From Volume 45, Issue 1, January 2018 | Pages 64-70
Hypophosphatasia has a wide clinical spectrum ranging from premature loss of primary teeth to neonatal death. The premature loss of primary teeth in a child with an otherwise unremarkable history may be the first sign of a more significant underlying disease. This report illustrates the role of the dental practitioner in facilitating the diagnosis of hypophosphatasia.
Hypophosphatasia is characterized by a defect in bone and tooth mineralization and a deficiency in bone and serum alkaline phosphatase activity. It is an inborn error of metabolism with a wide clinical spectrum, ranging from premature loss of primary teeth to neonatal death.1 The term ‘hypophosphatasia’ was first used by Rathbun in 1948, who described the case of a young boy who died at two months of age from what appeared to be a severe form of rickets with weight loss and low levels of alkaline phosphatase.2 The prevalence of hypophosphatasia of this severity is estimated to be one in 100,000, based on paediatric hospital records in the USA.3 However, the incidence of moderate forms of hypophosphatasia is largely unknown and expected to be much higher.4
Hypophosphatasia may be expressed through a number of clinical presentations ranging from stillbirth with skeletal hypomineralization to premature loss of teeth in the absence of systemic and/or skeletal abnormalities. There are six recognized clinical forms of hypophosphatasia,4 categorized primarily on the age at the time of diagnosis. These are summarized in Table 1. Previous reports have illustrated a range in clinical presentations for hypophosphatasia with varying inheritance patterns.5,6,7 However, the role of the dental practitioner in diagnosing the condition, particularly in young children, is often less discussed.
| Clinical Form | Inheritance | Bone Symptoms | Dental Symptoms | Clinical Diagnosis |
|---|---|---|---|---|
| Perinatal lethal | AR | Hypomineralization | na | Radiographs |
| Osteochondral spurs | ||||
| Prenatal benign | AD | Bowing of long bones | na | Ultrasonography |
| Benign post-natal | Clinical examination | |||
| Infantile | AR | Craniosynostosis |
Premature loss of deciduous teeth | Clinical examination |
| Rachitic ribs | Radiographs | |||
| Hypercalciuria | ||||
| Childhood | AR (frequent) or |
Short stature |
Premature loss of deciduous teeth | |
| Bone pain/fractures | ||||
| Adult | AR or AD | Stress fractures: metatarsal, tibia |
+/- | |
| Odontohypophosphatasia | AR or AD | Loss of alveolar bone | Exfoliation (incisors) | Clinical examination |
| Reduced thickness of the dentine | Biology (serum AP activity, PEA and PLP) | |||
| Enlarged pulp chambers of teeth | ||||
| Dental caries |
This clinical report demonstrates the importance of a comprehensive dental history and the value of the dental practitioner in initiating the diagnosis of hypophosphatasia.
A general dental practitioner referred a 22-month-old boy to the paediatric dental clinic due to the loss of his mandibular primary anterior teeth. The teeth had shed spontaneously with no history of dental trauma. The two teeth, LRA and LLA, had exfoliated with one being lost at 18 months and the other at the age of 22 months, respectively. The patient was the only child in the family and was born prematurely (31 weeks) with an extra pulmonary artery and a cardiac septal defect at birth that spontaneously closed.
Clinical and radiographic examination confirmed the patient to be in his primary dentition, with teeth LRA and LLA missing, with no other dental abnormalities (Figure 1). Therefore a provisional diagnosis of hypophosphatasia was made and the patient was referred for biochemical testing, which revealed abnormally low levels of serum alkaline phosphatase (Table 2). Subsequently, the patient was diagnosed to have a mild form of hypophosphatasia without any short stature, skeletal deformities, bone pain or skeletal fractures.
