1442 Correspondence

and proliferation reaches the top of the epidermis. Inflammatory lesions appear, looking like papulopustular rosacea, with D at a deeper level but in decreasing numbers in comparison with noninflammatory lesions. To our knowledge, demodicosis is a very frequent disease3 and SSSB, even a single one, is wholly sufficient in daily clinical practice for diagnosis and follow-up. A second SSSB performed at the same place would highly increase the sensitivity of this method. However, RCM appears to be a more sensitive method which could be used more in research or clinical studies or to follow up treatment or recurrence. 1

Department of Skin & Cosmetic Research, Shanghai Skin Disease Hospital, Shanghai, China 2 Research and Studies Center on the Integument (CERT); Clinical Investigation Center (CIC BT506), Department of Dermatology, Besancßon University Hospital, University of Franche-Comte, 3, Boulevard Alexandre Fleming, Besancon, France 3 Skinexigence, Besancßon, France 4 San Gallicano Dermatological InstituteIRCCS, Rome, Italy Correspondence: Philippe Humbert. E-mail: [email protected]

C. YUAN1 X.-M. WANG1 A. GUICHARD2 T. LIHOREAU2 S. MAC-MARY3 L. KHYAT2 M . A R D I G O 4 P. HUMBERT2

References 1 Ayres S. Pityriasis folliculorum (Demodex). Arch Dermatol Syph 1930; 21:19–24. 2 Chen W, Plewig G. Human demodicosis: revisit and a proposed classification. Br J Dermatol 2014; 170:1219–25. 3 Forton F, Germaux MA, Brasseur T et al. Demodicosis and rosacea: epidemiology and significance in daily dermatologic practice. J Am Acad Dermatol 2005; 52:74–87. 4 Longo C, Pellacani G, Ricci C et al. In vivo detection of Demodex folliculorum by means of confocal microscopy. Br J Dermatol 2012; 166:690–2. 5 Forton F, Seys B. Density of Demodex folliculorum in rosacea: a case control-study using standardized skin-surface biopsy. Br J Dermatol 1993; 128:650–9. 6 Sattler EC, Maier T, Hoffmann VS et al. Noninvasive in vivo detection and quantification of Demodex mites by confocal laser scanning microscopy. Br J Dermatol 2012; 167:1042–7. 7 Kligman AM, Christensen MS. Demodex folliculorum: requirements for understanding its role in human skin disease. J Invest Dermatol 2011; 131:8–10. 8 Forton FM. Papulopustular rosacea, skin immunity and Demodex: pityriasis folliculorum as a missing link. J Eur Acad Dermatol Venereol 2012; 26:19–28. Funding sources: none. Conflicts of interest: none declared. C.Y. and X.M.W. contributed equally to this study and share first authorship.

