• Antibiotics - treat infections (immunodeficiency)

• Calcium and vitamin D supplements - treat low calcium levels & Hypoparathyroidism

• Hormone replacement therapy - treat endocrine abnormalities

  PROCEDURES:

• Cardiac surgery - repair heart defects

• Cleft palate repair - to improve feeding

• Bone marrow transplant - thymus tissue and specialized cells (T cells)

  THERAPIES:

• Speech therapy

• Occupational therapy

• Physical therapy

• Developmental therapy

Resources:

• DiGeorge syndrome (22q11.2 deletion syndrome) - Diagnosis and treatment - Mayo Clinic

• DiGeorge Syndrome (22q11.2 Deletion Syndrome): What It Is, Symptoms & Treatment (clevelandclinic.org)

How does DiGeorge's Syndrome affect immune system?

• Thymic Hypoplasia or Aplasia

  - Hypoplasia: underdevelopment of the thymus

  - Aplasia: Absence of the thymus

  
  

• It is the developmental abnormalities in the thymus that leads to individuals with DiGerorge's syndrome to be immunodeficient.

  
  

• Thymus is a primary lymphoid organ that provides appropriate microenvironments for T lymphocyte maturation which orchestrate the adaptive immune response.

  
  

• There are key checkpoint in the T cell maturation and selection which occur in the medullary and cortical regions to establish central tolerance, eliminate self-reactive T cells and export naïve T cells to the periphery.

  
  

• Thymus-dependent T cell differentiation includes the expression of T cell receptor which are antigen-specific cell surface receptors, thymic "education", the negative selection involving the potential self-reactive T cells and positive selection to see if T cells have to capability to recognize antigens in the periphery. These thymic processes are crucial in ensuring that T cells are able to recognize antigens but do not elicit self-reactivity.

  
  

  Stages of T cell maturation in the Thymus:

  • Positive selection: thymocytes that are able to adequately recognize self-major histocompatibility complex (MHC) molecules will be selected for survival.

  • Negative selection: Thymocytes that strongly bind and recognize to self-antigens will be eliminated to prevent autoimmunity.

  • Surviving thymocytes will differentiate into either CD8+ cytotoxic T cells or CD4+ helper T cells which are then released into the peripheral blood.

  • Insufficient development of the thymus results in reduced amounts of mature T cells (CD4+ and CD8+ T cells) in the blood.

  • Reduction of T cells can compromise the body's ability to mount an effective immune response against antigens.

  
  

• Failure to develop a proper niche to generate mature thymocytes results in T cell lymphoenia and increase susceptibility of future infections in patients with DGS.

  - T cell lymphoneia is a conditions in which the blood has lower than normal T lymphocytes present.

  
  

• Without a properly functioning thymus, fewer precursor T cells such as CD4+ helper T cells and CD8+ cytotoxic T cells which play an essential role in the body's adaptive immunity can not mature.

  
  

• Various types of effector T cells mediate a diversified number of functions which include enhancing inflammatory responses, mediate direct cellular cytotoxicity against virally infected or tumour cells, class switching of different antibody isotopes and B cell differentiation to antibody-secreting cells.

  
  

• Dysfunction of the thymus results in cellular immunodeficiency and humoral defects.

  Cellular immunodeficiency:

  - dysfunction or underdevelopment of the thymus impairs processes which leads to a reduction of functional T cells. Dysfunctional thymus disrupts this process causing fewer mature functional T cells in circulation.

  - Reduced thymic output, limits the T cell receptor repertoire diversity, meaning that there are fewer variety of T cells available to recognize and respond to various antigens

  Humoral defects

  - although B cells, which are responsible for the production of antibody mature in the bone marrow and not the thymus, for B cells to function optimally, it depends on its interactions with T helper cells.

  - A dysfunctional thymus affects the B and T cell interactions.

  - B cells require the help from T helper cells to become activated and produce high affinity class switched antibodies. A decrease in the number of T cells will impact this process leading to suboptimal responses of antibodies.

  - Humoral immune defects of B cell immunity is observed in early on DGS.

  - The overall production of antibodies (immunoglobulins) can decrease due to inadequate T cell aid which may result in decrease levels of antibody isotypes such as IgM and IgG, low immunoglobulin levels, mostly affecting IgM.

  
  

• Autoimmune diseases which have been associated with DGS, is usually the consequence of T cell regulatory defects and impaired central tolerance.

  
  

• In DiGeorge syndrome, aplasia and thymic hypoplasia result in decrease of T cell production and maturation resulting in a reduced ability of the body to produce functional T cells resulting in increase in individuals to be susceptible to future infections.

  
  

Resources:

https://www.mayoclinic.org/diseases-conditions/digeorge-syndrome/symptoms-causes/syc-20353543

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2954737/

https://www.nhlbi.nih.gov/health/lymphopenia#:~:text=Lymphopenia%20(also%20called%20lymphocytopenia)%20is,but%20they%20have%20different%20functions.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065053/#:~:text=DiGeorge%20syndrome%20is%20an%20immunodeficiency%20characterized%20by,cells%20in%20DiGeorge%20syndrome%20show%20impaired%20maturation%2C

• DiGeorge's syndrome is primarily caused by a deletion in a region of chromosome 22.

