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Biomedical subjects

B S Emanuel

Publications and source records attributed to B S Emanuel.

At least 19 recordsLinked to original sources
PubMed1998

Lack of correlation between impaired T cell production, immunodeficiency, and other phenotypic features in chromosome 22q11.2 deletion syndromes.

Monosomic deletions of chromosome 22q11.2 are the leading cause of DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome. DiGeorge syndrome was originally described as an immunodeficiency disorder secondary to impaired T cell production due to thymic aplasia or hypoplasia; however, the frequency of immunodeficiency in the other clinical syndromes associated with the chromosome 22q11.2 microdeletion has not been previously investigated. This study examines the frequency and severity of impaired T cell production and immunodeficiency in chromosome 22q11.2 deletion syndromes and the relationship of the immunodeficiency to specific phenotypic features. Sixty patients over 6 months of age with the characteristic chromosome 22q11.2 deletion underwent immunologic evaluations. Seventy-seven percent of patients with chromosome 22q11.2 deletions were found to have evidence of immunocompromise. The severity of the immunodeficiency did not correlate with any particular phenotypic feature, nor was it restricted to patients who were categorized as having DiGeorge syndrome. Therefore, impaired T cell production and impaired immunologic function are common in patients with deletions of chromosome 22q11.2. The presence or severity of the immunocompromise cannot be predicted based on other phenotypic features and each child should be individually assessed for immune function.

Abnormalities, Multiple↗
PubMed1997

Skeletal anomalies and deformities in patients with deletions of 22q11.

Skeletal anomalies in patients with a 22q11.2 deletion are reported infrequently. We report the skeletal findings in 108 patients with a 22q11.2 deletion, of whom 37 (36%) had a skeletal anomaly. Twenty-two patients (20%) had anomalies of the limbs, 7 of the upper limb, including preaxial or postaxial polydactyly. An anomaly of the lower limb was found in 16 patients, including postaxial polydactyly, clubfoot, severely overfolded toes, and 2-3 toe cutaneous syndactyly. Chest films of 63 patients were examined; 30% of them had abnormal findings, most commonly supernumerary ribs (17%) or a "butterfly" vertebral body (11%). Hypoplastic vertebrae, hemivertebrae, and vertebral coronal clefts were also noted. Thus, skeletal anomalies are not uncommon in patients with a 22q11.2 deletion and may occur more frequently than recognized previously.

Adolescent↗
PubMed1997

Enlarged Sylvian fissures in infants with interstitial deletion of chromosome 22q11.

Two infants with chromosome 22q11 deletion syndrome were noted to have symmetrically enlarged Sylvian fissures on cranial MRI. We compared the size of the Sylvian fissures in neuroimaging studies from 17 other subjects with del 22q11 to age-matched disease controls. The mean anterior interopercular distance was used as an index of Sylvian fissure enlargement. Symmetric enlargement of the Sylvian fissures was present in 10 of 17 subjects with del 22q11. The age-incidence pattern, as well as follow-up scans in 2 patients, suggests delayed growth of the opercular region in these patients. Subjects with del 22q11 consistently had disproportionate enlargement of the left Sylvian fissure compared to the right. This observation suggests that a gene (or genes) in the deleted region affects the development of the left and right perisylvian cortex in different ways. Abnormal development of the operculum may explain some of the neurodevelopmental features that are common among individuals with 22q11 deletion syndrome.

Adult↗
PubMed1997

Isolation and characterization of a gene from the DiGeorge chromosomal region homologous to the mouse Tbx1 gene.

DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome, and isolated and familial forms of conotruncal cardiac defects have been associated with deletions of chromosomal region 22q11.2. This report describes the identification, cloning, and characterization of the human TBX1 gene, which maps to the center of the DiGeorge chromosomal region. Further, we have extended the mouse cDNA sequence to permit comparisons between human and mouse Tbx1. TBX1 is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes are transcription factors involved in the regulation of developmental processes. There is 98% amino acid identity between human and mouse TBX1 proteins overall, and within the T-box domain, the proteins are identical except for two amino acids. Expression of human TBX1 in adult and fetal tissues, as determined by Northern blot analysis, is similar to that found in the mouse. Additionally, using 3 'RACE, we obtained a differentially spliced message in adult skeletal muscle. Mouse Tbx1 has been previously shown to be expressed during early embryogenesis in the pharyngeal arches, pouches, and otic vesicle. Later in development, expression is seen in the vertebral column and tooth bud. Thus, human TBX1 is a candidate for some of the features seen in the 22q11 deletion syndrome.

Adult↗
PubMed1997

Unbalanced 15;22 translocation in a patient with manifestations of DiGeorge and velocardiofacial syndrome.

