Bullous lesions in acrodermatitis enteropathica delaying diagnosis...

J Cutan Pathol 2008: 35 (Suppl. 1): 1–13doi: 10.1111/j.1600-0560.2008.00981.xBlackwell Munksgaard. Printed in Singapore

Copyright # Blackwell Munksgaard 2008

Journal of

Cutaneous Pathology

Bullous lesions in acrodermatitisenteropathica delaying diagnosis of zincdeficiency: a report of two cases andreview of the literature

Acrodermatitis enteropathica (AE) is a rare disorder associated withpoor absorption of zinc. A variety of clinical and histological findingshave been reported in the literature, described mainly in isolated casereports. Because of the varied nature of these cases, the histologicalfeatures of AE are described often as non-specific. We describe lesionsof AE in two patients who presented with vesiculobullous and erosiveskin lesions, both showing intra-epidermal, inflammatory vesiculationwith surrounding eosinophilic epidermis and necrotic keratinocytes.The lack of clinical suspicion of AE led to their misdiagnosis. Wepresent these two patients to further characterize the bullous variant ofAE, and we review the previously reported clinical andhistopathological findings.

Jensen SL, McCuaig C, Zembowicz A, Hurt MA. Bullous lesions inacrodermatitis enteropathica delaying diagnosis of zinc deficiency:a report of two cases and review of the literature.J Cutan Pathol 2008; 35 (Suppl. 1): 1–13. # Blackwell Munksgaard2008.

Sarah L. Jensen1, CatherineMcCuaig2, Artur Zembowicz3,4,5

and Mark A. Hurt6

1Department of Dermatology, Saint LouisUniversity Hospital, St Louis, MO, USA,2Sainte-Justine Hospital, University ofMontreal, Montreal, Quebec, Canada,3Department of Pathology, MassachusettsGeneral Hospital, Boston, MA, USA,4Lahey Clinic, Burlington, MA, USA,5Harvard Vangard Medical Associates, Boston,MA, USA, and6Cutaneous Pathology, WCP Laboratory,Maryland Heights, MO, USA

The authors have not declared any conflicts ofinterest

Sarah L. Jensen, MD, Department of Dermatology,Saint Louis University, 1402 South Grand, St Louis,MO 63104, USATel: 314 256 3430Fax: 314 256 3431e-mail: [email protected]

Accepted for publication January 1, 2008

Deficiency of zinc occurs in a genetic and acquiredform. The condition presents as dermatitis, classicallylocated in the periorificial, intertriginous and acralareas. The lesions range from scaly, �eczematous’lesions to erosive lesions andmaypresent as avesicularor bullous eruption. Nail, mucosal and ocular findingsare associated in some cases. Severe complicationsinclude failure to thrive, impaired immune functionand propensity for secondary infection.Clinical and histopathological findings of acroder-

matitis enteropathica (AE) described in the literatureare diverse and mimic common dermatoses, partic-ularly atopic dermatitis and, therefore, often lead toa delay in diagnosis and treatment. Because of thevaried nature of the findings described in reports, the

clinical and histopathological findings are oftenreported as non-specific. Yet AE, particularly in itsbullous form, exhibits characteristic histologicalfeatures, which, in the appropriate clinical setting,allow for accurate diagnosis. Presented with a patientwith periorificial vesicles and/or bullae, certainhistological features may help to narrow the differen-tial and establish a diagnosis of zinc deficiency.

Bullous AE has characteristic histopathologicalfindings including intra-epidermal vesiculation, amongabsent to scant spongiosis. In place of epidermalspongiosis, AE exhibits vesiculation among a back-ground of eosinophilic epidermis with keratinocytenecrosis (personal observation). The combination ofperiorificial and acral bullae with histopathological

1

features of vesiculation in the presence of keratinocyteeosinophilia and/or necrosis should clue physicians toconsider AE in their differential diagnosis.

Presentation of patients

Patient 1

A 1-year-old white girl presented with a 2-weekhistory of a skin eruption. Arising initially on her leftknee, the condition soon spread bilaterally over herhands and feet, then onto her face. She was treatedwith topical steroids, cefadroxil and topical antifun-gals with no benefit.

She was premature, delivered at 34 weeks, becauseof preeclampsia but was otherwise healthy and eatinga broad diet. She was breast-fed for 1 week, thenbegan on formula for approximately 1 year, duringwhich solid foods were introduced gradually. Two to3 weeks after discontinuing her formula, the skineruption developed.

Physical examination revealed bright red, erodedplaques periorificially, as well as vesiculobullouslesions on her hands, knees and feet (Fig. 1A,B). The

differential diagnosis included immunoglobulin A(IgA) linear dermatosis, Sweet’s syndrome, epider-molysis bullosa simplex and infection.Histological examination of a skin biopsy from the

left knee revealed multiple intra-epidermal vesicles.The dermis contained a superficial, perivascularpredominantly lymphocytic and macrophagic infil-trate (Fig. 2A,B). Direct immunofluorescence andtissue cultures were negative.

Fig. 1. A) Periorificial pink, erosive plaques of patient 1. B) Acral

bullae and pink plaques of patient 1.

Fig. 2. A) Hematoxylin and eosin-stained (H&E) scanning magnifi-

cation of initial biopsy of patient 1 showing prominent intra-epidermal

vesiculation. B) H&E higher power of initial biopsy of patient 1 with

necrotic, eosinophilic keratocytes and intra-epidermal vesicles.

Jensen et al.

2

Based on the clinical and pathological findings, thedifferential diagnoses considered included viral erup-tion and allergic contact dermatitis.A recommendation was made for the patient to

avoid irritants and potential allergens. However, shecontinued to flare within 2 weeks of the initialevaluation.A second biopsy from the left dorsal hand was

obtained. This specimen exhibited orthokeratosis andsmall intra-epidermal vesicles surrounded by eosino-philic keratocytes. The vesicles were separated bystrands of necrotic keratocytes and contained a mod-erate number of neutrophils and lymphocytes. Thedermis contained a superficial infiltrate of lympho-cytes within a prominent vasculature (Fig. 3).Given the clinical findings of prominent acral and

periorificial lesions and her lack of response to aller-gen avoidance, the findings were consistent with AE.The diagnosis was confirmed by serological studiesrevealing reduced zinc levels at 14 mcg/dl (referencerange 60–130 mcg/dl). The patient began oral zincsupplementation, her skin eruption improved withina few days and the lesions resolved over the following2 weeks. She remains healthy on zinc therapy.

