabetes at school in Serbia indicates what happens in the school setting and suggests how to improve control of this disease and facilitate the complete integration of children with diabetes at school. BACKGROUND/AIM: Children with type 1 diabetes typically spend one-third of the day in school and they should achieve the same level of diabetes management there as they do outside the school environment. The aim of this study was to identify problems in diabetes management in children with type 1 diabetes at school according to the perceptions reported by children and parents. METHODS: This cross-sectional survey was carried out at nine public hospitals in Serbia with a cohort of 6-18-year old children/adolescents. The parents were personally informed about the objectives of the survey and the necessity to involve their children. The self-reporting questionnaire included demographic information as well as some questions that helped to evaluate the general situation of children with type 1 diabetes at school.

Neonatal Outcome in Pregnancies with Autoimmune Myasthenia Gravis.

INTRODUCTION: Acquired autoimmune myasthenia gravis (MG) is an autoimmune process in which antibodies (AB) directed against the acetylcholine nicotinic receptor (AChR) cause weakness and fatigue of striated muscles. OBJECTIVES: The objective of this study was to determine the range of clinical manifestations in newborns with transient neonatal myasthenia (TNM). METHODS: 62 newborns with mothers who had autoimmune MG were followed by: anthropometric parameters, gestational age, gender, type of delivery completion, Apgar score (AS) in the first and fifth minute, and the emergence of TNM symptoms. RESULTS: For fourteen consecutive years, from a total of 98,000 infants, 62 (0.06%) were born to mothers with autoimmune MG. Four of them (6.4%) had symptoms of TNM. CONCLUSION: Newborns of mothers with MG manifest clinical features of TNM relative to stage of mother's illness. These newborns need monitoring until the seventh day of life.

Prenatally Diagnosed Hemophilia in a Newborn: a Case Report.

Hemophilia is the most common inherited coagulation disorder, and approximately one-half of patients are diagnosed as newborns. For prenatal diagnosis of hemophilia A, genetic tests are performed using chorionic villi (biopsy PCR chorionic villi sampling [CVS]) at 10 weeks' of gestation. The result in this fetus demonstrated an inversion within intron 1 in part for hemophilia A. This male infant, who was his parents' first offspring, was born after an uneventful pregnancy. An uncle suffered from hemophilia A. This report describes a newborn who was prenatally diagnosed with hemophilia A. The timely diagnosis of hemophilia in a newborn enabled the provision of adequate therapy, which led to a favorable outcome.

Prophylactic thyroidectomy for asymptomatic 3-year-old boy with positive multiple endocrine neoplasia type 2A mutation (codon 634).

INTRODUCTION: The multiple endocrine neoplasia type 2A (MEN 2A) syndrome, comprising medullary thyroid carcinoma (MTC), pheochromocytoma and primary hyperparathyroidism (PHPT) is most frequently caused by codon 634 activating mutations of the RET (rearranged during transfection) proto-oncogene on chromosome 10. For this codon-mutation carriers, earlier thyroidectomy (before the age of 5 years) would be advantageous in limiting the potential for the development of MTC as well as parathyroid adenomas. CASE OUTLINE: This is a case report of 3-year-old boy from the MEN 2A family (the boy's father and grandmother and paternal aunt) in which cysteine substitutes for phenylalanine at codon 634 in exon 11 of the RET proto-oncogene, who underwent thyroidectomy solely on the basis of genetic information. A boy had no thyromegaly, thyroidal irregularities or lymphadenopathy and no abnormality on the neck ultrasound examination. The pathology finding of thyroid gland was negative for MTC. Two years after total thyroidectomy, 5-year-old boy is healthy with permanent thyroxine replacement. His serum calcitonin level is < 2 pg/ml (normal < 13 pg/ml), has normal serum calcium and parathyroid hormone levels and negative urinary catecholamines. Long-term follow-up of this patient is required to determine whether very early thyroidectomy improves the long-term outcome of PHPT. CONCLUSION: Children with familial antecedents of MEN 2A should be genetically studied for the purpose of determining the risk of MTC and assessing the possibilities of making prophylactic thyroidectomy before the age of 5 years.

Ketoacidosis at presentation of type 1 diabetes mellitus in children: a retrospective 20-year experience from a tertiary care hospital in Serbia.

