Adult-onset hypophosphatasia diagnosed after consecutive tooth loss during orthodontic treatment: a case report

Abstract

Background

Adult hypophosphatasia is an uncommon inherited disorder of mineral homeostasis affecting bone. It arises from mutations within the Alkaline Phosphatase, Biomineralization Associated (ALPL) gene, which encodes tissue-nonspecific alkaline phosphatase. Because of its low prevalence and non-specific clinical manifestations, underdiagnosis and misdiagnosis are frequent, particularly in Asian populations.

Case presentation

We present a case of a 38-year-old Japanese male diagnosed with adult hypophosphatasia following consecutive tooth loss during orthodontic treatment. Genetic analysis revealed a compound heterozygous mutation within the ALPL gene. The patient remained asymptomatic until orthodontic treatment, suggesting that increased mechanical stress overwhelmed residual enzyme activity, triggering the hypophosphatasia symptoms. Asfotase Alfa enzyme replacement therapy improved healing following tooth extraction.

Conclusion

This case highlights the significance of including adult hypophosphatasia in the differential diagnosis for obscure dental complications arising during orthodontic procedures, particularly in Asian patients where certain ALPL variants may be more prevalent. Effective diagnosis and management of adult hypophosphatasia necessitate collaboration between orthodontic practitioners and medical specialists. Improved awareness and a multidisciplinary approach are crucial for timely diagnosis and successful intervention.

Background

Hypophosphatasia (HPP) is a rare inherited metabolic bone disorder characterized by impaired mineralization owing to mutations in the Alkaline Phosphatase, Biomineralization Associated (ALPL) gene, encoding tissue-nonspecific alkaline phosphatase (TNSALP) [1]. HPP manifests in a spectrum of clinical presentations, categorized by age of onset and severity: perinatal, infantile, childhood, adult-onset, and odontohypophosphatasia (odonto-HPP) [2]. Adult-onset HPP presents a diagnostic challenge owing to its rarity and non-specific symptoms, such as bone fractures, muscle pain, and tooth loss, which are generally milder than those observed in childhood-onset HPP [3]. Consequently, adult-onset HPP is often overlooked, leading to delayed diagnosis and treatment. The reported incidence of severe HPP varies geographically, ranging from 1/100,000 to 1/300,000 in North America and Europe [4], and approximately 1/900,000 in Japan, including milder forms [5]. These figures likely underestimate the true prevalence owing to undiagnosed mild cases.

Over 400 mutations in the ALPL gene have been linked to HPP [6]. These mutations vary in type and location, impacting the degree of enzyme activity reduction and the severity of clinical manifestations [7]. Identifying the specific mutation is crucial for accurate diagnosis, prognosis, and genetic counseling. HPP inheritance follows an autosomal recessive or autosomal dominant pattern, with some autosomal dominant ALPL mutations exhibiting a dominant-negative effect [6].

Enzyme replacement therapy is the primary treatment for HPP. Asfotase Alfa (recombinant human TNSALP) administration aims to restore alkaline phosphatase (ALP) activity, improve bone mineralization, and alleviate systemic symptoms [8]. While the efficacy of Asfotase Alfa in treating pediatric HPP is well-established [9], evidence for its impact on adult-onset HPP is limited. However, studies suggest potential benefits in managing HPP across all age groups, including those with pediatric-onset disease [10]. Further research is necessary to determine the long-term efficacy and safety of Asfotase Alfa in adult-onset HPP.

Dentistry plays a growing role in recognizing HPP, as premature tooth loss and periodontal disease are frequent manifestations [11]. Dental procedures can be instrumental in prompting an HPP diagnosis [12]. Dentists should be vigilant for potential HPP cases to ensure timely diagnosis and appropriate interventions. The hallmark dental feature of HPP is early exfoliation of primary teeth owing to disrupted cementum formation, primarily affecting the anterior teeth [6]. Additional dental findings include enamel and dentin hypoplasia, reduced dentin thickness, enlarged pulp chambers, thin and short roots, and dental caries [6].

Previous case reports have documented various dental manifestations of adult-onset HPP, including premature tooth loss, periodontal disease, and atypical tooth morphology [13, 14]. Mori et al. [12], reported a case series of four adult patients with a history of early primary tooth loss who were subsequently diagnosed with HPP, highlighting the importance of considering HPP in adults presenting with dental abnormalities. Bloch-Zupan et al. [11], emphasized the dentist’s role in diagnosing mild HPP forms, where dental signs may be the sole manifestation.

A recent nationwide survey in Japan revealed significant differences in genetic and dental presentations between odonto-HPP and non-odonto HPP [15]. Early primary tooth exfoliation was observed in all patients with odonto-HPP, while tooth hypomineralization was more prevalent in non-odonto types. The study also documented cases of odonto-HPP progressing to childhood-type HPP with the emergence of skeletal symptoms, underlining the importance of monitoring patients with milder presentations [15].

