Acrodermatitis enteropathica

Overview

Acrodermatitis enteropathica is a rare inherited metabolic disorder in which the intestine cannot absorb zinc efficiently, leading to profound zinc deficiency. The condition typically manifests during infancy, often around the time of weaning from breast milk, though onset can occur earlier in formula-fed babies. Without treatment, the condition can be life-threatening, but daily zinc supplementation corrects the deficiency and prevents all clinical features. The disorder was first recognised as a distinct clinical entity in the early 20th century, though the underlying zinc deficiency was not identified until the 1970s. Exact prevalence is not well established, but the condition is considered rare across all populations. Both males and females are equally affected, reflecting the autosomal recessive inheritance pattern.

Symptoms & clinical features

The hallmark features of acrodermatitis enteropathica form a characteristic triad: skin rash, diarrhoea, and hair loss. The skin rash typically appears symmetrically around body openings such as the mouth, nappy area, hands, and feet, presenting as red, scaly, sometimes blistering patches that may become secondarily infected. Affected infants often develop chronic or intermittent diarrhoea, which can contribute to failure to thrive and growth delays. Hair changes include loss of scalp hair, eyebrows, and eyelashes, whilst nails may become brittle and dystrophic. Eye inflammation, including conjunctivitis and photophobia, is common. Mood and behavioural changes such as irritability and lethargy frequently accompany the physical features. Without treatment, affected children are vulnerable to recurrent bacterial, viral, and fungal infections due to impaired immune function. The severity of features can vary between individuals, though untreated cases invariably deteriorate without zinc replacement.

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Affected organs

The skin is the most visibly affected organ system, with the characteristic periorificial and acral dermatitis being the defining clinical feature. The gastrointestinal tract demonstrates impaired zinc absorption and is associated with chronic diarrhoea and malabsorption. The immune system becomes compromised, increasing susceptibility to opportunistic infections. Growth and development are impaired, affecting the musculoskeletal system and overall physical maturation. The eyes, hair follicles, and nail beds are also commonly affected. Because zinc is essential for numerous enzymatic processes throughout the body, untreated deficiency has wide-ranging effects on cellular function, wound healing, protein synthesis, and DNA replication across multiple organ systems.

Multiple body systems

Systemic involvement

Cellular impact

Mechanism at cellular level

Risks & severity

Without treatment, acrodermatitis enteropathica is severe and historically was fatal in early childhood. The condition typically presents during the first few months of life, most commonly between 4 and 10 weeks of age in formula-fed infants, or around the time of weaning in breastfed babies, as human breast milk contains zinc in a highly bioavailable form that can partially compensate for the absorption defect. The severity of clinical features can vary, with some individuals showing milder manifestations, though all affected individuals require lifelong zinc supplementation. With early diagnosis and appropriate zinc replacement therapy, the prognosis is excellent and individuals can expect normal growth, development, and life expectancy. Delays in diagnosis can lead to complications including severe growth retardation, developmental delays, and increased infection risk, though these typically resolve once treatment is established.

Genetic causes

Acrodermatitis enteropathica is caused by pathogenic variants in SLC39A4, which encodes a zinc transporter protein called ZIP4. This protein is predominantly expressed in the small intestine, where it facilitates the uptake of zinc from digested food into the intestinal cells and subsequently into the bloodstream. The ZIP4 transporter is particularly concentrated in the duodenum and jejunum, the primary sites of zinc absorption. When pathogenic variants disrupt the function of ZIP4, zinc cannot be efficiently transported across the intestinal lining, resulting in severe dietary zinc deficiency despite adequate zinc intake. Research suggests that ZIP4 activity is particularly critical during infancy and early childhood when zinc requirements for growth are highest. The loss of functional ZIP4 protein means that affected individuals cannot maintain adequate zinc levels through diet alone, necessitating pharmacological zinc supplementation at doses that overcome the absorption defect through alternative, less efficient uptake mechanisms.

