DiGeorge Syndrome

Epidemiology and Etiology

Epidemiology

• Incidence: 1 in 4,000–7,000 live births
• Most common human chromosomal deletion syndrome
• Growing prevalence due to the following factors: 
  • Surgical correction of cardiac defects improves the survival rate of affected patients, thus increasing their likelihood of passing on the condition.
  • Parents who were previously unaware of their genetic condition are being diagnosed as genetic testing becomes more available.
  • Earlier genetic techniques were not able to detect all deletions; newer technologies also cover atypical deletions.

Etiology

• Synonyms: velocardiofacial syndrome, Shprintzen syndrome, conotruncal anomaly face syndrome (CTAF), Takao syndrome
• Caused by a heterozygous deletion of part of the long arm Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm (q) of chromosome 22, region 1, band 1, sub-band 2 (22q11.2)
• The deletion of 22q11.2 is 10 times more common than the next most frequent deletion syndrome, suggesting that this region is inherently unstable.
• 93% of cases are de novo mutations during early fetal development.
• 7% of cases are inherited in autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance patterns from affected parents.

Pathophysiology

• Approximately 30–50 genes are affected by the 22q11.2 deletion. 
  • Disrupts the development of the 3rd and 4th pharyngeal pouches
  • Creates a defect in the embryonic development of the brain, neck, skeleton, and kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys
• TBX1 is the main gene responsible for the DiGeorge phenotype. It plays a vital role in organ formation and regulation, affecting the formation of:
  • Skull Skull The skull (cranium) is the skeletal structure of the head supporting the face and forming a protective cavity for the brain. The skull consists of 22 bones divided into the viscerocranium (facial skeleton) and the neurocranium. Skull bones
  • Mesenchyme of the face and palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Oral Cavity: Palate
  • Outflow tract of the heart
  • Thymus and parathyroid stroma 
• 22q11.2 deletions are associated with a higher risk of early onset Parkinson’s disease.

Clinical Presentation

DiGeorge syndrome has a marked variability in clinical expression among different individuals. Manifestations can include the following:

