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 correlates with the age of onset of symptoms. Fetuses detected in utero generally have the most severe form of hypophosphatasia, also known as the perinatal lethal form. Findings in this condition include profound undermineralization of the skeleton, lack of skull ossification resulting in a caput membraneceum, and shortened deformed limbs. Postnatal survival of affected infants is limited because of associated pulmonary hypoplasia and rachitic disease of the chest. Radiographic studies in the newborn are diagnostic. The infantile form of hypophosphatasia presents before the age of 6 months. The newborn can initially appear normal, but poor feeding subsequently develops, as do inadequate weight gain and symptoms of rickets. Additional problems include the development of craniosynostosis, increased intracranial pressure, hypercalcemia, renal failure, and seizures. Approximately 50% of affected infants die. The childhood form is variable in its clinical expression. It is characterized by premature loss of the deciduous teeth at an age of less than 5 years, resulting from abnormalities of the dental cementum, which is important for connection between the tooth roots and the periodontal ligament (Whyte, 1994). Affected children also have short stature, rickets, deformation of the legs, knees, ankles, and wrists, although some of these improve with age. Affected patients have characteristic abnormalities on radiographs, which include focal bony defects near the ends of the major long bones. These manifest as a tonguelike shape of radiolucency that projects from the growth plate into the metaphysis (Whyte, 1994). The adult form of hypophosphatasia generally presents during middle age. A childhood history of rickets or premature loss of deciduous teeth may or may not be present. In general, affected adults enjoy relatively good health as adolescents and young adults, but then develop recurrent metatarsal stress fractures and early loss of permanent teeth. The mildest form of hypophosphatasia is called “odontohypophosphatasia,” which is reserved for patients whose only clinical manifestation is dental disease. Most recently, it has become appreciated that there is another mild form that presents in fetal life with severe symmetric long bone bowing that resolves spontaneously (Moore et al., 1999; Pauli et al., 1999; Comstock et al., 2005). No absolute diagnostic criteria exist for the separation of the various clinical presentations. A continuous spectrum of symptoms exists. This chapter will focus on the two forms that present in the antenatal period.

The incidence of hypophosphatasia, based on data from Toronto, is 1 in 100,000 livebirths (Mulivor et al., 1978; Greenberg et al., 1990). Cases of hypophosphatasia have been described throughout the world, occurring in all races (Whyte, 1994). During the years 1977 to 1986, six neonates affected with hypophosphatasia were born in southern Manitoba. After these infants were identified, it was appreciated that Mennonites in southern Canada have a 1 in 25 chance of being a carrier for at least one mutation in the TNSALP gene. The birth incidence of affected infants with hypophosphatasia in Mennonites is 1 in 2500 (Chodirker et al., 1990). This unusually high incidence is presumably due to a founder effect with inbreeding.

The most striking abnormality described in cases of the severe form of perinatal hypophosphatasia is the absence of a normally formed fetal skull (Kousseff and Mulivor, 1981). The hallmarks for sonographic diagnosis of hypophosphatasia include a fetus that is small for gestational age with decreased echogenicity of the bones, a prominent falx cerebri due to undermineralization of the skull, various skeletal deformities, and the presence of polyhydramnios occurring later in gestation (Wladimiroff et al., 1985). Also, pulmonary hypoplasia may be documented as a result of a severely reduced thoracic volume due to abnormal and short ribs. In one report, Van Dongen et al. (1990) described sonographic studies performed in a family with a previously affected child. Even as early as 8 weeks of gestation, the crown-to-rump length was suggestive of a fetus 1.5 weeks younger than the actual gestational age. The family was lost to follow-up until 24 weeks of gestation, when severe polyhydramnios was noted. Other findings included an active fetus with shortened, bent, fixed limbs with markedly decreased echogenicity, which prevented separate visualization of the fingers and toes (Figure 98-1A and 98-1B). The falx cerebri and other central nervous system structures could be distinguished unusually clearly due to the low echogenicity of the skull bones (Figure 98-2A and 98-2B). This was described as being similar to the fetal appearance in hydrocephalus. In another report of prenatal diagnosis in a family at risk for recurrence of hypophosphatasia, the failure to outline a fetal head was noted at 16 weeks of gestation (Rudd et al., 1976). The skull was described as a very thin, faint circular outline. In addition, skip defects were noted in the cervical spine vertebral bodies.

In another case, with a negative family history, but a conception marked by consanguinity, underossification of the skull, facial bones, ribs, and limbs was noted at 27 weeks of gestation (DeLange and Rouse, 1990). In addition, underossification of the metacarpals, neural arches of the spine, and vertebral bodies was present. This group made a presumptive prenatal diagnosis of hypophosphatasia based on (1) the generalized underossification of the fetal bones, (2) shortening of the limbs, and (3) lack of ossification of groups of vertebral bodies, the neural arches, and the hands.