Patient 2

A term 8-month-old black female was hospitalized foran impetiginized �eczematous’ eruption. The erup-tion was primarily on the face and diaper areas,progressing since she was 2 months old. It wasworsening in spite of moderate treatment withcorticosteroids. She was formula fed, but anorexicwith failure to thrive. During her hospitalization, shewas diagnosed with buccal candidiasis and allergies tobovine milk and soy products.

Three months later, she was rehospitalized forsuspected bullous impetigo and irritant dermatitis andtreated with intravenous cloxacillin and topical 1%hydrocortisone cream. Child abuse and parentalnegligencewere suspected, and the patient was placedin foster care.

Her skin lesions improved initially, yet laterrecurred. At 13 months of age and suffering fromretarded growth, she was readmitted under childprotection. Her height and weight were below thethird percentile, and she was suffering from psycho-motor delay. Nasogastric supplementation wasrequired because of profound anorexia.

A dermatology consult was obtained during thisadmission. On physical examination, she had multi-ple hypopigmented, scaling and crusted plaques witha peripheral collarette (Fig. 4A,B). Thesewere locatedaround themouth, vulva and buttock. Similar patcheswere observed on acral areas bilaterally, specificallythe interdigital webs of the fingers, toes, elbows andknees. Small aphthae were present on the buccalmucosa. Her tongue was bright pink and denuded.She exhibited diffuse alopecia.

Fig. 3. Hematoxylin and eosin-stained biopsy of patient 1 showing

eosinophilic, necrotic epidermis with intra-epidermal bullae.

Fig. 4. A) Crusted plaque on elbow of patient 2. B) Hypopigmented,

crusted, acral plaques of patient 2.

Bullous lesions in AE delaying diagnosis of zinc deficiency

3

Given her clinical examination, a bullous disordersuch as epidermolysis bullosa was suspected. Biopsieswere performed from a scaly patch on the hand andlater a fresh blister on the foot. These biopsies wereinitially interpreted as an intra-epidermal vesiculardermatitis.

A histopathological consult was obtained froma dermatopathologist. The consulting physicianidentified mild spongiosis, scattered dyskeratotickeratocytes and prominent epidermal necrosis sur-rounding intra-epidermal vesiculation. There wasstranding of necrotic keratocytes lining the vesicles, inaddition to an inflammatory infiltrate consisting oflymphocytes and neutrophils. Within the dermis,there was a superficial and perivascular mononuclearinfiltrate (Fig. 5A,B). Direct immunofluorescence wasnegative. Based on the histopathological findings,a diagnosis of AE was suspected and confirmed by

a serum zinc level of 1.4 mmol/l (range 10.3–18.1 mmol/l).Zinc supplementation resulted in rapid and

significant improvement of the oral and cutaneouslesions. Her weight increased and psychomotordevelopment subsequently improved.She was discharged in her mother’s care with oral

zinc supplementation of 40 mg twice a day andNeocate 24 cal/oz. She remains healthy on a dietwith zinc supplementation.

Discussion

Pathophysiology

Zinc is the one of the most important trace elementsvital to humans, which is present in nuts, whole grains,leafy vegetables and shellfish. Deficiency of zincoccurs in a genetic and acquired form. The geneticform is known as AE and is a rare autosomal recessivecondition. The acquired form is simply referred to asdermatitis associated with zinc deficiency. Affected individ-uals suffer from zinc deficiency because of decreaseduptake of zinc in the duodenum1 and jejunum.2

The genetic condition arises usually few days toweeks after birth in infants fed solely bovine milk or itoccurs soon after weaning older babies from breast tobovine milk. While human and bovine milk containthe same concentrations of zinc, the zincwithin breastmilk is more bioavailable to infants than is bovinemilk. Zinc within human milk is bound to a low-molecular-weight ligand secreted by the pancreas,while bovine milk is bound to a high-molecular-weight ligand. The ligand binds to zinc in theintestinal lumen and aids in transport through themucosa. Malfunction in the production, structure orfunction of this low-molecular-weight ligand may bethe basic defect in AE.3

A gene thought to be involved in AE, SLC39A4,located on chromosome 8q24.3, was identifiedrecently in eight families affected with the disorder.The gene encodes a protein with features character-istic of a zinc/iron-regulated transporter-like proteinzinc transporter.4 The exact mechanism of this geneand its significance in AE have not been explainedfully; however, it is thought to be involved centrally inthe pathogenesis of AE.The acquired form of zinc deficiency results from

either interference with absorption of zinc orunsuspected deficient sources of zinc fed exogenouslyto the infant. Malabsorption can occur secondary tohigh-fiber diet or to malabsorption syndromes, suchas cystic fibrosis.5 Acquired zinc deficiency has alsobeen associated with chronic renal failure, malig-nancy, drugs, ethanol, pregnancy,6,7 malnutrition8

and total parenteral nutrition.9,10 Occasionally, zincdeficiency can be seen in infants fed maternal milk;

Fig. 5. Hematoxylin and eosin-stained (H&E) scanning magnifica-

tion of initial biopsy of patient 2 showing intra-epidermal bullae and

mononuclear infiltrate. B) H&E higher power of initial biopsy of

patient 2 showing eosinophilic, necrotic epidermis with intra-

epidermal bullae with scattered dyskeratotic keratocytes within the

surrounding epidermis.

Jensen et al.

4

these patients suffer from low zinc levels in thematernal milk and they improve clinically whenweaned off breast milk. This mimics hereditary zincdeficiency clinically and is simply an acute, dietaryzinc deficiency.6

Clinical presentation

The classic presentation of hereditary zinc deficiencyis a periorificial and acral cutaneous eruption. Thefindings are varied, as described inTable 1, and rangefrom �eczematous’ patches and psoriasiform plaquesto vesicles, bullae and erosions. While the lesions arecharacteristically periorificial and acral, they may bemore diffuse in severe cases. Nail changes includeonychodystrophy, onycholysis and paronychia.Mucosal lesions consist of stomatitis and angularcheilitis. Ocular findings include conjunctivitis andphotophobia. Failure to thrive because of anorexia,apathy and irritability may occur. Patients with zincdeficiency suffer from impaired immune function; theerosive and periorificial nature of the lesions led tosecondary infection.

