Homozygous SLC20A2 mutations cause congenital CMV infection-like phenotype.

BACKGROUND: Idiopathic basal ganglia calcification, also known as Fahr's disease, it is a neurological disease characterized by intracranial calcification caused by heterozygous SLC20A2 mutations. Patients with calcifications can either be asymptomatic or show a wide spectrum of neuropsychiatric symptoms, including parkinsonism, tremor, dystonia, ataxia, and seizures. OBJECTIVES: The aim of this study was to investigating the clinical implications of the SLCA20A2 gene and identifying a new phenotype through a family. METHODS: Two siblings with growth retardation, bilateral cataracts, microcephaly, and convulsion were included in the study. The MRI showed cerebral atrophy, corpus callosum hypoplasia, microcalcifications. Chromosomal microarray analysis was performed to identify the existence of copy number variation. The whole exome sequencing analysis of the individual IV-I was performed, and Sanger sequencing was performed for segregation. RESULTS: Whole exome sequencing revealed a homozygous NM_006749.5:c.1794 + 1G > A of the SLC20A2 gene. The Sanger sequencing confirmed the affected siblings were homozygous and the parents were heterozygous. CONCLUSIONS: SLC20A2 gene heterozygous mutations were associated with the adult-onset phenotype, while homozygous SLC20A2 mutations in the two affected siblings we reported in our study resulted in a severe clinic including growth retardation, bilateral cataracts, microcephaly, and convulsion. We showed that biallelic mutations in the SLC20A2 gene that cause the Fahr's disease lead to more severe phenotypes contrary to what is known. The two siblings, showing similar phonotypic and genotypic characteristics, would be the youngest cases in the pediatric age group published in the literature.

Molecular and clinical findings of Turkish patients with hereditary fructose intolerance.

OBJECTIVES: Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by a deficiency in aldolase B that can result in hypoglycemia, nausea, vomiting, abdominal pain, liver and kidney dysfunction, coma, and even death. This study aims to represent the clinical features and molecular genetic analysis data of the patients diagnosed with HFI in our study population. METHODS: The medical records of the 26 patients with HFI were evaluated retrospectively. Age, gender, clinical findings, metabolic crises, and the results of molecular analyses were recorded. RESULTS: The patients with HFI had a good prognosis and the aversion to sugar-containing foods was the main complaint. Seven different variants were identified in the Aldolase B (ALDOB) gene in HFI patients. The most frequent mutations were p.Ala150Pro, p.Ala175Asp had a prevalence of 61 and 30%, respectively, in agreement with the literature and other known variants were found with minor frequencies c.360-363del4(3.8%), p.Asn335Lys(3.8%), and three novel mutations c.113-1_15del4 (3.8%), p.Ala338Val(7.6%), and p.Asp156His(3.8%) were identified at a heterozygous, homozygous, or compound heterozygous level. CONCLUSIONS: This study results revealed three novel mutations in patients with HFI. On the basis of age of presentation, clinical symptoms, and metabolic crisis, there was no clear-cut genotype-phenotype correlation. This article also demonstrates the importance of screening suspected infants in cases of acute liver failure for prompt diagnosis and treatment of HFI.

Stepwise diet management in pediatric gastrointestinal graft versus host disease.

Gastrointestinal tract is one of the major systems affected by graft-versus-host disease (GVHD). Injury to the gut during conditioning therapy before stem-cell transplantation (SCT) plays a pivotal role in the initiation of inflammatory stimuli. We reviewed medical records of the patients who underwent SCT between April 2010 and June 2013 in our center. A stepwise upgrade diet was given to the children with acute GI-GVHD (Gastrointestinal GVHD) including parenteral and enteral nutrition. A total of 105 patients underwent SCT and seven patients developed grade III-IV acute GI-GVHD. Total parenteral nutrition (TPN) was initiated to all patients after the diagnosis of GI-GVHD and minimal enteral nutrition (1-2 ml/kg/day standard pediatric enteral formula/special meat soup) was given to the patients. GI-GVHD improved in all patients with no change in body weight, and recovery to a normal diet took 10-30 days. Stepwise diet management of oral nutrition contributed to rapid improvement of grades III-IV acute GI-GVHD.

