Diagnosis of CdLS
Currently, researchers find a gene change in about 75 percent of individuals with CdLS. A higher percentage may be identifiable as testing procedures become more sophisticated, and as additional genes are identified.
What are the long-term implications of gene discoveries?
Now that the basic causes of CdLS have been discovered, we can begin to understand how these changes result in the clinical differences seen in affected individuals. By studying how this occurs, researchers can understand the clinical problems that individuals with CdLS face on a very basic level. With time, we hope this results in better care for affected individuals.
Prenatal Diagnosis of CdLS
Research continues to support a low risk of recurrence, but for parents who have a child with CdLS, prenatal ultrasound can provide an evaluation of subsequent pregnancies. An ultrasound examination is recommended for all subsequent pregnancies at 18 to 20 weeks, most likely for reassurance. The timing of this scan allows a thorough study of the anatomy of the fetus and accurate dating of the pregnancy. In addition to the routine survey, careful attention should be made to the face, hands, heart, arms, and ventricles of the head. Anatomic abnormalities that have been described on prenatal studies of babies with CdLS include: limb abnormalities (particularly of the upper limbs), abnormal hearts, cleft lip, abnormal facial profile, diaphragmatic hernia, mild enlargement of the ventricles of the head, and gastrointestinal abnormalities.
The most distinctive of these abnormalities are those of the upper limb. Arm bones and fingers should be carefully examined and counted because these may be missing or abnormally short in CdLS. The femur, feet and arm bones should be measured to ensure that their lengths are within the normal range. In the face of a fetus with CdLS, one might find cleft palate, long eyelashes, a small chin, and a small upturned nose. The head tends to be short and small (microbrachycephaly) and should be measured and compared to tables. In many of the children, there are abnormalities of the heart and sometimes a diaphragmatic hernia or abdominal calcification (meconium peritonitis).
Ultrasound is not a perfect tool to diagnose CdLS, nor is it a perfect tool to exclude the possibility of CdLS. Nonetheless, many children with CdLS have fairly severe abnormalities that can be detected prenatally by careful ultrasound with radiologists or obstetricians.
Diagnosis of CdLS After Birth
Cornelia de Lange syndrome (CdLS), now known as Cornelia de Lange Spectrum Disorder, is a condition with variable involvement, and thus diagnosis can be made at many different ages. Sometimes there is a prenatal diagnosis, in which facial features (particularly the profile), malformations (such as absent digits or forearms, diaphragmatic hernia or congenital heart disease) and intrauterine growth retardation become recognizable as CdLS. Often, for the more severely involved individuals, there is a diagnosis made after birth in the newborn period. This is typically based on multiple findings: the small size for gestational age, typical facial features, hirsutism (excessive hair especially on forehead, face and back), small hands or absent digits or forearms, incomplete extension of the elbows, small feet and/or internal organ abnormalities such as diaphragmatic hernia, cleft palate, congenital heart disease, undescended testicles or micropenis in the male, or kidney anomalies. These are all typical, “classical” findings seen in CdLS.
For milder, less severely involved individuals, there are less physical features that are notable, so the diagnosis tends to be later. There continues to be small size, often feeding problems and/or the development of gastroesophageal reflux. There is often developmental delay with early milestones occurring later than average. Even in the most mildly affected children, speech will usually come in later. Facial features are present, but less striking, and there is less excessive hair. Also, the internal organs are usually intact. Behavior can develop into an issue as these children get older, developing ADHD and/or some aggressive or self-injurious behavior. A subset will have autism or autistic-like features. Clinical diagnosis for this group can occur at any age during childhood, often prior to age 8 years, but it can be more challenging. Occasionally, individuals reach adolescence or even early adulthood without a clinical genetic evaluation, and the diagnosis can be missed until that point. Other specialists who may suspect this condition include pediatric gastroenterologists, cardiologist or otolaryngologists.
Testing for CdLS
Genetic testing for CdLS can be used for future prenatal diagnosis for parents’ subsequent pregnancies, confirming a clinical diagnosis in a child who may need surgery or other interventions, or completing a diagnostic odyssey on a child with less clear findings. It should be kept in mind that CdLS gene mutations are detectable only in about 80% of affected individuals. For any molecular testing or genetic sequencing, insurance approval should be received prior to sending, since the cost can be very high. Some insurance companies will not approve any molecular or genetic testing, and the family would have to pay out of pocket costs. In that case a clinical diagnosis would have to be enough. Finally, about 20% of individuals with CdLS are mosaic for the gene change, meaning that it would not be detectable in blood but could be present in some other tissue (eg cheek swab or skin sample); in these situations, a portion of the body’s cells are positive for the gene change but not all. Overall, testing should be performed in conjunction with genetic counseling.