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Trichohepatoenteric Syndrome

Synonyms: Phenotypic Diarrhea of Infancy, Syndromic Diarrhea/Tricho-Hepato-Enteric Syndrome (SD/THE), THES

, MD, PhD, , PhD, , , PhD, , MD, PhD, and , PharmD, PhD.

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Estimated reading time: 16 minutes

Summary

Clinical characteristics.

Trichohepatoenteric syndrome (THES), generally considered to be a neonatal enteropathy, is characterized by intractable diarrhea (seen in almost all affected children), woolly hair (seen in all), intrauterine growth restriction, facial dysmorphism, and short stature. Additional findings include poorly characterized immunodeficiency, recurrent infections, skin abnormalities, and liver disease. Mild intellectual disability (ID) is seen in about 50% of affected individuals. Less common findings include congenital heart defects and platelet anomalies. To date 52 affected individuals have been reported.

Diagnosis/testing.

The diagnosis of THES is established in a proband with biallelic pathogenic variants in either TTC37 or SKIV2L.

Management.

Treatment of manifestations: To promote maximal weight gain and linear growth, most children initially require parenteral nutrition (PN). As tolerated, oral feeding (typically a semi-elemental diet) can be combined with PN. On the rare occasion that PN is unnecessary, anecdotal reports describe use of mainly an amino acid-based formula. To reduce the burden of infections, immunoglobulins can be supplemented in those with low immunoglobulin levels or immunoglobulin functional abnormalities. Patient-specific management of ID is based on age-appropriate assessments of cognitive development, speech and language development, and psychosocial skills.

Surveillance: For children not receiving PN: close monitoring of nutritional status by a pediatric nutritionist to assure prompt intervention as needed. Yearly assessment of: diarrhea for changes that could suggest inflammatory bowel disease; liver function and size; immunoglobulin serum concentration and functionality; TSH level for evidence of hypothyroidism. Periodic assessment of: cognitive development, speech and language, and psychosocial skills for evidence of ID.

Genetic counseling.

THES is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SKIV2L or TTC37 pathogenic variants have been identified in an affected family member, carrier testing of at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic diagnosis are possible.

Diagnosis

To date, no diagnostic algorithm for trichohepatoenteric syndrome (THES) has been published.

Suggestive Findings

THES should be suspected in individuals with the following clinical findings [Fabre & Badens 2014, Fabre et al 2014]:

  • Growth failure. * Intrauterine growth restriction (IUGR) / small for gestational age (SGA), short stature
  • Intractable/chronic diarrhea * beginning in infancy that persists despite bowel rest or, on rare occasion, shows very early-onset inflammatory bowel disease (VEOIBD) of infancy. Endoscopic evaluation is often normal, but can resemble IBD. Intestinal biopsy findings range from mild villous atrophy to severe villous atrophy [Goulet et al 2008, Fabre et al 2014].
  • Woolly, brittle, easily breakable hair. Hair analysis using light microscopy showed trichorrhexis nodosa in 42/52 individuals [Fabre & Badens 2014, Fabre et al 2014].
  • Immunodeficiency that is poorly characterized, but typically low immunoglobulin levels and/or poor antibody production after immunization. Monoclonal hyper-IgA has been described [Fabre & Badens 2014, Fabre et al 2014, Rider et al 2015].
  • Liver disease, mostly hepatomegaly and/or elevated liver enzymes; fibrosis or cirrhosis can occur. Hemochromatosis has been described, particularly when liver findings are significant [Verloes et al 1997, Hartley et al 2010].
  • Café au lait spots or dyschromic spots have been described in nearly half of individuals reported [Fabre et al 2014]. Of note, a subset of affected individuals from the Arabian peninsula have pelvic, girdle, and lower-limb skin hyperpigmentation [Monies et al 2015].

* The association of neonatal intractable diarrhea and IUGR suggests the diagnosis of THES.

Establishing the Diagnosis

The diagnosis of THES is established in a proband with biallelic pathogenic variants in TTC37 or SKIV2L (Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (serial single-gene testing or a multigene panel) and comprehensive genomic testing depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of THES is broad, children with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with diarrhea, liver disease, and immunodeficiency will be more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of THES, molecular genetic testing approaches can include serial single-gene testing or use of a multigene panel.

