The presence of germ line mosaicism in cleidocranial dysplasia.

Cleidocranial dysplasia (CCD) is typically an autosomal dominant condition. The possibility of alternative causes, such as an autosomal recessive form or germ line mosaicism, have been suggested in some families with CCD, but not proven. We present a family consisting of a mother having three sons affected with CCD. One of the affected boys is a half brother to the other two affected children. The diagnosis of CCD was confirmed by DNA analysis of the RUNX2 gene in all three of the boys in blood; however, initial DNA testing in the mother's blood did not detect the presence of a RUNX2 mutation in the mother. Further testing through heteroduplex analysis applying high-resolution melting analysis followed by subcloning detected low-level mosaicism in DNA isolated from maternal blood and buccal swab, confirming low-level mosaicism in somatic cells. We present the first case of confirmed germ line mosaicism in CCD.

Identification of genes associated with ovarian cancer metastasis using microarray expression analysis.

Although the transition from early- to advanced-stage ovarian cancer is a critical determinant of survival, little is known about the molecular underpinnings of ovarian metastasis. We hypothesize that microarray analysis of global gene expression patterns in primary ovarian cancer and metastatic omental implants can identify genes that underlie the metastatic process in epithelial ovarian cancer. We utilized Affymetrix U95Av2 microarrays to characterize the molecular alterations that underlie omental metastasis from 47 epithelial ovarian cancer samples collected from multiple sites in 20 patients undergoing primary surgical cytoreduction for advanced-stage (IIIC/IV) serous ovarian cancer. Fifty-six genes demonstrated differential expression between ovarian and omental samples (P < 0.01), and twenty of these 56 differentially expressed genes have previously been implicated in metastasis, cell motility, or cytoskeletal function. Ten of the 56 genes are involved in p53 gene pathways. A Bayesian statistical tree analysis was used to identify a 27-gene expression pattern that could accurately predict the site of tumor (ovary versus omentum). This predictive model was evaluated using an external data set. Nine of the 27 predictive genes have previously been shown to be involved in oncogenesis and/or metastasis, and 10/27 genes have been implicated in p53 pathways. Microarray findings were validated by real-time quantitative PCR. We conclude that gene expression patterns that distinguish omental metastasis from primary epithelial ovarian cancer can be identified and that many of the genes have functions that are biologically consistent with a role in oncogenesis, metastasis, and p53 gene networks.

Integration of clinical information and gene expression profiles for prediction of chemo-response for ovarian cancer.

Ovarian cancer is the fifth leading cause of cancer death among women in the United States and western Europe. Platinum drugs are the most active agents in epithelial ovarian cancer therapy. In order to improve the prediction of response to platinum-based chemotherapy for advanced-stage ovarian cancers, we describe an integrated model which combines clinical information tumor and treatment information, with gene expression profile. This integrated modeling framework is based on the support vector machine classifier that evaluates the contributions of both clinical and gene expression data. The results show that the integrated model combining clinical information and gene expression profiles improve the prediction accuracy compared to those made by using gene expression predictor alone.

Improving Reliability of Response Prediction to Platinum-Based Therapy by AdaBoost and Multiple Classifiers.

It is a challenge to construct a reliable classifier based on microarray gene expression data for prediction of chemotherapy response, because usually only a small number of samples are available and each sample has thousands of gene expressions. This paper uses boosting and bootstrap approaches to improve the reliability of prediction. Specifically, AdaBoost and multiple classifiers based methods are used, in which support vector machines (SVMs) are utilized as the classifiers due to their good generalization ability. We compare the performance of proposed methods with a single SVM classifier system using MAS gene expression dataset in prediction of the response to platinum-based therapy for advanced-stage ovarian cancers. Statistical tests show both of the proposed methods achieve better prediction performance and have good reliability in terms of mean and standard deviation of the prediction performance for different number of selected features.

Severe Lhermitte-Duclos disease with unique germline mutation of PTEN.

Germline mutations in the PTEN gene have recently been identified in some individuals with Cowden disease (CD), Lhermitte-Duclos disease (LDD), and Bannayan-Zonana syndrome. We report on a patient with CD and LDD in whom a unique de novo germline missense mutation is present in the PTEN gene. Direct sequence analysis detected a transitional change (T-->C) at nucleotide 335, resulting in substitution of the amino acid proline for leucine. The mutation is in exon 5, which has been proposed as a "hot-spot" for germline mutations. Comparison of this patient's clinical course with the previously reported cases of CD and LDD shows more extensive and more severe clinical findings than reported previously. Findings in this patient contribute to the current understanding of germline PTEN mutations and clinical outcome.

The genetic basis of Cowden's syndrome: three novel mutations in PTEN/MMAC1/TEP1.

