Hypophosphatemic Rickets (HR) is a rare, inherited disorder characterized by a persistent inability of the kidneys to retain the mineral phosphate. This condition results in chronically low levels of phosphate in the blood, a state known as hypophosphatemia. Phosphate is essential for energy metabolism, cellular signaling, and the proper mineralization of the skeleton. When phosphate levels remain too low, the process by which bone tissue hardens is severely impaired. This defect leads to distinct skeletal disorders depending on the patient’s age. In children, the condition manifests as rickets, causing softening and weakening of the growing bones. The equivalent condition in adults is osteomalacia, characterized by bone softening, pain, and an increased risk of fractures. Unlike nutritional rickets, HR is a genetic disorder that does not respond to standard Vitamin D supplementation alone. The disorder is a lifelong condition requiring continuous medical management.
Understanding the Underlying Mechanism
The root cause of hypophosphatemic rickets lies in a genetic malfunction that disrupts the body’s phosphate balance. The most common form is X-linked Hypophosphatemia (XLH), caused by an inactivating mutation in the PHEX gene. This gene normally produces an enzyme that regulates Fibroblast Growth Factor 23 (FGF23), often called a “phosphatonin.” In a healthy person, FGF23 acts on the kidneys to limit phosphate reabsorption. When the PHEX gene is mutated, its ability to regulate FGF23 is lost, leading to an excessive and uncontrolled buildup of this hormone in the bloodstream.
This overabundance of circulating FGF23 drives the core pathology by instructing the kidneys to excrete too much phosphate into the urine. FGF23 acts on the renal tubules, reducing the activity of proteins responsible for reclaiming phosphate back into the blood. This excessive phosphaturia, or phosphate wasting, creates the chronic state of hypophosphatemia. FGF23 excess also negatively impacts vitamin D metabolism by suppressing the kidney’s ability to convert inactive vitamin D into its active form, 1,25-dihydroxyvitamin D. This results in an inappropriately low level of active vitamin D, which further reduces the intestine’s capacity to absorb phosphate from food, compounding the deficiency.
Clinical Manifestations and Progression
The signs of hypophosphatemic rickets typically become apparent in children once they begin to bear weight and start walking. A hallmark presentation is the development of skeletal deformities, most notably the progressive bowing of the legs (genu varum) or knock-knees (genu valgum). These deformities arise because the soft, unmineralized bones bend under the strain of body weight. Growth failure is another consistent feature, resulting in a disproportionate short stature where the limbs may be shorter relative to the trunk.
Children may also experience bone pain, a waddling gait, and stiffness. Abnormal bone growth, called enthesopathy, can occur where tendons and ligaments attach to the skeleton, causing pain and reduced joint mobility. Dental issues are common and characteristic, often including spontaneous dental abscesses even in teeth without cavities. This occurs because the dentin layer is poorly mineralized, allowing bacteria to easily reach the tooth pulp.
If the condition remains inadequately treated into adulthood, the patient experiences osteomalacia. Adult symptoms include chronic, deep bone pain, joint stiffness, and muscle weakness that can severely limit mobility. The soft bones are susceptible to stress fractures and non-healing fractures, often appearing on X-rays as pseudofractures. These accumulated skeletal issues often lead to the development of early and severe osteoarthritis in compromised joints.
Confirming the Diagnosis
The diagnostic process begins with a thorough clinical assessment for characteristic physical signs, such as bowed legs or short stature. Laboratory testing is fundamental to confirming the diagnosis and differentiating it from other forms of rickets. Blood tests consistently show a low level of serum phosphate, the defining biochemical feature of the disorder. Serum calcium levels are typically normal, which helps distinguish HR from nutritional rickets where calcium is often low.
Blood tests will also show significantly elevated levels of alkaline phosphatase, an enzyme released by bone cells when the bone matrix is failing to mineralize. This elevated level indicates ongoing bone disease. A major diagnostic clue involves the levels of vitamin D metabolites and phosphate excretion in the urine. Although the body is phosphate-deficient, the levels of active vitamin D (1,25-dihydroxyvitamin D) are often inappropriately normal or low due to the suppressive action of FGF23.
Urine tests are essential, revealing excessive phosphate loss, which confirms renal phosphate wasting. Imaging studies, particularly X-rays of the wrists and knees, provide visual confirmation of the skeletal defects. In children, X-rays show the classic signs of rickets, including widening, cupping, and fraying of the growth plates. Genetic testing for mutations in the PHEX gene is often used to definitively confirm the specific form of the hereditary disorder.
Comprehensive Management Strategies
Management of hypophosphatemic rickets is a lifelong endeavor focused on correcting the phosphate imbalance, promoting proper bone mineralization, and mitigating skeletal and dental complications.
Traditional Therapy
Traditional therapy has historically relied on a dual approach involving high-dose oral phosphate supplements and an active vitamin D analog, such as calcitriol. Phosphate supplements are administered multiple times a day to overcome the kidney’s constant phosphate wasting. Calcitriol is necessary to enhance intestinal absorption of phosphate and calcium. However, this conventional treatment is often limited by modest efficacy in healing the rickets and a difficult side effect profile. High doses of phosphate can cause significant gastrointestinal distress. The combination of phosphate and calcitriol carries a substantial risk of hypercalciuria, which can lead to nephrocalcinosis (calcium deposits in the kidneys) and potential kidney damage over time.
Targeted Biological Therapy
A significant advancement in treatment is the introduction of targeted biological therapy, specifically the use of burosumab. Burosumab is a monoclonal antibody designed to directly counteract the disease’s root cause. It works by binding to and neutralizing the excessive Fibroblast Growth Factor 23 circulating in the bloodstream. By inhibiting FGF23, burosumab halts the excessive renal phosphate wasting, allowing the kidneys to reabsorb more phosphate and normalize serum phosphate levels. This inhibition also allows the body’s active vitamin D levels to rise appropriately, further supporting phosphate absorption from the gut. The goal of this targeted approach is to achieve sustained normalization of phosphate, which can lead to the healing of rickets in children and osteomalacia in adults, while reducing the risk of kidney complications associated with traditional therapy.
Supportive Care
Treatment goals extend beyond biochemical correction to include maximizing growth velocity in children, reducing bone pain, and healing fractures and pseudofractures. Supportive care is a necessary component of comprehensive management, including regular, specialized dental care to manage the characteristic dental abscesses. In cases of severe skeletal deformity, orthopedic interventions such as osteotomy are used to surgically correct the alignment of the long bones.