| Patient Education |
|
Click here for patient education.
|
|
You are in: eMedicine Specialties >
Pediatrics: General Medicine > Dermatology
Acrodermatitis Enteropathica
Article Last Updated: Sep 29, 2008
AUTHOR AND EDITOR INFORMATION
Section 1 of 10  
Author: KN Siva Subramanian, MD, Professor of Pediatrics and Obstetrics/Gynecology, Chief of Neonatology, Director of Nurseries, Georgetown University Medical Center
KN Siva Subramanian is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Nutrition, American Society for Parenteral and Enteral Nutrition, American Society of Law Medicine and Ethics, New York Academy of Sciences, and Southern Society for Pediatric Research
Coauthor(s):
Robert A Silverman, MD, Clinical Associate Professor, Department of Pediatrics, Georgetown University; Clinical Associate Professor, Departments of Pediatrics and Dermatology, University of Virginia at Charlottesville;
Aimee M Barton, MD, Fellow in Neonatal-Perinatal Medicine, Department of Pediatrics, Division of Neonatology, Georgetown University Medical Center;
Sepideh Montazami, MD, Assistant Professor, Department of Pediatrics, Section of Neonatal-Perinatal Medicine, Georgetown University School of Medicine
Editors: Kevin P Connelly, DO, Clinical Assistant Professor, Department of Pediatrics, Division of General Pediatrics and Emergency Care, Virginia Commonwealth University; Medical Director, Paws for Health Pet Visitation Program of the Richmond SPCA; Pediatric Emergency Physician, Emergency Consultants Inc, Chippenham Medical Center; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine; Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School; Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences; Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Author and Editor Disclosure
Synonyms and related keywords:
acrodermatitis enteropathica, AE, skin inflammation, periorificial dermatitis, acral dermatitis, alopecia, error of zinc metabolism, zinc deficiency, periorificial dermatitis, acral dermatitis, diarrhea, failure to thrive, anorexia, alopecia, nail dystrophy, malabsorption, geophagia, food allergy, growth retardation, photophobia, paronychia
Background
Acrodermatitis enteropathica (AE) is an inborn error of zinc metabolism that is inherited as an autosomal recessive disorder. Symptoms in infancy typically include periorificial and acral dermatitis, diarrhea, behavioral changes, and neurologic disturbances. In older children, failure to thrive, anorexia, alopecia, nail dystrophy, and repeated infections are most common.
Zinc deficiency may be due to inadequate intake, malabsorption, excessive loss, or a combination of these factors. If treated early, most of the symptoms are reversible and usually cause no sequelae.
Pathophysiology
The pathophysiology of AE remains unclear and continues to be debated. Zinc is an essential trace element for life. It is not only an important nutrient and cofactor of enzymes and transcription factors but also an intracellular mediator, similar to calcium.
Zinc homeostasis results from a coordinated regulation by different proteins involved in uptake excretion and intracellular storage of zinc. Intracellular molecular pathways were recently discovered to be involved in zinc homeostasis.
In 2001, Wang et al mapped the AE genetic locus to band 8q24.3.1 More recently, a group of proteins, the SLC39 proteins that are members of the broad ZIP family of metal ion transporters, were implicated in zinc uptake across the plasma membrane of various cell types.2 These proteins transport metal ions from the cell exterior or lumen of intracellular organelles into the cytoplasm. Their principal function is to provide zinc to new synthesized proteins, a process important for several functions, such as gene expression, immunity, reproduction, or protection against free-radical damage. The human genome encodes for 14 SLC39-related proteins. SLC39A4 is specifically implicated in the uptake of dietary zinc into intestinal enterocytes.3 Mutations in its gene have been identified in patients with AE.
