27. Syndromes
Syndromes
“Syndrome,” in medicine, refers to a collection of features that appears to occur over and over in a group of patients and are felt to be due to a specific chromosomal abnormality. In many syndromes, these chromosomal abnormalities can adversely affect the heart.
Turner Syndrome
Noonan Syndrome
Down Syndrome
Marfan Syndrome
Velo-Cardio-Facial Syndrome
VATER (VACTERL) Association
Ehlers-Danlos Syndrome (EDS)
Turner Syndrome
What is Turner syndrome?
• Turner syndrome was initially described by Dr. Henry Turner in 1938. Turner syndrome occurs in approximately 1 of 2,500 females. About 95 percent of fetuses are spontaneously miscarried during pregnancy and thus only 5 percent survive to term.
• Most cases of Turner syndrome occur randomly and thus do not carry a recurrence risk.
• Prenatal diagnosis is available through amniocentesis (sampling of the fluid which surrounds the baby before birth) to look for the abnormality of the X chromosome.
• Since patients with Turner syndrome are unable to have children, there is no risk of mother-daughter transmission.
• Although most women with Turner syndrome are infertile secondary to abnormal ovary development, there have been case reports of women with Turner syndrome becoming pregnant.
Is Turner syndrome marked by a genetic abnormality?
• Turner syndrome is characterized by an abnormality in the X chromosome. Normally females have two X chromosomes (and males have one X and one Y).
• In Turner syndrome, females often have only a single X chromosome. (This occurs in 60 percent of patients with Turner syndrome.)
• Patients may also have “cell line mosaicism”, meaning not all cells in the body have identical chromosomes. Normally all cells have the same chromosomes, but in some patients with Turner syndrome, some cells will have the normal XX pattern and some will have X0 (meaning only one X chromosome as opposed to the normal two chromosomes).
• There are a number of possible mosaic patterns. If a “Y” cell line is present, the patient is at higher risk for developing a particular type of cancer of the ovary and thus removal of the ovaries is recommended.
What are prominent features of Turner syndrome?
• In infancy, the diagnosis of Turner syndrome is often considered in females with swelling of the hands and feet. Other features, particularly involving the head, neck, and arms are described in Cincinnati Children’s Heart Encyclopedia.
• Turner syndrome may not be diagnosed until later in life when a girl undergoes medical evaluation for short stature or lack of pubertal development.
• What are common non-cardiac features of Turner syndrome?
• Turner syndrome patients often have a triangular face with downslanted eyes.
• The ears are often low set and rotated to the back. The neck is usually short with skin folds along the side, giving a webbed appearance.
• The upper jaw tends to be small.
• The hairline in the back is low on the neck and may extend onto the back.
• The chest is broad, with nipples that appear small and spaced far apart on the chest wall (a so-called “shield chest deformity”).
• Often there are abnormalities of the arms in the angle of the elbow, and deformities of the fourth and fifth fingers, and underdevelopment of the fingernails and toenails.
• Turner syndrome patients often have problems with curvature of the spine (scoliosis).
• They also may have multiple moles on the skin.
• Growth is delayed and the average adult height of Turner syndrome patients is about 4 feet 7 inches.
• Infertility and lack of normal pubertal development (e.g., breast and pubic hair) are common. This is due to abnormal development of the ovaries.
• Estrogen replacement is usually prescribed at puberty to enhance development of the adult female body but does not restore fertility.
• Recent advances in the treatment of infertility have made pregnancy possible through the use of a donor egg.
• Turner syndrome patients may also have underactive thyroid glands (hypothyroidism) or diabetes. They are at higher risk for tumors arising from neural tissues and also uterine cancer.
• Turner syndrome patients may have kidney abnormalities including a large single kidney that spans across the abdomen (“horseshoe kidney”) or duplication or malposition of kidney structure or bladder structures.
• Average intelligence is normal, although occasional patients will have some degree of mental retardation.
What are heart defects of Turner syndrome patients?
• Approximately 20 percent of Turner syndrome patients will have a heart defect. The most common problem is coarctation of the aorta, which is a narrowing of the main artery (the aorta) as it carries the red, oxygen-rich blood away from the left side of the heart to the body.
• There have been reports of rupture of the aorta in older individuals with Turner syndrome, presumably due to an abnormality in the strength of the aortic wall.
• Other common heart defects include a bicuspid aortic valve (two, rather than the normal three leaflets in the valve between the left ventricle and the aorta), aortic stenosis (narrowing of the aortic valve) and atrial septal defect (hole between the upper collecting chambers, or atria, of the heart).
What should I expect if my child has heart defects associated with Turner’s syndrome?
• If your child has a heart defect such as coarctation of the aorta, this may require some intervention depending on the degree of narrowing. If the narrowing is mild, nothing may need to be done except regular follow-up with the cardiologist and antibiotics before going to the dentist to prevent infection.
• If the narrowing is significant enough to need treatment, this will most commonly require surgery to remove the narrowed segment and reattach the two ends of the aorta together.
• In some cases treatment for coarctation can be performed in the cardiac catheterization laboratory by dilating the narrowed area with a balloon or putting a stent into the narrowed area.
