I recently attended my son Jared's college graduation. The commencement speaker, 2001 US Poet Laureate Billy Collins, began by telling the audience exactly how long he intended to speak. I quote, “I think an audience deserves to know that this will be a finite experience. It is well known in the world of public speaking that there is no pleasure you can give an audience that compares with the pleasure they get when it is over.” This morning I intend to speak for exactly 12 min. Hopefully, before the 13th, I'll have provided you with at least some measure of pleasure.

No major susceptibility genes for sporadically occurring congenital vertebral malformations (CVM) in humans have been identified to date. Body patterning genes whose mutants cause axial skeletal anomalies in mice are candidates for human CVM susceptibility. T (also known as Brachyury) and TBX6 are critical genes needed to establish mesodermal identity. We hypothesized that mutations in T and/or TBX6 contribute to the pathogenesis of human CVMs. The complete T and TBX6 coding regions, splice junctions, and proximal 500 bp of the promoters were sequenced in 50 phenotyped patients with CVM. Three unrelated patients with sacral agenesis, Klippel-Feil syndrome, and multiple cervical and thoracic vertebral malformations were heterozygous for a c.1013C>T substitution, resulting in a predicted Ala338Val missense alteration in exon 8. A clinically unaffected parent of each patient also harbored the substitution, but the variant did not occur in an ethnically diverse, 443-person reference population. The c.1013C>T variant is significantly associated with CVM (p < 0.001). Alanine 338 shows moderate conservation across species, and valine at this position has not been reported in any species. A fourth patient harbored a c.908-8C>T variant in intron 7. This previously unreported variant was tested in 347 normal control subjects, and 11 heterozygotes and 2 T/T individuals were found. No TBX6 variants were identified. We infer that the c.1013C>T substitution is pathogenic and represents the first report of an association between a missense mutation in the T gene and the occurrence of sporadic CVMs in humans. It is uncertain whether the splice junction variant increases CVM risk. TBX6 mutations do not seem to be associated with CVM. We hypothesize that epistatic interactions between T and other developmental genes and the environment modulate the phenotypic consequences of T variants.

BACKGROUND:Prior investigations have not identified a major locus for vertebral malformations, providing evidence that there is genetic heterogeneity for this condition. WNT3A has recently been identified as a negative regulator of Notch signaling and somitogenesis. Mice with mutations in Wnt3a develop caudal vertebral malformations. Because congenital vertebral malformations represent a sporadic occurrence, linkage approaches to identify genes associated with human vertebral development are not feasible. We hypothesized that WNT3A mutations might account for a subset of congenital vertebral malformations.METHODS:A pilot study was performed using a cohort of patients with congenital vertebral malformations spanning the entire vertebral column was characterized. DNA sequence analysis of the WNT3A gene in these 50 patients with congenital vertebral malformations was performed.RESULTS:A female patient of African ancestry with congenital scoliosis and a T12-L1 hemivertebrae was found to be heterozygous for a missense variant resulting in the substitution of alanine by threonine at codon 134 in highly conserved exon 3 of the WNT3A gene. This variant was found at a very low prevalence (0.35%) in a control population of 443 anonymized subjects and 1.1% in an African population.CONCLUSION:These data suggest that WNT3A does not contribute towards the development of congenital vertebral malformations. Factors such as phenotypic and genetic heterogeneity may underlie our inability to detect mutations in WNT3A in our patient sample.

BACKGROUND:We retrospectively query the clinical records of patients with cervical osteophytes to distinguish the clinical features of those presenting with symptomatic dysphagia and airway obstruction.STUDY DESIGN:Retrospective review of all patients presenting over a 20-year period (1985 to 2005) with the diagnosis of cervical osteophytes and dysphagia with or without airway compromise. Two hundred thirty-four patients were identified at Marshfield Clinic between 1985 and 2005; 9 (3.8%) met criteria for inclusion.RESULTS:Eight of nine patients presented with dysphagia. Three of nine patients presented with acute airway obstruction requiring intubation and tracheotomy. Osteophytes occurred at multiple levels, with C4, C5, and C6 being most commonly involved. Surgical decompression resulted in complete resolution of symptoms in four of five patients.CONCLUSIONS:Although commonly found and usually asymptomatic in the older population, anterior cervical osteophytes can be a source of considerable morbidity and potential life-threatening airway obstruction. Recognizing this clinical entity is imperative in establishing a diagnosis and initiating appropriate treatment. Surgical decompression appears to be beneficial in relieving symptoms.

