Alternative titles; symbols
SNOMEDCT: 254180002; ORPHA: 79397; DO: 0111346;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.13 | Epidermolysis bullosa simplex 2F, with mottled pigmentation | 131960 | Autosomal dominant | 3 | KRT5 | 148040 |
A number sign (#) is used with this entry because of evidence that epidermolysis bullosa simplex-2F with mottled pigmentation (EBS2F) is caused by heterozygous mutation in the keratin-5 gene (KRT5; 148040) on chromosome 12q13.
Epidermolysis bullosa simplex-2F with mottled pigmentation (EBS2F) is characterized by generalized skin blistering of intermediate severity beginning at birth, with mottled or reticulate pigmentation developing gradually. Focal keratoses of palms and soles and dystrophic, thickened nails develop over time. Although a single pathologic mutation in the KRT5 gene (P25L; 148040.0009) typically causes this phenotype, EBS patients with mottled pigmentation with other mutations in KRT5 or in other genes have been reported (summary by Has et al., 2020).
For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (131760).
Fischer and Gedde-Dahl (1979) reported a Swedish family in which 11 members presented with epidermolysis bullosa simplex with some unusual features, 10 of whom (1 male and 9 females) had a congenital mottled appearance of the skin. Both anomalies were inherited together in an autosomal dominant pattern. Recurrent blistering from birth resembled that of EBS Koebner, but in addition the patients showed 2- to 5-mm hyper- and hypopigmented spots giving the skin, especially of the limbs, a mottled 'dirty' appearance. 'Premature aging of the skin,' mild bruisability of the legs, and longitudinally curved nails were other features. The pigmentary anomaly was delayed in some individuals. Linkage with GPT (138200) on chromosome 8q was excluded. The epidermolysis without dyspigmentation in the eleventh individual suggested to the authors that the syndrome in the other 10 members may be due to genetic linkage of 2 independent genes and not to pleiotropism of a single mutant gene. Matthews and Peachey (1977) reported a father and daughter with EBS with pigmentation and palmar and plantar keratosis; pigmentation was delayed. Reports of other families (Sparrow et al., 1976; Verbov, 1980; Boss et al., 1981) suggested pleiotropism.
Histologically and ultrastructurally, the blistering in EBS with mottled pigmentation closely resembles that found in other EBS subtypes. This is consistent with a disorder of the basal keratinocyte cytoskeleton in which disease-causing mutations have been found within the central rod domains of keratins 5 and 14 (KRT14; 148066) (Irvine et al., 1997).
Horiguchi et al. (2005) studied a 3-generation Japanese family with EBSMP. In the proband (patient 1), small blisters on the distal extremities and abdomen appeared in infancy, diminished with age, and healed without scarring. Blisters occurred between the epidermis and the dermis with degeneration of the basal cells. Small spots of striking polygonal hyperpigmentation were present all over the trunk and extremities; the patient reported that most of these pigmented spots were not the result of apparent blistering. On the abdomen and back, whitish hypopigmented macules were also present, which with the hyperpigmentation gave an impression of dirty skin. Histology of a pigmented spot revealed liquifaction degeneration-like vacuolization in lower keratinocytes, deformed structure of the epidermal-dermal junction, and protrusion of the cytoplasm of vacuolized keratinocytes through discontinued basal lamina. Accumulated melanosomes were detected in some lower epidermal cells. The proband's cousin (patient 2) had similar but less severe blistering and pigmentation. Both patient 1 and 2 had small toenails. The mother of patient 1 and the father of patient 2, who were sibs, a younger brother of patient 1, and their grandmother also demonstrated blistering and pigmentation.
Shurman et al. (2006) studied a Mexican family and a Finnish family with EBSMP. In the Mexican family, a 34-year-old father and 5 of his 10 children were affected, with small blisters on palmoplantar surfaces. All affected individuals showed the characteristic mottled pigmentation of the skin, which consistently spared the face and was most apparent in the younger children; pigmentary changes in the father were subtle and had nearly resolved. In contrast, acral keratotic papules were much more striking in the older children (ages 13 and 14 years) and in the father. In all cases, mucosal surfaces were spared and there was no evidence of photosensitivity. In the Finnish family, the proband was a 47-year-old woman who had hyperpigmentation of the face, trunk, and legs in early childhood, as well as trauma-induced skin blistering without scarring or milia. She had severe diffuse palmoplantar keratoderma, papular hyperkeratotic lesions on the dorsal hands, and mild nail dystrophy. Her father, 2 sibs, 2 nieces, and 1 nephew were also affected; clinical information for those individuals was not reported. The authors stated that these were the first reported EBSMP patients of Hispanic or Finnish origin.
Tang et al. (2009) reported a 3-generation Chinese family with EBSMP. The proband and her affected sister had the typical features of herpetiform generalized blistering with mottled pigmentation, depigmentation, and nail dystrophy. The mottled pigmentation had a characteristic appearance, was more predominant on the lower abdomen and limbs, and did not seem to be the result of blistering. With age, the pigmented spots decreased and the depigmented maculae increased markedly. The sibs' mother reported that she had an identical presentation in childhood.
