What is Hypophosphatasia?

Hypophosphatasia or HPP is a rare, inheritable disorder that negatively affects the development of bones and teeth. Mineralization is a critical process in the formation of strong bones, wherein the body deposits minerals such as calcium and phosphorus in developing bones. HPP interrupts and disrupts mineralization, causing the bones and teeth to develop with weaknesses. The symptoms of this progressive condition can vary widely, and any person of any age can develop HPP.

Prenatal and Perinatal HPP

An ultrasound can detect signs of prenatal or perinatal hypophosphatasia — the latter is a fatal forms of HPP. A fetus with perinatal HPP may show signs of shortened and bowed limbs and underdeveloped ribs. After birth, the newborn may have severe respiratory issues due to rib malformations and underdeveloped lungs. Fetuses with prenatal benign HPP rather than perinatal HPP often have bowed limbs as well, though the malformations will generally improve rapidly after birth. As the child develops, their condition begins to resemble infantile HPP.

Hypophosphatasia in Infants

Some children with hypophosphatasia may have no signs or symptoms at birth. However, during the first several months, a child with infantile HPP may begin to exhibit symptoms. The child may struggle to gain weight or not grow at an expected rate. Their skulls may not develop properly, which can lead to increased pressure of the cerebrospinal fluid that surrounds the brain. This pressure may cause the eyes to swell or frequent headaches. Additionally, the infant’s bones may develop deformities, particularly in the chest and ribs.

HPP in Children

Childhood hypophosphatasia is extremely variable, and physicians may classify it as mild or severe. One of the primary symptoms of childhood hypophosphatasia is the loss of baby teeth. Before the age of five, a child may lose several or all of their deciduous baby teeth. At this age, bone deformities and issues similar to rickets also develop; this can delay a child’s ability to walk and cause significant muscle weakness or pain. In severe cases, the child’s cranial bones may fuse prematurely, causing more cranial pressure.

HPP in Adults

Like childhood HPP, adult HPP also possesses many possible symptoms. Some individuals experience early loss of their adult teeth. A majority of people with the condition also have osteomalacia, a softening of the bones, making stress fractures in the metatarsals of the feet particularly common. Additionally, pseudofractures may develop in the thighs. Due to the body’s inability to heal these fractures, a person with adult hypophosphatasia may experience severe chronic pain. Calcium crystals can also build up near joints, causing damage to the area and inflicting pain.

Odontohypophosphatasia

Odontohypophosphatasia is among the least severe forms of hypophosphatasia. Unlike other forms, it does not affect the entire body — rather, individuals with this condition experience abnormal tooth development. This may cause children to prematurely lose their deciduous teeth and adults to lose their fully-formed permanent teeth. The skeletal malformations of other forms of HPP do not occur. Radiographic and histologic studies of a patient with odontohypophosphatasia showed no evidence of rickets or osteomalacia.

Causes

Medical experts believe hypophosphatasia is the result of a molecular defect in a gene-encoding tissue, non-specific alkaline phosphatase or TNSALP. Low levels of this enzyme lead to buildups of inorganic pyrophosphate, which eventually disrupts the formation of hydroxyapatite, which accounts for up to 50 percent of the volume and 70 percent of the weight of bone. Without hydroxyapatite, children can develop rickets sand adults can develop osteomalacia.

Inheritance

Because hypophosphatasia is autosomal, meaning it affects any chromosome other than a sex chromosome, men and women are equally likely to develop it. Perinatal and infantile HPP are typically autosomal recessive traits. However, childhood HPP, adult HPP, and odontohypophosphatasia can be either autosomal recessive or dominant. It is difficult to quantify the exact number of HPP-affected individuals in the world due to the tendency of physicians to misdiagnose mild HPP when the symptoms are minor or resemble another bone disease.

Diagnosis

Physicians use many methods to diagnose hypophosphatasia. Ultrasounds allow technicians to see the skeletal changes of prenatal and perinatal HPP. Dentists frequently discover HPP due to the premature loss of deciduous baby teeth. The standard comprehensive metabolic panel is a panel of 14 blood tests that can detect one of the primary characteristics of HPP. Low serum activity of alkaline phosphatase enzyme, for which the panel tests, is a major characteristic of HPP.

Treatments

Before 2015, the majority of treatment for hypophosphatasia focused on addressing the specific symptoms of each patient. A group of specialists including pediatricians, dental specialists, and orthopedic surgeons would work together for a cohesive treatment plan, often involving non-steroidal anti-inflammatory drugs to treat joint pain and vitamin supplements to control seizures in children with cranial pressure. Adults prone to fractures frequently required internal fixations. A surgeon would insert rods into weak bones to provide more support and strength. In 2015, however, the Food and Drug Administration approved enzyme replacement therapy for HPP.

Enzyme Replacement Therapy

Perinatal, infantile, and childhood HPP were particularly difficult for physicians to treat. Enzyme replacement therapy aims to replace the TNSALP enzyme with a lab-produced glycoprotein with similar qualities. This drug proved to be so effective at treating HPP that the FDA granted it the breakthrough therapy designation. Along with administering the therapy, physicians continue to monitor calcium balance and prescribe additional treatments as necessary.