WISP3, the gene responsible for the human skeletal disease progressive pseudorheumatoid dysplasia, is not essential for skeletal function in mice

In humans, loss-of-function mutations in WISP3 cause the autosomal recessive skeletal disease progressive pseudorheumatoid dysplasia (PPD) (Online Mendelian Inheritance in Man database number 208230). WISP3 encodes Wnt1-inducible signaling protein 3, a cysteine-rich, multidomain, secreted protein, whose paralogous CCN (connective tissue growth factor/cysteine-rich protein 61/nephroblastoma overexpressed) family members have been implicated in diverse biologic processes including skeletal, vascular, and neural development. To understand the role of WISP3 in the skeleton, we targeted the Wisp3 gene in mice by creating a mutant allele comparable to that which causes human disease. We also created transgenic mice that overexpress human WISP3 in cartilage. Surprisingly, homozygous Wisp3 mutant mice appear normal and do not recapitulate any of the morphological, radiographic, or histological abnormalities seen in patients with PPD. Mice that overexpress WISP3 are also normal. We conclude, that in contrast to humans, Wisp3 is not an essential participant during skeletal growth or homeostasis in mice.     

Clinical, diagnostic and therapeutic features of keratocystic odontogenic tumors: a review

Keratocystic odontogenic tumors (KCOTs) are benign but locally aggressive lesions of the gnathic skeleton with high propensity to recur following surgical treatment. High proliferative activity of KCOTs epithelial cells is considered as one of the factors contributing to their aggressive clinical behavior. Aggressive growth within the jaws, tendency to invade surrounding anatomical structures and occasional malignant alteration are the features that distinguish KCOTs from other types of odontogenic tumors. Due to their unique clinical and biological features, KCOTs still present an important problem in oral and maxillofacial surgery. This is especially true when a choice of the most appropriate treatment modality should be made. Establishing balance between effective reduction of recurrence risk and selection of a less aggressive surgical procedure is an issue that should be carefully considered for each individual patient.     

Mental retardation and abnormal skeletal development (Dyggve-Melchior-Clausen dysplasia) due to mutations in a novel,evolutionarily conserved gene

Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC) are similar, rare autosomal recessive osteochondrodysplasias. The radiographic features and cartilage histology in DMC and SMC are identical. However, patients with DMC exhibit significant developmental delay and mental retardation, the major features that distinguish the two conditions. Linkage studies localized the SMC and DMC disease genes to chromosome 18q12-21.1, providing evidence suggesting that they are allelic disorders. Sequence analysis of the coding exons of the FLJ90130 gene, a highly evolutionarily conserved gene within the recombination interval defined in the linkage study, identified mutations in SMC and DMC patients. The affected individuals in two consanguinous DMC families were homozygous for a stop codon mutation and a frameshift mutation, respectively, demonstrating that DMC represents the FLJ90130-null phenotype. The data confirm the hypothesis that SMC and DMC are allelic disorders and identify a gene necessary for normal skeletal development and brain function.     

Neurofibromatosis type 1 is a disorder of dysplasia: The importance of distinguishing features,consequences, and complications

BACKGROUND : The disorder neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene, which influences the availability of activated Ras and the latter's control of cellular proliferation. Emphasis on this aspect of NF1 has focused attention on the tumor suppression function of NF1 and thereby displaced attention from the gene's role in initial normal tissue formation, maintenance, and repair. METHODS : Clinical and neuroimaging data systematically compiled over more than 30 years are analyzed to document the involvement of multiple organs and tissues, often with an embryonic origin. In addition, recent literature based on selective knockout mouse experiments is cited to corroborate embryonic dysplasia as an element of NF1 pathogenesis. RESULTS : Tissue dysplasia, both ab initio and as part of tissue maintenance and wound healing, is a key clinical and pathogenetic aspect of NF1 and thereby provides a rationale for differentiating the elements of NF1 into features, consequences, and complications. CONCLUSIONS : NF1 is a histogenesis control gene that also has properties that overlap with those of a tumor suppressor gene. Both its neoplastic and dysplastic manifestations become more amenable to understanding and treatment if they are differentiated at three levels—specifically, features, consequences and complications. Birth Defects Research (Part A), 2010. © 2009 Wiley‐Liss, Inc.     

