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Cornelia de Lange Syndrome

Overview

Cornelia de Lange syndrome (CdLS) is a multiple malformation syndrome consisting of characteristic facial features (well-defined eyebrows that meet in the midline, short upturned nose, and thin downward-turning lips), developmental delay/intellectual disability, behavior problems, low birth weight, slow postnatal growth, hirsutism, and other malformations. The diagnosis of CdLS syndrome is made clinically. Details can be found in the Diagnostic Criteria section below.

Other Names & Coding

Brachmann-de Lange syndrome Cohesinopathy De Lange Syndrome
ICD-10 coding

Q87.1, Congenital malformation syndromes predominantly associated with short stature

See ICD-10 for Congenital Malformation Syndromes Associated with Short Stature (icd10data.com) for further coding details.

Prevalence

The prevalence of CdLS has been estimated to be between 1:10,000 and 1:100,000. [Pearce: 1967] [Opitz: 1985] A more recent study in Europe estimated it at 1:50,000, but it may have missed individuals with the milder, more common phenotype. [Barisic: 2008]

Genetics

CdLS is a sporadic occurrence in nearly all cases. Mutations in 7 genes (NIPBL, SMC1A, SMC3, Rad21, HDAC8, ANKRD11 and BRD4) are known to cause CdLS, although mutations in the known genes account for only approximately 85% of cases diagnosed clinically. Mutations in NIPBL tend to cause more typical clinical and facial findings. In an individual with more severe congenital anomalies, it is more likely to find a mutation in NIPBL than the other genes. Mutations in SMC1A, SMC3, and HDAC8 can lead to severe cognitive deficits, but cause fewer congenital malformations and less typical facial features. Mutations in RAD21 lead to milder cognitive and structural involvement. Mutations in ANKRD11 cause a milder clinical phenotype as well, with less effect on growth. Mutations in BRD4 cause a more typical picture.
Gene mutations causing CdLS affect proteins originally identified to be involved in cohesion of sister chromatids (sister chromatids are chromatids located on the same chromosome). More recently, these proteins have also been shown to regulate gene expression and transcription. CdLS is considered to be one of the emerging class of disorders called "disorders of transcription regulation," and some of the clinical findings overlap with those in CdLS and other disorders with mutations in cohesin. [Olley: 2018] [Parenti: 2016] [Dorsett: 2009] [McNairn: 2008] [Liu: 2009] [Deardorff: 2012] [Deardorff: 2012]

Prognosis

Most children with CdLS have some intellectual disability and will often need supervised living and working situations as adults. (See the Portal's module on Intellectual Disability & Global Developmental Delay for diagnosis and management information.) Most children with CdLS live to adulthood, although a small percentage die earlier due to (in order of frequency): respiratory causes including aspiration/reflux and pneumonia, gastrointestinal disease including obstruction/volvulus, and congenital anomalies such as diaphragmatic hernia and heart defects.

Practice Guidelines

Kline AD, Moss JF, Selicorni A, Bisgaard AM, Deardorff MA, Gillett PM, Ishman SL, Kerr LM, Levin AV, Mulder PA, Ramos FJ, Wierzba J, Ajmone PF, Axtell D, Blagowidow N, Cereda A, Costantino A, Cormier-Daire V, FitzPatrick D, Grados M, Groves L, Guthrie W, Huisman S, Kaiser FJ, Koekkoek G, Levis M, Mariani M, McCleery JP, Menke LA, Metrena A, O'Connor J, Oliver C, Pie J, Piening S, Potter CJ, Quaglio AL, Redeker E, Richman D, Rigamonti C, Shi A, Tümer Z, Van Balkom IDC, Hennekam RC.
Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement.
Nat Rev Genet. 2018. PubMed abstract

Roles of the Medical Home

Individuals with CdLS need surveillance throughout their lives. The medical home will need to coordinate screenings (listed below) and provide support for gastrointestinal issues, behavioral issues, and more. The medical home should refer to subspecialists as needed, balancing the need for more information with the difficulty and expense of additional appointments. If the medical home clinician is not comfortable in this role, consider periodic referrals to genetics for guidance.
Children with CdLS and their families can access specialists familiar with the syndrome at various CdLS Foundation events, including the Biennial Conference (CdLS Foundation). The foundation also supports CdLS Multidisciplinary Clinics (CdLS Foundation) in Philadelphia, and a multidisciplinary clinic for adolescents and adults held in Maryland, a clinic in St Louis, MO, and a clinic through the Shriner’s Hospital in Salt Lake City, Utah. Transitioning the child from pediatric care and the school system to the adult world should begin by age 12. Plans for job training and work placement should begin early in high school so they are in place when needed.

