Am J Clin Dermatol DOI 10.1007/s40257-015-0119-7
SYSTEMATIC REVIEW
Epidermolysis Bullosa Pruriginosa: A Systematic Review Exploring Genotype–Phenotype Correlation Whan B. Kim • Afsaneh Alavi • Scott Walsh Song Kim • Elena Pope
•
Ó Springer International Publishing Switzerland 2015
Abstract Introduction Epidermolysis bullosa pruriginosa (EBP) is a clinical variant of dystrophic epidermolysis bullosa (DEB), characterized by intense pruritus and hypertrophic, lichenified, prurigo-like papules, plaques, and nodules secondary to scratching. These clinical findings have been attributed to various mutations in the COL7A1 gene. Previous reports have yielded inconsistent findings
W. B. Kim (&) Michael G. DeGroote School of Medicine, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada e-mail:
[email protected] A. Alavi S. Walsh E. Pope Division of Dermatology, Department of Medicine, University of Toronto, Toronto, ON, Canada A. Alavi Women’s College Hospital, Toronto, ON, Canada S. Walsh Sunnybrook Health Sciences Centre, Toronto, ON, Canada S. Kim Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada E. Pope University of Toronto Hospital for Sick Children, Toronto, ON, Canada
regarding a possible genotype–phenotype relationship in EBP. Objective Our aim was to conduct a systematic review aimed at assessing the genotype–phenotype correlation in EBP. Methods A systematic review was conducted using PubMed, Medline, EMBASE, and Cochrane databases for all reports of mutation-verified EBP, published from 1946 to September 2014. Statistical comparison of clinical findings between mutation types was performed using logistic regression analysis. Results The review included a total of 28 articles with 74 individuals, which consisted of level 4 non-controlled case series (grade C) and level 5 case reports (grade D). Previous reported mutation types included glycine substitution (GS, 52.7 %), in-frame skipping (IFS, 33.8 %), non-glycine substitution (NGS, 8.1 %), and premature termination codon (PTC, 5.4 %). The most common clinical findings were extremities involvement, linear configuration, and nail dystrophy. In comparison with GS mutation carriers, IFS carriers had a higher likelihood of (1) being male (OR 2.99; p = 0.043; 95 % CI 1.27–11.4) and (2) presenting with blisters (OR 4.10; p = 0.013; 95 % CI 1.34–12.5). Conclusions To our knowledge, this study is the first systematic review examining the relationship between mutation type and clinical presentation in EBP. The findings in this review (1) identify common clinical characteristics of EBP that may help in the assessment of patients with possible EBP; and (2) indicate that certain mutation carriers may have a higher likelihood of exhibiting particular phenotypes. In the case of potential diagnostic challenge, assessment for presence of common clinical findings as well as molecular testing may facilitate correct identification and prognostication.
W. B. Kim et al.
Key Points
conducted to identify all previous cases of mutation-verified EBP, and determine whether different EBP mutation types influence clinical presentation.
Based on small case series and case reports, the most common clinical findings in epidermolysis bullosa pruriginosa are extremities involvement, linear configuration, and nail dystrophy.
2 Methods
Compared with glycine substitution mutation carriers, in-frame skipping mutation carriers had a higher likelihood of being male and presenting with blisters. Assessing for presence of the common clinical findings in conjunction with molecular testing may facilitate correct identification and prognostication in patients with epidermolysis bullosa pruriginosa.
