Trichohepatoenteric syndrome

Summary

Trichohepatoenteric syndrome (MONDO:0009105) is a disease with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 26
• Phenotypes (HPO): 52
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		116	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated
Prevalence at birth	1-9 / 1 000 000	0.1	France	Validated

Signs & symptoms

Clinical features (HPO)

52 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0002041	Intractable diarrhea	Very frequent (80-99%)
HP:0002224	Woolly hair	Very frequent (80-99%)
HP:0002721	Immunodeficiency	Very frequent (80-99%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000337	Broad forehead	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001392	Abnormality of the liver	Frequent (30-79%)
HP:0001394	Cirrhosis	Frequent (30-79%)
HP:0001395	Hepatic fibrosis	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001518	Small for gestational age	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002299	Brittle hair	Frequent (30-79%)
HP:0003139	Panhypogammaglobulinemia	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0005599	Hypopigmentation of hair	Frequent (30-79%)
HP:0009886	Trichorrhexis nodosa	Frequent (30-79%)
HP:0011121	Abnormal skin morphology	Frequent (30-79%)
HP:0011220	Prominent forehead	Frequent (30-79%)
HP:0011473	Villous atrophy	Frequent (30-79%)
HP:0025156	Dependency on intravenous nutrition	Frequent (30-79%)
HP:0030056	Uncombable hair	Frequent (30-79%)
HP:0000957	Cafe-au-lait spot	Occasional (5-29%)
HP:0000958	Dry skin	Occasional (5-29%)
HP:0001627	Abnormal heart morphology	Occasional (5-29%)
HP:0001888	Lymphopenia	Occasional (5-29%)
HP:0001894	Thrombocytosis	Occasional (5-29%)
HP:0002583	Colitis	Occasional (5-29%)
HP:0002719	Recurrent infections	Occasional (5-29%)
HP:0005263	Gastritis	Occasional (5-29%)
HP:0011031	Abnormality of iron homeostasis	Occasional (5-29%)
HP:0011877	Increased mean platelet volume	Occasional (5-29%)
HP:0000023	Inguinal hernia	Very rare (<1-4%)
HP:0000089	Renal hypoplasia	Very rare (<1-4%)
HP:0000113	Polycystic kidney dysplasia	Very rare (<1-4%)
HP:0000501	Glaucoma	Very rare (<1-4%)
HP:0000778	Hypoplasia of the thymus	Very rare (<1-4%)
HP:0000821	Hypothyroidism	Very rare (<1-4%)
HP:0001629	Ventricular septal defect	Very rare (<1-4%)
HP:0001631	Atrial septal defect	Very rare (<1-4%)
HP:0001636	Tetralogy of Fallot	Very rare (<1-4%)
HP:0001643	Patent ductus arteriosus	Very rare (<1-4%)
HP:0001647	Bicuspid aortic valve	Very rare (<1-4%)
HP:0001659	Aortic regurgitation	Very rare (<1-4%)
HP:0001744	Splenomegaly	Very rare (<1-4%)
HP:0002884	Hepatoblastoma	Very rare (<1-4%)
HP:0004969	Peripheral pulmonary artery stenosis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	trichohepatoenteric syndrome
Mondo ID	MONDO:0009105
OMIM	222470
Orphanet	84064
DOID	DOID:0111414
ICD-11	1470910753
SNOMED CT	703406006
UMLS	C1857276
MedGen	347405
GARD	0005258
Is cancer (heuristic)	no

Also known as: phenotypic diarrhea · phenotypic diarrhoea · SD/THE · Syndromatic diarrhea · Syndromatic diarrhoea · syndromic diarrhea · syndromic diarrhea/Tricho-hepato-enteric syndrome · syndromic diarrhoea · THES1 · Tricho-hepato-enteric syndrome · Trichohepatoenteric syndrome · Trichohepatoenteric syndrome type 1

Data availability: 26 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › trichohepatoenteric syndrome

