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. Often, PSEK can be part of the clinical spectrum of other rare skin disorders, such as erythrokeratodermia variabilis or loricrin keratoderma.
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, regressing or disappearing sometime later during life. Rarely, waxing and waning may occur. In some patients, the chest and abdomen may become involved. Abnormally thickened or calloused skin on the palms and soles (palmoplantar keratoderma; PPK) is not uncommon and can be disabling.
The majority of individuals with features of PSEK belong to the clinical spectrum of erythrokeratodermia variabilis (EKV), hence a unifying name of ‘erythrokeratodermia variabilis et progressiva’ (EKVP) has been coined. The hallmark of classic EKV is the occurrence of figurate-outlined red patches, which seem to come and go quickly (so-called ‘fleeting erythema’), sometimes provoked by sudden temperature changes or other triggers. These red patches are more common in childhood and seem to disappear in adulthood. Features of both EKV and PSEK may be present within a single family, caused by a sequence change in a connexin gene. Extremely rarely, the sharply demarcated, thickened and red skin plaques may be distributed in a linear or whorl-like pattern due to mosaicism for a connexin gene mutation in a subset of epidermal skin cells.
Nevertheless, there are many other different forms and causes of PSEK, reflecting the clinical and genetic heterogeneity of this condition, which is delineated in the section below.
PSEK is typically caused by pathogenic variants (mutations) in any of the known genes or an as of yet unidentified gene. These conditions may occur at random (i.e., spontaneous new mutation) or be inherited in an autosomal dominant or autosomal recessive pattern.
Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene 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 non-working gene 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 working genes from both parents is 25%. The risk is the same for males and females.
Recent research has shown that PSEK may have several different causes and may be a feature of a variety of genetic skin disorders. Types of PSEK have been classified as follows based on genetic causes.
Autosomal dominant PSEK
Autosomal recessive PSEK
Information about the specific causal genes:
Erythrokeratodermia variabilis et progressiva: GJB3, GJB4, GJA1
The underlying cause of autosomal dominant inherited EKVP is sequence variants (mutations) in one of several connexin genes (GJB3, GJB4, GJA1), which produce components of gap junction channels. Gap junction channels of neighboring cells are assembled from hemichannels accumulating at the cellular membranes at points of cell-cell contact, and connect with another to allow the rapid exchange of ions and small molecules. Gap junction channels and hemichannels play an important role for control of cell volume, for a synchronized response of cells to stimuli and during growth and development. Disease-causing sequence variants on one copy of a connexin gene either have a toxic gain-of-function effect, leading to necrotic cell death due to augmented hemichannel function as shown for GJB3, and/or negatively interfere with the function of other connexins found in the top layers of the skin (epidermis). Very rarely, missense variants in both copies of the GJB3 gene are observed.
Loricrin keratoderma: LOR
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 in 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. Loricrin keratoderma is inherited in an autosomal dominant manner and caused by small nucleotide deletions/insertions on one copy of the LOR gene, which shift the reading frame and create a protein with significantly altered structural and biochemical characteristics, leading to its accumulation in the nucleus of keratinocytes.
Ceramide synthesis pathway gene KDSR
Autosomal recessive PSEK with or without thrombocytopenia; PERIOPTER (periorificial and ptychotropic erythrokeratoderma) syndrome: KDSR
KDSR-related PSEK has a broad spectrum of skin features of variable severity, with or without impaired platelet function (thrombocytopenia). Most reported individuals presented at birth with generalized redness, thickened, tight skin (collodion membrane) or severe features of Harlequin ichthyosis. Others had only localized involvement with red, thickened and scaly plaques in the diaper area, or developed thickened skin on palms and soles between 1-2 years of age. Hallmark of this form of PSEK are sharply demarcated, red, thickened, verrucous (wart-like) or scaly plaques or linear streaks on the cheeks, chin, nose, around eyes, mouth, and genital and anal regions, as well as palmoplantar keratoderma. Rarely, more extensive skin involvement on arms, legs and torso has been observed. At least half of the reported individuals developed already during infancy a reduced platelet count (thrombocytopenia), which is persistent and sometimes progressive, resulting in easy bruising or bleedings. This disorder is inherited in an autosomal recessive manner, and is caused by sequence variants on both copies of the KDSR gene. KDSR encodes an enzyme involved in the synthesis of complex lipids (ceramides) in skin and bone marrow. Disease-causing gene variants impair enzyme activity and lead to defective acylceramid biosynthesis, thus causing skin features and reduced platelet number and function.
Transient receptor potential channel gene TRPM4
Autosomal dominant PSEK:TRPM4
In three unrelated Chinese families, classic presentation of PSEK with palmoplantar keratoderma transgressing to the back of feet, ankles and lower legs, and fixed, sharp defined plaques around mouth, eyes, and genital areas has been reported in association with disease-causing variants in the TRPM4 gene. This gene encodes a transient receptor potential (TRP) channel that responds to various chemical and physical stimuli by mediating the influx of cations, such as potassium and sodium ions, in skin cells. They have been shown to be regulators of keratinocyte proliferation and differentiation. The reported sequence variants have a gain-of-function effect and increase baseline activity and membrane potential of cation channels, which in turn promotes cell proliferation. The disorder is inherited in an autosomal dominant pattern with a trend for spontaneous remission after puberty.
