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Hypophosphatasia – Three Case Studies

January 1, 2011
by Carla Cohn, DMD


Hypophosphatasia is not a new entity, it was first recognized by Rathburn in 1948.1 It is also not a common disorder, however, it is an important one for any dentist who treats children to be able to recognize. In keeping with the paradigm shift of early prevention and establishment of a dental home by the age of 12 months, it is more crucial than ever to recall the oral signs that are consistent with a diagnosis of hypophosphatasia. By seeing children for their first dental examination by the age of one year, it is even more likely that the dentist will be the first health professional to be able to diagnose a disorder such as hypophosphatasia. Hypophosphatasia is an inherited metabolic disorder that affects the mineralization of bone and teeth in the presence of low activity of serum and bone alkaline phosphatase. It has a wide and variable range of symptoms associated with it. One of the very first expressions of the disorder may be the premature loss of primary teeth. It is imperative to include hypophosphatasia in the list of differential diagnoses when a patient presents with a premature loss.

Hypophosphatasia is a rare metabolic disorder that involves a mutation in the gene that codes for tissue-nonspecific alkaline phosphatase. A deficiency of alkaline phosphatase leads to an increase in inorganic pyrophosphate, which is a mineralization inhibitor.2 Deposition of minerals such as calcium and phosphate are affected as well, as there is a reduced entry into the skeleton. As a result, there is defective bone and cementum mineralization. This is believed to be the source of the dental changes that are seen in hypophosphatasia. Dental changes mainly affect the primary dentition. These changes may include hypoplasia of the cementum, irregular calcification of the dentin, enlarged pulpal chambers and decreased alveolar bone height.3 A more recent theory suggests that although cementum is hypoplastic the actual resorption of the cementum occurs because of bacterial assault.4

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Hypophosphatasia is highly variable in it’s expression and can range from severe to mild. The age when diagnosis is made as well as the severity of the cases are a determinant of the clinical form. Six clinical forms are currently recognized: perinatal (lethal), perinatal benign, infantile, childhood, adult and odontohypophos­phatasia.5

All forms of hypophosphatasia, with the exception of the perinatal lethal form, experience premature loss of dentition. Severe forms of hypophosphatasia are seen in approximately 1 in 100,000 births. Milder cases are more common. Hypophosphatasia has been found in an increased frequency in children of Mennonite heritage in Manitoba, Canada where it has been reported in one in 2500 births.

Oral Clinical Signs of Hypophosphatasia
Oral clinical signs and symptoms of hypophosphatasia include the premature loss of primary teeth with or without a history of mild trauma.6,11 Radiographically we see enlarged pulp chambers and decreased alveolar bone height Histologically teeth are characterized by a lack of cementum.6,7,11

Laboratory Testing
Laboratory testing calls for blood and urine analysis to confirm all types of hypophosphatasia. Blood analysis is required to measure serum alkaline phosphatase (ALP). Urine analysis is required to measure phosphoethanolamine (PEA). Serum alkaline phosphatase (ALP) activity is markedly reduced in hypophosphatasia, while urinary phosphoethanolamine (PEA) is increased.12 Blood and urinalysis results are indistinguishable between mild forms of hypophosphatasia and odontohypophosphatasia.8-10 It is important to note that laboratory levels vary with age and gender and that higher levels are seen in children undergoing a growth spurt and in pregnant women.13 A study examining the root surfaces of teeth from children with or without periodontal diseases and with or without systemic diseases revealed that teeth from children with hypophosphatasia showed cementum aplasia.14 It has been found that not only the cementum, but also the dentin were affected in hypophosphatasia patients. The dental pulp cells were influenced in hypophosphatasia patients by the NSALP (nonspecific alkaline phosphatase) expression and may be related to the tooth calcification defect.15

Differential Diagnosis Premature Loss of Primary Teeth
Differential diagnoses of premature loss of primary teeth include, but are not limited to benign and malignant neoplasms, nutritional deficiencies, osteomyelitis, juvenile onset diabetes mellitus, peripheral blood leukocyte abnormalities, acrodynia, hystiocytosis x, Papillon Lefevre syndrome, hypophosphatasia and prepubertal periodontitis.1 The most common causes of premature loss of primary teeth are hypophosphatasia and prepubertal periodontitis. They are also the most difficult to distinguish without laboratory testing.16

