Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease.

We report a pleiotropic disease due to loss-of-function mutations in RHBDF2, the gene encoding iRHOM2, in two kindreds with recurrent infections in different organs. One patient had recurrent pneumonia but no colon involvement, another had recurrent infectious hemorrhagic colitis but no lung involvement and the other two experienced recurrent respiratory infections. Loss of iRHOM2, a rhomboid superfamily member that regulates the ADAM17 metalloproteinase, caused defective ADAM17-dependent cleavage and release of cytokines, including tumor-necrosis factor and amphiregulin. To understand the diverse clinical phenotypes, we challenged Rhbdf2-/- mice with Pseudomonas aeruginosa by nasal gavage and observed more severe pneumonia, whereas infection with Citrobacter rodentium caused worse inflammatory colitis than in wild-type mice. The fecal microbiota in the colitis patient had characteristic oral species that can predispose to colitis. Thus, a human immunodeficiency arising from iRHOM2 deficiency causes divergent disease phenotypes that can involve the local microbial environment.

Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease.

Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.

Hematopoietic Stem Cell Transplantation From Unrelated Donors in 2 Cases of Interleukin-10 Receptor Deficiency: Is Surgery Not a Requirement?

Mutations in interleukin-10 and its receptors cause infantile inflammatory bowel disease (IBD), a hyperinflammatory disorder characterized by severe, treatment-refractory colitis, multiple abscesses, and enterocutaneous fistulas. Patients with infantile IBD often require several surgical interventions, including complete colectomy, and hematopoietic stem cell transplantation is currently the only known medical therapy. Traditionally, operative management has been preferred before stem cell transplantation because of the latter's increased susceptibility to procedural complications; however, surgical intervention could be delayed, and possibly reconsidered, because our 2 patients with infantile IBD demonstrated a rapid response to treatment via engraftment.

SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome.

Syndromic diarrhea (or trichohepatoenteric syndrome) is a rare congenital bowel disorder characterized by intractable diarrhea and woolly hair, and it has recently been associated with mutations in TTC37. Although databases report TTC37 as being the human ortholog of Ski3p, one of the yeast Ski-complex cofactors, this lead was not investigated in initial studies. The Ski complex is a multiprotein complex required for exosome-mediated RNA surveillance, including the regulation of normal mRNA and the decay of nonfunctional mRNA. Considering the fact that TTC37 is homologous to Ski3p, we explored a gene encoding another Ski-complex cofactor, SKIV2L, in six individuals presenting with typical syndromic diarrhea without variation in TTC37. We identified mutations in all six individuals. Our results show that mutations in genes encoding cofactors of the human Ski complex cause syndromic diarrhea, establishing a link between defects of the human exosome complex and a Mendelian disease.

Percutaneous endoscopic gastrostomy in children: Is early feeding safe?

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is the preferred method to provide nutritional support for patients with normal gastrointestinal function but cannot be fed orally for a variety of reasons. Owing to safety concerns, the first feeding after PEG tube placement is generally delayed. Early feeding may be an option; however, childhood studies regarding early feeding after the PEG procedure are highly insufficient. METHODS: A prospective randomized controlled study was conducted to compare early (4th hour) and late (12th hour) feeding after the PEG procedure. The PEG process was performed with the standard pull technique. Prophylactic antimicrobial drugs were not used. Complications such as gastric residue after feeding, vomiting, fever, systemic signs of infection, and duration of hospital stay were recorded. Tube feeding training was given to parents during their stay in the hospital in both groups. In the first and third days following PEG, the patients were visited by an experienced nurse in their homes and evaluated in terms of potential complications. RESULTS: The study was completed with a total of 69 patients: 35 in the early feeding group and 34 in the late feeding group. The demographic characteristics of the groups were similar. Vomiting was rare and detected as similar in both groups (early feeding group 8.5% [3/35], late feeding group 8.8% [3/34], P = 1.00). Rarely, minor gastric residue was observed in both groups (early feeding group 11.4%, late feeding group 8.8% [P = 1.00]). The amount of gastric residue in the early feeding group was a maximum of 13.2 mL, whereas the late feeding group had a maximum of 14.3 mL. The average duration of stay in the hospital for the early and late feeding groups was calculated as 6.7 ± 0.64 and 28.3 ± 3.74 hours, respectively (P < 0.001). Leakage from gastrostomy fistulas, peritonitis, and aspiration were not observed in any patients. CONCLUSIONS: The feeding at the fourth hour after PEG placement was safe and well tolerated by patients and shortened the duration of the hospital stay. The use of prophylactic antibiotics seems to be unnecessary before the procedure.

