1148 Correspondence
(a) 3
4
5
6
7
(b)
8
9
with a registered methyl-5-aminolaevulinate cream and placebo. Br J Dermatol 2012; 166:137–46. Steinbauer JM, Schreml S, Babilas P et al. Topical photodynamic therapy with porphyrin precursors – assessment of treatment-associated pain in a retrospective study. Photochem Photobiol Sci 2009; 8:1111–16. Attili SK, Dawe R, Ibbotson S. A review of pain during topical photodynamic therapy – our experience in Dundee. Photodiagnosis Photodyn Ther 2011; 8:53–7. Wiegell SR, Wulf HC, Szeimies RM et al. Daylight photodynamic therapy for actinic keratosis: an international consensus. J Eur Acad Dermatol Venereol 2012; 26:673–9. Wiegell SR, Fabricius S, Heydenreich J et al. Weather conditions and daylight-mediated photodynamic therapy: protoporphyrin IX-weighted daylight doses measured in six geographical locations. Br J Dermatol 2013; 168:186–91. Wiegell SR, Skodt V, Wulf HC. Daylight-mediated photodynamic therapy of basal cell carcinomas – an explorative study. J Eur Acad Dermatol Venereol 2013; DOI: 10.1111/jdv.12076 [Epub ahead of print]. Wiegell SR, Fabricius S, Stender IM et al. A randomized, multicentre study of directed daylight exposure times of 1½ vs. 2½ h in daylight-mediated photodynamic therapy with methyl aminolaevulinate in patients with multiple thin actinic keratoses of the face and scalp. Br J Dermatol 2011; 164:1083–90. Wiegell SR, Fabricius S, Gniadecka M et al. Daylight-mediated photodynamic therapy of moderate to thick actinic keratoses of the face and scalp: a randomized multicentre study. Br J Dermatol 2012; 166:1327–32.
Funding sources: none.
Fig 2. (a) Pain profiles during simulated-daylight photodynamic therapy (SDL-PDT). During the illumination phase pain was assessed at the indicated time points using an 11-point visual analogue scale (VAS). Pain scores were documented for all 32 patients in the first SDL-PDT session. Triangles represent the VAS of individual patients at the indicated time points. (b) Mean pain values during the first SDLPDT session. Values from (a) are summarized as mean values; error bars indicate SDs.
ment, we suggest performing prospective and controlled studies to investigate fully the potential benefits of SDL-PDT.
Acknowledgments We thank electrician John Dietz for the installation of the illumination system. Dermatology Center Bonn Friedensplatz, Bonn, Germany Correspondence: Uwe Reinhold. E-mail: [email protected]
C. KELLNER S. BAURIEDL S. HOLLSTEIN U. REINHOLD
References 1 Braathen LR, Szeimies RM, Basset-Seguin N et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. J Am Acad Dermatol 2007; 56:125–43. 2 Dirschka T, Radny P, Dominicus R. Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a multicentre, randomized, observer-blind phase III study in comparison
British Journal of Dermatology (2015) 172, pp1132–1164
Conflicts of interest: C.K. has received travel grants from Biofrontera. U.R. has received speaker honoraria from and is a consultant for Biofrontera.
