Frequency of Ectopic Calcifications Among Patients With Hypophosphatasia in the Global HPP Registry
Authors: Linglart Agnes , Dahir Kathryn McCrystal , Kishnani Priya , Petryk Anna , Hoegler Wolfgang , Martos-Moreno Gabriel Angel , Fang Shona , Rockman-Greenberg Cheryl , Lothar Seefried , Ozono Keiichi 
Published: May 2021

Abstract
Ectopic calcifications have been observed in patients with hypophosphatasia (HPP)—a rare, inherited, metabolic disorder characterized by reduced enzymatic activity of tissue nonspecific alkaline phosphatase. The natural history of these calcifications is poorly understood. Using data from the Global HPP Registry, a cross-sectional, observational analysis was conducted to better understand the prevalence of nephrocalcinosis and eye calcifications in patients with HPP in the absence of treatment with the enzyme replacement therapy, asfotase alfa. The association between hypercalcemia (serum calcium ≤10.3 mg/dL [normal]; 10.4–11.9 mg/dL [mild hypercalcemia]; ≥12.0 mg/dL [moderate to severe hypercalcemia]) and ectopic calcification was also evaluated. Of the patients in the study population with renal ultrasound data (n=327), 11.0% had nephrocalcinosis; no patients had severe nephrocalcinosis. In children (aged &lt;18 years; n=174), 13.2% had nephrocalcinosis, and the median age at the first diagnosis of nephrocalcinosis was 4 years (range: 0–17 years). In adults (aged ≥18 years; n=153), 8.5% had nephrocalcinosis, and the median age at the first diagnosis of nephrocalcinosis was 52 years (range: 27–72 years). Data on serum calcium levels were available for 318 patients with renal ultrasounds. Of these patients, 73 patients (23.0%) had a history of hypercalcemia, of whom 10 (13.7%; children: n=9; adults: n=1) also had nephrocalcinosis. In patients with moderate to severe hypercalcemia (n=7), 6 patients (85.7%) were diagnosed with nephrocalcinosis; the majority (68.8%) of patients with nephrocalcinosis did not have a documented history of hypercalcemia. Of the patients who had ophthalmological assessments (n=137), 6 patients (4.4%) had eye calcifications; no patients had moderate or severe eye calcifications. The median age at the first diagnosis of eye calcifications was 16 years (range: 15–16 years) in children and 51 years (range: 30–57 years) in adults. Data on serum calcium levels were available for 80 patients with ophthalmological assessments. Coexistence of eye calcifications and reported hypercalcemia was observed in only 3 of these patients, all of whom had mild hypercalcemia; the remaining 3 patients with eye calcifications exhibited no hypercalcemia. No patients in this analysis presented with both nephrocalcinosis and eye calcifications. These results indicate that the prevalence of ectopic calcifications in patients with HPP is low during the natural course of the disease, with nephrocalcinosis being more common than eye calcifications. In addition, the higher prevalence of nephrocalcinosis in patients with moderate to severe hypercalcemia suggests that very high serum calcium may be a risk factor in some patients. Future studies are needed to assess the impact of treatment with asfotase alfa on ectopic calcifications in patients with HPP.