We report on an 8-year-old girl with an unbalanced 15;22 translocation and manifestations of DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), and other abnormalities. The main manifestations of our patient were feeding difficulties, respiratory infections, short stature, peculiar face with hypertelorism, prominent nose, abnormal ears, microstomia and crowded teeth, short broad neck and shield chest with pectus deformity and widely spaced nipples with abnormal fat distribution, heart defect, scoliosis, asymmetric limb development, abnormal hands and feet, and hyperchromic skin patches. Cytogenetic studies demonstrated a 45,XX,der(15)t(15;22)(p11.2;q11.2), -22 karyotype. Fluorescence in situ hybridization (FISH) studies confirmed loss of the proximal DiGeorge chromosomal region (DGCR). This case adds to the diversity of clinical abnormalities caused by deletions within 22q11.2.

Abnormalities, Multiple↗
PubMed1997

Nasal dimple as part of the 22q11.2 deletion syndrome.

The phenotype of the 22q11.2 microdeletion syndrome is quite variable. We describe 2 patients with a 22q11.2 deletion and a dimpled nasal tip, which, we suggest can be the extreme of the broad or bulbous nose commonly found in the 22q11.2 deletion syndrome, and should not be confused with the more severe nasal abnormalities seen in frontonasal dysplasia.

Chromosome Deletion↗
PubMed1997

Juvenile rheumatoid arthritis-like polyarthritis in chromosome 22q11.2 deletion syndrome (DiGeorge anomalad/velocardiofacial syndrome/conotruncal anomaly face syndrome).

OBJECTIVE: To investigate the association of polyarthritis and chromosome 22q11.2 deletions. METHODS: Eighty patients with chromosome 22q11.2 deletion syndrome followed up at The Children's Hospital of Philadelphia were examined for evidence of arthropathy or arthritis. Patients with chromosome 22q11.2 deletion syndrome and polyarthritis underwent laboratory evaluations of immunologic function to determine the relationship of their immunodeficiency to the polyarthritis. RESULTS: The prevalence of polyarthritis in patients with chromosome 22q11.2 deletion syndrome was markedly increased over the prevalence of polyarticular juvenile rheumatoid arthritis (JRA) in the general population. All 3 patients with polyarthritis had evidence of impaired T cell function. Two of the patients with polyarthritis also had IgA deficiency. CONCLUSION: The chromosome 22q11.2 deletion syndrome represents a primary T cell disorder which can be associated with a JRA-like polyarthritis. All 3 patients with polyarthritis had evidence of more extensive immunoregulatory derangements than those typically seen in patients with chromosome 22q11.2 deletion, and these derangements may have predisposed to the development of polyarthritis.

Arthritis↗
PubMed1997

Progress in the autosomal segmental aneusomy syndromes (SASs): single or multi-locus disorders?

Based on cytogenetic observations, several syndromes have been previously identified as microdeletion-based disorders. In this review, recent progress is presented regarding whether one or multiple genes can be implicated in the pathogenesis of these segmentally aneusomic syndromes. The syndromes discussed include Angelman, Alagille, Williams, Langer-Giedeon, Prader-Willi, Smith-Magenis, Miller-Dieker, and DiGeorge/velocardiofacial or the 22q11 deletion syndromes. For Angelman and Alagille syndromes, single genes have been identified, whereas for Williams and Langer-Giedion syndromes, more than one gene can be implicated. Although there has been significant progress in dissecting the molecular basis for the other disorders, the ultimate answer regarding one versus several genes remains to be determined.

Abnormalities, Multiple↗
PubMed1997

Structural and mutational analysis of a conserved gene (DGSI) from the minimal DiGeorge syndrome critical region.

The majority of patients with DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), conotruncal anomaly face syndrome (CTAFS) and some individuals with familial or sporadic conotruncal cardiac defects have hemizygous deletions of chromosome 22. Most patients with these disorders share a common large deletion, spanning > 1.5 Mb within 22q11.21-q11.23. Recently, the smallest region of deletion overlap has been narrowed to a 250 kb area, the minimal DGS critical region (MDGCR), which includes the locus D22S75 (N25). We have isolated and characterized a novel, highly conserved gene, DGSI, within the MDGCR. DGSI has 10 exons and nine introns encompassing 1702 bp of cDNA sequence and 11 kb of genomic DNA. The encoded protein has 476 amino acids with a predicted mol. wt of 52.6 kDa. The intron-exon boundaries have been analyzed and conform to the consensus GT/AG motif. The corresponding murine Dgsi has been isolated and localized to proximal mouse chromosome 16. The mouse gene contains the same number of exons and introns, and the predicted protein has 479 amino acids with 93.2% identity to that of the human DGSI gene. By database searching, both genes have significant homology to a Caenorhabditis elegans hypothetical protein, F42H10.7. Further, mutation analysis has been performed in 16 patients, who have no detectable 22q11.2 deletion and some of the characteristic clinical features of DGS/VCFS. We have detected eight sequence variants in DGSI. These occurred in the 5'-untranslated region, the coding region and the intronic regions adjacent to the intron-exon boundaries of the gene. Seven of the eight variants were also present in normal controls or unaffected family members, suggesting they may not be of etiologic significance.

