Hypophosphatasia is a rare and remarkably heterogeneous disease. Given the enormous range of symptoms at presentation, the index of suspicion for HPP may be low for many physicians. Furthermore, since there is no treatment available, HPP patients seek symptomatic relief from multiple specialties dependent on their symptoms (see figure below).
Signs & Symptoms across the Hypophosphatasia Disease Continuum
Clinical Markers/Laboratory Testing
- Alkaline Phosphastase: HPP is characterized by subnormal levels of alkaline phosphatase (ALP) in the blood. Clinicians should suspect HPP if ALP is at or below the lower range of normal. In general, the lower the age-adjusted serum ALP level, the more severe the clinical symptoms of HPP.
- Pyridoxal 5’-phosphate (PLP): Increased PLP level in the blood is the most sensitive substrate marker for HPP, and it often correlates with disease severity.
- Urinary inorganic pyrophosphate (PPi): PPi levels are elevated in most HPP patients and have been reported to accurately detect carriers, although this is typically only used in research.
- Phosphoethanolamine (PEA): Increased levels of PEA are observed in most HPP patients’ urine.
HPP is readily distinguished from other forms of rickets & osteomalacia and other conditions with low levels of alkaline phosphatase (see table below).
Differential Diagnosis of HPP
| HPP | Other Rickets | Hypophosphatasemia | |
| Rickets |  |
|
No |
| Alkaline phosphatase |  |
 |
 |
| Ca/PO4 | Normal/ |
 |
Normal |
| PPi, PLP, PEA | |
Normal | Normal |
| PTH | Normal/ |
|
Normal |
| 25-OH vitamin D | Normal | |
Normal |
| Premature loss of teeth | |
No | No |
Radiography
Despite patient-to-patient variability and the diversity of radiographic findings, the X-ray is diagnostic in perinatal and infantile HPP, and can reveal characteristic abnormalities in childhood.
- Some stillborn skeletons show almost no mineralization; others have marked bony undermineralization and severe rachitic changes; and occasionally, there can be peculiar complete or partial absence of ossification in one or more vertebrae29.
- In the skull, individual membranous bones may calcify only at their centers, making it appear that areas of the unossified calvarium have cranial sutures that are widely separated, when in fact they are functionally closed.
- Tongues of radiolucency often protrude from the metaphyses into the bone shaft.
- In some newly-diagnosed patients, an abrupt transition from relatively normal-appearing diaphyses to uncalcified metaphyses appears suggesting an abrupt metabolic change has occurred.
- Serial radiography studies may reveal the persistence of impaired skeletal mineralization (i.e. rickets), instances of sclerosis and gradual generalized demineralization.
Adults: In adults, x-rays may reveal bilateral femoral pseudofractures in the lateral subtrochanteric diaphysis. These psuedofractures may remain for years or worsen, but they may not heal until they break completely or the patient receives intramedullary fixation30. These patients may also experience recurrent metatarsal fractures.
Genetic Analysis
HPP is caused by mutations in the TNSALP gene, which is localized on chromosome 1p36.1 (ALPL; OMIM#171760). Approximately 204 distinct mutations have been described in the TNSALP gene. An up-to-date list of mutations is available online at www.sesep.uvsq.fr/database_hypo/Mutation.html. About 80% of the mutations are missense mutations. The number and diversity of mutations results in highly variable phenotypic expression30.
Mutation analysis is available in several laboratories (as reported on www.genetests.org).