INTRODUCTION: Germline variants in CDH1 are associated with elevated risks of diffuse gastric cancer and lobular breast cancer. It is uncertain whether there is an increased risk of colorectal neoplasia. METHODS: This was a retrospective analysis of colonoscopy outcomes in patients with germline CDH1 pathogenic/likely pathogenic variants. RESULTS: Eighty-five patients were included with a mean age of 46.9 years. Initial colonoscopy found adenomatous polyps in 30 patients (35.3%), including advanced adenomas in 9 (10.6%). No colorectal cancers were identified on index or subsequent colonoscopies (when available). DISCUSSION: CDH1 carriers have colorectal neoplasia identified at similar rates as in the general population. Despite potential difficulties after gastrectomy, colorectal cancer screening remains important in this population.

A family with three affected males and a second family with a single affected male with intellectual disability, microcephaly, ophthalmoplegia, deafness, and Involuntary limb movements were reported by Schimke and Associates in 1984. The affected males with Schimke X-linked intellectual disability (XLID) syndrome (OMIM# 312840) had a similar facial appearance with deep-set eyes, downslanting palpebral fissures, hypotelorism, narrow nose and alae nasi, cupped ears and spacing of the teeth. Two mothers had mild hearing loss but no other manifestations of the disorder. The authors considered the disorder to be distinctive and likely X-linked. Whole genome sequencing in the single affected male available and the three carrier females from one of the families with Schimke XLID syndrome identified a 2 bp deletion in theBCAP31gene. During the past decade, pathogenic alterations of theBCAP31gene have been associated with deafness, dystonia, and central hypomyelination, an XLID condition given the eponym DDCH syndrome. A comparison of clinical findings in Schimke XLID syndrome and DDCH syndrome shows them to be the same clinical entity. The BCAP31 protein functions in endoplasmic reticulum-associated degradation to promote ubiquitination and destruction of misfolded proteins.

Lynch syndrome (LS) is the most common inherited colorectal cancer (CRC) syndrome with lifetime CRC risks of up to 70%.1 Conventionally, CRC specimens are screened for LS postoperatively but preoperative diagnosis of LS could impact decisions, such as the extent of resection and the need for additional risk-reducing surgeries for uterine and ovarian cancers. Few studies have addressed this issue2-5 and surveys indicate that most gastroenterologists are unsure that LS can be screened for preoperatively.6 We compared the yield of preoperative versus postoperative screening of LS by immunohistochemistry (IHC) and microsatellite instability (MSI) in unselected patients with newly diagnosed CRC who underwent testing under real-life laboratory conditions to mimic clinical practice.

Key Points Question Can RNA genetic testing (RGT) improve the diagnostic outcome of DNA genetic testing (DGT) in patients with suspected hereditary cancer predisposition? Findings In this diagnostic study, performing RGT clarified 88% of inconclusive DGT results evaluated, and in 47% of cases, the results were consistent with a molecular diagnosis of hereditary cancer predisposition, compared with 41%, in which inconclusive results were clarified as negative. Of 307 812 patients who underwent DGT for hereditary cancer, 7265 had putative splicing variants that were identified as likely pathogenic or of uncertain significance, indicating that they could benefit from RGT. Meaning In this diagnostic study, RGT as a supplement to DGT was associated with an improved outcome of hereditary cancer predisposition genetic testing and could affect medical management in at least 1 in 43 patients if performed concurrently.

BACKGROUND:Historically, three founder mutations in the BRCA1/2 (OMIM 113705; OMIM 600185) genes have been the focus of cancer risks within the Ashkenazi Jewish (AJ) population. However, there are several additional mutations associated with increased susceptibility to cancer in individuals of AJ ancestry.METHODS:We report three patients who exemplify the need to keep these additional founder mutations in mind when pursuing hereditary cancer genetic testing of individuals in this population. All gene sequences in this paper were aligned to reference sequences based on human genome build GRCh37/UCSC hg19.RESULTS:review of the literature discusses that the combined risk is 12.36%-20.83% forhaving 1 of the 10 hereditary cancer AJ founder mutations in the BRCA1, BRCA2, CHEK2 (OMIM 604373), APC (OMIM 611731), MSH2 (OMIM 609309), MSH6 (OMIM 600678), and GREM1 (OMIM 603054) genes for individuals of AJ ancestry.CONCLUSION:We recommend testing for all 10 of these AJ founder cancer susceptibility mutations for individuals within this population as standard screening in order to ensure appropriate cancer risk management and cascade testing.

