Trichohepatoenteric Syndrome Research Articles

Mammalian RNA Decay Pathways Are Highly Specialized and Widely Linked to Translation.

SummaryRNA decay is crucial for mRNA turnover and surveillance and misregulated in many diseases. This complex system is challenging to study, particularly in mammals, where it remains unclear whether decay pathways perform specialized versus redundant roles. Cytoplasmic pathways and links to translation are particularly enigmatic. By directly profiling decay factor targets and normal versus aberrant translation in mouse embryonic stem cells (mESCs), we uncovered extensive decay pathway specialization and crosstalk with translation. XRN1 (5′-3′) mediates cytoplasmic bulk mRNA turnover whereas SKIV2L (3′-5′) is universally recruited by ribosomes, tackling aberrant translation and sometimes modulating mRNA abundance. Further exploring translation surveillance revealed AVEN and FOCAD as SKIV2L interactors. AVEN prevents ribosome stalls at structured regions, which otherwise require SKIV2L for clearance. This pathway is crucial for histone translation, upstream open reading frame (uORF) regulation, and counteracting ribosome arrest on small ORFs. In summary, we uncovered key targets, components, and functions of mammalian RNA decay pathways and extensive coupling to translation.

Ethanol lock and immunoglobulin load: Improving the clinical course of trichohepatoenteric syndrome

Ethanol lock and immunoglobulin load: Improving the clinical course of trichohepatoenteric syndrome

Tricho-Hepato-Enteric Syndrome mutation update: Mutations spectrum ofTTC37andSKIV2L, clinical analysis and future prospects

Tricho-Hepato-Enteric syndrome (THES) is a very rare autosomal recessive syndromic enteropathy caused by mutations of either TTC37 or SKIV2L genes. Very little is known of these two gene products in mammals nor of the pathophysiology of the disease. Since the identification of the genes, we have set up the molecular diagnostic of THES in routine, gathering a large cohort with clinical and molecular data. Here, we report the phenotype and genotype analysis of this cohort together with an extensive literature review of THES cases worldwide, that is, 96 individuals harboring mutations in one gene or the other. We set up locus-specific databases for both genes and reviewed the type of mutation as well as their localization in the proteins. No hot spot is evidenced for any type of mutation. The phenotypic analysis was first made on the whole cohort but is limited due to heterogeneity in clinical descriptions. We then examined the lab diagnostic cohort in detail for clinical manifestations. For the first time, we are able to suggest that patients lacking SKIV2L seem more severely affected than those lacking TTC37, in terms of liver damage and prenatal growth impairment.

OR33 The importance of detection of donor-chimerism and anti-donor or anti-recipeint HLA antibodies after liver-contained intestinal transplantation

Acute graft versus host disease (aGvHD) is a devastating complication of transplantation, with the highest incidence after liver-contained intestinal transplantation (LIT). Its prompt diagnosis with analysis of involved cell components is critical for treatment plan. Here we present two aGvHD cases after LIT, diagnosed with donor-chimerism by short tandem repeat assay along with detection of de novo anti-recipient or donor specific HLA antibodies (dRSA or dDSA). Case 1 : A 2-year girl presented with skin rash, and fever 2 weeks after LIT for trichohepatoenteric syndrome. On post operative day (POD) 15, donor-derived CD8 cell was detected with 60%, and peaked on POD 20 (74% CD8, 91% CD19) (Fig. 1A). Importantly, multiple dRSAs were also detected (Fig. 1B). The diagnosis of combined cellular and humoral aGvHD elicited anti-B cell therapy with bortezomib/rituximab. Subsequently, all dRSAs but DQ8 declined to Case 2: A 41-year man developed acute cellular rejection a week after LIT for metastatic carcinoid tumors. Rejection was resolved with thymoglobuline treatment, but DQ2 dDSA persisted on POD 31-100. Along with skin rash, donor-chimerism was detected on POD 62 (45% CD8, 53% CD19), and persisted for the next 40 days with absence of dRSA. Accordingly, cellular aGvHD was treated with photopheresis and steroid, with significant reduction of both DQ2 dDSA and donor-chimerism (Fig. 1C and D). After resolution of aGvHD, he developed intra-abdominal sepsis from surgical complication and died on POD 200. Simultaneous occurrence of aGvHD and circulating dDSA reflects lymphocyte reactivity from both recipient and donor. Even though both patients succumbed due to complicated courses, donor-chimerism and HLA antibody detection provided critical information of donor-derived T and B cell involvement that guided treatment plan for dRSA, dDSA, and aGvHD.

