Centogene AG, Am Strande 7, 18057, Rostock, Germany.
Department of Pediatrics, Jahra Hospital, Ministry of Health, Jahra City, Kuwait.
Orphanet J Rare Dis. 2019 Aug 27;14(1):209. doi: 10.1186/s13023-019-1183-5.
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.
玻璃样纤维瘤综合征（HFS）是一种罕见的临床病症，其特征是 ANTXR2 的双等位基因变异与细胞外玻璃样沉积物有关。它表现为多个皮肤结节、斑片状色素沉着过度、关节挛缩和运动时严重疼痛。HFS 与法伯病（FD）有一些临床表现上的重叠，FD 是一种隐性溶酶体贮积症。
我们在此报告了迄今为止报道的最大的一组独立的、经基因证实的 HFS 病例：在 19 名无关联的索引患者中，我们鉴定出了十个不同的纯合 ANTXR2 突变，其中三个是新的移码变异。相关的临床数据与之前的假设一致，即非截断变异位于末端外显子 13-17 中，导致相对较轻的表型。我们的研究队列中存在性别依赖性疾病表现的新观察结果得到了所有以前发表的病例的荟萃分析的支持。非靶向性基于血液的代谢组学分析显示，患者样本在生化上与对照样本不同。因此，可以鉴定出许多潜在的 HFS 生物标志物代谢物。我们还发现 HFS 患者的代谢组学图谱与 FD 患者的高度重叠。
我们的研究扩展了 HFS 的突变谱，提示了表现的性别依赖性，并提供了代谢组学数据的初步结果，用于生物标志物的鉴定和更好地了解该疾病的发病机制。