1 Introduction Epidermolysis bullosa pruriginosa (EBP) is a rare clinical variant of dystrophic epidermolysis bullosa (DEB) that is characterized by intense pruritus resulting in hypertrophic, lichenified, prurigo-like papules, plaques, and nodules secondary to scratching, arising predominantly on the lower extremities [1]. The spectrum of clinical findings and the various subtypes found in DEB have been attributed to a variety of inheritance patterns and mutations in the COL7A1 gene [1]. Although most cases of EBP demonstrate an autosomal dominant inheritance pattern, autosomal recessive and sporadic inheritance patterns have also been documented [2]. Reported mutations in COL7A1 implicated in the EBP phenotype include missense, nonsense, frameshift, and splice-site mutations, among which glycine substitutions occur most frequently [2]. Previous efforts to determine a genotype–phenotype correlation in EBP have been inconclusive and limited to individual case reports or small case series. Some studies describe consistent clinical findings among family members of identical genotypes, suggesting possible genotype– phenotype relationships [3, 4], while others report wide clinical variability within families [5–8]. In fact, it has been shown that intra-familial mutations can lead to both EBP and other manifestations of DEB [8–18]. To account for this heterogeneity, other environmental factors as potential disease modifiers of the pruriginosa phenotype have been explored; however, no factors to date have been found to be universal factors in EBP pathogenesis [5, 10, 16, 18]. In order to better understand the role of genotype– phenotype correlation in EBP, a systematic review was
We conducted a systematic review of the English literature from 1946 to September 2014 to identify all prior case reports and case series describing mutation-verified EBP. We used the PubMed, Ovid MEDLINE, EMBASE, and Cochrane databases with the following search terms: pruriginosa, dominant dystrophic epidermolysis bullosa pruriginosa, DDEB pruriginosa, and DDEB Pr. Additional articles were identified by hand-searching references of the included articles. Selected studies were included for qualitative analysis if the following criteria were met: (1) diagnosis of EBP was confirmed by histology; (2) mutation type was confirmed by mutation analysis [i.e., glycine substitution (GS), nonglycine substitution (NGS), in-frame skipping (IFS), and premature terminal codon (PTC)]; and (3) clinical findings of EBP were described (i.e., morphology, configuration, location, color, and other skin findings). Identified studies were also evaluated for their study design and level of evidence as delineated by the Oxford Center for EvidenceBased Medicine [19]. 2.1 Statistical Analysis Statistical analysis was performed using SPSS statistical software (version 19.0; SPSS Inc., Chicago, IL, USA). To assess genotype–phenotype correlation, we performed the logistic regression analysis to test whether different mutation types influence clinical presentation in EBP. We focused on the results of those with the more common mutation types (i.e., GS and IFS) because (1) the sample sizes for NGS and PTC are limited; and (2) the presence of cells with a frequency of 0 produces a numerical problem and interrupts the calculation process [20]. The frequency of clinical findings in the GS group was designated as a reference because there were more individuals with the GS than with the IFS mutation. We then identified the clinical findings that were more probable to occur in one mutation type than the other based on an odds ratio calculation. p \ 0.05 was considered significant. Although multiple comparisons were made, the Bonferroni method was not used to account for type I errors because (1) a single test of the ‘universal null hypothesis’ that all tests are not significant was not required; (2) it was not strictly imperative to avoid type I errors; and (3) the tests were carried out with preplanned hypotheses [21].
EB Pruriginosa: Genotype–Phenotype Correlation
3 Results We screened a total of 181 articles, out of which 66 were duplicates and 37 were excluded after title and abstract review (Fig. 1). After full-text retrieval and review of the remaining 78 articles, 28 articles with 74 patients met the predefined eligibility criteria and were included in the qualitative analysis [2, 5, 6, 9, 10, 12–14, 16–18, 22–39]. The selected studies consisted of level 4 non-controlled case series (11) and level 5 case reports (17). Table 1 describes the demographic information of the 74 patients with mutation-verified EBP included in the review. Table 2
summarizes the clinical findings grouped into five phenotypic categories (morphology, configuration, location, color, and other skin findings) and classified by mutation types [GS (52.7 %), IFS (33.8 %), NGS (8.1 %), and PTC (5.4 %)]. The most common clinical findings from each phenotype category were blister morphology (54.8 %), linear configuration (65.5 %), extremities involvement (98.5 %), violaceous color (46.7 %), and nail dystrophy (59.5 %) (Table 2). Of these, involvement of extremities (mean 99 %, SD 2.0 %), linear configuration (mean 83.4 %, SD 21.3 %), and nail dystrophy (mean 67.0 %, SD 15.5 %) were reported in approximately 50 % or more of patients in every mutation type (Table 2). Based on non-overlapping lower and upper thresholds of the mean percentage calculated from the standard error, the aforementioned phenotypes of extremities involvement (mean 99 %, range 99–100 %); linear configuration (mean 83.4 %; range 72.7–94.0 %); and nail dystrophy (mean 67.0 %; range 59.2–74.7 %) were found to occur at significantly greater frequency than other features included in each respective phenotype category. 3.1 Gender and Age of Onset
Fig. 1 PRISMA flow chart: data collection and selection of studies
The occurrence of EBP was found to be twice as common in females than males (66.2 % female: 33.8 % male; n = 74) (Table 1). Except for IFS carriers, patients with EBP were predominantly female (74.4, 83.3, 75 % for GS, NGS, and PTC carriers, respectively). Our logistic analysis revealed that compared with the GS group, IFS carriers were 2.99 times (p = 0.043; 95 % CI 1.27–11.4) as likely to be males. With respect to onset of the pruriginosa phenotype, the mean age of onset among 71 patients across all mutation types was 14 years [range 0 (birth)–71 years; r 15.7 years; lGS 16 years, lIFS 12 years, lNGS 17 years, lPTC 9 years).