• A narrowed aortic valve can also be dealt with non-surgically. An atrial septal defect will usually require surgical closure, although selected defects may be amenable to device closure in the cardiac catheterization lab.
Noonan Syndrome
Features, Heart Problems and Inheritance
What is Noonan syndrome?
• Noonan syndrome is a genetic disorder originally described by Noonan and Ehmke in 1963. The majority of early patients recognized to have this syndrome were boys, but it is now clear that girls are equally affected.
• Noonan syndrome occurs in about 1/1,000 to 1/2,500 live births. The actual genetic abnormality has not yet been discovered.
Noonan syndrome features found in infants
• Babies with Noonan syndrome may be diagnosed in infancy because of unusual facial features, including closely spaced and down-slanted eyes and ears that are positioned low on the head and rotated to the back.
• The vertical groove lying in the space between the upper lip and nose is deep and the jaw is small.
• There is excess neck skin and the hairline is low on the back of the neck.
• As the baby grows, the head appears larger than normal with prominent eyes and depression of the top of the nose. The face becomes less triangular in appearance.
• The baby’s birth weight and birth length are usually normal, but after birth the patient’s growth is delayed, with growth usually following along the 3rd percentile (i.e., the Noonan Syndrome patient is taller and heavier than only 3 percent of children his or her age).
Do the features of Noonan syndrome change as the patient grows up?
• In some young adults, the eyes become less prominent.
• Because the patient’s neck is relatively short, the “webbed” appearance of the neck is exaggerated.
• The patient’s skin may be wrinkled or transparent-appearing.
• The hairline in the front is high and the hair itself is usually described as curly or wooly in older children and teens.
How specific are the physical features of Noonan syndrome?
• The clinical features of Noonan syndrome can overlap with a number of other syndromes. In girls suspected of having Noonan syndrome, a chromosomal analysis will often be performed to rule out Turner Syndrome.
Heart in Noonan syndrome patients
• Heart problems occur in about two-thirds of Noonan syndrome patients, with the most common problem being an abnormal narrowing and often thickening of the pulmonary valve.
• Other relatively common heart defects are atrial septal defect (ASDs), ventricular septal defect (VSDs), patent ductus arteriosus (PDA), and abnormal thickening of the heart muscle itself (hypertrophic cardiomyopathy). Problems with the pulmonary valve can be minor, requiring no intervention.
• If the narrowing is significant it may require a procedure such as cardiac catheterization to dilate the narrowed area with a balloon.
• Unfortunately, children with Noonan’s and pulmonary stenosis often have multiple levels of narrowing which cannot be dilated and will require heart surgery.
Medical problems associated with Noonan syndrome
• Children with Noonan syndrome may have medical problems outside of the heart. Mild mental retardation is present in 35 percent of patients.
• An important feature of Noonan syndrome is an unexplained tendency to bleed that should be taken into consideration when procedures likely to cause bleeding are planned.
• The adolescent growth spurt is often blunted or delayed and 60 percent of males have undescended testes. In addition to delay in growth, sexual development is variable and may also be delayed.
• Adult women with Noonan syndrome are usually able to have children but carry a 50 percent risk of passing the disease to their children.
• Skeletal malformations are common. About 70 percent of patients with Noonan syndrome have abnormalities of the rib cage such as “pigeon breast” (pectus carinatum) or a sunken breastbone (pectus excavatum).
• Curvature of the spine (scoliosis) is an early important feature in 40 percent of patients, with half of the spine curves present by age 2 and the remaining 50 percent by age 5.
• Other abnormalities of the spine (the individual vertebrae) and of the arms and feet can also occur
Inheritance of Noonan syndrome
• Some experts believe that most cases of Noonan syndrome are sporadic (not inherited), although 30 percent to 50 percent may be inherited.
• Since the diagnosis of Noonan syndrome in patients without heart disease can be difficult, the actual percentage of inherited cases may be higher than estimated.
• It appears that the majority of inherited cases come from the mother, suggesting that men with Noonan syndrome are infertile. Some think that the risk of recurrence of the disease in siblings of the affected patient is approximately 50 percent, with an approximately 50 percent risk of a parent transmitting Noonan syndrome to his or her offspring.
Down Syndrome (Trisomy 21)
What is Down syndrome?
Down syndrome, also known as Trisomy 21, is the single most common genetic pattern of malformation in man.
Most text books quote the incidence of Down syndrome to be between one in 700 to 800 live births.
In 1866, John Langdon Haydon Down described the physical features and associated medical problems that have come to be known as Down syndrome.
In the 1930s, physicians established a relationship between advanced maternal age and Down syndrome. The chromosomal, or genetic, basis of Down syndrome was not established until 1959.
A normal human cell contains 23 pairs of chromosomes which carry all of a person’s genetic information. Due to several possible abnormal mechanisms of cell reproduction, patients with Down syndrome have an extra (third) copy of the 21st chromosome. Thus, Down syndrome is also called Trisomy 21.
Advanced maternal age is associated with a high incidence of Trisomy 21, but even women of typical child bearing age can have affected babies.
While the diagnosis may be strongly suggested by characteristic physical findings, the final diagnosis is often made only after chromosome analysis, which includes a complete count and visualization under a microscope of the chromosomes taken from cells in the blood.
