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Deborah A Driscoll

Publications and source records attributed to Deborah A Driscoll.

At least 19 recordsLinked to original sources
PubMed2006

Molecular and genetic aspects of DiGeorge/velocardiofacial syndrome.

Cytogenetic, molecular, and clinical genetic studies have contributed to our understanding of the etiology, pathogenesis, and natural history of DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). Submicroscopic deletions of chromosome 22ql 1.2 are the leading cause of both of these disorders. The 22q 11.2 deletion syndrome is recognized as one of the most common microdeletion syndromes. The clini'cal features are highly variable and include a variety of congenital anomalies, medical problems, and cognitive and neuropsychological difficulties. Infrequently, other chromosomal rearrangements are found in patients with DGS/VCFS, and, rarely, point mutations in the gene TBX1, a transcription factor, that maps to the deleted region. The most sensitive and widely used diagnostic test for detecting the 22ql 1.2 deletion is fluorescence in situ hybridization using probes from the commonly deleted region. Alternatively, polymerase chain reaction can be performed to confirm failure to inherit a parental allele in the region or to determine copy number. Prenatal diagnosis is also available, particularly when a conotruncal cardiac defect is identified during a pregnancy or when a parent carries a deletion. Genetic counseling is recommended before testing to review the natural history of the disorder, testing options, and test sensitivity and limitations.

Chromosome Deletion↗
PubMed2006

Evaluation of potential modifiers of the palatal phenotype in the 22q11.2 deletion syndrome.

OBJECTIVE: To evaluate potential modifiers of the palatal phenotype in individuals with the 22q11.2 deletion syndrome. DESIGN: Data from 356 subjects enrolled in a study of the 22q11.2 deletion syndrome were used to evaluate potential modifiers of the palatal phenotype. Specifically, subjects with and without velopharyngeal inadequacy and/or structural malformations of the palate were compared with respect to gender, race, and genotype for variants of seven genes that may influence palatal development. METHODS: The chi-square test or Fisher exact test was used to evaluate the association between palatal phenotype and each potential modifier. Odds ratios and their associated 95% confidence intervals were used to measure the magnitude of the association between palatal phenotype, subject gender and race, and each of the bi-allelic variants. RESULTS: The palatal phenotype observed in individuals with the 22q11.2 deletion syndrome was significantly associated with both gender and race. In addition, there was tentative evidence that the palatal phenotype may be influenced by variation within the gene that encodes methionine synthase. CONCLUSIONS: Variation in the palatal phenotype observed between individuals with the 22q11.2 deletion syndrome may be related to personal characteristics such as gender and race as well as variation within genes that reside outside of the 22q11.2 region.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2005

Prenatal diagnosis of Fanconi anemia (Group C) subsequent to abnormal sonographic findings.

Manifestations of Fanconi Anemia Complementation Group C (FA-C) include multiple major congenital malformations, hypoplastic radius, absent thumb, growth retardation, elfin-like facial features, microphthalmia, microcephaly, cafe-au-lait spots, early onset of hematologic disease and poor survival (Auerbach, 1997). We describe two cases in which second-trimester sonographic findings led to parental carrier testing for FA-C and subsequent prenatal diagnosis of affected fetuses.

Abnormalities, Multiple↗
PubMed2005

Impact of self-reported familiarity with guidelines for cystic fibrosis carrier screening.

OBJECTIVE: To assess the impact of self-reported familiarity with published guidelines on knowledge, implementation, and opinions of obstetrician-gynecologists regarding carrier screening for cystic fibrosis. METHODS: A questionnaire pertaining to cystic fibrosis screening guidelines was mailed to 1,165 members of the American College of Obstetricians and Gynecologists. RESULTS: Sixty-four percent of questionnaires were returned. Statistical analyses were limited to the 632 respondents whose primary medical specialty was gynecology (GynOnly) or obstetrics and gynecology (ObGyns). More ObGyns had thoroughly read or skimmed the guidelines (67.1%) than had GynOnlys (41.6%). Correctly responding to basic questions regarding cystic fibrosis was associated with having read the guidelines, although responding to a more complex question was not. Familiarity with the guidelines was associated with correctly identifying the recommendations for offering screening, with practice implementation of cystic fibrosis screening, and with self-ratings of qualifications and training to offer screening and to provide counseling. In contrast, familiarity with the guidelines was not associated with ObGyn's opinion that burden of disease is likely to be influential in patient acceptance of screening. Physicians who had thoroughly read the guidelines were more likely to disagree that the cystic fibrosis screening test is too inaccurate to risk influencing reproductive decision making (thoroughly read = 79% disagree, skimmed = 69%, not read = 58%, not heard of it = 50%). CONCLUSION: There was a strong association between self-reported familiarity with the American College of Obstetricians and Gynecologists/American College of Medical Genetics guidelines and physicians' knowledge, implementation, and ratings of training for offering cystic fibrosis carrier screening.

