Presentation
Children with Cornelia de Lange syndrome often present with unusual facial features that develop within a few weeks to months after birth. There is slowed growth combined with development of several other abnormalities which have been described below:
- Children with CdLS present with distinct facial features characterized by anteverted nostrils, thin lips, arched eyebrows, long eyelashes and long philtrum.
- Under developed upper extremities
- Severe amount of body hair
- Hearing problems
- Low birth weight
- Small size of head
- Small stature
- Problems in vision
- Seizures
- Cleft palate
- Behavioral problem [7]
- Self-injurious behavioral patterns [8]
- Hearing defects
- Communication problems [9]
- Hypoplastic genitalia
- Hands and feet are small
- Clindodactyly
- Feeding problems
- Gastrophageal reflux
Entire Body System
- Feeding Difficulties
Cornelia de Lange syndrome (CdLs), which is also called Brachmann de Lange syndrome, is a congenital disorder characterized by distinctive facial features, prenatal and postnatal growth deficiency, feeding difficulties, psychomotor delay, behavioral problems [ncbi.nlm.nih.gov]
Cornelia de Lange syndrome (CdLS) is a syndrome of multiple congenital anomalies characterized by a distinctive facial appearance, prenatal and postnatal growth deficiency, feeding difficulties, psychomotor delay, behavioral problems, and associated malformations [emedicine.medscape.com]
- Multiple Congenital Anomalies
The Cornelia de Lange syndrome is a multiple congenital anomaly syndrome characterised by dysmorphic facial features, hirsutism, severe growth and developmental delays, and malformed upper limbs. The prevalence is estimated to be one per 10,000. [ncbi.nlm.nih.gov]
- Sepsis
Neurological causes and accidents each accounted for 8%, sepsis for 4%, cancer for 2%, renal disease for 1.7%, and other causes, 9% of deaths. We also present 21 representative clinical cases for illustration. [ncbi.nlm.nih.gov]
RESULTS: Recurrent infections were reported at high frequency in CdLS patients and included chronic ear infections (53%), chronic viral respiratory infections (46%), pneumonia (42%), sinus infections (33%), oral candidiasis (13%), sepsis (6%), and bacterial [pediatrics.aappublications.org]
In one review of 295 cases of this syndrome, causes of death, in order of frequency, included: Respiratory disease Gastrointestinal disease Congenital anomalies Nervous system diseases Accidents Sepsis Cardiac disease Cancer Renal disease. [dermnetnz.org]
Respiratoric
- Pneumonia
His report was based on the clinical and autopsy features of an who died of pneumonia at the age of 19 days. [whonamedit.com]
Birth history showed that the patient was born by normal vaginal delivery,birth weight was 2 kg and did not cry immediately after birth for which patient was admitted in NICU for a duration of 7 days, patient had developed pneumonia,for which she was [nijp.org]
Main causes of death in such patients include pneumonia along with cardiac, respiratory and GI abnormalities. [ncbi.nlm.nih.gov]
- Aspiration
The patient was premedicated for aspiration prophylaxis with pantaprazole (0.8 mg/kg) and ondansetron (0.08 mg/kg) intravenously. In addition, Inj glycopyrrolate 0.04 mg, inj midazolam 0.5 mg, inj fentanyl 20 µg was administered. [apicareonline.com]
Providing anesthesia to patients with Brachmann-de Lange syndrome (BdLS) may be challenging, mainly because of intubation difficulty, gastroesophageal reflux disease, and aspiration complications. [ncbi.nlm.nih.gov]
Death most commonly is related to aspiration pneumonia. [secure.ssa.gov]
The majority of those affected have diminished sucking and swallowing capacity, failure to thrive, predisposition to respiratory tract infections, and frequent vomiting with aspiration pneumonia. Mental retardation is usually severe. [whonamedit.com]
Gastrointestinal
- Abdominal Pain
An 18-year-old female with Cornelia De Lange syndrome and abdominal pain was found to have a hematometra on ultrasound examination. [ncbi.nlm.nih.gov]
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. [medicalhomeportal.org]
Ears
- Hearing Impairment
All patients with the classic form of the disease showed severe hearing impairments, whereas 4 patients without hearing impairments had the mild form. [ajnr.org]
[…] long philtrum micrognathia microbrachycephaly, microcephaly or brachycephaly upper limb malformations short 1st metacarpal oligodactyly acheiria micromelia growth restriction including intrauterine growth restriction intellectual disability hirsutism hearing [radiopaedia.org]
OBJECTIVE: Cornelia de Lange syndrome (CdLS) is a multiple developmental disorder including hearing loss. The hearing impairment in CdLS patients is not only sensorineural but also conductive hearing loss (CHL). [ncbi.nlm.nih.gov]
impairments Vision abnormalities (e.g., ptosis, nystagmus, high myopia, hypertropia) Partial joining of the second and third toes Incurved 5th fingers Gastroesophageal reflux Seizures Heart defects Cleft palate Feeding problems Children with this syndrome [bionity.com]