Diagnosing adult-onset HPP remains challenging owing to the potential for mild and non-specific signs and symptoms [16]. The absence of standardized diagnostic guidelines further complicates the process [16]. A recent systematic review by Brandi et al. [16], proposed a framework for diagnosing adult HPP on the basis of expert consensus, incorporating four major and five minor diagnostic criteria. This approach holds promise for standardizing the diagnostic approach.

The present case report describes an adult patient with HPP diagnosed following consecutive tooth loss during orthodontic treatment. The rarity and variable presentation of adult-onset HPP emphasize the need for its inclusion in the differential diagnosis for patients with unexplained dental complications, particularly during orthodontic therapy. We aim to raise awareness among dental professionals regarding the oral manifestations of HPP and the importance of a multidisciplinary approach in managing this condition. Additionally, this case highlights the value of genetic testing in confirming the HPP diagnosis and guiding treatment decisions. The case adheres to the CARE guidelines for case reports [17].

Case presentation

Patient information

A 38-year-old Japanese man presented with a chief complaint of progressive tooth movement and loss, accompanied by persistent left thigh pain and numbness. He was referred to the Department of Oral and Maxillofacial Functional Rehabilitation at Ryukyu University Hospital, Okinawa, Japan, in 2020 for comprehensive evaluation and treatment.

The patient had a history of limb deformities noted at birth, initially suggestive of osteogenesis imperfecta. However, further evaluation ceased after age 4, with no documented history of early tooth loss or unusual permanent tooth eruption.

The patient’s dental history revealed the extraction of the lower left second molar in 2008 owing to mobility. Orthodontic treatment, initiated in 2010, revealed a missing lower left second molar on panoramic radiographs (Fig. 1). Subsequently, the patient experienced sequential loss of the right upper second molar, left lower first premolar, left lower second premolar, left lower first molar, and right lower first molar. He also experienced knee pain in 2015–2016, which was managed conservatively by a local orthopedic surgeon. Notably, there was no history of fractures.

Fig. 1

Pretreatment panoramic radiograph. A panoramic radiograph obtained at orthodontic treatment initiation (2010) reveals the absence of the lower left second molar

In 2019, the patient developed persistent left thigh pain and numbness. Treatment by the local orthopedic surgeon failed to resolve the symptoms. The patient had a medical history of controlled hypertension diagnosed at age 26 years, managed with oral amlodipine besylate at 10 mg once daily. He was also diagnosed with suspected glucose intolerance and asymptomatic proteinuria. No family history of short stature or bone dysplasia was reported.

Upon examination, the patient was of short stature (height: 152.3 cm, arm length: 140 cm) with short limbs, but in good general health, with normal grip strength (right: 19.9 kg, left: 20.7 kg). The patient had an asymmetrical face with no maxillary or mandibular bone abnormalities. Intraoral examination revealed missing teeth and a collapsed crown of the remaining right upper first premolar. Additionally, the right mandibular incisor to the left mandibular canine displayed mobility and required interdental wire fixation. The orthodontic appliances were canted owing to a 3 mm rightward deviation of the maxillary and mandibular midline (Fig. 2A and B).

Fig. 2

Pretreatment intraoral photographs and panoramic radiograph. A Intraoral photographs of the dentition show a collapsed crown of the right maxillary first premolar. Mobility is evident in the right mandibular incisor to the left mandibular canine, necessitating interdental wire fixation (red arrow). The orthodontic appliances are canted owing to a 3 mm rightward midline discrepancy. B The mandibular arch photograph highlights missing teeth and the interdental wire fixation. C A panoramic radiograph demonstrates extensive defects in multiple teeth. The remaining root of the right maxillary first premolar is visible. Horizontal alveolar bone resorption is observed from the right mandibular incisor to the left mandibular canine

Investigations

Panoramic radiographs showed extensive defects in multiple teeth (Fig. 2C), with the remaining root of the right upper first premolar visible. Horizontal bone resorption was observed in the alveolar bone from the right mandibular incisor to the left mandibular canine. Bone scintigraphy showed no significant abnormal bone accumulation throughout the body. Blood biochemistry tests revealed low levels of ALP (20.3 U/L; The International Federation of Clinical Chemistry and Laboratory Medicine), calcium (9.4 mg/dl), and inorganic phosphorus (3.8 mg/dl), with elevated phosphoethanolamine (451.2 μmol/g).

Confirmation of diagnosis, treatment, and follow-up

Given the patient’s clinical presentation, biochemical findings, and the onset of progressive tooth movement and loss following orthodontic treatment initiation, HPP was suspected as the most likely diagnosis. The mechanical stress from orthodontics may have overwhelmed the residual enzyme activity, triggering the manifestation of HPP symptoms as reported previously [18]. To confirm the diagnosis, genetic testing was performed, revealing compound heterozygous mutations (c.550C > T and p.F327L) in the ALPL gene, leading to the definitive diagnosis of adult-onset HPP.

