eMedicine Specialties > Allergy and Immunology > Immunodeficiencies

DiGeorge Syndrome

Author: Patrick Htain Win, MD, President/Director, Allergy, Asthma and Immunology Center, SC
Coauthor(s): Sridhar Guduri, MD, Consulting Staff, Allergy and Asthma Clinics of Ohio; Iftikhar Hussain, MD, Director of Allergy, Asthma, and Immunology Center, PC
Contributor Information and Disclosures

Updated: Feb 13, 2009

Introduction

Background

Conditions associated with DiGeorge syndrome are the other 22q11 deletion syndrome (22q11DS) known as the velocardiofacial syndrome (VCFS or Shprintzen syndrome), as well as conotruncal anomaly face syndrome, Cayler syndrome, Opitz-GBBB syndrome, and CHARGE (coloboma [eye], heart anomaly, atresia [choanal], retardation [mental and growth], genital anomaly, ear anomaly) syndrome.

DiGeorge anomaly (DGA) is a congenital immunodeficiency characterized by abnormal facies; congenital heart defects; hypoparathyroidism with hypocalcemia; cognitive, behavioral, and psychiatric problems; and increased susceptibility to infections. Pathological hallmarks include conotruncal abnormalities and absence or hypoplasia of thymus and parathyroid glands. Although this condition is commonly known as DiGeorge syndrome, the term DiGeorge anomaly is more appropriate. The constellation of defects is not a syndrome resulting from a single cause, but rather the failure of an embryological field to develop normally.

Harrington first noted the absence of the thymus gland in 1929.¹ This condition was later associated with congenital hypoparathyroidism by Lobdell in 1959.² Angelo DiGeorge first noted the immunological consequences associated with the above conditions and was the first to propose that the concurrent absence of the thymus and parathyroid glands might result from a perturbation in the development of the third and fourth pharyngeal pouches.³

Kelly in Philadelphia and de la Chapelle in France described partial monosomy of chromosome 22 associated with DiGeorge anomaly, providing the first clue to its genetic origin.⁴ Since then, a number of phenotypically similar syndromes have been described. Today, these are collectively grouped under the acronym CATCH-22 (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia resulting from 22q11 deletions); however, this acronym does not recapitulate the full spectrum of symptoms. This disorder varies greatly in expressivity. While some patients are mildly affected with learning disabilities and subtle craniofacial malformations, others die after birth with thymic aplasia and major cardiovascular defects.

How heterozygous microdeletion of approximately 30-50 genes on chromosome 22 leads to this diverse spectrum of phenotypes within the 22q11DS (VCFS and DiGeorge Syndrome), especially in the brain, is not clearly understood. The following 3 hypotheses exist to help explain this heterogeneity in phenotype:

1. 22q11DS may reflect haploinsufficiency, homozygous loss of function, or heterozygous gain of function of a single gene within the deleted region;
2. 22q11DS may result from haploinsufficiency, homozygous loss of function, or heterozygous gain of function of a few genes in the deleted region acting at distinct phenotypically compromised sites;
3. 22q11DS may reflect combinatorial effects of reduced dosage of multiple genes acting in concert at all phenotypically compromised sites.

In the current body of research on the chromosome 22q11 deletion syndromes, evidence supports each of these 3 hypotheses. A recent review article provides evidence favoring the third hypothesis, that 22q11DS reflects diminished expression of multiple 22q11 genes acting on common cellular processes during the development of the brain, heart, face, and limbs, and, subsequently, in the adolescent and adult brain.⁵

Pathophysiology

DiGeorge anomaly is characterized by malformations attributed to abnormal development of the pharyngeal arches and pouches. The common thread among all the organs involved in DiGeorge anomaly is that their development depends on migration of neural crest cells to the region of pharyngeal pouches.

Lammer and Opitz described DiGeorge anomaly as a field defect in which a group of tissues (field or neural crest and pharyngeal pouches in DiGeorge anomaly) that are interdependent on each other for normal development develop in an abnormal fashion.⁶ Although DiGeorge anomaly has traditionally been described as abnormal development of the third and fourth pharyngeal pouches, defects involving the first to sixth pouches are known to occur. Animal studies have shown that acute ethanol exposure in mice at a time when neural crest cells are migrating results in a craniofacial phenotype similar to that noted in DiGeorge anomaly. Features of DiGeorge anomaly have been described in children with evidence of fetal alcohol syndrome. Thus, it is postulated that any intrauterine insult to the facial neural crest can result in features of DiGeorge anomaly.

The disease mechanisms of 22q11.2 deletion syndromes involve 2 separate issues: mechanism of deletion and how the deletion results in the clinical phenotype(s) of the 22q11.2 deletions syndromes.

Since the early 1990s, the mechanism of deletion has been linked to low copy number repeats (LCRs). Four discrete blocks of LCRs (lettered A-D) are present in this genetic region, and every block consists of several modules of repeats that have various lengths and orientations within a block. Research from Saitta et al supports for the hypothesis that an aberrant unequal, interchromosomal meiotic exchange is the dominant mechanism 22q11.2 deletions.⁷ This comes from the identification of asynchronous replication at the site of the deletion.

