Impact of pediatric hypophosphatasia on behavioral health and quality of life

Elizabeth I. Pierpont, Jill H. Simmons, Katherine J. Spurlock, Ryan Shanley, Kyriakie M. Sarafoglou

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Background: Hypophosphatasia (HPP) is a rare genetic disorder caused by loss-of-function mutations in the ALPL gene encoding tissue nonspecific alkaline phosphatase. It is characterized by defective bone mineralization associated with low alkaline phosphatase activity. Clinical features of pediatric HPP are highly variable, and can include premature loss of teeth, musculoskeletal problems, and impaired mobility. The effects of pediatric HPP on sleep, mood, regulation of attention and behavior, and other aspects of behavioral health have not been comprehensively studied. Methods: Parents of 30 children with HPP (14 females, 16 males) between the ages of 3 and 16 years (mean age = 8.0 years) enrolled in this cross-sectional survey-based study. Molecular genetic and biochemical testing as well as clinical records were reviewed to verify diagnosis of HPP. The cohort included 15 patients with a more clinically severe presentation of HPP who had received treatment with enzyme replacement therapy (asfotase alfa) and 15 children with less severe HPP who were treatment-naïve. Parents provided information regarding psychopathological comorbidity, emotional and behavioral well-being, and quality of life. Results: Clinically significant behavioral health challenges were evident in 67% of children with HPP. The most common behavioral findings included sleep disturbance and symptoms of attention deficit hyperactivity disorder (ADHD), each of which were observed ≥ 50% of individuals. Sleep disturbance, pain interference, poor behavioral regulation, and mood/anxiety symptoms were associated with reduced physical and psychosocial quality of life. Behavioral concerns were evident among children with HPP receiving asfotase alfa treatment as well as among children with clinically less severe disease who had not initiated therapy. Although most children in the cohort (77%) had age-typical development of adaptive skills, emotional and behavioral challenges were associated with weaker adaptive function. Conclusions: Children with HPP are at increased risk for ADHD symptoms and other behavioral health challenges. There is likely an under-recognition of these findings in clinical practice.

Original languageEnglish (US)
Article number80
JournalOrphanet Journal of Rare Diseases
Issue number1
StatePublished - Dec 2021

Bibliographical note

Funding Information:
The authors would like to express gratitude to the families who?participated in this research and to the Soft Bones Foundation and MAGIC Foundation for assistance with participant recruitment. We would also like to acknowledge Loralie Peterson, Amy Hanson and Kristin Frenn for research coordination support.

Funding Information:
Funding for this research was provided by an investigator-initiated award provided by Alexion Pharmaceuticals (Grant No. CON73944) and by the National Institutes of Health’s National Center for Advancing Translational Sciences, Grants KL2TR002492 and UL1TR002494. Alexion has provided courtesy medical review; authors made the final decision on content and journal for submission of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2021, The Author(s).


  • Alkaline phosphatase
  • Attention deficit hyperactivity disorder
  • Behavior
  • Hypophosphatasia
  • Pediatric
  • Quality of life
  • Rare bone disease
  • Sleep disturbance


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