Background

DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a genetic disorder caused by the deletion of a small segment of chromosome 22. The syndrome is named after Dr. Angelo DiGeorge, who first described it in the 1960s. DiGeorge syndrome is characterized by a wide range of medical and developmental abnormalities that can affect various systems of the body.

The most common feature of DiGeorge syndrome is congenital heart disease, which occurs in the majority of affected individuals. The specific heart defects can vary but often involve abnormalities of the great vessels, such as an interrupted aortic arch or tetralogy of Fallot. Additionally, individuals with DiGeorge syndrome may have immune system deficiencies, leading to an increased susceptibility to infections.

Epidemiology

DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is estimated to occur in approximately 1 in 2,000 to 4,000 live births. The prevalence of the syndrome may vary depending on the population studied and the diagnostic methods used. It affects both males and females equally and occurs in individuals of all ethnic backgrounds.

DiGeorge syndrome is considered one of the most common chromosomal deletion syndromes, accounting for a significant proportion of cases with congenital heart defects. It is caused by a deletion of a small segment of chromosome 22, specifically at the 22q11.2 region. This deletion can occur spontaneously during early fetal development and is typically not inherited from parents. However, in some cases, a parent may carry the deletion in a milder form or without showing any symptoms.

The clinical presentation and severity of DiGeorge syndrome can vary widely among individuals. Some may have mild features or be asymptomatic, while others may have more pronounced symptoms and medical complications. The syndrome is characterized by a range of abnormalities affecting multiple systems, including congenital heart defects, immune system deficiencies, hypoparathyroidism, and developmental delays.

DiGeorge syndrome is associated with an increased risk of certain medical conditions, including congenital heart defects, particularly abnormalities of the great vessels. Approximately 75-80% of individuals with DiGeorge syndrome have some form of congenital heart disease. Immune system deficiencies are also common, with varying degrees of severity. Hypoparathyroidism, resulting in low levels of calcium, occurs in about 50-75% of individuals with DiGeorge syndrome.

Developmental delays, learning difficulties, and behavioral and psychiatric conditions may also be present. Given the variability in clinical presentation and the potential for mild or atypical features, DiGeorge syndrome can be challenging to diagnose accurately. Genetic testing, including fluorescence in situ hybridization (FISH) or chromosomal microarray analysis (CMA), is typically used to confirm the presence of the 22q11.2 deletion.

Anatomy

Pathophysiology

DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is caused by a deletion of a small segment of chromosome 22, specifically at the 22q11.2 region. This chromosomal deletion affects the normal development and differentiation of various tissues and organs during early fetal development, leading to the characteristic features and medical complications associated with the syndrome.

The 22q11.2 region contains multiple genes that play important roles in embryonic development, particularly in the development of the heart, parathyroid glands, thymus, and facial structures. The loss of these genes due to the deletion disrupts the normal processes involved in organogenesis, resulting in the pathophysiological manifestations of DiGeorge syndrome.

Here are some key aspects of the pathophysiology of DiGeorge syndrome:

• Cardiac abnormalities: The deletion of genes in the 22q11.2 region can lead to abnormal development of the heart and its major blood vessels. It is believed to disrupt the formation of neural crest cells, which are critical for cardiac development. This disruption can result in various congenital heart defects, including abnormalities of the great vessels such as interrupted aortic arch, tetralogy of Fallot, ventricular septal defects, and others.
• Thymic hypoplasia: The thymus gland, which plays a crucial role in the development and maturation of T lymphocytes (a type of immune cell), is affected in DiGeorge syndrome. The deletion of genes in the 22q11.2 region impairs the development and migration of thymic epithelial cells, leading to thymic hypoplasia or aplasia. As a result, individuals with DiGeorge syndrome often have reduced or absent T cell production, resulting in immune system deficiencies and increased susceptibility to infections.
• Parathyroid gland abnormalities: The parathyroid glands, responsible for regulating calcium and phosphate levels in the body, are also affected by the 22q11.2 deletion. The exact mechanisms are not fully understood, but it is believed that the loss of certain genes impairs the development and function of the parathyroid glands, leading to hypoparathyroidism. Hypoparathyroidism results in decreased production of parathyroid hormone (PTH), leading to low levels of calcium in the blood (hypocalcemia) and high levels of phosphate.
• Facial and craniofacial abnormalities: The deletion of genes in the 22q11.2 region can affect the development of facial structures, leading to characteristic facial features associated with DiGeorge syndrome. These may include a small chin, low-set ears, wide-set eyes, and a short or upturned nose.
• Neural crest cell migration defects: Neural crest cells, a group of cells that migrate from the developing neural tube to various parts of the body, are essential for the normal development of multiple organs and structures. The disruption of neural crest cell migration due to the 22q11.2 deletion can contribute to the diverse range of clinical features seen in DiGeorge syndrome.