Establishing the diagnosis

The definitive diagnosis is established by a reducedserum zinc level. Biopsy of clinical lesions is useful tofurther support the diagnosis and to rule out otherdiagnoses in the differential.

Treatment

Therapy requires supplementation with oral zinc.Lesions respond within 2–7 days of administration.Within 2–4 weeks, lesions are usually healed.3,6

Clinical and histopathological findings asreported in literature

A summary of the literature onAE is given inTable 1,including type of lesions, age at onset or presentation,presence of infection, whether the AE was consideredinnate or acquired, whether vesicles or bullae weredescribed and, when reported, any histopathologicalfindings.5–8,10–13,15–38

The reported clinical features of AE have beendescribed mainly through isolated case reports andrange clinically from erythematous, scaly patches topsoriasiform plaques and erosive to vesiculobullouslesions.3,14 Corresponding to the broad spectrum ofclinical lesions of AE, histopathological descriptionsin the literature are equally varied and includehyperkeratosis,10,11,14 parakeratosis, 8,10,11,39 acan-tholysis,10,11,12 epidermal pallor7,40 and dilated andtortuous capillaries.8,14,41

These histopathological features of AE are eitheromitted from these case reports or, more often,considered non-specific and, therefore, not used inestablishing the diagnosis.3,5,6,41

Because of the varied findings and lack of specificcriteria to diagnose AE, Gonzalez, Botet and San-chez42, in 1982, devised a prospective study to betterdefine the clinical and histopathological features of thelesions as they evolved over time. Their articledescribed 12 patients with AE. They identified fourcorresponding clinical and histopathological patterns.

In 1992, Borroni et al.43 further examined thehistopathological features of bullous lesions of AE.Two patients of their study had lesions �characterizedby intra-epidermal vacuolar changes with massiveballooning, leading to intra-epidermal vesiculationand blistering, with prominent epidermal necrosis butno acantholysis’. They averred that the histologicalfeatures of true bullae are rarely described in thiscondition.

Comparison of the histopathological findings of bullous AEwith its mimickers

The histopathological findings of our two patients aresimilar to those described by Borroni et al. The lesionsof patients in our study showed prominent intra-epidermal vesiculation, surrounded by clusters andstrands of highly eosinophilic, necrotic keratocyteswith mild, if any, spongiosis. The infiltrate within thevesicles comprised lymphocytes and neutrophils. Thedermis contained amoderate superficial, perivascularmononuclear infiltrate.

Considering these histopathological findings, theleading diagnosis in the differential is a spongioticdermatitis. The histopathology of AE differs fromthat of spongiotic dermatitis, showing prominentvesiculation in the midst of absent to scantspongiosis, adjacent eosinophilic to necrotic kera-tocytes and a predominately lymphoneutrophilicinfiltrate. The lack of immunofluorescence positiv-ity excludes an immunobullous disorder such aslinear IgA dermatosis. While infection may beconsidered and is sometimes secondarily present,the persistence of lesions, despite appropriate ther-apy, should motivate further evaluation for a moredefinitive diagnosis.

The findings of bullous AE vary subtly, butsignificantly, from other diagnoses within the differ-ential of vesicular lesions in the pediatric population.Given the appropriate clinical context, histopatho-logical features of individual and clustered necrotickeratocytes, intra-epidermal vesiculation and a pre-dominant lymphoneutrophilic infiltrate should alertthe pathologist to the diagnosis of AE, particularlywhen not considered in the clinical impression.


5

Table1.

Sum

maryof

priorreportsof

AE

References

Original

diagnosis

Gender

Ageatonset

ofdiseaseor

ageat

presentation

Skinlesions

Presence

ofbullae

Secondary

infection

Innateor

acquired

Family

history

Otherfeatures

ofdiseaseor

concom

itant

medicalconditions

Pathology

Brandt15(fourpatients

described

–patients

2,3and4being

siblings)

Patient1:ND;

patient2:ND;

patient3:ND;

patient4:ND

Patient1:M;

patient2:F;

patient3:M;

patient4:F

Patient1:17

months;patient

2:7–8months

ofage;patient

3:9–12

months

ofage;patient

8monthsofage

Patients1–4:perioral

andacralred

isolated

papules,confluentin

patcheswith

areasof

brow

nish

crusting,

variedpresence

ofvesiclesandpustules

overhandsandfeet,

scalpalopecia

Patient1:vesicles;

patient2:ND;

patient3:occa-

sionalvesicles;

patient4:ND

Patient1:Staphy-

lococcus

aureus;patient

2:ND;patient3:

ND;patient4:

ND

Patient1:innate;

patient2:innate;

patient3:innate;

patient4:innate

Patient1:brotherdied

at2.5yearsofage

becauseofskindis-

ease;patients2,3

and4aresiblings

Patient1:poorappetite,

thin;patient2:poor

appetite,thin,occa-

sionaldiarrhea;

patient3:poor

appetite,thin,signs

ofrickets,feverwith

diarrhea;patient4:

Occasionalcough

Patient1:hyperkeratosis,

degenerativechangesof

epidermis,sparseinflam-

matorycellinfiltrate;

patient2:ND;patient3:

ND;patient4:ND

DanboltandCloss

16

(originalpaperin

German,identified

AEas

adefinite

disease,later

summaryinEnglish

in1979)

Pustulardermatitisof

thenaturalopenings

ofthebody

andpro-

trudingpartsofthe

head,trunk

and

extrem

ities;alope-

cia;paronychiaand

mucousmem

brane

affections

Diarrhea

ND

Guy

17(threepatients

described)

Patient1:ND;

patient2:ND;

patient3:ND

Patient1:M;

patient2:M;

patient3:M

Patient1:

17years,

developedblis-

tersat1yearof

age;patient2:

9years;patient

3:7years

Patients1–3:bullae,

skinfragility,coated

tongue,erythem

a-tous

desquamation

atknees,elbows,

periorally

andhands

andfeet,dystrophic

nails

Patient1:Bullae;

patient2:bul-

lae;patient3:

bullae

Patient1:ND;

patient2:ND;

patient3:ND

Patient1:ND;patient2:

ND;patient3:ND


ND;patient3:ND


ND;patient3:ND

Patients1–3:parakeratosis,

mild

separationof

cornified

layer,moderate

acanthosiswith

paren-

chym

atousandinterstitial

edem

apresentintherete,

moderateperivascular

inflammatoryinfiltrate,

dilatedvesselsand

dermaledem

a;subepi-

dermalseparationwith

epidermalacanthosis,

parenchymatousand

interstitialedemainthe

rete,polym

orphonuclear

infiltrate,vesseldilatation

andendothelialswelling

anddermaledem

aDanbolt1

8Impetigo

F9months

Alopecia;exanthem

asymmetricallyon

eyelids,nasalopen-

ings

andmouth,as

wellasamarked

erythemaon

the

elbows,wrist,fin-

gers,knees

andtoes;

andparonychia

ND

ND

ND

ND

ND

ND

Ugland1

9ND

F1.5years

Erythemaon

posterior

thighs,conjunctival

injection,rhagadesin

lateralangleofleft

eye,gingivitis,red-

dish

tongue,thinned

hair,worsenedto

developeroded

plaquesand

aphthous

sores

ND

ND

ND

Unknown,twosiblings

died

at2and

9monthsofage

Cystic

fibrosis

ND

DillahaCJ,

Lorincz

AL,

AavickOR

ND

F2.5years

Recurrent,vesicular,

erythematous,

crusteddermatitis

oftheankles,heels,

knees,elbows,fingers,

wrists,andperioral

andanalareas

Vesicles

Candida

albicans

ND

No

Totalalopecia,tongue

coatingandsevere

halitosis

Impetigenized

superficial

dermatitiswith

marked

papillaryedem

a

Jensen et al.

6

Table1.Continued

References

Original

diagnosis

Gender

Ageatonset

ofdiseaseor

ageat

presentation

Skinlesions

Presence

ofbullae

Secondary

infection

Innateor

acquired

Family

history

Otherfeatures

ofdiseaseor

concom

itant

medicalconditions

Pathology

Bloom

andSobel20

Eczematoidepidermitis

andaphthous

sto-

matitiswith

per-

leche,epidermom

y-cosisand

onychomycosis,

cutaneousmonilia-

sis,epidermolysis

bullosa

M3months

Intermittentperianal

andinterglutealery-

them

a,erythemato-

vesiculo-pustular

scalyplaquesatac-

ralsitesandingroin

andbuttocks

Vesicles

Pathogenic

bacteriaand

C.albicans

Innate

ND

Scalpalopecia,w

hite

spotson

buccal

mucosa

Erythemato-bullous

lesion:

acanthoticepidermiswith

largeintra-epidermal

vesicles

filledwith

serum

andfewleukocytes,

dilateddermalbloodves-

selsandpapillarydermal

andperivascularlympho-

cytic

infiltrate;scaly,ery-

them

atousplaque:

hyperkeratosis,hypergra-

nulosisandepidermal

hyperplasia,dilatedblood

vesselsandasuperficial,

perivascularlymphocytic

infiltrate

Danbolt2

1(tw

opatients

described)

Patient1:ND;

patient2:ND

Patient1:F;patient

2:F

Patient1:pre-

sented

at2.5years,signs

ofeczemaat

1monthofage,

which

worsened

afterweaning

from

breastmilk

at1yearofage;

patient2:

8monthsold

Patients1–2:large,red,

weeping,crusted

areasofskinand

peripheralvesicles

andvesicopustules,

naildystrophy

Patients1and2:

vesicles

and

vesiculopus-

tulesatperiph-

eryoflesionsin

bothpatients

Patients1and

2:pastcultures

ofyellowhemo-

lytic

staphylo-

cocci

Patient1:ND;

patient2:ND

Patient1:no;patient2:

siblingdied

at1year

ofagewith

similar

diseaseas

patient

Patient1:ectropion

Patient1:ND;patient2:ND

Vedder22

5of12

siblings

affected

with

condition

and

described;N

D

Patient1:F;patient

2:M;patient3:

F;patient4:M;

patient5:F

Patient1:

8months;

patient2:

5months;

patient3:

4months;

patient4:

4weeks;

patient5:

5months

Patients1–5:lesions

around

body

orifices;

nailloss;extensive

vesicularcrusting;

erythematousle-

sionsintheface,

scalp,diaperarea

anddigitsandsevere

paronychia

Patients1,3and5:

ND;patients2

and4:vesicular

Patient1:C.albi-

cans,staphylo-

cocci;patient2:

C.albicans;

patient3:ND;

patient4:ND;

patient5:ND

Patients1–5:

innate

Patients1–5:yes

Patient1:recurred

duringpregnancy;

patient3:total

alopeciaand

photophobia

Patients1–5:ND

Piper11

ND

F46

years,devel-

oped

initiallyat

7yearsofage

(intermittently

affected

there-

after)

Scalingdermatitiswith

pustules

involving

distalextrem

ities,

perinealareaand

face;angularstom

a-titisandblepharitisas

wellasshallowacral

bullaewith

crusts

Bullous

Candidalparony-

chialinfection

Innate

ND

Thinning

ofhair,

anorexiaandfre-

quentstools

Intra-epidermalvesiculation,

markedhyperkeratosis

andparakeratosis,with

benign

dyskeratoticcells

present;subepidermal

separationwith

neutro-

phils

andeosinophils

WellsandWinkel-

mann2

3Patient1:AE;patient2:

congenitalectoder-

maldefect;pachyo-

nychiacongenital;

patient3:epider-

molysisbullosa,

celiacdisease,total

alopecia;patient4:

mediastinalsar-

coma,chronicgran-

ulom

atousdisease,

cysticlung

disease;

patient5:celiac

syndrome,monilia-

sis;patient6:neuro-

dermatitis

Patient1:F;patient

2:M;patient3:

F;patient4:M;

patient5:F;

patient6:M

Patient1:1week;

patient2:

14months;

patient3:

6weeks;

patient4:

15months;

patient5:

1week;patient

6:1month

Patients1–4:varied

clinicalappearance

including,erythema-

tous,impetiginous

dermatitisoverface,

ears,hands,fingers,

feet,perineum,but-

tocksandpostauric-

ularregions;

vesicularandbullous

lesionsofdiaper

region,face,exten-

sorsurfaces

ofel-

bows,kneesand

buttocks

Patient1:No;

patient2:no;

patient3:vesic-

ularandbullous

lesions;patient

4:Vesicularle-

sions;patient5:

ND;patient6:

bullous

and

pustularlesions

Patient1:C.albi-

cans;patient2:

C.albicansand

bacterialinfec-

tions

onocca-

sion;patient3:

C.albicans;

patient4:S.

aureus;patient

5:C.albicans;

patient6:pac-

terialinfection

andcandidiasis

Patient1:ND;

patient2:ND;

patient3:ND;

patient4:ND;

patient5:ND;

patient6:ND

Patient1:No;patient2:

No;patient3:

deceased

brother

with

similarhistory;

patient4:no;patient

5:ND;patient6:Yes

Patient1:conjunctivitis,

mucousmem

brane

involvem

ent,otitis;

patient2:conjuncti-

vitis,m

ucousmem

-braneinvolvem

ent,

perleche;patient3:

photophobia,mucous

mem

braneinvolve-

ment;patient4:con-

junctivitis,mucous

mem

branelesions,

anem

ia;patient5:

mucousmem

brane

lesions,anem

ia;

patient6:conjuncti-

vitis,stomatitis

Patient1:non-specific

changes;patient2:con-

sistentwith

erythroderma

ichthyosiform

congeni-

tum;patient3:No;patient

4:No;patient5:No;

patient6:diagnosedas

neurodermatitis


7

Table1.Continued

References

Original

diagnosis

Gender

Ageatonset

ofdiseaseor

ageat

presentation

Skinlesions

Presence

ofbullae

Secondary

infection

Innateor

acquired

Family

history

Otherfeatures

ofdiseaseor

concom

itant

medicalconditions

Pathology

Lindstrom24

Acrodermatitiscontinua

Hallopeau

M1.5years

Facialpapules,vesicles

andpustules;acral

andgenitalm

acera-

tionanderosion

Vesicles

ND

ND

Yes,twosiblings

died

ofsimilardiseaseat12

and14

yearsofage

Scalpalopecia,dizzi-

ness/vertigo,numb-

ness

andstiffness

ofextrem

ities

ND

Hansson

25

Patient1:eczema

impetiginosum

;patient2:ND

patient1:M;

patient2:M

Patient1:

5months;

patient2:

6months

Patients1and2

described

clinically

asskinlesions

characteristic

ofAE

ND

Patient2:

S.aureus,

beta-hem

olytic

streptococci

andC.albicans

culturedfrom

theskin

ND

ND

ND

Patient1:ND;patient2:skin

biopsy

show

ednon-

specificdermatitis

consistentwith

AE

RodinandGoldm

an26

(1969)

Factitialdermatitis

M6years

Eczematoidlesionsof

theelbows,knees

andglutealfolds;and

small,firm,ery-

them

atous,non-

tenderlesionsofthe

leftforearm;bullaeof

theleftthigh,legand

dorsalfoot

Bullous

lesions

ND

ND

ND

Diarrhea,depression

andanorexia,Pseu-

domonas

aeruginosa

sepsiscausingdeath

Necropsytissueshow

eddif-

fuse

andfocallym

pho-

cytic

infiltratewith

edem

aandcongestionas

wellas

largeareasofnecrosisto

deep

dermiswith

mixed

infiltrateofneutrophils,

lymphocytes,histiocytes

andeosinophils;bullous

lesionsshow

edsepara-

tionatthedermal–

epidermaljunctionwith

redbloodcells

within

Tompkinsand

Livingood2

7ND

F3months

Blistersandsores

described

asachild;

crustedeczematous

lesionsorpsoriasi-

form

plaquesas

anadult

Vesicles

inchildhood

S.aureus

ND

Yes,oldersiblingwith

similarillness,died

at1yearofage

Alopecia,depression,

blepharitis,

perleches,glossitis,

conjunctivitis,

stom

atitis,an

photophobiaand

dystrophicnails

ND

JuljulianandKurban

12

ND

F7months

Reddish,pruriticand

eroded

patches

overnape,face,

extrem

ities,

perigenitalregion

ND

ND

ND

ND

ND

Serratedandcleftedepider-

miscontaining

acantho-

lytic

cells,dermaledem

aandbasophilicdegenera-

tionofcollagen

JuliusR,

Schulkind

M,

SprinkleT,

RennertO28

ND

M1week

Scalingerythematous

facialdermatitis,

generalized

tohis

neck,shouldersand

chest

ND

ND

ND

ND

ND

Necropsytissueofskin

show

edfocalhyperkera-

tosiswith

anon-specific

infiltrateofmacrophages,

neutrophils

andeosino-

phils

Moynahanand

Barnes29

ND

F2months

Crusted

andscaled

eruptioninperivulvar

andperianalskin

ND

ND

Innate

Sisterwith

similar

eruption,treated

successfullywith

zinc

Loosestoolsand

psychicchanges

(irritabilityand

withdraw

al)

ND

VerbergDJ,BurgLI,

HoxtellEO,

MerrillLK3

0

ND

F21

yearsat

presentation,

firstdeveloped

dermatitis

periorificially

at10

weeks

ofage

Dermatitison

face

and

anogenitally

atdeliveryofbaby

ND

ND

Innate

Siblingdied

at1yearof

ageduewith

severe

diarrhea

and

dermatitis

Flareofdisease

occurred

during

pregnancy

ND

Jensen et al.

8

Table1.Continued

References

Original

diagnosis

Gender

Age

atonset

ofdiseaseor

ageat

presentation

Skinlesions

Presence

ofbullae

Secondary

infection

Innateor

acquired

Family

history

Otherfeatures

ofdiseaseor

concom

itant

medicalconditions

Pathology

NelderandHam

bidge3

1ND

F22

yearsattim

eof

publication,first

signsofdisease

at1.5yearsof

age

Erythematous

dermatitisofacral

areas,blisterforma-

tionon

kneesand

aphthous-likeoral

ulcerations,along

with

paronychia

Blisterformation

ND

Innate

ND

ND

ND

Olholm-Larsen3

2Tw

oaffected

siblings

described.Patient1:

impetigo,keratosis

cutis

hereditaria

and

acne

vulgaris;patient

2:keratosisdissem

-inatecongenital,fol-

liculitisuniversalis,

pustulosispedum,

psoriasis

Patient1:M;

patient2:F

Patient1:33

years

attim

eofpubli-

cation,devel-

oped

dermatitis

atfewmonths

ofage;patient

2:40

yearsat

timeofpublica-

tion,original

eruptionat

1.5years

Patients1–2:perioral

papules,pustules

anddeep

scars;

truncalpapules

and

pustules

with

scarring;bullaeand

erythemaatfeetand

paronychial

inflammationwith

normalnails

Patient1:bullae;

