Tenorio Syndrome

A number sign (#) is used with this entry because of evidence that Tenorio syndrome (TNORS) is caused by heterozygous mutation in the RNF125 gene (610432) on chromosome 18q12.

Description

Tenorio syndrome is characterized by overgrowth, macrocephaly, and intellectual disability (ID). Some patients may have mild hydrocephaly, hypoglycemia, and inflammatory diseases resembling Sjogren syndrome (270150) (summary by Tenorio et al., 2014).

Clinical Features

Tenorio et al. (2014) described 6 patients from 4 families with a syndrome of overgrowth, macrocephaly, intellectual disability, mild hydrocephaly, hypoglycemia, and inflammatory diseases resembling Sjogren syndrome. One patient had several episodes of Raynaud phenomena, dry conjunctivitis, and recurrent aphthous stomatitis, and another patient had continuous episodes of keratitis, conjunctivitis, limbitis, serous otitis, and pneumonia. All patients had overgrowth, macrocephaly with prominent and large forehead, and mild to moderate ID; other features were not observed in all patients.

Molecular Genetics

By SNP-array screening of 270 families from the Spanish Overgrowth Syndrome Registry with no molecular characterization of their disorder, Tenorio et al. (2014) identified 1 patient with a de novo 9-Mb deletion on chromosome 18 encompassing several candidate genes, including RNF125 AND RNF138 (616319). By screening for mutations in the RNF125 and RNF138 genes in all 270 families, they identified 3 heterozygous missense mutations in the RNF125 gene (610432.0001-610432.0003) in 5 patients from 3 families. In 1 proband, the missense mutation was de novo, and in the other 2 probands, the mutations were observed in their affected mothers. The mutations were not found in 600 chromosomes from healthy Spanish controls or in 350 exomes from Spanish controls. None of the 3 variants were present in the 1000 Genomes Project database; in the Exome Variant Server database, the M112I mutation (610432.0001) was not found but the other 2 variants were present in 1 (0.0077%) of 13,005 chromosomes. The mRNA levels of RNF125 were low in all patients compared with controls. Tenorio et al. (2014) applied whole-genome expression arrays and quantitative RT-PCR confirmation in the 3 main pathways in which RNF125 participates: RIGI (DDX58; 609631)-IPS1 (609676), PI3K (see 171834)-AKT (see 164730), and interferon signaling. They demonstrated that haploinsufficiency of RNF125 leads to upregulation of RIGI, IPS1, and MDA5 (IFIH1; 606951) and to misregulation of the 3 main pathways.