A geneticist most often performs this along with a clinical evaluation.
What are the physical characteristics of Down syndrome?
The physical characteristics of Down Syndrome in infancy typically involve low muscle tone, flat appearance of the face, upward slanting eye creases, small ears, single skin crease in the palm, extremely flexible joints, large tongue, and several others.
Physical characteristics may be very obvious, but sometimes are so subtle that the diagnosis can only be made after testing is completed. Physical findings do change as the child ages and certain features may become more or less noticeable with time.
Non-cardiac medical problems associated with Down syndrome
While this chapter focuses on the heart problems associated with Down syndrome, some of the other medical problems seen with Trisomy 21 are:
1. Developmental delay — All children with Down syndrome are delayed, although this may not be apparent until the child is beyond infancy. IQ scores range from 20 (severe mental retardation) to 85 (low normal). Overall learning abilities are usually equivalent to a 6 to 8 year old child without Down syndrome.
2. Gastrointestinal abnormalities — 2 percent to 5 percent of children have complete obstruction of the small bowel known as duodenal atresia. Another 2 percent have poor movement abilities of the colon and / or rectum known as Hirschsprung disease.
3. Hearing loss — Some degree of hearing loss is present in 40 percent to 75 percent of children with Down syndrome. Malformations may affect either the middle or inner ear structures. Ear infections can be a frequent, often difficult problem to treat.
4. Eye disorders — 60 percent of children have eye disorders that need monitoring and treatment. Congenital cataracts (loss of transparency of the lens of the eye), glaucoma (increased pressure within the eye), strabismus (cross-eyed) and major refractory errors (far sighted or near sighted) are the common problems.
5. Leukemia — Leukemia occurs in one of every 150 children with Down Syndrome. This is 20 times higher than the general population.
6. Thyroid disorders — Low thyroid levels are seen in approximately 5 percent of children with Down syndrome.
Congenital heart disease associated with Down syndrome
The overall incidence of congenital heart disease in the general population is 0.8 percent. The incidence of congenital heart disease in children with Down syndrome is up to 50 percent.
The types of heart defects in children with Down syndrome can be broken down into three broad categories:
1. Atrioventricular septal defects
2. Ventricular septal defect (VSD), atrial septal defect, or patent ductus arteriosus
3. Other complex heart disease
Atrioventricular septal defects (AV Canal) is greatly over-represented in these children, making up approximately 60 percent of the congenital heart disease found in Trisomy 21. For comparison, AV canals account for only 2.9 percent of the congenital heart defects in the general population.
Ventricular septal defects, atrial septal defects, and patent ductus arteriosus comprise another 20 percent of the congenital heart disease associated with Down syndrome, although these defects are much more common in the general population compared to AV canals.
Other complex congenital heart diseases including Tetralogy of Fallot and hypoplastic left heart syndrome comprise the rest of the heart disease seen in Trisomy 21.
In addition to the heart defects associated with Down Syndrome, isolated elevated blood pressure in the lungs (pulmonary hypertension) is seen with higher frequency in patients with Down syndrome. This high pressure may be related to malformation of the lung tissue, although the exact cause is not known.
The higher pressures may limit the amount of blood flow to the lungs and therefore decrease the likelihood of symptoms of congestive heart failure seen in babies with complete AV canals or large ventricular septal defects.
However, since the pulmonary hypertension can become irreversible, particularly if these large holes are not surgically corrected by a year of age, children with Down syndrome and AV canals or large ventricular septal defects are often referred for surgery earlier than a non-Down syndrome child with the same heart defect.
If the baby does have evidence of high pressures in the lungs, it may complicate postoperative management and hence prolong the recovery time.
Signs and symptoms of children with Down syndrome and congenital heart disease
Depending on the type of heart defect, children with Down syndrome and heart disease may have a variety of symptoms.
Babies with complete AV canal defects may have signs and symptoms of congestive heart failure such as a fast respiratory rate, labored breathing, difficulty completing feedings, sweating with feedings and poor weight gain.
Children with partial AV canals can be asymptomatic because the extra blood flow to the lungs is not enough to cause symptoms of congestive heart failure.
Even babies with large ventricular septal defects as part of their heart disease who should have large amounts of extra blood flowing to their lungs may have no symptoms due to high pressures in the lungs. These babies must be watched carefully to determine the proper timing for surgery.
Tests to diagnose congenital heart disease in babies with Trisomy 21
Most cardiologists would agree that all babies that have been diagnosed with Down syndrome should have a cardiology evaluation because of the high incidence of associated congenital heart defects.
What degree of cardiac evaluation remains controversial. A good history and physical examination should be performed by an experienced cardiologist to rule out any obvious heart defect.
Most cardiologists would perform an electrocardiogram, which can be very helpful in making the diagnosis of AV canal, even in the absence of physical findings.
Some cardiologists would be satisfied with this level of evaluation. There are those, though, who would argue that at least one echocardiogram should be performed to rule out subtle heart problems.
If the diagnosis of congenital heart disease is made, the cardiologist will follow the child with office visits on a fairly regular basis. Most patients can be watched clinically to determine if the child is having difficulty due to the heart defect.
