Dilated Cardiomyopathy in Children: Early Detection and Treatment
PLAIN RADIOGRAPHIC DIAGNOSIS OF CONGENITAL HEART DISEASE
PLAIN RADIOGRAPHIC DIAGNOSIS OF CONGENITAL HEART DISEASEPLAIN RADIOGRAPHIC DIAGNOSIS OF CONGENITAL HEART DISEASE
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4e-1. Pulmonary valvular stenosis. (Legend.)A. PA chest film demonstrates normal heart size. The pulmonary artery is abnormally convex with normal branch pulmonary arteries. The aortic arch is left-sided.
B. Right posterior oblique view demonstrates right ventricular dilation with increased convexity of the anterior chamber.
Pulmonary stenosis was originally described by Morgagni and may be classified as valvular, infundibular or supravalvular. Some form of pulmonary stenosis occurs in up to 20-30% of patients with congenital heart disease. One study from Toronto Children's reported pulmonary stenosis in 9.9% of all congenital heart lesions.
Anatomy: There are six types of pulmonary valve in association with stenosis including, domed, unicommissural, bicuspid, tricuspid, hypoplastic annulus, and dysplastic. Dysplastic pulmonary valvular stenosis is typical of that seen in Noonan's syndrome and less common conditions including LEOPARD and Watson syndromes.
Classification:
Physical findings: These obviously depend on severity of right ventricular outflow tract obstruction. In mild stenosis, the jugular venous pulse, pulses and precordium are normal. There is often a systolic ejection click secondary to doming of the valve, which moves closer to the first heart sound with increasing severity of the stenosis. The second heart sound is normally split and becomes increasingly split with increasing severity of stenosis. The pulmonary component of the second heart sound decreases with increasing severity. The murmur is typically an ejection systolic murmur located at the left upper sternal edge, which radiates to the back. The murmur duration and harshness increases with increasing obstruction and may even disappear with near total obstruction. The murmur increases in intensity following amyl nitrate inhalation, which is the opposite of aortic valve stenosis. Co-existent pulmonary regurgitation should be listened for in addition to a diastolic rumble of an associated atrial septal defect. Severe stenosis may be accompanied by elevated A waves in the JVP, a tapping apex beat, a right ventricular heave, a thrill in the left second intercostal space and a harsh long systolic murmur. The ejection click occurs close to the first heart sound and the second heart sound may be soft. There may be evidence of right heart failure.
ECG: There is almost always abnormality in severe PS, with right axis deviation and right ventricular hypertrophy. There may also be right atrial enlargement and T wave changes
Treatment: Transcatheter pulmonary balloon valvuloplasty in children was first performed by Kan in the early 80s. Balloon valvuloplasty is generally advocated if the gradient is greater than 40-50mmHg. Surgical valvectomy is rarely required in isolated pulmonary valve stenosis indicating the success of valvuloplasty.
