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


Facial Features of Infants with DiGeorge

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 1/2000 to 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 syndrome is quite often a spontaneous mutation, but it may be passed on in an autosomal dominant fashion. Some families have many members affected.

DiGeorge syndrome is a complex abnormality and patient cases vary greatly. The patients experience heart defects, immunodeficiency, learning difficulties and facial abnormalities. These facial abnormalities can be seen in the image seen to the right. [3] DiGeorge syndrome can affect many of the body systems.

The clinical manifestations of the chromosome 22 deletion are significant and can lead to poor quality of life and a shortened lifespan in general for the patient. As there is currently no treatment education is vital to the well-being of those affected, directly or indirectly by this condition. [2]

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

  • Mid 1960's, Angelo DiGeorge noticed a similar combination of clinical features in some children. He named the syndrome after himself. The symptoms that he recognised were hypoparathyroidism, underdeveloped thymus, conotruncal heart defects and a cleft lip/ palate. [4]
Angelo DiGeorge (right) and Robert Shprintzen (left)
  • 1974 Finley and others identified that the cardiac failure of infants suffering from DiGeorge syndrome could be related to abnormal development of structures derived from the pouches of the 3rd and 4th pouches in the pharangeal arches. [5]
  • 1975 Lischner and Huff determined that there was a deficiency in T-cells was present in 10-20% of the normal thymic tissue of DiGeorge syndrome patients . [6]
  • 1978 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. [7]
  • 1978 Cleveland determined that a thymus transplant in patients of DiGeorge syndrome was able to restore immunlogical function. [8]
  • 1980s technology develops to identify that these patients have part of a chromosome missing. [9]
  • 1981 De La Chapelle suspects that a chromosome deletion in 22q11 is responsible for DiGeorge syndrome [10]
  • 1982 Ammann suspects that DiGeorge syndrome may be caused by alcoholism in the mother during pregnancy. There appears to be abnormalities between the two conditions such as facial features, cardiovascular, immune and neural symptoms. [11]
  • 1989 Muller observes the clinical features and natural history of DiGeorge syndrome [12]
  • 1993 Pueblitz notes a deficiency in thyroid C cells in DiGeorge syndrome patients [13]
  • 1995 Crifasi uses FISH as a definitive diagnosis of DiGeorge syndrome [14]
  • 1998 Davidson diagnoses DiGeorge syndrome prenatally using echocardiography and amniocentesis. This was the first reported case of prenatal diagnosis with no family history. [15]
  • 1998 Matsumoto confirms bone marrow transplant as an effective therapy of DiGeorge syndrome [16]
  • 2001 Lee links heart defects to the chromosome deletion in DiGeorge syndrome [17]
  • 2001 Lu determines that the genetic factors leading to DiGeorge syndrome are linked to the clinical features of Tetralogy of Fallot. [18]
  • 2001 Garg evaluates the role of TBx1 and Shh genes in the development of DiGeorge Syndrome [19]
  • 2004 Rice expresses that while thymic transplantation is effective in restoring some immune function in DiGeorge syndrome patients, the multifaceted disease requires a more rounded approach to treatment [20]
  • 2005 Yang notices dental anomalies associated with 22q11 gene deletions [21]
  • 2007 Fagman identifies Tbx1 as the transcription factor that may be responsible for incorrect positioning of the thymus and other abnormalities in Digeorge [22]
  • 2011 Oberoi uses speech, dental and velopharyngeal features as a method of diagnosing DiGeorge syndrome [23]


It appears that DiGeorge Syndrome has a minimum incidence of about 1 per 2000-4000 live births in the general population, ranking as the most frequent cause of genetic abnormality at birth, behind Down Syndrome [24]. Due to the fact that 22q11.2 deletions can also result in signs that are predictive of velocardiofacial syndrome, there is some confusion over the figures for epidemiology [25]. 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 [26]. For example, the study by Goodship et al examined 170 infants, 4 of whom had ventricular septal defects. This study, performed by directly examining the infants, produced an estimate of 1 in 3900 births, which is quite similar to the predicted value of 1 in 4000 [27]. Other epidemiological analyses of DGS, such as the study performed by Devriendt et al, have referred to birth defect registries and produce an average incidence of 1 in 6935. However, this incidence is specific to Belgium, and may not represent the true incidence of DiGeorge Syndrome on a global scale [28].

The presentation of more severe cases of DiGeorge Syndrome is apparent at birth, especially with malformations. The initial presentation of DGS includes hypocalcaemia, decreased T cell numbers, dysmorphic features, renal abnormalities and possibly cardiac defects [27]. Cardiac defects are present in about 75% of patients[29]. A telltale sign that raises suspicion of DGS would be if the infant has a very nasal tone when he/she produces her first noise. Other indications of DiGeorge Syndrome are an unusually high susceptibility to infection during the first six months of life, or abnormalities in facial features.

