Associated malformations in cases with congenital diaphragmatic hernia

The etiology of congenital diaphragmatic hernia (CDH) is unclear and its pathogenesis is controversial. Because previous reports have inconsistently noted the type and frequency of malformations associated with CDH, we assessed these associated malformations ascertained between 1979 and 2003 in 334,262 consecutive births. Of the 115 patients with the most common type of CDH, the posterolateral, or Bochdalek-type hernia, 70 (60.8%) had associated malformations. These included: chromosomal abnormalities (n = 21, 30.0%); non-chromosomal syndromes (Fryns syndrome, fetal alcohol syndrome, De Lange syndrome, CHARGE syndrome, Fraser syndrome, Goldenhar syndrome, Smith-Lemli-Opitz syndrome, multiple pterygium syndrome, Noonan syndrome, and spondylocostal dysostosis); malformation sequences (laterality sequence, ectopia cordis); malformation complexes (limb body wall complex) and non syndromic multiple congenital anomalies (MCA) (n = 30, 42.9%). Malformations of the cardiovascular system (n = 42, 27.5%), urogenital system (n = 27, 17.7%), musculoskeletal system (n = 24, 15.7%), and central nervous system (n = 15, 9.8%) were the most common other congenital malformations. We observed specific patterns of malformations associated with CDH which emphasizes the need to evaluate all patients with CDH for possible associated malformations. Geneticists and pediatricians should be aware that the malformations associated with CDH can often be classified into a recognizable malformation syndrome or pattern (57.1%).     

Ophthalmo-acromelic syndrome

We report two sibships with children who had anophthalmia, multiple limb abnormalities, and consanguineous parents. The same association of malformations has already been reported. These further observations allow a better delineation of the syndrome and confirm its autosomal recessive mode of inheritance. We propose to name the syndrome ophthalmo-acromelic.     

Neural tube defects and associated anomalies in South Carolina

BACKGROUND: Neural tube defects (NTDs) occur as isolated malformations and in the company of other birth defects. This study was conducted to determine the frequency of coexisting anomalies and the relationship between them. METHODS: Since 1992, NTDs have been identified through prenatal and postnatal surveillance activities in South Carolina. The type of NTD and presence of associated anomalies were determined by prenatal ultrasound, postnatal and/or postmortem examination. RESULTS: During the ten-year period from 1992 to 2002, 564 NTDs were identified by the surveillance system. Seventeen percent of NTDs (98/564) had associated malformations. In approximately half (n = 51) of these cases, the NTDs and associated anomalies were components of a recognizable syndrome. In the remaining cases (n = 47), no syndrome was identified or suspected, but the associated anomalies were believed in most instances to be secondary to space limitation or neural crest abnormalities imposed by the NTD. CONCLUSION: Seventeen percent of NTDs in South Carolina have associated malformations. In most cases, the associated anomalies are considered either components of a multiple malformation syndrome or secondary to the NTD.     

13q deletion syndrome in an adult mentally retarded patient.

Clinical features of the 13q deletion syndrome are difficult to define and include retinoblastoma, mental and growth retardation, craniofacial abnormalities, brain, gastrointestinal, renal and heart malformations, anal atresia and limb and digit malformations. The critical region for development of major organ systems has been defined in 13q32 between the proximal marker 13S132 and distal marker D13S147. We report a severely mentally retarded male patient with a deletion of the distal part of chromosome 13 (13q32.3-->qter) without major organ malformations.     

Further clinical delineation in trisomy 1q32 syndrome.

A male newborn with multiple congenital abnormalities was studied. Clinically, he showed prominent forehead, facial dysmorphism, ear malformations, congenital heart defect and limb anomalies. The cytogenetic studies demonstrated a karyotype 46,XY, der(18) t(1;18)(q32;p11.3)pat with partial trisomy 1q32-qter and a monosomy 18p. The patient displayed clinical features of trisomy 1q but not of monosomy 18p. There are around 80 reports of trisomy 1q32. The purpose of this paper is to describe the first case of a translocation involving 1q and 18p chromosome breakpoints. Additional findings detected in the propositus permit us a further delineation of the trisomy 1q syndrome.     

Tetraphocomelia and bilateral femorotibial synostosis. A severe variant of the thrombocytopenia-absent radii (TAR) syndrome?

