Continuing Education Activity

Cornelia de Lange syndrome (CdLS) was initially described in 1933. CdLS is a genetic disorder that affects many organs, leading to various clinical presentations. Typical features of this rare disease include restricted growth, intellectual disability, craniofacial abnormalities, and hirsutism (excess body hair). Additional features include gastroesophageal reflux (GERD), limb dysplasia, genitourinary malformations, and heart defects. This activity describes the pathophysiology, clinical evaluation, and management of a patient with suspected Cornelia de Lange syndrome and explains the role of the health professional team in coordinating the care of patients with this condition.

Objectives:

• Describe the clinical features of Cornelia de Lange syndrome.
• Summarize the management options for Cornelia de Lange syndrome.
• Explain the potential complications that may accompany a diagnosis of Cornelia de Lange syndrome.
• Outline the clinical evaluation of a patient with suspected Cornelia de Lange syndrome and explain the role of the interprofessional team in coordinating the care of patients with this condition.

Introduction

Cornelia de Lange syndrome (CdLS) was described, in 1933, by the Dutch pediatrician, Cornelia Catharina de Lange, who illustrated two unrelated girls with similar features.[1] Previously, in 1849, the anatomist Willem Vrolik (1801–1863) reported a case as an extreme example of oligodactyly, and the German doctor Brachmann published, in 1916, a case of symmetric monodactyly, antecubital webbing, dwarfism, cervical ribs, and hirsutism. Throughout history, other names for the syndrome have included Amsterdam dwarfism, Bushy syndrome, or Brachmann syndrome.[1]

CdLS is a multisystemic disease expressing variable physical, cognitive, and behavioral characteristics. It is a genetic disorder that affects many organs, leading to various clinical presentations.[2] Typical features of the rare disease include restricted growth with prenatal onset (second trimester), intellectual disability, craniofacial abnormalities, upper limb anomalies, and hirsutism.[3][2] Additional features include gastroesophageal reflux (GERD), genitourinary malformations, and heart defects.[2]

Etiology

Multiple genes impacting the cohesin pathway's function have been the target of study in patients with CdLS.[1][4][5] The protein complex of cohesin and its regulators is essential for mitosis, as it is necessary for sister chromatid separation.[1][5] Furthermore, the complex participates in several most biological processes involving maintenance of genome stability, regulation of gene expression, chromatin structure, and genome organization. Several genes on different chromosomes participate in the complex development, and a total of 7 genes have been identified in association with CdLS.[4][5] Five main genes account for 70% of cases.[1][2] Of those five genes, Nipped-B-like (NIPBL) protein on chromosome 5 accounts for approximately 60% of cases and the remainder for the remaining 10% of genetic cases.[4][6] The other 30% of patients with CdLS are considered idiopathic.[4] Of note, the syndrome affects the sexes equally.[4] Although the disorder is genetic, almost all cases are sporadic (de novo heterozygous mutations).[1] Nevertheless, an autosomal dominant familial transmission or an x-linked dominant pattern has occasionally been observed as fewer than 1% of individuals with NIPBL-related CdLS have an affected parent.

Concerning mutations, they can involve different genes, including NIPBL, SMC1A, SMC3, BRD4, HDAC8, RAD21, ANKRD11. The mutation is associated with different clinical expressions of the syndrome. Of note, there is proof of mosaicism in up to 20% of individuals with typical CdLS features.[7]

Autosomal Genes Involved

• NIPBL (Nipped-B-like protein of chromosome 5): The mutation is associated with the classical CdLS phenotype.
• SMC3 (structural maintenance of chromosomes 3, 10q25): It is associated with atypical CdLS forms featuring predominant mental retardation.[8] 
• RAD21 (human homolog of Schizosaccharomyces pombe radiation-sensitive mutant 21): It is rarely observed and associated with a non-classic CdLS phenotype. 
• BRD4 (Bromodomain-containing protein 4): There are few cases reported to describe the precise phenotype. Research into this form has described mosaicism.[9]
• ANKRD11 (ankyrin repeat domain-containing protein 11): It is associated with a non-classic CdLS phenotype.