In infants with AE, absence of a binding ligand may contribute to zinc malabsorption during weaning. Such a ligand has been identified in normal pancreatic secretions, as well as in human milk. Other causes, such as high phytate concentrations found in cereals and soy milk, inhibit zinc absorption. Geophagia, which Prasad described, decreases zinc absorption.4
AE was reported as a presentation of food allergy. Serum total immunoglobulin E (IgE) and food-specific IgE levels to milk, soybean, wheat, and peanut have been measured to evaluate for food allergy. Undiagnosed food allergy can lead to profound zinc deficiency. Food allergy should be suspected in children with acquired AE.
Transient, symptomatic zinc deficiency has been reported in breastfed, low-birthweight infants and should be considered a rare but important disorder hallmarked by periorificial and acral dermatitis, with symptoms disappearing when nursing ends.5 These reports illustrate the importance of zinc in rapidly growing preterm infants.
Mortality/Morbidity
Untreated patients usually die in the first few years of life. They have severe growth retardation, dermatitis, alopecia, secondary bacterial and fungal infections, and neurologic and behavioral changes. All of these conditions are reversible with therapy. Therapy achieves a survival rate of 100%.
Race
No race predilection is reported.
Sex
No sex predilection is reported.
Age
Symptoms typically appear in the first few months of life, when an infant is weaned from breastfeeding. However, symptoms of AE can develop in full-term breastfed infants as a result of zinc deficiency in breast milk and decreased maternal plasma zinc levels.
AE-like symptoms have also been described in older children and adults who are receiving prolonged parenteral nutrition without zinc supplementation
History
In assessing patients with suspected acrodermatitis enteropathica (AE), obtain information any siblings or relatives who have similar symptoms. A history of diarrhea, anorexia, photophobia, or behavioral changes suggests AE as a possibility in the differential diagnosis.
Physical
In general, patients are miserable and depressed. Infants are inconsolable and may withdraw from contact.
- Dermatitis: Erythematous, vesiculobullous, or pustular lesions that lead to dry, scaly, or eczematoid lesions distributed around periorificial and acral areas of the body are characteristic of AE. The borders of affected areas are sharply demarcated and have an accentuation of craquelé-like scale at the periphery. Paronychia may be present.
- Alopecia: Partial or total hair loss may be evident. Wells and Winkelman (1961) described these symptoms in a series of 58 cases.6 They found that 91% of their patients had diarrhea, 98% had alopecia, 96% had nail dystrophy, and 100% had dermatitis.
Causes
Zinc deficiency causes all the aforementioned clinical symptoms, which are easily and rapidly reversible with zinc supplementation.
Atopic Dermatitis
Biotin Deficiency
Candidiasis
Epidermolysis Bullosa
Other Problems to be Considered
Other than acquired zinc deficiency, most differential diagnoses are easily excluded. A successful trial of zinc supplementation confirms the diagnosis. The following should also be considered:
- Acquired zinc deficiency of any cause
- Infants receiving inadequate supplementation in parenteral alimentation
- Infants who were born prematurely
- Full-term or premature breastfed infants
- Infants with malabsorption due to cystic fibrosis or small-bowel resection (especially those undergoing nasogastric decompression)
- Human immunodeficiency virus (HIV) disease
- Atypical epidermolysis bulbosa
- Generalized or localized candidiasis
- Abnormal metabolism of essential fatty acids
- Seborrheic dermatitis
- Kwashiorkor disease
- Iatrogenic deficiency of branched chain amino acids (isoleucine) in restrictive diets for maple syrup urine disease or methylmalonic aciduria
Lab Studies
- In patients with acrodermatitis enteropathica (AE), the zinc concentration of plasma is measured. Specimens are collected in plastic syringes or acid-washed Vacutainer tubes to prevent exogenous contamination that could lead to spuriously normal measurements.
- In most patients with AE, plasma zinc concentrations are low (<50 mcg/dL) but are not diagnostic.
- Zinc concentrations within the reference range have been reported in patients with AE, and low zinc concentrations have been reported in patients without AE.
- Most of the zinc accretion in a fetus occurs during the third trimester (at a rate of 850 mcg/kg/d). Therefore, in premature infants, a lack of stored zinc may precipitate symptoms early, especially if they are fed with formula.
