How Hypophosphatasia Is Diagnosed

Hypophosphatasia (HPP) is a rare, inherited skeletal disorder that causes bones and teeth to become soft and weak. With HPP, mineralization—the deposition of calcium and phosphorus into the bones and teeth—becomes impaired.

This leaves the bones vulnerable to fracture, underdevelopment, and deformity. It also causes premature tooth loss.

It is important to diagnose HPP as soon as possible so that treatment can start. But because HPP is so rare, diagnosing it is sometimes hard. This is because it shares signs and symptoms of other more common diseases and affects many different parts of the body.

This article will discuss how HPP is diagnosed using different methods, including self-checks, physical examination, lab work, and more.

Self-Checks

There are no home tests or self-exams to diagnose HPP. However, recognizing the signs and symptoms of each type of HPP can help you seek a timely diagnosis.

A failure to grow and meet milestones is one of the earliest signs of perinatal HPP. Perinatal means immediately before or after birth. A baby with HPP might be born with short limbs, an abnormal chest, and soft skull bones.

Perinatal HPP is characterized by significantly impaired mineralization while the baby is developing in the womb. This type of HPP is rare and often results in stillbirth or respiratory failure within days of birth.

Benign prenatal HPP is a milder form, characterized by limb shortening and bowing that resolves spontaneously. Symptoms will disappear only to return in childhood or adulthood.

Childhood HPP symptoms will vary from person to person. Symptoms may include:

• Short stature
• Bowed legs or knock knees
• Skeletal malformation
• Bone and joint pain
• Enlarged ankle or wrist joints
• Abnormal skull shape
• Premature loss of baby teeth

Symptoms of adult HPP might include:

• Unspecified musculoskeletal disorders
• Slow healing
• Frequent fractures of the femur (thigh bone) and metatarsal bones (long bones of the feet)
• Bone softening
• Premature tooth loss
• Chronic joint and inflammation
• Muscle pain

It is not usual for adults who receive an HPP diagnosis to report having had symptoms of the condition in childhood.

Odontohypophosphatasia is a type of HPP that only affects the teeth. It causes premature loss of baby teeth in children and premature loss of permanent teeth in adulthood. This type of HPP does not affect the bones.

Physical Examination

The first step in diagnosing HPP involves assessing visible signs and symptoms by asking the patient (or the parent) about symptoms and with a physical examination. A physical examination of HPP involves looking for and assessing the following signs of the condition.

Skeletal

Skeletal abnormalities of HPP include fractures that don’t heal well and these other bone conditions:

• Rickets affects bone development in infants and children. In HPP, it appears as soft, weak, and deformed bones. It may also cause bone pain and poor bone development.
• Osteomalacia (a softening of the bones) is seen in adult forms of HPP. In adults, recurrent fractures of the foot and thighs are common and often lead to chronic pain.
• Osteopenia occurs when the body can’t make new bone as quickly as it reabsorbs old bone. Osteoporosis is a bone condition where bones become weak and brittle. Both are sometimes found in adult-type HPP.
• Craniosynostosis is a birth defect where the bones of the baby’s skull join together before the brain is fully formed. HPP at an early age can induce premature fusion of one or more cranial sutures. Craniosynostosis can lead to permanent facial and head abnormalities, developmental delays, vision problems, breathing problems, and seizures.

Dental

The earliest dental sign of HPP in children is premature loss of primary teeth. Childhood HPP also causes the decreased height of the alveolar bone (the thick ridge of bone that contains the tooth sockets) and various malocclusions, including overbite, underbite, overcrowding, and spacing.

In adults, HPP leaves the gums and teeth vulnerable to periodontal disease and the loss of bony supports that hold the teeth to the jaw. Premature tooth loss is also common with HPP.

Muscular

Childhood HPP affects sitting, crawling, and walking, and might lead to developmental delays. Both adults and children with HPP can experience muscle pain, muscle weakness, and poor muscle tone. 

Respiratory

Infants with HPP often have chest and rib deformities that make them more vulnerable to pneumonia (lung infection). Some infants might develop pulmonary insufficiency and breathing difficulties.

A pediatrician will likely look for respiratory signs, including rachitic chest, a symptom commonly linked to rickets. A rachitic chest will reveal knobby deformities along the costochondral junctions (joints of the thoracic wall).

The weakened ribs will produce inflammation over the diaphragm, and the sternum will be pulled into what is called a pigeon breast deformity (pectus carinatum). Additional respiratory signs in infant and childhood HPP include fever and tender rib joints.

Adult HPP is also linked to severe respiratory and pulmonary problems. These are often the result of chest deformities.

Renal

Both children and adults with HPP can suffer from renal (kidney) symptoms, resulting from defective bone mineralization and impaired regulation of phosphorus and calcium. In fact, people with HPP are at a greater than the typical risk for kidney damage.

The treating physician will ask about burning, pain, or blood with urination, kidney pain, and frequent urination. They will also check blood pressure levels and ask about signs of high blood pressure, such as frequent headaches, blurred vision, nosebleeds, and fatigue.

Neurologic

Neurologic symptoms of HPP include increased intracranial pressure and seizures. The treating provider will ask about seizures, headache, blurred vision, confusion, vomiting, behavior changes, and lack of energy or severe fatigue. They will also check blood pressure and for signs of shallow breathing.

