Here we describe a patient with juvenile hyaline fibromatosis confirmed by clinical and histopathologic findings, and genetic analysis, which revealed a novel homozygous splice site mutation IVS14+1G→T on exon 14 in anthrax toxin receptor 2 gene.
Finally, and possibly providing insight into the pathophysiology of these diseases, analysis of fibroblasts derived from patients with JHF or ISH suggests that CMG2 mutations abrogate normal cell interactions with the extracellular matrix.
PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative.
Finally, we show that mutant CMG2 can be rescued in fibroblasts of some patients by treatment with proteasome inhibitors and that CMG2 is then properly transported to the plasma membrane and signalling competent, identifying the ER folding and degradation pathway components as promising drug targets for HFS.
This information provides insights on genotype-phenotype correlations, identifies a previously unreported mutation in ANTXR2, and improves the understanding of a recurrent mutation in HFS.
We now report the identification of 15 different mutations in the gene encoding capillary morphogenesis protein 2 (CMG2) in 17 families with JHF or ISH.
Systemic hyalinosis is an autosomal recessive disease that encompasses two allelic syndromes, infantile systemic hyalinosis (ISH) and juvenile hyaline fibromatosis (JHF), which are caused by mutations in the CMG2 gene.
Hyaline fibromatosis syndrome (HFS) is a rare clinical condition in which bi-allelic variants in ANTXR2 are associated with extracellular hyaline deposits.
Hemodynamic features of the site of NVC can be added to the preoperative simulation for MVD surgery, which may be useful for the diagnosis and treatment planning of TN and HFS.
The authors conducted a single-center retrospective study of 27 patients (28 separate E-MVD cases; 1 patient had bilateral E-MVD) diagnosed with HFS who underwent fully E-MVD from January 2013 to October 2016.
The presence of two polymorphisms (CDD943insC and CES 2 Exon3 6046 G/A) were associated with a non-statistically significant higher incidence of grade 3 hand-foot syndrome (HFS) (p=0.07) and grade 3-4 diarrhoea (p=0.09), respectively.
The serum levels of IL-1β, IL-6, IL-8 and TNF-α in either HFS or TN patients were significantly higher than that in healthy volunteers (p < 0.05), yet which were similar between TN and HFS patients (p > 0.05).