Occasionally, a repeat electrocardiogram, chest X-ray, or echocardiogram is performed to further evaluate clinical changes. These tests are likely to be repeated before surgical repair is recommended.
Rarely, a cardiac catheterization is required for complete evaluation prior to corrective surgery, especially in patients where elevated pressures in the lungs are a concern.
Treatment options for children with Down syndrome and congenital heart disease
Children with Down syndrome and symptoms of congestive heart failure can be initially managed medically with the use of diuretics, blood pressure medications to allow the heart to eject more blood out to the body rather than out to the lungs, and / or digoxin, a medication used to improve the pumping ability of the heart.
If the baby is having difficulty with feeding and weight gain, nasogastric tube feedings with high calorie formula or fortified breast milk can be used to help with growth.
These are all temporary solutions to allow the baby to grow while deciding if and when surgery is indicated. In general, atrial septal defects, ventricular septal defects, and AV canal defects are closed surgically if the child is demonstrating congestive heart failure that cannot be controlled with medication.
If the baby has no signs of heart failure or is controlled well with medications, the decision for surgical closure can be delayed. AV canals are usually repaired electively between 3 and 6 months of age.
Depending on the size of an atrial septal defect or a ventricular septal defect, surgery can be postponed even longer, keeping in mind the risk of developing irreversible high pressures in the lungs.
The decision must be individualized to each child’s physical state as well as the family’s concerns.
Long-term prognosis of babies with Down syndrome and congenital heart disease
Overall, survival beyond one year of age is 85 percent in all children with Down syndrome. Over 50 percent of individuals with Down syndrome live to be greater than 50 years old.
Congenital heart disease is the most common cause of death in early childhood. However, as of the late 1980s, 70 percent of children with Down syndrome and congenital heart disease lived beyond their first birthday. With improved medical and surgical care, these numbers continue to improve.
Marfan Syndrome
What is Marfan syndrome?
Marfan syndrome is a genetic disorder with an incidence rate of 1 per 5,000 individuals that affects the body’s connective tissues, or the tissues in between the main cells of each organ of the body.
All organs contain connective tissue, therefore, the manifestations of Marfan syndrome appear in many parts of the body, particularly the heart, skeletal system and eyes. The skin and lungs may also be involved.
The term “syndrome” refers to the collection of physical findings that occur together often enough to provide a recognizable pattern that allows the diagnosis to be made. It was first described in a 6-year-old girl by the French pediatrician, Antoine Marfan, in 1896.
Manifestations of Marfan syndrome
Cardiac
The heart is affected in nearly 80 percent of patients with this syndrome. The most important finding is enlargement or dilation of the aorta, the main blood vessel that carries blood to the body. The change in connective tissue in individuals with Marfan syndrome allows the first few inches of the aorta (where the vessel attaches to the lower, left chamber of the heart) to stretch and widen. If the aorta stretches and becomes significantly dilated, a tear or rupture of the vessel may result.
Additionally, as the aorta widens, the leaflets of the aortic valve may be stretched to a point where they fail to close completely and will thereby allow blood to leak back into the heart, causing the left ventricle to enlarge. If left untreated, the heart can go into failure. Another valve of the heart that frequently is affected is the mitral valve, which may also leak causing the heart to become large and work harder.
Skeletal
Skeletal involvement is evident in nearly all individuals with Marfan Syndrome. A person with Marfan syndrome will usually be tall, slender and somewhat loose jointed or limber. The arms, legs, fingers and toes may be disproportionately long when compared to the trunk. Scoliosis is common, and the breastbone may be either very prominent or depressed.
Eyes
Lenses in eyes of patients with Marfan syndrome are dislocated (ectopia lentis) in a high percentage of cases. The degree of visual disturbance associated with ectopia lentis may be mild or quite severe. Near-sightedness (myopia) is also common in individuals with Marfan syndrome. In addition, the retina of the eye may become detached and lead to blindness.
Skin
The skin often exhibits stretch marks, known as stria atrophicae. These can occur among individuals who do not have Marfan syndrome, particularly as a result of pregnancy or marked weight gain and loss. However, patients with Marfan syndrome tend to develop stria at an early age and without weight change. These stria commonly appear on the shoulders, hips and lower back.
Lungs
The lungs also need connective tissue to provide stability and elasticity to the tiny air sacs. Although the altered lung elasticity rarely causes any noticeable problems, patients with Marfan syndrome may develop spontaneous collapse (or pneumothorax) of a lung at a rate of about 50 times greater than the general population. This can occur after a minor blow to the chest or without any identified insult.
Diagnosis and Genetics of Marfan Syndrome
The cause of the Marfan syndrome has been identified. A gene located on chromosome 15 encodes a specialized protein called “fibrillin” that contributes to the production of normally functioning connective tissue in our body. In Marfan syndrome, a mutation of the fibrillin gene is present in the majority of patients (~75%).
Unfortunately, not all patients with Marfan syndrome have the same abnormal genetic protein. There may be slight variations or mutations in the fibrillin gene, which can produce the same findings in all patients. Unrelated patients or families appear to have different mutations in the fibrillin gene.
