SAT-794 Unspoken Signs: A Rare Case Of Hypophosphatasia In An Adult With Down Syndrome

Abstract Disclosure: K. Shaik: None. S. Rasmussen: None. R. Shaik: None. R.H. Castaneda: None. S. Shaik: None. Introduction: Hypophosphatasia (HPP) is a rare metabolic bone disorder resulting from mutations in the ALPL gene, leading to reduced activity of tissue-nonspecific alkaline phosphatase (TNSALP). While commonly identified in infancy or childhood due to skeletal abnormalities, adult presentations are under-recognized, particularly when masked by comorbid cognitive impairment. We present a diagnostically challenging case of HPP in a 43-year-old woman with Down syndrome and cognitive impairment, whose nonspecific musculoskeletal symptoms obscured the underlying metabolic pathology. Case Presentation: A 43-year-old female with known Down syndrome and hypothyroidism was evaluated for persistent leg pain, muscle weakness, and delayed ambulation (walked at age 3). She exhibited short stature, tremors, and poor exercise tolerance. Despite these findings, a definitive diagnosis remained elusive due to communication limitations and overlapping syndromic features. Laboratory testing revealed persistently low alkaline phosphatase levels (as low as 24 IU/L; ref: 37-127 IU/L) and markedly elevated plasma vitamin B6 (up to 99.4 ng/mL; ref: 2.1-21.7 ng/mL). Genetic testing confirmed hypophosphatasia in July 2024. Bone mineral density was within normal limits for age. She was started on asfotase alfa (Strensiq) at 2 mg/kg three times weekly with positive tolerance. Her mild chronic kidney disease and hypotension were monitored by nephrology and cardiology, respectively. Discussion: This case underscores the diagnostic complexity of HPP in adults with developmental and cognitive disorders, where atypical symptom presentation and coexisting conditions delay recognition. In HPP, persistently low alkaline phosphatase with elevated pyridoxal 5'-phosphate (vitamin B6) serves as a biochemical hallmark. Adult HPP often presents subtly with fatigue, myalgias, and fractures but can be overlooked without high clinical suspicion. Delayed diagnosis may lead to functional decline and compromised quality of life. Literature reports have highlighted HPP's phenotypic variability, with many adult cases previously misdiagnosed as fibromyalgia, osteoporosis, or other metabolic bone diseases. Conclusion: This case exemplifies the importance of maintaining a high index of suspicion for HPP in adults with nonspecific musculoskeletal symptoms and cognitive challenges. Recognizing biochemical red flags and utilizing confirmatory genetic testing is vital to initiating timely enzyme replacement therapy. Increased awareness is essential to improve outcomes in this underdiagnosed population. Presentation: Saturday, July 12, 2025