Primary care tomorrow

As the normal keratinocytes move upwards and differentiate they express different keratins. Keratins 5 and 14, which occur in the basal layer, are lost in the suprabasal cells and are replaced by two differentiationspecific keratins, Kl and K10. A gene defect of either Kl or K10 will cause fragility of the suprabasal cells, resulting in BCIE.1O-12 Keratin 2e, which like Kl is a type II keratin molecule, is also expressed in the outer layers of the normal epidermis, but at a more superficial level. McLean et al’ showed that the gene involved in IBS is keratin 2e. The same point mutation in the helix termination peptide was found in all the affected members of a five-generation family. When the K2e gene mutates, tonofilament aggregation occurs in the cells of the upper spinous layer. The different expression patterns of K2e and Kl or K10 thus help to explain the histological differences between BCIE and IBS. The defects in IBS patients are seen only in the granular and upper spinous layers and this distribution corresponds well with the site of expression of 2e keratin in normal skin.’3 By contrast, in BCIE filament clumping is found throughout the whole suprabasal compartment that expresses Kl and K10. Steijlen et all studied patients with IBS and ichthyosis exfoliativa and found co-segregation of the Kl and K2e genes that cluster on chromosome 12 in both conditions. Kremer et al9 likewise found the K2e mutation in both conditions, evidence that they are the same disease. EPPK is probably the commonest inherited form of palmar keratoderma. The soles and palms of affected infants become covered by thick brown fissured hyperkeratotic sheets with a livid red margin.. Keratin 9 is expressed only in the palms and soles and point mutations in the K9 gene cause EPPK." Thus there are at least six epidermal diseases that are probably due to keratin gene defects. In four of theseBCIE, IBS, EPPK, and the Dowling-Meara type of epidermolysis bullosa’-the mutation affects the highly conserved ends of the rod domain, the initiation and termination peptides. In the two milder variants of epidermolysis bullosa simplex (Weber-Cockayne and Kobner) the mutations in K5 and K14 are found in other locations and tonofilament clumping does not occur. Identification of specific gene mutations thus allows better classification of this confusing group of inherited blistering disorders, but we cannot yet explain why defective keratin filaments produce hyperkeratosis and why erythema occurs with some gene defects and not with others.

J L Burton Department of Dermatology, Bristol Royal Infirmary, Bristol, UK Epidermolysis bullosa simplex—a disorder of keratin. Lancet

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1992; 339: 29-30. Traupe H, Kolde G, Hamm H, Happle R. Ichthyosis bullosa of Siemens: a unique type of epidermolytic Dermatol 1986; 14: 1000-05.

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Steijlen PM, Perret CM, Schuurmans Steckhoven JH, Ruiter DJ, Happle R. Ichthyosis bullosa of Siemens: further delineation of the phenotype. Arch Dermatol Res 1990; 282: 1-5. Murdoch ME, Leigh IM. Ichthyosis bullosa of Siemens and bullous ichthyosiform erythroderma—variants of the same disease? Clin Exp

Dermatol 1990; 15: 53-56. Vakilzadeh F, Kolde G. Autosomal dominant ichthyosis exfoliativa. Br J Dermatol 1991; 124: 191-94. 6 Rothnagel JA, Traupe H, Wojcik S, et al. Mutations in the rod domain of keratin 2e in patients with ichthyosis bullosa of Siemens. Nature Genet 1994; 7: 485-90. 7 McLean WHI, Morley SM, Lane EB, et al. Ichthyosis bullosa of Siemens—a disease involving keratin 2e. J Invest Dermatol 1994; 103: 277-81. 8 Steijlen PM, Kremer H, Vakilzadeh F, et al. Genetic linkage of the keratin type II gene cluster with ichthyosis bullosa of Siemens and with autosomal dominant ichthyosis exfoliativa. J Invest Dermatol 1994; 103: 282-85. 9 Kremer H, Zeeuwen P, McLean WHI, et al. Ichthyosis bullosa of Siemens is caused by mutations in the keratin 2e gene. J Invest Dermatol 1994; 103: 286-89. 10 Cheng J, Syder AJ, Yu Q-C, Letai A, Paller AS, Fuchs E. The genetic basis of epidermolytic hyperkeratosis: a disorder of differentiationspecific epidermal keratin genes. Cell 1992; 70: 811-19. 11 Leigh IM, Lane EB. Mutations in the genes for epidermal keratins in epidermolysis bullosa and epidermolytic hyperkeratosis. Arch Dermatol 1993; 129 1571-77. 12 Lane EB. Keratin diseases. Curr Opin Genet Dev 1994; 4: 412-18. 13 Collin C, Moll R, Kubicka S, Ouhayoun J-P, Franke WW. Characterization of human cytokeratin 2, an epidermal cytoskeletal protein synthesized late during differentiation. Exp Cell Res 1992; 202: 132-41. 14 Reis A, Hennies H-C, Langbein L, et al. Keratin 9 gene mutations in epidermolytic palmoplantar keratoderma (EPPK). Nature Genet 1994; 6: 174-79.

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"I don’t see much in The Lancet on primary care: it’s a hot topic. Shall I help you put together some articles on the key issues?" I accepted this offer gladly, and the speaker and I mapped out the series of half-a-dozen articles that begins this week. Although the theme is global, we decided to concentrate on experience in Europe and the USA. Dr Barbara Starfield, from Johns Hopkins, starts us off by addressing the accusation (not unheard even in Baltimore) that primary-care medicine is second-rate medicine. We shall then proceed to specific issues-managed care, teamwork, prevention, shared care-and finish with some reflections from another noted US commentator, Dr Phil Lee, now Assistant Secretary of Health in Washington. And who was the begetter of this series? It was John Fry, of Beckenham, who by 40 years of research and example probably did more than any other doctor to raise the status of general practice. "Is primary care essential?", asks Dr Starfield. Alas, Dr Fry did not live to see the series in print-but his own answer to the question cannot be in doubt. Robin Fox The Lancet, London, UK