Perinatal lethal hypophosphatasia

Perinatal lethal hypophosphatasia is the most severe form of hypophosphatasia (HPP), a rare inherited metabolic disorder caused by deficiency of the tissue-nonspecific alkaline phosphatase (TNSALP) enzyme, encoded by the ALPL gene. This form manifests in utero or at birth and is characterized by profoundly impaired bone mineralization, leading to markedly shortened and deformed limbs, soft calvarium (skull bones), and a small thoracic cage. The severe skeletal undermineralization can be detected on prenatal ultrasound, and affected neonates often present with caput membranaceum (membrane-covered skull), respiratory insufficiency due to hypoplastic lungs and rachitic chest deformity, and hypercalcemia. Stillbirth is common, and most affected infants who are born alive survive only hours to days due to respiratory failure. The condition primarily affects the skeletal system, but secondary complications involve the respiratory, renal, and neurological systems. Hypercalcemia may lead to renal damage, and seizures responsive to pyridoxine (vitamin B6) can occur due to impaired metabolism of pyridoxal 5'-phosphate. Laboratory findings include markedly low or absent serum alkaline phosphatase activity and elevated levels of natural substrates including phosphoethanolamine, inorganic pyrophosphate, and pyridoxal 5'-phosphate in blood and urine. Historically, this condition was uniformly fatal with only supportive care available. However, enzyme replacement therapy with asfotase alfa (Strensiq), a bone-targeted recombinant TNSALP, was approved for the treatment of perinatal/infantile- and juvenile-onset hypophosphatasia and has shown some benefit in improving survival and skeletal mineralization in severely affected infants when initiated early. Despite this advance, the prognosis for the perinatal lethal form remains extremely poor, and management focuses on multidisciplinary supportive care including respiratory support and management of metabolic complications.

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