Extremely rare cause of congenital diarrhea: enteric anendocrinosis.

Congenital diarrheal disorders consist of a variety of chronic enteropathies. There are approximately 30 different diseases that can be classified into four groups according to the mechanisms involved in pathogenesis: (i) absorption and transport of nutrients and electrolytes; (ii) enterocyte differentiation and polarization; (iii) enteroendocrine cell differentiation; and (iv) modulation of the intestinal immune response. Affected patients often present with life-threatening diarrhea, in the first few weeks of life. A new disorder, enteric anendocrinosis, which is characterized by severe malabsorptive diarrhea and a lack of intestinal enteroendocrine cells has recently been described in six patients with recessively inherited mutations in the Neurogenin-3 gene. In this report we describe a seventh case with a review of the literature.

The frequency of vitamin B12, iron, and folic acid deficiency in the neonatal period and infancy, and the relationship with maternal levels.

AIM: The most important function of vitamin B12 is to accomplish DNA synthesis, which is necessary for cell division and proliferation. Deficiency of vitamin B12 causes megaloblastic anemia, retardation of growth, and delay in neuromotor maturation. Newborns whose mothers have vitamin B12 deficiency are born with low vitamin B12 storages, and are at risk in terms of vitamin B12 deficiency symptoms during infancy. The aim of our study was to investigate the frequency of anemia and deficiency of vitamin B12, folic acid, and iron in pregnant women living in our region, in their newborn babies, and during the infancy period of these babies. Another aim of our study was to investigate the correlation between the levels of these vitamins in newborns and in their mothers. MATERIAL AND METHODS: In our study, 250 pregnant women at 38-42 gestational weeks, who were admitted for delivery to Gynecology and Obstetrics Clinic and their babies with a birth weight over 2500 g were included in the study. RESULTS: We determined that 24.8% of the pregnant women had anemia, 28% had low ferritin levels, 90.4% had vitamin B 12 deficiency, and 22.4% had folic acid deficiency. Some 3.2% of the newborns had anemia, 2.8% had low ferritin levels, and 72.4% had vitamin B12 deficiency. Among the infants who presented for a follow-up visit at 6 months of age, 22.3% had anemia, 14.9% had low ferritin levels, 40.4% had vitamin B12 deficiency, and 1.06% had folic acid deficiency. In addition, we found that the levels of vitamin B12 and folic acid in newborns were related to the levels of vitamin B12 and folic acid in their mothers. CONCLUSION: Development of low vitamin B12 stores in newborns and the development of vitamin B12 deficiency during infancy, which may result in irreversible complications including neurologic complications, can be prevented by preventing vitamin B12 deficiency during pregnancy.

Hearing evaluation with ABR in pediatric patients with celiac disease.

BACKGROUND/AIMS: Celiac disease (CD) is an autoimmune and genetic disease that is triggered by gluten intolerance. We aimed to investigate whether Celiac disease have any effect on Auditory Brainstem Response (ABR) waves compare to a healthy control group, and present its association with sensorineural hearing loss (SNHL). MATERIALS AND METHODS: Thirty-eight patients aged 2 to 16 years old were included in the study. The patients had confirmed diagnosis of Celiac disease through duodenal biopsies and transglutaminase Antibody (Ab) (+). The control group consisted of 18 children aged 3 to 17 years old who were all admitted to the pediatric gastroenterology department due to complaints of constipation and transglutaminase Ab (-).All children underwent Auditory-Brain-Stem-Evoked Responses (ABR). The data were gathered using click stimulus at 10/s frequency 90dB HL. RESULTS: The results of ABR examination did not show any difference between the patient group and control group as regards the latency of the waves I, III, V. No difference was observed between the two groups in the interpeak latecies I-III, I-V and III-V. None of the patients was observed to have clinical hearing loss. DISCUSSION: The exact pathogenesis of neurological damages observed in Celiac disease is still unknown. Humoral immune mechanisms are the most frequently attributed cause. CONCLUSION: Although no significant difference was found in hearing values between the study group and healthy control group, there is a need for further research on this subject.

Pediatric Liver Transplantation: Our Experiences.

