The disorder is characterised by spondyloepiphyseal dysplasia, low bone mineral density and cataracts. The team carried out extensive clinical, radiological, biochemical and genetic investigations in a single patient in whom the first diagnostic evaluation had failed to yield an answer. Imaging included conventional X-rays, three-dimensional computed tomography and magnetic resonance imaging, allowing a detailed characterisation of the skeletal abnormalities.

Genetic analysis was performed using whole-exome sequencing on the patient, and the candidate variant was then validated by Sanger sequencing within the family. To assess the functional impact of the variant, the researchers used real-time PCR, comparing gene expression against samples from two healthy donors. The clinical investigations confirmed the characteristic features of Kondo-Fu syndrome: osteopenia, spondyloepiphyseal dysplasia, cataracts and intellectual disability.

But the patient also presented rare congenital anomalies that had not previously been reported in the syndrome, including an os odontoideum, a split atlas and a diaphragmatic hernia. Biochemical analysis added a further layer. The patient showed elevated alkaline phosphatase levels together with decreased high-density lipoprotein and vitamin D levels.

The authors suggest that this pattern could be associated with the observed osteopenia, pointing toward altered bone and mineral metabolism. The genetic investigation itself identified a novel homozygous variant, c.963+2T>A, in MBTPS1. The diagnosis of Kondo-Fu syndrome based on this variant was consistent with the patient's clinical manifestations.

Gene expression analysis demonstrated underexpression of MBTPS1 in the patient, which the researchers interpret as highlighting the deleterious effect of the variant. The authors frame their findings as an expansion of the phenotypic spectrum of Kondo-Fu syndrome, alongside exploratory biochemical findings that may provide preliminary insights into altered bone and mineral metabolism. Because the biochemical observations come from a single patient, they are hypothesis-generating rather than definitive: establishing whether the elevated alkaline phosphatase and reduced vitamin D and HDL pattern is a reproducible feature of the syndrome will require additional patients.

Subject of Research: A novel MBTPS1 splice-site variant and expanded clinical features in a patient with Kondo-Fu syndrome

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

Article References: Najjar, D., Maver, A., Chelly, I., Chikhaoui, A., Boussetta, R., Bouchoucha, S., Peterlin, B., & Yacoub-Youssef, H. (2026). Novel MBTPS1 variant associated with Kondo-Fu syndrome with expanded skeletal manifestations and a distinctive biochemical profile. Frontiers in Endocrinology, 17, Article 1951899. https://doi.org/10.3389/fendo.2026.1951899

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1951899

Keywords: Kondo-Fu syndrome, MBTPS1, splice-site variant, spondyloepiphyseal dysplasia, osteopenia, bone metabolism, whole-exome sequencing, cataracts, vitamin D, alkaline phosphatase, ultra-rare disease, phenotypic expansion