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

• Disability

  Cornelia de Lange syndrome is a well-known multiple congenital anomalies/intellectual disability syndrome with genetic heterogeneity and wide clinical variability, regarding the severity of both the intellectual disabilities and the physical features, [ncbi.nlm.nih.gov]

  Other medical problems and traits associated with CdLS are as follows: Signs and symptoms of CdL syndrome Intellectual disability Microcephaly (very small head) Delayed speech development Fine and gross motor delays/disabilities Low birthweight/intrauterine [forgottendiseases.org]

  Although the described clinical symptomatology is very broad, the majority of cases include growth impairment, learning disability and dysmorphic facies. The estimated incidence is at ~1:10,000-30,000 births 15. [radiopaedia.org]

  Like affected individuals with NIPBL gene mutations, those with HDAC8 gene mutations may have significant intellectual disability. In about 30 percent of cases, the cause of Cornelia de Lange syndrome is unknown. [encyclopedia.pub]

• Developmental Delay

  Cornelia de Lange syndrome is characterized by distinctive craniofacial features, developmental delays, variable congenital malformations, and growth retardation. [dnatesting.uchicago.edu]

  The first patient presented with developmental delay, hypospadias, inguinal hernia and dysmorphic features while, the second patient presented with developmental delay, characteristic facial features, hirsutism, and hand and feet anomalies, with the first [ncbi.nlm.nih.gov]

  These patients had low birth weight, usually less than five pounds; gastroesophageal reflux disease; mild to severe developmental delays, particularly language delay; behavioral issues such as self-injury behaviors; thick eyebrows and long eyelashes; [medexsupply.com]

• Developmental Disorder

  Abstract Cornelia de Lange syndrome (CdLS, also called Brachmann-de Lange syndrome - BdLS) is a multisystem developmental disorder characterized by distinctive facial features, growth and mental retardation, microcephaly, and various malformations. [ncbi.nlm.nih.gov]

  Over the last 10 years, genetic tests have been developed for the diagnosis of individuals with developmental disorders. [cdls.org.uk]

• Epilepsy

  The presence of epilepsy could be related to pathophysiological factors independent of those implicated in the characterization of main classical phenotypic features. [ncbi.nlm.nih.gov]

• 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]

  Anaesth Pain & Intensive Care 2016;20(1):62-64. INTRODUCTION Management of syndromic patients with mental and growth retardation has always been challenging for anesthesiologists. [apicareonline.com]

  Often, an underlying medical issue, pain, social anxiety, environmental or caregiver stress can be associated with a change behaviour. If pain or a medical issue is the cause, once treated, the behaviour diminishes. [en.wikipedia.org]

• 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]

• Heart Disease

  Congenital heart disease (CHD) is not a major criterion of the disease, but it affects many individuals. The objective of this study was to study the incidence and type of CHD in patients with CdLS. [ncbi.nlm.nih.gov]

  By using intrauterine growth retardation as a trigger for antenatal diagnosis, CdLS is diagnosed by abnormalities of upper arms, congenital heart diseases, and characteristic facies. [hindawi.com]

• 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]

• 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]

• Thin Lips

  The syndrome carries a wide spectrum of clinical features which include: facial dysmorphism low set hairline in the front and back long eyelashes bushy eyebrows synophrys (unibrow) 15 upturned nose with anteverted nostrils thin lips with long philtrum [radiopaedia.org]

  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. [symptoma.com]

  External examination showed a low hairline, synophrys, low-set ear, hypertrichosis, and smooth long philtrum with thin lips. The neck appeared short and broad. Finally, CdLS was diagnosed. [hindawi.com]

  Craniofacial features consist of a clown-like appearance with large, low and curly eyelashes, micrognathia, thin lips and downturned upper lip (carp mouth), cleft lip and palate, optic atrophy, an upturned nose, and hirsutism. [whonamedit.com]

  […] learning disabilities and language delays) and autism-like syndromes that affect socialisation and communication Distinctive facial features, such as synophrys (narrow eyebrows that meet in the middle), an upturned nose, uneven teeth, low-set ears and thin [dermnetnz.org]

• Global Developmental Delay

  Physical findings: In children, classic CdLS is characterized by: • Early feeding difficulties; • Global developmental delays with severe to profound intellectual disabilities; • Limited language; • Poor growth; • Skeletal abnormalities involving missing [secure.ssa.gov]

  History revealed that patient had global developmental delay. Clinical examination Development Mental retardation, grossly delayed milestones, low pitched, weak, growling, cry in infancy. Craniofacial Cranium: Micro brachycephaly. [nijp.org]

  Global developmental delay, in particular speech delay evolves towards intellectual disability ranging from mild to profound. [orpha.net]

  KBG syndrome is characterized by macrodontia of central upper incisors, mental retardation, dysmorphic facial features, short statue, skeletal anomalies and global developmental delay, seizures, and intellectual disability. [preventiongenetics.com]

  Haiming Yuan, Lina Zhang, Mengfan Chen, Junping Zhu, Zhe Meng and Liyang Liang, A de novo triplication on 2q22.3 including the entire ZEB2 gene associated with global developmental delay, multiple congenital anomalies and behavioral abnormalities, Molecular [doi.org]

• Agitation

  Behavior Checklist The Aberrant Behavior Checklist Reference Aman and Singh18 is a measure of problem behaviour incorporating a 58-item checklist with five factors based on observations of behaviour over the previous month, including: irritability, agitation [cambridge.org]

  A cautious approach is indicated for the use of SSRIs in patients with CdLS because of possible behavioural activation and worsening agitation. [nature.com]

• Delayed Milestone

  History revealed that patient had global developmental delay. Clinical examination Development Mental retardation, grossly delayed milestones, low pitched, weak, growling, cry in infancy. Craniofacial Cranium: Micro brachycephaly. [nijp.org]

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.

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 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

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.

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.

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.

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.

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.

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.

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2. 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.
3. 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.
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9. Sarimski K. Analysis of intentional communication in severely handicapped children with Cornelia-de-Lange syndrome. J Commun Disord. 2002; 35:483-500.
10. 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.