Hypophosphatasia: Symptoms, Types, Causes and Treatment

Hypophosphatasia (HPP) is a rare, inherited metabolic disorder that affects bone and tooth mineralization. Its symptoms can range from life-threatening skeletal abnormalities in newborns to subtle dental issues in adults. Understanding HPP is vital for timely diagnosis and effective management, especially as new therapies are transforming outcomes for many patients. This article provides a comprehensive overview of the symptoms, types, causes, and treatment strategies for hypophosphatasia, drawing on the latest research and clinical experience.

Symptoms of Hypophosphatasia

Hypophosphatasia can manifest in a variety of ways depending on age, disease severity, and individual genetic factors. While some individuals experience severe, life-threatening symptoms early in life, others may have only subtle signs that can be easily missed.

Symptom	Description	Common Age/Type	Source(s)
Bone pain	Persistent pain in bones/joints	Children, Adults	1 3 5
Fractures	Recurrent or poorly-healing fractures	All ages; often adults	1 3 5
Muscle weakness	Reduced muscle strength, fatigue	Children, Adults	3 5
Dental anomalies	Early tooth loss, dental caries	Infants, Children, Adults	2 4 5 10
Skeletal deformity	Bowing of legs, short stature	Infants, Children	2 10 12
Respiratory issues	Difficulty breathing, chest deformity	Perinatal/Infantile	2 6 12 16
Seizures	Pyridoxine-dependent seizures	Infants	6 12
Chondrocalcinosis	Calcium pyrophosphate deposits in joints	Adults, Women	1 5
Fatigue	General tiredness, low energy	Adults	5

Table 1: Key Symptoms

The Spectrum of Symptoms

Bone and Joint Manifestations
One of the hallmark signs of HPP is musculoskeletal pain, which can range from mild discomfort to severe, debilitating pain. Fractures are common, often occurring with minimal trauma and sometimes failing to heal properly. In adults, stress fractures—especially in the feet and hips—are frequent, and some may experience chondrocalcinosis, a form of crystal-induced joint disease that can mimic arthritis 1 3 5.

Muscle Weakness and Mobility Issues
Many patients, especially those with early-onset forms, report muscle weakness and fatigue. This can lead to difficulty walking, delayed motor milestones in children, and dependence on assistive devices in adults 3 5.

Dental Problems
Dental anomalies are a key feature of HPP. Premature loss of primary (baby) teeth, often with intact roots, is typical. Adults may have a history of early tooth loss or severe dental caries, sometimes as their only symptom 2 4 10.

Skeletal Deformities
In infants and children, rickets-like skeletal deformities, such as bowed legs, short stature, and abnormal gait, are common. Severe forms may present with profound skeletal hypomineralization visible on X-rays 2 6 10 12.

Respiratory and Neurological Symptoms
Life-threatening respiratory complications can occur in the most severe forms, usually due to chest deformity and weak rib bones. Some infants may also have seizures that respond to vitamin B6 (pyridoxine), due to altered metabolism of this vitamin 6 12.

Other Features
Fatigue is a frequent but nonspecific symptom, particularly in adults. Some women may develop calcium pyrophosphate deposits in joints, leading to additional joint pain and swelling 1 5.

Types of Hypophosphatasia

Hypophosphatasia is clinically classified based on the age at onset and the severity of symptoms. This classification helps guide diagnosis, management, and genetic counseling.

Type	Onset & Features	Severity	Source(s)
Perinatal (lethal)	In utero or at birth; severe skeletal defects	Most severe	2 6 9 12 16
Perinatal benign	Prenatal, improves spontaneously postnatally	Variable	2 6 9
Infantile	Within first 6 months; rickets, respiratory issues	Severe	2 10 12 16
Childhood	After 6 months to adolescence; bone deformity, short stature, dental loss	Moderate to severe	2 10
Adult	Adulthood; fractures, pain, dental issues	Mild to moderate	1 3 5
Odontohypophosphatasia	Any age; dental problems only	Mildest	2 4 10 9

Table 2: Clinical Types of Hypophosphatasia

Subtypes Explained

Perinatal (Lethal) Hypophosphatasia
This is the most severe form, presenting before or at birth. Affected infants often have profound skeletal hypomineralization, chest deformities, and respiratory failure, which is the leading cause of death 6 9 16.

Perinatal Benign Hypophosphatasia
Though symptoms may appear severe in utero, affected newborns sometimes improve spontaneously after birth. This variant highlights the unpredictable nature of HPP even within similar genotypes 2 6 9.

Infantile Hypophosphatasia
Infants typically present within the first six months with failure to thrive, severe rickets, respiratory distress, premature craniosynostosis (early closure of skull bones), and sometimes pyridoxine-responsive seizures 2 6 10 12.

Childhood Hypophosphatasia
Children may develop skeletal deformities (bowed legs, short stature), delayed walking, muscle weakness, and premature loss of primary teeth. The severity can range from mild to severe, with some children experiencing significant disability 2 10 12.

Adult Hypophosphatasia
Symptoms often include recurrent, poorly-healing fractures (especially in the feet and hips), chronic bone and joint pain, chondrocalcinosis, and dental problems. Some adults may not recall skeletal symptoms in childhood 1 3 5.

Odontohypophosphatasia
This mildest form is characterized mainly by dental manifestations—particularly premature loss of fully rooted teeth and/or severe dental caries—without overt bone disease. It can present at any age and may be the only sign of the disorder 2 4 10 9.

Causes of Hypophosphatasia

At the root of HPP lies a genetic defect that impairs a key enzyme necessary for bone and tooth mineralization. Understanding the molecular and genetic basis is crucial for diagnosis and future therapies.

