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eMedicine Specialties > Allergy and Immunology > Immunodeficiencies

DiGeorge Syndrome

Patrick Htain Win, MD, President/Director, Allergy, Asthma and Immunology Center, SC
Sridhar Guduri, MD, Consulting Staff, Allergy and Asthma Clinics of Ohio; Iftikhar Hussain, MD, Director of Allergy, Asthma, and Immunology Center, PC

Updated: Aug 3, 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.

Differential Diagnoses

Other Problems to Be Considered

Diagnosis of DiGeorge anomaly is based on the presence of congenital cardiac malformations, hypocalcemia secondary to hypoparathyroidism, and a small or absent thymus. Differential diagnoses include all 22q11 deletion syndromes (see Introduction) and exposure to teratogens during pregnancy, including alcohol, retinoids, bisdiamine, and maternal diabetes.

Conditions related to DiGeorge anomaly include the following:

22q11 deletion syndromes
Velocardiofacial syndrome (VCFS or Shprintzen syndrome)
Conotruncal anomaly face syndrome
Cayler syndrome
Opitz-GBBB syndrome
CHARGE syndrome (coloboma [eye], heart anomaly, atresia [choanal], retardation [mental and growth], genital anomaly, ear anomaly)

Workup

Laboratory Studies

  • Diagnosis
    • As aforementioned, most patients with the clinical phenotype of either of the 22q11.2 deletion syndromes have a hemizygous deletion of chromosome 22q11.2. This deletion can usually be detected in 2-3 days by fluorescent in situ hybridization (FISH).
    • Other means of diagnosis are being evaluated, including a rapid polymerase chain reaction (PCR)–based method.
    • When clinical features are present, but the 22q11.2 deletion is not, other possible explanations may exist, including TBX1 mutation, chromosome 10 deletion, mutation in the chromodomain helicase DNA-binding protein-7 (CHD7) gene, and prenatal exposure to isotretinoins or elevated blood glucose levels.21
    • Choosing who to screen poses a difficult clinical dilemma. Some patient characteristics, including neonatal hypocalcemia (74%), interrupted aortic arch (50-60%), velopharyngeal insufficiency (64%), and pulmonary atresia (33-45%) appear to be fairly good predictors of deletion, while others, eg, any cardiac lesion (1%), schizophrenia (0-6%), and tetralogy of Fallot (11-17%), do not. 
  • Assessment of immune system
    • In vitro studies of T-cell function offer the most reliable estimate of the extent of immunodeficiency. Although a finding of very low to absent T cells in peripheral blood suggests severe immunodeficiency, decisions regarding treatment should be based on T-cell proliferative responses to antigens, not on the number of T cells.
    • Flow cytometry is performed in vitro to estimate the number of T cells in peripheral blood and the proliferative responses to mitogens and antigens.
    • Advances in multicolor flow cytometry, noninvasive imaging techniques, and molecular assessments of thymic function have enabled a more comprehensive characterization of human thymic output in clinical settings than in the past. These techniques have been particularly valuable in monitoring human T cells after therapeutic thymic grafting for complete DiGeorge anomaly.
    • At times, a sudden increase in CD3+/CD4+ T cells is observed in patients with DiGeorge anomaly and is associated with modest mitogen response but no proliferative response to antigens. Response to antigens is the best predictor of the ability of the T cells to protect from infection and is the most clinically relevant of the in vitro tests of T-cell function.
    • Evaluation of humoral immunity reveals variable immunoglobulin levels and depends on the extent of T-cell deficiency. As would be expected (ie, because normal B-cell development requires normal T-cell function), the B-cell repertoire is normal in patients whose only measurable T-cell defect is a low number. Patients with partial DiGeorge anomaly generate good antibody response to protein vaccines, but no data are available on polysaccharide vaccines. Increased prevalence of immunoglobulin A deficiency has been observed in 4 of 32 patients with 22q11.2 deletion.
    • T-cell receptor excision circles (TRECs) and quantitative, real-time reverse transcriptase (RT) PCR: The thymus is crucial in reconstituting the T-cell compartment following lymphodepletion and also in establishing a normal, diverse T-cell receptor (TCR) repertoire after immune response to antigens. TCR alpha beta diversity is generated through rearrangements of the TCR alpha and TCR beta chain genes. The TCR delta chain locus lies within the TCR alpha chain locus, and its excision is the first step in TCR alpha chain gene rearrangement. The intervening excised DNA is circularized by the formation of a "signal joint" forming a DNA episome, termed a signal-joint T-cell receptor excision circle (sjTREC)

