Enteropathic acrodermatitis: a rare zinc-related disorder

Health information prepared under the supervisionof Arnaud, Ph.D. in Pharmacy. Sources: Orphanet (Inserm), Haute Autorité de Santé (HAS), FIMARAD (Rare Dermatological Diseases Network), French Society of Pediatrics. This article is for informational purposes only and is not a substitute for care provided at a rare disease referral center. If an infant shows signs suggestive of this condition, consult a pediatrician or dermatologist promptly.

What is enteropathic acrodermatitis?

Enteropathic acrodermatitis (EA) is a rare genetic disorder (estimated prevalence of approximately 1 in 500,000 births) characterized by impaired intestinal absorption of zinc, an essential trace element. This condition, classified as an orphan disease, is managed in France through the FIMARAD network (Health Network for Rare Dermatological Diseases).

Zinc plays a central role in growth, wound healing, immune system function, DNA synthesis, the activity of more than 300 enzymes, and brain development. Chronic zinc deficiency therefore leads to multisystemic consequences.

It is important to distinguish between two closely related clinical conditions:

• Hereditary enteropathic acrodermatitis (genetic form), linked to a mutation in the SLC39A4 gene, which typically manifests in infants after weaning.
• Acquired forms (sometimes called “acrodermatitis enteropathica-like” or PEAR) associated with non-genetic zinc deficiency: premature infants, infants exclusively breastfed by a mother who is herself zinc-deficient, secondary malabsorption (Crohn’s disease, IBD, cystic fibrosis, bariatric surgery, severe malnutrition, chronic alcoholism).

With early diagnosis and treatment, patients with AE can lead a normal life without long-term sequelae, provided they continue supplementation for life.

What are the symptoms of acrodermatitis enteropathica?

Symptoms typically appear a few weeks to a few months after weaning frombreast milk, as breast milk contains a form of zinc that is more easily absorbed. They may also occur later in atypical or acquired forms.

Classic clinical triad: dermatitis, diarrhea, and alopecia.

Skin manifestations (often the most prominent):

• Erythematous-squamous, vesicular-bullous, or ulcerated lesions distributed around body orifices (around the mouth, nose, eyes, anus, and genital region) and on the extremities (hands, feet, elbows, knees).
• Scabs, fissures, and chronic ulcerations resistant to standard treatment.
• Diffuse alopecia of the scalp and thinning of the eyebrows and eyelashes.
• Cheilitis, glossitis (inflammation of the tongue), and angular cheilitis.
• Nail changes: dystrophy, brittleness, paronychia.

Gastrointestinal manifestations:

• Chronic diarrhea, sometimes severe and leading to dehydration.
• Abdominal pain, loss of appetite.
• Failure to thrive, weight loss, malnutrition.

Neurobehavioral symptoms:

• Irritability, inconsolable crying, and sleep disturbances in infants.
• Psychomotor delay in cases of prolonged, untreated deficiency.

Immune manifestations:

• Recurrent skin infections (bacterial, viral, fungal—particularly Candida superinfections).
• Delayed healing of wounds.

The clinical presentation in infants is highly suggestive, and this characteristic triad should raise suspicion of the diagnosis.

What are the causes of acrodermatitis enteropathica?

The hereditary form of AE is caused by a mutation in the SLC39A4 gene, located on chromosome 8 (8q24.3). This gene encodes the ZIP4 protein (Zinc Transporter 4), a zinc transporter essential for zinc absorption in the small intestine (enterocytes).

When ZIP4 is nonfunctional or deficient, intestinal zinc absorption becomes severely impaired despite a normal dietary intake. Breast milk contains zinc ligands (likely cytidine and picolinic acid) that facilitate zinc absorption through other pathways, which explains the clinical tolerance during breastfeeding and the onset of symptoms after weaning.

Inheritance is autosomal recessive: the affected child has inherited a mutated copy of the SLC39A4 gene from each of their healthy carrier parents. When both parents are carriers, the risk of transmission with each pregnancy is 25%.

Acquired forms of severe zinc deficiency (PEAR) have other causes: prolonged parenteral nutrition without sufficient zinc intake, prematurity, IBD, malnutrition, malabsorption, etc.

How is acrodermatitis enteropathica diagnosed?

