Status of vitamins and minerals in children with screening-identified celiac disease: A case-control study.

OBJECTIVES: Micronutrient deficiencies characterize classical "late-diagnosed" celiac disease (CeD). This study aimed to identify the prevalence of micronutrient deficiencies among children with "early-diagnosed" screening-identified CeD to determine the clinical value of routine testing for deficiencies in those patients. METHODS: A case-control study was conducted on screening-identified CeD patients diagnosed during a mass screening study (84 patients, mean age 11.3 ± 2.6 years). The controls (443 children, mean age 10.8 ± 2.5 years) were negative for celiac disease serological screening. Hemoglobin, serum levels of iron, ferritin, folate, vitamin B12, vitamin A, vitamin E, 25-OH vitamin D, zinc, and selenium were measured. RESULTS: The mean serum levels of hemoglobin, iron, ferritin, vitamin D, zinc, copper, and selenium were significantly lower in CeD patients than in healthy controls (hemoglobin 12.56 vs. 13.02 g/dL [p = 0.04]; iron 10.61 vs. 17.6 µmol/L [p < 0.001], ferritin 25.7 vs. 48.3 µg/L [p < 0.001], vitamin D 29.1 vs. 37.5 nmol/L, zinc 11.9 vs. 21.7 µmol/L, copper 18.9 vs. 32.5 µmol/L, selenium 1.04 vs. 1.36 µmol/L; p < 0.001). Patients with celiac and severe intestinal damage (Marsh IIIb and IIIc) had significantly lower serum ferritin and vitamin A levels than patients with mild intestinal damage (Marsh II and IIIa) (ferritin 15 vs. 22 µg/L, p < 0.025; vitamin A 0.85 vs. 1.35 µmol/L, p = 0.007). CONCLUSION: Micronutrient deficiencies are still detectable in "early-diagnosed" screening-identified CeD cases, a clinically relevant result that strongly supports efforts for screening and early diagnosis of CeD.

Is HLA-DQ typing useful in screening for celiac disease among Arabs with type 1 diabetes? A case-control study.

OBJECTIVES: The data on the usefulness of DQ-typing in screening for celiac disease (CD) among type 1 diabetic (T1D) patients came from the West. We conducted this study among T1D patients to: (1) determine the frequency of DQ-genotypes, (2) assess the risk associated with human leukocyte antigen (HLA)-DQ genotypes, and (3) identify the cost-effective screening strategy. METHODS: HLA-DQ genotyping was performed on 67 T1D patients with CD (cases) (mean age 15 years) and 224 T1D patients without CD (controls) (mean age 18.29 years) (2021-2023). The entry criterion for the control group was duration of T1D ≥5 years and negative annual celiac serology assay. RESULTS: On comparison of the cases versus controls, T1D patients carrying homozygous DQ2.5 genotype (30% vs. 13.8%) or DR3-DQ2.5 haplotype (81.3% vs. 65.7%) showed significantly "higher risk" (odds ratio [OR] = 2.64, p = 0.002; OR = 2.3, p = 0.008, respectively) to develop CD. Only 4% do not harbor any of the CD-at risk genotypes (DQ2.5, DQ8, or DQ2.2) and none developed CD. Heterozygous DQ8 was associated with a significantly lower risk of developing CD with OR of 0.123 (1.5% in cases vs. 10.3% in controls, p = 0.022). CONCLUSION: Only 4% of Saudi patients with T1D carry DQ-genotypes at no risk to develop CD, which supports the European guidelines that recommend celiac serology test as the most cost-effective screening method. We identified the risk gradient associated with DQ-genotypes to develop CD in our population which could help in counseling patients for the risk to develop CD and planning follow-up serology tests.

Celiac Disease and Intussusception: A Common Association in Children.