However, whilst these above points have discussed incidences in which DiGeorge Syndrome is recognisable at birth, it has been well documented that there individuals who have relatively minor cardiac malformations and normal immune function, and may show no signs or symptoms of DiGeorge Syndrome until later in life. DiGeorge Syndrome may only be suspected when learning dysfunction and heart problems arise. DiGeorge Syndrome frequently presents with cleft palate, as well as congenital heart defects[30]. As would be expected, cardiac complications are the largest causes of mortality. Infants also 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 [31]. Depending on the severity of DiGeorge Syndrome, it may be diagnosed at varying age. Those that present with cardiac symptoms will most likely be diagnosed at birth; others may present much later in life and be diagnosed with DiGeorge Syndrome (up to 50 years of age).


DiGeorge Syndrome is a developmental field defect that is caused by a 1.5- to 3.0-megabase hemizygous deletion in chromosome 22q11 [32]. This region is particularly susceptible to rearrangements that cause congenital anomaly disorders, namely; Cat-eye syndrome (tetrasomy), Der syndrome (trisomy) and VCFS (Velo-cardio-facial Syndrome)/DGS (Monosomy). VCFS and DiGeorge Syndrome are the most common syndromes associated with 22q11 rearrangements, and as mentioned previously it has a prevalence of 1/2000 to 1/4000 [33].

A FISH image showing a deletion at chromosome 22q11.2

The microdeletion locus of chromosome 22q11.2 is comprised of approximately 30 genes [34], with the TBX1 gene shown by mouse studies to be a major candidate DiGeorge Syndrome, as it is required for the correct development of the pharyngeal arches and pouches [35]. Comprehensive functional studies on animal models revealed that TBX1 is the only gene with haploinsufficiency that results in the occurrence of a phenotype characteristic for the 22q11.2 deletion Syndrome [35]. Some reported cases show autosomal dominant, autosomal recessive, and X-linked modes of inheritance for DiGeorge Syndrome [36]. However more current research suggests that the majority of microdeletions are autosomal dominantt, with 93% of these cases originating from a de novo deletion of 22q11.2 and with 7% inheriting the deletion from a parent [37].

Cytogenetic studies indicate that about 15-20% of patients with DiGeorge Syndrome have chromosomal abnormalities, and that almost all of these cases are either unbalanced translocations with monosomy or interstitial deletions of chromosome 22 [38]. A recent study supported this by showing a 14.98% presence of microdeletions in 22q11.2 for a group of 87 children with DiGeorge Syndrome symptoms. This same study, by Wosniak Et Al 2010, showed that 90% of patients the microdeletion covered the region of 3 Mbp, encoding the full 30 genes [39]. Whereas a microdeletion of 1.5 Mbp including 24 genes was found in 8% of patients. A minimal DiGeorge Syndrome critical region ( MDGCR) is said to cover about 0.5 Mbp and several genes [40]. The remaining 2% included patients with other chromosomal aberrations [41].


The area 22q11.2 involved in microdeletion leading to DiGeorge Syndrome

DiGeorge Syndrome 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 microdeletions, which usually occur during meiosis. These microdeletions also tend to be new, hence DiGeorge Syndrome can present in families that have no previous history of DiGeorge Syndrome. However, DiGeorge Syndrome can also be inherited in an autosomal dominant manner [42].

There are multiple genes responsible for similar function in the region, resulting in similar symptoms being seen across a large number of 22q11.2 microdeletion syndromes. 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 face (CTAF) syndrome, as well as CATCH-22 syndrome [43]. The acronym of CATCH-22 also describes many signs of which DiGeorge Syndrome presents with, including Cardiac defects, Abnormal facial features, Thymic hypoplasia, Cleft palate, and Hypocalcemia. Variants also include Burn’s proposition of Cardiac abnormality, T cell deficit, Clefting and Hypocalcemia.

Genes involved in DiGeorge syndrome

The specific gene that is critical in development of DiGeorge Syndrome when deleted is the TBX1 gene [44]. 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 [43]. These symptoms are also accompanied by hypocalcemia as a direct result of the hypoparathyroidism; however, this may resolve within the first year of life. TBX1 is expressed in early development in the pharyngeal arches, pouches and otic vesicle; and in late development, in the vertebral column and tooth bud. This loss of TBX1 results in the cardiac malformations that are observed. It is also important in the regulation of paired-like homodomain transcription factor 2 (PITX2), which is important for body closure, craniofacial development and asymmetry for heart development. This gene is also expressed in neural crest cells, which leads to the behavioural and cognitive disturbances commonly seen [43]. The Crkl gene is also involved in the development of animal models for DiGeorge Syndrome.

Structures formed by the 3rd and 4th pharyngeal pouches

Embryologically, the 3rd and 4th pharyngeal pouches are structures that are formed in between the pharyngeal arches during development. [45]

The thymus is primarily active during the perinatal period and is developed by the third pharyngeal pouch, where it provides an area for the development of regulatory T-cells. The parathyroid glands are developed from both the third and fourth pouch.

Pathophysiology of DiGeorge syndrome

There are two main physiological points to discuss when considering the presentation that DiGeorge syndrome has. Apart from the morphological abnormalities, we can discuss the physiology of DiGeorge Syndrome below.

