This rare skin condition was first described in patients with zinc deficiency. This primary form of the disease is an autosomal recessive. However, similar appearing lesions have been described in patients with amino acid deficiencies. With the advent of nutritional support for chronically debilitated patients, monitoring of zinc status has become even more important to avoid the development of these skin lesions. Classically, the patients present with erythematous patches and plaques of dry, scaly, eczematous skin that may evolve into crusted, vesiculobullous, erosive and pustular lesions. The lesions are distributed in a periorificial and acral pattern, on the face, scalp, hands, feet, and anogenital areas. Paronychia as well as loss of scalp hair, eyebrows and eyelashes may occur. Secondary infection with Staphylococcus aureus and Candida albicans may occur. When this disease occurs in infants, symptoms such as withdrawal, photophobia and loss of appetite may occur. Abnormalities in the epithelium of the gut often leads to diarrhea. Treatment with zinc supplementation produces rapid improvement.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis and Treatment Commonly Used Terms
EPIDEMIOLOGY CHARACTERIZATION INCIDENCE 1 in 500,000 people in Denmark are affected AGE RANGE-MEDIAN Wide age range SEX (M:F) Both BREAST FEEDING
Symptomatic zinc deficiency in breast-fed term and premature infants.
Stevens J, Lubitz L.
Department of General Paediatrics, Royal Children's Hospital, Parkville, Victoria, Australia.
J Paediatr Child Health 1998 Feb;34(1):97-100 Abstract quote
Two 3-month-old exclusively breast-fed infants, one born at full-term and the other born prematurely, developed symptomatic zinc deficiency manifested by an acrodermatitis enteropathica-like eruption.
Inadequate breast milk zinc was demonstrated in both cases. A rapid clinical response followed oral zinc supplementation after which their serum zinc levels returned to normal. The infants remained asymptomatic following cessation of zinc therapy.
Reports of similar cases suggest that in a group of infants breast milk does not meet their nutritional zinc requirements. Inadequate breast milk zinc is thought to result from a defect in transfer of zinc from maternal serum to breast milk.
Zinc deficiency in exclusively breast-fed infants.
Piela Z, Szuber M, Mach B, Janniger CK.
Department of Dermatology, District Hospital, Rzeszow, Poland.
Cutis 1998 Apr;61(4):197-200 Abstract quote
Zinc deficiency in breast-fed infants is an important disorder. Unlike acrodermatitis enteropathica, it is transient and stops when nursing ends.
We report two cases of premature infants, breast-fed only, who showed skin lesions resembling acrodermatitis enteropathica. Results of laboratory investigations revealed a lowered zinc level in the infants' serum and in the mothers' milk and a normal level of zinc in the mothers' serum.
After the infants were given zinc supplements and their diets diversified, the skin lesions regressed and their serum zinc levels became normal.
DISEASE ASSOCIATIONS CHARACTERIZATION ANOREXIA NERVOSA
Acquired zinc deficiency in association with anorexia nervosa: case report and review of the literature.
Van Voorhees AS, Riba M.
Lansdale Medical Group, PA 19446.
Pediatr Dermatol 1992 Sep;9(3):268-71 Abstract quote
Zinc deficiency, whether a result of an acquired or inherited abnormality of zinc metabolism, is associated with characteristic cutaneous findings. The inherited variety is known as acrodermatitis enteropathica.
We present a case of zinc deficiency secondary to starvation induced by anorexia nervosa. Since the cutaneous stigmata of zinc deficiency and anorexia nervosa can initially be subtle and occasionally overlap, we believe that screening zinc levels in patients with anorexia nervosa with prominent cutaneous findings should be considered.
Zinc deficiency manifested by dermatitis and visual dysfunction in a patient with Crohn's disease.
Myung SJ, Yang SK, Jung HY, Jung SA, Kang GH, Ha HK, Hong WS, Min YI.
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
J Gastroenterol 1998 Dec;33(6):876-9 Abstract quote
We report a case of Crohn's disease with low serum zinc concentration in a 26-year-old woman. She demonstrated acrodermatitis enteropathica and decreased visual acuity during total parenteral nutrition. Subsequent intravenous zinc supplementation resulted in alleviation of the skin lesions and improvement of visual acuity.
This case supports the notion that depressed serum zinc in Crohn's disease may cause clinical manifestations, such as acrodermatitis enteropathica and retinal dysfunction, which may be correctable with zinc supplementation.
- Acrodermatitis enteropathica-like eruption and food allergy.
Martin DP, Tangsinmankong N, Sleasman JW, Day-Good NK, Wongchantara DR.
Department of Pediatrics, University of South Florida/All Children's Hospital, St Petersburg, Florida 33701, USA.
Ann Allergy Asthma Immunol. 2005 Mar;94(3):398-401. Abstract quote
BACKGROUND: Acrodermatitis enteropathica-like eruption (AE) is a distinct rash associated with profound zinc deficiency. It is seen in a variety of conditions but has not been reported as a presentation of food allergy.
OBJECTIVE: To report AE as an unusual presentation of food allergy in infants.
METHODS: Acrodermatitis enteropathica-like eruption was diagnosed by a characteristic rash and a low serum zinc level. The diagnosis of food allergy was made by history, serum total IgE and food specific IgE levels, or oral challenge with suspected foods.
RESULTS: Two infants with AE, diarrhea, and low serum zinc levels were evaluated. Food allergy was found in both infants. The first infant had a serum IgE level of 4642 IU/mL. Specific IgE levels to milk, soybean, wheat, and peanut were 39.04, 10.14, 5.65, and 102.61 kU/L, respectively. Oral challenges to milk and peanut were positive and to soybean were negative. The second infant had a serum IgE level of 991 IU/mL; specific IgE levels to soybean and milk were 36.9 and 0.53 kU/L, respectively. Evaluation for other possible causes of diarrhea revealed homozygous delta F508 in the first infant, confirming the coexistence of cystic fibrosis; findings in the second infant were negative.
CONCLUSIONS: Undiagnosed food allergy can lead to profound zinc deficiency. Food allergy should be suspected in a child with acquired AE.
Acrodermatitis enteropathica-like eruption in an infant with nonketotic hyperglycinemia.