- Hair, saliva, or urine zinc levels are rarely needed.
- Production of serum alkaline phosphatase depends on zinc; therefore, a low level of alkaline phosphatase may support a diagnosis of AE.
- Secondary infections may require cultures and additional therapy.
Procedures
- Skin or intestinal mucosal biopsy is rarely needed.
Histologic Findings
- Intestinal mucosal biopsy reveals a loss of villous architecture with increased cell infiltration in the lamina propria in patients with AE. The nuclei are enlarged with an open chromatin distribution.
- Complete normalization of the intestinal mucosa is observed in mucosal biopsy samples after zinc sulphate treatment.
- Histopathology of cutaneous lesions reveals intracellular edema and pallor of the upper third of the epidermis. This finding is not pathognomonic and may be observed in other states of nutritional deficiency.
Medical Care
- In patients with acrodermatitis enteropathica (AE), zinc gluconate or sulfate is administered orally at a dosage of 1-3 mg/kg/d. Although the intravenous dosage has not clearly been estimated, amounts of 300-1000 mcg/kg/d may be sufficient for rapid reversal of symptoms.
- Clinical response is observed within 5-10 days.
- In AE, maintain zinc therapy throughout the patient's life span, though periods of remission are reported.
- Exacerbation during pregnancy or the stress of disease may require an increase in therapy.
- In acquired zinc deficiency, treatment can be stopped after the precipitating cause is resolved.
- Warm compresses and petrolatum applied 3 times a day to areas of weeping or crusted dermatitis may enhance re-epithelialization when used concurrently with zinc replacement.
Consultations
- Consultation with pediatricians, dermatologists, pediatric gastroenterologists, and/or nutritionists may be necessary.
Diet
- The zinc content of some relatively zinc-rich foods is listed in Table 1 below.
Table 1. Zinc Content of Zinc-Rich Foods | Food | Serving Size | Zinc Content, mg |
|---|
| Oysters | 6 medium, cooked | 43.4 | | Dungeness crab | 3 oz, cooked | 4.6 | | Beef | 3 oz, cooked | 5.8 | | Turkey, dark meat | 3 oz, cooked | 3.5 | | Chicken, dark meat | 3 oz, cooked | 2.4 | | Pork | 3 oz, cooked | 2.2 | | Cashews | 1 oz | 1.6 | | Baked beans | 0.5 cup | 1.8 | | Yogurt, fruit | 1 cup (8 oz) | 1.8 | | Chickpeas (garbanzo beans) | 0.5 cup | 1.3 | | Almonds | 1 cup (8 oz) | 1.0 | | Milk | 1 cup (8 oz) | 1.0 | | Cheese cheddar | 1 oz | 0.9 | | Peanuts | 1 cup (8 oz) | 0.9 |
Table 2. Recommended Dietary Allowances for Zinc (elemental)| Life Stage | Age | Allowance, mg/d |
|---|
| Males | Females |
|---|
| Infants | 0-6 mo | 2 | 2 | | 7-12 mo | 3 | 3 | | Children | 1-3 y | 3 | 3 | | 4-8 y | 5 | 5 | | 9-13 y | 8 | 8 | | Adolescents | 14-18 y | 11 | 9 | | Pregnant, £19 y | NA | 12 | | Breastfeeding, £19 y | NA | 13 | | Adults | All, ³19 y | 11 | 8 | | Pregnant, ³19 y | NA | 11 | | Breastfeeding, ³19 y | NA | 12 |
NA = not applicable.
Drug Category: Zinc supplements
Zinc is essential to normal growth and tissue repair and is important to protein and carbohydrate metabolism.
| Drug Name | Zinc sulfate or gluconate (Verazinc, Zinca-Pak, Orazinc) |
|---|
| Description | Cofactor for >70 types of enzymes.
Plays a role in many metabolic processes.
