2011 Group Project 2

From Embryology
Note - This page is an undergraduate science embryology student group project 2011.
2011 Projects: Turner Syndrome | DiGeorge Syndrome | Klinefelter's Syndrome | Huntington's Disease | Fragile X Syndrome | Tetralogy of Fallot | Angelman Syndrome | Friedreich's Ataxia | Williams-Beuren Syndrome | Duchenne Muscular Dystrolphy | Cleft Palate and Lip

DiGeorge Syndrome


A congenital disorder is one which is present at birth. They are often abnormalities that arise from errors that occur during development of the fetus. Some congenital abnormalities are genetic, and often run in families while others are spontaneous and have no genetic linkages. DiGeorge syndrome is a congenital abnormality that is caused by the deletion of a part of chromosome 22. The symptoms and severity of the condition is thought to be dependent upon what part of and how much of the chromosome is absent. [1].

About 1/4000 children born are affected by DiGeorge syndrome, with 90% of these cases involving a deletion of a section of chromosome 22 [2]. DiGeorge is quite often a spontaneous mutation, but it may be passed on in an autosomal dominant fashion. Some families have many members affected.

DiGeorge is a complex syndrome and patient cases vary greatly. The common symptoms present across numerous patients include

  • Abnormal faces
  • Congenital heart defects
  • Hypoparathyroidism with hypocalcemia
  • Cognitive, behavioral, and psychiatric problems
  • Increased susceptibility to infections
  • Hypoplasia or absence of the thyroid and parathyroid glands [3]

DiGeorge is a serious syndrome affecting many of the body systems. The clinical manifestations of the chromosome 22 deletion are significant and can lead to poor quality and a shortened lifespan for the patient. As there is currently no treatment education is vital to the wellbeing of those affected, directly or indirectly by this condition. [4] Current and future research is aimed at how to prevent and treat the condition, there is still a long way to go but some progress is being made.

Historical Background

  • Angelo DiGeorge. In the mid 1960's, Angelo DiGeorge noticed a similar combination of clinical features in some children. He named the syndrom after himself. The symptoms that he recognised were hypoparathyroidism, underdeveloped thymus, conotruncal heart defects and a cleft lip/palate. [5]
  • 'Robert Shprintzen described patients with similar symptoms (cleft lip, heart defects, absent or underdeveloped thymus, hypocalcemia) and named the group of symptoms as velo-cardio-facial syndrome. [6]
  • 1980s technology develops to identify that these patients have part of a chromosome missing. [7]


It appears that DiGeorge syndrome has a minimum incidence of about 1 per 2000-4000 live births in the general population, ranking among the most frequent causes of genetic syndromes at birth [8]. Due to the fact that 22q11.2 deletions can also produce Velocardiofacial syndrome as well, there is some overlap of the figures for epidemiology [9] as both syndromes have rather similar presentation. Due to these afore mentioned factors, it is therefore difficult to generate an exact figure for the epidemiology of DiGeorge syndrome; the 1 in 4000 live births is the minimum estimate of incidence [10]. The presentation of more severe cases of DiGeorge syndrome is apparent at birth, especially with malformations. Within the first 6 months of life, susceptibility to infection may raise suspicion of DiGeorge syndrome. However, it has been well documented that there individuals who have relatively minor cardiac malformations and normal immune function, and may show no presentation of DGS until later in life, which may be resultant form a learning dysfunction. DiGeorge frequently presents with cleft palate, as well as congenital heart defects[11]. As would be suspected, it appears that cardiac complications are the largest causes of mortality. Infants face constant recurrent infection as a secondary result of T-cell immunodeficiency, caused by the hypoplastic thymus. There is no preference to either sex or race [12].



As mentioned in the introduction, the pathogenesis of DiGeorge is a 22q11.2 microdeletion. More precisely, DiGeorge is a result of a 2-3million base pair deletion from the long arm of chromosome 22. It seems that this particular region in chromosome 22 is particularly vulnerable to microdeletion, which is a result of complications that occur during meiosis. It seems that multiple genes exist in this region, which results in similar symptoms being seen across a large number of 22q11.2 microdeletion syndromes. As mentioned previously, this means that all 22q11.2 microdeletion syndromes have very similar presentation, making the exact pathogenesis difficult to treat, and unfortunately DiGeorge syndrome is well known by several other names, including (but not limited to) Velocardiofacial syndrome (VCFS), Conotruncal anomalies facie (CTAF) syndrome, as well as CATCH-22 syndrome[13].