British Journal of Dermatology (2015) 172, pp1436–1461

Myopathy in hereditary leiomyomatosis and renal cell cancer in an extended family DOI: 10.1111/bjd.13504 DEAR EDITOR, Fumarate hydratase (FH) catalyses the conversion of fumarate to malate as part of the tricarboxylic acid (TCA) cycle.1 Germline mutations in the FH gene may lead to autosomal recessive mutations causing FH deficiency (FHD),2 associated with neurological impairment in childhood and muscular hypotonia.3 Patients with heterozygous mutations may develop multiple cutaneous leiomyomas (CLs) and uterine leiomyomas (ULs), and they more frequently have type II papillary renal cell cancer (RCC) [hereditary leiomyomatosis and RCC (HLRCC)].4 In most patients with HLRCC the mutations in FH are located before codon 250, whereas in FHD these mutations usually develop after codon 250.5 Skeletal muscle obtains most of its energy production from the TCA cycle. Therefore it may be postulated that patients with FH mutations might also develop skeletal muscle clinical dysfunction. We describe two patients and an extended family with pain and skeletal muscle cramps (PSMC). Patient 1 is a 44-year-old woman who presented with a 2-year history of PSMC after exercise, with early muscle fatigue and morning stiffness. She was diagnosed as having fibromyalgia nonresponsive to treatment. She presented skin lesions diagnosed as CL (Fig. 1), nephrectomy due to a type II papillary RCC and a hysterectomy due to UL (III-11 in Fig. 2). Patient 2 is a 42-year-old man and a cousin of patient 1. He developed PSMC after exercise in a similar clinical presentation to patient 1, when he was 32 years old. Due to the presence of skeletal muscle findings identical to those of patient 1, an FH mutation was suspected. Neither CL nor RCC was found (III-19 in Fig. 2). Additionally, six more relatives presented with FH mutations. Four of them developed skeletal muscle symptoms at between 30 and 42 years of age, encompassing PSMC, early muscle fatigue and morning stiffness, similar to the symptoms observed in the proband (Fig. 2). CL, skeletal muscle and peripheral blood samples were obtained from the index case (III-11, Fig. 2). All exons and intronic splicing regions of the FH gene (NM_000143.3) were amplified by polymerase chain reaction from genomic DNA and sequenced with an ABI PrismTM 3130XL DNA Sequencer (Applied Biosystems, Foster City, CA, U.S.A.). A missense mutation (T>G transition) was detected in exon 4 of FH (c.419T>G, p.V140G) in all of the samples analysed from the index case (Fig. 3). Subsequently, we recommended analysis of this exon in all of the relatives at risk. Eight of the 14 relatives carried the same abnormality (Fig. 2). To the best of our knowledge, this mutation has not been previously described in the literature or in the Leiden Open Variation Database (http://chromium.liacs.nl/lovd_sdh/home.php? select_db=FH). © 2014 British Association of Dermatologists

Correspondence 1443

within the control group (patient 1, 20 nmol min 1 mg 1 protein and patient 2, 32 nmol min 1 mg 1 protein (control range 70–282 nmol min 1 mg 1 protein). No relevant decrease in the number or size of mitochondria was found by ultrastructural analyses of skeletal muscle. Based on the successful clinical response after treatment with L-carnitine (oral supplementation) in patients affected with metabolic myopathies, we decided to start treatment with carnitine (1 g per day) in both patients described and also in an aunt (patient II-6; Fig. 2), all of whom achieved total clinical remission of skeletal muscle symptoms within 2 months. All clinical and genetic findings in this family are shown in Figure 2. Patients with disorders associated with mitochondrial TCA cycle dysfunction may develop FHD1 or HLRCC.6 In these cases, the loss of FH function leads to elevated intracellular fumarate, causing stabilization of hypoxia-inducible factor7 (HIF, a protein implicated in the control of antiapoptotic and proliferative genes)8 and a metabolic shift to anaerobic glycolysis (the Warburg effect). These findings suggest a link between the loss of FH activity and tumorigenesis. ATP turnover and TCA cycle flux increase in skeletal muscle during exercise. Therefore, dysfunctions in the mitochondrial TCA cycle may produce changes in oxidative energy production, contributing to skeletal muscle manifestations. Patients

Fig 1. Cutaneous lesions. Patient 1 with multiple small erythematous and skin-coloured papules distributed on the right shoulder area. Similar isolated cutaneous lesions were found on the trunk and lower limbs.

We evaluated the frequency of the c. 419T>G mutation in 100 randomly selected controls. All of them carried the wildtype sequence at this codon, and any other changes in the exon 4 sequence were detected. Fumarate hydratase activity in the mitochondrial respiratory chain was measured spectrophotometrically in skeletal muscle and showed a level of activity 50% lower than the lowest value

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Fig 2. Pedigree of the family in this series. For individuals whose DNA samples were analysed, the same missense mutation (T>G transition) was detected in exon 4 of the fumarate hydratase (FH) gene (c.419T>G, p.V140G). In several members of this family genetic studies could not be performed (marked as ?). The index case (patient 1, III-11), patient 2 (III-19) and several relatives developed pain and skeletal muscle cramps (PSMC). Two relatives developed renal cell cancer (RCC). Those female patients who presented uterine leiomyoma (UL) and FH mutations (UL*) required hysterectomy. By contrast, female patients with UL and without FH mutation (UL) did not require hysterectomy. In most of the patients with FH mutations, cutaneous leiomyoma (CL) was found. BC, brain cancer; HC, head cancer. © 2014 British Association of Dermatologists