American Journal of Medical Genetics Part AVolume 140A, Issue 12 p. 1346-1348 Research Letter Evaluation of SLC35A3 as a candidate gene for human vertebral malformations† Nader Ghebranious, Nader Ghebranious Molecular Diagnostics Genotyping Laboratory, Marshfield Clinic, Marshfield, WisconsinSearch for more papers by this authorJames K. Burmester, James K. Burmester Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WisconsinSearch for more papers by this authorIngrid Glurich, Ingrid Glurich Office of Research Facilitation, Marshfield Clinic Research Foundation, Marshfield, WisconsinSearch for more papers by this authorElizabeth McPherson, Elizabeth McPherson Department of Medical Genetic Services, Marshfield Clinic, Marshfield, WisconsinSearch for more papers by this authorLynn Ivacic, Lynn Ivacic Molecular Diagnostics Genotyping Laboratory, Marshfield Clinic, Marshfield, WisconsinSearch for more papers by this authorJennifer Kislow, Jennifer Kislow Molecular Diagnostics Genotyping Laboratory, Marshfield Clinic, Marshfield, WisconsinSearch for more papers by this authorKristen Rasmussen, Kristen Rasmussen Department of Medical Genetic Services, Marshfield Clinic, Marshfield, WisconsinSearch for more papers by this authorVikram Kumar, Vikram Kumar Department of Pediatrics, Marshfield Clinic, Marshfield, WisconsinSearch for more papers by this authorCathleen L. Raggio, Cathleen L. Raggio Department of Pediatric Orthopedics, Hospital for Special Surgery, New York, New YorkSearch for more papers by this authorRobert D. Blank, Robert D. Blank University of Wisconsin Medical School, Madison, Wisconsin Geriatrics Research, Education, and Clinical Center, William S. Middleton Veterans Administration Medical Center, Madison, WisconsinSearch for more papers by this authorF. Stig Jacobsen, F. Stig Jacobsen Department of Orthopedic Spine Surgery, Marshfield Clinic, Marshfield, WisconsinSearch for more papers by this authorThomas Faciszewski, Thomas Faciszewski Department of Orthopedic Spine Surgery, Marshfield Clinic, Marshfield, WisconsinSearch for more papers by this authorJames Womack, James Womack Veterinary Pathobiology, Texas A&M University, College Station, TexasSearch for more papers by this authorPhilip F. Giampietro, Corresponding Author Philip F. Giampietro [email protected] Department of Medical Genetic Services, Marshfield Clinic, Marshfield, WisconsinDepartment of Medical Genetic Services, Marshfield Clinic, 1000 North Oak Avenue, Marshfield, WI 54449.Search for more papers by this author Nader Ghebranious, Nader Ghebranious Molecular Diagnostics Genotyping Laboratory, Marshfield Clinic, Marshfield, WisconsinSearch for more papers by this authorJames K. Burmester, James K. Burmester Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WisconsinSearch for more papers by this authorIngrid Glurich, Ingrid Glurich Office of Research Facilitation, Marshfield Clinic Research Foundation, Marshfield, WisconsinSearch for more papers by this authorElizabeth McPherson, Elizabeth McPherson Department of Medical Genetic Services, Marshfield Clinic, Marshfield, WisconsinSearch for more papers by this authorLynn Ivacic, Lynn Ivacic Molecular Diagnostics Genotyping Laboratory, Marshfield Clinic, Marshfield, WisconsinSearch for more papers by this authorJennifer Kislow, Jennifer Kislow Molecular Diagnostics Genotyping Laboratory, Marshfield Clinic, Marshfield, WisconsinSearch for more papers by this authorKristen Rasmussen, Kristen Rasmussen Department of Medical Genetic Services, Marshfield Clinic, Marshfield, WisconsinSearch for more papers by this authorVikram Kumar, Vikram