Trichohepatoenteric syndrome (THES), also called syndromic diarrhea, is a rare autosomal recessive multisystem disorder and the clearest example in the congenital diarrheas and enteropathies (CODEs) of an enteropathy caused by a defect in a housekeeping process rather than in any intestine-specific machinery. Biallelic variants in TTC37 (THES type 1) or SKIV2L (THES type 2) disable the two cofactor subunits of the human SKI complex, a heterotetrameric cofactor of the cytoplasmic RNA exosome that carries out mRNA surveillance and the decay of aberrant transcripts. This is a Mendelian disease of the RNA exosome pathway, and its phenotype is correspondingly multisystem: the classical form is defined by five signs - intractable diarrhea of infancy beginning in the first month of life, facial dysmorphism (prominent forehead and cheeks, broad nasal root, hypertelorism), woolly and easily removable hair with trichorrhexis nodosa, immunodeficiency from defective antibody production, and intrauterine growth restriction. Liver involvement (fibrosis, siderosis, cirrhosis) is inconsistent even between siblings and can precede the diarrhea. Mechanistically THES sits apart from the three main epithelial CODE classes: the enterocyte brush border is ultrastructurally NORMAL, so this is not an enterocyte-structural disease, yet multiple brush-border ion transporters show reduced expression or mislocalization with a different profile in each patient, so it is not a single-transporter defect either. The diarrhea is therefore attributed to loss of post-transcriptional control over many target proteins at once rather than to any one missing step. Most children require parenteral nutrition and immunoglobulin replacement, but - unlike the enterocyte-structural enteropathies - some can be weaned off both, and transplantation is not the expected endpoint.
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name: Trichohepatoenteric Syndrome
creation_date: "2026-08-22T00:00:00Z"
category: Mendelian
synonyms:
- THES
- SD/THE
- syndromic diarrhea
- phenotypic diarrhea of infancy
- tricho-hepato-enteric syndrome
description: >-
Trichohepatoenteric syndrome (THES), also called syndromic diarrhea, is a rare
autosomal recessive multisystem disorder and the clearest example in the
congenital diarrheas and enteropathies (CODEs) of an enteropathy caused by a
defect in a housekeeping process rather than in any intestine-specific
machinery. Biallelic variants in TTC37 (THES type 1) or SKIV2L (THES type 2)
disable the two cofactor subunits of the human SKI complex, a heterotetrameric
cofactor of the cytoplasmic RNA exosome that carries out mRNA surveillance and
the decay of aberrant transcripts. This is a Mendelian disease of the RNA
exosome pathway, and its phenotype is correspondingly multisystem: the
classical form is defined by five signs - intractable diarrhea of infancy
beginning in the first month of life, facial dysmorphism (prominent forehead
and cheeks, broad nasal root, hypertelorism), woolly and easily removable hair
with trichorrhexis nodosa, immunodeficiency from defective antibody
production, and intrauterine growth restriction. Liver involvement (fibrosis,
siderosis, cirrhosis) is inconsistent even between siblings and can precede
the diarrhea. Mechanistically THES sits apart from the three main epithelial
CODE classes: the enterocyte brush border is ultrastructurally NORMAL, so this
is not an enterocyte-structural disease, yet multiple brush-border ion
transporters show reduced expression or mislocalization with a different
profile in each patient, so it is not a single-transporter defect either. The
diarrhea is therefore attributed to loss of post-transcriptional control over
many target proteins at once rather than to any one missing step. Most children
require parenteral nutrition and immunoglobulin replacement, but - unlike the
enterocyte-structural enteropathies - some can be weaned off both, and
transplantation is not the expected endpoint.
references:
- reference: PMID:29334452
title: "Trichohepatoenteric Syndrome."
