Microsatellite DNA markers detects 95% of chromosome 22q11 deletions

Cono-truncal cardiac malformations account for some 50% of congenital heart defects in newborn infants. Recently, hemizygosity for chromosome 22q11.2 was reported in patients with the DiGeorge/Velo-cardio-facial syndromes (DGS/VCFS) and causally related disorders. We have explored the potential use of microsatellite DNA markers for rapid detection of 22q11 deletions in 19 newborn infants referred for cono-truncal heart malformations with associated DGS/VCFS anomalies. A failure of parental inheritance was documented in 84.2% of cases (16/19). PCR-based genotyping using microsatellite DNA markers located within the commonly deleted region allowed us either to confirm or reject a 22q11 microdeletion in 94.3% of cases (18/19) within 24 hours. This test is now currently performed in the infants referred to us for a cono-truncal heart malformation as a first intention screening for 22q11 microdeletion. Am. J. Med. Genet. 68:182–184, 1997 © 1997 Wiley-Liss, Inc.     

Penoscrotal transposition and associated anomalies: Report of five new cases and review of the literature

We present the largest single series of cases (n = 5) of penoscrotal transposition (PST) with carefully documented nongenitourinary/anal anomalies, none of which fell into categories of known syndromes, associations, sequences or chromosome disorders. Several unexpected anomalies were observed including coloboma of the iris and retina, hydrocephalus, microcephaly, diaphragmatic hernia, tracheo-esophageal fistula/esophageal atresia and cleft palate. The most frequent anomalies other than PST were renal defects (100%) such as renal agenesis and dysplasia, imperforate anus (60%), central nervous system anomalies (60%) and preaxial upper limb defects (40%). Cardiovascular defects (atrial septal defect, double aortic arch with vascular ring) were noted in only one case. The surviving patients (3/5) had postnatal growth failure and mental retardation. Our 5 PST patients are compared to 16 well-documented cases from the literature. The overall incidence of various extragenital abnormalities were: renal (90%), mental retarardation (60%), imperforate anus (33%), central nervous system (CNS) anomalies (29%), vertebral defects (29%), preaxial limb defects (24%) and congenital heart disease (19%). PST is a rare heterogenous anomaly, the detection of which should warrant careful clinical evaluation to rule out other anomalies, especially of the urinary system, gastrointestinal tract, upper limbs, craniofacial region and central nervous system. PST may be a localized field defect involving the genitourinary system; however, the wide variety of more distant defects noted in our series and the literature would raise doubt about that assumption. The high frequency of growth deficiency and mental retardation has also not been given due respect as accompanying problems associated with PST. © 1995 Wiley-Liss, Inc.     

Associated nonurinary congenital anomalies among infants with congenital anomalies of kidney and urinary tract (CAKUT)

Infants with congenital anomalies of kidney and urinary tract (CAKUT) often have other associated anomalies. The purpose of this investigation was to assess the prevalence and the types of associated anomalies in CAKUT in a defined population from northeastern France. The associated anomalies in CAKUT were collected in all livebirths, stillbirths and terminations of pregnancy during 26 years in 346,831 consecutive births of known outcome in the area covered by our population based registry of congenital anomalies. Of the 1678 infants with CAKUT born during this period (prevalence at birth of 48.4 per 10,000), 563 (34%) had associated anomalies. There were 119 (7%) patients with chromosomal abnormalities including 33 trisomies 18 (2%), and 168 (10%) nonchromosomal recognized dysmorphic conditions. There were no predominant recognized dysmorphic conditions, but VA(C)TER(L) association (3%). However, other recognised dysmorphic conditions were registered including Meckel–Gruber syndrome (2%), and prune belly syndrome (1%). Two hundred seventy six (16%) of the patients had multiple congenital anomalies, non syndromic, non chromosomal (MCA). Anomalies in the musculoskeletal, the digestive, the cardiovascular and the central nervous systems were the most common other anomalies. Prenatal diagnosis was obtained in 71% of dysmorphic syndromes with CAKUT. In conclusion the overall prevalence of associated anomalies, which was one in three infants, emphasizes the need for a thorough investigation of infants with CAKUT. The most commonly associated major nonurinary anomalies involved the musculoskeletal system, followed by the digestive, the cardiovascular and the central nervous systems. A routine screening for other anomalies may be considered in infants and in fetuses with CAKUT. One should be aware that the anomalies associated with CAKUT can be classified into a recognizable anomaly syndrome or pattern in one out of six infants with CAKUT.     