X-linked Genes

• HDAC8 (histone deacetylase 8): Although individuals display a non-classic phenotype, some individuals show classic CdLS features.
• SMC1A or SMC1L1 (structural maintenance of chromosomes 1A, Xp11.22-p11.21): It is associated with a non-classic phenotype.

Epidemiology

As mild cases of CdLS often are not reported, the incidence and prevalence are probably underestimated. Presently, the estimated incidence in the United States has been reported between 1 per 10000 to 1 per 50000 newborns.[1][4] The disorder affects males and females equally due to a dominant genetic pattern.[1] Forms that express a non-classical phenotype are reported in the literature as sporadic cases.

History and Physical

While in utero, patients with CdLS may present growth restriction. At birth, they present with failure to thrive, and their weight is often less than 2.2 kg. As the children grow older, they often continue to have delayed growth (usually below the 5th percentile).[2] Although classic (or typical) CdLS is easily recognized, less obvious forms can lead to diagnostic problems. The broad spectrum of anomalies associated with the syndrome must merit consideration. These multiple organ systems and phenotypical expressions may include:[4] 

• Craniofacial: A distinctive feature seen in children with CdLS is synophyrys, which are thick arched eyebrows that meet in the middle.[4] Patients with CdLS also may have a short upturned nose, thin vermillion border or philtrum, choanal atresia, cleft palate, wide-spaced teeth, or micrognathia.[10] Other distinctive features include long eyelashes, low set ears, external auditory canal (EAC) malformations, external auditory meatus atresia, brachycephaly (shorter skull), and microcephaly (smaller skull). As the children have hirsutism, they may also have a low frontal and neck hairline. Short neck, cervical webs, and micrognathia can also be present. 
• Neurodevelopmental: Children may have global developmental delays, along with intellectual disability.[2] Although a severe-to-profound pervasive developmental delay is observable in the classic CdLS, intellectual impairment is less evident in non-typical forms.
• Gastrointestinal: GERD is present in nearly all (85%) patients with CdLS, which can predispose patients to Barrett esophagus.[1] Other gastrointestinal findings include general complaints of nausea, vomiting, diarrhea, constipation, feeding difficulty, or poor appetite. More specific gastrointestinal abnormalities include pyloric stenosis, gastrointestinal rotation, and diaphragmatic hernias.[2]
• Genitourinary: Genital hypoplasia, cryptorchidism (in 73% of males), hypospadias, renal cyst, or renal hypoplasia are common. Reports exist of benign prostatic hypertrophy (BPH) in males with CdLS.[10]
• Ophthalmologic: Dysfunctional tear ducts, ptosis, strabismus, nystagmus, myopia, astigmatism, amblyopia, cataracts, glaucoma, detached retina, and blepharitis are often a feature in children with CdLS.[10] Overall, visual impairments occur in approximately 50% of individuals. 
• Cardiac: Cardiac findings in children with CdLS include murmurs, coarctation of the aorta, pulmonary stenosis, tetralogy of Fallot, and atrial or ventricular septal defects.[2]
• Neurological: Many patients (up to 25%) exercise seizure disorders requiring care by a neurologist. Autonomic dysfunctions and sleep-related problems (e.g., nightly apnoea and insomnia) have also been described.
• Psychiatric: Patients can have behavioral difficulties ranging from aggression, self-injury, to self-stimulatory behavior.[10] CdLS is often comorbid with attention deficit hyperactivity disorder (ADHD), depressive disorders, anxiety disorders, and obsessive-compulsive disorder (OCD).[10] 
• Dermatologic: Hirsutism or cutis marmorata (purple skin discoloration) can present during the dermatologic examination. 
• Musculoskeletal: Limb dysplasias, scoliosis (39%), partial toe fusion, clinodactyly (curved fifth digit), radial hypoplasia, radioulnar synostosis, shortened sternum, and pectus excavatum have been observed in patients with CdLS.[10]
• Respiratory: laryngeal anomalies are rare.
• Immunodeficiency: Because of antibody deficiency and/or impaired T-cell function, recurrent infections (chronic ear infections, chronic viral respiratory infections, and pneumonia) can affect a variable percentage of individuals affected by CdLS.