Etiology

DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is primarily caused by a deletion of a small segment of chromosome 22, specifically at the 22q11.2 region. This deletion occurs spontaneously during early fetal development and is usually not inherited from the parents. The 22q11.2 deletion can happen randomly and is not typically associated with any specific environmental factors or behaviors of the parents. However, in some cases, the deletion can be inherited from a parent who carries the same deletion in a milder or subclinical form.

In these cases, the parent may have fewer or milder features of DiGeorge syndrome or may be entirely asymptomatic. The specific genes and genetic elements within the 22q11.2 region that are responsible for the characteristic features of DiGeorge syndrome are still being studied. It is believed that the loss of these genes disrupts normal embryonic development, affecting the formation and differentiation of various tissues and organs.

While the majority of cases of DiGeorge syndrome are caused by the 22q11.2 deletion, there can be other rare genetic variations or rearrangements in the same chromosomal region that can lead to similar clinical features. These variations may include duplications, translocations, or other structural abnormalities within the 22q11.2 region. However, the 22q11.2 deletion accounts for the majority of cases. It’s important to note that DiGeorge syndrome is a heterogeneous condition, meaning that it can present a wide spectrum of clinical features and severity.

The extent of the deletion and the involvement of additional genetic and environmental factors may contribute to the variability in the clinical presentation and severity of the syndrome. Genetic testing, such as fluorescence in situ hybridization (FISH) or chromosomal microarray analysis (CMA), is typically used to confirm the presence of the 22q11.2 deletion and establish the diagnosis of DiGeorge syndrome. Identifying the underlying genetic cause can help with accurate diagnosis, genetic counseling, and appropriate medical management for individuals with the syndrome and their families.

Genetics

Prognostic Factors

The prognosis of DiGeorge syndrome, also known as 22q11.2 deletion syndrome, can vary widely depending on the specific features, medical complications, and individual characteristics of each person. The prognosis can range from mild to severe, and some individuals may have a relatively normal life expectancy and quality of life, while others may experience significant medical challenges and developmental disabilities. Here are some key factors that can influence the prognosis of DiGeorge syndrome:

• Medical complications: The presence and severity of medical complications, such as congenital heart defects, immune system deficiencies, and other associated conditions, can significantly impact the prognosis. Prompt diagnosis, appropriate medical management, and access to specialized care can help improve outcomes and reduce the risk of complications.
• Cardiac involvement: The prognosis can be influenced by the specific type and severity of the congenital heart defect. Some heart defects may be relatively mild and manageable, while others may require more complex surgical interventions. Close collaboration with a pediatric cardiologist and cardiac care team is crucial for optimizing cardiac outcomes.
• Immune function: Immune system deficiencies in DiGeorge syndrome can increase the risk of infections and other complications. Early recognition and management of immune-related issues, such as prompt treatment of infections and immunoglobulin replacement therapy when necessary, can help reduce the impact on overall health and improve prognosis.
• Developmental and cognitive outcomes: Developmental delays and intellectual disabilities are common in individuals with DiGeorge syndrome. The severity of these delays can vary widely, and early intervention services, educational support, and therapies can significantly improve developmental outcomes and quality of life.
• Other associated conditions: The presence of additional associated conditions, such as kidney abnormalities, hearing loss, or psychiatric and behavioral disorders, can impact the overall prognosis and require appropriate management and support.
• Individual variability: Each individual with DiGeorge syndrome is unique, and the prognosis can be influenced by factors specific to their genetic makeup, overall health, and access to medical care and support services. Early diagnosis, comprehensive medical management, and a supportive environment that addresses individual needs can contribute to better outcomes.