Glasz-Bona et al. (2010) reported a large 4-generation Hungarian pedigree with EBSMP. There were 10 affected members, 5 of whom were deceased. All had localized blistering and skin fragility in childhood, followed by the development of brownish, lentigo-like mottled pigmentation and hypopigmentation on the trunk and/or extremities during adolescence and adulthood. Two patients also had nail dystrophy.
Geller et al. (2013) described a 3-week-old girl with blistering on her hands, feet, and trunk from the time of birth. She had mucosal involvement but no nail abnormalities. Skin biopsy was suggestive of EBS. Upon follow-up at age 1 year, reticulated hypo- and hyperpigmentation of the axilla, lower abdomen, and inguinal folds were observed, supporting a diagnosis of EBSMP.
The transmission pattern of EBS2F in the families reported by Uttam et al. (1996) was consistent with autosomal dominant inheritance. The heterozygous mutation in the KRT5 gene in the patient with EBS2F reported by Irvine et al. (1997) occurred de novo.
In 2 unrelated families with EBSMP, one of which was the family originally described by Fischer and Gedde-Dahl (1979), Uttam et al. (1996) identified a mutation in the KRT5 gene (P25L; 148040.0009). The same mutation was found in a sporadic case (Irvine et al., 1997) and in the 2 families originally described by Boss et al. (1981) (Irvine et al., 2001), increasing the total number of EBSMP kindreds with this mutation to 7.
In 2 affected members of a Japanese family with EBSMP, Horiguchi et al. (2005) detected heterozygosity for a 1-basepair deletion in exon 9 of the KRT5 gene (c.1649delG; 148040.0017) resulting in frameshift and extension of the protein. Horiguchi et al. (2005) noted that this mutation had previously been identified in patients with EBS with migratory circinate erythema (EBS2E; 609352).
In a Mexican father, his 5 affected children, and a Finnish woman who all exhibited EBSMP, Shurman et al. (2006) identified heterozygosity for the P25L mutation in the KRT5 gene. The authors noted that these were the first reported EBSMP patients of Hispanic or Finnish origin, and that this strongly refuted a founder effect in EBSMP.
In 2 Chinese sibs with EBSMP and in their affected mother, Tang et al. (2009) detected heterozygosity for the c.1649delG mutation in KRT5.
In affected members of a Hungarian family with EBSMP, Glasz-Bona et al. (2010) identified heterozygosity for the previously reported P25L mutation in the KRT5 gene.
In a 1-year-old girl with EBSMP, who was negative for targeted analysis of the KRT5 and KRT14 genes for common EBS-associated mutations, Geller et al. (2013) sequenced the remainders of the KRT5 and KRT14 genes and identified heterozygosity for the c.1649delG mutation in KRT5. The authors noted that the same deletion previously had been reported in patients who had EBS with migratory circinate erythema as well as in other patients with EBSMP.
Roth et al. (2009) found that skin from Krt5-null mice showed increased levels of the inflammatory cytokines MCP1 (CCL2; 158105), CCL19 (602227), and CCL20 (601960), all of which are regulated by NFKB (see 164011) and involved in the recruitment, maturation, and migration of Langerhans cells in the epidermis. These changes were not observed in Krt14-null mice. The number of Langerhans cells were increased 2-fold in epidermis of neonatal Krt5-null mice. In contrast, TNFA (191160) was not changed, demonstrating the specificity of that process. The basal epidermis from Krt5-null mice also showed decreased p120-catenin (CTNND1; 601045). Enhanced Langerhans cell recruitment within the epidermis was found in 5 patients with various forms of EBS due to KRT5 mutations, but not in EBS patients with KRT14 gene mutations. These data provided an explanation for distinct, keratin-type-specific genotype-phenotype correlations in EBS, and suggested that the pathophysiology of EBS involves more than mutant keratins.
