HYPOPHOSPHATASIA

Definition and Background

• Rare inherited disorder characterized by low alkaline phosphatase levels in serum and bone.
• Results in defective bone and tooth mineralization, leading to osteomalacia and severe periodontal disease.
• Caused by mutations in the ALPL gene (tissue-nonspecific alkaline phosphatase isoenzyme).

Inheritance and Clinical Variants

• Perinatal and infantile forms: usually autosomal recessive.
• Milder forms (childhood or adulthood): can be autosomal dominant or autosomal recessive, depending on specific gene mutations.

Perinatal Lethal Hypophosphatasia

• Complete absence of alkaline phosphatase; estimated prevalence: ~1 in 100,000 births.
• Severe manifestations:
  • Lack of mineralized bone in utero → profound skeletal deformities.
  • Skin-covered osteochondral spurs on legs and forearms.
  • Rachitic chest deformities, hypoplastic lungs (respiratory compromise).
  • Premature craniosynostosis → ↑ intracranial pressure.
  • Seizures, hypercalcemia, nephrocalcinosis, and renal failure.
• Typically fatal early.

Childhood Hypophosphatasia

• Results from milder ALPL mutations.
• Skeletal abnormalities include:
  • Enlarged joints, focal metaphyseal changes, short stature.
  • Premature loss of deciduous teeth, especially incisors.
• Disease severity can fluctuate, sometimes improving spontaneously, then recurring later.

Adult-Onset Hypophosphatasia

• Often becomes symptomatic in 4th–5th decade of life.
• Clinical features:
  • Thigh pain from femoral pseudofractures or metatarsal stress fractures.
  • Chondrocalcinosis.
  • Odontohypophosphatasia: severe dental caries, loose teeth, early tooth loss.

Pathophysiology

• Tissue-nonspecific alkaline phosphatase (TNAP) is needed to generate inorganic phosphate for hydroxyapatite formation.
• Mutations reduce TNAP enzyme activity → impaired bone mineralization.
• Buildup of pyrophosphate also inhibits bone mineralization.

Laboratory Findings

• Low total alkaline phosphatase (ALP) in serum is a hallmark.
• Confirmed by increased blood and urine concentrations of organic phosphate compounds:
  • Phosphoethanolamine
  • Phosphorylcholine
  • Pyridoxal 5-phosphate
• Bone biopsy: same changes as other forms of rickets (unmineralized osteoid).
• Serum calcium and phosphorus are often normal in adults.

Genetic Testing

• Most ALPL mutations are missense; others include deletions, nonsense, or insertions.
• Disease severity correlates with residual enzyme activity:
  • Severe disease → negligible activity.
  • Mild disease → some preserved TNAP activity.

Treatment

• No current curative therapy.
• Management targets signs and symptoms:
  • Bone pain, fractures, dental issues, etc.
• Supportive care may involve orthopedic interventions, dental management, and sometimes experimental therapies.