Infrequent Variants Research Articles

Emerging insights into ethnic-specific TP53 germline variants.

The recent expansion of human genomics repositories has facilitated the discovery of novel TP53 variants in populations of different ethnic origins. Interpreting TP53 variants is a major clinical challenge because they are functionally diverse, confer highly variable predisposition to cancer (including elusive low-penetrance alleles), and interact with genetic modifiers that alter tumor susceptibility. Here, we discuss how a cancer risk continuum may relate to germline TP53 mutations on the basis of our current review of genotype-phenotype studies and an integrative analysis combining functional and sequencing datasets. Our study reveals that each ancestry contains a distinct TP53 variant landscape defined by enriched ethnic-specific alleles. In particular, the discovery and characterization of suspected low-penetrance ethnic-specific variants with unique functional consequences, including P47S (African), G334R (Ashkenazi Jewish), and rs78378222 (Icelandic), may provide new insights in terms of managing cancer risk and the efficacy of therapy. Additionally, our analysis highlights infrequent variants linked to milder cancer phenotypes in various published reports that may be underdiagnosed and require further investigation, including D49H in East Asians and R181H in Europeans. Overall, the sequencing and projected functions of TP53 variants arising within ethnic populations and their interplay with modifiers, as well as the emergence of CRISPR screens and AI tools, are now rapidly improving our understanding of the cancer susceptibility spectrum, leading toward more accurate and personalized cancer risk assessments.

De novo germline mutation in the dual specificity phosphatase 10 gene accelerates autoimmune diabetes

Insulin-dependent or type 1 diabetes (T1D) is a polygenic autoimmune disease. In humans, more than 60 loci carrying common variants that confer disease susceptibility have been identified by genome-wide association studies, with a low individual risk contribution for most variants excepting those of the major histocompatibility complex (MHC) region (40 to 50% of risk); hence the importance of missing heritability due in part to rare variants. Nonobese diabetic (NOD) mice recapitulate major features of the human disease including genetic aspects with a key role for the MHC haplotype and a series of Idd loci. Here we mapped in NOD mice rare variants arising from genetic drift and significantly impacting disease risk. To that aim we established by selective breeding two sublines of NOD mice from our inbred NOD/Nck colony exhibiting a significant difference in T1D incidence. Whole-genome sequencing of high (H)- and low (L)-incidence sublines (NOD/NckH and NOD/NckL) revealed a limited number of subline-specific variants. Treating age of diabetes onset as a quantitative trait in automated meiotic mapping (AMM), enhanced susceptibility in NOD/NckH mice was unambiguously attributed to a recessive missense mutation of Dusp10, which encodes a dual specificity phosphatase. The causative effect of the mutation was verified by targeting Dusp10 with CRISPR-Cas9 in NOD/NckL mice, a manipulation that significantly increased disease incidence. The Dusp10 mutation resulted in islet cell down-regulation of type I interferon signature genes, which may exert protective effects against autoimmune aggression. De novo mutations akin to rare human susceptibility variants can alter the T1D phenotype.

Phonological variations in typically-developing Italian-speaking children aged 3;0-4;11

ABSTRACT Normative data on phonological acquisition of a language are a prerequisite for evaluating children’s speech sound competences. To date, these data are not sufficiently available for Italian. This study, therefore, aimed to describe the phonological development of 183 typically developing monolingual Italian-speaking children aged 3;0–4;11 (four 6-months age bands). Participants were assessed through a picture naming task, and performances analysed in terms of number of phonological variations (Tokens), Types and percentage of occurrence of patterns, and number of infrequent variants (InfrVar) as a measure of stability in speech production. Two cut-off criteria to distinguish InfrVar from phonological patterns were applied. Results showed a gradual reduction of all measures with increasing age. Twenty-two patterns generally in line with previous Italian and cross-linguistic studies were observed, with only five patterns and two phonetic distortions occurring across all age groups. Eight patterns only emerged when applying the lower cut-off criterion, while further seven patterns only occurred with very low frequency or in isolated age groups. These findings highlight the influence of the selected cut-off criterion on the identification of patterns and raise the question of whether some patterns should rather be considered InfVar. Data on younger children are still needed to clarify whether low-frequency patterns are patterns of younger typically developing children that have almost resolved in the age groups assessed. At least half of the phonological variation Tokens fell into the category of InfrVar, indicating a need to pay more attention to this so far ignored measure.