Familial paraganglioma/pheochromocytoma (PGL/PCC) is genetically heterogenous with mutations in three of the four subunits of the heterotetrameric mitochondrial complex II enzyme succinate dehydrogenase (SDH) being causally responsible for the majority of cases. In addition to PGL/PCC an array of non‐paraganglial tumors have been described in affected individuals. We present a 30‐year follow‐up on the family of a deceased patient who synchronously developed malignant neuroblastoma (NBL), PCC, and renal cell carcinoma (RCC). Other family members with late onset disease have come to our attention, and molecular study revealed a mutation in the SDHB gene. Despite the embryologic relationship, NBL has been seen in only two previous patients with familial PGL/PCC, both with deletions of the SDHB gene. Review of the literature suggests the lack of a reported association between NBL and familial PGL/PCC may be an ascertainment bias. We further suggest that study of the SDH genes in NBL survivors who develop secondary solid tumors, particularly RCC, may correct this bias, and provide for more effective and comprehensive tumor screening in this patient population. © 2010 Wiley‐Liss, Inc.

Hunter–MacDonald syndrome (HMS) is a rare, autosomal dominant skeletal dysplasia with multiple malformations. The skeletal manifestations of HMS include short stature, scoliosis, epiphyseal dysplasia with early osteoarthritis leading to joint replacement, prominent humeral insertions for the deltoids, camptodactyly, subluxation of the thumbs, and malformed feet. Craniofacial manifestations include normal head circumference, tall forehead, bitemporal narrowing, ptosis, short palpebral fissures, and short philtrum. Decreased hearing acuity, transient cranial nerve palsies, congenital heart defects, and menigioma are also reported. Herein, we present two cases, and, through review of the manifestations of HMS in affected and at‐risk family members, we have observed that predisposition to brain tumor is a cardinal feature of this condition. © 2007 Wiley‐Liss, Inc.

Abstract Von Hippel–Lindau syndrome is a multisystem disorder inherited as an incompletely penetrant autosomal dominant trait. The chief features of the syndrome are tumors, both benign and malignant. Multiple visceral cysts are common as well. The von Hippel–Lindau gene, located on chromosome 3p25‐26 is a recessive tumor‐suppressor gene. Its function is complex. Some genotype‐phenotype correlation exists. Effective treatment can be accomplished by early clinical and molecular identification of gene carriers. Anticipatory guidance is the key.

We have identified a family segregating von Hippel-Lindau (VHL) disease with a previously unreported T547A mutation in exon 1 of the VHL gene that causes a Tyr112 to Asn missense alteration in the protein. The mutation was identified by nucleotide sequencing and confirmed by restriction enzyme digestion. The mutation cosegregated with the disease in all five tested affected individuals from the extended family. The family consists of more than 100 at-risk individuals over seven generations. To date, we have identified 13 affected individuals of whom seven have had renal cell carcinoma and one has had a pheochromocytoma. No other case of a neuroendocrine tumor of the pancreas or adrenal gland (pheochromocytoma) was found or recognized retrospectively. Other manifestations in this family include retinal angioma and hemangioblastoma of the central nervous system. We also found the T547A mutation in three asymptomatic members of the family, ages 12, 19, and 20. Another mutation, T547C, which causes Tyr112 to His, has been seen at the same position and has been associated with VHL type 2A (pheochromocytoma, but no renal cell carcinoma) in two families with a total of 22 affected individuals [Chen F, Slife L, Kishida T, Mulvihill J, Tisherman SE, Zbar B, 1996: J Med Genet 33:716-717]. Thus, different amino acid changes at the same position can cause very distinct clinical phenotypes. It will be interesting to elucidate the functional differences that underlie the different phenotypes.

