Pediatric Acrodermatitis Enteropathica 

Updated: Sep 05, 2019
Author: KN Siva Subramanian, MD, FAAP; Chief Editor: Dirk M Elston, MD 

Overview

Background

Zinc deficiency is an uncommon nutritional deficiency that can be inherited or acquired. Acrodermatitis enteropathica (AE) classically refers to the inborn error of zinc metabolism that is inherited as an autosomal recessive disorder.[1] Acquired zinc deficiency is more prevalent and may present in the same fashion. Signs and symptoms in infancy can include periorificial and acral dermatitis (see image below), diarrhea, behavioral changes, and neurologic disturbances. In older children, zinc deficiency is characterized by failure to thrive, anorexia, alopecia, nail dystrophy, and repeated infections.

Skin lesions in the diaper area. Skin lesions in the diaper area.

See 13 Common-to-Rare Infant Skin Conditions, a Critical Images slideshow, to help identify rashes, birthmarks, and other skin conditions encountered in infants.

Also, see the 21 Hidden Clues to Diagnosing Nutritional Deficiencies slideshow to help identify clues to conditions associated with malnutrition.

Acquired 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

Zinc is an essential trace element. It is an integral part of numerous metallo-enzymes and transcription factors and is an important intracellular mediator, similar to calcium. Zinc stabilizes cell membranes by reducing free radicals and preventing lipid peroxidation. It is required for normal immune function, wound healing, and fertility.[2] Zinc deficiency also produces a loss of epidermal Langerhans cells.[3]

More recently, the gene SLC39A4 was found to encode a solute carrier protein called human zinc/iron-regulated transporterlike protein (hZIP4).[4] This protein controls zinc uptake across the plasma membrane of various cell types, including the intestine.[5] Protein hZIP4 transports zinc ions from the cell exterior or lumen of intracellular organelles into the cytoplasm, where it is available to other newly synthesized proteins.[6, 7, 8]

In infants with AE, an absence of this binding ligand may contribute to zinc malabsorption during weaning from breast milk. Such a ligand has been identified in normal pancreatic secretions, as well as in human milk.

A second genetic cause of acrodermatitis enteropathica is due to a genetic mutation in a breastfeeding mother. The SLC30A2 gene encodes a zinc transporter, ZnT2. A mutation in this gene causes decreased zinc secretion. In a nursing mother, this effectively decreases the zinc transfer from serum to breast milk, producing a transient zinc deficiency in an exclusively breast fed child.[9]

Other causes, such as high phytate concentrations found in cereals and soy milk, inhibit zinc absorption. Geophagia, consumption of soil or clay, also decreases zinc absorption.[10]

AE has been 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 clinical symptoms of acquired AE.

Transient, symptomatic zinc deficiency has been reported in breastfed, low-birthweight, premature infants and should be considered a rare but important disorder hallmarked by periorificial and acral dermatitis, with symptoms disappearing when nursing ends.[11] These reports illustrate the importance of zinc in rapidly growing preterm infants.

Etiology

Zinc deficiency causes all the aforementioned clinical symptoms, which are easily and rapidly reversible with zinc supplementation, unless other concurrent diseases are present (eg, cystic fibrosis).

Epidemiology

Frequency

The estimated prevlance for inherited cases is 1 case per 500,000 population.

Race

No race predilection is reported.

Sex

No sex predilection is reported.

Age

The age of presentation depends on the underlying etiology of the zinc deficiency. Inadequate intake of zinc may occur in a neonate or young infant who is exclusively breastfed from a mother with the SCL30A2 genetic mutation or a premature infant receiving inadequate zinc supplementation, given the increased need and decreased body stores. Excessive loss of zinc through digestive fluids or increased urinary excretion (as in the case of diuretic use) can present at any age, from infancy to adulthood. In addition, malnutrition can cause a zinc deficiency that can present at any age.[12, 13]

Children with congenital AE typically develop symptoms in the first few months of life, when an infant is weaned from breastfeeding or during nursing in full-term infants as a result of zinc deficiency in breast milk (with either normal or low maternal plasma zinc levels).