      Approximately 70% of T cells emerging from the thymus contain 1-2 sjTRECs, depending on whether one or both TCR alpha loci genes are rearranged. As these long-lived naive T cells mature and proliferate, their sjTRECs are stable and do not divide. The thymus contributes naive T (CD45RA+) cells with TRECs to the peripheral immune system, but memory T cells (CD45RO+) contain few, if any, detectable TRECs. Quantification of thymic function is clinically relevant in settings with immunodeficiencies, after transplantation, and in patients with autoimmune disease. In humans, no specific phenotypic marker exists for recent thymic emigrants; therefore, the use of real-time quantitative RT PCR methods for absolute TREC quantification provides a novel tool for estimating recent thymic function in different clinical situations, including in patients with DiGeorge anomaly and those undergoing thymic transplantation.
  • Assessment of parathyroid function
    • The etiology of hypocalcemia is usually evident with low parathyroid hormone (PTH) levels.
    • Latent or subclinical hypoparathyroidism can be unmasked by performing a disodium edetate challenge.
    • Despite occasional normal calcium and PTH levels, the secretory reserve for PTH is usually diminished in patients with DiGeorge anomaly.

Imaging Studies

  • A lateral-view chest radiograph is useful in assessing the thymic shadow.
  • Although chest radiographs may reveal an absence of a thymus shadow, MRI is more reliable for estimating mediastinal thymus size. However, because the thymus has not descended into the mediastinum in this condition, imaging studies are not warranted.
  • The range of cardiovascular anomalies is wide, although conotruncal defects are the most frequent ones. Slight variations in defect might dictate a different surgical intervention, thus 2-dimensional and color-Doppler echocardiography is essential to define the anatomy; additionally, the thymus might be visualized in this way.  Additionally, cardiac catheterization may not be needed but can provide helpful information in some situations.

Other Tests

  • Genetic studies include the fluorescent in situ hybridization (FISH) technique for karyotyping, which is sensitive and readily available for chromosome analysis. A multiplex ligation-dependent probe amplification (MLPA) single tube assay was recently developed to detect deletions of the 22q11.2 region and other chromosomal regions associated with DiGeorge anomaly and velocardiofacial syndrome (VCFS). This method appears to be equivalent to the FISH technique.
  • Hearing, vision, and speech issues are typically addressed during infancy; thus, appropriate screening measures to pick up deficits in these areas is a key component to the multidisciplinary care DiGeorge anomaly patients.

Procedures

  • Diagnosis of cardiac abnormalities usually requires 2D-Doppler and may require invasive techniques, including cardiac catheterization.

Histologic Findings

  • Thymic biopsy findings are essentially normal, except for evidence of hypoplasia.
  • A study examining the skin biopsies of a small subset of complete DiGeorge anomaly patients known as "atypical complete" DiGeorge anomaly (clinically marked by eczematous dermatitis, oligoclonal T-cells, and lymphadenopathy) revealed exocytosis, parakeratosis, often confluent, and spongiosis in 100% of the biopsies taken.22  
    • Furthermore, neutrophilic abscesses (50%), dyskeratosis (67%), satellite cell necrosis (50%), and perieccrine and perivascular inflammation were seen in half of the cases. Eosinophils, most commonly in both the epidermis and dermis, were also identified in 83% of the biopsies. All of the lymphocytes were CD3 positive. Most (83%) of cases contained T-cell intracellular antigen 1 (TIA-1) positive cells, and spectratyping of the selected patients identified oligoclonal T-cell populations.
    • The authors concluded that the presence of dyskeratotic keratinocytes, satellite cell necrosis, and parakeratotic scale with neutrophils characterizes the cutaneous rash seen in this subset of complete DiGeorge syndrome patients. Thus, such lesions in patients with DiGeorge anomaly should alert the pathologist to the possible diagnosis of "atypical complete" DiGeorge anomaly.22