A specific gene that seems to be critical in DiGeorge syndrome is the TBX1 gene which, when deleted, causes the exact presentation of DiGeorge syndrome. [14] The TBX1 chromosomal section results in the failure of the third and fourth pharyngeal pouches to develop, resulting in several signs and symptoms which are present at birth. These include thymic hypoplasia, hypoparathyroidism, recurrent susceptibility to infection, as well as congenital cardiac abnormalities, craniofacial dysmorphology and learning dysfunctions[15].

Dianostic Tests

Diagnostic Test How it works Relevance to DiGeorge
Fluorescence in situ hybridisation (FISH) [16] FISH is a technique that attaches DNA probes that have been labeled with fluorescent dye to chromosomal DNA. When viewed under fluorescent light, the labelled regions will be visible. This test allows for the determination of whether or not chromosomes or parts of chromosomes are present. This procedure differs from others in that the test does not have to take place during cell division. [17] FISH is a significant test used to confirm a DiGeorge diagnosis. Since the syndrome features a loss of part or all of chromosome 22, the probe will have nothing or little to attach to. This will present as limited fluorescence under the light and the diagnostician will determine whether or not the patient has DiGeorge. As with any testing, it is difficult to rely on one result to determine the condition. The patient must present with certain clinical features and then FISH is used to confirm the diagnosis.
Based on symptoms DiGeorge patients often have similar symptoms even though it is a condition that affects a number of the body systems. These similarities can be used as early tools in diagnosis. Practitioners would be looking for features such as the following:
  • Hypoparathyroidism resulting in hypocalcaemia
  • Poorly developed or missing thyroid presenting as immune system malfunctions
  • Small heads
  • Kidney function problems
  • Heart defects
  • Cleft lip/ palate [18]
When considering a patient with a number of the traditional symptoms of DiGeorge, a practitioner would not rely solely on the clinical symptoms. It would be necessary to undergo further tests such as FISH to confirm the diagnosis. In addition, with modern technology and prenatal care advancing, it is becoming less common for patients to present past infancy. Many cases are diagnosed within pregnancy or soon after birth due to the significance of the heart, thyroid and parathyroid.
Ultrasound An ultrasound is a prenatal care test to determine how the fetus is developing and whether or not any abnormalities may be present. The machine sends high frequency sound waves into the area being viewed. The sound waves reflect off of internal organs and the fetus into a hand held device that converts the information onto a monitor to visualize the sound information. Ultrasound is a non-invasive procedure. [19] Ultrasound is able to pick up any abnormalities with heart beats. If the heart has any abnormalities is will lead to further investigations to determine the nature of these. It can also be used to note any physical abnormalities such as a cleft palate or an abnormally small head. Like diagnosis based on clinical features, ultrasound is used as an early indication that something may be wrong with the fetus. It leads to further investigations.
Amniocentesis Amniocentesis is a medical procedure where the practitioner takes a sample of amniotic fluid in the early second trimester. The fluid is obtained by pressing a needle and syringe through the abdomen. Fetal cells are present in the amniotic fluid and as such genetic testing can be carried out. Amniocentesis is performed around week 14 of the pregnancy. As DiGeorge symdrome presents with missing or incomplete chromosome 22, genetic testing is able to determine whether or not the child is affected. 95% of DiGeorge cases are diagnosed using amniocentesis. [20]
BACS- on beads technology BACS on beads technology is a fast, cost effective alternative to FISH. 'BACS' stands for Bacterial Artificial Chromosomes. The DNA is treated with fluorescent markers and combined with the BACs beads. The beads are passed through a cytometer and they are analysed. The amount of fluorescence detected is used to determine whether or not there is an abnormality in the chromosomes.This technology is relatively new and at the moment is only used as a screening test. FISH is used to validate a result. BACs is effective in picking up microdeletions. DiGeorge has microdeletions on the 22nd chromosome and as such is a good example of a syndrome that could be diagnosed with BACs technology. [21]

Clinical Manifestations

A syndrome is a condition characterized by a group of symptoms, which either consistently occur together or vary amongst patients. While all DiGeorge cases are caused by deletion of genes on the same chromosome, clinical phenotypes and abnormalities are variable [22]. The deletion has potential to affect almost every body system, the body systems involved, the combination and the degree of abnormality however, varies widely, even amongst family members [23] [24]. The most common signs and symptoms include:

• Congenital heart disease

• Defects of the palate/velopharyngeal insufficiency

• Recurrent infections

• Hypocalcaemia due to hypoparathyrodism

• Learning difficulties and behavioral abnormalities

• Abnormal facial features

• Significant feeding problems

• Renal abnormalities

A combination of the features listed above represents a typical clinical picture of DiGeorge Syndrome [25]. These common signs and symptoms often lead to the diagnosis of DiGeorge Syndrome and will be described in more detail in the following table. It should be noted however, that up to 180 different features are associated with 22q11.2 deletions, often leading to delay or controversial diagnosis [26].