• Congenital cardiovascular disease: 
  • Interrupted aortic arch Aortic arch The branchial arches, also known as pharyngeal or visceral arches, are embryonic structures seen in the development of vertebrates that serve as precursors for many structures of the face, neck, and head. These arches are composed of a central core of mesoderm, which is covered externally by ectoderm and internally by endoderm. Branchial Apparatus and Aortic Arches 
  • Patent truncus arteriosus Truncus arteriosus Truncus arteriosus (TA) is a congenital heart defect characterized by the persistence of a common cardiac arterial trunk tract that fails to divide into the pulmonary artery and aorta during embryonic development. Truncus arteriosus is a rare congenital malformation with a high mortality rate within the 1st 5 weeks of life if not managed promptly. Truncus Arteriosus 
  • Tetralogy of Fallot Tetralogy of Fallot Tetralogy of Fallot is the most common cyanotic congenital heart disease. The disease is the confluence of 4 pathologic cardiac features: overriding aorta, ventricular septal defect, right ventricular outflow obstruction, and right ventricular hypertrophy. Tetralogy of Fallot
  • Atrial or ventricular septal defect 
  • Vascular rings Vascular rings Vascular rings are a group of rare malformations featuring congenital abnormalities of the aortic arch. The aberrant arteries often form a ring around the esophagus and trachea, putting pressure on these structures. Vascular Rings (causing tracheal or esophageal compression)
• Abnormal craniofacial features:
  • Hypertelorism, tubular nose Nose The nose is the human body's primary organ of smell and functions as part of the upper respiratory system. The nose may be best known for inhaling oxygen and exhaling carbon dioxide, but it also contributes to other important functions, such as tasting. The anatomy of the nose can be divided into the external nose and the nasal cavity. Anatomy of the Nose, hooded eyes
  • Cleft palate cleft palate The embryological development of craniofacial structures is an intricate sequential process involving tissue growth and directed cell apoptosis. Disruption of any step in this process may result in the formation of a cleft lip alone or in combination with a cleft palate. As the most common craniofacial malformation of the newborn, the diagnosis of a cleft is clinical and usually apparent at birth. Cleft Lip and Cleft Palate
  • Low-set or posteriorly rotated ears
• Endocrine issues:
  • Hypoparathyroidism Hypoparathyroidism Hypoparathyroidism is defined as reduced parathyroid hormone (PTH) levels due to poor function of the parathyroid glands. The cause of hypoparathyroidism is most commonly iatrogenic following neck surgery, but it can also be associated with genetic or autoimmune disorders as well as infiltrative diseases causing destruction of the normal parathyroid tissue. Hypoparathyroidism (50% of cases; causes hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia, which can lead to seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures)
  • Growth hormone deficiency
• Thymic aplasia/hypoplasia (leads to immunodeficiency due to reduced T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells):
  • Complete DiGeorge syndrome: 
    • Only 1% of cases
    • Thymus is completely absent
    • Causes severe combined immunodeficiency Severe Combined Immunodeficiency Severe combined immunodeficiency (SCID), also called "bubble boy disease," is a rare genetic disorder in which the development of functional B and T cells is disturbed due to several genetic mutations that result in reduced or absent immune function. Severe Combined Immunodeficiency (SCID); manifests as recurrent infections, chronic diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, and failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive
    • Fatal unless promptly treated
  • Partial DiGeorge syndrome: 
    • Range of normal to deficient T cell numbers 
    • Approximately 75% of patients with thymic defect
    • Varying degree of immunodeficiency, although a normal number of T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells may be reached by adulthood (proliferation of existing T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells)
    • Associated with humoral immunodeficiencies of immunoglobulin A (IgA) deficiency
• Neurological problems:
  • Learning disabilities (up to 90% of cases), speech delay
  • High risk of early onset Parkinson’s disease
  • Conductive and sensorineural hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss 
• Psychiatric disorders: 
  • Depression, bipolar disorder Bipolar disorder Bipolar disorder is a highly recurrent psychiatric illness characterized by periods of manic/hypomanic features (distractibility, impulsivity, increased activity, decreased sleep, talkativeness, grandiosity, flight of ideas) with or without depressive symptoms. Bipolar Disorder
  • Attention deficit hyperactivity disorder Attention Deficit Hyperactivity Disorder Attention deficit hyperactivity disorder is a neurodevelopmental disorder characterized by a pattern of inattention and/or hyperactivity-impulsivity that occurs in at least 2 different settings for more than 6 months. Although the patient has normal intelligence, the disease causes functional decline. Attention Deficit Hyperactivity Disorder (ADHD)
  • Schizophrenia Schizophrenia Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia
• Miscellaneous: laryngotracheoesophageal defects, digestive motility issues, skeletal abnormalities, anomalies of the genitourinary and respiratory tract, autoimmune diseases such as Graves disease and rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis

Mnemonic

DiGeorge syndrome signs can be summarized using the mnemonic CATCH-22:

• C: Congenital heart disease
• A: Abnormal facies
• T: Thymic aplasia
• C: Cleft palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Oral Cavity: Palate
• H: Hypocalcemia/hypoparathyroidism
• 22: 22q11.2DS, found on chromosome 22

Diagnosis and Management

Diagnosis

Establishing a diagnosis is difficult due to the variability of phenotypes. Along with suggestive signs and symptoms, evaluation includes the following:

• Genetic testing—array comparative genomic hybridization (aCGH):
  • Preferred test
  • Detects deletions or duplications
• Lab work and imaging to identify associated defects:
  • Cardiology:
    • Electrocardiogram Electrocardiogram An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) ( ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG))
    • Echocardiography
  • Endocrine:
    • Serum calcium and phosphorus levels (↓ PTH, ↓ calcium, ↑ phosphorus)
    • Thyroid profile test
    • Chest X-ray (to check absence of thymus)
  • Immune function tests:
    • CBC to evaluate for lymphopenia, immunoglobulin levels, T- and B-cell subsets
    • Renal ultrasound (look for structural genitourinary tract abnormalities)

Management

Management is aimed at treating the associated features of the disease. Early intervention and developmental evaluation are key.

