Genetic, clinical and biochemical characterization of a large cohort of patients with hyaline fibromatosis syndrome
Abstract 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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-08-01
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| Series: | Orphanet Journal of Rare Diseases |
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| Online Access: | http://link.springer.com/article/10.1186/s13023-019-1183-5 |
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| author | Claudia Cozma Marina Hovakimyan Marius-Ionuț Iurașcu Nawal Makhseed Laila A. Selim Amal M. Alhashem Tawfeg Ben-Omran Iman G. Mahmoud Nihal M. Al Menabawy Mariam Al-Mureikhi Magi Martin Laura Demuth Zafer Yüksel Christian Beetz Peter Bauer Arndt Rolfs |
| author_facet | Claudia Cozma Marina Hovakimyan Marius-Ionuț Iurașcu Nawal Makhseed Laila A. Selim Amal M. Alhashem Tawfeg Ben-Omran Iman G. Mahmoud Nihal M. Al Menabawy Mariam Al-Mureikhi Magi Martin Laura Demuth Zafer Yüksel Christian Beetz Peter Bauer Arndt Rolfs |
| author_sort | Claudia Cozma |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-20T13:03:02Z |
| format | Article |
| id | doaj.art-ad6e189b819e470e8448785fa1427c99 |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-12-20T13:03:02Z |
| publishDate | 2019-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-ad6e189b819e470e8448785fa1427c992022-12-21T19:39:52ZengBMCOrphanet Journal of Rare Diseases1750-11722019-08-0114111010.1186/s13023-019-1183-5Genetic, clinical and biochemical characterization of a large cohort of patients with hyaline fibromatosis syndromeClaudia Cozma0Marina Hovakimyan1Marius-Ionuț Iurașcu2Nawal Makhseed3Laila A. Selim4Amal M. Alhashem5Tawfeg Ben-Omran6Iman G. Mahmoud7Nihal M. Al Menabawy8Mariam Al-Mureikhi9Magi Martin10Laura Demuth11Zafer Yüksel12Christian Beetz13Peter Bauer14Arndt Rolfs15Centogene AGCentogene AGCentogene AGDepartment of Pediatrics, Jahra Hospital, Ministry of HealthDivision of Neurology and Metabolism, Kasr Al Ainy School of Medicine, Cairo University Children HospitalPrince Sultan Military Medical City, PediatricsDivision of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical CorporationDivision of Neurology and Metabolism, Kasr Al Ainy School of Medicine, Cairo University Children HospitalDivision of Neurology and Metabolism, Kasr Al Ainy School of Medicine, Cairo University Children HospitalDivision of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical CorporationDivision of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical CorporationCentogene AGCentogene AGCentogene AGCentogene AGCentogene AGAbstract 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.http://link.springer.com/article/10.1186/s13023-019-1183-5ANTXR2BiomarkerFarber diseaseGenotype-phenotype correlationHyaline fibromatosis syndrome |
| spellingShingle | Claudia Cozma Marina Hovakimyan Marius-Ionuț Iurașcu Nawal Makhseed Laila A. Selim Amal M. Alhashem Tawfeg Ben-Omran Iman G. Mahmoud Nihal M. Al Menabawy Mariam Al-Mureikhi Magi Martin Laura Demuth Zafer Yüksel Christian Beetz Peter Bauer Arndt Rolfs Genetic, clinical and biochemical characterization of a large cohort of patients with hyaline fibromatosis syndrome Orphanet Journal of Rare Diseases ANTXR2 Biomarker Farber disease Genotype-phenotype correlation Hyaline fibromatosis syndrome |
| title | Genetic, clinical and biochemical characterization of a large cohort of patients with hyaline fibromatosis syndrome |
| title_full | Genetic, clinical and biochemical characterization of a large cohort of patients with hyaline fibromatosis syndrome |
| title_fullStr | Genetic, clinical and biochemical characterization of a large cohort of patients with hyaline fibromatosis syndrome |
| title_full_unstemmed | Genetic, clinical and biochemical characterization of a large cohort of patients with hyaline fibromatosis syndrome |
| title_short | Genetic, clinical and biochemical characterization of a large cohort of patients with hyaline fibromatosis syndrome |
| title_sort | genetic clinical and biochemical characterization of a large cohort of patients with hyaline fibromatosis syndrome |
| topic | ANTXR2 Biomarker Farber disease Genotype-phenotype correlation Hyaline fibromatosis syndrome |
| url | http://link.springer.com/article/10.1186/s13023-019-1183-5 |
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