Response of livedoid vasculopathy to rivaroxaban DOI: 10.1111/bjd.13428 DEAR EDITOR, We are writing in response to the article by Kerk et al.,1 ‘Rivaroxaban prevents painful cutaneous infarctions in livedoid vasculopathy’. At our institution, we have treated two additional patients with livedoid vasculopathy with rivaroxaban with similarly excellent results. Our first patient was a 52-year-old woman with an 8-year history of painful, recalcitrant ulcerations involving both lower extremities. The initial diagnosis was vasculitis, unsuccessfully treated with prednisone. A trial of warfarin led to improvement, but it was discontinued because of poor compliance and difficulty maintaining a therapeutic international normalized ratio. Ulcers and associated pain returned and worsened, restricting both her sleep and ability to complete daily ambulatory tasks. Topical moisturizing creams, corticosteroid creams and lidocaine patches were ineffective. On examination, tender, punched-out 1–2-mm stellate ulcerations were scattered on the lower extremities. Healed © 2014 British Association of Dermatologists
Correspondence 1149
ulcerations had the appearance of atrophie blanche. A background of venous pigmentation and bilateral leg oedema was also noted (Fig. 1, left). Punch biopsy showed dermal vessel thrombosis consistent with occlusive vasculopathy. Testing for hypercoagulation factors was negative. Venous studies demonstrated venous insufficiency. Pedal pulses were normal, and noninvasive vascular testing showed no evidence of large-vessel arterial disease. These findings indicated the diagnosis of ulcerations secondary to livedoid vasculopathy, with a component of venous insufficiency likely contributing. Our second patient was a 54-year-old woman with ulcers over her medial and lateral malleoli that healed spontaneously, leaving stellate white scars typical of atrophie blanche, followed by formation of new ulcers. Early moderately successful treatments included warfarin and fractionated and unfractionated low-molecular-weight heparin; however, the ulcers recurred and medications were discontinued. After courses of pentoxifylline, aspirin, triamcinolone cream with wet dressings, and prednisone failed, intravenous immunoglobulin use led to healing of most of her ulcers but little improvement in her pain. A panel of coagulation studies was positive for an elevated lipoprotein A level. Vascular testing showed normal PCO2 levels and mild venous insufficiency. Previous biopsy showed fibrin, thrombi and necrosis of the dermal vessel walls, supporting the diagnosis of livedoid vasculopathy. The patient continued to have severe pain and difficulty controlling her ulcers. Rivaroxaban was initiated in both patients (20 mg daily in the first patient, 10 mg daily in the second patient) and led to rapid improvement in both their pain and the size of their ulcers. The first patient’s pain resolved within 2 days, and the ulcers healed in 1 week. Her course was complicated by sleepiness, so rivaroxaban was discontinued as was pregabalin, which she had been taking for years previously without sleepiness. Her pain and ulcers recurred within a week. At her return appointment, rivaroxaban was restarted at 10 mg daily, which led to improvement in her pain and healing of her ulcers, albeit more slowly than they resolved with the previous 20-mg dose. When her dose was escalated to 20 mg
2 months later, her pain subsided completely; her ulcers, which had already cleared, did not return (Fig. 1, right); and she experienced no sleepiness. The second patient noted considerable relief in her pain and complete healing of her ulcers within 4 weeks of starting rivaroxaban 10 mg, and for the first time in years she was able to walk without severe limitation due to pain. Both patients believed that rivaroxaban relieved their symptoms better than previous medications. The improvement with rivaroxaban in these patients substantiates the report of Kerk et al.1 Evidence shows that livedoid vasculopathy results from vaso-occlusion that causes thrombosis of dermal blood vessels, resulting in tissue ischaemia and pain.2 Studies of patients with livedoid vasculopathy have investigated the role of prothrombotic mediators and have shown a high incidence of anticardiolipin antibodies and lupus anticoagulant, increased levels of plasminogen activator inhibitor and low levels of endogenous tissue plasminogen activator.3 Livedoid vasculopathy frequently develops in patients with hypercoagulation syndromes such as factor V Leiden gene mutation, prothrombin G20210A, and protein C and S deficiency, and there is an association between livedoid vasculopathy and medical diseases with hypercoagulable syndromes.4 Investigators have subsequently used anticoagulants such as subcutaneous heparin, warfarin and tissue plasminogen activator with some success.5,6 These medications are difficult to administer or require frequent monitoring, which may decrease patient compliance. After the three patients successfully treated by Kerk et al.,1 our two patients are the fourth and fifth reported patients with livedoid vasculopathy treated with rivaroxaban, an oral factor Xa inhibitor. Given the ease of administration and the fact that no laboratory monitoring is required, rivaroxaban may be a promising treatment for patients with livedoid vasculopathy. However, care should be taken because haemorrhage is a risk. In the first patient, sleepiness may have resulted from the combination of rivaroxaban with pregabalin; sleepiness has not been reported with rivaroxaban. Further studies should elucidate the use of rivaroxaban in livedoid vasculopathy, as well as sleepiness as an adverse effect, especially at doses higher than 10 mg.
