A rare, inherited, and sometimes fatal metabolic bone disease characterized by poor bone mineralization and profound skeletal defects.Hypophosphatasia is a rare and remarkably A variation in composition, quality, or structure.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 Regulates certain intracellular functions and extracellular crystal formation.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 A softening of bones in children leading to fractures and deformity, which is predominantly caused by a vitamin D deficiency.rickets & The adult form of rickets, which is a softening of the bones caused by defective bone mineralization.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 The process of bone formation.ossification in one or more vertebrae29.
- In the skull, individual A bone that forms directly within membranous connective tissue without previous cartilage formation. Examples include the clavicle and bones of the skull.membranous bones may calcify only at their centers, making it appear that areas of the unossified calvarium have A type of fibrous joint that resides between bones in the skull.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 The main section (shaft) of a long bone.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 The organized structure of DNA and proteins found in the cell nucleus. Chromosomes come in pairs, and a normal human cell contains 46 chromosomes.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 A mutation in which a single base change results in the insertion of a different amino acid, giving rise to an altered protein.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).