Comparative Study of Phenotypic Expression of Mice Trisomy 16 by Different Female Strains: Attempt at an Animal Model for Human Trisomy 21

ABSTRACT  Mouse trisomy 16, which was induced by mating males of Rb(16.17)7 Bnr/Rb(9.16)9Rma with three different strains of female, C57BL/6, C57BL/10 and C3H/He, was examined in fetuses and newborns in terms of incidence of occurrence, malformations and sex ratio. The incidence of trisomies tended to be higher in C3H/He than in C57BL/6 and C57BL/10. Trisomies could not survive beyond term in C57BL/6, which was most thoroughly examined in the three strains. Trisomy-associated generalized edema, beginning to appear on day 14 of pregnancy on fetus's back, reached the maximum on day 16 in all strains. On cardiovascular anomalies, persistent common atrioventricular canal was observed in virtually all trisomies from C57BL/10 and C57BL/6, while in about 80% from C3H/He. In conotruncal region, all trisomies from former two crossing exhibited double outlet right ventricle or persistent truncus arteriosus. In addition to these anomalies, riding aorta was found in C3H/He. Hydroureter and hydronephrosis developed from day 17 of pregnancy in trisomies other than those in C57BL/10. The histological study of gonads revealed that trisomy 16 tended to be predominant in males of each crossing. The anomalies encountered in mouse trisomy 16, such as edema, persistent common atrioventricular canal, and hydroureter and hydronephrosis appeared to be in common with human trisomy 21 embryos and fetuses. The tendency of predominance of mouse trisomies in males may provide further homology to human trisomy 21. It is supposed that genetic background by different female strains may affect phenotypic expression of malformations. The extremely high incidence of cardiovascular anomalies is regarded as suitable material for elucidation of pathogenesis.     

Animal Model for Congenital Anomalies Induced by Chromosome Aberrations*

Abstract: Animal model for congenital anomalies induced by chromosome aberrations is explained in mice. Exencephaly is the most conspicuous external malformations among mice trisomies and partial trisomies. Characteristic cardiovascular malformations are observed in Ts 16, 13 and 14. The association of persistent common atrioventricular (A-V) canal in Ts 16 provides an excellent morphological homology to human trisomy 21. Observations on A-V canal endocardial cushions of Ts 16 fetuses showed i) hypoplastic endocardial cushions, ii) delayed appearance of mesenchymal cells into cushions. and iii) failed fusion of endocardial cushions. The conotruncal malformations were observed in every fetus of Ts 16. Abnormal aortic arch was observed in about half of the cases. Further, the thymus was always hypoplastic. The combination of these anomalies suggests that Ts 16 had abnormal development similar to DiGeorge anomaly in these regions. In enlarged hearts of T^hp and t^wLub2, which have deletions on chromosome 17, the ventricular septum bulged so extremely into ventricle that the bilateral ventricular outflow tract was markedly obstructed. From 14 days of pregnancy on, generalized edema was often observed in some of trisomic and T^hP fetuses. Histological examination of Ts 16 and T^hp fetuses demonstrated that the essence of the fetal edema was cystic hygroma, which is sometimes encountered in human fetuses with chromosome aberrations. Investigations by an animal model with chromosome aberrations did offer new information which remains somewhat scanty in early embryonic stage.     

Cytogenetics of hepatoblastoma: further characterization of 1q rearrangements by fluorescence in situ hybridization: an international collaborative study

BACKGROUND: Hepatoblastoma (HBT) is the most common hepatic neoplasm in children. This notwithstanding, little is known about pathogenetic factors, such as genetic abnormalities, of importance for the development and progression of this tumor type. To date, only 33 cytogenetically abnormal HBT have been published, and trisomies for chromosomes 2 and 20 have been shown to be the most frequent aberrations. Recently, unbalanced translocations involving proximal 1q have been described in several HBT, suggesting that a pathogenetically important gene maps to 1q. PROCEDURE: Six primary and one recurrent HBT were cytogenetically analyzed after short-term tissue culture. In addition, fluorescence in situ hybridization (FISH) studies, using locus-specific probes, were performed on three of these pediatric HBT as well as on one previously reported adult HBT. RESULTS: Total or partial trisomy 8, gain of chromosome 20, and structural rearrangements of chromosome 1 were detected in three HBT, and overrepresentation of chromosome 2 material was found in two HBT. The adjacent chromosome bands 1q12 and 1q21 were involved in three translocations, t(1;2), t(1;4), and t(1;11), which were all unbalanced and resulted in gain of 1q material. The previously reported adult HBT displayed 1q deletions with breakpoints at 1q12-21. FISH analyses of the 1q rearrangements revealed that all breakpoints were within the heterochromatic region. CONCLUSIONS: These findings provide further support for the importance of trisomies 2, 8, and 20 and rearrangements of 1q in the development of HBT. Furthermore, the consistent localization of breakpoints within the heterochromatic segment of chromosome 1 suggests that the important pathogenetic consequence of 1q abnormalities is the resulting genomic imbalance rather than a specific gene rearrangement.     