Pathophysiology of DiGeorge syndrome


Hypocalcemia is a result of the parathyroid hypoplasia. Parathyroid hormone (PTH) is the main mechanism for controlling extracellular calcium and phosphate concentrations, and acts on the intestinal absorption, renal excretion and exchange of calcium between bodily fluids and bones. The lack of growth of the parathyroid glands results in a lack of the hormone PTH, resulting in the observed hypocalcemia[46].

Decreased Immune Function

Hypoplasia of the thymus is also observed in the early stages of DiGeorge syndrome. The thymus is the organ located in the anterior mediastinum and is responsible for the development of T-cells in the embryo. It is crucial in the early development of the immune system as it is involved in the exposure of lymphocytes into thousands of different antigens, providing an early mechanism of immunity for the developing child. The second role of the thymus is to ensure that these lymphocytes that have been sensitised do not react to any antigens presented by the body’s own tissue, and ensures that they only recognise foreign substances. The thymus is primarily active before parturition and the first few months of life[47]. Hence, we can see that if there is hypoplasia of the thymus gland in the developing embryo, the child will be more likely to get sick due to a weak immune system.

Diagnostic Tests

Fluorescence in situ hybridisation (FISH)

Technique Image
FISH is a technique that attaches DNA probes that have been labeled with fluorescent dye to chromosomal DNA. [48] 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. [49] FISH is a significant test used to confirm a DiGeorge syndrome 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 syndrome. 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.
FISH is able to detect missing regions of a chromosome

Symptomatic diagnosis

Technique Image
DiGeorge syndrome 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 [50]

When considering a patient with a number of the traditional symptoms of DiGeorge syndrome, 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.

Facial features of a DiGeorge patient


Technique Image
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. [51]

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.

Ultrasound technology is able to note any abnormal facial features


Technique Image
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 syndrome 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. [52]

BACS- on beads technology

Technique Image
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 syndrome has microdeletions on the 22nd chromosome and as such is a good example of a syndrome that could be diagnosed with BACs technology. [53]

The link below is a great explanation of BACs on beads technology. In addition, it compares the benefits of BACs against FISH


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 syndrome cases are caused by deletion of genes on the same chromosome, clinical phenotypes and abnormalities are variable [54]. The deletion has potential to affect almost every body system. However, the body systems involved, the combination and the degree of severity vary widely, even amongst family members [55] [56]. The most common signs and symptoms include:

  • Congenital heart defects
  • Defects of the palate/velopharyngeal insufficiency
  • Recurrent infections due to immunodeficiency
  • Hypocalcaemia due to hypoparathyrodism
  • Learning difficulties
  • Abnormal facial features

A combination of the features listed above represents a typical clinical picture of DiGeorge Syndrome [57]. Therefore 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 [58].

Abnormality Clinical presentation How it is caused
Congenital heart defects Congenital malformations of the heart can present with varying severity ranging from minimal symptoms to mortality. In more severe cases, the abnormalities are detected during pregnancy or at birth, where the infant presents with shortness of breath. More often however, no symptoms will be noted during childhood until changes in the pulmonary vasculature become apparent. Then, typical symptoms are shortness of breath, purple-blue skin, loss of consciousness, heart murmur, and underdeveloped limbs and muscles. These changes can usually be prevented with surgery if detected early [59] [60]. Congenital heart defects are commonly due to faulty development from the 3rd to the 8th week of embryonic development. Cardiac development includes looping of the heart tube, segmentation and growth of the cardiac chambers, development of valves and the greater vessels. Some of the genes involved in cardiac development are located on chromosome 22 [59] and in case of deletion can lead to various congenital heard disease. Some of the most common ones include patient ductus arteriosus, tetralogy of Fallot, ventricular septal defects and aortic arch abnormalities [61]. To give one example of a congenital heart disease, the tetralogy of Fallot will be described and illustrated in image below.
Defect of palate/velopharyngeal insufficiency
The anatomy of the normal palate in comparison to a cleft palate observed in DiGeorge syndrome
Velopharyngeal insufficiency or cleft palate is the failure of the roof of the mouth to close during embryonic development. Apart from facial abnormalities when the upper lip is affected as well, a cleft palate presents with hypernasality (nasal speech), nasal air emission and in some cases with feeding difficulties [62]. The from a cleft palate resulting speech difficulties will be discussed in the image on the left. The roof of the mouth, also called soft palate or velum, the posterior pharyngeal wall and the lateral 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. A cleft palate occur due to failure of fusion of the two palatine bones (the bone that form the roof of the mouth) during embryologic development and commonly occurs in DiGeorge syndrome [63].
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. it should be noted, that the variability amongst patients is high and that 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 [64]. The immune system has a specialized T-cell mediated immune response in which T-cells recognize and eliminate (kill) foreign antigens (bacteria, viruses etc.) [59]. T-cells arise from and mature in the thymus. Especially during childhood T-cells 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 have failure in T-cell mediated response due to hypoplasticity or lack of the thymus and therefore difficulties in dealing with infections [65].

