Hypophosphatasia (HPP)

Updated: Jun 05, 2023
  • Author: Ricardo R Correa Marquez, MD, EsD, FACP, FACE, FAPCR, CMQ, ABDA, FACHT; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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Hypophosphatasia (HPP) is a multisystem disease with deleterious effects that can appear at different ages and progress over time. In adults, the symptoms of HPP are often misdiagnosed and confused with other, more common, bone or rheumatologic diseases, leading to delayed diagnosis and inappropriate treatment, such as high-dose vitamin D supplementation, excessive calcium supplementation, and bisphosphonates that could be ineffective or even worsen the symptoms. [1] Patients presenting with abnormal bone features should undergo alkaline phosphatase and vitamin B6 testing to rule out this diagnosis.

Initially recognized by Rathbun in 1948, HPP is a rare inborn error of metabolism caused by mutations in the ALPL gene located on chromosome 1 (1p36.1) and consists of 12 exons distributed over 50 kb, encoding tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). [2] TNSALP is an ectoenzyme bound to the outer surface of osteoblasts. TNSALP is a phosphomonoesterase of 507 residues and is anchored at its carboxyl terminus to the plasma membrane by a phosphatidylinositol-glycan moiety. It dephosphorylates several substrates, including inorganic pyrophosphate (PPi), which inhibits bone mineralization produced by osteoblasts and chondrocytes. Accumulation of PPi when TNSALP is deficient impairs calcium/phosphate formation of hydroxyapatite, leading to accumulation of unmineralized osteoid (a feature of rickets and osteomalacia). [3, 4]

The clinical presentation of hypophosphatasia varies from devastating prenatal intrauterine disease to mild manifestations in adulthood. Six clinical forms have been identified: perinatal, prenatal benign (with spontaneous improvement of skeletal defects despite prenatal signs of disease), infantile, juvenile, adult form, and odontohypophosphatasia (no clinical changes in long bones, only biochemical and dental manifestations). [5]

Another condition, pseudohypophosphatasia, is clinically indistinguishable from infantile hypophosphatasia, but 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.

Patients may present with varying signs and symptoms, history, and inheritance patterns. The most severe forms of the disease have an autosomal recessive mode of inheritance, but the specific pattern of transmission of mild forms is variable. Analysis of the TNSALP gene aids prenatal diagnosis. Compound heterozygosity and autosomal dominant mutations in the TNSALP gene may cause childhood and adult hypophosphatasia. At least 2 mutations occur in specific populations and are lethal when homozygous: c.1559delT affects Japanese patients and gly317asp is found in a Canadian Mennonite population.



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 is known to cleave the phosphate-containing substrates PLP, PEA, and PPi, which are all extracellular substrates.

Patients with hypophosphatasia have low alkaline phosphatase activity levels, which leads to increased PPi, an inhibitor of hydroxyapatite crystal formation. The increase in PPi causes defects in calcium and phosphate balance.




United States

The exact prevalence of HPP is unknown and varies by form and region. [6, 7] In the United States, it affects approximately 500-600 individuals per year. In some inbred populations, such as Canadian Mennonites, the frequency is as high as 1 case per 2500 newborns. More than 250 distinct mutations have been described for the gene responsible for HPP, the vast majority (79%) of which are missense mutations.


International incidence is unknown. It appears that the disease is more prevalent in Japan and in a specific Mennonite population in Canada.


The most severe forms of HPP tend to occur before birth and in early infancy. Hypophosphatasia weakens and softens the bones, causing skeletal abnormalities similar to those of another childhood bone disorder called rickets. Affected infants are born with short limbs, an abnormally shaped chest, and soft skull bones. Additional complications in infancy include poor feeding and failure to gain weight, respiratory problems, and high levels of calcium in the blood (hypercalcemia), which can lead to recurrent vomiting and kidney problems. These complications are life-threatening in some cases. The mortality rate in infants with hypophosphatasia is 50% in patients who manifest within 6 months of birth. The most common cause of death in infants with hypophosphatasia is respiratory complications.

The forms of hypophosphatasia that appear in childhood or adulthood are typically less severe than those that appear in infancy. Early loss of primary (baby) teeth is one of the first signs of HPP in children. Affected children may have short stature with bowed legs or knock knees, enlarged wrist and ankle joints, and an abnormal skull shape. Adult forms of hypophosphatasia are characterized by a softening of the bones, known as osteomalacia. In adults, recurrent fractures of the feet and thigh bones can lead to chronic pain. Affected adults may lose their secondary (adult) teeth prematurely and are at increased risk for joint pain and inflammation. Patients may also present with nephrocalcinosis, neurologic damage secondary to vitamin B6 respondent seizures, increased intracranial pressure secondary to craniosynostosis, and joint problems secondary to calcium deposits. Adults may present with severe mobility impairment (about 23% require the use of a wheelchair; about 25% require the use of a walking device). On the other side of the spectrum, adults may be diagnosed incidentally after a low alkaline phosphatase level is detected.

The mildest form of HPP, called odontohypophosphatasia, affects only the teeth. People with this disorder typically experience abnormal tooth development and premature tooth loss but do not have the skeletal abnormalities seen in other forms of hypophosphatasia. [8]


Hypophosphatasia occurs in all races.


Males and females are equally affected.


Hypophosphatasia affects all age groups; however, the severity of the disease in general varies with age, from a lethal disorder in neonates to a less severe condition in some adults. Most cases are diagnosed during childhood and adolescence.



The most severe form is perinatal HPP, which is considered lethal in most cases. The infantile form is fatal in approximately 30% of patients. Longevity studies have not been conducted for the infantile and childhood forms. Individuals with the adult and odontohypophosphatasic forms have normal lifespans.


Patient Education

Genetic counseling is important for all families with affected individuals. A pedigree is essential, especially for the childhood, adult, or odontohypophosphatasic forms, which can have either autosomal dominant or recessive forms. Options for future pregnancies, such as prenatal testing for the perinatal form, should be discussed with parents.