Case Report: A Novel Homozygous Frameshift Mutation of the SKIV2L Gene in a Trichohepatoenteric Syndrome Patient Presenting With Short Stature, Premature Ovarian Failure, and Osteoporosis

Abstract

Background: Trichohepatoenteric syndrome (THES) is a rare Mendelian autosomal recessive genetic disease characterized by intractable diarrhea, woolly hair, facial abnormality, immune dysfunction, and intrauterine growth restriction. THES mutations are found in the TTC37 and SKIV2L genes, which encode two components of the human superkiller (SKI) complex. Methods and results: We report one case of a 32-year-old woman of Chinese descent with THES, who was born with a low weight (2000 g). She had intractable diarrhea during the neonatal period and was allergic to cow's milk and condensed milk, but did not require total parenteral nutrition. She experienced menarche at age 12 and amenorrhea at age 28. In May 2019, the patient presented with a left fibular head fracture and was diagnosed with osteoporosis. Genetic testing showed a novel mutation in exon1 [p.E5Afs∗37 (c.12_13del)] of SKIV2L, which is composed of 28 exons. After the diagnosis, hormone replacement therapy was prescribed, in addition to the routine calcium and vitamin D supplements. Conclusion: This case expands the clinical characteristic and phenotype spectrum of THES, providing further understanding of SKIV2L and its autoimmune influence.

Keywords: SKIV2L gene mutation; case report; intractable diarrhea; premature ovarian failure; trichohepatoenteric syndrome.

FIGURE 1

(A) The image shows that the proband was short in stature. (B) The graph shows that the patient had facial dysmorphism. (C) Pedigrees of the family diagnosed with trichohepatoenteric syndrome. (D) Sanger sequencing chromatograms of DNA samples from the proband and her mother and younger brother showing the autosomal recessive mutation, c 12_13del in SKIV2L. Arrows indicate the position of the mutation. (E) Amino acid sequences of wild-type and mutated SKIV2L. The mutation of SKIV2L results in a truncated protein composed of 40 amino acids, compared with the wild-type SKIV2L, which is composed of 1246 amino acids.

FIGURE 2

Difference between the wild-type and p.E5Afs*37 (c.12_13del) mutant protein of SKIV2L. (A) Three-dimensional model of wild-type SKIV2L. (B) Model of the mutant protein.