Fig 1. Left, our first patient before initiation of rivaroxaban. Note the many small ulcers. Right, at 5 weeks after restarting rivaroxaban, 10 mg daily. © 2014 British Association of Dermatologists
British Journal of Dermatology (2015) 172, pp1132–1164
1150 Correspondence
Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, U.S.A Correspondence: Mark D.P. Davis. E-mail: [email protected]
D.S. WINCHESTER L.A. DRAGE M.D.P. DAVIS
References 1 Kerk N, Drabik A, Luger TA et al. Rivaroxaban prevents painful cutaneous infarctions in livedoid vasculopathy. Br J Dermatol 2013; 168:898–9. 2 Hairston BR, Davis MD, Pittelkow MR, Ahmed I. Livedoid vasculopathy: further evidence for procoagulant pathogenesis. Arch Dermatol 2006; 142:1413–18. 3 Klein KL, Pittelkow MR. Tissue plasminogen activator for treatment of livedoid vasculitis. Mayo Clin Proc 1992; 67:923–33. 4 Prins MH, Lensing AW, Bauersachs R et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013; 11:21. 5 Hairston BR, Davis MD, Gibson LE, Drage LA. Treatment of livedoid vasculopathy with low-molecular-weight heparin: report of two cases. Arch Dermatol 2003; 139:987–90. 6 Davis MD, Wysokinski WE. Ulcerations caused by livedoid vasculopathy associated with a prothrombotic state: response to warfarin. J Am Acad Dermatol 2008; 58:512–15. Funding sources: none. Conflicts of interest: none declared.
A novel locus for primary focal hyperhidrosis mapped on chromosome 2q31.1 DOI: 10.1111/bjd.13383 DEAR EDITOR, Primary focal hyperhidrosis (PFH) is a disorder characterized by excessive sweating in specific body areas such as the palm, sole and axillae beyond physiological need, leading to severe psychological, social and occupational dysfunction.1,2 The cause of primary hyperhidrosis still remains unclear. It seems to be associated with neurohumoral or secretory cell metabolic abnormalities, but without structural defects in the sweat glands.3 Much evidence implies that PFH could be a genetic disorder with an autosomal dominant mode of transmission, incomplete penetrance and variable phenotype.4,5 Only one PFH locus has been mapped to chromosome 14q11.2–q13, but no disease-causing gene has been identified.6 A six-generation family with clinically diagnosed PFH originated from Fuzhou City, Fujian province of Southeast China. The pedigree shows that the disease is inherited as an autosomal dominant trait (Fig. 1). Twenty-one family members including 11 affected individuals (seven classified as severe, three as moderate, and one as mild) participated in this study. As well as the palms, other anatomic areas includBritish Journal of Dermatology (2015) 172, pp1132–1164
ing the soles and/or axillae can also be affected in some patients. The mean age of onset was about 8 (range 3–12) years. The excessive perspiration of clinical symptoms decreases with age after around 50 years of age. Two patients (V:4 and V:6) have undergone bilateral endoscopic thoracic sympathectomy (ETS), and were satisfied with the operative results. Linkage to the known PFH locus on chromosome 14q11.2– q13 was excluded by genotyping and linkage analysis with five microsatellite markers (D14S261, D14S283, D14S275, D14S70 and D14S288) in our family. Subsequently, the genome-wide single-nucleotide polymorphism (SNP) linkage analysis was performed using the Genome-Wide Human SNP Array 6.0. No linkage was found for most chromosomal regions except for a large contiguous region located on chromosome 2q22.1–q31.1 (Fig. 2). The boundaries of the locus, encompassing a 3678-Mb region, were determined by SNP exclusion between SNPs rs3113209 and rs10930685. The potential linkage region could be composed of two intervals: one weaker linkage of a 3126-Mb region flanked by