Table 1 Demographics of 74 patients with mutation-verified epidermolysis bullosa pruriginosa
3.2 Morphology
Characteristic
Blistering was the most frequently reported morphological finding across all mutation types with 40 of 73 (54.8 %) patients reporting this phenotype, followed by papule (n = 25/73; 34.2 %), plaque (n = 24/73; 32.9 %), nodule (n = 22/73; 30.1 %), and hypertrophic scar (n = 19/73; 26.0 %) (Table 2). Our logistic analysis revealed that most clinical features tended to occur more frequently in the GS group than others. However, in comparison with GS carriers, IFS carriers were 4.10 times as likely (p = 0.013; 95 % CI 1.34–12.5) to present with blisters.
% (n)
Gender Male
33.8 (25/74)
Female
66.2 (49/74)
Age of onset (years) 0–9
52.2 (36/69*)
10–19
21.7 (15/69)
20–29
11.6 (8/69)
30–39
4.3 (3/69)
40–49
5.8 (4/69)
50–59
2.9 (2/69)
60–69 70–79
0 (0/69) 1.4 (1/69)
* Age of onset was not reported in 5/74 cases
3.3 Configuration Out of 29 patients across mutation types, 19 reported linear configuration of lesions, of whom 10 (52.6 %) were IFS
W. B. Kim et al. Table 2 Prevalence of clinical findings in epidermolysis bullosa pruriginosa Total (n = 74)
Glycine substitution (n = 39)
In-frame skipping (n = 25)
Non-glycine substitution (n = 6)
Premature terminal codon (n = 4)
Morphology, % (n) Blister
54.8 (40/73)
43.6 (17/39)
76 (19/25)
66.7 (4/6)
0 (0/3)
Papule
34.2 (25/73)
43.6 (17/39)
32 (8/25)
0 (0/6)
0 (0/3)
Nodule
30.1 (22/73)
33.3 (13/39)
16 (4/25)
33.3 (2/6)
100 (3/3)
Plaque
32.9 (24/73)
28.2 (11/39)
32 (8/25)
66.7 (4/6)
33.3 (1/3)
Scar, hypertrophic
26.0 (19/73)
20.5 (8/39)
28 (7/25)
66.7 (4/6)
0 (0/3)
Configuration, % (n) Linear
65.5 (19/29)
77.8 (7/9)
55.6 (10/18)
100 (1/1)
100 (1/1)
37.9 (11/29)
22.2 (2/9)
50 (9/18)
0 (0/1)
0 (0/1)
Extremities
98.5 (67/68)
100 (34/34)
96 (24/25)
100 (6/6)
100 (3/3)
Trunk
23.5 (16/68)
29.4 (10/34)
16 (4/25)
16.7 (1/6)
33.3 (1/3)
4.4 (3/68)
2.9 (1/34)
4 (1/25)
16.7 (1/6)
0 (0/3)
0 (0/68)
0 (0/34)
0 (0/25)
0 (0/6)
0 (0/3)
Circular Location, % (n)
Head/neck Palm/sole Color, % (n) Violaceous
46.7 (21/45)
47.4 (9/19)
44 (8/18)
50 (3/6)
50 (1/2)
Skin color
6.7 (3/45)
10.5 (2/19)
0 (0/18)
16.7 (1/6)
0 (0/2)
Nail dystrophy
59.5 (44/74)
61.5 (24/39)
48 (12/25)
83.3 (5/6)
75 (3/4)
Milia
27.0 (20/74)
25.6 (10/39)
16 (4/25)
66.7 (4/6)
50 (2/4)
Other skin findings, % (n)
Scar, atrophic
5.4 (4/74)
7.7 (3/39)
4 (1/25)
0 (0/6)
0 (0/4)
Albopapuloid lesion Thickened toenail
9.5 (7/74) 5.4 (4/74)
12.8 (5/39) 5.1 (2/39)
0 (0/25) 8 (2/25)
16.7 (1/6) 0 (0/6)
25 (1/4) 0 (0/4)
carriers, 7 (36.8 %) were GS carriers, and 2 (10.5 %) were NGS and PTC carriers (Table 2). Circular configuration was reported in 11 of 29 patients, the majority of whom were IFS carriers (n = 9/11; 81.8 %) (Table 2). Hence, a higher prevalence of linear configuration was noted across all mutation types; however, IFS carriers exhibited a relatively higher tendency for circular configuration. 3.4 Location Involvement of the extremities was the most frequently reported clinical finding across mutation types, with 67 out of 68 individuals (98.5 %) presenting with this phenotype (Table 2). The frequency of head and neck involvement was distributed evenly among the GS, IFS, and NGS mutation groups. None reported presentation on the palms or soles. 3.5 Color Violaceous color was reported in 21 of 45 (46.7 %) cases that reported the color of lesions. The percentage of patients with violaceous-colored lesions was similar across the mutation groups with 47.4, 44, 50, and 50 % for GS,