Autoimmune diseases are thought to be due to T-cell regulatory defects and impair of tolerance for the body's own tissue [66].

Hypocalcaemia due to hypoparathyrodism Hypoparathyrodism (lack/little function of the parathyroid gland) causes hypocalcaemia (lack/low levels of calcium in the bloodstream). Hypocalcaemia in turn may cause seizures in the fetus [67]. 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[68]. The superior parathyroid glands as well as the parafollicular cells are formed from arch four in embryologic development and the inferior parathyroid glands are formed from arch three. Developmental failure of these arches may lead to incompletion or absence of parathyroid glands in DiGeorge syndrome. 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 calcium levels in the blood are decreased, which can cause sever problems if left untreated [69].
Learning difficulties Nearly all individuals with 22q11.2 deletion syndrome have learning difficulties, which are commonly noticed in primary school age. These learning difficulties include difficulties in solving mathematical problems, word problems and understanding numerical quantities. The reading abilities of most patients however, is in the normal range [70].

DiGeorge syndrome children appear to have an IQ in the lower range of normal or mild mental retardation[71].

While the exact reason for these learning difficulties remains unclear, studies show correlation between those and functional as well as structural abnormalities within the frontal and parietal lobes (front and side parts of the brain) [72]. Additionally studies found correlation between 22q11.2 and abnormally small parietal lobes [73].
Abnormal facial features
abnormal facial features observed in DiGeorge syndrome
To the common facial features of individuals with DiGeorge Syndrome belong [74]:
  • broad nose
  • squared shaped nose tip
  • Small low set ears with squared upper parts
  • hooded eyelids
  • asymmetric facial appearance when crying
  • small mouth
  • pointed chin
The abnormal facial features are, as all other symptoms, based on the genetic changes of the chromosome 22. While there are broad variations amongst patients, common facial features can be seen in the image on the left [74].

Tetralogy of fallot as on example of the congenital heart defects that can occur in DiGeorge syndrome

The images and descriptions below illustrate the each of the four features of tetralogy of fallot in isolation. In real life however, all four features occur simultaneously.

Drawing Of A Normal Heart.PNG
Ventricular Septal Defect.PNG
Obstruction of Right Ventricular Heart Flow.PNG
'Overriding' Aorta.PNG
Heart Defect E.PNG
The Normal heart

The healthy heart has four chambers, two atria and two ventricles, where the left and right ventricle are separated by the interventricular septum. Blood flows in the following manner: Body-right atrium (RA) - right ventricle (RV) - Lung - left atrium (LA) - left ventricle - body. The separation of the chambers by the interventricular septum and the valves is crucial for the function of the heart.

Ventricular septal defects

If the interventricular septum fails to fuse completely, deoxygenated blood can flow from the right ventricle to the left ventricle and therefore flow back into the systemic circulation without being oxygenated in the lung. [59]

Obstruction of right ventricular outflow

Outgrowth of the heart muscle can cause narrowing of the right ventricular outflow to the lungs, which in turn leads to lack of blood flow to the lungs and lack of oxygenation of the blood. [59].

"Overriding" aorta

If the aorta is abnormally located it connects to the left and also to the right ventricle, where it "overrides", hence blood from both left and right ventricle can flow straight into the systemic circulation. [59].

Right ventricular hypertrophy

Due to the right ventricular outflow obstruction, more pressure is needed to pump blood into the pulmonary circulation. This causes the right ventricular muscle to grow larger than its usual size (compare image A with image E). [59].


There is no cure for DiGeorge syndrome. Once a gene has mutated in the embryo de novo or has been passed on from one of the parents, it is not reversible [75]. However many of the associated symptoms, such as congenital heart defects, velopharyngeal insufficiency or recurrent infections, can be treated. As mentioned in clinical manifestations, there is a high variability of symptoms, up to 180, and the severity of these [76]. This often complicates the diagnosis. In fact, some patients are not diagnosed until early adulthood or not diagnosed at all, especially in developing countries [77] [78]. Once diagnosed, there is no single therapy plan. Opposite, each patient needs to be considered individually and consult various specialists, from example a cardiologist for congenital heard defect, a plastic surgeon for a cleft palet or an immunologist for recurrent infections, in order to receive the best therapy available. Furthermore, some symptoms can be prevented or stopped from progression if detected early. Therefore, it is of importance to diagnose DiGeorge syndrome as early as possible [79]. Despite the high variability, a range of typical symptoms raise suspicion for DiGeorge syndrome over a range of ages and will be listed below [77][80]:

  • Newborn: heart defects
  • Newborn: cleft palate, cleft lip
  • Newborn: seizures due to hypocalcaemia
  • Newborn: other birth defects such as kidney abnormalities or feeding difficulties
  • Late-occurring features: autoimmune disorders (for example, juvenile rheumatoid arthritis or Grave's disease)
  • Late-occurring features: Hypocalcaemia
  • Late-occurring features: Psychiatric illness (for example, DiGeorge syndrome patients have a 20-30 fold higher risk of developing schizophrenia)

Once alerted, one of the diagnostic tests discussed above can bring clarity.

