Skip to main content
SpringerLink
Log in

Epidemiology and Etiology

  • Chapter
Acrodermatitis Enteropathica

  • 501 Accesses

Abstract

AE is not specific to any ethnic population, as cases have been virtually reported from all around the world [1]. It is globally widespread with an estimated incidence of 1 in 500,000 children [1–4]. According to the cases reported in the literature, its prevalence seems higher in populations from the Mediterranean basin, probably because of their relatively high overall consanguinity [3]. There is also no gender predilection observed in AE [1, 3]. Compared for instance to the United States, the diagnosis of AE may be more difficult in developing countries where dietary zinc deficiencies are quite common, a problem emphasized in the World Health Report 2002 [5]. About two billion individuals may be zinc deficient in these regions of the world [6], where infants and children are the most affected. The regions particularly concerned by zinc deficiency problems include Southeast Asia and sub-Saharan Africa, since about 40 % of their preschool children have been reported to have zinc-related growth problems [7]. It has been reported that moderate zinc deficiency affects approximately 3 % of adolescents in rural areas of Middle East and North Africa [8]. Correcting this situation will have dramatic impacts on the morbidity and mortality of young children and modest effects on their growth. However, it is important to tackle malnutrition of these regions as a whole, instead of undertaking zinc deficiency in isolation. As a result, including zinc in a multiple micronutrient supplementation and promoting their use would be an effective method of dealing with this situation [9].

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Van Wouwe JP. Clinical and laboratory assessment of zinc deficiency in Dutch children. A review. Biol Trace Elem Res. 1995;49(2-3):211–25.

    Article  PubMed  Google Scholar 

  2. Küry S, et al. Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat Genet. 2002;31(3):239–40.

    Article  PubMed  Google Scholar 

  3. Schmitt S, et al. An update on mutations of the SLC39A4 gene in acrodermatitis enteropathica. Hum Mutat. 2009;30(6):926–33.

    Article  CAS  PubMed  Google Scholar 

  4. Wang K, et al. A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am J Hum Genet. 2002;71(1):66–73.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Guilbert JJ. The world health report 2002 – reducing risks, promoting healthy life. Educ Health (Abingdon). 2003;16(2):230.

    Article  CAS  Google Scholar 

  6. Prasad AS. Discovery of human zinc deficiency: its impact on human health and disease. Adv Nutr. 2013;4(2):176–90.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Brown KH, et al. International Zinc Nutrition Consultative Group (IZiNCG) technical document #1. Assessment of the risk of zinc deficiency in populations and options for its control. Food Nutr Bull. 2004;25(1 Suppl 2):S99–203.

    PubMed  Google Scholar 

  8. Prasad AS. Clinical and biochemical spectrum of zinc deficiency in human subjects. 1982.

    Google Scholar 

  9. Shrimpton R, et al. Zinc deficiency: what are the most appropriate interventions? BMJ. 2005;330(7487):347–9.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Brewer GJ, Prasad AS. Zinc metabolism. Current aspects in health and disease. New York: Alan R. Liss, Inc; 1977.

    Google Scholar 

  11. Hambidge KM, Walravens PA. Zinc deficiency in infants and preadolescent children. In: Trace elements in human health and disease, vol. 1. New York: Academic; 1976. p. 21–32.

    Google Scholar 

  12. Prasad AS. Clinical manifestations of zinc deficiency. Annu Rev Nutr. 1985;5(1):341–63.

    Article  CAS  PubMed  Google Scholar 

  13. Danbolt N, Closs K. Akrodermatitis enteropathica. Acta Derm Venerol. 1942;23:127–69.

    Google Scholar 

  14. Neldner KH, Hambidge KM. Zinc therapy of acrodermatitis enteropathica. N Engl J Med. 1975;292(17):879–82.

    Article  CAS  PubMed  Google Scholar 

  15. Evans GW, Johnson PE. Characterization and quantitation of a zinc-binding ligand in human milk. Pediatr Res. 1980;14(7):876–80.

