Burden of disease in pediatric patients with hypophosphatasia: results from the HPP Impact Patient Survey and the HPP Outcomes Study Telephone interview

Hypophosphatasia (HPP) is a rare, inherited, metabolic bone disease caused by deficiency of the tissue non-specific isoenzyme of alkaline phosphatase (TNSALP) [1]. Low TNSALP activity leads to the extracellular accumulation of its substrates including one of the key substrates involved in the pathogenesis of HPP, inorganic pyrophosphate (PPi). PPi is a potent inhibitor of bone mineralization [2]; in HPP, excess PPi contributes to skeletal hypomineralization, which can result in the premature loss of deciduous teeth, HPP-related rickets in infants and children, and osteomalacia in patients of any age [3].

HPP-related manifestations vary considerably between individuals and, aside from skeletal and dental manifestations, can include systemic complications such as respiratory difficulties, vitamin B6-dependent seizures, muscle weakness, nephrocalcinosis, and chronic pain [4‐6]. Mortality is high among those who present with HPP in the perinatal and infantile periods [1]; however, it is now recognized that significant complications associated with HPP can occur at any age, and that those individuals who survive infancy or who present with HPP-related manifestations after infancy often experience a high disease burden [7]. These manifestations of HPP are often debilitating and frequently include poor growth [7‐10], delayed motor milestones [9, 11], muscle weakness [7, 10], gait abnormalities, chronic bone, muscle and/or joint pain [12, 13], dental abnormalities [14], and recurrent low trauma fractures [7, 15]. As the disease progresses, these manifestations often lead to ambulatory difficulties and limitations in activities of daily living, which may result in individuals requiring assistance with daily tasks. Consequently, individuals with HPP frequently experience a diminished health-related quality of life (HRQoL) [7].

Several observational studies of pediatric patients with HPP have reported the clinical burden of the disease along specific parameters [1, 6, 10]. The results of these studies suggest that patients often experience a high burden of disease. Moreover, there are publications based on data from case reports reporting the loss of mobility over time in adults with HPP, suggesting that many patients experience a progressive worsening of the disease [16‐18]. However, limited evidence on the patient-reported burden of HPP and its impact on an individual’s HRQoL exists in the literature, and to the best of our knowledge, research published to date has focused on patient-reported disease burden in adults with HPP, but not children with the disease.

The aim of the current study was to evaluate and characterize the patient-reported burden of disease in pediatric patients with HPP.

This was a cross-sectional, survey-based study of adult and pediatric patients with HPP. Details of the materials and methods as well as the results for the adult population have been published previously [7]. This paper describes the results for the pediatric population (those younger than 18 years of age at the time the survey was administered). This paper was prepared according to the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) reporting guidelines for observational studies (Additional file 1) [19].

This study characterizes the impact of HPP on the HRQoL of pediatric patients with HPP as reported by the patients themselves or their caregivers. The findings of this study suggest that pediatric patients experience a high burden of disease and reduced HRQoL, and that burden of disease may increase and HRQoL reduce further over time as signs/symptoms that impact HRQoL worsen or new signs/symptoms manifest. Two-thirds of the patients reported that at least one of their HPP-related additional signs/symptoms had worsened over a 5-year period. Overall, the majority of pediatric patients with HPP reported that the disease often limited their ability to perform activities of daily living. Most patients identified physical reasons for these limitations, while 33.4% of patients surveyed stated that emotional problems were impeding their ability to perform daily activities. As such, this study highlights the substantial morbidity that children with HPP frequently experience, and that many patients experience worsening of their disease over time.

The findings of this pediatric analysis are broadly consistent with those reported previously in the analysis of 125 adults with HPP, which showed that HPP can confer a high burden of disease in adulthood [7]. Using the 12-item Short-Form Health Survey version 2, that analysis indicated that HPP has a wide-ranging and substantial impact on the HRQoL of adult patients, and that these patients often experience pain (95% of survey respondents), fractures (86%), multiple fractures (74%), muscle weakness (62%), and abnormal gait (52%). A high percentage (60%) of the patients surveyed also reported using assistive devices for mobility [7]. Similarly, in this analysis of pediatric patients, the most commonly reported signs/symptoms were pain, muscle weakness, and challenges with mobility. However, the reported frequency of occurrence of several HPP-related manifestations differed substantially between the two patient populations. For example, difficulty gaining weight, delayed walking, and skeletal abnormalities were reported more frequently by pediatric patients with HPP than by adult patients with HPP. Some of these differences may be attributed to growth during childhood, meaning some developmental and skeletal abnormalities are more likely to occur in children than in adults.