OBJECTIVE: The aim of our study was to evaluate our liver transplant pediatric patients and to report our experience in the complications and the long-term follow-up results. MATERIALS AND METHODS: Patients between the ages of 0 and 18 years, who had liver transplantation in the organ transplantation center of our university hospital between 1997 and 2016, were included in the study. The age, sex, indications for the liver transplantation, complications after the transplantation, and long-term follow-up findings were retrospectively evaluated. The obtained results were analyzed with statistical methods. RESULTS: In our organ transplantation center, 62 pediatric liver transplantations were carried out since 1997. The mean age of our patients was 7.3 years (6.5 months-17 years). The 4 most common reasons for liver transplantation were: Wilson's disease (n=10; 16.3%), biliary atresia (n=9; 14.5%), progressive familial intrahepatic cholestasis (n=8; 12.9%), and cryptogenic cirrhosis (n=7; 11.3%). The mortality rate after transplantation was 19.6% (12 of the total 62 patients). The observed acute and chronic rejection rates were 34% and 4.9%, respectively. Thrombosis (9.6%) was observed in the hepatic artery (4.8%) and portal vein (4.8%). Bile leakage and biliary stricture rates were 31% and 11%, respectively. 1-year and 5-year survival rates of our patients were 87% and 84%, respectively. CONCLUSION: The morbidity and mortality rates in our organ transplantation center, regarding pediatric liver transplantations, are consistent with the literature.

Total oxidant status, total antioxidant capacity and ischemia modified albumin levels in children with celiac disease.

In our study, we aimed to investigate ischemia modified albumin (IMA) as an oxidative stress marker, as well as other oxidant and antioxidant markers that have not been evaluated in children with celiac disease. A total of 37 pediatric patients who were diagnosed with celiac disease (CD) and 29 healthy children were enrolled in this prospective study. We evaluated the IMA, total oxidant status, total antioxidant capacity, sulfhydryl, and advanced oxidation protein products in all of the subjects. We also compared the levels at the time of the diagnosis, and following a gluten-free diet (GFD) in the children with CD. While the IMA and the other oxidant marker levels were significantly higher in the patient group compared to the control group, the antioxidant marker levels were found to be significantly lower in the patient group, compared to the control group. We also determined that the tissue transglutaminase IgA showed a highly positive correlation, and that the IMA showed a moderately positive correlation with the Marsh-Oberhuber histopathological stage. Additionally, the IMA and other oxidant marker levels were significantly lower, while the antioxidant marker levels were significantly higher after the GFD, compared to the pre-diet period. We detected that oxidative stress played a role in the pathogenesis of CD, and that this could be evaluated using oxidative stress markers, which would regress after the GFD. We also detected that IMA is a marker that shows a correlation with the histopathological stage, and may be used in the diagnosis.

Atypical manifestation of LRBA deficiency with predominant IBD-like phenotype.

BACKGROUND: Inflammatory bowel diseases (IBDs) denote a heterogeneous group of disorders associated with an imbalance of gut microbiome and the immune system. Importance of the immune system in the gut is endorsed by the presence of IBD-like symptoms in several primary immunodeficiencies. A fraction of early-onset IBDs presenting with more severe disease course and incomplete response to conventional treatment is assumed to be inherited in a Mendelian fashion, as exemplified by the recent discovery of interleukin (IL)-10 (receptor) deficiency. METHODS: We analyzed a patient born to consanguineous parents suffering from severe intestinal manifestations since 6 months of age and later diagnosed as IBD. Eventually, she developed autoimmune manifestations including thyroiditis and type I diabetes at the age of 6 and 9 years, respectively. Combined single-nucleotide polymorphism array-based homozygosity mapping and exome sequencing was performed to identify the underlying genetic defect. Protein structural predictions were calculated using I-TASSER. Immunoblot was performed to assess protein expression. Flow cytometric analysis was applied to investigate B-cell subpopulations. RESULTS: We identified a homozygous missense mutation (p.Ile2824Pro) in lipopolysaccharide-responsive and beige-like anchor (LRBA) affecting the C-terminal WD40 domain of the protein. In contrast to previously published LRBA-deficient patients, the mutant protein was expressed at similar levels to healthy controls. Immunophenotyping of the index patient revealed normal B-cell subpopulations except increased CD21 B cells. CONCLUSIONS: We describe a patient with a novel missense mutation in LRBA who presented with IBD-like symptoms at early age, illustrating that LRBA deficiency should be considered in the differential diagnosis for IBD(-like) disease even in the absence of overt immunodeficiency.

