Hypophosphatasia (HPP) is a rare, inherited metabolic disorder that directly impacts the strength and development of bones and teeth. It is characterized by defective mineralization, the process where calcium and phosphorus are deposited into the skeletal structure to make it rigid and strong. This genetic condition causes bones to become soft, leading to fragility, deformity, and a range of clinical issues depending on the age of onset. The severity of HPP exists on a broad spectrum, ranging from a life-threatening form evident before or shortly after birth to a milder type presenting only as premature tooth loss in adulthood.
The Role of Alkaline Phosphatase Deficiency
The underlying cause of Hypophosphatasia is a mutation in the ALPL gene, which provides instructions for making an enzyme called tissue-nonspecific alkaline phosphatase (TNSALP). This enzyme is normally found on the surface of bone-forming cells, known as osteoblasts, and cartilage cells. When the ALPL gene is defective, the body produces TNSALP that is either insufficient or ineffective, leading to a profound deficiency of alkaline phosphatase activity in the blood and bone.
The primary function of TNSALP is to break down certain molecules that inhibit mineralization. Specifically, the enzyme hydrolyzes inorganic pyrophosphate (PPi), a potent inhibitor of calcium phosphate crystal formation. When TNSALP is deficient, PPi builds up in the extracellular space, effectively blocking the formation of hydroxyapatite crystals necessary for bone hardening.
The accumulation of PPi prevents the proper deposition of minerals, resulting in soft, weak bones, a condition known as rickets in children and osteomalacia in adults. Another substrate that accumulates is pyridoxal 5′-phosphate (PLP), a form of Vitamin B6. Severe forms of HPP are inherited in an autosomal recessive pattern, while milder forms can follow either an autosomal recessive or autosomal dominant pattern.
Recognizing the Signs of Hypophosphatasia
The signs of Hypophosphatasia are highly variable, with clinical presentation determined by the age at which symptoms first appear and the severity of the enzyme deficiency. The most severe manifestation is the perinatal form, which often presents before birth with profound skeletal under-mineralization, sometimes resulting in stillbirth or death shortly after birth due to respiratory failure. In the infantile form, symptoms appear within the first six months of life, including poor feeding, failure to gain weight, and skeletal deformities that can cause breathing difficulties.
The childhood form typically surfaces after six months of age, often characterized by mobility issues, a waddling gait, and bone deformities like bowed legs. A hallmark symptom across multiple age groups is the premature loss of primary (baby) teeth, often with the root intact, which can occur before five years of age. Children may also experience bone and joint pain, muscle weakness, and delayed motor skills.
In adults, HPP may not be diagnosed until middle age. Adult-onset HPP is characterized by chronic bone pain, recurrent stress fractures—especially in the feet and thighs—and osteomalacia. Adults may also experience the premature loss of their permanent teeth and joint issues like chondrocalcinosis, where calcium deposits form in the cartilage.
Establishing a Diagnosis
The initial step in diagnosing Hypophosphatasia is a blood test that measures serum alkaline phosphatase (ALP) activity. A persistently low ALP level for the patient’s age and sex is the primary laboratory indicator of HPP, although other conditions can also cause low ALP. Because the enzyme’s normal range changes significantly with age, the result must be interpreted using age-specific reference values.
To confirm the diagnosis, healthcare providers look for elevated levels of TNSALP substrates in the blood or urine. Specifically, high levels of inorganic pyrophosphate (PPi) in plasma and pyridoxal 5′-phosphate (PLP) in the blood strongly support the clinical suspicion of HPP. High PLP levels are particularly helpful in diagnosis, as this molecule accumulates when the enzyme is deficient.
Imaging studies, such as X-rays, visualize the characteristic skeletal abnormalities resulting from defective mineralization. Radiographs can reveal findings like rickets, pseudofractures, or poorly healing fractures, which help distinguish HPP from other bone disorders. Genetic testing, involving sequencing the ALPL gene, provides definitive confirmation by identifying the specific mutation responsible for the enzyme deficiency.
Modern Treatment Strategies
Treatment for Hypophosphatasia is primarily managed through supportive care and targeted enzyme replacement therapy (ERT). The introduction of asfotase alfa, a bone-targeting recombinant alkaline phosphatase, has transformed the outlook for patients with severe forms of the condition. This medication is administered via subcutaneous injection multiple times per week, replacing the deficient TNSALP enzyme.
Asfotase alfa is approved for patients who developed symptoms in childhood and has demonstrated improvements in bone mineralization, respiratory function, and survival rates in those with perinatal and infantile onset. The drug is engineered to anchor to the calcium hydroxyapatite surface of the bone, delivering functional enzyme directly to the site of defective mineralization.
Supportive Care
Supportive management includes nonsteroidal anti-inflammatory drugs (NSAIDs) for chronic bone and joint pain, and physical therapy to maintain mobility and muscle strength. Dental care is also a major component, requiring regular monitoring and interventions for premature tooth loss and other dental abnormalities. In cases of severe infantile HPP, respiratory support for breathing problems and Vitamin B6 administration for seizures may be necessary.