Cowden's syndrome (CS) is an autosomal dominant disorder associated with an increased risk of developing benign and malignant tumors in a variety of tissues, including the skin, thyroid, breast and brain. Women with CS are felt to have an increased risk of developing breast cancer, and virtually all women with CS develop bilateral fibrocystic disease of the breast. Recently, a series of germline mutations have been identified from CS families in a gene known as PTEN/MMAC1/TEP1. In this study, we used heteroduplex analysis and direct sequencing analysis and identified three novel germline mutations in the PTEN/MMAC1/TEP1 coding sequence from unrelated individuals with CS. We report a de novo transition (T-->C) at nucleotide 335 in exon 5. This missense mutation resulted in a leucine to proline (CTA to CCA) change at codon 112. We also describe a novel splice site mutation (801+2T-->G) in intron 7 that caused exon skipping in PTEN/MMAC1/TEP1 mRNA. The third mutation we report is a missense mutation, consisting of a transition (T-->C) at nucleotide 202 in exon 3, resulting in a tyrosine to histidine (TAC to CAC) change at codon 68. Finally, we also detected a rare polymorphism in exon 7 of the PTEN/MMAC1/TEP1 coding sequence. These data confirm the observation that mutations of the PTEN/MMAC1/TEP1 coding sequence are responsible for at least some cases of CS, and further define the spectrum of mutations in this autosomal dominant disorder.

Inherited susceptibility to breast and ovarian cancer.

Approximately 5-10% of breast and ovarian cancer cases are due to an inherited susceptibility. The majority of inherited breast and ovarian cancer susceptibility is due to mutations in the BRCA1 and BRCA2 genes; however, other genes responsible for inherited susceptibility to these diseases are yet to be identified. A small proportion of inherited breast and ovarian cancers are due to other genetic cancer susceptibility syndromes including Li-Fraumeni syndrome, Cowden disease and hereditary non-polyposis colorectal cancer. It is recommended that individuals at risk for inherited susceptibility to breast and/or ovarian cancer who are requesting DNA testing be provided with pre-test genetic counseling and education and post-test counseling and follow-up to ensure that all aspects of genetic testing have been disclosed and that the patient has truly given informed consent.

Expanded phenotype of cranioectodermal dysplasia (Sensenbrenner syndrome)

Cranioectodermal dysplasia (CED) is an autosomal recessive condition characterized by defects of ectoderm-derived structures and characteristic bone anomalies. We report on a 27-month-old Caucasian girl with CED, pre- and postnatal growth retardation, microcephaly, hypoplasia of the posterior corpus callosum, photophobia, and aberrant calcium homeostasis. Since new traits were encountered, we reviewed all reported patients and one unpublished case and compared the frequency rates of the individual manifestations. The findings present in all patients are dolichocephaly and rhizomelia. Ectodermal dysplasia manifestations are variable. Short thorax and heart defect are inconsistent. Previously unreported anomalies include growth deficiency, delayed psychomotor development, microcephaly, photophobia, and abnormal calcium homeostasis. These clinical manifestations may facilitate the diagnosis of this condition.

Tracheoesophageal anomalies in oculoauriculovertebral (Goldenhar) spectrum.

Tracheoesophageal fistula, with or without esophageal atresia (TEF/EA) appears to be a defect of blastogenesis, as is the oculoauriculovertebral (Goldenhar) spectrum (OAVS), with which it has occasionally been associated. We reviewed the records of all OAVS patients evaluated through the University of South Florida Regional Genetics Program between 1985 and 1993. Of 60 OAVS patients, three had TEF/EA. These results suggest that TEF/EA in association with OAVS is underreported. The occurrence of TEF/EA should prompt a thorough search for other known anomalies of OAVS.

XXY male with X-linked dominant chondrodysplasia punctata (Happle syndrome)

Happle syndrome is an X-linked dominant disorder with presumed lethality in hemizygous males; familial occurrence is rare. We describe a family with Happle syndrome affecting individuals in 3 generations. A man in this family is the first known male patient with Happle syndrome. He is severely affected; this may be due to his 47,XXY karyotype.

Clitoromegaly in neurofibromatosis.

Genitourinary neurofibromas are rare and clitoral involvement in neurofibromatosis (NF) has been reported infrequently. However, when it occurs, clitoromegaly is often the presenting sign. In many cases, it is congenital. In 236 families with type 1 neurofibromatosis (NF-1) evaluated through the USF Regional Genetics Program between January 1982 and September 1993, four patients had clitoral involvement. In three, involvement was limited to the clitoris. Biopsy/surgical excision in two of them showed a neurofibroma in one and non-specific hamartomatous soft tissue overgrowth in the other. In the fourth patient, the involvement was asymmetric and extended to the labia majora and mons pubis. Endocrine studies and chromosomes in all patients were normal; there was no exposure to androgens, progestins, or coumadin. There was no gestational history of maternal luteomas. Review of the literature documented 26 patients with NF and clitoral involvement. Clitoral involvement in NF-1 appears to be more common than previously reported and the differential diagnosis of ambiguous genitalia should include clitoromegaly due to NF. Pathogenesis of clitoral lesions appears similar to other lesions of NF. Biopsy of such lesions appears to be justified only when malignancy is suspected.