Hypophosphatasia (ORPHA:436)
A rare, genetic metabolic disorder characterized by reduced activity of unfractionated serum alkaline phosphatase (ALP) and various symptoms from life-threatening, severely impaired mineralization at birth to musculo-skeletal pain in adulthood.
Epidemiology
Exact prevalence and incidence data for hypophosphatasia (HPP) are not available. In North and West Europe, the birth prevalence of severe forms of the disease (perinatal lethal and infantile forms) has been estimated to be 1/300 000. Because of possible dominant autosomal inheritance, moderate forms of HPP are expected to be more frequent and are estimated to have a prevalence of 1/6300.
Clinical description
Six different clinical forms of HPP have been described, although there is a continuum of severity. Perinatal lethal HPP involves significant hypomineralization and leads to hypercalcemia and respiratory insufficiency. Prenatal benign HPP involves prenatal skeletal manifestations that slowly resolve to become non-lethal. Infantile HPP is characterized by rickets developing between birth and six months of age. Childhood HPP ranges from low bone mineral density with unexplained fractures to rickets. Adult HPP involves early loss of adult dentition and stress fractures of the lower extremities in middle age. In the mildest form, adults may present with only unspecific signs like musculo-skeletal pain or osteoporosis. Lastly, odontoHPP includes premature exfoliation of primary teeth and/or severe dental caries.
Etiology
More than 400 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.
Diagnostic methods
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 5'pyridoxal phosphate (PLP) in blood and urinary phosphoethanolamine (PEA) are increased but the latter is 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.
Differential diagnosis
In the prenatal context, the differential diagnosis includes osteogenesis imperfecta, campomelic dysplasia, hypophosphatemic rickets and achondrogenesis. The main differential diagnosis in other forms is osteogenesis imperfecta.
Antenatal diagnosis
Prenatal diagnosis can be performed through mutation analysis following chorionic villus sampling.
Genetic counseling
Perinatal and severe infantile HPP are typically 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 both autosomal recessive and dominant hypophosphatasia, de novo mutations are exceptional. In autosomal dominant hypophosphatasia, affected patients may have an affected parent but penetrance appears to be low. 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. Since its availability, enzyme replacement therapy plays an increasing role, especially in pediatric severe forms.
Prognosis
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 childhood and adult forms or in odontohypophosphatasia.

                            Last update: 
                            February 2020


                            - Expert reviewer(s): 
                            Dr Severine BACROT  - Dr Etienne MORNET