SAT-735 - Multigenerational Hypophosphatasia Due to A Pathogenic ALPL Frameshift Variant: Diagnostic Challenges and Therapeutic Implications in Adult-Onset Disease

Background:

Hypophosphatasia (HPP) is a rare inherited metabolic bone disorder caused by loss-of-function mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP). Enzyme deficiency results in the accumulation of inorganic pyrophosphate and pyridoxal-5′-phosphate, impairing skeletal and dental mineralization. While severe pediatric forms are increasingly recognized, adult-onset HPP remains underdiagnosed due to phenotypic heterogeneity, preserved bone mineral density, and overlap with degenerative or inflammatory musculoskeletal disorders. Persistently low serum alkaline phosphatase (ALP) is the defining biochemical hallmark.

Case Description:

We report a multigenerational family with genetically confirmed hypophosphatasia. The 61-year-old proband displayed chronically low ALP (20–30 U/L) and elevated pyridoxal-5′-phosphate for over two decades. In childhood, she had inward-turning feet, required bracing, and experienced delayed primary tooth loss requiring extraction.

As an adult, she developed progressive musculoskeletal symptoms, including chondromalacia patellae, recurrent meniscal injuries, metatarsalgia, tendonitis, chronic joint pain, degenerative disease, and spinal stenosis. Imaging showed degenerative disc disease, advanced knee chondromalacia, osteophytes, and cuboid arthritis. Bone mineral density was preserved despite symptom burden.

Genetic testing identified a heterozygous pathogenic ALPL frameshift variant, c.480del p.(Val161Trpfs*4), predicted to result in protein truncation through a process called nonsense-mediated decay (a cellular mechanism that eliminates abnormal proteins). A sibling was found to carry the same pathogenic variant with similar musculoskeletal and dental problems. Both individuals began enzyme replacement therapy with recombinant mineral-targeted alkaline phosphatase (asfotase alfa), a manufactured form of the missing enzyme used as treatment since 2015 for pediatric-onset HPP. Following treatment, both patients reported less musculoskeletal pain and improved functional ability. Additional family members showed persistently low ALP levels and bone or dental features suggestive of HPP.

Conclusion:

This family case series underlines the broad clinical spectrum and diagnostic challenges of adult-onset hypophosphatasia. Preserved or elevated bone mineral density does not rule out HPP and may delay diagnosis. Persistently low alkaline phosphatase, even in adults with normal or elevated bone mineral density, should prompt evaluation for hypophosphatasia and ALPL genetic testing. Genetic confirmation enables precise diagnosis, family screening, and appropriate management. Adults with pediatric-onset manifestations may benefit symptomatically from disease-specific therapy, reinforcing the need for awareness and targeted intervention.

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