Hypophosphatasia 

Initially recognized by Rathbun in 1948, hypophosphatasia is a rare inborn error of metabolism caused by low activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP).^[1] TNSALP is a phosphomonoesterase of 507 residues and is anchored at its carboxyl terminus to the plasma membrane by a phosphatidylinositol-glycan moiety. Alterations in the TNSALP gene lead to rickets, osteomalacia, or both, which characterize this disorder. Incidence has been estimated at 1 per 100,000 births. Clinical presentation widely varies, from death in utero to cases in which pathologic fractures first present only in adulthood.

At least 6 clinical forms of hypophosphatasia have been reported, although form assignment is often challenging. The age when skeletal lesions are discovered determines the type. The types include perinatal (lethal), infantile, childhood, and adult. Two other forms include odontohypophosphatasia (no clinical changes in long bones are present, only biochemical and dental manifestations) and pseudohypophosphatasia. The latter is clinically indistinguishable from infantile hypophosphatasia, because serum alkaline phosphatase (ALP) activity is normal. Pseudohypophosphatasia has been suggested as a possible consequence of a mutant TNSALP gene that still has activity in vitro but not in vivo. Conversely, in these patients, phosphoethanolamine (PEA), inorganic pyrophosphate (PPi), and pyridoxal-5'-phosphate (PLP) levels are elevated in serum and urine despite normal or elevated alkaline phosphatase activity levels.

The different clinical forms have different modes of presentation, history, and inheritance. The most severe forms of the disease have an autosomal recessive mode of inheritance, but the specific pattern of transmission of mild forms is not clear. Analysis of the TNSALP gene aids prenatal diagnosis. In the case of infantile hypophosphatasia, the mutation has been mapped to band 1p36.1-34. Compound heterozygosity in the TNSALP gene may cause childhood and adult hypophosphatasia.

Alkaline phosphatase is present as 4 isomers, each with its own gene locus. Three of these isoforms are tissue specific and are known as germ cell, placental, and intestinal alkaline phosphatase. The fourth isoform, TNSALP, is found in the bone, liver, kidney, and other tissues. The enzyme is physiologically active when in its dimeric form. TNSALP cleaves PLP, PEA, and PPI, which are all extracellular substrates. The TNSALP gene is located on chromosome 1p36.1 and consists of 12 exons distributed over 50 kb. More than 190 distinct mutations have been described for this gene, the vast majority (79%) of which are missense mutations.

Patients with hypophosphatasia have defects in bone mineralization due to TNSALP deficiency. As a consequence, levels of TNSALP substrates (ie, PLP, PPi, PEA) are elevated in serum and urine, and TNSALP activity is reduced.

Frequency

United States

Incidence of the severe form is believed to be approximately 1 case per 100,000 live births.^[2] In some inbred populations, such as Canadian Mennonites, the frequency is as high as 1 case per 2500 newborns.

International

International incidence is unknown.

Mortality/Morbidity

The perinatal form is considered lethal, whereas the infantile form has a mortality rate of 50%. Individuals with the other forms can reach adulthood, although often with increased morbidity. Patients with the childhood form often have rachitic deformities, and those with the adult type may have increased morbidity from poorly healing stress fractures. All patients experience premature loss of dentition.

Race

Hypophosphatasia occurs in all races.

Sex

Males and females are equally affected.

Age

Hypophosphatasia affects all age groups; however, the severity of the disease varies with age, from a very severe disorder in neonates to a mild condition in adults.