UNLABELLED: Diabetic ketoacidosis (DKA) has significant morbidity and mortality and is common at diagnosis in children. The aim of this study was to determine the frequency and clinical characteristics of DKA over a 20-year period among children diagnosed with type 1 diabetes mellitus (T1DM) at University children's hospital in Belgrade, Serbia. The study population comprised of 720 patients (366 boys) diagnosed with type 1 diabetes aged <18 years between January 1992 and December 2011. Of all patients diagnosed with T1DM, 237 (32.9 %) presented with DKA. The majority had either mild (69.6 %) or moderate (22.8 %) DKA. Sixty (55.0 %) of all children under 5 years had DKA compared to sixty-two (20.9 %) in the 5- to 10-year-old group and one hundred fifteen (36.6 %) in the 11- to 18-year-old patients (p<0.01), while 2.5 % of the entire DKA cohort were in real coma. During the later 10-year period, children less often had DKA at diagnosis compared with the earlier 10-year period (28.0 vs. 37.4 %) (p<0.01), but the frequency of severe DKA was higher in the age group <5 year and in the age group >11 year during 2002-2011, compared with the earlier 10-year period (12.9 vs. 3.4 %, p<0.01 and 17.1 vs. 3.8 %, p<0.01). CONCLUSION: The overall frequency of DKA in children with newly diagnosed type 1 diabetes decreased over a 20-year period at our hospital. However, children aged <5 years and adolescents are still at high risk for DKA at diagnosis.

The effect of metabolic and hormonal parameters on microalbuminuria in adolescents with type 1 diabetes mellitus.

INTRODUCTION: The prevalence of microalbuminuria (MA), the most important early marker of incipient nephropathy in patients with type 1 diabetes mellitus (T1DM), increases during puberty, the period of exaggerated physiological insulin resistance. OBJECTIVE: To assess the prevalence of MA and the relationship between MA and metabolic risk factors and pubertal hormones in adolescents with T1DM. METHODS: In a cross-section study involving a group of 100 adolescents of both sexes of mean age 14.90+/-2.18 years and with mean duration ofT1DM 5.99+/-73.64 years, we assessed the presence of MA. In all patients, we determined albumin-to-creatinine ratio (ACR) in two or three morning first-void urine samples in the period up to 6 months. Persistent MA was confirmed in the patients with the finding of ACR rating 2.5-25 mg/mmol in males and 3.5-25 mg/mmol in females in two out of three first morning urine samples. RESULTS: MA developed in 16 (16.0%) patients. Predictors of MA determined by using multiple logistic regression were high HbA1c (OR 4.6; 95% CI 2.1-10.0), higher night-time SBP (OR 1.9; 95% CI 0.8-1.3) and higher insulin dose (OR 62.6; 95% CI 2.3-1678.5). Markers of insulin resistance such as higher body mass index (BMI) which was statistically significantly related to MA (p= 0.241, p<0.05) and higher dehydroepiandrosterone sulfate (DHEA-S) which was significantly higher in patients with MA (7.82 micromol/L vs. 5.02 micromol/L, p<0.01), were also identified as predictors but did not remain significant by multivariate analysis, possibly because of a small sample of subjects with persistent MA. CONCLUSION: In addition to poor glycemic control and higher night-time systolic blood pressure, markers of insulin resistance (higher insulin dose, higher BMI and higher DHEA-S) contribute to the increased risk of MA.

Is abandonment of nonoperative management of hypertrophic pyloric stenosis warranted?

AIM: Evaluation of the effectiveness of oral atropine versus surgical therapy for hypertrophic pyloric stenosis (HPS). METHODOLOGY: A total of 66 consecutive patients with HPS were treated at the University Children's Hospital between January 2006 and December 2011. The diagnosis was initially based on medical history and confirmed by ultrasonography (US). The patients were divided into two groups according to the treatment preferred by their parents. The conservatively treated group, consisting of 33 boys and 7 girls, mean age 22.25 days, was given water-soluble atropine sulfate therapy at an initial dose of 0.05 mg/kg/day divided into 8 single doses, and administered after stomach decompression, 20 minutes prior to feeding. If vomiting persisted, the daily dose was progressively increased up to 0.18 mg/kg. If vomiting did not stop and full oral feeding was not reestablished in a week, surgery was done. The second group of 26 patients, mean age 20.86 days, underwent an operative procedure, Ramstedt extramucosal pyloromyotomy after the initial resuscitation. US evaluation was performed on days 7, 14, and 21. The outcome of the treatment was tested by Yates modification of the χ2 test. RESULTS: In the group of patients treated with atropine sulfate, 10 (25%) failed to respond to therapy, therefore, 8 boys and 2 girls underwent surgical treatment between the fifth and seventh day following institution of therapy. The remaining patients who received atropine sulfate (75%) were discharged when vomiting ceased, between the sixth and eighth day. They continued to take oral medication for 4 to 6 weeks, and were followed up by an ultrasound examination. The operated patients were discharged between the third and fifth day after surgery. There was a significant statistical difference between the groups regarding the outcome at a significance level of p < 0.05 (Yates χ2 = 5.839), with no complications regardless of the treatment option. However, at the significance level of p < 0.01 (Yates χ2 = 7.661), these methods demonstrate a difference in favor of surgical treatment. CONCLUSION: Further investigation of oral, intravenous or combined atropine sulfate treatment may clarify its position as an alternative to pyloromyotomy.