31 cases with oculoauriculovertebral dysplasia (Goldenhar syndrome): clinical, neuroradiologic, audiologic and cytogenetic findings

Goldenhar syndrome (GS) or oculoauriculovertebral dysplasia (OAVD) is characterized by pre-auricular skin tags, microtia, facial asymmetry, ocular abnormalities and vertebral anomalies of different size and shape. The phenotypical findings of this syndrome are variable due to heterogenous aetiology. For that reason, the physician sometimes faces difficulty when making a definite diagnosis of OAVD. We reviewed the clinical and laboratory findings of 31 patients (15 boys and 16 girls) aged from 1 day to 16 years with the clinical diagnosis of GS. The characteristic features were pre-auricular skin tags (90%), microtia (52%), hemifacial microsomia (77%) and epibulbar dermoids (39%). Vertebral anomalies were noted in 70% of the patients. Cardiac malformations were found in 39% while a genitourinary anomaly was noted in 23% and various central nervous system malformations in 47%. There were 3 pregnancies following an intracytoplasmic sperm injection (ICSI) technique among the 31 patients. Two patients with GS came from the same family. Their relatives had hydrocephaly, myelomeningocele and neural tube defects. It is known that some chromosomal aberrations are seen in GS. We performed chromosome analysis of 29 patients. Among these cases, only one patient with severe mental and motor retardation had a 47,XX,+der(22)t(11,22)(q23; q11 karyotype due to a maternal balanced translocation t(11;22)(q23;q11). This translocation was demonstrated in her sister, brother and maternal uncle. Additionally CATCH 22 analysis in 13 cases with OAVD with a CATCH 22 phenotype revealed no deletion. OAVD patients present with different morphologic features and systemic manifestations. A multidisciplinary approach should be undertaken by departments such as pediatric cardiology, audiology, ophthalmology and plastic surgery when evaluating patients with OAVD. Chromosome analysis should be performed in every patient with Goldenhar syndrome.     

Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder. It is characterized by two principal features, microcephaly present at birth and nonprogressive mental retardation. The microcephaly is the consequence of a small but architecturally normal brain, and it is the cerebral cortex that shows the greatest size reduction. There are at least seven MCPH loci, and four of the genes have been identified: MCPH1, encoding Microcephalin; MCPH3, encoding CDK5RAP2; MCPH5, encoding ASPM; and MCPH6, encoding CENPJ. These findings are starting to have an impact on the clinical management of families affected with MCPH. Present data suggest that MCPH is the consequence of deficient neurogenesis within the neurogenic epithelium. Evolutionary interest in MCPH has been sparked by the suggestion that changes in the MCPH genes might also be responsible for the increase in brain size during human evolution. Indeed, evolutionary analyses of Microcephalin and ASPM reveal evidence for positive selection during human and great ape evolution. So an understanding of this rare genetic disorder may offer us significant insights into neurogenic mitosis and the evolution of the most striking differences between us and our closest living relatives: brain size and cognitive ability.     

Leydig-cell tumour in children: variable clinical presentation, diagnostic features, follow-up and genetic analysis of four cases