Kumar Department of Pediatrics, Marshfield Clinic, Marshfield, WisconsinSearch for more papers by this authorCathleen L. Raggio, Cathleen L. Raggio Department of Pediatric Orthopedics, Hospital for Special Surgery, New York, New YorkSearch for more papers by this authorRobert D. Blank, Robert D. Blank University of Wisconsin Medical School, Madison, Wisconsin Geriatrics Research, Education, and Clinical Center, William S. Middleton Veterans Administration Medical Center, Madison, WisconsinSearch for more papers by this authorF. Stig Jacobsen, F. Stig Jacobsen Department of Orthopedic Spine Surgery, Marshfield Clinic, Marshfield, WisconsinSearch for more papers by this authorThomas Faciszewski, Thomas Faciszewski Department of Orthopedic Spine Surgery, Marshfield Clinic, Marshfield, WisconsinSearch for more papers by this authorJames Womack, James Womack Veterinary Pathobiology, Texas A&M University, College Station, TexasSearch for more papers by this authorPhilip F. Giampietro, Corresponding Author Philip F. Giampietro [email protected] Department of Medical Genetic Services, Marshfield Clinic, Marshfield, WisconsinDepartment of Medical Genetic Services, Marshfield Clinic, 1000 North Oak Avenue, Marshfield, WI 54449.Search for more papers by this author First published: 11 May 2006 https://doi.org/10.1002/ajmg.a.31307Citations: 16 † How to cite this article: Ghebranious N, Burmester JK, Glurich I, McPherson E, Ivacic L, Kislow J, Rasmussen K, Kumar V, Raggio CL, Blank RD, Jacobsen FS, Faciszewski T, Womack J, Giampietro PF. 2006. Evaluation of SLC35A3 as a candidate gene for human vertebral malformations. Am J Med Genet Part A 140A:1346–1348. Read the full textAboutPDF 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 REFERENCES Agerholm JS, Bendixen C, Andersen O, Arnbjerg J. 2001. Complex vertebral malformation in holstein calves. J Vet Diagn Invest 13: 283– 289. Agerholm JS, Bendixen C, Arnbjerg J, Andersen O. 2004. Morphological variation of “complex vertebral malformation” in Holstein calves. J Vet Diagn Invest 16: 548– 553. Bruckner K, Perez L, Clausen H, Cohen S. 2000. Glycosyltransferase activity of Fringe modulates Notch-Delta interactions. Nature 406: 411– 415. Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, Oyama R, Ravasi T, Lenhard B, Wells C, Kodzius R, Shimokawa K, Bajic VB, Brenner SE, Batalov S, Forrest AR, Zavolan M, Davis MJ, Wilming LG, Aidinis V, Allen JE, Ambesi-Impiombato A, Apweiler R, Aturaliya RN, Bailey TL, Bansal M, Baxter L, Beisel KW, Bersano T, Bono H, Chalk AM, Chiu KP, Choudhary V, Christoffels A, Clutterbuck DR, Crowe ML, Dalla E, Dalrymple BP, de Bono B, Della Gatta G, di Bernardo D, Down T, Engstrom P, Fagiolini M, Faulkner G, Fletcher CF, Fukushima T, Furuno M, Futaki S, Gariboldi M, Georgii-Hemming P, Gingeras TR, Gojobori T, Green RE, Gustincich S, Harbers M, Hayashi Y, Hensch TK, Hirokawa N, Hill D, Huminiecki L, Iacono M, Ikeo K, Iwama A, Ishikawa T, Jakt M, Kanapin A, Katoh M, Kawasawa Y, Kelso J, Kitamura H, Kitano H, Kollias G, Krishnan SP, Kruger A, Kummerfeld SK, Kurochkin IV, Lareau LF, Lazarevic D, Lipovich L, Liu J, Liuni S, McWilliam S, Madan Babu M, Madera M, Marchionni L, Matsuda H, Matsuzawa S, Miki H, Mignone F, Miyake S, Morris K, Mottagui-Tabar S, Mulder N, Nakano N, Nakauchi H, Ng P, Nilsson R, Nishiguchi S, Nishikawa S, Nori F, Ohara O, Okazaki Y, Orlando V, Pang KC, Pavan WJ, Pavesi G, Pesole G, Petrovsky N, Piazza S, Reed J, Reid JF, Ring BZ, Ringwald M, Rost B, Ruan Y, Salzberg SL, Sandelin A, Schneider C, Schonbach C, Sekiguchi K, Semple CA, Seno S, Sessa L, Sheng Y, Shibata Y, Shimada H, Shimada