Skin features in myotonic dystrophy type 1: An observational study

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ScienceDirect Neuromuscular Disorders 25 (2015) 409–413 www.elsevier.com/locate/nmd

Skin features in myotonic dystrophy type 1: An observational study A. Campanati a,*,1, M. Giannoni a,1, L. Buratti b, C. Cagnetti b, K. Giuliodori a, G. Ganzetti a, M. Silvestrini b, L. Provinciali b, A. Offidani a a

Dermatological Clinic, Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy b Neurological Clinic, Department of Neurosciences, Marche Polytechnic University, Ancona, Italy Received 16 October 2014; received in revised form 17 February 2015; accepted 27 February 2015

Abstract Poor data regarding skin involvement in Myotonic Dystrophy, also named Dystrophia Myotonica type 1, have been reported. This study aimed to investigate the prevalence and types of skin disorders in adult patients with Myotonic Dystrophy type 1. Fifty-five patients and one hundred age- and sex-matched healthy subjects were referred to a trained dermatologist for a complete skin examination to check for potential cutaneous hallmarks of disease. No difference in prevalence of preneoplastic, neoplastic, and cutaneous lesions was detected between the two groups. Among morphofunctional, proliferative and inflammatory lesions, focal hyperhidrosis (p < 0.0001), follicular hyperkeratosis (p = 0.0003), early androgenic alopecia (p = 0.01), nail pitting (p = 0.003), pedunculus fibromas (p = 0. 01), twisted hair (p = 0.01), seborrheic dermatitis (p = 0.02), macules of hyperpigmentation (p = 0.03) were significantly more frequent in patients compared with controls. In patients with Myotonic Dystrophy type 1 significant differences according to sex were found for: early androgenic alopecia, twisted hair and seborrheic dermatitis, whose prevalence was higher in males (p < 0.0001). Our preliminary results seem to rule out an increased prevalence of pre-neoplastic, and neoplastic skin lesions in Myotonic Dystrophy type 1. On the other hand, an increased prevalence of morphofunctional, inflammatory, and proliferative diseases involving adnexal structures seems to characterize adult patients with Myotonic Dystrophy type 1. © 2015 Elsevier B.V. All rights reserved. Keywords: Myotonic dystrophy; Dystrophia myotonica type 1; Skin; Steinert’s syndrome; Cutaneous involvement

1. Introduction Myotonic Dystrophy or Dystrophia Myotonica type 1 (DM1) is the most frequent muscular dystrophy in adults, with an incidence of approximately 1 in 8000 people [1]. It is an inherited disorder with an autosomal dominant modality, characterized by multisystem clinical manifestations involving skeletal muscles (weakness and myotonia), eyes (early bilateral cataract), heart (conduction abnormalities), central nervous system (excessive daytime sleepiness and apathy in adults as well as learning difficulties with autism in the congenital form), gonads (atrophy and infertility), endocrine system (diabetes mellitus, thyroid dysfunction), smooth muscles (swallowing difficulty, constipation) and, to a lesser extent, also other organs. The

* Corresponding author. Dermatological Clinic, Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy. Tel.: +39 0715965358; fax: +39 0715963446. E-mail address: [email protected]; [email protected] (A. Campanati). 1 The two authors equally contributed to the manuscript. http://dx.doi.org/10.1016/j.nmd.2015.02.013 0960-8966/© 2015 Elsevier B.V. All rights reserved.

involvement of several different anatomical systems can lead to a wide variability in phenotypic presentation [2]. DM1 is due to dystrophia myotonica protein kinase (DMPK) gene mutation, leading to an amplification of an unstable trinucleotide (CTG) repeated in the 3′-untranslated region of chromosome 19q13.3, which accumulates in the nucleus in ribonuclear inclusions. Splicing factors accumulate within the inclusions, and this impairs pre-mRNA splicing. This is responsible for the widespread cellular effects which cause clinical features in many organ systems [1,3]. Based on these pathogenic considerations, cutaneous involvement in DM1 could be expected. However, poor data about skin involvement have been reported, mainly regarding androgenic alopecia [4] and pilomatricomas, resulting from the role of DMPK in calcium regulation [5]. Moreover, skin usually represents a target organ for several diseases with genetic background (genodermatoses) [6–8]. Thus, the identification of new skin hallmark of DM1 could help clinicians to characterize the phenotypic spectrum of the disease [9]. Accordingly, the aim of this study was to investigate the prevalence and characterization of skin disorders in a group of patients affected by DM1.

