Hyperphosphatasia

The term ‘Hyperphosphatasia’ may seem intimidating. Let’s understand it in simple words. 

‘Hyperphosphatasia’ can be split into 2 parts: Hyper (=excessive) and Phosphatasia (=phosphatase enzyme). In simple terms, Hyperphosphatasia can be described as a disorder with excessive phosphatase enzyme. The phosphatase enzyme breaks down phosphoric acid into a phosphate ion and alcohol, an important step for cell growth and signalling. 

The activity of the phosphatase enzyme depends upon the pH of the surrounding condition. 

Based on this activity, it is of two types: acid and alkaline. Acid phosphatase shows maximum activity at a pH around 6 (pH<7 is acidic) and alkaline phosphatase shows maximum activity at a pH around 11 (pH>7 is alkaline).¹ 

Hyperphosphatasia refers to an elevated level of Alkaline Phosphatase (ALP) enzyme in the blood. 

The general causes of elevated alkaline phosphatase are:²

• Bone diseases such as Paget's disease, Osteogenesis imperfecta, Osteogenic sarcoma, and Hyperparathyroidism 
• Liver diseases such as Hepatitis, Liver cirrhosis, and Cholangitis
• Genetic factors such as Hereditary hyperphosphatasia, Hypophosphatasia, and Wilson’s disease 

Hereditary hyperphosphatasia

Hereditary Hyperphosphatasia is a rare genetic bone disorder characterised by excessive bone deposition and resorption simultaneously due to a mutation (defect) in the TNFRSF11B gene (discussed later). It is seen during infancy or early childhood (2 to 3 years old). The affected bones are the skull, long bones, spine, and pelvis.

It is also known as:³

• Juvenile Paget's Disease
• Hyperostosis corticalis generalisata
• Familial idiopathic hyperphosphatasia
• Hyperostosis corticalis deformans juvenilis

Prevalence 

Prevalence refers to the number of cases in a population in a given time.
Hereditary hyperphosphatasia is a rare condition, affecting fewer than 1 in 10 million people.⁷

Genetic basis of hereditary hyperphosphatasia

Inheritance pattern

Hereditary Hyperphosphatasia is inherited as an Autosomal Recessive trait meaning the affected child must possess two copies of defective genes from both parents. There is a 25% chance of passing mutated genes from both parents to the offspring. 

That means only 1 out of 4 offspring who receive 1 mutated copy from each parent will be affected by the condition. 

2 out of 4 offspring who receive 1 mutated copy each from either of their parents will be disease carriers.

And 1 out of 4 offspring who do not receive any mutated copy will be unaffected.  

Males (Assigned Male At Birth) and females (Assigned Female At Birth) are equally affected. 

Genes involved

Hereditary Hyperphosphatasia arises due to a mutation (defect) in the TNFRSF11B gene which codes for a protein called osteoprotegerin (OPG). OPG regulates the activity of bone-resorbing cells called osteoclasts and prevents the bone from excess resorption. 

Hence, it plays a key role in bone turnover, the process of bone remodelling. It refers to the deposition and absorption of bone that occurs throughout life. This process helps in bone expansion while maintaining its shape and structure.³

Effects of gene mutation

Due to the mutation in the TNFRSF11B gene, there is a deficiency of OPG. Osteoprotegerin deficiency leads to increased bone resorption and abnormal bone formation. As a result, the rate of bone turnover is increased.³

Symptoms and clinical manifestations

Children affected with hereditary hyperphosphatasia appear normal at birth. Symptoms start appearing by the age of 2-3 years. Early symptoms include difficulty walking, pain in the legs, and the development of deformities in the legs. Some cases may even present with fractures. 

Bone-related symptoms

• Bowed legs
• Enlarged joints
• Enlarged skull
• Thickening of bones 
• Bone and joint pain
• Fragile bones
• Frequent bone fractures
• Short stature
• Abnormal curvature of spine
• Vertebral collapse

Additional possible symptoms

• Fever
• Hearing loss due to bone abnormalities in the skull
• Damage to the optic nerve, the nerve supply to the eye
• Angioid streaks (jagged lines radiating from the retina of the eyes) 
• Muscle weakness
• Fatigue

Diagnosis

Blood tests

The blood tests reveal 

• Elevated bone-specific alkaline phosphatase (BAP) levels 
• Elevated osteocalcin levels
• Normal Calcium and Phosphorus serum levels

Urine tests

The urine test reveals 

• Elevated urine hydroxyproline and proline-containing peptide levels.

Others

Several conditions can elevate the Alkaline Phosphatase enzyme in serum. A few tests can be performed to eliminate causes other than bone diseases 

The tests to differentiate between liver disease and bone-related causes of ALP are:

• Gamma-Glutamyl Transferase (GGT): Elevated GGT along with elevated ALP suggest liver disease, not the bone origin of elevated ALP⁴ 
• 5’-Nucleotidase (5’-NT): Similarly, elevated 5’-NT and ALP suggest a liver disease⁵ 
• Liver Function Test: Elevated Aspartate Transaminase (AST) and Alanine Transaminase (ALT) suggest liver damage

Genetic testing

Genetic testing is a medical test that determines changes on the genetic level. It can be done to confirm the diagnosis, plan treatment and improve quality of life. 