Abnormality Clinical presentation How it is caused
Congenital heart disease Congenital malformations of the heart can present with varying severity ranging from abnormalities that cause death to mild abnormalities with minimal symptoms[27]. In more severe cases the abnormality will be detected during pregnancy or right after birth. In DiGeorge Syndrome cardiac abnormalities are the most common cause of mortality however in many cases surgery can correct the abnormality. Particular genes located on the chromosome 22 play a role in the formation of the conotrucus. In embryologic development the heart forms from a single tube which assumes a S-shaped form in the forth week of embryologic development. At that stage the conotruncus lies in front of the primitive ventricle, which then together give rise to the right and left ventricle[28]. Conotruncal abnormalities are the most common cardiac abnormalities in DiGeorge Syndrome including truncus arteriosus, tetralogy of Fallot, interrupted aortic arch, pulmonary atresia with ventricular septal defects and ventricular septal defects [29]. However also many non-conotruncal case are seen in patients with DiGeorge Syndrome [30].
Defect of palate/velopharyngeal insufficiency Velopharyngeal insufficiency (VIP) presents commonly with hypernasality (nasal speech) and nasal air emission. In the english language only the sounds "m", "n" and "ng" should resonate nasally, however in hypernasality other sounds resonate through the nose as well to varying degrees. In order to pronounce strong consonants ("p", "b", "g", "t", and "d") the velopharygeal spincter must close off the nose, which does not occur in VIP resulting in difficulties to pronounce these strong consonantes[31]. The velum, which is the soft palate/roof of the mouth, the lateral pharyngeal wall and the posterior pharyngeal walls are the structures that come together to close off the nose from the mouth during speech. Incompetence of the soft palate to reach the posterior pharyngeal wall is often associated with cleft palate, however may as well be due to neuromuscular impairment. A cleft palate occur due to failure of fusion of the two palatine bones during embryologic development[32].
Recurrent infections due to immunodeficiency Many newborns with a 22q11.2 deletion present with difficulties in mounting an immune response against infections or with problems after vaccination. In most cases these problems cease before the first year of life, however some patients may have a persistent immunodeficiency and develop autoimmune diseases such as juvenile rheumatoid arthritis or graves disease. The immune system has a specialized T-cell mediated immune response in which T-cells recognize and eliminate (kill) foreign antigens (bacteria, viruses etc.) that are presented to T-cell receptors by antigen-presenting cells [33]. T-cells arise from and mature in the thymus where they, especially during childhood, arise from haemapoietic stem cells and undergo a selection process. In embryonic development the thymus develops from the third pharyngeal pouch, a structure at which abnormalities occur in the event of a 22q11.2 deletion. Hence patients with DiGeorge syndrome lack of T-cell mediated response may be caused by lack of or hypoplasticity of the thymus, which then in turn causes the difficulties in dealing with infections [34].

Autoimmune diseases are thought to be due to T-cell regulatory defects and impair of central tolerance [35].

Hypocalcaemia due to hypoparathyrodism Hypoparathyrodism (lack of or too little function of the parathyroid gland) causes hypocalcaemia (lack of or too low amounts of calcium circulating in the bloodstream). Hypocalcaemia in turn may cause seizures in the fetus[36]. However symptoms may as well be absent until adulthood. Typical signs and symptoms of hypoparathyrodism are for example seizures, muscle cramps, tingling in finger, toes and lips, and pain in face, legs, and feet[37]. The superior parathyroid glands as well as the parafollicular cells are formed from arch four and the inferior parathyroid glands are formed from arch three. In DiGeorge syndrome failure of the development or incomplete development of these arches may lead to lack of the parathyroid gland. The parathyroid gland normally produces parathyroid hormone, which functions by increasing calcium levels in the blood. However in the event of absence or insufficiency of the parathyroid glands calcium deposits in the bones to increased amounts and decreased calcium levels in the blood can cause sever problems as seen in DiGeorge Syndrome [38].