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This is an observational, cross-sectional study approved by the Local Ethical Committee of Marche Polytechnic University and conducted in accordance to the principles of the Helsinki Declaration and the International Conference of Harmonization – Good Clinical Practice. All subjects gave their signed informed consent for participation.

for non-melanoma or melanoma skin cancer was assessed by asking the patients and controls the following question: “Have your first-degree relatives ever had or do they have any skin tumour?” – to evaluate the correlation between DM1 severity and the degree of skin involvement. Nucleotide (CTG or CCTG) repeat expansion size was included in the analysis and correlated with the number of skin lesions detected, when the DNA testing results were available.

2.2. Study population

2.4. Statistical analyses

55 Caucasian patients, affected by genetically confirmed DM1 and suffering from a different grade of disease severity, according to Muscular Impairment Rating Scale (MIRS) [10], were referred to the outpatients service of the Dermatological Clinic from the Neurological Clinic of the University Hospital of Ancona and consecutively recruited between May 2011 and December 2012. Thirty-five were males and 20 females, and their ages ranged between 21 and 64 years (average: 48.86 years). One hundred Caucasian patients were used as control group. They were matched for age and sex, belonged to the same geographical area, and observed in the Dermatological Clinic during the same period in our “outpatient department for melanoma screening” for the routine clinical control of melanocytic nevi. None of the patients selected as controls had received a previous diagnosis for melanoma and non-melanoma skin cancer. Moreover, they were not at higher risk for melanoma and non-melanoma skin cancer compared to the general population in terms of sun exposure, familiarity and phototype.

Subjects were analysed according to their skin features. Results for qualitative variables were expressed as absolute and percent frequencies in contingency tables. Differences between groups were evaluated using the Chi-square test for qualitative variables. Linear regression was used to model the relationship between the variables. A level of significance was set up at 0.05. All data were evaluated through the GraphPad Prism 5 software.

2. Materials and methods 2.1. Design of the study

2.3. Procedure The primary outcome of the study was to evaluate the prevalence of neoplastic (melanoma and non-melanoma skin cancer), preneoplastic (actinic keratosis), proliferative, functional and inflammatory skin lesions (dermatofibromas, ruby angiomas, pedunculus fibromas, sebaceous cysts, seborrheic keratosis, focal hyperhidrosis, follicular hyperkeratosis, hypertrichosis, early androgenic alopecia, skin xerosis, pruritus sine materia, nail pitting, nail dystrophy, leukonychia, twisted hair, seborrheic dermatitis, macules of hyperpigmentation, guttate hypomelanosis, teleangiectasia, psoriasis, eczema, acne, folliculitis, acanthosis nigricans). Patients received a complete clinical examination of their skin and mucosae and an intra-vital digital videodermoscopy through the Fotofinder Dermoscope by a trained dermatologist to check for the presence of these skin lesions. Secondary outcomes of the study were: – to evaluate the prevalence of previous or familial history of non-melanoma or melanoma skin cancer, which was obtained by asking the patients and controls the following questions: “Have you ever had or do you have any skin tumour?” Participants under study who responded affirmatively to the option of tumour were asked to specify the anatomic site of origin, as suggested by Moxley et al. [11]. A familial history

3. Results Study and control groups were similar for age, Caucasian race, gender, and other relevant risk factors for melanoma and non-melanoma skin cancer (sun exposure, familial history, phototype). None of the patients or controls had received a previous diagnosis of melanoma or non-melanoma skin cancer. The MIRS score evaluated in all DM1 patients by a trained neurologist ranged from 1 to 4. Prevalence of the observed skin lesions in patients and controls is described in Table 1. No statistically significant difference was detected between the two groups. Among morphofunctional, inflammatory, and proliferative skin diseases, the following lesions were more prevalent in the group of patients with DM1: focal hyperhidrosis (p < 0.0001), follicular hyperkeratosis (p = 0.0003), early androgenic alopecia (p = 0.01), nail pitting (p = 0.003), pedunculus fibromas (p = 0.01), twisted hair (p = 0.01), seborrheic dermatitis (p = 0.02), and macules of hyperpigmentation (p = 0.03). In patients with DM1, androgenic alopecia (p < 0.0001), seborrheic dermatitis (p < 0.0001) and twisted hair (p < 0.0001) were selectively more expressed by males (Table 2). Familial and personal history of non-melanoma and melanoma skin cancer were similar between patients and controls (p = 0.63 and p = 0.55, respectively). Among DNA-confirmed DM1 patients (n = 48), the median CTG repeat expansion size was 680 (range = 70–1000). Moreover, there was no correlation between the degree of skin involvement, expressed as number of skin lesions affecting patients simultaneously, and repeat expansion size, or MIRS scores (Figs. 1 and 2). 4. Discussion This observational study was conducted to investigate skin involvement in DM1 patients. Our results show that, compared with controls, DM1 patients were more frequently affected by the following skin and

