SNOMEDCT: 37702000; ICD10CM: E83.2; ORPHA: 37; DO: 0050605;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8q24.3 | Acrodermatitis enteropathica | 201100 | Autosomal recessive | 3 | SLC39A4 | 607059 |
A number sign (#) is used with this entry because of evidence that the zinc deficiency type of acrodermatitis enteropathica (AEZ) is caused by homozygous or compound heterozygous mutation in the SLC39A4 gene (607059) on chromosome 8q24.
Acrodermatitis enteropathica of the zinc deficiency type (AEZ) is characterized by intermittent simultaneous occurrence of diarrhea and dermatitis with failure to thrive. Alopecia of the scalp, eyebrows, and eyelashes is a usual feature. The skin lesions are bullous. Noteworthy is the cure by diodoquin, or diiodohydroxyquinoline (Dillaha et al., 1953; Bloom and Sobel, 1955). Rodin and Goldman (1969) described autopsy findings, including pancreatic islet hyperplasia, absence of the thymus and of germinal centers, and plasmocytosis of lymph nodes and spleen.
Garretts and Molokhia (1977) described a patient who had somewhat elevated serum zinc levels, yet the patient responded strikingly with zinc treatment, relapsed with cessation of zinc, and again responded to reinstitution of treatment.
Ohlsson (1981) described a Saudi boy who, despite being breast fed, developed acrodermatitis enteropathica. The mother had zinc deficiency as indicated by low serum levels of zinc. Cranial computed tomography showed marked cortical atrophy that improved on treatment with zinc.
Michalczyk et al. (2003) pointed out that acrodermatitis enteropathica is distinct from zinc deficiency of neonates fed on breast milk (608118) in several ways. Zinc deficiency in breastfed babies is caused by low levels of zinc in the maternal milk, whereas in acrodermatitis enteropathica, the maternal milk is protective and the symptoms of zinc deficiency develop after weaning (Aggett, 1983). No impairment in zinc uptake in the gut was found in the breastfed zinc-deficient babies (Aggett et al., 1980). This is in contrast to acrodermatitis enteropathica, where mucosal zinc uptake in the small intestine of patients is lower than normal. Furthermore, cultured fibroblasts from patients with acrodermatitis enteropathica show decreased uptake of zinc.
See also 601979 for a description of hyperzincemia with functional zinc depletion.
Moynahan (1974) reported success with oral zinc therapy and Neldner and Hambidge (1975) confirmed it. Without therapy, plasma zinc concentration and serum alkaline phosphatase, as well as urinary excretion of zinc, were very low.
Evans and Johnson (1976) suggested that absence of a low molecular weight zinc-binding factor may be the cause of deficient zinc absorption. This binding factor is produced by the pancreas, binds dietary zinc, and transports it into epithelial cells. The binding factor is present in human breast milk, which has been known to ameliorate acrodermatitis enteropathica.
Ohlsson (1981) pointed out that serum alkaline phosphatase is low in patients with acrodermatitis enteropathica and that it returns to normal with zinc therapy. Alkaline phosphatase is a zinc metalloenzyme.
To map the gene responsible for AEZ, Wang et al. (2001) performed a genomewide screen of 17 individuals, including 4 affected individuals, in a consanguineous Jordanian family. All 4 affected individuals, as well as an affected member not genotyped in the genomewide screen, were found to be homozygous for a common haplotype, spanning approximately 3.5 cM, defined by markers D8S1713 and D8S2334 on chromosome 8q24.3. To support these mapping data, 7 consanguineous Egyptian families with 8 patients with AEZ were genotyped using these markers, and 6 patients from 5 families were found to be homozygous in this region. Multipoint analysis with all consanguineous families resulted in a maximum lod score of 3.89 between D8S1713 and D8S373.
The transmission pattern of AEZ in the families reported by Kury et al. (2002) was consistent with autosomal recessive inheritance.
Kury et al. (2002) observed that within the genomic region where the acrodermatitis enteropathica locus maps there is a gene, SLC39A4, that encodes a protein with significant similarity to members of the zinc/iron-regulated transporter-like protein (ZIP) family, which are thought to be involved in zinc uptake in Arabidopsis thaliana (Rogers et al., 2000) and humans. In affected members of 8 families with acrodermatitis enteropathica, Kury et al. (2002) identified mutations in the SLC39A4 gene (607059.0001-607059.0006).
Schmitt et al. (2009) provided a review of SLC39A4 mutations in acrodermatitis enteropathica and stated that 31 SLC39A4 mutations or unclassified variants had been identified. They noted that there were no apparent genotype/phenotype correlations.