K, Silva D, Sinclair B, Sperling S, Stupka E, Sugiura K, Sultana R, Takenaka Y, Taki K, Tammoja K, Tan SL, Tang S, Taylor MS, Tegner J, Teichmann SA, Ueda HR, van Nimwegen E, Verardo R, Wei CL, Yagi K, Yamanishi H, Zabarovsky E, Zhu S, Zimmer A, Hide W, Bult C, Grimmond SM, Teasdale RD, Liu ET, Brusic V, Quackenbush J, Wahlestedt C, Mattick JS, Hume DA, Kai C, Sasaki D, Tomaru Y, Fukuda S, Kanamori-Katayama M, Suzuki M, Aoki J, Arakawa T, Iida J, Imamura K, Itoh M, Kato T, Kawaji H, Kawagashira N, Kawashima T, Kojima M, Kondo S, Konno H, Nakano K, Ninomiya N, Nishio T, Okada M, Plessy C, Shibata K, Shiraki T, Suzuki S, Tagami M, Waki K, Watahiki A, Okamura-Oho Y, Suzuki H, Kawai J, Hayashizaki Y; FANTOM Consortium; RIKEN Genome Exploration Research Group and Genome Science Group (Genome Network Project Core Group). 2005. The transcriptional landscape of the mammalian genome. Science 309: 1559– 1563. Ghebranious N, Ivacic L, Mallum J, Dokken C. 2005. Detection of ApoE E2, E3, and E4 alleles using MALDI-TOF mass spectrometry and the homogeneous mass-extend technology. Nucleic Acids Res 33: e149. Giampietro PF, Raggio CL, Reynolds CE, Shukla SK, McPherson E, Ghebranious N, Jacobsen FS, Kumar V, Faciszewski T, Pauli RM, Rasmussen K, Burmester JK, Zaleski C, Merchant S, David D, Weber JL, Glurich I, Blank RD. 2005. An analysis of PAX1 in the development of vertebral malformations. Clin Genet 68: 448– 453. Ishida N, Yoshioka S, Chiba Y, Takeuchi M, Kawakita M. 1999. Molecular cloning and functional expression of the human Golgi UDP-N-acetylglucosamine transporter. J Biochem (Tokyo) 126: 68– 77. Maisenbacher MK, Han JS, O'Brien ML, Tracy MR, Erol B, Schaffer AA, Dormans JP, Zackai EH, Kusumi K. 2005. Molecular analysis of congenital scoliosis: A candidate gene approach. Hum Genet 116: 416– 419. Thomsen B, Horn P, Panitz F, Bendixen E, Petersen AH, Holm LE, Nielsen VH, Agerholm JS, Arnbjerg J, Bendixen C. 2006. A missense mutation in the bovine SLC35A3 gene, encoding a UDP-N-acteylglucosamine transporter, causes complex vertebral malformation. Genome Res 16: 97– 105. Citing Literature Volume140A, Issue1215 June 2006Pages 1346-1348 ReferencesRelatedInformation

Investigations have not identified a major locus for congenital vertebral malformations. Based on observations in mice, we hypothesized that mutations in DLL3, a member of the notch-signaling pathway, might contribute to human vertebral malformations. We sequenced the DLL3 gene in 50 patients with congenital vertebral malformations. A Caucasian male patient with VACTERL manifestations including a T5-T6 block vertebrae was heterozygous for a "G" to "A" missense mutation changing glycine to arginine at codon 269. This residue is conserved in mammals, including chimpanzee, mouse, dog, and rat. Additional testing in the patient did not show evidence of chromosome abnormalities. The patient's asymptomatic mother was also heterozygous for the missense mutation. Since this mutation was not observed in a control population and leads to an amino acid change, it may be clinically significant. The mutation was not found in a control population of 87 anonymous individuals. Several established mechanisms could explain the mutation in both the patient and his asymptomatic mother (susceptibility allele requiring additional environmental factors, somatic mosaicism, multigenic inheritance). Documenting the absence of the mutation in a larger control population or the presence of the mutation in additional affected patients, or documenting a functional difference in DLL3 would provide further evidence supporting its causal role.