Genetics of Paroxysmal Dyskinesia: Novel Variants Corroborate the Role of KCNA1 in Paroxysmal Dyskinesia and Highlight the Diverse Phenotypic Spectrum of KCNA1- and SLC2A1-Related Disorders.

Paroxysmal dyskinesias (PxD) are rare movement disorders with characteristic episodes of involuntary mixed hyperkinetic movements. Scientific efforts and technical advances in molecular genetics have led to the discovery of a variety of genes associated with PxD; however, clinical and genetic information of rarely affected genes or infrequent variants is often limited. In our case series, we present two individuals with PxD including one with classical paroxysmal kinesigenic dyskinesia, who carry new likely pathogenic de novo variants in KCNA1 (p.Gly396Val and p.Gly396Arg). The gene has only recently been discovered to be causative for familial paroxysmal kinesigenic dyskinesia. We also provide genetic evidence for pathogenicity of two newly identified disease-causing variants in SLC2A1 (p.Met96Thr and p.Leu231Pro) leading to paroxysmal exercise-induced dyskinesia. Since clinical information of carriers of variants in known disease-causing genes is often scarce, we encourage to share clinical data of individuals with rare or novel (likely) pathogenic variants to improve disease understanding.

The mutational landscape of the sensitivity of cancer to ionizing radiation.

3129 Background: The impact of common or rare gene mutations on the sensitivity of cancers to ionizing radiation remains largely unknown. We conducted a systematic, arrayed (single variant per well) profiling effort to identify gene mutations that alter cellular sensitivity to radiation and validated some of our findings using a clinical cohort of patients who received thoracic radiotherapy alone. Methods: Candidate mutations were prioritized on the basis of genotype-phenotype associations from our previously completed large-scale cancer cell line irradiation profiling study (doi: 10.1038/ncomms11428), location within conserved protein domains, and functional impact (MutationAssessor). We used site-directed mutagenesis to generate mutant clones (2 clones per variant) and transferred the ORFs into lentiviral vectors in SV40 lung primary immortalized cells (BEAS2B). For clinical validation, an IRB-approved study was used to identify patients treated with lung radiotherapy alone. 197 patients with primary (stage I–IV) or recurrent lung cancer and patients with other cancer types and solitary metastases or oligometastases to the lung were included. Death without evidence of local failure was treated as a competing event, and Fine and Gray regression modeling was used to examine potential predictors of local failure. Results: Over 600 cancer variants were tested in ̃1200 experimental replicates, comprising 91 genes. We identified known and new radioresistant and radiosensitive variants involved in several cellular functional categories including cellular signaling, cytoskeleton, cell cycle, apoptosis, DNA methylation, and DNA repair. Variants that conferred resistance in BEAS2B cells were significantly more likely to confer resistance in TERT-HU1 and NCI-H520 cells, suggesting that most functional variants are cellular context indifferent. Variants under somatic oncogenic selection (hotspot mutants) were significantly more likely to confer resistance to radiation. Several infrequent cancer variants ( < 1% prevalence in cancer), including those in ERBB3, SMAD4, TGFBR1, VHL, CTNNB1, and MAP2K1, conferred radiation resistance. Some genes (e.g. KEAP1) demonstrated significant intragenic allelic variation in the magnitude of conferred resistance and other genes (e.g. CTNNB1) displayed both resistance and sensitivity in a protein domain-dependent manner. KRAS (resistant; HR 2.23; P= 0.02) and CTNNB1 exon 3 (sensitive; HR 0.3; P = 0.04) mutants conferred resistance and sensitivity, respectively, to radiotherapy in our clinical cohort. Conclusions: We report on a large-scale profiling effort to identify mutant alleles that govern radiation survival. Our results reveal new insights into potentially actionable determinants of tumor sensitivity to radiotherapy and accelerate clinical validation of common and rare gene mutations that impact radiation sensitivity.

