2. • DiGeorge syndrome, also known as 22q11.2
deletion syndrome, is a congenital genetic
disorder caused by the deletion of a small piece
of chromosome 22.
• This chromosomal deletion leads to a wide
range of developmental and health issues
affecting multiple systems of the body. DiGeorge
syndrome was first described by Dr. Angelo
DiGeorge in 1968.
• The deleted portion of chromosome 22 is critical
for the normal development of several organs
and systems, and its absence can result in
various physical and intellectual challenges.
3. • One of the systems affected through this chromosomal abnormality is the Endocrine system.
Where dysfunction of the Thymus, Thyroid and other endocrine cells causes wide array of clinical
manifestations.
• Because of the dysfunction of the Thymus it leads to a state of immune deficiency which shows
Autosomal Dominant pattern.
• In different individuals there is variation in the organ system that is affected.
5. • Chromosome 22 contains 500-800 genes.
• The genes affected in Di George Syndrome are present at the Long arm of the chromosome 22
specifically 22q11.2.
• This region contains about 30-40 genes.
• The organ Dysfunction originates as a result of this deletion.
What causes the deletion?
1. Point Mutation – Non sense, Missense or Silent.
2. Frame shift Mutation – Delete or add nucleotide.
6. 1. TBX 1 - (T-Box transcription factor 1) – Major role in DGS. Involved in the development
of various organs such as heart, face and thymus.
2. C22orf32 - Involved in the development of parathyroid gland.
3. CRKL (CRK like protein) –Involved in signal transduction in endocrine systems
4. DGCR6 (Di George critical region 6) – Development of thymus.
5. COMT (catechol-o-Methyltransferase) – Breakdown of catecholamines.
10. • Introducing Alex, a 4-month-old male infant whose parents,
noticing developmental concerns and frequent respiratory
infections, sought medical advice. As an attentive parent,
you, the primary caregiver, express specific worries about his
feeding difficulties, facial features like a small mouth and
short nose, and slower-than-expected motor development.
After a thorough examination and genetic testing, you, along
with the healthcare team, diagnose Alex with DiGeorge
syndrome (22q11.2 deletion syndrome). The cardiovascular
abnormalities, including a heart murmur and tetralogy of
Fallot, become evident during the diagnostic process.
Notably, hypothyroidism is identified through lethargy and
other symptoms. You actively participate in the decision-
making process, discussing treatment options, initiating
thyroid hormone replacement therapy, and considering
potential cardiac interventions.
11. Thymus
• Thymus is an Endocrine organ which releases the hormone Thymopoietin. Thymopoietin is
responsible for the maturation of T lymphocytes and development of the Immune system.
Thyroid
• The thyroid gland produces hormones, primarily thyroxine (T4) and triiodothyronine (T3), which
are essential for regulating the body's metabolism. These hormones influence various
physiological processes, including growth, development, and energy metabolism.
12. Parathyroid Gland
• The parathyroid glands produce parathyroid hormone (PTH), which plays a crucial role in
regulating calcium and phosphorus levels in the blood. PTH helps to increase calcium levels by
stimulating the release of calcium from bones, increasing calcium absorption in the intestines,
and reducing calcium excretion by the kidneys.
Adrenal Gland
• The adrenal glands produce hormones such as cortisol and aldosterone. Cortisol is involved in
regulating metabolism and the body's response to stress, while aldosterone helps regulate
electrolyte balance and blood pressure.
14. Mechanism and Pathophysiology
• Hypothyroidism is one of the endocrine abnormalities associated with DiGeorge syndrome.
The thyroid gland plays a crucial role in regulating metabolism and energy balance by
producing thyroid hormones. In the context of DiGeorge syndrome, the mechanism leading
to hypothyroidism is often related to the developmental defects associated with the
disorder. The migration and differentiation of certain cells during fetal development,
including those contributing to the thyroid gland, can be disrupted due to the
chromosomal deletion.
• The pathophysiology of hypothyroidism in DiGeorge syndrome involves an insufficient
production of thyroid hormones, particularly thyroxine (T4) and triiodothyronine (T3). This
deficiency can occur due to structural abnormalities in the thyroid gland itself or
disruptions in the regulatory processes that govern hormone synthesis and release. As a
result, individuals with DiGeorge syndrome may experience decreased thyroid function,
leading to a range of clinical manifestations.
