Background
Acrodermatitis enteropathica (AE) can be classified into the following three main subtypes [1] :
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Hereditary AE
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Acquired AE
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Metabolic AE (acrodermatitis dysmetabolica)
Hereditary AE is a rare inherited form of zinc deficiency that typically presents in infants after weaning from breast milk or earlier in infants fed with formula. [1] It is an autosomal recessive condition, with most cases due to a loss of function mutation in the zinc-ligand binding protein ZIP4 (zinc-regulated [Zrt]/iron-regulated [Irt] protein 4), encoded by the SLC39A4 gene located on band 8q24.3, which results in deficient zinc absorption.
Acquired AE occurs as a consequence of a variety of factors, such as low zinc intake (low zinc in diet or in breast milk due to a maternal autosomal dominant mutation in SLC30A2 that results in defective zinc transfer from the mammary epithelium to breast milk) and low zinc storage or absorption associated with prematurity, gastrointestinal (GI) diseases, or malnutrition. [2, 3, 4, 5, 6, 7, 8, 9, 10, 11]
Metabolic AE (acrodermatitis dysmetabolica) occurs in association with various metabolic diseases. [12, 13, 14, 15, 16]
Although classically, infants with AE are said to presents with a triad (or tetrad) of symptoms that includes periorifical dermatitis, nail changes, diarrhea, and alopecia, only about 21% of infants present with all three symptoms of the classic dermatitis-diarrhea-alopecia triad, and 13.4% of infants present with periorifical dermatitis as their only symptom. [1]
Infants typically present with sharply demarcated erythematous periorificial and anogenital plaques that may be focally vesiculobullous, pustular, or erosive, depending on the plasma zinc level and the length of time for which zinc depletion has been present (see the image below).
Because zinc is the second most abundant trace mineral in the human body after iron and is essential for nucleic acid and protein synthesis, wound healing, and neurologic function, besides playing an important role in immune system, zinc deficiency has a broad spectrum of clinical symptoms that encompasses multiple systemic systems. [10] Irritability, behavioral changes, and other neurologic disturbances, as well as recurrent infections and failure to thrive, can potentially obscure the diagnosis. A number of other inborn errors of metabolism or diseases caused by malnutrition may mimic AE; some authors propose referring to such conditions as acrodermatitis dysmetabolica. [12, 16]
Pathophysiology
Zinc is an essential trace element and play a pivotal role in growth and development. [17, 10] It is an integral part of numerous metalloenzymes 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. [18] Zinc deficiency also produces a loss of epidermal Langerhans cells. [19]
AE is an autosomal recessive disorder occurring as a result of mutations in the SLC39A4 (solute carrier family 39 member A4) gene located on band 8q24.3. [20, 21, 22, 23] SLC39A4 encodes ZIP4, a protein that is required for zinc uptake. [24, 25] This protein is highly expressed in the enterocytes in the duodenum and jejunum [26, 27] ; consequently, affected individuals have a decreased ability to absorb zinc from dietary sources. Absence of a binding ligand needed to transport zinc may further contribute to zinc malabsorption.
Differentiating transient acquired zinc deficiency disorders from AE is difficult because the clinical presentation is similar. Transient neonatal zinc deficiency can occur in both premature and full-term infants as a consequence of a maternal autosomal dominant mutation in SLC30A2 that results in defective zinc transfer from the mammary epithelium to breast milk, with zinc concentrations falling below 25% of normal levels. [10, 18, 28, 9, 10, 11]
It is important to be aware that transient zinc deficiency can have other causes and that premature infants often have reduced zinc levels due to a combination of factors. Because normal mother-to-fetus zinc transfer occurs in the last 10 weeks of gestation, premature infants have lower than normal zinc storage, and their immature gut and kidneys render them less able to absorb zinc. In addition, premature infants have a greater physiologic demand for zinc, by virtue of their rapid growth and development. Finally, zinc levels in breast milk naturally decline with time, reaching their highest point (>3 mg/L) post partum and progressively declining to less than 1 mg/L within 6 months [10] .
