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also participate in the pigmentation cascade of certain eccrine
poromas. From the results of our immunohistochemical stain-
ing it is clear that the pigmented poroma showed strong
expression of ET-1, while its nonpigmented counterpart
showed weak or no ET-1 expression. Several groups have
reported a close association of enhanced ET-1 expression with
hyperpigmentation in epithelial tumours.9–11 Most of these
studies showed enhanced ET-1 expression by epidermal cells:
therefore, factors known to stimulate secretion of ET-1 in ker-
atinocytes, such as tumour necrosis factor (TNF)-a, were sug-
gested to be the proximal signal triggering the upregulation of
ET-1.9,11 However, none of our surgical specimens, pigmen-
ted or nonpigmented, showed marked expression of TNF-a(data not shown). Sakuraba et al. recently showed that pig-
mentation in different epithelial tumours may involve different
melanogenic pathways.12 We therefore believe that the path-
way in pigmented poroma may be different from those in
seborrhoeic keratosis and lentigo senilis. The question of why
ET-1 is upregulated in some lesions but not in others remains
to be elucidated. Another issue that needs to be addressed is
that as ultraviolet (UV) B radiation can induce ET-1 expression
on keratinocytes, whether UVB may also upregulate ET-1
expression on poroma cells.13 However, close examination of
our nonpigmented poroma specimens suggested that ET-1
expression in poroma cells was not directly related to sun
exposure. While a nonpigmented poroma from an area not
exposed to the sun (the foot) showed weak ET-1 expression,
a facial nonpigmented poroma lacked ET-1 expression. This
observation suggests that UVB exposure has no direct impact
on ET-1 expression by poroma cells.
It is well documented that sweat duct primordia contain
melanocytes during the 14th week of gestation that are lost
later in embryonic development.14 Therefore, it may be that
the tumour cells of pigmented poroma secrete significant
amounts of ET-1 that could result in migration and prolifer-
ation of epidermal melanocytes or activation of melanocytes
in the sweat gland acrosyringium after fetal life. Other growth
factors may be involved in the pigmentation process of
poroma, and further investigations are required in order to
elucidate the mechanism of melanin deposition and melano-
cyte colonization among poroma cells. Our present findings
indicate that enhanced expression of ET-1 is involved in the
hyperpigmentation of this tumour.
Departments of Dermatology and
�Pathology, Kaohsiung Medical University Hospital, no.100 Shih-Chuan 1st Road, Kaohsiung, Taiwan
*Department of Dermatology,
National Taiwan University Hospital and
National Taiwan University College of Medicine,
Taipei, Taiwan
�Faculty of Biomedical Laboratory Science,College of Health Sciences, Kaohsiung Medical University,
Kaohsiung, Taiwan
C-C.E . LAN
H-S . YU*
C-S . WU�K-B. TSA I�C-H. WEN�G-S . CHEN
Correspondence: Gwo-Shing Chen.
E-mail: [email protected]
References
1 Pinkus H, Rogin JR, Goldman P. Eccrine poroma. Arch Dermatol
1956; 74:511–21.2 Penneys NS, Ackerman AB, Indigin SN et al. Eccrine poroma. Br J
Dermatol 1970; 82:613–15.3 Hyman AB, Brownstein MH. Eccrine poroma: an analysis of 45
new cases. Dermatologica 1969; 138:29–38.4 Jin K, Nogita T, Toyoda H et al. Pedunculated pigmented eccrine
poroma of the scalp with increased urinary excretion of 5-s-cystei-nyldopa. J Dermatol 1990; 17:555–8.
5 Mousawi A, Kibbi AG. Pigmented eccrine poroma: a simulant ofnodular melanoma. Int J Dermatol 1995; 34:857–8.
6 Nakanishi Y, Matsuno Y, Shimoda T et al. Eccrine porocarcinomawith melanocyte colonization. Br J Dermatol 1998; 138:519–21.
7 Saitoh K, Saga K, Okazaki M et al. Pigmented primary carcinoma ofthe breast: a clinical mimic of malignant melanoma. Br J Dermatol
1998; 139:287–90.8 Imokawa G, Yada Y, Miyagishi M. Endothelins secreted from
human keratinocytes are intrinsic mitogens for human melano-cytes. J Biol Chem 1992; 267:673–80.
9 Manaka I, Kadono S, Kawashima M et al. The mechanism ofhyperpigmentation in seborrhoeic keratosis involves the high
expression of endothelin-converting enzyme-1a and TNF-a,which stimulate secretion of endothelin-1. Br J Dermatol 2001;
145:895–903.10 Vural P, Erzengin D, Canbaz M, Selcuki D. Nitric oxide and endo-
thelin-1,2 in actinic keratosis and basal cell carcinoma: change innitric oxide ⁄endothelin ratio. Int J Dermatol 2001; 40:704–8.
