NORD is very grateful to Gabriele Richard, MD, FACMG, Chief Medical Officer, GeneDx, Gaithersburg, Maryland, for assistance in the preparation of this report.
Progressive symmetric erythrokeratoderma (PSEK) represents a group of rare genetic skin disorders characterized by well-demarcated plaques of reddened, dry, and thickened skin. Typically, these lesions are distributed symmetrically on the body and tend to slowly expand and progress over time. The severity and progression of the disorder can vary greatly from one person to another, even among members of the same family. In some families, PSEK can be part of the clinical spectrum of other rare skin disorders, such as erythrokeratodermia variabilis or loricrin keratoderma. In the majority, the molecular cause of PSEKis not known.
The symptoms of PSEK usually develop shortly after birth or during the first year of life. Infants develop reddened plaques of thickened, rough and/or scaly skin, especially on the face, buttocks, arms and legs. Over time, these lesions can cover large areas of the body. The distribution of these lesions is almost perfectly symmetrical, meaning the size, shape and location of the lesions are extremely similar on both sides of the body. These plaques are slowly progressive increasing in number and size throughout early childhood before either stabilizing or disappearing sometime later during life. Rarely, waxing and waning may occur. In some cases, the chest and abdomen may become involved. Abnormally thickened or calloused skin on the palms and soles (palmoplantar keratoderma) is not uncommon.
The exact cause of PSEK in the majority of affected individuals is not known. In a subset of individuals with features of PSEK, there is clinical and molecular overlap with another skin disorder called erythrokeratodermia variabilis (EKV). In EKV, similar to PSEK, individuals gradually develop localized and sharply demarcated plaques of thickened or scaly skin. However, the hallmark of EKV is the coming and going of figurate-outlined red spots, which can be provoked by sudden temperature changes or other triggers. The underlying cause of autosomal dominant EKV are sequence variants (mutation) in several connexin genes (GJB3, GJB4, GJA1), which produce components of gap junction channels. Features of both EKV and PSEK have been observed within a single family, and the same disease-causing GJB4 (Connexin 30.3) variant was reported in individuals diagnosed either with EKV or PSEK. These findings indicate that EKV has a broad spectrum of features that may include those of PSEK. To reflect the occasional overlap between EKV and PSEK, sometimes the name ‘erythrokeratodermia variabilis et progressiva’ (EKVP) is used.
In another group of individuals, PSEK-like features are part of the clinical spectrum of loricrin keratoderma caused by a sequence variant (mutation) in the loricrin (LOR) gene. Individuals with loricrin keratoderma have generalized palmoplantar keratoderma with a honeycomb-like surface pattern and may develop circular constriction bands on their digits (so-called ‘mutilating palmoplantar keratoderma’). Individuals of two such families also had typical features of PSEK with well-demarcated red and thickened plaques on the extremities. A few other individuals with loricrin keratoderma were born with a collodion membrane and had generalized redness and scaling resembling congenital ichthyosis.
Nevertheless, most individuals with PSEK have no causative sequence change in the LOR or GJB3 gene. There is evidence that additional genes must be involved. More research is necessary to identify and confirm the specific genetic mutation(s) that cause PSEK and to determine the exact underlying mechanisms involved in the development of the disorder.
PSEK is typically caused by a genetic mutation in an as of yet unidentified gene(s), which may occur at random (i.e., spontaneous new mutation) or be inherited as an autosomal dominant trait. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to the offspring is 50 percent for each pregnancy regardless of the gender of the resulting child. To discuss the potential causes of PSEK, 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.
PSEK affects males and females in equal numbers. The prevalence of the disorder in the general population is unknown. The disorder was first described by Darier in 1911. Since then, fewer than 100 cases have been described in the medical literature.
A diagnosis of PSEK is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and specialized tests including genetic testing or surgical removal (biopsy) and microscopic evaluation of affected tissue.
The treatment of PSEK is directed toward the specific symptoms that are apparent in each individual such as reducing the thickening and cracking of the skin. Affected individuals may also benefit from treatment with skin softening ointments (emollients) such as petroleum jelly. Some but not all individuals with PSEK may also benefit from treatment with keratolytics. Keratolytics are drugs that cause the hardened outer layer of skin to come off (slough). Salicyclic acid is an example of a keratolytic agent that has been used to treat individuals with PSEK. Other keratolytics include lotions that contain alpha-hydroxy acids, propylene glycol, lactic acid, vitamin D analogs (calcipotriol), or urea. Some individuals with severe PSEK may respond to therapy with retinoids. Retinoids are synthetic versions of vitamin A that are used to treat many different skin conditions, but may have serious side effects or adverse reactions and require rigorous monitoring.
Other treatment is symptomatic and supportive.
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