tags:
- GeneReviews
disease_term:
preferred_term: trichohepatoenteric syndrome
term:
id: MONDO:0009105
label: trichohepatoenteric syndrome
inheritance:
- name: Autosomal recessive inheritance
description: >-
THES is autosomal recessive. Consanguinity is frequent in reported families;
the gene-discovery study used autozygosity mapping in eight patients from
consanguineous families.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:23302111
reference_title: "Syndromic diarrhea/Tricho-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The estimated prevalence is 1/1,000,000 births and the transmission is
autosomal recessive.
explanation: >-
States the mode of inheritance and the population prevalence. Evidence
source is OTHER because this is a review.
genetic:
- name: TTC37 loss-of-function variants
gene_term:
preferred_term: TTC37
term:
id: hgnc:23639
label: TTC37
association: Causative
relationship_type: CAUSATIVE
variant_origin: GERMLINE
subtype: THES type 1
features: >-
Biallelic TTC37 variants cause THES type 1. TTC37 encodes a
tetratricopeptide-repeat protein (thespin) that is the human ortholog of the
yeast SKI complex cofactor Ski3p. The gene was identified by autozygosity
mapping to 5q14.3-5q21.2 followed by candidate sequencing. Because the
protein acts in protein-protein interaction or chaperone-like roles within
the complex, its loss has a multisystem effect attributed to abnormal
stability or intracellular localization of its target proteins rather than
to loss of one enzymatic activity.
evidence:
- reference: PMID:20176027
reference_title: "Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Sequencing of candidate genes showed mutations in TTC37, which encodes the
uncharacterized tetratricopeptide repeat protein, thespin.
explanation: >-
The gene-discovery report identifying TTC37 as the cause of THES.
- reference: PMID:20176027
reference_title: "Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
TTC37 mutations have a multisystem effect, which may be owing to abnormal
stability and/or intracellular localization of TTC37 target proteins.
explanation: >-
States the proposed mechanism by which a single gene defect produces the
multisystem phenotype, and is explicitly hedged ("may be owing to"), which
is why the corresponding causal edge is not typed as direct.
- name: SKIV2L loss-of-function variants
gene_term:
preferred_term: SKIV2L
term:
id: hgnc:10898
label: SKIV2L
association: Causative
relationship_type: CAUSATIVE
variant_origin: GERMLINE
subtype: THES type 2
features: >-
Biallelic SKIV2L variants cause THES type 2, which is clinically
indistinguishable from type 1. SKIV2L encodes the RNA helicase subunit of the
same SKI complex. Its discovery is a clean worked example of
mechanism-directed gene finding: because TTC37 was recognised as the ortholog
of the yeast Ski-complex cofactor Ski3p, the authors sequenced a second
Ski-complex gene in six TTC37-negative patients with typical disease and
found mutations in all six. That both cofactors of one complex produce the
same disease is the strongest evidence that the pathogenic unit is the
complex rather than either protein.
evidence:
- reference: PMID:22444670
reference_title: "SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
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.
explanation: >-
The gene-discovery report for THES type 2, and evidence that the two genes
are alternative routes to one disease since the SKIV2L patients had typical
disease without TTC37 variants.
- reference: PMID:22444670
reference_title: "SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
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.
explanation: >-
States the conclusion that defines this disease's mechanistic class - a
Mendelian disease of the RNA exosome pathway.
pathophysiology:
- name: Loss of a Human SKI Complex Cofactor
description: >-
The initiating lesion. The SKI complex is a heterotetrameric cytoplasmic
cofactor of the RNA exosome, and TTC37 and SKIV2L encode two of its subunits
- a tetratricopeptide-repeat scaffold protein and an RNA helicase
respectively. Biallelic loss of either subunit disables the complex, and
because both routes produce clinically indistinguishable disease the
pathogenic unit is the complex rather than either individual protein. This is
a housekeeping lesion, not a gut-specific one: nothing about the SKI complex
is intestine-restricted, which is why the resulting disease is multisystem
and why the enteropathy needs explaining rather than being self-evident.