In this report we describe severe tetraphocomelia with complete femorotibial fusion in a second trimester male fetus. The association of severe tetraphocomelia-femorotibial synostosis has previously been reported in three patients as examples of a severe variant of the thrombocytopenia-absent radii (TAR) syndrome. In the present fetus no morphological abnormalities of the megakaryocytes were detected. This observation is not in favour of the hypothesis that abnormalities of the primordial megakaryocytes may be causally related with the pathogenesis of the limb malformations as present in this syndrome.     

Congenital developmental defects in the genetic monitoring system. I. The selection of developmental defects subject to dynamic observation

The requirements for selection of congenital malformations in the system of genetic monitoring as models have been studied. Model malformations have been shown to be easily and reliably diagnosed even in infancy. Their rate should be not less than 1:5000 births. The precise knowledge of the genetics of model forms is needed as well. Down's syndrome registration is the most convenient method for evaluation of mutations in a genome. We recommend registration in total all multiple congenital malformations (without Down's syndrome) for estimation of dominant mutability dynamics, as it was shown that more than 11% of all multiple malformations are caused by sporadic dominant mutations.     

Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation

CHARGE syndrome is a well-established multiple-malformation syndrome with distinctive consensus diagnostic criteria. Characteristic associated anomalies include ocular coloboma, choanal atresia, cranial nerve defects, distinctive external and inner ear abnormalities, hearing loss, cardiovascular malformations, urogenital anomalies, and growth retardation. Recently, mutations of the chromodomain helicase DNA-binding protein gene CHD7 were reported to be a major cause of CHARGE syndrome. We sequenced the CHD7 gene in 110 individuals who had received the clinical diagnosis of CHARGE syndrome, and we detected mutations in 64 (58%). Mutations were distributed throughout the coding exons and conserved splice sites of CHD7. Of the 64 mutations, 47 (73%) predicted premature truncation of the protein. These included nonsense and frameshift mutations, which most likely lead to haploinsufficiency. Phenotypically, the mutation-positive group was more likely to exhibit cardiovascular malformations (54 of 59 in the mutation-positive group vs. 30 of 42 in the mutation-negative group; P=.014), coloboma of the eye (55 of 62 in the mutation-positive group vs. 30 of 43 in the mutation-negative group; P=.022), and facial asymmetry, often caused by seventh cranial nerve abnormalities (36 of 56 in the mutation-positive group vs. 13 of 39 in the mutation-negative group; P=.004). Mouse embryo whole-mount and section in situ hybridization showed the expression of Chd7 in the outflow tract of the heart, optic vesicle, facio-acoustic preganglion complex, brain, olfactory pit, and mandibular component of the first branchial arch. Microarray gene-expression analysis showed a signature pattern of gene-expression differences that distinguished the individuals with CHARGE syndrome with CHD7 mutation from the controls. We conclude that cardiovascular malformations, coloboma, and facial asymmetry are common findings in CHARGE syndrome caused by CHD7 mutation.     

Morphological study of the removed fetus after therapeutic abortion for echographic anomalies (apropos of 42 cases)

In 42 cases, fetal abnormalities were diagnosed by obstetric ultrasonography and the pregnancy was terminated. The malformations included: anencephaly (22), severe hydrocephaly (4, one with a spina bifida), encephalocele and meningocele (2) amniotic band syndrome (4; a correct prenatal diagnosis was performed during the second trimester in two cases), major anterior abdominal wall defects (2), Pena-Shokeir syndrome type I? (I), severe renal abnormalities (2), conjoined twins, dicephalus type (2), cystic hygroma and hydrops fetalis (2), osteogenesis imperfecta, type II (I). Thus, there were 23 fetuses with a polygenetically determined status; five fetuses could be affected by an autosomal recessive disorder.     

Evaluation of routine prenatal ultrasound examination in detecting fetal chromosomal abnormalities in a low risk population