Patient2:ND

ND

Innate

Yes,twooffoursiblings

affected


flareduringpreg-

nancies,neurologi-

calsym

ptom

sand

depression

ND

BrazinandJohnson1

0ND

M17

years

Erythematous,tender,

�eruptive’lesionson

palm

aswellas

perinasalscalingand

erythema;angular

cheilitis,papulonod-

ules

overlyingjoints

ofhandsand

overpalmsand

paronychia

ND

ND

Acquiredsecondaryto

multiplesm

allbow

elresections

form

idgut

volvulus

andsuture

linenecrosis

ND

Granulationtissue

overlyingpriorarte-

riovenous

anasto-

moses

onbilateral

wrists

Hyperkeratosis,parakerato-

sis,extensivenecrosisof

thegranularlayerand

eosinophilicstaining

with

loss

ofnucleiofthe

stratummalpighii,also

exhibitingmicrovesicula-

tionwith

acantholysis,

elongatedreteridges,

spongiosis,exocytosisof

neutrophils

andmononu-

clearcells

Sjolin8

Dermatitisanddehy-

dration

F76

years

Dry,scaly,almost

ichthyoticskinwith

erosiveareasin

perioraland

perianal

regions

ND

ND

ND

ND

Poorgeneralcondition

Parakeratosis,irregular

acanthosiswith

club-

shaped

reteridges,

edem

aofepidermisand

papillarydermis,

elongatedandedem

atous

dermalpapillaewith

tortuous

dilated

capillarieswith

surround-

inglymphocytes

and

neutrophils

with

mild

exocytosis

Bonfazi33

ND

M55

days

Burn-likelesionsin

diaperregion,

buttocks,thighs,

kneesandelbows,

andatmouthand

eyes

and,later,on

fingersandtoes

ND

No

ND

ND

ND


9

Table1.Continued

References

Original

diagnosis

Gender

Ageatonset

ofdiseaseor

ageat

presentation

Skinlesions

Presence

ofbullae

Secondary

infection

Innateor

acquired

Family

history

Otherfeatures

ofdiseaseor

concom

itant

medicalconditions

Pathology

Owens34

Stasiseczema

F82

years

Itchy,confluent,

erythematousand

excoriatedrash

with

lichenificationon

bilaterallegsand,to

alesserextent,on

bothforearms,dorsal

hands,upperlegs,

kneesandinner

thighs

ND

ND

Acquired,low-protein

diet(associatedwith

lowzinc

levels)

ND

Brainstem

ischem

icepisode,Myocardial

infectionhistoryand

anterior

resectionofsigm

oid

colonforcarcinom

a,depression

Parakeratosisandchanges

compatiblewith

stasis

eczema

GonzalezJR,

BotetMV

SanchezJL

(12

patientsdescribed

anddividedinto

fourclinical

andpathological

stages)42

NDforanypatients

5males;7

females

Ages

ranged

from

19days

to5months

(Clinicalfindingsofall

stagesoccurred

inan

acraland

periorificial

distribution)Stage1:

early

reddishplaques

ND

ND

ND

ND

ND

Characterized

byloss

ofthe

granularlayer;slight

paleness

oftheupperone

third

oftheepidermis

Stage

2:brightlyreddish

scalyplaques

ND

ND

ND

ND

ND

Mainfeatures

included

paleness

oftheuppertwo

thirdsoftheepidermis

accompanied

byslightto

fully

developedpsoriasi-

form

hyperplasia

Stage

3:scalypsoriasi-

form

plaques

ND

ND

ND

ND

ND

Psoriasiform

hyperplasiaand

focalpallorwithinthe

upperepidermis

Stage

4:latereddishor

brow

nish

patches

with

desquamation

ND

ND

ND

ND

ND

Confluentparakeratosis,

slightepidermalhyper-

plasia,nopallorseen

Bronson

DM,

BarskyR,

BarskyS7

Herpesgestationis,

impetigo

herpetiformis

F23

years

Widespreadpustular,

vesiculobullous

and

psoriasiform

eruptionwith

elbows,knees,distal

extrem

ities

most

severelyaffected,as

wellasan

erosive

pustulardermatitisof

theperioraland

perinealregions,

thinnedhairand

glossitis

Vesiculobullous

eruption

Saureus,Proteus

mirabilis,

C.albicans

Probableinnatewith

exacerbationduring

pregnancy

Sisterdied

inearly

childhood

ofa

generalized

blisteringdisease

Eruptionoccurred

with

twoofpatient’s

pregnancies,also

hadasimilar

eruptionas

achild

at2yearsofage

with

partialand

then

completeremission

laterinchildhood

Initialbiopsy

atfirstpreg-

nancyshow

edsubcorneal

pustulosis;subsequent

eruptionwith

second

pregnancyshow

ed�spongiotic

dermatitis’

with

intra-epidermal

vesicles

andnumerous

neutrophils

andnegative

indirectanddirect

immunofluorescence

LeeMG,

HongKT,

KimJJ

6

ND

F5month

Erythematous,

desquamatingskin

eruptionperiorally,

scalp,face,perineal,

buttocksanddistal

extrem

ities,alsohad

crustedvesicles

and

blisterson

fingers

andtoes,aswellas

alopecia

Vesicles

and

blisters

Nofungus

identified

Uncertainifinnateor

acquired,thoughtto

besecondaryto

unexplainedlowzinc

levelsinmaternal

breastmilk

ND

Exclusivelybreast-fed,

otherwisehealthy

Non-specific

dermatitis

from

buttocklesion

Jensen et al.

