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Objective: To present the fetal features of Cornelia de Lange Syndrome (CdLS) with a molecular confirmation., Study Design: This was a retrospective study of 13 cases with CdLS diagnosed by prenatal and postnatal genetic testing and physical examination. Clinical and laboratory data were collected and reviewed for these cases, including maternal demographics, prenatal sonographic findings, chromosomal microarray and exome sequencing (ES) results, and pregnancy outcomes., Results: All of the 13 cases were detected to have a CdLS-causing variant, with 8 variants identified in the NIPBL gene, 3 in SMC1A, and 2 in HDAC8. Five had normal ultrasound scans during pregnancy; all were caused by variants of SMC1A or HDAC8. For the eight cases with NIPBL variants, all had prenatal ultrasound markers. Three had first trimester ultrasound markers including increased nuchal translucency in one and limb defects in three. Four presented with normal ultrasound in the first trimester, but abnormal ultrasound in the second trimester, including micrognathia in two, hypospadias in one and intrauterine growth retardation (IUGR) in one. IUGR as the isolated feature was identified in one case in the third trimester., Conclusion: The prenatal diagnosis of CdLS caused by NIPBLvariants is possible. It seems to remain challenging to detect non-classic CdLS only relying on ultrasound examination., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This study assesses a possible cardiac dysfunction in individuals with Cornelia de Lange syndrome (CdLS) without diagnosed congenital heart disease (CHD) and its association with other factors. Twenty patients and 20 controls were included in the study divided into three age-dependent groups (A: < 10 yrs, B: 10-20 yrs, C: > 20 yrs), and were evaluated using conventional echocardiography, tissue doppler imaging (TDI), two-dimensional speckle tracking and genetic and biochemical analyses. The left ventricular global longitudinal strain (GLS) was altered (< 15.9%) in 55% of patients, being pathological in the older group (A: 19.7 ± 6.6; B: -17.2 ± 4.7; C: -13.6 ± 2.9). The speckle tracking technique revealed a downward trend in the values of strain, strain rate and velocity, especially in the oldest group. Likewise, the ejection fraction (LVEF) and shortening fraction (LVFS) values, although preserved, also showed a decreased with age (p < 0.05). The analytical markers of cardiovascular risk and cardiac function showed no alterations. The molecular analyses revealed 16 individuals carrying pathogenic variants in NIPBL, two with variants in SMC1A, one with a variant in RAD21 and one with a HDAC8 variant. This is the first systematic approach that demonstrates that individuals with CdLS may present early cardiomyopathy, which can be detected by speckle tracking technique even before the appearance of clinical symptoms and the alteration of other echocardiographic or analytical parameters. For all these reasons, cardiological followup is suggested even in the absence of CHD, especially from adolescence onwards., (© 2022. The Author(s).)

Cornelia de Lange syndrome (CdLS) is a cohesinopathy, which is characterized by multiple structural anomalies as well as mental and growth retardation. A 36-yr-old nulliparous woman with oligomenorrhea was referred to us due to a mass in the uterine corpus. She had been clinically diagnosed with CdLS during infancy based on her specific facial features as well as growth and intellectual retardation. Imaging examinations and an endometrial biopsy revealed endometrial endometrioid carcinoma and polycystic ovary syndrome (PCOS). She underwent a hysterectomy and bilateral salpingo-oophorectomy. The tumor was mainly located at the uterine isthmus and exhibited diffuse exophytic growth. Microscopically, the grade 1 endometrioid carcinoma consisted of extremely well-differentiated glands and showed myometrial invasion. Both swollen ovaries had a thick fibrous cortex and multiple follicles. To the best of our knowledge, this is the first case report of a gynecologic malignancy in an adult patient with CdLS. Several gene mutations have been reported to be causative of CdLS; however, a potential role of these mutations in the pathogenesis of PCOS and subsequent endometrial cancer remains controversial. In this case, PCOS seemed to underlie the endometrial carcinogenesis and then concurrent loss of PTEN and PAX2 expression, confirmed by immunohistochemistry, can facilitate tumor progression. Our case suggests that adult female patients with CdLS can have PCOS and subsequent endometrial carcinoma. As patients with CdLS often have difficulties recognizing and/or reporting menstrual disorder, their care providers should pay particular attention to menstrual cycle irregularities due to the risk of endometrial cancer.

