Tricho-hepato-enteric syndrome: Retrospective multicenter experience in Saudi Arabia

Abstract

Background: Trichohepatoenteric syndrome (THES) is a very rare disorder that is characterized by intractable congenital diarrhea, woolly hair, intrauterine growth restriction, facial dysmorphism, and short stature. Our knowledge of THES is limited due to the small number of reported cases. Methods: Thirty patients diagnosed with THES, all molecularly confirmed by whole exome sequencing (WES) to have biallelic variants in TTC37 or SKIV2L , were included in the study. Clinical, biochemical, and nutritional phenotypes and outcome data were collected from all participants. Results: The median age of THES patients was 3.7 years (0.9–23 years). Diarrhea and malnutrition were the most common clinical features (100%). Other common features included hair abnormalities (96%), skin hyperpigmentation (87%), facial dysmorphic abnormalities (73%), psychomotor retardation (57%), and hepatic abnormalities (30%). Twenty-five patients required parenteral nutrition (83%) with a mean duration of 13.34 months, and nearly half were eventually weaned off. Parenteral nutrition was associated with a poor prognosis. The vast majority of cases (89.6%) had biallelic variants in SKIV2L , with biallelic variants in TTC37 accounting for the remaining cases. A total of seven variants were identified in TTC37 ( n = 3) and SKIV2L ( n = 4). The underlying genotype influenced some phenotypic aspects, especially liver involvement, which was more common in TTC37 -related THES. Conclusion: Our data helps define the natural history of THES and provide clinical management guidelines.

Long term outcomes in children with trichohepatoenteric syndrome

“…Our study highlights the heterogeneity of clinical findings and outcomes in THES, in line with previous reports (Alsaleem et al, 2021; Bourgeois et al, 2018; Fabre et al, 2014).…”

“…Previous reports have shown infection as the leading cause of mortality in THES (Alsaleem et al, 2021; Girault et al, 1994). We highlight specifically the high burden of respiratory comorbidity and the importance of good respiratory care.…”

SKI complex: A multifaceted cytoplasmic RNA exosome cofactor in mRNA metabolism with links to disease, developmental processes, and antiviral responses

“…For SKIV2L , only six mutation sets (five homozygous and one compound heterozygous) were observed in at most two unrelated families ( mut 3 , mut 7 , mut 8 , mut 20 , mut 22 , and mut10/mut41 ; Table 3). One mutation—c.3561_3581del, p.Ser1189_Leu1195del ( mut 32 ; Table 3)—was exceptionally recurrent, and noted in 21 families, mainly from Saudi Arabia (Figure 10) (Alsaleem et al, 2022). This is due to high rate of consanguineous marriages in this world region, and thus the incidence of THES in the Middle East is much higher than in the global population (~1/200,000).…”

Heterogeneity in biomarkers, mitogenome and genetic disorders of Arab population with special emphasis on large-scale whole-exome sequencing

“…genes) [92]; celiac disease (CPED1 gene) [93]; hereditary spherocytosis type 3 (SPTA1 gene) [89]; developmental delay, cerebellar hypoplasia, and myoclonic seizures (KCNMA1 gene) [74]; Cenani-Lenz syndrome (APC gene) [74]; Sjogren-Larsson syndrome (ELOVL4 gene) [74]; autism spectrum disorder (multigene) [94]; congenital heart disease (PRKD1 gene) [95]; ciliopathies [96]; Parkinsonism (PLA2G6 gene) [97]; retinal dystrophies (CLRN1, ABCA4, CERKL, AGBL5, CDH16, and DNAJC17 genes) [98][99][100]; Pediatric Asthma [101]; cardiovascular genetic diseases (LDLR gene) [102]; enteroendocrine dysfunction (PCSK1) [103]; tricho-hepato-enteric syndrome (TTC37 and SKIV2L) [104]; Wolcott-Rallison syndrome (EIF2AK3) [105], Fanconi-Bickel syndrome (SLC2A2) [105] and Alström syndrome (Exon 19 Skipping in ALMS1 Gene) [106,107]; using whole exome or whole genome analysis revealed disease markers in Saudi population. Families with autosomal recessive retinal dystrophies from various ethnicity including Saudis were analysed for candidate genes using WES, 45 unique deleterious variants including 18 novel variants observed [108].…”

“…Variants in the Mendeliome in Saudi ancestry – APC-related Cenani-Lenz syndrome, Steel syndrome, syndromic cataract, oral-facial-digital syndrome, CHARGE-like presentation, epileptic encephalopathy, Ehlers-Danlos-like syndrome, and congenital hydrocephalus – were reported either with compatible phenotypes (homozygous variant in 30 genes) or phenotypes different from the original reports (homozygous mutations in 18 candidate genes) [ 79 ]. Studies on systemic juvenile idiopathic arthritis ( LACC1 gene) [ 80 , 81 ]; recurrent pregnancy loss ( ASIC5 gene) [ 82 ]; tricho-hepato-enteric syndrome ( SKIV2L and TTC37 genes) [ 83 ]; STING-associated vasculopathy of infantile-onset ( STING1 gene) [ 84 ]; multiple congenital anomaly syndrome ( SMG9 gene) [ 85 ]; diabetic retinopathy ( NME3 , LOC728699 , and FASTK genes) [ 86 ]; congenital neutropenia with inflammatory bowel disease ( G6PC3 gene) [ 87 ]; skeletal dysplasia ( XYLT1 ) [ 88 , 89 ]; Wolf–Hirschhorn syndrome ( WHSC1 gene) [ 90 ]; lymphatic dysplasia with nonimmune hydrops fetalis ( PIEZO1 ) [ 89 ]; Cohen syndrome ( VPS13B gene) [ 91 ]; severe combined immunodeficiency disease ( AK2 , JAK3 , and MTHFD1 genes) [ 92 ]; celiac disease ( CPED1 gene) [ 93 ]; hereditary spherocytosis type 3 ( SPTA1 gene) [ 89 ]; developmental delay, cerebellar hypoplasia, and myoclonic seizures ( KCNMA1 gene) [ 74 ]; Cenani-Lenz syndrome ( APC gene) [ 74 ]; Sjogren-Larsson syndrome ( ELOVL4 gene) [ 74 ]; autism spectrum disorder (multigene) [ 94 ]; congenital heart disease ( PRKD1 gene) [ 95 ]; ciliopathies [ 96 ]; Parkinsonism ( PLA2G6 gene) [ 97 ]; retinal dystrophies ( CLRN1 , ABCA4 , CERKL , AGBL5 , CDH16 , and DNAJC17 genes) [ 98 – 100 ]; pediatric asthma [ 101 ]; cardiovascular genetic diseases ( LDLR gene) [ 102 ]; enteroendocrine dysfunction ( PCSK1 ) [ 103 ]; tricho-hepato-enteric syndrome ( TTC37 and SKIV2L ) [ 104 ]; Wolcott–Rallison syndrome ( EIF2AK3 ) [ 105 ], Fanconi–Bickel syndrome ( SLC2A2 ) [ ...…”