10

Table1.Continued

References

Original

diagnosis

Gender

Ageatonset

ofdiseaseor

ageat

presentation

Skinlesions

Presence

ofbullae

Secondary

infection

Innateor

acquired

Family

history

Otherfeatures

ofdiseaseor

concom

itant

medicalconditions

Pathology

MoriH,M

atsumotoY,

MatsumotoY,

TamadaY,

OhashiM

35

NDforanypatients

Patient1:F;patient

2:F;patient3:

M;patient4:M;

patient5:M;

patient6:M;

patient7:M

Patient1:

73years;

patient2:

73years;

patient3:

45years;

patient4:

78years;

patient5:

79years;

patient6:

65years;

patient7:

40years

Patient1:erythema,

vesicleandpustule;

patient2:erosion,

pigm

entation;

patient3:pustule;

patient4:pustule,

redpapule;patient5:

prust,pustule;

patient6:prust

pustule;patient7:

hyperkeratosis,

pigm

entation,

erythemaand

pustule

Patient1:vesicle;

patient2:ND;

patient3:ND;

patient4:ND;

patient5:ND;

patient6:ND;

patient7:ND

NDforany

patients

NDforany

patients

NDforany

patients

Patient1:gastric

cancer;patient2:

subarachnoidhem-

orrhage;patient3:

ileus;patient4:

cerebralthrombosis;

patient5:cerebral

thrombosis;patient

6:extram

ural

hemorrhage;patient

7:Crohn’sdisease

Pathologicalfindingsofall

sevenpatientsdescribed

inarticlewere

summarized

asshow

ing

intra-epidermal

vesiculationwith

lympho-

cytesandirregular

acanthosis.Som

elesions

show

edvesiculationwith

thepresence

ofapoptosis;

however,those

with

simplyhyperkeratosisdid

notshow

apoptosis

Kum

arS,

SehgalVN,

SharmaRC36

Fourpatientsdescribed;

noprevious

diagnosisdescribed

ND

Range

from

6to

9monthsofage

Vesiculobullous

eczematouslesions

involvinganogenital

region,periorificial

areasandacral

extrem

ities

Vesiculobullous

lesions

ND

ND

ND

Photophobiaintwo

cases,diarrhea

inanothertwo

ND

KhannaandD’Souza

37

ND

F8months

Psoriasiform

plaqueson

occiput,neck,

buttocks

and

extensorextrem

ities,

aswellasperioral

andperigenital

macerated

lesions

andparonychia

involvingseveral

fingersandtoes

ND

ND

ND

ND

Weightloss

ND

Ozkan

S,

Ozkan

H,

FetilE,

CorapciogluF,

Yilmaz

S,OzerE3

8

ND

M9months

Erythematous,scaly,

vesiculobullous

lesionsandcrusted

ulcerations

onface

(particularly

periorally),and

withinthediaper

area;com

missural

macerationpresent

aswell

Vesiculobullous

le-

sions

P.aeruginosa

withinblisteras

wellasoral

candidiasis

ND

ND

ND

Bullous

lesion

onright

glutealregionshow

edan

intra-epidermalblister,

perivascularlymphocytic

infiltrateandsuperficial

dermaledem

a

Ozturkcan

S,

IcagasiogluD,

AkyolM,CeritO41

ND

F17

months

Vesiculobullous

and

psoriasiform

lesions

locatedperiorally,

acrallyandwithinthe

perinealregion

Vesiculobullous

lesions

ND

ND

ND

ND

Biopsyfrom

anarea

ofplantardesquamation

show

ednon-specific

keratosis

Perafan-Riveros

C,

SayagoFranca

LF,

Alves

ANF,

Sanches

JAJr.3

ND

M21

month

Periorificialand

acral

erythematous,scaly

plaqueswith

crusts

andulcerations,

macerationand

fissureswithinthe

inguinalregions,

alopeciaand

paronychia

ND

S.aureus

ND

Brotherwith

similarskin

lesionsdied

at14

monthsofage

Chronic,intermittent

diarrhea,Klebsiella

sepsis

Biopsyofulcerated

plantarlesion

show

edanon-specificsuperficial

andpsoriasiform

perivas-

culardermatitis

AE,

acroderm

atitisenteropathica;

F,female;

M,male.

ND,notdiscussed.


11

Conclusions

Patients with the bullous form of AE may bemisdiagnosed for months after initial presentation,as in the case of our two patients. Our first patientwas originally diagnosed with allergic contactdermatitis. Only after further investigation,2 months following her initial presentation, shewas correctly diagnosed with AE. In our secondpatient, abuse was considered in the diagnosis andresulted in the child being placed in foster care. Herdiagnosis was eventually made after a delay of6 months. As evidenced by our patients’ cases, thebullous presentation of AE may elude a correctdiagnosis. Because of the rarity of the disease,clinicians and pathologists are often unaware of itsclinical and histological spectrum and, therefore, donot suspect the diagnosis initially.

The findings of our two patients, along with thosereported by Borroni et al., further establish thediagnostic features of bullous AE and should alertthe pathologist to the possibility of the diagnosis ofAE.In the appropriate clinical setting, the findings ofindividual and coalesced intra-epidermal necrotickeratocytes, intra-epidermal vesiculation amongscant spongiosis and a predominant lymphoneutro-philic infiltrate should alert the pathologist to thediagnosis of AE, particularly when not suspectedclinically. Bullous AE should be included in thedifferential of intra-epidermal vesiculation, in addi-tion to the more commonly encountered pediatricdermatitides.

Early recognition and treatment are necessary,particularly because of concerns of immunodeficiencyand infection in these patients. Skin biopsy playsa very important role in the diagnostic work up of AE.As illustrated by the reported cases, the histologicalfeatures are varied but may be specific enough toexclude clinical and histological mimickers of AE andto support the correct diagnosis.

We hope to raise physicians’ clinical and histopath-ological suspicion of AE when presented witha bullous dermatitis. The delay in achieving thecorrect diagnosis in our cases emphasizes the need fora high index of suspicion of zinc deficiency. Height-ened awareness of the bullous form of this conditionmay provide earlier diagnosis and therapeutic inter-vention for these patients.

References

1. Lombeck T, Schnippering HG, Ritzl F, Feinendegen LE,

Bremer HJ. Letter: absorption of zinc in acrodermatitis

enteropathica. Lancet 1975; 1: 855.

2. Atherton DJ, Muller DP, Aggett PJ, Harries JT. A defect in zinc

uptake by jejunal biopsies in acrodermatitis enteropathica. Clin

Sci 1979; 56: 505.

3. Perafan-Riveros C, Sayago Franca LF, Alves ANF, Sanches JA

Jr. Acrodermatitis enteropathica: case report and review of the

literature. Pediatr Dermatol 2002; 19: 426.

