Cutaneous Manifestations of Cornelia de Lange Syndrome

Updated: Jun 02, 2022
Author: Krystyna H Chrzanowska, MD, PhD; Chief Editor: William D James, MD 


Practice Essentials

Cornelia de Lange syndrome (CDLS) is a rare but well-known multiple congenital anomaly/mental retardation (MCA/MR) disorder. Cornelia de Lange syndrome is entry 122470 in the Online Mendelian Inheritance in Man (OMIM) database for Cornelia de Lange syndrome 1 (CDLS1), autosomal dominant; 300590 for Cornelia de Lange syndrome 2 (CDLS2), X-linked; 610759 for Cornelia de Lange syndrome 3 (CDLS3), autosomal dominant; 614701 for Cornelia de Lange syndrome 4 (CDLS4), autosomal dominant; and 300882 for Cornelia de Lange syndrome 5 (CDLS5), X-linked.

The essential features of this multisystem developmental disorder include prenatal and postnatal growth retardation, distinctive facial appearance, hirsutism, various structural limb abnormalities (mostly upper), neurodevelopmental delay, and behavioral problems. In 1849 Vrolic and in 1916 Brachmann reported the first cases in the literature,[1]  describing a child at autopsy with severe growth retardation, hirsutism, and an additional finding of upper limb deficiencies. In 1933, Cornelia de Lange described 2 unrelated infant girls with mental retardation and similar dysmorphic features under the designation typus degenerativus amstelodamensis.[2]  de Lange suggested that these manifestations comprised a new malformation syndrome.

Because of their contributions, both Brachmann's and de Lange's names have been attached to the syndrome, Brachmann-de Lange syndrome (BDLS). Several hundred cases have been reported. Consensus among clinical geneticists on the phenotypic dichotomy with classic and mild cases was reached at the 12th Annual D.W. Smith Workshop on Malformations and Morphogenesis in 1991.


Mutations in 5 genes, SCC2/NIPBL, SMC1A or SMC3, RAD21, and HDAC8, coding protein components of the cohesion pathway, cause approximately 65% of Cornelia de Lange syndrome (CDLS) cases. Genetic studies have revealed that genes of this pathway, whose fundamental role is in chromosomal cohesion and coordinated segregation of sister chromatids, are also involved in gene regulation during development. As a result of these findings, CDLS has been classified into a novel category of human genetic disorders called cohesinopathies.[3, 4]

The first CDLS gene, NIPBL (Nipped-B-Like), mapped to band 5p13.1 and cloned in 2004, codes for protein delangin.[5, 6] A loss or altered function of a single NIPBL gene allele, which is consistent with a dominant pattern of inheritance, has been subsequently identified in approximately 60% of individuals (75% of patients with classical phenotype).[5, 6, 7, 8, 9, 10, 11, 12, 13, 14] A trend toward a milder phenotype is observed in persons with missense mutations compared with those with truncating mutations.[6, 11, 12, 13]

In a series of 50 NIPBL mutation–negative patients, Bhuiyan et al found one with a deletion encompassing 2 exons, 41 and 42, by multiplex ligation-dependent probe amplification (MLPA) analysis.[15] Ratajska et al found 2 patients with a classic CDLS phenotype and large genomic deletions encompassing NIPBL and some others contiguous genes.[16] Of the 162 patients with CDLS, previously negative by sequencing, deletions containing NIPBL exons were observed in 7 subjects (< 5%), which means that large NIPBL rearrangements are probably infrequent events.[17]

Olley et al identified 2 individuals with CDLS and NIPBL mutations. In both these cases, the NIPBL mutations were associated with de novo BRD4 missense mutations. Both NIPBL and BRD4 bind at superenhancers, and mutations in these genes play a dual role in cohesinopathy.107 Notably, BRD4 also plays a role in DNA repair and signaling, raising the question of whether defective DNA repair is a feature of CDLS.[110]  

Other cohesin complex genes have also been implicated, particularly in atypical and mild CDLS cases.

