The metabolic bone disorder hypophosphatasia typically occurs once in every 100,000 births. There’s a lot clinicians need to know about the diagnosis and treatment of this rare and sometimes fatal condition.
The loss of the first baby tooth is generally seen in healthy kids between ages six and seven. The very early loss of baby teeth often before ages two or three, however, can be the signal of a very rare metabolic bone disorder known as hypophosphatasia (HPP).
“Generally, the number of deciduous teeth loss prematurely reflects the severity of hypophosphatasia,” says Michael Whyte, MD, professor of Medicine, Pediatrics, and Genetics at Washington University School of Medicine in St. Louis. Whyte co-authored a recent study in the June issue of Bone that evaluated 173 childhood cases of HPP.
Patients with the mild childhood form of this genetic disease, are typically quite functional, and grow along within the normal growth curve, he explains. “They are not physically disabled or in chronic pain.”
“In contrast, with severe childhood HPP there is muscle weakness often with a waddling gait, sometimes obvious rachitic deformities of the skeleton such as bowed legs or knocked knees, bony aches and pains, sometimes fracturing, and an increased likelihood of below average stature,” Whyte adds.
HPP is caused by mutations in the tissue-nonspecific alkaline phosphatase gene. When especially severe, it can be associated with seizures, respiratory failure, and premature death. The inheritance patterns indicate an equal number of affected males and females, but the prevalence of the various forms is not well understood, according to Whyte.
Milder cases can go undiagnosed or misdiagnosed, yet the National Organization for Rare Disorders estimates that severe forms of HPP affect 1 in 100,000 births in Canada.
An Often Missed, Yet Simple, Diagnosis
“A missed or incorrect diagnosis at first, or delayed diagnosis, is not uncommon for hypophosphatasia,” says Whyte.
“We do not really know without delving deeper into our files how many of our children were first considered as having something else,” he continues. “But we certainly know about children whose first worries included muscular dystrophy because of the weakness, concern about an underlying leukemia because of the nature of some of the radiographic changes, vitamin D deficiency as a cause of the rickets, and even osteomyelitis to explain the x-ray changes and bone and joint pains.”
Cheryl Rockman-Greenberg, MD, a professor in the Departments of Pediatrics & Child Health and Biochemistry and Medical Genetics at the University of Manitoba, says it’s not uncommon for people who have very rare disorders such as HPP to wait months, if not years, for a diagnosis. “It’s not because the healthcare professionals aren’t working carefully through the symptoms and signs described by the patient and his/her family,” she says. “But if you have not had much experience with the disease, then it’s not unusual for there to be a really long delay in making a diagnosis.”
Yet with HPP, both Whyte and Rockman-Greenberg stress that making a diagnosis comes down to ordering one standard blood test — measuring the enzyme alkaline phosphatase. “When you order blood tests, many healthcare professionals are looking for elevated enzymes,” Rockman-Greenberg says. “But we don’t pay enough attention to a low level of an enzyme, and in hypophosphatasia, there’s a deficiency of the activity of alkaline phosphatase.”
She adds that, “people also don’t have a good understanding that they have to look at the age of the patient and make sure they have the right age range for alkaline phosphatase that is reported.”
The levels of alkaline phosphatase change with age groups, she continues. The range of alkaline phosphatase in infants is different from children, and different from teenagers and adults. And different things can cause low alkaline phosphatase that should first be ruled out.
An Important Contraindication
An important aspect of treating patients with HPP is to know what treatment to avoid. “Adults with hypophosphatasia often get drugs called bisphosphonates, like Fosamax, and these actually exacerbate symptoms and are contraindicated in HPP,” says Rockman-Greenberg. “So it’s important to make an accurate diagnosis and just not offer the supportive therapy, but to know what to avoid.”
An article in the Journal of Bone and Mineral Research recently featured a case study illustrating the contraindication.
Author Tim Cundy, MD, from the Department of Medicine at the University of Auckland, New Zealand led a team of researchers who treated a 55-year-old man suffering from severe bone pain and multiple fractures that happened over a two-year period. The man had developed hypertension at age 40 and at age 50 had renal failure. He had been in excellent health before then.
“This patient had been asymptomatic so his condition had never been suspected until things dramatically changed when he went into renal failure,” Cundy explains. “And after having a metatarsal fracture and being incorrectly diagnosed with osteoporosis, he was started on a bisphosphonate.”
“The milder adult forms [of HPP] may have very little or nothing in the way of symptoms,” he says. “Physicians need to be alert that patients with fractures and bone density scans indicating ‘osteoporosis’ but low ALP levels might be mutation carriers.”
Cundy and his team stopped the bisphosphonate therapy and treated the patient with teriparatide for six months, followed by a kidney transplant. “We were able to reverse the bone disease.”
“The concern is that bisphosphonates can worsen the mineralization defect, cause osteomalacia, or inhibit bone turnover to the extent that ‘atypical’ femoral fractures can occur,” Cundy says. “We need more information and research in this area.”
Waiting for New Therapies
There are no medications or treatments yet approved to treat HPP but Whyte hopes the Food and Drug Administration (FDA) will soon approve the drug asfotase alfa for severely affected HPP patients. The biologic, being evaluated by Alexion Pharmaceuticals, is an enzyme replacement therapy for treating patients with pediatric-onset HPP. The FDA granted priority review for asfotase alfa in March.
“It behooves us in the medical profession who work with families and children with hypophosphatasia to make sure that people are aware of this disorder. It’s important to help support health professionals in terms of being able to make the diagnosis, and to help support families, to make sure that the right diagnosis is made in a timely way.”
— Cheryl Rockman-Greenberg, MD, professor, Departments of Pediatrics & Child Health and Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada
Rockman-Greenberg says in the meantime patients may benefit from supportive measures, including diet and careful orthopedic and pain management. Families coping with HPP also can benefit from psychosocial support, physiotherapy, and respite care, she explains.
“It behooves us in the medical profession who work with families and children with hypophosphatasia to make sure that people are aware of this disorder,” she says. “It’s important to help support health professionals in terms of being able to make the diagnosis, and to help support families, to make sure that the right diagnosis is made in a timely way.”
—Glenda Fauntleroy is a freelance writer based in Carmel, Ind., and a regular contributor to Endocrine News. She wrote about bariatric surgery emergencies in the June issue.