4. Kury S, Dreno B, Bezieau S, et al. Identification of SLC39A4,

a gene involved in acrodermatitis enteropathica. Nat Genet

2002; 31: 239.

5. Wells B, Winkelmann RK. Acrodermatitis enteropathica. Arch

Dermatol 1961; 84: 40.

6. Lee MG, Hong KT, Kim JJ. Transient symptomatic zinc

deficiency in a full-term breast-fed infant. J Am Acad Dermatol

1990; 23: 375.

7. Bronson DM, Barsky R, Barsky S. Acrodermatitis enter-

opathica. J Am Acad Dermatol 1983; 9: 140.

8. Sjolin KE. Zinc deficiency syndrome. J Cut Pathol 1979;

6: 88.

9. Ruiz-Maldonado R, Orozco-Covarrubias L. Nutritional dis-

eases. In Dermatology. London: Mosby, 2003; 706.

10. Brazin SA, Johnson WT. The acrodermatitis enteropathica-like

syndrome. Arch Dermatol 1979; 115: 597.

11. Piper E. Acrodermatitis in an adult. Arch Dermatol 1957; 76: 221.

12. Juljulian HH, Kurban AK. Acantholysis: a feature of

acrodermatitis enteropathica. Arch Dermatol 1971; 103: 105.

13. Dillaha CJ, Lorincz AL, Aavick OR. Acrodermatitis enter-

opathica: review of the literature and report of a case successfully

treated with diodoquin. J Am Med Assoc 1953; 152: 509.

14. Montgomery H. Genodermatosis. In Dermatopathology. New

York: Harper & Row, 1967; 81.

15. Brandt T. Dermatitis in children with disturbances of the

general condition and absorption of food elements. Acta Derm

Venereol 1936; 17: 513.

16. Danbolt N, Closs K. Akrodermatitis enteropathica. Acta Derm

Venereol 1942; 23: 127.

17. Guy WH. Epidermolysis bullosa. Arch Dermatol Syph 1927;

15: 30.

18. Danbolt N. Acrodermatitis enteropathica: report of two

additional cases. Acta Derm Venereol 1948; 28: 532.

19. Ugland J. Cortisone treatment of skin involvement, acroder-

matitis enteropathica, in a case of cystic fibrosis of the pancreas.

Acta Paediatr 1952; 41: 483.

20. Bloom D, Sobel N. Acrodermatitis enteropathica successfully

treated with diodoquin. J Invest Dermatol 1955; 24: 167.

21. Danbolt N. Acrodermatitis enteropathica. Acta Derm Venereol

1956; 36: 258.

22. Vedder JS. Acrodermatitis enteropathica (Danbolt-Closs) in five

siblings. J Pediat 1956; 48: 212.

23. Wells BT, Winkelmann RK. Acrodermatitis enteropathica:

a report of six cases. Arch Dermatol 1961; 84: 90.

24. Lindstrom B. Familial acrodermatitis enteropathica in an adult.

Acta Derm Venereol 1963; 43: 522.

25. Hansson O. Acrodermatitis enteropathica: report of two cases

with a hypothesis concerning the pathogenesis of the disease.

Acta Derm Venereol 1963; 43: 465.

26. Rodin AE, Golman AS. Autopsy findings in acrodermatitis

enteropathica. Am J Clin Pathol 1969; 51: 315.

27. Tompkins RR, Livingood CS. Acrodermatitis enteropathica

persisting into adulthood. Arch Dermatol 1969; 99: 190.

28. Julius R, Schulkind M, Sprinkle T, Rennert O. Acrodermatitis

enteropathica with immune deficiency. J Pediatr 1973; 83:

1007.

29. Moynahan EJ, Barnes PM. Zinc deficiency and a synthetic diet

for lactose intolerance. 1966; 59: 445.

30. Verberg DJ, Burg LI, Hoxtell EO, Merrill LK. Acrodermatitis

enteropathica and pregnancy. 1974; 44: 233.

Jensen et al.

12

31. Nelder KH, Hambidge KM. Zinc therapy of acrodermatitis

eneropathica. N Engl J Med 1975; 292: 879.

32. Olholm-Larsen P. Untreated acrodermatitis enteropathica in

adults. Dermatologica 1978; 156: 155.

33. Bonfazi E, Rigillo N, De Simone B, Meneghini CL. Acquired

dermatitis due to zinc deficiency in a premature infant. Acta

Derm Venereol 1978; 58: 349.

34. Owens CWI, Al-Khader AA, Al-Khader AAA, Jackson MJ,

Prichard BNC. A severe �stasis eczema,’ associated with lowplasma zinc, treated successfully with oral zinc. Br J Dermatol

1981; 105: 461.

35. Mori H, Matsumoto Y, Matsumoto Y, Tamada Y, Ohashi M.

Apoptotic cell death in formation of vesicular skin lesions in

patients with acquired zinc deficiency. J Cutan Pathol 1996; 23:

359.

36. Kumar S, Sehgal VN, Sharma RC. Acrodermatitis enter-

opathica. J Dermatol 1997; 24: 135.

37. Khanna N, D’Souza P. Acrodermatitis enteropathica. Indian

J Pediatr 1996; 33: 967.

38. Ozkan S, Ozkan H, Fetil E, Corapcioglu F, Yilmaz S, Ozer E.

Acrodermatitis enteropathica with Pseudomonas aeruginosa sepsis.

Pediatr Dermatol 1999; 16: 444.

39. V Vloten. Skin lesions in acquired zinc deficiency. Dermato-

logica 1977; 156: 175.

40. Ackerman AB. Superficial perivascular dermatitis. In Histo-

logic diagnosis of inflammatory skin diseases. Philadelphia: Lea

and Febiger, 1978; 169.

41. Oztrukcan S, Icagasioglu D, Akyol M, Cevit O. A case of

acrodermatitis enteropathica. J Dermatol 2000; 27: 475.

42. Gonzalez JR, Botet MV, Sanchez JL. The histopathology of

acrodermatitis enteropathica. Am J Dermatol 1982; 4: 303.

43. Borroni G, Brazzelli V, et al. Bullous lesions in acrodermatitis

enteropathica: histopathologic findings regarding two patients.

Am J Dermatopathol 1992; 14: 304.


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