Keratolytic Winter erythema (also known as Oudtshoorn disease or Oudtshoorn skin) is a rare

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosome, allosomal (sex chromosome) pairs, which may have different structures. The DNA in au ...

dominant

skin disease A skin condition, also known as cutaneous condition, is any medical condition that affects the integumentary system—the organ system that encloses the body and includes skin, nails, and related muscle and glands. The major function of this ...

of unknown cause which causes redness and peeling of the

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...

on the

palm Palm most commonly refers to: * Palm of the hand, the central region of the front of the hand * Palm plants, of family Arecaceae **List of Arecaceae genera * Several other plants known as "palm" Palm or Palms may also refer to: Music * Palm (ba ...

s and soles. Onset, increased prominence and severity usually occurs during

winter Winter is the coldest season of the year in polar and temperate climates. It occurs after autumn and before spring. The tilt of Earth's axis causes seasons; winter occurs when a hemisphere is oriented away from the Sun. Different cultures ...

. It is a type of

genodermatosis Genodermatosis is a hereditary skin disease with three inherited modes including single gene inheritance, multiple gene inheritance and chromosome inheritance. There are many different types of genodermatosis, the prevalence of genodermatosis rang ...

. The name "Oudtshoorn skin" derives from the town of

Oudtshoorn Oudtshoorn (, ), the "ostrich capital of the world", is a town in the Western Cape province of South Africa, located between the Swartberg mountains to the north and the Outeniqua Mountains to the south. Two ostrich-feather booms, during 1865– ...

in the

Western Cape The Western Cape is a province of South Africa, situated on the south-western coast of the country. It is the fourth largest of the nine provinces with an area of , and the third most populous, with an estimated 7 million inhabitants in 2020 ...

province of

South Africa South Africa, officially the Republic of South Africa (RSA), is the southernmost country in Africa. It is bounded to the south by of coastline that stretch along the South Atlantic and Indian Oceans; to the north by the neighbouring countri ...

, where the disorder was first described. It is one of several

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

s known to be highly prevalent among the

Afrikaner Afrikaners () are a South African ethnic group descended from Free Burghers, predominantly Dutch settlers first arriving at the Cape of Good Hope in the 17th and 18th centuries.Entry: Cape Colony. ''Encyclopædia Britannica Volume 4 Part 2: ...

population.

Presentation

KWE is characterized by a number of anomalies affecting the skin. Erythema causes redness of the skin, which is generally associated with

inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

and irritation. Including erythema and

hyperkeratosis Hyperkeratosis is thickening of the stratum corneum (the outermost layer of the epidermis, or skin), often associated with the presence of an abnormal quantity of keratin,Kumar, Vinay; Fausto, Nelso; Abbas, Abul (2004) ''Robbins & Cotran Pathologi ...

(thickening of the

stratum corneum The stratum corneum (Latin for 'horny layer') is the outermost layer of the epidermis. The human stratum corneum comprises several levels of flattened corneocytes that are divided into two layers: the ''stratum disjunctum'' and ''stratum compact ...

), naturally occurring keratolytic peeling and

scaling Scaling may refer to: Science and technology Mathematics and physics * Scaling (geometry), a linear transformation that enlarges or diminishes objects * Scale invariance, a feature of objects or laws that do not change if scales of length, energ ...

, 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 Malpighian layer (''stratum mucosum'' or ''stratum malpighii'') of the epidermis, the outermost layer of the skin, is generally defined as both the stratum basale (basal layer) and the thicker stratum spinosum (spinous layer/prickle cell laye ...

(the innermost layer of the

epidermis The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water rele ...

). Peeling and scaling are caused by spreading

dissection Dissection (from Latin ' "to cut to pieces"; also called anatomization) is the dismembering of the body of a deceased animal or plant to study its anatomical structure. Autopsy is used in pathology and forensic medicine to determine the cause o ...

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 The buttocks (singular: buttock) are two rounded portions of the exterior anatomy of most mammals, located on the posterior of the pelvic region. In humans, the buttocks are located between the lower back and the perineum. They are composed ...

and

torso The torso or trunk is an anatomical term for the central part, or the core, of the body of many animals (including humans), from which the head, neck, limbs, tail and other appendages extend. The tetrapod torso — including that of a human � ...

in severe cases. Facial

lesion A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals. Types There is no designated classifi ...

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. KWE is inherited in an autosomal dominant manner. This means that the defective gene responsible for the disorder is located on an

autosome An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosome, allosomal (sex chromosome) pairs, which may have different structures. The DNA in au ...