Attitude of Health Personnel↗
PubMed2005

Fragile X syndrome: diagnostic and carrier testing.

This guideline is designed primarily as an educational resource for medical geneticists and other health care providers to help them provide quality medical genetic services. Adherence to this guideline does not necessarily assure a successful medical outcome. This guideline should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient's record the rationale for any significant deviation from this guideline.

Fragile X Syndrome↗
PubMed2004

Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice.

Carney complex (CNC) is a familial multiple neoplasia syndrome characterized by cardiac and extracardiac myxomas in the setting of spotty skin pigmentation and endocrinopathy. We previously identified PRKAR1A (regulatory subunit 1alpha of protein kinase A) mutations in CNC. Mutational analyses of the PRKAR1A gene in 51 unrelated CNC probands now detect mutations in 65%. All mutations, except for one unique missense mutation, lead to PRKAR1A haploinsufficiency. Therefore, we studied the consequences of prkar1a haploinsufficiency in mice. Although we did not observe cardiac myxomas or altered pigmentation in prkar1a(+/-) mice, we did observe some phenotypes similar to CNC, including altered heart rate variability. Moreover, prkar1a(+/-) mice exhibited a marked propensity for extracardiac tumorigenesis. They developed sarcomas and hepatocellular carcinomas. Sarcomas were frequently associated with myxomatous differentiation. Tumors from prkar1a(+/-) mice did not exhibit prkar1a loss of heterozygosity. Thus, we conclude that although PRKAR1A haploinsufficiency does predispose to tumorigenesis, distinct secondary genetic events are required for tumor formation.

Alleles↗
PubMed2004

Independent de novo 22q11.2 deletions in first cousins with DiGeorge/velocardiofacial syndrome.

Deletions of chromosome 22q11.2 are found in the vast majority of patients with DiGeorge/velocardiofacial syndrome (DGS/VCFS). This most frequent microdeletion syndrome is estimated to occur in 1 in 4,000 live births. The majority of deletions are de novo, with 10% or less inherited from an affected parent. Here, we report two separate families with recurrence of a 22q11.2 deletion in first cousins. In each family, unaffected siblings (brother and sister) had an affected child. Fluorescence in situ hybridization (FISH) studies of the parents of each affected child were normal and hence, relatives were not considered at an increased risk for recurrence in another pregnancy. We used highly polymorphic microsatellite repeat markers from within 22q11.2 to determine the parental origin of each cousin's deletion and to assess whether parental germline mosaicism for the 22q11.2 deletion might be a factor in these cases. This analysis confirmed that in each case, the deletion occurred on a chromosome 22 derived from unrelated parents, consistent with independent de novo deletion events. Thus, we concluded that germline mosaicism as the underlying mechanism for affected cousins in these families was unlikely. Our findings underscore the high frequency with which the 22q11.2 deletion occurs in the general population and demonstrate the important role that PCR-based parental origin determination can have in recurrence risk counselling. Furthermore, relatives of affected individuals may benefit from genetic counselling and consider prenatal testing for the 22q11.2 deletion in future pregnancies, despite a low recurrence risk.

Abnormalities, Multiple↗
PubMed2003

Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion.