Treatment

Medical Care

  • Endocrine
    • Hypoparathyroidism and hypocalcemia are managed with calcium supplements and vitamin D administration.
  • Cardiac
    • As aforementioned, treat with surgical interventions as necessary (see below).
  • Gastrointestinal
    • Approach depends on phenotype and dysfunction.
  • Renal
    • Approach depends on phenotype and dysfunction.
  • Treatment of immunodeficiency
    • Use the usual prophylactic regimens for T- and B-cell deficiency.
    • Several therapies have been used to treat immunodeficiency associated with DiGeorge anomaly. Cases of immune reconstitution have been reported following transplantation of HLA-identical bone marrow, peripheral blood mononuclear cells, and fetal thymus. However, some of these patients may have had partial DiGeorge anomaly, and improvement may have been coincidental.
    • Markert et al reported a study of 5 patients with complete DiGeorge anomaly who were treated with allogeneic, cultured, postnatal thymus tissue. Of these patients, 4 developed immune reconstitution with T-cell proliferative responses to mitogens.23
    • Early thymus transplantation (ie, before the onset of infectious complications) may promote successful immune reconstitution. Although Goldsobel et al reported that the results of thymus transplantation are disappointing, a significant number of patients in their group were lost to follow-up, and if their results were corrected accordingly, the benefits of thymus transplantation would seem to be more impressive.24 T-cell function may improve in patients with partial DiGeorge anomaly; therefore, thymus transplantation is not indicated.
    • In 2007, Markert et al released a follow-up article that reviewed 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation. In this article, they discuss the outcome of 44 consecutive transplants. This large cohort has helped investigators evaluate the ability of thymus transplantation to reconstitute immune function in infants with complete DiGeorge anomaly. At the time of publication, 33 of the 44 subjects who received a transplant were alive (75%), with posttransplant follow-up as long as 13 years. All deaths were reported to have occurred within 12 months of transplantation. One year after transplantation, 25 of 25 subjects tested had developed polyclonal T-cell repertoires and proliferative responses to mitogens. Additionally, transplantation was fairly well tolerated; the most common adverse events were hypothyroidism and enteritis.25

Surgical Care

Correct cardiac malformations per standard surgical techniques. Irradiated cytomegalovirus-negative blood products must be administered because of the risk of graft versus host disease with nonirradiated products. Because the risk of infection is very high, a low index of suspicion must be used with regard to starting antibiotics.

Consultations

Obtain early consultation with a cardiologist and immunologist to evaluate disease manifestations.

Medication

The goals of pharmacotherapy are to prevent calcium deficiency, reduce morbidity, and prevent complications.

Calcium salts

These agents are used to treat or prevent calcium deficiency.


Calcium gluconate (Kalcinate)

Moderates nerve and muscle performance and facilitates normal cardiac function. Can be administered IV initially, and calcium levels maintained with high-calcium diet. Some patients require oral calcium supplementation. The 10% IV solution provides 100 mg/mL of calcium gluconate, which equals 9 mg/mL (0.46 mEq/mL) of elemental calcium.

Dosing

Adult

Doses expressed as calcium gluconate
2-3 g IV over 5-10 min; repeat q6h prn based on response and serum calcium levels; not to exceed 15 g/d
Alternatively: Repeat doses administered as 167 mg/kg IV infusion over 4-6h prn
Oral supplementation: 15 g/d PO divided tid/qid

Pediatric

Doses expressed as calcium gluconate
100-200 mg/kg IV over 5-10 min; then 500 mg/kg/d IV continuous infusion or divided doses q6-8h
Oral supplementation: 500-725 mg/kg/d PO divided qid

Interactions

May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; antagonizes effects of verapamil; large intakes of dietary fiber may decrease calcium absorption and levels

Contraindications

Documented hypersensitivity; renal calculi; hypercalcemia; hypophosphatemia; renal or cardiac disease; digitalis toxicity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in digitalized patients and patients with respiratory failure, acidosis, or severe hyperphosphatemia


Calcium carbonate (Os-Cal, Titralac, Oystercal, Caltrate)

Has higher oral bioavailability of calcium than other orally administered calcium salt products. Moderates nerve and muscle performance and facilitates normal cardiac function. Dose expressed as calcium carbonate.