Exome sequencing identifies a novel TTC37 mutation in the first reported case of Trichohepatoenteric syndrome (THE-S) in South Africa

BackgroundTrichohepatoenteric syndrome (THE-S) or phenotypic diarrhoea of infancy is a rare autosomal recessive disorder characterised by severe infantile diarrhoea, facial dysmorphism, immunodeficiency and woolly hair. It was first described in 1982 in two infants with intractable diarrhoea, liver cirrhosis and abnormal hair structure on microscopy. We report on two siblings from a consanguineous family of Somali descent who, despite extensive clinical investigation, remained undiagnosed until their demise. The index patient died of fulminant cytomegalovirus pneumonitis at 3 months of age.MethodsWhole exome sequencing (WES) was performed on a premortem DNA sample from the index case. Variants in a homozygous recessive state or compound heterozygous state were prioritized as potential candidate variants using TAPER™. Sanger sequencing was done to genotype the parents, unaffected sibling and a deceased sibling for the variant of interest.ResultsExome sequencing identified a novel homozygous mutation (c.4507C > T, rs200067423) in TTC37 which was confirmed by Sanger sequencing in the index case. The identification of this mutation led to the diagnosis of THE-S in the proband and the same homozygous variant was confirmed in a male sibling who died 4 years earlier with severe chronic diarrhoea of infancy. The unaffected parents and sister were heterozygous for the identified variant.ConclusionsWES permitted definitive genetic diagnosis despite an atypical presentation in the index case and suggests that severe infection, likely secondary to immunodeficiency, may be a presenting feature. In addition definitive molecular diagnosis allows for genetic counseling and future prenatal diagnosis, and demonstrates the value of WES for post-mortem diagnosis of disorders with a non-specific clinical presentation in which a Mendelian cause is suspected.

Emerging roles of the processing of nucleic acids and Toll-like receptors in innate immune responses to nucleic acids.

Nucleic acid (NA) is continuously degraded in lysosomes, cytoplasm, and nucleus. NA degradation has a key role in preventing hazardous activation of NA sensors. DNA degradation by lysosomal and cytoplasmic DNases prevents homeostatic activation of cytoplasmic DNA sensing pathways. Crude NA, however, is not sufficient for stimulating NA sensors. mRNAs and rRNAs need to be processed by inositol-requiring enzyme 1 (IRE-1) or RNase L before stimulating cytoplasmic RNA sensors. Activation of cytoplasmic RNA sensors by processed RNAs is tightly controlled by their degradation through the machineries, such as RNA editing, by adenosine (A) deaminases that act on RNA 1 (ADAR1) and the RNA exosome. Impaired degradation of processed RNAs in humans causes activation of cytoplasmic RNA sensors, leading to Aicardi-Goutières syndrome or trichohepatoenteric syndrome. Lysosomal TLRs are also dependent on NA processing in lysosomes. Digestion of dsDNA by DNase II is required for TLR9 response to ssDNA. TLR7 and TLR8 respond to ribonucleosides and oligoribonucleotides, instead of ssRNA itself, indicating requirement for RNA processing. NA-sensing TLRs themselves need to be processed by lysosomal proteases. Without processing, TLR8 and TLR9 fail to form dimers. In addition to NA degradation, the processing of NAs and TLRs by a variety of enzymes is an emerging concept on the control of innate immune responses to NAs.

