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Biomedical subjects

J J Mulvihill

Publications and source records attributed to J J Mulvihill.

At least 19 recordsLinked to original sources
PubMed2005

Down syndrome with pure partial trisomy 21q22 due to a paternal insertion (4;21) uncovered by uncultured amniotic fluid interphase FISH.

OBJECTIVE: To emphasize the usefulness and reliability of fluorescence in situ hybridization (FISH) on uncultured amniotic fluid cells in the prenatal diagnosis of common chromosomal aneuploidies. METHODS: FISH analyses utilizing centromeric, locus-specific or whole chromosome paint DNA probes specific for chromosomes X, Y, 13, 18, 21, and 4 were performed on uncultured amniotic fluid cells or the peripheral blood specimen from the father. Routine chromosome analysis was carried out as well. RESULTS: A prenatal case with partial trisomy 21 due to a paternal cryptic insertion (4;21) was ascertained by a rapid overnight FISH on uncultured amniotic fluid cells. The fetus was delivered at term and had classical features of Down syndrome. CONCLUSION: Our results stress the importance of FISH on uncultured amniotic fluid cells to supplement routine cytogenetics, especially in cases with abnormal ultrasound findings.

Adult↗
PubMed2004

A new genomic duplication syndrome complementary to the velocardiofacial (22q11 deletion) syndrome.

Fluorescence in situ hybridization (FISH) analysis can reveal undetected chromosomal rearrangements. We report a patient with cleft palate, hydronephrosis, and minor dysmorphic features, including low-set posteriorly rotated ears, down-slanting palpebral fissures, mandibular micrognathia, and brachymesophalangia. Routine chromosome analysis identified no abnormality of chromosome 22; FISH analysis with the TUPLE1 probe disclosed an interstitial duplication of 22q11.2. FISH analysis did not reveal the duplication on the initial testing of metaphase chromosomes, although, on review, the area was brighter on one chromosome in each metaphase spread. FISH analysis of interphase cells showed three TUPLE1-probe sites with two chromosome-specific identification probes in each cell. Family history showed two older full siblings, a brother with behavior problems, oppositional defiant disorder, and learning problems and a sister with hydronephrosis and mild delays. The father and both siblings had similar facial features, and all three had the same interstitial duplication of the TUPLE1 probe. This family illustrates the novel complementary duplication syndrome of the velocardiofacial syndrome, which adds it to the expanding list of genomic deletion/duplication syndromes. The laboratory results further show the utility and need for careful analysis of interphase cells even in samples where good quality metaphases are available.

Abnormalities, Multiple↗
PubMed2003

Chromosomal changes detected by fluorescence in situ hybridization in patients with acute lymphoblastic leukemia.