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Table 1 Skin features in DM1. Skin lesions

Patients [n] (%)

Controls [n] (%)

p

Focal hyperhidrosis Follicular hyperkeratosis Early androgenic alopecia Nail pitting Pedunculus fibromas Twisted hair Seborrheic dermatitis Macules of hyperpigmentation Skin xerosis Telangectasia Nail dystrophy Ruby angiomas Psoriasis Eczema Onychomicoses Leukonychia Onychocryptosis Dermatofibromas Pruritus sine materia Acanthosis nigricans Guttate hypomelanosis Aplasia cutis Acne Folliculitis Pityriasis versicolor Mucosal lentigines Anetoderma Sebaceous cysts Seborrheic keratosis Hypertrichosis Melanoma Basal cell carcinoma Squamous cell carcinoma Actinic keratosis

17 30 17 8 22 7 14 7

(33.3%) (60%) (33.3%) (16.6%) (43.3%) (13.3%) (26.6%) (13.3%)

3 33 13 6 26 7 16 4

(3%) (33%) (13) (6%) (26%) (7%) (16%) (4%)

**** *** ** ** * * * *

23 7 7 7 2 4 5 5 5 3 3 3 3 2 2 2 5 2 2 3 2 2 1 3 2 3

(46.6%) (13.3%) (13.3%) (13.3%) (6.6%) (13.3%) (10%) (10%) (10%) (6.6%) (6.6%) (6.6%) (6.6%) (3.3%) (3.3%) (3.3%) (10%) (3.3%) (3.3%) (6.6%) (3.3%) (3.3%) (1.8%) (5.4%) (3.6%) (6.6%)

43 16 15 12 4 15 9 10 8 8 8 4 9 1 5 5 10 2 2 7 3 3 1 4 4 6

(43%) (16%) (15%) (12%) (4%) (15%) (9%) (10%) (8%) (8%) (8%) (4%) (9%) (1%) (5%) (5%) (10%) (2%) (2%) (7%) (3%) (3%) (1%) (4%) (4%) (6%)

n.s. n.s. n.s n.s n.s. n.s n.s n.s n.s n.s n.s n.s n.s n.s n.s n.s n.s n.s n.s n.s n.s n.s n.s. n.s. n.s. n.s.

* p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001. n.s. = not significant.

Table 2 Skin features in patients with DM1, according to sex. Skin lesions

Males

Females

p

Early androgenic alopecia Twisted hair Seborrheic dermatitis

100% 73.4% 73.4%

0% 26.6% 26.6%

**** **** ****

**** p < 0.0001.

appendage disorders: follicular hyperkeratosis, pedunculus fibromas, focal hyperhidrosis, early androgenic alopecia, nail pitting (a peculiar hallmark of minimal psoriasis) [12–17], seborrheic dermatitis, twisted hair, and macules of hyperpigmentation (Fig. 3). The most intriguing finding was the highest prevalence of adnexal manifestations in these patients: follicular hyperkeratosis, nail pitting, focal hyperhidrosis, twisted hair, early androgenic alopecia, which have never been pointed out before in literature. The only adnexal involvement previously signalled in literature is related to sporadic cases of pilomatricoma [18–22] and follicular cyst [23] in DM1 patients. However, we failed to confirm these data in our DM1 patients.

Fig. 1. Number of skin lesions vs triplet repeated.

Fig. 2. Number of skin events according to MIRS score.

The authors, who signalled adnexal involvement, had already suggested the potential influence of the DM1 gene in the differentiation process of the cutaneous follicular stem cells [24]. Over the past 3 years, several Japanese investigators have been studying the relationship that exists between gene mutation and skin tumours in patients with DM1. They have observed that the CTG repeat expansion is more marked in tumoural than in non-tumoural tissues [25–27]. It could be argued that these repeat sequences lead to an instability of DNA, causing an increased predisposition to cancer in these patients [27]. Although we failed to demonstrate the presence of malignant or benign neoplasms, it would not be surprising that CTG repeat expansion leads to an instability of DMPK (Dystrophia myotonica protein kinase) in the skin, modifying its physiologic function and creating the prerequisite for cutaneous and adnexal manifestations [28]. Although the functional role of DMPK has not been fully described yet, there is some evidence about its role in Ca2+ homeostasis and signal transduction [24–28]. In epidermal cells, calcium modulates both the cells’ behaviour as well as their differentiation: at lower calcium concentrations (0.02–0.01 mM), there is a higher cell proliferation rate and a