Prognosis

Untreated patients with classic AE usually die in the first few years of life. They have severe growth retardation, diarrhea, dermatitis, alopecia, secondary bacterial and fungal infections, and neurologic and behavioral changes. All of these conditions are reversible with therapy.

Patients with AE uniformly respond to zinc therapy with a 100% survival rate. With zinc supplementation, various symptoms completely resolve or substantially improve.

Patient Education

Provide information regarding zinc deficiency as the cause of AE. Emphasize the importance of lifelong compliance in taking zinc supplements.

 

Presentation

History

In assessing patients with suspected acrodermatitis enteropathica (AE), inquire if any siblings or relatives had similar symptoms or required zinc supplementation. A history of diarrhea, anorexia, photophobia, taste changes, or behavioral changes suggests AE as a possible diagnosis. In the elderly, elicit a history of major life changes, such as the death of a spouse, which may create lifestyle changes including a restrictive diet.[13]

Certain medical conditions and medications can be predisposing factors for zinc deficiency. Some of the medical conditions include cirrhosis, diabetes mellitus, burns, end stage renal disease, Celiac disease, inflammatory bowel disease, and cystic fibrosis.[12, 14]

Physical Examination

In general, older patients are miserable and depressed. Infants are inconsolable, irritable, have a hoarse cry, and may withdraw from contact.

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.[15, 16, 17]

The borders of affected areas are sharply demarcated and have an accentuation of craquelé-like scale at the periphery. Paronychia may be present and may be bullous and confused with epidermolysis bullosa.[18]

See the images below.

Skin lesions in the diaper area. Skin lesions in the diaper area.
Facial lesions. Facial lesions.
Foot lesions. Foot lesions.

Partial or total hair loss may be evident. In a series of 58 cases, Wells and Winkelman found that 91% of their patients had diarrhea, 98% had alopecia, 96% had nail dystrophy, and 100% had dermatitis.[19]

Acquired zinc deficiency can have milder clinical features characterized by eczematous or psoriasiform dermatitis accompanied by perlèche. Areas of pressure or rubbing may also be involved. Some plaques appear annular or nummular and may not be as inflamed in chronically undiagnosed patients.

Signs of secondary infection (ie, candidiasis) may obscure the presentation.

 

DDx

Diagnostic Considerations

Acrodermatitis dysmetabolica (AD) is a new term used to describe the phenotypic appearance of other conditions that resemble acrodermatitis enteropathica (AE) but are associated with a normal plasma zinc level. Other than acquired zinc deficiency, most differential diagnoses are easily excluded. A successful trial of zinc supplementation confirms the diagnosis. However, if zinc supplementation does not improve the condition, AD should be considered. Biotin and zinc metabolism are closely linked. Both biotin deficiency and biotinidase deficiency may mimic acrodermatitis enteropathica.[20, 21]

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, small-bowel resection (especially those undergoing nasogastric decompression), or celiac disease [22]
  • Human immunodeficiency virus (HIV) disease

  • Atypical epidermolysis bullosa (AD)

  • Generalized or localized candidiasis (AD)

  • Abnormal metabolism of essential fatty acids (AD)

  • Seborrheic dermatitis

  • Kwashiorkor

  • Iatrogenic deficiency of branched chain amino acids (isoleucine) in restrictive diets for maple syrup urine disease, methylmalonic aciduria, or phenylketonuria (AD)

Differential Diagnoses

 

Workup

Laboratory Studies

In patients with acrodermatitis enteropathica (AE), the plasma zinc concentration is measured. Specimens are collected in plastic syringes or acid-washed Vacutainer tubes to prevent exogenous contamination that could lead to spuriously normal measurements. Red blood cell hemolysis prior to plasma separation can also lead to erroneous results. Around 60-80% of serum zinc is bound to albumin; thus, hypoalbuminemia must be accounted for when interpreting zinc levels.

