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Review
. 2007 May;76(2):72-82.

Disorders of keratinisation: from rare to common genetic diseases of skin and other epithelial tissues

W H Irwin McLean  1 , Alan D Irvine
Affiliations
Review

Disorders of keratinisation: from rare to common genetic diseases of skin and other epithelial tissues

W H Irwin McLean et al. Ulster Med J. 2007 May.
No abstract available

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Figures

Fig 1
Fig 1
An epithelial cell in culture stained with a keratin antibody (green) reveals a dense meshwork of keratin intermediate filament bundles. This protein scaffold and associated molecules represent the main stress-bearing structure within epithelial cells.
Fig 2
Fig 2
Keratin genes/proteins are differentially expressed according to the many epithelial cell compartments of the human body, exemplified here by the epidermis, stained for just three keratins. (a) Shows K2e expression in the outermost layers of the epidermis (green staining; nuclei counterstained blue). (b) Shows K5 expression (green) in the basal cells, the lowermost cell compartment where cell division takes place (nuclei counterstained red). (c) Shows K10 expression in all suprabasal layers (red staining) but not the basal layer (nuclei counterstained blue).
Fig 3
Fig 3
The clinical features of epidermolysis bullosa simplex (EBS). (a) A baby with the severe Dowling-Meara form of EBS, characterised by widespread clustered blisters. (b) The more common Weber-Cockayne type of EBS affects mainly hands and feet. (c) Recessive EBS is more common in certain cultures where consanguineous unions are prevalent. (d) EBS with mottled pigmentation, caused by certain mutations that appear to affect pigment transportation as well as causing mild skin blistering.
Fig 4
Fig 4
Keratin protein domain organisation. Keratins are rod-like proteins of two varieties, type I and type II, encoded by 54 different human genes. Specific pairs of type I and II proteins assemble into rope-like 10 nm intermediate filaments within epithelial cells (see Fig 1). During the assembly process, the areas shaded red, at either end of the rod domain, are in close contact and interact to allow elongation of the filament. It is these functionally important areas where the majority of the most severe keratin mutations are located since the latter disrupt the end-to-end interactions. Mutations elsewhere in the molecule allow filament assembly but the resultant filaments are weaker than normal. This type of mutation generally results in milder disease phenotypes.
Fig 5
Fig 5
Dowling-Degos disease is characterised by reticulate pigmentary changes in the skin, without skin blistering, typically on the sub-exposed areas (a), and in the skin folds, such as the inframammary region (b).
Fig 6
Fig 6
Hyperkeratotic disorders due to mutations in suprabasal keratins. (a) Newborn infants with mutations in K1 or K10, the major suprabasal keratins of the epidermis, are erythrodermic and may also blister, whereas later in life (b), they tend to have widespread epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma, BCIE). (c) Mutations in the palm/sole specific keratin, K9, give rise to epidermolytic palmoplantar keratoderma, EPPK, where epidermolytic hyperkeratosis is confined to palmoplantar epidermis. (d) Mutations in K2e, a keratin whose expression is limited to the uppermost layers of the epidermis (see Fig 2), result in ichthyosis bullosa of Siemens, IBS, a milder disorder closely related to and easily confused with BCIE.
Fig 7
Fig 7
Some keratins have complex expression patterns and are found in several specific subsets of epithelial cells, such as K6a, K6b, K16 and K17. Mutations in these keratins cause the two major forms of pachyonychia congenita (PC-1 caused by K6a/K16 mutations, and PC-2, due to K6b/K17 mutations). (a) These keratins are found in the epithelial cells under the nail (the nail bed) where cell fragility results in hypertrophic nail dystrophy, the hallmark of PC. (b) Patients with either form of PC can have a number of skin cysts but these tend to be more prominent in PC-2. (c) All four PC-related keratins are expressed in palm and sole but K6b/K17 are less prominent in this tissue and patient with PC-2, seen here. (d) K6a and K16 are more highly expressed in palm and sole and so PC-1 patients tend to have more severe keratoderma, which is often very painful and debilitating.
Fig 8
Fig 8
In pachyonychia congenita (PC, see also Fig 7), the keratins involved are expressed to varying degrees in the oral epithelia. (a) Shows a PC-1 patient carrying a K6a mutation, who has quite prominent lingual leukokeratosis. (b) The clinical appearance of these white oral lesions in PC, led to the discovery that mutations in the oral mucosal keratin, K4 and K13, cause white sponge nevus – a benign disorder often encountered by dentists.
Fig 9
Fig 9
(a) Slit lamp examination of Meesman epithelial corneal dystrophy shows myriad fine cystic lesions throughout the cornea. (b) Light micrograph showing abnormal corneal epithelium of the proband. Bowman's membrane presents as a homogeneous eosinophilic subepithelial band. The epithelium appears acanthotic and disordered. Many keratinocytes contain periodic acid Schiff (PAS) positive fibrillar material (PAS stain, x200).
Fig 10
Fig 10
Monilethrix is characterised by brittle hair with varying degrees of alopecia. (a) Often there is perifollicular keratosis and erythema. (b) Light microscopy clearly demonstrates the beaded nature of hair in monilethrix. Nodes are separated by abnormally weathered and thinned ‘internodes’.
Fig 11
Fig 11
Filaggrin expression in the stratified cornified epidermis. Expression is first noted in the granular layer, where the pro-protein profilaggrin constitutes the major protein of the characteristic intracytoplasmic granules. Cross-linked filaggrin and keratin filaments are major constituents of the stratum corneum.
Fig 12
Fig 12
Tangential lighting nicely demonstrates the subtle very fine scaling seen in ichthyosis vulgaris (a). Atopic dermatitis (eczema) is a common disease of childhood that is characterised by itchy inflamed and often excoriated skin that is frequently secondarily infected (b).
See this image and copyright information in PMC

References

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