Fluorescent in situ hybridization (FISH) reveals frequent and recurrent numerical and structural abnormalities in hepatoblastoma with no informative karyotype

BACKGROUND: Hepatoblastoma (HB) is the most frequent malignant liver tumor in children. The few cytogenetic studies available indicate that HB is associated with recurring trisomies of chromosomes 2, 8, and 20; recurrent t(1;4) (q12;q34) has been reported in few cases. The abnormalities of chromosome 1q are relatively frequent and usually lead to overexpression of 1q material. A cluster of breakpoints is located at the level of bands 1q12 and 1q21. More work is needed to clarify their real incidence and prognostic significance. Cytogenetic analysis is limited by the requirement of suitable cells in metaphase. A different method that increases analysis sensitivity is fluorescent in situ hybridization (FISH). PROCEDURE: We studied 10 cases of HB with no informative karyotype (normal karyotype or no metaphases). FISH was performed by the standard method, using cytospins and imprints obtained from frozen or cytogenetic samples of direct cultures. Alpha-satellite probes for centromeric DNA were used for chromosomes 2, 8, and 20 analysis; rearrangement of region 1q12-21 was detected with BAC (bacterial artificial chromosome) probe bA79E5. RESULTS: We detected at least one trisomic clone in 5/10 of these cases. Trisomy 20 was the most frequently detected abnormality, followed by trisomy of the chromosomes 2 and 8. Analysis of 1q12 band revealed that the rearrangement of 1q usually is in pericentromeric heterochromatin, it was present in 5/10 of studied cases. CONCLUSION: FISH analysis is recommended in all cases of HB with no informative karyotype to gain more information regarding the frequent trisomies encountered and their significance.     

Interchange trisomy 9 due to maternal t(6; 9) translocation

The occurrence of interchange trisomy due to a 3:1 malsegregation has been documented in only a few cases with trisomy 21. We describe the first case of interchange trisomy 9 due to a maternal t(6; 9) translocation. The patient, a boy neonate who died immediately after birth, had intra-uterine growth retardation, specific craniofacial features including microcephaly with a high forehead, low-set ears, upslanting short palpebral fissures, microphthalmia, bulbous nose and micrognathia, cryptorchidism, cystic kidney and various skeletal anomalies. His phenotype was consistent with that of the trisomy 9 syndrome. Cytogenetic analysis showed his karyotype of 47,XY,-6, + der(6), + der(9)t(6; 9)(q27;q21.1)mat. The present report indicates that a very rare interchange mode of a 3:1 segregation can give rise to a live birth with full trisomy 9 in female carriers with reciprocal translocations involving the proximal long arm of chromosome 9.     

Confined Placental Mosaicism and Stillbirth

The cause of stillbirth can usually be determined in only 20% of cases. An increased frequency of adverse pregnancy outcome, including pregnancy loss, intrauterine growth restriction, and premature labor, has been observed in association with confined placental mosaicism (CPM), which is characterized by a discrepancy between the karyotype of the fetus and placenta. Specific chromosomal trisomies have been observed in CPM more frequently than others, with trisomy of chromosomes 7, 16, and 18 being the most prevalent. In pregnancies with CPM it has been shown that the zygote is often trisomic, and postzygotic loss of the additional chromosome occurred in the embryonic progenitor cells leading to a dichotomy between the placenta and the embryo/fetus. In one third of such cases fetal uniparental disomy (UPD), which is the presence of both homologues of a chromosome derived from one parent, can be expected. The specific role of the trisomic placenta and the presence of fetal UPD in cases of altered intrauterine fetal development has not been fully established for various chromosomes. Therefore, to enhance our understanding of the pathogenesis of stillbirth it is imperative that cytogenetic analysis of both fetal and placental tissues be performed in all cases of unexplained stillbirth.     

