Correspondence 673
published cases of female patients carrying an EDAR gene mutation (Table 1).9,10 Recently, the role of a unique TNF pathway in mammary gland morphogenesis has been identified. The EDA/EDAR/NF-jB pathway seems to be a driver of hormone-independent ductal growth and branching.11 Thus we may suggest that women presenting with breast or nipple anomalies associated, or not, with breastfeeding difficulties should have a dermatological examination to exclude HED/EDA. If warranted, genetic testing including MLPA might be proposed in at-risk patients. 1
Department of Dermatology, Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC) and 2 Laboratoire de diagnostic moleculaire, H^opital Universitaire Necker-Enfants Malades, Assistance Publique-H^opitaux de Paris, 149 rue de Sevres, FR-75015 Paris, France 3 Institut Imagine, Universite Paris Descartes – Sorbonne Paris Cite, Paris, France Correspondence: Smail Hadj-Rabia. E-mail: [email protected]
F. AL MARZOUQI1 C. MICHOT2,3 S. DOS SANTOS2 J.-P. BONNEFONT2,3 C. BODEMER1,3 S. HADJ-RABIA1,3
References 1 Visinoni AF, Lisboa-Costa T, Pagnan NA, Chautard-Freire-Maia EA. Ectodermal dysplasias: clinical and molecular review. Am J Med Genet A 2009; 149A:1980–2002. 2 Cluzeau C, Hadj-Rabia S, Jambou M et al. Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases. Hum Mutat 2011; 32:70– 2. 3 Laurikkala J, Pispa J, Jung HS et al. Regulation of hair follicle development by the TNF signal ectodysplasin and its receptor Edar. Development 2002; 129:2541–53. 4 Mustonen T, Ilmonen M, Pummila M et al. Ectodysplasin A1 promotes placodal cell fate during early morphogenesis of ectodermal appendages. Development 2004; 131:4907–19. 5 Pummila M, Fliniaux I, Jaatinen R et al. Ectodysplasin has a dual role in ectodermal organogenesis: inhibition of Bmp activity and induction of Shh expression. Development 2007; 134:117–25. 6 Hadj-Rabia S, Rimella A, Smahi A et al. Clinical and histologic features of incontinentia pigmenti in adults with nuclear factor-jB essential modulator gene mutations. J Am Acad Dermatol 2011; 64:508–15. 7 Clarke A, Phillips DI, Brown R, Harper PS. Clinical aspects of X-linked hypohidrotic ectodermal dysplasia. Arch Dis Child 1987; 62:989–96. 8 Vincent MC, Biancalana V, Ginisty D et al. Mutational spectrum of the ED1 gene in X-linked hypohidrotic ectodermal dysplasia. Eur J Hum Genet 2001; 9:355–63. 9 Megarbane H, Cluzeau C, Bodemer C et al. Unusual presentation of a severe autosomal recessive anhydrotic ectodermal dysplasia with a novel mutation in the EDAR gene. Am J Med Genet A 2008; 146A:2657–62. 10 Haghighi A, Nikuei P, Haghighi-Kakhki H et al. Whole-exome sequencing identifies a novel missense mutation in EDAR causing autosomal recessive hypohidrotic ectodermal dysplasia with bilat© 2014 British Association of Dermatologists
eral amastia and palmoplantar hyperkeratosis. Br J Dermatol 2013; 168:1353–6. 11 Voutilainen M, Lindfors PH, Lefebvre S et al. Ectodysplasin regulates hormone-independent mammary ductal morphogenesis via NF-jB. Proc Natl Acad Sci USA 2012; 109:5744–9. Funding sources: no external funding. Conflicts of interest: none declared.
