Keratolytic winter erythema
Encyclopedia
Keratolytic Winter erythema (KWE), also known as erythrokeratolysis hiemalis, Oudtshoorn disease and Oudtshoorn skin, is a rare autosomal
dominant skin disease of unknown etiology
which causes erythema
(redness) and keratolysis (peeling) of the skin
on the palm
s and soles
. Onset, increased prominence and severity usually occurs during winter
. It is a type of genodermatosis
.
The name "Oudtshoorn skin" derives from the town of Oudtshoorn in the Western Cape
province of South Africa
, where the disorder was first described. It is one of several genetic disorder
s known to be highly prevalent among the Afrikaner
population.
and irritation. Including erythema and hyperkeratosis
(thickening of the stratum corneum
), naturally occurring keratolytic peeling and scaling
, with increased manifestation in winter, are prevailing features of the disorder.
Erythema in KWE has been attributed to necrobiosis
(cellular death) within the malpighian layer
(the innermost layer of the epidermis). Peeling and scaling are caused by spreading dissection
of the stratum corneum, correlating to the underlying necrobiosis.
The effects of KWE appear intermittently as patches on the skin of the palms and soles, with these patches appearing on the limbs
, buttocks
and torso
in severe cases. Facial lesion
s of this type have also been reported with the disorder, though this is considered to be an extremely rare occurrence.
Onset and cyclical recurrence of KWE have shown to be associated with the arrival of winter, or winter-like weather. Worsening of symptoms during this time may be considered as an indicator of recurrent onset in patients known to have the disorder, and age of initial onset can be from early childhood to young adulthood, with attenuation of symptoms sometimes happening after age 30. Patients first exhibiting the disorder at a younger age may also experience worsened symptoms. Currently, no specific correlating factor or reason for winter-related manifestation has been established, though the coldness and dryer air common to winter conditions may be suspect. Winter onset is, however, considered to be a distinguishing feature of KWE among other erythematic skin disorders.
When peeling of skin occurs, the newly exposed layer of skin underneath is moist, raw and very sensitive. While this may result in minor discomfort and inconvenience, in severe cases of KWE where large areas of raw skin are present, it is often life-altering and debilitating.
), South Africa, where KWE ("Oudtshoorn skin") was first described. The disorder is quite prevalent among Afrikaners of South Africa, a population which can be defined as caucasoid
native-speakers of Afrikaans
, with northwestern Europe
an lineage
. Among this group, KWE occurs at a rate of approximately 1/7,200.
This relatively high rate of occurrence has been attributed to the founder effect
, in which a small, often consanguinous
population is formed out of the larger ancestral
population, resulting in a loss of genetic diversity
. In the context of KWE, the founder effect was confirmed by haplotype
analysis, which indicates that the chromosomal
origin of a possible gene
tic mutation
responsible for the disorder is particularly common among affected Afrikaners. This is also true in other South Africans of European descent with KWE, and the chromosome of interest in both these and Afrikaner patients strongly points to an unspecified ancestor or ancestral group that may have settled around the Oudtshoorn area.
A second lineage known to exhibit KWE has been reported in Germany
, although there it is less prevalent and appears to involve the chromosome from a different ancestral origin than that seen in Afrikaners. KWE has also been noted in other countries around the northwestern region of Europe, such as Denmark
.
.
A candidate gene
is a gene that is suspected to cause a disease or disorder. In KWE, this gene is known to be located in the area between chromosome 8q22 and 8q23. Within this region, the occurrence of loss of heterozygosity
(simultaneous loss of function in both allele
s of a gene) has been associated with malignancy
, including certain types of breast
and lung cancer
. During the investigation for a KWE candidate gene in this same region, twelve protein
transcripts
were evaluated between microsatellite markers D8S550 and D8S1759, which is a critical area shown to be the source of KWE pathogenesis. Among the twelve transcripts identified, one corresponded to the BLK
gene, which encodes the enzyme
B-lymphoid tyrosine kinase. Four other of these transcripts included a myotubularin
(MTMR8), a potential human homologue
of the mouse
Amac1
enzyme, a transcript similar to the mouse L-threonine 3-dehydrogenase
gene, and one similar to a human oncogene
. The remaining seven transcripts did not resemble any currently known genes. In all, none of the twelve transcripts displayed any evidence of pathogenic involvement with KWE. As a transcriptional map of this critical area is being drawn, based on microsatellite identification, haplotype analysis and other measures; localization of the gene associated with KWE pathogenesis is an ongoing process.