Novel mutations in SKIV2L and TTC37 genes in Malaysian children with trichohepatoenteric syndrome

Trichohepatoenteric syndrome (THES) is a rare autosomal recessive disorder that is classically associated with intractable diarrhea with an onset within the first few months of life. Herein, we investigated and reported novel mutations in two causal genes in 3 Malaysian cases. Genomic DNA was extracted from peripheral blood obtained from patients in two Malaysian Chinese families. The exons of SKIV2L and TTC37 genes were amplified and sequenced by bi-directional sequencing to identify the point mutations within the coding sequence. Three Chinese boys from two families with characteristic features and clinical course were diagnosed with THES. In family-1, two point mutations were identified in the SKIV2L gene (c.1891G>A and c.3187C>T). In family-2, a single-nucleotide duplication (c.3426dupA) was found in the TTC37 gene. These mutations cause the production of abnormal non-functional gene product leading to the clinical manifestations in the patients. We reported three point mutations, which have not been previously described in other patients with THES in SKIV2L and TTC37 genes, including one nonsense, one frameshift, and one missense mutations.

Trichohepatoenteric Syndrome or Syndromic Diarrhea-Report of Three Members in a Family, First Report from Iran.

Introduction. Intractable diarrhea of infancy (IDI) includes several types of early onset diarrhea; one of the rare etiologies is trichohepatoenteric (THE) syndrome, also known as syndromic diarrhea (SD) which was primarily described by Stankler et al. Hereby we report a family with several affected members which to our knowledge is the first case report from Iran. Report of Cases. A three-year-old boy referred with short stature, poor weight gain, and intermittent steatotic diarrhea to our center. He was born to healthy, relative parents (cousins). He did not gain any weight after four months of age and began having intermittent steatotic diarrhea, abdominal distension, and fever. He was hospitalized several times. Two other children in the family also showed somewhat similar symptoms. Two sweat tests were negative for cystic fibrosis. Workup for Celiac disease was performed several times which was negative; however, gluten-free diet was tried several times which was not effective. Workup for Hirschsprung's disease was performed but colon was ganglionic. Evidence of liver involvement was approved by elevated liver enzymes and coarse echo of liver on sonography. Discussion. Trichoenterohepatic syndrome should be put in mind in cases of intractable diarrhea presenting in a family with several affected members. Early diagnosis would save patients from unnecessary workups.

An infant with trichohepato-enteric syndrome: case report

Trichohepato-enteric syndrome (THE-S) is a disease characterized by severe infantile diarrhea, failure to thrive, facial dysmorphism, woolly hair, and immune or hepatic dysfunction. We report the case of a boy who presented in early infancy with chronic watery diarrhea, dependent on total parenteral nutrition, along with other features of THE-S.

The role of enterocyte defects in the pathogenesis of congenital diarrheal disorders.

ABSTRACTCongenital diarrheal disorders are rare, often fatal, diseases that are difficult to diagnose (often requiring biopsies) and that manifest in the first few weeks of life as chronic diarrhea and the malabsorption of nutrients. The etiology of congenital diarrheal disorders is diverse, but several are associated with defects in the predominant intestinal epithelial cell type, enterocytes. These particular congenital diarrheal disorders (CDDENT) include microvillus inclusion disease and congenital tufting enteropathy, and can feature in other diseases, such as hemophagocytic lymphohistiocytosis type 5 and trichohepatoenteric syndrome. Treatment options for most of these disorders are limited and an improved understanding of their molecular bases could help to drive the development of better therapies. Recently, mutations in genes that are involved in normal intestinal epithelial physiology have been associated with different CDDENT. Here, we review recent progress in understanding the cellular mechanisms of CDDENT. We highlight the potential of animal models and patient-specific stem-cell-based organoid cultures, as well as patient registries, to integrate basic and clinical research, with the aim of clarifying the pathogenesis of CDDENT and expediting the discovery of novel therapeutic strategies.

Cases of Trichohepatoenteric Syndrome (Syndromic Diarrhea) with Underlying Crohn’s Disease

Tricho-hepato-enteric syndrome (syndromic, phenotypic diarrhea, SD/THES) is a rare inborn disease, which affects bowels. It is caused by the mutation of genes SKIV2L or TTC37. Manifestations include intrauterine hypotrophy, severe chronic diarrhea, which starts in infancy, characteristic facial features and hair growth abnormalities, immune disorders. There are data on two patients dealing with tricho-hepato-enteric syndrome with underlying Crohn’s disease. This is the first description of cases of aggravated tricho-hepatoenteric syndrome ever found in Russian medical literature.