Boss, J. M., Matthews, C. N. A., Peachey, R. D. G., Summerly, R. Speckled hyperpigmentation, palmo-plantar punctate keratoses and childhood blistering: a clinical triad, with variable associations (a report of two families). Brit. J. Derm. 105: 579-585, 1981. [PubMed: 6457621] [Full Text: https://doi.org/10.1111/j.1365-2133.1981.tb00803.x]
Fischer, T., Gedde-Dahl, T., Jr. Epidermolysis bullosa simplex with mottled pigmentation: a new dominant syndrome. I. Clinical and histological features. Clin. Genet. 15: 228-238, 1979. [PubMed: 421361] [Full Text: https://doi.org/10.1111/j.1399-0004.1979.tb00972.x]
Geller, L., Kristal, L., Morel, K. D. Epidermolysis bullosa simplex with mottled pigmentation due to a rare keratin 5 mutation. cutaneous findings in infancy. Pediat. Derm. 30: 631-632, 2013. [PubMed: 23889190] [Full Text: https://doi.org/10.1111/pde.12206]
Glasz-Bona, A., Medvecz, M., Viragh, Z., Hatvani, Z., Blazsek, A., Karpati, S. Epidermolysis bullosa simplex with mottled pigmentation--mutation analysis proved the diagnosis in a four-generation pedigree. Europ. J. Derm. 20: 698-700, 2010. [PubMed: 20923750] [Full Text: https://doi.org/10.1684/ejd.2010.1080]
Has, C., Bauer, J. W., Bodemer, C., Bolling, M. C., Bruckner-Tuderman, L., Diem, A., Fine, J. D., Heagerty, A., Hovnanian, A., Marinkovich, M. P., Martinez, A. E., McGrath, J. A., and 10 others. Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility. Brit. J. Derm. 183: 614-627, 2020. [PubMed: 32017015] [Full Text: https://doi.org/10.1111/bjd.18921]
Horiguchi, Y., Sawamura, D., Mori, R., Nakamura, H., Takahashi, K., Shimizu, H. Clinical heterogeneity of 1649delG mutation in the tail domain of keratin 5: a Japanese family with epidermolysis bullosa simplex with mottled pigmentation. J. Invest. Derm. 125: 83-85, 2005. [PubMed: 15982306] [Full Text: https://doi.org/10.1111/j.0022-202X.2005.23790.x]
Irvine, A. D., McKenna, K. E., Jenkinson, H., Hughes, A. E. A mutation in the V1 domain of keratin 5 causes epidermolysis bullosa simplex with mottled pigmentation. J. Invest. Derm. 108: 809-810, 1997. [PubMed: 9129237] [Full Text: https://doi.org/10.1111/1523-1747.ep12292263]
Irvine, A. D., Rugg, E. L., Lane, E. B., Hoare, S., Peret, C., Hughes, A. E., Heagerty, A. H. Molecular confirmation of the unique phenotype of epidermolysis bullosa simplex with mottled pigmentation. Brit. J. Derm. 144: 40-45, 2001. [PubMed: 11167681] [Full Text: https://doi.org/10.1046/j.1365-2133.2001.03950.x]
Matthews, C. N. A., Peachey, R. D. Epidermolysis bullosa with pigmentation and palmar and plantar keratoses. Brit. J. Derm. 97 (suppl. 5): 44-45, 1977. [PubMed: 141936] [Full Text: https://doi.org/10.1111/j.1365-2133.1977.tb14321.x]
Roth, W., Reuter, U., Wohlenberg, C., Bruckner-Tuderman, L., Magin, T. M. Cytokines as genetic modifiers in K5-/- mice and in human epidermolysis bullosa simplex. Hum. Mutat. 30: 832-841, 2009. [PubMed: 19267394] [Full Text: https://doi.org/10.1002/humu.20981]
Shurman, D., Losi-Sasaki, J., Grimwood, R., Kivirikko, S., Tichy, E., Uitto, J., Richard, G. Epidermolysis bullosa simplex with mottled pigmentation: mutation analysis in the first reported Hispanic pedigree with the largest single generation of affected individuals to date. Europ. J. Derm. 16: 132-135, 2006. [PubMed: 16581562]
Sparrow, G. P., Samman, P. D., Wells, R. S. Hyperpigmentation and hypohidrosis. (The Naegeli-Franceschetti-Jadassohn syndrome): report of a family and review of the literature. Clin. Exp. Derm. 1: 127-140, 1976. [PubMed: 939040] [Full Text: https://doi.org/10.1111/j.1365-2230.1976.tb01408.x]
Tang, H. Y., Du, W. D., Cui, Y., Fan, X., Quan, C., Fang, Q. Y., Zhou, F. S., Yao, F. M., Wang, J. F., Yang, S., Zhang, X. One novel and two recurrent mutations in the keratin 5 gene identified in Chinese patients with epidermolysis bullosa simplex. Clin. Exp. Derm. 34: e957-e961, 2009. [PubMed: 20055872] [Full Text: https://doi.org/10.1111/j.1365-2230.2009.03703.x]
Uttam, J., Hutton, E., Coulombe, P. A., Anton-Lamprecht, I., Yu, Q.-C., Gedde-Dahl, T., Jr., Fine, J.-D., Fuchs, E. The genetic basis of epidermolysis bullosa simplex with mottled pigmentation. Proc. Nat. Acad. Sci. 93: 9079-9084, 1996. [PubMed: 8799157] [Full Text: https://doi.org/10.1073/pnas.93.17.9079]
Verbov, J. Hereditary diffuse hyperpigmentation. Clin. Exp. Derm. 5: 227-234, 1980. [PubMed: 7438517] [Full Text: https://doi.org/10.1111/j.1365-2230.1980.tb01693.x]