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Peeling Skin Syndrome

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NORD is very grateful to Gabriele Richard, MD, FACMG, Chief Medical Officer, GeneDx, Gaithersburg, Maryland, for assistance in the preparation of this report

Synonyms of Peeling Skin Syndrome

Disorder Subdivisions

General Discussion

Peeling skin syndrome is a rare inherited skin disorder characterized by painless, continual, spontaneous skin peeling (exfoliation). Other findings may include blistering and/or reddening of the skin (erythema) and itching (pruritus). Peeling skin syndrome may clinically overlap with Netherton syndrome, which is also an autosomal recessive skin disorder belonging to the group of congenital ichthyoses, with onset in the neonatal period and infancy.

Symptoms

Peeling skin syndrome is a form of congenital ichthyosis. The ichthyoses comprise a group of dermatological disorders characterized by dry, thickened, scaly skin involving all or most of the body. Individuals with peeling skin syndrome exhibit lifelong spontaneous peeling of the outermost layer of the skin (horny layer, aka stratum corneum). Often, affected individuals and/or their caregivers can remove sheets of skin manually, comparable to skin peeling after a severe sunburn. Other findings associated with this disorder may include itching, short stature, and/or newly formed hairs that can be plucked out more easily than normal. The disorder is caused by a superficial detachment of the outermost horny layers of the skin. The generalized form of peeling skin syndrome has been further sub-classified into a non-inflammatory type (A) and an inflammatory type (B). In some cases, the condition is limited to the arms and legs (acral extremities), diagnosed as "acral peeling skin syndrome". In the acral types, most patients develop blisters and erosions on hands and feet at birth or during infancy, which is reminiscent of another blistering skin disorder, epidermolysis bullosa simplex.

Causes

The generalized inflammatory type of peeling skin syndrome is due to deleterious, autosomal recessive mutations in the corneodesmosin gene, CDSN. Corneodesmosin is a secreted glycoprotein that is involved in cell-cell adhesion within the outermost horny layers of the skin (corneodesmosomes) and is also found in hair follicles. While complete loss of corneodesmosin results in peeling skin syndrome, reduced protein function (due to deleterious mutations on only one copy of the gene) have been described in the autosomal dominant hair disorder ‘hypotrichosis simplex (MIM146520)’. The generalized inflammatory type of peeling skin syndrome may be reminiscent of skin features in individuals with Netherton syndrome, which is caused by autosomal recessive mutations in the SPINK5 gene, and also leads to detachment of the outer horny layers of the skin. The gene responsible for the acral form of peeling skin syndrome also has been identified. Investigators reported genetic changes or disruptions (mutations) of the transglutaminase-5 (TGM5) gene that result in loss of enzyme function of this important cross-linking protein in the uppermost skin layers. One specific mutation, p.Gly113Cys, is especially common among patients from Europe.

Neither the gene, nor the chromosomal location for the non-inflammatory type A of peeling skin syndrome has been determined.

Peeling skin syndrome is caused by genetic mutations that are inherited as an autosomal recessive trait. Genetic diseases are determined by specific genes associated with a particular trait. The genes are located on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits two abnormal copies of the disease gene, usually one from each parent. If an individual receives one normal gene copy and one abnormal gene copy for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene copy and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals are thought to be carriers for at least 4-5 abnormal recessive genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

To discuss the risk of having children with this disorder and the possibility of genetic testing, genetic counseling may be of benefit for affected individuals and their families.

Affected Populations

Peeling skin syndrome is a rare inherited disorder that, in theory, affects males and females in equal numbers. Less than 100 cases have been reported in the medical literature.

Related Disorders

Exfoliative dermatitis refers to a scaling skin disorder accompanied by distinct reddening (erythematous dermatitis) involving 90% or more of the skin surface. It is characterized by erythema and scaling involving the skin's surface that often obscures the primary lesions. It is frequently difficult for clinicians to find the cause of exfoliative dermatitis even though the history of illness prior to erythema and scaling is obtained. Often, biopsies and blood studies are required. The term red man syndrome is reserved for idiopathic exfoliative dermatitis in which no primary cause can be found, notwithstanding a variety of examinations and tests. This form of the disorder is characterized by marked hardening of the skin of the palms and soles, swelling (lymphadenopathy), and raised levels of immunoglobulin E.

Keratolysis exfoliativa congenital (also known as dyshidrosis lamellosa sicca) is limited to palms and soles with small, air-filled blisters and collarette-like scaling. It has been debated to be a subtype of dyshidrotic eczema, due to fungal infection, or drug reaction. Although this disorder shows microscopic evidence for premature falling-apart of the components of the outer horny layer of the epidermis (corneodesmolysis), no mutations were identified in TGM5 and other candidate genes, indicating that it is a distinct disorder from acral peeling skin syndrome.

Netherton syndrome is a rare type of autosomal recessive congenital ichthyosis characterized either by scaly plaques with a peculiar, double-edged border (so-called "ichthyosis linearis circumflexa") or by persistent, generalized redness, scaling, or, sometimes, peeling. The hair is often fragile and sparse due to a structural defect of the hair shafts that results in a ball-in-socket or bamboo stick-like appearance (trichorrhexis invaginata, "bamboo hair"). Another characteristic of Netherton syndrome is a predisposition to allergies such as asthma, or food allergies that cause skin eruptions. (For more information, choose "Netherton" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
A good history and physical exam are often sufficient to make the diagnosis, although specialized tests including surgical removal and microscopic evaluation (biopsy) of affected tissue may be necessary at times. The continual shedding of large sheets of skin distinguishes peeling skin syndrome from Netherton syndrome and from other types of autosomal recessive congenital ichthyosis, such as congenital ichthyosiform erythroderma. The skin of so-called "collodion babies" peels off after a few weeks and does not return, in contrast to patients with peeling skin syndrome whose symptoms return time after time.