OBJECTIVES: To investigate patients with acute lymphoblastic leukemia (ALL) for TEL/AML1 fusion, BCR/ABL fusion, MLL gene rearrangements, and numerical changes of chromosomes 4, 10, 17 and 21 by fluorescence in situ hybridization (FISH) and to determine the relationship and the significance of those findings. METHODS: Fifty-one American patients (34 men and 17 women) were included in this study. Of them there were 41 patients with pro-B cell type ALL, 9 with B cell type ALL and 1 with T cell type ALL. Chromosome metaphases of each sample were prepared according to standard protocols. Fluorescence in situ hybridization was performed using commercially available DNA probes, including whole chromosome painting probes, locus specific probes, specific chromosome centromere probes and dual color/multiple color translocation fusion probes. The digital image analysis was carried out using Cytovision and Quips FISH programs. RESULTS: An overall incidence of chromosomal anomalies, including t (9;22), MLL gene rearrangements, t (12;21), and numerical chromosomal anomalies of chromosomes 4, 10, 17 and 21 was found in 33 patients (65%). Thirty-one of them were pediatric patients and two adults. The t (12;21) was the commonest chromosomal anomaly detected in this population; 14 out of the 45 pediatric patients (31%) were positive for TEL/AML1 fusion, among which three had an additional derivative 21 [t (12;21)], four had a deletion of 12p and two had an extra copy of chromosome 21. All 14 patients with positive TEL/AML1 fusion had ALL pre-B cell or B-cell lineage according to standard immunotyping. The percentage of cells with fusion signals ranged from 20% to 80%. All fourteen patients positive for TEL/AML1 gene fusion were mosaic. Three out of the 14 patients positive for the TEL/AML1 gene fusion were originally reported to be culture failures and none of the remaining eleven samples had been found to have chromosome 12 abnormalities by conventional cytogenetic techniques. All pediatric patients with pre-T or T cell lineage and the six adults were negative for TEL/AML1 fusion. One patient had double Philadelphia chromosomes, three had a rearrangement or a deletion of the MLL gene, one had t (4;11) and two had a deletion of the MLL. One of the patients with an MLL deletion also had a large ring of chromosome 21, and r (21) was caused by AML1 gene tandemly duplicated at least five times. The second case with the MLL deletion was also unique, the patient had a t (12;21) as well. A total of 20 patients had numerical changes (gain or loss) of chromosomes 4, 10, 17 and 21. Eight patients were found to have trisomies of three or four different chromosomes. Interestingly, seven of these patients did not have TEL/AML1, BCR/ABL or the MLL gene rearrangement; one did have the TEL/AML1 gene fusion. Eleven patients with pro-B cell or B cell type ALL (9 children with ALL, 2 adults with ALL) had numerical changes of chromosome 21 (gain 1 or 2 chromosome 21), among them, 10 patients had no structural alteration of chromosome 21, and one was combined by t (12; 21). Four patients had a monosomy of chromosome 17 and three out of these patients with monosomy 17 also had a fusion signal of TEL/AML1. CONCLUSIONS: FISH plays an important role in detecting chromosome changes, especially in some cryptic chromosome translocations and patients with culture failures. This study found a trend towards a division between patients who had structural changes such as t (12;21) or a ring chromosome 21 and those who had numerical changes of chromosome 21 as well as the patients with TEL/AML1 fusion and patients with the coexistence of numerical chromosomal changes of chromosomes 4, 10 and 17. In our opinion there are two separate mechanisms which lead to the development or progression of leukemia.

Adolescent↗
PubMed2001

Cancer in siblings of children with cancer in the Nordic countries: a population-based cohort study.

BACKGROUND: In some rare inherited disorders such as Li-Fraumeni syndrome, relatives of children with cancer are at increased risk of cancer. We aimed to assess relations between childhood cancer and sibling risk, and evaluate the influence of recessive conditions in cancer causation. METHODS: We did a population-based cohort study in the Nordic countries of 42277 siblings of 25605 children with cancer. Children with cancer were identified from records in the five Nordic cancer registries, and their siblings from nationwide population registries. Cancers in siblings were documented through record linkage with cancer registries and compared with national incidence rates. We also assessed cancer incidence in parents to identify familial cancer syndromes. FINDINGS: 284.2 cancers were expected in siblings, whereas 353 were diagnosed (standardised incidence ratio 1.24 95% CI 1.12-1.38). Risk ratios for siblings were highest in the first decade of life (2.59, 1.89-3.46). We excluded 56 families with genetic syndromes linked to cancer, which reduced this ratio from 1.7 to 1.0 (0.7-1.3) for siblings younger than 20 years, and from 1.3 to 1.0 (0.8-1.3) for those aged 20-29 years. We found no new patterns of familial cancer that indicated inherited susceptibility, or evidence that recessive conditions might contribute to cancers not explained by syndromes. 40% of cancers in siblings that occurred before age 20 years could be attributed to known genetic factors, whereas 60% remained unexplained. INTERPRETATION: Apart from rare cancer syndromes, paediatric cancer is not an indicator of increased cancer risk in siblings.

Adolescent↗
PubMed2001

Single nucleotide polymorphism in prohibitin 3' untranslated region and breast-cancer susceptibility.

The RNA encoded by the 3' untranslated region of the prohibitin gene arrests cell proliferation by blocking the transition between the G1 and S phases of the cell cycle. The product of a variant allele (T allele) is inactive. We did a case-control study of prohibitin genotype in 205 women with breast cancer and 1046 healthy controls. The results showed an association between the T allele and breast cancer in women who reported a first-degree relative with the disease (odds ratio 2.5, p=0.005). An even stronger association was found in a subset of women diagnosed at or before age 50 years (4.8, p=0.003). These data suggest that prohibitin genotyping has value in assessing risk of breast cancer in women aged 50 years or younger with at least one first-degree relative with the disease.