OBJECTIVES: In young childhood, intestinal intussusception (IS) is the most common cause of small bowel obstruction. A lead point such as Meckel diverticulum, polyps, tumors, enlarged lymph nodes, cystic fibrosis, and Schoenlein-Henoch purpura are recognized causes. Association between celiac disease (CD) and IS has been well recognized in adults but rarely in children. Data on causes and outcome of intussusception among Saudi children are lacking in the literature. Our objectives were to characterize the pattern of IS among Saudi children and investigate the frequency, clinical presentation, and outcome of intussusception among children with CD. METHODS: We searched the hospital's picture archiving and communications system for abdominal imaging studies (ultrasound, magnetic resonance imaging, computed tomography scan, and barium contrast studies), performed between 2008 and 2019, using "intussusception" as a search key word. The hospital medical records of the identified cases of intussusception (aged 0-14 years) were then retrospectively reviewed to collect demographic, clinical, laboratory and imaging findings, management, and outcome. RESULTS: During the study period, 57 cases were identified as confirmed IS (31 boys, median age 1.95 years, range 0.33-11 years). Abdominal ultrasound was the diagnostic imaging study in 93%. An underlying cause (secondary IS) could be identified in 19 (33.3%) cases: CD in 6, malignancy and Henoch-Schoenlein purpura, 5 each, and Meckel diverticulum in 3; the remaining 38 (66.6%) cases of IS were idiopathic (primary IS). The presence of hypoalbuminemia and abdominal distension were significantly associated with secondary IS as compared with primary IS (P < 0.001, P = 0.006, respectively). All of the 6 cases of IS associated with CD resolved spontaneously, but 3 were recurrent. CONCLUSIONS: Secondary causes contributed to a large proportion of IS in our study cohort (33%) as compared with 5% to 10% in the literature. Celiac disease is an underrecognized cause of IS among children. A child with IS and hypoalbuminemia, anemia, or chronic diarrhea needs to be investigated for CD to avoid unnecessary surgery.

Fungal Dysbiosis in Children with Celiac Disease.

BACKGROUND: Although intestinal fungi are known to interact with the immune system, the relationship between intestinal fungi and childhood celiac disease (CeD), an immune-mediated condition, has rarely been reported. AIMS: The aim of this study was to describe gut fungal profiles in a cohort of children with new-onset CeD. METHODS: Mucosal and fecal samples were collected from children with CeD and controls and subjected to metagenomics analysis of fungal microbiota communities. DNA libraries were sequenced using Illumina HiSeq platform 2 × 150 bp. Bioinformatic analysis was performed to quantify the relative abundance of fungi. Shannon alpha diversity metrics and beta diversity principal coordinate (PCo) analyses were calculated, and DESeq tests were performed between celiac and non-celiac groups. RESULTS: Overall more abundant taxa in samples of children with CeD included Tricholomataceae, Saccharomycetaceae, Saccharomycetes Saccharomyces cerevisiae, and Candida, whereas less abundant taxa included Pichiaceae, Pichia kudriavzevii, Pneumocystis, and Pneumocystis jirovecii. Alpha diversity between CeD and control individuals did not differ significantly, and beta diversity PCo analysis showed overlap of samples from CeD and controls for both fecal or mucosal samples; however, there was a clear separation between mucosal and fecal overall samples CONCLUSIONS: We report fungal dysbiosis in children with CeD, suggesting a possible role in the pathogenesis of CeD. Further larger, controlled, prospective and longitudinal studies are needed to verify the results of this study and clarify the functional role of fungi in CeD.

A discarded synonymous variant in NPHP3 explains nephronophthisis and congenital hepatic fibrosis in several families.

Half of patients with a ciliopathy syndrome remain unsolved after initial analysis of whole exome sequencing (WES) data, highlighting the need for improved variant filtering and annotation. By candidate gene curation of WES data, combined with homozygosity mapping, we detected a homozygous predicted synonymous allele in NPHP3 in two children with hepatorenal fibrocystic disease from a consanguineous family. Analyses on patient-derived RNA shows activation of a cryptic mid-exon splice donor leading to frameshift. Remarkably, the same rare variant was detected in four additional families with hepatorenal disease from UK, US, and Saudi patient cohorts and in addition, another synonymous NPHP3 variant was identified in an unsolved case from the Genomics England 100,000 Genomes data set. We conclude that synonymous NPHP3 variants, not reported before and discarded by pathogenicity pipelines, solved several families with a ciliopathy syndrome. These findings prompt careful reassessment of synonymous variants, especially if they are rare and located in candidate genes.

ATP8B1, ABCB11, and ABCB4 Genes Defects: Novel Mutations Associated with Cholestasis with Different Phenotypes and Outcomes.