Mutations in SMC1A (structural maintenance of chromosomes 1A) the gene, localized on Xp11.2, were found to be responsible for the CDLS phenotype in 3 affected male siblings and in 1 sporadic case.[18] Two novel de novo mutations in this gene were identified by Borck et al in 2 boys.[19] In contrast to previous reports, Deardoff et al found 10 females among 14 total SMC1A mutation–positive patients.[20] Based on similar manifestations in affected males and females, they suggested an X-linked dominant mode of inheritance.

A single mutation in the SMC3 (structural maintenance of chromosomes 3) gene, localized on band 10q25, was found in 1 patient with a mild phenotype.[20]  A de novo mutation in SMC3, c.1942A>G, was discovered in a Chinese boy with CDLS.[106]

A genome array–based copy number analysis of 290 NIPBL -, SMC1A -, and SMC3 -negative probands led to identification of the boy with 8q21,4 microdeletion, which included the RAD21 gene. To date, only some RAD21 mutations have been identified.[21, 22]

The mutations in the X-linked gene HDAC8 ( Xq13.1) were identified as the cause of some CDLS cases. More HDAC8 -positive cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. Hemizygous males are more severely affected then heterozygous females.[23, 24]

Mutations in SMC1A, SMC3, RAD21, and HDAC8 genes contribute to approximately 5% of patients ascertained as having CDLS of the mild variant phenotype with predominant mental retardation, but the frequency remains uncertain.[20, 21, 23, 24, 25]

The etiology of a significant proportion of CDLS cases remains undetermined.

A deletion of 8p23.1 was found in a boy with CDLS characteristics and diaphragmatic hernia, and a novel candidate gene for CDLS, TANKYRASE1, mapping within a deleted segment, was proposed because of his function in regulating of a sister telomere cohesion.[26]

Parenti et al found heterozygous loss-of-function mutations in the ANKRD1 gene (16q24,3) in two patients with the clinical diagnosis of CDLS.[27]

A number of patients with CDLS were found to have one or another type of chromosomal aberration.[28, 29, 30, 31] A phenotypic overlap between CDLS and partial trisomy on band 3q26-27 was found, and it was proposed that the gene for CDLS may be located at band 3q26.3.[32] However, mutation screening for the gene in a series of CDLS individuals failed to detect patient-specific mutations.[5]

A deletion of 11q12.3-11q13.1, including the CDCA5 gene, which is a part of the cohesin pathway, was described by Boyle at al in a patient with intellectual disability and childhood facial features resembling CDLS.[33]

Most cases are sporadic, but a familial occurrence and parental consanguinity have been recorded. Autosomal dominant transmission, both maternal and paternal, has been documented in more than 25 families.[19, 34, 35] Recurrence when parents were clinically unaffected was also noted, and this has been explained by the possibility of germline mosaicism.[9, 36, 37] Paternal germline mosaicism of the NIPBL mutation was documented in analyzed sperm.[38]


Single-allele mutations at the NIPBL locus account for approximately 50-55% of affected individuals (70% with typical craniofacial phenotype), and mutations in SMC1A,SMC3, and HDAC8 locus account for a further 5% of Cornelia de Lange syndrome (CDLS) cases.[39] For details, see Pathophysiology.

Most cases are sporadic (>99% of mutations occur de novo), but familial occurrence and parental consanguinity have been recorded (< 1%). When parents are not affected, the risk of recurrence has been estimated at 1.5%; germinal mosaicism can be an explanation for unaffected parents having more than one affected child.[36] Numerous chromosomal rearrangements have been reported in patients with CDLS or a CDLS-like phenotype. Some of these rearrangements may be causative of a disease phenotype.

Genotype-phenotype correlations were analyzed in several cohorts of patients.[6, 8, 11, 12, 13, 40] In general, NIPBL mutation–positive patients were found to be more severely affected in comparison to mutation-negative patients, and a trend toward a milder phenotype is observed in persons with missense mutations in the NIPBL gene compared with those with truncating mutations.