Associated malformations in congenital diaphragmatic hernia cases in the last 15 years in a tertiary referral institute

This is a review of cases of perinatally diagnosed congenital diaphragmatic hernia (CDH) with associated malformations with regard to time of diagnosis, side of hernia, associated malformations, and outcome. The authors analyzed the data of CDH cases with associated malformations from records of the I. Department of Obstetrics and Gynecology, Semmelweis University Faculty of Medicine, Budapest, between July 1, 1990 and June 30, 2005. The observed period was analyzed in two parts. The pre- and postnatal examinations verified CDH in 100 cases, 71% of which were associated with other malformations. In 52% (37/71) CDH was diagnosed before the 24th week of gestation. The rate of early diagnosed cases doubled in the second period. Ten percent (7/71) of cases were verified postnatally. Between 1990 and 1997, the percentage of right-sided hernia was 6% (2/34) while in the second period it was 19% (7/37). The association with cardiovascular, chest, and craniofacial anomalies doubled in the second period, while association of central nervous system anomalies halved. Chromosome anomalies were verified in four cases. Pregnancy was terminated in 53% (34/64) and 13% (4/30) of newborn infants survived the perinatal period. Intrauterine or intrapartum death occurred in 8% (5/64) of cases. The prevalence of cardiovascular, pulmonary, and craniofacial anomalies doubled, while that of central nervous system malformations decreased. The prevalence of other associated malformations has not changed significantly between the two periods. The improvement of technical facilities and accumulated experience make it possible to identify a higher number of associated malformations before the 24th week of gestation.     

Associated anomalies in multi-malformed infants with cleft lip and palate: An epidemiologic study of nearly 6 million births in 23 EUROCAT registries

We studied 5,449 cases of cleft lip (CL) with or without cleft palate (CL/P) identified between 1980 and 2000 from the EUROCAT network of 23 registers (nearly 6 million births) in 14 European countries. We investigated specific types of defects associated with clefts. Among CL/P cases (prevalence = 9.1 per 10,000), 1,996 (36.6%) affected only the lip (CL) and 3,453 (63.4%) involved CL and palate (CLP). A total of 3,860 CL/P cases (70.8%) occurred as isolated anomalies and 1,589 (29.2%) were associated with other defects such as multiple congenital anomalies of unknown origin (970), chromosomal (455) and recognized syndromes (164). Associated malformations were more frequent in infants who had CLP (34.0%) than in infants with CL only (20.8%). Among multi-malformed infants, 2 unrelated anomalies were found in 351 cases, 3 in 242 cases, and 4 or more in 377 cases. Among 5,449 CL/P cases, 4,719 were live births (LB) (86.6%), 203 stillbirths (SB) (3.7%), while 508 (9.3%) were terminations of pregnancy (ToP). CL/P occurred significantly more frequently in males (M/F = 1.70), especially among total isolated cases (M/F = 1.87) and CLP isolated cases (M/F = 1.92). The study confirmed that musculoskeletal, cardiovascular, and central nervous system defects are frequently associated with CL/P. An association with reduction anomalies of the brain was found. This association suggests that clinicians should seek to identify structural brain anomalies in these patients with CL/P as the potential functional consequences may be important for rehabilitation and clinical management.     

Congenital heart defects. Frequency at autopsy

Autopsies were performed on 3,071 stillborns and decreased children up to the age of 16 years at the Institute of Pathology of the Charité from 1969 to 1983. Congenital heart disease (CHD) was found in 814, i.e. 26.5% of the autopsies. Results of re-examination of 642 hearts with CHD are discussed. The most common malformations are ventricular septal defects, d-transpositions of the great vessels, tetralogy of Fallot and aortic coarctations. CHD was more frequently found in boys than in girls (1.5 : 1). The majority of the deaths occurred during the first year of life (78.8%). 20.1% of these took place during the perinatal period and 47.2% within the first 6 months of life. Additional cardiac anomalies were associated with the main defect in 81.8% of cases. The most common such associated defects were atrial and ventricular septal defects, aortic coarctations and other aortic arch anomalies. The frequency of extracardiac malformations in CHD was 7.2%. The most common anomalies were of the central nervous system, the gastrointestinal tract and the urinary system. Malformation syndromes were identified in 5.6% of the CHD cases, including Down's syndrome in 1.4%.     