Chromosome 22q11.2 deletions are found in almost 90% of patients with DiGeorge/velocardiofacial syndrome (DGS/VCFS). Large, chromosome-specific low copy repeats (LCRs), flanking and within the deletion interval, are presumed to lead to misalignment and aberrant recombination in meiosis resulting in this frequent microdeletion syndrome. We traced the grandparental origin of regions flanking de novo 3 Mb deletions in 20 informative three-generation families. Haplotype reconstruction showed an unexpectedly high number of proximal interchromosomal exchanges between homologs, occurring in 19/20 families. Instead, the normal chromosome 22 in these probands showed interchromosomal exchanges in 2/15 informative meioses, a rate consistent with the genetic distance. Meiotic exchanges, visualized as MLH1 foci, localize to the distal long arm of chromosome 22 in 75% of human spermatocytes tested, also reflecting the genetic map. Additionally, we found no effect of proband gender or parental age on the crossover frequency. Parental origin studies in 65 de novo 3 Mb deletions (including these 20 patients) demonstrated no bias. Unlike Williams syndrome, we found no chromosomal inversions flanked by LCRs in 22 sets of parents of 22q11 deleted patients, or in eight non-deleted patients with a DGS/VCFS phenotype using FISH. Our data are consistent with significant aberrant interchromosomal exchange events during meiosis I in the proximal region of the affected chromosome 22 as the likely etiology for the deletion. This type of exchange occurs more often than is described for deletions of chromosomes 7q11, 15q11, 17p11 and 17q11, implying a difference in the meiotic behavior of chromosome 22.

Chromosome Aberrations↗
PubMed2003

Molecular basis of pubertal abnormalities.

The causes of abnormal pubertal development are numerous. Recent molecular investigation has increased our understanding of the genetic basis of pubertal disorders. Investigators have identified some of the genes that are critical for normal puberty and have begun to elucidate the genes and pathogenesis of genetic disorders associated with abnormal pubertal development. Identification of specific chromosomal abnormalities and gene mutations allows for diagnostic testing and enables the clinician to provide accurate counseling of the recurrence risk for relatives. In the future, knowledge of the genetic basis of these disorders will facilitate the development of novel therapies and approaches to the fertility assessment and treatment of individuals with pubertal disorders. Although great strides have been made in identifying these genes, questions remain. Why do some genetic mutations affect puberty differentially in males and females? What is the long-term impact in terms of future fertility, and what is the risk to the offspring of such patients? Further research is needed to address these issues and to identify additional genetic loci involved in pubertal development.

Adolescent↗
PubMed2003

Polycystic ovary syndrome in adolescence.

Polycystic ovary syndrome (PCOS) is a relatively common disorder among adolescent women. The typical clinical features including menstrual irregularities and hirsutism are usually not apparent until middle to late adolescence. Yet studies suggest that PCOS may begin in early puberty. Young women with premature pubarche, a family history of PCOS, Caribbean Hispanic and African American ancestry, and/or obesity are more likely to develop PCOS. Adolescents with PCOS may have elevated total or free testosterone, androstenedione, and luteinizing hormone levels; insulin resistance; and hyperinsulinemia. The laboratory evaluation and management of the adolescent with suspected PCOS should be individualized on the basis of the clinical features and symptoms. The cornerstone of most treatment strategies includes either a combination oral contraceptive or progestin to decrease testosterone levels and regulate the menstrual cycle. Consideration of insulin-sensitizing agents, antiandrogens, topical treatments for acne and excess facial hair, and hair removal is dependent on the patient's symptoms and concerns. A healthy approach to eating, in some cases weight loss, and exercise is encouraged to reduce the risk of cardiovascular disease and type 2 diabetes mellitus. Management of the adolescent with PCOS is challenging and often requires a supportive, multidisciplinary team approach for optimal results.

Adolescent↗
PubMed2003

Polycystic ovary syndrome in adolescence.

Polycystic ovary syndrome (PCOS) is a common disorder among reproductive-age women, yet the diagnosis may be overlooked during adolescence. Although the clinical and metabolic features are similar to those found in adult women, it can be difficult to distinguish the young woman with PCOS from a normal adolescent. Irregular menses, anovulatory cycles, and acne are not uncommon in adolescent women. Adolescents with a history of premature pubarche, a family history of PCOS, Caribbean-Hispanic and African-American ancestry, and/or obesity are at risk for PCOS and deserve close surveillance. The laboratory evaluation of the adolescent with suspected PCOS or hyperandrogenism should be individualized based on the history, symptoms, and examination findings. The cornerstone of management of PCOS in adolescence includes either a combination oral contraceptive or progestin. Consideration of insulin-sensitizing agents, antiandrogens, topical treatments for acne, and various treatments for hair removal are dependent on the patient's symptoms and concerns. Healthy eating, regular exercise, and for the overweight adolescent, weight reduction, are encouraged to reduce the risk of cardiovascular disease and type II diabetes mellitus. Numerous studies have shown that weight loss and exercise decrease androgen levels, improve insulin sensitivity, and lead to the resumption of ovulation. Although initial studies suggest that Metformin may be particularly useful for treating the PCOS adolescent with insulin resistance and obesity, additional studies are needed to determine the efficacy and long-term outcome. Management of the adolescent with PCOS is challenging and requires a supportive, multidisciplinary team approach for optimal results.