Some students will require the services of a trained teacher of the hearing impaired. Vision & Hearing: Some students with CdLS have both a vision and a hearing impairment. [tsbvi.edu]
Skin
- Hirsutism
DISCUSSION CdLS is a congenital anomaly syndrome characterized by distinctive facial dysmorphism, primordial short stature, hirsutism, and upper limb reduction defects, distinctcraniofacial features and low IQ ranges. [nijp.org]
There was a distinct facial dysmorphism with arched and bushy eyebrows, long philtrum, thin upper lip, depressed nasal bridge and hirsutism. [ncbi.nlm.nih.gov]
June 1966 Arch Dermatol. 1966;93(6):702-707. doi:10.1001/archderm.1966.01600240068011 Full Text The Cornelia de Lange or Brachman-de Lange syndrome is characterized by significant cutaneous and external manifestations, including hirsutism, cutis marmorata [jamanetwork.com]
Psychiatrical
- Psychomotor Retardation
Cornelia de Lange syndrome is a congenital disease, basically characterized by psychomotor retardation associated with a series of malformations, including mainly skeletal, craniofacial deformities together with gastrointestinal and cardiac malformations [ncbi.nlm.nih.gov]
They have prenatal growth deficiency, moderate-to-profound psychomotor retardation, and major malformations, which result in severe disability or death. [casesjournal.biomedcentral.com]
- Compulsive Behavior
Behavioral issues and specific psychiatric diagnoses, including self-injury, anxiety, attention-deficit disorder, autistic features, depression, and obsessive-compulsive behavior, often worsen with age. [ncbi.nlm.nih.gov]
Compulsive Behavior Checklist The Compulsive Behavior Checklist Reference Gedye19 is a questionnaire measure comprising 25 items grouped into five categories: Ordering, Completeness, Cleaning, Checking and Grooming. [cambridge.org]
behavior Obsessive compulsive behavior 0000722 Phthisis bulbi 0000667 Premature birth Premature delivery of affected infants Preterm delivery [ more ] 0001622 Ptosis Drooping upper eyelid 0000508 Radioulnar synostosis Fused forearm bones 0002974 Sensorineural [rarediseases.info.nih.gov]
Self-injurious behavior, self-restraint, and compulsive behaviors in Cornelia de Lange syndrome. Am J Ment Retard. 2002. 107:146-54. [Medline]. Ireland M, Donnai D, Burn J. Brachmann-de Lange syndrome. Delineation of the clinical phenotype. [emedicine.com]
Workup
No single test can diagnose CdLS. A thorough physical examination would be done to carefully study for the signs and symptoms of the disease. In addition, X-ray and genetic testing are carried out to figure out the genetic mutations.
Imaging studies such as CT scan of the temporal bone need to be done to determine any abnormalities in the middle and inner ear. Hearing conduction tests must also be conducted because 90% of CdLS patients have an associated hearing disorder [10].
Ultrasound of the renal tract is also a necessity to understand abnormalities associated with the renal system. Echocardiography is also indicated in patients with CdLS to determine the cardiac functioning.
Treatment
The major goal of treatment of CdLS is management of the symptoms to reduce discomfort associated with secondary anomalies. Treatment approach varies with age of the patient as the special needs of the child need to be catered to. This further means that a combined approach for correcting physical development and cognitive skills needs to be carried out.
Children with CdLS also suffer from various other associated disease conditions. Therefore appropriate treatment for each disease condition is also carried out.
Prognosis
Prognosis of the disease is usually unfavorable as affected children experience severe morbidity. Majority of the children die during the first few years of life. Those who survive these years have a short life span [5]. Retrospective reviews on CdLS patients shows that respiratory symptoms are the major cause of death [6].
Complications
Complications of CdLS include the following:
- Disorders of the central nervous system
- Respiratory problems such as bronchopulmonary dysplasia
- Impaired renal function
- Cleft palate
- Lack of sensation of pain
- Intolerance to heat
- Cardiovascular diseases
Etiology
The major factor that is known to play foul in the causation of Cornelia de Lange syndrome is genetic mutations [2]. A total of 4 genes were found to be responsible for causing the congenital disorder.
Out of the 4 genes, the most common genetic mutation that gives rises to 50% cases of CdLS is the NIPBL gene on the chromosome 5. Gene SMC1A on the chromosome X and gene SMC3 on the chromosome 10 account for rest of the cases [3]. The fourth gene known as HDAC8 on chromosome was discovered in the year 2012; however there is little evidence about the association of the gene with CdLS.
CdLS is not a heredity disorder and there are rare cases to prove that individuals living with such a syndrome would have children of their own.
Epidemiology
The exact incidence of CdLS is not known. However, with the available data it can be concluded that 1 in every 10,000 to 30,000 develops CdLS.
