The appeal of molecular medicine for the peeling skin syndrome
By Warren R. Heymann, MD
April 17, 2018
Credit: JAAD
The term “peeling skin syndrome” (PSS) was coined by Levy and Goldsmith, for a form of congenital ichthyosis characterized by lifelong peeling of stratum corneum, pruritus, short stature, and easily removed anagen hairs. They noted that this syndrome was probably identical to cases of a congenital ichyosiform erythroderma described by Wiley in 1924. (1). The three cases described by Wiley were from consanguineous cousins, and he was able to presume that autosomal recessive inheritance was responsible (2)
There are two types of peeling skin syndrome – generalized and acral. The generalized form is divided into 2 (or possibly 3) variants: Type A (non-inflammatory and asymptomatic, characterized by generalized peeling); Type B (presenting with congenital ichthyosiform erythroderma such as those described by Wiley), and possibly; Type C (beginning in infancy with severe palmoplantar subcorneal blistering, ichthyosis, and keratotic cheilitis). The acral variant is characterized by peeling of the palms and soles. (3,4)
Type A PSS is caused by mutations in the CHST8 gene encoding a Golgi transmembrane N-acetylgalactosamine-4-O-sulfotransferase. Histologically, hyperkeratosis, parakeratosis, reduction of the granular layer and acanthosis are seen. There is separation of the stratum corneum from the underlying granular layer. (4)
Type B PSS is caused by deleterious mutations in the CDSN gene encoding corneodesmosin. To date, 6 different loss of function CDSN mutations have been reported. (5) The epidermis is psoriasiform with an absent or reduced granular layer, with marked parakeratosis and acanthosis. The split occurs at the level of the granular layer. (4)
The localized, acral PSS is inherited as an autosomal dominant disorder, presenting at birth or early childhood with blisters and subsequent peeling of the palms and soles and, to a lesser degree, on the dorsum of the hands and feet. Trauma, humidity, and friction are exacerbating factors. Transglutaminase 5 (TG5) is expressed in the corneal layer and is responsible for the formation of crosslinks between key proteins in the cornification process (involving loricrin, involucrin, filaggrin, and others). (6) Mutations in the TG5 gene lead to enhanced proteolysis resulting in the clinical phenotype. (7)
Filaggrin (FLG) and filaggrin-2 (FLG2) are key proteins involved in barrier function; mutations have been associated with atopic dermatitis. Next generation whole exome sequencing has revealed that a generalized ichthyotic variant of PSS due to mutations in the FLG2 gene. This has been reported in an 11-year-old girl and her brother, from consanguineous Moroccan parents (8) and multiple members from a consanguineous Saudi family (9).
Unfortunately, there has been no response to the standard litany of dermatologic therapies for PSS, so emollients and keratolytics remain the cornerstone of treatment. With discoveries of the molecular basis of the variants of PSS, novel targeted treatments will be on the horizon — that is most appealing.
Point to remember: There are generalized and localized forms of the the peeling syndrome. Only the acral variant is caused by a mutation in transglutaminase.
1. Levy SB, Goldsmith LA. The peeling skin syndrome. J Am acad Dermatol 1982; 606-613.
2. Wile UJ. Familial study of three unusual cases of congenital ichthyosiform erythroderma. Arch Dermatol Syph 1924; 10; 487-98.
3. Bansal et al. Peeling skin syndrome. BMJ Case Rep 2015; July 6; 2015.
4. Singhal AK, et al. A case of peeling skin syndrome. Indian Dermatol Online J 2017; 8:208-10.
5. Teye K, et al. A founder deletion of corneodesmosin gene is prevalent in Japanese patients with peeling skin disease: Identification of 2 new cases. J Dermatol Sci 2016; 82: 129-41.
6. Ruiz Rivero J, et al. Acral peeling skin syndrome: A case report and review of the literature. Actas Dermosifiliogr. 2016; 107(8):702-4.
7. Pampalakis G, et al. Enhanced proteolytic activities in acral peeling skin syndrome: A role of transglutaminase 5 in epidermal homeostasis. J Invest Dermatol 2017; 137: 1808-11.
8. Bolling MC, et al. Generalized ichthyotic peeling skin syndrome due to FLG2 J Invest Dermatol 2018; Mar 2 [Epub ahead of print].
9. Alfares A, et al. Peeling skin syndrome associated with novel variant in FLG2 Am J Med Genet 2017; 173A: 3201-4.
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