Samady JA, Schwartz RA, Shih LY, Piela Z, Lambert WC, Janniger CK.
Dermatology, Pediatrics, Pathology, UMDNJ-New Jersey Medical School, Newark 07103-2714, USA.
J Dermatol 2000 Sep;27(9):604-8 Abstract quote
Acrodermatitis enteropathica is a rare inherited disorder characterized by zinc deficiency and a triad of dermatitis, diarrhea, and alopecia. It is an autosomal recessive condition thought to be due to the inability to absorb zinc from the gastrointestinal tract. Acquired zinc deficiency due to a variety of etiologies may produce a similar clinical picture. These causes include inadequate supply, malabsorption, and low zinc stores. In addition to zinc, deficiencies of other nutrients such as branched chain amino acids have induced an acrodermatitis enteropathica-like eruption.
We describe a case of a 26-month-old boy with a rare inborn error of metabolism known as nonketotic hyperglycinemia who developed an acrodermatitis enteropathica-like eruption. In addition to zinc deficiency, the patient was deficient in branched chain amino acids due to a low protein diet instituted to reduce his elevated glycine levels. The rash did not respond to zinc replacement alone, and therefore is most likely a combination of amino acid and zinc deficiency.
Acrodermatitis enteropathica-like eruptions have been described in other conditions that cause decreased serum amino acids, such as maple syrup urine disease and organic acidurias.
This is the first case describing an association between acrodermatitis enteropathica and nonketotic hyperglycinemia.
Acrodermatitis enteropathica with Pseudomonas aeruginosa sepsis.
Ozkan S, Ozkan H, Fetil E, Corapcioglu F, Yilmaz S, Ozer E.
Department of Dermatology, Faculty of Medicine, University of Dokuz Eylul, Izmir, Turkey.
Pediatr Dermatol 1999 Nov-Dec;16(6):444-7 Abstract quote
Acrodermatitis enteropathica is characterized by eczematous and scaly plaques on the face, scalp, acral, and anogenital regions. In addition to typical lesions, unusual prominent vesiculobullous lesions are also described.
We report a full-term, 9-month-old boy who has acrodermatitis enteropathica and Pseudomonas sepsis. In this patient there were clinical findings of sepsis and eczematous vesiculobullous lesions on the periorificial and acral areas. Serum zinc level was extremely low. Pseudomonas aeruginosa was identified in cultures of blood and fluid which was aspirated from the bullous lesions.
After oral zinc sulfate and intravenous antibiotic treatment his condition improved within 2 weeks.
PATHOGENESIS CHARACTERIZATION CHROMOSOMAL ABNORMALITIES
Mutation spectrum of human SLC39A4 in a panel of patients with acrodermatitis enteropathica.
Kury S, Kharfi M, Kamoun R, Taieb A, Mallet E, Baudon JJ, Glastre C, Michel B, Sebag F, Brooks D, Schuster V, Scoul C, Dreno B, Bezieau S, Moisan JP.
Laboratoire d'Etude du Polymorphisme de l'ADN, Faculte de Medecine, 1 rue Gaston Veil, 44035 Nantes cedex, France.
Hum Mutat. 2003 Oct;22(4):337-8. Abstract quote
Acrodermatitis enteropathica is rare autosomal recessive disorder characterized by a severe nutritional zinc deficiency.
We and others have recently identified the human gene encoding an intestinal zinc transporter of the ZIP family, SLC39A4, as the mutated gene in acrodermatitis enteropathica (AE). A first mutation screening in 8 AE families (15 patients out of 36 individuals) revealed the presence of six different mutations described elsewhere. Based on these results, we have evaluated the involvement of SLC39A4 in 14 patients of 12 additional AE pedigees coming either from France, Tunisia, Austria or Lithuania. A total of 7 SLC39A4 mutations were identified (1 deletion, 2 nonsense, 2 missense, and 2 modifications of splice site), of which 4 are novel: a homozygous nonsense mutation in 3 consanguineous Tunisian families [c.143T>G (p.Leu48X)], a heterozygous nonsense mutation (c.1203G>A (p.Trp401X)) in a compound heterozygote from Austria also exhibiting an already known missense mutation, and distinct homozygous mutations in families from France or Tunisia [c.475-2A>G and c.184T>C (p.Cys62Arg)]. Furthermore, two other potential mutations [c.850G>A (p.Glu284Lys) and c.193-113T>C] were also observed at homozygous state in a French family formerly described.
This study brings to 21 the number of reported SLC39A4 mutations in AE families.
Homozygosity mapping places the acrodermatitis enteropathica gene on chromosomal region 8q24.3.
Wang K, Pugh EW, Griffen S, Doheny KF, Mostafa WZ, al-Aboosi MM, el-Shanti H, Gitschier J.
Howard Hughes Medical Institute and Departments of Medicine and Pediatrics, University of California, San Francisco, CA, USA.
Am J Hum Genet 2001 Apr;68(4):1055-60 Abstract quote
Acrodermatitis enteropathica (AE) is a rare autosomal recessive pediatric disease characterized by dermatitis, diarrhea, alopecia, and growth failure. The disease results from insufficient uptake of zinc by the intestine and can be fatal unless the diet is supplemented with zinc.
To map the gene responsible for AE, a genomewide screen was performed on 17 individuals, including 4 affected individuals, in a consanguineous Jordanian family. Three markers-D8S373, D10S212, and D6S1021-had a pattern consistent with tight linkage to a recessive disease: one allele in the affected sibs and multiple alleles in unaffected sibs and parents. Two-point parametric linkage analysis using FASTLINK identified one region, D8S373, with a maximum LOD score >1.5 (1.94 at D8S373: recombination fraction.001). Twelve additional markers flanking D8S373 were used to genotype the extended family, to fine-map the AE gene. All five affected individuals-including one who was 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 chromosomal region 8q24.3.
To support these mapping data, seven consanguineous Egyptian families with eight patients with AE were genotyped using these markers, and six patients from five families were found to be homozygous in this region. Multipoint analysis with all consanguineous families, by Mapmaker/Homoz, resulted in a maximum LOD score of 3.89 between D8S1713 and D8S373. Sliding three-point analysis resulted in a maximum LOD score of 5.16 between markers D8S1727 and D8S1744.