Associated anomalies in Pierre Robin sequence

Pierre Robin sequence (PRS) is frequently co-occurring with other non-PRS congenital anomalies. The types and the prevalence of anomalies co-occurring with PRS vary in the reported studies. The aims of this report was to study the types and the prevalence of the anomalies co-occurring with PRS in a well-studied population northeastern France. The types and the prevalence of anomalies co-occurring in cases with PRS were ascertained in all terminations of pregnancy, stillbirths and live births in 387,067 births occurring consecutively during the period 1979–2007 in the area covered by our registry of congenital anomalies which is population-based, 89 cases of PRS were registered during the study period with a prevalence of 2.29 per 10,000 births, 69.7% of the cases had associated non-PRS anomalies. Chromosomal abnormalities were present in 10 (11.2%) cases including three 22 q11.2 deletion. Non-chromosomal recognizable conditions were diagnosed in 27 cases (30.3%) including 10 Stickler syndrome, 8 Treacher Collins syndrome, 3 cases with short stature and 6 other syndromes. Multiple congenital anomalies (MCA) were present in 25 cases (28.1%). The most frequent MCA were in the ear, face and neck (35 out of 98 anomalies, 35.7%), cardiovascular (18 anomalies, 18.4%), musculoskeletal (11 anomalies, 11.2%), central nervous (7 anomalies, 7.1%), urinary (6 anomalies, 6.1%), and eye (6 anomalies, 6.1%) system. The high prevalence of associated anomalies justifies a thorough screening for other congenital anomalies in cases with PRS.     

Associated anomalies in cases with achondroplasia

Associated congenital anomalies may be observed in cases with achondroplasia. The prevalence reported in the literature and the types of co-occurring congenital anomalies are variable between the reported studies. The aim of this study was to establish the prevalence and to describe the associated anomalies in cases with achondroplasia. This study included 25 cases ascertained from our registry of congenital anomalies including all terminations of pregnancy, stillbirths and live births between 1979 and 2007 in 387,067 consecutive births (the prevalence of achondroplasia was 6.4 per 100,000 births), and 223 cases ascertained from the French Little People organization built on the model of LPA (Little People of America, Inc.). Out of these 248 cases of achondroplasia 37 (14.9%) had associated anomalies including 4 (1.6%) cases with chromosomal abnormalities (2 trisomies 21, one 22 q11.2 deletion, and one 47, XXX), 2 (0.8%) cases with recognizable non-chromosomal conditions (one Moebius syndrome and one Pierre Robin sequence) and 31(12.5%) cases with MCA (multiple congenital anomalies). The 31 cases with MCA had 45 anomalies. Anomalies in the urogenital system (24.4%), the cardiovascular system (20.0%), the musculoskeletal system (15.5%), the central nervous system (11.1%), the eye (11.1%), and the orofacial system (8.8%) were the most common MCA. The overall prevalence of associated anomalies shows that the individuals with achondroplasia need a careful screening for other congenital anomalies.     

Congenital malformations among liveborn infants with trisomies 18 and 13

Trisomy 18 and trisomy 13 are associated with serious and/or fatal birth defects, with death frequently occurring in the first month of life. Previous studies are limited by small samples and are dated. This study characterized the comorbid birth defects associated with trisomy 18 and trisomy 13 among US liveborn infants using the Healthcare Cost and Utilization Project's Kids' Inpatient Database and Nationwide Inpatient Sample, two large, current and nationally representative databases. The occurrence of 39 commonly reported comorbid birth defects among infants with trisomies 18 and 13 was compared to the occurrence of malformations among newborns without trisomies. The prevalences of trisomy 18 and 13 were 1.29/10,000 and 0.85/10,000 live births, respectively. Among infants with trisomy 18, 61% were female, 45.4% with heart defects. Among those with trisomy 13, 53% were female, 38.4% had heart defects, 24.5% had orofacial anomalies, and 11.2% had central nervous system abnormalities. More than half of the newborns with both conditions died prior to discharge. This updated information can be used to inform clinical decision-making and may help providers better prepare families for infants with trisomies.     

