ARTICLE
ejd.2011.1497
Auteur(s) : Esteve Darwich1 chevedarwich@yahoo.es, Asunción
Vicente3, Maria C. Bolling6, Maria A. González-Enseñat3, Victoria Cusi4, Claudia Fortuny5, José A. Bombí2, Marcel F. Jonkman6, José M Mascaró Jr.1
1 Department of Dermatology
2 Department of Pathology,
Hospital Clínic and University School of Medicine, C/ Villarroel
170. CP: 08036 Barcelona, Spain
3 Department of Dermatology
4 Department of Pathology
5 Department of Pediatrics,
Hospital Sant Joan de Déu,
Esplugues de Llobregat, Spain
6 Department of Dermatology,
University Medical Center Groningen,
The Netherlands
Reprints: E. Darwich
Epidermolysis bullosa (EB) encompasses a heterogeneous group of
inherited skin disorders characterized by blistering and skin
fragility secondary to mechanical trauma. According to the level
where the blisters develop in the skin, EB is currently classified
in 4 major types: epidermolytic [EB simplex (EBS)], lucidolytic
[junctional EB (JEB)], dermolytic [dystrophic EB (DEB)] and Kindler
syndrome [1]. Of note, conventional histopathological evaluation is
not mentioned in the latest classification of inherited
epidermolysis bullosa and little literature is currently
available.
Herein, we report a patient who presented with extensive and
severe skin erosions at birth that rapidly progressed to involve
90% of her body surface area. Histological examination revealed the
presence of intraepidermal blisters with extensive acantholysis.
These findings led us to suspect two neonatal diseases – pemphigus
vulgaris and lethal acantholytic epidermolysis bullosa – which
presents with acantholysis as the main histological clue. However,
immunofluorescence examination, electron microscopy and molecular
studies confirmed a diagnosis of EBS of the Dowling-Meara type
(DM-EBS).
Case report
A white female newborn at term was referred to the neonatal
intensive care unit of our institution with extensive and severe
skin erosions that had started during delivery. She was the first
child of healthy, non-consanguineous parents. The mother's
pregnancy was uneventful and the baby weighed 3,330 g at birth. On
admission to the intensive care unit on the 7th day
postpartum, the child had skin erosions that covered 30% of her
body surface area. Large sheets of skin were detached, leaving
intensely red erosions without bleeding, hypergranulation tissue or
scarring. The lesions involved the trunk, limbs and cheeks in a
horse-shoe-shaped pattern. Skin erosions rapidly progressed to
involve 90% of the body surface area by the 10th day of
life (figure
1A). Nikolsky's sign was positive. A glove and socks
detachment pattern on the hands and feet was also present. Scarce
circinate vesicles were seen around large denuded areas. There were
also oral erosions (figure 1B),
and mild conjunctival hyperemia. Milia were noted on the ankles
(figure
1C). She had scalp hypotricosis but not palmoplantar
keratoderma. The nails were markedly thickened, with subungual
hemorrhages and periungual exfoliation (figure 1D).
A hoarse cry was evident.
Cultures from the skin lesions, umbilicus, nasopharynx and
conjunctivae were negative for staphylococcus. The patient
presented important transcutaneous fluid losses leading to severe
hydroelectrolytic and acid-base disturbances. Albumin infusions and
blood transfusions were necessary to improve her hypoproteinemia
and anemia. Pain relief with morphine and sedatives were also
necessary for skin care and dressing changes. During the first
month she presented recurrent bacterial skin infections and sepsis
(Stenotrophomonas maltophila and Enterococcus
faecalis) that were successfully managed with antibiotics. Over
the ensuing weeks, the patient showed a slow improvement of her
skin lesions and was discharged from the intensive care unit at the
age of two months. The child developed mild atrophic scars on her
limbs, hands and feet, as well as an impressive nail thickening and
onychogryphosis with shedding of some nails. Currently, one year
later, a few circinate blisters are present, but there has been a
significant improvement of her skin fragility, with the development
of only a few erosions. Dysphonia is also less evident and signs of
palmoplantar keratoderma have not developed.
Histopathological examination of a skin blister revealed a
suprabasal intraepidermal blister with extensive acantholysis of
the stratum spinosum (figure 2).
Direct immunofluorescence examination of perilesional skin was
negative. Indirect immunofluorescence examination of the mother
serum using monkey esophagus was also negative for
anti-intercellular space antibodies. Anti-desmoglein 1 and 3
antibodies, tested by ELISA, were negative both in the mother and
the baby's sera. Immunofluorescence antigen mapping performed from
a biopsy of perilesional skin revealed an intraepidermal blister
with remains of basal keratinocytes on the blister floor that
stained with keratin 14 (LL001). Staining for plectin (HD121), β4
integrin (58XB4), laminin 332 (GB3) and type VII collagen (LH7:2)
showed a normal linear basement membrane zone staining in the floor
of the blister. Staining with desmoplakin 1 rod domain (Dp2.17) and
plakoglobin (PG5.1) monoclonal antibodies demonstrated normal
pan-epidermal intercellular staining without intracellular
dislocation for either molecule.