Expression pattern, genomic structure and evaluation of the human SLC30A4 gene as a candidate for acrodermatitis enteropathica.
Kury S, Devilder MC, Avet-Loiseau H, Dreno B, Moisan JP.
Institut de Biologie de l'Hotel-Dieu, INSERM U 463, Centre Hospitalier Universitaire, 44035 Nantes Cedex, France.
Hum Genet 2001 Aug;109(2):178-85 Abstract quote
Slc30a4 is the fourth and last identified member of a mammalian proteins family presumably involved in the cellular transport of zinc, solute carrier family 30. The murine homologue of the human SLC30A4 gene has previously been investigated and found responsible for the lm, a phenotype due to zinc deficiency. According to the strong homology between mouse and human SLC30A4 coding sequences, and to the very similar clinical features encountered in the murine lm and in human acrodermatitis enteropathica, SLC30A4 has appeared to us to be a good candidate for acrodermatitis enteropathica.
Here we detail the genomic structure of human SLC30A4 together with its localization on chromosome 15q15-q21. We also report the mutational analysis of human SLC30A4 in ten families with acrodermatitis enteropathica, which enabled us to exclude this gene from any involvement in the disorder of the patients examined.
Genomic localization, organization and amplification of the human zinc transporter protein gene, ZNT4, and exclusion as a candidate gene in different clinical variants of acrodermatitis enteropathica.
Bleck O, Ashton GH, Mallipeddi R, South AP, Whittock NV, McLean WH, Atherton DJ, McGrath JA.
f Cell and Molecular Pathology, St John's Institute of Dermatology, The Guy's, King's College, and St Thomas' Hospitals' Medical School, St Thomas' Hospital, London, UK.
Arch Dermatol Res 2001 Aug;293(8):392-6 Abstract quote
Acrodermatitis enteropathica is an inherited disorder of zinc metabolism, the molecular basis of which is currently unknown. Recent transgenic mouse studies have highlighted the potential significance of certain zinc transport proteins, for example ZnT4, in providing clues to the pathogenesis of zinc-related disorders such as acrodermatitis enteropathica. Specifically, mice of any genotype suckled on ZnT4-deficient mice fail to absorb intestinal zinc and ZnT4-deficient mice also develop dermatitis, alopecia and stunted growth.
Therefore, to assess human ZnT4 as a candidate gene/protein in acrodermatitis enteropathica or related disorders, we characterized the intron-exon organization of the human ZNT4 gene, which comprises seven distinct exons spanning approximately 38.7 kb. High-resolution radiation hybrid mapping placed ZNT4 on 15q21.1. We also developed a PCR-based mutation detection strategy using primers placed on flanking introns followed by direct sequencing of the PCR products. Using this approach, we sequenced DNA from five individuals with acrodermatitis enteropathica; no mutations were identified.
Thus, ZNT4 is unlikely to be the correct candidate gene for this disorder. We also identified and characterized two common single nucleotide polymorphisms in exon 5 and in the 3' UTR of ZNT4, which will be useful for future genetic linkage studies in assessing ZNT4 as a candidate gene for other inherited disorders of zinc metabolism.
Acrodermatitis enteropathica and the relation to pellagra.
Med Hypotheses 1981 Apr;7(4):539-47 Abstract quote
A patient with a variant form of acrodermatitis enteropathica (AE) without hypozincemia is presented who showed a rise in plasma zinc and partial improvement on a pancreatic enzyme preparation, apparently because of its content of picolinic acid (PA). Complete recovery occurred on 60 mg zinc (1). This patient has now been treated with zinc PA (equal to only 5 mg zinc) and subsequently with PA. Both maintained elevated plasma zinc levels.
Because of the similarity of AE with pellagra and the common origin of PA and nicotinic acid from tryptophan, a hypothesis is presented which suggests that skin manifestations in the two disorders are due to PA deficiency since picolinic carboxylase forms NAD preferentially when there is competition for the common precursor.
The acrodermatitis enteropathica mutation affects protein expression in human fibroblasts: analysis by two-dimensional gel electrophoresis.
Grider A, Mouat MF.
Department of Foods and Nutrition, The University of Georgia, Athens, GA 30602, USA.
J Nutr 1998 Aug;128(8):1311-4 Abstract quote
The acrodermatitis enteropathica (AE) mutation affects zinc uptake in human fibroblasts. However, the specific biochemical lesion has not been identified.
We have used the technique of two-dimensional gel electrophoresis to identify protein differences in total cell lysate isolated from normal and AE fibroblasts. Two proteins with estimated molecular weights of 49.6 and 49.9 kDa and an isoelectric point of 5.1 were identified in normal fibroblasts but absent from AE fibroblasts. The proteins were purified, subjected to in-gel trypsin digest and the resulting peptides separated by HPLC. Sequences from three peptide fragments (8, 15 and 18 amino acids) were obtained after Edman degradation. None of the fragments exhibited homology to any amino acid sequences in the nonredundant Genbank database. The 15 and 18 amino acid fragments each exhibited 100% homology to a 136 amino acid expressed sequence tag that was homologous (43%) to adipophilin. However, the 15 and 18 amino acid fragments were only 30 and 44% homologous, respectively, to corresponding regions within the expressed sequence tag.
Therefore, the 49.6/49.9 kDa protein absent from AE fibroblasts was not related to adipophilin. The 8 amino acid fragment did not exhibit homology to any expressed sequence tag. Therefore, the 49.6/49.9 kDa proteins are novel and may be the cause of the reduced zinc uptake and abnormal zinc metabolism characteristic of fibroblasts carrying the AE mutation.
ZINC LEVELS AND METABOLISM
Picolinic acid in acrodermatitis enteropathica: evidence for a disorder of tryptophan metabolism.
Krieger I, Cash R, Evans GW.
J Pediatr Gastroenterol Nutr 1984;3(1):62-8 Abstract quote
Three children with acrodermatitis enteropathica (AE) were treated with oral zinc dipicolinate (zinc-PA).
The daily dose of zinc required to prevent exacerbations, when administered as the dipicolinate complex, was one-third the minimum amount of zinc required as the sulfate salt. The concentration of picolinic acid in the plasma of asymptomatic children with AE was significantly less than that of normal children. However, oral treatment with PA alone was ineffective. The plasma of the three AE children contained a measurable quantity of kynurenine which was undetectable in plasma from normal children. Absorption of an oral zinc load was normal.
