Acrodermatitis Enteropathica (AE) in Ophthalmology

Acrodermatitis enteropathica (AE) is a rare autosomal recessive disorder characterized by periorificial and acral dermatitis, alopecia, growth failure, gastrointestinal disturbance, and diarrhea. Symptoms of AE occur within the first few months after birth and tend to appear in nonbreastfed infants or in infants shortly after discontinuation of breastfeeding. Ocular complications include lid and surface involvement as well as secondary infections.[1]

The nature of the metabolic defect is currently attributed to a defect in zinc absorption. The AE mutation creates reduced zinc uptake and abnormal zinc metabolism in human fibroblasts. The gene defect is located on chromosome 8, characterized as the intestinal zinc transporter gene (ZIP4), or SLC39A4 gene, at locus 8q24.3.[2, 3, 4, 5]

An AE-like syndrome may also be seen in patients with severe nutritional deficiency who have chronic inflammatory disease such as severe allergy, who are receiving long-term total parenteral nutrition, or who live in resource-poor settings.[6]

Frequency

United States

Unknown

International

It is estimated that 1 in 500,000 people in Denmark have AE. An estimated 1.5 million people are affected in Brazil.[7]

Mortality/Morbidity

AE is lethal, usually within the first few years of life, if left untreated. However, an untreated adult survivor was reported.

Race

AE has no reported racial predilection.

Sex

AE has no reported sexual predilection.

Age

AE appears in the first few months after birth or after cessation of breastfeeding.

One case of biopsy-confirmed acquired AE has been reported in a 22-year-old woman with a zinc-deficient diet and no comorbidities.[8]

With early diagnosis and zinc supplementation, the prognosis of AE is good. Ophthalmic complications are far less severe when the systemic disease is treated. Advanced cases may have severe ophthalmic complications.

Ocular surface complications and infections may include the following:

• Blepharitis
• Conjunctivitis
• Keratitis, corneal ectasia, keratomalacia, and corneal neovascularization

Eyelid complications may include the following:

• Trichiasis and entropion with secondary corneal damage
• Ectropion, ptosis, lash loss, brow loss, and other lid deformities
• Symblepharon

Amblyopia may develop.

Dietary and genetic counseling are important.

Symptoms of acrodermatitis enteropathica (AE) occur within the first few months after birth in nonbreastfed infants or tend to appear in infants shortly after discontinuation of breastfeeding. A case report has described AE simultaneously developing in four-month-old twin girls shortly after being weaned from breastmilk.[9]

Ocular disease is a byproduct of lid, conjunctival, and ocular surface deficits.

Infants with AE display photophobia and blepharospasm, which may threaten deprivation amblyopia in severe cases.

Lid sloughing and secondary infections can be significant. Alopecia of the scalp, eyebrows, and cilia is common.

Chronic conjunctivitis, blepharitis, punctate keratopathy, and even keratomalacia further complicate the ocular picture.

Physical examination is significant for erythematous patches and plaques of dry, scaly, eczematous skin, which may evolve into crusted, vesiculobullous, erosive, and pustular lesions. Lesions are distributed in a periorificial and acral pattern, on the face, scalp, lids, hands, feet, and anogenital areas (see image below).[10]

Sharply demarcated, brightly erythematous periorificial plaque in an infant with acrodermatitis enteropathica.

Paronychia and alopecia with loss of scalp hair, eyebrows, and eyelashes may occur.

Ocular manifestations of AE may also include punctal stenosis, corneal changes, excessive lacrimation, and keratomalacia.

The cutaneous lesions may become secondarily infected with Staphylococcus aureus and Candida albicans.

Infants with AE also may experience withdrawal, growth failure, photophobia, and loss of appetite, leading to failure to thrive.

The appearance of AE shortly after the cessation of breastfeeding has led many to believe that human milk has a beneficial ligand, which bovine milk lacks. Evans and Johnson postulated picolinate as the ligand[11] ; Lonnerdal suggested citric acid[12] ; Cousins and Smith proposed that the protein concentration of human milk affects zinc bioavailability.[13]

The nature of the metabolic defect has been debated and clarified with the identification of the 8q24.3 locus. Fibroblast proteins that are absent in the fibroblasts of patients with AE have recently been discovered, suggesting that these proteins may be responsible for decreased zinc uptake and abnormal zinc metabolism. ZIP4 (SLC39A4 gene) is largely expressed in keratinocytes and has been shown to be an important regulator of epidermal differentiation, explaining the oculocutaneous manifestations of AE.[14]

Complications of AE may include the following:

• Ophthalmologic irritative complications and secondary infections, particularly with Staphylococcus and C albicans
• Lid disease including seborrheic and infectious blepharitis, trichiasis, and entropion
• Severe corneal disease including ectasia, infectious keratitis, and keratomalacia
• Secondary Sjögren syndrome and keratitis sicca
• Dermatologic irritative states and secondary infections, particularly with Staphylococcus and C albicans

Plasma zinc levels are low in patients with acrodermatitis enteropathica (AE), and characteristic histopathologic findings are seen on skin biopsy.