Electron microscopy of lesional and healthy skin revealed
suprabasal acantholysis with a split in the basal cell layer with
debris of keratinocytes on the blister floor. There were no evident
alterations of the desmosomes or hemidesmosomes (figure 3A).
Clumping of the tonofilaments within the cytoplasm of keratinocytes
was prominent (figure 3B).
DNA mutation analysis for KRT5 and KRT14 genes
revealed a heterozygous A to G transition at nucleotide position
368 of the KRT14, changing asparagine to serine at codon 123
(N123S) in the proband, but not in her parents, confirming a de
novo mutation in the KRT14 gene. All these findings were
diagnostic of DM-EBS.
Discussion
DM-EBS was originally described in 1954 [2]. It is the most
severe form of EBS and can be life-threatening in the neonatal
period. Neonates with DM-EBS can be clinically indistinguishable
from neonates with other types of EB, such as the Herlitz type of
JEB or recessive DEB. A hoarse cry is a classic sign of Herlitz
JEB, but has also been noted in some cases of DM-EBS [3].
Histological examination in DM-EBS usually shows a subepidermal
blister on light microscopy with very little inflammation. Bergman
et al. recently reviewed the histological features of DM-EBS
in a series of 4 patients, and showed that dyskeratosis in
individual keratinocytes in the epidermis was a characteristic
feature that was not found in other subtypes of EBS (like
Weber-Cockayne or Koebner) [4]. These findings would be the
histological counterpart of the characteristic intracellular
keratin aggregation and clumping that is seen on electron
microscopy. However, the authors of this study did not mention
acantholysis as a histologic feature of DM-EBS. No dyskeratosis as
observed in the aforementioned article was seen in the histological
examination of our patient, probably due to her very young age (7
days). Although some authors have actually seen acantholysis in the
spinous layer on DM-EBS skin specimens (Marcel Jonkman, unpublished
observation), this histological feature has not been well described
and has very rarely been reported in the literature. To our
knowledge, there has been just one case of severe DM-EBS showing
acantholysis reported in the literature. In their description of 3
cases of severe DM-EBS, Furumura et al. briefly mention the
presence of acantholysis in the histological examination of one of
their patients [5].
Intraepidermal acantholysis within the granular layer can be
observed in blistering diseases as neonatal pemphigus foliaceus and
staphylococcal scalded skin syndrome. However, in our patient,
acantholysis within the stratum spinosum was the most striking
histological feature. In fact, taking into account the histological
examination, our initial diagnosis was neonatal pemphigus vulgaris
(NPV) or lethal acantholytic epidermolysis bullosa (LAEB) (table 1). LAEB is a recently described severe
form of EBS caused by a desmoplakin gene mutation with only three
cases reported so far [6, 7]. NPV and LAEB show suprabasal
clefting, leaving basal cells attached to the blister floor like a
row of tombstones with spongiosis and acantholysis of the spinous
layer. The diagnosis of pemphigus was ruled out as direct
immunofluorescence was negative and both indirect
immunofluorescence and desmoglein ELISA from the mother and baby's
serum were also negative. Our patient showed many clinical features
(large sheets of skin detachment, cheeks erosions in a
horse-shoe-shaped pattern, gloves and socks detachment pattern on
the hands and feet) and histological similarities to LAEB.
Moreover, dysphonia can occur in LAEB (Marcel Jonkman, unpublished
observation). However, skin fragility is accompanied by universal
alopecia, anonychia, malformed ears and a rapid fatal outcome in
LAEB. In addition, immunofluorescence microscopy for desmoplakin 1
displayed no staining abnormalities.
Table 1 Differential diagnosis of the congenital
acantholytic bullous diseases.