role: trigger
biological_scale: MOLECULAR
molecular_functions:
- preferred_term: SKIV2L RNA helicase activity
term:
id: GO:0003724
label: RNA helicase activity
modifier: LOSS_OF_FUNCTION
cellular_components:
- preferred_term: Ski complex
term:
id: GO:0055087
label: Ski complex
evidence:
- reference: PMID:23302111
reference_title: "Syndromic diarrhea/Tricho-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The aetiology is a defect in TTC37, a TPR containing protein, or in the RNA
helicase SKIV2L, both constituting the putative human ski complex.
explanation: >-
Identifies the two subunits whose loss defines this node and states that
both constitute the same complex. Evidence source is OTHER because this is
a review.
downstream:
- target: Failure of Exosome-Mediated Cytoplasmic mRNA Surveillance
causal_link_type: DIRECT
- name: Failure of Exosome-Mediated Cytoplasmic mRNA Surveillance
description: >-
The rate-limiting step. The SKI complex delivers transcripts to the
cytoplasmic RNA exosome for degradation, so it is required both for normal
mRNA turnover and for the decay of aberrant or nonfunctional transcripts.
Losing it removes post-transcriptional quality control over the whole
cytoplasmic transcriptome rather than over any particular gene product. This
is the node that makes the disease multisystem, and it is also why THES
resists the tidy trigger-to-organ logic of the other congenital diarrheas:
the downstream consequences depend on which transcripts and proteins are most
sensitive to loss of surveillance in each tissue, which is not fully
characterised.
role: central_effector
biological_scale: MOLECULAR
biological_processes:
- preferred_term: Exosome-mediated mRNA decay
term:
id: GO:0000956
label: nuclear-transcribed mRNA catabolic process
modifier: DECREASED
- preferred_term: RNA surveillance and turnover
term:
id: GO:0006401
label: RNA catabolic process
modifier: DECREASED
evidence:
- reference: PMID:22444670
reference_title: "SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
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.
explanation: >-
States the function lost at this node - exosome-mediated RNA surveillance
covering both normal mRNA regulation and decay of nonfunctional transcripts.
downstream:
- target: Dysregulated Abundance and Localization of Target Proteins
causal_link_type: DIRECT
- name: Dysregulated Abundance and Localization of Target Proteins
description: >-
The proposed bridge between a general RNA-surveillance defect and the
tissue-specific phenotypes, and the least certain step in the chain. Loss of
the SKI complex is proposed to destabilize or mislocalize its downstream
target proteins rather than eliminate one activity. In the intestine this is
directly observable: several enterocyte brush-border ion transporters - NHE2,
NHE3, aquaporin 7, the sodium-iodide symporter and H/K-ATPase - show reduced
expression or mislocalization, and critically the profile differs between
patients. Basolateral Na/K-ATPase localization is by contrast unaltered, so
the effect is selective rather than a global collapse of membrane protein
trafficking. The absence of a single consistent transporter defect is what
distinguishes THES from the electrolyte-transport-related congenital
diarrheas, where one named transporter fails in every patient.
role: effector
biological_scale: CELLULAR
cell_types:
- preferred_term: Small-intestinal enterocyte
term:
id: CL:0000584
label: enterocyte
biological_processes:
- preferred_term: Apical membrane transporter localization
term:
id: GO:0072659
label: protein localization to plasma membrane
modifier: ABNORMAL
cellular_components:
- preferred_term: Enterocyte brush border
term:
id: GO:0005903
label: brush border
evidence:
- reference: PMID:20176027
reference_title: "Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
showed reduced expression or mislocalization in all THES patients with
different profiles for each
explanation: >-
Documents the multi-transporter, patient-variable abnormality this node
describes; in the source this clause completes a sentence listing NHE2,
NHE3, aquaporin 7, the sodium iodide symporter and H/K-ATPase. The quote is
trimmed to start after that list because the source writes "[ATPase]" in
brackets, and bracketed spans are stripped before snippet matching. The
authors label these studies "preliminary", which the node description
records rather than presenting as settled.