SMC1A and SMC3 mutations are responsible for a milder craniofacial phenotype of the syndrome with moderate psychomotor delay and less visible major structural defects, including absence of severe limb defects when compared with typical CDLS. More fullness of the eyebrows and a more prominent nose were noted in SMCA1 patients.SMC1A mutation can be associated with epilepsy and epileptic encephalopathy. A milder prenatal growth retardation that worsens in childhood and a few congenital heart defects were also reported in SMC3-positive patients.[7, 20, 21, 41, 42]

RAD21 -positive persons demonstrate only minor skeletal anomalies and less distinctive facial dysmorphism.[21]

The patients with HDAC8 mutations demonstrate the classical phenotype, but without significant limb malformations. Some distinct clinical features include delayed anterior fontanelle closure, hypertelorism, hooding of the eyelids. Hemizygous HDAC8 males are more severely affected then heterozygous females.[23, 24, 43]



Estimation of the overall prevalence of Cornelia de Lange syndrome (CDLS) is difficult because of the unknown proportion of milder cases. Birth prevalence was calculated from 1 in 100,000 live births[44] to as high as 1 in 10,000 live births, when patients with either the severe or mild form were considered.[45] A population-based epidemiological study of the classic form of CDLS using the European Surveillance of Congenital Anomalies (EUROCAT) database established a prevalence for the classic form CDLS to be 1.24 cases per 100,000 births and the overall CDLS prevalence to be 1.6-2.2 cases per 100,000 births.[46]


No racial predilection is reported for Brachmann-de Lange syndrome (BDLS). One of the largest clinical surveys in the United States, by Jackson et al in 1993, included 310 Cornelia de Lange syndrome (CDLS) patients, of which black, white, Hispanic, Asian groups were represented.[36]


No sex predilection is observed for Cornelia de Lange syndrome (CDLS). In a study of 246 individuals with CDLS from 15 nations, Dowsett et al found that 49% were female.[108]


Approximately one third of children with Brachmann-de Lange syndrome (BDLS) are delivered prematurely.

The characteristic facial gestalt of classic BDLS is present at birth and changes little throughout life.[47, 48, 40]

In mild BDLS, the typical facial appearance may become obvious only after 2-3 years. In addition, the patient's face loses the characteristic appearance by adulthood, with normalization of the dimensions. The faster changes in facial features than expected for age are typical in nearly all adolescents and adults.[48, 49]

During the neonatal period, respiratory and feeding difficulties (failure to thrive) predominate.

The low-pitched cry frequently noted in the newborn period or in early infancy may disappear in late infancy.[36]

Self-injury is common in patients older than 12 years. Groves et al have noted that behavior generally worsens as individuals with Cornelia de Lange syndrome (CDLS) age, and mental health tends to decline with age.[111]

Pubertal development and fertility are normal in BDLS individuals. Control of fertility in young adult women should be considered.

Some patients with BDLS survive to adulthood; 61 years and 54 years of survival in a woman and a man, respectively, have been recorded.[44]

A detailed natural history of aging in CDLS based on longitudinal follow-up observations of 49 patients has been presented by Kline et al.[40]


The prognosis for patients with the mild form of Cornelia de Lange syndrome (CDLS) is much better than that for patients with the classic form. Life expectancy is generally normal; patient survival to adult age is recorded. Most recorded deaths occur in infancy, and they mostly happen in severely affected individuals. Aspiratory pneumonia or apnea, cardiac defects, and/or GI anomalies are reported as the most frequent direct causes of death.

Patients with Brachmann-de Lange syndrome (BDLS) have a slightly elevated mortality rate. The most frequent direct causes of death are pneumonia, cardiac malformations, and GI malformations. Most recorded deaths (approximately two thirds) occur during the first year of life or in the following 2 years, and most deaths occur in patients with severe disease. The sudden deaths are strongly connected with GI complications, namely ileus.[36, 44, 50]

Patient Education

The patient's education level depends on the intellectual potential. Incidental attendance of children with Brachmann-de Lange syndrome (BDLS) to normal schools is reported,[51] but, in general, children need special education and care.[40, 52]




Patient history

The course of pregnancy and delivery offer clues. Preterm delivery is noted in approximately 30% cases.

Retardation of growth is often profound and of prenatal onset.[40, 52, 53]

The difficulties in weight and height gain persist in the postnatal period as a result of feeding difficulties

Sucking and swallowing problems and an inability to take an appropriate amount of food for age in the first months of life result in failure to thrive.