• Thymus transplantation or hematopoietic cell transplantation (HCT)
• Antibiotics (for treating frequent infections), IV immunoglobulins Immunoglobulins Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins 
• Cautionary use of blood transfusions and live attenuated vaccines
• Cardiac surgery Cardiac surgery Cardiac surgery is the surgical management of cardiac abnormalities and of the great vessels of the thorax. In general terms, surgical intervention of the heart is performed to directly restore adequate pump function, correct inherent structural issues, and reestablish proper blood supply via the coronary circulation. Cardiac Surgery to correct congenital heart abnormalities
• Lifelong vitamin D and calcium supplementation

Prognosis

There is no cure for DiGeorge syndrome. Life expectancy largely depends on the degree of cardiac defects (most important factor) and immunodeficiency.

• Complete DiGeorge syndrome:
  • Without transplantation, the life expectancy of infants is < 1 year.
  • In patients who undergo a transplant, most deaths occur in the first year post-transplant.
  • Majority of deaths attributed to cardiac complications
• Partial DiGeorge syndrome: prognosis dependent on severity of cardiac defect, patient’s intellectual development, and follow-up care provided for their associated deficiencies

Differential Diagnosis

• CHARGE Syndrome CHARGE Syndrome CHARGE syndrome is a rare genetic condition with autosomal dominant inheritance in which almost all body systems are affected. The acronym CHARGE stands for the constellation of clinical features seen with this condition: Coloboma, Heart defects, Atresia choanae, Growth retardation, Genetic Abnormalities, and Ear abnormalities. CHARGE Syndrome: a rare genetic condition with autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance inheritance. The abbreviation CHARGE stands for the constellation of clinical features seen with this condition: coloboma, heart defects, atresia choanae, growth retardation, genetic abnormalities, and ear abnormalities. Like, DGS, cardiac defects, cleft palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Oral Cavity: Palate and hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss are present but the other features listed are not seen in DGS. Genetic testing confirms the diagnosis. There is no 22q11 deletion in CHARGE syndrome. Treatment is symptomatic with management of the airway, heart defects, and feeding ability as the priorities in early life. 
• Zellweger syndrome Zellweger syndrome Zellweger syndrome (ZWS), also called cerebrohepatorenal syndrome, is a rare congenital peroxisome biosynthesis disorder and is considered an inborn error of metabolism. Zellweger syndrome is the most severe form of a spectrum of conditions called Zellweger spectrum disorder (ZSD), and is characterized by the reduction or absence of functional peroxisomes. Zellweger Syndrome (ZWS), also called cerebrohepatorenal syndrome, is a rare congenital peroxisome biosynthesis disorder and is considered an inborn error of metabolism. It is the most severe form of a spectrum of conditions called Zellweger spectrum disorders (ZSD). It is characterized by the reduction or absence of functional peroxisomes. Symptoms are present from the time of birth and include hypotonia, poor feeding, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures. Like DGS, there is craniofacial dysmorphism. But DGS does not typically have hepatomegaly with cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis. There is no cure for Zellweger syndrome Zellweger syndrome Zellweger syndrome (ZWS), also called cerebrohepatorenal syndrome, is a rare congenital peroxisome biosynthesis disorder and is considered an inborn error of metabolism. Zellweger syndrome is the most severe form of a spectrum of conditions called Zellweger spectrum disorder (ZSD), and is characterized by the reduction or absence of functional peroxisomes. Zellweger Syndrome. 
• Teratogen exposure: teratogens such as isotretinoin, ethanol or maternal conditions such as diabetes affect the fetus in utero and produce similar phenotype as DGS. The difference is genetic abnormality is present in DGS. Additionally, the abnormalities depend on the development period during which there was exposure.