As aforementioned, 30-50 genes are present within the commonly deleted region of chromosome 22q11.2. Chromosome 22 was fully sequenced in 1999, and within 2 years the gene mainly responsible for the phenotypic features of VCFS was identified as T-box transcription factor (TBX1). The development of a TBX1 -knockout mouse supported the importance of this gene in cardiac development and tracked the aberrant cardiac development to impaired formation of the fourth branchial arch artery, a precursor to the right ventricle and outflow tract.

Also, in mice, TBX1 is expressed in the pharyngeal mesenchyme and endodermal pouch. Pharyngeal pouches are the initial segmentation for structures of the face and upper thorax and are temporary structures. The third endodermal pouch gives rise to the thymus and parathyroid. Haplosufficiency for TBX1 leads to smaller precursor structures because of decreased proliferation of endodermal cells in the branchial arches. These branchial arches subsequently lead to defective development of facial structures, thymus, and parathyroid. TBX1 is also expressed in the region that gives rise to the cardiac outflow tract, the right ventricle, and the mesenchyme of the brain.

Patients with a chromosome 22q11.2 deletion syndrome have other defects that do not map to branchial arch structures. Cognitive, behavioral, and psychiatric disturbances are quite common, whereas distal organ (vertebral, renal) dysfunction is seen in relatively few patients. TBX1 is expressed in the developing brain that gives rise to various structures in the spinal column. Although the roles of TBX1 in these sites are not well understood, its expression pattern may provide insight into the framework for understanding the nonbranchial arch features of the 22q11.2 deletion syndromes phenotypes.

Although data supporting role of TBX1 in the phenotype of chromosome 22q11.2 deletion syndrome are fairly convincing, other data show evidence that other several other genes within the deleted region contribute to the phenotype as well. Haplosufficiency for glycoprotein Ib-β may contribute to the mild thrombocytopenia seen in some patients, and haplosufficiency for catechol-O -methyltransferase has been implicated in some studies for the behavioral and psychiatric disturbances seen in some patients.

Frequency

United States

Autopsy studies for DiGeorge anomaly accounted for 0.7% of 3469 postmortem examinations in the Seattle, Washington, area over a period of 25 years.

International

• One of the most widely cited estimates of prevalence rate for 22q11DS is that of Wilson and colleagues, who calculated a minimum of 1 in 4,000 livebirths on the basis of the presence of the deletion in 5% of patients with congenital cardiac defects.
• In the past, incidence of DiGeorge anomaly was estimated to be 1 case per 20,000 persons in Germany and 1 case per 66,000 persons in Australia.
• With the advent of fluorescent in situ hybridization (FISH) techniques to detect monosomy 22 and the inclusion of related syndromes, more recent estimates place the incidence of DiGeorge anomaly and VCFS in the range of 1 case per 3,000 persons.

Mortality/Morbidity

• A congenital heart defect is the main cause of morbidity and mortality. Ryan et al reported an 8% mortality rate in a series of 558 patients, with heart disease accounting for all but one of the cases.⁸ Most deaths occur within 6 months after birth.
• Infections due to severe immune deficiency are the second most common cause of mortality.

Sex

• No major difference is noted in the incidence of DiGeorge anomaly between males and females.

Age

• DiGeorge anomaly usually is diagnosed shortly after birth because of abnormal facies or cardiac manifestations.