  • Serial single-gene testing. Sequence analysis of TTC37 is performed first and – if no pathogenic variants are identified – followed by sequence analysis of SKIV2L. If only one pathogenic variant is found, gene-targeted deletion/duplication analysis could be considered; however, to date no exon or whole-gene deletions or duplications have been reported in either gene.
  • A multigene very early-onset IBD (VEOIBD) panel that includes SKIV2L and TTC37 and other genes of interest (see Differential Diagnosis) typically provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting identification of pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; conversely, given the rarity of THES, some panels for diarrhea, hepatic disease, and immunodeficiency may not include these genes. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders with diarrhea, hepatic disease, and immunodeficiency, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible, although not yet easily analyzed in a clinical setting.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Trichohepatoenteric Syndrome

Gene 1Proportion of THES
Attributed to Pathogenic
Variants in Gene
Proportion of Pathogenic Variants 2 Detectable by Method
Sequence
analysis 3
Gene-targeted deletion/
duplication analysis 4
SKIV2L16/52 5
(31%)
All variants reported to dateUnknown, none reported to date
TTC3736/52 6
(69%)
All variants reported to dateUnknown, none reported to date
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.
6.

Clinical Characteristics

Clinical Description

Trichohepatoenteric syndrome (THES) is considered a syndrome of neonatal enteropathy [Canani et al 2015]. THES is characterized by the association of intractable diarrhea (seen in almost all affected children), woolly hair (seen in all, but may not be obvious at a young age or due to cultural grooming practices), intrauterine growth restriction (IUGR), facial dysmorphism, and short stature, as well as poorly characterized immunodeficiency (sometimes with macrophage activation syndrome), recurrent infections, skin abnormalities, and liver disease. Intellectual disability (ID) is seen in about 50% of children. Less common findings include congenital heart defects and platelet anomalies. To date 52 affected individuals have been reported (see Table 1).

Intractable diarrhea usually begins in the first days of life but sometimes can be delayed until later in the first year of life. The diarrhea persists despite bowel rest (i.e., use of parenteral nutrition). Stools are watery; in rare cases blood can be found. The diarrhea leads to malabsorption and failure to thrive, which typically requires parenteral nutrition (see Management). To date, the diarrhea has appeared to be lifelong [Fabre & Badens 2014].

Very rarely, the clinical presentation can resemble so-called very early-onset inflammatory bowel disease (VEOIBD).

In the only instance in which immunodeficiency was reported to be the major clinical finding, the child never manifested the characteristic diarrhea [Rider et al 2015].

Woolly, brittle hair. Detailed clinical descriptions of the hair provided for 41 individuals included the following: woolly (n=22), poorly pigmented / light (n=18), easily removable / brittle (n=19), and unmanageable / unable to be combed (n=15) (e.g., Bozzetti et al [2013], Busoni et al [2017]).

Growth failure

  • Intrauterine growth restriction (IUGR) / small for gestational age (SGA). Most children are below the 10th centile at birth either for height or for weight [Fabre & Badens 2014, Fabre et al 2014].
  • Short stature. Despite adequate nutrition, the last recorded height in more than 50% of affected individuals was below the 3rd centile [Fabre & Badens 2014].
    Although to date no adult with THES has been described in detail, the heights in the three older individuals for whom that information was available were the following:

Immunodeficiency. Children are prone to recurrent infection [Girault et al 1994, Martinez-Vinson 2004, Zheng et al 2016, Bick et al 2017]. Both viral infections (respiratory syncytial virus [Lee et al 2016a], Epstein Barr virus [Martinez-Vinson 2004, Fabre & Badens 2014]) and bacterial infections [Martinez-Vinson 2004, Rider et al 2015] have been reported.

Nine of 15 individuals with THES had a transient hemophagocytic syndrome / macrophage activation syndrome [Fabre & Badens 2014]; however, no specific data were provided about diagnosis or management.

Infection was implicated in the death of seven of 21 patients.

Liver disease, found in about half of patients, is mostly cirrhosis and fibrosis [Fabre et al 2014]. In seven of 17 individuals for whom the cause of death was described, liver disease (mostly liver failure or cirrhosis) was implicated [Girault et al 1994, Verloes et al 1997, Kinnear et al 2017]. One patient developed a hepatoblastoma [Bozzetti et al 2013].