- reference: PMID:20176027
reference_title: "Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In contrast the basolateral localization of Na/K ATPase was not altered.
explanation: >-
Establishes that the mislocalization is selective for apical transporters
rather than a general failure of membrane protein delivery, which is what
separates this node from the enterocyte-trafficking enteropathies.
downstream:
- target: Intractable Infantile Diarrhea with a Structurally Normal Brush Border
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Multisystem Involvement Outside the Gut
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Intractable Infantile Diarrhea with a Structurally Normal Brush Border
description: >-
The intestinal output, and the finding that fixes this disorder's position in
the CODE nosology. Diarrhea begins in the first month of life - not at birth -
and is severe enough to require parenteral nutrition. On biopsy the mucosa
shows non-specific changes: initial subtotal villous atrophy that improves
with time, with a variable mixed inflammatory infiltrate, and severity of
diarrhea does not correlate with the histological change. Crucially the
enterocyte brush border is ultrastructurally NORMAL, which excludes the
enterocyte-structural mechanism of microvillus inclusion disease and tufting
enteropathy despite the villous atrophy the two classes share.
role: consequence
biological_scale: ORGANISM
locations:
- preferred_term: Small intestine
term:
id: UBERON:0002108
label: small intestine
evidence:
- reference: PMID:20176027
reference_title: "Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
On microscopy intestinal changes are non-specific; initial subtotal villous
atrophy improves with time (although severity of diarrhoea does not
correlate with the histological change)
explanation: >-
Documents the non-specific, improving mucosal histology and its lack of
correlation with symptom severity - evidence that the diarrhea is not
driven by the architectural change.
- reference: PMID:20176027
reference_title: "Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The enterocyte brush border is ultrastructurally normal.
explanation: >-
The decisive negative finding placing THES outside the enterocyte-structural
CODE class, and the reason this entry does not conform to
enterocyte_polarity_trafficking_failure.
- name: Multisystem Involvement Outside the Gut
description: >-
The extraintestinal output, expected of a housekeeping-gene disorder and
unusual among the congenital diarrheas. Hair is woolly, coarse, sparse and
fragile with trichorrhexis nodosa; facial features are distinctive
(hypertelorism, broad flat nasal bridge, prominent forehead); antibody
production is defective, giving low immunoglobulins and poor response to
childhood vaccination, though this often improves with age. Intrauterine
growth restriction is one of the five defining signs. Liver involvement -
hepatomegaly, fibrosis, siderosis, cirrhosis - is inconsistent even between
siblings, occurs irrespective of parenteral nutrition, and can precede the
onset of diarrhea, which is what establishes it as intrinsic to the disease
rather than a complication of treatment.
role: consequence
biological_scale: ORGANISM
evidence:
- reference: PMID:23302111
reference_title: "Syndromic diarrhea/Tricho-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The classical form is characterized by 5 clinical signs: intractable
diarrhea of infancy beginning in the first month of life, usually leading
to failure to thrive and requiring parenteral nutrition; facial dysmorphism
characterised by prominent forehead and cheeks, broad nasal root and
hypertelorism; hair abnormalities described as woolly and easily removable;
immune disorders resulting from defective antibody production; intrauterine
growth restriction.
explanation: >-
Enumerates the five defining clinical signs of the classical form, four of
which are the extraintestinal features of this node.