Clinical Assessment

Overview

Children with CdLS will need ongoing assessment in a number of areas, including:
  • Growth
  • Development
  • Speech/language
  • Hearing, at diagnosis and every few years
  • Vision, at diagnosis and annually
  • Gastrointestinal, for malformation risk and gastroesophageal reflux disease (GERD)
  • Genetics, particularly if parents are contemplating additional children
  • Dental
  • Behavior

Pearls & Alerts for Assessment

Gastroesophageal reflux is nearly always present

Consider an evaluation if there are frequent episodes of distress, irritability, and/or arching. Other signs of GERD include vomiting, weight loss or failure to gain expected weight, food refusal, dysphagia (difficulty swallowing), and/or hematemesis (vomiting of blood). It is recommended to screen everyone for this at diagnosis.

Consider obstruction

Because intestinal volvulus is relatively common in children with CdLS, acute abdominal pain, abdominal distention, and/or bilious emesis should prompt immediate evaluation for obstruction. If a child is gastrostomy tube dependent and there are significant feeding difficulties or high-volume gastric fluid output, obstruction should also be considered. Families should be given information about this potential problem.

Sudden changes in behavior or unusual body movements may be a sign of reflux

The appearance or recurrence of severe esophageal reflux or reflux esophagitis may cause changes in behavior such as crying, an increase in self-injurious behavior, refusal to eat, or unusual posturing movements of the head and neck (Sandifer syndrome).

Decreased but predictable growth

Children with CdLS have decreased growth but should follow a predictable pattern. Plotting height, weight, and head circumference on CdLS-specific growth charts (see Developmental Skills Chart (CdLS Foundation) (PDF Document 98 KB)) may be helpful. If children stray markedly from their usual pattern or these charts, consider other problems, such as decreased thyroid or growth hormone levels.

Middle ear effusion is common in children with CdLS

Middle ear effusion and sensorineural hearing loss are both observed. Consider an ENT evaluation if a middle ear effusion is present since this may be causing hearing loss in children who already have delays in speech and language.

Screening

For Complications

Recommended screenings include:
  • Gene testing at diagnosis to confirm the molecular basis should be considered
  • Echocardiogram
  • Renal ultrasound
  • Upper GI barium study to rule out malrotation and to assess for GERD
  • Audiology assessment
  • Ophthalmologic examination

Presentations

As more is learned about individuals with CdLS, it has become evident that both milder and more severe phenotypic forms of the syndrome exist. [Kline: 2007] [Allanson: 1997] More severe phenotypes are likely to have low birth weights; milder phenotypes may remain undiagnosed throughout life. Phenotype can also change with age.
Newborn with Cornelia de Lange Syndrome in a blanket
Child with CdLS wearing a hoodie and smiling at the camera
woman with CdLs looking at camera
Photos courtesy of the Cornelia de Lange Syndrome Foundation.

