Hereditary hypophosphataemic rickets is a group of genetic disorders where the body loses too much phosphate through the kidneys, leading to weakened bones, growth problems, and dental issues that can affect individuals throughout their lives.
Understanding Hereditary Hypophosphataemic Rickets
Hereditary hypophosphataemic rickets represents a collection of genetic conditions characterised by low levels of phosphate in the blood, a state known as hypophosphataemia. Phosphate is a mineral that plays a fundamental role in building and maintaining strong bones and teeth. When the body cannot hold onto enough phosphate, bones become soft and weak, unable to develop normally during childhood or maintain their strength in adulthood.[1]
The disorder affects how the kidneys handle phosphate. Normally, kidneys filter blood and remove waste, but they also carefully reclaim important minerals like phosphate back into the bloodstream. In people with hereditary hypophosphataemic rickets, this reabsorption process fails, causing the body to lose excessive amounts of phosphate through urine. Without adequate phosphate circulating in the blood, the skeletal system cannot mineralise properly, leading to a range of bone-related complications.[1]
Epidemiology
The most common form of hereditary hypophosphataemic rickets is X-linked hypophosphataemic rickets, abbreviated as XLH. This particular variant affects approximately 1 in every 20,000 newborns, making it the most frequently occurring inherited form of rickets that runs in families. The condition occurs across all populations and geographic regions, though exact prevalence rates may vary slightly between different countries and ethnic groups.[1][5]
Studies examining the broader population suggest that the prevalence ranges from 1.7 per 100,000 children to approximately 4.8 per 100,000 persons when both children and adults are counted. The incidence rate, which measures new cases, has been documented at roughly 3.9 per 100,000 live births. These figures highlight that while hereditary hypophosphataemic rickets is considered rare, it represents a significant health challenge for affected families and healthcare systems.[12]
Other forms of hereditary hypophosphataemic rickets beyond XLH are considerably rarer. These include autosomal dominant, autosomal recessive, and X-linked recessive patterns of inheritance. Some specific variants, such as hereditary hypophosphataemic rickets with hypercalciuria (excessive calcium in urine), have been identified in only a handful of families worldwide. The rarity of these alternative forms means that many healthcare professionals may encounter them infrequently, if at all, during their careers.[1]
Causes
Hereditary hypophosphataemic rickets arises from mutations in several different genes, though mutations in the PHEX gene are by far the most common. The PHEX gene, located on the X chromosome, provides instructions for making a protein that plays a crucial role in maintaining phosphate balance within the body. When this gene contains mutations, the resulting protein either doesn’t work properly or isn’t produced at all.[1]
The genetic defects associated with hereditary hypophosphataemic rickets disrupt the body’s ability to regulate a hormone called fibroblast growth factor 23, or FGF23 for short. This hormone is primarily produced by bone cells called osteocytes. FGF23 normally acts as a brake on phosphate reabsorption in the kidneys, preventing the body from holding onto too much phosphate. However, when genes like PHEX are mutated, the production of FGF23 increases dramatically, or the hormone cannot be broken down properly. The result is too much FGF23 activity, which tells the kidneys to release far more phosphate than they should.[1][3]
Different genes can cause different forms of hereditary hypophosphataemic rickets. Besides PHEX, mutations in genes such as FGF23, DMP1, ENPP1, FAM20C, SLC34A3, and CLCN5 have all been linked to various inherited forms of the condition. Each of these genes plays a role, either directly or indirectly, in controlling phosphate levels or FGF23 activity. The specific genetic mutation determines not only which form of the disease a person has but also influences the inheritance pattern and sometimes the severity of symptoms.[1][4]
Beyond the primary effect on phosphate handling, FGF23 overactivity causes another significant problem. It interferes with the kidneys’ ability to produce the active form of vitamin D, known as 1,25-dihydroxyvitamin D or calcitriol. This active vitamin D is essential for absorbing calcium from the intestines and maintaining proper bone mineralisation. When FGF23 levels are too high, the body cannot make enough active vitamin D, compounding the mineralisation problems caused by low phosphate alone.[3]
Risk Factors
The primary risk factor for developing hereditary hypophosphataemic rickets is having a family history of the condition. Because these disorders are genetic, children born to parents who carry the causative gene mutations face significantly elevated risk. In the case of X-linked hypophosphataemic rickets, if a father has the condition, all of his daughters will inherit the mutation and develop the disease, while none of his sons will be affected. This occurs because fathers pass their X chromosome only to daughters. When a mother has XLH, each of her children, whether sons or daughters, faces a 50% chance of inheriting the mutated gene and developing the condition.[5][6]
Interestingly, family history isn’t always present. In approximately 20 to 30 percent of cases, hereditary hypophosphataemic rickets occurs due to spontaneous or de novo mutations—meaning the genetic change appears for the first time in an individual without any previous family history of the condition. These spontaneous mutations can then be passed on to future generations, establishing a new family line affected by the disorder. This means that even without a known family history, individuals can develop hereditary hypophosphataemic rickets.[6][16]
While hereditary hypophosphataemic rickets is primarily a genetic condition, there exists a rare non-genetic form called tumour-induced osteomalacia. In this situation, certain benign tumours, typically mesenchymal tumours, produce excessive amounts of FGF23, mimicking the effects seen in hereditary forms. Although this isn’t technically a hereditary condition, it demonstrates that factors beyond inherited genetics can create similar phosphate-wasting states. This form is important to recognise because removing the tumour can resolve the condition entirely.[3][7]
