Journal of The Korean Society of Inherited Metabolic disease (대한유전성대사질환학회지)

The Korea Society of Inherited Metabolic Disease (대한유전성대사질환학회)
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A Case with Perinatal Hypophosphatasia Caused by the ALPL Mutations

ALPL 유전자의 돌연변이를 가진 양성 주산기 저인산증 1례

  • Kim, Joonil (Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine) ;
  • Kang, Eungu (Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine) ;
  • Kim, Yoon-Myung (Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine) ;
  • Lee, Beom Hee (Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine) ;
  • Kim, Gu-Hwan (Medical Genetics Center, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine) ;
  • Yoo, Han-Wook (Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine)
  • 김준일 (울산대학교 의과대학 서울아산병원 소아청소년과) ;
  • 강은구 (울산대학교 의과대학 서울아산병원 소아청소년과) ;
  • 김윤명 (울산대학교 의과대학 서울아산병원 소아청소년과) ;
  • 이범희 (울산대학교 의과대학 서울아산병원 소아청소년과) ;
  • 김구환 (울산대학교 의과대학 서울아산병원 의학유전학센터) ;
  • 유한욱 (울산대학교 의과대학 서울아산병원 소아청소년과)
  • Published : 2016.12.31
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Abstract

Hypophosphatasia is caused by the mutations in ALPL, which encodes tissue-nonspecific alkaline phosphatase (TNSALP). It can be inherited either in an autosomal dominant or recessive manner. Clinically, hypophophosphatasia is characterized by skeletal findings similar to those in rickets or osteomalacia, but serum alkaline phosphatase levels are decreased in the affected patients. Hypophosphatasia can be classified into six clinical forms according to age at diagnosis and severity of symptoms: perinatal lethal, infantile, childhood, adult, odontohypophosphatasia, and perinatal benign. As being a very rare disease, only one case has been reported in Korean population. Here we describe a case with perinatal benign hypophosphatasia with recessive ALPL mutations. Bowing of lower legs was detected in prenatal period and low serum alkaline phosphatase level was noted after birth. During the follow-up evaluation for 4.5 years, bone mineralization and legs bowing were improved but the growth retardation was persistent. As the recombinant bone-targeted human TNSALP became available, the clinical improvement of the affected patients is expected including the case described here with this treatment. More efforts are needed to identify the cases affected by hypophosphatasia.

저인산증은 드문 선천성 대사 이상 질환으로, 조직-비특이 알칼리 포스파테이스(TNSALP)의 결핍으로 인해 발생한다. 상염색체 우성 혹은 열성 유전이 모두 가능하며, 발생시기에 따라서 주산기, 영아기, 아동기, 성인기로 나뉘고, 증상이 일찍 발현할수록 예후가 나쁜 것으로 알려져 있다. 혈청 알칼리 포스파테이스가 감소해 있으면서 구루병 혹은 골연화증을 보이는 환자에서 ALPL 유전자 변이를 규명하는 것이 저인산증을 진단하는 가장 확실한 방법이다. 본 증례 보고는 산전 초음파에서 장골의 이상과 출생 후 저포스파테이스증이 확인되어 ALPL 유전자 검사를 통해 양성 주산기 저인산증으로 진단된 환자 보고이다. 환자는 출생 당시 호흡곤란이나 고칼슘혈증, 피리독신 의존성 발작 등의 합병증 없이 경과가 양호하였다. 생후 12개월 이후 성장 지연이 확인되었지만, 생후 53개월까지 골격의 무기질화가 호전된 양성 경과를 가지게 되었다. 현재 재조합 TNSALP인 asfotase alfa가 개발되어 주산기 및 영아기 저인산증 환아에서 조속한 진단과 치료가 더욱 중요해진 바, 좀더 많은 환자들의 진단이 이루어져야 하겠다.