SNPs rs12999055 and rs4668136 with heterogeneity LOD (HLOD) score 0772–1142, another significant evidence of linkage of a 459-Mb region between SNPs rs2683451 and rs643346 on chromosome 2q31.1 with HLOD score 2236–3033 (Fig. 2). The copy number variation (CNV) analysis of the whole genome indicated that CNV was not significantly associated with the hyperhidrosis phenotype. To confirm the genome-wide SNP linkage scan and define the critical region, microsatellite genotyping was performed with 11 microsatellite markers from the same chromosome region. Haplotype analysis showed that all patients and one unaffected carrier (V:8) shared the common haplotype, suggesting that disease penetration is incomplete in this family (Fig. 1). The boundaries of the region were determined by recombination events that occurred in affected individuals IV:7, V:4, V:6, VI:1 and healthy individual V:1. The proximal boundary was defined by the recombination event between markers D2S1776 and D2S376 in healthy individual V:1 and affected individual V:6, while the distal boundary was determined by the recombination event between D2S2188 and D2S2381 in affected individuals IV:7, V:4, V:6 and VI:1 (Fig. 1). The linkage analysis led us to obtain a maximum two-point LOD score of 3397 at recombination fraction (h) = 0 for D2S2177. The markers D2S1776, D2S2188 and D2S2981, outside the locus, gave negative LOD scores (Table 1). Combining the SNP and microsatellite marker data, therefore, proximal and distal boundaries of a 594-Mb locus linked to PFH were delimited by D2S1776 and SNP rs10930685 on chromosome 2q31.1, respectively (Fig. 2). The linked genomic area contains 72 annotated genes based on a human genome view (NCBI Homo sapiens Annotation Release 106, 2014). Three candidate genes, DYNC1I2, DLX1 and PDK1 within the mapped interval, were sequenced, but no putative mutations were detected. Subsequently, we performed the whole-exome sequencing analysis for three family members including two affected individuals. Unfortunately, this © 2014 British Association of Dermatologists
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
(a) 3
4
5
6
7
(b)
8
9
with a registered methyl-5-aminolaevulinate cream and placebo. Br J Dermatol 2012; 166:137–46. Steinbauer JM, Schreml S, Babilas P et al. Topical photodynamic therapy with porphyrin precursors – assessment of treatment-associated pain in a retrospective study. Photochem Photobiol Sci 2009; 8:1111–16. Attili SK, Dawe R, Ibbotson S. A review of pain during topical photodynamic therapy – our experience in Dundee. Photodiagnosis Photodyn Ther 2011; 8:53–7. Wiegell SR, Wulf HC, Szeimies RM et al. Daylight photodynamic therapy for actinic keratosis: an international consensus. J Eur Acad Dermatol Venereol 2012; 26:673–9. Wiegell SR, Fabricius S, Heydenreich J et al. Weather conditions and daylight-mediated photodynamic therapy: protoporphyrin IX-weighted daylight doses measured in six geographical locations. Br J Dermatol 2013; 168:186–91. Wiegell SR, Skodt V, Wulf HC. Daylight-mediated photodynamic therapy of basal cell carcinomas – an explorative study. J Eur Acad Dermatol Venereol 2013; DOI: 10.1111/jdv.12076 [Epub ahead of print]. Wiegell SR, Fabricius S, Stender IM et al. A randomized, multicentre study of directed daylight exposure times of 1½ vs. 2½ h in daylight-mediated photodynamic therapy with methyl aminolaevulinate in patients with multiple thin actinic keratoses of the face and scalp. Br J Dermatol 2011; 164:1083–90. Wiegell SR, Fabricius S, Gniadecka M et al. Daylight-mediated photodynamic therapy of moderate to thick actinic keratoses of the face and scalp: a randomized multicentre study. Br J Dermatol 2012; 166:1327–32.
Funding sources: none.
