ARTICLE
Auteur(s) : Maurice AM
Van Steensel, M Van Geel, PM Steijlen
Department of Dermatology, University Hospital Maastricht, PO
Box 5800, 6202 AZ Maastricht, The Netherlands
accepté le 22 Juin 2005
In the August 2004 issue of the Journal of Investigative
Dermatology we described a two year-old girl whom we first saw in
2002 with bilateral sensory deafness, mild nail dystrophy and mild
hypotrichosis. At the time, the clinical phenotype resembled that
of Clouston syndrome prompting us to analyse the skin expressed gap
junction genes for mutations. In GJB2 we found a heterozygous C to
G transversion in codon 14 resulting in the substitution of the
asparagine by a lysine (N14K) [1]. At the time, there were no other
associated symptoms. In particular, an erythrokeratoderma or a
mucositis as described by Brown et al., associated with a F142L
substitution in GJB2 [2], were not present and we therefore
considered the disease as distinct from other gap junction diseases
of the skin.Recently, we had the opportunity to examine the patient
again. During the past two years, the phenotype had progressively
changed. According to the mother, she now showed red spots on the
legs that migrated during the day, accompanied by slight scaling.
The lesions were slightly pruritic, had been diagnosed as eczema
and treated as such using local steroids, to no avail. In addition,
the oral mucosa, and the lips in particular, were red and painful,
with crusting. This had been attributed to thumb sucking and
treated with zinc oxide paste, which had not resulted in
improvement. The vaginal mucosa was said to be inflamed. The
patient was again referred to our department for therapy. Upon
examination, we noted pronounced redness with crusting and
fissuring of both lips as well as fissuring of the buccal mucosa (
(figure 1) ).
There was no peridontitis; the tongue and teeth appeared normal.
Hypotrichosis of the scalp was still present but it was less
pronounced than at the initial presentation two years ago.
Eyelashes and eyebrows were normal. In contrast to earlier
findings, the fingernails were severely dystrophic and dyschromic
with pronounced scaling and fracturing of the nail plates ( (figure 2) ). The
toenails showed similar abnormalities. On the lower legs, figurated
and sometimes slightly elevated erythematous patches with slight
white scaling were visible. The lesions were sharply demarcated (
(figures 3 A,B)
). Further examination showed vulvar redness but no other
abnormalities were found. The child communicated using sign
language. As she was very fearful of additional procedures, we
chose not to perform any biopsies.Our re-evaluation of the
development of hypotrichosis-deafness syndrome shows that the
phenotype is dynamic. Whereas hypotrichosis, thin nails and
deafness were the presenting symptoms, during the past two years
additional abnormalities have developed. The mucositis resembles
that found in the patient with the F142L mutation although it is
less severe. It would be of interest to examine patients with other
GJB2 associated skin diseases for the presence of mucositis. Like
deafness, it may be a symptom shared by phenotypes associated with
mutations in GJB2.The genotype-phenotype correlation of diseases
associated with mutations in GJB2 may not be as pronounced as was
previously thought, but the lack of follow-up on patients makes
this question difficult to answer. Of particular interest in this
regard is the presence of erythrokeratodermia variabilis (EKV)-like
skin lesions in our patient. To our knowledge, similar
abnormalities have not been reported in association with GJB2
mutations. The erythrokeratodermia that is associated with
keratitis-ichthyosis-deafness syndrome is characterized by a very
pronounced cobblestone-like hyperkeratosis, in contrast to that of
EKV, which tends to be fine and white. While the finding that a
GJB2 mutation can cause a disturbance of keratinization is not
unexpected, the fact that it looks like EKV is intriguing. In our
view, it raises the possibility that skin symptoms in gap junction
disease may actually share a common pathogenetic mechanism that may
not depend completely on the identity of the gap junction gene that
is affected. Other mutations in GJB2, notably N54K and G59R [3, 4],
are associated with a palmoplantar keratoderma. Hence, it may be
that the erythrokeratoderma we observe in our patient is unique to
N14K and incidentally resembles that found in EKV. A careful follow
up of patients with skin diseases caused by mutations in GJB2
should help in resolving this issue.Finally, our results indicate
that it would be of interest to examine patients with EKV not
associated with mutations in either GJB3 or GJB4 for the presence
of mutations in GJB2. Genetic heterogeneity is a feature of EKV [5,
6] and while incorrect clinical diagnoses may account for a
sizeable portion of such cases, there is now a distinct possibility
that mutations in GJB2 may mimic EKV.
Acknowledgements
This work was supported by Barrier Therapeutics NV and by the
Pachyonychia Congenita Foundation.
References
1 Van Steensel MA, Steijlen PM, Bladergroen RS,
et al. A Phenotype Resembling the Clouston Syndrome with
Deafness Is Associated with a Novel Missense GJB2 Mutation. J
Invest Dermatol 2004; 123: 291-3.
2 Brown CW, Levy ML, Flaitz CM, et al. A
novel GJB2 (connexin 26) mutation, F142L, in a patient with unusual
mucocutaneous findings and deafness. J Invest Dermatol 2003; 121:
1221-3.
3 Kelsell DP, Wilgoss AL, Richard G, et al.
Connexin mutations associated with palmoplantar keratoderma and
profound deafness in a single family. Eur J Hum Genet 2000; 8:
469-72.
4 Richard G, Brown N, Ishida-Yamamoto A,
et al. Expanding the phenotypic spectrum of Cx26 disorders:
Bart-Pumphrey syndrome is caused by a novel missense mutation in
GJB2. J Invest Dermatol 2004; 123: 856-63.
5 Van Geel M, Van Steensel MA, Steijlen PM.
Connexin 30.3 (GJB4) is not required for normal skin function in
humans. Br J Dermatol 2002; 147: 1275-7.
6 van Steensel MA. Gap junction diseases of the skin. Am J
Med Genet 2004; 131C: 12-9.
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