Assessment of the diagnosis, treatment, and follow-up of a group of Turkish pediatric glycogen storage disease type 1b patients with varying clinical presentations and a novel mutation.

OBJECTIVES: Glycogen storage disease (GSD) type 1b is a multisystemic disease in which immune and infectious complications are present, different from GSD type 1a. Treatment with granulocyte-colony stimulating factor (G-CSF) is often required in the management of neutropenia and inflammatory bowel disease. Recently, an alternative treatment option to G-CSF has been preferred, like empagliflozin. To report on the demographics, genotype, clinical presentation, management, and complications of pediatric patients with glycogen storage disease type 1b (GSD 1b). METHODS: A retrospective analysis of the clinical course of eight patients with GSD type 1b whose diagnosis was confirmed by molecular testing. RESULTS: The mean age at referral was four months. The diagnosis of GSD 1b was based on clinical and laboratory findings and supported by genetic studies. One patient presented with an atypical clinical finding in the form of hydrocephalus at the time of first admission. The first symptom was abscess formation on the scalp due to neutropenia in another patient. Other patients had hypoglycemia at the time of admission. All patients presented suffered from neutropenia, which was managed with G-CSF, except one. Hospitalizations for infections were frequent. One patient developed chronic diarrhea and severe infections, which have been brought under control with empagliflozin. CONCLUSIONS: Neutropenia is an essential finding in GSD 1b and responsible for complications. The coexistence of hypoglycemia and neutropenia should bring to mind GSD 1b. Empagliflozin can be a treatment option for neutropenia, which is resistant to G-CSF treatment.

The clinical variations and diagnostic challenges of deoxyguanosine kinase deficiency: a descriptive case series.

OBJECTIVES: Deoxyguanosine kinase (DGUOK) deficiency is one of the leading causes of the mitochondrial DNA-depletion syndromes (MDDS) associated with hepatocerebral involvement. Herein, we present four cases of DGUOK deficiency to emphasize the clinical variability of disease and the challenges in the diagnosis of DGUOK deficiency. CASE PRESENTATION: Hepatomegaly, hyperlactatemia, elevated alpha fetoprotein (AFP), alanine, and transaminase levels were detected in all patients, and cholestasis, coagulopathy, and hypotonia were common findings. All patients had a low birth weight, one patient underwent liver transplantation (LT). Clinical and laboratory findings of two patients and one patient suggested neonatal hemochromatosis and type 1 tyrosinemia, respectively. All patients were diagnosed with DGUOK deficiency by performing molecular genetic analysis. CONCLUSIONS: Mitochondrial DNA-depletion syndromes should be kept in mind in cases in which hypotonicity, lactic acidosis, and neonatal cholestasis are observed. DGUOK deficiency may present in different clinics suggesting neonatal hemochromatosis or tyrosinemia type 1.

GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension.

Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in endothelial cells. Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification. Thus, GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension. These findings provide new insight into the pathogenesis of portal hypertension, a major contributor to morbidity and mortality from liver disease.

Recessive Mutations in KIF12 Cause High Gamma-Glutamyltransferase Cholestasis.

Undiagnosed liver disease remains an unmet medical need in pediatric hepatology, including children with high gamma-glutamyltransferase (GGT) cholestasis. Here, we report whole-exome sequencing of germline DNA from 2 unrelated children, both offspring of consanguineous union, with neonatal cholestasis and high GGT of unclear etiology. Both children had a rare homozygous damaging mutation (p.Arg219* and p.Val204Met) in kinesin family member 12 (KIF12). Furthermore, an older sibling of the child homozygous for p.Val204Met missense mutation, who was also found to have cholestasis, had the same homozygous mutation, thus identifying the cause of the underlying liver disease. Conclusion: Our findings implicate rare homozygous mutations in KIF12 in the pathogenesis of cholestatic liver disease with high GGT in 3 previously undiagnosed children.

The effect of Helicobacter pylori eradication on functional dyspepsia in Turkish children.

BACKGROUND: The aim of this study was to evaluate the effect of Helicobacter pylori (H. pylori) eradication on dyspepsia symptom scores in children with functional dyspepsia (FD). MATERIALS AND METHODS: One hundred and fifty functional dyspeptic children (ages 8-18 years, mean: 13.3 ± 2.84 years; 30% male) were enrolled to this prospective study. Upper gastrointestinal endoscopy was performed on all patients, and the samples from the gastric antrum and corpus were obtained for the existence of H. pylori. 13 Carbon-urea breath test was performed to evaluate the eradication therapy's efficacy. The symptoms were assessed at first visit and at the 8th week and 16th week. RESULTS: Forty-nine (33%) children were in the H. pylori-positive group, and 101 (67%) children were in the H. pylori-negative group. Dyspepsia symptom scores improved at 8th week in both groups (P < .05). Helicobacter pylori was eradicated in 30 patients (61%), while in the H. pylori-eradicated group, all dyspepsia symptoms' scores decreased, and in the H. pylori-uneradicated group, only three symptoms' scores decreased. Symptom scores were lower in H. pylori-eradicated group than H. pylori-uneradicated group. CONCLUSIONS: Although the tests used for the diagnosis of H. pylori in functional dyspeptic patients increased the cost of health care, the dyspepsia symptom scores decreased with the eradication therapy in a high prevalence community. The findings may differ in low prevalence communities where the diagnostic tests for H. pylori infection are not recommended in children in the absence of alarm signs or symptoms.

CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis.

BACKGROUND: Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies. METHODS: We studied 11 patients with abdominal pain and diarrhea caused by early-onset protein-losing enteropathy with primary intestinal lymphangiectasia, edema due to hypoproteinemia, malabsorption, and less frequently, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease; the disorder followed an autosomal recessive pattern of inheritance. Whole-exome sequencing was performed to identify gene variants. We evaluated the function of CD55 in patients' cells, which we confirmed by means of exogenous induction of expression of CD55. RESULTS: We identified homozygous loss-of-function mutations in the gene encoding CD55 (decay-accelerating factor), which lead to loss of protein expression. Patients' T lymphocytes showed increased complement activation causing surface deposition of complement and the generation of soluble C5a. Costimulatory function and cytokine modulation by CD55 were defective. Genetic reconstitution of CD55 or treatment with a complement-inhibitory therapeutic antibody reversed abnormal complement activation. CONCLUSIONS: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (the CHAPLE syndrome) is caused by abnormal complement activation due to biallelic loss-of-function mutations in CD55. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Iron Overload in the Liver of 2 Children: Nonalcoholic Steatohepatitis and Juvenile Hemochromatosis.

BACKGROUND: Iron overload disorders are hereditary hemochromatosis and secondary etiologies other than hereditary hemochromatosis. We describe 2 boys presenting with iron overload. Juvenile hemochromatosis and nonalcoholic steatohepatitis (NASH) related iron overload are the genetic and secondary causes, respectively. OBSERVATIONS: Both patients benefited from phlebotomy even if they had different etiologies. CONCLUSIONS: In childhood, the diagnosis of iron overload syndromes is crucial because they do not confront us with obvious symptoms and findings. Early initiation of a phlebotomy program can prevent mortality. NASH might lead to iron overload and iron overload might aggravate the clinical course of NASH.

Favorable Response to Sirolimus in a Child With Blue Rubber Bleb Nevus Syndrome in the Gastrointestinal Tract.

Recently, sirolimus was demonstrated to be effective in treating vascular lesions and lessening the frequency of bleeding and secondary iron deficiency anemia. We present a child with blue rubber bleb nevus syndrome who had prolonged history of iron deficiency anemia secondary to unrecognized gastrointestinal bleeding. Treatment with propranolol, omeprazole and iron had failed. After 2.5 months of sirolimus therapy (trough levels 1 to 5 ng/mL), his hemoglobin concentration improved into the normal range and remained stable. Vascular malformations on both the patient's tongue and in the fundus of his stomach shrank within 5 months of the initiation of sirolimus. In gastrointestinal involvement of blue rubber bleb nevus syndrome sirolimus was found to be effective even in the tongue's vascular lesions.

Mutant neurogenin-3 in a Turkish boy with congenital malabsorptive diarrhea.

Congenital diarrheal disorders are caused by disruption in nutrient digestion, absorption, or transport, enterocyte development and functioning, or enteroendocrine functioning. Many additional rare forms of congenital diarrhea are expected to be linked to genes associated with appropriate intestinal fluid and electrolyte balance. Neurogenin-3 mutation, a very rare form of congenital diarrhea, disrupts enteroendocrine cell differentiation and is characterized by malabsorption and the absence of pancreatic islet cells. Diabetes mellitus is typically associated with malabsorptive diarrhea at early onset or at later presentation in neurogenin-3 mutation. Here, we describe the case of an infant with homozygous neurogenin-3 mutation who had severe malabsorptive diarrhea and episodes of hyperchloremic metabolic acidosis after birth. Remarkably, cholestyramine was effective at reducing stool volume and frequency and improved the consistency of the stools; diabetes was not present in this patient.

Chanarin-Dorfman syndrome: a novel mutation in a Turkish girl.

Chanarin-Dorfman syndrome (CDS) is an autosomal recessive disorder, characterized by intracellular accumulation of lipid droplets in most tissues. It is very difficult to find a correlation between the phenotypic and genotypic features due to the occurrence of novel ABHD5 [ α/ß hydrolase domain-containing protein-5; originally called CGI-58 (comparative gene identification-58)] mutations and the fact that there are only a few cases in the literature. The protein encoded by this gene is a cofactor for adipose triglyceride lipase (ATGL), which promotes the catabolism of stored fat. The clinical phenotype involves multiple organs and systems. Ichthyosis, nonbullous congenital ichthyosiform erythroderma and cytoplasmic accumulation of lipid droplets in granulocytes (Jordans' bodies) are always present. Peripheral blood smear is an easy method for diagnosing CDS; its use can also avoid unnecessary further testing. Herein, we report a patient with a homozygous mutation in ABHD5 that has never previously been described. Moreover, the case was diagnosed as Chanarin-Dorfman syndrome with only a peripheral blood smear.