Symptoms
The symptoms of hereditary hypophosphataemic rickets typically begin appearing in early childhood, though the timing and severity vary considerably, even among members of the same family. In most cases, signs become noticeable during the first two years of life, particularly when children begin bearing weight and learning to walk. The most visible symptom is progressive bowing of the legs, where the lower limbs curve outward instead of remaining straight. Some children develop the opposite problem, called knock knees, where the knees angle inward while the ankles remain apart.[1][9]
Growth problems represent another major feature of the condition. Affected children experience slow growth and end up significantly shorter than their peers. The shortness is often disproportionate, meaning the legs are particularly short compared to the trunk of the body. This pattern becomes more apparent after the first year of life and continues if the condition remains untreated. Walking may be delayed, and children often display a characteristic waddling gait with in-toeing, where the toes point inward rather than straight ahead.[1][14]
Bone pain is a common and distressing symptom that can affect both children and adults. The pain results from inadequate bone mineralisation, which leaves bones soft and prone to small fractures or deformities. Children may complain of tenderness in their bones, particularly in the legs, and may experience muscle weakness that affects their ability to run, jump, or participate in physical activities. Some children show enlargement of the wrists, knees, or ankles, similar to what’s seen in other forms of rickets.[5][10]
Dental problems occur frequently in people with hereditary hypophosphataemic rickets. The condition affects both the dentine (the hard tissue beneath tooth enamel) and enamel itself, leading to poorly mineralised teeth. Children often develop spontaneous dental abscesses without obvious decay, and teeth may be prone to cavities and early loss. These dental complications can be painful and require extensive dental care, adding to the burden of the disease.[1][3]
Some children experience premature fusion of the skull bones, a condition called craniosynostosis. When skull bones fuse too early, it can alter the shape of the head and potentially increase pressure inside the skull. Though less common than leg deformities, craniosynostosis requires careful monitoring and sometimes surgical intervention. Additional features may include hearing loss, which can begin as early as 11 years of age, and abnormal bone growth where tendons and ligaments attach to joints, known as enthesopathy.[1][3]
In adults, the condition manifests differently. Instead of rickets, adults experience osteomalacia, which means soft bones. This leads to chronic bone pain, muscle weakness, and an increased risk of fractures, particularly incomplete fractures called pseudofractures. Adults often develop stiffness, osteoarthritis, and enthesopathies that limit mobility and cause chronic discomfort. Musculoskeletal complications accumulate with age and can begin appearing in affected individuals as young as 20 years old. Many adults with unresolved childhood disease continue experiencing lower limb deformities and impaired mobility throughout their lives.[1][16]
Mildly affected individuals may have few obvious symptoms beyond low phosphate levels detected on blood tests. The variability in symptom presentation means that some people experience debilitating effects while others have relatively minor manifestations of the disease. This unpredictability makes each case somewhat unique and requires individualised assessment and care planning.[1]
Prevention
Preventing hereditary hypophosphataemic rickets in its truest sense is not currently possible because the condition results from inherited or spontaneous genetic mutations. However, several strategies can help manage the condition effectively, prevent complications, and improve outcomes for affected individuals and families.
Genetic counselling plays an important role for families affected by or at risk of hereditary hypophosphataemic rickets. Understanding the inheritance patterns helps families make informed decisions about family planning. For X-linked forms, knowing that affected fathers will pass the condition to all daughters but no sons, while affected mothers have a 50% chance of passing it to any child, enables families to understand their risks. Genetic testing can confirm diagnoses before symptoms appear, allowing for earlier intervention.[5][10]
Early diagnosis and treatment initiation are crucial for preventing the most severe complications. When treatment begins before significant bone deformities develop, outcomes improve dramatically. Healthcare professionals should maintain high suspicion for hereditary hypophosphataemic rickets in children showing signs of rickets who don’t respond to standard vitamin D supplementation, or in families with known history of the condition. Siblings of affected children should undergo evaluation, including laboratory testing and sometimes genetic testing, even if they appear healthy.[10]
Regular monitoring throughout childhood and adulthood helps prevent complications from worsening. Children with hereditary hypophosphataemic rickets benefit from multidisciplinary care involving specialists such as endocrinologists, nephrologists, orthopaedic surgeons, and dentists. Routine dental care is particularly important to prevent and manage dental abscesses and tooth problems before they become severe. Physiotherapy and appropriate exercise programmes can help maintain muscle strength and mobility without placing excessive stress on weakened bones.[12]
Avoiding activities that place extreme stress on bones during childhood may help prevent fractures and worsening deformities, though maintaining some level of physical activity remains important for overall health and bone strength. Healthcare teams work with families to find the right balance between protection and maintaining quality of life.
