53-year-old postmenopausal Caucasian female presented with low-trauma, recurrent metatarsal fractures. She reports her first metatarsal fracture at age 21, and since then had at least 8 more metatarsal fractures over her lifetime. On further inquiry, she reported history of gait disturbance as a child and dental issues (spacing and loosening). Labs showed normal serum calcium, phosphorus and PTH, but low serum ALP <20 IU/L and high bone turnover marker, N-telopeptide. Foot X-ray showed several healed and non-healed metatarsal fractures and bone densitometry revealed osteopenia. She was treated with calcium and vitamin D. A year later she had a new metatarsal fracture and a non traumatic pelvic fracture. Teriparatide therapy was subsequently attempted but not tolerated. Due to suspicion of HPP vitamin B6 levels were checked and found to be elevated at 263 mcg/L. Given her clinical presentation and low ALP levels with elevated vitamin B6, the diagnosis of HPP was made.
Discussion:
Hypophosphatasia (HPP) is a rare inborn error of metabolism due to a loss-of-function mutation in the gene for the tissue non-specific isoenzyme of alkaline phosphatase (TNSALP) that results in low levels of ALP. Over 300 mutations have been reported in the TNSALP gene, which is mostly expressed in liver, skeleton and developing teeth. TNSALP is expressed ubiquitously, and its physiological role is evident in bone mineralization. A deficiency in bone mineralization can manifest in many ways, including rickets or osteomalacia. HPP is classified into seven forms according to age of onset and severity: Perinatal (lethal), Prenatal benign, Infantile, Childhood, adult, Odontohypophosphatasia and Pseudohypophosphatasia. Early presentation and lower ALP levels are associated with worse prognosis. Schematically, the diagnosis relies on the clinical presentation and low alkaline phosphatase level. Elevated serum Vitamin B6, phosphoethanolamine and inorganic pyrophosphate support the diagnosis. Bisphosphonates are not helpful in the treatment, and the use of teriparatide is controversial. No established treatment for HPP was available until the recent FDA approval of enzyme replacement therapy (ERT). This bone-targeted recombinant tissue-nonspecific alkaline phosphatase (asfotase alfa) is approved for perinatal, infantile and juvenile HPP. It is expected that therapy with asfotase alfa will markedly improve the prognosis of HPP.
Conclusions:
The clinical presentation of HPP is variable and in adults can easily be misdiagnosed as other forms of osteomalacia. Clinicians should be attentive to a history of recurrent low trauma fractures, premature loss of deciduous teeth and persistently low serum ALP to suspect this diagnosis. Early case detection, with the availability of ERT may avoid years of undiagnosed morbidity.