Clinical History

Clinical history

The clinical history of DiGeorge syndrome, also known as 22q11.2 deletion syndrome, can vary widely among individuals due to the range of possible features and medical complications associated with the condition. Here are some key aspects of the clinical history of DiGeorge syndrome:

• Congenital heart defects: Many individuals with DiGeorge syndrome have congenital heart defects, which may include abnormalities of the great vessels, such as tetralogy of Fallot, interrupted aortic arch, or ventricular septal defects. The severity and specific type of heart defect can vary among individuals.
• Immune system deficiencies: DiGeorge syndrome is associated with immune system abnormalities, particularly involving the thymus gland. Thymic hypoplasia or aplasia results in reduced or absent production of T lymphocytes, a type of immune cell, leading to immune system deficiencies. This can result in increased susceptibility to infections, including recurrent respiratory tract infections, fungal infections, and viral infections.
• Hypoparathyroidism: Hypoparathyroidism, characterized by low levels of parathyroid hormone (PTH) and low calcium levels (hypocalcemia), is a common feature of DiGeorge syndrome. The parathyroid glands, responsible for regulating calcium and phosphate levels in the body, may be underdeveloped or absent in individuals with DiGeorge syndrome.
• Facial features: DiGeorge syndrome can be associated with characteristic facial features, although they may not be present in all individuals. These features may include a small chin, low-set ears, wide-set eyes, hooded eyelids, a short or upturned nose, and a prominent nasal bridge.
• Developmental and cognitive delays: Many individuals with DiGeorge syndrome experience developmental delays, particularly in speech and language skills. Intellectual disability or learning difficulties may also be present, although the severity can vary widely among individuals. Attention-deficit/hyperactivity disorder (ADHD) and other behavioral and psychiatric conditions may occur more frequently in individuals with DiGeorge syndrome.
• Other features: DiGeorge syndrome can involve various additional features, including feeding difficulties in infancy, growth retardation, hearing loss, kidney abnormalities, skeletal abnormalities, and gastrointestinal abnormalities such as gastroesophageal reflux disease (GERD).

Physical Examination

Physical examination

The physical examination findings in individuals with DiGeorge syndrome, also known as 22q11.2 deletion syndrome, can vary widely depending on the specific features and medical complications present. Here are some key aspects that may be observed during a physical examination:

• Facial features: Certain characteristic facial features may be present in individuals with DiGeorge syndrome. These can include a small chin, low-set ears, wide-set eyes, hooded eyelids, a short or upturned nose, and a prominent nasal bridge. However, it’s important to note that not all individuals with DiGeorge syndrome will have these facial features, and the severity can vary.
• Cardiac examination: DiGeorge syndrome is frequently associated with congenital heart defects. During a cardiac examination, the healthcare provider may assess for abnormalities such as murmurs, abnormal heart sounds, or signs of poor circulation.
• Thymus examination: The thymus gland, which is often underdeveloped or absent in individuals with DiGeorge syndrome, may be assessed during a physical examination. The healthcare provider may evaluate the presence or absence of a thymic shadow on a chest X-ray or perform imaging studies to assess the size and structure of the thymus gland.
• Growth assessment: Growth retardation may be observed in some individuals with DiGeorge syndrome. The healthcare provider may measure height, weight, and head circumference to assess growth parameters and track growth patterns over time.
• Other physical findings: Depending on the specific features present, the physical examination may include assessments related to other organ systems. These may involve examining the ears for hearing abnormalities, evaluating the palate for cleft palate or submucous cleft palate, assessing for signs of hypoparathyroidism (such as Chvostek’s or Trousseau’s sign), and examining the skeletal system for any abnormalities.
• Neurological examination: Individuals with DiGeorge syndrome may undergo a neurological examination to assess for developmental delays, intellectual disability, or neurological abnormalities such as muscle weakness or coordination difficulties.

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

Differential diagnosis

The diagnosis of DiGeorge syndrome, also known as 22q11.2 deletion syndrome, can be challenging due to its variable presentation and overlapping features with other conditions. Several conditions may be considered in the differential diagnosis of DiGeorge syndrome. These include:

• Velocardiofacial syndrome (VCFS): VCFS is another genetic disorder caused by a deletion in the 22q11.2 region, overlapping with DiGeorge syndrome. The clinical features of VCFS can be similar to those of DiGeorge syndrome, including cardiac abnormalities, immune system deficiencies, and characteristic facial features. However, VCFS may have additional features such as cleft palate, speech and language impairments, and learning disabilities.
• CHARGE syndrome: CHARGE syndrome is a rare genetic disorder characterized by a combination of features including coloboma of the eye, heart defects, choanal atresia, growth retardation, genital abnormalities, and ear abnormalities. Some features of CHARGE syndrome, such as heart defects and facial abnormalities, can overlap with DiGeorge syndrome. Genetic testing is usually necessary to differentiate between the two conditions.
• Velo-cardio-facial-like syndrome (VCFL): VCFL is a term used to describe individuals who have features similar to VCFS but do not meet the diagnostic criteria for a full diagnosis. VCFL can have clinical features resembling DiGeorge syndrome, including cardiac anomalies and facial dysmorphisms. However, the genetic cause may be different, and further evaluation and genetic testing may be required to differentiate between VCFL and DiGeorge syndrome.
• Other chromosomal abnormalities: There are other chromosomal abnormalities that can result in similar clinical features to DiGeorge syndrome, such as 10p deletion syndrome and 17q21.31 microdeletion syndrome. These conditions may have overlapping features, including cardiac abnormalities and intellectual disability, and genetic testing is necessary for accurate diagnosis.
• Non-syndromic congenital heart defects: Some isolated congenital heart defects, such as tetralogy of Fallot, interrupted aortic arch, and ventricular septal defects, can occur without the presence of DiGeorge syndrome. These heart defects can be part of the clinical spectrum of DiGeorge syndrome, but in the absence of other characteristic features, a diagnosis of DiGeorge syndrome may not be warranted.
• Other genetic and non-genetic conditions: There are several other genetic and non-genetic conditions that may present with similar clinical features to DiGeorge syndrome, including Noonan syndrome, Williams syndrome, Alagille syndrome, and various syndromes associated with congenital heart defects and immune system deficiencies. A thorough evaluation, including clinical examination and genetic testing, is necessary to differentiate between these conditions and DiGeorge syndrome.

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

The treatment of DiGeorge syndrome, also known as 22q11.2 deletion syndrome, aims to manage specific medical complications and provide supportive care for affected individuals. The treatment plan is typically individualized based on the unique needs and features of each person. Here are some key aspects of the treatment approach for DiGeorge syndrome:

• Cardiac management: If a congenital heart defect is present, individuals with DiGeorge syndrome may require cardiac interventions or surgeries to correct or manage the heart abnormalities. The specific treatment will depend on the type and severity of the heart defect and is typically coordinated with a pediatric cardiologist or a cardiac care team.
• Immune system support: Since DiGeorge syndrome is associated with immune system deficiencies, individuals may require immune system support and monitoring. This can involve regular assessment of immune function, immunizations according to a modified schedule, and prompt treatment of infections with appropriate antibiotics or antiviral medications. In severe cases, individuals may require immunoglobulin replacement therapy to help boost immune function.
• Calcium and vitamin D supplementation: Hypoparathyroidism, a common feature of DiGeorge syndrome, leads to low calcium levels in the blood. Treatment typically involves lifelong supplementation with calcium and vitamin D to maintain adequate calcium levels. The dosage and specific regimen may vary depending on the individual’s needs and response to treatment.
• Speech and language therapy: Many individuals with DiGeorge syndrome experience speech and language delays. Speech and language therapy can be beneficial in improving communication skills and addressing speech difficulties. Early intervention and ongoing therapy can help individuals develop their communication abilities.
• Developmental and educational support: Individuals with DiGeorge syndrome may benefit from early intervention services, educational support, and specialized educational programs to address developmental delays and learning difficulties. These may include individualized education plans (IEPs), speech therapy, occupational therapy, and other interventions as needed.
• Psychiatric and psychological support: Individuals with DiGeorge syndrome may be at an increased risk for psychiatric and psychological conditions, such as anxiety, depression, and attention-deficit/hyperactivity disorder (ADHD). Appropriate psychiatric and psychological support, including counseling and behavioral interventions, may be provided to address these challenges and promote mental well-being.
• Regular medical monitoring: Ongoing medical monitoring is crucial for individuals with DiGeorge syndrome to assess growth, development, and overall health. Regular check-ups with a pediatrician or a specialist familiar with the syndrome are important to monitor for any new medical issues, manage existing conditions, and coordinate care among different specialists as needed.

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Future Trends

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References

https://www.ncbi.nlm.nih.gov/books/NBK549798/