The diagnostic evaluation for this syndrome should be performed by physicians experienced with the condition. Evaluation includes a detailed family history and physical examination.
Since the syndrome involves many body systems, the syndrome can be divided into major and minor criteria.
Approximately 80 percent of patients with Marfan syndrome will have a positive family history, which is one major criterion of the syndrome. This requires a very specific diagnosis of the syndrome in other family members, not just someone who is unusually tall. In the rest of the patients, the syndrome results from a new mutation not present in other family members.
A second major criterion for diagnosing the syndrome involves the skeletal system. The most consistent and reliable measure is an abnormally low ratio of the upper trunk of the body to the lower extremities. This ratio is generally less than 0.87 in African-Americans and less than 0.92 in Caucasians.
Another abnormal measurement includes the comparison of the arm span to the total height of the individual, where the arm span to height ratio exceeds 1.05. Other features include abnormalities of the sternum (breastbone), joint hyperextensibility, and scoliosis.
A third major criterion for this diagnosis is ocular, or related to the eyes. Virtually all patients with Marfan syndrome have myopia or near-sightedness. About 70 percent of patients have ectopia lentis or dislocated lenses of the eyes. This may be very mild. Hence, determination of this abnormality requires dilation of the pupils and slit lamp examination by an experienced ophthalmologist.
The fourth major criterion is cardiovascular and includes aortic dilation or dissection.
Minor criteria include mitral valve prolapse, spontaneous pneumothorax, stretch marks, or recurrent hernias.
In order for the diagnosis of Marfan syndrome to be made in the first identifiable case of a family, at least two major criteria in different systems and involvement of a third system must be present. If there is a positive family history, a major criterion in one system and involvement of either major or minor criteria in a second system will permit the diagnosis to be made.
Treatment and Management of Marfan Syndrome
Although there is no “cure” for this condition, effective treatment is available. Management and treatment of the Marfan syndrome are best discussed and understood by directing attention to the affected organ systems.
The Heart and Aorta: Perhaps one of the most well-known and frightening complications of this syndrome is the sudden rupture of the aorta. Therefore, the first line of defense is detection of this abnormality. It can only be accurately diagnosed and monitored through routine imaging techniques.
The most common technique used is echocardiography, which is able to evaluate the size of the aorta, the progression and change in its dimensions, the overall size and function of the heart, and any heart valve involvement. Routine echocardiography for those patients without obvious cardiovascular problems can be performed on a yearly basis. Enlargement of the aorta, particularly significant enlargement, is often monitored every six months to observe sudden increases in the size of the aorta or progressive enlargement, which may require treatment.
If the aortic valve begins to leak or if the aorta begins to enlarge excessively, surgical intervention by repairing or replacing either the valve or the enlarged aorta may be necessary. Presently, Marfan patients are best advised to have this surgical intervention performed in a medical center that has experience with the syndrome. In some instances, magnetic resonance imaging (MRI) may be utilized to diagnose and regularly evaluate the size of the aorta after surgery or a rupture.
In addition to monitoring the size of the aorta once it is enlarged, several important medical recommendations are made. Patients with an enlarged aorta will be advised against participating in any high impact or high isometric or static activities, such as weight lifting, football, basketball, etc. These activities can cause sudden excessive enlargement of the aorta leading to tearing or possible rupture.
In addition, medications, called “beta blockers,” will be prescribed to regulate blood pressure and heart rhythm. These medications help blunt the sudden rise in blood pressure and/or heart rate that occur during activities and may prevent further enlargement of the aorta or reduce the aortic size. Stress tests may be ordered to help monitor the effectiveness of these drugs.
There is a trial underway through the Pediatric Heart Network investigating another group of drugs called angiotehsin II receptor blockers. The goal of this project is to evaluate its effect at slowing the rate of aortic root enlargement and the development of related complications. It is also being compared to the widely used Beta-blockers.
Skeletal System: In the skeletal system, severe curvature of the spine and / or deformity of the breast bone (sternum) represent the most serious problems, mostly related to the impact these have on lung function.
These skeletal abnormalities need to be evaluated by general surgeons or orthopedic surgeons who are experienced in the skeletal deformities, since many of the skeletal changes may require specialized surgery to correct them. Various surgical procedures can stabilize the spine if there is significant spinal deformity, and techniques are available to correct severe depression of the breast bone.
The Eyes: The major problem with the eyes is dislocation of the lenses. In most patients, dislocation of the lens is a minor problem. Dislocated lenses often interfere with vision and may require special eyeglasses or contact lenses. On rare occasions the lens may have to be removed. Because of the increased risk of retinal detachments, activities that involve blows to the head such as football, boxing and diving should be avoided.
Other Systems: Because of the risk of lung collapse (pneumothorax), Marfan syndrome patients should not subject themselves to extremes of air pressure or rapid changes in pressure. For example, Marfan syndrome patients should avoid riding in unpressurized aircraft or diving under water more than several feet.
As mentioned above, the stretch marks on the skin do not cause problems and, although they may be of cosmetic concern, cannot be prevented.
Inheritance of Marfan Syndrome
Marfan syndrome is inherited in an autosomal dominant manner. The term autosomal means that men and women are equally likely to inherit and / or pass on the condition. Dominant conditions typically affect individuals in every generation.