Recurrent respiratory tract infections, hyperactivity, nocturnal agitation, and behavioral problems may be atypical manifestations of gastroesophageal reflux (GER).

A diminished responsiveness to pain has been reported and was found to be associated both with mental retardation and with autism; it might contribute to self-injury behaviors.

Psychomotor development and behavioral findings

Most affected individuals with the classic phenotype have moderate-to-profound mental retardation.[40, 54]

Borderline-to-mild deficiency is usually observed in patients who are mildly affected; near-normal intelligence has occasionally been recorded.[45, 40, 51]

The cognitive profile is characterized by lack of or delayed verbal communication, with specific deficits in expressive language; receptive language and verbal comprehension are less affected. Expressive language is not reached by a significant number of subjects; those who acquire verbal language do so late.[55, 56] Visuospatial memory and perceptual organization are usually normal.

The behavioral manifestations include a wide spectrum of symptoms, such as abnormal emotional response, sleep disturbances, daily aggression and hyperactivity, poor relationship abilities, stereotypies, rigidity, autism, and self-injury. Activities of daily living are significantly affected with aggression and hyperactivity. Communication and socialization deficits can deteriorate in adulthood.[40, 57, 58, 59, 60, 61, 56, 62, 63]

Physical Examination

Cornelia de Lange syndrome (CDLS) is a highly variable multiple congenital anomaly/mental retardation (MCA/MR) syndrome, ranging from perinatal lethality with multiple malformations, including severe upper limb deficiency, to a degree of mildness compatible with reproduction and near-normal intellect. Diagnosis is based on the characteristic phenotype, in particular a striking facial gestalt, prenatal and postnatal growth retardation, various skeletal abnormalities, hypertrichosis, and developmental delay.[36, 48, 40, 64]

The phenotypic dichotomy, classic and mild cases, is now well established. The prognosis for patients with the mild phenotype is much better than that for patients with the classic form.[36, 48, 49, 65] A diagnostic scoring system for severity in CDLS has been proposed.[52]

The following is a classification system based on the clinical variability in CDLS:

  • CDLS type I (classic): Patients have the characteristic facial and skeletal changes, a prenatal growth deficiency that is progressive postnatally, moderate-to-profound psychomotor retardation, and major malformations resulting in severe disability or death.

  • CDLS type II (mild): Patients have facial and minor skeletal abnormalities similar to those seen in type I; however, they are distinguished by less severe psychomotor retardation and milder growth deficiency. The prognosis is more optimistic, but, paradoxically, behavior dysfunction may be more evident.

The following craniofacial characteristics are unique and of great diagnostic value:

  • Microbrachycephaly: The average head circumference remains less than the second percentile throughout life.

  • Low frontal hairline

  • Well-defined, arched "pencilled" eyebrows

  • Synophrys

  • Long, curly eyelashes

  • Short nose with anteverted nares

  • Triangular nasal tip

  • Long philtrum

  • Crescent-shaped mouth

  • Thin lips

  • Widely spaced (late-erupting) teeth

  • Micrognathia

  • Low-set and posteriorly rotated ears

See the images below.

Case study 1. Classic de Lange phenotype is shown. Case study 1. Classic de Lange phenotype is shown. Facial characteristics of a 10-month-old girl are pictured. Note well-defined eyebrows with synophrys, depressed nasal bridge, and long smooth philtrum.
Case study 1. Lateral facial profile is pictured. Case study 1. Lateral facial profile is pictured. The eyebrows are neat, arched, and well defined. The nasal bridge is depressed, and the nares are upturned.
Case study 1. The patient, aged 5 years, is shown; Case study 1. The patient, aged 5 years, is shown; note microbrachycephaly, well-defined eyebrows, anteverted nares, long and thin upper lip, down-turned angles of mouth, and widely spaced teeth.
Case study 1. Upper limb reduction anomalies are p Case study 1. Upper limb reduction anomalies are pictured with only 2 fingers present.
Case study 1. Note short hypoplastic fifth finger. Case study 1. Note short hypoplastic fifth finger.
Case study 1. Small feet with short hypoplastic to Case study 1. Small feet with short hypoplastic toes and syndactyly of the second and third toes is pictured.