  • There are many clinical features that can be accredited to the disease, and they include:

    • cardiac abnormalities

    • facial dysmorphology

    • palatal abnormalities

    • developmental delays and learning disabilities

    • endocrine disorders

    • immunodeficiency*

for this reflection, I will zoom into the lattermost point,(immunodeficiency).

It is important to note that in DiGeorge's syndrome, one of the primary causes of immunological deficiency is an abnormality concerning the central lymphoid organ, the Thymus. There are varying degrees of this phenomenon, from an underdeveloped Thymus to the complete absence of the Thymus. In a clinical aspect, this would be known as either Thymic hypoplasia or Thymic aplasia.

The Thymus is a primary lymphoid organ located in the anterior mediastinum, and it is primarily responsible for the maturation and differentiation of T cells/T-lymphocytes. Lymphoid progenitor cells from the bone marrow migrate to the thymus, where they undergo a series of developmental obstacles to ensure their immunocompetence.

These obstacles can be generalized into 4 stages, which include:

1. double negative stage; T-cell precursors lack both CD4 and CD8 co-receptors

2. double positive stage; Cells express CD4 and CD8 receptors and undergo positive selection to ensure they have the Major Histocompatibility Complex binding abilities.

3. single positive stage; these cells become either CD4+ or CD8+ cells, and they undergo negative selection to ensure they are not self-reactive T cells.

4. maturation (mature T cells); the fully mature but unactivated T cells enter the peripheral bloodstream to perform immunological functions.

Because of the deletion of the critical genes that are involved in thymic development, individuals with this disease have trouble trying to carry out these physiological processes, which can lead to different degrees of immunodeficiency.

T cells are very important components of the adaptive immune system. Simply put they can be divided into three types of T cells:

1. Helper T cells (CD4+): aids in B-cell activation and cytotoxic T cells.

2. Cytotoxic T cells (CD8+): directly kills virus infected cells and abnormal malignant cells through perforin and granzyme killing.

3. regulatory T cells: maintain immunotolerance and prevents autoimmunity.

It is an honorable mention as well, that even though B cells mature independently of the thymus, T-cells are extremely important for the activation of B cells.

Because of the Hypoplasia or the aplasia of the thymus, there will be a drastically lower T cell output into the body from onset from birth. This means that there will be a lower number of T cells in the peripheral immune system, affecting the quantity and diversity of the T cells.

With thymic epithelial cells playing a role in positive selection, the absence or impaired amount of these cells would mean that fewer or no T cells would undergo positive selection, which is essential to ensure that the T cells can recognize self-MHC molecules for antigen recognition. In the same way, negative selection can also be impaired for developing T cells, which could increase the risk of autoimmunity.

As for the numbers of T cells in general, a lower number of T cells means that inadequate amounts of cytokines can be produced, which could also spill over into affecting the innate immune system. B cell activation would also be highly affected, as there is also impaired help from CD4+ T cells to guide the class-switching and antibody production. Due to a lack of cytotoxic CD8+ cells, the individuals with this disease would also not be able to kill viral or tumor infected cells as efficiently, leaving them at greater risk for opportunistic infections, viral infections and carcinogenesis.

The types of opportunistic infections that individuals with this disease can attain include:

• fungal infections

• bacterial infections

• viral infections (most pronounced, due to reduced number of CD4+and CD8+ T cells.)

The issue with components such as bacterial and viral infections is that vaccination may also be of no use to these individuals. This is due to the fact that may vaccines rely on the inter and intracellular processes to provide artificially acquired immunity, especially vaccines that depend on the principle of T-cell dependent antigen processing. Live attenuated vaccines can also not be used, as they pose a greater risk for unchecked viral replications in these immunocompromised individuals.

All in all, the immunological aspects of this disorder is due to the essential role of the thymus in immune system function. The resulting immunodeficiency leads to increased susceptibility to infections and autoimmune disorders due to the dysfunction and dysregulation of the intricate processes that the Thymus plays an especially important role in.

references:

• https://www.mayoclinic.org/diseases-conditions/digeorge-syndrome/symptoms-causes/syc-20353543

• https://my.clevelandclinic.org/health/diseases/21182-digeorge-syndrome

• https://www.nhs.uk/conditions/digeorge-syndrome/

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

• https://rarediseases.org/rare-diseases/complete-digeorge-syndrome/

Some symptoms include:

1. Heart issues (lead to too little oxygen):

   Some examples of heart issues include:

   • A hole between the heart's lower chambers (AKA ventricular septal defect).

   • Only one large vessel rather than two vessels leading out of the heart (AKA truncus arteriosus).

   • Four problems with the heart's structure (AKA tetralogy of Fallot).

   • Heart murmur = sounds such as whooshing or swishing made by rapid, choppy (turbulent) blood flow through the heart.