Adult↗
PubMed2001

Pharmacogenetics, race, and ethnicity: social identities and individualized medical care.

Social categories such as race and ethnicity have long been used in interpreting patient symptoms, diagnosing disease, and predicting therapeutic response. DNA-based diagnostic tests and pharmacogenetic screens could make these uses of social categories largely irrelevant by allowing clinicians to base diagnosis and treatment decisions on the unique genetic features of individual patients. Despite this attractive vision of individualized care, however, social categories are likely to continue playing a significant role in the coming era of genetic medicine. Current uses of social categories in pharmacogenetic research, for example, illustrate how drug development and marketing will perpetuate the use of social categories such as race and ethnicity. Those uses may unintentionally blunt the precision of genetic technologies and pose new threats to socially identifiable populations. These implications suggest the need for greater caution in using social categories as indicators for specific tests or therapies and for federal legislation to protect against discriminatory uses of individuals' genetic information. In addition, more precise social classifications than those presently in use may allow us to realize the full potential of DNA-based technologies, thus minimizing social disparities in health care. Those more precise social classifications should reflect extended patient pedigrees and not the self-reported claims of racial and/or ethnic affiliation.

Delivery of Health Care↗
PubMed2000

Inheritance of pancreatic cancer in pancreatic cancer-prone families.

Families are being increasingly recognized as carrying an inherited susceptibility for pancreatic cancer, apparently unrelated to any currently recognized syndrome. The authors provide a review of the current evidence for familial susceptibility to pancreatic cancer. A formal segregation analysis of the pattern of inheritance of pancreatic cancer in 70 families from the National Registry for Familial Pancreatic Cancer is described. This analysis suggests a single major gene with an autosomal dominant mode of inheritance controlling susceptibility for pancreatic cancer in these families.

Adenocarcinoma↗
PubMed1998

Permanent Committee of the International Congress of Human Genetics.

For over three decades, the Permanent Committee of the International Congresses of Human Genetics has served the purpose of selecting a host and site for the quadrennial Congress, which is due next in 2001. The Committee has statutes and consists of one voting representative from 38 nations and other ex officio members, much like the General Assembly of the United Nations. It meets twice during each International Congress, otherwise conducting its business by mail and telecommunication. Its structure could be the beginnings of a truly global democratic body of human geneticists to address other issues and to serve other purposes, as human genetics becomes increasingly international, as inevitably it must.

Congresses as Topic↗
PubMed1998

Familial eosinophilia: clinical and laboratory results on a U.S. kindred.

We describe a five-generation kindred with familial eosinophilia (FE; MIM131400), characterized by the occurrence of sustained eosinophilia of unidentifiable cause in multiple relatives. The inheritance pattern is consistent with an autosomal dominant pattern. Among 52 related subjects studied, 19 were affected and 33 were unaffected. Ten unaffected spouses were also evaluated. Four subjects with sustained eosinophilia were diagnosed with cardiac abnormalities and two of them also had neurologic symptoms. In comparison with the unaffected or spouses, evaluation of complete blood counts showed that the affected relatives had, as expected, significantly higher white cell (P < 0.005) and absolute eosinophil counts (P < 0.001) and lower red cell counts (P < 0.05). Evaluation of serum cytokine levels (IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GMCSF) and serology for parasitic helminth infection demonstrated no differences between the affected and unaffected individuals; no individuals studied had serologic evidence for parasitic infection. There were also no differences in anti-nuclear antibody, serum cobalamin (vitamin B12) level, immunoglobulin level, leukocyte alkaline phosphatase, rheumatoid factor, HLA analysis, and stool findings for ova and parasites. Among eight affected persons who had peripheral blood or bone marrow karyotype analysis, two carried the same chromosome abnormality, a pericentric inversion of chromosome 10, inv (10) (p11.2q21.2). A gene mapping study is currently underway to study the underlying genetic mechanism(s) of this syndrome.

Adolescent↗
PubMed1998

The variable penetrance and spectrum of manifestations of multiple endocrine neoplasia type 1.