Microsomal triglyceride transfer protein gene mutations in Turkish children: A novel mutation and clinical follow up.

Abetalipoproteinemia (ABL; OMIM 200100) is a rare autosomal recessive disease that affects the absorption of dietary fats and fat soluble vitamins. Here, we describe the clinical and genetic characteristics of three patients with ABL. Two patients (patients 1 and 2) who were carriers of the c.398-399delAA mutation (previously known mutation) had developmental delay and hepatic steatosis developed at the age of five in patient 1. Patient 3 was the carrier of a novel mutation (g.10886-10902delAAGgtaagtttgtgttg in intron 3 and c.506A>T exon 5) in microsomal triglyceride transfer protein (MTP) gene and had hepatic steatosis.

Novel Abetalipoproteinemia Missense Mutation Highlights the Importance of the N-Terminal ß-Barrel in Microsomal Triglyceride Transfer Protein Function.

BACKGROUND: The use of microsomal triglyceride transfer protein (MTP) inhibitors is limited to severe hyperlipidemias because of associated hepatosteatosis and gastrointestinal adverse effects. Comprehensive knowledge about the structure-function of MTP might help design new molecules that avoid steatosis. Characterization of mutations in MTP causing abetalipoproteinemia has revealed that the central α-helical and C-terminal ß-sheet domains are important for protein disulfide isomerase binding and lipid transfer activity. Our aim was to identify and characterize mutations in the N-terminal domain to understand its function. METHODS AND RESULTS: We identified a novel missense mutation (D169V) in a 4-month-old Turkish male child with severe signs of abetalipoproteinemia. To study the effect of this mutation on MTP function, we created mutants via site-directed mutagenesis. Although D169V was expressed in the endoplasmic reticulum and interacted with apolipoprotein B (apoB) 17, it was unable to bind protein disulfide isomerase, transfer lipids, and support apoB secretion. Computational modeling suggested that D169 could form an internal salt bridge with K187 and K189. Mutagenesis of these lysines to leucines abolished protein disulfide isomerase heterodimerization, lipid transfer, and apoB secretion, without affecting apoB17 binding. Furthermore, mutants with preserved charges (D169E, K187R, and K189R) rescued these activities. CONCLUSIONS: D169V is detrimental because it disrupts an internal salt bridge leading to loss of protein disulfide isomerase binding and lipid transfer activities; however, it does not affect apoB binding. Thus, the N-terminal domain of MTP is also important for its lipid transfer activity.

3-HMG Coenzyme A Lyase Deficiency: Macrocephaly and Left Ventricular Noncompaction with a Novel Mutation.

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency, an inborn error of ketone body synthesis and leucine degradation, is a rare autosomal recessive disease. There are a few reports demonstrating clinical and neuroradiologic findings of this condition. The authors report case of an 8-mo-old infant with HMG-CoA lyase deficiency, who presented with macrocephaly, left ventricular noncompaction, recurrent pulmonary infections, nonketotic hypoglycemia, seizure and metabolic acidosis. There was no significant difference in brain magnetic resonance imaging after leucine-restricted diet and carnitine therapy and neurologic deterioration was not observed. Left ventricular noncompaction is an interesting finding for HMG-CoA lyase deficiency which has not been reported in the literature. The genetic analysis revealed a novel homozygote deletion in exon 3 and 4 in HMGCL gene. HMG-CoA lyase deficiency should be thought in the patients with hypoketotic hypoglycemia, hyperammonemia, elevated liver function tests, noncompaction left ventricle and characteristic white matter changes and in the differential diagnosis of macrocephaly.