    Article  CAS  PubMed  Google Scholar 

  16. Rebello T, Lonnerdal B, Hurley LS. Picolinic acid in milk, pancreatic juice, and intestine: inadequate for role in zinc absorption. Am J Clin Nutr. 1982;35(1):1–5.

    CAS  PubMed  Google Scholar 

  17. Bailey MM, et al. Effects of pre- and postnatal exposure to chromium picolinate or picolinic acid on neurological development in CD-1 mice. Biol Trace Elem Res. 2008;124(1):70–82.

    Article  CAS  PubMed  Google Scholar 

  18. Seal CJ, Heaton FW. Chemical factors affecting the intestinal absorption of zinc in vitro and in vivo. Br J Nutr. 1983;50(2):317–24.

    Article  CAS  PubMed  Google Scholar 

  19. Eckhert CD, et al. Zinc binding: a difference between human and bovine milk. Science. 1977;195(4280):789–90.

    Article  CAS  PubMed  Google Scholar 

  20. Casey CE, Walravens PA, Hambidge KM. Availability of zinc: loading tests with human milk, cow’s milk, and infant formulas. Pediatrics. 1981;68(3):394–6.

    CAS  PubMed  Google Scholar 

  21. Casey CE, Hambidge KM, Walravens PA. Zinc binding in human duodenal secretions. J Pediatr. 1979;95(6):1008–10.

    Article  CAS  PubMed  Google Scholar 

  22. Cousins RJ, Smith KT. Zinc-binding properties of bovine and human milk in vitro: influence of changes in zinc content. Am J Clin Nutr. 1980;33(5):1083–7.

    CAS  PubMed  Google Scholar 

  23. Lonnerdal B. Dietary factors influencing zinc absorption. J Nutr. 2000;130(5S Suppl):1378S–83.

    CAS  PubMed  Google Scholar 

  24. Sandstrom B. Dose dependence of zinc and manganese absorption in man. Proc Nutr Soc. 1992;51(2):211–8.

    Article  CAS  PubMed  Google Scholar 

  25. Sandstrom B, Cederblad A, Lonnerdal B. Zinc absorption from human milk, cow’s milk, and infant formulas. Am J Dis Child. 1983;137(8):726–9.

    CAS  PubMed  Google Scholar 

  26. Scholmerich J, et al. Bioavailability of zinc from zinc-histidine complexes. II. Studies on patients with liver cirrhosis and the influence of the time of application. Am J Clin Nutr. 1987;45(6):1487–91.

    CAS  PubMed  Google Scholar 

  27. Henkin RI, et al. A syndrome of acute zinc loss. Cerebellar dysfunction, mental changes, anorexia, and taste and smell dysfunction. Arch Neurol. 1975;32(11):745–51.

    Article  CAS  PubMed  Google Scholar 

  28. Lonnerdal B, Chen CL. Effects of formula protein level and ratio on infant growth, plasma amino acids and serum trace elements. II. Follow-up formula. Acta Paediatr Scand. 1990;79(3):266–73.

    Article  CAS  PubMed  Google Scholar 

  29. Hegenauer J, et al. Iron-supplemented cow milk. Identification and spectral properties of iron bound to casein micelles. J Agric Food Chem. 1979;27(6):1294–301.

    Article  CAS  PubMed  Google Scholar 

  30. Hurrell RF, et al. Iron absorption in humans as influenced by bovine milk proteins. Am J Clin Nutr. 1989;49(3):546–52.

    CAS  PubMed  Google Scholar 

  31. Hansen M, Sandstrom B, Lonnerdal B. The effect of casein phosphopeptides on zinc and calcium absorption from high phytate infant diets assessed in rat pups and Caco-2 cells. Pediatr Res. 1996;40(4):547–52.

    Article  CAS  PubMed  Google Scholar 

  32. Hansen M, et al. Casein phosphopeptides improve zinc and calcium absorption from rice-based but not from whole-grain infant cereal. J Pediatr Gastroenterol Nutr. 1997;24(1):56–62.