BACKGROUND: Testicular tumours are relatively uncommon in infants and children, accounting for only 1-2% of all paediatric solid tumours. Of these approximately 1.5% are Leydig-cell tumours. Further, activating mutations of the luteinizing hormone receptor gene (LHR), as well as of the G protein genes, such as Gsalpha (gsp) and Gialpha (gip2) subunits, and cyclin-dependent kinase gene 4(CDK4) have been associated with the development of several endocrine neoplasms. AIMS/METHODS: In this report, the clinical variability of Leydig-cell tumours in four children is described. The LHR-, gsp-, gip2- and CDK4 genes were investigated to establish the possible molecular pathogenesis of the variable phenotype of the Leydig-cell tumours. RESULTS: No activating mutations in these genes were found in the four Leydig-cell tumours studied. Therefore, the absence of activating mutations in LHR, as well as in both the 'hot spot' regions for activating mutations within the G-alpha subunits and in the regulatory 'hot spot' on the CDK4 genes in these tumours indicates molecular heterogeneity among Leydig-cell tumours. CONCLUSION: Four children with a variable phenotype caused by Leydig-cell tumours are described. A molecular analysis of all the 'activating' genes and mutational regions known so far was performed, but no abnormalities were found. The lessons learnt from these clinically variable cases are: perform ultrasound early and most importantly, consider discrepancies between testicular swelling, tumour size and androgen production.     

The co-expression of cytokeratin and p63 in epithelioid angiosarcoma of the parotid gland: a diagnostic pitfall

ABSTRACT: SUMMARY: Epithelioid angiosarcoma of the parotid gland is rare, and may pose a great diagnostic challenge. We report a case of primary epithelioid angiosarcoma in a 64-year-old male without history of radiation. The histopathological findings demonstrated a high grade epithelioid neoplasm. Immunostaining showed that the tumor was positive for the pancytokeratin, p63, cytokeratin18, Vimentin and vascular markers CD31, and was negative for CD34, cytokeratin5/6, cytokeratin7, cytokeratin20, CD68, CD30, S-100, HMB45, desmin, alpha- SMA and CD45. The tumor was diagnosed as an epithelioid angiosarcoma. To our knowledge, this is the first reported case of angiosarcoma which showed common positivity for cytokeratin and p63. In addition to cytokeratin, p63 is considered a useful marker for carcinoma. The co-expression of cytokeratin and p63 in epithelioid angiosarcoma represents a diagnostic pitfall. Thus, using a panel of antibodies is essential for distinguishing this tumor from poorly differentiated carcinoma. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6548916707504750.     

The challenge of biological control of Cosmopolites sordidus Germar (Col. Curculionidae): A review

The banana weevil (also known as banana root borer) Cosmopolites sordidus Germar (Coleoptera Curculionidae) is the major pest of banana and plantain. Because banana ranks 2nd in fruit production worldwide, this pest has substantial social and economic importance. The biological control of the C. sordidus remains challenging because of its behaviour and resistance to parasitism and predation. The last review concerning the biological control of C. sordidus was published two decades ago, and relevant knowledge and methods have developed in the interim. The present paper provides an update of that knowledge and summarizes past and current challenges as well as providing perspectives on achieving sustainable control of C. sordidus. We first discuss studies on the classical biological control of C. sordidus, underlining the limits of classical biological control methods such as the importation of predators, parasitoids or pathogens. Next, we consider conservation biological control of C. sordidus, with a focus on ants. We also highlight an ‘arthropod bias’ that has led to a lack of information on the role of vertebrates in the regulation of C. sordidus.     

An oro-facial disease 'noma (cancrum oris)' in a Japanese monkey (Macaca fuscata): clinical signs, clinicopathological features, and response to treatment

BACKGROUND: A Japanese monkey developed severe oro-facial lesions that were called noma in humans. Although extensive destruction of both the buccal regions occurred with rapid progress, author successfully treated the lesions with povidone-iodine, enrofloxacin, chymotrypsin, a glycyrrhizin preparation, and a basic fibroblast growth factor. METHODS: Author clinicopathologically investigated this disease during the treatment. RESULTS: In the subcutaneous and muscular tissues, the lesions developed characteristic changes such as dissolving collagen fibers and muscular tissues phagocytosed by giant and epitheloid cells. The monkey showed a notable increase in creatine kinase activities. The present examinations revealed severe invasive findings in muscular tissues, which were accompanied by infections of beta-hemolytic streptococcus Group C. This monkey was negative for simian immunodeficiency virus antibody; however, infection with simian D retrovirus was not ruled out. CONCLUSIONS: Simian noma was a rapidly devastating disease, which destroyed the muscle tissues of oro-facial structure. Nonhuman primates are the only species that develop oro-facial lesions, corresponding to noma in humans.     