Background: Intestinal malrotation is a potentially life-threatening congenital anomaly due to the risk of developing midgut volvulus. The reported incidence is 0.2%-1% and both apparently hereditary and sporadic cases have been reported. Intestinal malrotation is associated with a few syndromes with known genotype but the genetic contribution in isolated intestinal malrotation has not yet been reported. Rare copy number variants (CNVs) have been implicated in many congenital anomalies, and hence we sought to investigate the potential contribution of rare CNVs in intestinal malrotation., Methods: Analysis of array comparative genomic hybridization (aCGH) data from 47 patients with symptomatic intestinal malrotation was performed., Results: We identified six rare CNVs in five patients. Five CNVs involved syndrome loci: 7q11.23 microduplication, 16p13.11 microduplication, 18q terminal deletion, HDAC8 (Cornelia de Lange syndrome type 5 and FOXF1) as well as one intragenic deletion in GALNT14, not previously implicated in human disease., Conclusion: In the present study, we identified rare CNVs contributing pathogenic or potentially pathogenic alleles in five patients with syndromic intestinal malrotation, suggesting that CNV screening is indicated in intestinal malrotation with associated malformations or neurological involvements. In addition, we identified intestinal malrotation in two known syndromes (Cornelia de Lange type 5 and 18q terminal deletion syndrome) that has not previously been associated with gastrointestinal malformations., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Cornelia de Lange syndrome (CdLS) is an inherited condition with a wide spectrum of phenotypic anomalies, consisting mainly of growth impairment, multi-organ abnormalities, and neurocognitive delay. Clinical diagnostic criteria after birth are well defined, whereas when to suspect the syndrome during intrauterine life still remains undefined. This review summarizes the main possible prenatal findings in CdLS, suggesting that a skilled ultrasound scan in cases of intrauterine growth restriction associated with other fetal abnormalities may improve the chance of prenatal diagnosis of CdLS, especially in families known to be at high risk. We propose that, following a sequence of detailed scans and examinations, CdLS affected fetuses could be diagnosed in utero, when one or more conditions (among them, intrauterine growth restriction, limb defects, facial abnormalities, diaphragmatic hernia, and heart diseases) are detected, and possibly confirmed by specific molecular testing. Birth Defects Research 109:771-777, 2017. © 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc., (© 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc.)

Objective: Cornelia de Lange syndrome (CdLS) is a multiple developmental disorder including hearing loss. The hearing impairment in CdLS patients is not only sensorineural but also conductive hearing loss (CHL). The aim of this study was to elucidate hearing loss causes in CdLS patients and evaluate the effect of ventilation tube (v-tube) insertion in the cases of CHL., Methods: Thirty-two patients clinically diagnosed with CdLS were enrolled and analyzed with retrospective case review. Audiologic evaluations and imaging studies such as a temporal bone computed tomogram or brain magnetic resonance imaging (MRI) were performed for all patients. Hearing rehabilitation such as ventilation tube insertion, hearing aid fitting, or cochlear implantation was chosen depending on the audiological condition., Results: Among 32 CdLS patients who underwent auditory brainstem response test, 81.2% presented hearing loss. Imaging studies showed that only middle ear lesions without inner ear anomalies were identified in 56.3%. Notably, the soft tissue lesion in middle ear was identified even in the neonatal MRI. When 7 patients were thought to have CHL due to otitis media with effusion, v-tube insertion was applied first. However, v-tube insertion rarely improved CHL postoperatively. Moreover, middle ear lesion was not fluid effusion but soft tissue lesion according to the intraoperative finding. These lesions were not eradicated even after revision surgery of v-tube insertion., Conclusion: V-tube insertion is not effective to improve hearing or eradicate otitis media with effusion in CdLS patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Functional brain imaging with brain single photon emission computer tomography (Brain SPECT) has been used for many years in the evaluation of multiple neuro-degenerative and neuro-developmental disorders. Brain SPECT is a nuclear medicine tomographic study performed with a lipophilic radiopharmaceutical labeled with 99mTc-pertechnetate. It is a cerebral perfusion agent that depicts the global and regional perfusion patterns in the cortical gray matter and subcortical structures. Cornelia de Lange syndrome (CdLS) is a rare neuro-developmental and genetic condition, associated to several malformations. There are a limited number of cases reported in the medical literature and few of them report neuro-radiological and/or neuro-pathologic abnormalities. We report a case of a 15 year old patient, clinically diagnosed at birth with CdLS, who presents limited anatomical findings on Computed Tomography and Magnetic Resonance Imaging. To the best of our knowledge, this is the first report of the Brain SPECT findings in this syndrome.