KWE is inherited in an autosomal dominant manner. This means that the defective gene responsible for the disorder is located on an autosome
(chromosome 8 is an autosome), and one copy of the defective gene is sufficient to cause the disorder when inherited from a parent who also has the disorder.
KWE can begin as a spontaneous mutation, first appearing in an individual with no previous family history of the disorder. This may be due to a genetic predisposition for the disorder, possibly connected to the Oudtshoorn ancestral line.
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
dominant skin disease of unknown etiology
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
which causes erythema
Erythema
Erythema is redness of the skin, caused by hyperemia of the capillaries in the lower layers of the skin. It occurs with any skin injury, infection, or inflammation...
(redness) and keratolysis (peeling) of the skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
on the palm
Hand
A hand is a prehensile, multi-fingered extremity located at the end of an arm or forelimb of primates such as humans, chimpanzees, monkeys, and lemurs...
s and soles
Sole (foot)
The sole is the bottom of the foot.In humans the sole of the foot is anatomically referred to as the plantar aspect. The equivalent surface in ungulates is the hoof.- Human sole :...
. Onset, increased prominence and severity usually occurs during winter
Winter
Winter is the coldest season of the year in temperate climates, between autumn and spring. At the winter solstice, the days are shortest and the nights are longest, with days lengthening as the season progresses after the solstice.-Meteorology:...
. It is a type of genodermatosis
Genodermatosis
Genodermatoses are inherited genetic skin conditions often grouped into three categories: chromosomal, single gene, and polygenetic....
.
The name "Oudtshoorn skin" derives from the town of Oudtshoorn in the Western Cape
Western Cape
The Western Cape is a province in the south west of South Africa. The capital is Cape Town. Prior to 1994, the region that now forms the Western Cape was part of the much larger Cape Province...
province of South Africa
South Africa
The Republic of South Africa is a country in southern Africa. Located at the southern tip of Africa, it is divided into nine provinces, with of coastline on the Atlantic and Indian oceans...
, where the disorder was first described. It is one of several genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
s known to be highly prevalent among the Afrikaner
Afrikaner
Afrikaners are an ethnic group in Southern Africa descended from almost equal numbers of Dutch, French and German settlers whose native tongue is Afrikaans: a Germanic language which derives primarily from 17th century Dutch, and a variety of other languages.-Related ethno-linguistic groups:The...
population.
Characteristics
KWE is characterized by a number of anomalies affecting the skin. Erythema causes redness of the skin, which is generally associated with inflammationInflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
and irritation. Including erythema and hyperkeratosis
Hyperkeratosis
Hyperkeratosis is thickening of the stratum corneum, often associated with a qualitative abnormality of the keratin, and also usually accompanied by an increase also in the granular layer...
(thickening of the stratum corneum
Stratum corneum
The stratum corneum is the outermost layer of the epidermis, consisting of dead cells that lack nuclei and organelles. The purpose of the stratum corneum is to form a barrier to protect underlying tissue from infection, dehydration, chemicals and mechanical stress...
), naturally occurring keratolytic peeling and scaling
Desquamation
Desquamation , also called skin peeling, is the shedding of the outermost membrane or layer of a tissue, such as the skin.-Skin:Normal, nonpathologic desquamation of the skin occurs when keratinocytes, after moving apically over about 14 days, are individually shed unnoticeably...
, with increased manifestation in winter, are prevailing features of the disorder.
Erythema in KWE has been attributed to necrobiosis
Necrobiosis
Necrobiosis is defined as the physiological death of a cell, and can be caused by certain conditions such as basophilia, erythema or the presence of a tumor...
(cellular death) within the malpighian layer
Malpighian layer
The Malpighian layer of the skin is a term that is generally defined as both the stratum basale and stratum spinosum as a unit, although it is occasionally defined as the stratum basale specifically...