The prevalence of hidradenitis suppurativa in 1093 patients with inflammatory bowel disease DOI: 10.1111/bjd.13002 DEAR EDITOR, Hidradenitis suppurativa (HS), also known as acne inversa, is an inflammatory skin disease characterized by painful nodules, abscesses and fistulas.1 The groin, axillae and buttocks are the most frequently affected skin areas.2 Diseaseassociated factors include smoking, obesity, mechanical friction, genetic predisposition, hormonal influences and an aberrant innate immune response.1 The main treatment options include systemic antibiotics, such as clindamycin with rifampicin, surgery, and in severe cases antitumour necrosis factor-a biologics.3 HS has a reported prevalence of up to 4%, although it was recently estimated at six per 100 000 in the U.S.A.4 Inflammatory bowel disease (IBD) is an umbrella term that includes Crohn disease (CD) and ulcerative colitis (UC). The prevalence rates of adult CD and UC in the U.S.A. are 0201% and 0238%, respectively.5 HS has been reported to co-occur with CD, with several case reports suggesting an association.6 Recently, we estimated the prevalence of HS at 16% in a cohort of 158 patients with IBD, and we provided a comparison between HS and IBD.6 We also suggested that an association might demonstrate a similar pathogenic mechanism providing new therapeutic options for HS.6 In this sequel study, we present the self-reported prevalence of HS and its disease characteristics in a large cohort of patients with IBD. Patients diagnosed with IBD in the Department of Gastroenterology of the Erasmus University Medical Center in Rotterdam, and members of the Dutch Crohn and Ulcerative Colitis Patients Association (CCUVN), were requested to fill in a questionnaire. This questionnaire was available in print in the hospital setting and online for members of the CCUVN. Firstly, patients with IBD provided general characteristics and information about their CD or UC. Next, they were asked whether or not they had recurrent painful boils in the axillae and or groin. When the answer was yes, three prototypical colour pictures of HS by Hurley severity stage were shown to enable the patient to self-assess their HS severity. Thereafter several questions about their HS followed. As the questionnaire was filled in anonymously, no medical ethical committee approval was required under Dutch law.
British Journal of Dermatology (2014) 171, pp657–678
674 Correspondence
In addition, we compared the characteristics of patients with IBD with HS with those of patients with regular HS (RHS).2 The mean age of onset of HS was 31 years, which is notably later than that of RHS, which was 221 years.2 Another striking difference with RHS was that most patients with IBD and HS did not smoke (77%), whereas smoking has been reported in 90% of patients with RHS.2 The mean BMI of the IBD + HS population was 263, which is comparable with 256 in RHS.2 Also, the reported familial prevalence of 24% was not much different from the 26% in RHS.2 The anatomical distribution of HS was also not notably different from that in RHS, although in RHS the axillae seem to be affected more frequently (69% vs. 44% in this study).2 Interestingly, the groin seemed to be less frequently affected in IBD + HS (52%) than in IBD + RHS (90%).2 We expected that the buttocks would be more frequently affected in IBD + HS than in RHS, as perianal fistulas are also a hallmark of CD. This was indeed the case, with values of 37% for HS vs. 27% for RHS in the literature.2 However, the perianal area was less affected in HS + IBD (27%) vs. RHS (37%).2 The severity of HS in IBD was similar to that of RHS. Hurley stage I disease in HS vs. RHS was reported in 82% vs. 68%, Hurley II in 15% vs. 28% and Hurley III in 3% vs. 4%, respectively.
The questionnaire was filled in by 1093 patients with IBD, of whom 909 replied online. In total 688 had CD (63%) and 405 (37%) had UC. Overall 255 patients with IBD reported having HS (23%), with 26% of those with CD and 18% of those with UC having HS (Table 1). The mean age of patients with IBD and HS was 42 years, and 77% of them were female. Their mean body mass index (BMI) was 263, and most of them (77%) did not smoke. The mean age of onset of IBD was 27 years and of HS, 31 years. In total 24% the patients with HS had a first- or second-degree family member with HS. The most frequently HS-affected body areas were the groin (52%), axillae (44%), buttocks (37%) upper legs (34%) and perianal region (27%). Most patients (82%) reported having mild disease (Hurley I), 15% reported having severe disease (Hurley II) and 3% very severe (Hurley III). This study shows a 23% prevalence of HS in patients with IBD. This is slightly higher than our previous estimate of 16% in a smaller population,6 but with a comparable distribution of the HS prevalence in CD and UC: 26% in CD and 18% in UC vs. 16% and 14%, respectively, reported earlier.6 Patients with IBD and comorbid HS developed their IBD 4 years prior to their HS. When we compare the CD + HS with the UC + HS populations (Table 1), patients with CD + HS tend to smoke more often (28% vs. 13%) and have more severe disease.
