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D A Driscoll

Publications and source records attributed to D A Driscoll.

At least 19 recordsLinked to original sources
PubMed1997

Successful formation of a chimeric human thymus allograft following transplantation of cultured postnatal human thymus.

Transplantation of cultured postnatal human thymus was performed in a patient with complete DiGeorge syndrome. Biopsy of the graft 3 mo after implantation revealed normal CD1+ thymocytes in thymic cortical epithelial regions and CD1- thymocytes in thymic medullary epithelial regions, respectively. HLA analysis of graft thymocyte and thymic microenvironment components demonstrated that developing thymocytes and thymic macrophages were recipient derived, while thymic epithelial components were of donor origin. The patient, who initially had no T cells and had profoundly defective T cell function, developed normal T cell responses to mitogens and Ags, tolerance to donor in a mixed lymphocyte reaction, and normal Ab titers after tetanus toxoid and pneumovax immunization. Thus, transplantation of cultured postnatal human thymic tissue in humans can form functional chimeric thymic tissue, and may provide a strategy to reconstitute the peripheral T cell pool in select congenital and acquired immune deficiency syndromes.

Chimera↗
PubMed1996

Kabuki syndrome is not caused by a microdeletion in the DiGeorge/velocardiofacial chromosomal region within 22q 11.2.

Kabuki syndrome (KS) or Niikawa-Kuroki syndrome is a sporadic disorder characterized by postnatal growth retardation, developmental delay, mild to moderate retardation, and a characteristic facial appearance. Cardiovascular defects, clefts of the lip, palate, or both, and musculoskeletal abnormalities occur in about 50% of patients with KS. The cause of this multiple congenital anomaly syndrome is unknown, and investigators have speculated that KS is a contiguous gene-deletion syndrome. Based on the presence of congenital heart defects in patients with KS, it was suggested that this disorder might share a common cause with the 22q11 deletion syndromes. A preliminary study of 2 patients with KS failed to detect a deletion within 22q11. We report the results of fluorescence in situ hybridization with cosmid probes for loci D22S75 (N25) and D22S259 (R32) within the DiGeorge chromosomal region (DGCR) on metaphase spreads from an additional 5 patients, 2 non-Japanese and 3 Japanese, with KS. None of the 5 had deletions at either locus. It is unlikely that KS is caused by a deletion within 22q11.

Abnormalities, Multiple↗
PubMed1996

Identification of a mutation in a GATA binding site of the platelet glycoprotein Ibbeta promoter resulting in the Bernard-Soulier syndrome.

Bernard-Soulier Syndrome (BSS) is a rare congenital bleeding disorder due to absent or decreased expression of the glycoprotein Ib-IX-V (GpIb-IX-V) receptor complex on the platelet surface. To date, only mutations in GpIbalpha or GpIX have been reported in patients with BSS. GpIbbeta differs from the other proteins in this receptor in that the gene is more complex, and an alternative form is expressed in cells of non-megakaryocytic lineage, including endothelial cells. It appears that the megakaryocytic and endothelial cell mRNA species are transcribed from different start sites and have different proximal promoter regions. We have identified a patient with BSS who has a deletion on one chromosome 22, resulting in velocardiofacial syndrome. The GpIbbeta gene has been mapped to this deleted (22q11.2) region of chromosome 22. The patient has greatly reduced levels of GpIbbeta mRNA and no detectable platelet GpIbbeta protein, suggesting that his BSS results from a mutation in his remaining GpIbbeta allele. Sequence analysis revealed that the coding region of GpIbbeta is normal, but the 5'-upstream region contains a C to G transversion at base -133 from the transcription start site used in megakaryocytes. The mutation changes a GATA consensus binding site, disrupts GATA-1 binding to the mutated site, and decreases promoter activity by 84%. Thus, in this patient, Bernard-Soulier syndrome results from a deletion of one copy of GpIbbeta and a mutated GATA binding site in the promoter of the remaining allele, resulting in decreased promoter function and GpIbbeta gene transcription.

Alleles↗
PubMed1996

Latent hypoparathyroidism in children with conotruncal cardiac defects.

