Clinical, radiographic and biochemical characteristics of adult hypophosphatasia
- 685 Downloads
In this study, we report on clinical, radiographic and biochemical characteristics of 38 patients with adult hypophosphatasia. High-resolution peripheral quantitative computed tomography showed alterations of bone microstructure in a subgroup of 14 patients. Pyridoxal-5-phosphate levels correlated with the occurrence of fractures and the number of symptoms.
Hypophosphatasia (HPP) is a rare disorder with a wide range of clinical manifestations. A reduced enzymatic activity of alkaline phosphatase (ALP) is the key marker of the disease, causing an accumulation of ALP substrates such as pyridoxal-5-phosphate (PLP). The purpose of this retrospective study was to further characterize adult onset HPP.
We assessed clinical, radiographic and laboratory characteristics of 38 adult patients with HPP. Diagnosis of HPP was established by the combination of low-serum ALP, raised PLP levels and typical symptoms and was genetically confirmed in 32 patients. Dual-energy X-ray absorptiometry (DXA) and laboratory data were available in most patients. High-resolution peripheral quantitative computed tomography (HR-pQCT) was performed in 14 patients.
Clinical characteristics included a wide spectrum of symptoms. A history of fracture was present in 15 patients (39%). Twenty-one patients (55%) complained about recurring headaches, 23 patients (61%) had recurring muscle pain, 4 patients (11%) suffered from severe muscle weakness and 18 patients (47%) showed dental abnormalities. Z-scores assessed by DXA were only slightly reduced in most adult HPP patients. HR-pQCT of 14 patients showed microstructural changes of trabecular and cortical bone compared to reference values of healthy subjects. The occurrence of fractures and multiple symptoms (>2 typical HPP symptoms) were associated with significantly elevated levels of PLP.
Adult HPP presents with a wide range of clinical symptoms and is not associated with low bone mass in general. PLP seems to be a good marker for disease severity in adult patients as its level is correlated with the occurrence of fractures and number of symptoms.
KeywordsAlkaline phosphatase ALPL Pyridoxal-5-phosphate Rare bone diseases
Authors’ roles: Study design: TS, HM, FB, WR and MA. Study conduct: TS, HM and FB. Data collection: HM, TR, JH and TH. Data analysis: TS. Drafting manuscript: TS, HM and FB. Approving final version of manuscript: TS, HM, TS, TW, JH, WR, MA and FB. TS takes responsibility for the integrity of the data analysis.
Compliance with ethical standards
The local ethics committee approved the study (PV5272).
Conflict of interest
Tobias Schmidt, Haider Mussawy, Tim Rolvien, Thelonius Hawellek, Jan Hubert, Wolfgang Rüther, Michael Amling and Florian Barvencik declare that they have no conflict of interest. F.B. receives speaker and consultant fees from Alexion, Lilly, and MSD. M.A. receives speaker and consultant fees from Merck.
- 7.Silvent J, Gasse B, Mornet E, Sire JY (2014) Molecular evolution of the tissue-nonspecific alkaline phosphatase allows prediction and validation of missense mutations responsible for hypophosphatasia. J Biol Chem 289(35):24168–24179. doi: 10.1074/jbc.M114.576843 CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Whyte MP (1990) Heritable metabolic and dysplastic bone diseases. Endocrinol Metab Clin N Am 19(1):133–173Google Scholar
- 12.Riancho-Zarrabeitia L, Garcia-Unzueta M, Tenorio JA, Gomez-Gerique JA, Ruiz Perez VL, Heath KE, Lapunzina P, Riancho JA (2016) Clinical, biochemical and genetic spectrum of low alkaline phosphatase levels in adults. Eur J Intern Med 29:40–45. doi: 10.1016/j.ejim.2015.12.019 CrossRefPubMedGoogle Scholar
- 15.Whyte MP (2012) Hypophosphatasia. In: Glorieux FH, Pettifor JM, Juppner H (eds) Pediatric bone biology & diseases, 2nd edn. Elsevier, Amsterdam, pp 771–794Google Scholar
- 18.Whyte MP, Zhang F, Wenkert D, McAlister WH, Mack KE, Benigno MC, Coburn SP, Wagy S, Griffin DM, Ericson KL, Mumm S (2015) Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients. Bone 75:229–239. doi: 10.1016/j.bone.2015.02.022 CrossRefPubMedGoogle Scholar
- 22.Thomas L, Müller M, Schumann G, Weidemann G, Klein G et al (2005) Consensus of DGKL and VDGH for interim reference intervals on enzymes in serum. J Lab Med 29:301–308Google Scholar
- 23.Sampson DA, O'Connor DK Analysis of B-6 vitamers and pyridoxic acid in plasma, tissues and urine using high performance liquid chromatography. Nutr Res 9(3):259–272. doi: 10.1016/S0271-5317(89)80069-7
- 24.Burt LA, Liang Z, Sajobi TT, Hanley DA, Boyd SK (2016) Sex- and site-specific normative data curves for HR-pQCT. J Bone Miner Res 31(11):2041–2047. doi: 10.1002/jbmr.2873
- 30.Otero JE, Gottesman GS, McAlister WH, Mumm S, Madson KL, Kiffer-Moreira T, Sheen C, Millan JL, Ericson KL, Whyte MP (2013) Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy. J Bone Miner Res 28(2):419–430. doi: 10.1002/jbmr.1752 CrossRefPubMedGoogle Scholar
- 32.Whyte MP (2017) Hypophosphatasia: enzyme replacement therapy brings new opportunities and new challenges. J Bone Miner Res. doi: 10.1002/jbmr.3075
- 33.Sornay-Rendu E, Boutroy S, Munoz F, Delmas PD (2007) Alterations of cortical and trabecular architecture are associated with fractures in postmenopausal women, partially independent of decreased BMD measured by DXA: the OFELY study. J Bone Miner Res 22(3):425–433. doi: 10.1359/jbmr.061206 CrossRefPubMedGoogle Scholar
- 35.Nakagawa H, Kamimura M, Takahara K, Hashidate H, Kawaguchi A, Uchiyama S, Miyasaka T (2006) Changes in total alkaline phosphatase level after hip fracture: comparison between femoral neck and trochanter fractures. J Orthop Sci 11(2):135–139. doi: 10.1007/s00776-005-0990-9 CrossRefPubMedGoogle Scholar
- 37.Camacho PM, Mazhari AM, Wilczynski C, Kadanoff R, Mumm S, Whyte MP (2016) Adult Hypophosphatasia treated with teriparatide: report of two patients and review of the literature. Endocr Pract. doi: 10.4158/EP15890.OR
- 39.Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, Van Sickle BJ, Simmons JH, Edgar TS, Bauer ML, Hamdan MA, Bishop N, Lutz RE, McGinn M, Craig S, Moore JN, Taylor JW, Cleveland RH, Cranley WR, Lim R, Thacher TD, Mayhew JE, Downs M, Millan JL, Skrinar AM, Crine P, Landy H (2012) Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med 366(10):904–913. doi: 10.1056/NEJMoa1106173 CrossRefPubMedGoogle Scholar
- 40.Kishnani PS, Rockman-Greenberg C, Whyte MP et al (2012) Hypophosphatasia: enzyme replacement therapy (Asfotase alfa) decreases TNSALP substrate accumulation and improves functional outcome in affected adolescents and adults. American College of Medical Genetics and Genomics Annual Meeting, Charlotte, pp 27–31Google Scholar