Acrodermatitis enteropathica

Definition and Overview

• Acrodermatitis Enteropathica (AE) is a rare, autosomal recessive genetic disorder characterized by the inability to absorb zinc from the intestine.
• It represents a severe form of zinc deficiency caused by a primary defect in the intestinal zinc transport mechanism.
• The condition is historically significant as it highlighted the essential role of zinc in human nutrition and health.
• Without treatment, the disease is progressive and can be fatal, but it responds dramatically to zinc supplementation, allowing for a normal life expectancy.

Etiology and Genetics

• Genetic Basis: The disorder is caused by mutations in the SLC39A4 gene located on chromosome 8q24.3.
• Defective Protein: This gene encodes the ZIP4 transporter protein (Zrt- and Irt-like Protein 4).
• Normal Function of ZIP4: The ZIP4 transporter is expressed on the apical membrane of enterocytes (intestinal lining cells) and is responsible for the uptake of dietary zinc from the intestinal lumen into the cell.
• Pathogenic Mechanism: In AE, the mutation leads to a non-functional or absent ZIP4 transporter. Consequently, the intestine cannot absorb adequate amounts of zinc from the diet to meet the body's metabolic needs, leading to severe systemic zinc depletion.
• Inheritance Pattern: It follows an autosomal recessive pattern of inheritance, meaning a child must inherit two defective copies of the gene (one from each parent) to develop the disease. Consanguinity is a risk factor.

Pathophysiology

Zinc is a ubiquitous trace element essential for the function of over 200 metalloenzymes and transcription factors. The pathophysiology of AE is a direct result of zinc deficiency affecting multiple organ systems:

• Cellular Turnover: Zinc is critical for DNA and RNA synthesis and cell division. Tissues with high turnover rates, such as the skin (epidermis), gastrointestinal mucosa, and hair follicles, are most severely affected, leading to dermatitis, diarrhea, and alopecia.
• Immune Function: Zinc is required for the development and function of T-lymphocytes and maintenance of the mucosal barrier. Deficiency leads to thymic atrophy and a combined immunodeficiency state (affecting both cellular and humoral immunity), increasing susceptibility to infections (bacterial, fungal, and viral).
• Gene Expression: Zinc-finger proteins regulate gene expression. Deficiency disrupts protein synthesis and growth.
• Sensory and Neurological Function: Zinc is involved in neurotransmission and sensory organ maintenance (retina, taste buds).

Clinical Features

The clinical presentation of Acrodermatitis Enteropathica is classic and often described by a triad of symptoms.

Onset

• Timing: Symptoms typically appear in early infancy, often shortly after weaning from breast milk to cow's milk or cereal-based formulas (usually between 4 to 10 weeks of age).
• Protective Effect of Breast Milk: Full-term infants fed exclusively on breast milk usually do not manifest symptoms until weaning because breast milk contains a zinc-binding ligand (possibly picolinic acid or citrate) that facilitates zinc absorption via alternative pathways, or simply because zinc in breast milk has higher bioavailability compared to cow's milk.
• Preterm Infants: Deficiency may manifest earlier in premature infants due to lower hepatic reserves at birth and higher metabolic demands.

1. Dermatological Manifestations (The "Acrodermatitis")

The skin lesions are distinctive and often the presenting complaint.

• Distribution:
  • Periorificial: Lesions cluster around body orifices—the mouth (perioral), anus (perianal), and eyes (periocular).
  • Acral: Lesions involve the extremities, specifically the fingers, toes, heels, elbows, and knees.
  • Pressure Points: Areas subject to friction or pressure (buttocks, occiput) are frequently involved.
• Morphology:
  • Acute Phase: Lesions start as erythematous (red), vesicobullous (blistering), and pustular eruptions.
  • Chronic Phase: Over time, these evolve into dry, scaly, eczematous, and hyperkeratotic plaques.
  • Psoriasiform: The lesions may resemble psoriasis.
• Secondary Infection: The raw, eroded skin is highly susceptible to secondary infection, particularly with Candida albicans (yeast) and Staphylococcus aureus. Paronychia (inflammation of the nail folds) is common.

2. Gastrointestinal Manifestations (The "Enteropathica")

• Diarrhea: Chronic, severe diarrhea is a hallmark. It may be watery or steatorrheic (fatty stools) due to mucosal atrophy and malabsorption.
• Mucosal Inflammation:
  • Stomatitis: Inflammation of the mouth lining.
  • Glossitis: Inflammation of the tongue; the tongue may appear red and smooth (atrophic glossitis).
  • Cheilosis: Fissuring at the corners of the mouth.

3. Alopecia (Hair Loss)

• Generalized Loss: There is often total loss of hair (alopecia totalis).
• Specific Areas: Involves the scalp, eyebrows, and eyelashes ("broomstick eyelashes" may be seen).
• Hair Quality: Any remaining hair may be sparse, dull, brittle, and hypopigmented.