Rare disorders can be an underlying cause of cyclic vomiting: Familial Mediterranean fever, Helicobacter pylori gastritis, and cavernous transformation of the portal vein.

BACKGROUND/AIMS: Considering the etiology of cyclic vomiting syndrome (CVS) in childhood, a variety of underlying organic causes has been clearly identified in the literature. The aim of this study was to emphasize that endoscopic evaluation in the first step may help diagnosis and treatment in patients with CVS, unlike the CVS-related "North American Society for Pediatric Gastroenterology, Hepatology and Nutrition" (NASPGHAN) consensus statement in 2008. MATERIALS AND METHODS: The medical files of patients with vomiting complaints admitted to our tertiary center between the years 2007 and 2012 were analyzed retrospectively. Patients were identified according to the International Classification of Diseases (ICD) codes at their initial presentation, including vomiting. RESULTS: A total of 815 patients with vomiting complaints were evaluated. Of the 379 patients who presented with vomiting only, 336 patients were already being followed for chronic vomiting. Cyclic vomiting was detected in 31 out of 336 patients. CONCLUSION: In our series, familial Mediterranean fever (FMF), cavernous transformation of the portal vein, and Helicobacter pylori (HP) gastritis presented with CVS for the first time in the pediatric age group. We emphasize that endoscopic evaluation in patients with CVS should be performed as the first step for appropriate diagnosis and treatment.

Aspartate aminotransferase-to-platelet ratio index in children with cholestatic liver diseases to assess liver fibrosis.

To assess the relationship between aspartate aminotransferase-platelet ratio index (APRI) and liver fibrosis in children with chronic hepatocellular and biliary cholestatic liver diseases. A retrospective review of one hundred children's demographic and laboratory findings concurrent with liver biopsy, who were followed-up with prolonged cholestasis. The diagnostic accuracy of the APRI was assessed by receiver operating characteristic (ROC) curves. Advanced fibrosis was more common in the hepatocellular group. The APRI values of the two groups were similar. The patients with advanced fibrosis had significantly higher APRI values than patients with mild fibrosis, in both the hepatocellular and biliary groups. The areas under the ROC were 0.68 and 0.81 in the hepatocellular and biliary groups respectively. The cut-off values of APRI for discriminating advanced fibrosis were 0.93 (65% sensitivity, 69% specificity) in the hepatocellular group and 2.35 (62% sensitivity, 96% specificity) in the biliary group. APRI may be most efficient for discriminating between advanced and mild fibrosis in biliary cholestatic liver disease patients.

Chylous ascites after a living-donor liver graft, effectively treated in a child with octreotide.

Chylous ascites after a liver transplant is a rare complication of surgery. We report a 11-month-old girl with biliary atresia who was presented with chylous ascites after a liver transplant. On the seventh day after surgery, while being fed, chylous ascites was observed. Besides fasting and diuretics, total parenteral nutrition and somatostatin analogue (octreotide) were initiated. Chylous ascites resolved in 3 weeks. Abdominal distention recurred 1 week later; fasting and total parenteral nutrition, combined with octreotide, were administered again for 2 more weeks. Thereafter, enteral feeding was started without any complications.

Immune thrombocytopenic purpura in a liver transplant patient.

Thrombocytopenia is common during the early posttransplant period. Most cases are mild and recover in 1 month. Occasionally, severe thrombocytopenia may occur in the late posttransplant period. We report a 10-year-old boy with severe thrombocytopenia 3.5 years after liver transplant. We exclude secondary causes of thrombocytopenia. Bone marrow aspiration findings and treatment response were suggestive for immune thrombocytopenic purpura. The patient was treated with intravenous immunoglobulin at thrombocytopenia periods successfully. We continued tacrolimus, but preferred a reduced dose. In conclusion, immune thrombocytopenic purpura should be borne in mind as a reason of late onset, severe thrombocytopenia after liver transplant.

Jejunal stricture in a premature infant: Is cytomegalovirus the causative pathogen or a superinfection?

Cytomegalovirus infection can cause gastrointestinal disease, especially in immunocompromised patients and premature infants. In the neonatal period, however, gastrointestinal involvement is infrequent. A case of cytomegalovirus enteritis and jejunal stricture in a preterm neonate is presented. The diagnosis was established after the histopathology of the surgical specimen demonstrated the presence of cytomegalovirus inclusion bodies. Every neonatal gastrointestinal cytomegalovirus infection case has been described in the literature as a necrotizing enterocolitis-like illness, but none of them clearly identifies whether cytomegalovirus was the pathogen responsible for causing necrotizing enterocolitis or whether cytomegalovirus occured as an infection during the course of necrotizing enterocolitis.