A Case of MIRAGE Syndrome with Mutation and Refractory Infantile Diarrhea: Endoscopic Biopsy Evaluation via Light and Electron Microscopy.

An infant with intrauterine growth restriction, suspected of having MIRAGE syndrome based on prenatal ultrasound, presented with genital ambiguity, adrenal insufficiency, intractable diarrhea from birth, and a pathogenic mutation (). Endoscopic biopsies of the duodenum revealed complex light and electron microscopic abnormalities. Hypoplastic villi without signs of enteritis suggests a disorder of mucosal growth with reduced absorptive surface area contributes to intractable diarrhea.

Homozygous missense variants in YKT6 result in loss of function and are associated with developmental delay, with or without severe infantile liver disease and risk for hepatocellular carcinoma.

Purpose: YKT6 plays important roles in multiple intracellular vesicle trafficking events but has not been associated with Mendelian diseases.

Methods: We report 3 unrelated individuals with rare homozygous missense variants in YKT6 who exhibited neurological disease with or without a progressive infantile liver disease. We modeled the variants in Drosophila.

Intrahepatic Cholangiolitis in Cystic Fibrosis (ICCF): An Under-Appreciated Cause of Persistent Cholestasis in Infancy.

Liver histology in infants with cystic fibrosis (CF) and persistent cholestasis is seldom reported in detail. We extend previous observation of a distinctive intrahepatic cholangiopathy (ICCF) to 3 additional infants homozygous for pathological variants and a fourth infant with a heterozygous variant, summarizing our experience in 10 infants with variants and persistent cholestasis. Cholangiograms demonstrate abnormal extrahepatic ducts in 2 infants with CF, 1 with uniform dilatation interpreted as a choledochal cyst and the other with narrow patent ducts.

Clinical spectrum and genetic causes of mitochondrial hepatopathy phenotype in children.

Background: Alterations in both mitochondrial DNA (mtDNA) and nuclear DNA genes affect mitochondria function, causing a range of liver-based conditions termed mitochondrial hepatopathies (MH), which are subcategorized as mtDNA depletion, RNA translation, mtDNA deletion, and enzymatic disorders. We aim to enhance the understanding of pathogenesis and natural history of MH.

Methods: We analyzed data from patients with MH phenotypes to identify genetic causes, characterize the spectrum of clinical presentation, and determine outcomes.

A novel RYR1 variant in an infant with a unique fetal presentation of central core disease.

Ryanodine receptor type 1-related disorder (RYR1-RD) is the most common subgroup of congenital myopathies with a wide phenotypic spectrum ranging from mild hypotonia to lethal fetal akinesia. Genetic testing for myopathies is imperative as the diagnosis informs counseling regarding prognosis and recurrence risk, treatment options, monitoring, and clinical management. However, diagnostic challenges exist as current options are limited to clinical suspicion prompting testing including: single gene sequencing or familial variant testing, multi-gene panels, exome, genome sequencing, and invasive testing including muscle biopsy.

Biliary Atresia Remnants Revisited: Myogenesis, Hepatic Duct-Like Structures, and Fate of Peribiliary Glands.

Purpose And Context: Proximal levels of excised remnants from youngest infants may reveal early features of biliary atresia (BA).

Method: A targeted IHC survey was applied to 34 most proximal 2 levels in 17 BA remnants excised at age 10-74 days including 7 = <30 days old and 6 control hepatic ducts (HD).

Key Results: Severity of inflammation and extent of active fibroplasia do not distinguish proximal remnants in younger (n = 7) and older (n = 10) infants.

Serum biomarkers correlated with liver stiffness assessed in a multicenter study of pediatric cholestatic liver disease.

Background And Aims: Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis.

Approach And Results: A targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.

Stx4 is required to regulate cardiomyocyte Ca handling during vertebrate cardiac development.