    Article  CAS  PubMed  Google Scholar 

  33. Menard MP, Cousins RJ. Effect of citrate, glutathione and picolinate on zinc transport by brush border membrane vesicles from rat intestine. J Nutr. 1983;113(8):1653–6.

    CAS  PubMed  Google Scholar 

  34. Hurley LS, Lonnerdal B, Stanislowski AG. Zinc citrate, human milk, and acrodermatitis enteropathica. Lancet. 1979;1(8117):677–8.

    Article  CAS  PubMed  Google Scholar 

  35. Sang N, et al. Postsynaptically synthesized prostaglandin E2 (PGE2) modulates hippocampal synaptic transmission via a presynaptic PGE2 EP2 receptor. J Neurosci. 2005;25(43):9858–70.

    Article  CAS  PubMed  Google Scholar 

  36. Solomons NW, Jacob R. Studies on the bioavailability of zinc in humans: effects of heme and nonheme iron on the absorption of zinc. Am J Clin Nutr. 1981;34(4):475–82.

    CAS  PubMed  Google Scholar 

  37. Yip R, et al. Does iron supplementation compromise zinc nutrition in healthy infants? Am J Clin Nutr. 1985;42(4):683–7.

    CAS  PubMed  Google Scholar 

  38. Palmiter RD, Findley SD. Cloning and functional characterization of a mammalian zinc transporter that confers resistance to zinc. EMBO J. 1995;14(4):639–49.

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Palmiter RD, Cole TB, Findley SD. ZnT-2, a mammalian protein that confers resistance to zinc by facilitating vesicular sequestration. EMBO J. 1996;15(8):1784–91.

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Huang L, Gitschier J. A novel gene involved in zinc transport is deficient in the lethal milk mouse. Nat Genet. 1997;17(3):292–7.

    Article  CAS  PubMed  Google Scholar 

  41. Küry S, et al. Expression pattern, genomic structure and evaluation of the human SLC30A4 gene as a candidate for acrodermatitis enteropathica. Hum Genet. 2001;109(2):178–85.

    Article  PubMed  Google Scholar 

  42. Cragg RA, et al. A novel zinc-regulated human zinc transporter, hZTL1, is localized to the enterocyte apical membrane. J Biol Chem. 2002;277(25):22789–97.

    Article  CAS  PubMed  Google Scholar 

  43. Wang K, et al. Homozygosity mapping places the acrodermatitis enteropathica gene on chromosomal region 8q24.3. Am J Hum Genet. 2001;68(4):1055–60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Küry S, et al. Mutation spectrum of human SLC39A4 in a panel of patients with acrodermatitis enteropathica. Hum Mutat. 2003;22(4):337–8.

    Article  PubMed  Google Scholar 

  45. Grotz N, et al. Identification of a family of zinc transporter genes from Arabidopsis that respond to zinc deficiency. Proc Natl Acad Sci. 1998;95(12):7220–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Eng BH, et al. Sequence analyses and phylogenetic characterization of the ZIP family of metal ion transport proteins. J Membr Biol. 1998;166(1):1–7.

    Article  CAS  PubMed  Google Scholar 

  47. Guerinot ML, Eide D. Zeroing in on zinc uptake in yeast and plants. Curr Opin Plant Biol. 1999;2(3):244–9.

    Article  CAS  PubMed  Google Scholar 

  48. Gaither LA, Eide DJ. The human ZIP1 transporter mediates zinc uptake in human K562 erythroleukemia cells. J Biol Chem. 2001;276(25):22258–64.

    Article  CAS  PubMed  Google Scholar 

  49. Kasana S, Din J, Maret W. Genetic causes and gene-nutrient interactions in mammalian zinc deficiencies: acrodermatitis enteropathica and transient neonatal zinc deficiency as examples. J Trace Elem Med Biol. 2014;29C:47–62.

    Google Scholar 

  50. Küry S, et al. Clinical utility gene card for: acrodermatitis enteropathica. Eur J Hum Genet. 2012;20(3):1–4.

    Google Scholar 

  51. Kim B-E, et al. Zn2+-stimulated endocytosis of the mZIP4 zinc transporter regulates its location at the plasma membrane. J Biol Chem. 2004;279(6):4523–30.

