Abstract
Hypophosphatasia (HPP) is a rare inherited metabolic disorder caused by loss-of-function mutations in the ALPL gene, leading to deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP). This results in impaired bone and dental mineralization, causing a wide range of clinical manifestations, from perinatal lethality to mild adult-onset forms. We report a case of a 40-year-old female with a history of joint pain, multiple fractures, dental issues, and bipolar disorder, who was diagnosed with adult-onset HPP. Laboratory investigations revealed persistently low alkaline phosphatase (ALP) levels and elevated vitamin B6. Genetic testing confirmed a pathogenic ALPL mutation. The patient was initiated on enzyme replacement therapy (ERT) with asfotase alfa, resulting in significant symptom improvement. This case highlights the importance of recognizing HPP in adults with unexplained musculoskeletal symptoms and underscores the role of genetic testing in the diagnosis and management of this condition.
References
1. Khan AA, Josse R, Kannu P, Villeneuve J, Paul T, Van Uum S, Greenberg CR. Hypophosphatasia: Canadian update on diagnosis and management. Osteoporos Int. 2019: 1713 [PMID: 30915507, https://doi.org/10.1007/s00198-019-04921-y]
2. Buchet R, Millan JL, Magne D. Multisystemic functions of alkaline phosphatases. Methods Mol Biol. 2013: 27 [PMID: 23860646, https://doi.org/10.1007/978-1-62703-562-0_3]
3. Silvent J, Gasse B, Mornet E, Sire JY. Molecular evolution of the tissue-nonspecific alkaline phosphatase allows prediction and validation of missense mutations responsible for hypophosphatasia. J Biol Chem. 2014: 24168 [PMID: 25023282, https://doi.org/10.1074/jbc.M114.576843]
4. Whyte MP. Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016: 233 [PMID: 26893260, https://doi.org/10.1038/nrendo.2016.14]
5. Rathbun JC. Hypophosphatasia; a new developmental anomaly. Am J Dis Child (1911). 1948: 822 [PMID: 18110134, https://doi.org/10.1001/archpedi.1948.02030020840003]
6. Weiss MJ, Cole DE, Ray K, Whyte MP, Lafferty MA, Mulivor RA, Harris H. A missense mutation in the human liver/bone/kidney alkaline phosphatase gene causing a lethal form of hypophosphatasia. Proc Natl Acad Sci U S A. 1988: 7666 [PMID: 3174660, https://doi.org/10.1073/pnas.85.20.7666]
7. Tenorio J, Alvarez I, Riancho-Zarrabeitia L, Martos-Moreno GA, Mandrile G, de la Flor Crespo M, Sukchev M, Sherif M, Kramer I, Darnaude-Ortiz MT, Arias P, Gordo G, Dapia I, Martinez-Villanueva J, Gomez R, Iturzaeta JM, Otaify G, Garcia-Unzueta M, Rubinacci A, Riancho JA, Aglan M, Temtamy S, Hamid MA, Argente J, Ruiz-Perez VL, Heath KE, Lapunzina P. Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia. Am J Med Genet A. 2017: 601 [PMID: 28127875, https://doi.org/10.1002/ajmg.a.37991]
8. Mornet E. Hypophosphatasia. Metabolism. 2018: 142 [PMID: 28939177, https://doi.org/10.1016/j.metabol.2017.08.013]
9. Bianchi ML, Bishop NJ, Guanabens N, Hofmann C, Jakob F, Roux C, Zillikens MC, Rare Bone Disease Action Group of the European Calcified Tissue S. Hypophosphatasia in adolescents and adults: overview of diagnosis and treatment. Osteoporos Int. 2020: 1445 [PMID: 32162014, https://doi.org/10.1007/s00198-020-05345-9]
10. Sebastian-Serrano A, de Diego-Garcia L, Henshall DC, Engel T, Diaz-Hernandez M. Haploinsufficient TNAP Mice Display Decreased Extracellular ATP Levels and Expression of Pannexin-1 Channels. Front Pharmacol. 2018: 170 [PMID: 29551976, https://doi.org/10.3389/fphar.2018.00170]
