Search

Erythropoietic protoporphyria is a hereditary disorder of porphyrin metabolism caused by mutations in the ferrochelatase gene. Ferrochelatase catalyzes the chelation of ferrous iron into protoporphyrin IX to form heme. Mutation analysis was performed in four Spanish erythropoietic protoporphyria families resulting in the identification of four different mutations in the ferrochelatase gene. Two of them were novel mutations, a missense mutation (1157 A-->C, H386P) and a frameshift mutation (843delC) found in two Spanish families, respectively. The third and the forth Spanish patients carried already published ferrochelatase gene mutations, a nonsense mutation (343C-->T, R115X) and a missense mutation (557T-->C, I186T), respectively. The newly described frameshift mutation (843delC) predicted formation of an abrupt mRNA. The deleterious effect of His386 to Pro substitution as a result of mutation 1157 A-->C on the ferrochelatase activity was investigated by expressing the mutant ferrochelatase in Escherichia coli. The mutant ferrochelatase exhibited only 0.8% of the wild-type ferrochelatase activity. Prediction of the secondary structure of ferrochelatase suggested that the H386P mutation disrupted the original alpha-helical structure by way of introducing a turn, a rather drastic structural change of the enzyme sufficient to cause activity loss.

Genetic predisposition plays an important role in the development of nearly 10% of cases of cutaneous malignant melanoma (CMM). The CDKN2A gene has been described as responsible for melanoma susceptibility in a proportion of families with CMM linked to 9p. CDKN2A encodes a cyclin-dependent kinase inhibitor also implicated in the carcinogenesis of several sporadic tumors. Even though the incidence of other cancers is higher in CMM families, pancreatic adenocarcinoma is the only other well demonstrated cancer associated with CDKN2A mutations in some CMM pedigrees. We describe a family with four cases of CMM, eight patients affected by other cancers, and nine patients affected by dysplastic nevus (DN) syndrome. A CDKN2A frameshift mutation (358delG) was present in all the CMM patients, in at least three of the patients with other cancers (CDKN2A status is unknown in four patients), and in only two of the DN patients (CDKN2A status is unknown in one patient). An absence of linkage between chromosome 9p markers and the 358delG CDKN2A mutation and DN was detected, indicating genetic heterogeneity for DN and CMM in this family. The study strongly suggests that CDKN2A mutations are involved not only in the predisposition to CMM but also to several other types of cancer.

The porphyrias are uncommon diseases caused by enzymatic deficiencies in the heme pathway. In the 25 year period 1969-1994, the Department of Dermatology of the Hospital Clinic of Barcelona has been able to study 793 cases of porphyria (724 cases of PCT, 27 of EPP, 26 of PV, 5 of CEP, 5 of HEP, 5 of AIP, 1 of HCP). Homozygous expression of an enzymatic deficiency in the heme pathway produces severe disease. Commonly, clinical manifestations appear in the homozygous state (the autosomal recessive porphyrias). However, homozygous forms of autosomal dominant porphyrias may occur exceptionally. Moreover, there are cutaneous porphyrias whose clinical manifestations do not permit dermatologists to classify them clearly into one of the well-defined syndromes. These uncommon and atypical forms are difficult to recognize without biochemical and enzyme studies. The porphyrias have a wide clinico-biochemical spectrum, including a large proportion of well defined diseases. Nevertheless, atypical forms occur and may be difficult to evaluate. It is important to note the genetic heterogeneicity of porphyrias, which accounts for the varying phenotypic expression.

4 patients with chronic photocontact dermatitis were sensitive to cobalt salts. They presented as cases of contact dermatitis from cement or pig fodder with persistent lesions on exposed areas. Only 2 of them had standard patch test positive reactions to chromate and cobalt, but all showed positive photo-patch tests to cobalt. Photo-oxidation tests proved that cobalt salts are photosensitizing. Exposure to cobalt salts was responsible for the patients' chronic actinic dermatitis.

In our Department, the incidence of sensitization to cobalt has more than doubled in the last 5 years. 28% of cobalt-sensitive patients showed no other sensitivity. Of isolated cobalt sensitive patients, 68% were housewives. We determined by atomic absorption spectrophotometry with a graphite camera, the cobalt and nickel content of the 30 most popular Spanish domestic detergents and cleaners sold in 1985. 78.6% of them contain considerable amounts of cobalt.