Elemental zinc 1 mg = zinc sulfate 4.4 mg. Elemental zinc 1 mg = zinc gluconate 7.1 mg. |
|---|
| Adult Dose | Sulfate or gluconate salts: 1-3 mg/kg/d PO; alternatively 220 mg (as sulfate) PO tid |
|---|
| Pediatric Dose | Sulfate or gluconate salts: 1-3 mg/kg/d PO |
|---|
| Contraindications | Documented hypersensitivity |
|---|
| Interactions | May reduce fluoroquinolones, penicillamine and tetracycline (except doxycycline) bioavailability; some foods (eg, bran, protein) decrease zinc bioavailability |
|---|
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
|
|---|
| Precautions | Caution in renal impairment; gastric upset observed with high doses; long-term high doses may decrease levels of high-density lipoprotein cholesterol (HDL-C) and decrease function of lymphocytes and polymorphonuclear (PMN) cells |
|---|
Drug Category: Skin protectants
These protectants may enhance reepithelialization when used concurrently with zinc replacement.
| Drug Name | Petrolatum (Vaseline) |
|---|
| Description | Provides relief of minor skin irritations. |
|---|
| Adult Dose | Apply to affected areas tid |
|---|
| Pediatric Dose | Apply as in adults |
|---|
| Contraindications | Documented hypersensitivity |
|---|
| Interactions | None reported |
|---|
| Pregnancy | A - Fetal risk not revealed in controlled studies in humans
|
|---|
| Precautions | For external use only; do not apply to eyes |
|---|
Further Outpatient Care
- In infants and children with acrodermatitis enteropathica (AE), outpatient follow-up care is critical to ensure proper growth and development.
In/Out Patient Meds
- Zinc gluconate or sulfate therapy is lifelong for patients with AE.
Complications
- High-dose zinc supplementation occasionally causes gastric upset.
- High-dose zinc supplementation may also adversely affect copper metabolism.
Prognosis
- Patients with AE uniformly respond to zinc therapy with a 100% survival rate.
- With zinc supplementation, various symptoms completely resolve or substantially improve.
- In a noncompliant patient, many of the described complications (including death) can occur.
Patient Education
- Provide information regarding zinc deficiency as the cause of AE.
- Emphasize the importance of lifelong compliance in taking zinc supplements.
- Wang K, Pugh EW, Griffen S, et al. Homozygosity mapping places the acrodermatitis enteropathica gene on chromosomal region 8q24.3. Am J Hum Genet. Apr 2001;68(4):1055-60. [Medline].
- Eide DJ. The SLC39 family of metal ion transporters. Pflugers Arch. Feb 2004;447(5):796-800. [Medline].
- Wang S, Xue L, Guo ZP, Wang L, Yang Y. A novel SLC39A4 gene mutation in the family of an acrodermatitis enteropathica patient with an unusual presentation. Br J Dermatol. Aug 5 2008;[Medline].
- Prasad AS. Zinc: an overview. Nutrition. Jan-Feb 1995;11(1 Suppl):93-9. [Medline].
- Kiechl-Kohlendorfer U, Fink FM, Steichen-Gersdorf E. Transient symptomatic zinc deficiency in a breast-fed preterm infant. Pediatr Dermatol. Sep-Oct 2007;24(5):536-40. [Medline].
- Wells BT, Winkelmann RD. Acrodermatitis enteropathica. Report of 6 cases. Arch Dermatol. Jul 1961;84:40-52. [Medline].
- Arakawa T, Tamura T, Igarashi Y, et al. Zinc deficiency in two infants during total parenteral alimentation for diarrhea. Am J Clin Nutr. Feb 1976;29(2):197-204. [Medline].
- Barnes PM, Moynahan EJ. Zinc deficiency in acrodermatitis enteropathica: multiple dietary intolerance treated with synthetic diet. Proc R Soc Med. Apr 1973;66(4):327-9. [Medline].