The treatment plan for DiGeorge syndrome will be both treating current symptoms and preventing symptoms. A range of conditions and associated medical specialties should be considered. Some important and common conditions will be discussed in more detail in the table below.


Therapy options for congenital heart diseases
The classical treatment for severe cardiac deficits is surgery, where the surgical prognosis depends on both other abnormalities caused DiGeorge syndrome, such as a deprived immune system and hypocalcaemia, and the anatomy of the cardiac defects [81]. In order to achieve the best outcome timing is of importance [82].

Overall techniques in cardiac surgery have been adapted to the special conditions of patients with 22q11.2 deletion, which decreased the mortality rate significantly [83].

Plastic Surgery

Therapy options for cleft palate Image
Plastic surgery in clef palate patients is performed to counteract the symptoms. Here, two opposing factors are of importance: first, the surgery should be performed relatively late, so that growth interruption of the palate is kept to a minimum. Second, the surgery should be performed relatively early in order to facilitate good speech acquisition. Hence there is the option of surgery in the first few moth of life, or a removable orthodontic plate can be used as transient palatine replacement to delay the surgery[84]. Outcomes of surgery show that about 50 percent of patients attain normal speech resonance while the other 50 percent retain hypernasality [85]. However, depending on the severity, resonance and pronunciation problems can be reversed or reduced with speech therapy [86].
Repaired cleft palate


Therapy options for immunodeficiency
The immune problems in children with DiGeorge syndrome should be identified early, in order to take special precaution to prevent infections and to avoiding blood transfusions and life vaccines [87]. Part of the treatment plan would be to monitor T-cell numbers [88]. A thymus transplant to restore T-cell production might be an option depending on the condition of the patient. However it is used as last resort due to risk of rejection and other adverse effects [89].


Therapy options for hypocalcaemia
Hypocalcaemia is treated with calcium and vitamin D supplements. Calcium levels have to be monitored closely in order to prevent hypercalcaemic (too high blood calcium levels) or hypocalcaemic (too low blood calcium levels) emergencies and possible calcification of tissue in the kidney [90].

Current and Future Research

A detailed map of the typically deleted region of 22q11.2 using MLPA and other techniques

Advances in DNA analysis have been crucial to gaining an understanding of the nature of DiGeorge Syndrome. Recent developments involving the use of Multiplex Ligation-dependant Probe Amplification ( MLPA) have allowed for the beginning of a true analysis of the incidence of 22q11.2 syndrome among newborns [91]. See the image to the right for a detailed map of chromosome loci 22q11.2 that has been made using modern genetic analysis techniques including MLPA.

Due to the highly variable phenotypes presented among patients it has been suggested that the incidence figure of 1/2000 to 1/4000 may be underestimated. Hence future research directed at gaining a more accurate figure of the incidence is an important step in truly understanding the variability and prevalence of DiGeorge Syndrome among our population. Other developments in microarray technology have allowed the very recent discovery of copy number abnormalities of distal chromosome 22q11.2 in a 2011 research project [92], that are distinctly different from the better-studied deletions of the proximal region discussed above. This 2011 study of the phenotypes presenting in patients with these copy number abnormalities has revealed a complicated picture of the variability in phenotype presented with DiGeorge Syndrome, which hinders meaningful correlations to be drawn between genotype and phenotype. However, future research aimed at decoding these complex variable phenotypes presenting with 22q11.2 deletion and hence allow a deeper understanding of this syndrome.

A preoperative chest PA showing a narrowed superior mediastinum suggesting thymic agenesis, apical herniation of the right lung and a resultant left sided buckling of the adjacent trachea air column

There has been a large amount of research into the complex genetic and neural substrates that alter the normal embryological development of patients with 22q11.2 deletion syndrome. It is known that patients with this deletion have a great chance of having attention deficits and other psychiatric conditions such as schizophrenia [93], however little is known about how abnormal brain function is comprised in neural circuits and neuroanatomical changes [94]. Hence future research aimed at revealing the intricate details at the neuronal level and the relation between brain structure and function and cognitive impairments in patients with 22q11.2 deletion sydnrome will be a key step in allowing a predicted preventative treatment for young patients to minimize the expression of the phenotype [95]. Once the structural variation of DNA and its implications in various types of brain dysfunction are properly explored and these prodromes are understood preventative treatments will be greatly enhanced and hence be much more effective for patients with 22q11.2 deletion syndrome.

As there is no known cure for DiGeorge syndrome, there is much focus on preventative treatment of the various phenotypic anomalies that present with this genetic disorder. Ongoing research into the various preventative and corrective procedures discussed above forms a particularly important component of DiGeorge syndrome research, as this is currently our only form of treating DiGeorge affected patients. Hypocalcaemia, as discussed above, often presents as an emergency in patients, where immediate supplements of calcium can reverse the symptoms very quickly [96]. Due to this fact, most of the evidence for treatment of hypocalcaemia comes from experience in clinical environments rather than controlled experiments in a laboratory setting. Hence the optimal treatment levels of both calcium and vitamin D supplements are unknown. It is known however, that the reduction of symptoms in more severe cases is improved when a larger dose of the calcium or vitamin D supplement is administered [97]. Future research directed at analyzing this relationship is needed to improve the effectiveness of this treatment, which in turn will improve the quality of life for patients affected by this disorder.

