Cornelia de Lange syndrome

Cornelia de Lange syndrome (CdLS) is a genetic developmental disorder present from birth, although it is not always diagnosed immediately after delivery.
 It causes a wide range of physical and cognitive manifestations that affect many parts of the body. The features of this disorder vary greatly among affected individuals, ranging from relatively mild to severe. It affects both sexes equally. It can lead to serious developmental disorders, influencing both the mental and physical development of the child.

CdLS is estimated to affect approximately 1 in 30,000 to 300,000 newborns (for example, in 2006 there were about 2,500 people in the USA with this syndrome). The syndrome is considered rare, but this may not necessarily be the case, as it may simply be underdiagnosed.

Cause of the disorder:

Most cases arise as a result of a spontaneous genetic mutation in a reproductive cell.
 In 2004, scientists at the Children’s Hospital of Philadelphia identified a gene (NIPBL) on chromosome 5 that causes this syndrome. In 2006–2007, additional genes (SMC1A, SMC3, and HDAC8) were discovered that also cause CdLS when mutated. At least 35 percent of tested individuals with the syndrome do not have an identified gene mutation. It is therefore likely that other genes may also cause CdLS when mutated. Active research continues.

Studies suggest that SMC1A (approximately 5 percent of cases) and SMC3 mutations tend to cause milder symptoms than those associated with the NIPBL gene. Mutations in NIPBL have been identified in more than half of all people with this syndrome. The proteins produced by these genes help regulate the structure and organization of chromosomes and are involved in repairing damaged DNA. They also regulate the activity of certain genes involved in the development of limbs, the face, and other body parts.

Heredity:

Unlike most X‑linked genes, where males are more frequently affected and females are typically carriers, the X‑linked CdLS gene affects males and females equally. Fewer than 1 percent of individuals have affected parents. If the parents are clinically unaffected, the estimated risk for additional siblings is about 1.5 percent due to the possibility of germline mosaicism. If the mother carries the mutation that causes the disorder, the chance of transmitting it in each pregnancy is 50 percent. In a family with more than one affected individual, one of the parents is certainly a carrier of CdLS (either through inherited mutation or germline mosaicism — meaning the mutation occurred first in their germline cells). The probability that multiple children in the same family are affected due to a completely random gene mutation, without one parent being a carrier, is practically zero (though not impossible - much like winning the Euromillions twice, theoretically possible, but extremely unlikely). The mutation can also appear several generations later.

Individuals with CdLS often resemble one another. Interestingly, a mutation on the X chromosome typically causes more visible features in boys.

The most affected area is speech development. Many children with CdLS never learn to speak fluently; with support from family and a speech therapist, they may learn a few words. Children with a milder form may learn to speak well around the age of 5 to 6 years. Almost all children learn to walk between the ages of 2 and 5 years. Facial expression often lacks emotion (pain or laughter may be only slightly visible). Parents often report that their children are happy, feel love for other family members, and laugh with them. However, they tend to reject physical contact. They also experience difficulties with social interaction.

Diagnosis:

Clinical laboratory examinations are available that focus on identifying the characteristic phenotype (since 2006, tests for the NIPBL, SMC1A, SMC3, and HDAC8 genes have been performed). Ultrasound examinations monitor the child’s growth and assess the limbs, heart, diaphragm, and other organs or structures affected by CdLS. Growth abnormalities typically present in the second trimester. Up to 68 percent of cases with significant CdLS abnormalities are not detected by ultrasound. Despite today’s level of medical advancement, CdLS may still be insufficiently or incorrectly diagnosed.

Treatment:

There is no causal therapy for CdLS; treatment is supportive and focuses on managing somatic problems - it involves a comprehensive team of specialists (pediatricians, surgeons, orthopedists, ENT specialists, cardiologists, dentists, speech therapists, physiotherapists, etc.). It is important to focus on educational strategies and regularly monitor the condition of the eyes, ears, heart, kidneys, and any other abnormalities. The most important aspect, however, is to treat the child as you would treat a healthy child. Studies have shown that these children have abilities in perceptual organization, visuospatial memory, and fine motor skills. For this reason, visual teaching methods (e.g., computers with augmentative communication tools, or devices with pictures and symbols) are recommended over traditional verbal teaching approaches.

What you can expect:

In the past, many children with CdLS did not live very long or with good quality of life, because their medical needs were not well understood. Today, most individuals with a mild form of CdLS have a normal life expectancy. They are capable of managing everyday self‑care activities (eating, toileting, dressing). Some may live independently, have jobs, and form relationships, while others require support and assistance throughout their lives.

• low birth weight (usually under 2.5 kg); slow growth continues after birth
• delayed child development, often accompanied by mild, moderate, or severe intellectual disability (IQ ranges from 30–102, average around 53)
• skin manifestations – excessive body hair (hypertrichosis), especially on the back
• bone abnormalities – affecting the limbs (mainly hands and elbows)
• limbs are often small; the body appears disproportionately large compared to them – fingers may also be short and tapered
• visible differences in the limbs (length and appearance); sometimes entire limbs are missing, other times only parts
• frequent curvature of the 5th finger
• partial fusion of the 2nd and 3rd fingers
• characteristic facial features: thick, joined eyebrows; long eyelashes; low‑set ears; widely spaced small teeth; short upturned nose; thin lips and crescent‑shaped mouth
• spina bifida in severe cases (25% of cases)
• small head size (microcephaly) in severe cases
• many facial features become less pronounced in adulthood
• hearing and vision impairment (60–80% of cases); partial to complete hearing loss (reported in up to 80% of cases); narrowing of the ear canal (80% of cases)
• nearsightedness (60% of cases) up to blindness; glasses are poorly tolerated
• ptosis (45% of cases), nystagmus (37% of cases), hypertropia
• gastrointestinal problems: reflux (food returning from the stomach) – up to 90% of cases (vomiting and aspiration risk)
• intermittent and "poor" appetite
• constipation, bloating
• intestinal malrotation
• these problems may be acute or mild: heart and lung defects are common (up to 46% of cases); infections or inflammation of the lungs and upper respiratory tract (25% of cases) – often caused by silent reflux; coarctation of the aorta
• urogenital abnormalities: hypoplastic genitalia
• urinary tract reflux
• kidney cysts
• renal dysplasia and hypoplasia
• possible impaired renal (urinary) function
• behavioral problems: autism‑like behaviors – self‑stimulation (44% of cases), such as hitting the face, biting hands, fingers, or lips, or scratching the skin
• aggression (about 48% of cases)
• communication difficulties