Clinical

History

• Genetic
  • DiGeorge anomaly has been reported to be inherited in autosomal dominant, autosomal recessive, and X-linked fashions.
  • To date, sibling involvement has been observed only if a chromosome 22 deletion was found in a parent.
  • The frequency of this occurrence has been estimated at 8-25% of all syndromes associated with chromosome 22 deletion.
  • Approximately 17% of patients with phenotypic features of DiGeorge anomaly have no detectable genomic deletion. Several mutations in T-box transcription factor (TBX1) have been identified in patients without genetic deletion, including missense and frameshift mutations.
• Exposure history: History of exposure to alcohol and other toxins like isotretinoins is also relevant because the phenotype associated with fetal alcohol syndrome and isotretinoins resembles that of DiGeorge anomaly.
• Endocrine: Hypoparathyroidism leading to hypocalcemia (observed in 60% of patients) usually begins in the neonatal period, occasionally manifesting in the form of tetany or tonic convulsions.
• Cardiac
  • Various malformations are seen, particularly affecting the outflow tract.
  • In a series of 545 patients with 22q11 deletions, 20% had no cardiac defects (ie, based on clinical examination and echocardiography findings). The most common cardiac anomalies included tetralogy of Fallot (17%), ventricular septal defect and interrupted aortic arch (14% each), pulmonary atresia/ventricular septal defect (10%), and truncus arteriosus (9%).
  • Other anomalies included pulmonic stenosis, atrial septal defect, atrioventricular septal defect, and transposition of the great arteries.
• Immunologic
  • Thymic hypoplasia or aplasia leading to defective T-cell function is the hallmark of DiGeorge anomaly.
  • Depending on T-cell proliferative response to mitogens, DiGeorge anomaly can be classified as partial or complete. Patients with partial DiGeorge anomaly have below-normal proliferative response to mitogens, and the immune parameters may improve with time.
  • Patients with complete DiGeorge anomaly are rare and have no T-cell response to mitogens. These patients usually have very few detectable T cells in peripheral blood (1-2%) and usually require treatment.
  • Note that a normal-sized thymus is not necessary for normal T-cell development, and patients with a very small thymus, even in an ectopic location, may have a T-cell response to mitogens that ranges from below normal to normal. Mitogen responsiveness may be the most important parameter in assessing T-cell function, and peripheral T-cell numbers may not be indicative of T-cell response.
  • In the presence of significant T-cell defects, use caution with blood transfusions because nonirradiated blood may prove fatal owing to a graft-versus-host response.
• Other manifestations
  • Patients may have growth retardation.
  • Many patients with 22q11DS suffer from difficulty feeding very early in life because of pharyngo-esophageal dysfunction. Using high-resolution videomanometry, researchers have been studying swallowing dysfunction in children with velocardiofacial syndrome (VCFS). Interestingly, despite similar primary pathology and presenting symptoms, manometric characteristics of the swallowing disorder differed from subject to subject, but a wide range of upper esophageal sphincter dysfunction was observed, possibly indicating that a common underlying disorder of inhibitory nerves may be present in children with VCFS.⁹
  • Behavioral and psychiatric problems may be observed.¹⁰ Children and adults with DiGeorge anomaly have high rates of behavioral, psychiatric, and communication disorders. Children have high rates of ADHD, anxiety, and affective disorders. Adults have high rates of psychotic disorders, particularly schizophrenia. An estimated 25% of children with 22q11 deletion syndrome develop schizophrenia in late adolescence or adulthood.
  • Neurological abnormalities may include structural brain abnormality and seizures, among others.
  • Patients may have genitourinary malformation.
• Infectious
  • Patients with DiGeorge anomaly who present with infections as the first manifestation are unusual because cardiac malformations and hypocalcemia are so severe that they usually manifest in the neonatal period. However, recurrent infections are a major problem and an important cause of later mortality.
  • Increased susceptibility to infections caused by organisms typically associated with T-cell dysfunction is observed. These include systemic fungal infections, Pneumocystis jiroveci (previously Pneumocystis carinii) infection, and disseminated viral infections.^11,12
• Association with autoimmune and other diseases
  • As is true with other immunodeficiency syndromes, DiGeorge anomaly is associated with autoimmune disorders. Association with Graves disease has been reported sporadically.^13,14
  • Other associated diseases include immune cytopenias,¹⁵ immune thrombocytopenic purpura,¹⁶ juvenile rheumatoid arthritis–like polyarthritis,¹⁷ and severe eczema.¹⁸
  • DiGeorge anomaly and VCFS were recently found to be significantly associated with eczema and asthma but not with allergic rhinitis.¹⁹

Physical

• Facies: Patients' appearances are characterized by hypertelorism, micrognathia, short philtrum with fish-mouth appearance, antimongoloid slant, and telecanthus with short palpebral fissures.
• Otolaryngic: Patients have low-set ears, often with defective pinna; cleft palate; submucous cleft; and velopharyngeal insufficiency.

Causes

Microdeletion of chromosome 22 accounts for more than 90% of cases of DiGeorge anomaly. Deletions of chromosome 22q11.2 are found in the vast majority of patients with DiGeorge anomaly and VCFS. Most deletions are de novo, with 10% or less inherited from an affected parent. Exposure to alcohol and other toxins, such as retinoids in the intrauterine stage, can result in similar phenotypic syndromes.

• Genetic studies
  • DiGeorge anomaly is the most frequent contiguous gene deletion syndrome in humans. By use of fluorescent in situ hybridization (FISH) probes, more than 90% of patients with DiGeorge anomaly are found to have a microdeletion of 22q11.21 through 22q11.23, spanning approximately 2 megabase (Mb) in length. More detailed mapping defined a 250-kilobase (kb) DiGeorge critical region (DGCR), which has been sequenced in its entirety. Other anomalies reported in DiGeorge anomaly include deletions of 10p13, 17p13, and 18q21.
  • Although efforts have intensified to identify candidate gene(s), no single gene deletion has been shown to be sufficient for the development of DiGeorge anomaly. In addition to the aforementioned genetics information provided in the Pathophysiology section above, 2 other candidate genes worthy of mention that have been implicated in the pathogenesis of DiGeorge anomaly include HIRA (a transcriptional corepressor of cell cycle-dependent histone gene transcription and mammalian homolog of the yeast Hir1p and Hir2p proteins) and UFD1L (homolog of a highly conserved yeast gene involved in the degradation of ubiquinated genes).
  • T-box transcription factor TBX1, as aforementioned, likely plays a key genetic role in several of the characteristic features of DiGeorge anomaly, including the cardiac outflow tract dysmorphogenesis and aortic arch malformations.²⁰ A study focusing on the adaptor protein Crkol23 shows that other genes within the deleted regions might affect the same developmental pathways.

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