Related subtypes (40): B cell deficiency, complement deficiency, phagocyte bactericidal dysfunction, hepatic veno-occlusive disease-immunodeficiency syndrome, immunodeficiency with defective T-cell response to interleukin 1, Say-Barber-Miller syndrome, familial isolated congenital asplenia, X-linked immunoneurologic disorder, ectodermal dysplasia and immune deficiency, immunodeficiency 33, immunodeficiency 47, combined immunodeficiency due to moesin deficiency, immunodeficiency, X-linked, with deficiency of 115,000 Dalton surface glycoprotein, properdin deficiency, X-linked, combined immunodeficiency with faciooculoskeletal anomalies, recurrent infections associated with rare immunoglobulin isotypes deficiency, immunodeficiency 28, autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity, immunodeficiency 37, immunodeficiency 39, BENTA disease, primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection, immunodeficiency 49, chronic mucocutaneous candidiasis, hereditary hemophagocytic lymphohistiocytosis, immunoglobulin heavy chain deficiency, immuno-osseous dysplasia, lymphoproliferative syndrome, IL10-related early-onset inflammatory bowel disease, T-cell immunodeficiency with epidermodysplasia verruciformis, Aicardi-Goutieres syndrome, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, inflammatory bowel disease-recurrent sinopulmonary infections syndrome, A20 haploinsufficiency, NK cell deficiency, T cell and NK cell immunodeficiency, dendritic cell deficiency, immunodysregulation with variable immunodeficiency and autoimmunity, immune dysregulation with immunodeficiency due to AIOLOS haploinsufficiency, STAT5 haploinsufficiency

Subtypes (2): trichohepatoenteric syndrome 2, trichohepatoenteric syndrome 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

26 retrieved; paginated sample, class counts are floors:

11 likely pathogenic, 7 pathogenic, 6 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2635562	NM_006929.5(SKIC2):c.950del (p.Gln317fs)	LOC126859653	Pathogenic	criteria provided, single submitter
1033166	NM_006929.5(SKIC2):c.235C>T (p.Arg79Ter)	SKIC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323596	NM_006929.5(SKIC2):c.3187C>T (p.Arg1063Ter)	SKIC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1343627	NM_006929.5(SKIC2):c.3134C>A (p.Ser1045Ter)	SKIC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1683327	NM_006929.5(SKIC2):c.1637del (p.Gly546fs)	SKIC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3385179	NC_000006.11:g.(?31926951)(31937529_?)del	SKIC2	Pathogenic	criteria provided, single submitter
1426603	NM_014639.4(SKIC3):c.3807del (p.Pro1270fs)	SKIC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456349	NM_014639.4(SKIC3):c.860del (p.Lys287fs)	SKIC3	Pathogenic	criteria provided, multiple submitters, no conflicts
1708563	NM_014639.4(SKIC3):c.4102C>T (p.Gln1368Ter)	SKIC3	Pathogenic	criteria provided, multiple submitters, no conflicts
2168837	NM_014639.4(SKIC3):c.1166del (p.Leu389fs)	SKIC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2504053	NM_014639.4(SKIC3):c.3635del (p.Lys1212fs)	SKIC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734749	NM_014639.4(SKIC3):c.2921-2A>G	SKIC3	Pathogenic	criteria provided, multiple submitters, no conflicts
501317	NM_014639.4(SKIC3):c.3364del (p.Thr1122fs)	SKIC3	Pathogenic	criteria provided, multiple submitters, no conflicts
2445922	NM_006929.5(SKIC2):c.1207del (p.Leu403fs)	LOC126859653	Likely pathogenic	criteria provided, single submitter
2501187	NM_006929.5(SKIC2):c.1065-2A>G	LOC126859653	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1804785	NM_006929.5(SKIC2):c.3160G>T (p.Glu1054Ter)	SKIC2	Likely pathogenic	criteria provided, single submitter
2429227	NM_006929.5(SKIC2):c.1808del (p.Phe603fs)	SKIC2	Likely pathogenic	criteria provided, single submitter
1192253	NM_014639.4(SKIC3):c.1134+1G>T	SKIC3	Likely pathogenic	criteria provided, single submitter
1332713	NM_014639.4(SKIC3):c.2018G>A (p.Gly673Asp)	SKIC3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1804797	NM_014639.4(SKIC3):c.2114+2T>A	SKIC3	Likely pathogenic	criteria provided, single submitter
2152005	NM_014639.4(SKIC3):c.2114+5G>A	SKIC3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2429243	NC_000005.9:g.(94830722_94833119)_(94834296_94838583)del	SKIC3	Likely pathogenic	criteria provided, single submitter
2429244	NC_000005.9:g.(94877085_94877518)_(94886355_94890639)del	SKIC3	Likely pathogenic	criteria provided, single submitter
666990	NM_014639.4(SKIC3):c.772C>T (p.Gln258Ter)	SKIC3	Likely pathogenic	criteria provided, single submitter
1311355	NM_014639.4(SKIC3):c.642+1G>A	SKIC3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1428562	NM_014639.4(SKIC3):c.74C>T (p.Ala25Val)	SKIC3	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SKIC2	Definitive	Autosomal recessive	trichohepatoenteric syndrome 2	5
SKIC3	Definitive	Autosomal recessive	trichohepatoenteric syndrome 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SKIC2	Orphanet:84064	Trichohepatoenteric syndrome
SKIC3	Orphanet:84064	Trichohepatoenteric syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SKIC2	HGNC:10898	ENSG00000204351	Q15477	Superkiller complex protein 2	gencc,clinvar
SKIC3	HGNC:23639	ENSG00000198677	Q6PGP7	Superkiller complex protein 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SKIC2	Superkiller complex protein 2	Helicase component of the SKI complex, a multiprotein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways.
SKIC3	Superkiller complex protein 3	Component of the SKI complex, a multiprotein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SKIC2	Other/Unknown	no		Helicase_C-like, DEAD/DEAH_box_helicase_dom, Ski2/MTR4_C
SKIC3	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, Ski3/TTC37