Objectives: Cornelia de Lange syndrome (CdLS) is characterized by distinct facial features, growth retardation, upper limb reduction defects, hirsutism, and intellectual disability. NIPBL mutations have been identified in approximately 60% of patients with CdLS diagnosed postnatally. Prenatal ultrasound findings include upper limb reduction defects, intrauterine growth restriction, and micrognathia. CdLS has also been associated with decreased PAPP-A and increased nuchal translucency (NT). We reviewed NIPBL sequence analysis results for 12 prenatal samples in our laboratory to determine the frequency of mutations in our cohort., Methods: This retrospective study analyzed data from all 12 prenatal cases with suspected CdLS, which were received by The University of Chicago Genetic Services Laboratories. Diagnostic NIPBL sequencing was performed for all samples. Clinical information was collected from referring physicians., Results: NIPBL mutations were identified in 9 out of the 12 cases prenatally (75%). Amongst the NIPBL mutation-positive cases with clinical information available, the most common findings were upper limb malformations and micrognathia. Five patients had NT measurements in the first trimester, of which four were noted to be increased., Conclusion: We demonstrate that prenatally-detected phenotypes of CdLS, particularly severe micrognathia and bilateral upper limb defects, are associated with an increased frequency of NIPBL mutations., (© 2013 John Wiley & Sons, Ltd.)

Cornelia de Lange syndrome (CdLS) (also referred to as Brachmann-de Lange syndrome) constitutes a multisystem developmental anomaly which is characterized by facial dysmorphism, upper limb deformities, and mental retardation. We report on two subsequent pregnancies with antenatally diagnosed CdLS at 23 and 14 gestational weeks, respectively, of an otherwise healthy gravida. Molecular genetic testing revealed a rare case of gonadal mosaicism of a nonsense NIPBL gene mutation.

Aim: The objective is to present a rare case of late diagnosis of Cornelia de Lange syndrome., Case: A 27-year-old pregnant woman (gravida 1, para 0) was referred to our Fetal Medicine Department during her 33rd week of gestation due to intrauterine growth restriction (IUGR) and polyhydramnios. The ultrasound scanning confirmed the findings and furthermore, the 3-D examination revealed minor facial dysmorphisms, limb abnormalities, and hypertrichosis. The fetus died 1 week post-diagnosis due to unknown reason and the woman underwent an induction of labor. Postmortem examination confirmed the diagnosis of Cornelia de Lange syndrome., Conclusion: The prognosis of the syndrome is severe. Termination of pregnancy before viability is proposed. Genetic counseling is necessary.

Cornelia de Lange Syndrome (CdLS) is a multiple congenital anomaly characterized by distinctive facial features, upper limb malformations, growth and cognitive retardation. The diagnosis of the syndrome is based on the distinctive clinical features. The etiology is still not clear. Mutations in the sister chromatid cohesion factor genes NIPBL, SMC1A (also called SMC1L1) and SMC3 have been suggested as probable cause of this syndrome. We experienced a case of newborn with CdLS showing bushy eyebrows and synophrys, long curly eyelashes, long philtrum, downturned angles of the mouth and thin upper lips, cleft palate, micrognathia, excessive body hair, micromelia of both hands, flexion contracture of elbows and hypertonicity. We detected a NIPBL gene mutation in a present neonate with CdLS, the first report in Korea.

