What is the diagnosis and management for a 16-year-old female with a history of joint pain, hypocalcemia, and low alkaline phosphatase levels, suggestive of hypophosphatasia?

Diagnosis and Management of Hypophosphatasia in a 16-Year-Old Female

The combination of joint pain since age 8, hypocalcemia, and low alkaline phosphatase strongly indicates hypophosphatasia (HPP), which requires enzyme replacement therapy with asfotase alfa for optimal management of symptoms and prevention of complications.

Diagnostic Confirmation

The patient's presentation is highly suggestive of juvenile-onset hypophosphatasia:

• Persistently low alkaline phosphatase (ALP) at 60 U/L (reference range 109-364 U/L)
• Hypocalcemia (calcium 8.9 mg/dL, reference range 9.1-10.3 mg/dL)
• Chronic joint pain since age 8
• Adolescent presentation (juvenile-onset form)

Additional Diagnostic Steps:

1. Genetic testing for mutations in the ALPL gene to confirm diagnosis 1
2. Bone-specific ALP measurement - may be more sensitive than total ALP 2
3. Serum vitamin B6 (pyridoxal-5'-phosphate) level - typically elevated in HPP 3
4. Whole-body imaging to assess for:
   • Bone mineralization defects
   • Stress fractures or pseudofractures
   • Premature fusion of growth plates 4

Management Approach

First-line Treatment:

Enzyme replacement therapy with asfotase alfa (Strensiq) is indicated for patients with perinatal/infantile and juvenile-onset HPP 5:

• Dosing for juvenile-onset HPP: 2 mg/kg administered subcutaneously three times per week, or 1 mg/kg administered six times per week 5
• The dose may need adjustment based on clinical response
• Monitor for hypersensitivity reactions including anaphylaxis, especially during early treatment 5

Supportive Care:

1. Pain management:

   • Non-steroidal anti-inflammatory drugs (NSAIDs) for short periods
   • Physical therapy and rehabilitation 6
   • Consider consultation with pain specialists for persistent symptoms 6

2. Dental care:

   • Regular dental examinations (at least twice yearly)
   • Monitoring for dental abscesses and oral infections 6

3. Nutritional support:

   • Ensure adequate calcium intake (minimum 1g per day)
   • Low-sodium diet to reduce calciuria 7
   • Vitamin D supplementation if deficient 7

4. Orthopedic management:

   • Evaluation by an orthopedic surgeon with experience in metabolic bone disease
   • Assessment of limb length and alignment 6
   • Weight-bearing exercise as tolerated 6

Monitoring

1. Laboratory monitoring:

   • Serum ALP levels (marker of disease activity)
   • Calcium and phosphate levels
   • PTH levels (to detect secondary hyperparathyroidism)
   • Vitamin D status 6

2. Imaging follow-up:

   • Skeletal radiographs to assess bone healing and mineralization
   • Consider whole-body MRI to detect clinically silent lesions 6, 4

3. Functional assessment:

   • 6-minute walk test (6MWT) to quantify functional impact 6
   • Assessment of bone and joint pain, disability, and fatigue

Potential Complications to Monitor

1. Musculoskeletal:

   • Fractures and pseudofractures
   • Progressive joint deformities
   • Premature fusion of growth plates

2. Treatment-related:

   • Injection site reactions with asfotase alfa
   • Lipodystrophy at injection sites
   • Ectopic calcifications (eye and kidneys) 5
   • Hypersensitivity reactions including anaphylaxis 5

Important Considerations

• HPP is often misdiagnosed as fibromyalgia or other chronic pain syndromes 3
• Normal total ALP does not rule out HPP; bone-specific ALP may be low despite normal total ALP 2
• Avoid bisphosphonates and other antiresorptive therapies as they may trigger atypical femur fractures in HPP patients 3
• Consider enrollment in the HPP registry for long-term monitoring 5

Early diagnosis and treatment with enzyme replacement therapy can significantly improve quality of life and prevent serious complications in patients with juvenile-onset HPP.