Separation of Vowel Sequences by Consonant Addition in a Child’s Bilingual Development

Studying infrequent variants in child developmental speech is insightful for language representation and processing. Phonological processes like anticipation and perseveration account for such productions in children. How children process such infrequent variants during development has not been fully explored. In particular, there is no study on the separation of within-word vowel sequences by consonant addition in monolingual or bilingual children. The present study investigates this in a bilingual child’s phonological development in English and Greek, from age 2;7 to 3;9. Sufficient data were obtained for English diphthongs and hiatus and Greek hiatus. Results show that Greek, the stronger language by 1 MLU, interferes with perseverations in English between code-switched utterances. Such consonant additions, which are more frequent in the stronger language, decrease with age in both languages. While anticipation overall increases with age in both languages, within-word perseveration also increases. Word-position frequency of vowel sequences and of their added consonants in the words triggering them, as well as processing distance, are language and process (anticipation/perseveration) dependent. The results offer insights into error processing in child monolingual and bilingual speech.

Reviving the genitive. Prescription and practice in the Netherlands (1770-1840).

Historical metalinguistic discourse is known to often prescribe linguistic variants that are not very frequent in actual language use, and to proscribe frequent variants. Infrequent variants that are promoted through prescription can be innovations, but they can also be conservative forms that have already largely vanished from the spoken language and are now also disappearing in writing. An extreme case in point is the genitive case in Dutch. This has been in decline in usage from at least the thirteenth century onwards, gradually giving way to analytical alternatives such as prepositional phrases. In the grammatical tradition, however, a preference for the genitive case was maintained for centuries. When ‘standard’ Dutch is officially codified in 1805 in the context of a national language policy, the genitive case is again strongly preferred, still aiming to ‘revive’ the synthetic forms. The striking discrepancy between metalinguistic discourse on the one hand, and developments in language use on the other, make the genitive case in Dutch an interesting case for historical sociolinguistics. In this paper, we tackle various issues raised by the research literature, such as the importance of genre differences as well as variation within particular genres, through a detailed corpus-based analysis of the influence of prescription on language practices in eighteenth- and nineteenth-century Dutch.

Exonic variants of genes related to the vitamin D signaling pathway in the families of familial multiple sclerosis using whole-exome next generation sequencing.

IntroductionVitamin D (VD) deficiency has been associated with multiple sclerosis (MS) and other autoimmune diseases (AIDs). However, the effect of the genetics of VD on the risk of MS is subject to debate. This study focuses on genes linked to the VD signaling pathway in families with MS. The evaluation of gene variants in all the members of families could contribute to an additional knowledge on the information obtained from case‐control studies that use nonrelated healthy people.Material and MethodsWe studied 94 individuals from 15 families including at least two patients with MS. We performed whole‐exome next generation sequencing on all individuals and analyzed variants of the DHCR7, CYP2R1, CYP3A4, CYP27A1, GC, CYP27B1, LRP2, CUBN, DAB2, FCGR, RXR, VDR, CYP24A1, and PDIA3 genes. We also studied PTH, FGF23, METTL1, METTL21B, and the role of the linkage disequilibrium block on the long arm of chromosome 12, through analysis of the CDK4, TSFM, AGAP2, and AVIL genes. We compared patients with MS, other AIDs and unaffected members from different family types.ResultsThe study described the variants in the VD signaling pathway that appear in families with at least two patients with MS. Some infrequent variants were detected in these families, but no significant difference was observed between patients with MS and/or other AIDs and unaffected family members in the frequency of these variants. Variants previously associated with MS in the literature were not observed in these families or were distributed similarly in patients and unaffected family members.ConclusionThe study of genes involved in the VD signaling pathway in families that include more than one patient with MS did not identify any variants that could explain the presence of the disease, suggesting that VD metabolism could probably play a role in MS more as an environmental factor rather than as a genetic factor. Our study also supports the analysis of cases and unaffected individuals within families in order to determine the influence of genetic factors.

APOBEC-induced mutations and their cancer effect size in head and neck squamous cell carcinoma