11 Kadono S, Manaka I, Kawashima M et al. The role of the epidermal
endothelin cascade in the hyperpigmentation mechanism of lentigosenilis. J Invest Dermatol 2001; 116:571–7.
12 Sakuraba K, Hayashi N, Kawashima M, Imokawa G. Down-regula-ted PAR-2 is associated in part with interrupted melanosome trans-
fer in pigmented basal cell epithelioma. Pigment Cell Res 2004;17:371–8.
13 Imokawa G, Yada Y, Miyagishi M. Endothelins secreted fromhuman keratinocytes are intrinsic mitogens for human melano-
cytes. J Biol Chem 1992; 267:24675–80.14 Hashimoto K, Gross BG, Lever WF. The ultrastructure of the
human embryo skin. II. The formation of the intradermal portionof the eccrine sweat duct and of the secretory segment during the
first half of the embryonic life. J Invest Dermatol 1996; 46:513–29.
Conflicts of interest: none declared.
Novel mutation of connexin 31 causingerythrokeratoderma variabilis
DOI: 10.1111/j.1365-2133.2005.06561.x
SIR, Erythrokeratoderma variabilis (Mendes da Costa) (EKV) is
an autosomal dominant keratinization disorder described in
1925 by Mendes da Costa.1 It belongs to the group of eryth-
rokeratodermas2 and includes two independent morphological
features: transient erythema and fixed keratosis. The disease is
caused by mutations in connexin (Cx) 31 and 30.3. We report
� 2005 British Association of Dermatologists d British Journal of Dermatology 2005 152, pp1062–1094
1072 Correspondence
a novel Cx 31 mutation in a Swiss family including a total of
eight affected individuals in five generations (Fig. 1a).
We personally examined four affected members in this fam-
ily, once in 1998 and again in 2003.
Patient 1 (II 1) was a 72-year-old man. His lesions were
well-defined, irregular, partially confluent areas of brownish
thickened skin with focal scaling, mainly on the extensor sur-
faces (Fig. 1b). Discrete, well-demarcated erythematous pat-
ches were observed on the buttocks. Hyperkeratosis with
erythema was seen on the interior of the thighs.
Patient 2 (III 2) was a 47-year-old woman. Her eruption
started at the age of 5 years. She presented with erythematous
skin lesions on the buttocks, trunk, face and extremities as
well as brown, fixed, keratotic areas on the extensor surfaces.
Palmoplantar keratotic lesions predominated on pressure
points and extended to the calves.
Patient 3 (IV 2) was a 27-year-old woman. The eruption
started at the age of 1–2 years with erythematous patches on
pressure points, followed at the age of 3 years by palmoplan-
tar involvement and keratotic lesions, increasing until puberty.
At the first examination, well-demarcated brownish patches
were found on the limbs. There were islands of palmoplantar
keratoderma; those on the soles extended to the calves and the
dorsa of both feet. At the second examination, additional
hyperkeratoses on the palms and hyperpigmented patches on
the buttocks were found.
Patient 4 (V 1) was a 6-year-old boy. His eruption started
at 6 months with red patches on the buttocks. Hyperkeratosis
of the soles and palms developed 1 year later. At the first
examination, erythematous scaly lesions with frank demarca-
tion were observed on the right arm. At the second examina-
tion, there were some small islands of keratoses on the
pressure points accompanied by desquamation on the palms
and soles.
All patients experienced aggravation of their symptoms by
wind and cold, and fluctuation of the erythematous patches
overnight, whereas the keratotic plaques were fixed. An
improvement of the symptoms during pregnancies (patients 2
and 3) and since the menopause (patient 2) was also
observed.
Following informed consent, genomic DNA was extracted
from peripheral blood samples. Polymerase chain reaction
(PCR) amplification of Cx 26, 30, 30.3 and 31 was performed
(Cx31–416F: GTC AGA ACT CAG AAC ACT GCC; Cx31–
1522R: CCT ATA CCC GGC TAG ACA GC). Amplification con-
ditions were (94 �C for 60 s, 62 �C for 30 s, 72 �C for
90 s) · 35 for Cx 31. All PCR products were sequenced. We
searched for mutations in Cx 26, 30, 30.3 and 31 in patient 3
and for mutations in Cx 31 in patients 1 and 2.