Pathology showed iron overload and sometimes hemochromatosis [Hartley et al 2010, Fabre et al 2014]. In some instances, hemochromatosis improved with time [Fabre et al 2007].

Mild intellectual disability, described in about half of patients [Goulet et al 2008, Fabre & Badens, Fabre et al 2014], is poorly characterized.

Brain MRI – when performed – appears normal [Fabre & Badens 2014].

Skin abnormalities. The most common are café au lait spots that preferentially appear on the lower limbs [Monies et al 2015]. Later in life, xerosis and/or rubbery skin can be observed.

Congenital cardiac defects, which are seldom seen, vary. The following were observed among 12 patients with cardiac or aortic defects: ventricular septal defect (n=2) [Hartley et al 2010, Bick et al 2017]; atrial septal defect (n=2) [Chong et al 2015, Lee et al 2016a]; tetralogy of Fallot (n=1) [Hartley et al 2010]. Others had a bicuspid aortic valve with or without other anomalies, an aortic defect, or a mildly dilated aortic sinus.

Platelets can be enlarged with no known functional defect [Hartley et al 2010].

Facial dysmorphism that is mild and nonspecific is observed in nearly all affected individuals. The main findings (coarse features, a wide forehead, broad nasal root, and hypertelorism) can become more apparent with time [Fabre & Badens 2014, Fabre et al 2014].

Findings observed in a few affected individuals that could be part of the phenotypic spectrum of THES or unrelated findings include the following:

One individual each:

Phenotype Correlations by Gene

Current data suggest that individuals with biallelic pathogenic variants in either SKIV2L or TTC37 are indistinguishable clinically.

Genotype-Phenotype Correlations

Because most pathogenic variants are private, genotype/phenotype correlations are difficult.

Of note, the phenotypes were indistinguishable in the five individuals with the recurrent TTC37 variant (Trp936Ter) and those with other TTC37 pathogenic variants [Fabre et al 2014].

Prevalence

THES is rare. To date about 50 affected individuals have been reported.

The best estimate of prevalence is 1:1,000,000 births, based on the French cohort of Fabre & Badens [2014].

Affected individuals have been reported worldwide.

As with all autosomal recessive disorders, the prevalence may be increased in highly consanguineous populations.

Differential Diagnosis

Table 3.

Monogenic Disorders with Intractable Diarrhea to Consider in the Differential Diagnosis of Trichohepatoenteric Syndrome

DisorderGeneMOIDistinguishing Clinical Features of Differential Diagnosis Disorder
Congenital tufting enteropathy
(OMIM 613217)
EPCAMARSpecific intestinal pathology (tuft)
IPEX syndromeFOXP3XLLow regulatory T cells
Gastrointestinal defects and immunodeficiency syndrome (OMIM 243150)TTC7AARDuodenal atresia
Syndromic congenital tufting enteropathy (OMIM 270420)SPINT2ARSpecific intestinal pathology (tuft)
Choanal atresia

AR = autosomal recessive; IPEX = immune dysregulation, polyendocrinopathy, enteropathy, X-linked; MOI = mode of inheritance; XL = X-linked

See Diarrhea, congenital: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with trichohepatoenteric syndrome (THES), the following evaluations are recommended:

  • Nutritional evaluation by a specialist pediatric nutritionist
  • Immunologic assessment with serum IgG, IgM, IgA; immunophenotyping; if immunization has been performed before, evaluation of the level of specific antibodies to detect a rapid loss of protective antibodies, which would require immunoglobulin supplementation
  • Liver assessment: ultrasound evaluation; assessment of liver enzymes (ALT/AST, GGT); in case of abnormalities, consult a pediatric hepatologist for recommendations on additional investigations
  • Cardiac evaluation for congenital malformations
  • Age-appropriate assessment of cognitive development, speech and language development, and psychosocial skills
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

No specific treatment is available. The goals of the treatment are to promote maximal weight gain and linear growth, to reduce the burden of infections, and to provide patient-specific management of intellectual disability.

Weight gain. Most children, when first diagnosed, require parenteral nutrition (PN) to achieve appropriate weight gain and catch-up growth. Although PN is usually required, it can be combined (as tolerated) with oral feeding – typically a semi-elemental diet [Goulet et al 2008]. About 30%-50% of patients can become independent of parenteral nutrition after prolonged PN. Of note, promotion of oral feeding as tolerated (rather than enteral tube feeding) should help prevent future eating disorders.

