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BACKGROUND Cornelia de Lange syndrome (CdLS) is a congenital multisystemic genetic disorder. The expected lifespan of children with this disorder has been prolonged in parallel with the advances in medicine in recent years. However, they still more frequently undergo cardiac surgery. There are some challenges for clinicians when faced with CdLS patients. We present the perioperative management of a child with CdLS undergoing open-heart surgery. CASE SUMMARY Severe pulmonic and subpulmonic valvular stenosis, enlargement of the right side of the heart, mild tricuspid regurgitation, atrial septal defect, and patent ductus arteriosus were diagnosed in a 14-month-old boy with manifested cyanosis, developmental delay, and malnutrition. Attempted balloon valvuloplasty was unsuccessful due to a severe stenotic pulmonary valve, therefore it was decided to perform an open surgical repair. Following a successful and uncomplicated intraoperative course, the patient was extubated on postoperative day 5, and adrenalin and dopamine infusions were gradually decreased and stopped on postoperative days 6 and 10, respectively. Moderate laryngomalacia and suboptimal vocal cord movements were diagnosed, and tracheotomy and percutaneous endoscopic gastrostomy were performed under general anesthesia in the same session at postoperative day 32. The patient was discharged on postoperative day 85 after a challenging postoperative period with additional airway and nutritional problems. CONCLUSION This is the first report of the perioperative anesthetic and clinical management of a CdLS patient undergoing open-heart surgery.

There is a known association between Cornelia de Lange syndrome (CdLS) and congenital diaphragmatic hernia (CDH), with CDH being the cause of death in 5%-20% of CdLS cases. We aimed to identify and describe patients with CDLS and CDH. We hypothesized that CdLS would be associated with high-risk CDH and poor outcomes.CDH Study Group patients from 1995 to 2019 were included. Those with CdLS were reviewed retrospectively. Rates of repair and outcomes were compared between patients with and without CdLS.We identified 9,251 CDH patients. Of those, 21 had confirmed CdLS. CdLS patients had a lower birth weight (2.2±0.57 kg) than non-CdLS patients (2.9±0.64 kg) (p0.001). 5-min Apgar scores were lower in CdLS patients (6, 4-7) than non-CdLS patients (7, 5-8) (p=0.014). Only 33% of CdLS patients underwent diaphragmatic repair compared to 84.2% of non-CdLS patients (p0.001). Mortality was 76% for CdLS patients compared with 29% for non-CdLS patients (p0.001). Of the 7 CdLS patients who underwent repair, 5 survived to hospital discharge.Infants with CdLS and CDH have a poor prognosis. However, CdLS patients who undergo repair can survive to discharge; therefore, the concomitant diagnosis of CdLS and CDH is not necessarily a contraindication to repair. Early recognition of these anomalies can assist with counseling and prognostication.Retrospective comparative study LEVEL OF EVIDENCE: III.

WstępZespół Cornelii de Lange (Cornelia de Lange syndrome – CdLS, nazywany również Brachmann de Lange syndrome – BdLS) jest wrodzonym wielosystemowym schorzeniem rozwojowym, charakteryzującym się wyróżniającymi się rysami twarzy, opóźnieniem wzrostu i umysłowymi, anomaliami w obszarze kończyn oraz problemami behawioralnymi spowodowanymi deformacjami. Pomimo wysiłków naukowców, dotychczasowe próby oceny funkcjonalnej dzieci z CdLS koncentrowały się głównie na słuchu i wzroku. Cele badania były następujące: 1) przedstawić stan funkcjonalny dzieci z CdLS, 2) zaproponować jednolity protokół/narzędzie do jego oceny.Materiał i metodyBadaniu poddano 27 dzieci z CdLS, które oceniono pod kątem funkcjonowania i jego ograniczeń z wykorzystaniem kwestionariusza oraz badania obserwacyjnego.WynikiNajczęściej spotykane problemy funkcjonalne dotyczyły przykurczy (88,89%), deformacji (66,67%) oraz asymetrii tułowia (66,67%).WnioskiWyniki badania pokazują stan funkcjonalny dzieci z CdLS. Nawet wyniki wstępne mogą kształtować dalsze całościowe podejście do leczenia, rehabilitacji i opieki w tej grupie pacjentów. Prezentowana ocena może być dobrym punktem startowym do rozwoju nowych protokołów/narzędzi stosowanych w tak złożonych schorzeniach. Dalsze, szerzej zakrojone badania są potrzebne do zapewnienia pełniejszej i dokładniejszej diagnostyki, co wpłynie na efektywniejsze postępowanie terapeutyczne.