- Bilinski DL, Ehrenkranz RA, Cooley-Jacobs J, et al. Symptomatic zinc deficiency in a breast-fed, premature infant. Arch Dermatol. Sep 1987;123(9):1221-4. [Medline].
- Chimenti F, Aouffen M, Favier A. Zinc homeostasis-proteins: new drug targets for triggering cell fate. Curr Drug Targets. 2003;4:323-8.
- Dallaha CJ, Lorincz AL, Aarnik ON. Acrodermatitis enteropathica: Review of the literature and report on a case successfully treated with diodoquin. JAMA. 1953;152:509-12.
- Danbolt N, Closs K. Acrodermatitis enteropathica. Acta Derm Venerol. 1942;22:17.
- Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for vitamin A, vitamin K, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press; 2001:442-501. [Full Text].
- Graves K, Kestenbaum T, Kalivas J. Hereditary acrodermatitis enteropathica in an adult. Arch Dermatol. May 1980;116(5):562-4. [Medline].
- Grider A, Mouat MF. The acrodermatitis enteropathica mutation affects protein expression in human fibroblasts: analysis by two-dimensional gel electrophoresis. J Nutr. Aug 1998;128(8):1311-4. [Medline].
- Hambidge KM. The role of zinc and other trace metals in pediatric nutrition and health. Pediatr Clin North Am. Feb 1977;24(1):95-106. [Medline].
- Hurley LS, Eckhert CD, Duncan JR, et al. [Acrodermatitis enteropathica and human breast milk]. Lancet. Jan 22 1977;1(8004):195. [Medline].
- Kharfi M, Zaraa I, Kury S, et al. [Acrodermatitis enteropathica in full-term breast-fed infant]. Ann Dermatol Venereol. Mar 2005;132(3):246-8. [Medline].
- Kuramoto Y, Igarashi Y, Tagami H. Acquired zinc deficiency in breast-fed infants. Semin Dermatol. Dec 1991;10(4):309-12. [Medline].
- Lonnerdal B, Stanislowski AG, Hurley LS. Isolation of a low molecular weight zinc binding ligand from human milk. J Inorg Biochem. Jan 1980;12(1):71-8. [Medline].
- Martin DP, Tangsinmankong N, Sleasman JW, et al. Acrodermatitis enteropathica-like eruption and food allergy. Ann Allergy Asthma Immunol. Mar 2005;94(3):398-401. [Medline].
- Moynahan EJ. Letter: Acrodermatitis enteropathica: a lethal inherited human zinc-deficiency disorder. Lancet. Aug 17 1974;2(7877):399-400. [Medline].
- Moynahan EJ, Barnes PM. Zinc deficiency and a synthetic diet for lactose intolerance. Lancet. Mar 24 1973;1(7804):676-7. [Medline].
- Piela Z, Szuber M, Mach B, et al. Zinc deficiency in exclusively breast-fed infants. Cutis. Apr 1998;61(4):197-200. [Medline].
- Portnoy B, Molokhia M. Acrodermatitis enteropathica treated by zinc. Br J Dermatol. Dec 1974;91(6):701-3. [Medline].
- Samady JA, Schwartz RA, Shih LY, et al. Acrodermatitis enteropathica-like eruption in an infant with nonketotic hyperglycinemia. J Dermatol. Sep 2000;27(9):604-8. [Medline].
- Sivasubramanian KN, Henkin RI. Behavioral and dermatologic changes and low serum zinc and copper concentrations in two premature infants after parenteral alimentation. J Pediatr. Nov 1978;93(5):847-51. [Medline].
- Sivasubramanian KN, Hoy G, Davitt MK, et al. Zinc and copper changes after neonatal parenteral alimentation. Lancet. Mar 4 1978;1(8062):508. [Medline].
- Walravens PA, Hambidge KM, Neldner KH, et al. Zinc metabolism in acrodermatitis enteropathica. J Pediatr. Jul 1978;93(1):71-3. [Medline].
Acrodermatitis Enteropathica excerpt Article Last Updated: Sep 29, 2008
|