Hair, urine, and parotid saliva zinc levels, as well as serum alkaline phosphatase activity (which lowers later in the disease) may be helpful.

Maternal breast milk zinc concentrations also may help differentiate AE from acquired zinc deficiency.

The gene for AE is localized to chromosomal region 8q24.3 and the SLC39A4 gene, thereby identified as the gene for AE. SLC39A4 mutations have been demonstrated in several families with AE, and, in the initial Nakano study, two Japanese families with AE and with SLC39A4 mutations were described.[15] Their mutation detection strategy consisted of polymerase chain reaction amplification of all 12 exons and flanking of intronic sequences, followed by direct nucleotide sequencing. It revealed 3 novel mutations, 1017ins53, which creates a premature termination codon, and 2 mis-sense mutations, R95C and Q303H. These techniques can be used to identify carriers, newborns, or fetuses by amniocentesis.

Histopathologic examination of the skin and eyelids reveals parakeratosis of the stratum corneum with occasional neutrophils and intracellular edema. The granular cell layer is diminished, and the upper epidermis demonstrates pallor and edema. Focal dyskeratosis is seen. The epidermis may be psoriasiform or atrophic. Occasionally, subcorneal (cutaneous) pustules are seen.

One case report details the ocular histopathology of a child who died before efficacious treatment was available. The findings include corneal epithelial thinning and loss of polarity of corneal epithelial cells, anterior corneal scarring and loss of Bowman membrane, cataract formation, ciliary body atrophy, retinal degeneration, retinal pigment epithelium (RPE) depigmentation, and optic atrophy.

Systemic treatment for acrodermatitis enteropathica (AE) requires lifelong zinc supplementation.[16] Ocular therapy requires vigorous ocular surface supportive measures and intervention when secondary bacterial or candidal infection, trichiasis, or other complications occur. There is no known corrective genetic treatment available. Good copies of the defective gene have not yet been coupled to vectors capable of altering human phenotypes.

Advanced cases of AE may require oculoplastic surgical intervention including lid reconstruction, tarsorrhaphy, or epilation therapy. Ocular surface reconstruction with conjunctival transplantation or human amniotic membrane grafts also is a possibility in severe situations. Corneal transplantation may be required in cases of severe keratomalacia or infectious keratitis. These therapies are recommended with good judgment in the context of severe failure to thrive and limited predicted life span.

Consultation with a pediatrician, geneticist, dermatologist, and/or plastic surgeon may be useful.

Treatment of AE involves greater than 1-2 mg/kg of oral zinc supplementation per day for life. No special diet is necessary as long as zinc supplementation is continued.

No activity limitations are required in adequately treated patients. Patients with severe ocular-surface inflammation may require certain restrictions from dusty, dry, or dirty environments.

Long-term measures for AE include the following:

• Lifelong zinc supplementation (>1-2 mg/kg of oral zinc supplementation per day)
• Periodic ophthalmologic follow-up care, as indicated
• Periodic dermatologic follow-up care, as indicated

Severely ill infants with AE are admitted until stable. If untreated, cutaneous and lid lesions may become secondarily infected with S aureus and C albicans. Infants also may experience withdrawal, photophobia, and loss of appetite.

Further progression and even death from secondary infection may occur if AE is left untreated.

Inpatient and outpatient medications include the following:

• Zinc supplementation (>1-2 mg/kg of oral zinc supplementation per day)
• Topical ophthalmologic preparations for irritative or infectious complications, as indicated
• Topical dermatologic preparations for irritative or infectious complications, as indicated
• Systemic antibiotics for severe ocular or cutaneous infectious complications, as indicated

Treatment of patients with AE involves greater than 1-2 mg/kg of oral zinc supplementation per day for life.

Class Summary

These agents are used to reduce morbidity and to prevent complications.

Zinc gluconate (Verazinc, Zinca-Pak, Orazinc)

Cofactor for more than 70 types of enzymes; plays a role in many metabolic processes. One 10-mg tablet of zinc gluconate contains 1.4 mg of elemental zinc.