Biometry of face and brain in fetuses with trisomy 21

The aim of this study was to specify the early setting of the particular craniofacial morphology in Down syndrome during the fetal period from data based on postmortem examinations. The study included 1277 fetuses at 15-38 gestational weeks (GW): 922 control fetuses and 355 fetuses with trisomy 21, selected from fetopathology units in Paris. Body weight (BW) and nine dimensions of the face, skull, and brain were recorded: the outer and inner canthal distances (OCD, ICD), biparietal diameter (BPD), head circumference (HC), brain weight (BrW), occipitofrontal diameters of left and right hemispheres (lOFD, rOFD), weight of the infratentorial part of the brain (IBW), and maximal transversal diameter of the cerebellum (CTD). Four ratios were computed: BPD/HC, OCD/BPD, BrW/BW, IBW/BrW. Differences between trisomic fetuses and control fetuses were tested by age interval. Results showed that BW, rOFD, and lOFD were lower in trisomic fetuses as early as 15 GW. Cerebellar hypoplasia included lower IBW and CTD in trisomic fetuses. The IBW/BrW ratio was higher in trisomic fetuses, showing that growth restriction affected the infratentorial part of the brain less than the supratentorial part. Early brachycephaly was found in trisomic fetuses, with higher values of BPD and BPD/HC from 15 GW. ICD and OCD were not significantly different in the two groups, but OCD/DBP ratio was lower in trisomic fetuses. These results confirm the early phenotypical expression of trisomy 21 on craniofacial morphology, associated with a marked restriction of brain growth, especially in the supratentorial part.     

Severe Coronary Artery Disease in the Absence of Supravalvular Stenosis in a Patient with Williams Syndrome

Williams syndrome is a complex syndrome comprising developmental abnormalities, craniofacial dysmorphic features, and cardiac anomalies. The most common cardiac anomaly is supravalvular aortic stenosis. We report a case of a 6-year-old girl with Williams syndrome who presented with decompensated heart failure due to ischemic cardiomyopathy. Her only significant cardiac anomaly was severe stenosis of the left main coronary artery. She subsequently died despite surgical revascularization. Isolated coronary anomalies are rare in Williams syndrome but should be considered especially in the presence of heart failure or ischemia.     

A Case Report: Hypertelorism, Microtia, Cleft Palate with a de novo Balanced Chromosome Translocation, t(1q –; 7p+)

ABSTRACT One male Japanese patient diagnosed as probable Hypertelorism-Microtia-Clefting (HMC) syndrome was presented. In addition to the striking clinical findings including a cleft palate, and eye and ear anomalies, chromosomal analysis revealed a karyotype of 46,XY,t(1q-;7p+).
The radiographic examinations based on cephalometric analysis have been added to an appreciation of the craniofacial dysmorphology of this patient. The comparative study between the present case and 38 cleft palate patients without other anomalies clearly disclosed characteristic craniofacial dysmorphology of this case, including platybasia, bony orbital hypertelorism, short anterior face, and micrognathia. Particularly, this micrognathia was distinguished by marked antegonial notch, short ramus height, and clockwise rotation resulting in the steep mandible.     

One hundred three consecutive patients with anorectal malformations and their associated anomalies

OBJECTIVE: A long-term retrospective analysis of 103 infants with anorectal malformations (ARMs) was conducted to describe any associated congenital anomalies and surgical classifications. DESIGN: Retrospective medical record review. SETTING: This case series was conducted on all infants with ARMs born at, or referred to, any of 3 major medical centers in Wichita, Kan, for close to a 22-year period. PATIENTS: The 103 infants in this study represent a consecutive sample of patients with ARMs. Patients were separated into 2 groups: isolated ARMs without associated anomalies (n = 30), and ARMs with associated anomalies (n = 73). The male-female ratio was 2:1. MAIN OUTCOME MEASURES: Patients with associated anomalies were further classified into groups of ARMs with minor anomalies; major anomalies; chromosomal abnormalities; and malformation syndromes, associations, or sequences. Only anomalies that occurred more than once were reported. Malformations were also classified according to major organ systems. RESULTS: The incidence of ARMs in our study was approximately 1 in 2500 live births. Additional anomalies were found in 71% of infants with ARMs. Associated anomalies by major organ system included genitourinary anomalies (49%), musculoskeletal anomalies (43%), craniofacial anomalies (34%), cardiovascular anomalies (27%), gastrointestinal anomalies (18%), respiratory anomalies (13%), and central nervous system anomalies (12%). The most common chromosomal abnormalities were trisomies (8%), and ARMs were associated with VATER complex (vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, and radial and renal anomalies) in 11 cases (11%) and VACTERL (vertebral, anal, cardiac, tracheal, esophageal, renal, and limb anomalies) in 4 cases (4%). CONCLUSIONS: Patients with ARMs have a high incidence of associated congenital anomalies. Evaluation of the most commonly affected organ systems in these infants is essential because it is these associated anomalies that account for most of the morbidity and mortality that is associated with this condition.     

