Tricho-hepato-enteric syndrome

Symptoms

This rare syndrome appears in the first month as severe, persistent diarrhea. Affected infants are typically small at birth and later fail to grow, leading to a short adult height. Distinctive facial traits include a wide forehead, full cheeks, a broad nasal bridge, and eyes set far apart.

The hair is curly, fragile, and light in color. Liver problems like cirrhosis or fibrosis are common, with liver cells often storing excess iron. Many children also show some degree of intellectual disability.

Genetics

The syndrome appears to result from mutations in the TTC37 gene (also known as KIAA0372, MGC32587, or TPR repeat protein 37) or the SKIV2L gene. TTC37 is located on the Crick (minus) strand of chromosome 5 at 5q15, spans 91,113 bases, and contains 43 exons, with exons 1, 2, and 3 being non-coding. It encodes a protein of 1564 amino acid residues with twenty tetratricopeptide repeats, a predicted molecular weight of 175.486 kilodaltons, and a predicted pI of 7.47.

Its function is unknown but may involve adenylate cyclase activity. The gene is expressed in many tissues, including intestines, lungs, lymph nodes, pituitary, and vascular tissues. Homologs exist in frog, mouse, and rat.

Diagnosis

Typical facial features include low-set ears, prominent eyes with hypertelorism, a broad flat nose, prominent forehead, and large mouth. Liver biopsy may show fibrosis with bile duct proliferation, occasional giant cells, regenerative parenchymal nodules, and common siderosis. Small bowel biopsy reveals villous atrophy with low or no mononuclear cell infiltration of the lamina propria and no specific epithelial abnormalities; the degree of atrophy does not explain the diarrhea severity. Studies of enterocyte brush-border ion transporter proteins show reduced expression or mislocalization.

Hair microscopy shows twisted hairs of unequal size and shape (pili torti, aniso- and poikilotrichosis), longitudinal breaks, and trichorrhexis nodosa; scanning electron microscopy may reveal trichorrhexis blastysis. Biochemical analysis may show sulfur-deficient brittle hair (trichothiodystrophy). Platelets may be enlarged with disrupted canalicular system and missing alpha granules, but no increased bleeding tendency. Over 90% of patients have immune defects, including low immunoglobulin levels, defective antibody production after vaccination, monoclonal hyper IgA, or low lymphocyte count.

Did You Know?

• No specific treatment or cure exists; affected children usually need total parenteral nutrition through a central venous catheter.
• Diarrhea will likely continue even when food stops passing through the gastrointestinal system.
• The syndrome might be more common in areas with high levels of consanguinity.