Intraoperative chest AP film showing newly developed streaky and patch opacities in both upper lung fields. ETT above the carina is also shown

As discussed above, there are various surgical procedures that are commonly used to treat some of the phenotypic abnormalities presenting in 22q11.2 deletion syndrome. It has recently been noted by researchers of a high incidence of aspiration pneumonia and Gastroesophageal reflux developing in the perioperative period for patients with 22q11.2 deletion. This is of course a major concern for the patient in regards to preventing normal and efficient recovery aswell as increasing the risks associated with these surgeries [98]. Although this research did not attain a concise understanding of the prevalence of these surgical complications, it was suggested that active prevention during surgeries on patients with 22q11.2 deletion sydnrome is necessary as a safeguard. See the images on the right for some chest x-rays taken during this research project that illustrate the occurrence of aspiration pneumonia in a patient, as well showing some of the abnormalities present in patients with this syndrome. Further research into the nature of these surgical complications would greatly increase the success rates of these often complicated medical procedures as well as reveal further the extremely wide range of clinical manifestations of DiGeorge Syndrome.

Some other interesting 2011 Research Projects

  • Cleft Palate, Retrognathia and Congenital Heart Disease in Velo-Cardio-Facial Syndrome: A Phenotype Correlation Study[99] "Heart anomalies occur in 70% of individuals with VCFS, structural palate anomalies occur in 70% of individuals with VCFS. No significant association was found for congenital heart disease and cleft palate"
  • Novel Susceptibility Locus at 22q11 for Diabetic Nephropathy in Type 1 Diabetes[100] "Diabetic nephropathy affects 30% of patients with type 1 diabetes. Significant evidence was found of a linkage between a locus on 22q11 and Diabetic Nephropathy "
  • Cognitive, Behavioural and Psychiatric Phenotype in 22q11.2 Deletion Syndrome[101] "22q11.2 Deletion syndrome has become an important model for understanding the pathophysiology of neurodevelopmental conditions, particularly schizophrenia which develops in about 20–25% of individuals with a chromosome 22q11.2 microdeletion. The high incidence of common psychiatric disorders in 22q11.2DS patients suggests that changed dosage of one or more genes in the region might confer susceptibility to these disorders."
  • Case Report: Two Patients with Partial DiGeorge Syndrome Presenting with Attention Disorder and Learning Difficulties [102] "The acknowledgement of similarities and phenotypic overlap of DGS with other disorders associated with genetic defects in 22q11 has led to an expanded description of the phenotypic features of DGS including palatal/speech abnormalities, as well as cognitive, neurological and psychiatric disorders. DGS patients do not always have the typical dysmorphic features and may not be diagnosed until adulthood. For this reason, it is possible for patients with undiagnosed DGS to first be admitted to a psychiatry department. Both of our patients had psychiatric symptoms and initially presented to the Psychiatry Department"
  • SNPs and real-time quantitative PCR method for constitutional allelic copy number determination, the VPREB1 marker case [103] "Real-time quantitative PCR (qPCR) performed with standard curves has been proposed as a routine, reliable and highly sensitive assay for gene expression analysis.Two peculiar advantages of the qPCR method have been focused: the detection of atypical microdeletions undiagnosed by diagnostic standard FISH approach and the accurate mapping of deletion breakpoints. We feel that the qPCR approach could represent a valid alternative to the more classical and expensive cytogenetic analysis, and therefore a helpful clinical tool for the 22q11 screening in patients with a non-classic phenotype."

Related Links

Lecture - Early Vascular Development - The basis of vascular and cardiac development. Individuals with DiGeorge syndrome suffer from a number of abnormalities of the heart.

Head Development -- How the pharangeal arches should come together, and where abnormalities arise. DiGeorge develops as a result of pharangeal arch anomalies, such as the distorted development of the thymus.

Heart - DiGeorge Syndrome exemplifies abnormalities of the heart and its development.

Neural Crest Development - DiGeorge syndrome is an abnormality of neural crest origin, as seen in cognitive disturbances.

Thymus Development - The thymus is compromised in DiGeorge Syndrome, often hypoplastic.

2011 Lab 1 - Gametogenesis - The basis of inheritance. DiGeorge Syndrome is often passed on to children in an autosomal dominant fashion, with the deletion of chromosome 22q11.

2011 Lab 6 - Early Embryo - Pharangeal Arch development is an important concept in understanding DiGeorge Syndrome and why the characteristics develop.


