Faculty Bibliography

We report 10 cases of neonatal erosions or ulcerations in giant congenital melanocytic nevi. Histopathologic examination, performed in eight cases, demonstrated benign findings. Clinical follow-up for an average of 3.8 years (range 2 weeks to 8 years) has not revealed the development of cutaneous melanoma. We conclude that erosions or ulcerations in giant melanocytic nevi in neonates are often benign and do not necessarily signify the presence of cutaneous melanoma

We describe a 10-day-old term infant who presented to the emergency room with an acute pustular eruption. Laboratory tests and clinical outcome confirmed the diagnosis of erythema toxicum neonatorum. A full septic workup was performed and all cultures were negative. Wright-stained smear of pustular contents showed a predominance of neutrophils with 10% eosinophils. The white blood cell count was 19,000/mm3 with 10% eosinophils. The eruption resolved spontaneously at 15 days of age leaving no sequelae. This is the first fully documented case of erythema toxicum in a term infant occurring as late as 10 days of age. When erythema toxicum presents in an atypical fashion, diagnostic tests are important to exclude other causes of pustular dermatoses of the neonate

The pink-eyed dilution (p) locus is known to control the quantity of melanin pigment made within melanocytes and retinal pigment epithelium (RPE) in the eye. We have examined the effects of several mutant allele combinations at the murine p locus on the number and morphology of melanosomes in choroidal melanocytes and RPE cells as well as on the levels of four proteins known to be present within melanosomes: tyrosinase, tyrosinase-related proteins 1 and 2 (TRP-1 and TRP-2) and lysosome-associated membrane protein-1 (LAMP-1). By electron microscopy, we observed a modest diminution in the size and number of choroidal melanosomes in pbs/pJ mice but a more dramatic decrease in the RPE in comparison with wild-type P/P mice. By contrast, a drastic reduction in melanosome size and number was present in the choroid and RPE of pun/pun and p6H/pcp mice, and in the RPE of p6H/pcp mice, melanosomes were essentially undetectable. In wild-type mice, levels of tyrosinase, TRP-1 and TRP-2 were high at birth and showed a second peak of expression at 10-14 days of age, declining to undetectable levels by 42 days. All three mutant allele combinations reduced the levels of these melanosomal proteins with the relative severity of effects being p6H/pcp>pun/pun>pbs/pJ. In the null p6H/pcp mice, levels of these proteins were extremely low at birth, no postnatal peak was observed, and levels declined to undetectable by 14 days. Levels of LAMP-1 in wild-type mice rose initially and then declined whereas in the mutant mice, levels decreased gradually from birth. Higher levels of LAMP-1 were observed in each of the mutants than in the wild-type mice at 21 days of age. Our results demonstrate that mutations at the p locus affect the size, number, shape and contents of melanosomes, implicating the p gene product in the normal biogenesis of this organelle

Infantile hemangiomas are the most common tumor of infancy, occurring with an incidence of up to 10% of all births. They are benign but highly proliferative lesions involving aberrant localized growth of capillary endothelium. Although most hemangiomas occur sporadically and as single lesions, or in conjunction with pleiotropic genetic syndromes, we have previously identified six kindreds where hemangiomas appear to segregate as an autosomal dominant trait with high penetrance. Four such families contain affected individuals in three or more generations. In the current study, blood samples from five of these families were collected and used in a whole genome linkage search at 10-cM resolution. We established evidence for linkage to 5q in three families, and evidence for locus heterogeneity. The three 5q-linked families were further genotyped to generate haplotype information and narrow the candidate interval. Based on recombination breakpoint analysis, the interval exists between markers D5S2490 and D5S408, spanning 55 cM, and corresponding to 5q31-33. Using information from affected and unaffected individuals, the interval spans 38 cM between markers D5S1469 and D5S211. Three candidate genes involved with blood vessel growth map to this region: fibroblast growth factor receptor-4 (FGFR4), platelet-derived growth factor receptor-beta (PDG-FRB), and fms-related tyrosine kinase-4 (FLT4). The genes and gene products associated with familial hemangiomas may be involved somatically in the more common sporadic cases