Growth retardation

Retardation of growth, often of prenatal onset, is one diagnostic criterion for CDLS that can also help to discriminate classic cases from mild cases.[53, 65, 66] Profound prenatal growth deficiency (>2.5 standard deviations below the mean for gestation) becomes more severe postnatally (>3.5 standard deviations below the mean) and is characteristic for classic (type I) CDLS. Birth weight greater than 2500 g and less marked postnatal growth deficiency may help to classify a patient as having mild (type II) CDLS.

Growth persists below the normal curves in most of the patients throughout life.

Height velocity is equal to the reference range, and weight velocity is below the reference range throughout life until adolescence.

Skeletal abnormalities

Skeletal abnormalities characteristic for classic CDLS include major longitudinal reduction abnormalities of the upper limbs, including hypoplastic or absent ulnas and/or oligodactyly (which, if bilateral, can be asymmetric). This abnormality is not observed in persons with mild CDLS.[36, 65]

Severe malformations of the lower limbs are less common than upper limb anomalies. The limb findings in 378 individuals with CDLS presented by Mehta et al demonstrate a consistent pattern of laterality and symmetry involvement, and with increased severity of the right-side in individuals with asymmetric limb defects.[67]

Most patients have relatively small hands, feet, or both.

Limitation of extension at the elbows with accompanying radiological characteristics may help with the diagnosis because they are not frequently observed.

Other minor variable anomalies, such as shortened fourth metatarsal, clinodactyly, single palmar crease, digits hypoplasia, proximal placement of the thumb(s), and syndactyly of toes 2 and 3 are frequently observed in many other syndromes or in healthy individuals; therefore, they are of limited diagnostic aid.

Cutaneous manifestations

Common cutaneous manifestations include hypertrichosis in the form of synophrys, long eyelashes, and hirsutism on the back.[36, 48]

Cutis marmorata is noted in CDLS patients.

Hypoplastic nipples and umbilicus are observed most commonly in persons with the classic type and are observed less frequently in those with the mild phenotype.

Multiple capillary or cavernous hemangiomas are occasionally reported; these hemangiomas may cause the observed thrombocytopenia that is reported, most likely occurring as a result of a slow, consumptive coagulopathy.[47, 68, 69, 70]

Multiple pigmented nevi were observed incidentally.[71]

Ulerythema ophryogenes was reported in a 17-year-old girl with Brachmann-de Lange syndrome (BDLS).[72]

See the images below.

Case study 2. Mild de Lange syndrome is shown. The Case study 2. Mild de Lange syndrome is shown. The face of a 1.5-year-old girl is pictured. Note neat eyebrows with delicate synophrys, long eyelashes, depressed nasal bridge, upturned nares, long philtrum, thin upper lip, and small chin.
Case study 2. Lateral facial profile shows depress Case study 2. Lateral facial profile shows depressed nasal bridge, thin upper lip, and small mandible.
Case study 2. The patient, aged 8 years, is shown; Case study 2. The patient, aged 8 years, is shown; note delicate synophrys of the eyebrows, upturned nares, long philtrum, and thin upper lip.
Case study 2. Lateral facial profile of the patien Case study 2. Lateral facial profile of the patient, aged 8 years, is shown.
Case study 3. de Lange syndrome patient. Six-year- Case study 3. de Lange syndrome patient. Six-year-old patient with HDAC8 mutation. Some distinct clinical features such as hypertelorism and hooding of the eyelids are more characteristic for this type of mutation.

GI problems

GI problems occur with high frequency, and they contribute to feeding difficulties and failure to thrive.[36, 73, 74, 75]

Pyloric stenosis is the most frequent cause of persistent vomiting in the newborn period.