Diagnostic Criteria

Diagnostic criteria for CdLS from Diagnosis of CdLS (Cornelia de Lange Syndrome Foundation):
  1. Positive pathogenic mutation on CdLS gene testing, OR
  2. Nine or more points of which at least 2 are from the cardinal features (facial findings, diaphragmatic hernia, or oligodactyly) and the rest from either cardinal or suggestive features (developmental delay, growth retardation, microcephaly, small hands and/or feet, hirsutism, and brachydactyly 5th finger)
Facial features:
  • Synophrys (eyebrows that meet at the midline) and/or thick eyebrows
  • Long eyelashes
  • Short nose with concave nasal ridge (area and upturned nasal tip)
  • Long, prominent, protruding or smooth philtrum (area between upper lip and nose)
  • Broad or depressed nasal bridge
  • Small chin, may appear more square in adolescence or adulthood
  • Thin upper lip, or down-turned corners of mouth
  • High or cleft palate
  • Widely spaced or absent teeth
Other criteria:
  • Growth: 2 or more of the following:
    • Weight below 5th percentile for age
    • Height/length below 5th percentile for age
    • Head circumference below 5th percentile for age
  • Development: 1 or more of the following:
    • Developmental delay or intellectual disability
    • Learning disabilities
  • Behavior: 2 or more of the following:
    • Attention deficit disorder with hyperactivity or constant roaming
    • Obsessive-compulsive characteristics
    • Anxiety
    • Aggression
    • Self-injurious behavior
    • Extreme shyness or withdrawal
    • Autistic features
  • Musculoskeletal:
    • Limb deficiencies with missing hands or forearms
    • Small hands and feet and/or oligodactyly (missing digits)
    • 5th finger clinodactyly (curved 5th finger)
    • Abnormal palmar crease
    • Radial head dislocation/abnormal elbow extension
    • Short 1st metacarpal/proximally placed thumb
    • Bunion
    • Partial 2,3 syndactyly (webbing between 2nd and 3rd toes)
    • Scoliosis (curvature of the spine)
    • Pectus excavatum (chest or sternum deformity)
    • Hip dislocation or dysplasia
  • Neurosensory/Skin:
    • Ptosis (droopy eyelid)
    • Tear duct malformation or blepharitis (inflammation of eyelid)
    • Myopia (-6.00 D or more)
    • Major eye malformation or peripapillary anomaly
    • Deafness or hearing loss
    • Seizures
    • Cutis marmorata (mottled appearance to skin)
    • Hirsutism, generalized (excessive body hair)
    • Small nipples and/or umbilicus
Other major systems:
  • Gastrointestinal malformation/malrotation (approximately 10% of children with CdLS syndrome ) [Deardorff: 2016]
  • Diaphragmatic hernia (approximately 1% of children with CdLS syndrome ) [Deardorff: 2016]
  • Gastroesophageal reflux disease or GERD (majority of children with CdLS syndrome ) [Deardorff: 2016]
  • Cleft palate or submucous cleft palate
  • Micropenis
  • Hypospadias (abnormally placed opening of urethra on penis)
  • Cryptorchidism (undescended testes)
  • Renal or urinary tract malformation (approximately 12% of children with CdLS syndrome ) [Deardorff: 2016]

Differential Diagnosis

The facial features of children with CdLS are notable and quite consistent. The face, in addition to growth restriction, delayed development, and associated malformations, will usually lead to a correct diagnosis. Individual elements of the physical exam in children with CdLS may be observed in children with many different syndromes, as illustrated in the following examples:
  • Upper limb deformities are present in children with Roberts syndrome.
  • Hirsutism and small stature are seen in individuals with Rubinstein-Taybi syndrome.
  • Developmental, behavioral, and growth abnormalities are observed in children with fetal alcohol syndrome.
  • Developmental delay, behavioral disturbance, and sleep dysfunction are typically present in children with Smith-Magenis syndrome.
  • Microcephaly and autism-like features are observed in girls with Rett syndrome.
  • Growth restriction is observed in many syndromes.

History & Examination

Current & Past Medical History

Ask about growth and feeding problems. Pay particular attention to symptoms that might suggest gastroesophageal reflux (GERD), such as food refusal, abdominal pain, dental abnormalities, vomiting, and weight loss.

Family History

Family history is usually negative. Approximately 1% of families can have a second child with CdLS, although this varies based on which gene is causing CdLS in the child.

Pregnancy/Perinatal History

Ask about prenatal growth and birth weight. PAPP-A may be low on first-trimester screening. Ultrasound findings can be helpful, particularly facial profile and presence of intrauterine growth retardation.

Developmental & Educational Progress

Ask about developmental delays, paying particular attention to speech/language milestones. Be alert to slowing of the developmental trajectory and behavior problems that may arise as the child approaches adolescence. Ask families to bring early intervention and school progress reports. See Developmental Skills Chart (CdLS Foundation) (PDF Document 98 KB) for expected developmental milestones for children with CdLS.

Social & Family Functioning

Explore family financial and social resources. Assess social functioning of the child and family. Behavior problems may appear suddenly or worsen in adolescence.

Physical Exam

Some of the more common physical exam characteristics are listed below. There are many more that are less common. Children with CdLS may also have various cardiac abnormalities, renal and genital malformations, gastrointestinal malformations, and diaphragmatic hernia.

General

Autistic features, hyperactivity, anxiety, self-injurious behavior, and developmental delays may be present.

Growth Parameters

Weight, height/length, and head circumference below 5th percentile for age. See Growth Charts for Boys (CdLS Foundation) (PDF Document 874 KB) and Growth Charts for Girls (CdLS Foundation) (PDF Document 1.4 MB).

Skin

Look for mottling (cutis marmorata) and hirsutism.