11. Strazzulla LC, Cronstein BN. Regulation of bone and cartilage by adenosine signaling. Purinergic Signal. 2016: 583 [PMID: 27473363, https://doi.org/10.1007/s11302-016-9527-2]
12. Whyte MP. Hypophosphatasia: An overview For 2017. Bone. 2017: 15 [PMID: 28238808, https://doi.org/10.1016/j.bone.2017.02.011]
13. Garcia-Fontana C, Villa-Suarez JM, Andujar-Vera F, Gonzalez-Salvatierra S, Martinez-Navajas G, Real PJ, Gomez Vida JM, de Haro T, Garcia-Fontana B, Munoz-Torres M. Epidemiological, Clinical and Genetic Study of Hypophosphatasia in A Spanish Population: Identification of Two Novel Mutations in The Alpl Gene. Sci Rep. 2019: 9569 [PMID: 31267001, https://doi.org/10.1038/s41598-019-46004-2]
14. Fenn JS, Lorde N, Ward JM, Borovickova I. Hypophosphatasia. J Clin Pathol. 2021: 635 [PMID: 33931563, https://doi.org/10.1136/jclinpath-2021-207426]
15. Whyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann N Y Acad Sci. 2010: 190 [PMID: 20392236, https://doi.org/10.1111/j.1749-6632.2010.05387.x]
16. Baumgartner-Sigl S, Haberlandt E, Mumm S, Scholl-Burgi S, Sergi C, Ryan L, Ericson KL, Whyte MP, Hogler W. Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene. Bone. 2007: 1655 [PMID: 17395561, https://doi.org/10.1016/j.bone.2007.01.020]
17. Berkseth KE, Tebben PJ, Drake MT, Hefferan TE, Jewison DE, Wermers RA. Clinical spectrum of hypophosphatasia diagnosed in adults. Bone. 2013: 21 [PMID: 23352924, https://doi.org/10.1016/j.bone.2013.01.024]
18. Hofmann C, Girschick HJ, Mentrup B, Graser S, Seefried L, Liese J, Jakob F. Clinical Aspects of Hypophosphatasia: An Update. Clinical Reviews in Bone and Mineral Metabolism. 2013: 60 https://doi.org/10.1007/s12018-013-9139-0]
19. Mornet E. Hypophosphatasia. Orphanet J Rare Dis. 2007: 40 [PMID: 17916236, https://doi.org/10.1186/1750-1172-2-40]
20. Royce PM, Blumberg A, Zurbrugg RP, Zimmermann A, Colombo JP, Steinmann B. Lethal osteogenesis imperfecta: abnormal collagen metabolism and biochemical characteristics of hypophosphatasia. Eur J Pediatr. 1988: 626 [PMID: 3181205, https://doi.org/10.1007/BF00442478]
21. Unger S, Mornet E, Mundlos S, Blaser S, Cole DE. Severe cleidocranial dysplasia can mimic hypophosphatasia. Eur J Pediatr. 2002: 623 [PMID: 12424591, https://doi.org/10.1007/s00431-002-0978-9]
22. Wyckoff MH, El-Turk C, Laptook A, Timmons C, Gannon FH, Zhang X, Mumm S, Whyte MP. Neonatal lethal osteochondrodysplasia with low serum levels of alkaline phosphatase and osteocalcin. J Clin Endocrinol Metab. 2005: 1233 [PMID: 15562030, https://doi.org/10.1210/jc.2004-0251]
23. Henthorn PS, Raducha M, Fedde KN, Lafferty MA, Whyte MP. Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia. Proc Natl Acad Sci U S A. 1992: 9924 [PMID: 1409720, https://doi.org/10.1073/pnas.89.20.9924]
24. Dattagupta A, Petak S. A Case of Hypophosphatasia With Normal Alkaline Phosphatase Levels. AACE Clin Case Rep. 2024: 38 [PMID: 38523854, https://doi.org/10.1016/j.aace.2023.11.006]
25. Schmidt T, Mussawy H, Rolvien T, Hawellek T, Hubert J, Ruther W, Amling M, Barvencik F. Clinical, radiographic and biochemical characteristics of adult hypophosphatasia. Osteoporos Int. 2017: 2653 [PMID: 28547134, https://doi.org/10.1007/s00198-017-4087-z]
26. Bianchi ML. Hypophosphatasia: an overview of the disease and its treatment. Osteoporos Int. 2015: 2743 [PMID: 26245849, https://doi.org/10.1007/s00198-015-3272-1]
27. Bowden SA, Foster BL. Alkaline Phosphatase Replacement Therapy for Hypophosphatasia in Development and Practice. Adv Exp Med Biol. 2019: 279 [PMID: 31482504, https://doi.org/10.1007/978-981-13-7709-9_13]
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