Ab1264 rheumatologists beware of low alp: a case of hypophosphatasia misdiagnosed as fibromyalgia, causing long diagnostic delay

Background Hypophosphatasia(HPP), a rare, inherited metabolic disease featuring low serum alkaline phosphatase (ALP) activity due to ALPL (encoding tissue non-specific alkaline phosphatase) gene mutation [1,2] . A wide-ranging clinical spectrum is often seen due to defective mineralisation affecting teeth, bones, joints and muscles [1] . This disease has a prevalence of 1/6370 in Europe and is often misdiagnosed and underdiagnosed with a diagnostic delay of more than ten years [1] The treatment is often supportive for milder cases and enzyme replacement therapy in severe cases. Objectives To share this case to raise awareness among Rheumatologists. Methods This 58-year-old Caucasian female had her first HPP symptom as early eruption of deciduous teeth, along with recurrent dental infections and gum problems. She was diagnosed with flat feet at age five, had a big toe fracture at sixteen, followed by a metatarsal fracture. She experienced leg muscle cramps and aches, affecting her performance in sport during school life. At the age of thirty she began noticing weakness in arms and legs, which progressed over the years. She faced significant early morning stiffness along with painful ribs, hips, knees, shoulders, and small joints of feet when walking. She was diagnosed with Fibromyalgia at the age of forty-four. The following ten years she met numerous specialists including rheumatologist, pain specialist and physiotherapists. She was also diagnosed with early osteoarthritis, pernicious anaemia, hyperlipidemia, functional neurological syndrome, and central sensitization syndrome. She had multiple trials of steroids and opioids, all of which were stopped either due to side effects or inefficiency. A major flare of symptoms five years ago rendered her bedbound for three months, following which a chemical pathologist noticed a persistent low ALP levels and decided to investigate for HPP. It took another four years to complete these investigations due to the coronavirus pandemic. Currently, she is unable to weight bear or climb stairs and must stay indoors or in bed during flareup. She moved into a ground floor flat at the age of 54 and use a walking stick occasionally. By 58, she is unable to work and had given up her own business due to pain, weakness, and disability. Results On clinical assessment, her height is 160 cm, faced difficulty getting up from chair, has an antalgic waddling gait, with a 6-minute walking distance of 60 metre, stopped after three minutes, and had a Brief Pain Inventory pain severity score of 7/10. Her ALP level is 24 U/L and PLP/PA ratio is 18.8 (ref < 5), and genetic testing showed heterozygous missense variant of ALPL gene mutation. Conclusion It took more than forty years to reach a conclusive diagnosis of childhood onset HPP. Low ALP level is a signature of HPP and warrants investigations. Diagnosis can be challenging due to the rareness and variable presentation, however recognition of HPP features is crucial for timely referral, optimal disease management and potential improvement in quality of life. References [1]Högler W, Langman C, Gomes da Silva H, Fang S, Linglart A, Ozono K, Petryk A, Rockman-Greenberg C, Seefried L, Kishnani PS. Diagnostic delay is common among patients with hypophosphatasia: initial findings from a longitudinal, prospective, global registry. BMC Musculoskelet Disord. 2019 Feb 14;20(1):80. doi:10.1186/s12891-019- 2420-8. PMID: 30764793; PMCID: PMC6376686. [2]Injean P, Lee S, Downey C. Hypophosphatasia May Be Misdiagnosed as Fibromyalgia: A Single Center Experience [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/hypophosphatasia-may-be-misdiagnosed-as- ibromyalgia-a-single-center-experience/. Accessed January 14, 2023. [3]Lefever E, Witters P, Gielen E, Vanclooster A, Meersseman W, Morava E, Cassiman D, Laurent MR. Hypophosphatasia in Adults: Clinical Spectrum and Its Association With Genetics and Metabolic Substrates. J Clin Densitom. 2020 Jul-Sep;23(3):340- 48. doi: 10.1016/j.jocd.2018.12.006. Epub 2018 Dec 21. PMID: 30655187. Acknowledgements: NIL. Disclosure of Interests None Declared.