OBJECTIVES: To characterize the clinical, laboratory, histologic, molecular features, and outcome of gene-confirmed progressive familial intrahepatic cholestasis (PFIC) 1-3 among Arabs and to evaluate for "genotype-phenotype" correlations. STUDY DESIGN: We retrospectively reviewed charts of 65 children (ATP8B1 defect = 5, ABCB11 = 35, ABCB4 = 25) who presented between 2008 and 2019 with cholestasis. The clinical phenotype of a disease was categorized based on response of cholestasis and itching to ursodeoxycholic acid and ultimate outcome, into mild (complete response), intermediate (partial response, nonprogressive), and severe (progression to end-stage liver disease). RESULTS: Overall, 27 different mutations were identified (ATP8B1, n = 5; ABCB11, n = 11; ABCB4, n = 11), comprising 10 novel ones. Six patients with heterozygous missense mutations (ATP8B1, n = 2; ABCB11, n = 4) had transient cholestasis. Of the remaining 3 patients with PFIC1, 2 developed severe phenotype (splicing and frameshift mutations). Of the remaining 31 patients with PFIC2, 25 developed severe disease (15 due to frameshift and splicing mutations). Of 25 patients with PFIC3, 10 developed a severe phenotype (1 splicing and 3 frameshift mutations; 6 missense). Patients with PFIC2 had significantly shorter survival time and more rapid disease progression than patients with PFIC3 (P < .001). Patients with frameshift mutations in ABCB11 gene (p.Thr127Hisfs∗6) and ABCB4 gene (p.Phe210Serfs∗5) had significantly shorter survival time than missense mutations (P = .011; P = .0039, respectively). CONCLUSIONS: We identified genotype-phenotype correlations among mutations in ABCB11 and ABCB4 genes, which underscore the prognostic value of early genetic diagnosis. The disease course in patients with PFIC3 could be favorably modified by ursodeoxycholic acid therapy.

New paradigms of USP53 disease: normal GGT cholestasis, BRIC, cholangiopathy, and responsiveness to rifampicin.

Biallelic variants in the USP53 gene have recently been reported to segregate with normal gamma glutamyltransferase (GGT) cholestasis. Using whole-exome sequencing (WES), we detected two USP53 homozygous variants (c.951delT; p. Phe317fs and c.1744C>T; p. Arg582*) in five additional cases, including an unpublished cousin of a previously described family with intractable itching and normal GGT cholestasis. Three patients, a child and two adults, presented with recurrent episodes of normal GGT cholestasis, consistent with a diagnosis of benign recurrent intrahepatic cholestasis (BRIC). Cholangiopathic changes, possibly autoimmune in origin, were recognized in some patients. Additional phenotypic details in one patient included an enlarged left kidney, and speech/developmental delay. Notably, two patients exhibited a complete response to rifampicin, and one responded to ursodeoxycholic acid (UDCA). Two adult patients were suspected to have autoimmune liver disease and treated with steroids. This report describes new cases of USP53 disease presenting with normal GGT cholestasis or BRIC in three children and two adults. We also describe the novel finding of a dramatic response to rifampicin. The association of cholangiopathy with normal GGT cholestasis provides a diagnostic challenge and remains poorly understood.

Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans.

BACKGROUND AND AIMS: The clinical consequences of defective primary cilium (ciliopathies) are characterized by marked phenotypic and genetic heterogeneity. Although fibrocystic liver disease is an established ciliopathy phenotype, severe neonatal cholestasis is rarely recognized as such. APPROACH AND RESULTS: We describe seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one and necessitating liver transplant in two). Positional mapping revealed a single critical locus on chromosome 7. Whole-exome sequencing revealed three different homozygous variants in Tetratricopeptide Repeat Domain 26 (TTC26) that fully segregated with the phenotype. TTC26 (intraflagellar transport [IFT] 56/DYF13) is an atypical component of IFT-B complex, and deficiency of its highly conserved orthologs has been consistently shown to cause defective ciliary function in several model organisms. We show that cilia in TTC26-mutated patient cells display variable length and impaired function, as indicated by dysregulated sonic hedgehog signaling, abnormal staining for IFT-B components, and transcriptomic clustering with cells derived from individuals with closely related ciliopathies. We also demonstrate a strong expression of Ttc26 in the embryonic mouse liver in a pattern consistent with its proposed role in the normal development of the intrahepatic biliary system. CONCLUSIONS: In addition to establishing a TTC26-related ciliopathy phenotype in humans, our results highlight the importance of considering ciliopathies in the differential diagnosis of severe neonatal cholestasis even in the absence of more typical features.