The diagnosis is based on a combination of clinical, laboratory, and genetic findings:

1. Pediatric and dermatological examination: identification of the characteristic triad (perioral dermatitis, diarrhea, alopecia) in a weaned infant.
2. Zinc serum level measurement: decreased plasma zinc levels, generally below 70 µg/dL (10.7 µmol/L) in children. The sample must be collected under strict conditions (on an empty stomach, without contamination of the specimen) because false results are common.
3. Alkaline phosphatase (zinc-dependent enzyme)test: often decreased in cases of severe deficiency.
4. Therapeutic trial with zinc supplementation: dramatic improvement in skin lesions within 24 to 72 hours and in diarrhea within a few weeks, a nearly pathognomonic finding.
5. Genetic testing: sequencing of the SLC39A4 gene, which confirms the diagnosis of the hereditary form and allows for family genetic counseling. Performed at a specialized medical genetics center.

The differential diagnosis includes other forms of infantile dermatitis (atopic dermatitis, seborrheic dermatitis, eczema, extensive cutaneous candidiasis, and certain rare metabolic disorders). If the lesions do not respond to standard treatments, this should raise suspicion and prompt testing for zinc deficiency.

What is the treatment for acrodermatitis enteropathica?

Treatment consists of lifelong oral zinc supplementation under specialized medical supervision.

Supplementation guidelines:

• Zinc salts: zinc gluconate, zinc sulfate, or zinc acetate, which are well absorbed by the body.
• Initial dose for infants: 1 to 3 mg/kg/day of elemental zinc, to be adjusted based on clinical and laboratory findings.
• Take between meals (or away from foods rich in phytates, which chelate zinc).
• Lifelong treatment: Discontinuation leads to a rapid recurrence of symptoms.

Course of the disease during treatment:

• Improvement in skin lesions within 24 to 72 hours.
• Gradual resolution of diarrhea within a few weeks.
• Resumption of growth and development.
• Resolution of neurobehavioral symptoms.

Long-term medical monitoring:

• Periodic clinical and laboratory monitoring (serum zinc, alkaline phosphatase, complete blood count, serum copper, ceruloplasmin).
• Dose adjustment based on growth and changing needs (puberty, pregnancy, concurrent illness).
• Monitoring for long-term zinc overdose, which can lead to copper deficiency (anemia, neuropathy, immune deficiency): serum copper levels must be checked regularly.

Dietary sources: red meat, seafood (oysters are particularly rich in zinc), eggs, legumes, oilseeds, and pumpkin seeds. Dietalone is not sufficient to compensate for malabsorption but contributes to overall balance.

Any supplementation must be prescribed and medically monitored: excessive zinc intake is not harmless and can lead to side effects (digestive disorders, copper deficiency, immune system disruption). Self-prescribed supplementation in infants is strictly discouraged.

Is enteropathic acrodermatitis hereditary?

Yes, the classic form is an autosomal recessive hereditary disorder. A child must inherit two mutated copies of the SLC39A4 gene (one from each parent) to be affected.

If both parents are healthy carriers, the probabilities for each pregnancy are:

• 25%: The child inherits both mutated copies and develops the disease.
• 50%: The child is a heterozygous healthy carrier, with no symptoms but capable of passing on the condition.
• 25%: The child inherits no mutations.

Genetic counseling is recommended for families with a known case, ideally before any new pregnancy. Depending on the family situation, prenatal diagnosis may be discussed, under the supervision of medical genetics centers and in accordance with French law.

Acquired forms (PEAR-like) are not hereditary: they result from zinc deficiency linked to a medical condition (prematurity, malabsorption, maternal deficiency during breastfeeding).

Can enteropathic acrodermatitis be prevented?

There is no primary prevention for the hereditary genetic form, which is determined at conception. The main areas for intervention are:

• Early screening in at-risk families through targeted genetic testing.
• Prompt recognition of the first clinical signs after the infant is weaned, to begin treatment before complications arise.
• Genetic counseling for prospective parents in cases of a family history of the condition.
• Specialized follow-up at a reference center for rare diseases, integrated into a coordinated care pathway.

For acquired forms, prevention involves nutritional monitoring in at-risk populations: premature infants, infants exclusively breastfed by a mother with nutritional deficiencies (very restrictive diet, certain maternal conditions), patients with Crohn’s disease or IBD, those on prolonged parenteral nutrition, and those who have undergone bariatric surgery. A serum zinc level test may be recommended if suggestive symptoms are present.

This article is for informational purposes only. Enteropathic acrodermatitis is a rare orphan disease that requires management at a pediatric and dermatology referral center. If you have any concerns regarding an infant presenting with perioral lesions, diarrhea, or growth failure after weaning, consult a pediatrician promptly.