Trichohepatoenteric Syndrome 1

A number sign (#) is used with this entry because of evidence that trichohepatoenteric syndrome-1 (THES1) is caused by homozygous or compound heterozygous mutation in the TTC37 gene (614589) on chromosome 5q15.

Although the spectrum of phenotypic expression in trichohepatoenteric syndrome (THES) is broad, the characteristic features include intrauterine growth retardation, woolly hair, facial dysmorphism, intractable diarrhea in infancy requiring total parenteral nutrition, and immunodepression. Hepatic involvement contributes to the poor prognosis of affected patients (summary by Fabre et al., 2007).

Genetic Heterogeneity of Trichohepatoenteric Syndrome

Trichohepatoenteric syndrome-2 (THES2; 614602) is caused by mutation in the SKIV2L gene (600478) on chromosome 6p21.

Stankler et al. (1982) reported a seemingly 'new,' presumably autosomal recessive disorder in a sister and brother who died at 33 and 87 days of age, respectively, with severe unexplained diarrhea. Both were of low birth weight for dates and had large, low-set, simple ears, flat nasal bridge, and large mouth. Both had woolly, easily removed black hair showing an abnormality the authors dubbed 'trichorrhexis blastysis.' By scanning microscopy, the hairs showed projections at multiple sites arising from the convex surface of a kinked hair and suggesting buds (Gr. blastosis = bud). The hair had a low content of cystine and an abnormal content of several other amino acids. Both parents had normal hair microscopically and chemically. In both sibs, the diarrhea began in the third week of life and was preceded by excoriated buttocks. Both had galactosuria without galactosemia. At autopsy both had hepatic fibrosis and hemosiderosis and islet cell hyperplasia. Menkes disease (309400) and argininosuccinic aciduria (207900), which have somewhat similar findings in the hair, were excluded by chemical tests.

Girault et al. (1994) reported 8 children with severe secretory diarrhea beginning in the first 6 months of life (less than 1 month in 6 cases). All were small for gestational age and had facial dysmorphism and woolly, easily removable hair with trichorrhexis nodosa. Two children were from consanguineous marriages. Diarrhea was refractive to therapy, including bowel rest. All patients had jejunal biopsies that showed total or subtotal villous atrophy, defective antigen-specific skin tests, and defective antibody responses despite normal serum immunoglobulin levels. Two patients had hepatic cirrhosis, and 3 children had mental retardation. At the time of the report, 5 patients had died between the ages of 2 and 5 years, 2 were fed enterally, and 1 continued to receive total parenteral nutrition. Barabino et al. (2004) reported follow-up of the patient dependent on parenteral nutrition reported by Girault et al. (1994). At age 6 years, she achieved intestinal autonomy with discontinuation of the parenteral nutrition. At age 14 years, she had mild psychomotor and pubertal delay. She had chronic malabsorptive diarrhea, hypoalbuminemia, iron-deficiency anemia, osteoporosis, and impaired intestinal permeability. Immunologic defect was still present, but no other infections were recorded.

Verloes et al. (1997) used the term 'tricho-hepato-enteric syndrome' to describe the disorder in a brother and sister who were noted prenatally to have intrauterine growth retardation, hydramnios, and placental hyperplasia. Both had intractable diarrhea with normal histologic and enzymologic studies. Facial anomalies included hypertelorism, upturned noses, small mouths, and low-set ears. Hair texture and pattern were abnormal. Neurologically, they appeared grossly normal. The sister was noted to have cholestatic jaundice and hepatomegaly at 2 months of age, whereas the brother was noted to have hepatic dysfunction at birth with a high alpha-fetoprotein level. He also had mild and delayed hypermethioninemia. Both died at about 6 months of age. Pathologic examination of both children showed a similar pattern of multivisceral iron deposition compatible with a diagnosis of neonatal hemochromatosis, although the clinical picture of an asymptomatic neonatal period was unusual.

Goulet et al. (1998) studied the clinical and histopathologic features of 47 infants with intractable diarrhea and villous atrophy of varying degrees, dividing them into 2 groups, with or without lamina propria mononuclear cell infiltration. Of the 18 patients in the latter group, 8 had phenotypic abnormalities including facial dysmorphism and abnormal hair; 6 of the 8 patients had previously been reported by Girault et al. (1994).

Landers and Schroeder (2003) reported a 3-year-old girl with severe intractable diarrhea of infancy requiring lifelong total parenteral nutrition. Duodenal biopsy at age 2 months showed villous atrophy, but subsequent biopsies were normal. She had several episodes of line sepsis and pancytopenia on 1 hospitalization. Physical exam at age 3 years found facial dysmorphism with prominent forehead and cheeks, broad nasal root, hypertelorism, and mental retardation. Her hair was brittle with trichorrhexis nodosa in nearly all hair shafts. Hepatomegaly was noted, and liver biopsy showed cirrhosis. Laboratory studies showed mild anemia, leukopenia, and thrombocytopenia. At the time of the report, she was awaiting liver transplant.