Role of percutaneous liver biopsy in infantile cholestasis: cohort from Arabs.

BACKGROUND: Investigators from different parts of the world are calling for a re-evaluation of the role of liver biopsy (LB) in the evaluation of infantile cholestasis (IC), especially in the light of emerging non-invasive diagnostic technologies. Therefore, this retrospective single-center study was conducted to determine the impact of LB on the diagnosis and management of IC in a cohort from Arabs. METHODS: From 2007 until 2019, 533 cases of IC were referred for evaluation. All infants who underwent LB were included in the study. We categorized the yield of LB into: (1) defined specific diagnosis; (2) excluded an important diagnosis. A single pathologist reviewed and made the histology report. RESULTS: 122 LB specimens met the inclusion criteria. The main indication for LB was a high suspicion of biliary atresia (BA) [high gamma-glutamyl transferase (GGT) cholestasis and pale stool] in 46 cases (37.8%). Liver biopsy had sensitivity of 86.4%, specificity (66.7%), PPV (70.4%), NPV (84.2%) in diagnosing BA. LB had a direct impact on clinical management in 52 cases (42.6%): (1) The true diagnosis was suggested by LB in 36 cases; (2) LB excluded BA and avoided intraoperative cholangiogram in 16 cases with high suspicion of BA. Among the 76 cases with low suspicion of BA, LB suggested the true diagnosis or helped to initiate specific management in 8 cases only (10.5%). In contrast, molecular testing confirmed the diagnosis in 48 (63%). CONCLUSION: LB continues to be an important tool in the workup of cases with a high suspicion of BA. The low yield of LB in cases with low suspicion of BA calls for a re-evaluation of its role in these cases in whom early incorporation of cholestasis sequencing gene  panels can have a better diagnostic yield.

Diagnosing Coeliac Disease During Mass-Screening of General Paediatric Population: Is Biopsy Avoidable?

OBJECTIVES: Studies evaluating the correlation between tissue transglutaminase immunoglobulin antibody (TGA-IgA) levels and the degree of enteropathy in screening-detected coeliac disease (CD) patients from the general childhood population are scarce. The objectives of our study were to evaluate the correlation between the TGA-IgA titre and the degree of enteropathy and to evaluate whether the no-biopsy approach to diagnose CD in symptomatic patients proposed by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition could be extended to asymptomatic CD patients diagnosed during mass screening studies. METHODS: The present study is a sub-study of a cross-sectional mass screening study, "Exploring the Iceberg of Coeliacs in Saudi Arabia", conducted among school-aged children (6-15 years) in 2014-2015. The 93 biopsy-confirmed CD patients constituted the study cohort of the present study (mean age 11.4 ±â€Š2.6 years; 24 males). TGA-IgA titres and endomysial antibodies (EMA) at the time of biopsy and grade of enteropathy were assessed, and human leukocyte antigen DQ 2.2/2.5/8 genotyping was performed. RESULTS: Thirty-four patients had TGA-IgA titres >10× upper limit of normal (ULN; 36%); all had villous atrophy with positive EMA and DQ 2.2/2.5/8. The sensitivity and specificity of a TGA-IgA titre >10× ULN in correctly diagnosing CD was 100%. There was a significant positive correlation between the anti-TGA-IgA titre and the severity of enteropathy (P < 0.001). There was no significant difference in the TGA-IgA titre between the asymptomatic and symptomatic CD patients. CONCLUSIONS: Our results provide evidence that a TGA-IgA titre >10× ULN correlates with villous atrophy in CD patients detected by mass screening.

Deamidated Gliadin Antibodies: Do They Add to Tissue Transglutaminase-IgA Assay in Screening for Celiac Disease?