Possible Explanations For The Presence Of NF Clinical Features And A Negative Genetic Test
This month, I'd like to discuss the options that are available when an individual has clinical features of any of the three types of NF but genetic testing is negative.Genetic Testing for NF1 Next-generation sequencing (NGS), using blood or saliva samples, is the most frequently used genetic test to detect variants that cause the condition (referred to as "pathogenic variants") in the NF1 gene. NGS involves sequencing of the entire genome, or, in some cases, the entire component of the genome that is encodes for protein (referred to as the "exome"). A gene is encoded in segments, called exons, which code for the amino acids of a protein, separated by introns, which are intervening sequences. Most NGS technology is capable of detecting variants in the exons and around the borders of introns and exons. However, occasionally a variant exists deep in the intron that is more difficult to detect.RNA-Based Testing RNA-based testing might be used when a pathogenic variant cannot be identified using NGS. RNA is the molecule that copies the genetic information for a particular protein from DNA and moves it to the part of the cell where protein is made. The UAB Medical Genomics Laboratory can perform NF1 RNA testing, which can be done in cases of a negative or inconclusive NF1 result using NGS. RNA-based testing is a highly specialized, intensive process that requires well-trained technicians with distinct expertise. It detects an abnormality in the RNA copy (mRNA) of the NF1 gene and can be used to identify a genetic variant deep within the intron. Some individuals who have received an inconclusive result with NGS can receive an NF1 diagnosis with RNA-based testing.Mosaicism Mosaicism is also a possibility in individuals with clinical features of NF1 who receive a negative genetic test result. In these cases, the NF1 pathogenic variant affects some cells in the body but not all due to acquisition of a mutation during development. NGS can sometimes detect a minor cell population in the blood that can confirm mosaicism, but if cells with the variant are not present in blood in sufficient numbers, they will not be detected. The next best approach is testing of cells in neurofibromas or café-au-lait spots. The UAB Medical Genomics Laboratory is one of few labs anywhere equipped to perform testing of these tissues; this technique requires obtaining biopsies of tumors or café-au-lait spots (preferably two or more) and transporting tissue that contains Schwann cells (neurofibromas) or melanocytes (café-au-lait spots) to be grown in a cell culture system.While the UAB laboratory stopped tumor testing during the COVID-19 pandemic, they are currently performing final validation to resume tumor testing and have already resumed offering melanocyte cultures for café-au-lait spots. Because of the "two-hit" genetic mechanism that causes the development of tumors and café-au-lait spots in individuals with NF1, one would expect two NF1 pathogenic variants to be present in the tumor Schwann cells or café-au-lait spot melanocytes; one is an acquired mutation, and one is the mosaic variant. All people have two copies of the NF1 gene, one inherited from each parent. In individuals with NF1, one copy of the NF1 gene is altered (the variant) due to either inheriting the variant-containing gene from a parent, or a new mutation that occurs in the egg or sperm prior to conception, or from a mutation that occurs early in embryonic development. This represents the "first-hit" genetic variant. For a neurofibroma or café-au-lait spot to develop in someone with NF1, a random genetic mutation must occur to the other copy of the NF1 gene in the tissue that will become the neurofibroma or café-au-lait spot; this is referred to as the "second-hit" variant.
Genetic Testing for NF2 and Schwannomatosis Blood samples are often used to perform NGS to identify a pathogenic variant in the NF2 gene that confirms a diagnosis of NF2. However, many individuals with NF2 have mosaicism, which can only be detected by testing tumor tissue. For this testing, fixed tissue, even tissue that may have been archived for years, can be used. Mosaicism is also common in people who have schwannomatosis. Here, too, tumor testing, including testing of archived fixed tissue, can be done if blood testing is negative.When these approaches do not produce a definitive answer, it is important to note that, regarding NF2, both vestibular schwannomas and meningiomas can occur in individuals in the general population who do not have NF2. In the case of schwannomatosis, it is possible that other genes yet to be discovered may also be associated with the condition.
Individuals with Multiple Neurofibromas It is known that the gene product of NF1, neurofibromin, functions as a regulator of a protein called RAS. RAS is a key component of the RAS/MAPK cell signaling pathway that controls cell growth and development. This pathway involves multiple proteins that are involved in transmission of signals received at the cell surface to regulate genes in the cell nucleus. It has been learned that variants in genes that encode these other proteins in the pathway also can lead to medical disorders, which are collectively called "RASopathies."One of these disorders, Noonan syndrome, is a distinct disorder from NF1, but in rare instances can cause individuals to develop neurofibromas around the spine, similar to NF1. Noonan syndrome is characterized by short stature, cardiac defects, characteristic facial appearance, and learning and developmental problems. Genes associated with Noonan syndrome (there are several, all encoding proteins that act in the RAS signaling pathway) can be tested in individuals with multiple spinal neurofibromas who have negative NF1 testing. It should be noted that some people with NF1 have some features that overlap with Noonan syndrome, which is not surprising given that both conditions involve changes in genes that encode proteins acting in the RAS signaling pathway. Some of these individuals are given the label "NF-Noonan syndrome." It should be noted, though, that this is distinct from Noonan syndrome itself, due to changes in genes other than NF1; these individuals do not have two separate disorders, but rather have NF1 with some features reminiscent of Noonan syndrome.Also, some individuals who have NF-like symptoms such as café-au-lait spots and skin fold freckles may have a pathogenic variant in the SPRED1 gene that is associated with a condition called Legius syndrome, another disorder associated with disruptions in the RAS/MAPK pathway. This condition, which is also associated with learning disabilities, can be impossible to distinguish from NF1 in young children who have only café-au-lait spots and skin fold freckles and no family history of NF1. Diagnosis of Legius syndrome is confirmed by NGS of the SPRED1 gene, which is usually tested in a panel alongside the NF1 gene.