Table 1 Characteristics of patients with hidradenitis suppurativa (HS) with Crohn disease (CD) and ulcerative colitis (UC)
Age (years), mean SD Sex, % Male Female Age at onset of HS (years), mean SD Age at onset of IBD (years), mean SD BMI, mean SD Smoking, % No Yes Familial HS, %d Yes No Location, % Axillae Groin Legs Anus Buttocks Stomach Breasts Genitalia Other Severity, % Hurley I Hurley II Hurley III
IBD + HSa
n = 255
CD + HSb
n = 181
UC + HSc
n = 74
421 08
n = 255 n = 255
413 09
n = 181 n = 181
439 16
n = 74 n = 74
231 769 309 09 271 08 263 04
n n n n
= = = =
206 244 215 216
767 233
221 779 295 11 261 09 262 05
= = = =
143 175 149 149
718 282 n = 137
243 757
n = 99
n = 216
63 69 66 67
n = 38
n = 149
n = 67 45 51 33 24 33 21 16 1 7
n = 142 761 197 42
= = = =
29 71
443 523 349 282 388 161 154 54 107 n = 207
n n n n
87 13
23 77
442 516 344 270 367 177 158 42 98 815 151 34
n n n n
26 74 337 19 292 19 267 07
n = 65 92 6 2
IBD, irritable bowel disease; BMI, body mass index. a23% prevalence of HS in IBD; b26% prevalence of HS in CD; c18% prevalence of HS in UC; dfamilial HS is defined as a known case of HS in a first- or second-degree family member.
British Journal of Dermatology (2014) 171, pp657–678
© 2014 British Association of Dermatologists
Correspondence 675
A limitation of this study is that the diagnosis of HS was based on an unvalidated questionnaire that resembled a questionnaire used in a prevalence study in France.7 However, in our study, patients were additionally shown three clinical pictures of HS to improve accuracy. Nevertheless, an overestimation of HS prevalence cannot be excluded. In conclusion, this study suggests that HS frequently cooccurs with IBD. This probable association should be confirmed by physical examination of patients with IBD by an experienced dermatologist. 1
Department of Dermatology, Department of Gastroenterology and 3 Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands 2
H.H. VAN DER ZEE1 K. DE WINTER1 C.J. VAN DER WOUDE2 E.P. PRENS1,3
References 1 van der Zee HH, Laman JD, Boer J, Prens EP. Hidradenitis suppurativa: viewpoint on clinical phenotyping, pathogenesis and novel treatments. Exp Dermatol 2012; 21:735–9. 2 Canoui-Poitrine F, Revuz JE, Wolkenstein P et al. Clinical characteristics of a series of 302 French patients with hidradenitis suppurativa, with an analysis of factors associated with disease severity. J Am Acad Dermatol 2009; 61:51–7. 3 Jemec GB. Clinical practice. Hidradenitis suppurativa. N Engl J Med 2012; 366:158–64. 4 Vazquez BG, Alikhan A, Weaver AL et al. Incidence of hidradenitis suppurativa and associated factors: a population-based study of Olmsted County, Minnesota. J Invest Dermatol 2013; 133:97–103. 5 Kappelman MD, Rifas-Shiman SL, Kleinman K et al. The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States. Clin Gastroenterol Hepatol 2007; 5:1424–9. 6 van der Zee HH, van der Woude CJ, Florencia EF, Prens EP. Hidradenitis suppurativa and inflammatory bowel disease: are they associated? Results of a pilot study. Br J Dermatol 2010; 162:195–7. 7 Revuz JE, Canoui-Poitrine F, Wolkenstein P et al. Prevalence and factors associated with hidradenitis suppurativa: results from two case–control studies. J Am Acad Dermatol 2008; 59:596–601. Funding sources: none. Conflicts of interest: none declared.