HEENT/Oral

Look for synophrys, long eyelashes, short nose, upturned nasal tip, long and/or smooth philtrum, broad nasal bridge, concave nasal ridge, small chin, thin upper lip, with downturned corners, widely spaced or absent teeth, high or cleft palate, ptosis, myopia, blepharitis. Strabismus, nystagmus, and abnormal gaze behaviors are sometimes seen. Look for middle ear fluid. Sinusitis and nasal polyps may occur. Abnormalities of the inner ear may be observed on CT scan of temporal bone. Look for caries, enamel erosion, and discolored teeth as well as missing teeth, delayed tooth eruption, and delayed loss of primary teeth.

Chest

Pectus excavatum may be present.

Genitalia

Examine for undescended testicles in males, as well as hypospadias or micropenis (small penis). Females can have bicornuate uterus.

Extremities/Musculoskeletal

Upper limb deformities (significant in approximately 25%), small hands and feet, clinodactyly, abnormal palmar creases, incomplete extension of elbows, and webbing between 2nd and 3rd toes are often present. Assess for scoliosis and dislocated hips. Evaluate for contractures, especially ankles.

Testing

Sensory Testing

Refer for ophthalmological and audiological testing annually or as indicated. Infants with CdLS often experience improvement in their hearing over time.

Genetic Testing

May be ordered by the geneticist.

Other Testing

  • Evaluate or re-evaluate for GERD, when indicated, with EGD or esophageal pH probe. Evaluation information can be found at Gastroesophageal Reflux Disease.
  • Consider dual-energy X-ray absorptiometry (DXA) or bone densitometry for osteoporosis in adolescents with CdLS. See Osteoporosis and Pathologic Fractures.
  • Consider a modified barium swallow study (MBS) to rule out malrotation, as well as primary or secondary aspiration, in children with poor weight gain, oral aversion, coughing or choking with eating, and/or other feeding difficulties.
  • Speech/language assessments periodically

Specialty Collaborations & Other Services

Medical Genetics (see MT providers [8])

Periodic consultations may be helpful for genetic testing, education regarding screening, family planning, and other topics.

Pediatric Gastroenterology (see MT providers [15])

Consultation is recommended for reflux management, growth, and nutrition.

Developmental - Behavioral Pediatrics (see MT providers [8])

Referral may be helpful for overseeing developmental achievements, managing behavior issues, and overseeing educational progress.

Speech - Language Pathologists (see MT providers [55])

Refer for periodic assessments.

Treatment & Management

Pearls & Alerts for Treatment & Management

Provide critical care information

Provide family with information for care in the event of a medical emergency. Include a medical alert card regarding sometimes misdiagnosed problems in children with CdLS. See Critical Care Information (CdLS Foundation) for more information and a printable medical alert card.

Importance of speech/language therapy

Most individuals with CdLS, even those that develop the ability to speak in sentences, are delayed in speech-language acquisition; consider early speech/language therapy.

Growth hormone

Families may ask about the use of growth hormone for their child's small stature. Growth hormone has not been shown to be effective in CdLS except in children who also have growth hormone deficiency. See Growth Hormone in Children with CdLS (CdLS Foundation).

How should common problems be managed differently in children with Cornelia de Lange Syndrome?

Growth or Weight Gain

Condition-specific growth charts should be used to follow growth. See Growth Charts for Boys (CdLS Foundation) (PDF Document 874 KB) and Growth Charts for Girls (CdLS Foundation) (PDF Document 1.4 MB).

Development (Cognitive, Motor, Language, Social-Emotional)

Specific charts for CdLS should be used to follow development. See Publications about CdLS (CdLS Foundation).

Common Complaints

Some individuals with CdLS have crying episodes for no apparent reason. Physical causes such as gastroesophageal reflux, dental caries, constipation, and other causes of pain should be ruled out.

Other

Individuals with CdLS may have gastroesophageal reflux that goes untreated unless looked for and bowel malrotations or other congenital abnormalities that make obstruction more likely. Critical care information (see the Pearl above) should be given to all families of individuals with CdLS syndrome.

