ARTICLE
Auteur(s) : Laura Maintz1, Regina C
Betz2, Jean-Pierre Allam1, Jörg
Wenzel1, Axel Jaksche3, Nicolaus
Friedrichs4, Thomas Bieber1, Natalija
Novak1
1Department of Dermatology, University of Bonn,
Sigmund-Freud-Str. 25, 53105 Bonn, Germany
2Institute of Human Genetics, University of Bonn,
Wilhelmstr. 31, 53115 Bonn, Germany
3Department of Ophthalmology, University of Bonn,
Sigmund-Freud-Str. 25, 53105 Bonn, Germany
4Institute of Pathology, University of Bonn,
Sigmund-Freud-Str. 25, 53105 Bonn, Germany
accepté le 15 Juin 2005
We report the case of a 31-year-old black male from the Emirates
who came to our clinic suffering from cicatricial alopecia,
malodorous fistulating papillomas of the scalp (figures 1A and B),
the axillae (figures 2A, 2B) and purulent draining sinus of the
groins embedded in keloidal tissue. His skin was dry and scaled
since birth. He had congenital deafness and as a consequence never
developed speech. At the age of 15 years he developed an acne
conglobata of chest, back and face. Although the patient’s
condition improved, some draining cysts on the face and
hyperpigmented scars on the chest and back persisted. At age 22 he
developed papillomas of the scalp and both axillae, leading to
alopecia and dermal contraction with restricted extension of the
arms up to 70 degrees. He had no history of severe systemic
infections and no factors aggravating HS such as hyperandrogenism,
smoking or obesity. His intelligence was normal. His brother had a
history of acne comedonica. Apart from that, his family was
phenotypically healthy.He presented an ichthyosis cutis and a
diffuse transgredient palmoplantar keratoderma ( (figure 3) ). Due to the
hyperkeratosis, his knees and back of his feet showed a
pachydermatoglyphia in which dermatoglyphe crests were accentuated
in thickness and height ( (figure 4) ). His hips and
thighs presented fine hyperkeratosis with a slightly erythrodermic
aspect (figures 5A, 5B). The nails of his feet were dystrophic (
(figure 4)
).Slit lamp examination revealed bilateral vascularizing keratitis
( (figure 6A )
and B) and squamous blepharitis marginalis. In spite of these
findings, visual acuity was normal. A hearing test showed complete
hearing loss and no response wave in the evocated otoacoustic
emissions ( (figure
7) ), a sensorineural deafness. Additionally, he suffered
from myringitis of the right ear. FACS analysis showed no
immunodeficiency. Cultures of the draining abscesses of scalp,
axillae and groin yielded no growth or variously grew
Staphylococcus aureus, Corynebacterium and Bacteroides. The
histology from skin biopsies of the scalp revealed a scarring
folliculitis with rarefication of the adnexes and the follicles
embedded in dense connective tissue ( (figure 1B )). Skin
biopsies taken from the axillae showed cryptic formation within the
epithelium and dense connective tissue with a perifollicular
inflammatory infiltration ( (figure 2B )). Skin
biopsies from an erythrokeratodermic region showed
orthohyperkeratosis and segments of parahyperkeratosis above
acanthopapillomatosis (( figure 5B )).We diagnosed a
Keratitis-Ichthyosis-Deafneass (KID)-Syndrome with vascularizing
keratitis, ichthyosis cutis, erythrokeratoderma,
palmoplantarkeratoderma and congenital neurosensory deafness.
Additionally the patient fulfilled all the criteria of a follicular
occlusion triad, presenting acne conglobata, hidradenitis
suppurativa (HS) and dissecting cellulitis of the scalp. Under
therapeutic measures such as a keratolytic, rehydrating and
antiseptic external therapy, antibiotic and antimycotic treatment,
the clinical symptoms and infectious parameters were reduced.
Therapy with isotretinoin, started some years previously, was
without success. At admission of the patient to our department, we
began an acitretin therapy but finally chose the curative
possibility of surgery therapy of the axillar papillomas and of the
scalp, as conservative therapy of the follicular occlusion triad
shows a high rate of recurrence. The inflammatory papillomatous
regions of the axillae (department of Dermatology) and of the scalp
(department of Oral and Maxillofacial Surgery) were radically
debrided. Clean granulation was waited upon and covered in a second
session with a mesh graft from the thigh, achieving a satisfactory
result. With regard to the increased carcinogenic potential in both
KID syndrome and follicular occlusion triad, periodical follow-up
controls were scheduled.