Cornelia de Lange syndrome, also known as Brachmann–de Lange syndrome, is a congenital condition characterized by pre- and postnatal growth deficiency, limb deformities, typical face features, hirsutism, behavioral problems, cognitive delay, and failure to thrive after birth. This developmental genetic disorder ranges from mild to fatal with unknown etiology. The sonographic prenatal findings in a case of Cornelia de Lange syndrome at 22 weeks’ gestation, which demonstrated facial dysmorphism, upper and lower limb abnormalities, growth retardation, and cardiac abnormality and confirmed at 32 weeks and 2 days of gestation and at autopsy, are discussed. Fetal karyotyping was normal. Because 2D sonography is the primary imaging modality for evaluating the growing fetus, it is possible to use 3D sonography to precisely evaluate the facial dysmorphism and limb defects and make a specific diagnosis of this entity.

A mother of normal intelligence and her moderately mentally retarded son, both with the typical facial features of the Brachmann-de Lange syndrome, are reported. We discuss the variable expression of the Brachmann-de Lange syndrome by comparing the autosomal dominant cases with the sporadic or presumed autosomal recessive cases. The autosomal dominant cases show milder symptoms in general. In our opinion, a de novo autosomal dominant mutation causes the severe form of the syndrome, recurrence within sibships being explained by germline mosaicism. In all convincingly autosomal dominant cases we found that the mother is the transmitting parent, suggesting genomic imprinting.

We report on a family in which a girl and a boy in the same sibship show variable manifestations of a less severe type of Brachmann-de Lange syndrome without significant prenatal growth deficiency and reduction deformities of the forearms. Both parents are healthy and phenotypically normal, and no other family members are affected. All the affected sibs except one described so far with normal parents presented the severe type of Brachmann-de Lange syndrome (now sometimes classified as type I: "classic" or "full" Brachmann-de Lange syndrome), with major upper limb anomalies, severe growth and mental retardation and, frequently, early death. We discuss the possible role of genomic imprinting in the etiology of this syndrome.

We report renal abnormalities found in four cases of Brachmann-de Lange syndrome (BDLS). In two there were nephrogenic rests and renal cortical cysts, a further case showed cortical cysts, and the fourth had dilated collecting ducts. The literature describing renal abnormalities in BDLS has been reviewed, and this includes a report of one individual with BDLS who developed Wilms' tumor. The genetic basis of BDLS has not been elucidated, although a submmicroscopic abnormality of chromosome 3 seems likely. Nephrogenic rests may be Wilms' tumor precursor lesions and are seen in syndromes associated with Wilms' tumors. Mutations of genes on chromosome 11 are the most common genetic abnormalities associated with Wilms' tumor, but other chromosomes have also been implicated. The frequency of renal abnormalities in the BDLS suggests that the involved gene may be important in renal development and also possibly in Wilms' tumors.

A mother with mild phenotype and her severely affected son, both with classic manifestations of Brachmann-de Lange syndrome (BDLS), are described. This documented mother-to-child transmission supports the hypothesis of autosomal dominant transmission with intrafamilial variability. Known cases of BDLS with autosomal dominant inheritance are reviewed. Although most cases of BDLS are sporadic, a careful evaluation of parents of affected children is important for appropriate genetic counseling.

We report on familial occurrence of the Brachmann-de Lange syndrome (BDLS): a mildly affected father and his severely affected son and daughter who have different mothers. Both children are severely affected while the father has a much milder but definite BDLS phenotype. Our report documents the third example of male-to-male transmission and adds to the argument against exclusively maternal transmission in familial cases. In addition, our findings illustrate the occurrence of severe manifestations in cases of familial BDLS.