Disease-associated mutations in the actin-binding domain of filamin B cause cytoplasmic focal accumulations correlating with disease severity.

Dominant missense mutations in FLNB, encoding the actin-cross linking protein filamin B (FLNB), cause a broad range of skeletal dysplasias with varying severity by an unknown mechanism. Here these FLNB mutations are shown to cluster in exons encoding the actin-binding domain (ABD) and filamin repeats surrounding the flexible hinge 1 region of the FLNB rod domain. Despite being positioned in domains that bind actin, it is unknown if these mutations perturb cytoskeletal structure. Expression of several full-length FLNB constructs containing ABD mutations resulted in the appearance of actin-containing cytoplasmic focal accumulations of the substituted protein to a degree that was correlated with the severity of the associated phenotypes. In contrast, study of mutations leading to substitutions in the FLNB rod domain that result in the same phenotypes as ABD mutations demonstrated that with only one exception disease-associated substitutions, surrounding hinge 1 demonstrated no tendency to form actin-filamin foci. The exception, a substitution in filamin repeat 6, lies within a region previously implicated in filamin-actin binding. These data are consistent with mutations in the ABD conferring enhanced actin-binding activity but suggest that substitutions affecting repeats near the flexible hinge region of FLNB precipitate the same phenotypes through a different mechanism.

Microalbuminuria in relation to metabolic control and blood pressure in adolescents with type 1 diabetes.

INTRODUCTION: The objective of this study was to assess the frequency of microalbuminuria and the relationship with other risk factors for the development of diabetic nephropathy. MATERIAL AND METHODS: Our cross-section study involved a group of 60 adolescence of both sexes, mean age 15.3 ±2.43 years with mean duration of diabetes 7.74 ±3.44 years. Albumin excretion rate was measured on 2-3 samples of the first morning urine in the period below 6 months and persistent microalbuminuria was defined if its increased in two out of three urine specimens. Ambulatory blood pressure was monitored (ABPM, SpaceLabs 90207). RESULTS: Microalbuminuria developed in 13.3% of adolescents with mostly completed sexual development, statistically significantly poorer metabolic control (9.79% vs. 8.7%) and higher BMI (23.59 kg/m(2) vs. 20.85 kg/m(2)) than in the patients with normoalbuminuria. The mean night-time systolic blood pressure (SBP) was statistically significantly higher in microalbuminuric patients than in normoalbuminurics. The nocturnal dip was reduced in 41.7% of our patients; 38.5% of nondippers were in normoalbuminuric and 62.5% in microalbuminuric patients. CONCLUSIONS: Diabetic adolescents require particular attention in order to minimize the factors such as high HbA(1c), elevated body mass index and night-time SBP in the development of incipient nephropathy.

Successful sulfonylurea treatment of a neonate with neonatal diabetes mellitus due to a new KCNJ11 mutation.

Mutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the ATP-sensitive potassium channel, often result in neonatal diabetes. We describe a female neonate who is a heterozygous for a new missense mutation, V252L, in the KCNJ11 gene and who has been successfully transitioned from insulin to sulfonylurea therapy.

Reference values of capillary blood saturation in neonates and its difference from pulse oximetry.

INTRODUCTION: Haemoglobin saturation is an obligatory oxygen parameter in the assessment of neonatal oxygenation. Although, pulse oximetry is currently one of the major methods in the determination of haemoglobin saturation, capillary blood saturation is still present in the diagnostic process. As well known, haemoglobin saturation value of capillary blood is insufficiently accurate, but not as much as the difference in relation to the values determined by pulse oximetry. Until now published studies have reported that capillary samples are obtained according to a protocol by the principle of free blood outflow, which is practically almost unachievable in the neonate. OBJECTIVE: Determination of the reference values of oxygen saturation (SCO2) and partial pressure (pcO2) of capillary blood by squeezing of the foot. The determination of difference between ScO2 and pulse oximetry (SpO2). METHODS: In 134 term newborns, we determined SpO2. Subsequently, we measured the values of ScO2 and pcO2 from the same extremity. While withdrawing a capillary sample, we exerted multiple squeezing of the foot. The mean value of ScO2, pcO2, SpO2 and the difference between ScO2 and SpO2 were determined. RESULTS: Mean ScO2 value was 80.5 +/- 8.5%, pcO2 was 48.2 +/- 11.4 mm Hg and SpO2 was 98 +/- 1.9%. The difference between ScO2 and SpO2 values was 17.5 +/- 8.6% (t = 23.568; p = 0.000). CONCLUSION: There is a statistically highly significant difference between the values of ScO2 and SpO2. Having the knowledge of this difference can increase the accuracy of clinical evaluation and further diagnostics. Comparison in up-to-now conducted studies suggests that the squeezing of the foot for obtaining a capillary sample in relation to free blood outflow does not bear any significant influence on the resultant values of haemoglobin saturation.

