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Peer-reviewedCC BY 4.0Frontiers in Endocrinology

Molecular mechanisms underlying phenotypic overlap and AI-misclassification in rare bone diseases: Insights from SHOX-related signaling pathways in endochondral ossification

  • Isabel Fischer1
  • Sina Bialdiga1
  • Philipp Schmidt1
  • Eike Bolmer2
  • Behnam Javanmardi2
  • Klaus Mohnike1
  • Denny Schanze1
  1. 1Institute of Human Genetics, University Hospital Magdeburg, Otto von Guericke University
  2. 2Institute for Genomic Statistics and Bioinformatics, University of Bonn
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Abstract

The diagnosis of rare bone diseases (RBDs) is challenged by their heterogeneity and rare occurrence. However, correct and timely diagnosis is highly relevant for the best therapeutic outcome of patients. We regarded two AI-approaches developed by the Bone2Gene project that aim to support the diagnostic process by assigning hand radiographs to RBDs. We noticed a predominant misclassification of several RBDs into the group of SHOX -related short stature. To find potential genetic explanations for this overlap, we performed a literature research for SHOX-related signaling in endochondral ossification and connections to the signaling underlying other RBDs. We found that SHOX activates the expression of the structural protein aggrecan (ACAN) and represses FGFR3-induced RAS/RAF/MAPK signaling, displaying signaling connections to ACAN -related growth disorder as well as Hypochondroplasia and Achondroplasia, respectively. Additionally, we conclude that the high phenotypic variety of SHOX -related short stature also contributes to the misclassification of RBDs that do not show a direct connection to SHOX-related signaling. Overall, we deepened our understanding of the occurrence of misclassification in both Bone2Gene approaches. Complemented with genetic testing, Bone2Gene can be a valuable tool in the diagnostic process of RBDs.

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Cite

BibTeXRIS
BibTeX
@article{fischer2026molecular,
  title = {{Molecular mechanisms underlying phenotypic overlap and AI-misclassification in rare bone diseases: Insights from SHOX-related signaling pathways in endochondral ossification}},
  author = {Isabel Fischer and Sina Bialdiga and Philipp Schmidt and Eike Bolmer and Behnam Javanmardi and Klaus Mohnike and Denny Schanze},
  journal = {Frontiers in Endocrinology},
  year = {2026},
  month = nov,
  doi = {10.3389/fendo.2026.1996027},
  url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1996027/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Molecular mechanisms underlying phenotypic overlap and AI-misclassification in rare bone diseases: Insights from SHOX-related signaling pathways in endochondral ossification
AU  - Isabel Fischer
AU  - Sina Bialdiga
AU  - Philipp Schmidt
AU  - Eike Bolmer
AU  - Behnam Javanmardi
AU  - Klaus Mohnike
AU  - Denny Schanze
PY  - 2026
DA  - 2026/11/06
JO  - Frontiers in Endocrinology
DO  - 10.3389/fendo.2026.1996027
UR  - https://www.frontiersin.org/articles/10.3389/fendo.2026.1996027/full
AB  - The diagnosis of rare bone diseases (RBDs) is challenged by their heterogeneity and rare occurrence. However, correct and timely diagnosis is highly relevant for the best therapeutic outcome of patients. We regarded two AI-approaches developed by the Bone2Gene project that aim to support the diagnostic process by assigning hand radiographs to RBDs. We noticed a predominant misclassification of several RBDs into the group of SHOX -related short stature. To find potential genetic explanations for this overlap, we performed a literature research for SHOX-related signaling in endochondral ossification and connections to the signaling underlying other RBDs. We found that SHOX activates the expression of the structural protein aggrecan (ACAN) and represses FGFR3-induced RAS/RAF/MAPK signaling, displaying signaling connections to ACAN -related growth disorder as well as Hypochondroplasia and Achondroplasia, respectively. Additionally, we conclude that the high phenotypic variety of SHOX -related short stature also contributes to the misclassification of RBDs that do not show a direct connection to SHOX-related signaling. Overall, we deepened our understanding of the occurrence of misclassification in both Bone2Gene approaches. Complemented with genetic testing, Bone2Gene can be a valuable tool in the diagnostic process of RBDs.
SN  - 1664-2392
ER  -