British Journal of Dermatology (2015) 172, pp1436–1461

1444 Correspondence

70

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Fig 3. Germline FH mutation. The same missense mutation (T>G transition) was detected in exon 4 of the FH gene (c.419T>G, p.V140G) from cutaneous leiomyoma of patient 1, and from peripheral blood samples obtained from both the index case (patient 1) and patient 2.

with FHD showing FH activity in skeletal muscle below 10% may develop muscular hypotonia.3 In this study, our patients showed low levels of FH activity in skeletal muscle that could explain the presence of myopathy. Moreover, several close relatives with the same FH mutation presented similar skeletal muscle symptoms after exercise in addition to CL and UL, and one more developed RCC (Fig. 2). The carnitine cycle is necessary to shuttle long-chain fatty acids from the cytosol into the intramitochondrial space, where mitochondrial b-oxidation of fatty acids takes place. It has been demonstrated that L-carnitine restores the skeletal muscle oxidative metabolic phenotype,9 providing successful clinical response in several metabolic myophathies.10 These findings may explain the successful treatment with L-carnitine in our patients. Overall, the penetrance of clinical manifestations in patients with FH mutations is high. In a cohort of 93 patients with FH mutation, 69% of women had both CL and UL, 15% had only CL, 7% had only UL and in 9% the mutation was apparently nonpenetrant.6 In our series of patients with FH mutations, 62% of the patients developed skeletal muscle symptoms after exercise, 100% of the women developed UL and required hysterectomy, and 75% presented CL. Only one patient was apparently nonpenetrant (Fig. 2). Taken together, our findings raise the question of whether myopathy may be part of the clinical phenotype in patients with HLRCC, as a tissue-specific British Journal of Dermatology (2015) 172, pp1436–1461

response due to HIF-1a activation.7,8 However, to date, no clinical skeletal muscle phenotype has been described in subjects with HLRCC. It is not clear how mutations in FH may produce two different clinical phenotypes (FHD and HLRCC). Perhaps some types of mutations (such as truncations/deletions or N-terminal changes) are under-represented in FHD because they have severe effects as homozygotes or compound heterozygotes, but are less severe in HLRCC.5 In summary, our results underscore the importance of skeletal muscle manifestations in patients with HLRCC. Nevertheless, as no families affected with HLRCC and myopathy have been reported so far, the skeletal muscle symptoms observed in our cases could be considered an exceptional possible feature in patients with FH mutation, or myopathy is a coincidental finding. Analysing more families affected by HLRCC will clarify this issue. Departments of 1Dermatology, 2 Rheumatology, 3Genetics and 4Oncology, University Clinic of Navarra, School of Medicine, University of Navarra, PO Box 4209, Pamplona 31080, Navarra, Spain 5 IBC-Seccio d’Errors Congenits del Metabolisme, Hospital Clınic, Consejo Superior de Investigaciones Cientıficas (CSIC)

A . E S P A N~ A 1 E. ORNILLA2 R. ZARATE3 I. GIL-BAZO4 P. BRIONES5

© 2014 British Association of Dermatologists

Correspondence 1445

y Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain E-mail: [email protected]

