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Lethal hypophosphatasia successfully treated with enzyme replacement from day 1 after birth

  • Case Report
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European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Hypophosphatasia (HPP) is a rare metabolic bone disease caused by loss-of-function mutations in the gene ALPL encoding the tissue nonspecific alkaline phosphatase (TNSALP). There is a broad range of severity in the phenotype of HPP, and the most severe form exhibits perinatal lethality without mineralization of the skeleton. Here, we describe a female infant with perinatal lethal HPP diagnosed in utero. She was treated with a recombinant ALP (asfotase alfa) as an enzyme replacement therapy (ERT), which started from 1 day after birth. She required invasive ventilation immediately upon birth and demonstrated severe hypomineralization of whole body bone. Severe respiratory insufficiency was controlled by intensive respiratory care with high-frequency oscillation ventilation and nitric oxide inhalation and deep sedation just after birth. Bone mineralization improved with treatment; improvements were visible by 3 weeks of age and continued with treatment. Serum calcium levels decreased following treatment, resulting in hypocalcemia and convulsion, and calcium supplementation was required until 3 months of treatment. She was weaned from mechanical ventilation and has now survived more than 1 year.

Conclusion: This case demonstrates the success of ERT in treating the severest HPP and highlights the importance of early diagnosis and intervention for these patients.

What is Known:

• Severe neonatal hypophosphatasia has high mortality rate and is sometimes called a lethal type.

• Enzyme replacement therapy has been developed but its effects on the severest cases are rarely reported.

What is New:

• This report demonstrates the success of the earliest enzyme replacement therapy in treating perinatal lethal hypophosphatasia and highlights the importance of early diagnosis and respiratory and circulatory support.

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Abbreviations

ERT:

Enzyme replacement therapy

HFO:

High frequency oscillation

HPP:

Hypophosphatasia

iNO:

Nitric oxide inhalation

OI:

Oxygen index

TNSALP:

Tissue nonspecific alkaline phosphatase

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Acknowledgments

We acknowledge Alexion Pharmaceuticals and members of Alexion Pharma Japan and Alexion Pharmaceuticals, especially Dr. Hiroyuki Kishimoto for providing asfotase alfa. We also thank Ms. Kanako Tachikawa for technical assistance for genetic test of the ALPL gene. Genetic test was supported by a grant from Japanese Ministry of Health, Labor and Welfare (to T. M.).

Author’s contributions

Dr. Yoko Okazaki reviewed the medical literature, carried out the initial analysis, drafted the initial manuscript, and approved the final manuscript as submitted.

Drs. Hiroyuki Kitajima, and Narutaka Mochizuki carried out the initial analysis, reviewed and revised the manuscript and approved the final manuscript as submitted.

Dr. Taichi Kitaoka reviewed and revised the manuscript and approved the final manuscript as submitted.

Dr. Toshimi Michigami performed the mutation analysis, reviewed and revised the manuscript and approved the final manuscript as submitted.

Dr. Keiichi Ozono reviewed and finalized the manuscript.

All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Author information

Authors and Affiliations

  1. Department of Neonatal Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi, Osaka, Japan

    Yoko Okazaki, Hiroyuki Kitajima & Narutaka Mochizuki

  2. Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi, Osaka, Japan

    Toshimi Michigami

  3. Department of Pediatric Nephrology and Metabolism, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi, Osaka, Japan

    Toshimi Michigami

  4. Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, Japan

    Taichi Kitaoka & Keiichi Ozono

Authors
  1. Yoko Okazaki
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  2. Hiroyuki Kitajima
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  3. Narutaka Mochizuki
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  4. Taichi Kitaoka
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  5. Toshimi Michigami
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  6. Keiichi Ozono
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Corresponding author

Correspondence to Keiichi Ozono.

Ethics declarations

Funding

Genetic test was supported by a grant-in-aid for Research on Intractable Diseases from Japanese Ministry of Health, Labor and Welfare (to K. O. and T. M.).

Conflict of interest

All authors have no financial relationships relevant to this article to disclose. The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from the parents.

Note

Enzyme replacement therapy was supported by Alexion Pharmaceuticals as a compassionate use in the Case Report and followed by an investigator-initiated clinical trial [UMIN000014816]. The data during the clinical trial was not included in the Report.

Additional information

Communicated by Beat Steinmann

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Okazaki, Y., Kitajima, H., Mochizuki, N. et al. Lethal hypophosphatasia successfully treated with enzyme replacement from day 1 after birth. Eur J Pediatr 175, 433–437 (2016). https://doi.org/10.1007/s00431-015-2641-2

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  • DOI: https://doi.org/10.1007/s00431-015-2641-2

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