Pneumatosis cystoides intestinalis: A rare complication after hematopoietic stem cell transplantation.

BACKGROUND: Pneumatosis cystoides intestinalis (PCI) is a disorder in which widespread air sacs are present in mucosa, submucosa, subserosa, and intraabdominal area of the intestinal wall. It has a heterogeneous clinical presentation as a rare complication of intestinal graft-versus-host disease (GVHD). Computed tomography is the preferred imaging method for the diagnosis. Since the air sacs could be ruptured spontaneously, the presence of free air in the peritoneal cavity does not confirm intestinal perforation. The conservative treatment approach is sufficient in cases that do not require urgent surgical intervention, such as perforation or obstruction. CASE: Here, we present a 2.5-year-old patient diagnosed with primary hemophagocytic lymphohistiocytosis (pHLH), who underwent allogeneic hematopoietic stem cell transplantation from a matched unrelated donor (MUD) and developed PCI secondary to intestinal GVHD 14th months after HSCT. CONCLUSIONS: Pneumatosis cystoides intestinalis, which is a rare complication, should be kept in mind, especially in patients with intestinal GVHD and receiving intensive immunosuppressive, octreotide, and steroid treatment after HSCT.

Autoimmune atrophic gastritis: The role of Helicobacter pylori infection in children.

BACKGROUND: Autoimmune atrophic gastritis (AIG) is very rare in children. Despite a better understanding of histopathologic changes and serological markers in this disease, underlying etiopathogenic mechanisms and the effect of Helicobacter pylori (H pylori) infection are not well known. We aimed to investigate the relation between AIG and H pylori infection in children. MATERIALS AND METHODS: We evaluated the presence of AIG and H pylori infection in fifty-three patients with positive antiparietal cell antibody (APCA). Demographic data, clinical symptoms, laboratory and endoscopic findings, histopathology, and presence of H pylori were recorded. RESULTS: The children were aged between 5 and 18 years, and 28 (52.8%) of them were male. Mean age was 14.7 ± 2.6 years (median: 15.3; min-max: 5.2-18), and 10 (18.8%) of them had AIG confirmed by histopathology. In the AIG group, the duration of vitamin B12 deficiency was longer (P = .022), hemoglobin levels were lower (P = .018), and APCA (P = .039) and gastrin (P = .002) levels were higher than those in the non-AIG group. Endoscopic findings were similar between the two groups. Intestinal metaplasia was higher (P = .018) in the AIG group. None of the patients in the AIG group had H pylori infection (P = .004). One patient in the AIG group had enterochromaffin-like cell hyperplasia. CONCLUSIONS: Our results show that, in children, H pylori infection may not play a role in AIG. AIG could be associated with vitamin B12 deficiency, iron deficiency, and APCA positivity in children. APCA and gastrin levels should be investigated for the early diagnosis of AIG and intestinal metaplasia.

Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by IL-21 deficiency.

BACKGROUND: Alterations of immune homeostasis in the gut can result in development of inflammatory bowel disease (IBD). Recently, Mendelian forms of IBD have been discovered, as exemplified by deficiency of IL-10 or its receptor subunits. In addition, other types of primary immunodeficiency disorders might be associated with intestinal inflammation as one of their leading clinical presentations. OBJECTIVE: We investigated a large consanguineous family with 3 children who presented with early-onset IBD within the first year of life, leading to death in infancy in 2 of them. METHODS: Homozygosity mapping combined with exome sequencing was performed to identify the molecular cause of the disorder. Functional experiments were performed to assess the effect of IL-21 on the immune system. RESULTS: A homozygous mutation in IL21 was discovered that showed perfect segregation with the disease. Deficiency of IL-21 resulted in reduced numbers of circulating CD19(+) B cells, including IgM(+) naive and class-switched IgG memory B cells, with a concomitant increase in transitional B-cell numbers. In vitro assays demonstrated that mutant IL-21(Leu49Pro) did not induce signal transducer and activator of transcription 3 phosphorylation and immunoglobulin class-switch recombination. CONCLUSION: Our study uncovers IL-21 deficiency as a novel cause of early-onset IBD in human subjects accompanied by defects in B-cell development similar to those found in patients with common variable immunodeficiency. IBD might mask an underlying primary immunodeficiency, as illustrated here with IL-21 deficiency.

Celiac crisis with thrombocytopenia and coagulopathy in a child.

BACKGROUND: Celiac disease rarely presents with edema, hypoalbuminemia, acute metabolic deterioration, and electrolyte imbalances. This life-threatening condition is defined as a celiac crisis and may mimic disorders with metabolic derangement and sepsis. The crisis may present at onset or develop in celiac disease patients with poor compliance to a gluten-free diet. The fluid resuscitation and replacement of electrolyte deficits are life-saving modalities. CASE: A 14-month-old girl was admitted with fever, lethargy, severe dehydration, edema, hypotension, and commenced sepsis therapy. However, the patient had a growth delay and loss of weight with diarrhea and delayed motor skills. On admission, laboratory evaluation showed anemia, coagulopathy, hypoalbuminemia, electrolyte disturbances, and metabolic acidosis and developed thrombocytopenia during follow-up. The celiac serological tests and upper gastrointestinal endoscopic duodenal mucosa appearance, and duodenum histopathology findings suggested celiac disease. CONCLUSIONS: This case highlights that a celiac patient may present with a severe illness like sepsis and may be associated with cytopenia and coagulopathy in the celiac crisis.

UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking.

Variants in the UNC45A cochaperone have been recently associated with a syndrome combining diarrhea, cholestasis, deafness, and bone fragility. Yet the mechanism underlying intestinal failure in UNC45A deficiency remains unclear. Here, biallelic variants in UNC45A were identified by next-generation sequencing in 6 patients with congenital diarrhea. Corroborating in silico prediction, variants either abolished UNC45A expression or altered protein conformation. Myosin VB was identified by mass spectrometry as client of the UNC45A chaperone and was found misfolded in UNC45AKO Caco-2 cells. In keeping with impaired myosin VB function, UNC45AKO Caco-2 cells showed abnormal epithelial morphogenesis that was restored by full-length UNC45A, but not by mutant alleles. Patients and UNC45AKO 3D organoids displayed altered luminal development and microvillus inclusions, while 2D cultures revealed Rab11 and apical transporter mislocalization as well as sparse and disorganized microvilli. All those features resembled the subcellular abnormalities observed in duodenal biopsies from patients with microvillus inclusion disease. Finally, microvillus inclusions and shortened microvilli were evidenced in enterocytes from unc45a-deficient zebrafish. Taken together, our results provide evidence that UNC45A plays an essential role in epithelial morphogenesis through its cochaperone function of myosin VB and that UNC45A loss causes a variant of microvillus inclusion disease.

Pediatric dysphagia overview: best practice recommendation study by multidisciplinary experts.

BACKGROUND: Currently, there is no comprehensive and multidisciplinary recommendation study covering all aspects of pediatric dysphagia (PD). This study aimed to generate PD management recommendations with methods that can be used in clinical practice to fill this gap in our country and in the world, from the perspective of experienced multidisciplinary experts. METHODS: This recommendation paper was generated by a multidisciplinary team, using the seven-step process and a three-round modified Delphi survey via e-mail. First, ten open-ended questions were created, and then detailed recommendations including management, diagnosis, treatment, and follow-up were created with the answers from these questions. Each recommendation item was voted on by the experts as overall consensus (strong recommendation), approaching consensus (weak recommendation) and divergent consensus (not recommended). RESULTS: In the 1st Delphi round, a questionnaire of 414 items was prepared based on the experts' responses to ten open-ended questions. In the 2nd Delphi round, 59.2% of these items were accepted as pre-recommendation. In the 3rd Delphi round, 62.6% of 246 items were accepted for inclusion in the proposals. The final version recommendations consisted of 154 items. CONCLUSIONS: This study includes comprehensive and detailed answers for every problem that could be posed in clinical practice for the management of PD, and recommendations are for all pediatric patients with both oropharyngeal and esophageal dysphagia.

Cancer and constitutional Mismatch Repair Deficiency syndrome due to homozygous MSH 6 mutation in children with Café au Lait Spots and review of literature.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare childhood cancer predisposition syndrome resulting from biallelic germline mutations of mismatch repair (MMR) genes. CMMRD syndrome is characterised by early onset malignancies in children. CASE: Here we present affected children of consanguinous parents diagnosed with CMMRD syndrome due to germline bi-allelic MSH 6 gene mutations with café au lait spots and multiple family cancers from Turkey and reported cases with CMMRD syndrome associated MSH 6 mutation in English literature. Hence, we reviewed English literature from 1990 to 2020 using Pub-Med database. Keywords used to search included constitutional mismatch repair deficiency syndrome, childhood cancer and MSH 6 gene mutation. CONCLUSIONS: We emphasize that the inclusion of CMMRD syndrome in the differential diagnosis of a patient who presents with cafe´ au lait spots and/or hypopigmented skin lesions and cancer especially when consanguinity and/or a history of cancer coexist in children.

IgG4-related disease and ANCA positive vasculitis in childhood: a case-based review.

Autoimmune pancreatitis (AIP) type 1 is an IgG4-related disease (IgG4-RD), characterized by inflammatory pseudotumors and histologically by dense lymphoplasmacytic infiltrates rich in IgG4 positive plasma cells, storiform fibrosis, and obliterative phlebitis. Although quite rare, IgG4-RD was found to be associated with medium or small vessel vasculitides. A new overlap syndrome between IgG4-RD and ANCA-associated vasculitis (AAV) has recently been described in the adult population. Here we present a 16-year-old adolescent girl admitted with abdominal pain, episcleritis, palpable purpura, salivary gland enlargement, and bloody diarrhea. Laboratory investigations revealed findings of glomerulonephritis. Abdominal imaging surprisingly revealed a focal mass in the pancreatic tail, while the c-ANCA level was found to be quite high as well as serum IgG4 level. Biopsy of the pancreatic mass showed lymphoplasmacytic IgG4 positive cells infiltrating the pancreas with storiform fibrosis compatible with IgG4-related AIP. The renal biopsy that was done simultaneously showed necrotizing granulomatous vasculitis indicating AAV. Renal biopsy showed IgG4 positive plasma cells very rarely by immunohistochemical examination, which does not indicate any significance for IgG4-RD. Our diagnosis was IgG4-related AIP and AAV overlap syndrome, which has not been reported in the pediatric populations yet. IgG4-RD should be investigated in patients with ANCA-associated vasculitis who shows atypical organ involvement. We searched the Pubmed/Medline and Google Scholar databases to identify clinical findings, treatment, and outcome of the patients with IgG4-related AIP and AAV.

