Question

A 31-year-old Caucasian female with a history of seasonal rhinitis presents with a lifelong generalized red, scaly, pruritic rash. The patient states that the most noteworthy feature of the rash is the extensive and recurring skin peeling. On physical examination, there are broad, coalescing erythematous polycyclic patches and plaques with peripheral desquamative scale located on her upper extremities, lower extremities, chest, and back (Figure 1.).

Results from a 3mm punch biopsy are shown in Figure 2. A mutation in which of the following genes is responsible for her condition?

1. ATP2C1
2. SPINK5
3. KRT2
4. TGM5
5. HRAS

Correct Answer

Correct Answer: 2. SPINK5

Explanation

This patient’s clinical presentation and history coupled with a biopsy characterized by hyperkeratosis, focal hypergranulosis, epidermal acanthosis, and superficial perivascular lymphocytic infiltrate, is indicative of Netherton syndrome.^1-3 Netherton syndrome is a rare, autosomal recessive genodermatosis caused by mutations in the SPINK5 (B) gene, which encodes the serine protease inhibitor LEKTI. Deficiency in LEKTI prompts highly unregulated protease activity of KLK5 and KLK7, resulting in extensive desquamation of the stratum corneum, compromised skin barrier function, and heightened vulnerability to infections and allergic reactions.^1-4The clinical triad of Netherton syndrome includes: 1) Ichthyosis linearis circumflexa, marked by red, scaly annular plaques with the “text book” serpiginous, double-edged scaling; 2) Trichorrhexis invaginata, a hair shaft abnormality resulting in early broken hairs that appear as “bamboo hair” or “ball and socket” abnormalities under magnification; and 3) A spectrum of atopic disorders, including severe atopic dermatitis, asthma, food allergies, and metabolic imbalances. ^2,3

Netherton syndrome first presents in infancy and has no predilection for any race or gender. Although there is no approved treatment, management often includes protective emollients, topical corticosteroids, and off label systemic medications which more recently have included targeted therapies such as dupilumab. Of note, oral retinoids and topical calcineurin should be avoided in Netherton Syndrome. Integrating a multidisciplinary approach, including dermatologists and immunologists, is essential for further optimizing the quality of life for affected individuals.^1-4 .

Explanation of Incorrect Answers: Benign familial pemphigus (BFP), also known as Hailey-Hailey disease, is a rare autosomal-dominant genodermatosis caused by mutations in the ATP2C1 (A) gene, which disrupts calcium homeostasis of keratinocytes. ^5-7 The resulting dysfunction in desmosomes and cell-cell adhesion elicits impaired keratinocyte adhesion and widespread intraepidermal acantholysis. ^5-8 This chronic disease presents with episodic, painful, and pruritic plaques with flaccid vesicles and erosions (often described as stellate). Inguinal folds, inframammary folds, and axillae are the most common locations, and are typically bilateral.⁶ Heat, friction, and trauma are known to worsen active disease. BFP is usually diagnosed between the third and fourth decades of life. While there are no FDA approved treatments, antimicrobial washes, barrier protectants, and emollients are often used in conjunction with systemic therapies such as off label use of dapsone, oral retinoids, and botulinum toxin A. ^7,8

Ichthyosis bullosa of Siemens (IBS) is an autosomal dominant congenital ichthyosis clinically characterized by mild epidermolytic, hyperkeratosis on the limbs and lower trunk with flexural accentuation, intracorneal blistering, and the development of superficially denuded areas of hyperkeratotic skin (Mauserung phenomenon).^9-11 IBS manifests due to mutations in the KRT2 (C) gene. This gene encodes keratin 2, a structural protein crucial for maintaining the integrity of the upper epidermis. This disease can present as early as infancy and can persist into adulthood. Emollients and mild keratolytic preparations often provide effective therapy and can induce impressive remission. ^9,10

Acral peeling skin syndrome (APSS) is a rare, autosomal recessive genodermatosis characterized by shedding of the superficial layers of the epidermis, often accompanied by blister formation. APSS is caused by mutations in the TGM5 (D) gene, which is localized to chromosome 15q15. These mutations inhibit the cross-linking activity of the transglutaminase-5 enzyme. This enzyme is essential for the terminal differentiation of the epidermis and formation of the cornified cell envelop which is crucial for skin barrier integrity.^12,13 Patients with APSS have weakened cohesion of the stratum corneum which leads to the skin peeling that they experience. This painless peeling is typically located on the palmer, plantar, and dorsal surfaces of the hands and feet. Triggers include humidity, occlusion, immersion in water, and friction. APSS is not associated with other systemic symptoms, and treatment focuses on gentle skin care, hydration, and avoiding mechanical trauma.^12,13