Objective: The objective was to improve the prenatal diagnosis of Brachmann-de Lange syndrome (BDLS) by defining the sonographic criteria., Methods: Retrospective review of Fetal Medicine Unit (FMU) notes from 1998 to 2009 to identify all cases seen with a final diagnosis of BDLS. Literature review undertaken to ascertain all cases where sonographic features of BDLS had been described. Information was pooled to define the most common features., Results: Seven cases were identified from review of FMU records. The diagnosis was suspected prenatally in four of the seven. All had asymmetrical forearm defects with oligodactyly/polydactyly, five had intrauterine growth restriction (IUGR) and five had abnormal facial features including micrognathia and/or a long overhanging philtrum. A further 28 cases were identified in the literature, but the diagnosis was only suspected prenatally in nine. Overall the most common feature was IUGR (80%); upper limb anomalies were detected in nearly half of cases. Other common features included facial anomalies (40%), diaphragmatic hernia (34%), increased nuchal translucency/fold (37%) and cardiac anomalies (14%)., Conclusions: Identification of asymmetrical oligodactyly with or without forearm anomalies associated with microcephaly and/or IUGR or diaphragmatic hernia are findings that should arouse suspicion of BDLS, although definitive diagnosis at present would have to await delivery in the majority of cases., ((c) 2010 John Wiley & Sons, Ltd.)

Congenital anomalies of the umbilical vein are rare. We describe an aberrant course of the umbilical vein discovered by identifying an unusual umbilical venous catheter course on abdominal radiography in a patient with Cornelia de Lange syndrome. The umbilical vein bypassed the liver to insert directly into a right pelvic vein. Use of the lateral abdominal radiograph and sonography were helpful in determining the catheter location after identifying the unusual course of the catheter on the frontal radiograph.

We describe a fetus with Cornelia de Lange syndrome diagnosed after termination of pregnancy at 21 weeks. Prenatally, growth retardation, diaphragmatic hernia, cystic hygroma and a right hand with only three rays were diagnosed by ultrasound in the second trimester of pregnancy. Postnatal magnetic resonance imaging confirmed the prenatal findings, and the presence of the typical dysmorphic features led to the diagnosis of Cornelia de Lange syndrome. The diagnosis was confirmed by the finding of a truncating mutation in the NIPBL gene. This case illustrates that the diagnosis Cornelia the Lange syndrome can be suspected prenatally in the second trimester, and can be diagnosed in fetuses after induction or newborns at birth as the typical phenotype is present early., (2009 S. Karger AG, Basel.)

Background and Purpose: Cornelia de Lange syndrome is a rare developmental malformation syndrome with a high prevalence of hearing impairment. The purposes of this study were to describe the characteristic temporal bone CT findings in patients with Cornelia de Lange syndrome and to correlate audiometric data with radiologic findings in these patients., Materials and Methods: Ten children (6 girls and 4 boys; mean age, 42.0 months) who were clinically diagnosed with Cornelia de Lange syndrome (classic, n = 5; mild form, n = 5) were enrolled. Temporal bone CT was prospectively performed, and 32 aspects of each temporal bone CT were analyzed, 21 by direct measurement and 11 by visual inspection. Twenty age-matched children (n = 20 ears) with normal temporal bone CT scans served as a control group. Audiologic tests were also performed on all patients., Results: Characteristic temporal bone CT findings of Cornelia de Lange syndrome were external auditory canal stenosis, soft-tissue opacification of the hypoplastic tympanomastoid cavity, dysmorphic ossicle, hypoplastic cochlea, and dysplastic vestibule, all of which were more prevalent in patients with the classic form of the disease than in those with the mild form. Children who had more severe structural abnormalities on temporal bone CT had worse hearing levels compared with those without structural abnormalities., Conclusion: Temporal bone CT scans in Cornelia de Lange syndrome could document combined structural abnormalities of the external, middle, and inner ear, which were one of the characteristic clinical manifestations; CT abnormalities were well correlated with the audiometric data.

Purpose: This study reviews prenatal findings in two cases with a suspected diagnosis of Cornelia de Lange Syndrome, a multisystem disorder characterized by somatic defects and mental retardation, that were later confirmed by postmortem examination and molecular testing. Although the correlation between the Cornelia de Lange Syndrome genotype and phenotype is still unclear, preliminary data indicate several severe phenotypic features that are likely to be detected prenatally in NIPBL-mutated patients., Methods: We report on two prenatal/neonatal cases with unusual pathologic findings indicating Cornelia de Lange Syndrome. The first, with suspected Cornelia de Lange Syndrome after a set of typical dysmorphisms was noted by prenatal ultrasound, was confirmed by a physical examination after termination of the pregnancy. The second was diagnosed neonatally on the basis of typical clinical signs. Medical complications led to death within the first month of life., Results: Molecular analysis of NIPBL, the gene that codes for delangin (a component of the cohesin complex), performed postnatally detected two de novo mutations: a missense change (P2056L) in a highly conserved residue and a nonsense alteration (S2490 replaced by a stop codon)., Conclusion: We suggest that early diagnosis of Cornelia de Lange Syndrome would be made much easier by the assemblage of a set of prenatal diagnostic features and criteria in Cornelia de Lange Syndrome cases that have been confirmed by direct physical and molecular examinations. We also suggest that Cornelia de Lange Syndrome genotype-phenotype correlations need to be extended to prenatal cases.

