DiGeorge Syndrome

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DiGeorge Syndrome


Introduction
Background
Conditions associated with DiGeorge syndrome are 22q11 deletion syndromes, velocardiofacial syndrome (VCFS or Shprintzen syndrome), 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. This condition was later associated with congenital hypoparathyroidism by Lobdell in 1959. 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.

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. 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.
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 is dependent 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. 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.
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

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 3000 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. 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 is also relevant because the phenotype associated with fetal alcohol syndrome 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 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.
Behavioral and psychiatric problems may be observed. 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 (Marcinkowski, 2000; Sanchez-Velasco, 2001).
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 (Kawamura, 2000; Ham Pong, 1985).
Other associated diseases include immune cytopenias (DePiero, 1997), immune thrombocytopenic purpura (Levy, 1997), juvenile rheumatoid arthritis–like polyarthritis (Sullivan, 1997), and severe eczema (Archer, 1990).
DiGeorge anomaly and velocardiofacial syndrome (VCFS) were recently found to be significantly associated with eczema and asthma but not with allergic rhinitis (Staple, 2005).
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 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. Two of the candidate genes 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 is a key gene implicated in cardiac outflow tract dysmorphogenesis and aortic arch malformations observed in DiGeorge anomaly (Xu, 2004). 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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