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. 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.
CdLS is a multisystemic disease with expressing variable physical, cognitive, and behavioral characteristics. It is a genetic disorder that affects many organs, leading to various clinical presentations. Typical features of the rare disease include restricted growth with prenatal onset (second trimester), intellectual disability, craniofacial abnormalities, upper limb anomalies, and hirsutism. Additional features include gastroesophageal reflux (GERD), genitourinary malformations, and heart defects.
Multiple genes impacting the cohesin pathway's function have been the target of study in patients with CdLS. The protein complex of cohesin and its regulators is essential for mitosis, as it is necessary for sister chromatid separation. 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. Five main genes account for 70% of cases. 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. The other 30% of patients with CdLS are considered idiopathic. Of note, the syndrome affects the sexes equally. Although the disorder is genetic, almost all cases are sporadic (de novo heterozygous mutations). Nevertheless, an autosomal dominant familial transmission or an x-linked dominant pattern, have 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.
Autosomal genes involved
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. The disorder affects males and females equally due to a dominant genetic pattern. Forms that express a non-classical phenotype are reported in the literature as sporadic cases.
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). 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:
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. 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.
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.
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.
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.
An interprofessional team is necessary to manage a patient with CdLS effectively. It may include:
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.
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.
As CdLS affects multiple organ systems, complications may arise that require specialty-specific treatment, including:
Signs of premature aging, including osteoporosis or canities (greying of hair prematurely), have been observed in young patients with CdLS. Premature aging in CdLS may be a result of the cohesin pathway genetic mutation interrupting cell mitosis.
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]
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