| Case Number | Serum alkaline phosphatase (145–420 U/L) | Urine hydroxyproline (60–160 umol/mmol) | Urine phosphoethanolamine (2–17 umol/mmol) |
|---|---|---|---|
| Case 1 | 90 U/L | 223 umol/mmol | 63.3 umol/mmol |
| Case 2 | 90 U/L | 215 umol/mmol | 60.3 umol/mmol |
A general dental practitioner referred a 33-month-old boy to the paediatric dental clinic due to the ‘loss of upper and lower primary teeth’. The patient was fit and healthy with an unremarkable medical history and normal physical proportions. He weighed 16 kilograms (75th percentile), was 103 centimetres tall (90th percentile) and had a head circumference of 51.5 centimetres (75th percentile). The primary teeth had shed spontaneously with no history of dental trauma. The LRA had exfoliated at 18 months of age, followed by the remaining three mandibular incisors (LRB, LLA, LLB) at approximately 24 months of age and the URA exfoliated at 30 months of age (Figure 2).
When investigating his family medical history, his paternal great grandmother had type II diabetes and both his paternal grandparents were hypertensive. The patient's parents had no history of fractures and his mother had scoliosis as a teenager. However, both parents were of otherwise normal stature, none reporting having any dental problems. Notably, the patient's elder brother also experienced early exfoliation of his primary incisor tooth. The patient's mother had been well throughout pregnancy and the patient was born uneventfully at full-term and through normal vaginal delivery weighing 3.15 kilograms.
The patient did not exhibit dolicocephaly or kyphoscoliosis. He did not have skeletal deformities or joint swellings and the development of his hair and nails were normal. Examination of his heart, chest, abdomen, nervous system, along with renal and liver function tests, were all within normal limits. Furthermore, his developmental milestones were unremarkable.
Clinical examination revealed the patient to be in his primary dentition with generalized extrinsic black stains and no clinical evidence of carious lesions (Figure 3). Radiographic investigation found the permanent tooth germs developing appropriate to his chronologic age with no evidence of URA, LLA, LLB, LRA and LRB missing (previously exfoliated) (Figure 4). Therefore, a provisional diagnosis of hypophosphatasia was made and the patient was referred for biochemical testing which revealed low levels of serum alkaline phosphatase (Table 2). Subsequently, the patient was diagnosed with a mild form of hypophosphatasia without any short stature, skeletal deformities, bone pain or skeletal fractures.
Case 3 is a 5-year-old boy, who is an elder sibling of Case 2, with a history of early exfoliation of LLA (exfoliated at 3 years of age). Radiographic investigation revealed missing LLA with no evidence of developing teeth LL4, LL5, LR4, LR5 (Figure 5). Following biochemical testing, he was diagnosed with a mild form of hypophosphatasia, similar to that of his brother.
The cases described in this report exhibited similar characteristics, namely, premature exfoliation of unresorbed primary teeth, elevated levels of urine phosphoethanolamine, and lower levels of serum alkaline phosphatase levels. This facilitated the diagnosis to be a mild form of hypophosphatasia with no associated skeletal abnormalities.
Brittain and co-workers suggested the term of odonto-hypophosphatasia to describe mild cases of hypophosphatasia in which premature exfoliation of primary teeth was the main clinical manifestation.8 It has been proposed that both odonto-hypophosphatasia and hypophosphatasia are the same genetic condition represented as varying phenotypes related to gene dosage.9 Cheung suggested that it may be more appropriate to refer to the conditions as hypophosphatasia with or without premature exfoliation of teeth.10 Although previous studies have suggested an association with severe dental caries, due to hypercalcaemia resulting in a poor appetite and eating problems,11 this association was not observed in the patients described in this report.12,13,14 Conversely, the presence of extrinsic black staining was found in Case 2. Previous studies have suggested a correlation with similar extrinsic staining and a low caries experience in children.15
Total serum alkaline phosphate is markedly reduced in hypophosphatasia, as illustrated in the present clinical reports and this is the major indicator for hypophosphatasia. Serum alkaline phosphatase levels may also be tested via gingival crevicular fluid, as described by Chapple et al.16 Notably, the serum alkaline phosphatase level could be only slightly lower than normal, or even within the normal range, and several tests may be necessary for accurate assessment. An elevated concentration of phosphoethanolamine in the urine is the secondary indicator for hypophosphatasia. Furthermore, an increased pyridoxal 5’-phosphate is a definitive and more sensitive marker for diagnosing hypophosphatasia.