Recent studies have revealed the mutational signatures underlying the somatic evolution of cancer, and the prevalences of associated somatic genetic variants. Here we estimate the intensity of positive selection that drives mutations to high frequency in tumors, yielding higher prevalences than expected on the basis of mutation and neutral drift alone. We apply this approach to a sample of 525 head and neck squamous cell carcinoma exomes, producing a rank-ordered list of gene variants by selection intensity. Our results illustrate the complementarity of calculating the intensity of selection on mutations along with tallying the prevalence of individual substitutions in cancer: while many of the most prevalently-altered genes were heavily selected, their relative importance to the cancer phenotype differs from their prevalence and from their P value, with some infrequent variants exhibiting evidence of strong positive selection. Furthermore, we extend our analysis of effect size by quantifying the degree to which mutational processes (such as APOBEC mutagenesis) contributes mutations that are highly selected, driving head and neck squamous cell carcinoma. We calculate the substitutions caused by APOBEC mutagenesis that make the greatest contribution to cancer phenotype among patients. Lastly, we demonstrate via in vitro biochemical experiments that the APOBEC3B protein can deaminate the cytosine bases at two sites whose mutant states are subject to high net realized selection intensities—PIK3CA E545K and E542K. By quantifying the effects of mutations, we deepen the molecular understanding of carcinogenesis in head and neck squamous cell carcinoma.

Development of a new screening method to determine the main 52 mitochondrial haplogroups through a single minisequencing reaction

This work presents the design, development and optimization of a screening method based on single-base extension sequencing to simultaneously analyze a panel of 52 mitochondrial SNPs. This enables to recognize the main mitochondrial haplogroups and to discriminate even between lineages from the same phylogenetic branch that diverged in different continents. The unavailability of individuals harboring infrequent variants was a limitation to optimize the panel. To overcome this, we have modified DNA by site-directed mutagenesis to create the unavailable allelic variants. This allowed us to verify the reliability of this panel and its usefulness to be applied in biomedicine, forensic and population genetic studies.

The unusual association of inverse retinitis pigmentosa and Fuchs\u2019 heterochromic iridocyclitis

BackgroundClassic retinitis pigmentosa (RP) and other syndromic variants have previously been associated to Fuchs’ heterochromic iridocyclitis (FHI). Common immunogenic and inflammatory pathways have been proposed to explain the higher incidence of this uveitic phenomenon in patients with retinal dystrophies without definitive answers. Infrequent variants of RP such as inverse RP have not been previously reported in association with FHI. We believe that finding the way these entities connect can shed some light into their complex pathogenesis and help find ways to foresee and prevent the appearance of complications such as cataract and macular edema.Case presentationWe present a 15 year old mexican male with history of nyctalopia and rapid, progressive visual loss since infancy who had profound hyper and hypopigmented retinal pigment epithelium changes in the posterior pole together with pigment clumping in the macula of both eyes and an electroretinogram pattern consistent of rod-cone dystrophy. He was diagnosed with inverse RP. Three years after his first visit he was found to have a mild asymptomatic non granulomatous anterior uveitis in the right eye with fine stellate keratic precipitates and subtle iris stromal atrophy not associated with iris synechiae and without evidence of posterior uveitis or findings consistent with infectious etiology. Findings were consistent with FHI. As the patient was normotensive, the lens was transparent and there was no clinical evidence of macular edema, the patient was kept under observation without treatment.ConclusionsPatients with RP are prone to develop chronic, low grade inflammation responses similar to the ones present in FHI. This association makes us believe that immunogenetic pathways involved in the degenerative process that leads to photoreceptor loss may become a target in the prevention and treatment of inflammatory complications in RP and disease progression. It also suggests FHI may be a triggered response predisposed by an unidentified genetic factor that may be related to genes affected in RP and thus be identified before irreversible complications such as glaucoma occur.

Infrequent TRIB3 coding variants and coronary artery disease in type 2 diabetes.

Genes that modulate insulin sensitivity may also be involved in shaping the risk of coronary artery disease (CAD). The relatively common TRIB3 Q84R polymorphism (rs2295490) has been associated with abnormal insulin signaling, endothelial dysfunction, insulin resistance, and pro-atherogenic phenotypes. The aim of our study was to investigate the association between low-frequency TRIB3 coding variants and CAD in patients with type 2 diabetes (T2D). Three case-control studies for CAD from Italy and US were analyzed, for a total of 1565 individuals, all with type 2 diabetes. Infrequent variants were identified by re-sequencing TRIB3 exons in 140 "extreme cases" and 140 "super-controls" and then genotyped in all study subjects. TRIB3 infrequent variants (n = 8), considered according to a collapsing rare variants framework, were significantly associated with CAD in diabetic patients from Italy (n = 700, OR = 0.43, 95% CI 0.20-0.91; p = 0.027), but not from the US (n = 865, OR = 1.22, 95% CI 0.69-2.18; p = 0.49). In the Italian sets, the association was especially strong among individuals who also carried the common R84 variant. Although preliminary, our finding suggests a role of TRIB3 low-frequency variants on CAD among Italian patients with T2D. Further studies are needed to address the role of TRIB3 infrequent variants in other populations of both European and non-European ancestries.

PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation.

Much of the genetic basis for Alzheimer disease (AD) is unexplained. We sought to identify novel AD loci using a unique family-based approach that can detect robust associations with infrequent variants (minor allele frequency < 0.10). We conducted a genome-wide association study in the Framingham Heart Study (discovery) and NIA-LOAD (National Institute on Aging-Late-Onset Alzheimer Disease) Study (replication) family-based cohorts using an approach that accounts for family structure and calculates a risk score for AD as the outcome. Links between the most promising gene candidate and AD pathogenesis were explored in silico as well as experimentally in cell-based models and in human brain. Genome-wide significant association was identified with a PLXNA4 single nucleotide polymorphism (rs277470) located in a region encoding the semaphorin-3A (SEMA3A) binding domain (meta-analysis p value [meta-P] = 4.1 × 10(-8) ). A test for association with the entire region was also significant (meta-P = 3.2 × 10(-4) ). Transfection of SH-SY5Y cells or primary rat neurons with full-length PLXNA4 (TS1) increased tau phosphorylation with stimulated by SEMA3A. The opposite effect was observed when cells were transfected with shorter isoforms (TS2 and TS3). However, transfection of any isoform into HEK293 cells stably expressing amyloid β (Aβ) precursor protein (APP) did not result in differential effects on APP processing or Aβ production. Late stage AD cases (n = 9) compared to controls (n = 5) had 1.9-fold increased expression of TS1 in cortical brain tissue (p = 1.6 × 10(-4) ). Expression of TS1 was significantly correlated with the Clinical Dementia Rating score (ρ = 0.75, p = 2.2 × 10(-4) ), plaque density (ρ = 0.56, p = 0.01), and Braak stage (ρ = 0.54, p = 0.02). Our results indicate that PLXNA4 has a role in AD pathogenesis through isoform-specific effects on tau phosphorylation.

Whole-exome imputation of sequence variants identified two novel alleles associated with adult body height in African Americans.

Adult body height is a quantitative trait for which genome-wide association studies (GWAS) have identified numerous loci, primarily in European populations. These loci, comprising common variants, explain <10% of the phenotypic variance in height. We searched for novel associations between height and common (minor allele frequency, MAF ≥5%) or infrequent (0.5% < MAF < 5%) variants across the exome in African Americans. Using a reference panel of 1692 African Americans and 471 Europeans from the National Heart, Lung, and Blood Institute's (NHLBI) Exome Sequencing Project (ESP), we imputed whole-exome sequence data into 13 719 African Americans with existing array-based GWAS data (discovery). Variants achieving a height-association threshold of P < 5E-06 in the imputed dataset were followed up in an independent sample of 1989 African Americans with whole-exome sequence data (replication). We used P < 2.5E-07 (=0.05/196 779 variants) to define statistically significant associations in meta-analyses combining the discovery and replication sets (N = 15 708). We discovered and replicated three independent loci for association: 5p13.3/C5orf22/rs17410035 (MAF = 0.10, β = 0.64 cm, P = 8.3E-08), 13q14.2/SPRYD7/rs114089985 (MAF = 0.03, β = 1.46 cm, P = 4.8E-10) and 17q23.3/GH2/rs2006123 (MAF = 0.30; β = 0.47 cm; P = 4.7E-09). Conditional analyses suggested 5p13.3 (C5orf22/rs17410035) and 13q14.2 (SPRYD7/rs114089985) may harbor novel height alleles independent of previous GWAS-identified variants (r(2) with GWAS loci <0.01); whereas 17q23.3/GH2/rs2006123 was correlated with GWAS-identified variants in European and African populations. Notably, 13q14.2/rs114089985 is infrequent in African Americans (MAF = 3%), extremely rare in European Americans (MAF = 0.03%), and monomorphic in Asian populations, suggesting it may be an African-American-specific height allele. Our findings demonstrate that whole-exome imputation of sequence variants can identify low-frequency variants and discover novel variants in non-European populations.

Phonological variant recognition: representations and rules.