There is no cure for DiGeorge syndrome because it is a genetic abnormality which is due to inheritance or de novo mutations of genes on chromosome [39]. However many of the associated symptoms can be cured or treated. Therefor the earlier the diagnosis the better. Due to the high variability of symptoms amongst DiGeroge patients, a diagnosis might not occur before adulthood. In the case of severe heart defects, seizures due to hypocalcaemia or feeding difficulties Digeorge Sydnrome is diagnosed in the newborn, while some of the late occurring symptoms might be autoimmune disorders, or psychiatric illness [40].

It is important to note, that each individual with a 22q11.2 deletion presents differently, hence that there is no single treatment plan. The patient has rather to be looked at individually in order to provide to best medical therapy available. Treatment options are for example available for cardiac abnormalities, immune problems, cleft palate, hypoparathyrodism and many more. To give examples some of the most commonly treated symptoms in DiGeorge syndrome will be discussed below.

Further research possibilities


Antigen a substance or molecule which will trigger an immune response when introduced into the body

Autoimmune of or relating to disease caused by antibodies or lymphocytes produced against substances naturally present in the body (against oneself)

Autoimmune disease caused by mounting of an immune response including antibodies and/or lymphocytes against substances naturally present in the body

Chromosome genetic material in each nucleus of each cell arranged and condensed strands. In humans there are 23 pairs of chromosomes of which 22 pairs make up autosomes and one pair the sex chromosomes

Congenital preset from birth

Facies appearance of facial expression of an individual that is typical for a particular disease or condition

Graves disease symptoms due to too high loads of thyroid hormone, caused by an overactive thyroid gland

Haemapoietic stem cells multipotent cells that give rise to all blood cells

Hypocalcaemia deficiency of calcium in the blood stream

Hypoparathyrodism diminished concentration of parthyroid hormone in blood, which causes deficiencies of calcium and phosphorus compounds in the blood and results in muscular spasm

Immunodeficiency insufficiency of the immune system to protect the body adequately from infection

Lateral anatomical expression meaning of, at towards, or from the side or sides

Palate the roof of the mouth, separating the cavities of the nose and the mouth in vertebraes

Parathyroid glands four glands that are located on the back of the thyroid gland and secrete parathyroid hormone

Parathyroid hormone regulates calcium levels in the body

Pharynx part of the throat situated directly behind oral and nasal cavity, connecting those to the oesophagus and larynx

Phenotype set of observable characteristics of an individual resulting from a certain genotype and environmental influences

Posterior anatomical expression for further back in position or near the hind end of the body

Renal of or relating to the kidneys

Rheumatoid arthritis a chronic disease causing inflammation in the joints resulting in painful deformity and immobility especially in the fingers, wrists, feet and ankles

Schizophrenia a long term mental disorder of a type involving a breakdown in the relation between thought, emotion and behaviour, leading to faulty perception, inappropriate actions and feelings, withdrawal from reality and personal relationships into fantasy and delusion, and a sense of mental fragmentation. There are various different types and degree of these.

Sign an indication of a disease detected by a medical practitioner even if not apparent to the patient

Symptom a physical or mental feature that is regarded as indicating a condition of a disease, particularly features that are noted by the patient

Syndrome group of symptoms that consistently occur together or a condition characterized by a set of associated symptoms

T-cell a lymphocyte that is produced and matured in the thymus and plays an important role in immune response

Third Pharyngeal pouch pocked-like structure next to the third pharyngeal arch, which develops into neck structures

Thyroid Gland large ductless gland in the neck that secrets hormones regulation growth and development through the rate of metabolism


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  2. http://www.bbc.co.uk/health/physical_health/conditions/digeorge1.shtml
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  5. http://www.chw.org/display/PPF/DocID/23047/router.asp
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  32. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3125299/?tool=pmcentrez
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  39. 22http://www.ncbi.nlm.nih.gov/pubmed/21049214
  40. http://www.ncbi.nlm.nih.gov/pubmed/16027702%20/

2011 Projects: Turner Syndrome | DiGeorge Syndrome | Klinefelter's Syndrome | Huntington's Disease | Fragile X Syndrome | Tetralogy of Fallot | Angelman Syndrome | Friedreich's Ataxia | Williams-Beuren Syndrome | Duchenne Muscular Dystrolphy | Cleft Palate and Lip