Introduction
Acrodermatitis enteropathica, also known as Danbolt-Cross syndrome, Brandt syndrome, or congenital zinc deficiency, is a rare genetic disorder resulting from a micronutrient-zinc deficiency in the body. The deficiency clinically expresses itself on the skin of the affected infants; although manageable, it can be fatal when ignored.
What Is the Normal Dietary Requirement of Zinc?
An average human requires:
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Adults- 11 mg/day in males and 8 mg/day in females.
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Lactating and Pregnant Mothers- 11 to 12 mg/day.
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Infants- 2 to 3 mg/day.
What Are the Types of Acrodermatitis Enteropathica?
The deficiency is categorized into two types:
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Congenital Acrodermatitis Enteropathica: It is an autosomal recessive genetic abnormality caused due to mutations in the SLC39A4 gene located on chromosome 8q24.3. This indicates that the offspring shows the deficiency and symptoms only if the mutated gene is present in both parents. In contrast, the presence of the altered gene in only one of the parents results in a carrier offspring that often does not exhibit any symptoms. The mutation disturbs the transport, uptake, and regulation of zinc primarily by hampering the absorption of zinc in the small intestine.
- Acquired Acrodermatitis Enteropathica: This deficiency develops after birth; the infant carries the normal variant of the SLC39A4 gene. The deficiency is due to:
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Uptake Inadequacy: Deficient in breast milk (due to mutation in SLC30A2 gene in chromosome 1p36.11) or nutritional supplement, anorexia, chronic alcoholism, co-intake of phytates, calcium, and phosphates, or a vegan diet.
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Malabsorption: Surgical dissection or bypass of the upper segment of the small intestine, cystic fibrosis, pancreatitis, use of antibiotics like Penicillin, Ciprofloxacin, Levofloxacin, Tetracycline, Diuretics, Sodium valproate, etc.
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Increased Excretion: In kidney disease, burns, hemodialysis, hemolysis, diarrhea, or urinary loss by alcohol use or diuretics.
Who Is Susceptible to Acrodermatitis Enteropathica?
Acrodermatitis enteropathica is a rare condition, seen in one to nine individuals in a population of 10,00,000 and one of every 5,00,000 newborns globally. There is no racial or ethnic dominance. Congenital type manifests in infancy, often when breastfeeding is weaned, earlier if the infant is formula-fed, while the acquired type can occur at any age.
What Are the Signs and Symptoms of Acrodermatitis Enteropathica?
Acrodermatitis enteropathica is characterized by:
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Chronic diarrhea.
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Steatorrhea (presence of fats in stool).
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Inflammation of the skin (sharply-demarcated, dry, scaly erythematous plaques) around:
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Mouth.
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Anus.
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Eyes.
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Elbows.
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Feet.
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Hands.
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Knees.
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Nails (paronychia).
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Abnormal nails.
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Delayed wound healing.
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Skin pigmentation.
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Partial or total alopecia (hair loss) on the scalp, eyebrows, and eyelids.
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Blistered skin lesions (as in psoriasis).
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Irritability.
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Lethargy.
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Anorexia (an eating disorder that leads to low body weight).
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Growth retardation.
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Anemia (deficiency of red blood cells).
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Amenorrhea (lack of menstruation).
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Neuropsychiatric problems.
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Perinatal morbidity (death of a fetus in the womb).
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Hypogonadism (testes or ovaries do not function adequately).
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Hyposmia (decreased sense of smell).
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Hypogeusia (decreased taste sensation).
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Eye abnormalities- conjunctivitis, blepharitis, corneal opacities, and photophobia.
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Immunological abnormalities.
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Staphylococcus aureus and Candida albicans infections.
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Viral infections like the common cold, diarrhea, chronic hepatitis C, or human immunodeficiency virus (HIV).
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Bacterial infections- shigellosis or Helicobacter pylori.
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Parasitic infestations such as acute cutaneous leishmaniasis or malaria.
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Autoimmune diabetes.
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Rheumatoid arthritis.
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Transplant rejections.
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Emotional lability.
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Mental disturbances.
Even after adequate management, the condition can recur during puberty, pregnancy, and lactation.
What Is the Pathophysiology of Acrodermatitis Enteropathica?
Zinc plays critical roles in various functions of the human body, such as:
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Hematopoiesis (formation of components of blood).
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Cell maturation and cell differentiation.
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Cell cycle progression.
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Proper function of immune cells.