We recently reported that a majority of hybrids generated in vitro between weakly metastatic mouse Cloudman S91 melanoma cells and human or mouse macrophages showed enhanced metastatic potential. With few exceptions, hybrids with enhanced metastatic potential also had elevated basal melanin content and increased responsiveness to MSH compared to parental cells. Here we investigated the hybrid melanotic phenotype in more detail, comparing the pigmentary systems of hybrids and parental Cloudman S91 cells by several techniques. Cells were studied by electron microscopy, cell lysates were analyzed for tyrosinase (E.C.1.14.18.1) activity, and melanosomal proteins were analyzed by gel electrophoresis and immunoblotting. Melanosomes in parental Cloudman melanoma cells were few in number and relatively amorphous, whereas those in the hybrids were numerous and heavily pigmented, containing highly organized lattice structures. Both basal and MSH-inducible tyrosinase activities were elevated several fold in hybrids compared to parental cells. Tyrosinase, TRP-2, and LAMP-1 from hybrids migrated more slowly on gels compared to the same proteins from parental melanoma cells, consistent with increased glycosylation. Migration of LAMP-1 from hybrids was similar to that from peritoneal macrophages, which also appeared to be more heavily glycosylated than LAMP-1 from Cloudman cells. By using 3H-glucosamine as a marker of N-glycosylation, its incorporation into tyrosinase and LAMP-1 was found to be elevated in hybrids, suppressed by N-glycosylation inhibitors, and stimulated by MSH to a greater degree in hybrids compared to parental cells. These results indicate N-glycosylation as an important regulatory pathway for MSH-induced melanogenesis and further suggest that altered N-linked glycosylation may be an underlying mechanism for regulation of both melanogenesis and metastasis in macrophage x melanoma hybrids

BACKGROUND: The pathogenesis of infantile hemangiomas is not yet understood. Growth factors and hormonal and mechanical influences have been thought to affect the focal abnormal growth of endothelial cells in these lesions. However, these influences may represent secondary responses to an underlying primary molecular event leading to the development of hemangiomas. OBSERVATIONS: We report the rare familial occurrence of hemangiomas and/or vascular malformations in 6 kindreds, suggesting autosomal dominant inheritance. In these families, multiple generations (2-4) were affected by hemangiomas or vascular malformations. In contrast to the generally accepted female-male ratio of 3:1 to 4:1 associated with sporadic hemangiomas, the families with hemangiomas in our study demonstrated a 2:1 ratio. Additionally, vascular malformations and hemangiomas were present in different members of the same family. The vascular lesions appeared to be transmitted in an autosomal dominant fashion with moderate to high penetrance. CONCLUSIONS: We have identified 6 families demonstrating autosomal dominant segregation of childhood hemangiomas. Additionally, family members with vascular malformations were identified in these kindreds. Physicians caring for children with hemangiomas and vascular malformations should include in their medical histories inquiries about vascular lesions in other family members, even when obvious lesions are not present in the parents. The identification of the mutation(s) underlying vascular lesions will provide insight into the pathogenesis of these familial hemangiomas and, potentially, common sporadic hemangiomas. In addition, such research would shed light on the regulation of angiogenic processes during development

Malignant cutaneous melanomas and metastases were taken directly from in situ lesions of genetically identical (C57BL/6 strain) Tyr-SV40E transgenic mice, and samples were analyzed by Western immunoblotting with antisera specific for the COOH terminus of each of four melanocytic proteins. These were tyrosinase, TRP-1, TRP-2, and Pmel 17/silver. Of the 13 melanomas examined, there were 5 melanotic primary tumors, 5 amelanotic primary tumors, and 3 amelanotic metastases. The melanotic tumors expressed all of the markers to some extent. In contrast, the amelanotic tumors lacked detectable levels of one, two, or three of the proteins, except for an apparently amelanotic tumor sample in which all were expressed, but in which some melanotic cells were likely to have been present. Thus, despite some variability, there is clearly a downward trend in the presence of these proteins as the tumors become amelanotic, a pigmentary change associated with ongoing malignant progression. In the amelanotic tumors, tyrosinase was most often deficient, whereas TRP-2 was most often persistently expressed. These results, obtained from melanomas of syngeneic origin, indicate that tumors in the relatively early stages of malignancy might be more responsive than later-stage tumors to immunotherapy involving an ensemble of antigenic peptides of the tested gene products. Moreover, TRP-2 peptides may be especially useful for therapeutic intervention at the later stages