Adult Hypophosphatasia: More Than a Skeletal Problem

Hypophosphatasia (HPP) is a rare diagnosis manifesting commonly by musculoskeletal pain. Herein, we describe a case of adult HPP where the diagnosis was initially missed and use of asfotase alfa provided significant benefits beyond improvements in motor function and muscle pain.

Case Description:

A 48-year-old female was initially referred to endocrinology for hypercalcemia with single corrected Ca 10.8 (8.5-10.2 mg/dL). Work up for primary hyperparathyroidism was negative. Calcium subsequently normalized without intervention. However, it was noted during examination that she was suffering from severe fatigue, generalized pain, and decreased concentration/cognitive function that had been ongoing for years. Pain flares were debilitating and preventing her from carrying daily activities, to the point that she was considering disability and quitting her job as a nurse. She had consequently been diagnosed with fibromyalgia. In her third decade, she had multiple metacarpals and metatarsals fractures and loss of teeth. She had degenerative osteoarthritis in her hands and left hip requiring multiple corticosteroid injections. Family history is significant for early teeth loss and kidney stones in several family members. Review of medical records revealed persistently low alkaline phosphatase (ALP) over the last 16 years with the highest value of 32 (34-123 U/L). Vitamin B6 was elevated to 225.1 (20-125 nmol/L). Interestingly, she had no childhood history of skeletal or dental issues apart from pain in the lower limbs. Genetic testing revealed a heterozygous variant of uncertain significance in the ALPL gene (c.318G >C [p.Gln106His]) which was reported in an infant with hypophosphatasia and severe epileptic encephalopathy. Patient was diagnosed with HPP and subsequently started on asfotase alfa. With this treatment, patient experienced dramatic improvements in muscle function and strength along with reduced pain. One of her most pronounced improvements, however, was not in the musculoskeletal domain but rather with improvement in her cognitive functioning.

Discussion:

In adults, the diagnosis of HPP is commonly missed. This is in part due to its similarity with other conditions such as fibromyalgia and osteoarthritis. Additionally, low ALP is often overlooked as a normal variation. Despite its rarity, this missed diagnosis can lead to delay in appropriate treatment as was the case here. It is also important to note that the improvements seen with asfotase alfa are more than musculoskeletal ones but also cognitive in nature. This has been demonstrated in trials looking at improvements in pediatric patients but not as much discussed for patients diagnosed and treated during adulthood.