American Journal of Medical GeneticsVolume 80, Issue 5 p. 533-534 Letter to the Editor Functioning carotid paraganglioma in the von Hippel-Lindau syndrome R. Neil Schimke, Corresponding Author R. Neil Schimke Department of Medicine, Division of Endocrinology and Genetics, Kansas University Medical School, Kansas City, KansasDepartment of Medicine, Kansas University School of Medicine, 39th and Rainbow Blvd., Kansas City, KS 66160-7318Search for more papers by this authorDebra L. Collins, Debra L. Collins Department of Medicine, Division of Endocrinology and Genetics, Kansas University Medical School, Kansas City, KansasSearch for more papers by this authorPaul G. Rothberg, Paul G. Rothberg Molecular Genetics Laboratory, Children's Mercy Hospital, Kansas City, MissouriSearch for more papers by this author R. Neil Schimke, Corresponding Author R. Neil Schimke Department of Medicine, Division of Endocrinology and Genetics, Kansas University Medical School, Kansas City, KansasDepartment of Medicine, Kansas University School of Medicine, 39th and Rainbow Blvd., Kansas City, KS 66160-7318Search for more papers by this authorDebra L. Collins, Debra L. Collins Department of Medicine, Division of Endocrinology and Genetics, Kansas University Medical School, Kansas City, KansasSearch for more papers by this authorPaul G. Rothberg, Paul G. Rothberg Molecular Genetics Laboratory, Children's Mercy Hospital, Kansas City, MissouriSearch for more papers by this author First published: 29 January 1999 https://doi.org/10.1002/(SICI)1096-8628(19981228)80:5<533::AID-AJMG21>3.0.CO;2-CCitations: 18AboutRelatedInformationPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessClose modalShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume80, Issue528 December 1998Pages 533-534 RelatedInformation RecommendedUrinary bladder paraganglioma in a case of von Hippel‐Lindau diseaseRP Athyal, H Al-Khawari, N Arun, F Abul, J Patrick, Australasian RadiologyParaganglioma SyndromeFRANCESCA SCHIAVI, THEODOROS SAVVOUKIDIS, FRANCO TRABALZINI, FRANCO GREGO, MICHELE PIAZZA, PIETRO AMISTÀ, SERENA DEMATTÈ, ANTONELLA DEL PIANO, MARIA ENRICA CECCHINI, ZORAN ERLIC, PAOLA DE LAZZARI, FRANCO MANTERO, GIUSEPPE OPOCHER, Annals of the New York Academy of SciencesMalignant pheochromocytoma with progressive paraparesis in von Hippel–Lindau diseaseR. Mössner, M. Keidel, European Journal of NeurologySomatostatin receptor expression in multiple endocrine neoplasia and in von hippel–lindau disease Lamberts, Hofland, A. J. V. D. Lely, De Herder, Journal of Internal MedicineOutcome of surgical treatment for carotid body paragangliomaJ. T. M. Plukker, E. P. Brongers, A. Vermey, A. Krikke, J. J. A. M. van den Dungen, BJS (British Journal of Surgery)

von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome predisposing to multifocal bilateral renal cell carcinomas (RCCs), pheochromocytomas, and pancreatic tumors, as well as angiomas and hemangioblastomas of the CNS. A candidate gene for VHL was recently identified, which led to the isolation of a partial cDNA clone with extended open reading frame, without significant homology to known genes or obvious functional motifs, except for an acidic pentamer repeat domain. To further characterize the functional domains of the VHL gene and assess its involvement in hereditary and nonhereditary tumors, we performed mutation analyses and studied its expression in normal and tumor tissue. We identified germline mutations in 39% of VHL disease families. Moreover, 33% of sporadic RCCs and all (6/6) sporadic RCC cell lines analyzed showed mutations within the VHL gene. Both germ-line and somatic mutations included deletions, insertions, splice-site mutations, and missense and nonsense mutations, all of which clustered at the 3' end of the corresponding partial VHL cDNA open reading frame, including an alternatively spliced exon 123 nt in length, suggesting functionally important domains encoded by the VHL gene in this region. Over 180 sporadic tumors of other types have shown no detectable base changes within the presumed coding sequence of the VHL gene to date. We conclude that the gene causing VHL has an important and specific role in the etiology of sporadic RCCs, acts as a recessive tumor-suppressor gene, and appears to encode important functional domains within the 3' end of the known open reading frame.

Recently, we evaluated a 27-month-old boy with congenital generalized nonspecific myopathy, Möbius sequence, Robin sequence, and failure to thrive. We think the child has the same entity described by Carey, Fineman, and Ziter in 1982 [J Pediatr 101:353-364] and as such represents only the third example of this unusual syndrome. Review of the large number of conditions in which the Robin sequence occurs supports heterogeneity. Our case strengthens the Möbius-Robin association and further defines the Carey-Fineman-Ziter syndrome as a viable entity. It is most likely inherited as an autosomal recessive trait.

