Study Finds Poor Mineralization in Teeth of XLH Children

Study Finds Poor Mineralization in Teeth of XLH Children
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The teeth of children with X-linked hypophosphatemia (XLH) are marked by defects in mineralization affecting the three layers of hard dental tissue — enamel, dentin and cementum — a small study reports.

The study, “Mineralization Defects in the Primary Dentition Associated with X-linked Hypophosphatemic Rickets,” was published in the Journal of the American Society for Bone and Mineral Research.

XLH is caused by mutations in the PHEX gene that provides instructions for making a protein active in bones and teeth. PHEX protein is involved in regulating phosphate, which is an essential mineral for bone formation.

People with XLH have low levels of phosphate in their blood. This leads to skeletal deformities, which include softening and weakening of bones in children (a condition known as rickets) and short stature. Dental abnormalities also are common.

While adequate levels of phosphate are required for teeth formation, just like bones, researchers are still trying to understand how XLH genetics and disease severity leads to dental alterations.

In this study, researchers at the Ohio State University and Nationwide Children’s Hospital analyzed the teeth of six young XLH patients, four girls and two boys, ages 5 to 12.

Mutations in the PHEX gene, all previously unknown, were detected in five of the participants. The sixth child was diagnosed based on clinical presentation and family history, along with biochemical and radiographic findings.

All patients had low phosphate levels (hypophosphatemia) and five had elevated levels of an enyme called alkaline phosphatase (ALP), a marker of active rickets. Bowed legs were present in most patients, and two had knock-knee deformity.

Shortly after diagnosis, all patients were treated with calcitriol (the active form of vitamin D) and oral phosphate. This regimen was kept from four to 10 years, before switching to treatment with Crysvita (burosumab), approved to treat XLH in the U.S. and European Union.

Analysis of dental records in all but one patient showed extensive decay. The two boys in the study had severe dental issues, including teeth extractions or premature loss, abscesses (buildup of pus inside the teeth), and fistulas — usually the result of an infection caused by abscessed gums or teeth.

The researchers went on to use high resolution micro-CT scan to analyze a total of 15 teeth from the six children. The images showed clear signs of interglobular dentin, a result of low mineralization, which is not found in healthy children (controls) matched in age. Dentin is the yellowish tissue that makes up the bulk of all teeth and is immediately underneath enamel, which is the outer covering of the tooth.

Three XLH patients showed enamel density indicative substantial mineralization defects. Also, the mean dentin density was reduced by 10% in the XLH group.

Additional tooth tissues, including mantle dentin (closest to enamel), circumpulpal dentin, which is the other type of primary dentin, and proximal pulp were reduced markedly in their mineral density in XLH patients.

Compared to controls, children with XLH had large predentin, the newly formed dentin before calcification and maturation, with an irregular border. Cementum, the layer of hard dental tissue covering the roots of teeth, was observed in all XLH teeth, but was thinner in two patients.

A quantitative analysis showed a 45-times increase of interglobular dentin and an eight-times increase of predentin thickness in XLH teeth. The mean thickness of cementum was reduced by 50%.

Overall, the findings show “dental mineralization defects associated with XLH, finding a wide range of severity, with dentin more significantly and consistently defective across the spectrum of XLH,” the researchers wrote.

Limitations of the study, they said, include the small number of patients and their variable age.

Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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José holds a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.

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Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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