Amniocentesis - the sampling of amniotic fluid using a hollow needle inserted into the uterus, to screen for developmental abnormalities in a fetus

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

Arch of aorta - first part of the aorta (major blood vessel from heart)

Attention Deficits - Disorders such as ADD or ADHD which are characterised by persistent impulsiveness, short attention span and often hyperactivity

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

Autosomal Dominant - a method by which diseases can be passed down through families. It refers to a disease that only requires one copy of the abnormal gene to acquire the disease

Autosomal Recessive -a method by which diseases can be passed down through families. It refers to a disease that requires two copies of the abnormal gene in order to acquire the disease

Aspiration Pneumonia - inflammation of the lungs and airways caused by breathing in foreign material

Cardiac - relating to the heart

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

Cleft Palate - refers to the condition in which the palate at the roof of the mouth fails to fuse, resulting in direct communication between the nasal and oral cavities

Clinical - within a hospital

Congenital - present from birth

Copy Number Abnormalities - A form of structural variation in DNA that results in an abnormal number copies of one or more sections of the DNA

Cytogenetic - A branch of genetics that studies the structure and function of chromosomes using techniques such as fluorescent in situ hybridisation

De novo - A mutation/deletion that was not present in either parent and hence not transmitted

Ductus arteriosus - duct from the pulmonary trunk (the blood vessel that pumps blood from the heart into the lung) to the aorta that closes after birth

Dysmorphia - refers to the abnormal formation of parts of the body.

Echocardiography - the use of ultrasound waves to investigate the action of the heart

Gastroesophageal Reflux - A condition where the stomach contents leak backwards from the stomach irritating the oesophagus causing heartburn and other symptoms

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

Genes - a specific nucleotide sequence on a chromosome that determines an observed characteristic

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

Haploinsufficiency - When only a single functional copy of a gene is active (other copy is inactivated by mutation), leading to an abnormal or diseased state.

Hemizygous - An individual with one member of a chromosome pair or chromosome segment rather than two

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

Hypoplasia - refers to the decreased growth of specific cells/tissues in the body

Interstitial deletions - A deletion that does not involve the ends or terminals of a chromosome.

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

Locus - The location of a gene, or a gene sequence on a chromosome

Lymphocytes - specialised white blood cells involved in the specific immune response and the development of immunity

Malformation - see dysmorphia

Mediastinum - the membranous portion between the two pleural cavities, in which the heart and thymus reside

Meiosis - the process of cell division that results in four daughter cells with half the number of chromosomes of the parent cell

Micro-array technology - Refers to technology used to measure the expression levels of particular genes or to genotype multiple regions of a genome

Microdeletions - the loss of a tiny piece of chromosome which is not apparent upon ordinary examination of the chromosome and requires special high-resolution testing to detect

Minimum DiGeorge Critical Region - The minimum interstitial deletion that is required for the appearance DiGeorge phenotypes.

MLPA - (Multiplex Ligation-Dependant Probe Analysis) A technique for genetic analysis that permits multiple gene targets to be amplified with a single primer pair. Each probe is comprised of oligonucleotides. This is one of the only accurate and time efficient techniques used to detect genomic deletions and insertions.

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

Perioperative - Referring to the three phases of surgery; preoperative, intraoperative, and postoperative

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

Platelets - round and flat fragments found in blood, involved in blood clotting

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

Prenatal Care - health care given to pregnant women.

Prodrome - An early sign of developing a particular condition

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.

Seizure - a fit, very high neurological activity in the brain that causes wild thrashing movements

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

Substrate - A Substance on which an enzyme acts

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

TBX1 Gene - A human gene located on chromosome 22 at position 11q.21. A loss of this gene is thought responsible for many of the features of DiGeorge Syndrome.

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

Tetralogy of Fallot - is a congenital heart defect

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

Unbalanced translocations - An abnormality caused by unequal rearrangements of non homologous chromosomes, resulting in extra or missing genes.

Velocardiofacial Syndrome - another congenitalsyndrome quite similar in presentation to DiGeorge syndrome, which has abnormalities to the heart and face.

Ventricular septum - membranous and muscular wall that separates the left and right ventricle

