Dental Defects Associated with Clinical Subtypes of Pediatric Hypophosphatasia (HPP)

Objectives: Hypophosphatasia (HPP) is the heritable mineralization disorder caused by mutations in the ALPL gene and featuring insufficient activity of the tissue-nonspecific isozyme of alkaline phosphatase (TNAP). HPP clinical subtypes range from life-threatening in infancy to milder forms that manifest skeletal disease later or affect primarily the dentition. Premature loss of primary teeth due to cementum defects occurs across all HPP subtypes, however, other dental defects in enamel and dentin are sometimes inconsistently reported. We quantified HPP effects on dental tissues and correlated these to clinical subtypes.
Methods: Primary teeth from children with infantile, mild/severe childhood, or odonto-HPP (20 teeth from 9 subjects) were analyzed by high resolution micro-CT and histology and compared with healthy control teeth. Dentoalveolar tissues from the Alpl knockout (Alpl^-/-) mouse model of severe infantile HPP were contrasted to wild-type (WT) controls.
Results: Root length was substantially longer in HPP vs. control teeth, reflecting premature exfoliation and attachment defects. Micro-CT indicated lack of mineralized cementum on HPP teeth from all subtypes. Enamel thickness and density were affected only in severe infantile HPP. Crown and root dentin thickness decreased in proportion to HPP clinical severity and serum ALP levels. Overall dentin density was unaffected by HPP, however further analysis revealed outer mantle dentin density was substantially decreased across all HPP subtypes. Alpl^-/- mice featured significant reductions in both enamel and dentin volumes vs. WT (15% p<0.01; 20% p<0.001, respectively), also exhibiting lack of cementum, periodontal detachment, and reduced alveolar bone density (7% p<0.0001).
Conclusions: Our study for the first time quantified by microCT the impact of clinical subtypes of HPP on dental mineralized tissues, identifying trends in enamel and dentin mineralization defects reflecting the severity of HPP clinical subtypes. The Alpl^-/- mouse also showed enamel and dentin effects from severe HPP, as well as periodontal defects.