Pulmonary atresia with ventricular septal defect is a rare

birth defect A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities ca ...

characterized by pulmonary valve atresia occurring alongside a defect on the right ventricular outflow tract. It is a type of congenital heart disease/defect, and one of the two recognized subtypes of

pulmonary atresia Pulmonary atresia is a congenital malformation of the pulmonary valve in which the valve orifice fails to develop. The valve is completely closed thereby obstructing the outflow of blood from the heart to the lungs. The pulmonary valve is located ...

, the other being pulmonary atresia with intact ventricular septum.

Signs and symptoms

The condition consists of atresia affecting the pulmonary valve and a hypoplastic right ventricular outflow tract. The

ventricular septal defect A ventricular septal defect (VSD) is a defect in the ventricular septum, the wall dividing the left and right ventricles of the heart. The extent of the opening may vary from pin size to complete absence of the ventricular septum, creating one ...

doesn't impede the in and outflowing of blood in the ventricular septum, which helps it form during fetal life. The spectrum of symptoms exhibited by children with this condition depends on the severity of the condition, while some barely show symptoms, others might develop complications such as

congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...

. In symptomatic children, symptoms become apparent soon after birth, these usually consist of the following: * Cyanosis *Breathing difficulties *Feeding difficulties *Exhaustion while being fed *

Heart murmur Heart murmurs are unique heart sounds produced when blood flows across a heart valve or blood vessel. This occurs when turbulent blood flow creates a sound loud enough to hear with a stethoscope. Turbulent blood flow is not smooth. The sound di ...

*Excessive daytime sleepiness *Sticky skin Other features can occur alongside this birth defect, including other congenital anomalies such as

polydactyly Polydactyly or polydactylism (), also known as hyperdactyly, is an anomaly in humans and animals resulting in supernumerary fingers and/or toes. Polydactyly is the opposite of oligodactyly (fewer fingers or toes). Signs and symptoms In human ...

microcephaly Microcephaly (from New Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it ...

congenital hearing loss Congenital hearing loss is a hearing loss present at birth. It can include hereditary hearing loss or hearing loss due to other factors present either in-utero (prenatal) or at the time of birth. Genetic factors Genetic factors are thought to ...

(sensorineural type),

renal agenesis Renal agenesis is a medical condition in which one (unilateral) or both (bilateral) fetal kidneys fail to develop. Unilateral and bilateral renal agenesis in humans, mice and zebra fish has been linked to mutations in the gene GREB1L. It has also ...

dextrocardia Dextrocardia (from Latin ''dextro'', meaning "right hand side," and Greek ''kardia'', meaning "heart") is a rare congenital condition in which the apex of the heart is located on the right side of the body, rather than the more typical placement t ...

, etc. The condition has been called a severe form of

Tetralogy of Fallot Tetralogy of Fallot (TOF), formerly known as Steno-Fallot tetralogy, is a congenital heart defect characterized by four specific cardiac defects. Classically, the four defects are: *pulmonary stenosis, which is narrowing of the exit from the r ...

. If deformed blood vessels coming from the

thoracic aorta The descending thoracic aorta is a part of the aorta located in the thorax. It is a continuation of the aortic arch. It is located within the posterior mediastinal cavity, but frequently bulges into the left pleural cavity. The descending thoracic ...

appear alongside this condition, the phenotype is renamed to ''pulmonary atresia with ventricular septal defect and major aortopulmonary collaterals.''

Complications

Children with this condition are at a higher risk of developing the following complications: *

Failure to thrive Failure to thrive (FTT), also known as weight faltering or faltering growth, indicates insufficient weight gain or absence of appropriate physical growth in children. FTT is usually defined in terms of weight, and can be evaluated either by a low ...

*Recurrent chest infections *

Endocarditis Endocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually involves the heart valves. Other structures that may be involved include the interventricular septum, the chordae tendineae, the mural endocardium, or the ...

Epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrica ...

* Stroke * Arrhythmia * Heart failure *

Premature death Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...

