Dental manifestations in adult hypophosphatasia and their correlation with biomarkers

Abstract

Hypophosphatasia (HPP) is a genetic condition with broad clinical manifestations caused by alkaline phosphatase (ALP) deficiency. Adults with HPP exhibit a wide spectrum of signs and symptoms. Dental manifestations including premature tooth loss are common. Much of the published literature reporting dental manifestations consists of case reports and series of symptomatic patients, likely biased towards more severe dental manifestations. The objective of this study was to systematically explore the dental manifestations among adults with HPP by conducting a comprehensive dental evaluation. To minimize bias, the study explored dental manifestations in an unselected cohort of adults with HPP. Participants were identified searching electronic health record (EHR) data from a rural health system to discover adults with persistent ALP deficiency. Heterozygotes with pathogenic (P), likely pathogenic (LP), or uncertain variants (VUS) in ALPL and at least one elevated ALP substrate were defined as adults with HPP and underwent genetic, dental, oral radiographic, and biomarker evaluation. Twenty-seven participants completed the study. Premature tooth loss was present in 63% (17/27); 19% (5/27) were missing eight or more teeth. Statistically significant associations were found between premature permanent tooth loss and HPP biomarkers ALP (p = 0.049) and bone-specific ALP (p = 0.006). Serum ALP (ρ = -0.43, p = 0.037) and bone-specific ALP (ρ = -0.57, p = 0.004) were negatively correlated with number of teeth lost prematurely. As noted with tooth loss, periodontal breakdown was associated with bone-specific ALP. An inverse association between periodontal breakdown and bone-specific ALP was observed (p = 0.014). These findings suggest a role for ALP in maintenance of dentition.

Keywords: alkaline phosphatase; asfotase alfa; dental; enzyme replacement therapy; hypophosphatasia; periodontal breakdown; tooth loss.

FIGURE 1

Study design. Design of the study illustrating ascertainment, recruitment, and enrollment of participants, study procedures, and relationship between the previously published study (Study 1) and the current study (Study 2). Also shown are data collection and statistical methods employed in the study

FIGURE 2

Relative frequency of number of teeth lost prematurely among HPP participants. Premature tooth loss was present in 63% (N = 17) of HPP patients. Three patients had premature tooth loss but an unknown number of teeth lost

FIGURE 3

Serum ALP was negatively associated with number of teeth lost (Incidence ratio: 0.952, p < 0.001). Participant age was also associated with the number of teeth lost with participants aged 65 and older experiencing more teeth lost independent of serum ALP levels (p = 0.002). The incident rate of tooth loss among participants age 65 and older are 1.82 times the incident rate of younger participants. Estimates are from a Poisson model regressing number of teeth lost on serum ALP and age indicator. Excludes participants with premature tooth loss but unknown number (N = 3)

FIGURE 4

Bone‐specific ALP was negatively associated with number of teeth lost (Incidence ratio: 0.757, p < 0.001). Participant age was also associated with the number of teeth lost with participants aged 65 and older experiencing more teeth lost independent of bone‐specific ALP levels (p = 0.019). The incident rate of tooth loss among participants age 65 and older are 1.59 times the incident rate of younger participants. Estimates are from a Poisson model regressing number of teeth lost on bone‐specific ALP and age indicator. Excludes participants with premature tooth loss but unknown number (N = 3)

FIGURE 5

Participants with periodontal breakdown had significantly lower bone‐specific ALP (p = 0.014) than participants without periodontal breakdown and marginally lower serum ALP (p = 0.091)