Hyperphosphatemic Hypophosphatesia (HPP)

What is Hyperphosphatemic Hypophosphatesia?

Hyperphosphatemic Hypophosphatesia, also known as HPP or Rathbun disease, is a rare bone disorder that results when mineralization in bones fails to occur, making them soft and prone to fracture and deformity. When mineralization, a process that causes bones to be strong and hard, is impaired in the body, tooth loss can take place as well.

What causes Hyperphosphatemic Hypophosphatesia?

HPP is caused when mutations exist in the ALPL gene. Mutations in this gene lower the activity of the enzyme, a specialized protein that the ALPL gene creates, called TNSALP. This leads to the accumulation of phosphoethanolamine (PEA), pyridoxal 5’-phosphate (PLP), and inorganic pyrophosphate (PPi) which inhibits the mineralization and mineral entry into the body’s bones. In other words, when there is less enzyme activity, less mineralization takes place due to the presence of more PEA, PLP, and PPi, and therefore, HPP is more severe. Higher levels of PPi prevent calcium and phosphorus from being absorbed by the bone.

Symptoms of Hyperphosphatemic Hypophosphatesia

The severity spectrum of HPP is wide-ranging, even among members of the same family. There are five major categories that are defined by the age of when symptoms set in, starting with the most severe form which is called Perinatal HPP. The five major forms of HPP are as follows:

Perinatal HPP presents at birth or on a prenatal ultrasound beforehand and is almost always fatal shortly after birth. Typical clinical features reveal short or bowed legs and obvious skeletal abnormalities, such as chest wall deformities, due to the skeleton being hypomineralized.

Infantile HPP is diagnosed in children by 6 months of age when they fail to grow appropriately and experience vitamin B-6 responsive seizures. We use X-rays to measure changes in rickets, a childhood disease caused by a vitamin D deficiency, and fractures.

Childhood HPP typically manifests itself after six months of age in the form of a delay in gross motor milestones, static myopathy, and a premature loss of deciduous teeth.

Adult HPP is diagnosed when patients have micro fractures, and/or denture disease and/or joint disease and deformities as well as foggy mind, mood changes in addition to abnormal Alk Phos and B6 levels. It’s not uncommon to be diagnosed as an adult after having had symptoms during childhood.

Odontohypophosphatasia is the mildest form of HPP and presents itself in dental abnormalities while no other skeletal disease is identified.

When to see an Endocrinologist (Diagnosis)

If you have any of the symptoms listed above or a family history of hypophosphatasia, we recommend you come in for an evaluation. We will conduct a series of tests, including checking your alkaline phosphatase activity which can differentiate hypophosphatasia from other metabolic disorders. Misdiagnoses are common since signs and symptoms of hypophosphatasia can overlap with other diseases.        

What is the difference between hypophosphatasia and hypophosphatemia?

Hypophosphatasia is an inherited metabolic disorder in patients with deficient enzymatic activity and manifestations ranging from early loss of deciduous teeth to impaired bone mineralization and seizures. Hypophosphatemia is a vitamin D-resistant rickets that is characterized by low levels of phosphate in the blood due to kidney processing abnormalities.