Novel and recurrent p14 mutations in Italian familial melanoma.

CDKN2A and CDK4 are the only known high-penetrant genes conferring proneness to cutaneous melanoma. The CDKN2A locus consists of four exons and encodes several alternate transcripts, two of which are p16(INK4a) and p14(ARF), and originate from different open reading frames. Exon 1alpha is specific for p16(INK4a), while exon 1beta characterizes p14(ARF). Most CDKN2A mutations are located in exons 1alpha and 2, while exon 1beta variations have been identified in rare melanoma-prone pedigrees. In a previous study, we investigated 155 Italian melanoma cases, including 94 familial melanomas (FAMs) and 61 sporadic multiple primary melanomas (MPMs), for p16(INK4a)/CDK4 germline alterations and identified 15 p16(INK4a) and 1 CDK4 point mutations. In the present work, we extended our search to p14(ARF) mutations and CDKN2A deletions in the remaining samples. We identified the recurrent g.193+1G> A mutation in two FAM cases, while an additional pedigree displayed the previously undescribed variant g.161G> A. Multiplex ligation-dependent probe amplification (MLPA) screening for copy variations resulted negative in all cases. In Italy, the overall frequency of p14(ARF) mutations is 3.2% in FAM and 0% in sporadic MPM. Re-evaluation of our patients' cohort emphasizes that the chance of identifying CDKN2A/CDK4 mutations in FAM is mainly influenced by the number of affected family members and the presence of one or more MPM cases. Accordingly, mutation rate rises to 61% in selected cases. Further studies are expected in order to investigate CDKN2A rarer mutations, including atypical deletions and inherited epimutations.

Role of fibroblast-derived growth factors in regulating hyperpigmentation of solar lentigo.

BACKGROUND: Cutaneous pigmentation is regulated by a complex melanogenic network in which both keratinocytes and fibroblasts synthesize growth factors and cytokines. Solar lentigo (SL) is characterized by hyperpigmented lesions occurring on photodamaged skin areas. Despite the association of SL to ultraviolet (UV) exposure, the mechanisms underlying the development of these spots are not completely defined. OBJECTIVES: To analyse the involvement of the fibroblast-derived growth factors, hepatocyte growth factor (HGF), keratinocyte growth factor (KGF) and stem cell factor (SCF) in SL hyperpigmentation; to evaluate whether the photoageing process occurring in fibroblasts could be responsible for the altered expression of these cytokines; and to investigate a new possible role of KGF in regulating pigmentation through the specific induction of melanogenic cytokines by keratinocytes. METHODS: We performed immunohistochemical analysis of HGF, KGF and SCF on SL biopsies. We analysed the mRNA expression of these cytokines using an in vitro model of photoageing induced on fibroblasts. Finally, we evaluated the effects of KGF on the expression of melanogenic cytokines at the mRNA and protein levels on keratinocytes. RESULTS: We found positive staining for HGF, KGF and SCF in the upper dermis of SL lesions and a significant induction of the three cytokines in photoaged fibroblasts. We also demonstrated the contribution of KGF to pigmentation, showing its ability specifically to modulate the expression of SCF in keratinocytes. CONCLUSIONS: Fibroblasts may be persistently activated by UV exposure to release melanogenic growth factors; this inducible cytokine network acts both directly and indirectly through keratinocytes and may contribute to the hyperpigmentation of SL.

Microsatellite instability and loss of heterozygosity in melanoma.

Alterations in the repeat length of microsatellites have been identified recently in tumors arising in patients with hereditary nonpolyposis colon cancer and in several human sporadic tumors. We examined 40 sporadic melanomas and their corresponding nontumorous skin for microsatellite instability (MSI) and loss of heterozygosity (LOH) at chromosomes 2q, 3p25-26, 5q11.2-13.3, 5q21, 6q27, 9p21, 9p22-pter, 17p12, 17p12-p11.1, and 18q23. Specific loci were amplified by polymerase chain reaction, electrophoresed on polyacrylamide gels, transferred onto nylon membranes, and hybridized with 33P-end-labeled oligonucleotides. MSI was observed in eight of 40 (20%) melanomas at one of 10 loci examined. LOH was found at chromosome region 9p21 in 40%, at 9p22 in 22%, and at 17p in 13% of the informative cases. Comparison between clinicopathologic features of patients with and without MSI revealed no obvious differences. LOH at 9p21 was observed only in lesions greater than 1.5 mm in depth, suggesting that it does not represent an early event in sporadic melanoma. Our results indicate that 1) MSI is a genetic alteration in a proportion of sporadic melanoma, which may reflect a defect in genes involved in DNA replication fidelity; and 2) LOH at chromosome region 9p21 is a significant event in sporadic melanoma. The latter finding further supports the hypothesis that the 9p21 region may contain one or more tumor suppressor genes (e.g., MTS1/CDNK2) involved in the pathogenesis of melanoma.

