Tricho-hepato-enteric Syndrome

Overview

Tricho-hepato-enteric syndrome (THES), also known as syndromic diarrhea or phenotypic diarrhea of infancy, is a rare autosomal recessive genetic disorder characterized by intractable diarrhea beginning in early infancy, along with distinctive hair abnormalities, liver disease, growth failure, and immune system dysfunction. First described in the 1980s, THES is a multisystem condition that presents significant challenges in neonatal care and early childhood development. The disorder affects multiple organ systems and often requires lifelong medical management. Early diagnosis and intervention are crucial to improving clinical outcomes and reducing complications.

Causes

Tricho-hepato-enteric syndrome is caused by mutations in one of two genes:

TTC37 gene: Mutations in this gene account for the majority of THES cases. It encodes a protein involved in RNA degradation as part of the SKI complex, which regulates cellular RNA stability.
SKIV2L gene: Also part of the SKI complex, mutations here are associated with a subset of THES patients and result in similar clinical features.

Both genes are inherited in an autosomal recessive manner, meaning a child must inherit two defective copies (one from each parent) to develop the syndrome. The disruption in RNA metabolism due to these mutations affects various biological processes, leading to the multisystem manifestations of the disorder.

Symptoms

The clinical presentation of THES typically begins in the neonatal period or early infancy and includes a wide range of symptoms affecting the gastrointestinal system, liver, hair, immune system, and overall development. Common features include:

Gastrointestinal symptoms: Intractable, watery, and often life-threatening diarrhea that begins within the first few months of life, leading to dehydration and malnutrition.
Liver involvement: Hepatomegaly (enlarged liver), liver fibrosis, elevated liver enzymes, and in some cases, cirrhosis or liver failure.
Hair abnormalities: Brittle, woolly, easily breakable hair; some children may have sparse scalp hair or unusual pigmentation.
Growth failure: Severe malnutrition, failure to thrive, and delayed physical development due to malabsorption and chronic illness.
Facial dysmorphism: Some patients exhibit distinctive facial features such as a prominent forehead, broad nasal bridge, or thin upper lip.
Immunodeficiency: Recurrent infections due to immune dysfunction; many patients have low immunoglobulin levels or lymphocyte abnormalities.
Developmental delay: Cognitive and motor delays may occur, particularly in severely affected individuals.

Diagnosis

Diagnosing tricho-hepato-enteric syndrome involves a combination of clinical evaluation, laboratory tests, imaging, and genetic analysis. Diagnostic steps include:

Clinical assessment: Recognition of early-onset intractable diarrhea, failure to thrive, and associated features such as hair and liver abnormalities.
Hair analysis: Microscopy of scalp hair may show abnormal shaft structures such as trichorrhexis nodosa or pili torti.
Liver function tests: Elevated liver enzymes, bilirubin, and imaging studies such as ultrasound or MRI can assess liver size and architecture.
Immunologic workup: Assessment of immunoglobulin levels and lymphocyte subsets to evaluate immune function.
Genetic testing: Whole exome sequencing or targeted gene panels to detect mutations in the TTC37 or SKIV2L genes, confirming the diagnosis.
Family history: Consanguinity or affected siblings may support the diagnosis due to the autosomal recessive inheritance pattern.

Treatment

There is currently no cure for THES, and treatment focuses on supportive care, managing complications, and improving quality of life. Management typically involves a multidisciplinary team including pediatric gastroenterologists, hepatologists, immunologists, and nutritionists. Key treatment components include:

Nutritional support: Total parenteral nutrition (TPN) is often necessary, especially in the early years, due to severe intestinal malabsorption.
Management of diarrhea: Antidiarrheal medications may provide limited benefit; care is focused on fluid and electrolyte replacement.
Liver monitoring: Regular assessment for liver disease progression; some cases may require liver transplantation.
Infection prevention: Immunoglobulin replacement therapy for patients with antibody deficiencies and prompt treatment of infections.
Developmental support: Physical, occupational, and speech therapy for children with developmental delays.
Genetic counseling: Recommended for affected families to understand inheritance risks and consider testing for future pregnancies.

Prognosis

The prognosis of tricho-hepato-enteric syndrome is variable and largely depends on the severity of symptoms, early diagnosis, and quality of medical care. Key aspects include:

Mortality: High infant mortality rates have been reported in untreated or severe cases due to complications such as dehydration, liver failure, or sepsis.
Growth and development: Many patients continue to have growth retardation and developmental delays, even with nutritional and supportive therapy.
Long-term outcomes: Some individuals can achieve improved stability and partial enteral feeding with age, but long-term dependence on parenteral nutrition is common.
Quality of life: Varies greatly depending on organ involvement, infection control, and access to specialized care.

Advances in genetic diagnosis, immunological management, and nutritional support have improved survival and clinical outcomes in recent years, but tricho-hepato-enteric syndrome remains a complex and challenging condition requiring lifelong care.