BACKGROUND: DiGeorge anomaly is characterized by hypoplasia or atresia of the thymus and parathyroid glands resulting in T cell-mediated deficiency, hypocalcemic hypoparathyroidism, and conotruncal cardiac defects. It usually is associated with deletions of chromosomal region 22q11. We hypothesized that the stimulated (secretory reserve) but not the constitutive secretion of parathyroid hormone would be reduced in normocalcemic children with conotruncal cardiac defects but no overt immune deficiency and would be related to the presence of a deletion in the DiGeorge chromosomal region of 22q11. METHODS AND RESULTS: Blood-ionized calcium and serum-intact parathyroid hormone were measured at baseline and seven more times during hypocalcemia induced during cardiopulmonary bypass in 22 patients and 10 control subjects with an atrial septal defect. Chromosomal deletions were detected by fluorescent in situ hybridization and DNA dosage analysis. There were no differences in basal calcium and parathyroid hormone levels between patients and control subjects. All had increased parathyroid hormone in response to hypocalcemia; despite lower calcium levels, parathyroid hormone levels were lower in patients. The parathyroid hormone secretory reserve in 14 of 22 patients was reduced compared with control subjects; 4 of the 14 had deletions. CONCLUSIONS: A significant number of children with conotruncal cardiac defects have normocalcemia and a normal constitutive level of parathyroid hormone but deficient parathyroid hormone secretory reserve; about 30% also have 22q11 deletions. Such children may be at risk for the later development of hypocalcemic hypoparathyroidism.

Adolescent↗
PubMed1996

Recognition of tubo-ovarian abscess in adolescents with pelvic inflammatory disease.

PURPOSE: Ultrasonography of the pelvis is commonly used to diagnose tubo-ovarian abscess (TOA) in patients with pelvic inflammatory disease (PID). Our objective was to determine whether the clinical features of PID differ in adolescents with and without TOA. METHODS: A retrospective design was used to derive and validate a clinical model differentiating adolescents with PID who did and did not have TOA. The study population consisted of hospitalized adolescents with a discharge diagnosis of PID. Of the 208 patients discharged from January 1, 1990, to July 31, 1993, 87 (42%) met published criteria for PID and comprised the derivation set. Of the 63 patients from August 1, 1993, to June 24, 1994, 30 (48%) met criteria and comprised the validation set. All patients had pelvic ultrasonography performed during hospitalization. The ultrasonography records were reviewed retrospectively for TOA, ovarian and uterine size, clarity of tissue planes, and endometrial or cul-de-sac fluid. Medical records were reviewed for sociodemographic characteristics, medical and sexual history, physical examination, laboratory results, and hospital course. RESULTS: TOA was present in 17% of the derivation set and 20% of the validation set. A six-variable model developed on the derivation set performed best in differentiating the TOA and non-TOA groups: last menstrual period > 18 days prior to admission (60% and 17%), previous PID (53% and 22%), palpable adnexal mass (13% and 3%), white blood cell count > or = 10,500/microliters (33% and 64%), erythrocyte sedimentation rate > 15 mm/h (33% and 64%), and heart rate > 90/min (40% and 78%). In the derivation and validation sets, the model correctly identified 78 and 83% of the TOA groups and 88 and 77% of the non-TOA groups. The area under the receiver operating characteristic curve of the model was 0.92 in the derivation set and 0.87 in the validation set. CONCLUSIONS: We conclude that clinical characteristics help identify adolescents with acute PID who have TOA. These patients may have fewer signs of acute illness than those without TOA and may develop symptoms later in the menstrual cycle.

Abscess↗
PubMed1995

Autosomal dominant "Opitz" GBBB syndrome due to a 22q11.2 deletion.

We report on a family with autosomal dominant paternally inherited "Opitz" GBBB syndrome and an additional case with findings which have been reported in that syndrome. In each case the propositus presented with a vascular ring. Since a vascular ring may be a sign of a 22q11.2 deletion [Zacki et al., 1995], FISH (fluorescence in situ hybridization) studies were performed. These studies demonstrated a 22q11.2 deletion in the 3 affected individuals. Review of Opitz GBBB syndrome and the 22q11.2 microdeletion syndrome demonstrates significant overlap of manifestations including both facial characteristics and structural anomalies. Based on the phenotypic overlap and the presence of a 22q11.2 deletion in our patients with Opitz GBBB syndrome and the presence of a deletion in a patient with lung hypoplasia, absent pulmonary artery, and long segment tracheomalacia, we propose that, in some cases, the Opitz GBBB syndrome may be due to a 22q11.2 deletion. This enlarges the list of "syndromes" associated with the 22q11.2 deletion, which presently includes most patients with DiGeorge, velocardiofacial, and conotruncal anomaly face syndrome.

Abnormalities, Multiple↗
PubMed1995

Preliminary phenotypic map of chromosome 4p16 based on 4p deletions.

We have collected and analyzed clinical information from 11 patients with chromosome 4p deletions or rearrangements characterized by various molecular techniques. Comparing the extent of these patients' deletions with their respective clinical presentations led to the proposal of a preliminary phenotypic map of chromosome 4p. This map consists of regions which, when deleted, are associated with specific clinical manifestations. Nonspecific changes such as mental and growth retardation are not localized, and probably result from the deletion of more than one gene or region. The region associated with most of the facial traits considered typical in Wolf-Hirschhorn syndrome (WHS) patients coincides with the currently proposed WHS critical region (WHSCR), but some anomalies commonly seen in WHS appear to map outside of the WHSCR. The observation of clinodactyly in 2 patients with nonoverlapping deletions allows assignment of these defects to at least 2 separate regions in 4p16. These initial observations and attempts at genotype/phenotype correlation lay the groundwork for identifying the genetic basis of these malformations, a common objective of gene mapping efforts and chromosome deletion studies.

