Dental Defects Associated with Biallelic Mutations in ALPL and Hypophosphatasia

Objectives: ALPL encodes tissue-nonspecific alkaline phosphatase (TNAP), an enzyme expressed primarily in bones, teeth, liver, and kidney. ALPL loss-of-function mutations cause hypophosphatasia (HPP), an inborn error-of-metabolism that produces skeletal and dental mineralization defects. HPP can affect all dental hard tissues: enamel, dentin, and cementum. However, case reports to date use widely varying criteria and rely on descriptive observations, making it unclear how dental defects correlate to genetic mutations, biochemical effects, and skeletal severity. We hypothesized that all dental mineralized tissues would exhibit effects of HPP and aimed to establish quantitative measurements of dental tissues in this HPP subject.
Methods: A female child (proband) was diagnosed with HPP based on compound heterozygous ALPL mutations (exon 5: c.346G>A, p.A116T; exon 10: c.1077C>G, p.I359M). Dental effects in the primary dentition were analyzed by radiography, high-resolution micro-CT, and histology.
Results: Primary teeth from the proband were exfoliated prematurely, reflecting defective cementum attachment, and exhibited greater remaining root structure vs. controls. Cementum was not detectable by micro-CT analysis, likely due to reduced thickness and/or density. Enamel density and thickness were not adversely affected by HPP; however, density variation was greater vs. control teeth. HPP teeth featured decreased crown dentin density, but no difference in root dentin density compared to controls. Surprisingly, analysis of the mantle dentin layer revealed 20% decreased density in HPP teeth vs. controls, despite no differences in circumpulpal or proximal pulpal dentin density. Histology of HPP teeth supported micro-CT results, revealing altered mantle dentin, little to no cementum, and also an unusual accumulation of plaque on root surfaces.
Conclusions: In a subject with novel biallelic ALPL mutations, premature tooth exfoliation, increased root length, lack of functional cementum, and crown dentin mineralization defects were identified. The characterization of novel mantle dentin defects provides new insights into the dental pathology in HPP.