*3.5.2 Clinical manifestations*

HPP is classified into six forms depending on the onset age and the clinical severity [72]. As shown in **Table 4**, HPP may exhibit perinatal presentation: a severe and possibly fatal infantile form within 6 months of life; milder childhood disease: presenting at childhood or late adolescence as early as 6–24 months; adult disease: a form of odontohypophosphatasia; or a rare benign prenatal form. Among them, odontohypophosphatasia, the least severe form without skeletal ailment, characterized by taurodontism with absence of root cementum. The latter is associated with inadequate/ineffective attachment apparatus of the tooth hence giving raise to premature exfoliation of deciduous teeth (**Figures 17** and **18**).

#### *3.5.3 Diagnosis*

HPP diagnosis is based on clinical manifestations, laboratory assays, and genetic testing. Clinical manifestations and low alkaline phosphatase activity can confirm a diagnosis of HPP [72, 75]:

1.Prominent clinical symptoms of HPP include the following: i) Dental: premature or nontraumatic tooth loss with the root intact; ii) Skeletal: severe hypomineralization, skeletal deformities, craniosynostosis, rachitic chest, rickets, bowing, short stature, osteomalacia, bone pain, frequent fractures; iii) Muscular: muscle weakness, hypotonia, muscular/joint pain, waddling gait, difficulty walking. Other Symptoms may include: i) Respiratory: respiratory insufficiency, respiratory failure; ii) Neurologic: vitamin B6-responsive


*AD, autosomal dominant; AR, autosomal recessive.*

#### **Table 4.**

*Clinical forms of hypophosphatasia (HPP).*

#### **Figure 17.**

*Oral manifestations of a boy at 2- (upper panels)/7-years old (lower panels) with hypophosphatasia (HPP), odontohypophosphatasia form.*

#### **Figure 18.**

*Exfoliated deciduous teeth showing intact root with distinct lack of cementum. Clinical views of the exfoliated mandibular right lateral incisor (tooth 82): the intact root with hypoplasia of the cementum and external apical root resorption (A, B), Cone beam CT image of the tooth 82 (C) with enlargement of the pulp chamber and root canal.*

seizures, increased intracranial pressure; iii) Renal: hypercalciuria, nephrocalcinosis, renal damage; iv) Growth: failure to thrive, delayed or missed motor milestone, short stature.


HPP is often misdiagnosed because its signs and symptoms can overlap with those of other disorders, including nutritional rickets, X-linked hypophosphatemic rickets, and osteogenesis imperfecta. ALP can differentiate HPP from nutritional rickets and other metabolic disorders (**Table 5**).

#### *3.5.4 Treatment*

HPP treatment varies depending on its stage and classification and focus on supportive therapy to minimize disease-related systemic manifestations [72, 75, 77], including: i) Vitamin B6 for seizures in affected patients; ii) Surgery to relieve intracranial pressure or repair fractures, experts recommend managing pseudofractures secondary to hypophosphatasia by internal fixation with a load-bearing