A rare cause of protein losing enteropathy: collagenous sprue.

Collagenous sprue is a clinicopathological entity with an unknown etiology. Its clinical features include progressive malabsorption, diarrhea, weight loss, unresponsiveness to treatment, and high mortality rates. The age interval of collagenous sprue is quite broad and ranges between 2 and 85 years. As far as to our knowledge, the presented case is the first reported case in infancy.

Reversible pulmonary arterial hypertension in cobalamin-dependent cobalamin C disease due to a novel mutation in the MMACHC gene.

UNLABELLED: Methylmalonic aciduria and homocystinuria, cobalamin C (CblC) disease (OMIM 277400), is the most frequent inborn error of vitamin B12 (cobalamin, Cbl) metabolism and is caused by an inability of the cell to convert Cbl to its active forms (MeCbl and AdoCbl). More than 75 mutations have been identified in the MMACHC gene which is responsible for CblC disease. We present a case with CblC disease and pulmonary arterial hypertension (PAH) as the main symptom. The patient improved dramatically with parenteral hydroxocobalamin treatment. Most cases of CblC disease have a multisystemic disease with failure to thrive, developmental delay, hypotonia, visual impairment, and hematologic manifestations. This patient had isolated pulmonary hypertension and hyperhomocysteinemia which is thought to be an important factor in the pathogenesis of PAH. Genetic analysis identified a novel homozygous mutation (c.484G > T; p.Gly162Trp) in the MMACHC gene. CONCLUSION: CblC disease should be considered in the differential diagnosis of pulmonary hypertension.

Viral etiology in infants hospitalized for acute bronchiolitis.

Acute bronchiolitis is predominantly a viral disease. Respiratory syncytial virus is the most common agent, but other newly identified viruses have also been considered as causes. The aim of the present study is to determine the respiratory viruses causing acute bronchiolitis in hospitalized infants. Infants younger than 2 years of age who were hospitalized for acute viral bronchiolitis in a children's hospital between November 2011 and May 2012 were evaluated for the presence of viruses as etiologic agents using a realtime polymerase chain reaction method.A total of 55 infants were included in this study. The mean age of the children was 6.98±5.53 months, and 63.6% were male. In the 55 children, 63 viruses were detected. A single viral pathogen was detected in 47 (85.5%) patients, and two viruses were co-detected in 8 (14.6%) patients. Respiratory syncytial virus was the most common virus identified, accounting for 25 (45.5%) cases, followed by rhinovirus (n=9, 16.4%), and human metapneumovirus (n = 8, 14.5%).Although respiratory syncytial virus remains the major viral pathogen in infants hospitalized for acute broncholitis, more than half of bronchiolitis cases are associated with other respiratory viruses.

The association between vitamin D status and recurrent wheezing.

OBJECTIVE: To investigate association between vitamin D status and recurrent wheezing in infants. METHODS: Thirty infants with recurrent wheezing and 45 healthy, similar aged infants without any history of acute or chronic illness were included in the study. The clinical features of infants were recorded and serum 25-hydroxyvitamin D [25(OH)D] levels were measured. Data analysis was performed using SPSS 13 package program. RESULTS: The mean value of 25 (OH) D vitamin levels were 22.1 ± 8.9 IU/L and 18.8 ± 11 IU/L for the control and recurrent attack group respectively. Seventy-three percent of subjects with recurrent wheezing had vitamin D levels in the deficient range (<20 ng/ml) and 48.9 % had vitamin D levels under < 20 ng/ml in the control group. The percentage of insufficient vitamin D levels (<30 ng/ml) were 90 and 77.8 for the patient and control group respectively. Eight patients had extremely deficient vitamin D (<10 ng/ml) levels. There was no statistical significance between the groups in terms of the distribution of 25 (OH)D level. CONCLUSIONS: The present study did not demonstrate significant association between vitamin D status and recurrent wheezing in the infants.