Amino Acid Sequence↗
PubMed1997

Disruption of the clathrin heavy chain-like gene (CLTCL) associated with features of DGS/VCFS: a balanced (21;22)(p12;q11) translocation.

The smallest region of deletion overlap in the patients we have studied defines a DIGeorge syndrome/velocardiofacial syndrome (DGS/VCFS) minimal critical region (MDGCR) of approximately 250 kb within 22q11. A de novo constitutional balanced translocation has been identified within the MDGCR. The patient has some features which have been reported in individuals with DGS/VCFS, including: facial dysmorphia, mental retardation, long slender digits and genital anomalies. We have cloned the breakpoint of his translocation and shown that it interrupts the clathrin heavy chain-like gene (CLTCL) within the MDGCR. The breakpoint of the translocation partner is in a repeated region telomeric to the rDNA cluster on chromosome 21p. Therefore, it is unlikely that the patient's findings are caused by interruption of sequences on 21p. The chromosome 22 breakpoint disrupts the 3' coding region of the CLTCL gene and leads to a truncated transcript, strongly suggesting a role for this gene in the features found in this patient. Further, the patient's partial DGS/VCFS phenotype suggests that additional features of DGS/VCFS may be attributed to other genes in the MDGCR. Thus, haploinsufficiency for more than one gene in the MDGCR may be etiologic for DGS/VCFS.

Abnormalities, Multiple↗
PubMed1997

A region of mouse chromosome 16 is syntenic to the DiGeorge, velocardiofacial syndrome minimal critical region.

DGS and VCFS, haploinsufficiencies characterized by multiple craniofacial and cardiac abnormalities, are associated with a microdeletion of chromosome 22q11.2. Here we document synteny between a 150-kb region on mouse chromosome 16 and the most commonly deleted portion of 22q11.2. Seven genes, all of which are transcribed in the early mouse embryo, have been identified. Of particular interest are two serine/threonine kinase genes and a novel goosecoid-like homeobox gene (Gscl). Comparative sequence analysis of a 38-kb segment reveals similarities in gene content, order, exon composition, and transcriptional direction. Therefore, if deletion of these genes results in DGS/VCFS in humans, then haploinsufficiencies involving this region of chromosome 16 should recapitulate the developmental field defects characteristic of this syndrome.

Abnormalities, Multiple↗
PubMed1997

Molecular studies of an ependymoma-associated constitutional t(1;22)(p22;q11.2).

We previously described a patient with a de novo constitutional translocation, t(1;22)(p22;q11.2), who developed a malignant ependymoma at age 5, and we proposed that the translocation predisposed the child to the development of the tumor. As a step toward isolation of a putative cancer gene, we have characterized the breakpoints of the (1;22) translocation at the molecular level. The chromosome 22 breakpoint has been narrowed to a region between ARVCF and D22S264. The chromosome 1 breakpoint has been mapped onto a doubly-linked Whitehead YAC contig by PCR analysis of the STS contents of the patient's derivative chromosomes isolated in somatic cell hybrids. Loss-of-heterozygosity (LOH) studies of the patient's ependymoma and of sporadic ependymomas showed no evidence of consistent loss in the breakpoint regions, suggesting that activation of an oncogene, rather than inactivation of a tumor suppressor gene, is the more likely molecular mechanism involved in this case. The gene for Edg-1, a neurally expressed, seven-segment transmembrane receptor, maps to the region of the chromosome 1 breakpoint but does not appear to be interrupted by the translocation. Molecular characterization of the breakpoint regions reported here represents an important step in the identification of the gene(s) affected by this translocation.

Animals↗
PubMed1997

Genetic disorders of cardiac morphogenesis. The DiGeorge and velocardiofacial syndromes.