- reference: PMID:20176027
reference_title: "Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Hepatic involvement is inconsistent, even among siblings, and irrespective
of parenteral nutrition can include hepatomegaly, fibrosis, siderosis and
cirrhosis (even before the onset of diarrhoea).
explanation: >-
Establishes the liver disease as intrinsic and variable rather than a
consequence of parenteral nutrition, since it occurs irrespective of it and
can precede the diarrhea.
has_subtypes:
- name: THES type 1
display_name: Trichohepatoenteric syndrome type 1 (TTC37-related)
subtype_term:
preferred_term: trichohepatoenteric syndrome 1
term:
id: MONDO:0024541
label: trichohepatoenteric syndrome 1
description: >-
Caused by biallelic TTC37 variants affecting the tetratricopeptide-repeat
subunit of the SKI complex. Clinically indistinguishable from type 2.
genes:
- preferred_term: TTC37
term:
id: hgnc:23639
label: TTC37
- name: THES type 2
display_name: Trichohepatoenteric syndrome type 2 (SKIV2L-related)
subtype_term:
preferred_term: trichohepatoenteric syndrome 2
term:
id: MONDO:0013818
label: trichohepatoenteric syndrome 2
description: >-
Caused by biallelic SKIV2L variants affecting the RNA helicase subunit of the
same SKI complex. Clinically indistinguishable from type 1; the split is
molecular, not phenotypic.
genes:
- preferred_term: SKIV2L
term:
id: hgnc:10898
label: SKIV2L
phenotypes:
- name: Intractable Infantile Diarrhea
category: Gastrointestinal
description: >-
Severe diarrhea beginning in the first month of life - characteristically not
at birth but weeks to months after - leading to failure to thrive and
requiring parenteral nutrition.
phenotype_term:
preferred_term: Intractable infantile diarrhea
term:
id: HP:0002014
label: Diarrhea
temporality: CHRONIC
frequency: VERY_FREQUENT
evidence:
- reference: PMID:29334452
reference_title: "Trichohepatoenteric Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
intractable diarrhea (seen in almost all affected children)
explanation: >-
GeneReviews quantifies the diarrhea as present in almost all affected
children, which supports VERY_FREQUENT rather than the OBLIGATE band this
record previously asserted. Evidence source is OTHER because GeneReviews is
a curated review.
- reference: PMID:23302111
reference_title: "Syndromic diarrhea/Tricho-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
intractable diarrhea of infancy beginning in the first month of life,
usually leading to failure to thrive and requiring parenteral nutrition
explanation: >-
Names intractable infantile diarrhea as the first of the five defining
signs, supporting the OBLIGATE band.
- name: Woolly Hair
category: Dermatological
description: >-
Hair is woolly, coarse, sparse, fragile and easily removable, with
trichorrhexis nodosa on microscopy indicating weakness of the hair shaft.
This is the "tricho-" of the syndrome name and is one of the five defining
signs.
phenotype_term:
preferred_term: Woolly hair
term:
id: HP:0002224
label: Woolly hair
frequency: OBLIGATE
evidence:
- reference: PMID:29334452
reference_title: "Trichohepatoenteric Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
characterized by intractable diarrhea (seen in almost all affected
children), woolly hair (seen in all), intrauterine growth restriction,
facial dysmorphism, and short stature
explanation: >-
GeneReviews states woolly hair is seen in ALL affected individuals, which
is what supports the OBLIGATE band; the same sentence qualifies diarrhea as
"almost all", which is why that phenotype carries VERY_FREQUENT rather than
OBLIGATE. Evidence source is OTHER because GeneReviews is a curated review.
- reference: PMID:23302111
reference_title: "Syndromic diarrhea/Tricho-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
hair abnormalities described as woolly and easily removable
explanation: >-
Names the hair phenotype among the five defining clinical signs.
- name: Trichorrhexis Nodosa
category: Dermatological
description: >-
Nodal weakening and fracture of the hair shaft, the microscopic correlate of
the clinically woolly, fragile hair.
phenotype_term:
preferred_term: Trichorrhexis nodosa
term:
id: HP:0009886
label: Trichorrhexis nodosa
evidence:
- reference: PMID:20176027
reference_title: "Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
abnormal hair (coarse, sparse and fragile with trichorrhexis nodosa)
explanation: >-
Documents trichorrhexis nodosa as the microscopic hair abnormality of the
syndrome.