Explanations for Negative Genetic Tests If all genetic testing options are exhausted, there are additional possibilities. First, the clinical diagnosis of NF may be inaccurate and should be reevaluated. For example, the individual could have symptoms of another disorder, such as a RASopathy, that overlaps with NF features. Another explanation is that there are other genetic mechanisms yet to be identified that are associated with the clinical features. Newer genomic testing technologies may be able to identify these genes in the future. Still, patients with clinical features for whom genetic testing is negative should be followed clinically by an NF specialist.Heart Disease: Types, Causes, And Symptoms
There are many types of heart disease, and each one has its own symptoms and treatment. For some, lifestyle changes and medicine can make a huge difference in improving your health. For others, you may need surgery to make your ticker work well again.
Find out about some of the common types of heart disease and how to prevent them as well as how they're treated.
CAD is the most common heart problem. With CAD, you may get blockages in your coronary arteries -- the vessels that supply blood to your heart. That can lead to a decrease in the flow of blood to your heart muscle, keeping it from getting the oxygen it needs. The disease usually starts as a result of atherosclerosis, a condition sometimes called hardening of the arteries.
Coronary heart disease can give you pain in your chest, called angina, or lead to a heart attack.
Some things that may put you at a higher risk of coronary artery disease are:
When you have an arrhythmia, your heart has an irregular beating pattern. Serious arrhythmias often develop from other heart problems but may also happen on their own.
With heart failure, your heart doesn't pump blood as well as it should to meet your body's needs. It is usually caused by coronary artery disease, but it can also happen because you have thyroid disease, high blood pressure, heart muscle disease (cardiomyopathy), or certain other conditions.
Your heart has four valves that open and close to direct blood flow between your heart's four chambers, the lungs, and blood vessels. An abnormality could make it hard for a valve to open and close the right way. When that happens, your blood flow could be blocked or blood can leak. Your valve may not open and close right.
The causes of heart valve problems include infections such as rheumatic fever, congenital heart disease, high blood pressure, coronary artery disease, or as a result of a heart attack.
Diseases of the heart valves include:
Any disease of the pericardium, the sac that surrounds your heart, is called a pericardial disease. One of the more common diseases is pericarditis or inflammation of the pericardium.
It's usually caused by an infection with a virus, inflammatory diseases such as lupus or rheumatoid arthritis, or injury to your pericardium. Pericarditis often follows open heart surgery.
Cardiomyopathy is a disease of your heart muscle, or myocardium. It gets stretched, thickened, or stiff. Your heart may get too weak to pump well.
There are many possible causes of the disease, including genetic heart conditions, reactions to certain drugs or toxins (such as alcohol), and infections from a virus. Sometimes, chemotherapy causes cardiomyopathy. Many times, doctors can't find the exact cause.
Congenital heart disease happens when something goes wrong while the heart is forming in a baby that's still in the womb. The heart abnormality sometimes leads to problems right after birth, but other times there aren't any symptoms until you become an adult.
Septal abnormalities are among the most common congenital heart problems. These are holes in the wall that separates the left and right sides of your heart. You can get a procedure to patch the hole.
Another type of abnormality is called pulmonary stenosis. A narrow valve causes a decrease in the flow of blood to your lungs. A procedure or surgery can open or replace the valve.
In some babies, a small blood vessel known as the ductus arteriosus doesn't close up at birth as it should. When this happens, some blood leaks back into the pulmonary artery, which puts strain on your heart. Doctors can treat this with surgery or a procedure or sometimes with medication.
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