Treatment
Treating peeling skin syndrome by applying skin softening (emollient) ointments, especially after a bath while the skin is moist, may offer some relief. Plain petroleum jelly or Vaseline is preferred. None of the corticosteroids or systemic retinoids (vitamin A derivatives) is indicated or effective, and all may have serious side effects or adverse reactions.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

Organizations related to Peeling Skin Syndrome

References

TEXTBOOKS
Richard G, Ringpfeil F. Ichthyoses, erythrokeratodermas and related disorders. In: Bolognia J, Jorizzo J, Rapini, et al (eds). Dermatology. Philadelphia, Mosby; 2003.

Champion RH, Burton JL, Ebling FJG, eds. Textbook of Dermatology. 5th ed. Blackwell Scientific Publications. London, UK; 1992.

JOURNAL ARTICLES
Chang YY, van der Velden J, van der Wier G, Kramer D, Diercks GF, van Geel M, Coenraads PJ, Zeeuwen PL, Jonkman MF. Keratolysis exfoliativa (dyshidrosis lamellosa sicca): a distinct peeling entity. Br J Dermatol. 2012 Nov;167(5):1076-84.

Cabral RM, Kurban M, Wajid M, Shimomura Y, Petukhova L, Christiano AM. Whole-exome sequencing in a single proband reveals a mutation in the CHST8 gene in autosomal recessive peeling skin syndrome. Genomics. 2012 Apr;99(4):202-8.

van der Velden JJ, Jonkman MF, McLean WH, Hamm H, Steijlen PM, van Steensel MA, van Geel M. A recurrent mutation in the TGM5 gene in European patients with acral peeling skin syndrome. J Dermatol Sci. 2012 Jan;65(1):74-6.

Telem DF, Israeli S, Sarig O, Sprecher E. Inflammatory peeling skin syndrome caused a novel mutation in CDSN. Arch Dermatol Res. 2012 Apr;304(3):251-5.

Israeli S, Zamir H, Sarig O, Bergman R, Sprecher E. Inflammatory peeling skin syndrome caused by a mutation in CDSN encoding corneodesmosin. J Invest Dermatol. 2011 Mar;131(3):779-81.

Kiritsi D, Cosgarea I, Franzke CW, Schumann H, Oji V, Kohlhase J, Bruckner-Tuderman L, Has C. Acral peeling skin syndrome with TGM5 gene mutations may resemble epidermolysis bullosa simplex in young individuals. J Invest Dermatol. 2010 Jun;130(6):1741-6.

Ilknur T, Demirtasoglu M, Akarsu S, et al. Peeling skin syndrome. Eur J Dermatol. 2006;16:287-9.

Cassidy AJ, van Steensel MAM, Steijlen PM, et al. A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome. Am J Hum Genet. 2005;77:909-17.

Garcia EG, Carreno RG, Martinez Gonzalez MA, Reyes JJ. Acral peeling skin syndrome: report of two cases. Ultrastruct Pathol. 2005;29:65-70.

Geyer AS, Ratajczak P, Pol-Rodriguez M, et al. Netherton syndrome with extensive skin peeling and failure to thrive due to a homozygous frameshift mutation in SPINK. Dermatol. 2005;210(4):308-14.

Levy-Nissenbaum E, Betz RC, Frydman M, Simon M, Lahat H, Bakhan T, Goldman B, Bygum A, Pierick M, Hillmer AM, Jonca N, Toribio J, Kruse R, Dewald G, Cichon S, Kubisch C, Guerrin M, Serre G, Nothen MM, Pras E Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin. Nat Genet 2003;34(2):151-153.

Zvulunov A, Cagnano E, Kachko L, et al. A new variant of autosomal recessive exfoliative ichthyosis. Pediatr Dermatol. 2002;19:382-87.

Sardy M, Fay A. Karpati S, et al. Comel-Netherton syndrome and peeling skin syndrome type B: overlapping syndromes or one entity. Int J Dermatol. 2002;41:264-68.

Hashimoto K, Hamzavi I, Tanaka K, et al. Acral peeling skin syndrome. J Am Acad Dermatol. 2000;43:1112-19.

Schneider I, Sebok B, Kosztolanyi G, et al. Comel-Netherton syndrome: evolution of manifestation in a 20-year follow-up and phenotypic overlap with peeling skin syndrome type B. Acta Derma Venereol. 2000;80:209-10.

Tastan HB, Akar A, Gur AR, et al. Peeling skin syndrome. Int J Dermatol. 1999;38:208-10.

Brusasco A, Veraldi S, Tadini G, et al. Localized peeling skin syndrome: case report with ultrastructural study. Br J Dermatol. 1998;139:492-95.

INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Peeling Skin Syndrome, Acral Type. Entry No: 609796: Last Update:2/22/11. Available at http://omim.org/entry/609796 Accessed:March 13, 2013.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Peeling Skin Syndrome. Entry No: 270300: LastUpdate;2/22/11. Available at http://omim.org/entry/270300 Accessed:March 13, 2013.

Report last updated: 2013/03/19 00:00:00 GMT+0