Families with a history of Hereditary Hyperphosphatasia can opt for genetic testing and counselling. 

Imaging

X-rays reveal distinct radiographic features which further aid in confirming the diagnosis. These features include:⁶

• Skull: widened and thickened skull bones with a patchy cotton wool appearance
• Long bones: thickened outer layer of bone (cortical thickening) with bowed legs
• Spine: fish vertebrae (biconcave shaped) with height loss
• Pelvis: defect in the hip joint

Treatment and management

Medications

Treatment of Hereditary Hyperphosphatasia is usually supportive based on the affected person’s symptoms. 

Bisphosphonates 

Bisphosphonates are drugs known for their action on bone-resorbing cells called osteoclasts. They reduce osteoclast activity. Hence, slowing down bone resorption.
Several case studies reveal effective treatment of hereditary hyperphosphatasia with bisphosphonates such as pamidronate, zoledronate or etidronate.^7,8,9,10

These drugs can reduce:⁷

• Rapid bone turnover
• Bone pain
• Prevent bone deformity 
• Improve hearing

Calcitonin

Calcitonin is a drug that mimics the human calcitonin hormone and controls excess calcium levels in the blood.
Calcitonin acts by various mechanisms such as:

• Retraction of osteoclasts, thereby, reducing their activity and bone resorption
• Increase activity of bone-forming cells (osteoblasts)  
• Decrease reabsorption of calcium by kidneys, thereby, reducing calcium levels in the blood

Denosumab

Denosumab is a monoclonal antibody that mimics the effects of osteoprotegerin. In simpler words, it is a bone anti-resorptive drug. 

It can be used to reduce:

• Bone pain
• Bone loss
• Fractures

Recombinant osteoprotegerin 

Treatment with recombinant osteoprotegerin show:¹¹

• Suppressed bone loss
• Increased bone mass

Physical therapy

Physical therapy plays a crucial role in the management of hereditary hyperphosphatasia. Depending upon the case and the severity of the bone deformity, the approach to physical therapy should be personalised and gentle. 

Benefits of physical therapy

Skeletal deformities may not be corrected entirely but with the help of medications and physical therapy, you can improve your health in the following ways:

• Reduce bone and joint pain through various exercises
• Strengthen muscles to support the bones and body weight
• Improve joint mobility for easier limb and body movement
• Increase body flexibility and reduce stiffness
• Enhance balance and coordination and prevent fractures
• Reduces dependency on others for daily life activities
• Releases feel-good hormones such as dopamine and serotonin
• Boosts self-esteem and confidence

Various physical exercises that can be performed under the guidance of a physiotherapist or a specialised trainer are: 

• Gentle stretching of leg muscles
• Slow and controlled walking
• Resistance band training
• Light weight training
• Body-weight exercises such as gentle squats, easy push-ups and lunges
• Core muscle training such as crunches and situps
• Standing balance exercises
• Gait and posture training
• Stationary cycling
• Aqua therapy

Read more here: What Are Bow Legs And Can They Be Corrected?

Surgery (in severe cases)

Surgical intervention is reserved for severe cases of hereditary hyperphosphatasia. There is no definitive surgical therapy; it is based on the severity of the skeletal deformity, joint damage, or fracture. It must be planned carefully because the bones are fragile and prone to fractures. Hence, other treatment modalities are preferred first and surgery is the last resort. 

Various surgical options are:

• Osteotomy (Bone-cutting) to correct bony defects and deformities
• Arthroplasty (Joint replacement) to replace and repair severely damaged joints
• Bone grafting to fill bone defects and enhance bone healing
• Fracture fixation to stabilise the fracture fragments and promote healing
• Nerve decompression procedures to manage the secondary symptoms in the eye and ear

Prognosis and long-term outlook

Variability in severity

The likely course (prognosis) of Hereditary Hyperphosphatasia depends majorly on the severity of the condition.

Some individuals may lead relatively normal lives with proper management. Others may experience severe bone-related complications. For effective management and compliance, the healthcare provider must provide adequate knowledge and information about the condition to the affected person. 

Importance of early diagnosis and intervention

Early diagnosis and intervention can save the person affected by hereditary hyperphosphatasia from the trials and tribulations of everyday life. 

It can help prevent complications like fractures, deformities, and hearing loss.

Hence, families with a history of this condition must seek genetic testing and prenatal genetic counselling for a good quality of life. 

Summary

Hereditary Hyperphosphatasia is a rare genetic bone disorder with elevated levels of the enzyme Alkaline Phosphatase in serum. It affects the bone structure and growth. Children are typically born without any visible symptoms. The symptoms such as pain in the legs, difficulty walking, and bowing of legs start appearing around 2 to 3 years of age. Thickened bones, cotton-wool patches and other bony defects can be seen on radiographs. The severity varies from individual to individual. Some may lead relatively normal lives while others may be afflicted with severe skeletal deformities that hamper basic daily life tasks. It can be managed with a combination of medications such as bisphosphonates, physical therapy and occasionally surgery. Since it is a rare disease, there is a lack of adequate data, information and awareness. With continued research, we can expect new effective treatments and genetic therapies soon.