Systems

Development (general)

Children with CdLS should have developmental services initiated at diagnosis, starting with Early Intervention, followed by special education (preschool through high school) as needed. The majority of children with CdLS will have intellectual disability, although some children have normal intelligence. A large percentage of children with CdLS have hearing loss, and a smaller proportion have visual abnormalities. These children should be referred to vision and hearing developmental programs, often available through the state's services for the hearing and vision impaired. Given that expressive speech is one of the weakest areas of performance, there should be a reduced threshold to consider augmentative and alternative communication in children with CdLS who are non-verbal.
See Augmentative Communication (AAC) and the Developmental Skills Chart (CdLS Foundation) (PDF Document 98 KB) for expected age ranges for common developmental milestones. The Portal's module on Hearing Loss and Deafness provides further management information.

Specialty Collaborations & Other Services

Developmental - Behavioral Pediatrics (see MT providers [8])

May be helpful for overseeing developmental achievements, managing behavior issues, and overseeing educational progress

Special Education/Schools (see MT providers [86])

In some states, the intervener program is available for children who are BOTH hearing and vision impaired.

Speech - Language Pathologists (see MT providers [55])

There should be a reduced threshold for considering augmentative and alternative communication in children with CdLS who are non-verbal.

Early Intervention for Children with Disabilities/Delays (see MT providers [27])

Children with CdLS should have developmental services initiated at diagnosis, starting with Early Intervention, followed by special education (preschool through high school) as needed.

Cornelia de Lange Syndrome Clinics (see MT providers [0])

Speciality clinics for children with CdLS may be available in some states.

Gastro-Intestinal & Bowel Function

The majority of children with CdLS have gastroesophageal reflux disease (GERD). They may also have malrotation of the intestine or other congenital malformations that may cause acute abdominal distress due to volvulus. Constipation is also a common problem and should be treated aggressively. See Constipation for treatment details.
  • If GERD is present, medical treatment (H2 blockers, proton pump inhibitors, prokinetics or surgical treatment (Nissen fundoplication and possibly placement of a gastrostomy tube)) is usually necessary. For treatment information, see Gastroesophageal Reflux Disease.
  • In addition to short-term pain from reflux esophagitis, long-term esophagitis may lead to a precancerous condition called Barrett's esophagus. Eosinophilic esophagitis may require further evaluation (food allergy testing) and treatment.
  • At diagnosis, an upper GI study should be done to rule out malrotation; repair is indicated if present.
  • Acute abdominal pain should prompt evaluation for malrotation and volvulus, which may be fatal. Families should have a Medical Alert Card (CdLS Foundation)) to alert clinicians to this possibility.

Specialty Collaborations & Other Services

Pediatric Gastroenterology (see MT providers [15])

Consultation is recommended for management of reflux and growth/nutrition issues.

Nutrition/Growth/Bone

Children with CdLS usually have growth retardation that begins prenatally, and they are small with respect to height, weight, and head circumference. These parameters should be plotted on CdLS-specific growth charts (Growth Charts for Boys (CdLS Foundation) (PDF Document 874 KB) Growth Charts for Girls (CdLS Foundation) (PDF Document 1.4 MB)) to assure growth is appropriate. Nutrition services may be helpful if weight gain is less than expected.
Feeding difficulties occur in up to 70% of children with CdLS and may result in not meeting weight gain expectations. Problems may include immature feeding/swallowing patterns, gastroesophageal reflux, or adverse reactions to oral feeding following a period of tube feeding, as well as slow bowel motility. Consultation with a gastroenterologist may be helpful in deciding whether the child may be helped by increasing caloric intake, power packing (see Missing issue with id: 90b0ad6d.xml), or a gastrostomy tube (G-tube) (see Feeding & Nutrition and Feeding Tubes & Gastrostomies in Children). As there are often emotional issues surrounding G-tube insertion, advise families that they can be temporary, can be removed fairly easily (especially percutaneous ones), and that children may usually still be fed orally (unless aspiration is present) even if tube feeding is used.
G-tubes come in several different types, including percutaneous endoscopic gastrostomy tubes (PEGs). PEG insertion usually requires a shorter hospital stay than surgically placed tubes. Parents should understand that G-tubes do not stop gastroesophageal reflux and, in a small percentage of patients, GERD may worsen. G-tubes will not prevent aspiration of secretions, liquids, or solids fed by mouth.
Osteoporosis is also observed frequently. Consider referral to endocrinology for children with fractures and osteoporosis on bone densitometry studies (DXA scan) to consider bisphosphonate treatment. This is particularly important if they are on medications that may increase bone loss, such as seizure medications (e.g., valproic acid), or proton pump inhibitors.

