Autosomal Dominant Hypophosphatemic RicketsEdit

Autosomal Dominant Hypophosphatemic Rickets (ADHR) is a hereditary disorder characterized by renal phosphate wasting that leads to chronic hypophosphatemia and impaired mineralization of bone. The condition is caused by gain-of-function mutations in the gene encoding fibroblast growth factor 23 (fibroblast growth factor 23), or by alterations in regulatory pathways that increase FGF23 activity. Inheritance follows an autosomal dominant pattern, so an affected individual has a 50% chance of passing the condition to each child. Clinical presentation typically emerges in childhood with growth delay, limb bowing, and signs of rickets, though there is notable variability in onset and severity. With advances in diagnosis and treatment, people with ADHR can experience substantial improvement in bone health, growth, and quality of life, particularly with modern therapies that target the underlying phosphate-wasting mechanism.

ADHR sits within a broader group of disorders known as hypophosphatemic rickets, which share the common feature of phosphate wasting by the kidneys. It is distinguished from X-linked hypophosphatemia (X-linked hypophosphatemia) by its autosomal dominant inheritance rather than an X-linked pattern, and from other rare forms caused by different genetic mutations that affect phosphate handling. The clinical course can range from relatively mild to significant skeletal deformities and dental problems, and lifelong management may be necessary. The emergence of targeted therapies that address FGF23 signaling has reshaped expectations for outcomes in ADHR, reducing the burden of skeletal complications and improving growth trajectories when started early.

Signs and symptoms

Short stature and delayed growth in childhood
Bone deformities, most commonly bowing of the legs (genu varum) and deformities of the lower limbs
Bone pain, increased fracture risk, and delayed bone healing
Dental problems such as dental abscesses or accelerated dental disease
Evidence of rickets on radiographs, including metaphyseal cupping and fraying
In adults, symptoms can include osteomalacia, bone pain, and an increased risk of stress fractures or insufficiency fractures

Clinically, these features reflect chronic low phosphate availability for bone mineralization, despite normal or near-normal calcium and parathyroid hormone levels. Alkaline phosphatase is often elevated, signaling increased bone turnover as the skeleton attempts to mineralize properly.

Genetics and pathophysiology

ADHR results from mutations in the gene that encodes FGF23, a hormone produced by bone cells that regulates phosphate handling in the kidneys. These mutations cause increased activity of FGF23, which reduces phosphate reabsorption in the renal tubules and suppresses 1,25-dihydroxy vitamin D production, contributing to phosphate wasting and impaired mineralization. See fibroblast growth factor 23 for background on the pathway.
The condition is inherited in an autosomal dominant fashion, meaning a single altered copy of the gene is sufficient to cause disease. Penetrance can be variable, and some individuals with FGF23 mutations may have milder or later-onset manifestations.
Other mechanisms that influence FGF23 signaling or phosphate handling can interact with the primary genetic defect, contributing to the range of clinical presentations seen in ADHR.

Pathophysiology centers on renal phosphate wasting driven by FGF23 activity, which reduces the kidney’s ability to reclaim phosphate and lowers circulating phosphate levels necessary for proper bone mineralization. This mismatch between phosphate availability and bone formation leads to rickets in children and osteomalacia in adults, with secondary effects on dental health and overall skeletal strength.

Diagnosis

Clinical suspicion rises from growth delay, bone deformities, and dental issues in a child or young adult with persistent hypophosphatemia.
Laboratory findings typically show low serum phosphate with inappropriately normal or low 1,25-dihydroxy vitamin D, normal calcium, and usually normal or only mildly abnormal PTH. Alkaline phosphatase is often elevated.
Urinary studies reveal phosphate wasting, demonstrated by an inappropriately high fractional excretion of phosphate for the degree of serum phosphate.
Imaging (radiographs) reveals metaphyseal changes consistent with rickets, and bone scans may show areas of active mineralization deficiency.
Genetic testing confirms mutations in the gene encoding fibroblast growth factor 23 (or other regulator pathways when available) to establish an autosomal dominant diagnosis. See FGF23 as the core diagnostic pathway.
Differential diagnosis includes other forms of hypophosphatemic rickets, such as XLH (_X-linked hypophosphatemia) and other rare phosphate-wasting disorders, which share similar biochemical features but differ in inheritance pattern and gene involvement.

Management and treatment

Traditional management has relied on oral phosphate supplements to raise serum phosphate and active vitamin D analogs (such as calcitriol) to enhance intestinal phosphate absorption and bone mineralization. This approach requires careful monitoring to avoid complications such as nephrocalcinosis, secondary hyperparathyroidism, and gastrointestinal side effects.
Burosumab, a monoclonal antibody targeting FGF23, represents a modern targeted therapy that directly addresses the disease mechanism by reducing phosphate wasting. It has shown improvements in serum phosphate, linear growth, and healing of rickets in trials and real-world use, with the potential to reduce skeletal deformities and dental problems. See burosumab and FGF23-related discussion.
Supportive care includes physical therapy to improve mobility and strength, orthopedic interventions for residual deformities when needed, and dental care to manage recurrent dental disease.
Monitoring is essential and typically includes regular measurement of serum phosphate, calcium, alkaline phosphatase, 1,25-dihydroxy vitamin D, PTH, renal function, and urinary phosphate excretion, as well as imaging to track bone healing and growth.
Access to advanced therapies and the cost of treatment remain practical considerations, with ongoing debates about payer coverage and long-term safety data for newer agents like burosumab. See phosphate and calcitriol for related pharmacology.

Prognosis and long-term outlook

With appropriate treatment—whether standard phosphate supplementation with active vitamin D or targeted therapies such as burosumab—growth and bone mineralization can improve substantially, and the risk of skeletal deformities can be reduced. Dental health remains a focus of ongoing care. Long-term outcomes depend on the timeliness of diagnosis, adherence to treatment, monitoring quality, and access to effective therapies. Lifelong management is often necessary, and research continues to refine the balance between efficacy, safety, and cost for newer treatments.

Controversies and debates

Access and cost of targeted therapies: Burosumab offers clear clinical benefits for many patients, but its high price has sparked debates about who should receive coverage and how to allocate limited healthcare resources. Proponents argue that addressing the root cause—FGF23-mediated phosphate wasting—can reduce long-term disability and healthcare costs, while critics urge strong evidence of cost-effectiveness and careful patient selection.
Long-term safety and real-world effectiveness: While early results for burosumab are encouraging, some clinicians and payers call for continued post-marketing data and longer follow-up to fully understand long-term safety, optimal dosing, and durability of response across diverse patient populations.
Traditional therapy vs. modern approaches: Some practitioners emphasize tried-and-true phosphate and calcitriol regimens with careful monitoring, particularly in settings where access to newer agents is limited or where individual patient factors favor a stepwise approach. Advocates for newer therapies argue that early, direct intervention on the FGF23 axis can prevent irreversible skeletal damage and improve quality of life.
Patient advocacy and regulatory pressures: As with many rare diseases, patient groups and advocacy organizations play a significant role in accelerating research and access to therapies. Critics sometimes view these dynamics through a cost-benefit lens, while supporters emphasize the moral case for providing treatment to those with limited alternatives.
Debates about language and policy discourse: In broader conversations about health policy, some critics push back against expansive regulatory pathways or “orientation” arguments around healthcare spending, arguing for outcomes-based pricing and accountability. It is important to separate policy critique from clinical care to ensure patients receive evidence-based, compassionate treatment.