The life and work in the field of clinical genetics of one of the most outstanding Dutch pediatricians of the first half of the twentieth century, Cornelia C. de Lange (1871–1950), is described against the background of the development of pediatrics, anthropogenetics, and clinical genetics in the Netherlands. Cornelia de Lange specialized in and worked on all aspects of the broad field of pediatrics. During her 50 years of practice she collected an immense series of observations on pediatric disorders. As theories on human genetics developed during the 1920s and 1930s, her interest in congenital disorders and heredity increased as she saw the implications for the pediatric clinic. She benefitted from her vast experience and her knowledge of the national and international literature when she recognised and described new entities, one of which is named after her: the Brachmann-De Lange syndrome. © 1994 Wiley-Liss, Inc.

We report on a male infant with Brachmann-de Lange syndrome (BDLS) and ulnar hemimelia and monodactyly but also absence of both tibiae, the right distal femur being bifurcated. One similar observation was published earlier. The question is raised whether these malformations are coincidental or a rare component of BDLS. © 1993 Wiley-Liss, Inc.

Brachmann-de Lange syndrome (BDLS) is a rare/multiple congenital anomaly/mental retardation (MCA/MR) syndrome with variable expression, making diagnosis of mild cases difficult. The most consistent manifestations appear to be the characteristic face, which can be subtle in children who are mildly affected [Ireland and Burn, 1991: Twelfth Annual David W. Smith Workshop on Malformations and Morphogenesis]. Other aspects of the syndrome include variable degrees of mental retardation, growth retardation, structural abnormalities of the limbs, and behavior abnormalities, noted to be “autistic” [Jones, 1988: “Smith's recognizable patterns of human malformation”]. Johnson et al. [1976: Pediatr Res 10:843–850] described a behavior phenotype felt to be common in patients with BDLS. They predicted that patients with BDLS may respond to “behavioral intervention”. Other behavior abnormalities in BDLS have been reported [Barr et al., 1971: Neuropadiatrie 3:46–66; Hawley et al., 1985: Am J Med Genet 20:453–459]. We report on a 6-year-old boy with the facial characteristics of BDLS, normal birth weight, prenatal onset of a small head relative to length, postnatal onset growth deficiency, nearly normal psychomotor development with onset of clear developmental delays by 2 years. He developed behavior problems similar to those seen in other patients with BDLS. These behaviors are most consistent with Pervasive Development Disorder-NOS (PDD), and Autistic Disorder [DSM-III-R, 1987] which encompasses a spectrum of mild to severe autistic behaviors. We report successful in-patient care utilizing medical and behavioral techniques to reduce the frequency of the behaviors. We feel that the presence of the characteristic behaviors may be helpful in confirming the diagnosis of BDLS. © 1993 Wiley-Liss, Inc.

Seven patients, including two sibs, with the Brachmann-de Lange syndrome (BDLS) are presented as representative of the different types of BDLS in a proposed classification system. Type I (“classic”) patients have the characteristic facial and skeletal changes of BDLS using the criteria in the diagnostic index of Preus and Rex. Type I is distinguished from the other subtypes by prenatal growth deficiency (< 2.5 S.D. below mean for gestation) becoming more severe postnatally (< 3.5 S.D. below the mean), moderate to profound psychomotor retardation, and major malformations which result in severe disability or death. Type II (“mild”) BDLS patients have similar facial and minor skeletal abnormalities to those seen in type I; however, these changes may develop with time or may be partially expressed. Patients with type II BDLS are distinguished from those with other types by mild to borderline psychomotor retardation, less severe pre-and postnatal growth deficiency, and the absence of (or loss severe) major malformations. Behavioral problems can be a significant clinical problem in type II BDLS. Type III (“phenocopies”) BDLS includes patients who have phenotypic manifestations of BDLS which are causally related to chromosomal aneuploidies or teratogenic exposures. © 1993 Wiley-Liss, Inc.