BACKGROUND: Some experts maintain that (1) > 90% of patients with multiple endocrine neoplasia type 1 (MEN1) are first seen with hyperparathyroidism (HPTH) so that routine screening for other features is unnecessary and (2) MEN1 has > or = 94% penetrance by age 50 years. METHODS: We constructed a regional registry of patients with or at risk for MEN1 and examined phenotypic profiles in 34 patients. MEN1 was defined as (1) endocrinopathy of 2 of the 3 principal related tissues (parathyroid, gastrointestinal endocrine, pituitary) or (2) 1 such feature plus a first-degree relative with MEN1. RESULTS: The initial feature of MEN1 was HPTH in 50%, pituitary tumor in 18%, and gastrointestinal endocrine tumor in 32% of patients, with overall incidences of 82%, 65%, and 74%, respectively. HPTH developed by age 50 years in 73% of patients and by age 70 years in 83%. Penetrance of MEN1 at age 50 years was 82%. Associated features included renal (1) and rectal (1) cancer, malignant thymic carcinoid (1), and malignant pheochromocytoma (1). CONCLUSIONS: Expression of MEN1 can vary considerably from established patterns. In our geographic region HPTH does not routinely precede other features of MEN1 and cannot be used to distinguish affected patients among those at risk. MEN1 can be inapparent until late in life and may be significantly underdiagnosed.

Adolescent↗
PubMed1998

Genetic disease in offspring of long-term survivors of childhood and adolescent cancer.

Numerous case series have addressed the concern that cancer therapy may damage germ cells, leading to clinical disease in offspring of survivors. None has documented an increased risk. However, the methodological problems of small series make it difficult to draw firm conclusions regarding the potential of cancer treatments to damage the health of future offspring. We conducted a large interview study of adult survivors of childhood cancer treated before 1976. Genetic disease occurred in 3.4% of 2,198 offspring of survivors, compared with 3.1% of 4,544 offspring of controls (P=.33; not significant); there were no statistically significant differences in the proportion of offspring with cytogenetic syndromes, single-gene defects, or simple malformations. A comparison of survivors treated with potentially mutagenic therapy with survivors not so treated showed no association with sporadic genetic disease (P=.49). The present study provides reassurance that cancer treatment using older protocols does not carry a large risk for genetic disease in offspring conceived many years after treatment. With 80% power to detect an increase as small as 40% in the rate of genetic disease in offspring, this study did not do so. However, we cannot rule out the possibility that new therapeutic agents or specific combinations of agents at high doses may damage germ cells.

Adolescent↗
PubMed1998

Surgical management of spinal cord compression from plexiform neurofibromas in patients with neurofibromatosis 1.

OBJECTIVE: Plexiform neurofibromas with sizable intraspinal extensions and resultant spinal cord compromise pose challenging management problems, because these lesions may involve multiple nerves and engulf adjacent vascular and visceral structures. In this report, we review our experience with the surgical treatment of these lesions. METHODS: Patients were identified by a detailed review of hospital medical records and the database of our multidisciplinary neurofibromatosis clinic. Ten patients had large plexiform neurofibromas that extended intraspinally, producing a combination of myelopathy and radiculopathy. Two patients exhibited single-level intraspinal growth, and eight showed multilevel involvement. Four patients showed bilateral plexiform neurofibromatous growth intraspinally, with "hourglass" compression of the spinal cord. Operative approaches and outcomes were reviewed in detail. RESULTS: Gross total resection of the symptomatic intraspinal tumor component was achieved for nine patients. The management of the extraspinal component was individualized, depending on the pattern and extent of involvement of the surrounding structures. Nine patients experienced complete recovery of neurological function postoperatively; the remaining patient demonstrated significant functional improvement. With a median follow-up period of 4 years, only one patient has developed recurrent intraspinal compression, in this case from tumor involvement by the same plexiform lesion at a lower spinal level. Two patients treated early in the series using standard laminectomy approaches developed significant kyphotic deformities, necessitating subsequent fusion. Based on these initial results, osteoplastic laminotomy techniques were used in the last five cases, allowing anatomic reconstruction of the involved levels; none of these latter patients has developed significant kyphosis, with a median follow-up period of 3 years. CONCLUSION: Radical resection of intraspinal tumor components in patients with neurofibromatosis 1 and large plexiform neurofibromas can help to preserve excellent neurological function. Technical factors in the management of these lesions are presented.

