Trichohepatoenteric Syndrome 2
A number sign (#) is used with this entry because of evidence that trichohepatoenteric syndrome-2 (THES2) is caused by homozygous or compound heterozygous mutation in the SKIV2L gene (600478) on chromosome 6p21.
DescriptionTrichohepatoenteric syndrome (THES) is a rare and severe disease characterized by intrauterine growth retardation, facial dysmorphism, hair abnormalities, intractable diarrhea, and immunodeficiency (summary by Fabre et al., 2012).
For a discussion of genetic heterogeneity of trichohepatoenteric syndrome, see THES1 (222470).
Clinical FeaturesEgritas et al. (2009) reported a 4.5-year-old Turkish girl who was small for gestational age at preterm birth (32 weeks) and developed intractable mucoid and occasionally bloody diarrhea within the first 3 months of life. Examination revealed low hairline, poorly pigmented woolly hair, facial dysmorphism including square forehead, prominent cheeks, and a broad nasal root, and hepatomegaly. Microscopic hair examination showed trichorrhexis nodosa. Laboratory evaluation revealed hypochromic microcytic anemia compatible with iron deficiency, but liver enzymes were normal and stool examination was unremarkable, as were metabolic, glycosylation, chromosomal, and viral studies. Liver biopsy showed nonspecific mild chronic hepatitis; upper and lower gastrointestinal endoscopy was normal; and duodenal biopsy specimens showed normal villous patterns, whereas colonic mucosal biopsies showed cryptitis, cryptic abscesses, and polymorphonuclear and mononuclear infiltration in the lamina propria, consistent with a diagnosis of diffuse mild colitis with active-chronic inflammation. Egritas et al. (2009) considered this patient to represent a case of THES. She had a brother with cryptogenic liver disease who had no history of chronic diarrhea, facial dysmorphism, or hair abnormalities. Their parents were nonconsanguineous.
Fabre et al. (2012) studied 6 unrelated children with typical trichohepatoenteric syndrome who were known to be negative for mutation in the TTC37 gene (614589), including the Turkish girl originally reported by Egritas et al. (2009). All 6 patients presented with severe and intractable diarrhea that occurred between 1 and 12 weeks after birth, hair abnormalities involving sparse, fragile, and uncombable hair, and trichorrhexis nodosa, and facial dysmorphism characterized by hypertelorism, broad flat nasal bridge, and prominent forehead. All children received parenteral nutrition, but the amount of time varied between individuals and ranged from a few weeks to several years. Immunodeficiency was mostly due to low immunoglobulin levels and to the absence of an immune response to vaccines. Fabre et al. (2012) noted that the clinical presentation in these 6 patients was indistinguishable from that of THES patients with mutation in TTC37 (see 222470).
MappingIn a consanguineous family with trichohepatoenteric syndrome, Fabre et al. (2012) performed linkage analysis in which the TTC37 interval was excluded, revealing instead a region of homozygosity on chromosome 6p24.3-p21.2.
Molecular GeneticsIn 6 unrelated patients with typical trichohepatoenteric syndrome, Fabre et al. (2012) sequenced the candidate gene SKIV2L (600478) and identified homozygosity or compound heterozygosity for 8 different mutations, respectively, in all patients (see, e.g., 600478.0001-600478.0003). All of the unaffected parents available for analysis were heterozygous for 1 of the mutations identified in their child.