    Article  CAS  PubMed  Google Scholar 

  52. Andrews GK. Regulation and function of Zip4, the acrodermatitis enteropathica gene. Biochem Soc Trans. 2008;36(Pt 6):1242–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Dufner-Beattie J, et al. The acrodermatitis enteropathica gene ZIP4 encodes a tissue-specific, zinc-regulated zinc transporter in mice. J Biol Chem. 2003;278(35):33474–81.

    Article  CAS  PubMed  Google Scholar 

  54. Dufner-Beattie J, et al. The mouse acrodermatitis enteropathica gene Slc39a4 (Zip4) is essential for early development and heterozygosity causes hypersensitivity to zinc deficiency. Hum Mol Genet. 2007;16(12):1391–9.

    Article  CAS  PubMed  Google Scholar 

  55. Geiser J, et al. A mouse model of acrodermatitis enteropathica: loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity. PLoS Genet. 2012;8(6), e1002766.

    Article  PubMed Central  PubMed  Google Scholar 

  56. Kambe T, Andrews GK. Novel proteolytic processing of the ectodomain of the zinc transporter ZIP4 (SLC39A4) during zinc deficiency is inhibited by acrodermatitis enteropathica mutations. Mol Cell Biol. 2009;29(1):129–39.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Wang F, et al. Acrodermatitis enteropathica mutations affect transport activity, localization and zinc-responsive trafficking of the mouse ZIP4 zinc transporter. Hum Mol Genet. 2004;13(5):563–71.

    Article  CAS  PubMed  Google Scholar 

  58. Küry S, et al. A nine-year experience with the genetic testing of the rare disease acrodermatitis enteropathica; (Abstract #1062T). 2011: Presented at the 12th International Congress of Human Genetics/61st annual meeting of The American Society of Human Genetics, 13 Oct 2011. Montreal.

    Google Scholar 

  59. Michalczyk AA, Ackland ML. hZip1 (hSLC39A1) regulates zinc homoeostasis in gut epithelial cells. Genes Nutr. 2013;8(5):475–86.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Küry S, et al. Deciphering the genetics of inherited zinc deficiencies; (Abstract #P01.132). 2013: Presented at the European Human Genetic Conference 2013, 8–11 June 2013. Paris.

    Google Scholar 

  61. Chowanadisai W, Lönnerdal B, Kelleher SL. Identification of a mutation in SLC30A2 (ZnT-2) in women with low milk zinc concentration that results in transient neonatal zinc deficiency. J Biol Chem. 2006;281(51):39699–707.

    Article  CAS  PubMed  Google Scholar 

  62. Itsumura N, et al. Compound heterozygous mutations in SLC30A2/ZnT2 results in low milk zinc concentrations: a novel mechanism for zinc deficiency in a breast-fed infant. PLoS One. 2013;8(5), e64045.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Lasry I, et al. A dominant negative heterozygous G87R mutation in the zinc transporter, ZnT-2 (SLC30A2), results in transient neonatal zinc deficiency. J Biol Chem. 2012;287(35):29348–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Lova Navarro M, et al. Transient neonatal zinc deficiency due to a new autosomal dominant mutation in gene SLC30A2 (ZnT‐2). Pediatr Dermatol. 2014;31(2):251–2.

    Article  PubMed  Google Scholar 

  65. Miletta MC, et al. Transient neonatal zinc deficiency caused by a heterozygous G87R mutation in the zinc transporter ZnT-2 (SLC30A2) gene in the mother highlighting the importance of Zn 2. Int J Endocrinol. 2013;2013.

    Google Scholar 

  66. Kelleher SL, et al. Mapping the zinc‐transporting system in mammary cells: molecular analysis reveals a phenotype‐dependent zinc‐transporting network during lactation. J Cell Physiol. 2012;227(4):1761–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Fukada T, Kambe T. Molecular and genetic features of zinc transporters in physiology and pathogenesis. Metallomics. 2011;3(7):662–74.