We describe a patient with Cornelia de Lange syndrome (CdLS) and a severely calcified bicuspid aortic valve. Cornelia de Lange syndrome is characterized by altered Notch signaling, and recent studies have provided a link between Notch signaling and heart valve development and calcific bicuspid aortic valve disease. In this case report, we propose that altered Notch signaling in CdLS may be causally linked to the calcific bicuspid aortic valve disease in these patients. Patients with CdLS should undergo routine echocardiographic examination for possible congenital cardiac defects including bicuspid aortic valve.

Cornelia De Lange syndrome is a relatively uncommon, multiple congenital anomaly / mental retardation disorder of unknown etiology. Its incidence has been reported to vary from 1 : 30,000 to 1 : 50,000 of live births, without any known racial predilection. However, it has been considered to be due to a new dominant mutation. Main clinical features of this syndrome include growth retardation, developmental delay, hirsutism, structural limb abnormalities, mental retardation and facial growth discrepancies. Main causes of death in such patients include pneumonia along with cardiac, respiratory and GI abnormalities.

Brachmann-de Lange syndrome is a congenital disease characterized by severe mental retardation, pre- and postnatal symmetric growth delay, limb defects, visceral anomalies, hirsutism, and a typical face. The authors describe the prenatal sonographic pattern of Brachmann-de Lange syndrome suspected at 20 weeks of gestation, with severe intrauterine growth retardation, facial dysmorphism, cardiac abnormality, and micromelia without the typical defects of the upper limbs. Fetal karyotyping was normal. The diagnosis of a 'minor' form of Brachmann-de Lange syndrome was confirmed at 28 weeks of gestation by using three-dimensional sonography in order to assess precisely the facial dysmorphism and by performing a three-dimensional computed tomography of the upper limbs in order to identify the subtle abnormalities of the radial head and of the first metacarpal bone., (Copyright 2004 S. Karger AG, Basel)

Objective: Our investigation of fetal swallowing has identified potential limitations in the use of color Doppler imaging for detection of amniotic fluid flow and discrimination of respiratory from ingestive activity. The objective of this study was to evaluate an alternative imaging modality, power Doppler sonography, as a technique to enhance detection of amniotic fluid flow in the upper aerodigestive tract., Methods: We applied a standardized 4-axis sonographic examination of upper aerodigestive structures and used power Doppler imaging to document amniotic fluid flow. Normal aerodigestive activities from 62 healthy control subjects were compared with 4 abnormal cases., Results: Our longitudinal experience with 66 subjects showed that a directed evaluation of the fetal upper aerodigestive tract with power Doppler imaging provided a systematic approach for studying the physiologic development of this region in both healthy and at-risk fetuses., Conclusions: A standardized 4-axis examination with power Doppler imaging is a useful adjunct in addressing ingestive and respiratory functions in the developing fetus.

Background: Cornelia de Lange syndrome is a genetic disorder associated with delayed growth and characteristic facial features. There is no definitive biochemical or chromosomal marker for the prenatal diagnosis of this syndrome. We describe a case of Cornelia de Lange syndrome associated with an increased nuchal translucency in the first trimester., Case: A large nuchal translucency was identified in a fetus during a first trimester ultrasound. Subsequent second- and third-trimester sonograms demonstrated severe fetal growth restriction, limb shortening, and abnormal facial features, despite normal fetal karyotype per chorionic villus sampling. Neonatal evaluation confirmed the diagnosis of Cornelia de Lange syndrome., Conclusion: Sonographic finding of an increased nuchal translucency in early pregnancy is associated with fetal aneuploidy and various structural and genetic abnormalities. Increased nuchal translucency may identify fetuses that require vigilant assessment, especially when found in association with other abnormalities.

We present a case of Brachmann-de Lange syndrome, in which prenatal ultrasonographic evaluation demonstrated increased nuchal translucency, early onset of intrauterine growth retardation, and limb abnormalities in the first, second, and third trimester, respectively.