FGFR2 point mutations in 466 endometrioid endometrial tumors: relationship with MSI, KRAS, PIK3CA, CTNNB1 mutations and clinicopathological features

Mutations in multiple oncogenes including KRAS, CTNNB1, PIK3CA and FGFR2 have been identified in endometrial cancer. The aim of this study was to provide insight into the clinicopathological features associated with patterns of mutation in these genes, a necessary step in planning targeted therapies for endometrial cancer. 466 endometrioid endometrial tumors were tested for mutations in FGFR2, KRAS, CTNNB1, and PIK3CA. The relationships between mutation status, tumor microsatellite instability (MSI) and clinicopathological features including overall survival (OS) and disease-free survival (DFS) were evaluated using Kaplan-Meier survival analysis and Cox proportional hazard models. Mutations were identified in FGFR2 (48/466); KRAS (87/464); CTNNB1 (88/454) and PIK3CA (104/464). KRAS and FGFR2 mutations were significantly more common, and CTNNB1 mutations less common, in MSI positive tumors. KRAS and FGFR2 occurred in a near mutually exclusive pattern (p = 0.05) and, surprisingly, mutations in KRAS and CTNNB1 also occurred in a near mutually exclusive pattern (p = 0.0002). Multivariate analysis revealed that mutation in KRAS and FGFR2 showed a trend (p = 0.06) towards longer and shorter DFS, respectively. In the 386 patients with early stage disease (stage I and II), FGFR2 mutation was significantly associated with shorter DFS (HR = 3.24; 95% confidence interval, CI, 1.35-7.77; p = 0.008) and OS (HR = 2.00; 95% CI 1.09-3.65; p = 0.025) and KRAS was associated with longer DFS (HR = 0.23; 95% CI 0.05-0.97; p = 0.045). In conclusion, although KRAS and FGFR2 mutations share similar activation of the MAPK pathway, our data suggest very different roles in tumor biology. This has implications for the implementation of anti-FGFR or anti-MEK biologic therapies.     

Analysis of the hemochromatosis gene (HFE) mutations, C282Y and H63D, in the populations of Central Asia

Analysis of the C282Y and H63D mutations in the HFE gene was carried out in 594 individuals representing seven indigenous populations of Central Asia. Among the populations examined, mutation C282Y was found in Uighurs with the frequency of 0.009, and in Kazakhs and Tajiks with the frequency of 0.012. The mutation was absent in Uzbeks, Kyrgyzes, Kurds, and Turkmens. Mutation H63D was detected in all populations studied with the frequencies ranging from 0.024 (Tajiks) to 0.139 (Turkmens). Judging by the frequencies of the mutations of interest, the populations examined occupied the intermediate position between the European and Eastern Asian populations, which corresponded to their geographical position.     

Analysis of the hemochromatosis gene (HFE) mutations, C282Y and H63D, in the populations of Central Asia

Analysis of the C282Y and H63D mutations in the HFE gene was carried out in 594 individuals representing seven indigenous populations of Central Asia. Among the populations examined, mutation C28Y was found in Uighurs with the frequency of 0.009, and in Kazakhs and Tajiks with the frequency of 0.012. The mutation was absent in Uzbeks, Kyrgyzes, Kurds, and Turkmens. Mutation H63D was detected in all populations studied with the frequencies ranging from 0.024 (Tajiks) to 0.139 (Turkmens). Judging by the frequencies of the mutations of interest, the populations examined occupied the intermediate position between the European and Eastern Asian populations, which corresponded to their geographical position.