DiGeorge syndrome

ALSO KNOWN AS: Chromosome 22 interstitial deletion, 22q11.2 deletion syndrome

ANATOMY OR SYSTEM AFFECTED: Glands, heart, immune system, lymphatic system, mouth

DEFINITION: A pediatric syndrome caused by a missing piece of chromosome 22 and characterized by congenital heart defects, the absence or hypoplasia of the thymus and parathyroid glands, cleft palate, and dysmorphic facial features.

CAUSES: Chromosomal abnormality resulting in absence of thymus and parathyroid glands

SYMPTOMS: Recurrent viral infections, reduced or absent T lymphocytes, defects in antibody production, congenital heart disease, cleft palate, learning difficulties

DURATION: Lifelong

TREATMENTS: Growth hormone, speech therapy, surgery to correct heart defects and cleft palate

Causes and Symptoms

Chromosomes possess two parts. The upper arms are called “p” arms and the lower arms are called “q” arms. Patients with DiGeorge syndrome have a chromosome mutation, specifically a deletion, in which a tiny piece is missing from inside the long arm of chromosome 22. The specific region inside the long “q” arm is labeled 11.2. Thus, DiGeorge syndrome is also referred to as 22q11.2 deletion syndrome or chromosome 22 interstitial deletion.

Most microdeletions such as these cannot be observed under a microscope because they are so tiny. A molecular cytogenetic test known as fluorescence in situ hybridization (FISH) is used. It includes the use of probes made from the DiGeorge chromosomal region (DGCR). A green fluorescent probe is used to identify chromosome 22, while a red probe is specific to the DGCR. In DiGeorge syndrome, one of the chromosomes will lack the red fluorescence.

About 93 percent of patients have a spontaneous (de novo) deletion of a 22q11.2, and 7 percent inherit the deletion from a parent. The very high de novo rate indicates that the deletion recurs with a high frequency as a result of new mutations occurring in the population. This deletion is inherited in an autosomal dominant manner. The offspring of persons with the deletion have a 50 percent chance of inheriting it. This interstitial deletion encompasses about three million base pairs of DNA in the majority of patients. About 90 percent of patients have the same three million base pair deletion, while 10 percent have a 1.5 million base pair deletion. Therefore, the deletion is large enough to contain nearly one hundred genes.

DiGeorge syndrome is initiated by defective embryonic development of the third and fourth pharyngeal pouches during the fifth week of development. These pouches normally become the thymus and the parathyroid glands. In the absence of a thymus, T lymphocyte maturation is stopped at the precell stage. DiGeorge syndrome is one of the most severe forms of deficient T-cell immunity. Children with DiGeorge syndrome develop recurrent viral infections and have abnormal cellular immunity, as characterized by severely reduced or absent T lymphocytes. They also have defects in T-cell-dependent antibody production. A spectrum of abnormal phenotypes may develop. These defects arise from the absence of key genes that are not available for normal development when a 22q microdeletion is present. Infants with this disease may suffer from congenital heart disease of various types, palatal abnormalities (such as cleft palate), and learning difficulties.

Treatment and Therapy

Children with a 22q11.2 deletion may exhibit a wide spectrum of problems and much variation in the severity of symptoms. A patient with DiGeorge syndrome may have several organs or systems affected. DiGeorge syndrome may result in problems in different body systems, such as the heart or palate, and in cognition, such as learning style. Consequently, a multidisciplinary approach is needed for management of a specific patient.

In the neonatal period, the following clinical and laboratory studies are pursued. The serum is tested for calcium; a low concentration points to the need for supplementation. The lymphocytes are measured; a low absolute count means referral to an immunologist, who will look at T- and B-cell subsets. A renal ultrasound examination should be performed because of the high incidence of structural renal abnormalities. A chest x-ray is needed to identify vertebral anomalies. A cardiac evaluation is recommended for all patients with DiGeorge syndrome because possible malformations may include tetralogy of Fallot, ventricular septal defect, interrupted aortic arch, or truncus arteriosus. Pediatric cardiologists are necessary to provide treatment and therapy. An endocrinologist could follow up possible growth-hormone deficiencies. Since there is a high incidence of speech and language delay, speech therapy and early educational intervention are highly recommended. All children with the 22q deletion should be seen by a cleft-palate team to diagnose problems and schedule surgery if necessary.

Other medical needs of children are met through evaluation by a feeding specialist, especially in the newborn period; a neurologist, for possible seizure disorders or problems with balance; a urologist, for possible kidney problems; and an otorhinolaryngologist (ear, nose, and throat doctor) for problems in this region.

Perspective and Prospects

A 2018 study published in the medical journal Wiener Klinische Wochenschrift found that DiGeorge syndrome is relatively common, occurring with a frequency of one in three thousand to six thousand live births. Therefore, this disorder is a significant health concern in the general population. Since the phenotype associated with it is broad and variable, many types of clinical and laboratory specialists are needed. The medical geneticist is the most likely person to have an overview of the diagnosis. A yearly evaluation is beneficial in answering questions. Parents should be tested to determine their chromosomal status. Genetic counseling could provide individuals and families with information on the nature, inheritance, and implications of DiGeorge syndrome to help them make informed medical and personal decisions. Current and future research using model organisms may help to explain the problems of phenotypic variability in DiGeorge syndrome.

Bibliography

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Emanuel, Beverly S., et al. “The 22q11.2 Deletion Syndrome.” Advances in Pediatrics, vol. 48, 2001, pp. 39–73.

King, Richard A., et al., editors. The Genetic Basis of Common Diseases. 2nd ed., Oxford UP, 2002.

Kraus, Christoph, et al. "DiGeorge Syndrome." Wiener Klinische Wochenschrift, vol. 130, no. 7, 18 Apr. 2018, 283–287, doi: 10.1007/s00508-018-1335-y. Accessed 31 Mar. 2024.

Maroni, Gustavo. Molecular and Genetic Analysis of Human Traits. Blackwell Science, 2001.

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Reed, Robyn C., et al. "Chromosomal Abnormalities." Stocker and Dehner's Pediatric Pathology, edited by Aliya N. Husain et al., 4th ed., Wolters Kluwer, 2016, pp. 77–102.

Sullivan, Kathleen E., and Donna M. McDonald-McGinn. "DiGeorge Syndrome: A Serendipitous Discovery." Primary Immunodeficiency Disorders: A Historic and Scientific Perspective, edited by Amos Etzioni and Hans D. Ochs, Elsevier, 2014, pp. 229–40.

Turnpenny, Peter, and Sian Ellard. Emery’s Elements of Medical Genetics. 15th ed., Elsevier, 2017.