AUTHORS:
Alexander K. C. Leung, MD^1,2 • Benjamin Barankin, MD³ • Kin Fon Leong, MD⁴

AFFILIATIONS:
¹Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
²Alberta Children’s Hospital, Calgary, Alberta, Canada
³Toronto Dermatology Centre, Toronto, Ontario, Canada
⁴Pediatric Institute, Kuala Lumpur General Hospital, Kuala Lumpur, Malaysia

CITATION:
Leung AKC, Barankin B, Leong KF. An atlas of nail disorders, part 11. Consultant. 2020;60(9):20-22. doi:10.25270/con.2020.09.00003

DISCLOSURES:
The authors report no relevant financial relationships.

CORRESPONDENCE:
Alexander K. C. Leung, MD, #200, 233 16th Ave NW, Calgary, AB T2M 0H5, Canada (aleung@ucalgary.ca)

Nail Changes in Dystrophic Epidermolysis Bullosa

Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of rare inherited connective tissue disorders characterized by markedly mechanical fragility of epithelial tissue with blisters and erosions in skin and mucosal membranes in response to rubbing or frictional trauma.¹ A positive family history is supportive.

Based on the precise location at which skin cleavage or blistering occurs, EB is classified into 4 major categories: EB simplex (intraepidermal skin cleavage), junctional EB (skin cleavage within the lamina lucida or central basement membrane zone), dystrophic EB (cleavage below the lamina lucida), and Kindler syndrome (cleavage at multiple levels: intraepidermal, intra–lumina lucida, and sub–lumina lucida).² By far, EB simplex is the most common type of EB, accounting for approximately 80% of cases. On the other hand, nail changes are most common in dystrophic EB.³

Dystrophic EB is caused by mutations in the COL7A1 gene, which encodes the α1 chain of type VII collagen, the major component of the anchoring fibrils.^3-5 The disorder is inherited as either an autosomal dominant or autosomal recessive trait.^3,6

Dystrophic EB is characterized by skin fragility, mucocutaneous blistering in response to minor trauma with subsequent scarring, milia formation, and nail dystrophy (Figure 1).^2,6,7 Nail changes include periungual granulomatous tissue, nail erosions, onychogryphosis, and anonychia due to scarring and atrophy of the nail matrix and nail bed (Figures 2 and 3).²

Figure 1. Dystrophic EB is characterized by skin fragility, mucocutaneous blistering in response to minor trauma with subsequent scarring, milia formation, and nail dystrophy.

Figure 2. Nail changes in dystrophic EB include periungual granulomatous tissue, nail erosions, onychogryphosis, and anonychia due to scarring and atrophy of the nail matrix and nail bed.

Figure 3. In autosomal dominant dystrophic EB, nail dystrophy is common, and anonychia may occur.

In the severe form of autosomal recessive dystrophic EB, blisters are present at birth or shortly thereafter.^3,8 The blisters can affect the whole body.³ Other clinical manifestations include aplasia cutis congenita, chronic nonhealing wounds, intractable skin ulcers, scarring, contractures, pseudosyndactyly of fingers, nail dystrophy, ankyloglossia, microstomia, corneal erosions/scarring, esophageal erosions/strictures, deformed and carious teeth, urethral erosions/strictures, anal erosions, and malnutrition.^3,8-10

In the localized and generalized form of autosomal recessive dystrophic EB, the clinical manifestations are milder.³ The blistering is often localized to the hands, elbow, knees, and feet but can be more widespread to involve the trunk, but without the mutilating scarring seen in the severe form of autosomal recessive dystrophic EB.³ Nail dystrophy is often present.^3,8

In autosomal dominant dystrophic EB, the clinical manifestations are mild, and blistering is often limited to the hands, elbows, and knees.³ On the other hand, nail dystrophy is common, and anonychia may occur (Figures 2 and 3).³ In fact, onychodystrophy is the most important clue to the diagnosis of autosomal dominant dystrophic EB, especially in adults, because most patients have only limited scars that become less obvious with age.^2,3,11

REFERENCES:

1. Hon KLE, Li JJ, Cheng BL, et al. Age and etiology of childhood epidermolysis bullosa mortality. J Dermatolog Treat. 2015;26(2):178-182. doi:10.3109/09546634.2014.915002
2. Laimer M, Bauer J, Murrell DF. Epidemiology, pathogenesis, classification, and clinical features of epidermolysis bullosa. UpToDate. Updated August 17, 2018. Accessed August 12, 2020. https://www.uptodate.com/contents/epidemiology-pathogenesis-classification-and-clinical-features-of-epidermolysis-bullosa
3. Pfendner EG, Lucky AW. Dystrophic epidermolysis bullosa. GeneReviews. August 21, 2006. Updated September 13, 2018. Accessed August 12, 2020. https://www.ncbi.nlm.nih.gov/books/NBK1304/
4. Dănescu S, Şenilă S, Leluţiu L, Nedevschi S, Cosgarea R. Dystrophic epidermolysis bullosa: two case reports. Rom J Morphol Embryol. 2011;52(3):919-922.
5. Kern JS, Kohlhase J, Bruckner-Tuderman L, Has C. Expanding the COL7A1 mutation database: novel and recurrent mutations and unusual genotype-phenotype constellations in 41 patients with dystrophic epidermolysis bullosa. J Invest Dermatol. 2006;126(5):1006-1012. doi:10.1038/sj.jid.5700219
6. Sawamura D, Goto M, Yasukawa K, et al. Genetic studies of 20 Japanese families of dystrophic epidermolysis bullosa. J Hum Genet. 2005;50(10):543-546. doi:10.1007/s10038-005-0290-4
7. Akasaka E, Nakano H, Takagi Y, Toyomaki Y, Sawamura D. Multiple milia as an isolated skin manifestation of dominant dystrophic epidermolysis bullosa: evidence of phenotypic variability. Pediatr Dermatol. 2017;34(2):e106-e108. doi:10.1111/pde.13047
8. Grover S. Generalised recessive dystrophic epidermolysis bullosa in two sisters. Indian J Dermatol Venereol Leprol. 2001;67(4):205-206.
9. Ayman T, Yerebakan Ö, Çiftçioǧlu MA, Alpsoy E. A 13-year-old girl with recessive dystrophic epidermolysis bullosa presenting with squamous cell carcinoma. Pediatr Dermatol. 2002;19(5):436-438. doi:10.1046/j.1525-1470.2002.00202.x
10. Lee C-W, Song K-H, Kim K-H. A case of recessive dystrophic epidermolysis bullosa with esophageal stenosis treated with endoscopic bougienage. J Dermatol. 2002;29(10):628-632. doi:10.1111/j.1346-8138.2002.tb00192.x
11. Tosti A, Piraccini BM, Scher RK. Isolated nail dystrophy suggestive of dominant dystrophic epidermolysis bullosa. Pediatr Dermatol. 2003;20(5):456-457. doi:10.1046/j.1525-1470.2003.20422.x

NEXT: Nail Changes in Darier Disease

Nail Changes in Darier Disease

Darier disease, also known as keratosis follicularis, is a rare genodermatosis characterized clinically by keratotic papules and plaques in seborrheic areas and characterized histologically by acantholysis, dyskeratosis, and hyperkeratosis.^1,2 The disease is inherited as an autosomal dominant trait with high penetrance and variable expressivity.^3,4 The disease is caused by mutations in ATP2A2 (ATPase, Ca²⁺ transporting 2) gene that encodes a sarcoplasmic/endoplasmic reticulum Ca²⁺ adenosine triphosphatase isoform 2 protein (SERCA2).^1,3,4 Sporadic mutations are common.⁵ The sex ratio is approximately equal.^5,6 Typically, patients present at between 6 and 20 years of age, with onset peaking around puberty.^5,7

Skin changes are characterized by greasy, discrete, flat-topped, hyperkeratotic papules that occur in seborrheic areas such as the trunk, lateral sides of the neck, scalp, limbs, and forehead.^2,4,5 The distribution is often symmetric. Lesions are itchy, skin-colored, yellow-brown, brown, or red-brown, and feel like coarse sandpaper.^2,8,9 They may coalesce to form large, crusted papillomatous or verrucous plaques/masses.^4,5,10 Lesions may have a foul odor if there is secondary infection or colonization.² In intertriginous areas, lesions may present as large, malodorous, fleshy, warty, vegetative, exuberant growths, sometimes with painful fissures.^4,6,7 On the palms and soles, lesions often appear as hyperkeratotic papules, centrally depressed pits, and, less frequently, hemorrhagic macules (Figure 1).^1,4,9,11,12 Flat verrucous papules known as acrokeratosis verruciformis may be seen on the dorsa of hands and feet.^2,9,13 In severe cases, palmoplantar hyperkeratosis may occur.⁴ Other cutaneous features include café au lait spots and leukodermic macules.^11,14,15

Figure 1. On the palms and soles, Darier disease lesions often appear as hyperkeratotic papules, centrally depressed pits, and, less frequently, hemorrhagic macules.