The results support the hypothesis that the genetic defect in AE is in the tryptophan pathway, although the role of PA in zinc metabolism remains to be defined.
Clinical, endocrinological and biochemical effects of zinc deficiency.
Clin Endocrinol Metab 1985 Aug;14(3):567-89 Abstract quote
The essentiality of zinc for humans was recognized in the early 1960s. The causes of zinc deficiency include malnutrition, alcoholism, malabsorption, extensive burns, chronic debilitating disorders, chronic renal disease, certain diuretics, the use of chelating agents such as penicillamine for Wilson's disease, and genetic disorders such as acrodermatitis enteropathica and sickle cell disease. The requirement of zinc is increased in pregnancy and during the growing age period.
The clinical manifestations in severe cases of zinc deficiency included bullous-pustular dermatitis, alopecia, diarrhoea, emotional disorder, weight loss, intercurrent infections, hypogonadism in males and it is fatal if untreated. A moderate deficiency of zinc is characterized by growth retardation and delayed puberty in adolescents, hypogonadism in males, rough skin, poor appetite, mental lethargy, delayed wound healing, taste abnormalities and abnormal dark adaptation. In mild cases of zinc deficiency in human subjects, we have observed oligospermia, slight weight loss and hyperammonaemia. Zinc is a growth factor. As a result of its deficiency, growth is affected adversely in many animal species and in man. Inasmuch as zinc is needed for protein and DNA synthesis and cell division, it is believed that the growth effect of zinc is related to its effect on protein synthesis. Testicular functions are affected adversely as a result of zinc deficiency in both humans and experimental animals. This effect of zinc is at the end organ level and the hypothalamic--pituitary axis is intact in zinc-deficient subjects. Inasmuch as zinc is intimately involved in a cell division, its deficiency may adversely affect testicular size and thus its function. In mice, the incidence of degenerate oocytes, and hypohaploidy and hyperhaploidy in metaphase II oocytes were increased due to zinc deficiency. Zinc at physiological concentrations reduced prolactin secretion from the pituitary in vitro and it has been suggested that this trace element may have a role in the in vivo regulation of prolactin release. Thymopoietin, a hormone needed for T-cell maturation, has also been shown to be zinc dependent.
It is clear that zinc may have several roles in biochemical and hormonal functions of various endocrine organs. Future research in this area is very much needed.
The acrodermatitis enteropathica mutation transiently affects zinc metabolism in human fibroblasts.
Grider A, Young EM.
Department of Human Ecology, University of Texas, Austin 78712, USA.
J Nutr 1996 Jan;126(1):219-24 Abstract quote
The acrodermatitis enteropathica (AE) mutation has been shown to affect zinc transport in human intestinal biopsies. However, whether the mutation is also expressed in human fibroblasts has not been determined. The activity of the zinc-dependent enzyme, 5' nucleotidase, and cell zinc content were measured in normal and AE fibroblasts 2 and 4 d after subculturing to determine the effect of the AE mutation on zinc metabolism.
The activity of 5' nucleotidase in AE cells was 68% of normal at 2 d after subculturing. Although 5' nucleotidase activity had decreased significantly in both normal and AE fibroblasts at 4 d after subculturing, there was no significant difference between the two genotypes. The zinc content of AE fibroblasts was also significantly reduced. Acrodermatitis enteropathica fibroblasts contained 62% less zinc than normal fibroblasts at 2 d. By 4 d the normal fibroblast zinc content had decreased to that of the AE fibroblasts. The uptake and transport of 65Zn into AE fibroblasts at 2 d was measured because these cells exhibited reduced 5' nucleotidase activity and cell zinc content at this time. The uptake of zinc over a 90-min time period was the same in the two genotypes. However, AE fibroblasts incubated with 2-10 mumol Zn/L for 15 min had significantly slower zinc transport compared with normal fibroblasts. In both genotypes, Michaelis-Menten kinetics were observed. Normal and AE fibroblasts had similar affinities for zinc (Km), but AE fibroblasts exhibited a Vmax which was reduced by 38%.
These results indicate that the phenotypic expression of the AE mutation occurs in a time-dependent manner, is not restricted to the intestine and is also transiently expressed in human fibroblasts, resulting in abnormal zinc metabolism in these cells.
Differences in the cellular zinc content and 5'-nucleotidase activity of normal and acrodermatitis enteropathica (AE) fibroblasts.
Grider A, Lin YF, Muga SJ.
Department of Foods and Nutrition, The University of Georgia, Athens 30602, USA.
Biol Trace Elem Res 1998 Jan;61(1):1-8 Abstract quote
The acrodermatitis enteropathica (AE) mutation affects zinc (Zn) metabolism in human fibroblasts. We hypothesize that the mutation affects the cell Zn content, which subsequently affects the activity of various zinc-dependent enzymes, such as 5'-nucleotidase.
Therefore, normal and AE fibroblasts were grown in normal medium containing physiological levels of Zn (16 micromol/L) for approximately 24 h. The medium was replaced by normal medium (16 micromol/L Zn), Zn-depleted medium (1.5 micromol/L Zn), or Zn-supplemented medium (200 micromol/L Zn) for another 24 h. Regardless of the Zn concentration of the growth medium, the AE fibroblasts contained significantly less Zn than normal fibroblasts grown in comparable medium. Nevertheless, growth of the fibroblasts in 200 micromol/L Zn medium significantly increased the cell Zn content fourfold of both normal and AE fibroblasts. The activity of 5'-nucleotidase in the AE fibroblasts grown in 16 micromol/L Zn or 1.5 micromol/L Zn medium was also significantly lower than in normal fibroblasts. Changing the growth medium from 16 micromol/L Zn to 1.5 micromol/L Zn medium did not affect the activity of the enzyme in either genotype. Cells grown in 200 micromol/L Zn medium exhibited threefold greater 5'-nucleotidase activity in AE fibroblasts, but had no affect on enzyme activity in normal cells.
