eMedicine Specialties > Ophthalmology > Dermatologic Disorders

Acrodermatitis Enteropathica

John D Sheppard Jr, MD, MMSc, Professor of Ophthalmology, Microbiology and Molecular Biology, Clinical Director, Thomas R Lee Center for Ocular Pharmacology, Program Director, Ophthalmology Residency Training, Eastern Virginia Medical School; President, Virginia Eye Consultants
Timothy G Woodall, MD, Dermatology, Carolinas Medical Center - Pineville

Updated: Jun 8, 2009

Introduction

Background

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

Pathophysiology

The nature of the metabolic defect is currently attributed to 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, or SLC39A4 gene, at locus 8q24.3.^2,3

Frequency

United States

Unknown

International

It is estimated that 1 in 500,000 people in Denmark are affected.

Mortality/Morbidity

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

Race

No racial predilection exists.

Sex

No sexual preference exists.

Age

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

Clinical

History

• Symptoms of AE occur within the first few months after birth in nonbreastfed infants or tend to appear in infants shortly after discontinuation of breastfeeding.
• Ocular disease is a byproduct of lid, conjunctival, and ocular surface deficits.
• Infants 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

• 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.⁴
• Paronychia and alopecia with loss of scalp hair, eyebrows, and eyelashes may occur.
• Ocular manifestations may also include punctal stenosis, corneal changes, and keratomalacia.
• The cutaneous lesions may become secondarily infected with Staphylococcus aureus and Candida albicans.
• Infants also may experience withdrawal, growth failure, photophobia, and loss of appetite, leading to failure to thrive.

Causes

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 ligand⁵ ; Lonnerdal suggested citric acid⁶ ; Cousins and Smith proposed that the protein concentration of human milk affects zinc bioavailability.⁷

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.

Differential Diagnoses

Other Problems to Be Considered

Acquired zinc deficiency
Alopecia
Atopic dermatitis
Biotin and multiple decarboxylase deficiencies
Candidiasis (cutaneous)
Candidiasis (mucosal)
Cystic fibrosis
Essential fatty acid deficiencies
Epidermolysis bullosa
Glucagonoma syndrome
Histiocytosis X
Kwashiorkor
Seborrheic dermatitis
Glutaric aciduria type 1
Leucinosis
Nonketotic hyperglycinemia
Food allergy

Workup

Laboratory Studies

• Plasma zinc levels are low 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.

Other Tests

• 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, 2 Japanese families with AE and with SLC39A4 mutations were described.⁸ Their mutation detection strategy consisted of polymerase chain reaction amplification of all 12 exons and flanking 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.

Histologic Findings

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.

Treatment

Medical Care

Systemic treatment requires lifelong zinc supplementation. 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.

Surgical Care

Advanced cases 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.

Consultations

Consultation with pediatrics, genetics, dermatology, or plastic surgery may be useful.

Diet

Treatment of patients with 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.

Activity

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

Medication

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

Mineral supplements

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.

Dosing

Adult

1 mg/kg/d for life

Pediatric

Not established

Interactions

May reduce penicillamine and tetracycline effects

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Renal impairment

Follow-up

Further Inpatient Care

• Severely ill infants 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.

Further Outpatient Care

• Zinc supplementation as already described
• Periodic ophthalmologic follow-up care as indicated
• Periodic dermatologic follow-up care as indicated

Inpatient & Outpatient Medications

• Zinc supplementation as previously described
• 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

Deterrence/Prevention

• Genetic counseling may be important to parents inquiring about conceiving additional children. Additional family members at risk also may be discovered.

Complications

• 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

Prognosis

• With early diagnosis and zinc supplementation, the prognosis 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
  • Blepharitis
  • Conjunctivitis
  • Keratitis, corneal ectasia, keratomalacia, and corneal neovascularization
• Eyelid complications
  • Trichiasis and entropion with secondary corneal damage
  • Ectropion, ptosis, lash loss, brow loss, and other lid deformities
  • Symblepharon
• Amblyopia

Patient Education

• Dietary and genetic counseling are important.

Miscellaneous

Medicolegal Pitfalls

• Early diagnosis and treatment should preclude any medical/legal pitfalls. Follow-up care with the appropriate specialists, and clear instructions for zinc supplementation are essential. Delayed diagnosis presents the most urgent cause for litigation risk, which usually lies within the realm of the pediatrician.

Special Concerns

• AE can be diagnosed by the astute pediatrician familiar with its presentation. Dermatologic consultation may be key, while the ophthalmologist rarely is called upon to finalize the diagnosis. AE may only be diagnosed accurately through dietary zinc restriction and withdrawal, since a genetically based test currently is unavailable. Patients with AE must remain on zinc supplementation for life. Differentiating AE from acquired zinc deficiencies can be difficult since both present in the same manner. Low zinc levels in the mother's milk may produce an acquired zinc deficiency in full-term, breastfed infants.
• Zimmerman et al have proposed that some acquired zinc deficiencies may be caused by a defect in mammary zinc secretion. Their studies may dispute the claim that human breast milk has a protective effect against zinc deficiency. Acquired zinc deficiency also occurs in premature infants, whether maternal zinc levels are low or normal, due to the infants' greater bodily demand and immaturely developed bodily zinc storage.
• Infections are an important finding in AE. Zinc deficiency diminishes antibody- and cell-mediated responses in both humans and animals. The moderate deficiencies in zinc noted in sickle cell anemia, renal disease, chronic gastrointestinal disorders, and AE cause variable degrees of morbidity and mortality secondary to infection.