Prenatal diagnosis performed by fetal ultrasound scan is now a routine part of antenatal care in many countries. We have used our registry of congenital malformations to determine how many fetal anomalies and consequently how many chromosomal abnormalities are detected by this procedure. In our region, evaluation of prenatal diagnosis of chromosomal abnormalities in women of 38 years and younger (chromosomal prenatal diagnosis is offered to women 38 years) with no personal or familial history of chromosomal anomaly was performed in 119 099 consecutive pregnancies of known outcome from 1980 to 1987. At least one ultrasonographic examination seeking congenital malformations was performed in more than 95% of the pregnant women studied. The total number of chromosomal anomalies during the study period was 199, 123 of these being Down syndrome. Only 41 (34.5%) of the 119 fetuses with chromosomal abnormalities and congenital malformation examined had been found to have a malformation at ultrasound examination. This low sensitivity was different for the diverse chromosomal abnormalities. Only 10 out of the 54 fetuses with Down syndrome and malformations (18.5%) were detected and only 3 out of 24 (12.5%) atrioventricular canal defects in those trisomie 21 patients were detected. Only 5 out of 11 (45.4%) fetuses with trisomy 13, 13 out of 26 (50.0%) fetuses with trisomy 18, 7 out of 12 patients with monosomy X (58.3%) and 6 out of 27 (22.2%) fetuses with other chromosomal abnormalities were diagnosed. Moreover, the time of detection of these anomalies was early enough to allow amniocentesis and termination of pregnancy in the case of a chromosomal abnormality in only 15 out of these 41 patients, including 7 cases of cystic hygroma in fetuses with monosomy X. This low sensitivity is not the result of the quality of the ultrasound equipment. It may be explained by the inadequate qualification of some operators and by the insufficient duration of the routine examination. In conclusion, our study has shown that the sensitivity of the detection of chromosomal abnormalities by routine prenatal ultrasound screening is low. Other screening methods are needed.     

Absence of nasal bone and brachydactyly: A probable new familial syndrome

Brachydactyly is a relatively common congenital abnormality and can be associated with many other malformations. However, brachydactyly in association with absence of nasal bone is rare. Two Chinese siblings with a combination of nasal bone absence and brachydactyly are presented, apparently without other abnormalities. This combination of features do not fit into any previously described syndrome and we suggest that this case represents a new familial syndrome. Molecular genetics screening didn't revealed any specific pathogenic variants in the two siblings.     

Microdeletion on 17p11.2 in a Smith-Magenis syndrome patient with mental retardation and congenital heart defect: first report from China

Smith-Magenis syndrome (SMS) is a rare syndrome with multiple congenital malformations, including development and mental retardation, behavioral problems and a distinct facial appearance. SMS is caused by haploinsufficiency of RAI1 (deletion or mutation of RAI1). We describe an eight-year-old female Chinese patient with multiple malformations, congenital heart defect, mental retardation, and behavioral problems (self hugging, sleeping disturbance). High-resolution genome wide single nucleotide polymorphism array revealed a 3.7-Mb deletion in chromosome region 17p11.2. This chromosome region contains RAI1, a critical gene involved in SMS. To the best of our knowledge, this is the first report of an SMS patient in mainland China.     

Biochemical and genetic aspects of 7-dehydrocholesterol reductase and Smith-Lemli-Opitz syndrome

In recent years, several inherited human disorders caused by defects in cholesterol biosynthesis have been identified. These are characterized by malformations, multiple congenital anomalies, mental and growth retardation and/or skeletal and skin abnormalities indicating a pivotal role of cholesterol in morphogenesis and embryonic development. The first recognized and most common of these developmental disorders is Smith-Lemli-Opitz syndrome, an autosomal recessive trait caused by mutations in the DHCR7 gene resulting in a deficiency of the encoded sterol Delta(7)-reductase, alternatively called 7-dehydrocholesterol reductase (EC 1.3.1.21). This enzyme catalyzes the final step in cholesterol biosynthesis, which is the reduction of the Delta(7) double bond of 7-dehydrocholesterol to produce cholesterol.     

婴儿期Klippel-Trenaunay综合征并精神运动发育迟缓病例报道及文献复习

Klippel-Trenaunay综合征(KTS)又称先天性静脉畸形骨肥大综合征,好发于儿童及青少年。临床以多发性皮肤血管瘤、肢体静脉曲张、骨及软组织肥大为特征。其病因尚不清楚,可能为遗传性血管壁间质组织发育异常所致。目前尚无特异的治疗方法,手术及介入治疗主要是减轻症状和治疗并发症。对于婴儿期出现偏侧肢体肥大并血管瘤的患儿应长期随访,早期诊断,早期干预以防止并发症。近年来有报道利用超声进行产前诊断,对及时发现和处理有重要意义。本文报道1例婴儿期KTS,以口腔黏膜血管瘤伴出血、颜面及肢体不对称性肥大为特点,并伴精神运动发育迟缓,CT见侧脑室、三脑室扩张。     

Partial and complete trisomy 9: Delineation of a trisomy 9 syndrome

Summary Two infants with trisomy involving chromosome 9 are described. One had complete trisomy 9 and the other karyotype 47,XX,+der(9),t(7;9)(p22;q32)mat. A trisomy 9 syndrome is delineated, consisting of features of the trisomy 9p syndrome and various other malformations. These include abnormalities of the cardiovascular and urogenital systems, cranial suture anomalies, dislocation of the hips and knees and early death. A possible relationship of some of these findings to regions of 9q involved in cases of partial trisomy 9 is suggested.     