Mutation analysis of the GJB2 gene
We used genomic DNA of the patient extracted from paraffin-embedded
tissue samples for mutation analysis of the GJB2 gene. The DNA was
extracted using Quiagen Kit. PCR was performed using standard
conditions with primer pairs covering the coding region of the GJB2
gene (primer sequences and PCR conditions are available on
request). The PCR products were purified with the GFXTM
PCR DNA Purification Kit (Amersham Biosciences) and directly
sequenced using the BigDye® Terminator v1.1 Cycle
Sequencing Kit (Applied Biosystems) on an ABI 3100 genetic analyser
(Applied Biosystems). The sequencing analysis showed in addition to
a known polymorphism (– 34C→T; NCBI ref SNP ID: 15 9578260) a
heterozygous 148G→A transition in connexin 26 (Cx26) resulting in
substitution of aspartic acid with asparagine in codon 50 (D50N).
Discussion
KID syndrome (MIM 148210) was first reported 1915 by Burns as a
generalized congenital keratoderma with ocular and mucosal
involvement, but the acronym KID syndrome was coined 1981 by
Skinner et al. to highlight the main features of the syndrome [1].
Caceres-Rios et al. stated 1996 that approximately seventy cases,
most of them sporadic, had been reported [2]. All of them showed
cutaneous and auditory abnormalities, 90% sensorineural deafness,
89% erythrokeratoderma, 79% alopecia, 41% reticulated
hyperkeratosis of the palms and soles and 95% had ophthalmologic
defects, most of them (79%) had vascularizing keratitis.
Caceres-Rios proposed the name keratoderatous ectodermal dysplasia,
as the KID acronym does not accurately define this entity and the
skin condition does not always show ichthyosis, but rather
keratodermatous skin. However, a change in terminology has not been
accepted yet.
Both an autosomal dominant form [3] and an autosomal recessive
form [4] have been described, but numerous sporadic cases [5] have
also been reported. Heterozygous missense mutations in the GJB2
gene localized on chromosome 13q11-q12 encoding a gap junction
protein called connexin-26 were found to be associated with the
KID-syndrome [6-8]. Connexines are universal integral membrane
proteins forming inter- and intracellular channels for ion and
molecule transfer, aqueous gap junction channels, thus influencing
a wide range of cellular activity [9]. Intercellular signalling
through gap junctions is essential for tissue homeostasis, tissue
growth and development, and cellular response to external stimuli
[10]. KID and Hystrix Ichthyosis Deafness (HID) syndrome share the
same connexin-26 mutation [8]. Chronic cutaneous bacterial and
mycotic infections may develop and contribute to alopecia, nail
dystrophy and body odour. Death in infancy from overwhelming
infection has been reported in several patients with KID syndrome
[11, 12]. The susceptibility of KID to viral, bacterial and mycotic
infections and the severity of infections (septicemia) suggest a
primary immunodeficiency in addition to an imperfect cutaneous
barrier to micoorganisms. An increased oncogenic potential with
invasive squamous cell carcinoma arising within the hyperkeratotic
lesions has been reported in several KID patients [6, 13]. Other
disorders as hypohidrosis, dermoskeleton dystrophies, cerebellar
hypoplasia, Hutchinson’s triad symptoms, cryptorchidisma and
peripheral neuropathy may be associated. Cases of Carotenaemia,
generalized cytomegalia infection, malignant histiocytoma and hair
follicle tumours have been described. Congenital sensorineural
deafness is evident during infancy in most patients. In typical KID
syndrome, progressive corneal vascularization occurs in childhood,
often after a febrile illness, and leads to blindness by
adolescence. Delayed onset of the keratitis has been reported.
Intellect is unaffected but the combined disabilities of deafness,
blindness and disfigurement impose severe limitations and hardship
on the individual. The major differential diagnosis of KID is
Keratosis palmoplantaris mutilans Vohwinkel with or without
deafness [14], but, unlike KID, without ophthalmological changes
(details shown in table 1( Table 1 )).
The treatment consists of a keratolytic, rehydrating and antiseptic
external therapy, antibiotic and antimycotic treatment and systemic
retinoids.
The follicular occlusion triad is constituted by acne
conglobata, hidradenitis suppurativa and dissecting cellulitis of
the scalp [15]. The assumed pathophysiology of these disorders is
occlusion of the follicular pores and a subsequent granulomatous
response to the ruptured duct contents [16]. HS is a recurrent
disease manifested by abscesses, sinus tracts and scarring, with a
predilection for intertriginous areas. It affects an estimated 4.1%
of the population with a female preponderance, except for patients
with axillary lesions [17]. There is often a family history with
autosomal dominant inheritance [18] and the onset is usually in
late adolescence. Aetiological factors such as hyperandrogenism,
obesity, smoking [19] and chemical irritants are not consistently
associated with the affection, but in some patients may be relevant
aggravating factors. Potential complications include dermal
contractions, local or systemic infection due to the spread of
microorganisms, systemic amyloidosis, arthropathy, and squamous
cell carcinoma.