Children whose PAVSD is caused by DiGeorge syndrome (also known as 22q11.2 deletion syndrome) are more likely to suffer from the post-surgical complications (especially respiratory ones) associated with surgeries that treat this defect. Women with PAVSD are at a slightly higher risk of being infertile and having

miscarriages Miscarriage, also known in medical terms as a spontaneous abortion and pregnancy loss, is the death of an embryo or fetus before it is able to survive independently. Miscarriage before 6 weeks of gestation is defined by ESHRE as biochemical ...

or children with a congenital heart defect.

Airway hyperresponsiveness Bronchial hyperresponsiveness (or other combinations with airway or hyperreactivity, BH used as a general abbreviation) is a state characterised by easily triggered bronchospasm (contraction of the bronchioles or small airways). Bronchial hyperresp ...

is a commonly seen co-morbidity among those afflicted with PAVSD.

Pathogenesis

Pulmonary atresia in PAVSD takes place during the first 8 weeks of fetal life, when the pulmonary valve that is supposed to form, fails to form, this doesn't allow blood to flow through the pulmonary artery from the right ventricle. The ventricular septal defect associated with PAVSD lets the right ventricule form. In some cases of PAVSD, major aortopulmonary collateral arteries develop; in a normal fetus, these arteries usually develop but then start deteriorating after pulmonary arteries grow, in fetuses with PAVSD, the pulmonary arteries don't develop, and this gives a chance to the major aortopulmonary collateral arteries to develop fully.

Pathophysiology

The mildest variant of ''pulmonary atresia with ventricular septal defect'' involves pulmonary atresia with normally developed main pulmonary artery and branch pulmonary arteries, the blood that flows to the lungs from the right side of the heart goes to the left side of the heart through the ventricular septum which then flows through the

patent ductus arteriosus ''Patent ductus arteriosus'' (PDA) is a medical condition in which the ''ductus arteriosus'' fails to close after birth: this allows a portion of oxygenated blood from the left heart to flow back to the lungs by flowing from the aorta, which has ...

. The most severe variant involves the presence of severely hypoplastic main pulmonary arteries and branch pulmonary arteries, alongside agenesis of the patent ductus arteriosus. Blood flow to the lungs comes from various dysplastic (malformed) blood vessels from the

called major aortapulmonary collateral arteries, these blood vessels narrow down as time goes on.

Causes

Although this birth defect is congenital, the exact cause is unknown, and it may vary between children with the condition, the following factors have been known to influence the risk of a baby being born with the condition:

Genetics

The molecular genetics of this condition isn't known in most people with PA(VSD), however, there have been candidate genes found to be possibly implicated in the pathogenesis of this condition: *

DNAH10 Dynein axonemal heavy chain 1 is a protein that in humans is encoded by the DNAH1 gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' o ...

DST Daylight saving time (DST), also referred to as daylight savings time or simply daylight time (United States, Canada, and Australia), and summer time (United Kingdom, European Union, and others), is the practice of advancing clocks (typicall ...

FAT1 Protocadherin FAT1 is a protein that in humans is encoded by the ''FAT1'' gene. Function This gene is an ortholog of the ''Drosophila'' fat gene, which encodes a tumor suppressor essential for controlling cell proliferation during Drosophila d ...

HMCN1 Hemicentin-1 is a protein that in humans is encoded by the ''HMCN1'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' o ...

* HNRNPC * TEP1 *

TYK2 Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the ''TYK2'' gene. Tyk2 was the first member of the JAK family that was described (the other members are JAK1, JAK2, and JAK3). It has been implicated in IFN-α ...

NDRG4 Protein NDRG4 is a protein that in humans is encoded by the ''NDRG4'' gene. This gene is a member of the N-myc downregulated gene family which belongs to the alpha/beta hydrolase superfamily. The protein encoded by this gene is a cytoplasmic prot ...

TBX5 T-box transcription factor TBX5, (T-box protein 5) is a protein that in humans is encoded by the ''TBX5'' gene. This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes ...

* NKX2.5 *

GATA4 Transcription factor GATA-4 is a protein that in humans is encoded by the ''GATA4'' gene. Function This gene encodes a member of the GATA family of zinc finger transcription factors. Members of this family recognize the GATA motif which is pr ...

