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Hypophosphatasia (HPP) is a rare heritable metabolic disorder characterized by defective mineralization of bone and/or teeth in the presence of reduced activity of unfractionated serum alkaline phosphatase (ALP). The clinical spectrum is extremely wide, from stillbirth at one end to fractures of the lower extremities in adulthood, at the other, or even no bone manifestations (odontohypophosphatasia).
ORPHA:436Classification level: Disorder
Exact prevalence and incidence data for hypophosphatasia are not available. The prevalence ofsevere forms of the disease has been estimated to be 1/300,000 births in Europe.
Six different clinical forms of HPP have been described. Prenatal benign hypophosphatasia involves prenatal skeletal manifestations that slowly resolve to become the milder childhood or adult form. Perinatal lethal hypophosphatasia involves significant hypomineralization and leads to hypercalcemia and respiratory insufficiency. Infantile hypophosphatasia is characterized by rickets developing between birth and six months of age. Childhood-onset hypophosphatasia ranges from low bone mineral density with unexplained fractures to rickets. Adult hypophosphatasia involves early loss of adult dentition and stress fractures of the lower extremities in middle age. Lastly, odontohypophosphatasia includes premature exfoliation of primary teeth and/or severe dental caries. Rare cases of infantile hypophosphatasia that have normal serum alkaline phosphatase activity are known as ''pseudohypophosphatasia''.
More than 250 different mutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia. The gene encodes alkaline phosphatase, tissue-nonspecific isozyme (TNSALP) involved in skeletal mineralization.
The diagnosis is based on laboratory testing and molecular genetic testing of the ALPL gene to detect causative mutations. Serum alkaline phosphatase (AP) activity is markedly reduced while urinary phosphoethanolamine (PEA) is increased but these abnormalities are not pathognomonic. Ultrasound is used in prenatal and perinatal forms. Clinical examinations and radiographs help to establish the diagnosis in infantile, childhood and adult forms.
The differential diagnosis includes osteogenesis imperfecta and campomelic dysplasia in early diagnosis, and hypophosphatemic rickets and achondrogenesis in later diagnosis (see these terms).
Prenatal diagnosis can be performed through mutation analysis following chorionic villus sampling.
Perinatal and severe infantile HPP are inherited as autosomal recessive traits. Prenatal benign, moderate infantile, childhood HPP, adult HPP and odontohypophosphatasia can be inherited in an autosomal recessive or autosomal dominant manner, depending on the specific effect the gene mutation has on TNSALP activity. The less severe the disease, the more likely it is dominantly inherited. The range of inheritance patterns partially explains the clinical heterogeneity. In autosomal recessive hypophosphatasia, rare de novo mutations have been reported. In autosomal dominant hypophosphatasia, affected patients may have an affected parent but penetrance appears to be low and de novo mutations have not been reported. HPP displays highly variable expressivity. Genetic counseling is complicated by these factors but should be offered to affected families.
Management and treatment
Supportive symptomatic treatment in childhood and adult forms includes non-steroidal anti-inflammatory drugs (children), teriparatide (adults) and orthopedic management. Dental monitoring and care are essential. Enzyme replacement therapy also plays a role. Bisphosphonates are generally contraindicated in hypophosphatasia.
The perinatal form is almost always fatal within days or weeks. Respiratory complications lead to high mortality rates in the infantile form. Life expectancy is not thought to be affected in the adult form or in odontohypophosphatasia.
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