Members of the North American Spine Society (NASS) have expressed concern regarding recent commentary on spine surgery by Deyo, Nachemson, and Mirza, published in the New England Journal of Medicine [ [1] Deyo R.A. Nachemson A. Mirza S.K. Spinal-fusion surgery—the case for restraint. N Engl J Med. 2004; 350: 722-726 Crossref PubMed Scopus (436) Google Scholar ]. These authors question the value of performing spine fusion surgery for pain from degenerative conditions and immediately following cervical discectomy. They also criticize the benefit of surgical implants, and imply that spinal fusion is rarely, if ever, indicated for conditions other than severe scoliosis, spondylolisthesis, spinal tuberculosis and fractures. There is a need for a balanced presentation of these and other important spine care topics. The commentary by Deyo et al. [ [1] Deyo R.A. Nachemson A. Mirza S.K. Spinal-fusion surgery—the case for restraint. N Engl J Med. 2004; 350: 722-726 Crossref PubMed Scopus (436) Google Scholar ] prompted a voluntary multidisciplinary group from the Board of the North American Spine Society to assess the commentary in detail, including its clinical critiques of spine surgery and all of the references accompanying the article. This multidisciplinary panel of authors practice within the fields of clinical psychology, internal medicine, neurosurgery and orthopedic spine surgery. As concerned members of the spine care community and practicing health care professionals, we are obligated to highlight some of the specific weaknesses in the Deyo et al. [ [1] Deyo R.A. Nachemson A. Mirza S.K. Spinal-fusion surgery—the case for restraint. N Engl J Med. 2004; 350: 722-726 Crossref PubMed Scopus (436) Google Scholar ] commentary and add important caveats regarding their reasoning or oversights that resulted in some of their misleading conclusions on spine care. Specifically, the article had numerous stated or implied observations on spine fusion surgery with regard to: •The "overuse" of spinal fusion surgery •Comparisons of total hip replacement surgical rates to spinal fusion surgery rates •Geographic variation of the prevalence rate of surgical fusion procedures •The controversy over fusion for discogenic pain •The "overuse" of spinal instrumentation •Lack of justification for the use of instrumentation to aid fusion •Complication rates with the use of spinal instrumentation •The published literature for the evaluation of spinal fusion surgery •Cervical fusion after cervical discectomy •Vision loss following spinal surgery •Placebo-controlled trials: sham surgery •Evolving medical technologies and the "learning curve" of surgical techniques

OBJECTIVEGenetic and environmental factors influencing spinal development in lower vertebrates are likely to play a role in the abnormalities associated with human congenital scoliosis (CS) and idiopathic scoliosis (IS). An overview of the molecular embryology of spinal development and the clinical and genetic aspects of CS and IS are presented. Utilizing synteny analysis of the mouse and human genetic databases, likely candidate genes for human CS and IS were identified.DESIGNReview and synteny analysis.METHODSA search of the Mouse Genome Database was performed for "genes," "markers" and "phenotypes" in the categories Neurological and neuromuscular, Skeleton, and Tail and other appendages. The Online Mendelian Inheritance in Man was used to determine whether each mouse locus had a known human homologue. If so, the human homologue was assigned candidate gene status. Linkage maps of the chromosomes carrying loci with possibly relevant phenotypes, but without known human homologues, were examined and regions of documented synteny between the mouse and human genomes were identified.RESULTSSearching the Mouse Genome Database by phenotypic category yielded 100 mutants of which 66 had been mapped. The descriptions of each of these 66 loci were retrieved to determine which among these included phenotypes of scoliosis, kinky or bent tails, other vertebral abnormalities, or disturbances of axial skeletal development. Forty-five loci of interest remained, and for 27 of these the comparative linkage maps of mouse and human were used to identify human syntenic regions to which plausible candidate genes had been mapped.CONCLUSIONSynteny analysis of mouse candidate genes for CS and IS holds promise due to the close evolutionary relationship between mice and human beings. With the identification of additional genes in animal model systems that contribute to different stages of spine development, the list of candidate genes for CS and IS will continue to grow.