MON-498 When to Sweat the Details: A Case of Adult Hypophosphatasia

Introduction: Hypophosphatasia (HPP) is characterized by defective mineralization of bone due to low activity of serum bone alkaline phosphatase. Adult forms are characterized by stress fractures and pseudofractures of the lower extremities and early loss of adult dentition. Here we present a case of adult HPP with a novel variant of the ALPL gene (p.Ala105Asp). Case Description: A 59-year old male with past medical history of chronic pain, polyarthralgia, multiple tendon/muscle tears, severe periodontal disease, requiring multiple fillings and crowns since his early 20s, and calcium pyrophosphate deposition disease (CPPD) presents with progressively worsening peripheral neuropathy in his feet. He has a left fifth metatarsal small avulsion non-healing fracture and old left non-union tibial sesamoid fracture with loss of physical function impacting ADLs, requiring assistance with mobility. Vitamin B6 was 127.7 ng/mL [2.1-21.7 ng/mL] and alkaline phosphatase was 18 U/L [53-128 U/L]. Genetic testing was done which revealed he has a heterozygous variant of ALPL gene (p.Ala105Asp). He has 3 family members with variants of ALPL gene and have since been diagnosed with hypophosphatasia. Rest of the family are asymptomatic. The patient is currently undergoing evaluation for treatment with recombinant alkaline phosphatase, asfotase alfa. Discussion: Adult HPP may be inherited in an autosomal recessive or autosomal dominant manner, depending on the effect that the ALPL pathogenic variant has on TNSALP activity. Heterozygotes (carriers) are either asymptomatic (may manifest biochemically but not clinically) or symptomatic. This patient had a heterozygous variant in the ALPL gene (p.Ala105Asp), which, to our knowledge, has not been reported in association with ALPL-related conditions, however other variants flanking this position in the gene (p. Asn102_Asn104del, p.G1n106His) have been associated with adult, perinatal, and infantile HPP, suggesting a change at this position adversely affects protein structure and/or function. Furthermore, this variant has not been reported in the broad dataset (individuals without severe childhood onset disease). Conclusion: Adult HPP is a rare disorder that is often underdiagnosed due to varying nonspecific symptoms. Awareness of the disease and identification of patients who have findings such as elevated vitamin B6 and low alkaline phosphatase is essential prior to confirming diagnosis with genetic testing. Diagnosis is paramount as patients with this disorder can now be treated with recombinant alkaline phosphatase. This case was remarkable as this patient has a heterozygous novel variant in the ALPL gene (p.Ala105Asp).