OBJECTIVES: Use of deamidated gliadin peptide (DGP) test kits as adjunctive to tissue-transglutaminase-IgA (TTG-IgA) for the diagnosis of celiac disease (CD) has been a controversial issue. The objectives of our study were to evaluate the diagnostic performance of DGP antibodies compared with TTG-IgA and to evaluate the correlation between DGP-antibody titers and degree of enteropathy. METHODS: We included children who underwent endoscopy and biopsies because of positivity of any of the serology tests in the "celiac profile" (TTG-IgA, DGP-IgA, and DGP-IgG) from 2012 to 2019. We divided children into clinically suspected cases of CD (group 1) and asymptomatic cases screened as they were from a high-risk group (group 2). RESULTS: Group 1 constituted 52 children and group 2 included 81 children (76 type-1 diabetes [T1D]). The sensitivity and positive-predictive value (PPV) of DGP-IgG in group 1 (90%, 98%) and group 2 (91%, 85.5%) were comparable with TTG-IgA (98%, 92% in group 1; 100%, 80% in group 2). By adding DGP-IgG to TTG-IgA, the performance of TTG-IgA has improved marginally in group 1 (sensitivity 100%, PPV 92.3%). All cases with DGP-IgG titer 2 times ULN in group 1, and >4 times ULN in group 2 had villous atrophy. All T1D patients with TTG IgA >10 times ULN had villous atrophy. CONCLUSIONS: DGP-IgG assay did not add to the performance of TTG-IgA. DGP-IgG titer correlated with enteropathy. The diagnosis of CD can be made in asymptomatic T1D child with TTG-IgA titer >10 times ULN and positive endomyseal antibodies.

What Do Saudi Children Ingest?: A 10-Year Retrospective Analysis of Ingested Foreign Bodies From a Tertiary Care Center.

OBJECTIVES: Few studies investigated the correlation between foreign body (FB) ingestion and occurrence of complications. The local literature is limited to case reports and small case series on esophageal FBs. We conducted this study to identify the high-risk factors predisposing to complications among Saudi children ingesting FBs. METHODS: The medical records of 436 children (boys, 59.6%; mean age, 4.4 ± 2.7 years) presenting to the emergency department (ED) between 2007 and 2016 were retrospectively reviewed. Relative risk analysis of clinical variables was performed between 2 groups: The first group constituted children without FB-related complications (n = 389), and the second group included those with major complications (n = 14). Major complication was defined as any event associated with significant morbidity such as esophageal stricture, esophageal perforation, esophageal fistula, and intestinal perforation or fistula formation. RESULTS: Most of the 436 cases presented between ages 2 and 4 years (35.1%). Coin was the most commonly ingested FB (22.9%) followed by button battery (19.5%). Most of the ingested FBs passed spontaneously without intervention (69%). Upper endoscopy was performed in 121 cases (27.7%). By multivariate analysis, the variables that were significantly associated with major complications included the following: very young age group (0-2 years; odds ratio [OR], 11.5), button battery (OR, 4), FB impacted at upper esophagus (OR, 8.7), and longer time duration to visit the ED (OR, 14.7). CONCLUSION: Button battery impaction at upper esophagus in very young children and delayed presentation to the ED were the most significant risk factors of FB-related complications.

Phenotypic delineation of the retinal arterial macroaneurysms with supravalvular pulmonic stenosis syndrome.

Retinal arterial macroaneurysms with supravalvular pulmonic stenosis (RAMSVPS), also known as Familial Retinal Arterial Macroaneurysms (FRAM) syndrome, is a very rare multisystem disorder. Here, we present a case series comprising ophthalmologic and systemic evaluation of patients homozygous for RAMSVPS syndrome causative IGFBP7 variant. New clinical details on 22 previously published and 8 previously unpublished patients are described. Age at first presentation ranged from 1 to 34 years. The classical feature of macroaneurysms and vascular beading involving the retinal arteries was universal. Follow up extending up to 14 years after initial diagnosis revealed recurrent episodes of bleeding and leakage from macroaneurysms in 55% and 59% of patients, respectively. The majority of patients who underwent echocardiography (18/23) showed evidence of heart involvement, most characteristically pulmonary (valvular or supravalvular) stenosis, often requiring surgical correction (12/18). Four patients died in the course of the study from complications of pulmonary stenosis, cerebral hemorrhage, and cardiac complications. Liver involvement (usually cirrhosis) was observed in eight patients. Cerebral vascular involvement was observed in one patient, and stroke was observed in two. We conclude that RAMSVPS is a recognizable syndrome characterized by a high burden of ocular and systemic morbidity, and risk of premature death. Recommendations are proposed for early detection and management of these complications.