A case of new mutation in maturity-onset diabetes of the young type 3 (MODY 3) responsive to a low dose of sulphonylurea.

We describe a girl aged 10.5 years with hyperglycemia, whose mother and maternal father had insulin treated diabetes since adolescence. Using genetic analysis in mother and child, we identified identical new mutation of the HNF-1alpha sequence. Treatment with small doses of sulphonylurea was initiated and that therapy gave good results.

[Transient neonatal pseudohypoparathyroidism].

INTRODUCTION: Pseudohypoparathyroidism (PHP) is a heterogeneous group of diseases characterized by end organ unresponsiveness to parathormone (PTH), due to receptor or postreceptor defects. The characteristic biochemical disturbances include hypocalcaemia, hyperphosphataemia and high serum parathormone levels. CASE OUTLINE: We present a 17-day-old male baby who was brought to our hospital because of seizures. He was found to have hypocalcaemia, hyperphosphataemia and an elevated serum level of parathyroid hormone. The diagnosis of PHP was based on the elevated serum level of PTH during hypocalcaemia and persistence of normocalcaemia after administering alphacalcidiol with oral calcium. After 4 months of therapy, with tapering of the oral calcium doses, the treatment was discontinued. During the following six months without therapy, the infant did not have seizures and the serum levels of calcium and phosphorus were normal, so we established the final diagnosis of transient neonatal pseudohypoparathyroidism. CONCLUSION: At the time when the newborn was diagnosed to have PHP, there was no indication whether it was of a permanent or transient form. A considerably lower number of patients have a transitory form of PHP, which is then confirmed in the infant period by a gradual reduction and withdrawal of therapy, with sustaining serum calcium and PTH within normal limits.

[Congenital hiatus hernia associated with reflux esophageal stenosis]. / Kongenitalna hijatusna hernija udruzena s refluksnom stenozom jednjaka.

A small group of three patients presented in our study represents extraordinary and very complicated problem of congenital hiatus hernia in infant period from 6th to 9th month of life, associated with gastroesophageal reflux and consecutive esophageal stenosis. There are two very rare and delicate entities within differential diagnosis, in the domain of the same pathology: congenitally short esophagus and congenital esophageal stenosis; with completely different surgical options for their treatment. That is why an optimal diagnostics and an adequate operative technique are extremely important for the treatment of hiatus hernia. The uppergastrointestinal barium radiography is definitely the method of diagnosing hiatus hernia, which provides typical, almost pathognomonic image of hiatus hernia accompanied by the esophageal stenosis. Nissen fundoplication is the technique of choice for its surgical treatment, with gastrostomy for probable postoperative esophageal dilatation. The results are more than satisfying: early peroral feeding, with spontaneous resolving of esophageal stenosis, which significantly diminishes the need for esophageal bougienage.

[Initial antibiotic therapy of neonatal sepsis]. / Inicijalna antibiotska terapija neonatusne sepse.

It is certain that in the past the types of bacterial agents responsible for neonatal sepsis and their sensitivity to antibiotics were not the same in all historical periods. However, the reports confirming the conclusion have been published only in the last three years. According to these facts, the bacterial causes of neonatal sepsis were analyzed in patients treated at the University children's hospital in Belgrade (S&M) as well as their sensitivity to antibiotics to determine the most effective initial therapy. Between January 2001 and June 2004, 35 neonates, aged from 1-30 days, with positive blood culture were treated. Gram-negative bacteria were the cause of sepsis in 57% of patients (Pseudomonas--20%, Klebsiella--20%, E. coli--8.5%, Acinetobacter--8.5%), gram-positive in 43% (coagulase-negative Staphylococci--14%, Staphylococcus epidermidis--14%, Staphylococcus aureus--9%, Streptococcus group B--3%, Listeria monocytogenes--3%). The bacteria were the most sensitive to carbapenems (85-89%), amikacin (68%), third-generation cephalosporins (47-50%), while the sensitivity to gentamicin was less than expected (48.5%). Sensitivity to ampicillin (8%) confirmed a high level of resistance to this antibiotic. All isolated Staphylococci were sensitive to vancomycin, and the overall methicillin resistance was 46%. Combined cefotaxime and amikacin therapy was the most effective of all suggested initial combinations of antibiotics (74%). The sensitivity to all other combinations of antibiotics was 51-71%. The most adequate initial combination of antibiotics for the treatment of neonatal sepsis is cefotaxime plus amikacin. The most adequate antibiotic for the treatment of nosocomial neonatal sepsis is carbapenem.