ARTICLE
Auteur(s) : Paulo Morais1,
Alberto Mota1, Teresa Baudrier1, José Manuel
Lopes2, Rita Cerqueira3, Purificação
Tavares3, Filomena Azevedo1
1Department of Dermatology and Venereology,
Hospital S. João, Alameda Professor Hernâni Monteiro,
4200-319 Porto, Portugal; Faculty of Medicine, University
of Porto, Alameda Professor Hernâni Monteiro,
4200-319 Porto, Portugal
2Department of Pathology, Hospital S. João, Alameda
Professor Hernâni Monteiro, 4200-319 Porto, Portugal; Faculty
of Medicine, University of Porto, Alameda Professor
Hernâni Monteiro, 4200-319 Porto, Portugal
3Center of Clinical Genetics, Rua Sá da Bandeira,
706 - 1°, 4000-432 Porto, Portugal
accepté le 25 Février 2009
Epidermolytic hyperkeratosis (EHK; OMIM #113800), also known as
bullous congenital ichthyosiform erythroderma of Brocq, is a rare
form of congenital ichthyosis with a prevalence of 1 in
200,000-300,000 persons [1]. The histology of this condition was
described by Nikolski in 1897 [2]. In 1902, Brocq clinically
defined it as bullous congenital ichthyosiform erythroderma, to
distinguish the entity from the non-bullous form of congenital
ichthyosiform erythroderma [3]. The term “epidermolytic
hyperkeratosis”, applied by Frost and Van Scott in 1966, describes
the distinctive, but not unique, histopathological features of the
epidermis [4].
Case report
A 12-year-old Caucasian female living in an orphanage and with an
unknown family history is presented. As narrated by the caregiver,
at birth the girl presented a burned child aspect, with redness and
a few erosions and blisters all over her body, which gradually
diminished in subsequent days, giving place to thick dry scales
(figure 1A). She
was referred to our Department at 3 years of age. On examination
she presented generalized dryness, areas of denuded skin and
yellowish to light brown verrucous hyperkeratotic plaques, most
prominently in the scalp, over the joints and around flexures, such
as the neck, elbow, wrist, hip, knee and ankle, with a relative
sparing of the skin between the joints (figures 1B, C). The
plaques had a cobblestone pattern and a foul odour. Fissures in the
intertriginous areas, and smooth palmar and plantar hyperkeratosis
were both evident (figure 1D). The hair,
nails and mucosal surfaces were not significantly involved.
Except for mild hypoalbuminemia and hyponatremia, the remaining
routine blood panel, urinalysis and imaging studies were
unremarkable. A skin biopsy showed pronounced hyperkeratosis,
acanthosis, vacuolar degeneration involving the upper epidermis,
with cleft formation, and presence of darkly staining intracellular
granules or inclusions, many of them larger than normal
keratohyalin granules (figure 2A). Electron
microscopy revealed hyperkeratosis, and a variable degree of
intracellular edema and vacuolar degeneration of keratinocytes,
especially in the superficial part of the intermediate epidermal
level. The normal filamentous cytoskeleton was grossly altered,
with evident aggregation of the tonofilaments around the nucleus,
in tight intracellular clumps and relatively regular borders (figure 2B).
Based on the clinical, histological and ultrastructural
findings, the diagnosis of epidermolytic hyperkeratosis with
palmoplantar keratoderma was made. The patient underwent treatment
with a variety of topical therapies, including antiseptic
cleansers, emollients, keratolytics, such as salicylic acid, urea
or alpha-hydroxyacids, and with the vitamin D analogue
calcipotriol. The recurrent skin infections were controlled with
topical (fusidic acid) and/or systemic antibiotics (flucloxacillin,
cefuroxime-axetil), and were frequently associated with
foul-smelling macerated scales and purulent discharge. Oral
acitretin (0.5 mg/kg/day) was attempted but it was
discontinued in the fourth month of treatment due to persistently
altered liver function tests, and exacerbation of erythema,
desquamation and blistering.
Recently, the molecular genetic study was performed. Sequencing
exon 6 of KRT10 gene identified a point mutation in codon 452 (CTG
to CCG) that altered a leucine residue to proline (L452P) in the 2B
helical domain of the protein (2B: L113P) (figure 3). The
parents were not available for further molecular testing, therefore
it is unknown if the mutation in this case was spontaneous or was
transmitted from the mother or father in an autosomal dominant
pattern.
At present, the patient is clinically improved, without
electrolyte imbalance or skin infections in the last 3 years. She
is currently being managed with antibacterial cleansers, emollients
and keratolytic agents.
Discussion
EHK is a disorder of cornification type 3 caused by mutations in
the genes encoding keratin 1 (KRT1) or keratin 10 (KRT10), located
on chromosomes 12q13.3 and 17q21.2, respectively [5, 6]. These two
keratins are important structural proteins, present in suprabasal
and granular layers of the epidermis. Around 50 different types of
mutations have been reported in either KRT1 or KRT10, mainly point
mutations causing an amino acid change and located in two of the
conserved domains of the α-helix, 1A and 2B [6-8]. Keratin
mutations have a dominant negative effect and lead to instability
of intermediate filaments with tonofilament aggregation,
cytoskeletal disruption, keratinocyte fragility and cellular lysis
[9]. Despite its autosomal dominant pattern of inheritance,
spontaneous mutations account for about half of the cases of EHK
[10, 11]. Recently, Müller et al. [12] described for the first
time a family with recessive inheritance of EHK. Sequence analysis
revealed a homozygous mutation in the affected family members,
whereas the clinically unaffected consanguineous parents were both
heterozygous carriers of the mutation [12].