Olmsted syndrome with erythromelalgia caused by recessive transient receptor potential vanilloid 3 mutations DOI: 10.1111/bjd.12951
DEAR EDITOR, Olmsted syndrome (OS; OMIM#614594) is a rare genodermatosis typically characterized by bilateral palmoplantar keratoderma and periorificial keratotic plaques, but showing considerable clinical heterogeneity.1–3 Reported cases of OS are mostly sporadic, although familial cases with different © 2014 British Association of Dermatologists
modes of inheritance have also been described. The gene most frequently mutated in OS is transient receptor potential vanilloid 3 (TRPV3), with several dominant heterozygous missense mutations; recently, a homozygous recessive mutation has been identified.4–8 A missense mutation in membrane-bound transcription factor protease, site 2 (MBTPS2) has also been implicated in X-linked recessive OS.9 We describe two patients from a French family with atypical OS. The family comprises two affected brothers (patients 1 and 2, aged 14 and 10 years old, respectively), and their two healthy parents. The parents are nonconsanguineous, which is suggestive of recessive inheritance. The clinical presentation of patient 1 included severe plantar keratoderma associated with intense erythromelalgia, which led to acute flares of hyperalgesia, severe itch, erythema, vasodilatation, and warmth of the legs and extremities (hands, feet and ears). These features first emerged at the age of 25 years, with keratosis distributed in islands on the pressure points and which extended to most of the plantar surface and thickened over time (Fig. 1a). Owing to plantar pain, the patient walked on his hands and knees, and developed pachyderma and keratosis pilaris on his knees. As a consequence, the use of a wheelchair became necessary. Plantar keratoderma was associated with severe erythromelalgia in this patient from the age of 4 years (Fig. 1b). The clinical features of patient 2 started earlier, at the age of 11 months, but were much milder and progressed slowly. Patient 2 presented with moderate and focal plantar keratoderma (Fig. 1c). Erythromelalgia, which was less severe than in his brother, started when he was 9 years old. Additionally, from the age of 4 years, patient 2 showed xerosis, eczema of the ears and blepharitis associated with the loss of his eyelashes. Eyelash trichomegaly was more pronounced in patient 2 than in patient 1 (Fig. 1d,e). While both patients had hyperhidrosis of the feet, thin and dry hair, and normal fingerand toenails, neither had mutilating plantar keratoderma or periorificial keratotic plaques, which are classically observed in OS. Therefore, the two affected siblings displayed significant differences in the clinical expression of the disease. Histological analysis of a skin biopsy from patient 1 revealed marked epidermal hyperplasia with papillomatosis, acanthosis and a thickened stratum granulosum covered by very thick and compact hyperkeratosis with areas of parakeratosis. Hypergranulosis alternated with foci of hypogranulosis. Keratinocytes occasionally showed vacuolar alterations with no epidermolytic features (Fig. 1f). The cutaneous features and clinical course of the disease were highly suggestive of OS. No mutation in SCN9A, which is defective in primary erythermalgia (OMIM #133020), was identified by sequencing.10 At the time the patients were referred to our laboratory, the genetic basis for OS was not known. Hence, we performed whole-exome sequencing (Appendix S1; see Supporting Information). We identified a heterozygous c.1702G > T variation (NM_001258205.1) in exon 13 of TRPV3, leading to p.Gly568Cys. TRPV3 encodes a nonselective, tetrameric cation channel, predominantly expressed in keratinocytes and sensory neurons, which is actiBritish Journal of Dermatology (2014) 171, pp657–678