• SLC39A4
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Inheritance pattern

Acrodermatitis enteropathica follows an autosomal recessive inheritance pattern, meaning an affected individual has inherited a pathogenic variant in SLC39A4 from both parents. Parents of an affected child are typically carriers, each possessing one working copy and one non-working copy of the gene. Carriers do not show symptoms of zinc deficiency because one functional copy of SLC39A4 is sufficient for normal zinc absorption. When both parents are carriers, each pregnancy has a 25% chance of resulting in an affected child, a 50% chance of producing a carrier child, and a 25% chance of a child with two working copies. Siblings of affected individuals have a two-in-three chance of being carriers if they are unaffected. Genetic counselling can help families understand these risks and discuss reproductive options, including carrier testing for at-risk relatives.

Diagnosis & testing

Diagnosis of acrodermatitis enteropathica is typically suspected based on the characteristic clinical triad of skin rash, diarrhoea, and hair loss in an infant or young child. Confirmation requires demonstrating low serum or plasma zinc levels, usually markedly below the normal reference range. Additional laboratory findings may include low alkaline phosphatase activity, as this zinc-dependent enzyme becomes deficient. Genetic testing to identify pathogenic variants in SLC39A4 provides definitive confirmation and is particularly useful in atypical presentations or to distinguish inherited acrodermatitis enteropathica from acquired zinc deficiency. Within the NHS Genomic Medicine Service, testing for SLC39A4 can be accessed through appropriate clinical genetics or metabolic medicine referrals. The relevant PanelApp panel for inherited metabolic disorders includes SLC39A4. Referral to clinical genetics services is appropriate for definitive diagnosis, family counselling, and cascade testing of relatives.

Management & lifestyle

The cornerstone of management is lifelong oral zinc supplementation, typically using zinc sulphate or zinc acetate preparations. Treatment doses are substantially higher than normal dietary requirements to overcome the intestinal absorption defect, with exact dosing determined by clinical response and monitoring of serum zinc levels. Clinical improvement is often dramatic, with skin lesions beginning to heal within days to weeks of initiating therapy, and complete resolution of symptoms expected within several weeks. Regular monitoring of zinc levels and clinical assessment ensures adequate supplementation whilst avoiding excessive intake. Affected individuals require ongoing follow-up with metabolic or genetic specialists within NHS care pathways. Attention to nutrition, growth monitoring, and developmental surveillance forms part of comprehensive care. During periods of increased physiological demand such as illness, growth spurts, or pregnancy, zinc requirements may increase and dose adjustments may be necessary. Genetic counselling is recommended for families to discuss inheritance, recurrence risks, and family planning. No dietary restrictions are required beyond ensuring adequate zinc supplementation.

UK care pathway

Within the NHS Genomic Medicine Service, individuals with suspected acrodermatitis enteropathica are typically referred to specialist metabolic or clinical genetics services. Genetic testing for SLC39A4 can be arranged through appropriate R-code pathways for suspected inherited metabolic disorders. Initial referrals often come from paediatrics, dermatology, or general practice when the characteristic clinical features are recognised. Access to genetic counsellors is an important component of the care pathway, providing families with information about inheritance patterns, recurrence risks, and implications for wider family members. Ongoing metabolic follow-up ensures treatment optimisation and monitoring. Regional genetic services coordinate diagnostic testing, cascade screening of relatives where appropriate, and provide long-term support to affected families.

Related conditions

Several conditions may present with similar features to acrodermatitis enteropathica and should be considered in the differential diagnosis. Acquired zinc deficiency can occur secondary to inadequate dietary intake, malabsorption disorders, increased zinc losses, or certain medications, producing identical clinical features but without the genetic basis. Biotinidase deficiency and holocarboxylase synthetase deficiency are other inherited metabolic conditions that can present with similar skin rashes and developmental concerns. Atopic dermatitis, seborrhoeic dermatitis, and other inflammatory skin conditions may occasionally be confused with the periorificial rash of acrodermatitis enteropathica. Distinguishing inherited acrodermatitis enteropathica from acquired zinc deficiency and these other conditions relies on measuring zinc levels, assessing dietary history and risk factors, and performing genetic testing where appropriate.

Frequently asked questions

References

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