Keywords

References

  1. Whyte MP. Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment. Nature reviews Endocrinology 2016;12:233-46. https://doi.org/10.1038/nrendo.2016.14
  2. Tissue nonspecific alkaline phosphatase gene mutations database [Internet]. SESEP [online]. 2015. Available from: http://www.sesep.uvsq.fr/03_hypo_mutations.php.
  3. Whyte MP, Zhang F, Wenkert D, McAlister WH, Mack KE, Benigno MC, et al. Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients. Bone 2015;75:229-39. https://doi.org/10.1016/j.bone.2015.02.022
  4. Mornet E, Yvard A, Taillandier A, Fauvert D, Simon-Bouy B. A molecular-based estimation of the prevalence of hypophosphatasia in the European population. Annals of human genetics 2011;75:439-45. https://doi.org/10.1111/j.1469-1809.2011.00642.x
  5. Millan JL. Alkaline Phosphatases : Structure, substrate specificity and functional relatedness to other members of a large superfamily of enzymes. Purinergic signalling 2006;2:335-41. https://doi.org/10.1007/s11302-005-5435-6
  6. Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. The New England journal of medicine 2012;366:904-13. https://doi.org/10.1056/NEJMoa1106173
  7. Scott LJ. Asfotase Alfa: A Review in Paediatric-Onset Hypophosphatasia. Drugs 2016;76:255-62. https://doi.org/10.1007/s40265-015-0535-2
  8. Ozono K, Yamagata M, Michigami T, Nakajima S, Sakai N, Cai G, et al. Identification of novel missense mutations (Phe310Leu and Gly439Arg) in a neonatal case of hypophosphatasia. The Journal of clinical endocrinology and metabolism 1996;81:4458-61.
  9. Orimo H, Hayashi Z, Watanabe A, Hirayama T, Hirayama T, Shimada T. Novel missense and frameshift mutations in the tissue-nonspecific alkaline phosphatase gene in a Japanese patient with hypophosphatasia. Human molecular genetics 1994;3:1683-4. https://doi.org/10.1093/hmg/3.9.1683
  10. Fraser D. Hypophosphatasia. The American journal of medicine 1957;22:730-46. https://doi.org/10.1016/0002-9343(57)90124-9
  11. Shohat M, Rimoin DL, Gruber HE, Lachman RS. Perinatal lethal hypophosphatasia; clinical, radiologic and morphologic findings. Pediatric radiology 1991;21:421-7. https://doi.org/10.1007/BF02026677
  12. Wenkert D, McAlister WH, Coburn SP, Zerega JA, Ryan LM, Ericson KL, et al. Hypophosphatasia: nonlethal disease despite skeletal presentation in utero (17 new cases and literature review). Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2011;26:2389-98. https://doi.org/10.1002/jbmr.454
  13. Lundgren T, Westphal O, Bolme P, Modeer T, Noren JG. Retrospective study of children with hypophosphatasia with reference to dental changes. Scandinavian journal of dental research 1991;99:357-64.
  14. Royce PM, Blumberg A, Zurbrugg RP, Zimmermann A, Colombo JP, Steinmann B. Lethal osteogenesis imperfecta: abnormal collagen metabolism and biochemical characteristics of hypophosphatasia. European Journal of Pediatrics 1988;147:626-31. https://doi.org/10.1007/BF00442478
  15. El-Gharbawy AH, Peeden JN, Jr., Lachman RS, Graham JM, Jr., Moore SR, Rimoin DL. Severe cleidocranial dysplasia and hypophosphatasia in a child with microdeletion of the C-terminal region of RUNX2. American journal of medical genetics Part A 2010;152a:169-74. https://doi.org/10.1002/ajmg.a.33146
  16. Scriver CR, Cameron D. Pseudohypophosphatasia. The New England journal of medicine 1969;281:604-6. https://doi.org/10.1056/NEJM196909112811107
  17. Michigami T, Uchihashi T, Suzuki A, Tachikawa K, Nakajima S, Ozono K. Common mutations F310L and T1559del in the tissue-nonspecific alkaline phosphatase gene are related to distinct phenotypes in Japanese patients with hypophosphatasia. Eur J Pediatr 2005;164:277-82. https://doi.org/10.1007/s00431-004-1612-9
  18. Cahill RA, Wenkert D, Perlman SA, Steele A, Coburn SP, McAlister WH, et al. Infantile hypophosphatasia: transplantation therapy trial using bone fragments and cultured osteoblasts. The Journal of clinical endocrinology and metabolism 2007;92:2923-30. https://doi.org/10.1210/jc.2006-2131
  19. Millan JL, Narisawa S, Lemire I, Loisel TP, Boileau G, Leonard P, et al. Enzyme replacement therapy for murine hypophosphatasia. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2008;23:777-87.
  20. Park EG, Cho SY, Lee J, Kim J, Cho H, Kim J, et al. First Korean Case of Infantile Hypophosphatasia with Novel Mutation in ALPL and Literature Review. Annals of clinical and laboratory science 2016;46:302-7.