Dissecting cellulitis (also called Hoffmann’s disease or
perifolliculitis capitis abscedens et suffodiens) manifests with
perifollicular pustules, nodules, abscesses and sinuses that evolve
into scarring alopecia. It occurs predominantly in African American
men between 20-40 years of age [20], but can occasionally affect
other races [21] and women [22], too. Associated musculoskeletal
findings are sometimes reported. Dissecting cellulitis must be
distinguished from several other chronic scarring bacterial scalp
conditions summarized in table 2( Table
2 ). The course of both dissecting cellulitis and HS is
chronic and relapsing, and treatment is often difficult. Medical
therapies include an external antiseptic treatment, retinoids,
antibiotics, oral zinc and steroids. Destructive therapies include
surgical excision with skin grafting for both, X-ray therapy and
laser epilation in patients with dissecting cellulitis of the scalp
[23-25].
Montgomery et al. found a novel heterozygous point mutation
(C119T) in GJB2 in a patient with features of KID syndrome and the
follicular occlusion triad [26]. Though our patient showed the same
clinical features, we only identified the pathogenic mutation D50N
found in the majority of KID patients [6-8, 12, 27-29]. The
follicular occlusion triad was more severe than in the white
patient described by Montgomery, which might be due to his ethnic
group. Darker-skinned persons have higher incidence rates of
dissecting cellulitis of the scalp [20] and complications of acne
such as postinflammatory hyperpigmentation and keloidal scarring
[20, 30]. Features of the follicular occlusion triad in patients
with KID syndrome might result from the hyperproliferative
epidermis leading to obstruction of follicular orifices, cyst
formation, rupture and secondary inflammatory response to the
extruded keratin and secretions [26]. Cx26 is expressed in the skin
most commonly on the palms and soles and there is a high expression
of Cx26 in hair follicles and eccrine sweat glands [10]. Whether
Cx26 mutations are associated with disorders of the sebaceous
glands besides hyperkeratotic skin diseases, hearing loss,
ophthalmological and neurological changes, remains to be
elucidated.
Table 1 Differential diagnosis of KID syndrome
|
Keratoderma
|
Eponyms
|
Encoding
|
Special features
|
|
Keratoderma with prelingual deafness (MIM 148210)
|
KID-syndrome Erythokeratoderma progressiva Burns
|
Connexin-26
|
•Vascularizing keratitis,
|
|
•Erythrokeratoderma, •Palmoplantar Keratosis,
|
|
•Deafness
|
|
Cicatrizing keratoderma with hearing loss (MIM 124500)
|
Vohwinkel, Keratoma hereditarum mutilans
|
Connexin-26
|
•Papular lesions becoming confluent,
|
|
•Starfish keratosis,
|
|
•Pseudo-ainhum,
|
|
•mild hearing impairment
|
|
Loricrin keratoderma (MIM 604117)
|
Camisa Variant Vohwinkel
|
Loricrin
|
•Mild Ichthyosis,
|
|
•Honeycomb pattern
|
|
•Keratoderma,
|
|
•Pseudo-ainhum (cicatricial bands around digits)
|
|
•No deafness
|
Table 2 Differential diagnosis of Dissecting
cellulitis
|
Chronic scarring bacterial scalp conditions acquired scalp
alopecia
|
Characteristics
|
|
Dissecting cellulitis
|
Painful nodules, purulent drainage, burrowing interconnecting
abscesses and cicatricial alopecia
|
|
Acne keloidalis nuchae
|
Keloidal plaques on the back of the neck
|
|
Tufted hair folliculitis
|
Multiple hair tufts emerge from dilated follicular orifices
|
|
Folliculitis decalvans
|
Central scarred patches of alopecia and atrophy without nodules or
sinuses
|
|
Pseudopelade of Brocq
|
Atrophy
|
|
Tinea capitis
|
Positive fungal culture and palpable lymph nodes
|
|
Follicotropic mycosis fungoides
|
Large-cell transformation
|
Acknowledgements
We thank Jana Pforr for excellent technical assistance. RCB is
supported by an Emmy Noether research grant from the Deutsche
Forschungsgemeinschaft (DFG).
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