388 distinct mutations have been described in the tnsalp gene. "the tissue nonspecific alkaline phosphatase gene mutations database". archived from the original on 2016-03-04. retrieved 2009-08-14. about 80% of the mutations are missense mutations. the number and diversity of mutations results in highly variable phenotypic expression, and there appears to be a correlation between genotype and phenotype in hypophosphatasia”. mutation analysis is possible and available in 3 laboratories. treatment as of october 2015, asfotase alfa (strensiq) has been approved by the fda for the treatment of hypophosphatasia. some evidence exists to support the use of teriparatide in adult-hpp. current management consists of palliating symptoms, maintaining calcium balance and applying physical, occupational, dental and orthopedic interventions, as necessary. hypercalcemia in infants may require restriction of dietary calcium or administration of calciuretics. this should be done carefully so as not to increase the skeletal demineralization that results from the disease itself. vitamin d sterols and mineral supplements, traditionally used for rickets or osteomalacia, should not be used unless there is a deficiency, as blood levels of calcium ions (ca2+), inorganic phosphate (pi) and vitamin d metabolites usually are not reduced. craniosynostosis, the premature closure of skull sutures, may cause intracranial hypertension and may require neurosurgical intervention to avoid brain damage in infants. bony deformities and fractures are complicated by the lack of mineralization and impaired skeletal growth in these patients. fractures and corrective osteotomies (bone cutting) can heal, but healing may be delayed and require prolonged casting or stabilization with orthopedic hardware. a load-sharing intramedullary nail or rod is the best surgical treatment for complete fractures, symptomatic pseudofractures, and progressive asymptomatic pseudofractures in adult hypophosphatasia patients. dental problems: children particularly benefit from skilled dental care, as early tooth loss can cause malnutrition and inhibit speech development. dentures may ultimately be needed. dentists should carefully monitor patients’ dental hygiene and use prophylactic programs to avoid deteriorating health and periodontal disease. physical impairments and pain: rickets and bone weakness associated with hypophosphatasia can restrict or eliminate ambulation, impair functional endurance, and diminish ability to perform activities of daily living. nonsteroidal anti-inflammatory drugs may improve pain-associated physical impairment and can help improve walking distance bisphosphonate (a pyrophosphate synthetic analog) in one infant had no discernible effect on the skeleton, and the infant’s disease progressed until death at 14 months of age. bone marrow cell transplantation in two severely affected infants produced radiographic and clinical improvement, although the mechanism of efficacy is not fully understood and significant morbidity persisted. enzyme replacement therapy with normal, or alp-rich serum from patients with paget’s bone disease, was not beneficial. phase 2 clinical trials of bone targeted enzyme-replacement therapy for the treatment of hypophosphatasia in infants and juveniles have been completed, and a phase 2 study in adults is ongoing. pyridoxine, or vitamin b6 may be used as adjunctive therapy in some cases, which may be referred to as pyridoxine responsive seizures. history it was discovered initially in 1936 but was fully named and documented by a canadian pediatrician, john campbell rathbun (1915-1972), while examining and treating a baby boy with very low levels of alkaline phosphatase in 1948. the genetic basis of the disease was mapped out only some 40 years later. hypophosphatasia is sometimes called rathbun's syndrome after its principal documenter.