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Key Points

  • Rare hereditary metabolic bone disorder characterized by deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP).

  • Incidence is 1 in 100,000 births in most ethnic groups but 1 in 2500 in Canadian Mennonites.

  • Two forms present perinatally: severe (lethal) and benign, which resolves spontaneously.

  • In the severe form sonographic findings include increased nuchal translucency measurement, undermineralized skull, shortened, bent, fixed limbs with decreased echogenicity, and lack of ossification of vertebral bodies, neural arches, and hands. The benign perinatal form presents with symmetric bowing of long bones.

  • Differential diagnosis includes anencephaly, osteogenesis imperfecta types II and III, thanatophoric dysplasia, campomelic dysplasia, achondrogenesis, and cleidocranial dysplasia.

  • Amniocentesis should be offered to rule out anencephaly, confirm fetal karyotype, assay alkaline phosphatase activity, and check for DNA mutation(s).

  • Causative gene is TNSALP.

  • Severe form is recessively inherited with two mutations. Milder form is dominantly inherited with one mutation.

  • Genetic consultation and counseling are indicated.


The term hypophosphatasia was first used by Rathbun in 1948 to describe an infant with severe rickets and very low alkaline phosphatase activity in serum and tissues (Henthorn and Whyte, 1992; Whyte et al., 1995). Hypophosphatasia is a rare inherited metabolic bone disorder characterized by deficient activity of the liver/bone/kidney isoenzyme of alkaline phosphatase. This isoenzyme is also known as the tissue-nonspecific form of alkaline phosphatase (TNSALP).

Alkaline phosphatase was first discovered in 1923, when Robert Robinson noted a large amount of phosphatase activity within ossifying bone and cartilage in rats and rabbits. He was the first to suggest that this catalytic action was important for mineralization of the skeleton due to hydrolysis of a phosphate ester, which would result in the local increase of inorganic (free) phosphate (Whyte, 1994). He subsequently showed that the enzyme functioned optimally at a distinctly alkaline pH, although he never specifically used the term alkaline phosphatase. Later, alkaline phosphatase was also demonstrated in tissues that normally do not mineralize, such as the liver, intestines, and placenta; thus, the role of alkaline phosphatase in skeletal mineralization was questioned. It is now known that at least four distinct genes encode four different human alkaline phosphatase isoenzymes. The TNSALP liver bone kidney form is especially rich in mineralizing bone. The location of this gene is on the short arm of chromosome 1, band p36.1-34 (Henthorn and Whyte, 1992; Whyte et al., 1995). The other three genes are found in a cluster on the end of the long arm of chromosome 2. These include pla-cental, intestinal, and placental-like isoenzymes of alkaline phosphatase. Each of the alkaline phosphatase genes have now been sequenced, and the TNSALP gene is the largest of the four (Whyte, 1994).

Hypophosphatasia is a clinically variable condition. Mutations in the TNSALP gene are responsible for perinatal hypophosphatasia, in which the severity of the disease usually ...

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