In summary, altering the cell Zn content of normal fibroblasts did not result in a significant change in their 5'-nucleotidase activity. However, AE fibroblasts grown in 200 micromol/L Zn medium exhibited recovery of their 5'-nucleotidase activity to normal levels. These results support the hypothesis that the AE mutation affects the cellular Zn content. The lower cell Zn content subsequently affects the activity of 5'-nucleotidase.
Acrodermatitis enteropathica Reversibility of cerebral atrophy with zinc therapy.
Acta Paediatr Scand 1981 Mar;70(2):269-73 Abstract quote
A six-month-old Saudi boy with acrodermatitis enteropathica confirmed by low serum zinc and alkaline phosphatase levels is described. Both the patient and a sibling developed acrodermatitis enteropathica while entirely breastfed. The mother had low serum zinc levels. Cranial computed tomography initially showed marked central and cortical "atrophy" that improved on treatment with zinc sulphate.
The importance of zinc for normal brain growth and function is well known and the improvement on cranial computed tomography could be explained by improved myelination.
LABORATORY MARKERS LIPID LEVELS
Fatty acid composition of plasma lipids in acrodermatitis enteropathica before and after zinc supplementation.
Koletzko B, Bretschneider A, Bremer HJ.
Eur J Pediatr 1985 Mar;143(4):310-4 Abstract quote
The fatty acid composition of different plasma lipid fractions has been estimated in a 6-month-old girl with acrodermatitis enteropathica before and after zinc supplementation. Linoleic acid and its metabolites were extremely reduced in triglycerides and sterol-esters. In contrast, n-3-fatty acids were increased in sterol-esters and phospholipids. Zinc supplementation led to quick clinical improvement, and linoleic and arachidonic acid increased rapidly in triglycerides and sterol-esters to the values of healthy infants. Fatty acids of phospholipids remained relatively stable.
Our findings could be explained by impaired enteral absorption of linoleic acid. Further attention should be directed to the supply and metabolism of essential fatty acids in acrodermatitis enteropathica.
Serum and hair zinc as predictors of clinical symptoms in acrodermatitis enteropathica.
Anttila P, Simell O, Salmela S, Vuori E.
J Inherit Metab Dis 1984;7(1):46-8 Abstract quote
Hair- and serum-zinc concentrations were measured in six patients with acrodermatitis enteropathica before and sequentially after cessation of zinc supplementation; supplementation was restarted when symptoms appeared.
Serum zinc correlated accurately with zinc dosage and was lowest when symptoms of deficiency appeared. Hair zinc was initially age- and body size-related and was minimally influenced by the supplementation break. Adult patients had continuously normal concentrations. In paediatric patients hair zinc was low.
Their serum concentrations should probably be maintained slightly above or at the upper limit of reference values for prolonged periods for normalization of hair and perhaps tissue zinc contents.
Serum alkaline phosphatase and serum zinc levels in the diagnosis and exclusion of zinc deficiency in man.
Weismann K, Hoyer H.
Am J Clin Nutr 1985 Jun;41(6):1214-9 Abstract quote
In the present study we monitored serum zinc (Zn) and serum alkaline phosphatase (AP) levels during Zn supplementation in (A) a young zinc depletion syndrome (ZDS) patient with severe Zn deficiency, (B) three acrodermatitis enteropathica (AEP) patients with mild Zn deficiency and (C) 7 elderly and 3 younger patients without Zn deficiency.
In (A) serum Zn and serum AP values were low, but following parenteral Zn the parameters rose to normal levels (r = +0.79, p less than 0.001). In (B) serum Zn and serum AP levels decreased when oral Zn was stopped, but shortly returned to normal upon reinitiation of Zn. In (C) Zn therapy caused a rise in the serum Zn concentration whereas the serum AP activity decreased (r = -0.01, p greater than 0.1).
The results suggest that serial determinations of serum Zn and serum AP during Zn supplementation may be a valid tool in the diagnosis of severe and mild Zn deficiency as well as in the exclusion of the diagnosis.
Acrodermatitis enteropathica, zinc metabolism, copper status, and immune function.
Sandstrom B, Cederblad A, Lindblad BS, Lonnerdal B.
Research Department of Human Nutrition, Royal Veterinary and Agricultural University, Frederiksberg, Denmark.
Arch Pediatr Adolesc Med 1994 Sep;148(9):980-5 Abstract quote
OBJECTIVE: To study zinc metabolism, copper status, and immune function in a patient with acrodermatitis enteropathica.
RESEARCH DESIGN: Case report.
PATIENT: A 16-year-old boy with acrodermatitis enteropathica.
INTERVENTION: Change of zinc supplementation dosage from 1000 to 525 mumol/d.
MEASUREMENTS AND RESULTS: Zinc metabolism was studied with an oral dose of zinc chloride Zn 65 and whole-body counting at both zinc dosages. Zinc, copper status, and immune indexes were also measured at both dosages. The higher dosage of zinc supplementation was found to induce a state of low copper status and immune dysfunction. Lowering the dosage normalized these indexes. Zinc absorption in this patient was found to be within the reference range for healthy subjects. At the lower dosage, zinc retention and the rate of whole-body turnover also normalized. These results suggest that the primary lesion in acrodermatitis enteropathica is a cellular defect in zinc metabolism rather than an impairment of zinc absorption.
CONCLUSION: Zinc and copper status and immune function should be monitored regularly in patients with acrodermatitis enteropathica to provide a proper dosage of zinc during different physiologic stages.
Clinical and laboratory assessment of zinc deficiency in Dutch children. A review.
Van Wouwe JP.
Department of Pediatrics, Drechtsteden Hospital Jacobus, Zwijndrecht, The Netherlands.
Biol Trace Elem Res 1995 Aug-Sep;49(2-3):211-25 Abstract quote
The clinical spectrum of acrodermatitis enteropathica (n = 226) is compared with symptoms reported in other Zn deficiencies: total parenteral nutrition without Zn (n = 21), protein energy malnutrition (n = 24), gastrointestinal disease (n = 79), geophagia (n = 227), and dietary low intake (n = 23).