IFS, NGS, and PTC mutation groups, respectively. The prevalence of skin-color lesions was lower in all mutation carriers, with 2 of 19 (10.5 %) GS and 1 of 6 (16.7 %) NGS carriers reporting skin color. 3.6 Other Skin Findings Nail dystrophy occurred with the greatest prevalence in all mutation groups (61.5, 48, 83.3, and 75 % in GS, IFS, NGS, and PTC, respectively), followed by the presence of milia (25.6, 16, 66.7, 50 %), albopapuloid lesion (12.8, 0, 16.7, 25 %), atrophic scar (7.7, 4, 0, 0 %) and thickened toenail (5.1, 8, 0, 0 %).
4 Discussion To our knowledge, this study is the first systematic review examining the relationship between mutation type and clinical presentation in EBP with 74 patients from 28 different case reports and case series. From the systematic review and the logistic regression analysis performed in our study, we identified findings that exhibited significantly higher prevalence in certain mutation carriers, with the GS
EB Pruriginosa: Genotype–Phenotype Correlation
group as reference. Compared with GS carriers, IFS carriers had a higher likelihood of (1) being male (OR 2.99; p = 0.043; 95 % CI 1.27–11.4) and (2) presenting with blisters (OR 4.10; p = 0.013; 95 % CI 1.34–12.5). Otherwise, our logistic analysis revealed that most clinical features tended to occur more frequently in the GS group than others. The small number of existing cases might limit the conclusiveness of these findings. For instance, the observation that there is an association of IFS mutations with male gender may not necessarily be reflected in clinical practice. However, the finding that carriers of IFS mutation are more likely to present with blisters may be explained by the fact that IFS mutations incur a larger impact on the functionality and expression of collagen VII. The most common clinical findings reported in the cases were extremities involvement, linear configuration, and nail dystrophy. These phenotypes exhibited the highest prevalence in each mutation group and also occurred at significantly higher prevalence than any other reported feature included in each respective phenotype category. Only one female patient, with age of onset at 4 years, lacked involvement of the extremities and dystrophy of the nails. Other common findings were female gender, age of onset of \20 years, blister morphology, and violaceous color. For the clinician, these findings suggest that the presence of lesions of linear configuration with nail dystrophy and involvement of the extremities may be a more valuable and sensitive means of clinically diagnosing EBP than any other clinical feature associated with EBP. Although a hallmark of EBP has previously been the variable age of onset and delayed presentation of signs and symptoms—both of which potentially propose diagnostic challenges—, our study shows that a comparatively large proportion of patients exhibit the pruriginosa phenotype before 20 years of age: almost three-quarters of patients demonstrated EBP signs and symptoms before 20 years, 13.7 % of whom developed EBP at birth (Table 1). With respect to morphology, the presence of intact or previous blisters was the most common finding across all mutation types with twice the prevalence compared with hypertrophic scars; this finding suggests that although intact blisters are rare, making diagnosis difficult, further questioning on history for previous blisters may in fact facilitate diagnosis. Previous reports have yielded contradictory theories with respect to the potential genotype–phenotype correlation in EBP. For instance, while Saito et al. [39] suggested a possible association between skipping of exon 87 in the COL7A1 gene with the dominant inheritance pattern of EBP, others have noted that the mutations that result in the pruriginosa phenotype may not differ from those that result in other subtypes of DEB [8–18]. Given the previous
