Tricho-hepatic-enteric syndrome (THES) without intractable diarrhoea.

Tricho-hepatic-enteric syndrome (THES) is a genetically heterogeneous rare syndrome (OMIM: 222470 (THES1) and 614602 (THES2)) that typically presents in the neonatal period with intractable diarrhoea, intra-uterine growth retardation (IUGR), facial dysmorphism, and hair and skin changes. THES is associated with pathogenic variants in either TTC37 or SKIV2L; both are components of the human SKI complex, an RNA exosome cofactor. We report an 8 year old girl who was diagnosed with THES by the Undiagnosed Disease Program-WA with compound heterozygous pathogenic variants in SKIV2L. While THES was considered in the differential diagnosis, the absence of protracted diarrhoea delayed definitive diagnosis. We therefore suggest that SKIV2L testing should be considered in cases otherwise suggestive of THES, but without the characteristic diarrhoea. We expand the phenotypic spectrum while reviewing the current knowledge on SKIV2L.

Two females with mutations in USP9X highlight the variable expressivity of the intellectual disability syndrome.

The genetic causes of intellectual disability (ID) are heterogeneous and include both chromosomal and monogenic etiologies. The X-chromosome is known to contain many ID-related genes and males show a marked predominance for intellectual disability. Here we report two females with syndromic intellectual disability. The first individual was relatively mild in her presentation with mild-moderate intellectual disability, hydronephrosis and altered pigmentation along the lines of Blaschko without additional congenital anomalies. A second female presented shortly after birth with dysmorphic facial features, post-axial polydactyly and, on follow-up assessment, demonstrated moderate intellectual disability. Chromosomal studies for Individual 1 identified an X-chromosome deletion due to a de novo pericentric inversion; the inversion breakpoint was associated with deletion of the 5'UTR of the USP9X, a gene which has been implicated in a syndromic intellectual disability affecting females. The second individual had a de novo frameshift mutation detected by whole-exome sequencing that was predicted to be deleterious, NM_001039590.2 (USP9X): c.4104_4105del (p.(Arg1368Serfs*2)). Haploinsufficiency of USP9X in females has been associated with ID and congenital malformations that include heart defects, scoliosis, dental abnormalities, anal atresia, polydactyly, Dandy Walker malformation and hypoplastic corpus callosum. The extent of the congenital malformations observed in Individual 1 was less striking than Individual 2 and other individuals previously reported in the literature, and suggests that USP9X mutations in females can have a wider spectrum of presentation than previously appreciated.