Defective sexual development in an infant with 46, XY, der(9)t(8;9)(q23.1;p23)mat

We report on a male infant with ambiguous genitalia (scrotal hypospadias, sinus urogenitalis) trisomic for 8q23-ter and monosomic for 9p23-ter, who shared craniofacial and other abnormalities with either phenotype. Gonadal histology was nearly normal for age. Normal endocrinological findings and exclusion of mutations in SRY, androgen receptor and alpha-reductase genes point to supplementary gene(s) located in 9p2305-ter, haplo-insufficiency (by deletion) of which is expected to cause defective male morphogenesis. Conclusion This observation lends further support to the hypothesis that genetic factors are located at 9p23-ter which are involved in normal sex determination. Received: 26 February 1998 / Accepted: 28 May 1998     

Congenital heart defects--chromosomal anomalies, syndromes and extracardiac malformations

AIM: To register chromosomal anomalies, syndromes and extracardiac malformations in patients with Congenital heart defects (CHDs). METHOD: Population-based prospective observational study. RESULTS: Of 57 027 live births during 1982-2005, CHDs were detected in 662 (11.6 per 1000), of whom 146 (22%) had associated anomalies. Of these 52 (36%) had chromosomal anomalies (exclusive microdeletions), 26 (18%) genetic syndromes/microdeletions, 1 (0.7%) a teratogenous syndrome and 67 (46%) extracardiac malformations. In perimembraneous ventricular septal defects (VSDs), associated anomalies occurred in 22 of 70 (31%) compared to 27 of 298 (9%) in VSDs located in the muscular part of the septum (p < 0.0001). The prevalence of CHDs with associated disorders increased significantly from the cohort born during 1982-1993 to those born during 1994-2005 (2.0 vs. 3.1 per 1000, respectively; p < 0.0001), mainly caused by an increase of chromosomal trisomies (0.5 vs. 1.1 per 1000; p = 0.026). The percentage of women giving live birth at 35 years of age or more was 7.6% for the period 1982-1993 compared to 13.4% for 1994-2005 (p = 0.001). CONCLUSIONS: Chromosomal anomalies, syndromes and extracardiac malformations occurred in nearly one-fourth of CHD cases. Muscular VSDs had a low prevalence of such conditions. The prevalence of CHDs with chromosomal trisomies increased, and was probably related to an increasing age of women giving birth.     

Prognostic cytogenetic markers in childhood acute lymphoblastic leukemia

Objective To evaluate children with acute lymphoblastic leukemia (ALL) showing resistance to immediate induction chemotherapy in relation to conventional and advanced cytogenetic analysis. Methods This work was conducted on 63 ALL children (40 males and 23 females) with age range 4.5 months–16 years (mean = 7.76 years). They included 37 cases attained true remission and 26 complicated by failure of remission, early relapse or death. They were subjected to history, clinical examination and investigations including CBC, BM examination, karyotyping, FISH for translocations and flowcytometry for immunophenotyping and minimal residual disease diagnosis. Results Cases aged < 5 years; male sex with organomegaly had better remission although statistically insignificant. Initially low HB < 8 gm/dl, high WBCs and platelet counts > 50.000/mm³ also showed better but non-significant remission rates. Most of the present cases were L₂ with better remission compared to other immunophenotypes. Forty informative karyotypes were subdivided into 15 hypodiploid, 10 pseudodiploid, 8 normal diploid and 7 hyperdiploid cases; the best remission rates were noticed among the most frequent ploidy patterns. Chromosomes 9, 11 and 22 were the most frequently involved by structural aberrations followed by chromosomes 5, 12 and 17. Resistance was noted with aberrations not encountered among remission group; deletions involving chromosomes 2p, 3q, 10p and 12q; translocations involving chromosome 5; trisomies of chromosomes 16 and 21; monosomies of 5 and X and inversions of 5 and 11. Conclusion Some cytogenetic and molecular characterizations of childhood ALL could add prognostic criteria for proper therapy allocation.     