Different scoring systems have been proposed to graduate the severity of the syndrome based on the phenotypic characteristics. Recently, the first international consensus statement on diagnosis and management of CdLS introduced a tool for the diagnosis of the syndrome.[4] The authors proposed to distinguish cardinal features from suggestive characteristics. The former include synophrys and/or thick eyebrows, short nose, concave nasal ridge and/or upturned nasal tip, long and/or smooth philtrum, thin upper lip vermilion, and/or downturned corners of the mouth, hand oligodactyly and/or adactyly, and congenital diaphragmatic hernia. Suggestive features comprise global developmental delay and/or intellectual disability, prenatal growth retardation, postnatal growth retardation, microcephaly (prenatally and/or postnatally), small hands, and/or feet, short fifth finger, and hirsutism. If present, each cardinal feature is scored with 2 points, whereas a score of 1 point is assigned to each suggestive feature. A total score ≥ of 11 points (with at least 3 are cardinal) indicates a classic CdLS; 9 or 10 points (at least 2 cardinal) is suggestive for a non-classic CdLS. Moreover, 4 to 8 points (at least 1 cardinal) requires molecular testing, whereas a score of fewer than 4 points is insufficient to indicate further exams.

Evaluation

Although CdLS is a clinical diagnosis, genetic testing to confirm the diagnosis is the recommendation in patients with equivocal findings on history and physical examination. Genetic testing also can confirm the diagnosis in children with mild or uncommon presentations.

Genetic Testing 

In individuals with the typical CdLS phenotype, the first-line molecular diagnostic approach should be next-generation sequencing (NGS)-based screening (whole-exome sequencing, WES, or whole-genome sequencing, WGS) focused on NIPBL, SMC1A, SMC3, RAD21, BRD4, HDAC8, and ANKRD11 genes. This is the preferred approach to the simple targeted sequencing of the NIPBL gene. In the case of non-typical CdLS phenotype, genetic testing (WES or WGS) is an option on a case-by-case analysis. If genetic testing is negative, mosaicism requires investigation in tissues other than blood, such as fibroblasts, buccal swabs, or bladder epithelial cells from urine. In turn, if this approach aimed at mosaicism detection is negative, deletion and duplication testing of NIPBL should be performed using multiplex ligation-dependent probe amplification (MLPA) or chromosome microarray.

Clinical and Instrumental Evaluation  

The clinician should obtain the following laboratory, imaging, and other tests for patients with CdLS. 

• Body mass index (BMI), with growth charts
• Complete blood count (CBC)
• Complete metabolic panel (CMP)
• Hearing and vision screen
• Ophthalmologic evaluation (with cycloplegic refraction)
• Echocardiogram
• Electrocardiogram (ECG)
• Upper GI series 
• Endoscopy or pH probe
• Renal ultrasound 
• Facial Dysmorphology Novel Analysis (FDNA) is a novel technology developed to detect genetic disorders characterized by facial dysmorphology.[11] The systems detection rate was proven to be comparable to clinical experts.[11]

Antenatal diagnosis can be suspected by ultrasound, which can reveal intrauterine growth retardation, craniofacial alterations (50%), and limb abnormalities (66%). As the sensitivity is not 100%, the result of the examination must be well explained to the parents. Furthermore, the patient can have prenatal molecular testing performed. These investigations can take place on samples obtained from chorionic villous sampling or amniocentesis, or by testing embryonic cells (in vitro fertilization). In families in which parental transmission of the disease has been detected and in which the gene mutation has been identified, a genetic diagnosis can also be proposed in parents who do not seem to be carriers of the mutation, to exclude the risk of germinal mosaicism.