If an individual has an autosomal dominant condition like Marfan syndrome, they have a 50% or 1 in 2 chance of passing the condition on to each of their children. Because of the variable expression of the Marfan gene, it is not possible to predict how severely a child who inherits the gene will be affected.
Prognosis for Patients with Marfan Syndrome
While Marfan syndrome is a lifelong disorder that is chronic and often progressive, the outlook has improved in recent years. Early diagnosis and advances in medical technology have enhanced the quality of life for people with the Marfan syndrome and lengthened their lifespan.
In addition, early identification of risk factors (such as aortic dilation) allows doctors to intervene and prevent or delay complications. Advances being made by researchers provide hope for the future. With early diagnosis and appropriate management, the life expectancy for someone with Marfan syndrome is similar to that of the average person.
Velocardiofacial Syndrome (VCFS)
Shprintzen Syndrome, Craniofacial Syndrome or Conotruncal Anomaly Face Syndrome
What is velocardiofacial syndrome?
Velocardiofacial Syndrome might be referred to by other names including Shprintzen Syndrome, Craniofacial Syndrome, or Conotruncal Anomaly Face Syndrome.
The name Shprintzen Syndrome comes from physician Dr. Robert Shprintzen of the Center for Craniofacial Disorders, who, in 1978, described a series of 12 children with a cleft palate (incomplete closure of the roof of the mouth), heart defects (abnormalities of the heart from the time of birth) and similar facial characteristics.
The name Velocardiofacial Syndrome comes from the Latin words “velum” meaning palate, “cardia” meaning heart, and “facies” having to do with the face thus incorporating the most common features of cleft palate, heart defects, and a characteristic facial appearance.
Velocardiofacial syndrome is the most common syndrome associated with a cleft palate. It is estimated that 1 in 2,000 to 5,000 children per year are born with velocardiofacial syndrome, and over 130,000 individuals in the United States have this syndrome.
Other common findings include minor learning problems and speech and feeding problems.
Since the initial description of this syndrome, many other parts of the body have been reported to be involved.
Many of the systems that influence the development of a child such as the:
• Immune system (helps to fight off infections)
• Endocrine system (the series of glands that secrete important compounds called hormones for normal growth and development)
• Neurological system (brain control centers for learning, speech and hearing, and moods) have also been reported to be affected
The Velocardiofacial Syndrome Education Foundation Center for the Diagnosis, Treatment and Study of VCF Syndrome currently lists 185 reported findings in patients with velocardiofacial syndrome. It is important to realize none of these occurs 100 percent of the time.
It has also been realized that children with velocardiofacial syndrome are born with these features and that they do not progress over time. This comprehensive list serves as a guide for evaluating each individual to determine which areas may be affected so that the most complete therapeutic interventions can be provided to the child and their families.
Velocardiofacial syndrome causes
Researchers have been interested in this question for a number of years. While the exact cause of velocardiofacial syndrome remains unknown, investigators have identified an associated chromosomal defect in people with velocardiofacial syndrome.
Most children identified as having velocardiofacial syndrome are missing a small piece of chromosome 22. This so-called “deletion” is located at a region of the chromosome called 22q11.2.
Which gene or genes located on this part of chromosome 22 are missing and responsible for causing the features of velocardiofacial syndrome remain unknown.
There is a genetic test for the diagnosis of this condition called a “FISH analysis” that can be performed in many medical centers, including the Heart Center at Cincinnati Children’s Hospital Medical Center.
In studying some families with velocardiofacial syndrome, scientists have determined that it is an autosomal dominant disorder. This means that only one of the parents needs to have the chromosomal change in order to pass it along to a child.
A parent with velocardiofacial syndrome has a 50/50 chance of having a child with it. However, it is estimated that velocardiofacial syndrome is inherited this way in only 10 to 15 percent of cases.
Most of the time neither of the parents has the syndrome nor carries the defective gene and the cause of the deletion is called “sporadic.”
Deletions in this area of chromosome 22 have also been associated with other syndromes, including DiGeorge syndrome and one type of OPITZ G/BBB syndrome.
What kinds of problems might a child have?
In addition to the characteristic physical features, a child with velocardiofacial syndrome may have:
• Long face with prominent upper jaw
• Flattening of the cheeks
• Underdeveloped lower jaw
• Bluish color below the eyes
• Prominent nose with narrow nasal passages
• Thin upper lip with a down-slanted mouth
A child with velocardiofacial syndrome may have:
• Multiple abnormalities of the heart including Ventricular septal defect (VSD), pulmonary atresia, tetralogy of Fallot, truncus arteriosus, interrupted or right-sided aortic arch and transposition of the great arteries.
• Learning disabilities in one or more areas
• Hearing loss
• Speech problems
• Extremes of behaviors/mood swings
Will my child need surgery?
For any child with velocardiofacial syndrome, depending on the presence and severity of various features, the following surgeries might be necessary:
• Repair of heart defects (see list of specific congenital heart defects)
• Repair of cleft palate
• Repair / reconstruction of the lower jaw
• Reconstructive surgery of the ears
VACTERL or VATER Association
What is VACTERL association?