The current research explores the role of lexical representations and processing in the recognition of phonological variants. Two alternative approaches for variant recognition are considered: a representational approach that posits frequency-graded lexical representations for variant forms and inferential processes that mediate between the spoken variant and the lexical representation. In a lexical decision task (Experiment 1) and in a phoneme identification task (Experiment 2) using real words, low-frequency variants, but not high-frequency variants, show improved recognition rates following additional experience with the variants. This knowledge generalized to novel variant forms. Experiment 3 replicated these results using an artificial lexicon and showed that recognition of low-frequency variants was influenced by similarity to a high-frequency variant form. Similarity to a high-frequency variant alone, however, was insufficient to explain recognition of the infrequent variants (Experiments 4 and 5). The results support a hybrid account of variant recognition that relies on both multiple frequency-graded representations and inference processes.

Benign cutaneous neural tumors

Benign cutaneous neural neoplasms are one of the most frequent benign mesenchymal tumors in the skin. Because peripheral sheath nerve is composed of different cells, the tumors raised in these structures are varied and usually contain many of these cells. Most of these tumors are easy to diagnose, as usually present characteristic features well-recognized and express -specific immunohistochemical proteins. However, there are so many infrequent variants that many times require distinction from others spindle-cell tumors including melanoma. The tumors differ from one another by displaying a different proportion and arrangement of the various constituents of a peripheral nerve. In this article, we present the most characteristic clinical and histopathological features of many of these frequent benign cutaneous neural tumors including their uncommon variants.

Genetic variations of patients with familial or multiple melanoma in Southern Brazil

Patients with familial melanoma or multiple primary melanoma represent a high-risk population to hereditary melanoma. Mutations in susceptibility genes, such as CDKN2A, CDK4 and MC1R, have been associated with the development of melanoma. The purpose of this study was to determine the genotypic background of patients with familial and/or multiple melanoma in southern Brazil. This study analysed 33 cases (5 patients with multiple primary melanoma and 28 patients from families with at least two well documented cases) and 29 controls. Genomic analysis of CDKN2A and CDK4 genes by PCR-SSCP analysis and sequencing and direct sequencing of MC1R were performed in all individuals. No functional mutations in CDKN2A or CDK4 were detected in the 62 individuals. Infrequent variants in polymorphic loci of CDKN2A gene were identified in 15 participants (24.2%) and 24/33 (72.8%) cases and 19/27 (70.4%) controls reported at least one infrequent variant in MC1R (P = 0.372). Furthermore, a non-significant tendency towards an association between melanoma risk and MC1R variants G274A and C451T and a non-significant linear tendency to the number of infrequent high-risk variants in MC1R were observed. These results suggest that in southern Brazilian population, CDKN2A or CDK4 germinal alterations may have a weaker influence than previously thought and environmental risk factors may play a central role in melanoma susceptibility. However, considering the tendency observed for gene MC1R, low-penetrance genes may be a relevant aetiological factor in southern Brazil with fair skin population and high sunlight exposure.

Frequency maDDers, but phonology and formality maTTer, too.

In cases of allophonic variation, the frequency of a variant has been claimed to influence phonological representations, affecting the perception and recognition of words. For example, Connine (2004) found stronger Ganong effects in words with frequent variants (e.g., intervocalic tap in the word pretty) than in words with infrequent variants (e.g., [t] in the word pretty). Specifically, in a phoneme‐monitoring task, listeners reported more PRETTY responses when listening to a pre[D]y‐bre[D]y continuum than a pre[t]y‐bre[t]y continuum. If this bias is due to variant frequency, we might expect this effect to generalize across variants, independent of other factors (context, within‐paradigm alternations). However, a diverse set of variants and alternate explanatory factors contributing to the effect have not yet been investigated. For example, the roles of paradigm variants (e.g., baiting‐bait versus pretty‐*pret) and filler type (e.g., testing for intervocalic [t] in the context of carefully versus casually articulated fillers) might also explain these effects. This study builds on Connine (2004) and examines both paradigmatic relations and filler type across two allophonic alternations (tapping, final [t] glottalization). Ultimately, the results show that variant frequency alone is insufficient to account for this effect. An integrated theory of speech perception is proposed.