Malformations in a cohort of 284 women with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH)

ABSTRACT: BACKGROUND: The aim of this retrospective study was to describe the spectrum of genital and associated malformations in women with Mayer-Rokitansky-Kuster-Hauser syndrome using evaluated diagnostic procedures and the Vagina Cervix Uterus Adnex -- associated Malformation classification system (VCUAM). METHODS: 290 women with MRKH syndrome were clinically evaluated with using clinical examinations, abdominal and perineal/rectal ultrasound, MRI, and laparoscopy. RESULTS: Classification of female genital malformation according to the Vagina Cervix Uterus Adnex -- associated Malformation classification system was possible in 284 women (97.9%). Complete atresia of Vagina (V5b) and bilateral atresia of Cervix (C2b) were found in 284 patients (100%). Uterus: bilateral rudimentary or a plastic uterine horns were found in 239 women (84.2%). Adnexa: normal Adnexa were found in 248 women (87.3%). Malformations: associated malformations were found in 126 of 282 evaluable women (44.7%), 84 women (29.6%) had malformations of the renal system. Of 284 women with Mayer-Rokitansky-Kuster-Hauser syndrome 212 women (74.7%) could be classified as V5bC2bU4bA0. The most frequent classification was V5bC2bU4bA0M0 (46.8%) diagnosed in 133 of 284 women. CONCLUSIONS: Complete atresia of vagina and cervix were found in all patients, variable malformations were found with uterus and adnexa. A variety of associated malformations were present, predominantly of the renal system. It is therefore recommended that all patients with genital malformations should be evaluated for renal abnormalities.     

Congenital malformations and maternal smoking during pregnancy

The relationship between smoking during pregnancy and congenital malformations was studied in prospective studies of 33,434 live births in the Kaiser-Permanente Birth Defects Study and 53,512 live births in the Collaborative Perinatal Project (CPP). In the Kaiser study, statistically significant positive associations (P less than .05) were observed for ventral hernias, omphaloceles, and "other major gut abnormalities," but, for each comparison the estimates were based on one or two unexposed cases. Statistically significant negative associations were found for ventricular septal defects (odds ratio, 0.5 [95% confidence interval, 0.2-0.96]), hydroceles (0.7 [0.6-0.9]), clubfoot (0.7 [0.6-0.9]), pigmented nevi (0.7 [0.6-0.9]), hemangiomas (0.8[0.7-0.98]) and Down syndrome (0.2 [0.1-0.9]). To determine if the findings noted above were an artifact of multiple comparisons, seven of these nine malformations were analyzed by smoking status for women in the CPP. All but one of the associations were not confirmed in the CPP. Previously described associations between smoking and specific congenital malformations were also tested using data from the CPP. We conclude that smoking is unlikely to be responsible for a large increase in malformations at birth.     

Syndrome of renal, genital and feet malformations.

We report a 2 months old girl affected by renal hypoplasia, genital abnormalities, syndactyly and a pattern of minor anomalies. Although the pattern of malformations overlaps the Townwes-Brock syndrome and that reported by Green et al in 1996, differential diagnosis was made with other several syndromes including acral and renal anomalies.     

The pathology of trisomy 13 syndrome

Summary Anatomical and histopathological findings in 12 cases of trisomy 13 syndrome (nine with classic full trisomy and three with trisomy 13 and an unbalanced Robertsonian 13/13 translocation) are reported. Emphasis is on the brain defects, cardiovascular anomalies, and histological organ dysplasia. Eight patients showed abnormal development of the forebrain and midline facial structures (holoprosencephaly). Cardiovascular malformations were invariably present, the leading malformation being an infundibular ventricular septal defect often in combination with dextroposition of the aorta and abnormalities of the semilunar valves. Histological abnormalities giving evidence of organ dysplasia were observed in the central nervous system, eyes, pancreas, kidneys, and ovaries. Mild cystic renal dysplasia was a constant feature. Foci of persistent nodular renal blastema were found in six cases. The pancreatic dysplasia appears to be pathognomonic for trisomy 13. These observations illustrate the importance of pathological studies in the recognition of chromosome abnormalities and, more specifically, of trisomy 13 syndrome. Based on autopsy data, trisomy 13 can be diagnosed — or ruled out — with certainty, even in the absence of karyotyping.