- name: Hypertelorism
category: Craniofacial
description: >-
Part of the characteristic facial dysmorphism, together with a broad flat
nasal bridge and prominent forehead and cheeks.
phenotype_term:
preferred_term: Hypertelorism
term:
id: HP:0000316
label: Hypertelorism
frequency: VERY_FREQUENT
evidence:
- reference: PMID:23302111
reference_title: "Syndromic diarrhea/Tricho-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
facial dysmorphism characterised by prominent forehead and cheeks, broad
nasal root and hypertelorism
explanation: >-
Names hypertelorism within the defining facial dysmorphism.
- name: Decreased Circulating Immunoglobulin Concentration
category: Immunological
description: >-
Immunodeficiency from defective antibody production, with low serum
immunoglobulins and poor immunological response to childhood vaccination.
It often, but not always, improves with age, and many children need
immunoglobulin replacement.
phenotype_term:
preferred_term: Decreased circulating immunoglobulin concentration
term:
id: HP:0004313
label: Decreased circulating immunoglobulin concentration
frequency: VERY_FREQUENT
evidence:
- reference: PMID:20176027
reference_title: "Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Immunodeficiency is a consistent feature with low serum concentrations of
immunoglobulins (which often, but not always, improves with age) and a poor
immunological response to childhood vaccination.
explanation: >-
Describes the immunodeficiency and its natural history; "a consistent
feature" supports the VERY_FREQUENT band.
- name: Intrauterine Growth Retardation
category: Growth
description: >-
Intrauterine growth restriction is one of the five defining signs of the
classical form, so the disease is manifest before birth.
phenotype_term:
preferred_term: Intrauterine growth retardation
term:
id: HP:0001511
label: Intrauterine growth retardation
frequency: VERY_FREQUENT
evidence:
- reference: PMID:23302111
reference_title: "Syndromic diarrhea/Tricho-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The classical form is characterized by 5 clinical signs: intractable
diarrhea of infancy beginning in the first month of life, usually leading
to failure to thrive and requiring parenteral nutrition; facial dysmorphism
characterised by prominent forehead and cheeks, broad nasal root and
hypertelorism; hair abnormalities described as woolly and easily removable;
immune disorders resulting from defective antibody production; intrauterine
growth restriction.
explanation: >-
Names intrauterine growth restriction as the fifth of the five defining
clinical signs of the classical form, which supports the VERY_FREQUENT
band. The complete sentence is quoted rather than the trailing clause so
the quote stands on its own.
- name: Mild Intellectual Disability
category: Neurological
description: >-
Mild intellectual disability affects about half of reported individuals.
GeneReviews recommends age-appropriate assessment of cognitive, speech and
language, and psychosocial development as part of routine surveillance.
phenotype_term:
preferred_term: Mild intellectual disability
term:
id: HP:0001256
label: Mild intellectual disability
frequency: FREQUENT
evidence:
- reference: PMID:29334452
reference_title: "Trichohepatoenteric Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Mild intellectual disability (ID) is seen in about 50% of affected
individuals.
explanation: >-
A directly quantified frequency (about 50%), which falls in the FREQUENT
band (30-79%). Evidence source is OTHER because GeneReviews is a curated
review.
- name: Short Stature
category: Growth
description: >-
Short stature is one of the cardinal features listed by GeneReviews,
alongside intrauterine growth restriction.
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:29334452
reference_title: "Trichohepatoenteric Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
intrauterine growth restriction, facial dysmorphism, and short stature
explanation: >-
Lists short stature among the defining clinical characteristics. No
frequency band is asserted because the source gives no quantifier for this
feature specifically. Evidence source is OTHER because GeneReviews is a
curated review.