More than 95% of persons with Darier disease have nail changes that may include white and red longitudinal bands (longitudinal erythronychia), onychorrhexis, onycholysis, brittle nails, splinter hemorrhages, longitudinal ridges of nails, wedge-shaped subungual hyperkeratosis, and V-shaped nicking/notching at the distal end of the nail plate (Figure 2).^{2,3,6,8,10-13} These changes may precede other signs of the disease.^2,12 While red longitudinal stripes are characteristic of Darier disease, the combined “sandwich” of white and red longitudinal bands resembling candy canes, often with a notch or onycholysis at the free margin of the nail, is pathognomonic.^1,4,7,8 Fingernails are affected more than toenails.³

Figure 2. Nail changes in Darier disease may include white and red longitudinal bands, onychorrhexis, onycholysis, brittle nails, splinter hemorrhages, longitudinal ridges of nails, wedge-shaped subungual hyperkeratosis, and V-shaped nicking/notching at the distal end of the nail plate.

Papules with a central depression, fissures, and ulcers may develop on the palate, buccal mucosa, or tongue.² The oral mucosa may assume a cobblestone appearance.^8,11 Intermittent parotid gland swelling is an infrequent but notable feature.^7,12 Affected patients often have dry eye syndrome with and more often without Sjögren syndrome, keratotic plaques on the eyelid, corneal opacities, and focal keratinization in the limbal conjunctiva.¹⁶

REFERENCES:

1. Chacon GR, Wolfson DJ, Palacio C, Sinha AA. Darier’s disease: a commonly misdiagnosed cutaneous disorder. J Drugs Dermatol. 2008;7(4):387-390.
2. Leung AKC, Barankin B. Itchy, smelly lesions and streaked nails in a teenager: Darier’s disease. Consultant Pediatricians. 2014;13(3):118-121.
3. Hohl D. Darier disease. UpToDate. Updated August 1, 2019. Accessed August 12, 2020. https://www.uptodate.com/contents/darier-disease
4. Green EK, Gordon-Smith K, Burge SM, et al. Novel ATP2A2 mutations in a large sample of individuals with Darier disease. J Dermatol. 2013;40(4):259-266. doi:10.1111/1346-8138.12082
5. Engin B, Kutlubay Z, Erkan E, Tüzün Y. Darier disease: a fold (intertriginous) dermatosis. Clin Dermatol. 2015;33(4):448-451. doi:10.1016/j.clindermatol.2015.04.009
6. Suryawanshi H, Dhobley A, Sharma A, Kumar P. Darier disease: a rare genodermatosis. J Oral Maxillofac Pathol. 2017;21(2):321. doi:10.4103/jomfp.JOMFP_170_16
7. Burge SM, Wilkinson JD. Darier-White disease: a review of the clinical features in 163 patients. J Am Acad Dermatol. 1992;27(1):40-50. doi:10.1016/0190-9622(92)70154-8
8. Halteh P, Jorizzo JL, Lipner SR. Darier disease: candy-cane nails and hyperkeratotic papules. Postgrad Med J. 2016;92(1089):425-426. doi:10.1136/postgradmedj-2016-134002
9. Takagi A, Kamijo M, Ikeda S. Darier disease. J Dermatol. 2016;43(3):275-279. doi:10.1111/1346-8138.13230
10. Schmieder SJ, Rosario-Collazo JA. Keratosis follicularis (Darier disease). StatPearls. Updated December 21, 2019. Accessed August 12, 2020. https://www.ncbi.nlm.nih.gov/books/NBK519557/
11. Gupta I, Dayal S, Kumar S. Guttate leukoderma in Darier disease: a rare presentation. Indian Dermatol Online J. 2019;10(3):337-340. doi:10.4103/idoj.IDOJ_314_18
12. Sehgal VN, Srivastava G. Darier’s (Darier-White) disease/keratosis follicularis. Int J Dermatol. 2005;44(3):184-192. doi:10.1111/j.1365-4632.2004.02408.x
13. Morin CB, Netchiporouk E, Billick RC, Srolovitz HD, Roshdy O. Hypopigmented segmental Darier disease. J Cutan Med Surg. 2015;19(1):69-72. doi:10.2310/7750.2014.13176
14. Bleiker TO, Burns DA. Darier’s disease with hypopigmented macules. Br J Dermatol. 1998;138(5):913-914. doi:10.1046/j.1365-2133.1998.02242.x
15. Terrom M, Dhaille F, Baltazard T, et al. Guttate leukoderma in Darier disease: case report and review. J Eur Acad Dermatol Venereol. 2016;30(12):e205-e209. doi:10.1111/jdv.13536
16. Lagali N, Dellby A, Fagerholm P. In vivo confocal microscopy of the cornea in Darier-White disease. Arch Ophthalmol. 2009;127(6):816-818. doi:10.1001/archophthalmol.2009.100