Notably, fractures occurred less frequently in pediatric patients than in adults with HPP (36% versus 86%, respectively) and none of the pediatric survey respondents reported fracture to be a first HPP sign/symptom. The prevalence of more than one fracture among children with HPP (15%) was similar to the prevalence in healthy children, which data indicate is 15–20% [21]. In general, the occurrence of two or more long bone fractures in those under 10 years of age, or three or more long bone fractures in those from age 10 to less than 16 years, or the occurrence of a vertebral compression fracture is considered abnormal [21]. While detailed information about the mechanism of fracture or fracture location was not collected as part of this study, it is remarkable that 10.2% of patients have experienced 2–5 fractures, and 5.1% of patients reported 6–10 fractures. The report of pseudofractures and non-healing fractures is also noteworthy, as they are reflective of underlying HPP-related rickets or osteomalacia [4, 18]. Pseudofractures are considered to be a type of insufficiency fracture that can occur in several forms of rickets and osteomalacia, both genetic (e.g. HPP and X-linked hypophosphatemia) and acquired (e.g. severe vitamin D deficiency), [22] and therefore the occurrence of such fractures is not expected among the general pediatric population. Non-healing fractures occur in the general pediatric population in the absence of specific risk factors at a rate of approximately 0.002% per fracture [23].

Consistent with the previous study among adults with HPP, the respondents in the current survey scored below the general child population norm in both the physical and mental components of the SF-10. Although the mean MCS scores for pediatric and adult patients reported by the two studies were comparable (45.6 versus 46.4, respectively), the mean PCS score was substantially lower among pediatric patients with HPP than among the adult patients who were surveyed (23.7 versus 32.8, respectively), and the general population (50.0). The high patient-reported physical burden of HPP is reflected in the prevalent use of assistive devices, including wheelchairs and in-shoe orthotics, by the adults and children surveyed in both analyses [7]. While overall levels of use of assistive devices were similar in adults and pediatric patients, the types of devices used differed between the two study groups. For example, only 3% of children reported using crutches compared with 30% of adults [7].

Although studies looking at the burden of disease from the patient perspective offer important insights into how patients themselves perceive their HRQoL, the data collected from such studies have several notable limitations. In this study, HPP diagnosis was not confirmed by a third party or by examination of patients’ medical records, and the criteria by which a diagnosis of HPP was made were not defined. Also, the study population may not be fully representative of the overall population of individuals with HPP because patients were invited to participate in the research through their association with patient advocacy groups or a referral by their clinician. Therefore, an element of self-selection was permitted by the study design, which may have biased the study population towards one with a disproportionate number of highly motivated patients/caregivers. In addition, the findings from this study are based on a relatively small cohort of patients but, considering the rarity of HPP, may be considered adequate for drawing conclusions based on the analyses conducted. Recall bias is an inherent limitation of patient-reported data. This study required respondents to state how their reported first signs/symptoms of HPP changed from the time of their first occurrence to the time of the survey, and to state how their reported additional HPP signs/symptoms had changed compared with 5 years before participating in the survey. These long recall periods may have reduced the accuracy of these patient-reported data.

To the best of our knowledge, this is the first study to characterize the patient-reported burden of disease among children with HPP. This study highlights that HPP is associated with a high disease burden and can significantly affect patients’ HRQoL. Although some patients can experience improvement of some signs or symptoms, two-thirds experienced worsening of at least one of their HPP-related signs/symptoms over time. Future analyses of data collected by the HPP registry established in 2015 should extend our current understanding of the natural history, clinical course, and burden of disease in children and adults with HPP.