published cases of female patients carrying an EDAR gene mutation (Table 1).9,10 Recently, the role of a unique TNF pathway in mammary gland morphogenesis has been identified. The EDA/EDAR/NF-jB pathway seems to be a driver of hormone-independent ductal growth and branching.11 Thus we may suggest that women presenting with breast or nipple anomalies associated, or not, with breastfeeding difficulties should have a dermatological examination to exclude HED/EDA. If warranted, genetic testing including MLPA might be proposed in at-risk patients. 1
Department of Dermatology, Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC) and 2 Laboratoire de diagnostic moleculaire, H^opital Universitaire Necker-Enfants Malades, Assistance Publique-H^opitaux de Paris, 149 rue de Sevres, FR-75015 Paris, France 3 Institut Imagine, Universite Paris Descartes – Sorbonne Paris Cite, Paris, France Correspondence: Smail Hadj-Rabia. E-mail: [email protected]
F. AL MARZOUQI1 C. MICHOT2,3 S. DOS SANTOS2 J.-P. BONNEFONT2,3 C. BODEMER1,3 S. HADJ-RABIA1,3
References 1 Visinoni AF, Lisboa-Costa T, Pagnan NA, Chautard-Freire-Maia EA. Ectodermal dysplasias: clinical and molecular review. Am J Med Genet A 2009; 149A:1980–2002. 2 Cluzeau C, Hadj-Rabia S, Jambou M et al. Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases. Hum Mutat 2011; 32:70– 2. 3 Laurikkala J, Pispa J, Jung HS et al. Regulation of hair follicle development by the TNF signal ectodysplasin and its receptor Edar. Development 2002; 129:2541–53. 4 Mustonen T, Ilmonen M, Pummila M et al. Ectodysplasin A1 promotes placodal cell fate during early morphogenesis of ectodermal appendages. Development 2004; 131:4907–19. 5 Pummila M, Fliniaux I, Jaatinen R et al. Ectodysplasin has a dual role in ectodermal organogenesis: inhibition of Bmp activity and induction of Shh expression. Development 2007; 134:117–25. 6 Hadj-Rabia S, Rimella A, Smahi A et al. Clinical and histologic features of incontinentia pigmenti in adults with nuclear factor-jB essential modulator gene mutations. J Am Acad Dermatol 2011; 64:508–15. 7 Clarke A, Phillips DI, Brown R, Harper PS. Clinical aspects of X-linked hypohidrotic ectodermal dysplasia. Arch Dis Child 1987; 62:989–96. 8 Vincent MC, Biancalana V, Ginisty D et al. Mutational spectrum of the ED1 gene in X-linked hypohidrotic ectodermal dysplasia. Eur J Hum Genet 2001; 9:355–63. 9 Megarbane H, Cluzeau C, Bodemer C et al. Unusual presentation of a severe autosomal recessive anhydrotic ectodermal dysplasia with a novel mutation in the EDAR gene. Am J Med Genet A 2008; 146A:2657–62. 10 Haghighi A, Nikuei P, Haghighi-Kakhki H et al. Whole-exome sequencing identifies a novel missense mutation in EDAR causing autosomal recessive hypohidrotic ectodermal dysplasia with bilat© 2014 British Association of Dermatologists
eral amastia and palmoplantar hyperkeratosis. Br J Dermatol 2013; 168:1353–6. 11 Voutilainen M, Lindfors PH, Lefebvre S et al. Ectodysplasin regulates hormone-independent mammary ductal morphogenesis via NF-jB. Proc Natl Acad Sci USA 2012; 109:5744–9. Funding sources: no external funding. Conflicts of interest: none declared.