Anophthalmia,intracerebral cysts,and cleft lip/palate: Expansion of the phenotype in oculocerebrocutaneous syndrome?

We report on a patient with multiple congenital anomalies including anophthalmia, cleft lip and palate, and central nervous system anomalies similar to the case reported by Leichtman et al. [1994: Am J Med Genet 50:39–41] and to oculocerebrocutaneous (Delleman) syndrome. Although the two cases and those with oculocerobrocutaneous syndrome may represent separate but overlapping entities, our patient and the case described by Leichtman et al. [1994: Am J Med Genet 50:39–41] may represent a more severe form of oculocerebrocutaneous syndrome. Am. J. Med. Genet. 68:39–42, 1997 © 1997 Wiley-Liss, Inc.     

Severe spondylocostal dysostosis associated with other congenital anomalies: A clinical/epidemiologic analysis and description of ten cases from the Spanish registry

We describe 10 cases born to nondiabetic mothers who presented with severe spondylocostal dysostosis (SCD) associated with other anomalies, identified among 20,526 malformed liveborn infants from the Spanish Collaborative Study of Congenital Malformations (ECEMC). We analyze the associated malformations in the 10 cases with severe SCD, as well as in all cases with less severe SCD among children with MCA patterns of unknown cause. Cases with SCD were preferentially associated with caudal dysgenesis, diaphragmatic hernia, and central nervous system anomalies. © 1994 Wiley-Liss, Inc.     

Associated anomalies in cases with congenital clubfoot

Congenital clubfoot CTEV is a common congenital anomaly, its etiology is unclear and its pathogenesis is controversial. Cases with CTEV often have other non‐CTEV associated congenital anomalies. The purpose of this study was to assess the prevalence and the types of these associated anomalies in a defined population. The associated anomalies in cases with CTEV were collected in all livebirths, stillbirths, and terminations of pregnancy during 29 years in 387,067 consecutive births in the area covered by our population‐based registry of congenital malformations. Of the 504 cases with CTEV, representing a prevalence of 13.02 per 10,000, 107 (21.2%) had associated anomalies. There were 31 (6.1%) cases with chromosomal abnormalities, and 21 (4.2%) non‐chromosomal recognized dysmorphic conditions including syndromes: 6 arthrogryposis multiplex congenita, 2 22q11.2 microdeletion, and one fetal alcohol syndrome. Fifty‐five (10.9%) of the cases had nonsyndromic multiple congenital anomalies (MCA). Anomalies in the cardiovascular, the central nervous, the urinary, the orofacial, and the musculoskeletal systems were the most common other anomalies in the cases with MCA. The anomalies associated with CTEV could be classified into a recognizable malformation syndrome in 52 of the 107 cases (48.6%) with associated anomalies. This study included special strengths: it is population‐based, each affected child was examined by a geneticist, all elective terminations were ascertained, and the surveillance for anomalies was continued until 2 years of age. In conclusion the overall prevalence of associated anomalies, one of five cases, emphasizes the need for a screening for other anomalies in cases with CTEV.     

Complete trisomy 9 in two liveborn infants.

Two unrelated newborn infants with multiple malformations were found to have complete trisomy 9 in all cells examined. In both, the phenotype was similar, consisting of characteristic facial appearance (microphthalmia, bulbous nose, micrognathia, cleft palate, low set ears), skeletal abnormalities (dislocated joints, flexion contractures of the fingers), cardiovascular malformations (persistent left superior vena cava, ventricular septal defect), hypoplastic genitalia, renal anomalies, and central nervous system malformations. Both died during the first few hours of life. Comparison of these two infants with the previously reported cases reveals a consistent pattern of malformations and very short survival associated with trisomy 9. These cases illustrate the importance of doing chromosome studies on infants with congenital malformations dying in the newborn period and the usefulness of such studies in counselling parents regarding the risk of recurrence.     