Labs and Tests

HPP is caused by mutations in the ALPL gene that produces an enzyme called tissue nonspecific alkaline phosphatase (TNSALP). This enzyme is responsible for breaking down different substances, including inorganic pyrophosphate (PPi), pyridoxal 5'-phosphate (PLP), and phosphoethanolamine (PEA). 

An ALPL mutation results in TNSALP that cannot break down PPi, PLP, and PEA. These substances will accumulate to abnormal levels in the body. The accumulation of PPi is responsible for defective mineralization in HPP.

Different lab tests, including blood and urine, can assist in making an HPP diagnosis. 

• Alkaline phosphatase (ALP): People with HPP have reduced ALP levels. However, ALP testing on its own isn’t enough for diagnosis because genetic carriers of HPP will have low ALP and not necessarily develop symptoms. Low ALP is also seen in severe vitamin or mineral deficiencies or chronic diseases that cause malnutrition like celiac disease.
• PLP: Another way to support an HPP diagnosis is with a blood test that measures PLP, a form of vitamin B6. People with HPP have elevated PLP even with mild HPP. 
• PEA: Blood and urine can be checked for increased PEA, another chemical that is normally broken down by TNSALP. Elevated PEA is preferred over other chemical testing methods because it is more sensitive and precise, and less expensive than other testing methods.

Genetic Testing 

Genetic testing for the ALPL gene mutation is not always necessary. However, lab testing can be helpful for milder forms of HPP and ruling out other conditions that cause similar symptoms. Genetic testing is also helpful for people who have a family history of HPP and plan future pregnancies.

During pregnancy, chorionic villus sampling (CVS) can test for ALPL gene mutations. With CVS, tissue samples from the placenta are taken for analysis to confirm or rule out an HPP.

Imaging

Ultrasounds, X-rays, magnetic resonance imaging (MRI), and computed tomography (CT) scans are used to aid in making an HPP diagnosis.

• Ultrasound: In pregnancy, ultrasound scans help alert doctors of a potential HPP diagnosis. They might help to reveal short or bowed long bones. They may also show poor mineralization of the cranium and ribs in the latter part of pregnancy.

X-rays, MRIs, and CT scans can help diagnose HPP at all stages of life—from birth into adulthood. They can also help determine the severity of the condition based on how affected bones are.

• X-rays: X-rays can reveal bone abnormalities common in childhood HPP and severe forms of perinatal and infantile HPP types. Traditional X-rays can look for fractures in both adults and children. They might also show evidence of different types of arthritis and affected joints.
• CT and MRI: CT scans and MRIs can help evaluate additional bone problems related to HPP. Prenatal diagnosis of HPP can be confirmed with an MRI or CT. Other types of HPP rely more heavily on X-ray.
• Bone scans: In adults, bone density testing through dual-energy x-ray absorptiometry (DEXA) can scan for bone changes, including changes to bone mineral density. DEXA scans can also detect conditions that cause low bone mass, such as osteopenia and osteoporosis.

Odontohypophosphatasia

Adults and children with odontohypophosphatasia do not have bone disease findings on imaging. A treating physician will rely on analysis of signs, symptoms, and lab work to determine the type of HPP.

In children with HPP, a major sign of odontohypophosphatasia is the loss of baby teeth before the fifth birthday. However, premature loss of baby teeth does not always mean HPP.

If HPP is suspected based on blood and other lab work, doctors rely on cone-beam computed tomography (CBCT) to assess the causes of premature tooth loss. CBCT dental imaging can show short tooth roots, decreases in alveolar bone heights, and various dental malocclusions.

Differential Diagnosis

In determining whether a person has HPP, it is important to rule out other conditions whose symptoms might be similar.

Conditions that need to be ruled out or considered (differential diagnosis) include osteomalacia due to hypophosphatemia and osteomalacia due to vitamin D deficiency, rickets, and other types of other skeletal dysplasias (e.g., osteogenesis imperfecta, campomelic dysplasia, achondrogenesis subtypes, hypochondrogenesis, cleidocranial dysplasia).

What sets HPP aside from similar conditions is the serum concentrations of ALP, PLP, and PEA. Additionally, genetic testing for ALPL mutations can confirm a diagnosis, if uncertain.

Imaging studies are not always reliable, as their findings can overlap with other skeletal dysplasias. Certain features—hypomineralization, bone spurs, and others—might be helpful, but ALPL gene mutation testing is the easiest and most accurate way to confirm a diagnosis when other lab findings are inclusive.

Summary

Hypophosphatasia is a rare inherited condition that affects the development of bones and teeth. HPP leads to defective mineralization—where bones are soft and prone to fractures—and premature tooth loss.

It is diagnosed by identifying signs and symptoms, looking at medical history, performing a physical examination, and lab tests and imaging. Lab work and genetic testing are the most accurate tools for confirming an HPP diagnosis.

A Word From Verywell

Hypophosphatasia is a lifelong condition, and getting a diagnosis can be life-altering for the person affected and their family.

Support and advocacy groups can be a helpful way to connect with others living with HPP. Check online to research these groups, including at the National Organization for Rare Disorders website.

You can also connect with other families living with HPP in groups hosted by a variety of social media platforms. These families can be helpful resources for advice on making life with HPP easier for your child and family.