The prevalence of hidradenitis suppurativa in 1093 patients with inflammatory bowel disease DOI: 10.1111/bjd.13002 DEAR EDITOR, Hidradenitis suppurativa (HS), also known as acne inversa, is an inflammatory skin disease characterized by painful nodules, abscesses and fistulas.1 The groin, axillae and buttocks are the most frequently affected skin areas.2 Diseaseassociated factors include smoking, obesity, mechanical friction, genetic predisposition, hormonal influences and an aberrant innate immune response.1 The main treatment options include systemic antibiotics, such as clindamycin with rifampicin, surgery, and in severe cases antitumour necrosis factor-a biologics.3 HS has a reported prevalence of up to 4%, although it was recently estimated at six per 100 000 in the U.S.A.4 Inflammatory bowel disease (IBD) is an umbrella term that includes Crohn disease (CD) and ulcerative colitis (UC). The prevalence rates of adult CD and UC in the U.S.A. are 0201% and 0238%, respectively.5 HS has been reported to co-occur with CD, with several case reports suggesting an association.6 Recently, we estimated the prevalence of HS at 16% in a cohort of 158 patients with IBD, and we provided a comparison between HS and IBD.6 We also suggested that an association might demonstrate a similar pathogenic mechanism providing new therapeutic options for HS.6 In this sequel study, we present the self-reported prevalence of HS and its disease characteristics in a large cohort of patients with IBD. Patients diagnosed with IBD in the Department of Gastroenterology of the Erasmus University Medical Center in Rotterdam, and members of the Dutch Crohn and Ulcerative Colitis Patients Association (CCUVN), were requested to fill in a questionnaire. This questionnaire was available in print in the hospital setting and online for members of the CCUVN. Firstly, patients with IBD provided general characteristics and information about their CD or UC. Next, they were asked whether or not they had recurrent painful boils in the axillae and or groin. When the answer was yes, three prototypical colour pictures of HS by Hurley severity stage were shown to enable the patient to self-assess their HS severity. Thereafter several questions about their HS followed. As the questionnaire was filled in anonymously, no medical ethical committee approval was required under Dutch law.
British Journal of Dermatology (2014) 171, pp657–678
674 Correspondence
In addition, we compared the characteristics of patients with IBD with HS with those of patients with regular HS (RHS).2 The mean age of onset of HS was 31 years, which is notably later than that of RHS, which was 221 years.2 Another striking difference with RHS was that most patients with IBD and HS did not smoke (77%), whereas smoking has been reported in 90% of patients with RHS.2 The mean BMI of the IBD + HS population was 263, which is comparable with 256 in RHS.2 Also, the reported familial prevalence of 24% was not much different from the 26% in RHS.2 The anatomical distribution of HS was also not notably different from that in RHS, although in RHS the axillae seem to be affected more frequently (69% vs. 44% in this study).2 Interestingly, the groin seemed to be less frequently affected in IBD + HS (52%) than in IBD + RHS (90%).2 We expected that the buttocks would be more frequently affected in IBD + HS than in RHS, as perianal fistulas are also a hallmark of CD. This was indeed the case, with values of 37% for HS vs. 27% for RHS in the literature.2 However, the perianal area was less affected in HS + IBD (27%) vs. RHS (37%).2 The severity of HS in IBD was similar to that of RHS. Hurley stage I disease in HS vs. RHS was reported in 82% vs. 68%, Hurley II in 15% vs. 28% and Hurley III in 3% vs. 4%, respectively.
The questionnaire was filled in by 1093 patients with IBD, of whom 909 replied online. In total 688 had CD (63%) and 405 (37%) had UC. Overall 255 patients with IBD reported having HS (23%), with 26% of those with CD and 18% of those with UC having HS (Table 1). The mean age of patients with IBD and HS was 42 years, and 77% of them were female. Their mean body mass index (BMI) was 263, and most of them (77%) did not smoke. The mean age of onset of IBD was 27 years and of HS, 31 years. In total 24% the patients with HS had a first- or second-degree family member with HS. The most frequently HS-affected body areas were the groin (52%), axillae (44%), buttocks (37%) upper legs (34%) and perianal region (27%). Most patients (82%) reported having mild disease (Hurley I), 15% reported having severe disease (Hurley II) and 3% very severe (Hurley III). This study shows a 23% prevalence of HS in patients with IBD. This is slightly higher than our previous estimate of 16% in a smaller population,6 but with a comparable distribution of the HS prevalence in CD and UC: 26% in CD and 18% in UC vs. 16% and 14%, respectively, reported earlier.6 Patients with IBD and comorbid HS developed their IBD 4 years prior to their HS. When we compare the CD + HS with the UC + HS populations (Table 1), patients with CD + HS tend to smoke more often (28% vs. 13%) and have more severe disease.