Common features of deficiency are diarrhea, recurrent infection, and growth retardation. Dermatitis is less common in other types of deficiency than in acrodermatitis enteropathica (9 vs 88% of cases). Anorexia and/or hypogeusia is reported more frequently in the other types of deficiency (30 vs 16%). T
he main symptoms in acrodermatitis enteropathica vary with age. These differences in the clinical picture of Zn deficiency are discussed in relation to the degree of the deficiency (acute, subacute, or chronic; severe, mild, or subclinical). The results of the conventional laboratory tests to diagnose Zn deficiency (Zn levels in serum, urine, or hair) are reviewed. In healthy Dutch infants and children, the mean values of these levels vary by a factor of 1.6-3.0. Also, the clinical interpretation of their results is prone to errors.
Therefore, we advocate the erythrocytic 65Zn uptake test. Its mean varies by 1.3. However, its reference values for different age intervals need to be established. From the comparison of the results of three conventional tests of samples taken concurrently (serum, urine, and hair) in groups of Dutch children with symptoms common in Zn deficiency (diarrhea, recurrent infection, or growth retardation), it is estimated that +/- 1% of Dutch children with minor complaints suffer from either acute or subacute Zn deficiency. Other deficiencies occur occasionally. In order to detect the individual patient with deficiency, the erythrocytic 65Zn uptake test is promising and needs to be evaluated.
Therefore, we review a set of reference laboratory tests with results that alter during sequential stages of overload and deficiency. Such a scheme is advocated as a guidance for future clinical research on deficiency, and solves the problem of differentiating those conditions that identify the individual patients who need treatment by supplementation.
- Acquired acrodermatitis enteropathica: case report of an atypical presentation.
Departments of Pathology and Dermatology, Wake Forest University Baptist Medical Center, Winston-Salem, NC, USA.
- J Cutan Pathol. 2007 Jun;34(6):490-3. Abstract quote
Acrodermatitis enteropathica (ADE) is a rare genetic or acquired disorder of hypozincemia. It can be caused by impaired intestinal absorption of zinc or by poor consumption of the mineral. It is characterized by skin lesions on acral and periorificial areas and may be associated to alopecia, diarrhea and increased frequency of infections.
We present an atypical presentation of ADE in a 33-year-old women with a history of mental retardation and psoriasis that presented with lesions on the periorificial areas and extremities, and low plasma zinc levels.
VARIANTS NORMAL ZINC LEVELS
Acrodermatitis enteropathica with normal serum zinc levels: diagnostic value of small bowel biopsy and essential fatty acid determination.
Mack D, Koletzko B, Cunnane S, Cutz E, Griffiths A.
Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.
Gut 1989 Oct;30(10):1426-9 Abstract quote
We report a patient with acrodermatitis enteropathica and a normal serum zinc level in whom the diagnosis was confirmed by plasma phospholipid fatty acid and a small bowel biopsy response to oral zinc therapy.
Acrodermatitis enteropathica is a rare autosomal recessive condition of zinc deficiency characterised by chronic diarrhoea associated with failure to thrive, periorificial dermatitis and alopecia, susceptibility to infections and behavioural changes. Diagnosis is usually established by reduced serum zinc levels (classical acrodermatitis enteropathica). Paneth cell abnormalities on electron microscope of a small bowel biopsy can be supportive. A few cases with the typical picture of acrodermatitis enteropathica without hypozincaemia (variant acrodermatitis enteropathica) have been described.
The diagnosis of variant acrodermatitis enteropathica to date has been based on an entirely empiric, but nonetheless convincing clinical response to oral zinc therapy. Laboratory aids to diagnosis have been lacking.
Self-limiting acrodermatitis enteropathica. A follow-up study of three interrelated families.
Sharma NL, Sharma RC, Gupta KR, Sharma RP.
Department of Dermatology, Indira Gandhi Medical College, Shimla, India.
Int J Dermatol 1988 Sep;27(7):485-6 Abstract quote
A variant of acrodermatitis enteropathica is described that has its onset before weaning and clears when the child starts its normal solid diet.
A pedigree with three interrelated families is reported where 10 children were afflicted with this variant. They had symptoms of hypozincemia for a brief period during infancy. At the time of this study, they were symptom-free and their serum zinc levels were found to be within normal limits.
The term "self-limiting acrodermatitis enteropathica" is proposed for the variant. In one lactating mother, the mammary zinc secretion was determined and was found to be deficient and unresponsive to oral zinc supplements. The possible mode of inheritance is also discussed.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
Ileal Paneth cells and IgA system in rats with severe zinc deficiency: an immunohistochemical and morphological study.
Wilson ID, McClain CJ, Erlandsen SL.
Histochem J 1980 Jul;12(4):457-71 Abstract quote
Morphological abnormalities in Paneth cells occur in patients with acrodermatitis enteropathica, a hereditary disease associated with zinc deficiency; furthermore, rat Paneth cells contain large amounts of zinc.
This study was conducted to assess the effect of severe zinc deficiency in Sprague-Dawley rats on various parameters of Paneth cells. Morphology at both the light microscopical and ultrastructural levels, Paneth cell numbers per crypt and the intracellular distribution of lysozyme were not altered by zinc deficiency. A weak correlation (r = +0.38, P = 0.05) was noted between ileal zinc concentration and numbers of IgA-containing Paneth cells per crypt.
These findings indicate that the morphological abnormalities noted in human Paneth cells in patients with acrodermatitis enteropathica cannot be reproduced by experimental severe zinc deficiency in rats.
Furthermore, these generally negative findings suggest that the severe diarrhoea often associated with zinc deficiency is not attributable to abnormalities induced in Paneth cells by zinc deficiency.
Acquired zinc deficiency syndrome during total parenteral alimentation. Clinical and histopathological findings.
Ferrandiz C, Henkes J, Peyri J, Sarmiento J.
Dermatologica 1981;163(3):255-66 Abstract quote
An acute zinc deficiency state developed in 6 patients on total parenteral alimentation, which allegedly included zinc 37 mumol/l. The actual concentration of this trace element when measured by us, was 3 mumol/l. The clinical picture consisted of an acrodermatitis enteropathica-like syndrome, with subsequent development of distinctive nail lesions, which consisted of white transverse bands in all finger- and toenails.
Histopathological examination of several of these cutaneous lesions revealed distinctive changes, which we consider rather specific of zinc deficiency states. They consisted in parakeratosis, cleavage and detachment of the superficial layers of the epidermis, mainly intracellular and also extracellular edema of the epidermal cells, development of microvesicles at different epidermal levels, and severe vacuolar alteration of the dermoepidermal junction. These changes also affected the outer root sheath of the hair follicles.