Brachmann-de Lange syndrome (BDLS) is a well-delineated and relatively common syndrome. However, prenatal diagnosis has never been reported, even if in some cases ultrasonography demonstrated one or more manifestations of the syndrome. We report on 3 cases: in the first 2 cases, prenatal ultrasonography demonstrated some signs of the condition. The third represents, to our knowledge, the first prenatal diagnosis of BDLS. We also present a review of the literature concerning pre- and postnatal findings in this syndrome.

Brachmann-de Lange syndrome is a well-described congenital disorder. Skeletal anomalies and respiratory infections are its hallmarks. To the known imaging signs, the authors add tracheomegaly, which has not been reported so far.

Cornelia de Lange syndrome is a congenital malformation characterized by severe growth failure, mental retardation, and multiple physical anomalies. A variety of gastrointestinal anomalies have been described, including malrotation, colonic duplication, and nonfixation of the colon. Two patients with Cornelia de Lange syndrome presented to our institution with acute distal bowel obstruction. In both cases, emergency laparotomy showed cecal volvulus with necrosis of the terminal ileum, cecum, and ascending colon, secondary to nonfixation of the colon. Resection and an end-ileostomy were performed and later successfully reversed in both patients. Intestinal obstruction is a known cause of death in these children, and nonfixation of the colon has been identified during autopsy. Parents of children with Cornelia de Lange syndrome should be counseled as to the possibility of bowel obstruction resulting from cecal volvulus. This awareness may lead to earlier identification and treatment of this potentially lethal gastrointestinal tract anomaly.

The Brachmann-de Lange syndrome (BDLS) is diagnosed in children on the basis of a distinctive clinical phenotype which includes retarded physical growth. Because there are no genetic or biochemical tests at present, the antenatal detection of the syndrome may depend upon identification of some aspect of the phenotype in the fetus using ultrasound imaging. We studied the growth of 23 subsequently diagnosed fetuses with the BDLS using standard biometric parameters defined by prenatal ultrasound imaging. Sonographic studies were obtained through a national parents' group, the Cornelia de Lange Syndrome Foundation. Assessment of fetal growth was made using four standardized measurements: the biparietal diameter, head circumference, femur length, and abdominal circumference. These values were compared to established tables of normal fetal growth and established ratios of fetal body proportions. The cross-sectional growth curve derived using all measurements collected as a composite group indicates that growth retardation would be first detected as early as 25 weeks. In five fetuses with measurements both before and after 25 weeks of gestation, longitudinal growth curves indicated that the diagnosis of "small for gestational age" would have been suggested between 20 and 25 weeks. The mean fetal weight estimates closely followed the fifth centile curve of normal fetuses both before and after 25 weeks. Cephalic indices in BDLS fetuses indicated either frank brachycephaly (25%), or were at the upper portion of the normal range. Femur lengths were relatively short (less than 90% of their expected length) ion 4 of the 11 fetuses where such information could be obtained.(ABSTRACT TRUNCATED AT 250 WORDS)

Brachmann-de Lange syndrome (BDLS) is a well-delineated disorder consisting variably of pre- and postnatal growth deficiency, microbrachycephaly, characteristic face, hypertrichosis, visceral anomalies, and limb defects consisting primarily of variable limb reduction defects, micromelia, and elbow abnormalities. The course is usually marked by initial hypertonicity, low-pitched weak cry, feeding problems, and behavioral problems with marked mental deficiency. In classical cases there is rarely any difficulty in making the diagnosis, but for mildly affected cases, it may be difficult to feel secure about the diagnosis. In an effort to increase the precision of diagnosis for mildly affected cases, we reviewed roentgenograms in 21 cases of Brachmann-de Lange syndrome, as well as previously published descriptions of the radiological manifestations. Unusual radiologic manifestations were related primarily to the limb anomalies, and these were often asymmetric. These manifestations included digital abnormalities, which ranged from acheiria to oligodactyly, hypoplasia of the thumb and first metacarpal, clinodactyly of the fifth finger, or ectrodactyly. Long bone abnormalities included ulnar a/hypoplasia, dysplasia of the radial head, or fusion of the elbow. When there was a single forearm bone, there was often fusion at the elbow and oligodactyly, which made it difficult to determine whether the radius or ulna was absent. Other radiologic manifestations included 13 ribs with precocious sternal fusion, and micrognathia. We suggest that these radiologic manifestations could increase diagnostic precision in mildly affected cases.