Abnormalities, Multiple↗
PubMed1995

Classical Noonan syndrome is not associated with deletions of 22q11.

Deletions of 22q11 cause DiGeorge sequence (DGS), velo-cardio-facial syndrome (VCFS), conotruncal anomaly face syndrome, and some isolated conotruncal heart anomalies. Demonstration of a 22q11 deletion in a patient with manifestations of DGS and Noonan syndrome (NS) has raised the question of whether NS is another of the chromosome 22 microdeletion syndromes. This prompted us to evaluate a cohort of patients with NS for evidence of 22q11 deletions. Five of 6 NS propositi studied in our laboratory with marker N25 (D22S75) did not have a 22q11 deletion. A 2-month-old infant with several findings suggestive of NS did have a 22q11 deletion, suggesting that a small number of 22q11 deletion propositi may present with a NS-like picture. However, most cases of NS must have another cause.

Adolescent↗
PubMed1995

Humoral immunity in DiGeorge syndrome.

OBJECTIVE: To assess humoral immunity after immunization and natural infection in patients with clinical manifestations of the DiGeorge anomalad. DESIGN: Retrospective review of cases. SETTING: Ambulatory immunology clinic of a tertiary care teaching hospital. PATIENTS: The 13 patients had a symptom complex including congenital heart disease, characteristic facies of the DiGeorge anomalad, possible hypocalcemia, and thymic hypoplasia or aplasia. Molecular and cytogenic studies of 12 patients demonstrated that all had 22q11 microdeletions. METHODS: Serial studies included lymphocyte population enumeration by flow cytometry, lymphocyte proliferation assays with the mitogens phytohemagglutinin and pokeweed mitogen and Staphylococcus aureus, and immunoglobulin quantitation. Specific antibody studies included virus neutralization assays for poliovirus antibodies, and enzyme-linked immunosorbent assay for diphtheria, tetanus, measles, rubella, varicella-zoster virus (VZV), and cytomegalovirus (CMV) antibodies. Avidity of rubella, VZV, and CMV antibodies was tested by enzyme-linked immunosorbent assay modified to include a mild protein denaturant in the first wash after incubation with sera. RESULTS: All patients had a CD3+ cell count greater than 0.500 x 10(9)/L and a CD4+ cell count greater than 0.350 x 10(9)/L). One patient had low proliferation responses to S. aureus, and one to phytohemagglutinin and pokeweed mitogen. Immunoglobulin levels, compared with those in age-related control subjects, were normal except that two patients had transient, borderline low IgG levels and two had elevated IgA levels. Specific antibody tests showed (No. of patients with positive results/No. tested) the following: diphtheria (13/13); tetanus (13/13); poliomyelitis caused by polio virus type 1 (5/9), type 2 (9/9), and type 3 (8/9); measles (11/13); rubella (11/13); and infection with VZV (5/5) and CMV (7/13). There were no significant differences in antibody avidity results between patients and control subjects for rubella (mean avidity index, 83.5 +/- 8.79 vs 85 +/- 17.6), VZV (81.6 +/- 3.98 vs 65.1 +/- 12.38), or CMV (69.3 +/- 22.31 vs 73.3 +/- 12.46). CONCLUSIONS: Patients with "partial" DiGeorge anomalad, defined by clinical and immunologic criteria, can be immunized and for the most part can generate good antibody responses.

Adolescent↗
PubMed1995

Cloning a balanced translocation associated with DiGeorge syndrome and identification of a disrupted candidate gene.

DiGeorge syndrome (DGS), a developmental defect, is characterized by cardiac defects and aplasia or hypoplasia of the thymus and parathyroid glands. DGS has been associated with visible chromosomal abnormalities and microdeletions of 22q11, but only one balanced translocation--ADU/VDU t(2;22)(q14;q11.21). We now report the cloning of this translocation, the identification of a gene disrupted by the rearrangement and the analysis of other transcripts in its vicinity. Transcripts were identified by direct screening of cDNA libraries, exon amplification, cDNA selection and genomic sequence analysis using GRAIL. Disruption of a gene in 22q11.2 by the breakpoint and haploinsufficiency of this locus in deleted DGS patients make it a strong candidate for the major features associated with this disorder.

Amino Acid Sequence↗
PubMed1995

Cerebellar atrophy in a patient with velocardiofacial syndrome.