Treatment / Management

An interprofessional team is necessary to manage a patient with CdLS effectively. It may include: 

• Primary care, otolaryngology, gastroenterology (e.g., for addressing GERD), ophthalmology, cardiology, urology, nephrology, dermatology, dentist, and orthodontist.
• Neurology: Antiepileptic drugs (AEDs) are required to manage seizure disorders in CdLS. 
• Psychiatry/Psychology: Medications can help to treat self-injurious or aggressive behaviors. Other therapeutic modalities include individual psychotherapy or applied behavioral analysis (ABA). 
• Surgery: Surgical management for feeding difficulties, gastrointestinal complications (e.g., fundoplication if reflux is severe), vesicoureteral reflux, cryptorchidism, or skeletal abnormalities may be beneficial. 
• Ancillary Services: Children with CdLS require physical therapy (PT), speech therapy (ST), occupational therapy (OT), and special education programs due to delayed growth and intellectual disability. For all children with neurodevelopmental disorders, hearing and vision screening are highly recommended. Consult with a nutritionist may be necessary to address feeding difficulties.

Management of individuals affected by CdLS encompasses an annual gastrointestinal evaluation combined with monitoring of growth and psychomotor development. Furthermore, recommendations include routine eye and hearing evaluations and monitoring of heart and kidney functions. 

Differential Diagnosis

Because in individuals with CdLS the clinical presentation can vary widely, the syndrome can closely resemble other genetic disorders. Therefore genetic testing is recommended to diagnose the syndrome definitively and to rule out other genetic disorders, especially in non-classical CdLS phenotypes.[4]

• Autism spectrum disorder 
• Rett syndrome[12]
• Roberts syndrome
• Nicolaides-Baraister syndrome 
• DiGeorge syndrome[13][14][13]
• Deletions of chromosome 2q31
• Partial duplication of 3q
• Fryns syndrome
• CHOPS syndrome
• Bohring-Opitz syndrome
• TAF6 or TAF1

Prognosis

There have been only a very few cases of Cornelia de Lange syndrome have been reported in adults. Life expectancy is relatively unaffected but if the patients develop any complications of the syndrome then prognosis mainly depends on the severity and management of that complication.

Complications

As CdLS affects multiple organ systems, complications may arise that require specialty-specific treatment, including: 

• Gastroenterology: Repair of pyloric stenosis, malrotation, volvulus, or congenital diaphragmatic hernia may be necessary in early infancy.[10] GERD may predispose children to Barrett esophagus (in 10%) or aspiration pneumonia.[1][10]
• Urology: Cryptorchidism or hypospadias are often seen in males with CdLS during infancy. Orchidopexy to repair cryptorchidism is recommended, due to the risk of testicular carcinoma.[15] Genital hypoplasia is seen equally in both male and female patients. 
• Nephrology: Renal cyst and renal hypoplasia are common complications in children with CdLS. 

Signs of premature aging, including osteoporosis or canities (greying of hair prematurely), have been observed in young patients with CdLS.[10] Premature aging in CdLS may be a result of the cohesin pathway genetic mutation interrupting cell mitosis.[10]

Deterrence and Patient Education

An interdisciplinary team is required to manage patients with CdLS.[4] Questions regarding treatment or management should be directed towards this team of specialists.[4] More information on the disorder is also available through the Cornelia de Lange Syndrome Foundation (CdLS Foundation).

Enhancing Healthcare Team Outcomes

Cornelia de Lange syndrome is best managed by an interprofessional team, including primary care providers, geneticists, neurologists, and multiple other specialists and ancillary staff. Specialty care nurses in neuroscience and development are involved in direct care, patient and family education, monitoring, and facilitate communication between team members. Pharmacists review prescriptions for antiepileptic drugs, check for interactions, and provide education about the importance of compliance and potential side effects. This interprofessional interplay can improve outcomes in patients with this rare disorder. [Level 5]