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Early and accurate diagnosis of hypophosphatasia (HPP) in neonates and infants is critical.1,2

Manifestations of hypophosphatasia in neonates and infants can include

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  • Skeletal
  • Growth and development
  • Respiratory
  • Neurologic
  • Renal
Vitamin B6–responsive seizures10
Neurologic complications of craniosynostosis
  • Increased intracranial pressure1,2,6
  • Seizures11
  • Intracranial hemorrhage1,9
  • Papilledema1,6,9

Historically, 73% of neonates with untreated hypophosphatasia have died before the age of 5.12,a

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About mortality risk in neonates and infants with hypophosphatasia.

Skeletal manifestations have devastating results in infants with hypophosphatasia.1,6

Severe hypomineralization of the rib cage can lead to decreased thoracic volume and pulmonary hypoplasia.1,7,8,10

3 weeks of age13,b

Small rib cage with shortened and thinned ribs with diffuse lung collapse

3 years of age14,b

Respiratory insufficiency requiring tracheostomy tube

Skeletal hypomineralization can be seen on radiographs of neonates and infants with hypophosphatasia.1

Healthy infant15

Healthy, mineralized bone

6 months of age1,b

Hypomineralized bone in a patient with hypophosphatasia

Respiratory failure is the most common cause of death in infants and neonates with hypophosphatasia.1,8

Neonates and infants with hypophosphatasia have a high risk of mortality.1,12

Respiratory insufficiency has historically resulted in a fatal outcome.1,8,12

Vitamin B6–responsive seizures have historically been a fatal prognostic indicator in infants with hypophosphatasia.1,8,12

Manifestations of hypophosphatasia may not be recognized immediately after birth.6

Failure to thrive is a common early symptom in infants with hypophosphatasia.1,6,12

Signs of failure to thrive include16
  • Poor feeding
  • Inadequate weight gain
  • Irritability/excessive crying
Hypercalcemia may cause episodes of recurrent vomiting that can contribute to failure to thrive6,17

Craniosynostosis may develop in infants with hypophosphatasia.1

Hypomineralization of the calvarium
14 weeks of age18,b

In infants, hypomineralization can create an illusion of wide open cranial sutures despite “functional” craniosynostosis6

Consequences of severe craniosynostosis with copper-beaten appearance of skull
3 years of age18,b

Craniosynostosis can persist and become more pronounced in childhood, resulting in neurologic complications and the need for cranial surgery6

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Learn about disease progression in an infant with hypophosphatasia.

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How might hypophosphatasia impact children and adolescents in your practice?

aData from a noninterventional, retrospective chart review study designed to understand the natural history of 48 patients ≤5 years of age with severe perinatal- and infantile-onset hypophosphatasia. Patients included in the study were those diagnosed with hypophosphatasia based on at least one of the following: serum biomarker levels (below-normal alkaline phosphatase [ALP] and above-normal PLP or PEA), below-normal ALP and radiographic abnormalities, or genetic analysis of the ALPL gene. Additionally, onset of hypophosphatasia must have occurred prior to 6 months of age based on signs that included at least one of the following: respiratory compromise, rachitic chest deformity, and/or vitamin B6–responsive seizures.12

bRadiographs are from different patients with hypophosphatasia.

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  1. Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. 2013;10(suppl 2):380-388.
  2. Mornet E, Nunes ME. Hypophosphatasia. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993. Published November 20, 2007. Updated February 4, 2016. Accessed October 26, 2017.
  3. Zankl A, Mornet E, Wong S. Specific ultrasonographic features of perinatal lethal hypophosphatasia. Am J Med Genet Part A. 2008;146A(9):1200-1204.
  4. Wiebe S, Suchet I, Lemire EG. Radiographic and prenatal ultrasound features of perinatal lethal hypophosphatasia—differentiation from osteogenesis imperfecta type II. S Afr J Radiol. 2007;11(2):32-35.
  5. Whyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann N Y Acad Sci. 2010;1192:190-200.
  6. Whyte MP. Hypophosphatasia. In: Thakker RV, Whyte MP, Eisman JA, Igarashi T, eds. Genetics of Bone Biology and Skeletal Disease. London, UK: Academic Press; 2013:337-360.
  7. Silver MM, Vilos GA, Milne KJ. Pulmonary hypoplasia in neonatal hypophosphatasia. Pediatr Pathol. 1988;8(5):483-493.
  8. Baumgartner-Sigl S, Haberlandt E, Mumm S, et al. Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene. Bone. 2007;40(6):1655-1661.
  9. Caswell AM, Russell RGG, Whyte MP. Hypophosphatasia: pediatric forms. J Pediatr Endocrinol Metab. 1989;3(2):73-92.
  10. Balasubramaniam S, Bowling F, Carpenter K, et al. Perinatal hypophosphatasia presenting as neonatal epileptic encephalopathy with abnormal neurotransmitter metabolism secondary to reduced co-factor pyridoxal-5'-phosphate availability. J Inherit Metab Dis. 2010;33(3):25-33.
  11. Craniosynostosis. MedlinePlus website. Updated October 3, 2017. Accessed October 26, 2017.
  12. Whyte MP, Leung E, Wilcox W, et al; for Study 011-10 Investigators. Hypophosphatasia: a retrospective natural history study of the severe perinatal and infantile forms. Poster presented at: 2014 Pediatric Academic Societies and Asian Society for Pediatric Research Joint Meeting; May 3-6, 2014; Vancouver, BC.
  13. Rodriguez E, Bober MB, Davey L, et al. Respiratory mechanics in an infant with perinatal lethal hypophosphatasia treated with human recombinant enzyme replacement therapy. Pediatr Pulmonol. 2012;47(9):917-922.
  14. Simmons JH. Best practices in: recognizing and diagnosing hypophosphatasia. Clinical Endocrinology News website. Published September 30, 2013. Accessed October 26, 2017.
  15. Data on file, Alexion Pharmaceuticals.
  16. Failure to thrive. MedlinePlus website. Updated October 3, 2017. Accessed October 26, 2017.
  17. Stephens MB, Gentry BC, Michener MD, Kendall SK. What is the clinical workup for failure to thrive? J Fam Pract. 2008;57(4):264-266.
  18. Millán JL, Whyte MP. Alkaline phosphatase and hypophosphatasia. Calcif Tissue Int. 2016;98(4):398-416.