To date nine individuals have been reported in whom PN was unnecessary [Kotecha et al 2012, Chong et al 2015, Rider et al 2015, Lee et al 2016a, Mahjoub et al 2016, Zheng et al 2016]. In three of the nine, the diet was an amino acid formula [Lee et al 2016a, Lee et al 2016b, Zheng et al 2016]; it is not clear if weight gain was adequate, or if catch-up growth was achieved.

When early-onset manifestations are those of inflammatory bowel disease (IBD), infections should be ruled out and routine management of IBD with steroids, azathioprine, and anti-TNF (tumor necrosis factor) antibody can be considered; however, this routine IBD management may result in only transient improvement, or no improvement [Busoni et al 2017, Kammermeier et al 2017].

Growth. Anecdotal experience shows no efficacy of growth hormone treatment [Fabre & Badens 2014].

Infection. Immunoglobulin supplementation for those with low immunoglobulin levels appears to lower the rate of infection [Fabre et al 2014, Rider et al 2015].

Of note, hematopoietic stem cell transplantation (HSCT) – reported twice to date – has been unsuccessful: one patient succumbed to infection [Girault et al 1994] and the other showed only mild improvement [Kammermeier et al 2014].

Intellectual disability is managed specifically according to the results of age-appropriate assessments of cognitive development, speech and language development, and psychosocial skills.

Tooth shape abnormalities. Evaluation of abnormal dentition in children is especially important because teeth are required for development of speech, nutrition, self-esteem, and well-being. The National Foundation for Ectodermal Dysplasias (NFED) website provides further resources and information.

Hair changes. Fragile hair and hair loss can have a deeper-than-expected emotional impact on a patient and family. Counseling may be helpful. Also, hair prosthetics (wigs) are available through Locks of Love and other organizations; some insurance provides two wigs per year in growing children with alopecia. A prescription for a cranial prosthesis may or may not aid insurance reimbursement.

Surveillance

Although there are no consensus guidelines, the following surveillance is recommended:

  • For children not receiving parenteral nutrition, close monitoring of nutritional status by a pediatric nutritionist to assure prompt intervention should nutritional deficiency become a concern
  • Yearly assessment of the following main features:
    • Diarrhea. If the nature of the diarrhea changes (e.g., appearance of bloody diarrhea), investigation of possible inflammatory bowel disease (IBD) is warranted [Busoni et al 2017].
    • Liver function. Ultrasound examination and measurement of liver enzymes (AST, ALT, GGT), International Normalized Ratio (INR), and bilirubin
    • Serum concentration of IgG, IgM, IgA, and immunoglobulin functionality (i.e., immunophenotyping) even if results at the time of initial evaluation were normal. Consultation with an immunologist is warranted if immunoglobulin levels are low or if normal immunoglobulin levels are associated with a loss of specific protective antibody.
    • TSH level for evidence of hypothyroidism
  • Assessment of cognitive development, speech and language, and psychosocial skills for evidence of intellectual disability at ages 2, 4, 8, 12, and 15 years unless concerns appear earlier
  • As evolution of the dermatologic features (mostly hypo- or hyperpigmented patches and hair abnormalities) is unknown, regular evaluation by a dermatologist seems reasonable.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Trichohepatoenteric syndrome (THES) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one SKIV2L or TTC37 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

  • The offspring of an individual with THES syndrome are obligate heterozygotes (carriers) for a pathogenic variant in SKIV2L or TTC37.
  • To date, no individuals with THES syndrome have had children; however, many affected individuals have not yet reached reproductive age.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SKIV2L or TTC37 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for relatives at risk requires prior identification of the SKIV2L or TTC37 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the SKIV2L or TTC37 pathogenic variants have been identified in an affected family member, prenatal testing for a further pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Trichohepatoenteric Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Trichohepatoenteric Syndrome (View All in OMIM)

222470TRICHOHEPATOENTERIC SYNDROME 1; THES1
600478SKI2-LIKE RNA HELICASE; SKIV2L
614589TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 37; TTC37
614602TRICHOHEPATOENTERIC SYNDROME 2; THES2

Molecular Pathogenesis

Trichohepatoenteric syndrome (THES) is caused by loss of function of either protein in the human Ski complex: TTC37 (a TPR-containing protein) or SKIV2L (an RNA helicase). The Ski complex, a heterotetrameric cytoplasmic cofactor of the RNA exosome in eukaryotic and archeal (prokaryotic) cells, is required for exosome-mediated RNA surveillance including the regulation of normal mRNA and decay of nonfunctional mRNA [Brown et al 2000].