• VACTERL or VATER association is an acronym used to describe a series of characteristics which have been found to occur together.
• V stands for vertebrae, which are the bones of the spinal column.
• A stands for imperforate anus or anal atresia, or an anus that does not open to the outside of the body.
• C is added to the acronym to denote cardiac anomalies.
• TE stands for tracheoesophageal fistula, which is a persistent connection between the trachea (the windpipe) and the esophagus (the feeding tube).
• R stands for renal or kidney anomalies.
• L is often added to stand for limb anomalies (radial agenesis).
• Babies who have been diagnosed as having VACTERL association usually have at least three or more of these individual anomalies. There is a wide range of manifestation of VACTERL association so that the exact incidence within the population is not exactly known.
What are the heart problems seen with VACTERL association?
• Up to 75 percent of patients with VACTERL association have been reported to have congenital heart disease.
• The most common heart defects seen with VACTERL association are ventricular septal defect (VSD), atrial septal defects and tetralogy of Fallot.
• Less common defects are truncus arteriosus and transposition of the great arteries. Babies may have a murmur at birth, however absence of a murmur does not rule out congenital heart disease. If a baby is suspected of having VACTERL association, consultation with a pediatric cardiologist is recommended.
Other defects seen with VACTERL association
• Vertebral anomalies, or defects of the spinal column, usually consist of small (hypoplastic) vertebrae or hemivertebra where only one half of the bone is formed.
• About 70 percent of patients with VACTERL association will have vertebral anomalies. In early life these rarely cause any difficulties, although the presence of these defects on a chest X-ray may alert the physician to other defects associated with VACTERL.
• Later in life these spinal column abnormalities may put the child at risk for developing scoliosis, or curvature of the spine.
• Anal atresia or imperforate anus is seen in about 55 percent of patients with VACTERL association. These anomalies are usually noted at birth and often require surgery in the first days of life. Sometimes babies will require several surgeries to fully reconstruct the intestine and anal canal.
• Esophageal atresia with tracheo-esophageal fistula (TE fistula) is seen in about 70 percent of patients with VACTERL association, although it can frequently occur as an isolated defect.
• Fifteen percent to 33 percent of patients with TE fistulas will also have congenital heart disease. However these babies usually have uncomplicated heart defects, like a VSD, which may not require any surgery.
• Renal or kidney defects are seen in approximately 50 percent of patients with VACTERL association. In addition, up to 35 percent of patients with VACTERL association have a single umbilical artery (there are usually two) which can often be associated with kidney or urologic problems.
• These defects can be severe with incomplete formation of one or both kidneys or urologic abnormalities such as obstruction of outflow of urine from the kidneys or severe reflux (backflow) of urine into the kidneys from the bladder.
• These problems can cause kidney failure early in life and may require kidney transplant. Many of these problems can be corrected surgically before any damage can occur.
• Limb defects occur in up to 70 percent of babies with VACTERL association and include absent or displaced thumbs, extra digits (polydactyly), fusion of digits (syndactyly) and forearm defects.
• Babies with limb defects on both sides tend to have kidney or urologic defects on both sides, while babies with limb defects on only one side of the body tend to have kidney problems on that same side.
• Many babies with VACTERL are born small and have difficulty gaining weight. However, they tend to have normal development and intelligence.
VACTERL association causes
• No specific genetic or chromosome problem has been identified with VACTERL association. VACTERL can be seen with some chromosomal defects such as Trisomy 18 and is more frequently seen in babies of diabetic mothers. VACTERL association, however, is most likely caused by multiple factors.
What if my baby is diagnosed with VACTERL association?
• The important thing is to identify all of the possible associated defects and treat them accordingly. Unless there are several very severe defects, babies with VACTERL association do well and can lead normal productive lives.
Ehlers-Danlos Syndrome (EDS)
What is Ehlers-Danlos syndrome (EDS)?
EDS is a genetic condition that affects connective tissue, the most abundant type of tissue in the body which provides support, structure, stability and normal scar formation. Currently, six sub-types of EDS have been defined, the majority of which are characterized by joint hypermobility, skin extensibility and tissue fragility. While these three cardinal features are present in most types of EDS, considerable differences exist in severity of involvement.
The term “syndrome” refers to the collection of physical findings that occur together often enough to provide a recognizable pattern that allows a diagnosis to be made. This condition was named after two physicians, Edvard Lauritz Ehlers and Henri-Alexandre Danlos.
Manifestations of Ehlers-Danlos Syndrome
Specific manifestations depend upon the type of EDS an individual or family has. The two most common types of EDS are the classic type and hypermobile type. These types feature soft skin with varying degrees of stretchiness and poor wound healing. In addition, some individuals with EDS (up to 25%) may have cardiac complications.
Classic EDS is characterized by joint laxity, hyperextensibility of skin, and poor wound healing. The skin often has a soft and velvety texture and can be easily stretched. The skin is fragile and bruises easily. Individuals with classic EDS also experience abnormal scarring including thin and atrophic scars following trauma or surgical procedures. Additional skin involvement includes molluscoid pseudotumors (small spongy tumors found over scars and pressure points which consist of fat surrounded by a fibrous capsule).
