Cornelia De Lange Syndrome
- Author: Mustafa Tekin, MD; Chief Editor: Maria Descartes, MD more...
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 that mainly involve the upper extremities. Cornelia de Lange first described it as a distinct syndrome in 1933, although Brachmann had described a child with similar features in 1916. Diagnosing classic cases of Cornelia de Lange syndrome is usually straightforward; however, diagnosing mild cases may be challenging, even for an experienced clinician. See the images below.
More than 99% of cases are sporadic. Cornelia de Lange syndrome is occasionally transmitted in an autosomal dominant pattern, according to several instances in which a usually mildly affected parent had one or more affected offspring. Twins with concordance and discordance have been reported. Although possible autosomal recessive inheritance has been reported in some families, these instances were likely to be due to germline mosaicism. The recurrence risk is 0.5-1.5% if parents are unaffected and 50% if a parent is affected.
Heterozygous mutations in a gene named NIPBL, the human homolog of the Drosophila melanogaster Nipped-B gene, have been identified in approximately 50% of individuals with Cornelia de Lange syndrome.[5, 6, 7] Although the exact function of the protein product of NIPBL in humans (delangin) remains unknown, its homologs in other species are known to play roles in developmental regulation and in cohesion of sister chromatids. Mutations in genes, coding for two other proteins involved in cohesion of sister chromatids, SMC1A and SMC3, have been reported in 5% and 1% of patients with Cornelia de Lange syndrome, respectively. Thus, Cornelia de Lange syndrome is considered to be a cohesinopathy, along with Roberts syndrome/SC phocomelia.
Inheritance is autosomal dominant in families with NIPBL and SMC3 mutations and is X-linked dominant in families with SMC1A mutations.
All types of NIPBL mutations, including missense, splice-site, nonsense, and frameshift mutations, have been reported to result in the Cornelia de Lange syndrome phenotype. The most likely effect of these mutations is haploinsufficiency. The mutation-detection rate is approximately 50%. Genomic deletions and duplications of the NIPBL locus are rare.[9, 10] Reported mutations of SMC1A include missense mutations and in-frame deletions. One reported SMC3 mutation is an in-frame deletion.
The correlation between genotype and phenotype suggested that individuals with an identifiable mutation in NIPBL have a phenotype more severe than the phenotype of those without mutations. Moreover, missense mutations in NIPBL are associated with mild phenotypic features. Patients with mutations in SMC1A and SMC3 consistently have a milder phenotype, with absence of severe limb defects and other structural anomalies. The phenotype in some patients is close to those with nonsyndromic mental retardation.
A study by Gil-Rodríguez et al of SMC3 -associated phenotypes in 16 patients found a tendency toward the following :
Less distinctive syndrome-related craniofacial features (although, as in other cases of Cornelia de Lange syndrome, microcephaly is characteristic)
Fewer associated congenital heart defects
Normal limbs (as mentioned above)
Milder prenatal growth retardation (although it becomes more severe in childhood)
A phenotype similar to that of Cornelia de Lange syndrome may be observed in patients with a duplication of band q26-27 on chromosome 3. Molecular studies of genes mapped to this region of chromosome arm 3q have failed to reveal mutations in patients with Cornelia de Lange syndrome.
Some autopsy data have indicated cerebral dysgenesis, with a decreased number of neurons, neuronal heterotopias, and focal gyral folding abnormalities as causes of psychomotor delay.
The incidence is 1 case per 10,000-50,000 live births. No differences based on sex or race have been described.
A retrospective review of 295 propositi with Cornelia de Lange syndrome found that respiratory issues (eg, aspiration, reflux, pneumonia) were the most common causes of death (31%), followed by gastrointestinal disease, including obstruction/volvulus (19%), congenital anomalies (15%), neurological causes, (8%), accidents (8%), sepsis (4%), acquired cardiac disease (3%), cancer (2%), renal disease (1.7%), and other causes (9%).
A prenatal diagnosis is made after Cornelia de Lange syndrome (CdLS)-related abnormalities are carefully evaluated using prenatal ultrasonography. These abnormalities include growth retardation, limb defects, diaphragmatic hernia, hypoplastic forearms, underdeveloped hands, and typical facial defects.
The availability of molecular diagnosis should substantially improve prenatal diagnosis. Prenatal diagnosis with molecular genetic techniques is currently available if a mutation is known in the family.
Failure to detect a mildly affected parent may result in incorrect risk estimation for future pregnancies.
Anatomic abnormalities of the face and neck may cause difficulties during intubation. GI obstruction or feeding difficulties may occur. Early feeding management is important.
Severe speech delay and poor communication are concerns. The patient may have congenital heart disease.
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|Parameter||1 point||2 point||3 point|
|Birth weight||Above 2,500 g||2,000–2,500 g||Below 2,000 g|
|Sitting alone||< 9 mo||9–20 mo||>20 mo|
|Walking alone||< 18 mo||18–42 months||>42 mo|
|Saying first word||< 24 mo||24–48 mo||>48 mo|
|Upper limb malformation||No defect||Partial defect (>2 digits)||Severe defect (< 2 digits)|
|Number of other major malformations||0-1||2-3||>3|
|A score of less than 15 points indicates mild involvement, a score of 15-22 points indicates moderate involvement, and a score of more than 22 points indicates severe involvement.|