Sequencing of the PCR products of patient 3 revealed a
CfiT substitution at nucleotide 625 in the GJB3 gene
encoding Cx 31, replacing the 209-leucine residue with phe-
nylalanine (Fig. 2). This mutation was found in patients 1–3.
The mutation was not detected in three healthy members of
a
b
Fig 1. Clinical features of erythrokeratoderma variabilis. (a) Pedigree
of the family. (b) Patient 1. Symmetrically distributed, geographically
outlined, red-brown hyperkeratotic plaques with focal scaling on the
calves.
Fig 2. L209F mutation. Identification of the mutation of the GJB3
gene in patient 3.
� 2005 British Association of Dermatologists d British Journal of Dermatology 2005 152, pp1062–1094
Correspondence 1073
the family. No mutation was found in Cx 26, 30 or 30.3 in
patient 3.
EKV is caused by a mutation in either Cx 31 or Cx
30.3, respectively encoded by genes GJB3 and GJB4,3,4 that is
underlined by our demonstration of the functional interaction
of these two Cxs, providing a molecular explanation for the
similarity of EKV phenotypes.5 The discovery of this L209F
mutation in Cx 31 permits us to confirm our clinical diagnosis
and to extend the field of Cx mutations causing EKV.
*Institute of Cell Biology, ETH Zurich,
Switzerland
�Dermatogenetic Unit and Laboratoryfor Cutaneous Biology,
Department of Dermatology,
University Hospital, Lausanne,
Switzerland
�Department of Dermatology,Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Correspondence: Daniel Hohl.
E-mail: [email protected]
L . FE LDMEYER*�L . PLANTARD�B. MEVORAH�
M. HUBER�D. HOHL*�
References
1 Mendes da Costa S. Erythro- et keratoderma variabilis in a motherand daughter. Acta Derm Venereol (Stockh) 1925; 6:225–58.
2 Hohl D. Towards a better classification of erythrokeratodermias. Br JDermatol 2000; 143:1133–7.
3 Richard G, Smith LE, Bailey RA et al. Mutations in the human conn-exin gene GJB3 cause erythrokeratodermia variabilis. Nat Genet 1998;
20:366–9.4 Macari F, Landau M, Cousin P et al. Mutation in the gene for conn-
exin 30.3 in a family with erythrokeratodermia variabilis. Am J Hum
Genet 2000; 67:1296–301.5 Plantard L, Huber M, Macari F et al. Molecular interaction of conn-
exin 30.3 and connexin 31 suggests a dominant-negative mechan-ism associated with erythrokeratodermia variabilis. Hum Mol Genet
2003; 12:3287–94.
Conflicts of interest: none declared.
Efficacy of transdermal nicotine patches foreosinophilic pustular folliculitis
DOI: 10.1111/j.1365-2133.2005.06564.x
SIR, Eosinophilic pustular folliculitis (EPF) is characterized by
erythematous patches with pruritic follicular papules and ster-
ile pustules; it most commonly affects the face, trunk and
upper arms. Histopathologically, the inflammation is charac-
terized by the infiltration of hair follicles by eosinophils with
some neutrophils and mononuclear cells.1 At present there is
no consistently effective therapy.
We demonstrated previously that transdermal nicotine pat-
ches were effective in the treatment of skin disorders with eo-
sinophilic infiltration.2 As a continuation of our investigation
into the efficacy of nicotine in eosinophilic dermatoses, we
describe two patients with EPF whose skin lesions responded
well to treatment with transdermal nicotine patches.
Patient 1. A 22-year-old woman was referred with itchy skin
lesions that had appeared 3 months earlier. There was an erythe-
matous patch on her left cheek that harboured, especially on the
margin, a number of 1–2 mm diameter pustules (Fig. 1a).
Biopsy showed infiltration of eosinophils and mononuclear cells
into hair follicles and sebaceous glands. Infiltrates were also seen
in the vicinity of the capillaries in the dermis (Fig. 2). Her
a b
Fig 1. Patient 1. (a) Before treatment, an erythematous patch
harbouring a number of 1–2 mm pustules was present on the left
cheek. (b) After 2 weeks of treatment with transdermal nicotine
patches, the erythema disappeared and the pustules improved
remarkably.
a b
Fig 2. Patient 1. (a) Photomicrograph showing infiltrate of
eosinophils and mononuclear cells in hair follicles and sebaceous
glands. Infiltrates were also seen in the vicinity of the capillaries in the
dermis. (b) Close-up view of hair follicle and sebaceous gland
infiltrated by numerous eosinophils (haematoxylin and eosin; original
magnification: a, · 100; b, · 400).
� 2005 British Association of Dermatologists d British Journal of Dermatology 2005 152, pp1062–1094
1074 Correspondence