Noonan's Syndrome in Association with Acute Leukemia

Noonan's syndrome (NS) is a syndrome with multiple congenital anomalies, characterized by craniofacial anomalies, congenital heart disease, skeletal and genital abnormalities, and mild mental retardation. Chromosomal abnormalities have been found in only a few cases. The combination of NS and acute leukemia has been reported in only three cases. Two additional cases are described here.     

Bis(dicholroacetyl)diamine-induced Craniofacial Anomalies in Jcl: ICR and A/J Mice

Abstract Craniofacial anomalies induced by bis(dichloroacetyl)diamine (bisdiamine) were studied in two strains of mice, Jcl:ICR and A/J. Bisdiamine was given by oral intubation at a dose of 3,200 mg/kg/day at days 7.5 and 8.5, 8.5 and 9.5, 9.5 and 10.5 or 10.5 and 11.5 of pregnancy (VP = day 0). A/J was more susceptible to embryolethal effects of bisdiamine and had a longer sensitive period to teratogenic effects of bisdiamine. The most susceptible period for craniofacial anomalies induced by bisdiamine in A/J was one day later than that in Jcl:ICR. In both strains, median facial anomalies, cleft palate, protuberance(s) on the forehead and open eyelids were commonly induced craniofacial anomalies. Median facial anomalies were more frequent and also more severe in Jcl:ICR, while lateral cleft lip was observed only in A/J.
Strain differences for embryolethality and types and frequencies of craniofacial anomalies are discussed on the basis of genetic homozygosity, craniofacial development and embryonic face shape immediately before the fusion of the nasal prominences. Neural crest cells are thought to be the target of bisdiamine.     

Role of the dysmorphologic evaluation in the child with developmental delay

This article focuses on the dysmorphologic evaluation of the child who has developmental delay or cognitive impairment. Attention is focused on minor anomalies, because those are often considered to be the dysmorphic features that are the component manifestations of a particular syndrome. This article provides a brief discussion of craniofacial, skin, and limb anomalies (which are more likely to be noted not only by clinicians but also by allied health workers) and notes which features are particularly helpful clues to common syndromes, metabolic disorders, or autism syndromes.     

Delineation of robertsonian translocations in man by means of chromosome banding

Robertsonian translocations from thirteen unrelated individuals were studied by G, Q and C banding, and by autoradiography. Each of three D-D translocations involved chromosomes 13 and 14, all four D-G translocations involved chromosomes 14 and 21, and five of six G-G translocations involved two chromosomes 21 while the sixth involved 21 and 22. Two centromeres were noted in a single 21-21 translocation chromosome by C banding. Autoradiography was much less useful in identifying the chromosomes involved in the thirteen translocations. G and Q banding were consistently accurate.Supported in part by Special Project No. 900, Division of Health Services, MCHS, HSMHA, DHEW, and by a grant from the National Foundation-March of Dimes. This work fulfilled in part the requirement of Fontaine S. Hill, Jr. for the Master of Science degree at Memphis State University     

Hajdu-Cheney syndrome associated with serpentine fibulae and polycystic kidney disease

Six patients who presented with craniofacial anomalies, musculoskeletal anomalies including elongated and bowed (serpentine) fibulae, and polycystic kidneys are reported. This association of anomalies is referred to as serpentine fibula polycystic kidney syndrome (SFPKS) and is currently interpreted as a manifestation of Hajdu-Cheney syndrome (HCS). We report a new instance of this association of anomalies and review the clinical and radiographic features of HCS and of the reported cases of SFPKS.     

Trisomy 9p. Report of two new cases

Trisomy 9p is a chromosome abnormality caused by duplication of the short arm of chromosome 9. Clinically it is characterized by psychomotor retardation, malformations that can affect various organs and sometimes epilepsy. Trisomy 9p may be the fourth most common autosomal trisomy, after trisomies 21, 13 and 18. Two new cases of trisomy 9p are described. Previous cases reported in Spain, associated clinical features, and the diagnostic and therapeutic approach to these patients are revised.