Hypophosphatasia is a rare, inherited disorder that disrupts the body’s metabolic processes, leading to defective mineralization of the skeleton and teeth. HPP has a wide spectrum of severity, with the most severe forms appearing in infancy and the mildest presenting primarily with dental issues later in life. The estimated incidence of severe forms is approximately one in 100,000 live births.
The Genetic and Metabolic Basis
The root cause of Hypophosphatasia lies in mutations of the ALPL gene, which provides instructions for making the tissue-nonspecific alkaline phosphatase (TNSALP) enzyme. This crucial enzyme is active in the liver, kidney, developing teeth, and the skeleton. Over 400 different variants in the ALPL gene have been identified, and the specific mutation often determines the clinical severity of the disease.
A loss-of-function mutation in ALPL results in a deficiency or complete absence of functional TNSALP enzyme activity. TNSALP is a phosphomonoesterase whose normal role is to remove phosphate groups from various molecules, a process called dephosphorylation. With insufficient enzyme activity, specific molecules that TNSALP would normally break down begin to accumulate in the body.
One of the most important accumulating substrates is inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. Excess PPi prevents the formation of hydroxyapatite crystals, the primary mineral component of bone tissue. This metabolic block leads to the accumulation of unmineralized bone matrix, resulting in rickets in children and osteomalacia in adults. Two other substrates, pyridoxal 5′-phosphate (PLP) and phosphoethanolamine (PEA), also build up, with PLP accumulation potentially contributing to seizures in severe infantile cases.
How Hypophosphatasia Affects the Body
The clinical manifestations of HPP vary significantly, largely depending on the age of onset and the severity of the TNSALP deficiency. The most severe form, perinatal HPP, is often detected before birth or immediately after and is characterized by profound skeletal hypomineralization and short, bowed limbs. This form frequently leads to life-threatening complications like respiratory failure due to underdeveloped lungs and a soft, deformed chest cavity.
Infantile HPP, appearing within the first six months of life, is marked by rickets, failure to gain weight, and soft bones. Infants may also experience craniosynostosis (premature skull bone fusion) and seizures responsive to vitamin B6. Childhood HPP, presenting after six months, ranges in severity and often involves skeletal malformations, delayed motor development, and a waddling gait.
A distinctive feature across many forms is the premature loss of deciduous (baby) teeth, often with the root intact, a condition sometimes classified as odontohypophosphatasia. This dental manifestation can occur in isolation as the mildest form or accompany skeletal symptoms.
Adults with HPP, even those with milder childhood symptoms, often experience chronic musculoskeletal pain, muscle weakness, and recurrent stress fractures or pseudofractures, particularly in the feet and thighs. Accumulation of PPi in the joints can also lead to rheumatologic symptoms like chondrocalcinosis.
Confirming a Diagnosis
A diagnosis of HPP begins with the recognition of characteristic clinical signs, such as unexplained rickets, premature tooth loss, or recurrent stress fractures. The defining laboratory finding is a persistently low level of serum alkaline phosphatase (ALP) activity. Low ALP is a lifelong indicator for patients with HPP, but it is not sufficient on its own to confirm the diagnosis.
To support the diagnosis, specific substrates of the TNSALP enzyme are measured to confirm their elevated levels. Elevated plasma levels of pyridoxal 5′-phosphate (PLP) are a common and sensitive marker for HPP, as PLP is not properly broken down. Elevated levels of phosphoethanolamine (PEA) in the urine may also be detected, though this test is considered less specific than PLP measurement.
The final confirmation of HPP involves genetic testing, which is used to identify a disease-causing mutation in the ALPL gene. Sequencing the ALPL gene can confirm the diagnosis and help determine the inheritance pattern. Genetic analysis is particularly useful because the clinical presentation can overlap with other skeletal disorders, making biochemical and genetic evidence necessary for a definitive conclusion.
Therapeutic and Supportive Care
The primary treatment for the underlying metabolic problem in HPP is enzyme replacement therapy (ERT). This therapy uses a specialized drug, Asfotase alfa (Strensiq), a bone-targeting recombinant form of the TNSALP enzyme. Asfotase alfa is designed to be anchored to the bone surface, where it locally restores the function of the missing enzyme.
This treatment has been shown to improve survival and respiratory function in infants and children with severe forms of HPP. By providing the functional enzyme, ERT helps to decrease the accumulation of PPi, thereby promoting better bone mineralization and reducing skeletal deformities. The therapy has also demonstrated efficacy in improving bone health, reducing pain, and enhancing physical function in adults who had the disease onset in childhood.
Alongside ERT, comprehensive supportive care is necessary to manage the multisystem effects of HPP. This includes pain management, often utilizing nonsteroidal anti-inflammatory drugs (NSAIDs) for musculoskeletal discomfort. Orthopedic interventions may be needed to address fractures, correct skeletal deformities, or manage joint issues. Physical therapy is also important to help maintain muscle strength and improve mobility.