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 (SKIC2; 600478) on chromosome 6p21.

Trichohepatoenteric syndrome-2 (THES2) 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).

Egritas 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 and mutation in the SKIV2L gene, 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).

Monies et al. (2015) reported 5 patients from 3 consanguineous Saudi families (families 1, 3, and 4) with THES and mutation in the SKIV2L gene. The patients shared the characteristic features of THES, including congenital intractable diarrhea, facial dysmorphisms, and woolly uncombable hair. Onset of diarrhea occurred within the first 2 weeks of life, resulting in failure to thrive and necessitating total parenteral nutrition for a period ranging from 4 months to 2 years. In addition, all 5 patients exhibited numerous congenital cafe-au-lait spots limited to skin below the waist, distributed over the pelvis and lower extremities. The 2 oldest patients (family 1), a brother (II-1) and sister (II-2) aged 23 and 14 years, respectively, underwent small bowel biopsy that revealed normal villi with active chronic inflammation; liver biopsies showed fibrosis in both sibs. The brother and a 10-year-old affected sister (II-3) also had peg teeth, but the authors suggested that given the extensive consanguinity in Saudi families, this might be associated with a second recessive condition in the family.

Zheng et al. (2016) described a 17-month-old Han Chinese boy with THES and mutation in the SKIV2L gene. He had intrauterine growth retardation and failure to thrive postnatally, with development of frequent watery diarrhea at age 1 month. During a hospitalization for incarcerated inguinal hernia, he was reported to have ascites and hepatic cirrhosis. At age 17 months, he had intractable diarrhea with protein energy malnutrition, poorly pigmented woolly hair that showed trichorrhexis nodosa on light microscopy, and facial dysmorphisms including square forehead, prominent cheeks, hypertelorism, and a broad nasal root. Immunologic evaluation revealed low IgG, IgM, C3, and C4 levels, and T-cell analysis showed a profile of high CD4+ and low CD8+ lymphocytes, with high CD4+/CD8+ cells and low natural killer cells. Abdominal ultrasound showed hepatomegaly and cirrhosis. The authors considered this to represent a relatively mild phenotype, with long-term survival on oral feeding; they noted that over an 18-month follow-up period, the diarrhea persisted but there was no sign of progression of liver disease.

The transmission pattern of THES2 in the families reported by Fabre et al. (2012) was consistent with autosomal recessive inheritance.

In 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.

In 6 unrelated patients with typical trichohepatoenteric syndrome, including the Turkish girl originally reported by Egritas et al. (2009), who were all negative for mutation in the TTC37 gene (614589), Fabre et al. (2012) sequenced the candidate gene SKIV2L (SKIC2; 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.

In 5 sibs from 3 consanguineous Saudi families (families 1, 3, and 4) with THES and who also exhibited cafe-au-lait spots below the waist, Monies et al. (2015) identified homozygosity for a 21-bp deletion in the SKIV2L gene (600478.0004) that was confirmed by Sanger sequencing and segregated with disease in each family.

In a 17-month-old Han Chinese boy with THES, Zheng et al. (2016) analyzed the SKIV2L gene and identified compound heterozygosity for a nonsense mutation (R374X; 600478.0005) and a missense mutation (G631S; 600478.0006). Sanger sequencing confirmed the mutation and showed that his unaffected parents were each heterozygous for 1 of the mutations.