NORD is very grateful to Gabriele Richard, MD, FACMG, Chief Medical Officer, GeneDx, Gaithersburg, Maryland, for assistance in the preparation of this reportrt
Peeling skin syndrome is a form of congenital ichthyosis with autosomal recessive inheritance. 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, painless, shedding or 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 people, 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.
To date, genetic changes in several distinct genes have been reported to cause the generalized type of peeling skin syndrome. These genes encode proteins that are important for formation, integrity and continual renewal of the outermost horny layer of the epidermis called stratum corneum.
PSS1, the inflammatory type, is caused by deleterious loss-of-function changes in the corneodesmosin gene, CDSN. Corneodesmosin is a secreted glycoprotein and main component of cell-cell adhesion structures called corneodesmosomes within the stratum corneum and is also found in hair follicles. While complete loss of corneodesmosin results in generalized peeling skin syndrome, abnormal corneodesmosin (due to sequence changes on only one copy of the gene) have been described in the autosomal dominant hair disorder ‘hypotrichosis simplex (MIM146520)’. In Japanese individuals, a particularly common cause of PSS1 is a genomic deletion of 6 genes including the entire CDSN gene. 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.
In only very few families with generalized, non-inflammatory PSS, loss-of-function changes in the carbohydrate sulfotransferase gene CHST8 causing PSS3, or in the protease inhibitor cystatin A gene CSTA causing PSS4 have been reported.
Finally, the transglutaminase-5 (TGM5) gene is responsible for the acral, localized form of peeling skin syndrome. Disease-causing genetic variants in TGM5 result in loss of function of this important cross-linking enzyme in the upper skin layers. One specific variant, p.Gly113Cys, is especially common among patients from Europe. Also CSTA-related peeling skin syndrome may be limited to hands and feet, thus demonstrating the overlap between generalized and acral forms.
All known forms of peeling skin syndrome are inherited as autosomal recessive traits. Genetic disorders are caused by changes or variants in 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 altered 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.
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. Peeling skin syndrome due to variants in the CHST8 and CSTA genes were reported in consanguineous Pakistani and in Bedouin families, respectively.
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.
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.
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