Very long chain fatty acid elongation gene ELOVL4
Spinocerebellar ataxia-erythrokeratoderma (SCA34): ELOVL4
Spinocerebellar ataxia and erythrokeratoderma (type Giroux-Barbeau; OMIM 133190) is a very rare form of ataxia originally described in a large French-Canadian family. Affected individuals manifested during childhood with symmetrical, well-demarcated, fleeting erythematous patches and scaling or hyperkeratotic plaques on dorsum of hands and feet and on limbs. While the skin lesions disappear in the 3rd decade of life, progressive gait ataxia due to cerebellar atrophy manifests in the fourth and fifth decade. Exome sequencing uncovered a pathogenic missense variant (p. L168F) in the ELOVL4 gene that completely co-segregates with the disorder and appears to have a dominant-negative effect. Other missense variants were reported in additional families, some with ataxia but without skin findings. Loss-of-function variants on one copy of the ELOVL4 gene cause isolated macular degeneration of the eyes, while complete loss of this enzyme due to variants on both copies of ELOVL4 have been associated with ichthyosis, intellectual disability, and spastic quadriplegia, resembling the autosomal recessive neuro-ichthyosis Sjoegren-Larsson syndrome. ELOVL4 encodes an enzyme of the elongase family responsible for the elongation of very long-chain fatty acids, which are crucial for formation of complex lipids in the skin, retina and CNS.
Desmosomal gene PERP
Autosomal dominant or recessive (erythro) keratoderma: PERP
One individual with generalized redness and thickening (hyperkeratosis) of the skin, severe palmoplantar keratoderma with thick plaques over pressure points, and wooly hair was shown to have a loss-of-function variant on both copies of the PERP gene (autosomal recessive inheritance). More frequently, protein truncating variants were observed on one copy of this gene, causing a different clinical presentation consistent with Olmsted syndrome. Affected individuals developed cheilitis, red, thick and scaly plaques around the mouth and outer ears, on buttocks, groin and abdomen, and palmoplantar keratoderma that extends to the dorsum of hands, feet, wrists and ankles (transgredient PPK). In addition, nails were thickened and hair was wooly or curly and yellow. The PERP gene codes for a transcription factor and apoptosis mediator that is also a protein component of desmosomes and other cell junctions. Disease-causing variants likely result in immature desmosomes, reduced cell-cell adhesion in response to mechanical stress and hyperproliferation of the epidermis.
Erythrokeratodermia-cardiomyopathy (EKC) syndrome- DSP
Erythrokeratodermia associated with cardiomyopathy manifests initially at or after birth as generalized erythrokeratoderma with thickened, peeling and cracking of skin on palms and soles and occasionally hyperkeratotic papules. The disorder involves also other ectodermal tissues, as evidenced by sparse or absent hair, nail dystrophy, enamel defects with widespread caries, hoarse voice and photophobia with corneal opacities leading to vision impairment. Skin lesions are very itchy (pruritus) and unresponsive to oral steroids and antihistamine treatment. There is failure to thrive, and in early childhood affected children develop progressive, left-ventricular dilated cardiomyopathy which can be fatal. This disorder is caused by specific, sporadic occurring missense variants in the DSP gene, which each introduce a proline residue in the spectrin repeat 6 (SR6) of desmoplakin. Desmoplakin is an abundant desmosomal protein in skin and heart responsible for proper cell-cell adhesion, and many other sequence variants have been shown to cause autosomal dominant or autosomal recessive disorders involving the skin, heart, or both, such as wooly hair, palmoplantar keratoderma and cardiomyopathy (Carvajal syndrome), lethal acantholytic epidermolysis bullosa, striate palmoplantar keratoderma, or arrhythmogenic cardiomyopathy (ARVC).
Other, not yet identified genes
Not all individuals with features of PSEK have causative sequence changes in the epidermal gene discussed above, and 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 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, more than 100 cases have been described in the medical literature. Autosomal recessive inherited forms of PSEK have been reported more commonly in Middle Eastern populations with a higher degree of marriage among blood relatives (consanguinity).
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 narrow-band UV-B light or systemic retinoids. Retinoids are synthetic versions of vitamin A that are used to treat many different skin conditions, and may be highly effective for EKVP and KDSR-related PSEK, but also may have serious side effects or adverse reactions and require rigorous monitoring. Other treatment is symptomatic and supportive.
To discuss the potential causes of PSEK, the risk of having children with this disorder and the possibility of genetic testing, genetic counseling is recommended for affected individuals and their families.
Novel therapeutic strategies aimed at specifically inhibiting the function of overactive connexin hemichannels (such as antimalarial agents, gentamycin) are being investigated and might be promising for connexin-related EKVP.
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.
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