Hereditary coproporphyria: unusual nervous system involvement in two cases.

Two cases of hereditary coproporphyria showed unusual nervous system involvement, one epilepsy with onset in childhood, and the other chronic central and peripheral nervous system damage. The literature is briefly discussed.

Cytogenetic findings in 20 melanomas.

We report cytogenetic studies performed on 20 patients with cutaneous malignant melanoma, characterized by clinical and histological parameters. Cytogenetic analyses were performed on peripheral blood lymphocytes, in order to exclude the presence of constitutional chromosomal aberrations, and on primary cell cultures obtained from neoplastic skin lesions. A metastasis was also cultured in order to characterize chromosome markers. Specific markers found in more than one patient were t(1;14)(q21;q32) and aberrations of the 4q21,8q24 and 10q24q26 regions. The research aims to identify possible subtypes of melanomas related to specific chromosomal markers. It is hoped that this will contribute to understanding of the aetiology and evolution of the disease in order to obtain a more exact classification. We compare our results with the data reported in the literature and discuss the possible role of the cytogenetic analyses in human malignant melanoma.

Reduced expression of CDKN2a/P16INK4a in mycosis fungoides.

Alterations in the CDKN2a gene have been demonstrated in a wide range of human tumors including hematopoietic malignancies. To verify whether altered CDKN2a expression is involved in the pathogenesis of mycosis fungoides (MF), we examined mRNA expression in 20 patients with MF by RT-PCR and dot blot hybridization. CDKN2a mRNA expression was undetectable in 5 of the 20 patients (25%), intermediate in 13 (65%) and high in 2 (10%). Immunohistochemical studies, which were performed in ten patients, revealed that in the four patients showing no mRNA, p16INK4a was expressed in <1% of neoplastic lymphocytes whereas in the four patients with an intermediate mRNA level, specific nuclear staining was present in 1-25% of tumor cells. In the two patients with high levels of CDKN2a mRNA, >25% of neoplastic lymphocytes stained positively. No direct correlation between clinicopathological and molecular findings was evident in our patients. DNA mutational analysis revealed no alterations in a total of six patients examined. Our results indicate that the lack of CDKN2a expression, as found in 25% of the patients, may have a pathogenetic role in MF even though the absence of CDKN2a mRNA was not associated with point mutations or minor gene deletions.

Diffuse febrile dermatosis in a patient with active ulcerative colitis under treatment with steroids and azathioprine: a case of Sweet's syndrome. Case report and review of literature.

Ulcerative colitis is an inflammatory bowel disease often associated with extra-intestinal manifestations, such as dermatological disorders. Of these, the most frequent are erythema nodosum and pyoderma gangrenosum, the two neutrophilic forms of dermatosis. Another is Sweet' s syndrome, which results in a sudden eruption of tender, raised erythematous or violaceous plaques/papules or nodules, less frequent vesicles, pustules or bullae, involving face, neck, arms and trunk. This skin disorder is frequently observed in patients with leukaemia or connective tissue diseases, while it is very rare in patients with inflammatory bowel disease. The present report deals with the case of a febrile diffuse skin eruption in a 53-year-old patient with moderately active ulcerative colitis after few days' treatment with steroids and azathioprine. At first, the dermatosis was addressed to an idiosyncrasy to azathioprine, which was, therefore, promptly discontinued. Histological examination of skin biopsies revealed the presence of features typical of a Sweet's syndrome. The eruption gradually improved as well as the patient's general condition, until complete regression was achieved following steroid treatment.

Porphyrins in Rotor's syndrome: a study on an Italian family.

