Dermatology Online Journal
- Author(s): Maverakis, Emanual
- Lynch, Peter J
- Fazel, Nasim
- et al.
Acrodermatitis enteropathicaUniversity of California, Davis Department of Dermatology. email@example.com
Emanual Maverakis MD, Peter J Lynch MD, and Nasim Fazel MD, DDS
Dermatology Online Journal 13 (3): 11
A 13-year-old girl presented with a history of red scaly plaques involving the chest, arms and legs beginning in infancy. Punch biopsy revealed psoriasiform hyperplasia and pallor of the epidermis. The patient's serum zinc level was 36 μg/dl [nl. 66-144 μg/dl]. A diagnosis of acrodermatitis enteropathica was established and the patient responded well to zinc replacement therapy. Acrodermatitis enteropathica is a rare autosomal recessive disorder caused by mutations in SLC39A4, which encodes the tissue-specific zinc transporter ZIP4.
A 13-year-old girl was referred to the UC Davis dermatology clinic for evaluation of red scaly plaques covering 20 percent of her body surface area. The patient had initially presented at age 22 months at which time she was hospitalized for evaluation of a chronic diaper rash and erosions of her chest, arms, and legs. During this hospitalization she was treated with IV cefazolin and prednisone. Her serum zinc level was low and a skin biopsy was consistent with deficiency dermatitis. Zinc replacement therapy was added to her medical regimen at a dose of 21 mg daily. She was discharged after partial clinical improvement was noted. Unfortunately, she never completely cleared and experienced a waxing and waning course over the following decade. Her past medical history was otherwise unremarkable, except for poor school performance and mild obesity.
|Figure 1||Figure 2|
|Figure 1: Symmetric sharply demarcated erythematous scaly plaques involving the acral, periorificial and anogenital areas|
Figure 2: Psoriasiform spongiotic dermatitis with focal epidermal pallor and parakeratosis.
Upon presentation to the UC Davis department of dermatology at age 13, clinical examination revealed large well-defined and confluent erythematous plaques with grey to white scale over the extremities. Similar lesions were located periorally and perinasally. There was distal onycholysis of her toenails. With this clinical picture and her apparent history of unresponsiveness to zinc replacement therapy, a clinical diagnosis of psoriasis was made and the patient was started on fluocinonide (Lidex) ointment. At the time serum zinc level was checked and measured at 36 μg/dl (nl. 66-144 μg/dl). The mother was instructed to bring her daughter's zinc replacement regimen to a follow-up appointment in 1 month.
At the 1-month follow-up visit the patient's mother informed us that her daughter's dose of zinc was 147 mg of zinc sulfate per day. Interestingly, at this visit periorificial lesions, which had been absent at her last visit, were now marked (Fig. 1). Subsequent histopathologic examination revealed psoriasiform spongiotic dermatitis with focal epidermal pallor and keratinocyte necrosis (Fig. 2). Her physical exam, low serum zinc level, histopathological features, and lack of response to topical steroid lead to a conclusive diagnosis of AE. The patient's zinc replacement was increased from 147 mg zinc sulfate daily to 660 mg daily. At this dose her skin lesions almost entirely resolved within 1 month.
Acrodermatitis enteropathica is a rare autosomal recessive disorder of zinc deficiency. Although a deficiency dermatitis caused by low dietary zinc has the exact clinical and histologic features of AE, the term AE should be reserved only for genetic causes of zinc deficiency. In humans AE, first described by Danbolt and Closs in 1943 , is the only known hereditary defect of zinc metabolism. Individuals with AE suffer from severe zinc deficiency derived from a defective uptake of zinc in the duodenum and jejunum . AE usually presents in infancy within days if an infant is bottle-fed and soon after weaning in infants breast-fed, such as our patient. Several studies have tried to explain this well characterized difference [3, 4, 5] and as of yet there is no consensus. Initially, the cause of AE was unknown and the disease was often fatal. The link between zinc deficiency and human pathology was not realized until 30 years after the initial clinical description of AE [6, 7, 8]. Homozygosity mapping of consanguineous Jordanian and Egyptian kindreds with AE localized the genetic defect to 8q24 . Soon thereafter the defective gene was identified as SLC39A4 [10, 11], which encodes a ZIP protein, ZIP4. ZIP proteins are characterized by eight transmembrane domains organized into two blocks of three and five, which are separated by a histidine rich cytoplasmic metal binding site [12, 13]. The function of ZIP4 has been well characterized [14, 15, 16, 17, 18]. This tissue-specific zinc-regulated zinc transporter is abundantly expressed in enterocytes and functions to absorb dietary zinc. Zinc deficiency causes increased expression of ZIP4 whereas zinc supplementation causes decreased expression.
Zinc is the second most abundant trace metal in humans. Given that there are multiple genes encoding zinc transporters, it is surprising that there are only a few inherited diseases known to involve zinc metabolism. The only known mutation in mouse zinc metabolism is found in the lethal milk (lm) mouse. These mice have an autosomal recessive defect resulting in low breast milk levels of zinc [19, 20]. Pups of any genotype who suckle a lm/lm dam die before weaning. The defective gene in lm mice is Znt4 .
Interestingly, there can be a great deal of overlap between the clinical presentation of deficiency dermatitis caused by low zinc and psoriasis. For example, chronic lesions of AE may appear psoriasiform with accompanying nail dystrophy. Characteristic lesions of AE and acquired deficiency dermatitis caused by low zinc, include dry scaly eczematous plaques of the face, scalp and anogenital area, as well as generalized alopecia; none of which were present at our patient's initial clinic visit. Establishing a diagnosis of zinc deficiency may be further complicated by the fact that, zinc levels may fall during states of inflammation. The mechanism for this has not been entirely elucidated but recently IL-6 has been shown to upregulate the Zinc transporter Zip14 . This upregulation, which occurs in the liver, is thought to contribute to the hypozincemia of the acute-phase response. Thus, checking a serum zinc level may not be helpful in differentiating between psoriasis and a deficiency dermatitis caused by low zinc. In addition, the zinc level may be within normal limits in deficiency dermatitis that nevertheless responds to zinc replacement therapy. A low serum alkaline phosphatase (a zinc dependent enzyme) may aid in the diagnosis of zinc deficiency and is therefore worth checking. In general the clinical presentation should raise the question of a deficiency dermatitis at which time further work-up is warranted.
Histopathologic and laboratory studies are helpful but cannot definitively make a diagnosis of zinc deficiency. The histopathologic features of psoriasis and AE (or acquired deficiency dermatitis caused by low dietary zinc) can also be very similar. For example, psoriasiform hyperplasia is a common feature of zinc deficiency dermatitis. Other characteristic histopathologic features of zinc deficiency dermatitis include pallor of the upper part of the epidermis due to intracellular edema, diminution of the granular layer and focal dyskeratosis.
For AE, zinc replacement therapy should be started at 3 mg/kg/day of elemental zinc (there is 50 mg of elemental zinc per 220 mg zinc sulfate). Serum zinc levels should be monitored and the dose of zinc sulfate should be adjusted appropriately. Patients may require a higher dose than 3mg/kg/day of zinc sulfate to normalize their genetic defect of zinc metabolism. In deficiency dermatitis caused by low dietary zinc, replacement therapy should be initiated at 1mg/kg/day of elemental zinc.
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