Fig 2. (a) Pain profiles during simulated-daylight photodynamic therapy (SDL-PDT). During the illumination phase pain was assessed at the indicated time points using an 11-point visual analogue scale (VAS). Pain scores were documented for all 32 patients in the first SDL-PDT session. Triangles represent the VAS of individual patients at the indicated time points. (b) Mean pain values during the first SDLPDT session. Values from (a) are summarized as mean values; error bars indicate SDs.
ment, we suggest performing prospective and controlled studies to investigate fully the potential benefits of SDL-PDT.
Acknowledgments We thank electrician John Dietz for the installation of the illumination system. Dermatology Center Bonn Friedensplatz, Bonn, Germany Correspondence: Uwe Reinhold. E-mail: [email protected]
C. KELLNER S. BAURIEDL S. HOLLSTEIN U. REINHOLD
References 1 Braathen LR, Szeimies RM, Basset-Seguin N et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. J Am Acad Dermatol 2007; 56:125–43. 2 Dirschka T, Radny P, Dominicus R. Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a multicentre, randomized, observer-blind phase III study in comparison
British Journal of Dermatology (2015) 172, pp1132–1164
Conflicts of interest: C.K. has received travel grants from Biofrontera. U.R. has received speaker honoraria from and is a consultant for Biofrontera.
Response of livedoid vasculopathy to rivaroxaban DOI: 10.1111/bjd.13428 DEAR EDITOR, We are writing in response to the article by Kerk et al.,1 ‘Rivaroxaban prevents painful cutaneous infarctions in livedoid vasculopathy’. At our institution, we have treated two additional patients with livedoid vasculopathy with rivaroxaban with similarly excellent results. Our first patient was a 52-year-old woman with an 8-year history of painful, recalcitrant ulcerations involving both lower extremities. The initial diagnosis was vasculitis, unsuccessfully treated with prednisone. A trial of warfarin led to improvement, but it was discontinued because of poor compliance and difficulty maintaining a therapeutic international normalized ratio. Ulcers and associated pain returned and worsened, restricting both her sleep and ability to complete daily ambulatory tasks. Topical moisturizing creams, corticosteroid creams and lidocaine patches were ineffective. On examination, tender, punched-out 1–2-mm stellate ulcerations were scattered on the lower extremities. Healed © 2014 British Association of Dermatologists
Correspondence 1149
ulcerations had the appearance of atrophie blanche. A background of venous pigmentation and bilateral leg oedema was also noted (Fig. 1, left). Punch biopsy showed dermal vessel thrombosis consistent with occlusive vasculopathy. Testing for hypercoagulation factors was negative. Venous studies demonstrated venous insufficiency. Pedal pulses were normal, and noninvasive vascular testing showed no evidence of large-vessel arterial disease. These findings indicated the diagnosis of ulcerations secondary to livedoid vasculopathy, with a component of venous insufficiency likely contributing. Our second patient was a 54-year-old woman with ulcers over her medial and lateral malleoli that healed spontaneously, leaving stellate white scars typical of atrophie blanche, followed by formation of new ulcers. Early moderately successful treatments included warfarin and fractionated and unfractionated low-molecular-weight heparin; however, the ulcers recurred and medications were discontinued. After courses of pentoxifylline, aspirin, triamcinolone cream with wet dressings, and prednisone failed, intravenous immunoglobulin use led to healing of most of her ulcers but little improvement in her pain. A panel of coagulation studies was positive for an elevated lipoprotein A level. Vascular testing showed normal PCO2 levels and mild venous insufficiency. Previous biopsy showed fibrin, thrombi and necrosis of the dermal vessel walls, supporting the diagnosis of livedoid vasculopathy. The patient continued to have severe pain and difficulty controlling her ulcers. Rivaroxaban was initiated in both patients (20 mg daily in the first patient, 10 mg daily in the second patient) and led to rapid improvement in both their pain and the size of their ulcers. The first patient’s pain resolved within 2 days, and the ulcers healed in 1 week. Her course was complicated by sleepiness, so rivaroxaban was discontinued as was pregabalin, which she had been taking for years previously without sleepiness. Her pain and ulcers recurred within a week. At her return appointment, rivaroxaban was restarted at 10 mg daily, which led to improvement in her pain and healing of her ulcers, albeit more slowly than they resolved with the previous 20-mg dose. When her dose was escalated to 20 mg