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
pituitary gland	1
right lobe of liver	1
adrenal tissue	1
calcaneal tendon	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SKIC2	134	ubiquitous	yes	right lobe of liver, pituitary gland, adenohypophysis
SKIC3	294	ubiquitous	marker	calcaneal tendon, adrenal tissue, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SKIC2	2,818
SKIC3	1,829

Intra-cohort edges

A	B	Sources
SKIC2	SKIC3	intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SKIC2	Q15477	11
SKIC3	Q6PGP7	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Deadenylation-dependent mRNA decay	2	878.5×	6e-06	SKIC2, SKIC3
mRNA decay by 3’ to 5’ exoribonuclease	2	713.8×	6e-06	SKIC2, SKIC3
Metabolism of RNA	2	41.7×	0.001	SKIC2, SKIC3
Chaperonin-mediated protein folding	1	150.3×	0.009	SKIC2
Association of TriC/CCT with target proteins during biosynthesis	1	146.4×	0.009	SKIC2
Protein folding	1	129.8×	0.009	SKIC2
Metabolism of proteins	1	6.2×	0.155	SKIC2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
nuclear-transcribed mRNA catabolic process, 3’-5’ exonucleolytic nonsense-mediated decay	2	5617.3×	8e-08	SKIC2, SKIC3
rescue of stalled cytosolic ribosome	2	481.5×	8e-06	SKIC2, SKIC3
nuclear-transcribed mRNA catabolic process, non-stop decay	1	2106.5×	6e-04	SKIC2
nuclear-transcribed mRNA catabolic process	1	383.0×	0.003	SKIC3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SKIC2	0	0
SKIC3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SKIC3	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SKIC2, SKIC3

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SKIC2	0	—
SKIC3	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04499040	Not specified	UNKNOWN	Clinical and Biological Characterization of Patients and Collection of Samples