inconclusive findings, our systematic review has merit; it includes the most diverse collection of patients with mutation-verified EBP thus far in sufficient numbers to determine the prevalence of common clinical findings and to draw potential genotype–phenotype associations while reducing the impact of founder bias and genetic background. Indeed, the triad of clinical findings that demonstrated statistically significant association with certain mutation types may hint toward the role of genotype in the clinical manifestation of EBP. This finding suggests that in face of potential diagnostic challenge, molecular testing may facilitate correct identification and prognostication. 4.1 Limitations Our study is limited by lack of high-quality, high-powered, controlled studies, as well as possible incompleteness of reporting in existing primary reports. Moreover, the limited pool of existing cases makes it difficult to produce meaningful results with regard to studying the association between specific mutations and pruriginosa phenotype. Although this study has explored the genotype–phenotype relationship by the type of mutation, it would be a worthy endeavor to investigate any relationships between the specific mutations, along with the mode of inheritance, with a larger number of cases.
5 Conclusion Although the potential genotype–phenotype correlation in EBP has been inconclusive, the data summarized in this review indicates that certain mutation carriers may have a higher likelihood of exhibiting particular phenotypes, and thus suggest possible relationships between mutation and clinical manifestations of EBP. Moreover, given the high prevalence of extremities involvement, linear configuration, and nail dystrophy across all mutation types, assessing for the presence of these clinical findings may be a valuable and sensitive means of establishing or confirming diagnosis of EBP. Overall, it is difficult to draw generalizable conclusions due to the lack of large, controlled studies available in current literature. Additional studies are required to better characterize this rare condition and further explore associations between genotype and phenotype. Such studies with a growing number of cases and a more uniform way of reporting will pave the way in offering highly valuable prognostic information to the clinician and shaping optimal management for the patient despite the rarity of this blistering condition. Disclosures
Funding:
No funding was received.
W. B. Kim et al. Conflicts of interest W. Kim, A. Alavi, S. Walsh, S. Kim, and E. Pope declare that they have no conflicts of interest. 16.
References 1. Fine JD, Eady RA, Bauer EA, Bauer JW, Buckner-Tuderman L, Heagerty A, et al. The classification of inherited epidermolysis bullosa (EB): report of the third international consensus meeting on diagnosis and classification of EB. J Am Acad Dermatol. 2008;58(6):931–50. 2. Tey HL, Lee AD, Almaani N, McGrath JA, Mills KC, Yosipovitch G. Epidermolysis bullosa pruriginosa masquerading as psychogenic pruritus. Arch Dermatol. 2011;147(8):956–60. 3. McGrath JA, Schofield OM, Eady RA. Epidermolysis bullosa pruriginosa: dystrophic epidermolysis bullosa with distinctive clinicopathological features. Br J Dermatol. 1994;130(5):617–25. 4. Banky JP, Sheridan AT, Storer EL, Marshman G. Successful treatment of epidermolysis bullosa pruriginosa with topical tacrolimus. Arch Dermatol. 2004;140(7):794–6. 5. Schumann H, Has C, Kolhase J, Bruckner-Tuderman L. Dystrophic epidermolysis bullosa pruriginosa is not associated with frequent FLG gene mutations. Br J Dermatol. 2008;159(2):464–9. 