GER and its sequelae are thought to be the most underappreciated medical problems in persons with BDLS. Approximately two thirds of children are first seen with clinical signs that might be referred to this area.[76, 75, 77]

Pathological GER was found in 65% individuals. Silent GER can cause esophageal damage and symptoms of pulmonary congestion and irritation due to chemical pneumonitis.[36, 74, 75]

The most severe complications of GER include Barrett esophagus and the Sandifer complex, which is characterized by torticollis, opisthotonus, and paroxysmal dystonic posture.[40, 77, 78]

Two other GI-related problems are intestinal malrotation with volvulus[79] and congenital diaphragmatic hernia.[80, 81] The latter anomaly might be more common than initially realized.

Omphalocele was reported in one patient.[82]

Constipation occurs in 30% of patients, more often in adolescence and adulthood.

Gallstones are not so rare in CDLS children and adults.

The occurrence of sudden death caused by peritonitis has been noted.

Cardiovascular problems

Cardiovascular problems in the form of congenital heart malformations are diagnosed in approximately 14%-70% of children. Most common are ventricular and atrial septal defects, pulmonic stenosis, and ventricular septal defect; various other anomalies occasionally occur.[36, 61, 83]

Respiratory problems

Most respiratory problems are probably initiated and/or complicated by undetected GER. Upper respiratory tract infections and pneumonias are reported in 25% of individuals. Severe complications due to bronchopulmonary dysplasia have also been described. Choanal atresia was diagnosed at birth in 3 children. Cleft palate occurs in 30% of patients.

Hearing problems

Hearing problems occur frequently.[36] Hearing deficits from mild to severe may be present in 60-100% of all CDLS patients. Stenosis of the external auditory canals is found in 80% of examined children. Hearing aids are poorly tolerated.

Ophthalmologic problems

Ophthalmologic problems occur in a high proportion of children with CDLS.[40, 84, 85, 86] Myopia was reported in 60% of patients, ptosis in 45%, nystagmus in 37%, microcornea in 21%, and nasolacrimal duct obstruction in 16%. Chronic blepharitis is a frequent complication. Glasses are poorly tolerated.

Other problems

Urinary tract anomalies are common and include hydronephrosis, urethral reflux, subcortical renal cysts, and renal dysplasia or hypoplasia.[12, 87]

There is a significant rate of autonomic neuropathy among patients with CDLS.[113]

Male hypogonadism and cryptorchidism are present in more than half the boys.[36, 76]

Seizures are reported in 23-26% of individuals.[36, 40, 88]

Heat intolerance and absence of pain sensation have been observed in several patients.[36]

One described patient had rosacea, most likely an incidental finding.[89]

Chronic ear infections, respiratory infections (mostly viral), and sinus infections are common in CDLS patients, although immunologic tests revealed rather normal results.[61]



Differential Diagnoses



Laboratory Studies

When the diagnosis of Cornelia de Lange syndrome (CDLS) is considered, a standard karyotypic analysis is recommended, even though it is expected to be normal. The following genetic tests are recommended to verify a clinical diagnosis:

  • Molecular analysis of the NIPBL gene allows confirmation of a disease-causing mutation in a proportion of cases (approximately 50%), and it provides the basis for prenatal diagnosis in families with parental transmission or proven paternal gonadal mosaicism.[5, 6, 8, 9, 10, 11, 12, 13, 19] To find a genetics or prenatal diagnosis clinic, see the Laboratory Directory at GeneTests.

  • In NIPBL mutation–negative patients, sequence analysis of the SMC1A,SMC3, RAD21, and HDAC8 genes allows identification of the mutation in 5% of probands.[18, 20, 21, 23, 24, 43]

  • Large genomic rearrangements in NIPBL occur infrequently, but they can be detected by using multiplex ligation-dependent probe amplification (MLPA).[8, 16, 17]

  • If molecular test results are negative, a genome-wide array comparative genomic hybridization (array-CGH) is worthwhile to identify copy number alterations[90] ; high-resolution chromosomal analysis can delineate cases of chromosomal aberrations with phenotypic overlap with CDLS.

Endocrinologic studies are warranted in patients with severe growth retardation.[52, 53, 91]

Periodical evaluations, including routine blood cell counts, iron metabolism testing, liver and renal function tests, urinalysis, and a search for stool blood, are recommended, especially in first years of life. Anemia (normochromic or hypochromic) may occur as a consequence of GI problems such as malnutrition or recurrent episodes of pneumonia. Thrombocytopenia, most probably related to cavernous or capillary hemangiomas, has occasionally been reported.