References 1 Briere JJ, Favier J, Gimenez-Roqueplo AP, Rustin P. Tricarboxylic acid cycle dysfunction as a cause of human diseases and tumor formation. Am J Physiol Cell Physiol 2006; 291:C1114–20. 2 Deschauer M, Gizatullina Z, Schulze A et al. Molecular and biochemical investigations in fumarase deficiency. Mol Genet Metab 2006; 88:146–52. 3 Ottolenghi C, Hubert L, Allanore Y et al. Clinical and biochemical heterogeneity associated with fumarase deficiency. Hum Mutat 2011; 32:1046–52. 4 Alam NA, Rowan AJ, Wortham NC et al. Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol Genet 2003; 12:1241–52. 5 Tomlinson IP, Alam NA, Rowan AJ et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002; 30:406–10. 6 Alam NA, Olpin S, Leigh IM. Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer. Br J Dermatol 2005; 153:11–17. 7 Lehtonen HJ. Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics. Fam Cancer 2011; 10:397–411. 8 Pollard PJ, Briere JJ, Alam NA et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1a in tumours which result from germline FH and SDH mutations. Hum Mol Genet 2005; 14:2231–9. 9 Rubio-Gozalbo ME, Bakker JA, Waterham HR, Wanders RJA. Carnitine-acylcarnitine translocase deficiency, clinical, biochemical and genetic aspects. Mol Aspects Med 2004; 25:521–32. 10 Nicolson GL, Ash ME. Lipid replacement therapy: a natural medicine approach to replacing damaged lipids in cellular membrane and organelles and restoring function. Biochim Biophys Acta 2014; 1838:1657–79. Funding sources: none. Conflicts of interest: none declared.

A quantitative assessment of ultraviolet radiation transmission through compression socks DOI: 10.1111/bjd.13541 DEAR EDITOR, The level of protection against ultraviolet radiation (UVR) afforded by commercially available compression socks is not widely presented in the literature. This was brought to our attention by a patient who was a very keen runner and who was required to wear compression socks. While the compression sock is designed to improve circulation © 2014 British Association of Dermatologists

in the legs and prevent the discomfort of varicose veins, we evaluated their status as protective accessories for patients who are undergoing laser therapy. For example, patients typically receive six individual laser treatments, with a 4–6-week interim period between each treatment, during which time they are advised to restrict sunlight exposure to the treated areas. Failure of the patient to manage their aftercare advice can have a significant negative impact on their treatment success. However, a patient’s quality of life can be profoundly affected by this treatment constraint and efforts should be made to improve their treatment management both inside and rather importantly outside of the clinic. Our objective was to measure the UVR transmission through a selection of compression socks that were readily available in a dermatology outpatient department. Our assessments enabled us to determine which sock should afford the best photoprotection1 of the lower legs. This information would be used to guide patients who wish to continue leading an active lifestyle, for example running, during the course of their treatment. We gathered nine common types of compression socks, Activaâ and Mediâ consisting of different compression classes, along with various sizes and colours (Table 1). Firstly, we measured the UVA radiation (315–400 nm) from a calibrated bank of six vertical Philips R-UVA 100 W fluorescence lamps using an IL1400 meter (International Light Technologies, Peabody, MA, U.S.A.) and a UVA detector positioned at a working distance of 30 cm inside a dressing applicator with a 12-cm diameter. The average UVA irradiance was 7
84 mW cm 2. Initially, no sock was placed over the dressing applicator and the UVA irradiance recorded served as the control. The fluorescence lamps were warmed up for 5 min before each irradiance measurement was recorded. Also, the lamps were allowed to cool down for 5 min between successive irradiance measurements. Each compression sock was placed in turn over the dressing applicator and in contact with the front face of the UVR detector (Fig. 1). The transmission of UVB irradiation (280– 315 nm) through the socks was also measured, only this time using six vertical calibrated Philips TL01 100 W fluorescence lamps and a UVB detector. The average UVB irradiance was 3
00 mW cm 2. Each sock measurement was repeated three times. Also, each sock was placed over the applicator for the duration of the 5-min lamp warm-up period with the detector reading recorded immediately at the 5-min time point. During the cool-down period the existing sock was replaced with the next sock. The percentage of UVA and UVB radiation blocked by each sock was then calculated from the irradiance measurements. We found that the class 3, large and extra extra large, sandcoloured socks provided the greatest UVB protection with 91% and 92%, respectively, and 90% UVA protection from both socks. The class 1 and 2, large black-coloured socks blocked 71% and 76% of UVB radiation and 63% and 71% of UVA radiation, respectively. The one-way ANOVA test revealed a significant difference between the class 3 sand-coloured socks and the black-coloured socks for UVB protection (P < 0
05) British Journal of Dermatology (2015) 172, pp1436–1461