Hypophosphatasia (
HPP) is a rare inherited systemic
metabolic disease caused by mutations in the tissue-nonspecific
alkaline phosphatase (TNSALP) gene. TNSALP is expressed in the liver, kidney and bone, and its substrates include TNSALP inorganic
pyrophosphate, pyridoxal-5'-phosphate (PLP)/
vitamin B6 and
phosphoethanolamine (PEA). Autosomal recessive and dominant forms of the disease result in a range of clinical entities. Major hallmarks are low
alkaline phosphatase (ALP) and elevated PLP and PEA levels. Very severe infantile forms of
HPP cause premature death as a result of
respiratory insufficiency and also present with hypo-mineralisation leading to deformed limbs with, in some cases, the near-absence of bones and skull altogether.
Respiratory failure,
rib fractures and
seizures due to
vitamin B6 deficiency are indicative of a poor prognosis.
Craniosynostosis is frequent.
HPP leads to an unusual presentation of
rickets with high levels of
calcium and
phosphorus, resulting in
hypercalciuria,
nephrocalcinosis and low ALP levels. Hypercalcaemic crisis,
failure to thrive and growth retardation are concerns in infants. Fractures are common in both infantile and adult forms of the disease, concomitantly occurring with unexplained
chronic pain and
fatigue. Dental clinical presentations, which include the premature loss of teeth, are also commonly found in
HPP and specifically manifest as
odontohypophosphatasia. A novel
enzyme therapy for human
HPP,
asfotase alfa, which is specifically targeted to mineralised tissues, has been developed in the past decades. While this treatment seems very promising, especially for infantile
HPP, many questions regarding its long-term effects, the management of treatment, and any potential secondary adverse effects remain unresolved.