-
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.
Bullous lesions in AE delaying diagnosis of zinc deficiency
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
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.
References
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patients.
Am J Dermatopathol 1992; 14: 304.
Bullous lesions in AE delaying diagnosis of zinc deficiency
13