Specialty Collaborations & Other Services

Nutrition Assessment Services (see MT providers [1])

For children with nutritional issues such as failure to gain weight, osteoporosis, and others, a consultation with a dietician may be helpful.

Pediatric Gastroenterology (see MT providers [15])

Consider referral for help with increasing caloric intake.

Pediatric Endocrinology (see MT providers [14])

Consider referral for children with fractures and osteoporosis on bone densitometry studies (DXA scan) to consider bisphosphonate treatment.

Pediatric Orthopedics (see MT providers [18])

Some individuals with CdLS can be born with hip dysplasia, club foot, other skeletal differences, or can develop contractures related to toe-walking in their Achilles tendons. Referral is recommended if these conditions are suspected/observed.

Mental Health/Behavior

Children with CdLS often have similar behavioral problems, sometimes called a "behavioral phenotype," which includes intellectual disability, self-injurious behavior, poor communication (30-85% have no verbal communication), aggression, compulsions, stereotypical behaviors (in 57-80%) and/or autism-like behaviors. [Basile: 2007] Self-injurious behavior can be severe in frequency and intensity, leading to injury in individuals who might otherwise be well functioning. For a systematic review of behavior in CdLS, see [Mulder: 2017].
When dealing with a particular behavior problem, the medical home should first rule out causes of physical discomfort, including gastroesophageal reflux, dental problems, ear and sinus infections, and constipation. Sensory neuropathy may cause painful or tingling sensations, numbness, or insensitivity to pain, and it may present behaviorally if the child has no way to communicate. Discolored hands and feet may be due to Raynaud syndrome, which may cause pain. Specific psychiatric disorders may become evident in adolescence, including depression, obsessive-compulsive disorder, anxiety, and aggression or opposition. (The Portal's module on Depression provides further diagnosis and management information for this condition.)
Once a medical cause for a new behavior is ruled out, obtain details about the behavior from parents, teachers, or other caregivers. Reasons for problem behaviors may include sensory reinforcement, task avoidance, boredom, and an attempt to communicate. A psychologist or behaviorist may design a program to decrease specific behaviors, which may include increasing the child's communication when possible. Medications may be helpful, including tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), alpha-2 agonists, benzodiazepines, seizure medications, and atypical antipsychotics. Consultation with a child psychiatrist is recommended if the medical home clinician is uncomfortable using these medications. Questions in the "Ask the Specialist" regarding Behavior in Children with CdLS (CdLS Foundation) may be helpful for providers and families. Behavioral modification can be extremely helpful, and consultation with a behavioral psychologist is recommended if behaviors escalate.

Specialty Collaborations & Other Services

Behavioral help is often necessary for children with CdLS. Depending on local expertise, developmental pediatrics and/or psychiatry may be helpful.

Psychiatry/Medication Management (see MT providers [19])

For children who may need medication to help with behavior problems

General Counseling Services (see MT providers [147])

Refer as needed for help with behavioral issues.

Developmental - Behavioral Pediatrics (see MT providers [8])

For children who may need behavioral help, including behavioral family plans and medication

Sleep

Children with CdLS often may have very disrupted sleep patterns. [Rajan: 2012]
  • Consider physical causes of disrupted sleep, such as constipation, obstructive sleep apnea, and pain from gastroesophageal reflux and/or ear and sinus infections.
  • Consider poor sleep hygiene (total sleep time, time to go to bed and to rise, quietness of the room, etc.) and suggest behavioral interventions. It might be helpful to ask the family to record sleep difficulties for a week or 2 to see the overall sleep pattern.
Medications may be necessary if behavioral measures fail (melatonin, ramelteon (Rozerem), trazodone, and clonidine).

Specialty Collaborations & Other Services

Sleep Disorders (see MT providers [4])

For children who are not sleeping appropriately, a consultation with a sleep medicine specialist may be helpful.

Neurology

Seizures occur in about 25% of children with CdLS but, unless the child has the SMC1A mutation, they are often responsive to treatment. [Symonds: 2017] Treatment will depend on the age of the child, the type of seizures, and associated medical conditions. The Portal's Seizures/Epilepsy provides management information.

Specialty Collaborations & Other Services

Pediatric Neurology (see MT providers [15])

Children with seizures will often need periodic visits.

Maturation/Sexual/Reproductive

Puberty may occur later than in unaffected individuals, and a minority of children with CdLS never enter puberty. Adolescents with CdLS will need education regarding sexuality that is individualized to developmental abilities. Females with CdLS may require hormonal therapy for management of menstruation and/or pregnancy prevention. For more details, see Intellectual Disability & Global Developmental Delay and Contraception & Menstrual Management.