• Approximately half of individuals with classic EDS are delivered prematurely due to premature rupture of fetal membranes.
• Up to 1/3 of individuals have cardiac abnormalities which may include mitral valve prolapse and aortic root dilatation.
• The joint hypermobility may lead to the onset of osteoarthritis in the third or fourth decade.
• Musculoskeletal features include scoliosis and pes planus ( flat feet).
Classic EDS (formerly EDS types I and II) is characterized by:
• Joint laxity / hypermobility (being “double-jointed”)
• Soft, velvety, stretchy skin
• Abnormal scars (thinned or atrophic)
• Poor wound healing
• Easy bruising
Hypermobile EDS is characterized primarily by hyperextensibility of large and small joints and soft, velvety skin. Individuals with hypermobile EDS have normal scarring but may have stretchy skin. Molluscoid pseudotumors are absent.
Individuals with hypermobile EDS may also have cardiac involvement similar to that in the classic type with mitral valve prolapse and occasional dilation and/or rupture (rare) of the ascending aorta. Musculoskeleteal features seen in classic EDS such as pes planus and scoliosis are also common.
Hypermobile EDS (formerly EDS type III) is characterized by:
• Joint laxity / hypermobility (being “double jointed”)
• Soft, velvety skin which does not stretch as much as the classic type
• Normal scar formation
• Poor wound healing
• Chronic joint pain (more common in the hypermobile type than the classic type)
Individuals with vascular EDS have a characteristic facial appearance with a thin, delicate appearing, and somewhat “pinched” nose, thin lips, hollow-appearing cheeks and occasionally a staring appearance due to decreased adipose (fatty) tissue below the eyes. In addition, individuals with vascular EDS have thin, translucent skin with easy bruisability; scar formation is usually normal. Often, vasculature is easily visible beneath the skin. Affected individuals are at high risk for life-threatening rupture of the intestine, uterus, or medium-sized arteries. Stroke and uterine rupture following delivery is also common. Individuals with vascular EDS typically have hypermobility of the small joints (i.e., fingers) but do not have the level of joint hypermobility observed in classic and hypermobile EDS.
The kyphoscoliosis type is characterized by early onset of joint laxity, kyphoscoliosis (presence of kyphosis and scoliosis; spinal deformity combining sideways curvature and hunching forward of the upper part of the spine) and hypotonia (low muscle tone). Scleral (white, protective, outer layer of the eyeball) fragility associated with ocular globe rupture is observed in a minority of patients. Skin fragility, easy bruisability, and skin hyperextensibility occur to some extent in most patients, although they are less prominent than in patients with classical EDS. Like those with the vascular form, those with the kyphoscoliosis form of EDS are at risk of having a potentially catastrophic arterial rupture. Most patients have radiologically detectable osteopenia.
The arthrochalasia type of Ehlers-Danlos syndrome is characterized by extreme joint laxity, multiple joint dislocations and congenital hip dislocations that are often difficult to repair surgically. Skin findings include tissue fragility and widened scars, however, these findings are less prominent than in the classical form of EDS.
The dermatospraxis type of EDS is characterized by striking dermal fragility. The skin is lax but not stretchy, and joint dislocation is usually not a feature. Infants have been reported with premature rupture of membranes, and umbilical / inguinal hernias may occur.
Diagnosis and Genetics of EDS
For all types of EDS, diagnosis is based on medical and family histories and physical examination. Genetic testing for the vascular type of EDS is available and useful for confirmation of a clinical diagnosis and for either confirming or ruling out a diagnosis in at-risk family members.
Classic Type
Skin hyperextensibility, widened atrophic scars and joint hypermobility are the major diagnositic criteria for the classical form of EDS.
Underlying Defect: Abnormal type V collagen observed in one-half of families
Genes: COL5A1, COL5A2
Diagnostic Testing: Fulfillment of clinical criteria
Hypermobile Type
Stretchy and velvety skin in addition to joint hypermobility are the major diagnostic criteria for hypermobile EDS.
Underlying Defect: Not known
Genes: Not known
Diagnostic Testing: Fulfillment of clinical criteria
Vascular Type
Characteristic facial appearance, thin, translucent skin, arterial / intestinal / uterine fragility or rupture, and extensive bruising are the major diagnostic criteria.
Underlying Defect: Abnormal type III collagen
Genes: COL3A1
Diagnostic Testing: Molecular testing / confirmation available (blood sample)
Kyphoscoliosis Type
Major diagnositic criteria include generalized joint laxity, severe muscle hypotonia at birth, progressive scoliosis at birth or within the first year of life, and scleral fragility and rupture of the ocular globe.
Underlying Defect: Enzyme deficiency (lysyl hydroxylase)
Genes: PLOD1
Diagnostic Testing: Measurement of the ratio of pyridinium cross-links (urine)
Arthrochalasia Type
Severe generalized joint hypermobility with recurrent subluxations and congenital, bilateral hip dislocation are the major diagnostic criteria. Minor criteria include tissue fragility with widened atrophic scars, kyphoscoliosis and stretchy skin.
Underlying Defect: Unknown
Genes: COL5A1, COL5A2
Diagnostic Testing: None available