Differences in iron deficiency anemia and mean platelet volume between children with simple and complex febrile seizures.

OBJECTIVE: The relationship between iron deficiency anemia and febrile seizures (FSs) were examined in several studies before. The aim of our study is to find out the differences regarding iron deficiency anemia, demographic characteristics and mean platelet volume (MPV) which is an inflammatory marker between simple and complex febrile seizure groups. METHODS: In this study, the authors investigated the recordings of 493 children with a diagnosis of simple and complex febrile seizure, aged between 6 months and 6 years, followed between 2002 and 2010 retrospectively. RESULTS: Mean age and male/female ratio were similar in two groups. There was no significant difference regarding with age, gender and family history of FS between two groups. We found significant difference statistically with respect to gestational age, consanguinity, family history of epilepsy and birth weight between two groups. The mean levels of Hb, Htc, MCV were lower and Plt and RDW levels were higher in children with CFS than SFS group, the differences were statistically significant (p: 0.001). A higher proportion of children with CFS (16.2%) had iron deficiency anemia compared to SFS group (12.1%). Mean platelet volume (MPV) of CFS (7.99±0.96fL) were significantly lower than that of SFS group (8.77±0.75) (p<0.001). CONCLUSIONS: The results of this study suggests that iron deficiency anemia is more frequently seen among the patients with CFS than the patients with SFS. The lower levels of MPV as an inflammatory marker, supports the idea that CFS is a brain inflammatory disease and the consequence of this inflammatory mechanism is the development of the epilepsy. Further studies are necessary to highlight the relationship between iron metabolism, inflammation and seizures.

Clinical and epidemiological features of Turkish children with 2009 pandemic influenza A (H1N1) infection: experience from multiple tertiary paediatric centres in Turkey.

BACKGROUND: In April 2009 a novel strain of human influenza A, identified as H1N1 virus, rapidly spread worldwide, and in early June 2009 the World Health Organization raised the pandemic alert level to phase 6. Herein we present the largest series of children who were hospitalized due to pandemic H1N1 infection in Turkey. METHODS: We conducted a retrospective multicentre analysis of case records involving children hospitalized with influenza-like illness, in whom 2009 H1N1 influenza was diagnosed by reverse-transcriptase polymerase chain reaction assay, at 17 different tertiary hospitals. RESULTS: A total of 821 children with 2009 pandemic H1N1 were hospitalized. The majority of admitted children (56.9%) were younger than 5 y of age. Three hundred and seventy-six children (45.8%) had 1 or more pre-existing conditions. Respiratory complications including wheezing, pneumonia, pneumothorax, pneumomediastinum, and hypoxemia were seen in 272 (33.2%) children. Ninety of the patients (11.0%) were admitted or transferred to the paediatric intensive care units (PICU) and 52 (6.3%) received mechanical ventilation. Thirty-five children (4.3%) died. The mortality rate did not differ between age groups. Of the patients who died, 25.7% were healthy before the H1N1 virus infection. However, the death rate was significantly higher in patients with malignancy, chronic neurological disease, immunosuppressive therapy, at least 1 pre-existing condition, and respiratory complications. The most common causes of mortality were pneumonia and sepsis. CONCLUSIONS: In Turkey, 2009 H1N1 infection caused high mortality and PICU admission due to severe respiratory illness and complications, especially in children with an underlying condition.

The relationship between vitamin D receptor gene polymorphisms and bone density, osteocalcin level and growth in adolescents.