Table 1 Characteristics of patients with hidradenitis suppurativa (HS) with Crohn disease (CD) and ulcerative colitis (UC)
Age (years), mean SD Sex, % Male Female Age at onset of HS (years), mean SD Age at onset of IBD (years), mean SD BMI, mean SD Smoking, % No Yes Familial HS, %d Yes No Location, % Axillae Groin Legs Anus Buttocks Stomach Breasts Genitalia Other Severity, % Hurley I Hurley II Hurley III
IBD + HSa
n = 255
CD + HSb
n = 181
UC + HSc
n = 74
421 08
n = 255 n = 255
413 09
n = 181 n = 181
439 16
n = 74 n = 74
231 769 309 09 271 08 263 04
n n n n
= = = =
206 244 215 216
767 233
221 779 295 11 261 09 262 05
= = = =
143 175 149 149
718 282 n = 137
243 757
n = 99
n = 216
63 69 66 67
n = 38
n = 149
n = 67 45 51 33 24 33 21 16 1 7
n = 142 761 197 42
= = = =
29 71
443 523 349 282 388 161 154 54 107 n = 207
n n n n
87 13
23 77
442 516 344 270 367 177 158 42 98 815 151 34
n n n n
26 74 337 19 292 19 267 07
n = 65 92 6 2
IBD, irritable bowel disease; BMI, body mass index. a23% prevalence of HS in IBD; b26% prevalence of HS in CD; c18% prevalence of HS in UC; dfamilial HS is defined as a known case of HS in a first- or second-degree family member.
British Journal of Dermatology (2014) 171, pp657–678
© 2014 British Association of Dermatologists
Correspondence 675
A limitation of this study is that the diagnosis of HS was based on an unvalidated questionnaire that resembled a questionnaire used in a prevalence study in France.7 However, in our study, patients were additionally shown three clinical pictures of HS to improve accuracy. Nevertheless, an overestimation of HS prevalence cannot be excluded. In conclusion, this study suggests that HS frequently cooccurs with IBD. This probable association should be confirmed by physical examination of patients with IBD by an experienced dermatologist. 1
Department of Dermatology, Department of Gastroenterology and 3 Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands 2
H.H. VAN DER ZEE1 K. DE WINTER1 C.J. VAN DER WOUDE2 E.P. PRENS1,3
References 1 van der Zee HH, Laman JD, Boer J, Prens EP. Hidradenitis suppurativa: viewpoint on clinical phenotyping, pathogenesis and novel treatments. Exp Dermatol 2012; 21:735–9. 2 Canoui-Poitrine F, Revuz JE, Wolkenstein P et al. Clinical characteristics of a series of 302 French patients with hidradenitis suppurativa, with an analysis of factors associated with disease severity. J Am Acad Dermatol 2009; 61:51–7. 3 Jemec GB. Clinical practice. Hidradenitis suppurativa. N Engl J Med 2012; 366:158–64. 4 Vazquez BG, Alikhan A, Weaver AL et al. Incidence of hidradenitis suppurativa and associated factors: a population-based study of Olmsted County, Minnesota. J Invest Dermatol 2013; 133:97–103. 5 Kappelman MD, Rifas-Shiman SL, Kleinman K et al. The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States. Clin Gastroenterol Hepatol 2007; 5:1424–9. 6 van der Zee HH, van der Woude CJ, Florencia EF, Prens EP. Hidradenitis suppurativa and inflammatory bowel disease: are they associated? Results of a pilot study. Br J Dermatol 2010; 162:195–7. 7 Revuz JE, Canoui-Poitrine F, Wolkenstein P et al. Prevalence and factors associated with hidradenitis suppurativa: results from two case–control studies. J Am Acad Dermatol 2008; 59:596–601. Funding sources: none. Conflicts of interest: none declared.