EHK may vary from a mild to a severe disease that is socially
disabling for the patients. It usually manifests at birth with
redness, blistering and peeling. With time, erythema and blisters
become less frequent and generalized hyperkeratosis develops,
mainly in flexural surfaces [1, 11]. Six clinical phenotypes have
been described, depending on the presence of severe palmoplantar
keratoderma (PPK): three subgroups with palm/sole hyperkeratosis
(PS1-3), associated with KRT1 mutations, and the other three
subgroups with no palm/sole involvement (NPS1-3), usually linked to
KRT10 mutations [1]. The basis for the absence of PPK in most
patients with KRT10 mutations is that palmoplantar skin expresses
KRT9, which is a functional substitute for KRT10, and consequently
reduces the symptoms. In contrast, there is no known replacement
for KRT1. Since some patients with KRT10 mutations develop PPK
anyway, as was the case of our patient and of others recently
reported [7, 13, 14], it is possible that certain types of KRT10
mutation cause such a severe disturbance of the filament
polymerization that a normal KRT9 protein is not sufficient to
balance it. Interestingly, the same mutation detected in our
patient (L452P or 2B: L113P) was previously described by McLean
et al. [15] but apparently not associated with PPK, suggesting
that other factors must be involved.
The mosaic form of EHK, or linear epidermolytic hyperkeratosis
(LEH), is characterized by unilateral or bilateral streaks of
hyperkeratosis that follow the lines of Blaschko and resemble
verrucous epidermal nevi but with distinctive epidermolysis. LEH is
caused by somatic mutations in KRT1 or KRT10 arising
postzygotically during early embryogenesis [16-18]. There are a few
reports of children born with generalized EHK where one of the
parents had LEH, i.e. mutations may also involve gonadal cells and
then be transmitted from the germline to the offspring [18,
19].
EHK is usually a clinical diagnosis, but sometimes diagnostic
techniques, such as histopathology, immunohistochemistry and
electron microscopy of skin biopsy specimens are required [11].
Prenatal diagnosis, initially based on fetal skin biopsy analysis,
is now performed using molecular analysis of fetal DNA from
chorionic villi or amniotic fluid samples [11]. In fact, EHK was
the first genodermatosis where a DNA-based prenatal diagnosis was
made possible [20].
EHK is a severe form of ichthyosis with no curative treatment
and available therapies are not usually very satisfactory.
Treatment includes regular baths with antiseptic cleansers,
application of emollients containing urea, glycerol and others,
keratolytics, namely alpha-hydroxyacids, salicylic acid or urea
> 5%, topical calcipotriol, N-acetylcysteine or liarozole,
topical or systemic antibiotics to control bacterial infection, and
topical or oral retinoids, such as isotretinoin and the aromatic
retinoids (acitretin, etretinate), in more severe cases [21-24].
Retinoid therapy, given topically or systemically, is more
effective in patients with mutations in KRT10, possibly because
they are less vulnerable to the undesirable down-regulation of KRT2
[8, 14, 24]. Unfortunately, this was not the case of our patient,
who had a poor response to retinoids, despite the presence of a
KRT10 mutation. In the future, molecular-based therapies will
presumably provide a novel approach in the treatment of patients
with EHK. A major challenge in this context is the
dominant-negative effects of KRT1 and KRT10 mutations, requiring
silencing of the mutant allele [8, 24]. Recently, this approach was
suggested to be effective in the treatment of pachyonychia
congenita (PC), by the use of small interfering RNAs (siRNA) that
selectively and potently inhibit a mutant allele of KRT6A, the most
commonly affected PC keratin [25]. These molecules are particularly
attractive and have great promise as therapeutic agents for the
treatment of PC or other dominant-negative genetic disorders [25].
Physicians must always be aware for the risk of skin infection,
dehydration, electrolyte imbalance or sepsis [21]. EHK is a
lifelong and serious condition but, in some patients, symptoms may
ameliorate over time.
Despite the attempts to correlate genotypes and phenotypes in
EHK [1], our results, in concordance with other authors [7, 13,
14], confirm that not all patients with KRT10 mutations lack
palmoplantar involvement, suggesting, at least for this gene, that
correlation cannot be made in an absolute way. To date, the only
correlation found seems to be between KRT1 mutations and PPK [8,
14]. On the other hand, despite the usually positive response to
retinoids observed in patients with KRT10 mutations, some
exceptions have been described [8, 14], which are confirmed in our
case. We consider that more research in this area is necessary for
a better understanding of the mechanism of action of retinoids and
the genotype/phenotype correlation of this disease.
Acknowledgements
Financial support: none. Conflict of interest: none.
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