Imaging Studies

In Cornelia de Lange syndrome (CDLS), skeletal radiography may help increase diagnostic precision. A high incidence of microcephaly, various distal limb defects, a dislocated and/or hypoplastic radial head, and delayed ossification are stressed. Chest anomalies often involve a short sternum with premature fusion and the occurrence of 13 pairs of ribs. Pattern profiles commonly show shortness of the first metacarpal and fifth distal phalanx.[92, 67]

Barium esophagography under fluoroscopic control may allow demonstration of hiatal hernia, gastroesophageal reflux (GER), and esophageal dysmotility.[73, 75, 77, 80, 92]

Gastric scintigraphy can also be used to document GER.

Temporal bone CT scanning could document combined structural abnormalities of the external, middle, and inner ear. Kim et al found good correlation of CT abnormalities with the audiometric results.[93]

Echocardiography can be used for imaging structural heart abnormalities.

Assessment of gallbladder and assessment of the genitourinary system may require abdominal ultrasonography or radiologic examination, such as urography or cystoureterography.

Other Tests

Ear examination and hearing assessment are strongly recommended for all children as soon as possible. Hearing deficits frequently occur in patients with Brachmann-de Lange syndrome (BDLS) and are related to the significant developmental and speech delays that are experienced in many of the children. Specific testing appropriate for individuals with mental retardation is required; such testing includes brain-evoked response audiometry (BERA).[36]

Ophthalmologic examination is important in early care of the child. Myopia is common, but glasses are often poorly tolerated.

EEG is recommended in patients with seizures.

Esophagoscopy with biopsy is a superior diagnostic technique for evaluation of GER, and it may reveal the presence of Barrett esophagitis. The severity and frequency of reflux can be documented by using continuous pH monitoring in the distal esophagus or by using apnea evaluations with the thermistor oxygenation pneumocardiography.[73]

Assessment of the growth rate with serial anthropometric measurements of height, weight, and occipitofrontal circumference is recommended. Specific growth charts for Cornelia de Lange syndrome (CDLS) individuals have been developed and are available on the CdLS-USA Foundation Web site.

Evaluation of symptoms of autistic disorder has been made mostly by means of the Child Autism Rating Scale (CARS), Autism Diagnostic Observation Schedule (ADOS), and Autism Diagnostic Interview-Revised (ADI-R) tools.[55]

Histologic Findings

Postmortem examination has revealed various congenital malformations of the internal organs, including cardiac defects, pulmonary hypoplasia, diaphragmatic hernias, GI anomalies, and genitourinary anomalies.[44, 87] Microscopy of the internal organs has shown no consistent abnormalities. Microcytic changes of the kidney have been observed in some individuals.[65] Histological examination of the brain has demonstrated neuronal heterotopias in the cerebellum and ectopic neurons in the cerebral white matter in one newborn.[65] A detailed neuropathologic analysis of a 35-year-old patient has revealed abnormal convolution patterns of the cerebral gyri and frontal lobe hypoplasia.[94]



Medical Care

A review of management and treatment for Cornelia de Lange syndrome (CDLS) has been published by FitzPatrick and Kline,[95] and management recommendations for older individuals have been reported.[40] Most comprehensive anticipatory guidance includes detailed clinical evaluation at the time of diagnosis, and assessment of different age groups until adulthood.[52]

The results of medical therapy are better in infants than in older children.

Patients with symptoms of gastroesophageal reflux (GER) require intensive medical therapy. Frequent use of antacids, histamine-2 blockers, and metoclopramide can be helpful.[96] Feeding by a nasogastric tube and by having the patient sit upright may be beneficial.

Application of appropriate hearing aids is recommended in children with hearing deficits, although tolerance is poor.

Antiepileptic treatment may be required in a proportion of patients.