Liver Failure Among Young Saudi Infants: Etiology, Clinical Presentation, and Outcome.

OBJECTIVES: The published data on early infantile liver failure (EILF) are scarce and limited to Caucasians. We conducted this study to describe the etiology and outcome of EILF among Arabs and identify prognostic factors. METHODS: We retrospectively reviewed our database of 524 infants presenting with liver impairment from 2008 to 2018, and identified cases of EILF defined as presence of biochemical pattern of liver disease and INR ≥2 (unresponsive to vitamin K) with onset before 3 months of life. Primary outcomes included death or liver transplantation (LT) (poor outcome group) and survival with native liver (good outcome group). RESULTS: Forty-two cases of EILF (22 girls) were identified (8%). The etiology was indeterminate in 14 (33.3%) and established in 27 (64.3%): galactosemia (7 cases, 16.6%), tyrosinemia (5, 12%), neonatal hemochromatosis (NH), and hemophagocytic lymphohistiocytosis (HLH) (4 each, 9.5%]) mitochondrial hepatopathy (3, 7%), and miscellaneous (5, 12%). LF resolved in 15 cases (35.7%), either spontaneously or in response to specific therapy, 23 (54.7%) died, and 4 underwent LT (9.5%). ROC analysis for the best cut-off value of serum total bilirubin for prediction of study outcomes was 120 µmol/L (sensitivity 81.5%, specificity 80%). Among the diagnostic groups, galactosemia and tyrosinemia predicted good outcome, whereas the idiopathic diagnosis predicted poor outcome (OR = 13). CONCLUSIONS: Similar to Western countries, galactosemia, tyrosinemia, NH, HLH, and mitochondrial hepatopathy are the main players in EILF in Saudi Arabia. Galactosemia and tyrosinemia predict good prognosis and idiopathic diagnosis predicts poor prognosis.

Mass Screening for Celiac Disease Among School-aged Children: Toward Exploring Celiac Iceberg in Saudi Arabia.

OBJECTIVES: We conducted this mass screening study to determine the prevalence of celiac disease (CD) and characterize the celiac iceberg among Saudi pediatric population in Riyadh, the capital city of Saudi Arabia. METHODS: During the study period (January 2014-June 2016), we have conducted a cross-sectional, mass screening, immunoglobulin A-tissue transglutaminase (TTG-IgA)-based study on 7930 Saudi students from primary and intermediate schools in Riyadh. Students with positive TTG-IgA (>20 U/L) were called in the hospital to undergo a repeat of TTG-IgA; in those with borderline positive TTG-IgA (20-60 U/L), IgA-endomyseal antibody (EMA-IgA) test was performed. Children with TTG-IgA >60 U/L and children with borderline positive TTG-IgA and positive EMA-IgA were advised to undergo upper endoscopy and intestinal biopsies. RESULTS: We identified 221 students with positive TTG-IgA (2.8%). CD was diagnosed in 119 cases (1.5%, 1:67 Saudi children) (mean age 11.5 ±â€Š2.62 years; girls 81 [68%]). Another 51 children had persistently borderline positive TTG-IgA but negative EMA (0.64%) and the remaining 51 had transiently positive TTG-IgA. We have identified 3 clinical patterns in the screening-identified cases with CD: a silent form (37%), a mild symptomatic form characterized by gastrointestinal symptoms in presence of normal growth or overweight/obesity (48%), and gastrointestinal symptoms associated with impaired growth in 15%. CONCLUSIONS: Our study provided evidence of a high prevalence of CD among Saudi children (1.5%), a rate that is at least twice the average prevalence rate in Europe and North America.

Bile Acid Synthesis Disorders in Arabs: A 10-year Screening Study.

