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

ABSTRACT: 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.

SUBMITTER: Rider NL

PROVIDER: S-EPMC4311608 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Rider Nicholas L NL Boisson Bertrand B Jyonouchi Soma S Hanson Eric P EP Rosenzweig Sergio D SD Cassanova Jean-Laurent JL Orange Jordan S JS

Frontiers in pediatrics 20150130

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 ...[more]

PMID: 25688341

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Project description:Background & aimsTrichohepatoenteric 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.MethodsTwelve 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.ResultsPreviously 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.ConclusionsTHES 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.

Project description:BackgroundTrichohepatoenteric syndrome (THES) is a rare autosomal recessive genetic disease caused by pathogenic mutations in TTC37 or SKIV2L gene. The presentation is variable, including intractable diarrhea, woolly hair abnormality, immune dysfunction, intrauterine growth restriction (IUGR), facial dysmorphism, and sometimes liver and skin abnormalities. Although four Chinese children affected with THES syndrome 1 have been described in Singapore, Taiwan (China) and Malaysia, to our knowledge, this is the first report of a patient with THES in Mainland China, harboring classical platelets features, clinical course, and novel mutations in TTC37 gene.Case descriptionThe male infant had symmetrical IUGR, and was born at 37+1 weeks with a birth weight of 1,480 g. He presented with feeding difficulties and vomiting from the 12th day after birth during the stay in neonatal intensive care unit, and had excessive diarrhea from the 21st day after birth. From the 35th day after birth, even slightly hypotonic oral rehydration solution caused watery stools. The blood glucose level was lower than 3.3 mmol/L even when the glucose infusion rate was up to 14 mg/kg/min on the parenteral alone, which has not been reported in previous literature. Normal α-granules were observed occasionally in THES platelets. Whole-exome sequencing analysis identified compound heterozygous mutations (c.4130C > G: p.S1377X) and (Exon11-13 del) in the TTC37 gene, which had been inherited from his father and mother, respectively. To our knowledge, the above mutations have not been described in any database or previous literature. Total parenteral nutrition was employed as mainstay of therapy, and hydrocortisone (1 mg/kg/dose, every 4 hours) was used to maintain blood glucose levels. The patient's final prognosis was poor after discharged from the hospital.ConclusionsThis case presented with mild platelet abnormality and intractable hypoglycemia, which extends the known mutation and phenotype of THES. The clinical features of Chinese patient are consistent with other ethnicity. Molecular diagnosis is useful for patients with unexplained intractable diarrhea, which puts an end to a long diagnostic odyssey.

Project description:Syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) is a rare, autosomal recessive and severe bowel disorder mainly caused by mutations in the tetratricopeptide repeat domain 37 (TTC37) gene which act as heterotetrameric cofactors to enhance aberrant mRNAs decay. The phenotype and immune profiles of SD/THE overlap those of primary immunodeficiency diseases (PIDs). Neonates with intractable diarrhea underwent immunologic assessments including immunoglobulin levels, lymphocyte subsets, lymphocyte proliferation, superoxide production, and IL-10 signaling function. Candidate genes for PIDs predisposing to inflammatory bowel disease were sequencing in this study. Two neonates, born to nonconsanguineous parents, suffered from intractable diarrhea, recurrent infections, and massive hematemesis from esopharyngeal varices due to liver cirrhosis or accompanying Trichorrhexis nodosa that developed with age and thus guided the diagnosis of SD/THE compatible to TTC37 mutations (homozygous DelK1155H, Fs*2; heterozygous Y1169Ter and InsA1143, Fs*3). Their immunologic evaluation showed normal mitogen-stimulated lymphocyte proliferation, superoxide production, and IL-10 signaling, but low IgG levels, undetectable antibody to hepatitis B surface antigen and decreased antigen-stimulated lymphocyte proliferation. A PubMed search for bi-allelic TTC37 mutations and phenotypes were recorded in 14 Asian and 12 non-Asian cases. They had similar presentations of infantile onset refractory diarrhea, facial dysmorphism, hair anomalies, low IgG, low birth weight, and consanguinity. A higher incidence of heart anomalies (8/14 vs 2/12; P = 0.0344, Chi-square), nonsense mutations (19 in 28 alleles), and hot-spot mutations (W936Ter, 2779-2G>A, and Y1169Ter) were found in the Asian compared with the non-Asian patients. Despite immunoglobulin therapy in 20 of the patients, 4 died from liver cirrhosis and 1 died from sepsis. Patients of all ethnicities with SD/THE with the characteristic triad of T nodosa, hepatic cirrhosis, and intractable enteropathy have low IgG, poor vaccine response and/or decreased antigen-stimulated lymphocyte proliferation. This is now better classified into the subgroup of "well-defined syndromes with immunodeficiency" (the update termed as "combined immunodeficiencies with associated or syndromic features") than "predominantly antibody deficiencies" in the update PIDs classification, and requires optimal interventions.

Dataset Information

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

Publications

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

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