Histopathological study of transient acrodermatitis enteropathica due to decreased zinc in breast milk.
Niemi KM, Anttila PH, Kanerva L, Johansson E.
Department of Dermatology, University Central Hospital, Helsinki, Finland.
J Cutan Pathol 1989 Dec;16(6):382-7 Abstract quote
Two children, one born prematurely and the other born at full term developed acrodermatitis enteropathica due to marginal or low levels of zinc in their mothers' breast milk.
Skin from both patients was studied with light and electron microscopy. The most characteristic light microscopic features were parakeratosis, absence of the granular layer, and pallor of the upper epidermal cells. Normal flattening of the upper Malphighian cells did not occur. Electron microscopic examination revealed that keratohyalin was decreased to absent, and the upper malpighian cells were edematous with vacuoles and large numbers of ribosomes, but small numbers of tonofilaments. Large amounts of keratinosome-derived-lamellae were found in the intercellular spaces in the keratinization area. The keratinosome-derived-lamellae were focally intermingled with opaque lipid plaques or myelin figures, probably derived from keratinosomes.
The electron microscopic findings show abnormal keratinization and suggest that it is related to a disturbance of keratinosome metabolism due to zinc deficiency.
Bullous lesions in acrodermatitis enteropathica. Histopathologic findings regarding two patients.
Borroni G, Brazzelli V, Vignati G, Zaccone C, Vignoli GP, Rabbiosi G.
Department of Human and Hereditary Pathology, University of Pavia, Italy.
Am J Dermatopathol 1992 Aug;14(4):304-9 Abstract quote
Acrodermatitis enteropathica (AE) is an autosomic recessive disorder affecting early infancy. Two cases of infantile AE with low plasma zinc levels are reported in which unusually prominent bullous and vesicobullous lesions were seen on the hands and feet, in addition to the more typical erythematous and scaly patches.
Both psoriasiform and bullous lesions responded dramatically to oral zinc-sulfate supplementation. The histopathologic features of the bullous lesions of AE have not previously been fully examined.
Histologically, the bullous lesions were characterized by intraepidermal vacuolar changes with massive ballooning, leading to intraepidermal vesiculation and blistering, with prominent epidermal necrosis and with no acantholysis. The bullous lesions did not arise on erythematous patchy lesions, but developed ex novo on unaffected skin. The histopathologic differential diagnosis with other bullous conditions is discussed.
Polarization microscopy of hair in acrodermatitis enteropathica.
Traupe H, Happle R, Grobe H, Bertram HP.
Pediatr Dermatol 1986 Sep;3(4):300-3 Abstract quotes
We studied the hair of a 10-month-old girl who was suffering from acrodermatitis enteropathica, using light and polarizing microscopy before and after institution of zinc therapy.
The hair was very thin and brittle. On light microscopy the shafts showed uneven diameter and some displayed atypical trichorrhexis nodosa with stretched fractures. Ten percent of the hair fibers exhibited nodal swellings of the pseudomonilethrix type. Polarization microscopy disclosed in 70% of all hair shafts an irregular pattern of alternating dark and bright bands. This anomaly was still present in 10% of the hair shafts after one and one-half years of zinc therapy, but could no longer be detected after two years of zinc supplementation. Repeated determinations of hair probes before and after treatment gave a low cystine content, however, being still in the normal range.
We assume that the observed changes and the low hair cystine content can be attributed to the underlying zinc deficiency.
CHARACTERIZATION ELECTRON MICROSCOPY
Ultrastructural alterations of Paneth cells in infants associated with gastrointestinal symptoms.
Kobayashi Y, Suzuki H, Konno T, Tada K, Yamamoto TY.
Tohoku J Exp Med 1983 Mar;139(3):225-30 Abstract quote
Paneth cells containing abundant and large inclusion bodies found in patients with acrodermatitis enteropathica have been considered as a consistent and characteristic abnormality of this disease.
We examined 34 children with gastrointestinal symptoms due to a wide variety of basic diseases and found similar abnormal Paneth cells in most of them, particularly in infants under the age of one year. This abnormality, according to our findings, is attributed to the secondary effect of zinc deficiency due to malnutrition.
Bullous acrodermatitis due to zinc deficiency during total parenteral nutrition: an ultrastructural study of the epidermal changes.
Welsmann K, Kvist N, Kobayasi T.
Acta Derm Venereol 1983;63(2):143-6 Abstract quote
A 5 1/2-year-old girl with idiopathic intestinal pseudo-obstruction became severely depleted of zinc during total parenteral nutrition and developed a vesico-bullous rash on face, hands and feet such as is seen in acrodermatitis enteropathica.
Light and electron microscopy of a bullous lesion on one foot revealed a pronounced extracellular edema with cyst and cleft formation in the deep part of the epidermis. A few acantholytic cells were seen.
In the electron microscope degenerate keratinocytes showed multiple vacuoles in the dark cytoplasm and slender, finger-like protrusions. Desmosomes were few. The basal lamina was well-preserved forming deep invaginations, which may serve to distinguish the condition from other bullous diseases of the skin.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES GLUTARIC ACIDURIA
Acrodermatitis acidemica secondary to malnutrition in glutaric aciduria type I.
Niiyama S, Koelker S, Degen I, Hoffmann GF, Happle R, Hoffmann R.
Department of Dermatology, Philipp University, Deutschhausstrasse 9, D-35033 Marburg, Germany.
Eur J Dermatol 2001 May-Jun;11(3):244-6 Abstract quote
We encountered a patient with glutaric aciduria type I (GA-I) associated with skin lesions resembling acrodermatitis enteropathica (AE).
This child was being fed with a low-protein diet when the skin disorder developed. A deficiency in plasma levels of essential amino acids, particularly isoleucine, and zinc was confirmed. Supplementation of a high-caloric, protein-rich diet together with zinc, selenium and vitamins led to a prompt improvement of the skin lesions. We assume that in our patient the skin lesions were the result of malnutrition, rather than being primarily associated with the underlying metabolic disease.
To our knowledge, no other report is so far available concerning GA-I complicated by skin eruptions.