- name: Hepatic Fibrosis
category: Hepatic
description: >-
Liver involvement ranging from hepatomegaly through fibrosis and siderosis to
cirrhosis. It is inconsistent even between siblings and can precede the
diarrhea, establishing it as intrinsic to the disease rather than caused by
parenteral nutrition.
phenotype_term:
preferred_term: Hepatic fibrosis
term:
id: HP:0001395
label: Hepatic fibrosis
frequency: OCCASIONAL
evidence:
- reference: PMID:20176027
reference_title: "Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Hepatic involvement is inconsistent, even among siblings, and irrespective
of parenteral nutrition can include hepatomegaly, fibrosis, siderosis and
cirrhosis (even before the onset of diarrhoea).
explanation: >-
Supports both the phenotype and the OCCASIONAL band, since the source
describes hepatic involvement as inconsistent even within families.
diagnosis:
- name: TTC37 and SKIV2L sequencing
description: >-
Diagnosis is initially clinical, based on the five defining signs, and is
confirmed by direct sequencing of TTC37 and SKIV2L. Because the two genotypes
are clinically indistinguishable, both must be tested.
evidence:
- reference: PMID:23302111
reference_title: "Syndromic diarrhea/Tricho-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The diagnosis SD/THE is initially based on clinical findings and confirmed
by direct sequencing of TTC37 and SKIV2L.
explanation: >-
States the diagnostic pathway - clinical recognition confirmed by
sequencing both SKI complex genes.
- name: Intestinal biopsy to exclude other causes
description: >-
Biopsy is used to distinguish THES from the other causes of intractable
infantile diarrhea rather than to make the diagnosis positively: histology is
non-specific and the brush border is ultrastructurally normal, which excludes
the enterocyte-structural enteropathies.
evidence:
- reference: PMID:23302111
reference_title: "Syndromic diarrhea/Tricho-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Differential diagnosis with the other causes of intractable diarrhea is
easily performed by pathologic investigations.
explanation: >-
Supports the role of histopathology as a discriminator against the other
congenital enteropathies rather than as a positive diagnostic test.
treatments:
- name: Parenteral Nutrition
description: >-
Most children require parenteral nutrition to maintain life and growth. The
important prognostic difference from the enterocyte-structural enteropathies
is that dependence is not necessarily permanent: some children can be weaned
to full enteral feeding over time, and transplantation is not the expected
endpoint.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Total Parenteral Nutrition
term:
id: NCIT:C29484
label: Total Parenteral Nutrition
target_mechanisms:
- target: Intractable Infantile Diarrhea with a Structurally Normal Brush Border
treatment_effect: BYPASSES
description: >-
Intravenous nutrition bypasses the failing intestine; it does not act on
the SKI complex defect or restore transporter localization.
evidence:
- reference: PMID:23302111
reference_title: "Syndromic diarrhea/Tricho-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
During their clinical course, most of the children require parenteral
nutrition and often immunoglobulin supplementation. With time, some of
them can be weaned off parenteral nutrition and immunoglobulin
supplementation.
explanation: >-
Documents both the requirement for parenteral nutrition and the
possibility of weaning, which distinguishes the prognosis here from the
enterocyte-structural enteropathies.
- name: Immunoglobulin Replacement
description: >-
Immunoglobulin supplementation addresses the defective antibody production
that is one of the five defining features. Like parenteral nutrition it can
sometimes be withdrawn with time as the humoral defect improves with age.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
target_mechanisms:
- target: Multisystem Involvement Outside the Gut
treatment_effect: INHIBITS
description: >-
Replacing immunoglobulin offsets the defective antibody production arm of
the extraintestinal phenotype without acting on its cause.
evidence:
- reference: PMID:23302111
reference_title: "Syndromic diarrhea/Tricho-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
most of the children require parenteral nutrition and often
immunoglobulin supplementation
explanation: >-
Documents immunoglobulin supplementation as standard management for the
immunodeficiency arm.
prevalence:
- population: Worldwide
measure_type: BIRTH_PREVALENCE
prevalence_class: BELOW_1_IN_1000000
rate_per_100000: 0.1
notes: >-
Estimated prevalence 1/1,000,000 births, i.e. 0.1 per 100,000. An earlier
estimate from the gene-discovery paper gave a higher incidence of 1 in
400,000 to 1 in 500,000 live births; the lower review figure is recorded
here and the discrepancy is noted rather than averaged.