2 months later, her pain subsided completely; her ulcers, which had already cleared, did not return (Fig. 1, right); and she experienced no sleepiness. The second patient noted considerable relief in her pain and complete healing of her ulcers within 4 weeks of starting rivaroxaban 10 mg, and for the first time in years she was able to walk without severe limitation due to pain. Both patients believed that rivaroxaban relieved their symptoms better than previous medications. The improvement with rivaroxaban in these patients substantiates the report of Kerk et al.1 Evidence shows that livedoid vasculopathy results from vaso-occlusion that causes thrombosis of dermal blood vessels, resulting in tissue ischaemia and pain.2 Studies of patients with livedoid vasculopathy have investigated the role of prothrombotic mediators and have shown a high incidence of anticardiolipin antibodies and lupus anticoagulant, increased levels of plasminogen activator inhibitor and low levels of endogenous tissue plasminogen activator.3 Livedoid vasculopathy frequently develops in patients with hypercoagulation syndromes such as factor V Leiden gene mutation, prothrombin G20210A, and protein C and S deficiency, and there is an association between livedoid vasculopathy and medical diseases with hypercoagulable syndromes.4 Investigators have subsequently used anticoagulants such as subcutaneous heparin, warfarin and tissue plasminogen activator with some success.5,6 These medications are difficult to administer or require frequent monitoring, which may decrease patient compliance. After the three patients successfully treated by Kerk et al.,1 our two patients are the fourth and fifth reported patients with livedoid vasculopathy treated with rivaroxaban, an oral factor Xa inhibitor. Given the ease of administration and the fact that no laboratory monitoring is required, rivaroxaban may be a promising treatment for patients with livedoid vasculopathy. However, care should be taken because haemorrhage is a risk. In the first patient, sleepiness may have resulted from the combination of rivaroxaban with pregabalin; sleepiness has not been reported with rivaroxaban. Further studies should elucidate the use of rivaroxaban in livedoid vasculopathy, as well as sleepiness as an adverse effect, especially at doses higher than 10 mg.
Fig 1. Left, our first patient before initiation of rivaroxaban. Note the many small ulcers. Right, at 5 weeks after restarting rivaroxaban, 10 mg daily. © 2014 British Association of Dermatologists
British Journal of Dermatology (2015) 172, pp1132–1164
1150 Correspondence
Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, U.S.A Correspondence: Mark D.P. Davis. E-mail: [email protected]
D.S. WINCHESTER L.A. DRAGE M.D.P. DAVIS
References 1 Kerk N, Drabik A, Luger TA et al. Rivaroxaban prevents painful cutaneous infarctions in livedoid vasculopathy. Br J Dermatol 2013; 168:898–9. 2 Hairston BR, Davis MD, Pittelkow MR, Ahmed I. Livedoid vasculopathy: further evidence for procoagulant pathogenesis. Arch Dermatol 2006; 142:1413–18. 3 Klein KL, Pittelkow MR. Tissue plasminogen activator for treatment of livedoid vasculitis. Mayo Clin Proc 1992; 67:923–33. 4 Prins MH, Lensing AW, Bauersachs R et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013; 11:21. 5 Hairston BR, Davis MD, Gibson LE, Drage LA. Treatment of livedoid vasculopathy with low-molecular-weight heparin: report of two cases. Arch Dermatol 2003; 139:987–90. 6 Davis MD, Wysokinski WE. Ulcerations caused by livedoid vasculopathy associated with a prothrombotic state: response to warfarin. J Am Acad Dermatol 2008; 58:512–15. Funding sources: none. Conflicts of interest: none declared.