Von Hippel Lindau disease (VHL) is a hereditary syndrome, associated with tumors and cysts in multiple organ systems, whose expression and age of onset are highly variable. The availability of a genetic test for the early and reliable detection of individuals carrying the defective gene would be beneficial for VHL patients and their relatives, since many of the manifestations of VHL can be successfully treated if detected in their early stages, while the complications of undetected disease can be devastating. We have previously shown that the VHL gene maps to chromosome 3p. To provide genetic markers for the development of a reliable diagnostic test, and to further narrow and eventually clone the VHL defect, we have generated DNA markers for chromosome 3p. With these markers, we have performed a multipoint genetic linkage analysis in 28 VHL pedigrees, comprising 470 individuals, 164 of whom were affected with VHL. Here we report the identification of tightly linked markers, including flanking markers that bracket the VHL gene to a small region on chromosome 3p25-p26. This finding has several major implications. While visceral cysts of the kidney, pancreas, and epididymis are commonly found in VHL and are considered diagnostic criteria for this disorder, they also occur in the general population. The presence of cysts, unaccompanied by other more typical lesions such as retinal and cerebellar hemangioblastoma, may therefore represent a major diagnostic problem, leading to errors in the assessment of disease status. The application of flanking markers for the VHL gene for presymptomatic diagnostic testing confirms that epididymal cysts are indeed not suitable as a diagnostic criterion in this disorder. Pheochromocytomas occur nonuniformly in VHL families and may also be associated with other hereditary tumor syndromes; our genetic studies imply that the phenotype in VHL families with and without pheochromocytomas is caused by defects within the same gene. The absence or presence of this tumor type is therefore due to the pleiotropic expression of a single gene rather than to the existence of several different genes for VHL. The region on chromosome 3p13-p14 known to contain several chromosomal translocation breakpoints in families with "pure familial renal cell carcinoma" is quite proximal to the VHL locus in 3p25-p26 we have identified. Chromosome 3p may therefore contain two loci for renal cell carcinoma: one gene (or genes) in 3p13-p14 and the VHL gene in 3p25-p26, whose aberration is also associated with other typical manifestations of VHL. Since renal cell carcinoma, pheochromocytoma, and visceral cysts can occur sporadically even in young people and may also be associated with other tumor syndromes, the availability of flanking markers for the VHL gene will be useful in identifying VHL gene carriers, particularly among those individuals at risk in whom these are the only manifestations of disease. The isolation and characterization of the VHL gene, based on the identification of flanking markers, will have important implications for diagnosis and treatment of patients with VHL, as well as for a much larger number of individuals having the sporadic counterparts of VHL-associated tumor types.

Von Hippel-Lindau disease (VHL) is an autosomal dominant disorder with inherited susceptibility to various forms of cancer, including hemangioblastomas of the central nervous system, phaeochromocytomas, pancreatic malignancies, and renal cell carcinomas. Renal cell carcinomas constitute a particularly frequent cause of death in this disorder, occurring as bilateral and multifocal tumours, and presenting at an earlier age than in sporadic, non-familial cases of this tumour type. We report here that the VHL gene is linked to the locus encoding the human homologoue of the RAF1 oncogene, which maps to chromosome 3p25 (ref. 4). Crossovers with the VHL locus suggest that the defect responsible for the VHL phenotype is not a mutation in the RAF1 gene itself. An alternative or prior event to oncogene activation in tumour formation may be the inactivation of a putative 'tumour suppressor' which can be associated with both the inherited and sporadic forms of the cancer. Sporadic renal cell carcinomas have previously been associated with the loss of regions on chromosome 3p (refs 5, 6). Consequently, sporadic and VHL-associated forms of renal cell carcinoma might both result from alterations causing loss of function of the same 'tumour suppressor' gene on this chromosome.

A case of proximal 3p deletion is reported in tumor cells from a patient with renal cell carcinoma and von Hippel-Lindau disease. This is the first report of this deletion with renal cell carcinoma. With the previously detected translocations at the same breakpoint, this report confirms the 3p14 breakpoint as critical in this neoplasm. This strongly suggests that renal cell carcinoma results from a change in the genetic material in the proximal short arm of chromosome #3.

American Journal of Medical GeneticsVolume 17, Issue 3 p. 706-706 Letter to the Editor Response to Serville et al William A. Horton, William A. Horton Medical Genetics Program Department of Pediatrics University of Texas Health Science Center Houston, TexasSearch for more papers by this authorDavid J. Harris, David J. Harris Children's Mercy Hospital and University of Missouri School of Medicine at Kansas City Kansas City, MissouriSearch for more papers by this authorDebra L. Collins, Debra L. Collins Departments of Medicine and Pediatrics University of Kansas Medical Center Kansas City, KansasSearch for more papers by this author William A. Horton, William A. Horton Medical Genetics Program Department of Pediatrics University of Texas Health Science Center Houston, TexasSearch for more papers by this authorDavid J. Harris, David J. Harris Children's Mercy Hospital and University of Missouri School of Medicine at Kansas City Kansas City, MissouriSearch for more papers by this authorDebra L. Collins, Debra L. Collins Departments of Medicine and Pediatrics University of Kansas Medical Center Kansas City, KansasSearch for more papers by this author First published: March 1984 https://doi.org/10.1002/ajmg.1320170323AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References Bouvet JP, Maroteaux P, Feingold J (1974): Etude génétique du nanism thanatophore. Ann Genet 17: 181–188. Volume17, Issue3March 1984Pages 706-706 ReferencesRelatedInformation

Renal cell carcinomas occurred in 6 of 17 subjects with the von Hippel-Lindau syndrome (HLS). In 4 patients, the tumors were discovered by abdominal computed tomography (CT) during a prospective study. Abdominal CT is recommended as a safe and accurate method for screening patients with HLS for renal cell carcinoma. Renal cell carcinoma in HLS tends to be multifocal and bilateral. Because of this, it is recommended that the tumors be treated by surgical enucleation rather than by more extensive surgical procedures which might ultimately lead to the need for dialysis.