Case Study #1
DD, a male child age 2 years and 11 months presented to the office for investigation of premature loss of his primary teeth. His medical history is unremarkable. Family history is unremarkable as well. He has two healthy parents and a healthy sister. His mother is of German Mennonite descent and his father is of French Canadian back ground. DD had one instance of hospitalization for a hernia repair at the age of 1 year. He is a healthy looking child within normal growth parameters. His development is normal for a child of his age. The patient had some mild trauma when he collided with a door at age 2 years and 7 months. Two months post trauma tooth #81, primary lower right central incisor, was extracted due to extensive mobility. Within one month tooth # 73, primary lower left canine, exfoliated spontaneously and was reported to have been swallowed by the patient. DD’s parents were distraught at the loss of these teeth and were searching for an explanation. They were suspicious that such a mild trauma could lead to loss of two teeth and the subsequent mobility of other anterior teeth.

Upon clinical examination the primary two central incisors, teeth #51 and #61, displayed class I mobility. The primary central lower left incisor, tooth # 71, displayed class II mobility. Clinically, DD’s anterior teeth have a “splayed ” appearance. Tooth #71 measured 3mm recession on the labial aspect.

Radiographic examination revealed reduce alveolar bone height in the anterior mandibular and maxillary regions. A large defect was evident surrounding tooth # 61. Posterior radiographs revealed very large pulp chambers on the mandibular molars in particular (Figure 1).

The exfoliated teeth were sent for microscopic examination. This examination revealed the decalcified specimens to consist of serial longitudinal and cross sections exhibiting wide pulp chambers, wide peripulpal and submantel globular type dentin, lack of cementum and evidence of external root resorption. There was evidence of bacterial colonization in the resorption lacunae.These microscopic features together with the clinical features supported the diagnosis of hypophosphatasia. Laboratory results for the blood analysis revealed a low level of alkaline phosphatase, but unremarkable phosphoethanolamine in the urine analysis. Later through genetic counseling it was confirmed that this patient is a carrier of hypophosphatasia. DD has been followed closely with 3 month intervals of recall / re-examination appointments. Mobility testing is carried out at each recall as well as caries assessment.

Due to the hypocalcification of the teeth as well as the enlarged pulp chambers it is of utmost importance to treat any incipiencies immediately and to provide prevention as called for.

Case Study # 2
KD is the younger sister of patient in case study #1. Her medical history had been unremarkable as w
ell. She presented to the office at the age of 2 years and 7 months. Clinically, upon examination teeth # 51 and # 61, primary maxillary central incisors, displaying class I mobility, # 71, primary left central mandibular incisor, rotated with 1 mm gingival recession (Figure 2). At 2 years and 10 months # 61 exfoliated and she has since tested positive for hypophosphatasia.

Case Study # 3
PB, a healthy female child presented to the office at the age of 1 year and 3 months. The child presented to the office with her mother. There were no concerns from the mother and she was presenting for a “well-child” examination. Examination was done in a lap-to-lap fashion. PB was not co-operative for the examination however it was evident that her 2 lower anterior incisors were splayed. The position of these teeth clinically was very unusual for a child of this age. Upon clinical examination teeth #71 and # 81 had a class III mobility, gingival recession and gingival inflammation. Tooth # 71 exfoliated 3 weeks after initial appointment and was sent for laboratory testing (Figure 3). Radiographic examination was not possible due to the patients age and thus co-operation. Microscopic testing revealed a decalcified incisor exhibiting vital pulp, dysplastic dentin and an absence of cementum. Blood analysis revealed a marked decrease in alkaline phosphatase and urine analysis revealed a increase in phosphoethanolamine. All findings were consistent with hypophosphatasia (Figure 3).

Conclusion
The above case studies reinforce the importance of the children’s dentist in the diagnosis of this condition. Premature loss of primary teeth may be the first sign or symptom of the disease, particularly in the milder types of the disease. Familiarity with hypophosphatasia is important for all dentists who treat children in their practices.  OH

Dr. Cohn graduated from the Faculty of Dentistry at the University of Manitoba in 1991. She then went on to complete a post-graduate internship in Children’s Dentistry at Health Science Centre Children’s Hospital in Winnipeg, MB. In addition to private practice, Dr. Cohn has surgical privileges at Western Surgery Centre, a private surgical clinic. She is a clinical instructor, part-time, in the department of Preventive Sciences at the University of Manitoba. Dr. Cohn has lectured on risk assessment, prevention, behaviour management and restorative treatment options.

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References
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