(the innermost layer of the epidermis). Peeling and scaling are caused by spreading dissection
Dissection
Dissection is usually the process of disassembling and observing something to determine its internal structure and as an aid to discerning the functions and relationships of its components....
of the stratum corneum, correlating to the underlying necrobiosis.
The effects of KWE appear intermittently as patches on the skin of the palms and soles, with these patches appearing on the limbs
Limb (anatomy)
A limb is a jointed, or prehensile , appendage of the human or other animal body....
, buttocks
Buttocks
The buttocks are two rounded portions of the anatomy, located on the posterior of the pelvic region of apes and humans, and many other bipeds or quadrupeds, and comprise a layer of fat superimposed on the gluteus maximus and gluteus medius muscles. Physiologically, the buttocks enable weight to...
and torso
Torso
Trunk or torso is an anatomical term for the central part of the many animal bodies from which extend the neck and limbs. The trunk includes the thorax and abdomen.-Major organs:...
in severe cases. Facial lesion
Lesion
A lesion is any abnormality in the tissue of an organism , usually caused by disease or trauma. Lesion is derived from the Latin word laesio which means injury.- Types :...
s of this type have also been reported with the disorder, though this is considered to be an extremely rare occurrence.
Onset and cyclical recurrence of KWE have shown to be associated with the arrival of winter, or winter-like weather. Worsening of symptoms during this time may be considered as an indicator of recurrent onset in patients known to have the disorder, and age of initial onset can be from early childhood to young adulthood, with attenuation of symptoms sometimes happening after age 30. Patients first exhibiting the disorder at a younger age may also experience worsened symptoms. Currently, no specific correlating factor or reason for winter-related manifestation has been established, though the coldness and dryer air common to winter conditions may be suspect. Winter onset is, however, considered to be a distinguishing feature of KWE among other erythematic skin disorders.
When peeling of skin occurs, the newly exposed layer of skin underneath is moist, raw and very sensitive. While this may result in minor discomfort and inconvenience, in severe cases of KWE where large areas of raw skin are present, it is often life-altering and debilitating.
Epidemiology
Oudtshoorn is a town in Western Cape (formerly Cape ProvinceCape Province
The Province of the Cape of Good Hope was a province in the Union of South Africa and subsequently the Republic of South Africa...
), South Africa, where KWE ("Oudtshoorn skin") was first described. The disorder is quite prevalent among Afrikaners of South Africa, a population which can be defined as caucasoid
Caucasian race
The term Caucasian race has been used to denote the general physical type of some or all of the populations of Europe, North Africa, the Horn of Africa, Western Asia , Central Asia and South Asia...
native-speakers of Afrikaans
Afrikaans
Afrikaans is a West Germanic language, spoken natively in South Africa and Namibia. It is a daughter language of Dutch, originating in its 17th century dialects, collectively referred to as Cape Dutch .Afrikaans is a daughter language of Dutch; see , , , , , .Afrikaans was historically called Cape...
, with northwestern Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
an lineage
Kinship
Kinship is a relationship between any entities that share a genealogical origin, through either biological, cultural, or historical descent. And descent groups, lineages, etc. are treated in their own subsections....
. Among this group, KWE occurs at a rate of approximately 1/7,200.
This relatively high rate of occurrence has been attributed to the founder effect
Founder effect
In population genetics, the founder effect is the loss of genetic variation that occurs when a new population is established by a very small number of individuals from a larger population. It was first fully outlined by Ernst Mayr in 1942, using existing theoretical work by those such as Sewall...
, in which a small, often consanguinous
Consanguinity
Consanguinity refers to the property of being from the same kinship as another person. In that respect, consanguinity is the quality of being descended from the same ancestor as another person...
population is formed out of the larger ancestral
Ancestor
An ancestor is a parent or the parent of an ancestor ....
population, resulting in a loss of genetic diversity
Genetic diversity
Genetic diversity, the level of biodiversity, refers to the total number of genetic characteristics in the genetic makeup of a species. It is distinguished from genetic variability, which describes the tendency of genetic characteristics to vary....