6. Broekaert SM, Knauss-Scherwitz E, Biedermann T, et al. Epidermolysis bullosa pruriginosa due to a glycine substitution mutation in the COL7A1-gene. Acta Derm Venereol. 2006;86(6):556–7. 7. Jones RR. Epidermolysis bullosa. Report of a family and discussion of the dominant dystrophic types. Clin Exp Dermatol. 1979;4(3):303–8. 8. Dang N, Klingberg S, Marr P, Murrell DF. Review of collagen VII sequence variants found in Australasian patients with dystrophic epidermolysis bullosa reveals nine novel COL7A1 variants. J Dermatol Sci. 2007;46(3):168–78. 9. Lee JY, Pulkkinen L, Liu HS, Chen YF, Uitto J. A glycine-toarginine substitution inthe triple-helical domain of type VII collagen in a family with dominant dystrophic epidermolysis bullosa pruriginosa. J Invest Dermatol. 1997;108(6):947–9. 10. Mellerio JE, Ashton GH, Mohammedi R, Lyon CC, Kirby B, Harman KE, et al. Allelic heterogeneity of dominant and recessive COL7A1 mutations underlying epidermolysis bullosa pruriginosa. J Invest Dermatol. 1999;112(6):984–7. 11. Whittock NV, Ashton GH, Mohammedi R, Mellerio JE, Matthew CG, Abbs SJ, et al. Comparative mutation detection screening of the type VII collagen gene (COL7A1) using the protein truncation test, fluorescent chemical cleavage of mismatch, and conformation sensitive gel electrophoresis. J Invest Dermatol. 1999;113(4):673–86. 12. Murata T, Masunaga T, Shimizu H, Takizawa Y, Ishiko A, Hatta N, et al. Glycine substitution mutations by different amino acids in the same codon of COL7A1 lead to heterogeneous clinical phenotypes of dominant dystrophic epidermolysis bullosa. Arch Dermatol Res. 2000;292(10):477–81. 13. Jiang W, Bu D, Yang Y, Zhu X. A novel splice site mutation in collagen type VII gene in a Chinese family with dominant dystrophic epidermolysis bullosa pruriginosa. Acta Derm Venereol. 2002;82(3):187–91. 14. Nakamura H, Sawamura D, Goto M, Sato-Matsumura KC, LaDuca J, Lee JY, et al. The G2028R glycine substitution mutation in COL7A1 leads to marked inter-familiar clinical heterogeneity in dominant dystrophic epidermolysis bullosa. J Dermatol Sci. 2004;34(3):195–200. 15. Chuang GS, Martinez-Mir A, Yu HS, Sung FY, Chuang RY, Cserhalmi-Friedman PB, et al. A novel missense mutation in the
17.
18.
19.
20.
21. 22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
COL7A1 gene underlies epidermolysis bullosa pruriginosa. Clin Exp Dermatol. 2004;29(3):304–7. Drera B, Castiglia D, Zoppi N, Gardella R, Tadini G, Floriddia G, et al. Dystrophic epidermolysis bullosa pruriginosa in Italy: clinical and molecular characterization. Clin Genet. 2006;70(4): 339–47. Ee HL, Liu L, Goh CL, McGrath JA. Clinical and molecular dilemmas in the diagnosis of familial epidermolysis bullosa pruriginosa. J Am Acad Dermatol. 2007; 56(5 suppl):S77–S81. Almaani N, Liu L, Harrison N, Tanaka A, Lai-Cheong J, Mellerio JE, et al. New glycine substitution mutations in type VII collagen underlying epidermolysis bullosa pruriginosa but the phenotype is not explained by a common polymorphism in the matrix metalloproteinase–1 gene promoter. Acta Derm Venereol. 2009;89(1):6–11. Oxford Centre for Evidence-based Medicine—levels of evidence. University of Oxford, Medical Sciences Division. March 2009. http://www.cebm.net/oxford-centre-evidence-based-medicinelevels-evidence-march-2009/. Accessed 03 Dec 2014. De Irala J, Navajas RF, del Castillo AS. Abnormally wide confidence intervals in logistic regression: interpretation of statistical program results. Pan Am J Public Health. 1997;1(3):230–4. Armstrong RA. When to use the Bonferroni correction. Ophthalmic Physiol Opt. 2014;34:502–8. Nagy N, Tanaka A, Techanukul T, McGrath JA. Common IL-31 gene haplotype associated with non-atopic eczema is not implicated in epidermolysis bullosa pruriginosa. Acta Derm Venereol. 