OBJECTIVES: Early diagnosis of bile acid synthesis disorders (BASDs) is important because, untreated, these conditions can be fatal. Our objectives were to screen children with cholestasis or unexplained liver disease for BASD and in those with confirmed BASD to evaluate the effectiveness of cholic acid therapy. METHODS: A routine serum total bile acid measurement was performed on children with cholestasis, liver cirrhosis, and liver failure. Patients were screened for BASD by fast atom bombardment ionization-mass spectrometry (FAB-MS) analysis of urine, and molecular analysis confirmed diagnosis. Treatment response to oral cholic acid (10-15 mg/kg bw/day) was assessed from liver function tests and fat-soluble vitamin levels. FAB-MS analysis of urine was used to monitor compliance and biochemical response. RESULTS: Between 2007 and 2016, 626 patients were evaluated; 450 with infantile cholestasis. Fifteen cases of BASD were diagnosed: 12 presented with infantile cholestasis (2.7%, 7 boys), an 8-year-old boy presented with cirrhosis, and two 18-month-old boys presented with hepatomegaly and rickets. Eleven were caused by 3ß-hydroxy-Δ-C27-steroid oxidoreductase dehydrogenase deficiency, 3 from Δ-3-oxosteroid 5ß-reductase deficiency, and 1 had Zellweger spectrum disorder. In all but 1, serum total bile acids were normal or low. With cholic acid therapy, 10 are alive and healthy with their native liver. Liver failure developed in 3 infants despite therapy; 2 died and 1 underwent liver transplantation. CONCLUSIONS: BASDs are rare but treatable causes of metabolic liver disease in Saudi Arabia. BASD should be considered in infants with cholestasis and low or normal serum total bile acid concentrations.

Fibrinogen Gamma Chain Mutations Provoke Fibrinogen and Apolipoprotein B Plasma Deficiency and Liver Storage.

p.R375W (Fibrinogen Aguadilla) is one out of seven identified mutations (Brescia, Aguadilla, Angers, Al du Pont, Pisa, Beograd, and Ankara) causing hepatic storage of the mutant fibrinogen γ. The Aguadilla mutation has been reported in children from the Caribbean, Europe, Japan, Saudi Arabia, Turkey, and China. All reported children presented with a variable degree of histologically proven chronic liver disease and low plasma fibrinogen levels. In addition, one Japanese and one Turkish child had concomitant hypo-APOB-lipoproteinemia of unknown origin. We report here on an additional child from Turkey with hypofibrinogenemia due to the Aguadilla mutation, massive hepatic storage of the mutant protein, and severe hypo-APOB-lipoproteinemia. The liver biopsy of the patient was studied by light microscopy, electron microscopy (EM), and immunohistochemistry. The investigation included the DNA sequencing of the three fibrinogen and APOB-lipoprotein regulatory genes and the analysis of the encoded protein structures. Six additional Fibrinogen Storage Disease (FSD) patients with either the Aguadilla, Ankara, or Brescia mutations were investigated with the same methodology. A molecular analysis revealed the fibrinogen gamma p.R375W mutation (Aguadilla) but no changes in the APOB and MTTP genes. APOB and MTTP genes showed no abnormalities in the other study cases. Light microscopy and EM studies of liver tissue samples from the child led to the demonstration of the simultaneous accumulation of both fibrinogen and APOB in the same inclusions. Interestingly enough, APOB-containing lipid droplets were entrapped within the fibrinogen inclusions in the hepatocytic Endoplasmic Reticulum (ER). Similar histological, immunohistochemical, EM, and molecular genetics findings were found in the other six FSD cases associated with the Aguadilla, as well as with the Ankara and Brescia mutations. The simultaneous retention of fibrinogen and APOB-lipoproteins in FSD can be detected in routinely stained histological sections. The analysis of protein structures unraveled the pathomorphogenesis of this unexpected phenomenon. Fibrinogen gamma chain mutations provoke conformational changes in the region of the globular domain involved in the "end-to-end" interaction, thus impairing the D-dimer formation. Each monomeric fibrinogen gamma chain is left with an abnormal exposure of hydrophobic patches that become available for interactions with APOB and lipids, causing their intracellular retention and impairment of export as a secondary unavoidable phenomenon.

Savary Dilation Is Safe and Effective Treatment for Esophageal Narrowing Related to Pediatric Eosinophilic Esophagitis.