Brummerstedt (1977) suggested that a disease of Friesian cattle may be homologous. Thymic hypoplasia is a feature. Zinc supplementation 'cures' the disease, including reconstitution of the thymus.
Piletz and Ganschow (1978) showed that the 'lethal milk' (lm) syndrome of mice is zinc deficiency; see 602095. Homozygous lm/lm mice develop normally if nursed on normal milk but their own litters die unless provided with supplementary zinc because the lethal milk mother is not able to transport zinc from the blood to the milk.
Aggett, P. J., Atherton, D. J., More, J., Davey, J., Delves, H. T., Harries, J. T. Symptomatic zinc deficiency in a breast-fed preterm infant. Arch. Dis. Child. 55: 547-550, 1980. [PubMed: 7192074] [Full Text: https://doi.org/10.1136/adc.55.7.547]
Aggett, P. J. Acrodermatitis enteropathica. J. Inherit. Metab. Dis. 6 Suppl. 1: 39-43, 1983. [PubMed: 6413773] [Full Text: https://doi.org/10.1007/BF01811322]
Bloom, D., Sobel, N. Acrodermatitis enteropathica successfully treated with diodoquin. J. Invest. Derm. 24: 167-177, 1955. [PubMed: 14354277] [Full Text: https://doi.org/10.1038/jid.1955.29]
Bohane, T. D., Cutz, E., Hamilton, J. R., Gall, D. G. Acrodermatitis enteropathica, zinc, and the Paneth cell: a case report with family studies. Gastroenterology 73: 587-592, 1977. [PubMed: 196972]
Brenton, D. P., Jackson, M. J., Young, A. Two pregnancies in a patient with acrodermatitis enteropathica treated with zinc sulphate. Lancet 318: 500-502, 1981. Note: Originally Volume II. [PubMed: 6115249] [Full Text: https://doi.org/10.1016/s0140-6736(81)90884-9]
Brummerstedt, E. Animal model of human disease: acrodermatitis enteropathica, zinc malabsorption. Am. J. Path. 87: 725-728, 1977. [PubMed: 559415]
Cash, R., Berger, C. K. Acrodermatitis enteropathica: defective metabolism of unsaturated fatty acids. J. Pediat. 74: 717-729, 1969. [PubMed: 4888314] [Full Text: https://doi.org/10.1016/s0022-3476(69)80134-4]
Der Kaloustian, V. M., Musallam, S. S., Sanjad, S. A., Murib, A., Hammad, W. D., Idriss, Z. H. Oral treatment of acrodermatitis enteropathica with zinc sulfate. Am. J. Dis. Child. 130: 421-423, 1976. [PubMed: 946739] [Full Text: https://doi.org/10.1001/archpedi.1976.02120050079015]
Dillaha, C. J., Lorincz, A. L., Aavik, O. R. Acrodermatitis enteropathica: review of the literature and report of a case successfully treated with diodoquin. J. Am. Med. Assoc. 152: 509-512, 1953. [PubMed: 13044560] [Full Text: https://doi.org/10.1001/jama.1953.03690060025009]
Evans, G. W., Johnson, P. E. Zinc-binding factor in acrodermatitis enteropathica. (Letter) Lancet 308: 1310 only, 1976. Note: Originally Volume II. [PubMed: 63790] [Full Text: https://doi.org/10.1016/s0140-6736(76)92082-1]
Garretts, M., Molokhia, M. Acrodermatitis enteropathica without hypozincemia. J. Pediat. 91: 492-494, 1977. [PubMed: 894428] [Full Text: https://doi.org/10.1016/s0022-3476(77)81333-4]
Gordon, E. F., Gordon, R. C., Passal, D. B. Zinc metabolism: basic, clinical, and behavioral aspects. J. Pediat. 99: 341-349, 1981. [PubMed: 6455508] [Full Text: https://doi.org/10.1016/s0022-3476(81)80315-0]
Graves, K., Kestenbaum, T., Kalivas, J. Hereditary acrodermatitis enteropathica in an adult. Arch. Derm. 116: 562-564, 1980. [PubMed: 7377790]
Kury, S., Dreno, B., Bezieau, S., Giraudet, S., Kharfi, M., Kamoun, R., Moisan, J.-P. Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nature Genet. 31: 239-240, 2002. [PubMed: 12068297] [Full Text: https://doi.org/10.1038/ng913]
Leupold, D., Poley, J. R., Meigel, W. N. Zinc therapy in acrodermatitis enteropathica. Helv. Paediat. Acta 31: 109-115, 1976. [PubMed: 955933]
Lindstrom, B. Familial acrodermatitis enteropathica in an adult. Acta Derm. Venerol. 43: 522-527, 1963.