Psychoeducational and cognitive-behavioral interventions have been strongly recommended. Clinicians should consider autistic features and refer for further psychological and psychiatric evaluation in order to expedite appropriate intervention.[56]

Surgical Care

During anesthesia, special attention should be given to the risk of malignant hyperthermia (with use of halothane and nitrous oxide), hyperactive airway resulting in bronchospasm, anatomical abnormalities, drug sensitivity, convulsions, and cardiac arrhythmia, because these complications have been reported in children with Cornelia de Lange syndrome (CDLS).[97, 98, 99] Propofol and sevoflurane are recommended most often, because after ketamine, hyperreactivity was noted not infrequently.[99] Endotracheal intubation in this group is associated with an increased risk of complications.[98]

Operative procedures, including Nissen fundoplication and gastrostomy tube (G-tube) placement for feeding, may be necessary in patients with severe esophagitis and in those with worsening failure to thrive despite conservative intervention.

Surgical repair may also be indispensable in patients with diaphragmatic hernia, cardiac defects, or severe skeletal deformities.


Patients may require various specialist consultations, depending on the clinical manifestations and the physical examination findings. Specialists may include the following:

  • Gastroenterologist

  • Cardiologist

  • Pulmonologist

  • Laryngologist/audiologist

  • Ophthalmologist

  • Neurologist

  • Nephrologist/urologist

  • Endocrinologist

Genetic counseling provides families with information on the nature of the disease and the low risk of recurrence. Careful clinical examination of the parents for minor signs is recommended because autosomal dominant inheritance has been implicated in some families (see Prevention).


In general, children with Cornelia de Lange syndrome (CDLS) have difficulty accepting sudden changes in their daily routine and environment.

Activities that stimulate the vestibular system, including swinging, bouncing, swimming, and horseback riding, are pleasurable to the patient.

The use of sign language can help the patient to overcome frustration caused by expressive speech delay.


Genetic counseling and prenatal diagnosis may be offered.

Most cases are sporadic (>99%) and are caused by de novo mutations.

In families with parental transmission of the disease (< 1%), an autosomal dominant or an X-linked dominant mode of inheritance is possible.

In the case of an autosomal dominant mutation in the NIPBL or RAD 21 gene, the risk of transmitting the mutation to offspring is 50%; males and females are affected equally.

In the case of an X-linked dominant mutation in the SMC1A or HDAC8 gene, the risk of transmitting the mutation to offspring is also 50%; however, the affected female will pass the mutation to half of her daughters and sons, and the affected male will pass the mutation to all of his daughters but not to sons.

When parents are not affected, the risk of recurrence has been estimated at 1.5% (germinal mosaicism).[36, 38]

Prenatal diagnosis is possible in families at increased risk of recurrence for Cornelia de Lange syndrome (CDLS), if the mutation (in the NIPBL,SMC1A,SMC3, RAD21, or HDAC8 gene) is precisely identified in the proband before pregnancy. See Lab Studies and the Laboratory Directory at GeneTests.

Ultrasonographic screening for evidence of the manifestations of the syndrome (ie, intrauterine growth retardation, limb defects, diaphragmatic hernia, nuchal translucency) may be helpful.[80, 81, 100, 101, 102] Nuchal translucency has been observed in 46-70% of cases.[103]

A second trimester maternal serum pregnancy-associated plasma protein-A (PAPP-A) measurement may have predictive value as an addition to ultrasonography.[104, 103]

Detection of a mild form of Brachmann-de Lange syndrome (BDLS) using 3-dimensional ultrasonography combined with 3-dimensional computed tomography has been reported.[105]

Long-Term Monitoring

Associated developmental abnormalities and disabilities determine further outpatient care.

A systematic auxology evaluation of growth rate using the specific growth chart is recommended. Specifically, this should include standard growth curves for weight, height, and head circumference from birth through adulthood based on serial measurements of patients with clinically confirmed diagnoses of Cornelia de Lange syndrome (CDLS). Ear examination and hearing assessment are recommended for all children every 2-3 years. See the CdLS-USA Foundation website.



Guidelines Summary

In 2018, the International CdLS Consensus Group published a consensus statement on the diagnosis and management of Cornelia de Lange syndrome.[112]