Acrodermatitis Enteropathica

Etiology

The gene SLC39A4 on chromosome 8q24.3 codes for the zinc-ligand binding protein ZIP 4, zinc or iron-regulated transporter-like protein. It is a histidine-rich transmembrane protein that works as a zinc uptake protein to transport zinc ions from the cell exterior or lumen into the cytoplasm, where they are available for other proteins. Therefore, the autosomal recessive mutation in this particular gene results in defective zinc absorption, and consequently, the affected individuals manifest signs of zinc deficiency. Another mutation has been reported in mothers in SLC30A2 gene on chromosome 1p36.11 and results in decreased secretion of zinc into breast milk.[4][5]

Epidemiology

The prevalence of AE is 1 to 9:1,000,000, with a global incidence rate of 1:500,000 newborns. It appears among all groups, independent of ethnicity or sex. The disease usually manifests during infancy, during the time infants fed on breast milk are weaned, and earlier in infants who are formula-fed. Acquired zinc deficiency can manifest at any age.[5]

Pathophysiology

Zinc plays an important role in cellular processes, being an integral part of various metalloenzymes and transcription factors. It is particularly important in nucleic acid and protein synthesis, wound healing, normal immune function, and free-radical scavenging. As there is no free exchange of stored zinc, the metabolic needs must be met by the dietary supply of zinc. Human breast milk is a rich source of zinc, especially in the first 1 to 2 months of lactation, and there also is a zinc-binding ligand in breast milk which increases the bioavailability of zinc in human breast milk which is absent in animal milk. Enteral zinc absorption occurs through the small intestine, primarily in the jejunum through the transporting protein ZIP4. Mutations in gene coding this protein prevent proper enteric zinc absorption, and the affected individuals manifest with features of zinc deficiency.[6]

Histopathology

The histology is typical but depends on the age of the lesion. Early lesions reveal a decrease in the granular layer with confluent parakeratosis. There is also an infiltrate of PMNs and mild spongiosis. With age, there is significant ballooning and reticular degeneration, with necrosis of keratinocytes. In the end stage of disease, one may see psoriasiform hyperplasia of the epidermis.

History and Physical

The presentation is usually at the time of weaning in infants who are breastfed and earlier when they are formula-fed. In some cases, an infant who is breastfed may present with the manifestations of acrodermatitis enteropathica even before weaning. This could be due to the decreased secretion of zinc into breast milk due to a mutation in the mothers. The characteristic skin findings include sharply-demarcated, dry, scaly erythematous plaques that are usually periorificial on the face or the anogenital area. The upper lip usually is spared. The plaques can be psoriasiform, eczematous, vesiculobullous, pustular, or erosive with the characteristic crusted border in the periphery. Nail changes, including paronychia, may be present, and the hair becomes brittle, dry, and lusterless. In profound deficiency, diffuse alopecia may be seen. Angular cheilitis delayed wound healing and pigmentary abnormalities also have been reported.

The systemic features include diarrhea, irritability, lethargy, anorexia, growth retardation, anemia, amenorrhea, neuropsychiatric problems, perinatal morbidity, hypogonadism, hyposmia, and hypogeusia, and eye abnormalities including conjunctivitis, blepharitis, corneal opacities, and photophobia. Immunological abnormalities also are seen. Superinfection with Staphylococcus aureus and Candida albicans is reported. The classical triad of acrodermatitis enteropathica includes alopecia, diarrhea, and a periorificial and acral cutaneous rash. If untreated, the disease could be fatal. The differential diagnoses of AE include protein-energy malnutrition, psoriasis, seborrheic dermatitis, and glucagonoma syndrome. Acrodermatitis dysmetabolic is the term used for metabolic disorders that result in a clinical presentation resembling AE. The causes most often reported include acquired deficiencies of zinc, amino acids, or biotin.

Evaluation

The measurement of plasma zinc levels helps to confirm the diagnosis. A level of less than 70 microgram/L in fasting or less than 65 microgram/dL in non-fasting individuals is considered diagnostic. However, adequate care must be exercised while testing for zinc levels to obtain accurate values. The use of contaminated tubes, catheters, needles, or rubber stoppers may lead to erroneously high levels of zinc. The zinc levels may vary with the time of day, stress, or inflammation. The sample should be drawn in the morning using specially acid-washed glass bulbs or tubes. Low albumin levels may lead to a low zinc level; therefore, serum albumin also should be measured. Measurement of alkaline phosphatase, a zinc-dependent enzyme, also may be useful in some cases. In cases where the diagnosis is doubtful, histopathological examination of the affected skin may be helpful but is not diagnostic. The characteristic changes include a psoriasiform hyperplasia with necrolysis, a term used for describing cytoplasmic pallor, confluent parakeratosis, spongiosis, and focal dyskeratosis.

Treatment / Management

The management of the disease usually involves enteral or parenteral supplementation of zinc. A lifelong supplementation with 3 mg/kg/day of elemental zinc may be required. Several formulations are available, and zinc sulfate is the preferred oral formulation. Four milligrams of zinc sulfate contains about 1 mg of elemental zinc. Zinc chloride is preferred for parenteral supplementation. The clinical response is often dramatic and occurs shortly after initiating treatment, usually within a few days. The first sign of response to treatment less irritability. Shortly after that, improvement in skin lesions is noted. While on therapy, regular monitoring of certain parameters is also required. This includes periodic measurement of zinc levels, complete blood counts, erythrocyte indices, serum copper level, and occult blood in the stool. Alkaline phosphate levels also may rise during treatment with zinc supplementation. High zinc levels in plasma may inhibit copper absorption due to competitive inhibition of a common cationic transporter; therefore, hypocupremia may result during therapy and should be monitored. Other adverse effects of zinc supplementation therapy could be gastric irritation and gastric hemorrhage.[7][8][9](B3)

In cases of acquired zinc deficiency, the doses required for zinc supplementation are variable, depending on the underlying cause. Patients with malabsorption may need higher doses for response to treatment. Compresses and emollients applied at the affected areas may help in re-epithelialization when used along with zinc supplementation.

Differential Diagnosis

• Acquired zinc deficiency
• Atopic dermatitis
• Biotin and multiple decarboxylase deficiencies
• Cutaneous candidiasis
• Dietary iatrogenic deficiency of branched-chain amino acids 
• Epidermolysis bullosa
• Essential fatty acid deficiencies
• Human immunodeficiency virus 
• Glutaric aciduria type 1
• Kwashiorkor
• Leucinosis
• Malabsorption syndromes 
• Mucosal candidiasis
• Nonketotic hyperglycinemia
• Seborrheic dermatitis

Prognosis

With adequate zinc supplementation, the prognosis is excellent with an expected response rate of 100%. Untreated acrodermatitis enteropathica is fatal within the first few years of life. Morbidity associated with the disease includes growth retardation, dermatitis, alopecia, as well as secondary bacterial and fungal infections which can vary in severity. 

Complications

• Secondary bacterial and fungal infection
• Growth retardation
• Alopcia
• Behavior disturbances in children