References

1. Tabanlioglu D, Ersoy-Evans S, Karaduman A. Acrodermatitis enteropathica-like eruption in metabolic disorders: acrodermatitis dysmetabolica is proposed as a better term. Pediatr Dermatol. Mar-Apr 2009;26(2):150-4. [Medline].

2. Andrews GK. Regulation and function of Zip4, the acrodermatitis enteropathica gene. Biochem Soc Trans. Dec 2008;36:1242-6. [Medline].

3. Kambe T, Andrews GK. Novel proteolytic processing of the ectodomain of the zinc transporter ZIP4 (SLC39A4) during zinc deficiency is inhibited by acrodermatitis enteropathica mutations. Mol Cell Biol. Jan 2009;29(1):129-39. [Medline].

4. Jensen SL, McCuaig C, Zembowicz A, Hurt MA. Bullous lesions in acrodermatitis enteropathica delaying diagnosis of zinc deficiency: a report of two cases and review of the literature. J Cutan Pathol. Oct 2008;35 Suppl 1:1-13. [Medline].

5. Evans GW, Johnson PE. Characterization and quantitation of a zinc-binding ligand in human milk. Pediatr Res. Jul 1980;14(7):876-80. [Medline].

6. Lonnerdal B, Stanislowski AG, Hurley LS. Isolation of a low molecular weight zinc binding ligand from human milk. J Inorg Biochem. Jan 1980;12(1):71-8. [Medline].

7. Cousins RJ, Smith KT. Zinc-binding properties of bovine and human milk in vitro: influence of changes in zinc content. Am J Clin Nutr. May 1980;33(5):1083-7. [Medline].

8. Nakano A, Nakano H, Nomura K. Novel SLC39A4 mutations in acrodermatitis enteropathica. J Invest Dermatol. 2003;Jun;120(6):963-6. [Medline]. [Full Text].

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Keywords

acrodermatitis enteropathica, AE, autosomal recessive zinc deficiency, ocular disease, photophobia, blepharospasm, amblyopia, lid sloughing, chronic conjunctivitis, seborrheic blepharitis, punctate keratopathy, keratomalacia, lid deficit, conjunctival deficit, ocular surface deficit, paronychia, alopecia, trichiasis, entropion, lash loss, brow loss, punctal stenosis, corneal changes, keratitis sicca, infectious keratitis

Contributor Information and Disclosures

Author

John D Sheppard Jr, MD, MMSc, Professor of Ophthalmology, Microbiology and Molecular Biology, Clinical Director, Thomas R Lee Center for Ocular Pharmacology, Program Director, Ophthalmology Residency Training, Eastern Virginia Medical School; President, Virginia Eye Consultants
John D Sheppard Jr, MD, MMSc is a member of the following medical societies: American Academy of Ophthalmology, American Society for Microbiology, American Society of Cataract and Refractive Surgery, American Uveitis Society, and Association for Research in Vision and Ophthalmology
Disclosure: Nothing to disclose.

Coauthor(s)

Timothy G Woodall, MD, Dermatology, Carolinas Medical Center - Pineville
Timothy G Woodall, MD is a member of the following medical societies: American Academy of Dermatology, American Society for Dermatologic Surgery, and South Carolina Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Andrew A Dahl, MD, Director of Ophthalmology Teaching, Mid-Hudson Family Practice Institute, The Institute for Family Health; Assistant Professor of Surgery (Ophthalmology), New York College of Medicine
Andrew A Dahl, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Ophthalmology, American College of Surgeons, American Medical Association, American Society of Cataract and Refractive Surgery, and Wilderness Medical Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Simon K Law, MD, PharmD, Assistant Professor of Ophthalmology, Jules Stein Eye Institute; Chief of Section of Ophthalmology Surgical Services, Department of Veterans Affairs Healthcare Center, West Los Angeles
Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, American Glaucoma Society, and Association for Research in Vision and Ophthalmology
Disclosure: Nothing to disclose.

Managing Editor

Christopher J Rapuano, MD, Professor, Department of Ophthalmology, Jefferson Medical College of Thomas Jefferson University; Co-Chairman of the Cornea Service, Co-Chairman of Refractive Surgery Department, Wills Eye Institute
Christopher J Rapuano, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery, Contact Lens Association of Ophthalmologists, Cornea Society, Eye Bank Association of America, International Society of Refractive Surgery, and Pan-American Association of Ophthalmology
Disclosure: Allergan Honoraria Speaking and teaching; Allergan Consulting fee Consulting; Alcon Honoraria Speaking and teaching; Inspire Honoraria Speaking and teaching; RPS Ownership interest Other; Vistakon Honoraria Speaking and teaching

CME Editor

Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri
Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology
Disclosure: Nothing to disclose.

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