Dermatology

Acrodermatitis enteropathica (Brandt syndrome, Danbolt - Close syndrome, Danbolt syndrome, Danbolt’s syndrome, Hereditary acrodermatitis enterohepatica, Primary zinc malabsorption)

Acrodermatitis enteropathica Disease (Acrodermatitis enteropathica, Acrodermatitis enteropathica syndrome, Brandt syndrome, Brandt’s syndrome, Danbolt - Close syndrome, Danbolt syndrome, Danbolt-Closs syndrome, Danbolt’s syndrome, Hereditary acrodermatitis enterohepatica, Primary zinc malabsorption, Primary zinc malabsorption syndrome, Syndrome, Brandt’s, Syndrome, Danbolt, Syndrome, Danbolt-Closs) [ICD-9-CM 686.8]

Are You Confident of the Diagnosis?

What you should be alert for in the history

The vast majority of infants and children with zinc deficiency appear systemically well. Premature infants, patients with longstanding diarrhea, and those with chronic illness are at risk for zinc deficiency. Rashes that do not respond to standard topical measures, such as emollients, antimicrobial agents and corticosteroids should prompt one to consider zinc .deficiency.

Characteristic findings on physical examination

Zinc deficiency rashes may appear psoriasiform, eczematous, vesiculobullous and verrucous. Despite this variable appearance, zinc deficiency dermatitis uniformly involves acral and periorificial sites. Early in the course of the disorder or in patients who are mildly affected, a single area, such as in the angles of the eyes and mouth or in the perianal region may be affected. Other cutaneous findings include glossitis, conjunctivitis, blepharitis, paronychia, nail dystrophy, and hair thinning. Affected areas may become secondarily infected with Staphylococcus aureus, Streptococcus pyogenes and Candida albicans.

Expected results of diagnostic studies

Histopathology is variable and correlates with lesional morphology. Lesions that are psoriasiform or eczematous show confluent parakeratosis associated with a reduced granular layer. There may be exocytosis of neutrophils, acanthosis and spongiosis. Similar to other nutritional disorders, there may be pallor of the upper third of the epidermis (Figure 1); however, epidermal pallor is not always present. Vesiculobullos lesions show subcorneal and intraepidermal clefts, and necrotic keratinocytes. There may be confluent necrosis of the epidermis.

Figure 1.

Nutritional deficiency. Pallor of the upper third of the epidermis. (Courtesy of Bryan Anderson, MD)

Serum or plasma zinc is the diagnostic test of choice. Plasma zinc levels less than 70 g/dl and serum zinc less than 50 g/dl are suggestive of zinc deficiency. Serum and plasma zinc levels can be decreased during acute inflammatory states and increased if the sample is hemolyzed. Blood samples should be drawn in the morning before the first meal.

Alkaline phosphatase is a zinc-dependent enzyme and can be decreased in zinc deficiency. Serum albumin should be measured because zinc binds to albumin and zinc levels will be falsely low in hypoalbuminemic states. Zinc levels in breast milk may be helpful in equivocal cases. Testing for the SLC39A4 gene is not commercially available.

Diagnosis confirmation

Patients with zinc deficiency may appear as if they have seborrheic dermatitis, psoriasis, atopic dermatitis, and epidermolysis bullosa,.

Who is at Risk for Developing this Disease?

Zinc deficiency may be inherited in an autosomal recessive manner (acrodermatitis enteropathica) due to a mutation in SLC39A4, encoding ZIP4 transporter. There is no predilection for race or sex and it is estimated to occur in 1 per 500,000 live births. Infants with acrodermatitis enteropathica who are bottle-fed show symptoms shortly after birth, whereas breast-fed infants show symptoms days to weeks after weaning. In infants with high metabolic demands for zinc and low zinc stores, such as is seen in prematurity, symptoms may occur while breast-feeding.

Acquired forms of zinc deficiency are much more common, especially in developing countries. In certain populations of Southeast Asia and sub-Saharan Africa, inadequate zinc intake affects up to 30% of the population and 40% of preschool children may show growth-related effects of zinc deficiency.

What is the Cause of this Disease?

Etiology

Clinical signs of zinc deficiency occur when demand for zinc exceeds the body’s supply. Zinc deficiency may result from decreased absorption, increased consumption, and increased excretion.

Conditions producing decreased zinc absorption

  • -acrodermatitis enteropathica

  • -Crohn disease

  • -celiac disease

  • -short bowel syndrome

  • -pancreatic insufficiency

  • -low zinc in breast milk

  • -diet high in phytates

  • -total parenteral nutrition

Conditions producing Increased metabolic demand

  • -extensive burns

  • -prematurity

  • -systemic cancer

  • -increased growth periods

  • Condition producing increased excretion

  • -renal tubular dysfunction

Zinc has many important functions within the human body including, catalytic, structural and regulatory.

Systemic Implications and Complications

Severe zinc deficiency produces widespread systemic effects because of its role in many important metabolic pathways. Patients may develop growth delay, mental slowing, poor wound healing, anemia, photophobia, hypogeusia, hypogonadism, photophobia, immune deficiency, and anorexia.

Treatment Options

Zinc should be replaced with 3mg/kg/day of elemental zinc and then adjusted based upon clinical response.

Optimal Therapeutic Approach for this Disease

Inherited zinc deficiency requires lifelong zinc replacement. Acquired forms of zinc deficiency should have the underlying disorders treated and zinc tapered as necessary.

Patient Management

Zinc levels should be checked every 3-6 months. Care must be taken when samples are taken, since zinc contamination may occur if the sample is collected in glass containers with rubber stoppers. Samples should be collected in acid-washed sterile plastic tubes and acid washed plastic syringes. Patients should be evaluated for other nutritional deficiency and treated accordingly.

Unusual Clinical Scenarios to Consider in Patient Management

Infants with zinc deficiency may have normal serum zinc levels

Zinc replacement is safe but can cause nausea and vomiting. Zinc is exchanged for copper at the level of the renal tubules and low levels of copper can be seen. Low copper may in the short run cause neurtropenia, decreased calcification of bone, and hypochromic anemia. Long-term copper deficiency results in neurologic deficits, such as mental retardation.

What is the Evidence?

Maverakis, E, Fung, MA, Lynch, PJ, Draznin, M, Michael, DJ, Ruben, B, Fazel, N. "Acrodermatitis enteropathica and overview of zinc metabolism". J Am Acad Dermatol. vol. 56. 2007. pp. 116-24.

(This is a thoughtful review of clinical features of zinc deficiency. Underlying mechanisms of disease are emphasized.)

Ackland, ML, Michalczyk, A. "Zinc deficiency and its inherited disorders – a review". Genes Nutrition. vol. 1. 2006. pp. 41-50.

(A comprehensive review of zinc deficiency with emphasis on basic science.)

Dinulos, JGH, Zembowicz, A. "A 10-year-old girl with recurrent oral lesions and cutaneous bullae". N Engl J Med. vol. 359. 2008. pp. 1718-24.

(This article reviews a rare presentation of zinc deficiency in a “CPC” format.)

Gehrig, KA, Dinulos, JG. "Acrodermatitis due to nutritional deficiency". Curr Opin Pediatr. vol. 22. 2010 Feb. pp. 107-12.

(This article reviews the current evidence of nutritional deficiency dermatitis.)
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