Hypophosphatasia (/ˌhaɪpoʊˈfɒsfeɪtˌeɪʒə/; also called deficiency of alkaline phosphatase, phosphoethanolaminuria,[5] or Rathbun's syndrome;[1] sometimes abbreviated HPP[6]) is a rare, and sometimes fatal, inherited[7] metabolic bone disease.
[8] Clinical symptoms are heterogeneous, ranging from the rapidly fatal, perinatal variant, with profound skeletal hypomineralization, respiratory compromise or vitamin B6 dependent seizures[6] to a milder, progressive osteomalacia later in life.
Tissue non-specific alkaline phosphatase (TNSALP) deficiency in osteoblasts and chondrocytes impairs bone mineralization, leading to rickets or osteomalacia.
[13] One case report details a 35-year old female with low serum ALP and mild pains but no history of rickets, fractures or dental problems.
Profound hypomineralization results in caput membranaceum (a soft calvarium), deformed or shortened limbs during gestation and at birth, and rapid death due to respiratory failure.
Neonates who manage to survive suffer increasing respiratory compromise due to softening of the bones (osteomalacia) and underdeveloped lungs (hypoplastic).
[citation needed] Infantile hypophosphatasia presents in the first 6 months of life, with the onset of poor feeding and inadequate weight gain.
Elevated calcium in the blood (hypercalcemia) and urine (hypercalciuria) are also common, and may explain the renal problems and recurrent vomiting seen in this disease.
[20] Patients may experience delayed walking, a characteristic waddling gait, stiffness and pain, and muscle weakness (especially in the thighs) consistent with nonprogressive myopathy.
In severely-affected infants and young children, cranial bones can fuse prematurely, despite the appearance of open fontanels on radiographic studies.
Radiographs reveal pseudofractures in the lateral cortices of the proximal femora and stress fractures, and patients may experience osteopenia, chondrocalcinosis, features of pyrophosphate arthropathy, and calcific periarthritis.
[22] Odontohypophosphatasia is present when dental disease is the only clinical abnormality, and radiographic and/or histologic studies reveal no evidence of rickets or osteomalacia.
TNSALP hydrolyzes several substances, including mineralization-inhibiting inorganic pyrophosphate (PPi) and pyridoxal 5’-phosphate (PLP), a major form of vitamin B.
[26] Perinatal and infantile hypophosphatasia are inherited as autosomal recessive traits with homozygosity or compound heterozygosity for two defective TNSALP alleles.
The highest incidence of hypophosphatasia has been reported in the Mennonite population in Manitoba, Canada where one in every 25 individuals are considered carriers and one in every 2,500 newborns exhibits severe disease.
[31] Urinary inorganic pyrophosphate (PPi) levels are elevated in most hypophosphatasia patients and, although it remains only a research technique, this increase has been reported to accurately detect carriers of the disease.
[34] Skeletal defects are found in nearly all patients and include hypomineralization, rachitic changes, incomplete vertebrate ossification and, occasionally, lateral bony spurs on the ulnae and fibulae.
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.
Serial radiography studies can reveal the persistence of impaired skeletal mineralization (i.e. rickets), instances of sclerosis, and gradual generalized demineralization.
[35] All clinical sub-types of hypophosphatasia have been traced to genetic mutations in the gene encoding TNSALP, which is localized on chromosome 1p36.1-34 in humans (ALPL; OMIM#171760).
[38][39][40][41] Current management consists of palliating symptoms, maintaining calcium balance and applying physical, occupational, dental and orthopedic interventions, as necessary.
[8] 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.