Adolescent↗
PubMed1997

Spectrum of malignancy and premalignancy in Carney syndrome.

Carney syndrome is a rare, autosomal dominant, multi-system disorder comprising 8 well-characterized findings, only 2 of which need be present for a definitive diagnosis. Benign neoplasms are frequent, but malignancies are thought to be uncommon. We have studied a family to clarify the diagnosis and spectrum of clinical manifestations of the syndrome and to develop guidelines for management. The proposita, a 34-year-old woman had classic findings of Carney syndrome, invasive follicular carcinoma of the thyroid gland, Barrett metaplasia of the esophagus, neoplastic colonic polyps, bipolar affective disorder, and atypical mesenchymal neoplasm of the uterine cervix distinct from the myxoid uterine leiomyoma usually seen in this syndrome. Although thyroid gland neoplasm is rare in Carney syndrome, this patient's most aggressive manifestation was her thyroid carcinoma. The diagnosis of Carney syndrome was established in her 9-year-old son and is a probable diagnosis in her 12-year-old daughter. Endocrine manifestations were prominent in the family with at least 9 relatives in 3 generations affected with various endocrine abnormalities. The findings in this family indicate that the spectrum of manifestations in this pleiotropic gene apparently includes a malignant course with premalignant and endocrinologic disorders not previously recognized.

Adult↗
PubMed1997

Interstitial lung disease in an adult with Fanconi anemia: clues to the pathogenesis.

We have studied a 38-year-old man with a prior diagnosis of Holt-Oram syndrome, who presented with diabetes mellitus. He had recently taken prednisone for idiopathic interstitial lung disease and trimethoprim-sulfamethoxazole for sinusitis. Thrombocytopenia progressed to pancytopenia. The patient had skeletal, cardiac, renal, cutaneous, endocrine, hepatic, neurologic, and hematologic manifestations of Fanconi anemia (FA). Chest radiographs showed increased interstitial markings at age 25, dyspnea began in his late 20s, and he stopped smoking at age 32. At age 38, computerized tomography showed bilateral upper lobe fibrosis, lower lobe honeycombing, and bronchiectasis. Pulmonary function tests, compromised at age 29, showed a moderately severe obstructive and restrictive pattern by age 38. Serum alpha-1 antitrypsin level was 224 (normal 85-213) mg/dL and PI phenotype was M1. Karyotype was 46,XY with a marked increase in chromosome aberrations induced in vitro by diepoxybutane. The early onset and degree of pulmonary disease in this patient cannot be fully explained by environmental or known genetic causes. The International Fanconi Anemia Registry (IFAR) contains no example of a similar pulmonary presentation. Gene-environment (ecogenetic) interactions in FA seem evident in the final phenotype. The pathogenic mechanism of lung involvement in FA may relate to oxidative injury and cytokine anomalies.

Adult↗
PubMed1997

Cholesterol and bile acid replacement therapy in children and adults with Smith-Lemli-Opitz (SLO/RSH) syndrome.

Tint et al. [N Engl J Med 1994, 330:107-113], working with blood samples from the Smith-Lemli-Opitz syndrome (SLOS) patients of Irons and Elias showed the biochemical basis of this disorder to be a cholesterol biosynthesis defect [Irons et al., Lancet, 1993, 341:1414]. Based on this finding, clinical protocols for cholesterol and bile acid replacement therapy were established in a few centers including the University of Pittsburgh. We report our experience with bile acid and/or cholesterol replacement therapy in six patients with SLOS, now aged 3-27 years, with a confirmed biochemical diagnosis. Levels of plasma cholesterol and 7-dehydrocholesterol were correlated with periodic clinical evaluations over 8-27 months of therapy. There was a marked improvement in the growth of all the children. There was also an increase in the plasma cholesterol level in all the children and an overall increase in their percent sterol as cholesterol. Subjective improvement was also noted in their development. Although there was no significant change in the plasma cholesterol level of the older patients, there was a marked improvement in their behavior and in their quality of life.

Adolescent↗