Impact of pediatric hypophosphatasia on behavioral health and quality of life

Orphanet J Rare Dis. 2021 Feb 12;16(1):80. doi: 10.1186/s13023-021-01722-7.


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.

Keywords: Alkaline phosphatase; Attention deficit hyperactivity disorder; Behavior; Hypophosphatasia; Pediatric; Quality of life; Rare bone disease; Sleep disturbance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Alkaline Phosphatase / therapeutic use
  • Child
  • Child, Preschool
  • Cross-Sectional Studies
  • Enzyme Replacement Therapy
  • Female
  • Humans
  • Hypophosphatasia* / drug therapy
  • Hypophosphatasia* / genetics
  • Male
  • Quality of Life*
  • Surveys and Questionnaires


  • Alkaline Phosphatase