| Disease |
Clinical features |
Prognosis |
Histopathology |
IF |
IFI Mapping |
Targeted proteins |
Ultrastructural findings |
Inheritance pattern |
| NPV |
Generalized blisters and erosions with mucous
membranes involvement. Mother with pemphigus vulgaris |
Improves within 3 weeks [13] |
Suprabasal clefting with acantholysis leaving
basal cells attached to the blister floor like a row of
tombstones |
Intercellular IgG and C3deposits in the epidermis
(autoantibodies transferred from the mother) |
Usually not performed |
Desmogleins 1 and 3 |
Widening of the ICS with stretched desmosomes,
intracellular cleavage behind the desmosomal plaque, swollen and
irregular mitochondria, condensation of tonofilaments without
clumping and free-floating desmosomes between cells [14] |
NA |
| NPF |
Flaccid blisters, erosions and crusts with no
mucous membranes involvement. Mother with pemphigus foliaceus |
Improves within 2 weeks [15, 16] |
Superficial intraepidermal blister with
acantholysis |
Intercellular IgG and C3deposits in the epidermis
(autoantibodies transferred from the mother) [17] |
Usually not performed |
Desmoglein 1 |
Desmosomal changes are similar to NPV [18] |
NA |
| ED-SFS [19, 20] |
Skin fragility with superficial erosions and
crusts, alopecia, nail distrophy, painful palmoplantar keratoderma
and hypohidrosis |
Skin fragility improves with age. Crusting and
erosions in trauma-prone and perioral areas are common |
Thickening of the epidermis, widening of spaces
between adjacent keratinocytes extending from the first suprabasal
layer upwards. Acantholysis in mid- and upper-spinous layers |
Negative |
Absence or markedly reduced staining for
plakophilin 1 |
Plakophilin 1 |
Widening of intercellular spaces and detachment of
cells. Desmosomes are small and reduced in number. Condensed and
compacted tonofilaments in a perinuclear distribution, lacking
their connections to desmosomes. |
AR |
| LAEB |
Skin and mucous membranes erosions without
vesicles or blisters, universal alopecia, nail loss, malformed
ears, cardiomyopathy and rapid postnatal demise |
Lethal (in first month) |
Identical to NPV |
Negative |
Absent staining for carboxy-terminus of
desmoplakin |
Desmoplakin |
Perinuclear retraction of intermediate filaments
that are disconnected from the IDP of desmosomes [6] ± hypoplastic
desmosomes and loss of the IDP [7] |
AR |
| DM-EBS |
Circinate pattern of widespread blisters, varying
degrees of muco-cutaneous erosions, nail dystrophy and palmoplantar
keratoderma |
Skin fragility improves with age |
Suprabasal clefting. Dyskeratosis of isolated
keratinocytes and acantholysis (rare) |
Negative |
Linear staining for collagen IV and basal keratins
along the dermal floor of the blister |
Keratin 5 and/or 14 |
Cytolisis in the lower portion of the basal layer
keratinocytes and intracytoplasmic clumping of tonofilaments
[9, 10] |
AD |
| Congenital SSSS [21-23] |
Erythema and exfoliation in flexures and
periorificial areas |
Mortality <5% in neonates, but higher in
congenital cases |
Superficial intraepidermal blister with
acantholysis into the granular layer |
Negative |
Usually not performed |
Desmoglein 1 |
Disruption of desmosomes between granular cells.
Thickened tonofilaments among dilated endoplasmic reticulum
[24] |
NA |
NPV: neonatal pemphigus vulgaris; NA: not applicable; NPF:
neonatal pemphigus foliaceus; ED-SFS: ectodermal dysplasia-skin
fragility syndrome; LAEB: letal acantholytic epidermolysis bullosa;
DM-EBS: dowling-meara-epidermolysis bullosa simplex; SSSS:
staphylococcal scalded skin syndrome; ICS: intercellular cement
substance; IDP: inner dense plaque; K-10: keratin 10; AR: autosomal
recessive; AD: autosomal dominant; IF: direct immunfluorescence;
IFI: indirect immunofluorescence.
Transmission electron microscopy (EM) is the only non-molecular
laboratory technique that can identify patients with DM-EBS [8].
Ultrastructural studies demonstrate dense, circumscribed clumps of
keratin filaments in the subnuclear cytoplasm of basal
keratinocytes [9, 10]. The intracellular aggregation of
tonofilaments seems to correlate with the histological detection of
isolated dyskeratotic keratinocytes in the epidermis of these
patients [4]. In the present case, ultrastructural findings
revealed the characteristic clumps of keratin filaments of DM-EBS,
whereas the perinuclear retraction of tonofilaments or the
hypoplastic desmosomes lacking the inner dense plaques seen in LAEB
were not observed. Molecular studies showed the N123S mutation in
keratin 14. This mutation, located in a part of the keratin 14
protein that is important for proper keratin filament formation,
has been previously described in other DM-EBS patients, normally
associated with a severe phenotype [11, 12]. No mutations in
desmoplakin genes were found.
In conclusion, we describe a severe case of DM-EBS that
presented with extensive erosions and scarce vesicles, showing
intraepidermal cleft with extensive acantholysis as the main
histological sign. Therefore, this entity should be considered in
the differential diagnosis of congenital intraepidermal blistering
disorders showing acantholysis as a main feature.
Disclosure
Financial support: none. Conflicts of interest: none.
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