DIGEORGE SYNDROME: SYMPTOMS, CAUSES, TREATMENT - MEDICINE - 2025

The DiGeorge syndrome is a disease of genetic origin that is manifested by the development of related malformations of the heart structure, the face, the thymus and the parathyroid glands.

On a clinical level, they will produce a wide variety of medical complications, among which are immune deficiencies, hypocalcemia, heart disease and psychiatric disorders.

Regarding the etiological origin, it is associated with a genetic alteration of chromosome 22. Due to this, it is also called 22q11.2 deletion syndrome.

Diagnosis is based on the identification of cardinal clinical signs through physical examination and various laboratory tests: analytical and immunological examination, abdominal ultrasounds, echocardiograms, and genetic study, fundamentally based on fluorescent in situ hybridization (FISH).

Finally, the treatment of this pathology focuses on the correction of organic malformations and the control of medical complications. Thus, T lymphocyte therapy, calcium supplements, corrective surgery, etc. are usually used.

History and discovery

This pathology was first described by the American pediatric specialist Angelo M. DiGeorge in 1965. In his clinical report, DiGeroge described a congenital pathology defined by the deficient development or absence of the parathyroid gland and the thymus.

Later, Chapelle in 1918, specifically described the congenital defects derived from this pathology. Thus, DiGeorge syndrome was referred to as the second cause of congenital heart defects after Down syndrome.

Finally, this pathology was characterized clinically through the classic triad of immunodeficiency, endocrinopathy with hypocalcemia, and heart disease.

Furthermore, in many cases, the wide symptomatic heterogeneity of the deletions located on chromosome 22 implies the differentiation of three different types of pathologies at the clinical level:

- DiGeorge syndrome

- Velocardiofacial Syndrome

- Cardiofacial Syndrome

Characteristics of DiGeorge syndrome

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DiGeorge syndrome, also known as the 22q11.2 deletion syndrome, is a disease caused by a genetic defect that results in the development of various body and organic malformations.

In this sense, this syndrome derives fundamentally from defective development processes during the prenatal or gestation phase, located mainly during the 3rd and 8th week of gestation.

Specifically, around the 5th week of gestation, the embryonic structures begin a process of formation and development of different structures and organs (Vera de Pedro et al., 2007).

Thus, a group of certain cells will give rise to the development of the face, various parts of the brain, the thymus, the heart, the aorta and the parathyroid glands.

This "field of cells" is usually located around the area or area behind the neck of the embryo in gestation. In this way, for the rest of the structures to begin to form and differentiate, it is essential that these cells move towards the different specific areas for each structure.

In this phase of development, pharyngeal bursae, arches and fissures, the thymus and parathyroid glands are formed, and later, part of the cranial and facial structures or various portions of the connective tissue.

In this way, the genetic abnormalities typical of DiGeroge syndrome give rise to a systematic alteration of this prenatal formation process, causing serious developmental failures.

Most affected areas

As a consequence, the most affected areas are usually:

- Heart: this structure constitutes one of the vital organs for our survival. It is part of the circulatory system and its essential function is to pump blood to the rest of the body.

- Facial Configuration: the formation of the facial structure depends on the correct formation of the skull, eyeballs, buccal system, ears, etc.

- Thymus: this structure plays a fundamental role within the immune system, since it is responsible for the maturation of lymphocytes or T cells.

- Parathyroid glands: they are constituted by a set of endocrine glands that have a staked role in the regulation of calcium, among other factors.

Thus, the areas most affected in DiGeorge syndrome are related to the defect of embryonic formation in areas associated with the neck and adjacent regions.

Statistics

DiGeroge syndrome has an estimated prevalence of 1 case per 4,000 people in the general population.

However, numerous epidemiological studies indicate a higher prevalence mainly due to the heterogeneity of its clinical course and the difficulty of establishing an early diagnosis.

In addition, both in the United States and internationally, DiGeorge syndrome is considered one of the most common causes of congenital heart defects and facial malformations.

On the other hand, in terms of epidemiological characteristics of a sociodemographic nature, a prevalence of 1 case per 6,000 people of Caucasian, Asian and Afro-descendant origin has been identified, while in the case of Hispanics, the prevalence amounts to one case for every 3,800 individuals.

Signs and symptoms

In the case of the most frequent signs and symptoms in DiGeorge syndrome, we must point out that it presents a clinical course with variable expressiveness.

In this case, in some patients, medical complications present a severe status, which can lead to early death. In other cases, the characteristics usually present a minimal compromise for the survival and functionality of the affected person.

Therefore, not all those affected by Di George syndrome will present the same affectation, however, they usually include one or more related alterations.

Anomalies in facial configuration

The alterations related to facial configuration constitute one of the most striking visual features of DiGeorge syndrome, generally they are defined by:

- Microcephaly: the head develops with a smaller or smaller dimension than expected for the level of development and chronological age of the affected person. In addition, a tubular nasal structure usually develops accompanied by flat or poorly accentuated cheeks.

- Mandibular hyploplasia and retrognathia: the structure of the jaw is not fully developed. Thus, in many cases it has a reduced size or an altered position, located further back than usual.

- Ocular alteration: generally the eyes tend to be included towards the inferior plane, in addition, microphthalmia (underdevelopment of one of the eyeballs), cataracts (opacity of the ocular lens) or cyanosis (blue coloration) around the eyes may appear.

- Alteration of the pinna: it is possible to identify an asymmetry in the configuration of the ears. They usually have a low implantation with the presence of malformations in the lobes and other outer areas of the pinna.

- Oral malformations: the configuration of the mouth usually presents an arched appearance towards the superior plane, characterized by the presence of a long and accentuated nasolabial sulcus and cleft palate.

Malformations and heart defects

Cardiac abnormalities often include a wide variety of defects. However, the most affected areas are related to the aorta and associated cardiac structures:

- Septal defects: the wall or structure that separates the heart chambers responsible for pumping blood, can be incompletely or defectively formed.

- Malformation of the aortic arch: various anomalies can also be described in the aortic segment located between the ascending and descending pathways.

- Tetralogy of Fallot: this pathology refers to the presence of alterations in the ventricular septal defect, significant narrowing of the pulmonary artery, abnormal position of the aorta and a thickening of the right ventricular area.

Immunodeficiency

People affected by DiGeorge syndrome tend to have a significant susceptibility to contracting various types of pathologies, mainly of an infectious nature (viruses, fungi, bacteria, etc.).

This fact is due to the presence of a dysfunction of the immune system, due to a deficient development of the type and the production of lymphocytes and T cells.

The immune system is made up of a wide variety of organs, structures, tissues and cells that together protect us from environmental and internal disease agents.

In this sense, DiGeorge syndrome produces a deficient or incomplete formation of the thymus, leading to alterations in its functionality and final location.

Generally, the most prominent anomaly is the hypofunctionality of T lymphocytes, essential in the production of immunoglobulins and antibodies.

Hypocalcemia

In this case, people affected by Digeorge syndrome usually have abnormally low levels of calcium concentration in the body and in the bloodstream.

This medical condition derives fundamentally from the presence of abnormalities in the parathyroid glands, due to an underdevelopment of its components (PrimaryInmune, 2011).

These glands are located in the neck, and are in a position close to the thyroid. However, in this case they have a reduced volume, so it will have a significant impact on the control of metabolism and calcium balance in the body.

Thus, in this case, the level of calcium in the blood is usually below 2.1-8.5 mm / dl, causing different medical complications such as cramps, muscle irritability, numbness, mood swings, cognitive deficits, etc.

Neurological and psychiatric disorders

In addition to the signs and symptoms described above, it is possible to identify others related to the cognitive and intellectual sphere of those affected.

Especially in diagnosed cases, learning difficulties, moderate intellectual deficit, attention deficit, mood disturbances, anxiety disorders, among others, have been described.

Causes

The genetic origin of DiGeorge syndrome is associated with the presence of alterations in chromosome 22, specifically in the 22q11.2 location. Specifically, it is due to the absence of a DNA sequence, composed of a number of 30 to 40 different genes.

Although many of the genes involved have not yet been identified in detail, the absence of this large group occurs in more than 90% of cases as a de novo mutation, while approximately 7% is due to hereditary factors.

Diagnosis

For the establishment of the diagnosis of DiGeorge syndrome, it is essential to identify the cardinal clinical signs of this pathology:

- Facial Defects.

- Heart Defects.

- Immunodeficiency.

- Hypocalcemia.

In this sense, along with the analysis of the medical history and physical examination, it is essential to perform various laboratory tests such as echocardiography, ultrasound, immunological examination and serum analytical studies.

Furthermore, an important aspect is the genetic examination, this is carried out mainly through fluorescent in situ hybridization (FISH).

Treatment

As we pointed out in the initial description, the treatment is mainly intended to control and correct the signs and symptoms caused by this type of disease.

In the case of hypocalcemia, it is usually treated through the administration of calcium and / or vitamin D supplements.

On the other hand, in the case of immune deficiency, although they tend to improve with age, various approaches can be used, such as transplantation of part of the thymus tissue, T lymphocyte therapy, or bone marrow transplantation.

As for facial and oral malformations, surgical repairs are usually used, which improve the physical appearance and the functionality of these bone.

Finally, in the case of cardiac alterations, both drugs can be administered for its treatment and correction through surgery.

Forecast

In most cases, affected people usually reach adulthood, however, a significant percentage of them begin to develop important immunological and / or cardiac abnormalities causing premature death, especially within the first year of life.

References

1. Bertrán, M., Tagle, F., & Irarrázaval, M. (2015). Psychiatric manifestations of 22q11.2 deletion syndrome: a literature review. Neurology.
2. Chemocare. (2016). Hypocalcemia (low calcium levels). Obtained from Chemocare.
3. Mayo Clinic. (2014). DiGeorge syndrome. Obtained from Mayo Clinic.
4. McDonald-McGinn, D., & Zackai, E. (2012). 22q11.2 deletion syndrome. Obtained from Orphanet.
5. NIH. (2016). 22q11.2 deletion syndrome. Obtained from Genetics Home Reference
6. NORD. (2016). Chromosome 22q11.2 Deletion Syndrome. Obtained from National Organization for Rare Disorders.
7. primaryimmune. (2016). DiGeorge Syndrome. Obtained from primaryimmune.
8. Sierra Santos, L., Casaseca García, P., García Moreno, A., & Martín Gutiérrez, V. (2014). DiGeorge syndrome. REV CLÍN MED FAM, 141-143.