Barabino et al. (2004) reported a girl who developed chronic diarrhea at 15 days of age. Total parenteral nutrition was started and then discontinued at 1 year. She had the typical facial features, hair abnormalities, and intestinal findings consistent with what the authors termed 'syndromic diarrhea.' At age 17 years, she showed severe growth delay but normal pubertal development. She had mild mental impairment, intermittent diarrhea, and frequent upper respiratory infections. Intestinal histology had improved. An older sister died during infancy from unexplained diarrhea.

Dweikat et al. (2007) reported a female infant, born of first-cousin parents, with hemochromatosis, intractable diarrhea, dysmorphic features, and hair abnormality. She was born at term and had a normal neonatal course. Failure to thrive was noted at age 1 month. Watery diarrhea began at age 50 days and continued despite dietary changes and 3 weeks of bowel rest. Physical exam at age 3 months showed decreased physical growth, sparse, thin, curly hair, hypertelorism, broad nose, prominent eyes, and umbilical and bilateral inguinal hernias. Laboratory studies showed abnormally increased liver enzymes and increased serum iron content. Liver biopsy showed edema, fibrosis, and iron deposition. Hypermethioninemia was not present. Psychomotor development was normal until her death at age 10 months from intractable diarrhea. Dweikat et al. (2007) noted the phenotypic similarities to the patients reported by Stankler et al. (1982) and Verloes et al. (1997).

Fabre et al. (2007) reported 2 unrelated male infants with THE syndrome. Both developed intractable watery diarrhea requiring total parenteral nutrition at ages 1 and 3 months, respectively. Both also had facial dysmorphism with large forehead, hypertelorism, and broad nasal root, and trichorrhexis nodosa. Other common features included hepatic cirrhosis and mild humoral immunodeficiency. In 1 child, duodenal biopsy showed total villous atrophy at 1 month, and subsequent testing at 20 months showed moderate villous atrophy. Fabre et al. (2007) suggested that THE syndrome and the 'syndromic diarrhea' described by Barabino et al. (2004) are the same disease entity.

Hartley et al. (2010) studied 12 affected children from 11 families with THES, 8 of which were consanguineous. All children exhibited the characteristic facial features and trichorrhexis nodosa of the hair on microscopy. There was a high incidence of preterm delivery and intrauterine growth retardation. Diarrhea developed between 2 weeks of age and 7 months, and all children required parenteral nutrition in infancy; in 2 patients, parenteral nutrition could be discontinued due to improvement in diarrhea. Histologic examination of serially obtained jejunal biopsy specimens suggested that the villous atrophy can improve with age and the inflammatory infiltrate is not consistent. Serum immunoglobulin levels were low in 11 of the 12 children, requiring supplementation during the neonatal period. Cardiac anomalies were present in 5 children, including aortic insufficiency in 2, peripheral pulmonary stenosis in 1, ventricular septal defect in 1, and tetralogy of Fallot in 1. Developmental delay was present in all 7 children who were old enough to be assessed. Previously unrecognized platelet abnormalities were identified in 6 of the children, with large platelets observed in 5 and thrombocytosis in 4; transmission electron microscopy revealed reduced platelet alpha-granules, unusual stimulated alpha-granule content release, abnormal lipid inclusions, abnormal platelet canalicular system, and reduced number of microtubules.

Hartley et al. (2010) performed genomewide linkage analysis in 8 children with trichohepatoenteric syndrome from consanguineous families and identified 3 extended regions of homozygosity shared by all 8 children. Further genotyping in all available family members using microsatellite markers excluded 2 of the regions and confirmed linkage to chromosome 5q14.3-q21.2, defining a 12.9-Mb interval between markers D5S815 and D5S409. Multipoint linkage analysis yielded a maximum lod score of 5.8 (theta = 0) at D5S1462.

In 12 children from 11 unrelated families with trichohepatoenteric syndrome mapping to chromosome 5q14.3-q21.2, Hartley et al. (2010) identified homozygosity or compound heterozygosity for 9 different mutations in the candidate gene TTC37 (see, e.g., 614589.0001-614589.0005). All mutations segregated with disease status in the family, and none were detected in at least 350 ethnically matched South Asian and Caucasian control chromosomes.

Fabre et al. (2011) analyzed the TTC37 gene in 12 THES patients from 11 families, including the 2 boys originally reported by Fabre et al. (2007), and identified homozygosity or compound heterozygosity for 11 different mutations in 9 of the patients (see, e.g., 614589.0006-614589.0008). The phenotypes of the 3 female patients in whom no mutation in TTC37 was detected were reevaluated and confirmed as being typical THES, suggesting that at least 1 other gene may be implicated in the disease.