   • Bluish skin due to poor circulation of blood (AKA cyanosis).

2. Frequent infections:

   • Thymus gland is either underdeveloped or completely absent.

   • Function of thymus gland -> development and maturation of T lymphocytes (T cells) which aids our immune system in fighting off pathogens and protecting us from infections.

   • Absence of thymus gland/underdeveloped thymus gland = poor immune function -> more susceptible to contracting frequent and severe infections.

3. Distinctive facial features:

   • Underdeveloped chin.

   • Ears that look different.

   • Wide-set eyes.

   • Hooded eyes.

   • An enlarged nose tip.

   • Asymmetric crying facies (ACF) -> when a baby cries, their mouth is pulled downward on one side while not moving on the other side. This facial weakness only affects the lower lip.

4. A gap in the roof of the mouth (cleft palate), or other problems with the palate such as:

   • structural problems -> hard to swallow or make certain sounds in speech.

   • Contributes to failure to gain weight as structural problems in the palate -> difficulty in eating properly etc.

5. Hearing loss:

   • Due to frequent ear infections.

6. Kidney problems (malformations or abnormalities):

   • Possibility of contracting UTI(s) due to the difficulty in completely emptying the bladder.

   • Kidney reflux -> Urine flows backward from the bladder to the kidneys = damages kidneys over time.

   • Kidney failure -> kidney function can deteriorate significantly in some cases.

   • Parathyroid glands work alongside kidneys to maintain calcium and phosphorus homeostasis, if there's a kidney dysfunction -> kidneys unable to effectively excrete excess phosphorus = Secondary Hyperparathyroidism which may lead to high calcium levels in the blood.

7. Hormone problems (underdeveloped parathyroid glands):

   • Reduced production in parathyroid hormone -> regulates the amounts of calcium, phosphorus and magnesium in the bones and blood.

   • Lead to tremors and seizures.

References:

Asymmetric crying facies (CULLP). Facial Palsy UK. (2024, March 7). https://www.facialpalsy.org.uk/causesanddiagnoses/asymmetric-crying-facies/

Department of Health & Human Services. (2001, May 28). Parathyroid glands. Better Health Channel. https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/parathyroid-glands

Mayo Foundation for Medical Education and Research. (2024, January 13). DiGeorge syndrome (22q11.2 deletion syndrome). Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/digeorge-syndrome/symptoms-causes/syc-20353543#:~:text=A%20common%20condition%20of%2022q11,Distinct%20facial%20features.

Mayo Foundation for Medical Education and Research. (2024, January 13). DiGeorge syndrome (22q11.2 deletion syndrome). Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/digeorge-syndrome/symptoms-causes/syc-20353543#:~:text=Heart%20issues.&text=For%20example%2C%20problems%20may%20include,also%20known%20as%20truncus%20arteriosus.

Mayo Foundation for Medical Education and Research. (2023, October 28). Tetralogy of Fallot. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/tetralogy-of-fallot/symptoms-causes/syc-20353477

Mayo Foundation for Medical Education and Research. (n.d.). Heart murmurs. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/heart-murmurs/symptoms-causes/syc-20373171

NHS. (n.d.). NHS choices. https://www.nhs.uk/conditions/digeorge-syndrome/

Professional, C. C. medical. (n.d.-b). Thymus: The function of the gland & why it is important. Cleveland Clinic. https://my.clevelandclinic.org/health/body/23016-thymus

DiGeorge syndrome (DGS) is a congenital disorder which results predominantly from the microdeletion of chromosome 22 at 22q11.2 locus. This mutation results in the failure of appropriate development of pharyngeal pouches, which are responsible for the embryologic development of the thymus and many other organs.

This is concerning because the thymic tissue is the organ responsible for T lymphocyte development, the maturation and differentiation of T cells. A complete absence of the thymus, though very rare, is associated with a form of severe combined immunodeficiency (SCID) as the body cannot produce a sufficient number of mature T cells.

T cells are major components and play a critical role in the adaptive immune system, and they are required for almost all adaptive immune responses. This includes helping B cells produce antibodies and macrophages to destroy ingested microbes, help activate cytotoxic T cells to kill infected target cells, establish a long-term immune memory through memory T cells, and regulating other immune cells.

Which is why DiGeorge’s syndrome affects primarily the adaptive immune system since this immunity involving specialized immune cells and antibodies that attack and destroy foreign invaders and are able to prevent disease in the future by remembering the antigens, will be affected.

Hence, DiGeorge’s syndrome compromises the adaptive immune system due to the defective development of the thymus, leading to a deficiency in T cells. This weakens the adaptive immune system response which can increase susceptibility to infections, and can also impair the humoral immune response since T-helper cells are necessary for optimal antibody production by B cells.

Resources:

• https://pubmed.ncbi.nlm.nih.gov/31747205/

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

• https://www.ncbi.nlm.nih.gov/books/NBK26827/#:~:text=Helper%20T%20cells%20are%20arguably,to%20kill%20infected%20target%20cells.