Requirements for vesicle fusion within the heart remain poorly understood, despite the multitude of processes that necessitate proper intracellular trafficking within cardiomyocytes. Here, we show that Syntaxin 4 (STX4), a target-Soluble -ethylmaleimide sensitive factor attachment receptor (t-SNARE) protein, is required for normal vertebrate cardiac conduction and vesicular transport. Two patients were identified with damaging variants in .

Hypoplasia of Extrahepatic Biliary Tree and Intrahepatic Cholangiolopathy in Cystic Fibrosis Imperfectly Mimic Biliary Atresia in 4 Infants With Cystic Fibrosis and Kasai Portoenterostomy.

Four male infants with cystic fibrosis and prolonged neonatal jaundice underwent Kasai procedure to relieve biliary obstruction due to apparent biliary atresia. The excised remnants had viscid mucus accumulation in hypoplastic gallbladders and distended peribiliary glands. Main hepatic ducts were narrow and/or malformed.

Novel Pathogenic Variants in Primary Ciliary Dyskinesia: Association with Visceral Heterotaxia and Neonatal Cholestasis.

The dynein axonemal heavy chain 5 gene codes for a subunit of axonemal dynein necessary for ciliary motor function. Though research has elucidated the consequences of some variants in this gene, it is still unclear whether many variants in the locus are benign or pathogenic due to the rarity of primary ciliary dyskinesia (PCD, of which Kartagener's syndrome is a subset). Here, we introduce the case of an infant boy presenting with the classical findings of PCD along with visceral heterotaxia and neonatal cholestasis.

A Diet High in Fat and Fructose Induces Early Hepatic Mitochondrial Aging.

To investigate the effect of high fructose diet on ultrastructure and content of hepatic mitochondria, we randomized 6-8 weeks old male C57Bl6/J mice to ad lib chow or high-fat-high-fructose (HF2) diet for 32 weeks. HF2-fed mice gained more weight, had higher plasma alanine aminotransferase, and fasting glucose levels and increased hepatic triglyceride content at all time points compared to chow-fed mice. HF2-fed mice had lower mitochondrial to nuclear DNA ratio compared to chow-fed mice.

Hepatic LDL receptor-related protein-1 deficiency alters mitochondrial dynamics through phosphatidylinositol 4,5-bisphosphate reduction.

The LDL receptor-related protein 1 (LRP1) is a multifunctional transmembrane protein with endocytosis and signal transduction functions. Previous studies have shown that hepatic LRP1 deficiency exacerbates diet-induced steatohepatitis and insulin resistance via mechanisms related to increased lysosome and mitochondria permeability and dysfunction. The current study examined the impact of LRP1 deficiency on mitochondrial function in the liver.

Congenital Portosystemic Shunts in Children: Associations, Complications, and Outcomes.

Background: Congenital portosystemic shunt (CPSS) is a rare malformation in which splanchnic venous flow bypasses the liver. CPSS is associated with other congenital anomalies and syndromes and can be associated with life-threatening complications. CPSS and their management remain underreported in the literature.

Small bowel-small bowel intussusception with high grade obstruction due to intramural submucosal ileal hamartoma in a 5-year-old child: A case report.

Introduction: Intussusception is a common cause of emergency in children. We report a unusual case of intestinal obstruction due to small bowel-small bowel intussusception with an intestinal hamartoma as the lead point.

Presentation Of The Case: A 5 year old boy presented to the ED with worsening abdominal pain, emesis and bloody diarrhea.

Guidelines for synoptic reporting of surgery and pathology in Hirschsprung disease.

Background/purpose: Synoptic, or standardized, reporting of surgery and pathology reports has been widely adopted in surgical oncology. Patients with Hirschsprung disease may experience morbidity related to surgical factors or underlying pathology and often undergo multiple operations. Our aim is to improve the postoperative outcome and care of patients with Hirschsprung disease by proposing a standardized set of data that should be included in every surgery and pathology report.

Fontan-associated liver disease: A review.

