Genetic, clinical and biochemical characterization of a large cohort of patients with hyaline fibromatosis syndrome.
ANTXR2
Biomarker
Farber disease
Genotype-phenotype correlation
Hyaline fibromatosis syndrome
Journal
Orphanet journal of rare diseases
ISSN: 1750-1172
Titre abrégé: Orphanet J Rare Dis
Pays: England
ID NLM: 101266602
Informations de publication
Date de publication:
27 08 2019
27 08 2019
Historique:
received:
20
12
2018
accepted:
16
08
2019
entrez:
29
8
2019
pubmed:
29
8
2019
medline:
1
7
2020
Statut:
epublish
Résumé
Hyaline fibromatosis syndrome (HFS) is a rare clinical condition in which bi-allelic variants in ANTXR2 are associated with extracellular hyaline deposits. It manifests as multiple skin nodules, patchy hyperpigmentation, joint contractures and severe pain with movement. HFS shows some clinical overlap to Farber disease (FD), a recessive lysosomal storage disorder. We here present the largest cohort of independent, genetically confirmed HFS cases reported to date: in 19 unrelated index patients, we identified ten distinct homozygous ANTXR2 mutations, three of which are novel frame-shift variants. The associated clinical data are consistent with the previous hypothesis of non-truncating variants in the terminal exons 13-17 to confer rather mild phenotypes. The novel observation of gender-dependent disease manifestation in our cohort received support from a meta-analysis of all previously published cases. Untargeted blood-based metabolomics revealed patient samples to be biochemically distinct from control samples. Numerous potential HFS biomarker metabolites could thus be identified. We also found metabolomics profiles of HFS patients to highly overlap with those from FD patients. Our study extends the mutational spectrum for HFS, suggests gender-dependency of manifestation, and provides pilot metabolomics data for biomarker identification and a better pathomechanistic understanding of the disorder.
Sections du résumé
BACKGROUND
Hyaline fibromatosis syndrome (HFS) is a rare clinical condition in which bi-allelic variants in ANTXR2 are associated with extracellular hyaline deposits. It manifests as multiple skin nodules, patchy hyperpigmentation, joint contractures and severe pain with movement. HFS shows some clinical overlap to Farber disease (FD), a recessive lysosomal storage disorder.
RESULTS
We here present the largest cohort of independent, genetically confirmed HFS cases reported to date: in 19 unrelated index patients, we identified ten distinct homozygous ANTXR2 mutations, three of which are novel frame-shift variants. The associated clinical data are consistent with the previous hypothesis of non-truncating variants in the terminal exons 13-17 to confer rather mild phenotypes. The novel observation of gender-dependent disease manifestation in our cohort received support from a meta-analysis of all previously published cases. Untargeted blood-based metabolomics revealed patient samples to be biochemically distinct from control samples. Numerous potential HFS biomarker metabolites could thus be identified. We also found metabolomics profiles of HFS patients to highly overlap with those from FD patients.
CONCLUSIONS
Our study extends the mutational spectrum for HFS, suggests gender-dependency of manifestation, and provides pilot metabolomics data for biomarker identification and a better pathomechanistic understanding of the disorder.
Identifiants
pubmed: 31455396
doi: 10.1186/s13023-019-1183-5
pii: 10.1186/s13023-019-1183-5
pmc: PMC6712857
doi:
Substances chimiques
ANTXR2 protein, human
0
Biomarkers
0
Receptors, Peptide
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
209Références
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