4. Neurological and Behavioral Changes

• Mood Changes: One of the earliest signs is a change in the child's temperament. The infant becomes profoundly irritable, lethargic, withdrawn, and emotionally labile.
• Sleep Disturbances: Frequent crying and inability to be consoled.
• Development: Psychomotor delay may occur if left untreated.

5. Ophthalmic Manifestations

• Photophobia: Severe sensitivity to light is a common feature.
• Conjunctivitis: Inflammation of the conjunctiva.
• Blepharitis: Inflammation of the eyelids.

6. Growth and Systemic Effects

• Failure to Thrive: Severe growth retardation and weight loss occur due to anorexia (loss of appetite), chronic diarrhea, and metabolic inefficiency.
• Hypogonadism: In untreated adolescents, delayed sexual maturation and hypogonadism are prominent.
• Wound Healing: Delayed wound healing and breakdown of old scars (resembling scurvy) may be observed.

Diagnosis

The diagnosis is based on the characteristic clinical triad supported by laboratory confirmation of zinc deficiency.

Clinical Diagnosis

• Suspicion should be high in any infant presenting with periorificial dermatitis, alopecia, and diarrhea, especially after weaning.
• Refractory diaper dermatitis or eczema that does not respond to standard therapy should raise suspicion.

Laboratory Investigations

• Plasma/Serum Zinc Levels:
  • This is the gold standard for diagnosis.
  • Low Levels: Levels are markedly reduced, typically < 60 mcg/dL (Normal range: 60–150 mcg/dL or 9–23 micromol/L).
  • Precaution: Special trace element-free collection tubes must be used to prevent contamination. Hemolysis can falsely elevate results (zinc is released from RBCs).
• Serum Alkaline Phosphatase (ALP):
  • ALP is a zinc-dependent enzyme.
  • Low Levels: Serum ALP activity is consistently low in AE and may serve as a supportive diagnostic marker, especially if zinc assays are not immediately available. Levels rise with zinc therapy.
• Albumin: Since zinc circulates bound to albumin, hypoalbuminemia (common in malnutrition) can lower total serum zinc levels even if free zinc is normal. Interpretation must account for albumin levels.
• Molecular Genetics: Identification of biallelic mutations in the SLC39A4 gene confirms the diagnosis.

Differential Diagnosis

The clinical appearance can mimic several other dermatological and nutritional conditions:

• Acquired Zinc Deficiency: Seen in severe protein-energy malnutrition (PEM), malabsorption syndromes (Celiac disease, Cystic Fibrosis), or prolonged Total Parenteral Nutrition (TPN) without zinc supplementation. The clinical features are identical to AE but the etiology is nutritional rather than genetic.
• Biotinidase Deficiency / Biotin Deficiency: Presents with periorificial dermatitis, alopecia, and neurological signs (seizures, hypotonia). Distinguished by metabolic acidosis and response to biotin.
• Essential Fatty Acid Deficiency: Causes dry, scaly skin and alopecia; usually history of fat-free TPN.
• Severe Protein-Energy Malnutrition (Kwashiorkor): "Flaky paint" dermatosis can resemble AE lesions.
• Epidermolysis Bullosa: Blistering skin disease.
• Psoriasis: Hyperkeratotic plaques may look similar.
• Candidiasis: Often superinfects AE lesions, leading to misdiagnosis as primary fungal infection.

Management

Acrodermatitis Enteropathica is a treatable condition with an excellent prognosis if managed early. Therapy is lifelong.

1. Zinc Supplementation (Mainstay of Treatment)

• Formulations: Oral zinc sulfate, zinc gluconate, or zinc acetate.
• Dosage: The typical therapeutic dose is 1 to 3 mg/kg/day of elemental zinc.
• Administration: It is usually given in divided doses. It can be mixed with water or breast milk.
• Duration: Therapy must be continued lifelong. Stopping the medication will result in a relapse of symptoms.

2. Clinical Response

The response to zinc supplementation is dramatic and diagnostic:

• 24–48 hours: Mood and irritability improve significantly; the child becomes happier and appetite returns.
• 1 week: Diarrhea resolves, and skin lesions begin to heal (re-epithelialization).
• 1 month: Normal hair growth resumes, and immune function is restored.
• Growth: Catch-up growth is achieved rapidly.

3. Monitoring

• Zinc Levels: Periodic monitoring of plasma zinc levels is recommended to adjust dosages as the child grows.
• Copper Status: Chronic high-dose zinc supplementation can compete with copper absorption, potentially leading to secondary copper deficiency (anemia, neutropenia). Monitor copper levels and hematological parameters periodically.
• Growth: Regular anthropometric assessment to ensure normal growth velocity.

4. Supportive Care

• Infection Control: Treatment of secondary bacterial (antibiotics) or fungal (antifungals) infections of the skin lesions.
• Nutrition: Management of malnutrition if severe wasting is present at diagnosis.

Prognosis

• With adequate compliance to zinc therapy, the prognosis is excellent. Patients can lead a normal, healthy life with normal growth, development, and fertility.
• Without treatment, the course is intermittent but progressive, leading to severe malnutrition, recurrent severe infections, and death in childhood.