Brachmann-de Lange syndrome (BDLS) is a variable multiple congenital anomaly syndrome that occasionally includes congenital diaphragmatic hernia (CDH). CDH per se is commonly diagnosed antenatally and has been corrected with increasing success in utero and by neonatal repair with extracorporeal membrane oxygenation (ECMO). In utero repair requires normal karyotype as well as the absence of other lethal anomalies. Postnatal repair in combination with ECMO has resulted in improved neonatal outcome and has been recommended in all cases not having in utero repair. We describe a fetus diagnosed with a diaphragmatic hernia at 18 weeks of gestation in a woman whose only other pregnancy has been a 16 week abortus diagnosed with Fryns syndrome (FS). FS is a lethal, variable congenital anomaly syndrome that includes CDH, which is thought to contribute to the lethality of the syndrome. In utero repair was considered, but rejected because of the position of the liver and suspected FS. The patient elected to carry the pregnancy to term. Postnatal repair with ECMO was considered; however, the infant died at several hours of age because of severe pulmonary hypoplasia, being considered ineligible for ECMO. The diagnosis of BDLS was made at autopsy and suggests that the first case may, in fact, have been BDLS. In spite of recent success in the repair of CDH both in et ex utero, CDH in association with BDLS is likely lethal, and women with fetuses diagnosed antenatally with CDH and BDLS should be counseled as such.

Brachmann-de Lange syndrome is a congenital disorder of uncertain cause characterized by severe mental retardation, small stature, microbrachycephaly, hirsutism, limb deformities, and characteristic facies. Although more than 300 neonatal cases have been reported, a lack of specific fetal markers has precluded successful antepartum diagnosis. We describe a case of Brachmann-de Lange syndrome identified at 15 weeks' gestation by a low maternal serum alpha-fetoprotein (MSAFP) value. Sonography revealed a fetus with a posterior nuchal cystic hygroma and early-onset symmetrical intrauterine growth retardation (IUGR). The fetal karyotype was 46,XX, but the infant fulfilled the phenotypic criteria of the Brachmann-de Lange syndrome at delivery. The triad of an abnormally low MSAFP value, early-onset symmetrical IUGR, and characteristic ultrasound findings during the second trimester of pregnancy may define adequate criteria for prenatal diagnosis of Brachmann-de Lange syndrome.

After a short review of our method, we compared the results of the radiographs of 18 cases of CdLS to the results of our normal material. All of our normal statistical data was obtained from AP and lateral view radiographs at a distance of 1 m, in the prevailing conditions of everyday practice in a radiological department. We studied quantitative changes such as microcephaly and brachycephaly, and for the first time we introduced qualitative changes such as occipital rotation and the study of obliquity of the foramen magnum (line BAO). We found microcephaly in all our cases of CdLS and brachycephaly in only 72%. Furthermore, we found a lack of positive occipital rotation in all our cases of CdLS and the line BAO turned posteriorly with O higher than BA. The same conditions were observed on our normal material only in an early postnatal stage.

Children with Cornelia de Lange (CDL) syndrome present with feeding problems related to swallowing incoordination, poor esophageal motility, and gastroesophageal reflux (GER). These abnormalities of esophageal function result in failure to thrive and life-threatening aspiration pneumonia. Severe GER was documented in four patients with CDL syndrome. Three were managed successfully with an antireflux procedure (Nissen fundoplication) and a concomitant feeding gastrostomy. These observations confirm the high incidence of abnormal esophageal function in patients with CDL syndrome, and suggest that an antireflux procedure and feeding gastrostomy are important considerations in their clinical management.

Fifteen cases of the de Lange syndrome are presented. Personal and family histories, clinical features, detailed radiological findings, laboratory data, chromosome studies and dermatoglyphic patterns are reported. A Negro patient and his autopsy findings are described. Radiological diagnostic features are stressed; in particular, the combined presence of a hypoplastic middle phalanx of the index fingers and variable short metatarsal appear to be two additional features which are diagnostically helpful. The etiology of the syndrome is unknown; however, there is some evidence to suggest a genetic basis. The literature is briefly reviewed.