A total of 31 cases previously diagnosed as having Brachmann-de Lange syndrome were ascertained and examined, of which 11 were thought to have been misdiagnosed. Of those correctly diagnosed, there appeared to be a phenotypic dichotomy with classical and mild cases. Those facial findings of greatest diagnostic value were the combination of the characteristic eyebrows, long philtrum, thin lips and crescent-shaped mouth. The characteristic eyebrows were neat, well defined and arched as though they had been pencilled. This combination of anomalies was absent in postpubertal males but not in postpubertal females. Facial abnormalities most likely to lead to incorrect use of the eponym were hypertrichosis, synophrys, and bushy eyebrows. © 1993 Wiley-Liss, Inc.

We have obtained serial measurements on 180 patients with clinically confirmed Brachmann-de Lange syndrome (BDLS) in order to derive standard growth curves. The patients were evaluated in our genetics department and through meetings of the Cornelia de Lange Syndrome Foundation, a support group for families of affected individuals. The data were obtained from the records of pediatricians, other physicians, schools and parents, as well as from personal examination on each of these patients at least once, often periodically. The growth curves include height, weight and head circumference measurements from birth through adulthood. Prenatal growth and birth weights are below the 5th centile in most (68%) cases, with an average birth weight of 2,277 g. Growth persists below the normal curves in most of the patients throughout life. Height velocity is equal to the normal range but there is slower pubertal growth. Weight velocity is below the normal range throughout life until late adolescence. Average head circumference remains below the second centile. Thin body habitus coupled with slow growth and proportionate small stature is a manifestation of the syndrome, but is commonly mistaken for failure to thrive. © 1993 Wiley-Liss, Inc.

We report on 4 individuals (3 sibs and their father) with a syndrome of growth retardation, microcephaly, minor facial anomalies reminiscent of a mild Brachmann-de Lange syndrome (BDLS), severe metatarsus adductus, developmental delay, and unusual dermatoglyphics. The syndrome, which seems to be inherited as an autosomal dominant trait with variable expressivity, resembles mild BDLS.

Background Brachmann de Lange syndrome (BDLS) is a multiple congenital anomaly syndrome characterized by a distinctive facial appearance, prenatal and postnatal growth deficiency, psychomotor delay, behavioral problems, and malformations of the upper extremities. Case presentation Here we present for the first time a case of BDLS from Sudan, a 7-month-old female infant, who was referred as a case of malnutrition. The patient was from a Sudanese western tribe. Clinical investigation showed that the child was a classical case of BDLS, but with some additional clinical findings not previously reported including crowded ribs and tied tongue. Conclusion Reporting BDLS cases of different ethnic backgrounds could add nuances to the phenotypic description of the syndrome and be helpful in diagnosis.

The only known twin pair evidently discordantly affected for the BDLS (Brachmann-de Lange syndrome) and who had been considered monozygotic (MZ) based on blood analysis remained a problem because biological zygosity determination needed further typing. In this report we review the clinical findings of this pair of twins at the age of 20. The use of DNA fingerprinting with three multilocus probes, F10, DNF24, and 33.6, allowed us to present evidence of monozygosity with a high degree of certainty. The significance of this confirmation of discordance in determining the cause of BDLS is discussed. Intensive comparative genomic studies of the discordant twin sisters may be useful to unravel the molecular genetics of this enigmatic pattern of malformation.

To review the ocular surface and anterior segment findings in Brachmann-de Lange syndrome and describe a new case involving aniridia and congenital glaucoma.A newborn presented 2 days after birth with bilateral cloudy corneas, photophobia, and epiphora. We provide a 5-year descriptive history and clinical course with review of the literature on Brachmann-de Lange syndrome.Multiple ocular surgeries were performed for ocular sequelae from aniridia and congenital glaucoma including Ahmed valve placement and penetrating keratoplasties in both eyes. At 5.5 years of age, the child had a clear graft OD and amblyopia from graft failure OS following recurrent graft infections. A review of Brachmann-de Lange syndrome found 43 patients with ocular surface and anterior segment findings. The most common findings included conjunctivitis, blepharitis, microcornea, and corectopia. Aniridia and congenital glaucoma were not previously reported with Brachmann-de Lange syndrome.Ocular surface and anterior segment abnormalities must be considered when examining patients with Brachmann-de Lange syndrome. Ocular findings may include vision-threatening anomalies, as in our case with aniridia and congenital glaucoma. To our knowledge, these findings are previously unreported in Brachmann-de Lange syndrome.