OBJECTIVES: Data on management of esophageal narrowing related to eosinophilic esophagitis (EoE) in children are scanty. The aim of the present study is to assess the safety and effectiveness of esophageal dilation in pediatric EoE from the largest case series to date. METHODS: Children diagnosed with EoE during 2004 to 2015 were reviewed for the presence of esophageal narrowing. Esophageal narrowing was categorized as short segment narrow caliber, long segment narrow caliber, and single short stricture. The characteristics of the narrowed esophagus, therapeutic approach, clinical outcome, and complications were reviewed. RESULTS: Of the 50 EoE cases diagnosed during the study period, 11 cases (9 boys; median age 9 years, range 4-12) were identified with esophageal narrowing (22%). Six had short segment narrow caliber esophagus and 5 had long segment narrow caliber esophagus (median length of the narrowing was 4 cm, range 3-20 cm). Three cases with narrow caliber esophagus also had esophageal stricture 2 to 3 cm below the upper esophageal sphincter. Nineteen dilation sessions were performed in 10 cases using Savary dilator. Esophageal size improved from median 7 mm to median 13.4 mm. Good response was obtained in all cases. Following the dilation procedure, longitudinal esophageal mucosal tear occurred in all cases without esophageal perforation or chest pain. CONCLUSIONS: Esophageal dilation using Savary dilator is safe and highly effective in the management of esophageal narrowing related to EoE in children. Dilation alone does not improve the inflammatory process, and hence a combination with dietary or medical intervention is required.

Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort.

BACKGROUND & AIMS: Proprotein convertase 1/3 (PC1/3) deficiency, an autosomal-recessive disorder caused by rare mutations in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, has been associated with obesity, severe malabsorptive diarrhea, and certain endocrine abnormalities. Common variants in PCSK1 also have been associated with obesity in heterozygotes in several population-based studies. PC1/3 is an endoprotease that processes many prohormones expressed in endocrine and neuronal cells. We investigated clinical and molecular features of PC1/3 deficiency. METHODS: We studied the clinical features of 13 children with PC1/3 deficiency and performed sequence analysis of PCSK1. We measured enzymatic activity of recombinant PC1/3 proteins. RESULTS: We identified a pattern of endocrinopathies that develop in an age-dependent manner. Eight of the mutations had severe biochemical consequences in vitro. Neonates had severe malabsorptive diarrhea and failure to thrive, required prolonged parenteral nutrition support, and had high mortality. Additional endocrine abnormalities developed as the disease progressed, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism. We identified growth hormone deficiency, central diabetes insipidus, and male hypogonadism as new features of PCSK1 insufficiency. Interestingly, despite early growth abnormalities, moderate obesity, associated with severe polyphagia, generally appears. CONCLUSIONS: In a study of 13 children with PC1/3 deficiency caused by disruption of PCSK1, failure of enteroendocrine cells to produce functional hormones resulted in generalized malabsorption. These findings indicate that PC1/3 is involved in the processing of one or more enteric hormones that are required for nutrient absorption.

Clinical and molecular characteristics of mitochondrial DNA depletion syndrome associated with neonatal cholestasis and liver failure.

OBJECTIVE: To determine the frequency of mitochondrial DNA depletion syndrome (MDS) in infants with cholestasis and liver failure and to further clarify the clinical, biochemical, radiologic, histopathologic, and molecular features associated with MDS due to deoxyguanosine kinase (DGUOK) and MPV17 gene mutations. STUDY DESIGN: We studied 20 infants with suspected hepatocerebral MDS referred to our tertiary care center between 2007 and 2013. Genomic DNA was isolated from blood leukocytes, liver, and/or skeletal muscle samples by standard methods. Mitochondrial DNA copy number relative to nuclear DNA levels was determined in muscle and/or liver DNA using real-time quantitative polymerase chain reaction and compared with age-matched controls. Nuclear candidate genes, including polymerase γ, MPV17, and DGUOK were sequenced using standard analyses. RESULTS: We identified pathogenic MPV17 and DGUOK mutations in 11 infants (6 females) representing 2.5% of the 450 cases of infantile cholestasis and 22% of the 50 cases of infantile liver failure referred to our center during the study period. All of the 11 patients manifested cholestasis that was followed by a rapidly progressive liver failure and death before 2 years of life. Mitochondrial DNA depletion was demonstrated in liver or muscle for 8 out of the 11 cases where tissue was available. Seven patients had mutations in the MPV17 gene (3 novel mutations), 4 patients had DGUOK mutations (of which 2 were novel mutations). CONCLUSION: Mutations in the MPV17 and DGUOK genes are present in a significant percentage of infants with liver failure and are associated with poor prognosis.