Assessing risk for Mendelian disorders in a Bronx population.

BACKGROUND: To identify variants likely responsible for Mendelian disorders among the three major ethnic groups in the Bronx that might be useful to include in genetic screening panels or whole exome sequencing filters and to estimate their likely prevalence in these populations. METHODS: Variants from a high-density oligonucleotide screen of 192 members from each of the three ethnic-national populations (African Americans, Puerto Ricans, and Dominicans) were evaluated for overlap with next generation sequencing data. Variants were curated manually for clinical validity and utility using the American College of Medical Genetics (ACMG) scoring system. Additional variants were identified through literature review. RESULTS: A panel of 75 variants displaying autosomal dominant, autosomal recessive, autosomal recessive/digenic recessive, X-linked recessive, and X-linked dominant inheritance patterns representing 39 Mendelian disorders were identified among these populations. CONCLUSION: Screening for a broader range of disorders could offer the benefits of early or presymptomatic diagnosis and reproductive choice.

Large-cell transformation of a composite lymphoma.

Composite lymphoma is a rarely reported entity, defined as two or more morphologically distinct types of lymphoma at the same anatomic site, occurring either synchronously or metachronously. Since 1978, about 100 case reports of composite lymphoma have been cited, many involving combinations of low-grade B-cell lymphomas. To our knowledge, no cases of large-cell transformation of composite lymphoma have yet been described. We report the case of a patient who presented with diffuse large B-cell lymphoma (DLBCL) fifteen years after successful treatment for a mature B-cell lymphoma. Reassessment of the patient's lymph node from 1995, using techniques not previously available, resulted in a revised diagnosis of composite lymphoma, comprising both follicular lymphoma (FL) and small lymphocytic lymphoma (SLL). Analysis of B-cell gene rearrangement studies using BIOMED-2-based PCR, and of t(14;18) rearrangements by both FISH and PCR, provided evidence that the DLBCL evolved from transformation of the composite lymphoma, specifically from its FL component. B-cell gene rearrangement studies also supported a clonal relationship between the FL and SLL components of the composite lymphoma.

Ménétrier's disease associated with Kaposi's sarcoma.

Ménétrier's Disease is a giant fold gastropathy whose precise etiology has remained enigmatic. However, mucosal changes characteristic of Ménétrier's Disease have been linked to diverse pathologies, both infectious and malignant. Here, we describe a novel association: Ménétrier's mucosa developing on top of underlying Kaposi's Sarcoma. Two male patients, ages 24 and 31, with HIV/AIDS underwent gastric biopsies that demonstrated Kaposi's Sarcoma. When the former patient expired, a more complete postmortem histologic examination of his stomach was undertaken. For each patient, endoscopic findings at the time of biopsy revealed thickened gastric mucosa overlying the Kaposi's changes. Microscopically, this thickened mucosa comprised hyperplastic foveolar cells that extended to the muscularis mucosa, characteristic of Ménétrier's mucosa. In both cases, special stains confirmed this impression. Dissection of the 24 year-old patient's stomach at autopsy demonstrated that the Ménétrier's mucosa was limited to areas where there was underlying Kaposi's Sarcoma, and that this mucosa was not present when the underlying stroma was normal. Our findings indicate, therefore, an association between Ménétrier's mucosal changes and Kaposi's Sarcoma; such an association has not, to our knowledge, been described previously in the literature.

Metastatic patterns of cancers: results from a large autopsy study.

CONTEXT: Many studies have addressed metastatic patterns seen among various cancers. No recent studies, however, provide quantitative analyses of such patterns arising from a broad range of cancers based primarily on postmortem tissue analyses. OBJECTIVE: To provide a quantitative description of metastatic patterns among different primary cancers based on data obtained from a large, focused autopsy study. DESIGN: Review of data from 3827 autopsies, performed between 1914 and 1943 on patients from 5 affiliated medical centers, comprising 41 different primary cancers and 30 different metastatic sites. RESULTS: Testicular cancers were most likely to metastasize (5.8 metastases per primary cancer), whereas duodenal cancers were least likely to do so (0.6 metastases per primary cancer). Preferred metastatic sites varied among the primary cancers analyzed. Overall, regional lymph nodes were the most common metastatic target (20.6% of total), whereas testes were the least common (0.1% of total). CONCLUSIONS: Not surprisingly, different primary cancers tended to metastasize, with differing frequencies, to different sites. These varying metastatic patterns might be helpful in deducing the origins of cancers whose primary sites are unclear at presentation.

CADASIL Notch3 mutant proteins localize to the cell surface and bind ligand.

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a vascular dementia arising from abnormal arteriolar vascular smooth muscle cells. CADASIL results from mutations in Notch3 that alter the number of cysteine residues in the extracellular epidermal growth factor-like repeats, important for ligand binding. It is not known whether CADASIL mutations lead to loss or gain of Notch3 receptor function. To examine the functional consequences of CADASIL mutations, we engineered 4 CADASIL-like mutations into rat Notch3 and have shown that the presence of an unpaired cysteine does not impair cell-surface expression or ligand binding.