Lungarotti, M. S., Rufini, S., Calabro, A., Mariotti, G., Ghebregzabher, M., Monaldi, B. Treatment of acrodermatitis enteropathica with zinc sulphate. Helv. Paediat. Acta 31: 117-120, 1976. [PubMed: 955934]
Margileth, A. M. Acrodermatitis enteropathica: case report and review of literature. Am. J. Dis. Child. 105: 285-291, 1963. [PubMed: 13933009]
Michalczyk, A., Varigos, G., Catto-Smith, A., Blomeley, R. C., Ackland, M. L. Analysis of zinc transporter, hZnT4 (Slc30A4), gene expression in a mammary gland disorder leading to reduced zinc secretion into milk. Hum. Genet. 113: 202-210, 2003. [PubMed: 12743795] [Full Text: https://doi.org/10.1007/s00439-003-0952-2]
Moynahan, E. J. Acrodermatitis enteropathica: a lethal inherited human zinc deficiency disorder. Lancet 304: 399-400, 1974. Note: Originally Volume II. [PubMed: 4136854] [Full Text: https://doi.org/10.1016/s0140-6736(74)91772-3]
Neldner, K. H., Hambidge, K. M. Zinc therapy of acrodermatitis enteropathica. New Eng. J. Med. 292: 879-882, 1975. [PubMed: 1090826] [Full Text: https://doi.org/10.1056/NEJM197504242921702]
Ohlsson, A. Acrodermatitis enteropathica: reversibility of cerebral atrophy with zinc therapy. Acta Paediat. Scand. 70: 269-273, 1981. [PubMed: 7234413] [Full Text: https://doi.org/10.1111/j.1651-2227.1981.tb05556.x]
Oleske, J. M., Westphal, M. L., Shore, S., Gorden, D., Bogden, J. D., Nahmias, A. Zinc therapy of depressed cellular immunity in acrodermatitis enteropathica: its correction. Am. J. Dis. Child. 133: 915-918, 1979. [PubMed: 112858] [Full Text: https://doi.org/10.1001/archpedi.1979.02130090043007]
Piletz, J. E., Ganschow, R. E. Zinc deficiency in murine milk underlies expression of the 'lethal milk' (lm) mutation. Science 199: 181-183, 1978. [PubMed: 619449] [Full Text: https://doi.org/10.1126/science.619449]
Rodin, A. E., Goldman, A. S. Autopsy findings in acrodermatitis enteropathica. Am. J. Clin. Path. 51: 315-322, 1969. [PubMed: 4885296] [Full Text: https://doi.org/10.1093/ajcp/51.3.315]
Rogers, E. E., Eide, D. J., Guerinot, M. L. Altered selectivity in an Arabidopsis metal transporter. Proc. Nat. Acad. Sci. 97: 12356-12360, 2000. [PubMed: 11035780] [Full Text: https://doi.org/10.1073/pnas.210214197]
Schmitt, S., Kury, S., Giraud, M., Dreno, B., Kharfi, M., Bezieau, S. An update on mutations of the SLC39A4 gene in acrodermatitis enteropathica. Hum. Mutat. 30: 926-933, 2009. [PubMed: 19370757] [Full Text: https://doi.org/10.1002/humu.20988]
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Sturtevant, F. M. Zinc deficiency, acrodermatitis enteropathica, optic atrophy, subacute myelo-optic neuropathy, and 5,7-dihalo-8-quinolinols. Pediatrics 65: 610-613, 1980. [PubMed: 6444713]
Vedder, J. S. Acrodermatitis enteropathica (Danbolt-Closs) in five siblings: efficacy of diodoquin in its management. J. Pediat. 48: 212-219, 1956. [PubMed: 13295966] [Full Text: https://doi.org/10.1016/s0022-3476(56)80167-4]
Wang, K., Pugh, E. W., Griffen, S., Doheny, K. F., Mostafa, W. Z., al-Aboosi, M. M., el-Shanti, H., Gitschier, J. Homozygosity mapping places the acrodermatitis enteropathica gene on chromosomal region 8q24.3. Am. J. Hum. Genet. 68: 1055-1060, 2001. [PubMed: 11254458] [Full Text: https://doi.org/10.1086/319514]
Weismann, K., Flagstad, T. Hereditary zinc deficiency (Adema disease) in cattle, an animal parallel to acrodermatitis enteropathica. Acta Derm. Venerol. 56: 151-154, 1976. [PubMed: 58525]