A rare outcome of iron deficiency and pica: Rapunzel syndrome in a 5-year-old child iron deficiency and pica.

Bezoar is defined as the accumulation of organic or nonbiological substances inside the gastrointestinal system. Trichobezoars are the most frequently detected ones and are mostly present in patients with neuropsychiatric disorders. The continuance of the trichobezoar tail-shaped extension over the duodenum and jejunum is described in Rapunzel syndrome. Both conditions are rarely reported in children. The present case submitted here is related to a 5-year-old girl referred with an abdominal mass and anemia, diagnosed with Rapunzel syndrome and developing trichobezoar due to iron deficiency and pica.

A very rare cause of acute pancreatitis: Berardinelli-Seip congenital lipodystrophy.

Pancreatitis is among rare diseases in pediatrics clinics. It is usually presented with a sign of underlying systemic disease. Berardinelli-Seip congenital lipodystrophy (BSCL) is a very rare disease characterized by near absence of adipose tissue resulting in apparent muscle hypertrophy from birth or early infancy associated with severe insulin resistance. Common clinical features are hypertriglyceridemia, acanthosis nigricans, hepatomegaly with or without splenomegaly and high stature. Acromegaloid features, cardiomyopathy and mental retardation can also be present. We describe a 7-year-old Turkish boy with these clinical features of BSCL and presented with acute pancreatitis.

The role of Bifidobacterium lactis B94 plus inulin in the treatment of acute infectious diarrhea in children.

BACKGROUND/AIMS: In contrast to many other studies of probiotic species, the number of publications evaluating Bifidobacterium lactis and its combinations with prebiotics as treatments for acute infectious diarrhea is limited. We investigated the synbiotic effects of B. lactis B94 plus inulin on acute infectious diarrhea. MATERIALS AND METHODS: The study was conducted on children with acute diarrhea between the ages of 2 and 60 months. The patients were administered 5×1010 colony-forming units (CFU) of B. lactis B94 plus 900 mg inulin or placebo, once a day for five days. Stools were examined for Rotavirus, Adenovirus, Entamoeba histolytica, Salmonella, Shigella, Campylobacter, Clostridium difficile, Cryptosporidium, and parasites. RESULTS: We examined 79 patients in the synbiotic group and 77 patients in the placebo group. The duration of diarrhea was significantly reduced in the synbiotic group in comparison with the placebo group (3.9±1.2 days vs. 5.2±1.3 days, respectively; p<0.001). Moreover, the number of diarrheal stools on the third day was significantly lower in the synbiotic group than in the placebo group (5.5±2.9 vs. 8.3±3.01, respectively; p<0.001). Diarrhea in the synbiotic-group patients with rotavirus infection was of a significantly shorter duration (3.2±1.3 days vs. 5.2±1.3 days, respectively; p=0.001). Duration of diarrhea in patients who started the synbiotic treatment within the first 24 h was shorter than that in the patients who started the treatment later (3.9±1.1 days vs. 4.8±1.8 days, respectively; p=0.002). CONCLUSION: Treatment with 5 × 1010 CFU of B. lactis B94 plus 900 mg inulin shortened the duration of acute watery diarrhea by an average of 31 h. This decrease was most pronounced in cases of Rotavirus diarrhea.

Bilateral congenital cataracts in an infant with Klinefelter syndrome.

Congenital cataract is one of the most treatable causes of visual impairment and blindness during infancy, with an estimated prevalence of approximately 2.5:10,000 infants under the age of 1 year. Congenital cataract can be observed with certain chromosomal abnormalities, such as trisomies, deletions, translocations and Turner syndrome. In Klinefelter syndrome, however, ocular complications and cataract are not commonly encountered, so reports in the literature are very rare. In this manuscript, we present a 3-month-old male infant who had congenital cataracts. Chromosomal analysis revealed that his karyotype was 47,XXY. He did not show any of the main clinical signs of Klinefelter syndrome because of his very young age. To the best of our knowledge, our patient is only the second-ever case reported in the literature in which congenital cataracts have been found in an infant with a nonmosaic 47,XXY karyotype. The aim of the present report is to both describe the ocular abnormalities that can sometimes be found in Klinefelter syndrome and to emphasize the importance of performing a karyotype analysis in order to rule out chromosome abnormalities in patients with congenital cataracts.