Thus, acquired reduced zinc levels in premature infants are often attributable to a combination of factors, and not all infants who have an AE-like presentation have hereditary AE. [2, 3, 29, 11, 10, 9, 30]
Etiology
Hereditary AE is inherited in an autosomal recessive fashion and is most often attributable to a loss of function mutation in the zinc-ligand binding protein ZIP4, encoded by SLC39A4 on band 8q24.3. [1, 20, 21, 22, 24, 25, 26, 31, 23] ZIP4 is a histidine-rich transmembrane protein that is specifically expressed on the apical side of enterocytes in the small intestine, as well as in the kidney, and is responsible for zinc absorption. [32] Thus, infants with an autosomal recessive mutation of this gene cannot adequately absorb dietary zinc. A case has been reported of a patient with a mutation of SLC39A4 associated with normal zinc levels and a mild phenotype. [31]
Transient neonatal zinc deficiency is due to a maternal autosomal dominant mutation in SLC30A2 on band 1p36.11, which results in defective zinc transfer from the mammary epithelium into the breast milk. [5, 33, 11, 10, 9]
External causes, such as high casein in bovine milk and phytate concentrations in cereals and soy milk, inhibit zinc absorption. Geophagia (consumption of soil or clay) also decreases zinc absorption. In addition, AE can also occur as a result of insufficient zinc levels in some total parenteral nutrition (TPN) preparations, in which case it rapidly resolves once zinc is added. [4]
It is also important to note that the zinc concentration in breast milk is independent of maternal dietary intake and that after 6 months post partum, when zinc levels in breast milk are at their lowest, the infant then become dependent on other sources of dietary zinc. [10] Although bovine milk contains a moderate level of zinc, it contains casein, a zinc-binding ligand that reduces zinc bioavailability; this explains why some infants develop AE manifestations after weaning from breast milk and switching to bovine milk.
Epidemiology
US and international statistics
The exact incidence of AE is unknown; however, the condition has been estimated to occur 1 in 500,000 live births, with approximately 1.5 million people in the world affected. [34, 35, 1]
Age-, sex-, and race-related demographics
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 mutation or in a premature infant receiving inadequate zinc supplementation. Excessive loss of zinc through digestive fluids or increased urinary excretion (as in the case of diuretic use or nephrotic syndrome) can present at any age, from infancy to adulthood. In addition, malnutrition can cause a zinc deficiency that can present at any age. [3, 18]
Children with congenital AE typically develop symptoms in the first few months of life after being 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). [27, 5]
Acrodermatitis enteropathica has no known sex- or race-based predilections.
Prognosis
Untreated infants exhibit severe growth retardation, failure to thrive, dermatitis, alopecia, secondary bacterial and fungal infections, and neurologic and behavioral changes. All of these symptoms are typically reversible with appropriate zinc supplementation. Without appropriate zinc supplementation, however, AE usually proves fatal within the first few years of life.
Adequate zinc replacement should improve signs and symptoms rapidly, but lifelong zinc supplementation is required. Zinc supplementation alone, however, may be insufficient in some infants, primarily those who also have other metabolic disorders (eg, cystic fibrosis, maple syrup urine disease, methylmalonic acidemia, ornithine transcarbamylase deficiency, propionic acidemia, phenylketonuria, biotinidase deficiency, or Hartnup disease). [1]
Patient Education
Patients should be informed regarding zinc deficiency as the cause of acrodermatitis enteropathica and advised regarding the importance of lifelong compliance with zinc supplementation.
Genetic counseling is recommended for family members of parents with the congenital form of acrodermatitis enteropathica.
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Sharply demarcated, brightly erythematous periorificial plaque in infant with acrodermatitis enteropathica.
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Skin lesions in diaper area in infant with acrodermatitis enteropathica.
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Skin lesions in diaper area in infant with acrodermatitis enteropathica (see preceding image) weeks after treatment with zinc.
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Facial lesions in acrodermatitis enteropathica.
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Foot lesions in acrodermatitis enteropathica.