Following the diagnosis of HPP, the patient commenced enzyme replacement therapy with asfotase alfa (80 mg subcutaneously, thrice weekly) in April 2021. Then, 10 months after initiating asfotase alfa treatment, the retained root of the right upper first premolar was extracted. The post-extraction healing process and bone volume restoration were satisfactory (Fig. 3A–C). The patient continues to be monitored with periodic intraoral examinations and radiography.

Fig. 3

Post-treatment panoramic radiograph and intraoral photographs. A A panoramic radiograph obtained in February 2022, 10 months after initiating asfotase alfa treatment, reveals the healing post-extraction site of the right maxillary first premolar (black arrow). B, C Intraoral photographs of the dentition demonstrate satisfactory healing and restoration of bone volume at the extraction site (white arrow)

Discussion and conclusions

This case report describes a 38-year-old male with adult-onset HPP diagnosed following consecutive permanent tooth loss during orthodontic therapy. Despite limb deformities present since birth, the absence of early dental complications and a negative family history contributed to the delayed diagnosis. The present case exemplifies the diagnostic challenges associated with adult-onset HPP owing to its often milder presentation compared with childhood-onset forms [3]. Moreover, similar to a report by Högler et al. [19], it emphasizes the role of dentists in suspecting HPP during dental interventions.

Our case suggests that the proximity of orthodontic treatment initiation to symptom onset points to a possible association between mechanical stress and HPP manifestation. Orthodontic forces are known to induce bone remodeling and alter the local cellular environment [18, 20]. In individuals with compromised TNSALP function, as seen in HPP, increased mechanical stress may overwhelm the already diminished capacity for bone mineralization and remodeling [18]. This could exacerbate existing dental and skeletal abnormalities or unmask previously subclinical HPP. Further investigation is warranted to elucidate the potential role of orthodontic treatment in triggering or exacerbating HPP symptoms.

Genetic analysis revealed a compound heterozygous mutation in the ALPL gene (c.550C > T and p.F327L). The c.550C > T mutation exhibits a dominant-negative effect [21], while p.F327L leads to moderately reduced enzyme activity [14, 22]. This combination explains the adult-onset presentation. Remarkably, the patient remained asymptomatic until orthodontic treatment, suggesting that residual enzyme activity was initially sufficient to prevent symptoms. The case highlights the phenotypic variability associated with HPP, where individuals with similar genotypes may exhibit childhood bone symptoms [23] or remain asymptomatic until adulthood [24]. These observations underscore the complex interplay between genotype and phenotype. The patient’s genetic profile aligns with findings by Mornet et al. [25], suggesting that compound heterozygosity involving severe and moderate alleles can cause mild HPP.

Dental complications in HPP include premature tooth loss, shortened roots, and inadequate alveolar bone calcification [25], often accompanied by rapid periodontal disease progression [26]. Our patient experienced multiple permanent tooth losses and significant horizontal alveolar bone resorption after orthodontic treatment initiation. These observations emphasize the importance of careful treatment planning and close monitoring for HPP patients undergoing dental procedures. Favorable healing was observed following tooth extraction 10 months into Asfotase Alfa treatment. Asfotase Alfa promotes bone and tooth calcification by increasing ALP levels [27]. Whereas the effectiveness in pediatric HPP is well-established, evidence for its impact on adult-onset HPP is limited. The accelerated alveolar bone healing in this patient suggests potential benefits, highlighting the need for further research on the optimal timing and duration of treatment for HPP-related dental issues. These findings are consistent with Okawa et al. [28] who reported improved tooth and mandibular bone mineralization in a child with HPP treated with Asfotase Alfa.

A recent review by Brandi et al. [16] highlights that the prognosis and long-term management of adult-onset HPP depend on disease severity and individual treatment response. Patients with milder forms may have a better prognosis but still require close dental monitoring. Regular dental check-ups, periodontal assessments, and preventive measures are crucial to minimize tooth loss and other complications. Enzyme replacement therapy with Asfotase Alfa may be necessary in severe cases to improve bone mineralization and dental health [16]. Additionally, orthognathic surgery and other interventions may be considered for patients with significant skeletal or dental abnormalities [16]. A multidisciplinary approach involving dentists, orthodontists, and medical specialists is essential for optimal management of adult-onset HPP, as emphasized by the recently published consensus guidelines [16].

In summary, this case report underscores the importance of considering HPP in the differential diagnosis of unexplained dental complications, particularly during orthodontic treatment. The rarity and variable presentation of adult-onset HPP necessitate a high index of suspicion and a multidisciplinary approach for timely diagnosis and effective management. Further research is needed to elucidate the potential link between orthodontic treatment and HPP, and to develop evidence-based guidelines for the diagnosis, treatment, and monitoring of adult-onset HPP. The proposed diagnostic criteria by Brandi et al. [16] hold promise for standardizing the diagnostic approach and facilitating earlier recognition of this condition.