Adolescent↗
PubMed2003

Screening for aneuploidy in twin pregnancies: maternal age- and race-specific risk assessment between 9-14 weeks.

The aim of this study was to calculate the risk for aneuploidy in twin pregnancies between 9-14 weeks utilizing maternal age, race and dizygotic twinning rates. Using previously published risks for aneuploidy in singletons and twins at the time of amniocentesis and at term, we calculated new risk estimates for twins at 9-14 weeks gestation or at the time of chorionic villus sampling. Using these tables, the risk for trisomy 21 in at least one fetus of a twin gestation in a 32-year-old at 9-14 weeks is 1/285 for Whites and for African-Americans. This is equivalent to the risk for trisomy 21 (1/265) in a 35-year-old woman with a singleton at the same gestational age. The risks for trisomies 18 and 13 also follow similar trends. In counseling women with twin pregnancies at the time of first trimester nuchal translucency screening or chorionic villus sampling, it should be noted that the maternal age-related risk for aneuploidy for a 32-year-old is equivalent to that of a 35-year-old woman with a singleton gestation.

Aneuploidy↗
PubMed2003

Chromosome 22q11 deletion in patients with ventricular septal defect: frequency and associated cardiovascular anomalies.

BACKGROUND: A ventricular septal defect (VSD) is the most common form of congenital heart disease and is one of the most common cardiovascular anomalies in individuals with chromosome 22q11 deletion syndrome. However, the frequency of a chromosome 22q11 deletion in patients with a VSD is not known. In addition, among patients with a VSD, it is not clear whether particular types of VSD or associated cardiovascular phenotypic features are associated with a chromosome 22q11 deletion. METHODS: We prospectively enrolled 125 patients with a conoventricular (n = 100), posterior malalignment (n = 14), or conoseptal hypoplasia (n = 11) VSD who were admitted to Children's Hospital of Philadelphia between November 1991 and December 2001. Patients were studied for a chromosome 22q11 deletion by using fluorescence in situ hybridization. RESULTS: A chromosome 22q11 deletion was detected in 12 (10%) of the 125 patients. Anatomic features that were significantly associated with a chromosome 22q11 deletion included abnormal aortic arch sidedness, an abnormal aortic arch branching pattern, a cervical aortic arch, and discontinuous pulmonary arteries. There was no correlation between the type of VSD and chromosome 22q11 deletion. Of 20 patients with an abnormal aortic arch and/or discontinuous pulmonary arteries, 45% had a chromosome 22q11 deletion compared with only 3% of those with a left aortic arch, normal aortic arch branching pattern, and continuous branch pulmonary arteries CONCLUSIONS: A chromosome 22q11 deletion is common in individuals with a conoventricular, posterior malalignment, or conoseptal hypoplasia VSD and anomalies of the aortic arch or branch pulmonary arteries. On the basis of these findings, at a minimum, we recommend testing for a chromosome 22q11 deletion in patients with these types of VSD who have abnormalities of aortic arch sidedness or branching, a cervical aortic arch, and/or discontinuous pulmonary arteries. Testing of patients with these types of VSD but a normal aortic arch and pulmonary arteries may be performed routinely or guided by the presence of associated noncardiovascular features of chromosome 22q11 deletion syndrome.

Chromosome Deletion↗
PubMed2002

Omodysplasia: an affected mother and son.

We describe a second family with mother to son transmission of omodysplasia, a rare skeletal dysplasia characterized by shortened humeri, shortened first metacarpals and craniofacial dysmorphism. The mother in this family had been diagnosed previously with Robinow syndrome; subsequently, her diagnosis was reclassified. Her pregnancy was closely monitored antenatally with serial ultrasound examinations. Delayed ossification of the humerus was noted prenatally. Her son had ambiguous genitalia and similar skeletal manifestations as his mother. A comparison to other known and suspected cases of dominant omodysplasia is presented. Our observations confirm the existence of a dominant variant of omodysplasia, document genital hypoplasia as an important feature of this syndrome in males and highlight the need to differentiate this entity from Robinow syndrome.

Abnormalities, Multiple↗