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What Is Hypophosphatasia? Symptoms, Causes, Diagnosis, Treatment, and Prevention

July 14, 2020

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Signs and Symptoms of Hypophosphatasia

The signs and symptoms of hypophosphatasia vary widely and can appear anytime from before birth to adulthood. Every case is different. Some children will develop severe complications early on, where others might have a milder form that might improve as they grow older, according to the National Organization for Rare Diseases.

Perinatal HPP symptoms include skeletal abnormalities, such as deformities of the chest wall, or legs that are short, or bowed, or both, notes the Mayo Clinic.

For infants, failure to grow at the expected rate for age and gender may be the first sign of HPP.They may be born with short limbs, an abnormal chest, and soft skull bones, according to the Genetic and Rare Diseases Information Center (GARD).

Symptoms of childhood cases vary but may include:

Short stature with bowed legs or knock knees
Decreased mobility
Skeletal malformations
Bone and joint pain
Enlarged wrist or ankle joints
Abnormal skull shape
Losing baby teeth earlier than usual

Symptoms of adult HPP include:

Softening of the bones
Frequent fractures of the foot and thigh bones
Premature loss of teeth
Joint pain and inflammation

According to the Mayo Clinic, it’s not unusual for adults with HPP who receive a diagnosis later in life to report having had symptoms in childhood.

Odontohypophosphatasia is characterized by the premature loss of baby teeth in childhood, or premature loss of teeth in adulthood. With this form of HPP, there are no symptoms that affect or involve the bones.

Causes and Risk Factors of Hypophosphatasia

Hypophosphatasia is caused by mutations in the ALPL gene. This gene provides instructions for making an enzyme called tissue-nonspecific alkaline phosphatase (TNSALP), which plays an essential role in mineralization, as well as in the absorption of and retention of minerals of the bones and teeth. Mutations in the ALPL gene affect the ability of TNSALP to do its job, and this is what leads to defective bones and teeth, according to MedlinePlus.

You are at risk for hypophosphatasia if one or both of your parents carry a mutated ALPL gene. If you inherit two copies of the mutated gene from your parents, you may have a more severe form of HPP. If you inherit only one mutated copy, from only one parent, you may have a milder form.

How Is Hypophosphatasia Diagnosed?

It’s important to diagnose HPP as soon as possible, and if healthcare providers and parents decide on a course of treatment, it should begin as early as possible after birth, according to an article published in October 2018 in Pediatric Radiology.

Diagnosis is based on identifying characteristic signs and symptoms, medical history, physical examination, and lab tests. Lab tests may include X-rays and biochemical tests that measure the activity of alkaline phosphatase in the blood.

During pregnancy, chorionic villus sampling (CVS) is used to test for ALPL gene mutations. In CVS, tissues of the placenta are removed for analysis to confirm the diagnosis before delivery, notes the Mayo Clinic.

Ultrasounds during pregnancy may also show short and bowed long bones.

According to a study published in February 2019 in BMC Musculoskeletal Disorders, cases of childhood HPP were most frequently diagnosed between ages 2 and 10.

What to Eat and What to Avoid for Osteoporosis Prevention

Adult HPP is often diagnosed after middle age, per research published in the May–August 2017 issue of Clinical Cases In Mineral and Bone Metabolism.Adults may not know they have the condition, but will report joint pain and a history of poorly healing fractures. It may also happen that an individual is asymptomatic, and the HPP is diagnosed after routine tests show an elevated vitamin B6 level or low alkaline phosphatase activity, according to an article published in July 2017 in the Journal of Bone and Mineral Research.

Odontohypophosphatasia can be diagnosed when there are dental abnormalities, including premature tooth loss, but no other skeletal disease, notes the Mayo Clinic.

Prognosis of Hypophosphatasia

Perinatal HPP is often fatal. Mortality among patients with perinatal or infantile HPP has ranged from 58 to 100 percent within the first year of life.

But in 2015, the U.S. Food and Drug Administration (FDA) approved Strensiq (asfotase alfa), which is an alkaline phosphatase enzyme replacement therapy (ERT). It’s the first and only prescription treatment for perinatal, infantile, and childhood HPP. Infants treated with ERT can experience significant improvement in skeletal mineralization, improved respiratory function, and reduced mortality, according to the Mayo Clinic.

Treatment and Medication Options for Hypophosphatasia

Strensiq is used to treat perinatal, infantile, and juvenile onset HPP.

Forteo (teriparatide), a man-made form of parathyroid hormone used to treat osteoporosis, has been shown to help fracture healing in adults with HPP, according to a review published in August 2019 in Therapeutic Advances in Musculoskeletal Disease.