    Article  CAS  PubMed  Google Scholar 

  68. Kambe T, Weaver BP, Andrews GK. The genetics of essential metal homeostasis during development. Genesis. 2008;46(4):214–28.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Lichten LA, Cousins RJ. Mammalian zinc transporters: nutritional and physiologic regulation. Annu Rev Nutr. 2009;29:153–76.

    Article  PubMed  Google Scholar 

  70. Huang L, Tepaamorndech S. The SLC30 family of zinc transporters–A review of current understanding of their biological and pathophysiological roles. Mol Aspects Med. 2013;34(2):548–60.

    Article  CAS  PubMed  Google Scholar 

  71. Palmiter RD, Huang L. Efflux and compartmentalization of zinc by members of the SLC30 family of solute carriers. Pflugers Arch. 2004;447(5):744–51.

    Article  CAS  PubMed  Google Scholar 

  72. Liuzzi JP, Cousins RJ. Mammalian zinc transporters. Annu Rev Nutr. 2004;24:151–72.

    Article  CAS  PubMed  Google Scholar 

  73. Bloß T, Clemens S, Nies DH. Characterization of the ZAT1p zinc transporter from Arabidopsis thaliana in microbial model organisms and reconstituted proteoliposomes. Planta. 2002;214(5):783–91.

    Article  PubMed  Google Scholar 

  74. Michalczyk AA, et al. Constitutive expression of hZnT4 zinc transporter in human breast epithelial cells. Biochem J. 2002;364(Pt 1):105–13.

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Zhao H, Eide D. The yeast ZRT1 gene encodes the zinc transporter protein of a high-affinity uptake system induced by zinc limitation. Proc Natl Acad Sci. 1996;93(6):2454–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Jiang Y, et al. Genome wide identification, phylogeny and expression of zinc transporter genes in common carp. PLoS One. 2014;9(12), e116043.

    Article  PubMed Central  PubMed  Google Scholar 

  77. Martin AB, et al. Gastric and colonic zinc transporter ZIP11 (Slc39a11) in mice responds to dietary zinc and exhibits nuclear localization. J Nutr. 2013;143(12):1882–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Yu Y, et al. Characterization of the GufA subfamily member SLC39A11/Zip11 as a zinc transporter. J Nutr Biochem. 2013;24(10):1697–708.

    Article  CAS  PubMed  Google Scholar 

  79. Liuzzi JP, Blanchard RK, Cousins RJ. Differential regulation of zinc transporter 1, 2, and 4 mRNA expression by dietary zinc in rats. J Nutr. 2001;131(1):46–52.

    CAS  PubMed  Google Scholar 

  80. McMahon RJ, Cousins RJ. Regulation of the zinc transporter ZnT-1 by dietary zinc. Proc Natl Acad Sci. 1998;95(9):4841–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Hambidge KM, et al. Changes in zinc absorption during development. J Pediatr. 2006;149(5 Suppl):S64–8.

    Article  CAS  PubMed  Google Scholar 

  82. Zemann N, et al. Differentiation-and polarization-dependent zinc tolerance in Caco-2 cells. Eur J Nutr. 2011;50(5):379–86.

    Article  CAS  PubMed  Google Scholar 

  83. Franklin R, et al. Human ZIP1 is a major zinc uptake transporter for the accumulation of zinc in prostate cells. J Inorg Biochem. 2003;96(2):435–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of British Columbia, Vancouver, British Columbia, Canada

    Pooya Khan Mohammad Beigi MSc, MD

  2. New York Medical College, Valhalla, NY, USA

    Pooya Khan Mohammad Beigi MSc, MD

  3. University of California Davis, Sacramento, CA, USA

    Emanual Maverakis MD

Authors
  1. Pooya Khan Mohammad Beigi MSc, MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emanual Maverakis MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Beigi, P.K.M., Maverakis, E. (2015). Epidemiology and Etiology. In: Acrodermatitis Enteropathica. Springer, Cham. https://doi.org/10.1007/978-3-319-17819-6_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-17819-6_2

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-17818-9

  • Online ISBN: 978-3-319-17819-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation