DiGeorge syndrome

Chapters:

Watch video only

Introduction0:00–0:23

. DeGeorge syndrome, named after Doctor Angelo DeGeorge, who first described the condition, is a genetic condition caused by a microdeletion on chromosome 22.
It's also called 22Q 11.2 deletion syndrome, where 22 refers to the chromosome involved, Q refers to the long arm of the chromosome, and 11.2 refers to the region on the long arm that's affected.

Causes0:23–1:44

A microdilation in this region results in a unique combination of congenital abnormalities, including heart defects, dysmorphic facial features, cleft palate, and underdevelopment of the thymus and parathyroid glands.
Now, building a human is a complex process that requires a lot of instructions. The blueprint that organizes these instructions is our DNA which is packed into structures called chromosomes.
Chromosomes are divided into two sets of arms, with the short arms labeled P and long arms labeled Q. These arms are further divided into regions which contain smaller sections called genes.
On chromosome 22's long arm, the 11.2 region contains approximately 30 to 40 genes. These genes help regulate development of the pharyngeal arches and pouches during embryogenesis.
One gene in particular, TBX1, plays a critical role in this process. The 3rd pharyngeal pouch gives rise to the thymus and inferior parathyroid glands, while the 4th pouch forms the superior parathyroid glands.

Pathophysiology1:44–3:33

At the same time, neural crest cells migrate into the pharyngeal arches and contribute to the formation of craniofacial structures and the cardiac outflow tract.
When a cell divides, chromosomes are copied so that each new cell carries the same genetic blueprint, but sometimes a part of a chromosome can be missing.
This loss of genetic material is called a deletion, and it's a type of genetic mutation. Deletions can vary in size, ranging from the loss of a single DNA base pair to the loss of a large portion of a chromosome.
And that's exactly what happens in DeGeorge syndrome. In these individuals, the 22Q11.2 region is missing.
This mutation usually occurs spontaneously as a new or de novo mutation and is not inherited from either parent. Because it involves only a small segment of the chromosome, it's classified as a microdeletion.
Alright, so losing the genes carrying blueprints for the 3rd and 4th pharyngeal pouches is like taking away blueprints for key building blocks.
Without them, future head and neck structures can form incorrectly, or in some cases, not at all. Since the size and exact location of deletions in the 22Q11.2 region can vary, DeGeorge syndrome covers a wide range of clinical manifestations.
First, let's focus on cardiac defects. In DeGeorge syndrome, neural crest cells fail to migrate properly during early development.
As a result, the heart fails to develop properly, resulting in conattruncal malformations. These refer to malformations in the region of the heart's outflow tracts where blood exits the ventricles and enters either the aorta or pulmonary artery.

Diagnosis and treatment3:33–4:14

Examples of conotruncal malformations include the tetrology of flow, pulmonary atresia, truncus arteriosis, and transposition of the great arteries.
Newborns with one of these defects typically exhibit symptoms soon after delivery, including rapid breathing, poor feeding, or cyanosis.
Next up are abnormalities in the formation of craniofacial structures. These occur when neural crest cells fail to migrate, proliferate, or differentiate properly into the bones and connective tissue of the face.

Review4:14–9:31

As a result, individuals often present with characteristic dysmorphic features, including a long face, broad nasal bridge with a bulbous tip, small and low set ears, and wide set or almond shaped eyes.
Moving on to thymic abnormalities, which occur because the 3rd pharyngeal pouch fails to form properly, disrupting normal thymus formation.
Moreover, thymic malformations can range from hypoplasia or underdevelopment to aplasia or complete absence of the thymus.
Without a functional thymus, immature T cells fail to mature and differentiate into specialized T cells. As a result, T cells remain immature and low in number, eventually impairing the body's immunity and leaving individuals vulnerable to infections such as viral and fungal infections.
Next up is the cleft palate, which also occurs because neural crest cells fail to migrate properly, disrupting the formation of the palate.
The severity can range from partial submucosal clefts to full cleft palate and lip defects. Submucosal clefts might not cause any symptoms at all, but more severe clefts often cause difficulties with breathing or feeding early after delivery.
Finally, there are parathyroid abnormalities, primarily hypoparathyroidism. This occurs because the 3rd and 4th pharyngeal pouches fail to form properly, disrupting the formation of parathyroid glands.
As a result, the glands are either underdeveloped or completely absent, leading to variable degrees of hypoparathyroidism.
In this condition, the body lacks parathyroid hormone, which is responsible for maintaining normal calcium and phosphorus levels.
Without enough hormone, hypocalcemia and hyperphosphatemia develop. Hypocalcemia causes a syndrome of involuntary muscle spasms called tetany and a prolonged QT interval, while hyperphosphatemia can contribute to abnormal calcium phosphate deposits in tissues over time.
Now, to remember the main features of DeGeorge syndrome, you can use the pneumonic catch-22, where C stands for cardiac defects, A for abnormal facies, T for thymic abnormalities, C for cleft palate, and H for hypoparathyroidism.
There's also number 22, to remind that the deletion occurs on chromosome 22. Along with physical manifestations, individuals with DeGeorge syndrome might also have a variety of psychiatric illnesses, such as schizophrenia.
Now, moving on to diagnosis, some hints are visible right away, like cardiac defects, distinctive facial features, and cleft palate.
These signs might suggest that something unusual happened during development. Other clues hide in lab results.
Low T cell number or T cell lymphopenia suggests thymic abnormalities, while low calcium levels and high phosphorus levels reflect hypoparathyroidism.
Another piece of the puzzle comes from a chest X-ray. If you can't see a thymic shadow, think of thymic abnormalities.
But to confirm the diagnosis and put all the pieces together, we need genetic testing that specifically identifies the 22Q11.2 microdeletion.
This can be done with either fluorescence in situ hybridization, also called fish, or with chromosomal microarray analysis.
Finally, let's go over treatment. There is no cure or specific treatment for Deeorge syndrome, so management focuses on the individual clinical manifestations.
Physical defects such as cardiac malformations and cleft palate require surgical repair. Hypocalcemia needs correction through oral calcium replacement, while T-cell lymphopenia and increased risk of infections might require prophylactic antibiotics.
All right, as a quick recap. DeGeorge syndrome, also known as the 22Q11.2 deletion syndrome, is a genetic condition resulting from a microdeletion in the Q11.2 region on chromosome 22.
As a result, neural crest cells fail to migrate properly, and the 3rd and 4th pharyngeal pouches fail to develop properly.
Eventually this results in a unique combination of congenital abnormalities, including cardiac defects, abnormal facial features, thymic hypoplasia, cleft palate, and hypoparathyroidism, which can be recalled using the pneumonic