Specialty Collaborations & Other Services

Gynecology: Pediatric/Adolescent; Special Needs (see MT providers [3])

A consultation with a gynecologist familiar with working with children with special health care needs may be beneficial for the adolescent girl and her family. Medications to help control or minimize menses can be helpful to the family.

Eyes/Vision

Structural and acquired eye problems are common in individuals with CdLS, including synophrys (99%), long lashes (99%) hypertrichosis of the brows (96%), ptosis (44%), epiphora (22%), nasolacrimal duct obstruction (16%), and blepharitis (25%). Myopia is also found in about 58% of individuals. [Avgitidou: 2015] Children with CdLS should have at least 1 visit with a pediatric ophthalmologist for an evaluation, even if no problems are reported to parents or observed in the medical home visit. At the first referral visit, follow-up should be specified by the consulting pediatric ophthalmologist.

Specialty Collaborations & Other Services

Pediatric Ophthalmology (see MT providers [14])

Provides early intervention of potentially reversible vision problems.

Ears/Hearing

Hearing loss is extremely common (85-90%) in individuals with CdLS and audiology testing should be performed regularly, even if the individual passed the newborn hearing screen. [Kline: 2018] Hearing loss is often conductive, due to anatomic abnormalities such as high arched palate, narrow external ear canals, and/or cleft or submucous cleft palate that contribute to excess middle ear fluid, and tympanostomy tubes are commonly needed, sometimes several times, to maximize hearing. Hearing loss should be treated promptly with hearing aids to maximize language ability.

Specialty Collaborations & Other Services

Pediatric Otolaryngology (ENT) (see MT providers [5])

Refer for children with CdLS and hearing loss, especially if they have frequent ear infections, middle ear fluid, drooling and/or swallowing problems should be referred to otolaryngology.

Audiology (see MT providers [49])

Hearing evaluations are sometimes available through the school district at no charge or through the state's Department of Health on a sliding fee basis. Private providers are also an option, although the audiologist should be familiar with issues seen in children with disabilities.

Dental

Children with CdLS should have early and frequent referrals to pediatric dentistry. Common dental problems include small jaw, small crowded teeth, missing teeth, delayed eruption, difficult oral hygiene, and GER leading to enamel erosion. Caries or periodontal disease may contribute to behavior problems. Sedation may be required for routine oral procedures, such as cleaning and sealant application. Concurrent scheduling of other needed evaluations, such as endoscopy and ophthalmology exams, will limit exposure to anesthetics and mean less appoints for the family. Underlying problems with anatomy and GER may adversely affect teeth.

Specialty Collaborations & Other Services

Pediatric Dentistry (see MT providers [53])

Consult early and at approximately 6-month intervals. Consider hospital-based dental care if indicated.

No Related Issues were found for this diagnosis.

Ask the Specialist

My patient has no history or physical signs of gastroesophageal reflux and growth is appropriate for the CdLS growth charts. Would I still need to obtain a GI work-up for reflux?

Because reflux is so common in CdLS (80-90%), it is recommended that all individuals diagnosed with CdLS undergo at least an upper GI (gastrointestinal) series, if not an EGD (esophagogastroduodenoscopy), to rule out hidden reflux. Reflux can occur after it has been initially ruled out, and symptoms suggestive of reflux also should prompt a work-up.

In general, what is the minimum medical work-up to do after diagnosis of CdLS?

An echocardiogram, renal ultrasound, upper GI series to assess for reflux and also to rule out malrotation, pediatric ophthalmology evaluation, and audiology testing are generally recommended; most individuals should also have CdLS specific molecular testing.

Are prostheses recommended for individuals with CdLS without digits or with abnormal forearms?

Most individuals with absent digits and/or ulnar bones learn to manipulate everything with the few digits they have, and most do not seem to benefit greatly from hand and/or forearm prostheses. That said, a few individuals have used these with great success. Families considering their options may connect with others through the Cornelia de Lange Syndrome Foundation.

What are the typical causes of death in CdLS?

