Hypophosphatemic rickets is a rare genetic disorder that impacts the healthy development of bones and teeth. This condition is characterized by persistently low levels of phosphate in the blood, a mineral that is a building block for strong bones. Unlike other forms of rickets, which are often caused by vitamin D deficiency, hypophosphatemic rickets arises from a different underlying mechanism.
Understanding the Causes
Hypophosphatemic rickets is primarily a genetic condition, with the most common form being X-linked dominant hypophosphatemia (XLH). This type is caused by mutations in the PHEX gene, located on the X chromosome. The PHEX gene normally helps regulate phosphate levels in the body.
When the PHEX gene is mutated, it leads to an overproduction of a hormone called fibroblast growth factor 23 (FGF23). FGF23 is produced by bone cells and plays a role in phosphate metabolism by signaling the kidneys to excrete more phosphate and by reducing the production of active vitamin D. The excess FGF23 activity results in too much phosphate being lost through the kidneys and impaired vitamin D metabolism, which ultimately means insufficient phosphate is available for proper bone mineralization. While XLH is the most prevalent, other rarer genetic forms of hypophosphatemic rickets exist, including autosomal dominant and autosomal recessive types, involving different genes and pathways.
Identifying the Symptoms
The symptoms of hypophosphatemic rickets often become noticeable in early childhood, typically around the time a child begins to walk. Common signs include bowed legs or knock-knees, bone deformities more apparent with weight-bearing activities. Children may also experience slow growth, leading to shorter stature, and bone pain.
Dental issues are also frequently observed, including dental abscesses, delayed tooth eruption, and unusually large dental pulp chambers. Muscle weakness and fatigue can also be present, affecting mobility and overall activity levels. In adults, the condition may manifest differently, with more pronounced joint pain, pseudofractures, or a softening of the bones known as osteomalacia, rather than the classic rickets deformities seen in growing children.
Diagnosis and Evaluation
Diagnosing hypophosphatemic rickets involves a combination of clinical assessment, laboratory tests, and imaging studies. Doctors evaluate a patient’s medical history and perform a physical examination to look for skeletal abnormalities. Blood tests measure levels of phosphate, calcium, alkaline phosphatase, parathyroid hormone, and vitamin D. In hypophosphatemic rickets, blood phosphate levels are low, calcium levels are typically normal, and alkaline phosphatase levels are often elevated.
Urine tests assess kidney phosphate excretion, which is typically high. X-rays of bones, especially wrists, knees, ankles, and long bones, visualize abnormalities and assess rickets or osteomalacia. Genetic testing, particularly for PHEX gene mutations, can confirm the diagnosis.
Current Treatment Strategies
The main goals of treatment for hypophosphatemic rickets are to increase phosphate levels in the blood and improve bone mineralization. Conventional therapy typically involves daily oral phosphate supplements combined with active vitamin D analogs, such as calcitriol. These medications work together to help the body absorb and retain more phosphate, supporting bone health. However, this traditional approach can have side effects, including gastrointestinal issues like diarrhea and abdominal pain, as well as potential long-term complications such as kidney stones or calcium buildup in the kidneys due to elevated calcium levels in the urine.
A newer, targeted therapy for X-linked hypophosphatemia (XLH) is burosumab (Crysvita), a monoclonal antibody. Burosumab works by directly addressing the root cause of XLH: excessive FGF23 activity. It binds to FGF23, preventing it from signaling the kidneys to waste phosphate, thereby restoring renal phosphate reabsorption and increasing the body’s ability to absorb phosphate from the intestines by raising active vitamin D levels. This targeted approach can normalize phosphate levels, improve rickets in children, and help heal fractures in adults, often with a better side effect profile compared to conventional therapy. Additionally, consistent dental care is an important part of managing the condition to address dental issues.
Living with the Condition
Living with hypophosphatemic rickets requires ongoing medical management and a proactive approach to care. Regular follow-up appointments are necessary to monitor blood and urine levels of phosphate, calcium, and other relevant markers, allowing for adjustments to treatment as needed. This continuous monitoring helps ensure the effectiveness of therapy and helps minimize potential side effects.
Despite treatment, individuals with hypophosphatemic rickets may still face potential complications. These can include kidney stones or nephrocalcinosis from conventional therapy, the development of osteoarthritis, or hearing loss. Strategies for managing these complications include careful medication adjustments and specific interventions as they arise. A multidisciplinary care team, involving endocrinologists, nephrologists, dentists, and orthopedists, is often recommended to provide comprehensive and coordinated care for individuals throughout their lives.