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Fig. 3. Skin features in DM1; (a) follicular hyperkeratosis, (b) pedunculus fibromas, (c) macules of hyperpigmentation, (d) nail pitting, (e) early androgenic alopecia, (f) seborrheic dermatitis, (g) focal hyperhidrosis, (h) androgenic alopecia.

lower terminal differentiation [28]. Therefore, an imbalance between cell proliferation and differentiation could finally be responsible for adnexal abnormalities. Such considerations can stimulate further investigation about the expression of DMPK in epidermal tissues. In our study, we failed to demonstrate any significant difference in skin manifestations between males and females except for androgenic alopecia and twisted hair, whose prevalence was higher in males, as occurs in healthy subjects also [29].

Finally, dermatological manifestations did not correlate with the severity of the illness measured through the nucleotide (CTG or CCTG) repeat expansion size, and this could depend on the wide spectrum of clinical severity of DM1. 5. Conclusions This study adds new details to characterize the phenotype of DM1 patients. Our observation does not support the existence of cutaneous specific hallmarks in DM1 and rules out a higher prevalence of preneoplastic and neoplastic cutaneous

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lesions in this disease. Although there is a spectrum of skin manifestations in DM1 which is adnexal and not properly discussed in the literature, this study may provide some insight into the underlying pathogenesis of the disease and also raise awareness among clinicians in their treatment of patients. This last aspect deserves further consideration in order to clarify the possible role of DMPK in the development of cutaneous and adnexal lesions. References [1] Romeo V. Myotonic dystrophy type 1 or Steinert’s disease. Adv Exp Med Biol 2012;724:239–57. [2] Machuca-Tzili L, Brook D, Hilton-Jones D. Clinical and molecular aspects of the myotonic dystrophies: a review. Muscle Nerve 2005;32:1–18. [3] Gladman JT, Mandal M, Srinivasan V, Mahadevan MS. Age of onset of RNA toxicity influences phenotypic severity: evidence from an inducible mouse model of myotonic dystrophy (DM1). PLoS ONE 2013;8(9):e72907. [4] Finsterer J, Fellinger J. Alopecia as a prominent feature of myotonic dystrophy type 1. Rev Invest Clín 2011;63(3):322–4. [5] Sherrod QJ, Chiu MW, Gutierrez M. Multiple pilomatricomas: cutaneous marker for myotonic dystrophy. Dermatol Online J 2008;14(7):22. [6] Schulz EJ. Genodermatoses. Dermatol Clin 1994;12(4):787–96. [7] Campanati A, Marconi B, Penna L, Paolinelli M, Offidani A. Pronounced and early acne in Apert’s syndrome: a case successfully treated with oral isotretinoin. Eur J Dermatol 2002;12(5):496–8. [8] Ganzetti G, Campanati A, Offidani A. Alopecia areata: a possible extraintestinal manifestation of Crohn’s disease. J Crohns Colitis 2012;6(9):962–3. [9] Campanati A, Lagalla G, Penna L, Gesuita R, Offidani A. Local neural block at the wrist for treatment of palmar hyperhidrosis with botulinum toxin: technical improvements. J Am Acad Dermatol 2004;51(3):345–8. [10] Mathieu J, Boivin H, Meunier D, Gaudreault M, Bégin P. Assessment of a disease-specific muscular impairment rating scale in myotonic dystrophy. Neurology 2001;56:336–40. [11] Das M, Moxley RT 3rd, Hilbert JE, et al. Correlates of tumor development in patients with myotonic dystrophy. J Neurol 2012;259(10):2161–6. [12] Campanati A, Giuliodori K, Ganzetti G, Liberati G, Offidani AM. A patient with psoriasis and vitiligo treated with etanercept. Am J Clin Dermatol 2010;11(Suppl. 1):46–8. [13] Campanati A, Goteri G, Simonetti O, et al. CTACK/CCL27 expression in psoriatic skin and its modification after administration of etanercept. Br J Dermatol 2007;157(6):1155–60. [14] Ferretti G, Bacchetti T, Campanati A, Simonetti O, Liberati G, Offidani A. Correlation between lipoprotein(a) and lipid peroxidation in psoriasis: role of the enzyme paraoxonase-1. Br J Dermatol 2012;166(1):204–7.

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