Hypophosphatasia, often abbreviated as HPP, is a rare, inherited metabolic bone disorder that significantly impacts the body’s ability to mineralize bones and teeth. The root cause of this condition is a genetic defect that leads to insufficient activity of the tissue-nonspecific alkaline phosphatase (TNSALP) enzyme. This enzyme is necessary for the proper hardening of the skeleton, and its deficiency results in a wide spectrum of health issues, from severe skeletal malformations to premature tooth loss. The life expectancy for an individual with HPP varies drastically, depending almost entirely on the age at which symptoms first appear and the subsequent severity of the disease presentation.
Understanding the Spectrum of HPP Severity
The prognosis for an individual with HPP is directly tied to the timing and intensity of the first clinical manifestations, which allows for classification into distinct forms. The most severe form is Perinatal HPP, where symptoms are evident before or immediately after birth, often involving profound skeletal hypomineralization. Infants with this classification frequently experience complications such as rib fractures and respiratory compromise, making it historically the most lethal form.
A slightly less severe, but still life-threatening, form is Infantile HPP, which manifests before six months of age with failure to thrive, rickets, and poor feeding. Even some severe cases show a “benign” prenatal course, where initial skeletal signs improve after birth, leading to a milder outcome.
Childhood HPP, with onset after six months, presents with variable severity, typically involving premature loss of baby teeth and skeletal deformities like bowed legs. The mildest forms, Adult HPP and Odontohypophosphatasia, often feature only chronic musculoskeletal pain, stress fractures, or dental issues, and usually carry a normal life expectancy.
Historical Life Expectancy and Prognosis
Before the development of modern therapeutic options, the outlook for patients with the severe, early-onset forms of HPP was grim. Historically, the perinatal and infantile classifications were associated with mortality rates ranging from 50% to 100%, with the majority of deaths occurring within the first year of life. This poor prognosis was predominantly a result of respiratory failure.
The profound lack of mineralization in the rib cage created a soft, unstable chest wall, often referred to as a rachitic chest. This deformity prevented the lungs from fully expanding, leading to pulmonary hypoplasia and recurrent respiratory infections. For historical control patients with severe HPP, the median survival time was only 8.9 months, with a 58% probability of death by the age of one year.
The Impact of Enzyme Replacement Therapy on Survival
The landscape of HPP prognosis changed dramatically with the introduction of enzyme replacement therapy (ERT) using asfotase alfa (Strensiq). This treatment is a bone-targeted recombinant human TNSALP enzyme designed to replace the missing or defective alkaline phosphatase. It works by delivering the functional enzyme directly to the bone surface, thereby promoting the necessary mineralization process.
Clinical trials have shown that ERT significantly improves survival rates for patients with the previously life-threatening perinatal and infantile forms. For those treated with asfotase alfa, the survival rate increased to 95% at age one year, compared to 42% in historical control groups. This improvement was sustained, with treated patients showing an 84% survival rate at five years of age, compared to only 27% for untreated controls.
The benefit of ERT extends beyond survival, specifically addressing the respiratory complications that were once the primary cause of death. Among patients who required mechanical ventilation, 76% of those treated survived, allowing many to be successfully weaned off respiratory support. This functional improvement is linked to radiographic evidence of improved skeletal mineralization, particularly in the ribs, which stabilizes the chest wall and supports lung function. The effectiveness of ERT means many children who would have died in infancy are now surviving into childhood and adolescence.
Factors Influencing Long-Term Outcomes and Quality of Life
While ERT has revolutionized survival for severe HPP, the focus is now on managing the long-term morbidity and quality of life for survivors. Individuals who received ERT may still experience residual skeletal deformities and chronic pain that require ongoing orthopedic management. The chronic nature of the disease necessitates continuous attention to musculoskeletal health.
Mobility issues, muscle weakness, and joint pain remain common complaints in pediatric-onset HPP patients who reach adulthood. Premature tooth loss, or odontohypophosphatasia, is a near-universal feature and requires specialized dental care throughout the patient’s life. Continuous management is needed to maintain gains in physical function and pain scores achieved through ERT. The transition from pediatric specialists to adult care providers is complex, emphasizing the need for a multidisciplinary team approach to address persistent skeletal, dental, and neurological challenges.