50 Years Ago in CORR: Parosteal Osteogenic Sarcoma: Treatment by Block Resection Everett J. Gordon MD CORR 1959;14:171-178

As with most diseases, the concepts and terminology of bone sarcomas have changed over time. In the early part of the 20th century after the ready availability of biopsy and radiographs, doctors recognized only a few types of recognized primary malignant bone tumors. In his 1937 textbook, McMurray listed but three major bone tumors: osteogenic sarcoma, “Ewing’s Tumour,” and multiple myelomata [7]; Campbell, in 1939, listed five: chondromyxosarcoma, osteoblastic, chondroblastic, chondrosarcoma, and osteolytic [1]. While these numbers in common textbooks should not reflect the state of knowledge of malignant tumors, they do reflect the relative paucity of recognized types or subtypes of tumors. Osteogenic sarcomas, for example, were subsequently subtyped based primarily on differing prognoses. Among these subtypes were the various “juxtacortical” or “surface osteosarcomas,” including parosteal and periosteal tumors. The implication of these terms is that the tumors lie outside the medullary cavity, when in fact a small percent do not. Gordon, in 1959 in CORR [4], ascribed the original description of parosteal tumors to Geschickter and Copeland in 1951 [2]. The tumor was juxtacortical and had a histologic appearance similar to that of myositis ossificans and was considered to have benign and malignant forms, and with propensity to recur after resection or to metastasize. In their 13 cases, seven recurred after local resection and four of those patients died with metastases. They recommended amputation with recurrences owing to the rather grave prognosis. Clearly, the tumors were either inadequately resected or extended into the medullary cavity, and were associated with a worse prognosis. By 1959, Gordon noted a number of names ascribed to these sorts of tumors: periosteal osteogenic sarcoma, parosteal osteoma, juxtacortical osteogenic sarcoma, and parosteal osteogenic sarcoma. He also noted the difficulty of distinguishing this tumor from others: osteogenic sarcoma, exostosis, and osteochondroma (Fig. 1). He believed these lesions should not be biopsied owing to the potential for seeding, and rather recommended “local resection” (which we would likely consider marginal resection today). Gordon recommended en bloc resection for small lesions, but amputation “in most instances of parosteal osteogenic sarcoma.” Fig. 1 August, 1955, preoperative roentgenogram. Cortical mass, metaphysis, lower femur, no medullary involvement. (Reprinted with permission and ©Lippincott Williams & Wilkins, from Gordon EJ. Parosteal osteogenic sarcoma: Treatment by block ... While classic osteosarcoma constitutes the large majority of lesions, variants account for perhaps 20–25% with the following frequencies: telangiectatic 3.5–11%, parosteal 3–4%, periosteal 1–2%, gnathic 6–9%, and small cell 1% [5]. The high grade surface lesions are infrequent variants [6, 9]. With the exception of these latter lesions, surface sarcomas generally have a better prognosis than the intramedullary lesions and the parosteal sarcoma being better than the periosteal sarcoma. The subtypes reflect changes in thinking about these tumors. Contemporary imaging and histologic grading are crucial for determining how surface osteosarcomas should be treated: low grade parosteal tumors limited to the surface may be treated with wide or segmental resection, while high grade tumors or those extending into the intramedullary cavity should be treated with segmental resection and chemotherapy. Genetic characterization appears to relate to malignant potential: a subgroup of parosteal tumors have ring chromosomes with amplified material from chromosome 12 (12q13-15) and high grade osteosarcomas more frequently have amplified genetic sequences on the short arm of chromosome 12 than the low grade [3]. Furthermore, MDM2 and CDK4 genes are frequently co-amplified in two separate amplicons in parosteal OS and less frequently in classical high-grade OS [8]. Differential gene expression may imply different mechanisms or etiologies for the development of osteosarcoma variants. Genetically characterizing malignant potential will undoubtedly supplement imaging and help clinicians select more patient-specific treatment in the near future. In contrast to the aggressive recommendation of Gordon in 1959, most surgeons today rely on high quality imaging to select treatment and to avoid amputations when less radical surgery will suffice.

Artritis temporomandibular por Mycobacterium bovis. Un problema diagnóstico

Infrequent variants of extrapulmonary tuberculosis pose a challenging public health problem because of the delay in their diagnosis and treatment. Joint involvement is usually encountered in major joints (hip, elbow, knee and ankle). Tuberculous involvement of the temporomandibular joint is extremely uncommon but must be considered in patients with pain, inflammation or joint stiffness not resolved with conventional treatment.