HPP is caused by a deficiency in "tissue non-specific form" of alkaline phosphatase (TNSALP), an enzyme that plays a key role in regulating bone mineralization . Without TNSALP, inorganic pyrophosphate (PPi) accumulates extracellulary and inhibits skeletal mineralization, leading to rickets in pediatric patients or osteomalacia (soft bones) in adults.
The severity of HPP reflects the age at which symptoms first appear and the reduction in TNSALP levels1. The most severe form presents in the perinatal or infantile period, leading to a profound lack of bone mineralization and often compromised respiratory function that can lead to death. Osteomalacia, a debilitating and sometimes progressive complication of HPP, occurs in adults2. Morbidity is cumulative and can worsen with age.
HPP presents itself in remarkably variable ways, ranging from death in utero to relatively simple problems with tooth development. A number of clinical sub-types of the disease have been described based on the age at which skeletal lesions are discovered but HPP spans a great range of disease severity2. However the disease shares common underlying bone pathology (defective mineralization) across all ages.
HPP in the Perinatal Period
- When diagnosed in the perinatal period HPP can be fatal. There is profound skeletal hypomineralization and deformed or shortened limbs.
- These patients suffer increasing respiratory compromise due to rachitic chest disease, which can ultimately lead to respiratory failure and death3.
- Vitamin B6-responsive seizures can occur and may be lethal (vide infra).
- Excessive osteoid may encroach on the marrow space and result in myelophthisic anemia4.
- Stillbirth is common.
HPP in the Infantile Period
- Infants who present with symptoms of HPP in the first 6 months of life1 may experience inadequate weight gain and develop rickets.
- Skulls of severely-affected infants and young children often have large areas of hypomineralized calvarium, creating the illusion of widely "open" fontanels on x-rays when they are actually functionally closed. True premature bony fusion of cranial sutures can lead to frontal bossing, elevated intracranial pressure, and brain damage.
- Rib fractures and rachitic deformity can lead to flail chest and subsequent respiratory compromise and pneumonia.
- Increased levels of calcium in the blood and urine are also common, and may explain the calcium salt deposition in the kidney, renal compromise, and episodes of recurrent vomiting2, 23.
- Mortality is approximately 50% in new patients.
HPP in the Childhood Years
- A hallmark of HPP in children is premature exfoliation of deciduous teeth (before age 5) due to inadequate mineralization of dental cementum, a substance that plays a key role in tooth anchoring.
- Patients may also experience delayed walking, hypermobile joints, and a characteristic waddling gait. Many complain of stiffness and pain and symptoms consistent with nonprogressive myopathy5. Disability can restrict or prevent the patient from being able to walk6.
- Typically, x-rays show rachitic deformities with characteristic bony defects near the ends of major long bones.
- Growth retardation, short stature, fractures, osteomalacia and osteopenia are common.
- Childhood cases of multifocal inflammatory bone lesions have been reported7, 8.
HPP in Adults
- Adult HPP usually presents during middle age9. Frequently, there is a history of mild rickets, premature loss of deciduous teeth, and other dental problems.
- Some adults may only be considered carriers of HPP until they manifest the disease.
- Because their bones are softened, adults with HPP often experience recurrent foot (metatarsal) fractures that heal poorly and cause pain.
- Bilateral femoral pseudofractures can cause discomfort in the thighs or hips. They may remain for years or worsen, but they may not heal until they break completely or receive intramedullary fixation10.
- Some patients suffer from calcium pyrophosphate dihydrate crystal deposition with overt attacks of arthritis (pseudogout)7, 11. They may also suffer articular cartilage degeneration and pyrophosphate arthropathy.
Other Presentations of HPP
- Odontohypophosphatasia is diagnosed when dental disease is the only apparent clinical abnormality. Patients may experience premature exfoliation of their deciduous teeth. Odontohypophosphatasia may explain some cases of early-onset periodontitis .
- Benign in utero HPP is present when bowing of major long bones is seen with sonography in utero, but does not worsen at birth or lead to respiratory compromise. Instead, spontaneous improvement in bony deformities occurs, and patients subsequently experience a milder form of HPP (similar to childhood HPP) 12, 13, 14.