Genetic, clinical and biochemical characterization of a large cohort of patients with hyaline fibromatosis syndrome

Claudia Cozma,Amal M Alhashem,Nihal M Al Menabawy,Laila A Selim,Tawfeg Ben-Omran,Peter Bauer,Marina Hovakimyan,Nawal Makhseed,Iman G Mahmoud,Marius-Ionuț Iurașcu,Mariam Al-Mureikhi,Christian Beetz,Laura Demuth,Zafer Yüksel,Arndt Rolfs,Magi Martin

doi:10.1186/s13023-019-1183-5

Abstract

BackgroundHyaline 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.ResultsWe 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.ConclusionsOur 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.

Highlights

Hyaline fibromatosis syndrome (HFS) is a rare clinical condition in which bi-allelic variants in ANTXR2 are associated with extracellular hyaline deposits
Nineteen unrelated index cases are homozygous for known or novel variants in ANTXR2 Sanger sequencing of the ANTXR2 gene, as requested for nine patients that had received a clinical diagnosis of HFS, readily identified a single homozygous variant in eight cases
All 19 patients received a genetic diagnosis of ANTXR2-related HFS (Table 1)

Summary

Introduction

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. Hyaline fibromatosis syndrome (HFS, MIM #22860) is characterized by the accumulation of clear (hyaline) substance in body tissues. Such noncancerous masses may grow under the skin and the gums resulting in bumps/nodules and gingival hypertrophy, respectively. HFS is a recessive, genetically homogeneous disorder; it is caused by bi-allelic variants in ANTXR2 [5] [6]. With the exception of a mutational hotspot at c.1072_1076, pathogenic variants are more or less distributed over the coding sequence [7]

Methods

Results

Discussion

Conclusion