Acrodermatitis enteropathica-like syndrome secondary to isoleucine deficiency during treatment of maple syrup urine disease.
Giacoia GP, Berry GT.
Department of Pediatrics, University of Oklahoma College of Medicine, Tulsa 74136.
Am J Dis Child 1993 Sep;147(9):954-6 Abstract quote
We describe a patient with maple syrup urine disease in whom an acrodermatitis enteropathica-like syndrome developed while he was receiving a branched-chain amino acid-free formula. Iatrogenically induced isoleucine deficiency developed and resulted in a decreased protein accretion and persistent increase in the plasma concentrations of leucine. A rapid clinical response to isoleucine supplementation was noted.
This observation underscores the risks of using amino acid-free formulas without adequate supplementation of deficient amino acids.
Iatrogenic isolated isoleucine deficiency as the cause of an acrodermatitis enteropathica-like syndrome.
Bosch AM, Sillevis Smitt JH, Van Gennip AH, Abeling NG, Schutgens RB, Bakker HD, Wijburg FA.
Department of Paediatrics, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Br J Dermatol 1998 Sep;139(3):488-91 Abstract quote
We present two patients with a suspected inborn error of metabolism. A female newborn presented with dysmorphic features and convulsions. Metabolic screening suggested a defect in isoleucine degradation. Within 2 weeks after the introduction of an isoleucine-restricted diet, she developed a severe acrodermatitis enteropathica-like syndrome. The plasma level of isoleucine was low with a normal leucine/isoleucine ratio. The second patient, a female infant deficient in leucine as a result of a leucine-restricted diet, did not develop a dermatosis.
Isoleucine is essential for normal growth and differentiation of keratinocytes and enterocytes. Deficiency of isoleucine, and not leucine or an imbalance in the leucine/isoleucine ratio, may result in an acrodermatitis enteropathica-like syndrome.
Acrodermatitis enteropathica-like cutaneous lesions in organic aciduria.
De Raeve L, De Meirleir L, Ramet J, Vandenplas Y, Gerlo E.
Department of Dermatology, Academisch Ziekenhuis, Vrije Universiteit Brussel, Belgium.
J Pediatr 1994 Mar;124(3):416-20 Abstract quote
Cutaneous lesions resembling acrodermatitis enteropathica were present in two infants with methylmalonic acidemia and in one infant with propionic acidemia. All three infants were being fed a low-protein diet limited in branched-chain amino acids when the skin lesions developed. A deficiency in plasma levels of essential amino acids, particularly isoleucine, was confirmed. Supplementation of the diet with isoleucine in one of the patients led to a prompt improvement of the skin lesions.
We conclude that dietary deficiencies associated with the treatment of organic aciduria should be added to the causes of acrodermatitis enteropathica-like cutaneous lesions.
Methylmalonic acidemia, cobalamin C type, presenting with cutaneous manifestations.
Howard R, Frieden IJ, Crawford D, McCalmont T, Levy ML, Rosenblatt DS, Sweetman L, Goodman SI, Ohnstad C, Hart K, Berrios M, Packman S.
Department of Dermatology, University of California, San Francisco, USA.
Arch Dermatol 1997 Dec;133(12):1563-6 Abstract quote
BACKGROUND: Erosive dermatitis resembling the skin lesions of acrodermatitis enteropathica has been described in a number of aminoacidopathies and organic acidemias. In some, the dermatitis is a manifestation of untreated disease, while in others, including methylmalonic acidemia, skin lesions have been ascribed to nutritional deficiency due to therapeutic amino acid restrictions.
OBSERVATIONS: We report 2 cases of methylmalonic acidemia presenting with cutaneous manifestations in the perinatal period before restrictive nutritional interventions. The cutaneous involvement consisted of cheilitis and diffuse erythema with erosions and desquamation. Methylmalonic acidemia, cobalamin C type, was subsequently diagnosed in both cases.
CONCLUSIONS: An erosive, desquamating dermatitis with histopathologic characteristics resembling acrodermatitis enteropathica may be a presenting sign in cobalamin C methylmalonic acidemia, even in the absence of long-standing nutritional restrictions or deficiency.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS TREATMENT Replacement of Zinc
Correction of conditions which may lead to zinc deficiency
Impact of zinc supplementation on intestinal permeability in Bangladeshi children with acute diarrhoea and persistent diarrhoea syndrome.
Roy SK, Behrens RH, Haider R, Akramuzzaman SM, Mahalanabis D, Wahed MA, Tomkins AM.
Clinical Sciences Division, International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh.
J Pediatr Gastroenterol Nutr 1992 Oct;15(3):289-96 Abstract quote
Zinc has been shown to enhance intestinal mucosal repair in patients suffering from acrodermatitis enteropathica; but the impact on mucosal integrity during acute (AD) or persistent (PD) diarrhoea is unknown.
One hundred eleven children with AD and 190 with PD aged between 3 and 24 months received, randomly and blind to the investigators, either an elemental zinc supplement of 5 mg/kg body wt/day or placebo in multivitamin syrup for 2 weeks while intestinal permeability and, biochemical and anthropometric markers were serially monitored. The permeability test was administered as an oral dose of 5 g lactulose/l g mannitol in a 20-ml solution followed by a 5-h urine collection. The ratio of the urinary probe sugars was correlated to clinical, biochemical, and microbiological parameters. At presentation, lactulose excretion was increased and mannitol excretion decreased in both AD and PD as compared with age-matched asymptomatic children. The lactulose/mannitol ratio (L/M) was higher in subjects with mucosal invasive pathogens (rotavirus and enteropathogenic Escherichia coli) compared with children excreting Vibrio cholera and enterotoxigenic E. coli. Two-week zinc supplementation significantly reduced lactulose excretion in both AD and PD, whereas the change in mannitol excretion and L/M was similar between study groups in both studies. Changes in lactulose excretion were significantly influenced by zinc supplementation in children with E. coli, Shigella sp., and Campylobacter jejuni stool isolates.
The greatest reduction in total lactulose excretion was seen in supplemented children who on presentation were lighter (wt/age less than 80%), thinner (wt/ht less than 85%), and undernourished [middle upper arm circumference (MUAC) less than 12.5 cm] or with hypozincaemia (less than 14 mumol/L).
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