Subsequently Eckard et al [2014] have suggested that SKIV2L and TTC37 have different and independent functions as the cells of persons with SKIV2L pathogenic variants have an interferon 1 signature whereas cells from persons with TTC37 pathogenic variants do not.

SKIV2L

Gene structure. The SKIV2L transcript NM_006929.4 has 28 exons.

Pathogenic variants. The majority of pathogenic variants are nonsense or small deletions or insertions.

Normal gene product. The helicase SKI2W protein NP_008860.4 comprises 1,246 amino acids, has helicase with ATPase activity, and is thought to be involved in exosome-mediated RNA decay.

Abnormal gene product. See discussion of human SKI complex above.

TTC37

Gene structure. The transcript NM_014639.3 comprises all 43 exons, the first three of which are noncoding.

Pathogenic variants are missense, nonsense, or splice abnormalities.

Normal gene product. The tetratrichopeptide repeat protein 37 (NP_055454.1) comprises 1,564 amino acids.

The protein contains 20 TRP repeated domains. TPR repeats (which mediate protein-protein interactions and the assembly of multiprotein complexes) are a component of the SKI complex involved in exosome-mediated RNA decay.

Abnormal gene product. Pathogenic variants of TTC37 have reduced or absent protein expression or proteins that are mislocalized in cells.

