Keratolytic Winter Erythema

A number sign (#) is used with this entry because of evidence that keratolytic winter erythema (KWE) is caused by heterozygous duplication in a cis-acting regulatory element enhancer upstream of the CTSB gene (116810) on chromosome 8p23.

Description

Keratolytic winter erythema, also known as Oudtshoorn skin disease, manifests during childhood with recurrent episodes of palmoplantar erythema and centrifugal epidermal peeling. Lateral and dorsal aspects of the hands and feet can be involved. A less common finding is a slowly migratory, annular erythema that is seen mostly on the extremities. Between flares, the skin may appear unremarkable. Hyperhidrosis, associated with a pungent odor, is invariably present, and itching can occur. Peeling is preceded by the formation of dry blisters due to keratolysis, whereas formation of vesicles or bullae is rare. Cold weather, moisture, febrile diseases, and physical and mental stress can trigger exacerbations. In severely affected individuals, skin manifestations persist unremittingly. Penetrance of the disease is high, but expressivity is variable, even within the same family (summary by Ngcungcu et al., 2017).

Clinical Features

Findlay et al. (1977) observed a large number of individuals in South Africa with a hitherto undescribed inherited dermatosis traceable to certain 19th-century inhabitants of the province of Oudtshoorn. The disorder consisted of intermittent and recurrent centrifugal peeling with redness, particularly of the palms and soles. In more severe cases, similar patches were found extending up the limbs to the buttocks and the trunk. In most patients the disorder caused moderate inconvenience, but in some patients the disorder was incapacitating. The age of onset varied from infancy to early adulthood. It tended to subside in intensity after age 30. A striking feature was the onset and recurrence with cold weather, starting in March or April and continuing through the winter until August to October.

Starfield et al. (1997) referred to an apparently 'spontaneous' (new mutation) form of KWE reported in a 4-year-old girl with unusually severe involvement of the trunk (Krahl et al., 1994).

Huntington and Jassim (2006) reported a 12-year-old Norwegian girl with chronic, recurrent, painless nonpruritic palmar peeling that appeared in late autumn and resolved over the summer. Examination revealed thick hyperkeratotic cracking palms, but otherwise findings were normal. Her brother and a male cousin, as well as her paternal grandfather, were similarly affected; her father exhibited only subtle peeling of his fingertips. Skin biopsy of affected skin showed a thickened hyperkeratotic crust, mild acanthosis of the epidermis, and spotty areas of superficial perivascular chronic inflammation in the dermis. The authors concluded that these changes were consistent with Outdshoorn skin disease.

Inheritance

The transmission pattern of Oudtshoorn skin disease in the families reported by Findlay et al. (1977) was consistent with autosomal dominant inheritance.

Population Genetics

The prevalence of the disorder in the South African Afrikaans-speaking Caucasoid population was estimated to be 1 in 7,000 (Starfield et al., 1997).

Noting that all South African families with KWE could be traced back to Captain Francois Renier Duminy, born in Lorient, France, in 1747, Ngcungcu et al. (2017) stated that this founder effect resulted in the high prevalence of KWE in white Africaans speakers.

Mapping

Starfield et al. (1997) performed linkage studies in South African families and in a large German family and found linkage to the microsatellite marker D8S550 on chromosome 8p23-p22. Haplotype analysis supported a founder effect in the South African KWE families; the chromosome segregating with the disease in the German family demonstrated a different haplotype, suggesting that these chromosomes did not have a common origin.

Appel et al. (2002) constructed a physical and transcription map of the critical region for KWE using exon trapping, cDNA selection, genomic sequencing, and sequence analyses. A BAC contig located between the markers D8S550 and D8S1759 was constructed, generating a genomic sequence of 634 kb.

In a Norwegian family with KWE (family D), Ngcungcu et al. (2017) found significant linkage (maximum lod score, 3.3) between KWE and an approximately 6.6-Mb region (chr8:9,231,148-15,837,977, GRCh37) encompassing the KWE critical region.

Exclusion Studies

Reis (1994) demonstrated that KWE is not linked to the keratin clusters on chromosome 12 or chromosome 17.

Huntington and Jassim (2006) analyzed the markers D8S550 and D8S265 in a Norwegian family with KWE, but found that affected members did not share a common haplotype. The authors concluded that the disease in the Norwegian family must be due to a different gene than that of the previously reported South African families with KWE.

Molecular Genetics

In 7 South African families with KWE (families A, B, C, F, G, H, and I), Ngcungcu et al. (2017) identified a noncoding 7.67-kb tandem duplication within the KWE critical region on chromosome 8 that segregated with disease and was not found in 127 controls. In 2 Norwegian families with KWE (families D and E), they identified a 15.93-kb tandem duplication on chromosome 8 that segregated with disease and overlapped the South African duplication. Both duplications were located upstream of the CTSB gene (116810), and the 2.62-kb region of overlap encompasses an active enhancer element in keratinocytes that was shown to be associated with increased epidermal expression of CTSB.

Exclusion Studies

Appel et al. (2002) identified 12 transcripts within the critical region for KWE and analyzed their expression patterns by RT-PCR. One of the transcripts corresponded to the B-lymphocyte specific tyrosine kinase gene (BLK; 191305), and another corresponded to the myotubularin-related protein 8 gene (MTMR8; 606260). Each exon belonging to a transcript was screened for mutations by direct sequencing of genomic DNA from KWE patients of the German pedigree, previously linked to this region by Starfield et al. (1997). No potentially pathogenic mutation was identified in any of these transcripts.

In 4 South African families with KWE mapping to 8p23.1-p22 (designated KWE23, KWE36, KWE46, and KWE50), in which haplotype analysis was consistent with a founder effect, Hobbs et al. (2012) excluded the candidate genes CTSB (116810) and FDFT1 (184420).

Hull et al. (2013) screened the DUB3 gene (USP17L2; 610186) in KWE-affected individuals from 4 South African families and identified no pathogenic mutations.