Pediatrics

Acrodermatitis enteropathica

OVERVIEW: What every practitioner needs to know

Are you sure your patient has this disease? What are the typical findings for this disease?

Acrodermatitis enteropathica (AEZ) is a rare autosomal recessive disorder caused by a defective zinc binding protein in the gut, resulting in a characteristic acral and periorificial skin eruption, diarrhea, hair loss, and poor growth after weaning from breast milk.

The most common symptoms of AEZ include the classic triad of diarrhea, dermatitis, and dementia (or listlessness). The dermatitis consists of scaly, crusted, vesiculobullous patches involving the distal extremities and periorificial areas (eyes, nose, mouth, anus, genitals). Hair loss and failure to thrive are common features, and diarrhea may be severe.

Clinical findings usually appear within 4-6 weeks of weaning from breast milk. Children with good initial growth and development suddenly fall off the growth curve as the classic symptoms appear. There is often an increased susceptibility to infection, and wound healing may be impaired. Cutaneous candidiasis, particularly in eroded areas such as the diaper area, occurs commonly.

What other disease/condition shares some of these symptoms?

Zinc-deficient diets, total parenteral hyperalimentation without zinc supplementation, and gastrointestinal disorders associated with zinc malabsorption, such as inflammatory bowel disease and cystic fibrosis, can produce a clinical picture indistinguishable from AEZ. However, gastrointestinal disease can also result in protein, fat, calorie, multiple vitamin, and trace element deficiencies, which are only partially corrected by zinc supplementation.

What caused this disease to develop at this time?

In AEZ, a defective zinc-binding protein in the infant gut results in selective zinc malabsorption. Human milk contains a transporter protein that potentiates zinc absorption and compensates for the defect in affected infants. After weaning, the compensatory zinc transporter is no longer available, and zinc stores are depleted within 4-6 weeks.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The diagnosis is dependent on demonstrating a deficiency of plasma zinc (normal concentration >55 µg/dL). Infants with AZE usually have levels less than 55 μg/dL, and levels may be as low as 20 µg/dL. Urinary zinc levels are also usually low.

Care must be taken to use syringes and collection tubes free of detectable zinc. Levels of zinc-dependant metalloenzymes, such as alkaline phosphatase, are also low; they are easy and quick to assess and suggestive of the diagnosis. Specific genetic markers are not available.

Would imaging studies be helpful? If so, which ones?

Imaging studies are of no value in evaluating patients with suspected AEZ.

Confirming the diagnosis

Unfortunately it may be difficult to distinguish AEZ from other disorders associated with zinc deficiency, such as cystic fibrosis, especially when symptoms have been persistent for long periods, e.g., over a few months. However, zinc supplementation alone results in clearing of AEZ (and isolated acquired nutritional zinc deficiency) but provides only minimal improvement for the other nutritional deficiency disorders.

If you are able to confirm that the patient has this disease, what treatment should be initiated?

Treatment of AEZ requires zinc supplementation. The normal daily allowance of zinc in adults is 15 mg, and 100-mg doses of zinc sulfate (containing only 22 mg of elemental zinc) have been noted to produce dramatic improvement in adults within a few days.

The recommended dose for infants is 5-10 mg/kg/day of zinc sulfate. Lifelong zinc supplementation is required, and higher doses may be necessary during the adolescent growth spurt and pregnancy.

What are the adverse effects associated with each treatment option?

The primary complication associated with zinc therapy is diarrhea. This may be minimized by administering zinc gluconate, which is usually better tolerated, with less diarrhea than seen with zinc sulfate.

What are the possible outcomes of this disease?

Early diagnosis is important, and the prognosis is excellent with lifelong zinc supplementation.

What causes this disease and how frequent is it?

AEZ occurs worldwide at an estimated frequency of 1 in 500,000 children and has no predilection for race or sex. Although dietary zinc deficiency is not a problem in most industrialized countries, it is a major factor in the developing world, where up to 40% of children may be affected.

The defect in this autosomal recessive disorder was localized to 8q24, and the specific defect was identified in the gene SLC9A4, which encodes the ZIP4 transporter. Routine testing for mutations in SLC9A4 is not yet available.

How do these pathogens/genes/exposures cause the disease?

The presence of defects in zinc transporters results in defective zinc absorption in the gut, abnormal intracellular zinc regulation, decreased synthesis and function of zinc-dependent enzymes, and the clinical findings of AEZ.

What complications might you expect from the disease or treatment of the disease?

Delay in diagnosis may result in all of the manifestations of AEZ discussed above and ultimately in death from infection and malnutrition.

Are additional laboratory studies available; even some that are not widely available?

Testing for defects in gene SLC9A4 may be available in certain research laboratories.

How can this disease be prevented?

Increased zinc supplementation in affected women during pregnancy will prevent subtle or overt expression of AEZ because of the increased demand for zinc. Manifestations of zinc deficiency resulting from diets low in zinc can be prevented by zinc supplementation, particularly in young children in the developing world.

The gene is rare and inheritance is autosomal recessive, so genetic counseling should focus on early diagnosis in infants presenting with the typical clinical findings.

What is the evidence?

Maverakis, E, Fung, MA, Lynch, PJ. "Acrodermatitis enteropathica and an overview of zinc metabolism". J Am Acad Dermatol. vol. 56. 2007. pp. 116-24.

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