Recombination aneusomy of chromosome 5 associated with multiple severe congenital malformations

A male infant is described in whom congenital anomalies were recognized prenatally by ultrasound examination. The infant was delivered following spontaneous labor and died approximately 15 min after birth. An autopsy revealed major anomalies in the central nervous system (holoprosencephaly with premaxillary agenesis), the gastrointestinal system (esophageal atresia) and the heart (tetralogy of Fallot). Chromosomal studies revealed recombinant chromosome 5 [46,XY, rec(5), dup q, inv(5)(p15q32)], resulting in partial trisomy 5q and partial monosomy 5p. Cytogenetic investigation of the family revealed a pericentric inversion of chromosome 5 in the father and paternal grandmother, 46,XY (and XX, respectively,) inv(5)(p15q32). The congenital anomalies in this infant are more extensive and severe than previously reported in cases of recombination aneusomy involving chromosome 5.     

Teenage pregnancy and congenital anomalies: which system is vulnerable?

BACKGROUND: Teenage pregnancy may be associated with some forms of congenital anomalies. The objective of this study was to identify the types of congenital anomalies associated with teenage pregnancy. METHODS: We carried out a retrospective cohort study of 5 542 861 nulliparous pregnant women younger than 35 years of age with a live singleton birth between 1995 and 2000 in the USA. RESULTS: Compared with adult pregnancy (20-34 years old), and after adjustment for confounding variables, teenage pregnancy (13-19 years old) was associated with increased risk of central nervous system anomalies [odds ratio (OR) 1.08; 95% confidence interval (CI): 1.01, 1.16], gastrointestinal anomalies (OR: 1.39; 95% CI: 1.31, 1.49) and musculoskeletal/integumental anomalies (OR: 1.06; 95% CI: 1.03, 1.10). The teenage pregnancy associated increase in risk for central nervous system anomalies was mainly attributable to anomalies other than anencephalus, spina bifida/meningocele and hydrocephalus and microcephalus; for gastrointestinal anomalies the risk was mainly attributable to omphalocele/gastroschisis; and for musculoskeletal/integumental anomalies the risk was mainly attributable to cleft lip/palate and polydactyly/syndactyly/adactyly. No increased risk was found for circulatory/respiratory anomalies, urogenital anomalies, or Down's syndrome. CONCLUSIONS: Teenage pregnancy increases the risks of congenital anomalies in central nervous, gastrointestinal and musculoskeletal/integumental systems.     

CHARGE syndrome: Report of 47 cases and review

The acronym CHARGE refers to a syndrome of unknown cause. Here we report on 47 CHARGE patients evaluated for the frequency of major anomalies, namely coloboma (79%), heart malformation (85%), choanal atresia (57%), growth and/or mental retardation (100%), genital anomalies (34%), ear anomalies (91%), and/or deafness (62%). In addition, we comment on anomalies observed very frequently in neonates and infants with the CHARGE syndrome, including, minor facial anomalies, neonatal brain stem dysfunction with cranial nerve palsy, and, mostly, internal ear anomalies such as semicircular canal hypoplasia that were found in each patient that could be tested. We propose several criteria for poor survival including male gender, central nervous system and/or oesophageal malformations, and bilateral choanal atresia. No predictive factor regarding developmental prognosis could be identified in our series. A significantly higher mean paternal age at conception together with concordance in monozygotic twins and the existence of rare familial cases support the role of genetic factors such as de novo mutation of a dominant gene or subtle sub-microscopic chromosome rearrangement. Finally, the combination of malformations in CHARGE syndrome strongly supports the view that this multiple congenital anomalies/mental retardation syndrome is a polytopic developmental field defect involving the neural tube and the neural crests cells. Am. J. Med. Genet. 76:402–409, 1998. © 1998 Wiley-Liss, Inc.     