Cause	Mechanism	Inheritance	Source(s)
ALPL gene mutation	Loss-of-function in tissue-nonspecific alkaline phosphatase (TNSALP)	Autosomal recessive or dominant	2 11 12 13 14 19
TNSALP deficiency	Accumulation of substrates (PPi, PLP, PEA) inhibits mineralization	Varies with mutation severity	12 19
Genotype-phenotype variability	Different mutations, dominant-negative effects, modifier genes	Broad clinical spectrum	7 9 13 14

Table 3: Causes and Mechanisms

The Genetic and Biochemical Basis

The ALPL Gene and TNSALP
HPP is caused by mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP). TNSALP is essential for breaking down molecules that inhibit bone mineralization, notably inorganic pyrophosphate (PPi) 2 11 12 19. Over 300 different mutations, mostly missense, have been identified—this diversity explains the wide variability in clinical presentation 14 19.

Inheritance Patterns
Severe forms (perinatal, infantile) are generally inherited in an autosomal recessive manner, requiring two defective gene copies. Milder forms, including adult and odontohypophosphatasia, can be inherited in either a recessive or autosomal dominant manner. The presence of dominant-negative mutations (where the mutant protein interferes with normal protein function) can also influence disease severity 7 13 14.

Enzyme Deficiency and Substrate Accumulation
When TNSALP activity is low, its substrates—PPi, pyridoxal 5'-phosphate (PLP, a form of vitamin B6), and phosphoethanolamine (PEA)—accumulate. PPi inhibits mineralization, leading to rickets or osteomalacia and causing the characteristic bone and dental symptoms. Elevated PLP can disrupt neurological function, while PEA is often high in urine and blood 12 19.

Genotype-Phenotype Correlations
The type and combination of ALPL mutations greatly affect disease severity. Some mutations have dominant-negative effects, while others allow for residual enzyme activity. Even among patients with the same mutation, symptoms can vary, suggesting that other genetic or environmental factors modify disease expression 7 9 13.

Treatment of Hypophosphatasia

While there is currently no cure for hypophosphatasia, significant progress has been made in managing the disease, especially for severe pediatric forms. Treatment focuses on symptom relief, prevention of complications, and, most recently, enzyme replacement therapy (ERT).

Treatment	Purpose	Main Use	Source(s)
Enzyme replacement (asfotase alfa)	Replaces deficient TNSALP, improves bone health	Pediatric-onset HPP; some adults	15 16 17 18 19
Supportive care	Pain relief, physical therapy	All forms	2 5 8
Orthopedic/dental intervention	Fracture repair, dental care	Moderate/severe forms	3 5 4
Vitamin B6 (pyridoxine)	Controls seizures	Severe infantile	12
Genetic counseling	Family risk assessment	All forms	2 12 14

Table 4: Treatment Approaches

Advances in Enzyme Replacement Therapy

Asfotase Alfa: A Breakthrough
The development and approval of asfotase alfa, a recombinant, bone-targeted TNSALP, has revolutionized the treatment of severe forms of HPP. Clinical trials show that asfotase alfa can dramatically improve survival, bone mineralization, growth, and physical function in infants and children with perinatal and infantile HPP 15 16 17 19.

• In one pivotal study, 95% of treated infants survived to age 1, versus 42% of historical controls 16.
• Children treated for up to 5 years showed sustained improvements in bone health, mobility, and quality of life 17.
• Adults and adolescents with pediatric-onset HPP may also benefit from asfotase alfa, experiencing improved functional abilities and normalization of biomarkers over five years 18.

Considerations and Limitations

• Asfotase alfa is generally approved for pediatric-onset HPP, although some adults may receive it on a case-by-case basis 18 19.
• The most common side effects are mild to moderate injection site reactions 17 18.
• Enzyme replacement does not address all complications, such as dental anomalies, so ongoing multidisciplinary care is essential.

Supportive and Symptomatic Care

Pain Management and Physical Therapy
Pain relief (e.g., with non-steroidal anti-inflammatory drugs), physical therapy, and assistive devices are often needed for mobility and comfort 2 5 8. Muscle strengthening and rehabilitation can improve function and quality of life.

Orthopedic and Dental Interventions
Surgical repair of fractures, dental restoration, and specialized dental care are often necessary, particularly in childhood and adult forms 3 4 5. Dentists play a key role in early recognition and referral 4.

Seizure Control
For infants with pyridoxine-dependent seizures, vitamin B6 supplementation can be lifesaving 12.

Genetic Counseling and Prenatal Diagnosis

Given the variable inheritance and expression, genetic counseling is crucial for affected families. Molecular diagnosis can also allow for prenatal assessment in families at risk for severe forms 2 12 14.

Conclusion

Hypophosphatasia is a complex, highly variable metabolic disorder that presents unique challenges for diagnosis and management. However, recent advances—especially in enzyme replacement therapy—are offering hope to many patients and families.

Key Takeaways:

• Symptoms: Wide-ranging, from severe skeletal and respiratory issues in infants to subtle dental problems in adults.
• Types: Six main clinical forms, classified by age of onset and severity.
• Causes: Genetic mutations in the ALPL gene lead to deficient TNSALP, disrupting bone and tooth mineralization.
• Treatment: Supportive care remains important; asfotase alfa ERT has transformed outcomes for pediatric-onset HPP.

Ongoing research and improved awareness among clinicians, dentists, and families are critical to optimize outcomes and deliver timely, effective care to those living with hypophosphatasia.