In the newborn period, these would include diaphragmatic hernia and/or severe congenital heart disease. Most children with CdLS live to adulthood, although a small percentage die earlier due to (in order of frequency): respiratory causes including aspiration/reflux and pneumonia, gastrointestinal disease including obstruction/volvulus, and congenital anomalies such as diaphragmatic hernia and heart defects. [Schrier: 2011]

Resources for Clinicians

On the Web

Information for Professionals (CdLS Foundation)
Materials addressing common issues and challenges related to CdLS - available at no cost to professionals. Additionally, professionals can call and speak with a Family Service Coordinator or use an Ask the Expert form; Cornelia de Lange Syndrome Foundation.

Cornelia de Lange Syndrome (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Helpful Articles

PubMed search for Cornelia de Lange syndrome in children, last 4 years.

Ansari M, Poke G, Ferry Q, Williamson K, Aldridge R, Meynert AM, Bengani H, Chan CY, et al.
Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism.
J Med Genet. 2014;51(10):659-68. PubMed abstract / Full Text

Basel-Vanagaite L, Wolf L, Orin M, Larizza L, Gervasini C, Krantz ID, Deardoff MA.
Recognition of the Cornelia de Lange Syndrome Phenotype with Facial Dysmorphology Novel Analysis.
Clin Genet. 2015. PubMed abstract

Cochran L, Moss J, Nelson L, Oliver C.
Contrasting age related changes in autism spectrum disorder phenomenology in Cornelia de Lange, Fragile X, and Cri du Chat syndromes: Results from a 2.5 year follow-up.
Am J Med Genet C Semin Med Genet. 2015;169(2):188-97. PubMed abstract

Moss J, Penhallow J, Ansari M, Barton S, Bourn D, FitzPatrick DR, Goodship J, Hammond P, Roberts C, Welham A, Oliver C.
Genotype-phenotype correlations in Cornelia de Lange syndrome: Behavioral characteristics and changes with age.
Am J Med Genet A. 2017;173(6):1566-1574. PubMed abstract

Clinical Tools

Clinical Checklists & Visit Tools

Management and Treatment Guidelines (CdLS Foundation) (PDF Document 44 KB)
Highlights routine care for people with CdLS at different ages, including infancy, early and late childhood, adolescence, and adulthood.

Developmental Skills Chart (CdLS Foundation) (PDF Document 98 KB)
A chart of the reported ages of completion for gross motor, fine motor, personal/social, and language milestones in children with CdLS ages 1 month to 12 years; Cornelia de Lange Syndrome Foundation.

Growth/BMI Charts

Growth Charts for Boys (CdLS Foundation) (PDF Document 874 KB)
Since children with CdLS are often compared to a typical child’s growth rate, many are incorrectly diagnosed with “failure to thrive,” a condition that focuses primarily on weight gain, so CdLS Foundation Medical Director Antonie D. Kline, MD, and her colleagues, developed gender-specific growth charts based on research and data collected over many years.

Growth Charts for Girls (CdLS Foundation) (PDF Document 1.4 MB)
Since children with CdLS are often compared to a typical child’s growth rate, many are incorrectly diagnosed with “failure to thrive,” a condition that focuses primarily on weight gain, so CdLS Foundation Medical Director Antonie D. Kline, MD, and her colleagues, developed gender-specific growth charts based on research and data collected over many years.

Patient Education & Instructions

Cornelia de Lange Syndrome FAQs (CdLS Foundation)

Resources for Patients & Families

Information on the Web

Cornelia de Lange Syndrome (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

Genetic Testing (CdLS Foundation)
A list of facilities that offer genetic testing for CdLS.

Spotlight on Cornelia de Lange Syndrome (PBS)
A compelling, 5-minute video about CdLS featured on Public Television stations nationwide.

National & Local Support

Support (CdLS Foundation)
Provides extensive information and support, including outreach programs and social workers to help families connect with local resources.

Studies/Registries

Research Studies in CdLS (CdLS Foundation)

Services for Patients & Families in Montana (MT)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: May 2013; last update/revision: May 2020
Current Authors and Reviewers:
Authors: Lynne M. Kerr, MD, PhD
Reviewer: Antonie Kline, MD
Authoring history
2016: update: Lynne M. Kerr, MD, PhDR; Antonie Kline, MDR
2013: first version: Lynne M. Kerr, MD, PhDA; Antonie Kline, MDA; Molly O'Gorman, MDCA; Matthew Deardorff, MD, Ph.D.R
AAuthor; CAContributing Author; SASenior Author; RReviewer

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Contrasting age related changes in autism spectrum disorder phenomenology in Cornelia de Lange, Fragile X, and Cri du Chat syndromes: Results from a 2.5 year follow-up.
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