References

Literature Cited

  • Barabino AV, Torrente F, Castellano E, Erba D, Calvi A, Gandullia P. "Syndromic diarrhea" may have better outcome than previously reported. J Pediatr. 2004;144:553–4. [PubMed: 15069414]
  • Bick D, Fraser PC, Gutzeit MF, Harris JM, Hambuch TM, Helbling DC, Jacob HJ, Kersten JN, Leuthner SR, May T, North PE, Prisco SZ, Schuler BA, Shimoyama M, Strong KA, Van Why SK, Veith R, Verbsky J, Weborg AM Jr, Wilk BM, Willoughby RE Jr, Worthey EA, Dimmock DP. Successful application of whole genome sequencing in a medical genetics clinic. J Pediatr Genet. 2017;6:61–76. [PMC free article: PMC5423809] [PubMed: 28496993]
  • Bozzetti V, Bovo G, Vanzati A, Roggero P, Tagliabue PE. A new genetic mutation in a patient with syndromic diarrhea and hepatoblastoma. J Pediatr Gastroenterol Nutr. 2013;57:e15. [PubMed: 23974064]
  • Brown JT, Bai X, Johnson AW. The yeast antiviral proteins Ski2p, Ski3p, and Ski8p exist as a complex in vivo. RNA. 2000;6:449–57. [PMC free article: PMC1369926] [PubMed: 10744028]
  • Busoni VB, Lemale J, Dubern B, Frangi F, Bourgeois P, Orsi M, Badens C, Fabre A. IBD-like features in syndromic diarrhea/trichohepatoenteric syndrome. J Pediatr Gastroenterol Nutr. 2017;64:37–41. [PubMed: 28027214]
  • Canani RB, Castaldo G, Bacchetta R, Martín MG, Goulet O. Congenital diarrhoeal disorders: advances in this evolving web of inherited enteropathies. Nat Rev Gastroenterol Hepatol. 2015;12:293–302. [PubMed: 25782092]
  • Chong JH, Jamuar SS, Ong C, Thoon KC, Tan ES, Lai A, Aan MK, Tan WL, Foo R, Tan EC, Lau YL, Liew WK. Tricho-hepato-enteric syndrome (THE-S): two cases and review of the literature. Eur J Pediatr. 2015;174:1405–11. [PubMed: 25976726]
  • Eckard SC, Rice GI, Fabre A, Badens C, Gray EE, Hartley JL, Crow YJ, Stetson DB. The SKIV2L RNA exosome limits activation of the RIG-I-like receptors. Nat Immunol. 2014;15:839–45. [PMC free article: PMC4139417] [PubMed: 25064072]
  • Fabre A, André N, Breton A, Broué P, Badens C, Roquelaure B. Intractable diarrhea with "phenotypic anomalies" and tricho-hepato-enteric syndrome: two names for the same disorder. Am J Med Genet A. 2007;143A:584–8. [PubMed: 17318842]
  • Fabre A, Badens C. Human Mendelian diseases related to abnormalities of the RNA exosome or its cofactors. Intractable Rare Dis Res. 2014;3:8–11. [PMC free article: PMC4204543] [PubMed: 25343120]
  • Fabre A, Breton A, Coste ME, Colomb V, Dubern B, Lachaux A, Lemale J, Mancini J, Marinier E, Martinez-Vinson C, Peretti N, Perry A, Roquelaure B, Venaille A, Sarles J, Goulet O, Badens C. Syndromic (phenotypic) diarrhoea of infancy/tricho-hepato-enteric syndrome. Arch Dis Child. 2014;99:35–8. [PubMed: 24108068]
  • Fabre A, Charroux B, Martinez-Vinson C, Roquelaure B, Odul E, Sayar E, Smith H, Colomb V, Andre N, Hugot JP, Goulet O, Lacoste C, Sarles J, Royet J, Levy N, Badens C. SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome. Am J Hum Genet. 2012;90:689–92. [PMC free article: PMC3322239] [PubMed: 22444670]
  • Fabre A, Martinez-Vinson C, Roquelaure B, Missirian C, André N, Breton A, Lachaux A, Odul E, Colomb V, Lemale J, Cézard JP, Goulet O, Sarles J, Levy N, Badens C. Novel mutations in TTC37 associated with tricho-hepato-enteric syndrome. Hum Mutat. 2011;32:277–81. [PubMed: 21120949]
  • Girault D, Goulet O, Le Deist F, Brousse N, Colomb V, Césarini JP, de Potter S, Canioni D, Griscelli C, Fischer A, et al. Intractable infant diarrhea associated with phenotypic abnormalities and immunodeficiency. J Pediatr. 1994;125:36–42. [PubMed: 8021782]
  • Goulet O, Vinson C, Roquelaure B, Brousse N, Bodemer C, Cézard JP. Syndromic (phenotypic) diarrhea in early infancy. Orphanet J Rare Dis. 2008;3:6. [PMC free article: PMC2279108] [PubMed: 18304370]
  • Hartley JL, Zachos NC, Dawood B, Donowitz M, Forman J, Pollitt RJ, Morgan NV, Tee L, Gissen P, Kahr WH, Knisely AS, Watson S, Chitayat D, Booth IW, Protheroe S, Murphy S, de Vries E, Kelly DA, Maher ER. Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy). Gastroenterology. 2010;138:2388–98. [PMC free article: PMC3166659] [PubMed: 20176027]
  • Kammermeier J, Drury S, James CT, Dziubak R, Ocaka L, Elawad M, Beales P, Lench N, Uhlig HH, Bacchelli C, Shah N. Targeted gene panel sequencing in children with very early onset inflammatory bowel disease--evaluation and prospective analysis. J Med Genet. 2014;51:748–55. [PubMed: 25194001]