Pathophysiology
Cornelia de Lange syndrome is a genetic disorder arising from mutation of multiple genes. During the early developmental years, mutations of the genes NIPBL, SMC1A, SMC3 and HDAC8 are known to trigger series of events that send across faulty information giving rise to unusual facial features, developmental delay, and underdeveloped upper extremities and feeding problems [4]. Researchers have pointed towards the fact that 99% cases of CdLS are sporadic in nature.
Prevention
Many cases of the disease can be prevented using prenatal diagnostic testing. Ultrasound examination during pregnancy can show intrauterine growth retardation. However, studies showed that about 68% of the cases of CdLS were not detected by this method. Therefore, proper examination during the second trimester for detection of few typical characteristics such as cystic hygroma, diaphragmatic hernia and right hand with 3 rays can provide information about CdLS. In addition, maternal serum testing for pregnancy associated plasma protein during the second trimester can also help in detecting CdLS.
Summary
Cornelia de Lange syndrome, abbreviated as CdLS is a congenital disorder causing developmental delay in children. This disorder is typically not diagnosed at birth and presents with severe physical and mental challenges.
CdLS was first described in the year 1933 by the scientist Cornelia de Lange [1]. However, Brachmann also described characteristics similar to this disorder in the year 1916. Cornelia de Lange syndrome is characterized by behavioral problems, developmental delay, distinctive facial features, malformed upper extremities and growth deficiency. Genetic mutations are the major factor that gives rise to development of CdLS.
Patient Information
Definition
Cornelia de Lange syndrome (CdLS) is a congenital disorder characterized by slowed growth, poor development and unusual distinct facial features in affected children. Such a type of syndrome occurs due to genetic mutations. Affected children have a poor life expectancy as they are unable to survive the various associated disease conditions they suffer from. Children with CdLS also suffer from behavioral problems and have delayed cognitive development.
Cause
Cornelia de Lange syndrome occurs due to genetic mutations of 4 genes namely NIPBL, SMC1A, SMC3 and HDAC8. Researchers have also pointed towards the fact that about 99% cases of CdLS are sporadic in nature.
Symptoms
Children with CdLS are born with distinct facial features characterized by long eyelashes, thin lips, typically thick eyebrows that join at midline, low set ears and upturned nose. In addition, some of the other symptoms include presence of severe body hair, small head, small hands and feet, under developed upper extremities, vision impairment, hearing problems, seizures, feeding problems, heart abnormalities, hypoglastic genetalia and cleft palate.
Diagnosis
Diagnosis of CdLS includes thorough physical examination of the signs and symptoms. In addition, genetic testing is carried out to study the genetic mutations. In addition, ultrasound of the renal tract and echocardiogram are necessary to study abnormalities of the kidneys and heart.
Treatment
Treatment of CdLS includes management of the several disease conditions the child is suffering from. In addition, speech and behavioral therapy also forms a major part of the treatment regime.
References
- de Lange C. Sur un type nouveau de degeneration (typus amstelodamensis). Arch Med Enfants. 1933; 36:713-9.
- Huisman SA, Redeker EJ, Maas SM, Mannens MM, Hennekam RC. High rate of mosaicism in individuals with Cornelia de Lange syndrome. J Med Genet. May 2013; 50(5):339-44.
- Deardorff MA, Kaur M, Yaeger D, et al. Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation. Am J Hum Genet. Mar 2007; 80(3):485-94.
- Wilmink FA, Papatsonis DN, Grijseels EW, Wessels MW. Cornelia de lange syndrome: a recognizable fetal phenotype. Fetal Diagn Ther. 2009; 26(1):50-3.
- Kline AD, Grados M, Sponseller P, Levy HP, Blagowidow N, Schoedel C, et al. Natural history of aging in Cornelia de Lange syndrome. Am J Med Genet C Semin Med Genet. Aug 15 2007; 145C (3):248-60.
- Schrier SA, Sherer I, Deardorff MA, Clark D, Audette L, Gillis L, et al. Causes of death and autopsy findings in a large study cohort of individuals with Cornelia de Lange syndrome and review of the literature. Am J Med Genet A. Dec 2011; 155A (12):3007-24.
- Kline AD, Krantz ID, Sommer A, et al. Cornelia de Lange syndrome: Clinical review, diagnostic and scoring systems, and anticipatory guidance Am J Med Genet Part A 143A:1287-1296. Am J Med Genet A. Sep 24 2008; 146A (20):2713.
- Moss J, Oliver C, Hall S, et al. The association between environmental events and self-injurious behaviour in Cornelia de Lange syndrome. J Intellect Disabil Res. 2005; 49:269-77.
- Sarimski K. Analysis of intentional communication in severely handicapped children with Cornelia-de-Lange syndrome. J Commun Disord. 2002; 35:483-500.
- Marchisio P, Selicorni A, Pignataro L, et al. Otitis media with effusion and hearing loss in children with Cornelia de Lange syndrome. Am J Med Genet A. Feb 15 2008; 146A (4):426-32.