Spitz nevi are benign melanocytic lesions that have clinical and pathological features similar to melanoma. Genetic mutations frequently implicated in Spitz nevi include HRAS (E) and BRAF mutations, which activate the RAS-MAPK signaling pathway, promoting melanocyte proliferation. Additionally, fusion genes involving kinases such as ALK, ROS1, NTRK1, or BRAF are identified in a subset of cases, driving tumor development.^14-16 Spitz nevi can usually be monitored, but particularly atypical lesions are often treated with surgical excision due to their pathologic overlap with melanoma.¹⁶

References

References 1. Stevanovic DV. Multiple defects of the hair shaft in Netherton’s disease: Association with ichthyosis linearis circumflexa. Br J Dermatol. 1969;81:851-7. 2. Chavanas S, Bodemer C, Rochat A, Hamel-Teillac D, Ali M, Irvine AD, et al. Mutations in SPINKS, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet. 2000;25: 141-2. 3.Netherton syndrome. Journal of the American Academy of Dermatology. March 2010; Volume 62, Issue 3, AB71. 4. Abdalrheem, W., Alluhayyan, O., Alharbi, A. A Case Report on Netherton Syndrome. Cureus. July 2020; 12(7): e9166. 5. Deng H, Xiao H. The role of the ATP2C1 gene in Hailey-Hailey disease. Cell Mol Life Sci. 2017;74(20):3687-3696. doi: 10.1007/s00018-017-2544-7 6. Kieffer, J., Le Duff, F., Montaudie, H., Chiaverini, C., Lacour, J., Passeron, T. Treatment of Severe Hailey-Hailey Disease with Apremilast. JAMA Dermatology. December 2018; 154(12): 1453-1456. 7. Antonanzas, J., Tomas-Valazquez, A., Rodriguez-Garijo, N., Estenaga, A., Silido-Vallejo, R. Apremilast in Combination with Botulinum Toxin-A Injection for Recalcitrant Hailey-Hailey Disease. International Journal of Dermatology. October 2021; 61(5): 600-602. 8. Mansilla-Polo, M., Abril-Perez, C., Navarro-Mira, M., Botella-Estrada, R. Recalcitrant Hailey-Hailey Disease with Satisfactory Response to Apremilast. Actas Dermo-Sifiliograficas. June 2023. 9. Ang-Tiu, C., Nicolas, M. Ichthyosis bullosa of Siemans. Journal of Dermatological Case Reports. September 2012; 6(3)L 78-81. 10. Traupe, H., Kolde, G., Hamm, H., Happle, R. Icthyosis bullosa of Siemens: a unique type of epidermolytic hyperkeratosis. Journal of American Academy of Dermatology. June 1986; 14(6): 1000-1005. 11. Sanclemente, G., Falabella, R., Escobar, C. Ichthyosis Bullosa of Siemens: A Topical Therapy Option. JAMA Dermatology. February 1999; 135(2): 217-218. 12. Sticova, E., Kveton, M., Dubska, M., Kubatova, A. Acral peeling skin syndrome: An underdiagnosed skin disorder. Indian Journal of Dermatology, Venereology and Leprology. 2019; 85(3): 316-318. 13. Rivero, J., Dominguez, M., Blanco, P., Fernandez, R. Acral Peeling Skin Syndrome: A Case Report and Literature Review. ACTAS Dermo-Sifiliograficas. October 2016; 107(8): 702-704. 14. Sarin, K., Sun, B., Bangs, C. Activating HRAS Mutation in Agminated Spitz Nevi Arising in a Nevus Spilus. JAMA Dermatology. September 2013; 149(9): 1077-1081. 15. Casso, E., Grin-Jorgensen, C., Grant-Kels, J. Spitz nevi. Journal of the American Academy of Dermatology. December 1992; 27(6): P901-913. 16. Gelbard, S., Tripp, J., Marghoob, A., Koenig, K., Kim, J., Bart, R. Management of Spitz nevi: A survey of dermatologists in the United States. Journal of the American Academy of Dermatology. August 2002; 47(2): P224-230.