Biochemical testing does not always distinguish hypophosphatasia from other skeletal diseases, such as osteogenesis imperfecta, rickets and achondrogenesis. In observing the premature exfoliation of a primary tooth, it is crucial to consider and investigate for other differential diagnoses, such as Papillon-Lefėvre syndrome, Chediak-Higashi syndrome, Ehlers-Danlos syndrome, Langerhans' cell histiocytosis, neutropenia, leukemia, trauma, self-inflicted injury and localized aggressive periodontitis. A flowchart to guide the dental practitioner in facilitating the diagnosis of hypophosphatasia is illustrated in Figure 6.
Alternatively, screening for mutations in the tissue non-specific alkaline phosphatase gene may assist in confirming the diagnosis of hypophosphatasia. Genomic sequencing may detect approximately 95% of mutations in a severe case of hypophosphatasia. However, patients with milder forms often carry only one mutated allele, which is likely due to heterozygous expression of the disease.7
A common diagnostic feature of hypophosphatasia is the premature loss of primary teeth, usually before the age of 3, particularly in the mandibular incisor region. These primary teeth exfoliate spontaneously with their roots intact and minimal or no cementum present.17 The first sign is often tooth mobility, which leads the patient and his/her family to seek dental advice. Therefore, the dental practitioner is frequently one of the first healthcare professionals to identify and facilitate the diagnosis of hypophosphatasia following appropriate investigation, particularly in young children.11
Literature on the longer-term consequences of hypophosphatasia remains equivocal. Reduced alveolar bone support, abnormal root resorption and premature loss of permanent teeth have all been reported as long-term consequences of hypophosphatasia.18 In this report, only Case 3 demonstrates hypodontia in the permanent dentition as well as premature loss of primary teeth. Given the young age at the time of diagnosis, the long-term consequences on the permanent dentition may be under reported. Therefore, long-term follow-up of these cases is required.
The prosthetic replacement of primary teeth in young children is not often undertaken due to the possibility of interfering with growth and development of the dental arches. However, treatment options to replace the missing permanent teeth are usually recommended. The options include fixed or partial prostheses or dental implants, with or without orthodontic therapy.
When performing restorative treatment in patients with hypophosphatasia, the increased size of the pulp chamber must be considered to avoid inadvertent pulp exposure.19 Dental abnormalities, such as bulbous crowns with cervical constriction, wide pulp chambers, taurodontism, short roots, enamel defects and altered eruption of teeth, may also be present and should be investigated.11
Several authors have also described an association between hypophosphatasia and periodontitis.20,21,22 Hypophosphatasia commonly affects the cementum and periodontal ligament rather than the quality of the alveolar bone. The use of dental implants to replace lost teeth is a viable option. Lynch and co-workers reported on the long-term success of dental implants in a young adult with hypophosphatasia.23 Nevertheless, a multidisciplinary approach, with both short- and long-term treatment options, is advisable to meet the specific needs of the patient.
The cases described in this report illustrate the role of the dental practitioner in facilitating the diagnosis of hypophosphatasia. Therefore, a sound knowledge of the physiologic norms and variations in developing children is essential to identify such otherwise unnoticed conditions. Nevertheless, the premature loss of primary teeth in a child with an otherwise unremarkable history may be the first sign of a more significant underlying disease. Children with hypophosphatasia require regular review for the maintenance of good oral hygiene and the establishment of preventive regimens to minimize periodontal risk factors. The cases presented in this report exhibit milder forms of hypophosphatasia which may lead to difficulties in diagnosis and it is possible that many similar cases may have been overlooked and consequently have either been misdiagnosed or never been diagnosed.
