Multiple granular cell tumors are an associated feature of LEOPARD syndrome caused by mutation in PTPN11

We report a patient with a clinical and molecular diagnosis of LEOPARD syndrome (LS) associated with multiple granular cell tumors (MGCT). Bidirectional sequencing of exons 7, 12, and 13 of the PTPN11 gene revealed the T468M missense mutation in exon 12. This mutation has been previously reported in patients with LS. To our knowledge, this is the first report of MGCT associated with molecularly characterized LS and provides the first molecular evidence linking granular cell tumors (GCT) to the Ras/mitogen-activated protein (MAP) kinase pathway. We propose that MGCT can be associated with LS. Analysis of GCT from this case tested negatively for loss of heterozygosity (LOH) at the PTPN11 and NF1 loci and did not show deletions of the PTEN gene. The absence of LOH of PTPN11 supports published functional data that T468M is a dominant-negative mutation.     

Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations

Lynch syndrome or hereditary non-polyposis colorectal cancer is caused by mutations of DNA mismatch repair (MMR) genes. The extracolonic tumour spectrum includes endometrial, ovarian, gastric, small bowel, pancreatic, hepatobiliary, brain, and urothelial neoplasms. Families were referred on the basis of clinical criteria. Tumour immunohistochemistry and microsatellite testing were performed. Appropriate patients underwent sequencing of relevant exons of the MMR genes. Proven and obligate mutation carriers and first-degree relatives (FDRs) with a Lynch syndrome spectrum cancer were considered mutation carriers, as were a proportion of untested, unaffected FDRs based on the proportion of unaffected relatives testing positive in each age group. Kaplan–Meier analysis of risk to 70 years was calculated. One hundred and eighty-four Lynch syndrome spectrum extracolonic cancers in 839 proven, obligate, or assumed mutation carriers were analysed. Cumulative risk for females of an extracolonic tumour is 47.4% (95% CI 43.9–50.8). The risk to males is 26.5% (95% CI 22.6–30.4). There was no reduction in gynaecological malignancies due to gynaecological screening (examination, transvaginal ultrasound scan, hysteroscopy and endometrial biopsy). Males have a higher risk of gastric cancer than females (p = 0.0003). Gastric cancer risk in those born after 1935 does not justify surveillance. These penetrance estimates have been corrected for ascertainment bias and are appropriate for those referred to a high-risk clinic.     

Success of carotid endarterectomy in veterans: high medical risk does not equate with high surgical risk

BACKGROUND: The safety and efficacy of carotid endarterectomy (CEA) in stroke prevention has been well documented. But "high-risk" patients have traditionally been excluded from these studies and may be offered alternate therapies. We examined the safety of CEA in veterans, a medically high-risk group with multiple comorbidities. STUDY DESIGN: The records of all patients having CEAs performed between 1995 and 1999 in the Connecticut Veterans Affairs (VA) hospital were reviewed. Survival and freedom from stroke were determined using Kaplan-Meier survival analysis. The effects of risk factors on outcomes were analyzed with Cox regression. RESULTS: There were 128 CEAs performed in 120 patients, with a mean followup of 8.5 years. Most patients were symptomatic preoperatively and had a high incidence of hypertension (83%), coronary artery disease (64%), diabetes (37%), and pulmonary disease (22%). Incidences of perioperative (30-day) mortality (0.8%), stroke (1.6%), and myocardial infarction (0.8%) were low. Survival rates at 8.9 and 12 years were 50% and 13%, respectively, with 90% patient followup. Freedom from ipsilateral stroke was 90% at 12 years. Age (hazards ratio [HR] 1.1, p=0.004), hypertension (HR 2.6, p=0.04), and elevated creatinine (HR 3.7, p=0.001) were significant risk factors for mortality. Age (HR 0.8, p=0.07) and diastolic blood pressure (HR 1.2, p=0.06) were predictive of ipsilateral stroke. CONCLUSIONS: Despite poor health and symptomatic presentation, patients treated with CEA achieved excellent perioperative outcomes and were protected from stroke for the remainder of their lives. Multiple medical comorbidities should not be used as exclusion criteria for CEA.     

Grip and pinch strength: norms for 6- to 19-year-olds

The purpose of this study was to establish normative data for 6- to 19-year-olds on four tests of hand strength. The Jamar dynamometer was used to measure grip strength and a pinch gauge was used to measure tip, key, and palmar pinch. A sample of 231 males and 240 females from the seven-county Milwaukee area was tested, using standardized positioning and instructions. Results of this study indicate that increases in grip and pinch strength coincide with increases in chronological age, that males are stronger than females in all age groups, and that hand dominance does not significantly affect hand strength scores. Normative data collected in this study were slightly higher than norms from previous American and Australian studies.     

Linkage of a familial platelet disorder with a propensity to develop myeloid malignancies to human chromosome 21q22.1-22.2

Linkage analysis was performed on a large pedigree with an autosomal dominant platelet disorder and a striking propensity in affected family members to develop hematologic malignancy, predominantly acute myelogenous leukemia. We report the linkage of the autosomal dominant platelet disorder to markers on chromosome 21q22. Four genetic markers completely cosegregate with the trait and yield maximum logarithm of difference scores ranging from 4.9 to 10.5 (theta = .001). Two flanking markers, D21S1265 and D21S167, define a critical region for the disease locus of 15.2 centimorgan. Further analysis of this locus may identify a gene product that affects platelet production and function and contributes to the molecular evolution of hematologic malignancy.     

Splenic lymphoma with villous lymphocytes involves B cells with extensively mutated Ig heavy chain variable region genes

Splenic lymphoma with villous lymphocytes (SLVL) is a recently defined subgroup of chronic B-cell lymphoproliferative diseases. The characteristic morphology of the tumor cells, together with phenotypic and cytogenetic findings, indicate that it is a distinct entity, but the nature of the cell or origin and its relationship to other low- grade lymphomas is unclear. For B-cell tumors, analysis of the variable region heavy chain (VH) genes used to encode the clonal Ig has shown marked differences between histologic categories, both in gene usage and extent of somatic mutation. An investigation of VH genes used in five typical cases of SLVL has shown somatic hypermutation from germline sequences in all cases, indicating that the cell of origin has been exposed to the hypermutation mechanism. However, no clonal heterogeneity was detectable, demonstrating that the tumor cell does not accumulate further mutations. These characteristics are similar to those found in mature postfollicular B cells, such as plasma cells. The distribution of mutations leading to replacement amino acids differed among the cases, with three of five cases showing clear evidence for antigen selection.