There have also been copy number variants described in the medical literature as associated with PA(VSD): *Deletion in chromosome 16p11.2 *Deletion in chromosome 5q35.3 *Deletion in chromosome 5p13.1 * Deletion in chromosome 22q11.2 *Deletion in chromosome 15q11.2 *Deletion in chromosome 8p23.2 *Deletion in chromosome 17p13.2 *Duplication in chromosome 5q14.1 *Duplication in chromosome 10p13 A 1998 study done in

Britain Britain most often refers to: * The United Kingdom, a sovereign state in Europe comprising the island of Great Britain, the north-eastern part of the island of Ireland and many smaller islands * Great Britain, the largest island in the United King ...

revealed that children with a mother who had a congenital heart defect (including PAVSD) had a higher risk of being born with a congenital heart defect themselves than those whose father had a congenital heart defect.

Syndromes

Some cases of PA(VSD) have been associated with genetic syndromes such as

VACTERL association The VACTERL association (also VATER association, and less accurately VACTERL syndrome) refers to a recognized group of birth defects which tend to co-occur (see below). This pattern is a recognized association, as opposed to a syndrome, because th ...

Alagille syndrome Alagille syndrome is a genetic disorder that affects primarily the liver and the heart. Problems associated with the disorder generally become evident in infancy or early childhood. The disorder is inherited in an autosomal dominant pattern, and t ...

, CHARGE syndrome,

trisomy 13 A trisomy is a type of polysomy in which there are three instances of a particular chromosome, instead of the normal two. A trisomy is a type of aneuploidy (an abnormal number of chromosomes). Description and causes Most organisms that reprodu ...

, 18, and 21.

Environmental

While congenital heart defects can't be acquired, they can also be caused by environmental factors the mother exposed herself to before and/or during pregnancy, these include: * Smoking *Certain medications (e.g.

thalidomide Thalidomide, sold under the brand names Contergan and Thalomid among others, is a medication used to treat a number of cancers (including multiple myeloma), graft-versus-host disease, and a number of skin conditions including complications o ...

, retinoids, or

vitamin A Vitamin A is a fat-soluble vitamin and an essential nutrient for humans. It is a group of organic compounds that includes retinol, retinal (also known as retinaldehyde), retinoic acid, and several provitamin A carotenoids (most notably ...

coegers) *

Alcohol consumption An alcoholic beverage (also called an alcoholic drink, adult beverage, or a drink) is a drink that contains ethanol, a type of alcohol that acts as a drug and is produced by fermentation of grains, fruits, or other sources of sugar. The cons ...

*Vehicle exhaust components *By-products of disinfectants * Incinerators (proximity) *Agricultural pesticides * Solvents *Landfill sites *Heavy metals Maternal exposure to carbon monoxide from smoke (e.g. from cigarettes) has been known for having the ability of quickly crossing the placenta into the fetus, which then attaches itself to fetal haemoglobin, leaving a shortage of nutrients and oxygen as a result. A relation between these events and congenital heart disease (including PAVSD) has been showed in 3 recent meta-analyses. Paternal smoking (that is, smoking by the father) has also been shown to be a contributing factor to congenital heart disease; while light smoking slightly increased the risk of the man's offspring having a (congenital) conotruncal heart defect, heavy smoking of more than 14 cigarettes a day doubled the risk for said man to have a child with congenital heart disease. Higher amounts than this were linked to a higher risk of having children with septal defects and/or obstruction of the left ventricular outflow tract. Other risk factors include maternal

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

, rubella, indomethacin tocolysis, phenylketonuria, or elderly age.

Multifactorial: involving genetic and environmental factors at the same time

A link between certain genes and maternal smoking has been shown to increase the chance of having children with congenital heart disease (including PAVSD): mothers who have a CC genotype at position 677 of the

MTHFR Methylenetetrahydrofolatereductase (MTHFR) is the rate-limiting enzyme in the methyl cycle, and it is encoded by the ''MTHFR'' gene. Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahyd ...

gene have an increased chance of having a CHD-ridden child. Other genes that increase the chance of a child with CHD in smoker mothers who carry genetic variations in them include

ERCC1 DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ''ERCC1'' gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination. Many aspects of these two gene ...

, ERCC5, PARP2, and OSGEP.