We analyzed the metacarpophalangeal pattern profile (MCPP) of 19 individuals with Brachmann-de Lange syndrome (BDLS) and calculated a mean syndrome profile. Fourteen of 19 individuals with BDLS had significant positive correlations which indicated clinical homogeneity. Discriminant analysis of individuals with BDLS compared with a sample of normal individuals produced a correct classification rate of 100% based on a function of 2 MCPP variables that may provide a useful tool for assisting in the diagnosis of BDLS. An average pattern variability index calculated for the BDLS patients was 1.9 indicating an abnormal hand pattern in this syndrome.

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.

We report on a father and son with mild Brachmann-de Lange syndrome. Previous reports have documented apparent autosomal dominant transmission; however, only one example of male-to-male transmission of possible Brachmann-de Lange syndrome has been reported. This case provides further evidence of the existence of an autosomal dominant form of Brachmann-de Lange syndrome.

Brachmann-De Lange syndrome (BDLS, MIM No. 122470) is a well-described genetic syndrome of mental retardation and multiple congenital anomalies, with an estimated birth prevalence of 1/10,000. The authors set out to test the hypothesis that some cases of BDLS are associated with uniparental disomy for chromosome 3, especially for 3q21-qtre. The following DNA polymorphic markers were used to test for uniparental disomy:SST maps on 3q28; GLUT2 on 3q26.1-q26.3; D3S196 on 3q24-q26, D3S1101 on 3p21-cen and D3S1206 on 3q21-q24. The order of these loci in the linkage map of chromosome 3 is pter-D3S1101-cen-D3S1206-D3S196-GLUT2-SST [NIH/CEPH Collaborative Mapping Group, 1992]. All of these polymorphisms are due to dinucleotide repeats and genotypes in the families were obtained as described. In 22 families UPD3q has been excluded. Four families were not informative for the markers used. There were no families with UPD3q. The authors concluded that UPD3q is not associated with most cases of BDLS; however, this study does not exclude the possibility of UPD for a small portion of 3q, that has not been examined with the markers used.

The Brachmann-de Lange syndrome is a disorder with a high degree of clinical variability, generally associated with moderate to severe mental retardation. To date, 7 previous cases of Brachmann-de Lange syndrome with normal intelligence (IQ > 70) have been described. We report the eighth case of Brachmann-de Lange syndrome with normal intelligence. In reviewing thr literature, consistent clinical menifestations seen in these 8 patients that are of prognostic value are the absence of significant limb anomalies and birth weight > 2,500 g. © 1993 Wiley-Liss, Inc.

We report on a mother and daughter with the Brachmann-de Lange syndrome which supports the view that in some families this disorder is due to autosomal dominant inheritance. A review of the literature concerning autosomal and recessive inheritance of this syndrome is presented.

One hundred twenty-two patients with clinically confirmed Brachmann-de Lenge syndrome (BDLS) were evaluated developmentally. Recruitment was made from our genetics department and through meetings of the Cornelia de Lange Syndrome Foundation parent support group. Developmental information was obtained from records of physicians, schools and developmental centers, or from parents on each of the 122 individuals, allowing division in to four groups for study: group 1 (n = 48) underwent formal developmental assessments, which generated intelligence or developmental quotients, and had a completed parental questionnaire with specific developmental questions regarding ages of skills mastered; group II (n = 23) had additional developmental records available without formal testing, as well as the questionnaire; group III (n = 22) had a only a completed questionnaire; and group IV (n = 29) had formal developmental testing or other developmental records but no available questionnaire. These data were analyzed in order to be able to predict attainable psychomotor development. Average scores on formal testing were found to be in the mild to moderate level of mental retardation, ranging from below 30 to 85, with an average intelligence quotient of 53, higher than previously reported. Visual-spatial memory and perceptual organization skills were found to be strengths. Younger individuals born before 1980 demonstrated higher scores on testing. Early intervention appears to play a major role in the level of developmental achievement. © 1993 Wiley-Liss, Inc.