The phenotype associated with a 22q11 deletion is highly variable and still under investigation. Of particular interest to cardiologists and cardiac developmental biologists is the finding that many patients with a 22q11 deletion have conotruncal cardiac defects and aortic arch anomalies. Despite the phenotypic variability, the vast majority of patients have a similar large deletion spanning approximately 2 megabases. The low-frequency repeated sequences at either end of the commonly deleted region may be responsible for the size of the deletion and account for the instability of this chromosomal region. Molecular studies of patients with the DGS/VCFS phenotype and unique chromosomal rearrangements have allowed a minimal critical region for the disease to be defined. Multiple genes have been identified in the minimal critical and larger deleted region. These genes are being investigated for their potential role in the disease pathophysiology by screening for mutations in nondeleted patients with the phenotype and by analysis of the pattern of expression in the developing mouse embryo. Further experimentation in the mouse mammalian model system will be of great utility to help determine whether haploinsufficiency of one critical gene or several genes within the DGCR results in the disease phenotype. Modifying factors, both genetic and environmental, must also be considered. Further investigation into the disease mechanism leading to the DGS/VCFS phenotype will hopefully further our understanding of cardiac development and disease.

Chromosome Deletion↗
PubMed1997

Detection of a 22q11.2 deletion in cardiac patients suggests a risk for velopharyngeal incompetence.

OBJECTIVE: Conotruncal cardiac anomalies frequently occur in patients with DiGeorge or velocardiofacial syndrome. Additionally, these patients may have overt or submucousal cleft palate, as well as velopharyngeal incompetence (VPI). Previous studies have demonstrated that the majority of these patients have a submicroscopic deletion of chromosome 22q11.2. We hypothesized that a subpopulation of newborns and children with congenital heart defects caused by a 22q11.2 deletion are at a high risk for having unrecognized palatal abnormalities. Therefore, we proposed to evaluate a cohort of patients with conotruncal cardiac malformations associated with a 22q11.2 deletion to determine the frequency of palatal abnormalities. METHODS: We identified 14 deletion-positive patients with congenital cardiac defects who had no overt cleft palate. Of the 14 patients evaluated for the 22q11.2 deletion, 8 patients were recruited from a previous study looking for deletions among patients with isolated conotruncal cardiac anomalies. Informed consent was obtained in these cases. The remaining patients had the deletion study on a clinical basis, ie, conotruncal cardiac defect and an absent thymus, immunodeficiency, or minor dysmorphia appreciated by the clinical geneticist. These patients were evaluated by a plastic surgeon and speech pathologist looking for more subtle palatal anomalies such as a submucousal cleft palate, absence of the musculous uvuli, and VPI. Some patients underwent videofluoroscopy or nasendoscopy depending on their degree of symptoms and age. VPI was not ruled out until objective evaluation by a speech pathologist and plastic surgeon was obtained. In addition, the child had to be old enough to provide an adequate speech sample. RESULTS: Of the 14 patients evaluated, 6 patients older than 1 year were found to have VPI. It is noteworthy that 3 of these patients were older than 5 years and had remained unrecognized until this study. The remaining 6 patients had inconclusive studies based on their age (younger than 26 months) and their inability to participate in adequate speech evaluations. Two of these patients, however, had histories of nasal regurgitation suggesting VPI and, in addition, had incomplete closure of the velopharyngeal mechanism during crying and swallowing observed during nasendoscopic examination-consistent with the diagnosis of VPI. Thus, 8 of 14 patients evaluated had evidence of VPI by history and examination. The remaining 6 patients will require further study when they are older before a definitive palatal diagnosis can be made. CONCLUSIONS: A significant number of patients with a 22q11.2 deletion in a cardiac clinic may have unrecognized palatal problems. Recognition of such abnormalities will afford patients the opportunity for intervention as needed, ie, speech therapy and/or surgical intervention. Notably, two of our patients with findings suggesting VPI were infants and will, therefore, be afforded the opportunity for close follow-up and early intervention. Furthermore, three school-aged children had palatal abnormalities that were unrecognized until this study. Thus, we recommend 22q11.2 deletion studies in patients with conotruncal cardiac malformations, followed by extensive palatal and speech evaluations when a deletion is present.

Abnormalities, Multiple↗
PubMed1997

The DiGeorge syndrome minimal critical region contains a goosecoid-like (GSCL) homeobox gene that is expressed early in human development.

The majority of patients with DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS) have deletions of chromosomal region 22q11.2. The abnormalities observed in these patients include conotruncal cardiac defects, thymic hypoplasia or aplasia, hypocalcemia, and characteristic facial features. To understand the genetic basis of these disorders, we have characterized genes within the region that is most consistently deleted in patients with DGS/VCFS, the minimal DiGeorge critical region (MDGCR). In this report, we present the identification and characterization of a novel gene, GSCL, in the MDGCR, with homology to the homeodomain family of transcription factors. Further, we provide evidence that this gene is expressed in a limited number of adult tissues as well as in early human development. The identification of GSCL required a genomic sequence-based approach because of its restricted expression and high GC content. The early expression, together with the known role of homeobox-containing proteins in development, make GSCL an outstanding candidate for some of the abnormalities seen in DGS/VCFS.

Abnormalities, Multiple↗