15. Clinical Manifestations
Clinical manifestations of hypothyroidism in
DiGeorge syndrome can be subtle or more
pronounced, depending on the severity of the
thyroid hormone deficiency. Common symptoms
include fatigue, weight gain, cold intolerance,
constipation, dry skin, and hair loss. Since thyroid
hormones play a crucial role in the normal growth
and development of the body, children with
DiGeorge syndrome and hypothyroidism may
exhibit delayed growth and developmental
milestones. Additionally, hypothyroidism can
impact cognitive function, contributing to learning
difficulties in affected individuals.
16. Mechanism and pathophysiology
• The mechanism underlying hypoparathyroidism in DiGeorge syndrome is primarily
attributed to the abnormal embryonic development of the third and fourth pharyngeal
pouches during gestation. These pouches give rise to various structures, including the
thymus and the parathyroid glands. The 22q11.2 deletion disrupts this developmental
process, resulting in either the absence or underdevelopment of the parathyroid
glands. Without properly functioning parathyroid glands, the production and secretion
of parathyroid hormone (PTH) are compromised, leading to hypoparathyroidism.
• The pathophysiology of hypoparathyroidism in DiGeorge syndrome revolves around
the deficiency of PTH, a hormone crucial for maintaining calcium and phosphorus
homeostasis. PTH normally stimulates the release of calcium from bones, enhances
calcium absorption in the intestines, and promotes the retention of calcium by the
kidneys. In the absence of sufficient PTH, these regulatory mechanisms are impaired,
leading to decreased serum calcium levels and elevated serum phosphorus levels. The
imbalance in these electrolytes can have widespread effects on various organs and
physiological processes.
17. Clinical manifestations
• Clinical manifestations of hypoparathyroidism in DiGeorge syndrome can be diverse and
may manifest at any age. Common symptoms include muscle cramps, tetany, and
numbness or tingling in the extremities, all of which are consequences of decreased
ionized calcium levels affecting neuromuscular function. Additionally, affected individuals
may experience seizures, as the lowered calcium levels impact neuronal excitability.
Other symptoms may include fatigue, dry skin, and brittle nails.
19. Clinical manifestations
• . The most prominent clinical consequence of thymic hypoplasia is immunodeficiency,
leading to recurrent infections, particularly viral and fungal infections.
20. Mechanism
• COMT-mediated catecholamine degradation occurs in various tissues, including the brain
and peripheral organs. The enzyme COMT methylates catecholamines by transferring a
methyl group from S-adenosyl methionine to the hydroxyl group of the catechol ring.
This process results in the formation of methylated catecholamines, which are then
excreted from the body. In individuals with DiGeorge syndrome, the genetic
abnormalities may affect the development and function of COMT, potentially leading to
altered catecholamine metabolism.
21. Clinical manifestations
• The dysregulation of catecholamine degradation can contribute to neurological and
cardiovascular abnormalities observed in DiGeorge syndrome. Catecholamines, such as
dopamine, play a crucial role in regulating mood, attention, and movement. Disruptions
in their metabolism may contribute to behavioral and cognitive issues seen in affected
individuals. Additionally, alterations in cardiovascular function may result from the
impact of catecholamines on heart rate and blood pressure.
22. Pathophysiology
• The pathophysiology of autoimmunity in DiGeorge syndrome is linked to the impaired
development and function of the thymus. Without proper thymic education, there is an
increased likelihood of T cells escaping into the periphery that may be autoreactive,
meaning they can attack the body's own tissues. The compromised thymic function in
DiGeorge syndrome can lead to a reduced pool of mature, self-tolerant T cells and an
increased risk of autoimmunity.
23. Clinical manifestations
• The clinical manifestations of autoimmunity in DiGeorge syndrome can include various
immune-related disorders. Some individuals may experience autoimmune cytopenia's,
where the immune system attacks and destroys its own blood cells, leading to conditions
such as autoimmune haemolytic anaemia or immune thrombocytopenia. Other
autoimmune conditions may manifest as rheumatoid arthritis, lupus-like syndromes, or
thyroid disorders, as the immune system mistakenly targets specific organs or tissues.