Gastroesophageal abnormalities occur with increased frequency in patients with Brachmann-de Lange syndrome (BDLS) and contribute to problems with feeding, emesis and failure to thrive. Comprehensive evaluation including longitudinal assessment of growth and development of 8 patients with BDLS was performed. Clinically significant feeding problems occurred in 6 of the 8 patients and the affected children were subsequently evaluated for gastrointestinal abnormalities. Findings in these patients included tracheal aspiration, esophageal dysmotility, gastroesophageal reflux, hiatal hernia, and esophagitis. Medical treatment was instituted where appropriate, and surgical treatment was performed if the problems did not resolve with medical treatment. Improvement in weight centiles occurred in all patients fed by nasogastric or feeding gastrostomy tube but only one patients appeared to experience increase in rate linear growth. Careful monitoring of symptoms and growth parameters, and prompt institution of appropriate medical and surgical measures can improve the health and physical outcome of many patients with BDLS. © 1993 Wiley-Liss, Inc.

Severe Mental retardation is the most handicapping disability for individuals with Brachmann-de Lange syndrome (BDLS). Reports of higher functioning patients with suspected BDLS have invariably described those with a “mild” BDLS somatic phenotype. Here we report on 2 high-functioning females, ages 3.7 and 10.6 years, with the classic BDLS somatic phenotype, i.e., all growth parameters at 4–5 standard deviations bellow the mean prenatally and postnatally. These 2 patients serve to extend the spectrum of classic BDLS to include cognitive function in the mild-to -moderate range of mental retardation. © 1993 Wiley-Liss, Inc.

The results of the clinical and radiographic study of 7 patients support the view of a unimodal and rather narrow phenotypic spectrum in the Brachmann-de Lange syndrome (BDLS) and reject the existence of a “classic” type of patient and a “mild phenotype” without upper limb defects who survive with moderate to severe mental retardation. Similarity among all patients is greater than their phenotypic differences. Strict clinical definition of the syndrome warrants easier access to the still unknown cause, most probably a single gene mutation with autosomal dominant inheritance. © 1993 Wiley-Liss, Inc.

Brachmann-de Lange syndrome (BDLS) is a relatively common multiple congenital anomaly/mental retardation syndrome, whose cause is unknown. The clinical variability of this condition is well-known. Recently some reports suggested the possible existence of a mild BDLS phenotype. We report on 30 patients in whom a diagnosis of BDLS was made or strongly suspected in 12 different Italian hospitals. Based on clinical evaluation we divided them into two groups, classical and mild BDLS cases. We compare the clinical data of these patients and we discuss the problems which arise in trying to define clear criteria of distinction between these two groups. © 1993 Wiley-Liss, Inc.

Two children with the Brachmann–de Lange syndrome and severe gastroesophageal reflux are described. Both had esophagitis, recurrent severe anemia, and one had recurrent episodes of aspiration pneumonia and clubbing. Medical treatment failed in both children. One child responded dramatically to surgery, but the other died before surgery could be attempted. Our experience and a review of the literature suggest that early recognition and surgical treatment of gastroesophageal reflux will reduce morbidity and mortality in children with this syndrome.

We report on a girl with recurrent hypoglycemia since age 2 days and severe impairment of physical and neurological development. Panhypopituitarism was recognized at age 5 months. The diagnosis of Brachmann-De Lange syndrome (BDLS) was also made. Replacement therapy has avoided further episodes of hypoglycemia, improved growth, and allowed partial psychomotor catch-up. Though we are not aware of any other report of panhypopituitarism in patients with BDLS, we suggest that hormonal derangement may play a role in the manifestations of this syndrome.