BACKGROUND/OBJECTIVE: The relationship between vitamin D receptor gene polymorphisms and bone density, osteocalcin and growth was investigated. SUBJECTS: Eighty eight adolescents aged between 8-15, with no history of illness influencing the level of bone parameters, were examined in our study. METHODS: Areal BMD for lumbar spine (L1-4) was assessed by dual energy X-ray absorptiometry (DEXA). Height and weight were measured on the day of the DEXA scans. Serum osteocalcin level was determined by using ELISA method. DNA was extracted from white blood cells, amplified by the polymerase chain reaction (PCR) and the polymorphic sites were analyzed by using ApaI, TaqI and FokI restriction enzymes. RESULTS: The most frequent genotypes were FF (% 54.6), Aa (% 53.4) and Tt (% 48.8). No significant relationship was found between VDR genotypes and areal BMD, osteocalcin level or growth in either sex. But there was a strong tendency for a higher BMD at the lumbar spine of TT and AA genotypes compared to tt and Aa genotypes. The children with TT genotype were taller and heavier than the children with tt genotype CONCLUSION: Our results suggest that VDR gene TaqI polymorphism may be associated with body weight and bone mass, but more studies with larger groups should be conducted.

Donohue syndrome in a neonate with homozygous deletion of exon 3 of the insulin receptor gene.

Donohue syndrome describes the clinical consequences of the most severe genetic loss of insulin receptor function. The cardinal features are severe linear growth impairment pre- and postnatally with abnormal glucose metabolism and a characteristic pattern of soft tissue overgrowth. We report a 5 day old neonate with refractory hyperglycemia and paradoxical hypoglycemia, severe intrauterine growth retardation, typical 'elfin' facies (hypertrichosis, large and low-set ears, broad nasal tip, flared nares, thick lips), reduced subcutaneous fat, distended abdomen, and enlarged external genitalia and nipples. Fasting serum insulin and C-peptide were severely elevated at >2,100 pmol/l and >2,331 pmol/l, respectively. In addition, hepatic, ovarian and renal enlargement was demonstrated by ultrasonography. The neonate died within two months secondary to hypoglycemia. Diplex PCR analysis of the insulin receptor gene revealed the neonate to be homozygous for deletion of exon 3. Both parents were heterozygous for this deletion but were metabolically healthy. As such a deletion has previously been reported in Israel, we suggest that it may show a founder effect in the Middle East.

Valproate-associated coagulopathies in children during short-term treatment.

Valproic acid is one of the most frequently prescribed antiepileptic drugs for the therapy of generalized and focal epilepsies. Valproate induces a variety of hemostatic disorders such as thrombocytopenia, abnormal platelet function, hypofibrinogenemia, and decreased concentrations of von Willebrand factor, and it rarely causes serious bleeding complications. It may also lead to atherosclerosis and thrombosis. However, there is still lack of knowledge about the incidence and occurrence of these particular side effects. In this prospective systematic study, we assessed the early effects of sodium valproate on both pro- and anticoagulatory factors, homocysteine, and lipoprotein (a) in 24 newly diagnosed epileptic children treated with valproate. Valproate causes decreased factor VII levels, platelet count, factor VIII, Protein C, fibrinogen, and increased lipoprotein (a) levels. To the best of our knowledge, our report is the first in the medical literature, which describes that valproate significantly reduces factor VII levels even during short-term therapy.

Management of central diabetes insipidus with oral desmopressin in a patient with ectrodactyly and cleft lip/palate (ECP) syndrome.

We present a female infant with facial abnormalities such as bilateral cleft lip and palate, ectrodactyly and central diabetes insipidus. She had a history of recurrent hypernatremic attacks and she was treated successfully with oral desmopressin. As an alternative to the nasal route, long-term management was achieved using oral route and she had a favorable growth and development during infancy.

Acute hemorrhagic pancreatitis due to the use of valproic acid in a child.

Acute pancreatitis is rarely seen in children, and it is often drug induced. Valproic acid (VPA) is one of the most widely used anticonvulsants for children all over the world. We present 11-year-old boy developing pancreatitis after 6 months of therapy with VPA. The symptoms of pancreatitis subsided within 2 weeks after discontinuation of VPA. It seems that the prognosis of VPA-associated acute pancreatitis depends on early diagnosis, timely withdrawal of the offending agent and the treatment.