Pathophysiology
The underlying mechanism of hereditary hypophosphataemic rickets centres on a disruption in how the body handles phosphate at the kidney level. Normally, the kidneys filter blood through tiny structures called nephrons, which separate waste products from valuable nutrients and minerals. The proximal tubules within nephrons perform the critical job of reclaiming phosphate from the filtered fluid, returning it to the bloodstream. In hereditary hypophosphataemic rickets, this reabsorption process fails, causing excessive phosphate loss in urine, a phenomenon termed renal phosphate wasting.[3][7]
The primary culprit behind this phosphate wasting is elevated levels or excessive activity of fibroblast growth factor 23. FGF23 is a hormone-like protein produced mainly by osteocytes, which are mature bone cells embedded within the bone matrix. When functioning normally, FGF23 acts on the kidneys to fine-tune phosphate levels, ensuring the body doesn’t accumulate too much. It does this by reducing the activity of sodium-phosphate co-transporters in the proximal tubules, the molecular pumps responsible for moving phosphate back into the blood.[3]
In hereditary hypophosphataemic rickets, genetic mutations lead to either overproduction of FGF23 or reduced breakdown of the hormone. For example, PHEX gene mutations, which cause X-linked hypophosphataemic rickets, result in loss of function of the PHEX protein. While the exact mechanism isn’t completely understood, this loss appears to trigger increased FGF23 secretion from osteocytes. Similarly, mutations directly in the FGF23 gene itself, which cause autosomal dominant forms, prevent the hormone from being properly cleaved and inactivated, allowing it to persist and continue its phosphate-wasting effects.[4][8]
Excessive FGF23 causes two major problems. First, it dramatically increases phosphate excretion by the kidneys, creating hypophosphataemia. Second, it interferes with vitamin D metabolism by inhibiting the enzyme that converts inactive vitamin D into its active form (1,25-dihydroxyvitamin D or calcitriol) and by increasing the activity of the enzyme that breaks down active vitamin D. The result is that active vitamin D levels remain inappropriately normal or even low when they should be elevated in response to low phosphate. This creates a double problem: low phosphate combined with inadequate active vitamin D, both of which are essential for proper bone mineralisation.[3][7]
The combination of hypophosphataemia and relative vitamin D deficiency leads to defective mineralisation of the bone matrix. In children, this affects the growth plates, areas of developing cartilage near the ends of long bones where growth occurs. Normally, cartilage cells in the growth plate undergo a programmed sequence of proliferation, maturation, and eventual death, allowing the cartilage to be replaced by mineralised bone. Hypophosphataemia prevents this normal progression by inhibiting the death of these cells, causing them to accumulate in an unmineralised state. This produces the widened, irregular growth plates characteristic of rickets visible on X-rays.[2]
Beyond the growth plates, the entire skeleton suffers from poor mineralisation. New bone formed during growth and bone remodelling throughout life fails to mineralise properly, remaining soft and weak. This softness makes bones vulnerable to bending under the force of weight-bearing and muscle pull, producing the characteristic deformities like bowed legs. In adults, where growth plates have closed, the process manifests as osteomalacia, where existing bone becomes progressively demineralised and weak.[3]
The skeletal problems extend beyond just mineral deficiency. Evidence suggests that FGF23 may directly affect bone cells themselves, potentially impairing the function of osteoblasts (cells that build new bone) beyond just the effects of low phosphate. This adds another layer of complexity to the pathophysiology and helps explain why bone problems can be so severe even when phosphate levels are partially corrected with treatment.[3]
Dental problems arise through similar mechanisms. Teeth require proper mineralisation of both dentine and enamel during development. The same phosphate deficiency and vitamin D insufficiency that affects bones impairs the mineralisation of dental tissues, producing weak, poorly formed teeth prone to abscesses and decay. The severity of dental problems often correlates with the degree of phosphate deficiency during the critical periods of tooth development.[12]
One variant form, hereditary hypophosphataemic rickets with hypercalciuria, demonstrates different pathophysiology. In this condition, mutations in the SLC34A3 gene disrupt a different sodium-phosphate co-transporter. Interestingly, affected individuals have normal or low FGF23 levels. Their bodies respond appropriately to hypophosphataemia by producing adequate active vitamin D, but this leads to increased calcium absorption from the intestines and subsequent high calcium levels in the urine. This distinguishes this form from the more common FGF23-driven forms and requires different treatment approaches.[3][7]
Understanding these underlying mechanisms has proven crucial for developing targeted therapies. Traditional treatments aimed at replacing phosphate and providing active vitamin D address the downstream effects. Newer treatments targeting FGF23 itself represent a more direct approach to correcting the fundamental problem driving the disease. Both strategies have their place in managing this complex disorder, with treatment choices depending on the specific form and individual patient factors.[12]