Because of the elevated vitamin B6 level, low ALP level, dental loss, and nonhealing fractures, genetic testing was performed in this patient. She was found to have a novel heterozygous variant in the ALPL gene (p.Ala105Asp), which encodes for tissue-nonspecific alkaline phosphatase (TNSALP). Three of her family members also have low ALP levels; one of them was tested and found to have the same variant in the ALPL gene, without any signs or symptoms of the disease.
Hypophosphatasia is caused by a mutation in the ALPL gene on chromosome 1, which encodes TNSALP. TNSALP is an ectoenzyme bound to the outer surface of osteoblasts. It dephosphorylates several substrates, including inorganic pyrophosphate (PPi), which inhibits bone mineralization produced by osteoblasts and chondrocytes. Accumulation of PPi when TNSALP is deficient impairs calcium/phosphate formation of hydroxyapatite, leading to accumulation of unmineralized osteoid (a feature of rickets and osteomalacia).[1,2]
The exact prevalence of hypophosphatasia varies, depending on the form and the region.[3,4] In the United States, it affects approximately 500-600 individuals. Hypophosphatasia disrupts mineralization, in which such minerals as calcium and phosphorus are deposited in developing bones and teeth. Mineralization is critical for the formation of bones that are strong and rigid and teeth that can withstand chewing and grinding.
The signs and symptoms of hypophosphatasia vary widely and can appear anytime from before birth to adulthood. The most severe forms of the disorder tend to occur before birth and in early infancy. Hypophosphatasia weakens and softens the bones, causing skeletal abnormalities, similar to rickets. Affected infants are born with short limbs, an abnormally shaped chest, and soft skull bones. Additional complications in infancy include poor feeding and a failure to gain weight; respiratory problems; and high levels of calcium in the blood (hypercalcemia), which can lead to recurrent vomiting and kidney problems. These complications are life-threatening in some cases.
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