  • Kammermeier J, Dziubak R, Pescarin M, Drury S, Godwin H, Reeve K, Chadokufa S, Huggett B, Sider S, James C, Acton N, Cernat E, Gasparetto M, Noble-Jamieson G, Kiparissi F, Elawad M, Beales PL, Sebire NJ, Gilmour K, Uhlig HH, Bacchelli C, Shah N. Phenotypic and genotypic characterisation of inflammatory bowel disease presenting before the age of 2 years. J Crohns Colitis. 2017;11:60–69. [PMC free article: PMC5885808] [PubMed: 27302973]
  • Kinnear C, Glanzmann B, Banda E, Schlechter N, Durrheim G, Neethling A, Nel E, Schoeman M, Johnson G, van Helden PD, Hoal EG, Esser M, Urban M, Möller M. Exome sequencing identifies a novel TTC37 mutation in the first reported case of trichohepatoenteric syndrome (THE-S) in South Africa. BMC Med Genet. 2017;18:26. [PMC free article: PMC5351214] [PubMed: 28292286]
  • Kotecha UH, Movva S, Puri RD, Verma IC. Trichohepatoenteric syndrome: founder mutation in Asian Indians. Mol Syndromol. 2012;3:89–93. [PMC free article: PMC3542929] [PubMed: 23326254]
  • Lee WI, Huang JL, Chen CC, Lin JL, Wu RC, Jaing TH, Ou LS. Identifying mutations of the tetratricopeptide repeat domain 37 (TTC37) gene in infants with intractable diarrhea and a comparison of Asian and non-Asian phenotype and genotype: a global case-report study of a well-defined syndrome with immunodeficiency. Medicine (Baltimore). 2016a;95:e2918. [PMC free article: PMC4782876] [PubMed: 26945392]
  • Lee WS, Teo KM, Ng RT, Chong SY, Kee BP, Chua KH. Novel mutations in SKIV2L and TTC37 genes in Malaysian children with trichohepatoenteric syndrome. Gene. 2016b;586:1–6. [PubMed: 27050310]
  • Mahjoub FE, Imanzadeh F, Mahdavi Izadi S, Nahali Moghaddam A. Trichohepatoenteric syndrome or syndromic diarrhea-report of three members in a family, first report from Iran. Case Rep Pathol. 2016;2016:9684910. [PMC free article: PMC4736587] [PubMed: 26881168]
  • Martinez-Vinson MC. Les Diarrhées Graves Syndromiques. Medical thesis. Paris, France: Université Paris Diderot. 2004.
  • Monies DM, Rahbeeni Z, Abouelhoda M, Naim EA, Al-Younes B, Meyer BF, Al-Mehaidib A. Expanding phenotypic and allelic heterogeneity of tricho-hepato-enteric syndrome. J Pediatr Gastroenterol Nutr. 2015;60:352–6. [PubMed: 25714577]
  • Morgan NV, Hartley JL, Setchell KD, Simpson MA, Brown R, Tee L, Kirkham S, Pasha S, Trembath RC, Maher ER, Gissen P, Kelly DA. A combination of mutations in AKR1D1 and SKIV2L in a family with severe infantile liver disease. Orphanet J Rare Dis. 2013;8:74. [PMC free article: PMC3659031] [PubMed: 23679950]
  • Oz-Levi D, Weiss B, Lahad A, Greenberger S, Pode-Shakked B, Somech R, Olender T, Tatarsky P, Marek-Yagel D, Pras E, Anikster Y, Lancet D. Exome sequencing as a differential diagnosis tool: resolving mild trichohepatoenteric syndrome. Clin Genet. 2015;87:602–3. [PubMed: 25335910]
  • Rider NL, Boisson B, Jyonouchi S, Hanson EP, Rosenzweig SD, Casanova JL, Orange JS. Novel TTC37 Mutations in a patient with immunodeficiency without diarrhea: extending the phenotype of trichohepatoenteric syndrome. Front Pediatr. 2015;3:2. [PMC free article: PMC4311608] [PubMed: 25688341]
  • Stankler L, Lloyd D, Pollitt RJ, Gray ES, Thom H, Russell G. Unexplained diarrhoea and failure to thrive in 2 siblings with unusual facies and abnormal scalp hair shafts: a new syndrome. Arch Dis Child. 1982;57:212–6. [PMC free article: PMC1627586] [PubMed: 7073301]
  • Verloes A, Lombet J, Lambert Y, Hubert AF, Deprez M, Fridman V, Gosseye S, Rigo J, Sokal E. Tricho-hepato-enteric syndrome: further delineation of a distinct syndrome with neonatal hemochromatosis phenotype, intractable diarrhea, and hair anomalies. Am J Med Genet. 1997;68:391–5. [PubMed: 9021008]
  • Zheng B, Pan J, Jin Y, Wang C, Liu Z. Targeted next-generation sequencing identification of a novel missense mutation of the SKIV2L gene in a patient with trichohepatoenteric syndrome. Mol Med Rep. 2016;14:2107–10. [PubMed: 27431780]

Chapter Notes

Acknowledgments

We deeply thank Cécile Mouradian, from the CRB-TAC, for DNA extraction and transfer, as well as for excellent cell culture and technical help. We also thank the reviewers for their useful comments.

Revision History

  • 11 January 2018 (bp) Review posted live
  • 29 December 2016 (af) Original submission
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