Other treatments target specific symptoms and complications.

These treatments include:

Nonsteroidal anti-inflammatory drugs (NSAIDs) to treat bone and joint pain
Vitamin B6 to help to control seizures in severely affected infants
Regular dental care beginning early on
Physical and occupational therapy

Surgery may also be recommended. Adults suffering from repeated fractures may undergo a procedure called rodding, in which an orthopedic surgeon places a metal rod through the center opening of a bone to make it stronger and more stable.

Children may be given orthotic braces to encourage stability, and in-sole orthotics may be used by both adults and children.

Research published in December 2020 in the journal Bone suggests that bisphosphonates, which are medications administered to treat the bone loss associated with osteoporosis, may cause fractures in those with HPP.For that reason, you may want to discuss with your healthcare provider whether you should discontinue bisphosphonates.

Related: What to Eat — and Avoid — for Strong Bones if You Have Ankylosing Spondylitis

Prevention of Hypophosphatasia

Hypophosphatasia cannot be prevented, but treatments such as the ones outlined above are available to help manage the symptoms.

Research and Statistics: Who Has Hypophosphatasia?

Because HPP is rare, and often goes undiagnosed, and there isn’t a great deal of research on the rate at which the condition affects populations, the exact incidence and prevalence is unknown. One frequently cited Canadian study has estimated an incidence of 1 in 100,000; another frequently cited European study has reported a prevalence of 1 in 300,000, according to a review published in August 2016 in the International Journal of Medicine.

In general, HPP affects males and females in equal numbers.

There is not a great deal of research on race, ethnicity, and HPP, but what research there is suggests that the condition occurs primarily in white individuals and is very rare among African American individuals.

Resources We Love

The MAGIC Foundation

This charitable nonprofit organization was created to provide support for the families of children afflicted with conditions and diseases that affect a child's growth, including hypophosphatasia. The organization can help parents of newly diagnosed children connect with other parents whose children are living with the disease.

Soft Bones

Soft Bones exists to provide information and support to people living with hypophosphatasia (HPP) and their caregivers. The nonprofit’s Resource Library is a go-to source for recent news articles, helpful fact sheets, podcasts, and webinars. Their online community form, HPP and Me, can connect you with other patients, families, and caregivers.

With additional reporting by Carlene Bauer.

Editorial Sources and Fact-Checking

References

Högler W, Langman C, Gomes da Silva H, et al. Diagnostic Delay Is Common Among Patients With Hypophosphatasia: Initial Findings From a Longitudinal, Prospective, Global Registry. BMC Musculoskeletal Disorders. 2019.
Schini M, Eastell R. Establishing Race-, Gender- and Age-Specific Reference Intervals for Pyridoxal 5′-Phosphate in the NHANES Population to Better Identify Adult Hypophosphatasia. Bone. December 2020.
Kaur J, Nourabadi S, Chavez L, Sachmechi I. A Concise Review on Hypophosphatasia With Case Report. International Journal of Medicine. 2016.
Campomelic Dysplasia. MedlinePlus. June 1, 2014.
Achondrogenesis. Genetic and Rare Diseases Information Center.
Rare Disease Database: Hypophosphatasia. National Organization for Rare Disorders (NORD). 2017.
Medical Professionals: Endocrinology: Hypophosphatasia. Mayo Clinic. October 23, 2014.
Hypophoshatasia. Genetic and Rare Diseases Information Center (GARD). February 1, 2016.
Hypophosphatasia. MedlinePlus. August 18, 2020.
Chorionic Villus Sampling. Mayo Clinic. November 12, 2020.
Offiah AM, Vockley J, Munns CF, Murotsuki J. Differential Diagnosis of Perinatal Hypophosphatasia: Radiologic Perspectives. Pediatric Radiology. January 2019.
Conti F, Ciullini L, Pugliese G. Hypophosphatasia: Clinical Manifestation and Burden of Disease in Adult Patients. Clinical Cases In Mineral and Bone Metabolism. May-August 2017.
Choida V, Bubbear JS. Update on the Management of Hypophosphatasia. Therapeutic Advances in Musculoskeletal Disease. August 1, 2019.
Shapiro JR, Lewiecki EM. Hypophosphatasia in Adults: Clinical Assessment and Treatment Considerations. Journal of Bone and Mineral Research. July 2017.

Sources

ALPL Gene. MedlinePlus. August 18, 2020.
Vogt M, Girschick H, Schweitzer T, et al. Pediatric Hypophosphatasia: Lessons Learned From a Retrospective Single-Center Chart Review of 50 Children. Orphanet Journal of Rare Diseases. August 2020.