Novel TTC37 Mutations in a Patient with Immunodeficiency without Diarrhea: Extending the Phenotype of Trichohepatoenteric Syndrome.

Unbiased genetic diagnosis has increasingly associated seemingly unrelated somatic and immunological phenotypes. We report a male infant who presented within the first year of life with physical growth impairment, feeding difficulties, hyperemesis without diarrhea, and abnormal hair findings suggestive of trichorrhexis nodosa. With advancing age, moderate global developmental delay, susceptibility to frequent viral illnesses, otitis media, and purulent conjunctivitis were identified. Because of the repeated infections, an immunological evaluation was pursued and identified impaired antibody memory responses following pneumococcal vaccine administration. Immunoglobulin replacement therapy and nutritional support were employed as mainstays of therapy. The child is now aged 12 years and still without diarrhea. Whole exome sequencing identified compound heterozygous mutations in the TTC37 gene, a known cause of the trichohepatoenteric syndrome (THES). This case extends the known phenotype of THES and defines a potential subset for inclusion as an immune overlap syndrome.

A New Genetic Mutation in a Patient With Syndromic Diarrhea and Hepatoblastoma

A small-for-gestational-age preterm infant presented with prominent forehead and cheeks, broad nasal root, hypertelorism, and woolly and brittle hair. Intractable diarrhea began at 1 month. Upper endoscopy showed no abnormality, and histology showed mild and nonspecific villous atrophy with a normal brush border (Fig. 1). Microscopic analysis of the hair shaft revealed trichorrhexis nodosa (twisted hair, longitudinal breaks, cuticolar cell disruption) (Fig. 2). She died after 12 months from hepatic failure. Autopsy revealed a multinodular liver, with fibrosis and a macrotrabecluar-type hepatoblastoma (an area of immature hepatic cells arranged in trabecular structures and ribbons with intraluminar bilious thrombi) (Fig. 3).FIGURE 1: Microscopic findings. Semithin slide under optical microscope shows a short intestinal villus.FIGURE 2: Hair findings. Microscopic analysis of a hair shaft reveals abnormalities, including twisted hair (pili torti), longitudinal breaks, and cuticolar cell disruptions leading to the separation and fragmentation of the cortical fibers with the formation of nodes. These features are pathognomonic of trichorrhexis nodosa.FIGURE 3: Postmortem liver histology. A small hepatic nodule showing macrotrabecular structure, resembling a degeneration area of hepatoblastoma and cirrhosis.We suspected trichohepatoenteric syndrome (THES), a congenital entheropathy causing diarrhea in infants born small for gestational age. The syndrome is associated with nonspecific villous atrophy, facial dysmorphism, immune disorders, liver disease, and trichorrhexis nodosa (1). Hartley et al (2,3) identified the THES locus mapped to 5q14.3–5q21.2. A new homozygous mutation of the THES locus was identified in our patient (C2921-2G>A, skipping of the exon 29). This mutation, together with the occurrence of hepatoblastoma, has not been previously reported. Acknowledgments We thank Dr Antonello Villa of Milano-Bicocca University for the electronic microscopy, Prof ssa Margherita Silengo of Turin University for the evaluation of the hair shaft, Dr ssa Francesca Crosti and the genetic laboratory of San Gerardo Hospital for genetic supervision, Prof Jane Hartley of Birmingham Children's Hospital for the genetical analysis, and the medical and nursing staff of San Gerardo's NICU for the attention and the care paid to this patient.

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.

P10 Whole-exome-Sequencing-based discovery of novel syndromic form of neonatal cholestasis

IntroductionTwo cousins from a consanguineous family presented with low γ glutamyl transferase (GGT) cholestasis, trichorrhexis nodosa (TN) and severe hypoglycaemia which required diazoxide to stabilise. One child also had life...

