Identifying adult hypophosphatasia in the rheumatology unit

Abstract

Background The most frequent manifestation in adult hypophosphatasia (HPP) is musculoskeletal pain. The unspecific nature of its clinical presentation may prevent correct diagnosis. The aim of the study was to assess the prevalence of ALPL mutations in adult patients treated in rheumatological outpatient facilities with evident musculoskeletal symptoms typical for HPP. Methods Over a period of 10 years 9,522 patients were screened in the rheumatology outpatient clinic of the Hanusch hospital Vienna. Serum ALP levels ≤ 40 U/L were found in 524 patients. After screening for secondary causes, 73 patients were invited for clinical evaluation. Genetic testing was performed in 23 patients with suspected HPP. Logistic regression models with Firth penalisation were used to estimate the unadjusted and BMI-adjusted association of each clinical factor with HPP. Results Mutations in the ALPL gene were observed in 57% of genetically screened patients. Arthralgia, fractures, and pain were the leading symptoms in individuals with ALPL mutation. Chondrocalcinosis (OR 29.12; 95% CI 2.02–1593.52) and dental disease (OR 8.33; 95% CI 0.93–143.40) were associated with ALPL mutation, independent of BMI. Onset of symptoms in patients with ALPL mutation was at 35.1 (14.3) years, with a mean duration from symptoms to diagnosis of 14.4 (8.1) years. Bone mineral density (BMD) and trabecular bone score (TBS) as well as bone turnover markers were not indicative for HPP or ALPL mutation. Conclusion HPP can mimic rheumatologic diseases. Thus, HPP should be considered as a possible diagnosis in adult patients presenting with musculoskeletal pain of unknown origin in rheumatology outpatient clinics. In patients with persistently low ALP serum levels and unclear musculoskeletal pain, HPP as the underlying cause has to be considered.

Detection of hypophosphatasia in hospitalised adults in rheumatology and internal medicine departments: a multicentre study over 10 years

“…Similarly, Feurstein et al found 5.5% of patients with at least one low ALP value under 40 UI/L, with only 13.9% of patients presenting persistent low ALP levels and musculoskeletal symptoms; they represented 0.8% of the whole population from a rheumatology outpatient clinic in Vienna specialised in rheumatology and rare bone diseases. 15 …”

Clinical and Genetic Characteristics of Hypophosphatasia in Chinese Adults

“…According to a literature review, the BMD of adults with HPP only slightly decreased [ 37 , 38 , 39 ]. In contrast, higher vertebral BMD (possibly owing to excessive PPi deposition) is associated with an increased risk of fractures in adult HPP [ 37 ].…”

“…According to the global HPP Registry, the average age at diagnosis of adult HPP is 48.9 years old [ 30 ]. A study showed that the average interval from symptoms to diagnosis was 14.4 years [ 39 ]. On the other hand, the prevalence of HPP is high.…”

Hypophosphatasia Presenting as a Chronic Diffuse Pain Syndrome with Extra-Articular Calcifications

“…A large retrospective study identified US adult patients with persistent hypophosphatasemia and showed more frequent radiographic calcific periarthritis, diffuse idiopathic skeletal hyperostosis (DISH), and chondrocalcinosis (p < 0.001) [19]. In another case series of 29 patients with low ALP identified in a rheumatology unit, Feurstein et al demonstrated that patients with ALPL pathogenic variants/mutations have significantly more peri-articular calcifications (but also dental problems) [20]. Out of 22 adults diagnosed with hypophosphatasia, the Mayo Clinic identified radiographic calcium pyrophosphate deposition disease in 27% and documented pyrophosphate arthropathy in 14% [7], while 6 out of 16 patients had symptomatic chondrocalcinosis [21] and 21% had crystal disease in another cohort [8].…”