2010;90(6):631–2. Mangold AR, Cole CM, DiCaudo DJ, Pittelkow MR, Sekulic A. Treatment of epidermolysis bullosa pruriginosa using systemic and topical agents. J Am Acad Dermatol. 2014;70(6):e136–7. Vivehanantha S, Carr RA, McGrath JA, Taibiee SM, Madhogaria S, Ilchyshyn A. Epidermolysis bullosa pruriginosa: a case with prominent histopathologic inflammation. JAMA Dermatol. 2013;149(6):727–31. Tang MM, Leong KF, Cristina H, Bruckner-Tuderman L. Dystrophic epidermolysis bullosa pruriginosa: the first report of a family in Malaysia. Med J Malaysia. 2013;68(1):81–5. Fortuna G, Di Lorenzo M, Cepeda-Valdes R, Garcia-Garcia C, Salas-Alanis JC. The largest family of the Americas with dominant dystrophic epidermolysis bullosa pruriginosa: a 18-year longitudinal genotype-phenotype study. J Dermatol Sci. 2013; 71(3):217–21. Yang CS, Lu Y, Farhi A, Nelson-Williams C, Kashgarian M, Glusac EJ, et al. An incompletely penetrant novel mutation in COL7A1 causes epidermolysis bullosa pruriginosa and dominant dystrophic epidermolysis bullosa phenotypes in an extended kindred. Pediatr Dermatol. 2012;29(6):725–31. Yajima M, Nakano H, Sawamura D, Miyachi Y, Kabashima K. Case of dominant dystrophic epidermolysis bullosa pruriginosa with a c.7868G[A (G2623D) mutation in type VII collagen. J Dermatol. 2012;39(12):1087–8. Jiang W, Sun TT, Lei PC, Zhu XJ. Genotype-phenotype correlation in Chinese patients with dystrophic epidermolysis bullosa pruriginosa. Acta Derm Venereol. 2012;92(1):50–3. Brick K, Hand JL, Frankel AS, Siegel DH, Thomas KB, ElAzhary R, et al. Epidermolysis bullosa pruriginosa: further clarification of the phenotype. Pediatr Dermatol. 2012;29(6): 732–7. Pruneddu S, Castiglia D, Floriddia G, Cottoni F, Zambruno G. COL7A1 recessive mutations in two siblings with distinct subtypes of dystrophic epidermolysis bullosa: pruriginosa versus nails only. Dermatology. 2011;222(1):10–4. Murase K, Kanoh H, Ishii N, Hashimoto T, Nakano H, Sawamura D, et al. Bullous dermolysis of the newborn and dystrophic epidermolysis bullosa pruriginosa within the same family: two
EB Pruriginosa: Genotype–Phenotype Correlation
33.
34.
35.
36.
phenotypes associated with a COL7A1 mutation. Acta Derm Venereol. 2011;91(6):730–1. Hayashi M, Kawaguchi M, Hozumi Y, Nakano H, Sawamura D, Suzuki T. Dystrophic epidermolysis bullosa pruriginosa of elderly onset. J Dermatol. 2011;38(2):173–8. Covaciu C, Grosso F, Pisaneschi E, Zambruno G, Gregersen PA, Sommerlund M, et al. A founder synonymous COL7A1 mutation in three Danish families with dominant dystrophic epidermolysis bullosa pruriginosa identifies exonic regulatory sequences required for exon 87 splicing. Br J Dermatol. 2011;165(3):678–82. Cole C, Sekulic A, DiCaudo D. Epidermolysis bullosa pruriginosa: novel compound heterozygote splice site mutations. J AM Acad Dermatol. 2011;64(2 Suppl):AB94. Shi BJ, Feng J. A novel missense mutation in the COL7A1 gene causes epidermolysis bullosa pruriginosa. Clin Exp Dermatol. 2009;34(8):e975–8.
37. Ren X, Liu JY, Zhai LY, Yao Q, Dai X, Cai Z. A splicing mutation in the COL7A1 gene causes autosomal dominant dystrophic epidermolysis bullosa pruriginosa. Br J Dermatol. 2008;158(3):618–20. 38. Wang Y, Zhao J, Tu P, Jiang W, Zhu X. A novel missense mutation in COL7A1 in a Chinese pedigree with epidermolysis bullosa pruriginosa. J Dermatol Sci. 2007;46(3):211–3. 39. Saito M, Masunaga T, Ishiko A. A novel de novo splice-site mutation in the COL7A1 gene in dominant dystrophic epidermolysis bullosa (DDEB): specific exon skipping could be a prognostic factor for DDEB pruriginosa. Clin Exp Dermatol. 2009;34(8):e934–6.