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Act as a ‘danger signal’ for immune cells.
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Expression of pro-inflammatory acute phase proteins (immune response initiating cells).
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Intracellular killing of harmful pathogens.
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Cytokine production (a protein that helps in the production and growth of other immune response cells).
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ROS (reactive oxygen species) production (ROS helps in cell production, growth, and immune response).
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Development of NK cells (natural killer cells).
Hence, zinc deficiency results in the malfunction of processes in all organs, which shows up as various signs throughout the body.
What Studies Are Required to Diagnose Acrodermatitis Enteropathica?
Laboratory Studies Show:
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Serum zinc levels of less than 70 microgram/L in fasting or less than 65 microgram/dL in non-fasting individuals.
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Serum alkaline phosphatase levels of 18-50 μ/L.
Histopathological Studies Show:
In Early Disease:
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Decrease in the granular layer with confluent parakeratosis (immature cells with retained nuclei in the granular layer-third layer of the skin).
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Infiltration of PMNs-polymorphonuclear leukocytes (cells of immune response actively present).
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Mild spongiosis (accumulation of fluid between the skin cells).
In Moderately Aged:
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Significant ballooning and reticular degeneration (swelling and dying cells).
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Necrosis of keratinocytes (dead skin cells).
In the End-Stage of the Disease:
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Psoriasiform hyperplasia of the epidermis (plaque-like and reddish overgrowth of the 2nd layer of the skin).
How to Treat Acrodermatitis Enteropathica?
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Acrodermatitis enteropathica can be treated by prescribing the patient Zinc supplements through oral or intravenous routes.
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Management of the condition requires lifelong administration of 3 mg/kg/day of elemental zinc. The patient is provided with tablets of 12 mg of Zinc sulfate per day (4 mg of Zinc sulfate contains about 1 mg of elemental Zinc) or Zinc chloride intravenously.
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Periodic measurement of zinc levels in serum plasma is essential to keep track of the disease.
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Along with that, complete blood counts, erythrocyte counts, serum copper levels, blood in the stool, and alkaline phosphatase levels need to be observed.
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Hypocupremia - Deficiency of copper due to competitive inhibition from zinc may occur. Compressions and moisturizing ointments are applied over the affected skin for rapid epithelization.
What Is the Differential Diagnosis of Acrodermatitis Enteropathica?
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Acquired zinc deficiency.
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Atopic dermatitis (itching or xeroderma on the skin).
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Biotin and multiple decarboxylase deficiencies.
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Cutaneous candidiasis (candida-a fungal infection of the skin).
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Dietary iatrogenic deficiency of branched-chain amino acids.
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Epidermolysis bullosa (a type of genetic skin disorder).
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Essential fatty acid deficiencies (omega-3 and omega-6 fatty acid deficiencies).
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HIV-Human immunodeficiency virus.
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Glutaric aciduria type 1 (the body cannot process certain amino acids).
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Kwashiorkor (protein-deficient malnutrition).
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Leucinosis (a hereditary metabolic disease).
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Malabsorption syndromes.
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Mucosal candidiasis (fungal infection of mucosa).
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Nonketotic hyperglycinemia (abnormal amount of glycine in the body).
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Seborrheic dermatitis (red, scaly patches of the scalp).
What Are the Complications of Acrodermatitis Enteropathica?
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Secondary bacterial and fungal infection.
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Growth retardation.
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Alopecia (hair loss).
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Behavior disturbances in children.
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Single or multiple organ failure.
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Various bacterial and viral infections.
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Gastric perforation.
What Is the Prognosis of Acrodermatitis Enteropathica?
Acrodermatitis enteropathica is a reasonably manageable disease. Just by consuming zinc supplements, the condition can be 100 % controlled. This is fatal only during the first few years; after that, just the morbidities need to be managed. Each complication can be treated with its own set of precautions and protocols.
Conclusion
Congenital acrodermatitis enteropathica is the concerning variant of the disease. The only way to avoid any complications is by being vigilant. With the advancements in the field of neonatal screening, most genetic or hereditary deficits can be confirmed utilizing a simple genetic screening test of the amniotic fluid. The newborns must be observed for any signs or symptoms, especially rashes around the mouth or genital regions. Such signs can be easily misinterpreted as diaper rashes or candidiasis, so a rheumatologist has to be consulted, with haste, for an early diagnosis and to establish a management protocol. Acrodermatitis enteropathica is a lesser devil to deal with rather than its complications.