. In the context of KWE, the founder effect was confirmed by haplotype
Haplotype
A haplotype in genetics is a combination of alleles at adjacent locations on the chromosome that are transmitted together...
analysis, which indicates that the chromosomal
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
origin of a possible gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
tic mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
responsible for the disorder is particularly common among affected Afrikaners. This is also true in other South Africans of European descent with KWE, and the chromosome of interest in both these and Afrikaner patients strongly points to an unspecified ancestor or ancestral group that may have settled around the Oudtshoorn area.
A second lineage known to exhibit KWE has been reported in Germany
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
, although there it is less prevalent and appears to involve the chromosome from a different ancestral origin than that seen in Afrikaners. KWE has also been noted in other countries around the northwestern region of Europe, such as Denmark
Denmark
Denmark is a Scandinavian country in Northern Europe. The countries of Denmark and Greenland, as well as the Faroe Islands, constitute the Kingdom of Denmark . It is the southernmost of the Nordic countries, southwest of Sweden and south of Norway, and bordered to the south by Germany. Denmark...
.
Pathophysiology
KWE is of unknown etiology (unknown cause), as at the present time, no specific mutation of any gene has been established as the cause of the disorder. Research has shown, however, that the gene involved is located on human chromosome 8Chromosome 8 (human)
Chromosome 8 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 8 spans about 145 million base pairs and represents between 4.5 and 5.0% of the total DNA in cells....
.
A candidate gene
Candidate gene
A candidate gene is a gene, located in a chromosome region suspected of being involved in the expression of a trait such as a disease, whose protein product suggests that it could be the gene in question...
is a gene that is suspected to cause a disease or disorder. In KWE, this gene is known to be located in the area between chromosome 8q22 and 8q23. Within this region, the occurrence of loss of heterozygosity
Loss of heterozygosity
Loss of heterozygosity in a cell is the loss of normal function of one allele of a gene in which the other allele was already inactivated. This term is mostly used in the context of oncogenesis; after an inactivating mutation in one allele of a tumor suppressor gene occurs in the parent's germline...
(simultaneous loss of function in both allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
s of a gene) has been associated with malignancy
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, including certain types of breast
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
and lung cancer
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
. During the investigation for a KWE candidate gene in this same region, twelve protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
transcripts
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
were evaluated between microsatellite markers D8S550 and D8S1759, which is a critical area shown to be the source of KWE pathogenesis. Among the twelve transcripts identified, one corresponded to the BLK
BLK (gene)
Tyrosine-protein kinase BLK also known as B lymphocyte kinase is an enzyme that in humans is encoded by the BLK gene.-Interactions:The tyrosine-protein kinase BLK has been shown to interact with UBE3A.-Further reading:...
gene, which encodes the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
B-lymphoid tyrosine kinase. Four other of these transcripts included a myotubularin
Myotubularin
Myotubularin domain represents a region within eukaryotic myotubularin-related proteins that is sometimes found with . Myotubularin is a dual-specific lipid phosphatase that dephosphorylates phosphatidylinositol 3-phosphate and phosphatidylinositol -bi-phosphate...
(MTMR8), a potential human homologue
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
of the mouse
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
Amac1
CCL18
Chemokine ligand 18 is a small cytokine belonging to the CC chemokine family that was previously called PARC . CCL18 is approximately 60% identical in amino acid sequence to CCL3...
enzyme, a transcript similar to the mouse L-threonine 3-dehydrogenase
L-threonine 3-dehydrogenase
In enzymology, a L-threonine 3-dehydrogenase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are L-threonine and NAD+, whereas its 3 products are L-2-amino-3-oxobutanoate, NADH, and H+....
gene, and one similar to a human oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
. The remaining seven transcripts did not resemble any currently known genes. In all, none of the twelve transcripts displayed any evidence of pathogenic involvement with KWE. As a transcriptional map of this critical area is being drawn, based on microsatellite identification, haplotype analysis and other measures; localization of the gene associated with KWE pathogenesis is an ongoing process.
Genetics
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
(chromosome 8 is an autosome), and one copy of the defective gene is sufficient to cause the disorder when inherited from a parent who also has the disorder.
KWE can begin as a spontaneous mutation, first appearing in an individual with no previous family history of the disorder. This may be due to a genetic predisposition for the disorder, possibly connected to the Oudtshoorn ancestral line.