X-linked - An inherited trait controlled by a gene on the X-chromosome


  1. http://www.ncbi.nlm.nih.gov/books/NBK22179/
  2. 2.0 2.1 http://www.bbc.co.uk/health/physical_health/conditions/digeorge1.shtml
  3. http://emedicine.medscape.com/article/135711-overview
  4. http://www.chw.org/display/PPF/DocID/23047/router.asp
  5. <pubmed>4854619</pubmed>
  6. <pubmed>1096976</pubmed>
  7. http://digital.library.pitt.edu/c/cleftpalate/pdf/e20986v15n1.11.pdf
  8. <pubmed>1148386</pubmed>
  9. http://www.chw.org/display/PPF/DocID/23047/router.asp
  10. <pubmed>7250965</pubmed>
  11. <pubmed>6812410</pubmed>
  12. <pubmed>3044796</pubmed>
  13. <pubmed> 8372031 </pubmed>
  14. <pubmed>7490915</pubmed>
  15. <pubmed> 9160392</pubmed>
  16. <pubmed>9827824</pubmed>
  17. <pubmed>1488286</pubmed>
  18. <pubmed>11455393</pubmed>
  19. <pubmed>11412027</pubmed>
  20. <pubmed>15547821</pubmed>
  21. <pubmed>16252847</pubmed>
  22. <pubmed>17164259</pubmed>
  23. <pubmed>21721477</pubmed>
  24. <pubmed> 9733045 </pubmed>
  25. <pubmed> 8230155 </pubmed>
  26. http://www.sciencedirect.com/science/article/pii/S0140673607616018
  27. 27.0 27.1 <pubmed> 9875047 </pubmed>
  28. <pubmed> 9733045 </pubmed>
  29. http://omim.org/entry/188400
  30. <pubmed>21846625</pubmed>
  31. http://www.ncbi.nlm.nih.gov/pubmed?term=21846625
  32. <pubmed> 2871720 </pubmed>
  33. <pubmed> 11715041 </pubmed>
  34. <pubmed> 21134246 </pubmed>
  35. 35.0 35.1 <pubmed> 11971873 </pubmed>
  36. <pubmed> 3146281 </pubmed>
  37. <pubmed> 21573985 </pubmed>
  38. <pubmed> 1715550 </pubmed>
  39. <pubmed> 21134246 </pubmed>
  40. <pubmed> 9326327 </pubmed>
  41. <pubmed> 21134246 </pubmed>
  42. <pubmed> 9733045 </pubmed>
  43. 43.0 43.1 43.2 <pubmed> 17950858 </pubmed>
  44. http://www.ncbi.nlm.nih.gov/pubmed?term=20301696
  45. Schoenwolf et al, Larsen’s Human Embryology, Fourth Edition, Church Livingstone Elsevier Chapter 16, pp. 577-581
  46. Guyton A, Hall J, Textbook of Medical Physiology, 11th Edition, Elsevier Saunders publishing, Chapter 79, p. 985
  47. Guyton A, Hall J, Textbook of Medical Physiology, 11th Edition, Elsevier Saunders publishing, Chapter 34, p. 440-441
  48. http://www.springerlink.com/content/u3t2g73352t248ur/fulltext.pdf
  49. http://www.genome.gov/10000206
  50. http://www.chw.org/display/PPF/DocID/23047/router.asp
  51. http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Ultrasound_scan
  52. http://medical-dictionary.thefreedictionary.com/DiGeorge+syndrome
  53. http://www.ngrl.org.uk/Wessex/downloads/tm10/TM10-S2-3%20Susan%20Gross.pdf
  54. <pubmed> 21049214</pubmed>
  55. <pubmed>9475599</pubmed>
  56. <pubmed>14736631</pubmed>
  57. <pubmed> 21049214</pubmed>
  58. <pubmed>16027702</pubmed>
  59. 59.0 59.1 59.2 59.3 59.4 59.5 59.6 Kumar, V., Abbas, A., Fausto, N., Mitchell, R. N. (2007). Robbins Basic Pathology. In Saunders Elsevier (Ed 8), Philadelphia. https://evolve.elsevier.com/productPages/s_1221.html
  60. <pubmed>18636635</pubmed>
  61. <pubmed> 18770859 </pubmed>
  62. <pubmed> 21861138 </pubmed>
  63. <pubmed>21738760</pubmed>
  64. <pubmed> 21049214</pubmed>
  65. <pubmed>19521511</pubmed>
  66. <pubmed>21049214</pubmed>
  67. <pubmed>21049214</pubmed>
  68. <pubmed>18956803</pubmed>
  69. <pubmed>448529</pubmed>
  70. <pubmed>19213009</pubmed>
  71. <pubmed>17845235</pubmed>
  72. <pubmed>17928237</pubmed>
  73. <pubmed>11339378</pubmed>
  74. 74.0 74.1 <pubmed>20573211</pubmed>
  75. <pubmed> 21049214</pubmed>
  76. <pubmed>16027702</pubmed>
  77. 77.0 77.1 <pubmed>16027702</pubmed>
  78. <pubmed>15754359</pubmed>
  79. <pubmed> 21274400</pubmed>
  80. <pubmed>9350810</pubmed>
  81. <pubmed>18636635</pubmed>
  82. <pubmed>2811420</pubmed>
  83. <pubmed>5696314</pubmed>
  84. <pubmed>11772163</pubmed>
  85. <pubmed> 21740170</pubmed>
  86. <pubmed>8884403</pubmed>
  87. <pubmed> 21049214</pubmed>
  88. <pubmed> 21485999</pubmed>
  89. <pubmed>17284531</pubmed>
  90. <pubmed>20094706</pubmed>
  91. <pubmed> 20075206 </pubmed>
  92. <pubmed> 21671380 </pubmed>
  93. <pubmed> 17049567 </pubmed>
  94. <pubmed> 12349872 </pubmed>
  95. <pubmed> 2977984 </pubmed>
  96. <pubmed> 2604478 </pubmed>
  97. <pubmed> 2413335 </pubmed>
  98. <pubmed> 3121095 </pubmed>
  99. <pubmed>21763005</pubmed>
  100. <pubmed>21909410</pubmed>
  101. <pubmed>21573985</pubmed>
  102. <pubmed>21750639</pubmed>
  103. <pubmed>21545739</pubmed>

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