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Peer-reviewedCC BY 4.0Frontiers in Endocrinology

Novel MBTPS1 variant associated with Kondo-Fu syndrome with expanded skeletal manifestations and a distinctive biochemical profile

  • Dorra Najjar1
  • Aleš Maver2
  • Imen Chelly3,4
  • Asma Chikhaoui1
  • Rim Boussetta1,5
  • Sami Bouchoucha5
  • Borut Peterlin2
  • Houda Yacoub-Youssef1
5 affiliations
  1. 1Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, Tunis El Manar University
  2. 2Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana
  3. 3Department of Paediatrics, Habib Bougatfa Hospital
  4. 4Faculty of Medicine in Tunis, LR99ES10 Laboratory of Human Genetics, University of Tunis El Manar
  5. 5Department of Pediatric Orthopedic Surgery, Bechir Hamza Children’s Hospital, Faculty of Medicine of Tunis, Tunis El Manar University
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Abstract

Introduction: Kondo-Fu syndrome is an ultra-rare genetic disorder caused by variants in the MBTPS1 gene, which plays a key role in lysosomal function and skeletal homeostasis. Clinical presentation is characterized by spondyloepiphyseal dysplasia, low bone mineral density, and cataracts. This study aimed to expand the clinical spectrum by describing distinctive phenotypic features and highlighting novel genetic findings and biochemical alterations relevant to bone metabolism.

Methods: We conducted extensive clinical, radiological (X-ray, 3D-CT scan, MRI), biochemical, and genetic investigations in a patient with Kondo-Fu syndrome in whom initial diagnostic evaluation was inconclusive. Whole-exome sequencing was performed on the proband, and the candidate variant was validated by Sanger sequencing in the family. We further evaluated its functional impact using real-time PCR, compared to two healthy donors.

Results: Clinical investigations revealed the characteristic clinical features of Kondo-Fu syndrome, including osteopenia, spondyloepiphyseal dysplasia, cataracts, and intellectual disability. Furthermore, the patient presented previously unreported rare congenital anomalies, including os odontoideum, split atlas, and diaphragmatic hernia. Biochemical analysis revealed elevated alkaline phosphatase levels and decreased high-density lipoprotein and vitamin D levels, which could be associated with osteopenia and suggest altered bone and mineral metabolism. Genetic investigation revealed a novel homozygous variant, c.963 + 2T>A, in MBTPS1 , leading to the diagnosis of Kondo-Fu syndrome, which was consistent with the patient’s clinical manifestations. Gene expression analysis demonstrated the under expression of MBTPS1 , highlighting the deleterious effect of this variant.

Conclusions: This study identifies a novel variant underlying Kondo-Fu syndrome and reveals previously unreported phenotypic features alongside exploratory biochemical findings that may provide preliminary insights into altered bone and mineral metabolism.

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Cite

BibTeXRIS
BibTeX
@article{najjar2026novel,
  title = {{Novel MBTPS1 variant associated with Kondo-Fu syndrome with expanded skeletal manifestations and a distinctive biochemical profile}},
  author = {Dorra Najjar and Aleš Maver and Imen Chelly and Asma Chikhaoui and Rim Boussetta and Sami Bouchoucha and Borut Peterlin and Houda Yacoub-Youssef},
  journal = {Frontiers in Endocrinology},
  year = {2026},
  month = oct,
  doi = {10.3389/fendo.2026.1951899},
  url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1951899/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Novel MBTPS1 variant associated with Kondo-Fu syndrome with expanded skeletal manifestations and a distinctive biochemical profile
AU  - Dorra Najjar
AU  - Aleš Maver
AU  - Imen Chelly
AU  - Asma Chikhaoui
AU  - Rim Boussetta
AU  - Sami Bouchoucha
AU  - Borut Peterlin
AU  - Houda Yacoub-Youssef
PY  - 2026
DA  - 2026/10/27
JO  - Frontiers in Endocrinology
DO  - 10.3389/fendo.2026.1951899
UR  - https://www.frontiersin.org/articles/10.3389/fendo.2026.1951899/full
AB  - Introduction: Kondo-Fu syndrome is an ultra-rare genetic disorder caused by variants in the MBTPS1 gene, which plays a key role in lysosomal function and skeletal homeostasis. Clinical presentation is characterized by spondyloepiphyseal dysplasia, low bone mineral density, and cataracts. This study aimed to expand the clinical spectrum by describing distinctive phenotypic features and highlighting novel genetic findings and biochemical alterations relevant to bone metabolism.  Methods: We conducted extensive clinical, radiological (X-ray, 3D-CT scan, MRI), biochemical, and genetic investigations in a patient with Kondo-Fu syndrome in whom initial diagnostic evaluation was inconclusive. Whole-exome sequencing was performed on the proband, and the candidate variant was validated by Sanger sequencing in the family. We further evaluated its functional impact using real-time PCR, compared to two healthy donors.  Results: Clinical investigations revealed the characteristic clinical features of Kondo-Fu syndrome, including osteopenia, spondyloepiphyseal dysplasia, cataracts, and intellectual disability. Furthermore, the patient presented previously unreported rare congenital anomalies, including os odontoideum, split atlas, and diaphragmatic hernia. Biochemical analysis revealed elevated alkaline phosphatase levels and decreased high-density lipoprotein and vitamin D levels, which could be associated with osteopenia and suggest altered bone and mineral metabolism. Genetic investigation revealed a novel homozygous variant, c.963 + 2T>A, in MBTPS1 , leading to the diagnosis of Kondo-Fu syndrome, which was consistent with the patient’s clinical manifestations. Gene expression analysis demonstrated the under expression of MBTPS1 , highlighting the deleterious effect of this variant.  Conclusions: This study identifies a novel variant underlying Kondo-Fu syndrome and reveals previously unreported phenotypic features alongside exploratory biochemical findings that may provide preliminary insights into altered bone and mineral metabolism.
SN  - 1664-2392
ER  -