Descriptive epidemiology of Cornelia de Lange syndrome in Europe

Cornelia de Lange syndrome (CdLS) is a multiple congenital anomaly/mental retardation syndrome consisting of characteristic dysmorphic features, microcephaly, hypertrichosis, upper limb defects, growth retardation, developmental delay, and a variety of associated malformations. We present a population-based epidemiological study of the classical form of CdLS. The data were extracted from the database of European Surveillance of Congenital Anomalies (EUROCAT) database, a European network of birth defect registries which follow a standard methodology. Based on 23 years of epidemiologic monitoring (8,558,346 births in the 1980-2002 period), we found the prevalence of the classical form of CdLS to be 1.24/100,000 births or 1:81,000 births and estimated the overall CdLS prevalence at 1.6-2.2/100,000. Live born children accounted for 91.5% (97/106) of cases, fetal deaths 2.8% (3/106), and terminations of pregnancy following prenatal diagnosis 5.7% (6/106). The most frequent associated congenital malformations were limb defects (73.1%), congenital heart defects (45.6%), central nervous system malformations (40.2%), and cleft palate (21.7%). In the last 11 years, as much as 68% of cases with major malformations were not detected by routine prenatal US. Live born infants with CdLS have a high first week survival (91.4%). All patients were sporadic. Maternal and paternal age did not seem to be risk factors for CdLS. Almost 70% of patients, born after the 37th week of gestation, weighed 相似文献   

Cryptococcus neoformans var. gattii in the koala (Phascolarctos cinereus): a review of 43 cases of cryptococcosis.

Details of 11 previously reported cases and 32 new cases of cryptococcosis in captive and wild koalas were analysed. Cryptococcus neoformans var. gattii accounted for all 29 cases in which varietal status was determined. No age or sex predisposition was observed. The respiratory tract was the primary focus of disease in 77% of cases. Although the lower respiratory tract was affected most commonly (60% of cases), 30% of cases had upper respiratory tract lesions and 14% had both. Dissemination was common, especially to the central nervous system (37% cases). Local extension to surrounding tissues was a feature of upper respiratory tract disease. Other tissues showing cryptococcal invasion included lymph nodes (19%), gastrointestinal tract (12%), kidneys (12%), spleen (9%) and skin (7%). Only three cases (7%) had no respiratory tract or central nervous system involvement, two cases of primary skin inoculation and one case of primary lymphadenopathy. Late presentation was a likely factor in the high proportion of cases with disseminated disease (40%). The proportion of koala cases with involvement of the central nervous system, lower respiratory tract and skin, parallels what has been reported for immunocompetent people. Cryptococcosis in the koala appears to be an excellent naturally occurring model for examination of the cryptococcal host-parasite relationship in all species.     

Neural tube defects and associated anomalies in a fetal and perinatal autopsy series

Neural tube defects (NTDs) are congenital malformations of the central nervous system (CNS) secondary to abnormal closure of the neural tube during embryonic development. This study provides information on NTD rate, distribution, associated morphologic anomalies and organ weights in a Danish fetal and perinatal autopsy series during a 16 year period. The data were extracted from the autopsy reports of a consecutive series of 1984 fetal and perinatal autopsies from the Copenhagen area performed in the period 1989-2004. Registered parameters included: The location and morphology of the NTD, associated morphological anomalies, and organ weights. Organ weights were evaluated according to new fetal autopsy standards and grouped as low, normal or high. Ninety-seven NTD cases were found (4.9%): Spina bifida (38 cases), cephalocele (17 cases) and anencephaly (42 cases). 63% of NTD cases had associated morphologic anomalies. Among the most common were hydrocephalus, NTD in another region, and anomalies in the urogenital system. 58% of the NTD cases had abnormal weight of one or more organs. Most notable was low adrenal weight not only in anencephalic fetuses but also in cases with cephalocele, suggesting a possible association.     

Tandem duplication of 11p12-p13 in a child with borderline development delay and eye abnormalities: Dose effect of the PAX6 gene product?

We report on a girl with a duplication of chromosome band 11p12→13, which includes the Wilms tumor gene (WT1) and the aniridia gene (PAX6). The girl had borderline developmental delay, mild facial anomalies, and eye abnormalities. Eye findings were also present in most of the 11 other published cases with partial trisomy 11p, including 11p12→13. Recently, it was shown that introduction of additional copies of the PAX6 gene into mice caused very variable eye abnormalities. Therefore, a PAX6 gene dosage effect is likely to be present in mice and humans. The central nervous system may be less sensitive to an altered PAX6 gene dosage, which is consistent with the borderline developmental delay in the present patient. Urogenital abnormalities were absent in this patient and in most of the other patients with partial trisomy of 11p. Therefore, the effect of a WT1 gene duplication on the embryological development of the urogenital tract remains uncertain. Am. J. Med. Genet. 73:267–271, 1997. © 1997 Wiley-Liss, Inc.