Mutations in TTC37 Cause Trichohepatoenteric Syndrome (Phenotypic Diarrhea of Infancy)

Trichohepatoenteric syndrome (THES) is an autosomal-recessive disorder characterized by life-threatening diarrhea in infancy, immunodeficiency, liver disease, trichorrhexis nodosa, facial dysmorphism, hypopigmentation, and cardiac defects. We attempted to characterize the phenotype and elucidate the molecular basis of THES. Twelve patients with classic THES from 11 families had detailed phenotyping. Autozygosity mapping was undertaken in 8 patients from consanguineous families using 250,000 single nucleotide polymorphism arrays and linked regions evaluated using microsatellite markers. Linkage was confirmed to one region from which candidate genes were analyzed. The effect of mutations on protein production and/or localization in hepatocytes and intestinal epithelial cells from affected patients was characterized by immunohistochemistry. Previously unrecognized platelet abnormalities (reduced platelet alpha-granules, unusual stimulated alpha granule content release, abnormal lipid inclusions, abnormal platelet canalicular system, and reduced number of microtubules) were identified. The THES locus was mapped to 5q14.3-5q21.2. Sequencing of candidate genes showed mutations in TTC37, which encodes the uncharacterized tetratricopeptide repeat protein, thespin. Bioinformatic analysis suggested thespin to be involved in protein-protein interactions or chaperone. Preliminary studies of enterocyte brush-border ion transporter proteins (sodium hydrogen exchanger 2, sodium hydrogen exchanger 3, aquaporin 7, sodium iodide symporter, and hydrogen potassium adenosine triphosphatase [ATPase]) showed reduced expression or mislocalization in all THES patients with different profiles for each. In contrast the basolateral localization of Na/K ATPase was not altered. THES is caused by mutations in TTC37. TTC37 mutations have a multisystem effect, which may be owing to abnormal stability and/or intracellular localization of TTC37 target proteins.

Syndromic (phenotypic) diarrhea in early infancy

Syndromic diarrhea (SD), also known as phenotypic diarrhea (PD) or tricho-hepato-enteric syndrome (THE), is a congenital enteropathy presenting with early-onset of severe diarrhea requiring parenteral nutrition (PN). To date, no epidemiological data are available. The estimated prevalence is approximately 1/300,000–400,000 live births in Western Europe. Ethnic origin does not appear to be associated with SD. Infants are born small for gestational age and present with facial dysmorphism including prominent forehead and cheeks, broad nasal root and hypertelorism. Hairs are woolly, easily removed and poorly pigmented. Severe and persistent diarrhea starts within the first 6 months of life (≤ 1 month in most cases) and is accompanied by severe malabsorption leading to early and relentless protein energy malnutrition with failure to thrive. Liver disease affects about half of patients with extensive fibrosis or cirrhosis. There is currently no specific biochemical profile, though a functional T-cell immune deficiency with defective antibody production was reported. Microscopic analysis of the hair show twisted hair (pili torti), aniso- and poilkilotrichosis, and trichorrhexis nodosa. Histopathological analysis of small intestine biopsy shows non-specific villous atrophy with low or no mononuclear cell infiltration of the lamina propria, and no specific histological abnormalities involving the epithelium. The etiology remains unknown. The frequent association of the disorder with parental consanguinity and/or affected siblings suggests a genetic origin with an autosomal recessive mode of transmission. Early management consists of total PN. Some infants have a rather milder phenotype with partial PN dependency or require only enteral feeding. Prognosis of this syndrome is poor, but most patients now survive, and about half of the patients may be weaned from PN at adolescence, but experience failure to thrive and final short stature.Syndromic diarrhea – Phenotypic diarrhea – Tricho-hepato-enteric syndrome – Intractable diarrhea of infancy with facial dysmorphism – Trichorrhexis nodosa and cirrhosis – Neonatal hemochromatosis phenotype with intractable diarrhea and hair abnormalities – Intractable infant diarrhea associated with phenotypic abnormalities and immune deficiency.