Diagnosis

There are various ways of diagnosing this congenital heart defect both prenatally and postnatally, these methods include: *

Ultrasound Ultrasound is sound waves with frequencies higher than the upper audible limit of human hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hear it. This limit varies ...

Pulse oximetry Pulse oximetry is a noninvasive method for monitoring a person's oxygen saturation. Peripheral oxygen saturation (SpO2) readings are typically within 2% accuracy (within 4% accuracy in 95% of cases) of the more accurate (and invasive) reading o ...

*Chest

X-ray An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 picometers to 10 nanometers, corresponding to frequencies in the range 30&nb ...

Echocardiogram An echocardiography, echocardiogram, cardiac echo or simply an echo, is an ultrasound of the heart. It is a type of medical imaging of the heart, using standard ultrasound or Doppler ultrasound. Echocardiography has become routinely used in th ...

* Electrocardiogram * Cardiac catheterization *Cardiac CT scan *Genetic testing (particularly if other systemic birth anomalies are seen alongside the pulmonary atresia and ventricular septal defect).

Management

When the disorder is detected (usually before or soon after birth), prostaglandin will be temporarily used as soon as possible in order to keep the ductus arteriosus open for as long as possible until surgery can be done, this is done so that blood can keep flowing to the lungs, since the bodies of babies with pulmonary atresia usually use the ductus arteriosus for lung blood flow pre-natally until birth, after which it closes. Afterwards, this anomaly is usually managed with surgeries for improvement of blood flow and function of the heart, although what kind of treatment one gets depends on the structure of the cardiorespiratory system. The surgical methods that can be used to treat (for the long-term) this condition include: *

Catheter procedure Interventional radiology (IR) is a medical specialty that performs various minimally-invasive procedures using medical imaging guidance, such as x-ray fluoroscopy, computed tomography, magnetic resonance imaging, or ultrasound. IR performs b ...

for pulmonary artery branches *Systemic-to-pulmonary artery shunt * Neonatal complete repair * One-stage complete repair *

Balloon septostomy Balloon septostomy is the widening of a foramen ovale, patent foramen ovale (PFO), or atrial septal defect (ASD) via cardiac catheterization (heart cath) using a balloon catheter. This procedure allows a greater amount of oxygenated blood to ente ...

* *Staged unifocalization

Frequency

Frequency estimates vary between populations, estimates range from 0.01% to 0.2% of live births with PAVSD. It is believed to make up for 1-2% of cases of congenital heart defects worldwide. Of all patients with PAVSD, around 25-32% of them have a microdeletion of the 22q11.2 chromosome.

Prognosis

Without treatment, it is a highly life-threatening condition, so prognosis is poor. If surgery isn't performed in severe cases, the child can (and will) die, since the phenotype of pulmonary atresia is not compatible with life due to the pulmonary valve atresia resulting in reduced blood oxygenation. Life expectancy for untreated children with PAVSD is 10 years. Survival rates for untreated people with this defect have been reported to be 50% at the tenth decade and 10% at the twentieth decade, and out of these untreated patients, those who do not have major aortopulmonary arteries have a higher chance of living to their 30s than those who do have them, as the latter have a 40% chance of surviving to the tenth decade and a 20% chance of doing so to the thirtieth decade. Prognosis after surgical intervention is generally good.

History

This combination of birth defects was first described in 1980 by DiChiara et al., their patients were a father and his son from the

United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...

both of which had pulmonary atresia and a ventricular septal defect. Up until that point, there had been no familial cases of PA with a VSD. A multifactorial etiology (that is, a cause involving genetics and the environment) was suspected in these patients and they were offered medical counseling for the condition. As of 2011, the oldest patient with untreated PAVSD was a 59-year old woman from Japan. Her condition was discovered in childhood but she refused to get any surgery to treat it (including cardiac catheterization), she developed

dyspnea Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing di ...

during her teenage years. Radiological studies showed a ventricular septal defect alongside cardiac and arterial anomalies (heart silhouette enlargement, elevation of the cardiac apex, presence of a right aortic arch, enlargement affecting the main pulmonary arteries and their major branches, high pulmonary artery vascularity, and ventricular septal defect).

References

{{reflist Congenital vascular defects