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 not reliable.

Production of serum alkaline phosphatase depends on zinc; therefore, a low level of alkaline phosphatase supports 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 (acrodermatitis dysmetabolica). Skin biopsy may identify other primary cutaneous diseases in the differential diagnosis

 

Treatment

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. See the following images.

Skin lesions in the diaper area. Skin lesions in the diaper area.
Skin lesions in the diaper area (see image above) Skin lesions in the diaper area (see image above) a few weeks after treatment with zinc.

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.

Substantial evidence for improvement with topical zinc application is not available.

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 (Open Table in a new window)

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

Cheddar cheese

1 oz

0.9

Peanuts

1 cup (8 oz)

0.9

Table 2. Recommended Dietary Allowances for Zinc (elemental) (Open Table in a new window)

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, ≥19 y

11

8

Pregnant, ≥19 y

NA

11

Breastfeeding, ≥19 y

NA

12

NA = not applicable

Complications

High-dose zinc supplementation may cause gastric upset. High-dose zinc supplementation may also adversely affect copper metabolism.

Long-Term Monitoring

In infants and children with acrodermatitis enteropathica (AE), outpatient follow-up care is critical to ensure proper growth and development.

 

Medication

Zinc supplements

Class Summary

Zinc is essential to normal growth and tissue repair and is important to protein and carbohydrate metabolism.

Zinc (Galzin, ZnCl2)

Zinc is a cofactor for more than 70 types of enzymes. It plays a role in many metabolic processes. Zinc sulfate 4.4 mg is equal to elemental zinc 1 mg. Zinc gluconate 7.1 mg is equal to elemental zinc 1 mg.

Skin protectants

Class Summary

These protectants may enhance reepithelialization when used concurrently with zinc replacement.

Petrolatum topical (Aveeno Skin Relief Healing Ointment, Neosporin Lip Health Overnight Renewal Therapy)

Topical petrolatum provides relief of minor skin irritations.

 

Questions & Answers

Overview

What is pediatric acrodermatitis enteropathica (AE)?

What is the pathophysiology of pediatric acrodermatitis enteropathica (AE)?

What causes pediatric acrodermatitis enteropathica (AE)?

What is the prevalence of pediatric acrodermatitis enteropathica (AE)?

What are the racial predilections of pediatric acrodermatitis enteropathica (AE)?

What are the sexual predilections of pediatric acrodermatitis enteropathica (AE)?

Which age groups have the highest prevalence of pediatric acrodermatitis enteropathica (AE)?

What is the prognosis of pediatric acrodermatitis enteropathica (AE)?

What is included in patient education about pediatric acrodermatitis enteropathica (AE)?

Presentation

Which clinical history findings are characteristic of pediatric acrodermatitis enteropathica (AE)?

Which physical findings are characteristic of pediatric acrodermatitis enteropathica (AE)?

DDX

Which conditions are included in the differential diagnoses of pediatric acrodermatitis enteropathica (AE)?

What are the differential diagnoses for Pediatric Acrodermatitis Enteropathica?

Workup

What is the role of lab tests in the workup of pediatric acrodermatitis enteropathica (AE)?

What is the role of biopsy in the workup of pediatric acrodermatitis enteropathica (AE)?

Which histologic findings are characteristic of pediatric acrodermatitis enteropathica (AE)?

Treatment

How is pediatric acrodermatitis enteropathica (AE) treated?

Which specialist consultations are beneficial to patients with pediatric acrodermatitis enteropathica (AE)?

Which dietary modifications are used in the treatment of pediatric acrodermatitis enteropathica (AE)?

What are the possible complications of pediatric acrodermatitis enteropathica (AE) treatment?

What is included in the long-term monitoring of pediatric acrodermatitis enteropathica (AE)?

Medications

Which medications in the drug class Skin protectants are used in the treatment of Pediatric Acrodermatitis Enteropathica?

Which medications in the drug class Zinc supplements are used in the treatment of Pediatric Acrodermatitis Enteropathica?