Porphyrins in urine, plasma, erythrocytes and feces have been tested in two brothers affected by Rotor's syndrome and in three of their phenotypically normal relatives. In all five subjects normal values of delta-aminolevulinic acid and porphobilinogen in urine, and of prophyrins in plasma, erythrocytes and feces, were found. The two patients showed a marked increase in total urinary coproporphyrin excretion with a high percentage of isomer I. These observations confirm the hypothesis of a different route of the porphyrin excretion in Rotor's syndrome with a shift from the fecal route to the urinary one, and do not agree with the suggestion of an increased hepatic porphyrin production in this type of hyperbilirubinemia.

[Dowling-Degos disease and Verneuil disease]. / Maladie de Dowling-Degos et maladie de Verneuil.

In 8 out of a series of 21 cases Dowling-Degos disease was associated with Verneuil's disease (chronic hidradenitis suppurativa). This association might be more common, since both diseases are characterized by a single defect (follicular occlusion) and occur in similar cutaneous areas.

[Weary hereditary sclerosing poikiloderma]. / Poïkilodermie sclérosante héréditaire de Weary.

INTRODUCTION: Hereditary sclerosing poikiloderma is a genodermatosis with dominant autosomal transmission and variable penetration. The first case was described by Weary in 1969 in 7 members of two black families. CASE REPORT: A 10-year-old girl had localized regional poikiloderma of the fingers and club toes. These lesions were associated secondarily with linear symmetric bands of sclerotic tissue in the axiallary regions. On the X-ray examinations of the distal phalanges of the fingers and the toes showed a proximal growth foyer and absent ungueal phalanges, excepting in the fourth finger of the left hand. Capillaroscopy of the supra-ungueal fold of the fingers showed abnormal capillary circulation. Histology and ultrastructural examinations did not reveal any pathognomonic alterations. DISCUSSION: This case is the first reported in a white patient. The radiological aspect and the results of the capillaroscopy of the fingers and the toes have not been reported previously in this rare genodermatosis. Inheritance of this genodermatosis is poorly defined.

[Perforating pilomatrixoma in adults]. / Pilomatricoma perforante dell'adulto.

Two rare cases of perforating pilomatrixoma similar to those reported in the literature are described. Clinical examination showed in two old-women a reddish inflammatory exophytic tumor, 1 cm in diameter, with central erosive surface, with a rapid growth (3-5 months). Histologic examination showed: multiple masses of basophilic cells situated in the upper dermis making contact with the epidermis in a "follicle-like" opening; occurrence of transepithelial elimination phenomena.

[Congenital smooth muscle hamartoma. Clinical-histological considerations (3 cases)]. / Amartoma muscolare liscio congenito. Considerazioni clinico-istologiche (3 casi).

The Authors report 3 cases of "Congenital Smooth Muscle Hamartoma" (CSMH). CSMH presents as congenital patches or slightly indurated plaques with prominent overlying hair, often hyperpigmented. Histopathologic examination showed increased numbers of well-defined smooth muscle bundles in the superficial and deep dermis. CSMH and Becker's nevus should be considered in the differential diagnosis of any congenital hairy hamartoma.

[Verruciform xanthoma of the penis]. / Xantoma verruciforme del pene.

Verruciform xanthoma is a solitary verrucous lesion, usually occurring on the oral mucosa. It is characterized histologically by the presence of foam cells within elongated dermal papillae. Only few extra-oral case of V.X. have been reported. An unusual location of verruciform xanthoma of the penis is described.

Acne and smoking.

BACKGROUND.: Post-adolescent acne is an inflammatory disorder, whose cause is unknown. Contrasting data are available on correlation between acne and smoking habit. OBJECTIVES.: To verify the frequency of clinically non-inflammatory (atypical) post-adolescent acne (APAA) among women, a possible correlation with cigarette smoking, possible differences in sebum composition in a group of female smokers with acne compared to healthy smokers and non-smokers. METHOD AND RESULTS.: 1046 randomly selected women (25-50-years-old) participated at the study. In 60 selected female subjects we analyzed sebum composition for alpha-tocopherol, squalene and squalene monohydroperoxide. We found a high prevalence of APAA among women (74.6%), a strong correlation with smoking habit (p < 0.0001), as well as an increase in the grade of sebum peroxidation (p < 0.05) with a reduction in vitamin E (p = 0.02), in the subjects with acne compared to the controls. CONCLUSIONS.: Clinical evidence and experimental data showed a straight correlation between smoking habit and post-pubertal acne in which the clinically non-inflammatory type-APAA-is the most frequent. In the more severe cases we could consider APAA as a new entity (smoker's acne).