Congenital Diarrhea and Cholestatic Liver Disease: Phenotypic Spectrum Associated with MYO5B Mutations.

Myosin Vb (MYO5B) is a motor protein that facilitates protein trafficking and recycling in polarized cells by RAB11- and RAB8-dependent mechanisms. Biallelic MYO5B mutations are identified in the majority of patients with microvillus inclusion disease (MVID). MVID is an intractable diarrhea of infantile onset with characteristic histopathologic findings that requires life-long parenteral nutrition or intestinal transplantation. A large number of such patients eventually develop cholestatic liver disease. Bi-allelic MYO5B mutations are also identified in a subset of patients with predominant early-onset cholestatic liver disease. We present here the compilation of 114 patients with disease-causing MYO5B genotypes, including 44 novel patients as well as 35 novel MYO5B mutations, and an analysis of MYO5B mutations with regard to functional consequences. Our data support the concept that (1) a complete lack of MYO5B protein or early MYO5B truncation causes predominant intestinal disease (MYO5B-MVID), (2) the expression of full-length mutant MYO5B proteins with residual function causes predominant cholestatic liver disease (MYO5B-PFIC), and (3) the expression of mutant MYO5B proteins without residual function causes both intestinal and hepatic disease (MYO5B-MIXED). Genotype-phenotype data are deposited in the existing open MYO5B database in order to improve disease diagnosis, prognosis, and genetic counseling.

Novel mutations of SAR1B gene in four children with chylomicron retention disease.

BACKGROUND: Intestinal lipid malabsorption, resulting from an impaired formation or secretion of chylomicrons and associated with severe hypobetalipoproteinemia (HBL), may be due to biallelic mutations in APOB (homozygous FHBL type-1), MTTP (abetalipoproteinemia), or SAR1B (chylomicron retention disease). OBJECTIVE: We investigated four children, each born from consanguineous parents, presenting with steatorrhea, malnutrition, accumulation of lipids in enterocytes, and severe hypocholesterolemia with an apparent recessive transmission. METHODS: We sequenced a panel of genes whose variants may be associated with HBL. RESULTS: Case 1, a 9-month-old male, was found to be homozygous for a SAR1B variant (c.49 C>T), predicted to encode a truncated Sar1b protein devoid of function (p.Gln17*). Case 2, a 4-year-old male, was found to be homozygous for a SAR1B missense variant [c.409 G>C, p.(Asp137His)], which affects a highly conserved residue close to the Sar1b guanosine recognition site. Case 3, a 6-year-old male, was found to be homozygous for an ∼6 kb deletion of the SAR1B gene, which eliminates exon 2; this deletion causes the loss of the ATG translation initiation codon in the SAR1B mRNA. The same homozygous mutation was found in an 11-month-old child (case 4) who was related to case 3. CONCLUSIONS: We report 4 children with intestinal lipid malabsorption were found to have chylomicron retention disease due to 3 novel variants in the SAR1B gene.

Carotid intima-media thickness and arterial stiffness as early markers of atherosclerosis in pediatric celiac disease.

The association between pediatric celiac disease (CD) and atherosclerosis is unknown. Our aim was to investigate whether pediatric CD patients have an increased risk of atherosclerosis. We evaluated the premature atherosclerosis by pulse wave velocity (PWV) and carotid intima-media thickness (cIMT). A total of 37 CD patients (20 girls, mean age 13±3.3 years) and 36 healthy age and sex matched controls were enrolled. Mean duration of CD was 47.1±32.3 months and 40.5% of patients had positive tissue transglutaminase antibody (tTg) IgA. Total cholesterol level was lower in CD (p=0.026) and cIMT was lower in tTg IgA antibody negative CD (p=0.030). cIMT was significantly correlated with tTg IgA antibody positivity (r=0.336; p=0.042). Adherence to strict gluten-free diet is associated with decreased cIMT, suggesting that gluten withdrawal seems to have a beneficial effect on premature atherosclerosis.

Euprolactinemic galactorrhea secondary to domperidone treatment.

Milk leakage from the breast, which is known as galactorrhea, can be caused by a number of pharmacological, physical, and tumoral factors. Galactorrhea is a well-known side effect of domperidone, and is usually associated with hyperprolactinemia. However, euprolactinemic galactorrhea secondary to domperidone is very rarely seen and has yet to be reported in children before. Here, we report an adolescent with euprolactinemic galactorrhea caused by domperidone.