A novel locus for primary focal hyperhidrosis mapped on chromosome 2q31.1 DOI: 10.1111/bjd.13383 DEAR EDITOR, Primary focal hyperhidrosis (PFH) is a disorder characterized by excessive sweating in specific body areas such as the palm, sole and axillae beyond physiological need, leading to severe psychological, social and occupational dysfunction.1,2 The cause of primary hyperhidrosis still remains unclear. It seems to be associated with neurohumoral or secretory cell metabolic abnormalities, but without structural defects in the sweat glands.3 Much evidence implies that PFH could be a genetic disorder with an autosomal dominant mode of transmission, incomplete penetrance and variable phenotype.4,5 Only one PFH locus has been mapped to chromosome 14q11.2–q13, but no disease-causing gene has been identified.6 A six-generation family with clinically diagnosed PFH originated from Fuzhou City, Fujian province of Southeast China. The pedigree shows that the disease is inherited as an autosomal dominant trait (Fig. 1). Twenty-one family members including 11 affected individuals (seven classified as severe, three as moderate, and one as mild) participated in this study. As well as the palms, other anatomic areas includBritish Journal of Dermatology (2015) 172, pp1132–1164
ing the soles and/or axillae can also be affected in some patients. The mean age of onset was about 8 (range 3–12) years. The excessive perspiration of clinical symptoms decreases with age after around 50 years of age. Two patients (V:4 and V:6) have undergone bilateral endoscopic thoracic sympathectomy (ETS), and were satisfied with the operative results. Linkage to the known PFH locus on chromosome 14q11.2– q13 was excluded by genotyping and linkage analysis with five microsatellite markers (D14S261, D14S283, D14S275, D14S70 and D14S288) in our family. Subsequently, the genome-wide single-nucleotide polymorphism (SNP) linkage analysis was performed using the Genome-Wide Human SNP Array 6.0. No linkage was found for most chromosomal regions except for a large contiguous region located on chromosome 2q22.1–q31.1 (Fig. 2). The boundaries of the locus, encompassing a 3678-Mb region, were determined by SNP exclusion between SNPs rs3113209 and rs10930685. The potential linkage region could be composed of two intervals: one weaker linkage of a 3126-Mb region flanked by SNPs rs12999055 and rs4668136 with heterogeneity LOD (HLOD) score 0772–1142, another significant evidence of linkage of a 459-Mb region between SNPs rs2683451 and rs643346 on chromosome 2q31.1 with HLOD score 2236–3033 (Fig. 2). The copy number variation (CNV) analysis of the whole genome indicated that CNV was not significantly associated with the hyperhidrosis phenotype. To confirm the genome-wide SNP linkage scan and define the critical region, microsatellite genotyping was performed with 11 microsatellite markers from the same chromosome region. Haplotype analysis showed that all patients and one unaffected carrier (V:8) shared the common haplotype, suggesting that disease penetration is incomplete in this family (Fig. 1). The boundaries of the region were determined by recombination events that occurred in affected individuals IV:7, V:4, V:6, VI:1 and healthy individual V:1. The proximal boundary was defined by the recombination event between markers D2S1776 and D2S376 in healthy individual V:1 and affected individual V:6, while the distal boundary was determined by the recombination event between D2S2188 and D2S2381 in affected individuals IV:7, V:4, V:6 and VI:1 (Fig. 1). The linkage analysis led us to obtain a maximum two-point LOD score of 3397 at recombination fraction (h) = 0 for D2S2177. The markers D2S1776, D2S2188 and D2S2981, outside the locus, gave negative LOD scores (Table 1). Combining the SNP and microsatellite marker data, therefore, proximal and distal boundaries of a 594-Mb locus linked to PFH were delimited by D2S1776 and SNP rs10930685 on chromosome 2q31.1, respectively (Fig. 2). The linked genomic area contains 72 annotated genes based on a human genome view (NCBI Homo sapiens Annotation Release 106, 2014). Three candidate genes, DYNC1I2, DLX1 and PDK1 within the mapped interval, were sequenced, but no putative mutations were detected. Subsequently, we performed the whole-exome sequencing analysis for three family members including two affected individuals. Unfortunately, this © 2014 British Association of Dermatologists
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