(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.

Genetics

KWE is inherited in an autosomal dominant manner. This means that the defective gene responsible for the disorder is located on an

Pathophysiology

KWE is of 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 8 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 (the building material of DNA) and represents between 4.5 and 5.0% of the total DNA ...

. The function of enzymes in general are fundamentally subject to temperature. A

candidate gene The candidate gene approach to conducting genetic association studies focuses on associations between genetic variation within pre-specified genes of interest, and phenotypes or disease states. This is in contrast to genome-wide association studies ...

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 (LOH) is a type of genetic abnormality in diploid organisms in which one copy of an entire gene and its surrounding chromosomal region are lost. Since diploid cells have two copies of their genes, one from each parent, a sing ...

(simultaneous loss of function in both

allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chro ...

s of a gene) has been associated with

malignancy Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...

, including certain types of

breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and secret ...

and

lung cancer Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissue (biology), tissues of the lung. Lung carcinomas derive from tran ...

. During the investigation for a KWE candidate gene in this same region, twelve

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

transcripts were evaluated between

microsatellite A microsatellite is a tract of repetitive DNA in which certain DNA motifs (ranging in length from one to six or more base pairs) are repeated, typically 5–50 times. Microsatellites occur at thousands of locations within an organism's genome. ...

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 Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

''B-lymphoid tyrosine kinase''. Four other of these transcripts included a

myotubularin Myotubularin domain represents a region within eukaryotic myotubularin-related proteins that is sometimes found with the GRAM domain . Myotubularin is a dual-specific lipid phosphatase that dephosphorylates phosphatidylinositol 3-phosphate Phosp ...

('' MTMR8''), a potential human homologue of the

mouse A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

'' Amac1'' enzyme, a transcript similar to the mouse ''

L-threonine 3-dehydrogenase In enzymology, a L-threonine 3-dehydrogenase () is an enzyme that catalyzes the chemical reaction :L-threonine + NAD+ \rightleftharpoons L-2-amino-3-oxobutanoate + NADH + H+ Thus, the two substrates of this enzyme are L-threonine and NAD+, ...

'' gene, and one similar to a human

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

. 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.

Diagnosis

Treatment

Epidemiology

Oudtshoorn is a town in Western Cape (formerly

Cape Province The Province of the Cape of Good Hope ( af, Provinsie Kaap die Goeie Hoop), commonly referred to as the Cape Province ( af, Kaapprovinsie) and colloquially as The Cape ( af, Die Kaap), was a province in the Union of South Africa and subsequen ...

), 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 The Caucasian race (also Caucasoid or Europid, Europoid) is an obsolete racial classification of human beings based on a now-disproven theory of biological race. The ''Caucasian race'' was historically regarded as a biological taxon which, de ...

native-speakers of

Afrikaans Afrikaans (, ) is a West Germanic language that evolved in the Dutch Cape Colony from the Dutch vernacular of Holland proper (i.e., the Hollandic dialect) used by Dutch, French, and German settlers and their enslaved people. Afrikaans gra ...

, with northwestern

Europe Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a Continent#Subcontinents, subcontinent of Eurasia ...

lineage Lineage may refer to: Science * Lineage (anthropology), a group that can demonstrate its common descent from an apical ancestor or a direct line of descent from an ancestor * Lineage (evolution), a temporal sequence of individuals, populati ...

. 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 An ancestor, also known as a forefather, fore-elder or a forebear, is a parent or (recursively) the parent of an antecedent (i.e., a grandparent, great-grandparent, great-great-grandparent and so forth). ''Ancestor'' is "any person from whom ...

population, resulting in a loss of genetic diversity. In the context of KWE, the founder effect was confirmed by

haplotype A haplotype ( haploid genotype) is a group of alleles in an organism that are inherited together from a single parent. Many organisms contain genetic material ( DNA) which is inherited from two parents. Normally these organisms have their DNA or ...

analysis, which indicates that the

chromosomal A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...

origin of a possible

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

tic

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

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,, officially the Federal Republic of Germany, is a country in Central Europe. It is the second most populous country in Europe after Russia, and the most populous member state of the European Union. Germany is situated betwe ...

, 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 ) , song = ( en, "King Christian stood by the lofty mast") , song_type = National and royal anthem , image_map = EU-Denmark.svg , map_caption = , subdivision_type = Sovereign state , subdivision_name = Danish Realm, Kingdom of Denmark ...

References

External links

{{Urticaria and erythema Autosomal dominant disorders Genodermatoses Rare diseases Genetic disorders with OMIM but no gene