Olmsted syndrome with erythromelalgia caused by recessive transient receptor potential vanilloid 3 mutations DOI: 10.1111/bjd.12951
DEAR EDITOR, Olmsted syndrome (OS; OMIM#614594) is a rare genodermatosis typically characterized by bilateral palmoplantar keratoderma and periorificial keratotic plaques, but showing considerable clinical heterogeneity.1–3 Reported cases of OS are mostly sporadic, although familial cases with different © 2014 British Association of Dermatologists
modes of inheritance have also been described. The gene most frequently mutated in OS is transient receptor potential vanilloid 3 (TRPV3), with several dominant heterozygous missense mutations; recently, a homozygous recessive mutation has been identified.4–8 A missense mutation in membrane-bound transcription factor protease, site 2 (MBTPS2) has also been implicated in X-linked recessive OS.9 We describe two patients from a French family with atypical OS. The family comprises two affected brothers (patients 1 and 2, aged 14 and 10 years old, respectively), and their two healthy parents. The parents are nonconsanguineous, which is suggestive of recessive inheritance. The clinical presentation of patient 1 included severe plantar keratoderma associated with intense erythromelalgia, which led to acute flares of hyperalgesia, severe itch, erythema, vasodilatation, and warmth of the legs and extremities (hands, feet and ears). These features first emerged at the age of 25 years, with keratosis distributed in islands on the pressure points and which extended to most of the plantar surface and thickened over time (Fig. 1a). Owing to plantar pain, the patient walked on his hands and knees, and developed pachyderma and keratosis pilaris on his knees. As a consequence, the use of a wheelchair became necessary. Plantar keratoderma was associated with severe erythromelalgia in this patient from the age of 4 years (Fig. 1b). The clinical features of patient 2 started earlier, at the age of 11 months, but were much milder and progressed slowly. Patient 2 presented with moderate and focal plantar keratoderma (Fig. 1c). Erythromelalgia, which was less severe than in his brother, started when he was 9 years old. Additionally, from the age of 4 years, patient 2 showed xerosis, eczema of the ears and blepharitis associated with the loss of his eyelashes. Eyelash trichomegaly was more pronounced in patient 2 than in patient 1 (Fig. 1d,e). While both patients had hyperhidrosis of the feet, thin and dry hair, and normal fingerand toenails, neither had mutilating plantar keratoderma or periorificial keratotic plaques, which are classically observed in OS. Therefore, the two affected siblings displayed significant differences in the clinical expression of the disease. Histological analysis of a skin biopsy from patient 1 revealed marked epidermal hyperplasia with papillomatosis, acanthosis and a thickened stratum granulosum covered by very thick and compact hyperkeratosis with areas of parakeratosis. Hypergranulosis alternated with foci of hypogranulosis. Keratinocytes occasionally showed vacuolar alterations with no epidermolytic features (Fig. 1f). The cutaneous features and clinical course of the disease were highly suggestive of OS. No mutation in SCN9A, which is defective in primary erythermalgia (OMIM #133020), was identified by sequencing.10 At the time the patients were referred to our laboratory, the genetic basis for OS was not known. Hence, we performed whole-exome sequencing (Appendix S1; see Supporting Information). We identified a heterozygous c.1702G > T variation (NM_001258205.1) in exon 13 of TRPV3, leading to p.Gly568Cys. TRPV3 encodes a nonselective, tetrameric cation channel, predominantly expressed in keratinocytes and sensory neurons, which is actiBritish Journal of Dermatology (2014) 171, pp657–678