evidence:
- reference: PMID:23302111
reference_title: "Syndromic diarrhea/Tricho-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The estimated prevalence is 1/1,000,000 births and the transmission is
autosomal recessive.
explanation: >-
Source for the recorded birth-prevalence estimate.
discussions:
- discussion_id: thes_rna_surveillance_to_enteropathy
kind: KNOWLEDGE_GAP
prompt: >-
How does loss of a general cytoplasmic RNA-surveillance complex produce a
severe, organ-selective enteropathy while the enterocyte brush border remains
ultrastructurally normal?
rationale: >-
THES has a secure gene-to-disease link and an unusually clear molecular
lesion, but the step from that lesion to the intestinal phenotype is the
weakest part of the chain. The SKI complex is a housekeeping cofactor with no
intestine-restricted role, yet the enteropathy is severe and early. The one
intestinal observation available - reduced expression or mislocalization of
several brush-border transporters, with a different profile in each patient
and with basolateral Na/K-ATPase spared - is described by its authors as
preliminary and does not identify which transcripts or proteins mediate the
effect. The gap matters for classification as much as for biology: without it,
THES cannot be assigned to any of the three epithelial CODE mechanism modules,
and its causal edges to both outputs are typed
INDIRECT_UNKNOWN_INTERMEDIATES rather than direct.
proposed_experiments:
- experiment_id: thes_patient_enteroid_transcriptomics
name: Transcriptome-wide RNA stability profiling in THES patient enteroids
description: >-
Measure transcript half-lives and steady-state abundance genome-wide in
patient-derived intestinal enteroids carrying TTC37 or SKIV2L variants
versus controls, to identify which transcripts escape decay and whether the
affected set is enriched for apical transporters or their trafficking
machinery.
- experiment_id: thes_transporter_localization_panel
name: Systematic brush-border transporter localization panel across genotypes
description: >-
Quantify apical versus intracellular localization of the full panel of
brush-border transporters in biopsies from a genotyped THES cohort, testing
whether the patient-to-patient variability in profile tracks genotype,
residual SKI complex function, or neither.
notes: >-
THES deliberately conforms to none of the three epithelial CODE mechanism
modules, and the reason is recorded here because the temptation to attach it is
real. It is not enterocyte_polarity_trafficking_failure: that module requires
loss of a functionally polarized apical surface, and the decisive finding in
THES is that the enterocyte brush border is ultrastructurally NORMAL
(PMID:20176027), with basolateral Na/K-ATPase localization also preserved. It
is not electrolyte_transport_related_diarrhea: several transporters are
affected with a different profile in each patient, rather than one named
transporter failing in every patient, and the diarrhea has no
ion-specific systemic signature. It is not diet_induced_osmotic_diarrhea: no
dietary substrate is implicated and no elimination is therapeutic. The villous
atrophy THES shares with the structural enteropathies is non-specific,
improves with time, and does not correlate with diarrhea severity, so it should
not be used to force a conformance.
Gene symbol note: GeneReviews (PMID:29334452) uses the current HGNC symbols
SKIC3 (formerly TTC37) and SKIC2 (formerly SKIV2L). This entry binds
hgnc:23639 and hgnc:10898, which are those genes; the gene_term labels carry
whatever the local HGNC cache reports, and the older symbols are retained in
the prose because every cited primary paper uses them.
Lump/split decision: MONDO:0009105 is an OMIM phenotypic series (OMIMPS:222470)
with two gene-defined children, THES type 1 (TTC37) and type 2 (SKIV2L). They
are curated here as has_subtypes of one entry rather than as two entries,
because the sources describe them as clinically indistinguishable and both act
by disabling the same complex - the split is molecular, not phenotypic. Should
a genotype-phenotype difference be established, splitting would be
straightforward since the subtypes already carry their genes.