The Fontan procedure has led to increased long-term survival of patients with single ventricle congenital heart disease. Hemodynamic changes associated with the Fontan circulation, including elevated central venous pressure and diminished cardiac output are responsible for the development of Fontan-associated liver disease (FALD). Liver fibrosis is a universal feature following the Fontan operation.

CNTNAP1-Related Congenital Hypomyelinating Neuropathy.

Background: Congenital hypomyelinating neuropathy is a rare form of hereditary peripheral neuropathy characterized by nonprogressive weakness, areflexia, hypotonia, severely reduced nerve conduction velocities, and hypomyelination. Mutations in contactin-associated protein 1 (CNTNAP1) were recently described as a cause of congenital hypomyelinating neuropathy. CNTNAP1-associated congenital hypomyelinating neuropathy is characterized by severe hypotonia, multiple distal joint contractures, and high mortality in the first few months of life.

Inborn Errors of Bile Acid Metabolism.

Inborn errors of bile acid metabolism are rare causes of neonatal cholestasis and liver disease in older children and adults. The diagnosis should be considered in the context of hyperbilirubinemia with normal serum bile acids and made by urinary liquid secondary ionization mass spectrometry or DNA testing. Cholic acid is an effective treatment of most single-enzyme defects and patients with Zellweger spectrum disorder with liver disease.

Inflammation, Active Fibroplasia, and End-stage Fibrosis in 172 Biliary Atresia Remnants Correlate Poorly With Age at Kasai Portoenterostomy, Visceral Heterotaxy, and Outcome.

Published histologic studies of the hilar plate or entire biliary remnant at the time of Kasai portoenterostomy (KHPE) have not provided deep insight into the pathogenesis of biliary atresia, relation to age at surgery, prognosis or the basis for successful drainage. We report detailed histologic findings in 172 centrally reviewed biliary remnants with an average of 6 sections per subject. Active lesions were classified as either necroinflammatory (rare/clustered in a few subjects) or active concentric fibroplasia with or without inflammation (common).

Long-Term Cholic Acid Therapy in Zellweger Spectrum Disorders.

Zellweger spectrum disorders (ZSDs), a subgroup of peroxisomal biogenesis disorders, have a generalized defect in peroxisome function. Liver disease in ZSDs has been linked to accumulation of C-bile acid intermediates due to the lack of peroxisomal β-oxidation of these intermediates to form primary C-bile acids. Oral treatment with primary bile acid, cholic acid (CA), inhibits formation of hepatotoxic C-bile acids by restoring normal physiologic feedback inhibition on bile acid synthesis.

Intrahepatic cholangiocarcinoma after Fontan procedure in an adult with visceral heterotaxy.

Hepatic dysfunction, including development of hepatocellular carcinoma and other liver lesions has been increasingly reported following Fontan procedure for congenital heart disease. We report a unique case of intrahepatic cholangiocarcinoma 28 years after a Fontan procedure in a 31year old female with heterotaxy syndrome. The subcapsular mass-forming tumor was composed of poorly differentiated tumor cells arranged in small vague glandular or slit-lumen nests, and focally fused or anastomosing large trabecular patterns within the prominent fibrotic stroma.

Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia.

Biliary atresia is a progressive infantile cholangiopathy of complex pathogenesis. Although early diagnosis and surgery are the best predictors of treatment response, current diagnostic approaches are imprecise and time-consuming. We used large-scale, quantitative serum proteomics at the time of diagnosis of biliary atresia and other cholestatic syndromes (serving as disease controls) to identify biomarkers of disease.

Zebrafish abcb11b mutant reveals strategies to restore bile excretion impaired by bile salt export pump deficiency.

Unlabelled: Bile salt export pump (BSEP) adenosine triphosphate-binding cassette B11 (ABCB11) is a liver-specific ABC transporter that mediates canalicular bile salt excretion from hepatocytes. Human mutations in ABCB11 cause progressive familial intrahepatic cholestasis type 2. Although over 150 ABCB11 variants have been reported, our understanding of their biological consequences is limited by the lack of an experimental model that recapitulates the patient phenotypes.