Hypophosphatasia is an inherited metabolic (chemical) bone disease that results from low levels of an enzyme called alkaline phosphatase (ALP). Enzymes are proteins that act in the body's chemical reactions by breaking down other chemicals. ALP is normally present in large amounts in bone and liver. In hypophosphatasia, abnormalities in the gene that makes ALP lead to production of inactive ALP. Subsequently, several chemicals -including phosphoethanolamine, pyridoxal 5'-phosphate (a form of vitamin B6) and inorganic pyrophosphate - accumulate in the body and are found in large amounts in the blood and urine of people with Hypophosphatasia. It appears that the accumulation of inorganic pyrophosphate is the cause of the characteristic defective calcification of bones in infants and children (rickets) and in adults (osteomalacia). Nevertheless, the severity of hypophosphatasia is remarkably variable from patient-to-patient.
Symptoms & Diagnosis
The most severely affected fail to form a skeleton in the womb and are stillborn. The most mildly affected patients may show only low levels of ALP in the blood, yet never suffer bony problems. In general, patients are categorized as having "perinatal", "childhood" or "adult" hypophosphatasia depending on the severity of the disease, which in turn is reflected by the age at which bony manifestations are first detected. Odontohypophosphatasia refers to children and adults who have only dental, but not skeletal, problems (premature loss of teeth). The x-ray changes are quite distinct to the trained eye. Similarly, the diagnosis of hypophosphatasia is largely substantiated by measuring ALP in the blood (a routine test) that is low in Hypophosphatasia. However, it is important that the doctors use appropriate age ranges for normals when interpreting an ALP level.
It has been estimated that severe forms of hypophosphatasia occur in approximately one per 100,000 live births. The more mild childhood and adult forms are probably somewhat more common. About one out of every 200 individuals in the United States may be a carrier for hypophosphatasia.
Depending on the severity of the skeletal disease, there may be deformity of the limbs and chest. Pneumonia can result if chest distortion is severe. Recurrent fractures can occur. Teeth may be lost prematurely, have wide pulp (inside) chambers, and thereby be predisposed to cavities.
The severe perinatal and infantile forms of hypophosphatasia are inherited as autosomal recessive conditions. The patient receives one defective gene from each parent. Some more mild (childhood or adult) hypophosphatasia cases are also inherited this way. Other mild adult and odonto hypophosphatasia cases seem to be inherited in an autosomal dominant pattern (the patient gets just one defective gene, not two, transmitted from one of his/her parents). In this form, mild hypophosphatasia can occur from generation-to-generation. The perinatal form of hypophosphatasia can often be detected during pregnancy by ultrasound and by measuring ALP activity in chorionic villus samples from amniocentesis. Individuals with hypophosphatasia and parents of children with hypophosphatasia are encouraged to seek genetic counseling to explain the likelihood and severity of hypophosphatasia recurring in their families.
(chart can be found at hypophosphatasia.com/hcp)
(chart can be found at hypophosphatasia.com/hcp)
Prognosis The outcome following a diagnosis of hypophosphatasia is very variable. In general, the earlier the diagnosis is made the more severe the skeletal manifestations. Cases detected in the womb or with severe deformity at birth almost always have a lethal outcome within days or weeks. When the diagnosis is made before six months of age, some infants have a downhill and fatal course, others survive and may even do well. When diagnosed during childhood, there can by presence or absence of skeletal deformity from underlying rickets, but premature loss of teeth (less than five years of age) is the most common manifestation. Adults may be troubled by recurrent fractures in their feet and painful, partial fractures in their thigh bones.
For many years, treatment has been generally directed toward preventing or correcting the symptoms or complications. Procedures such as rodding, especially in adults, can be helpful with painful partial fractures in their thigh bones. Expert dental care and physical therapy are recommended. Monitoring levels such as alkaline phosphatase, B6, and calcium (which are/can be outside the limits of normal in hypophosphatasia) should be undertaken and are dependent upon how the patient is being treated.
In October 2015, a new treatment was introduced in the form of the targeted enzyme replacement therapy Strensiq (asfotase alfa). Strensiq is a tissue-nonspecific alkaline phosphatase indicated for the treatment of perinatal, infantile, and juvenile-onset hypophosphatasia (HPP), and works by replacing alkaline phosphatase. Since it’s approval, many of our families have chosen to begin this therapy. Careful consideration and consultation with a physician knowledgeable about this treatment, and the disorder hypophosphatasia itself, is recommended before starting this therapy. We have many resources available to patients and providers who are considering starting this drug to treat their hypophosphatasia. Please see the resources section below for general MAGIC information, and additional resources regarding hypophosphatasia and it’s treatment with Strensiq.
Michael P. Whyte. M.D.
Medical Director, Metabolic Research Unit
Shriners Hospital, St. Louis, Missouri
Hypophosphatasia, Affected Adult
A Personal Story
My name is Cassie Mendenhall Gutierrez and when I was 12 years old I was diagnosed with Hypophosphatasia. Hypophosphatasia is a metabolic bone disease that can affect many different systems in the body and varies highly from person to person. It is a genetic disorder, meaning it was passed on to me from birth and was not the result of some accident or event. It is a part of me as much as the shape of my nose or my blood type.
While at the time of my diagnosis there was no treatment available, just having a name to use when describing my ailments was empowering, even if I often had to explain to doctors what HPP was and bring along literature for them to peruse. As a young adult, I struggled at times to make myself understood to doctors and would often have to correct their assumptions that I had misheard or misunderstood my diagnosis because I did not present with the more severe symptoms doctors at that time associated with the disease. I was knowledgeable about my disorder though, owing to my mother’s wise insistence that I be able to recite my medical history before I left for university, and knew that I needed to stand my ground and make myself heard. I learned to be my own advocate.
After graduating college in 2009 with a BA in Teaching English as a Second Language, I spent two years working and living in Gwangju, South Korea as an English Teacher at a private kindergarten. I loved everything about Korea and its people but found many aspects of the country difficult because of my disorder. I had no car and relied on walking or public transportation to get around, which was actually quite manageable so long as the hills and snow were willing to cooperate. Hiking was also a popular hobby in my city owing to the many small mountains dotting the landscape, but I often chose to visit the local arcade in lieu of these activities. I became a very proficient at the Taiko: Drum Master video game (look it up, it’s awesome) and was the go-to person in my group for restaurant recommendations.
Upon returning to the US, I was encouraged to participate in the adult research studies for asphotase alfa (Strensiq) and have now been receiving treatment for several years. It took some time for me to accept that this treatment could help me as I had long ago accepted what my own limitations would be and how I would be able to live my life. I was nervous to begin treatment, especially a treatment that I would be required to continue for the rest of my life, but my family encouraged me to try and I am so happy I did.
I was lucky to have been introduced to The MAGIC Foundation at a young age and always enjoyed making friends at our annual convention. While these were kids I only saw once a year in Chicago, we shared our struggles and accepted each other in ways our school friends weren’t always able to. Before the internet we exchanged addresses and wrote letters all year, unable to wait for that weekend in July when we’d be able to go on the Friday Field Trip and swim together in the hotel pool. During university, we were able to use email to share tales of overzealous school nurses and RA’s that needed explanations as to why we needed syringe disposal units in the dorm. As an adult, I love coming to our convention and seeing children and adolescents build similar relationships. I am very happy to be able to work with The MAGIC Foundation to continue to support families and individuals affected by HPP and other endocrine disorders just as they have supported me.