Trichohepatoenteric Syndrome

Curly hair; trichorrhexis nodosa; pili torti; hyperpigmentation; hypopigmentation; café-au-lait spots.

Tricho-hepato-enteric syndrome (THES) is a rare autosomal-recessive multisystem disorder caused by mutations in either the TTC37 or SKIV2L gene. It typically leads to diarrhea—often resistant to treatment— failure to thrive, characteristic hair changes, facial dysmorphism, immunodeficiency, and variable liver involvement.

The prevalence is estimated at approximately 1: 1,000,000 live births. m: w = 1: 1;

The condition is caused by biallelic pathogenic variants in genes that encode components of the cytoplasmic SKI complex. This complex directs defective or no-longer-needed RNA to the RNA exosome for controlled degradation. Its dysfunction disrupts RNA homeostasis and leads to multi-organ dysfunction, particularly in tissues with a high cell turnover rate—such as the intestinal epithelium, the immune system, the liver, and hair follicles.

Two distinct phenotypes have been described, caused by mutations in the following genes:  

• THES Type 1 TTC37 gene 5q15
• THES Type 2 SKIV2L gene 6p21.33

Both forms are inherited in an autosomal recessive manner and are largely indistinguishable from one another clinically. Approximately 60% of cases with a molecular genetic diagnosis are attributed to SKIC3/TTC37, and approximately 40% to SKIC2/SKIV2L.

Chronic diarrhea is thought to have multifactorial causes; histologically, variable, often nonspecific changes are observed, such as villous atrophy, crypt changes, and inflammatory infiltration of the lamina propria.

Symptoms usually appear in the first weeks or months of life:

Intestinal: severe, persistent watery diarrhea, malabsorption, dehydration, and marked failure to thrive; often requiring temporary or long-term parenteral nutrition.

Skin

• (Hair): fine, light-colored, brittle, woolly, or “wire-like” scalp hair; microscopically, in particular, trichorrhexis nodosa, pili torti, or hair shaft twists.
• Dry or eczematous skin, hyper- or hypopigmentation, and café-au-lait spots.
• Growth: frequent intrauterine growth restriction and postnatal short stature.

Face: broad forehead, prominent cheeks, broad nasal bridge, hypertelorism, and low-set ears.

Immune system: Hypogammaglobulinemia, impaired production of specific antibodies, and recurrent, sometimes severe bacterial or viral infections.

Liver: Elevated transaminases, hepatomegaly, steatosis, fibrosis progressing to cirrhosis; liver involvement is variable and not mandatory.

Additional findings: mild developmental delay or intellectual disability, platelet abnormalities, and occasionally congenital heart defects.

The severity varies considerably; milder forms of the disease without classic therapy-resistant diarrhea are rarely described. Severe infections and progressive liver disease significantly determine the prognosis. pmc.ncbi.nlm.nih.gov

The presumptive diagnosis is based on a combination of chronic diarrhea in early childhood, characteristic hair abnormalities, failure to thrive, and immunodeficiency. Diagnostic workup includes analysis of hair shaft abnormalities (hair microscopy), assessment of immune status—including immunoglobulins and vaccine-induced antibodies—liver function tests, gastrointestinal histology, and molecular genetic analysis of SKIC3 and SKIC2.

No causal treatment is currently available. Treatment is multidisciplinary and symptom-oriented:

• specialized enteral nutrition and, if necessary, parenteral nutrition,
• consistent fluid and electrolyte replacement,
• immunoglobulin replacement in cases of antibody deficiency,
• prompt treatment or prevention of infections,
• regular monitoring of liver function and nutritional status,
• in individual cases, liver or intestinal transplantation.

1. Alrammal A et al. (2024) Trichohepatoenteric syndrome type 1: expanding the clinical spectrum of THES type 1 due to a homozygous variant in the SKIC3 gene. BMC Pediatrics 24:444.
2. Fabre A et al. (2018) Trichohepatoenteric Syndrome. GeneReviews®. University of Washington, Seattle; first published in 2018, continuously updated. NIH
3. Fabre A et al. (2013) Syndromic diarrhea/Tricho-hepato-enteric syndrome. Orphanet J Rare Dis. 2013;8:5. doi:10.1186/1750-1172-8-5.
4. Fabre A et al. (2017) Management of syndromic diarrhea/tricho-hepato-enteric syndrome: A review of the literature. Intractable Rare Dis Res. 6:152–157. doi:10.5582/irdr.2017.01040.
5. Fabre A et al. (2912) SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome. Am J Hum Genet 90:689–692.
6. Lee KY et al. (2014) Long-term outcomes in children with trichohepatoenteric syndrome. Am J Med Genet A 194:141–149.