Velocardiofacial syndrome and DiGeorge syndrome have not previously been associated with central nervous system degeneration. We report a 34 year old man who presented for neurological evaluation with cerebellar atrophy of unknown aetiology. On historical review, he had neonatal hypocalcaemia, an atrial septal defect, and a corrected cleft palate. His physical examination showed the characteristic facies of velocardiofacial syndrome as well as dysmetria and dysdiadocho-kinesia consistent with cerebellar degeneration. Molecular cytogenetic studies showed a deletion of 22q11.2. This man is the first reported patient with the association of a neurodegenerative disorder and 22q11.2 deletion syndrome.

Abnormalities, Multiple↗
PubMed1994

Velo-cardio-facial syndrome and DiGeorge sequence with meningomyelocele and deletions of the 22q11 region.

Approximately 5% of children with neural tube defects (NTDs) have a congenital heart defect and/or cleft lip and palate. The cause of isolated meningomyelocele, congenital heart defects, or cleft lip and palate has been largely thought to be multifactorial. However, chromosomal, teratogenic, and single gene causes of combinations of NTDs with congenital heart defects and/or cleft lip and palate have been reported. We report on 3 patients with meningomyelocele, congenital heart defects, and 22q11 deletions. Two of the children had the clinical diagnosis of velo-cardio-facial syndrome (VCFS); both also have bifid uvula. The third child had DiGeorge sequence (DGS). The association of NTDs with 22q11 deletions has not been reported previously. An accurate diagnosis of the 22q11 deletion is critical as this micro-deletion and its associated clinical problems is transmitted as an autosomal dominant trait due to the inheritance of the deletion-bearing chromosome. We recommend that all children with NTDs and congenital heart defects, with or without cleft palate, have cytogenetic and molecular studies performed to detect 22q11 deletions.

Adult↗
PubMed1994

Prenatal diagnosis of the derivative chromosome 22 associated with cat eye syndrome by fluorescence in situ hybridization.

Cytogenetic studies of cultured amniocytes demonstrated a karyotype of 46,XX/47,XX, +mar. A bisatellited, dicentric, distamycin-DAPI negative, NOR-positive marker was present in 76 per cent of the metaphases examined. Similar markers have been associated with cat eye syndrome (CES). We report on the utilization of fluorescence in situ hybridization (FISH) with a 14/22 alpha-satellite probe and a chromosome 22-specific cosmid for locus D22S9 to determine the origin of the prenatally detected supernumerary marker chromosome. FISH studies demonstrated that the marker is a derivative of chromosome 22 and enabled us to provide the family with additional prognostic information.

Adult↗
PubMed1994

Genetic basis of DiGeorge and velocardiofacial syndromes.

DiGeorge syndrome and velocardiofacial syndrome have been shown to be associated with microdeletions of chromosome 22q11. More recently, 22q11 deletions have also been detected in individuals with some types of conotruncal cardiac defects as well as conotruncal anomaly face syndrome. Fluorescence in situ hybridization of metaphase chromosomes using cosmid probes from the DiGeorge chromosomal region has been shown to be an efficient method for the detection of 22q11 deletions in at-risk patients, families, and pregnancies. This review summarizes recent cytogenetic, molecular, and phenotypic studies of patients with DiGeorge syndrome and velocardiofacial syndrome as well as recent efforts to identify genes within 22q11 that may play a role in the development of the phenotypic features observed in these disorders.

Abnormalities, Multiple↗
PubMed1993

DiGeorge anomaly with renal agenesis in infants of mothers with diabetes.

We report on 2 infants with the DiGeorge anomaly born to diabetic mothers treated with insulin. Both infants had unilateral renal agenesis. One of the mothers has manifestations suggestive of velo-cardio-facial syndrome (VCFS). Cytogenetic studies on both patients and the mother with apparent VCFS were normal. Molecular studies utilizing probes from the DiGeorge critical region did not demonstrate a 22q11 microdeletion in either patient or the mother with apparent VCFS. We conclude that maternal diabetes is a pathogenetic factor in the DiGeorge anomaly, and infants of diabetic mothers who have this anomaly should also be screened for renal agenesis.

Adult↗
PubMed1993

Velo-cardio-facial syndrome. Intrafamilial variability of the phenotype.

We describe a mother and son with velo-cardio-facial syndrome (VCFS) in whom cytogenetic and DNA molecular studies demonstrate an interstitial deletion of the long arm of chromosome 22. Although these two individuals manifest the typical facial and cognitive features of VCFS, they are discordant for the cardiovascular and palatal anomalies, which are seminal manifestations of the disorder. Previously, this degree of phenotypic variability had not been well appreciated within a single family segregating the VCFS deletion. A review of other familial cases of VCFS suggests that the family described in this article is not atypical. Because a microdeletion would be expected to be inherited without alteration within individual families, the phenotypic variability observed in these families appears to be an intrinsic quality of the syndrome and not wholly due to genetic heterogeneity.

Abnormalities, Multiple↗