24. • Prevalence: DiGeorge syndrome is estimated to occur in approximately 1 in 3,000 to 1 in 6,000
live births. However, the prevalence may vary in different populations and geographic regions.
• Ethnic Variation: There is some evidence of ethnic variation in the prevalence of DiGeorge
syndrome. The condition has been reported to be more common in certain populations, such as
individuals of Northern European descent.
• Genetic Basis: DiGeorge syndrome is primarily caused by a microdeletion in the long arm of
chromosome 22 (22q11.2). The majority of cases (about 90-95%) are due to de novo mutations,
meaning they occur spontaneously and are not inherited from the parents. In rare cases, the
deletion may be inherited from an affected parent.
• Gender Distribution: DiGeorge syndrome affects both males and females, with no significant
gender predilection.
25. • Variable Expression: The clinical presentation of DiGeorge syndrome can vary widely, leading to
challenges in accurately diagnosing and estimating its prevalence. The spectrum of symptoms
includes congenital heart defects, immune system abnormalities, hypoparathyroidism, facial
dysmorphisms, and developmental delays.
• Underdiagnosis and Misdiagnosis: Due to the variability in clinical features and the lack of
awareness among healthcare professionals, DiGeorge syndrome is sometimes underdiagnosed or
misdiagnosed. Improved awareness and advances in genetic testing have led to better detection
of the syndrome in recent years.
• Antenatal Diagnosis: Prenatal diagnosis of DiGeorge syndrome can be challenging, but advances
in genetic testing techniques, such as chromosomal microarray analysis and fluorescence in situ
hybridization (FISH), have improved the ability to identify the 22q11.2 deletion during pregnancy.
• Multisystem Involvement: DiGeorge syndrome affects multiple organ systems, including the
cardiovascular, immune, and endocrine systems, contributing to the variable clinical
manifestations observed in affected individuals.
26. Physical
1. Physical examination will reveal cardiac
murmur
2. Facial abnormalities
3. Pharyngeal abnormalities
4. Micrognathia
5. Urogenital malformation
T cell Analysis
1. Absolute lymphocyte count of peripheral
blood
2. Flow cytometry measuring CD45RA+ T
and CD45RO+ cells
3. RT PCR Assay
4. Antibody response
27. Genetic Analysis
• Result of FISH analysis using LSI probe (TUPLE 1) from
DiGeorge/velocardiofacial syndrome critical region.
TUPLE 1 (HIRA) probe was labelled in Spectrum Orange
and Arylsulfatase A (ARSA) in Spectrum Green as
control. Absence of the orange signal indicates deletion
of the TUPLE 1 locus at 22q11.2
1. Array comparative Genomic
Hybridization (aCGH) for
detecting 22q11 deletion
2. Karyotyping
3. FISH can be requested if aCGH
is unavailable
4. Mulitplex ligand binding for
TBX1 Deletions
28. Imaging
• Brain computer tomography cuts of the person,
demonstrating basal ganglia and periventricular
calcification
• CT, MRI and X ray.
• Echocardiography
• Angiography
29. Surgical Treatment
1. Cardiac Anomalies require immediate
surgical management through three stage
palliation procedures (Blalock-Taussig
Shunt, Glenn Procedure and Fontan
Procedure) or other reconstructive
approaches
2. Craniofacial abnormalities are also
corrected based on the severity of airflow
compromise
Medical management
1. Hypocalcemia is managed by Vitamin D
and Calcium supplementation
2. Live vaccination is contraindicated in
patients with DGS
3. Trimethoprim/sulfamethoxazole is
prescribed to those with very low T-cell
count
30. Immunological treatment
1. Live vaccines are contraindicated due to severe allergic reactions
2. MMR can be safely administered
3. Thymus transplantation has been explored as a good therapeutic approach for patients
with complete DGS, with 76% survival rates at 2 years
4. Bone marrow transplant is also another therapeutic approach.
5. Allogeneic processed thymus tissue has been approved in October 2021 by the FDA for
use in patients with athymia as a possible therapeutic approach for pediatric patients.
6. They should receive prophylaxis for Pneumocystis jerovici immediately prior to
undergoing major surgery
7. All blood products should be irradiated to prevent graft-vs-host disease
