bullous lesions in acrodermatitis enteropathica delaying diagnosis...
TRANSCRIPT
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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
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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
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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
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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
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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.
Bullous lesions in AE delaying diagnosis of zinc deficiency
5
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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
Patient1:ND;patient2:
ND;patient3:ND
Patient1:ND;patient2:
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
Bullous lesions in AE delaying diagnosis of zinc deficiency
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
Patient1:ND;patient2:
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
Bullous lesions in AE delaying diagnosis of zinc deficiency
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.
Bullous lesions in AE delaying diagnosis of zinc deficiency
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.
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Bullous lesions in AE delaying diagnosis of zinc deficiency
13