Dosing

Adult

5-10 g/d PO divided tid/qid

Pediatric

112.5-162.5 mg/kg/d PO divided qid

Interactions

May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; antagonizes effects of verapamil; large intakes of dietary fiber may decrease calcium absorption and levels

Contraindications

Documented hypersensitivity; renal calculi; hypercalcemia; hypophosphatemia; renal or cardiac disease; digitalis toxicity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in digitalized patients and patients with respiratory failure, acidosis, or severe hyperphosphatemia

Vitamin D supplements

These supplements help treat, prevent, or manage hypocalcemia.


Ergocalciferol, vitamin D-2 (Drisdol)

Vitamin D-2 analog converted in liver to an active intermediate and then further converted to most active form in kidneys. Effectively increases renal reabsorption of calcium, intestinal absorption of calcium, and calcium mobilization from bone to plasma.

Dosing

Adult

25,000-200,000 U/d PO along with calcium supplements

Pediatric

Administer as in adults

Interactions

Colestipol, mineral oil, and cholestyramine may decrease absorption of ergocalciferol from small intestine; thiazide diuretics may increase effects of vitamin D

Contraindications

Documented hypersensitivity; hypercalcemia; malabsorption syndrome

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Pregnancy category C in doses >400 U/d; caution in patients with cardiac disease, arteriosclerosis, renal impairment, and renal stones; caution during breastfeeding

Follow-up

Further Inpatient Care

  • Close monitoring of the calcium level is required.
  • Prevention of infections should remain a top priority.
  • Treatment of immunodeficiency includes the following:
    • Use the usual prophylactic regimens for T- and B-cell deficiency.
    • Several therapies have been used to treat immunodeficiency associated with DiGeorge anomaly. Cases of immune reconstitution have been reported following transplantation of HLA-identical bone marrow, peripheral-blood mononuclear cells, and fetal thymus. However, some of these patients may have had partial DiGeorge anomaly, and improvement may have been coincidental.
  • Markert et al reported a study of 5 patients with complete DiGeorge anomaly who were treated with allogeneic, cultured, postnatal thymus tissue. Of these patients, 4 developed immune reconstitution with T-cell proliferative responses to mitogens.23
  • Early thymus transplantation (ie, before the onset of infectious complications) may promote successful immune reconstitution. Goldsobel et al reported that the results of thymus transplantation are disappointing. However, a significant number of patients in their group were lost to follow-up, and if their results are corrected accordingly, the benefits of thymus transplantation seem to be more impressive.24 T-cell function may improve in patients with partial DiGeorge anomaly; therefore, thymus transplantation is not indicated.

Further Outpatient Care

  • Genetic counseling and screening
    • Approximately 8% of the patients with DiGeorge anomaly or velocardiofacial (VCFS) studied by Driscoll et al showed familial transmission of 22q11 deletion.26
    • Because subjects with 22q11 deletion have a 50% risk of transmitting the deletion, they should be offered genetic counseling and fluorescent in situ hybridization (FISH) for prenatal detection as early as 10-12 weeks of gestation by chorionic villus sampling.
    • Recent studies show that 22q11 deletions occur in 20-30% of newborns with isolated conotruncal cardiac malformations. Therefore, screen all patients with conotruncal anomalies for 22q11 deletions, identify other family members at risk, and assess the risk in future pregnancies.
  • Multidisciplinary care
    • The complex medical care of patients needs a multidisciplinary approach, and every patient has his own unique clinical features that need a tailored approach. Patients with chromosome 22q11.2 deletion syndrome might have a high level of functioning, but most often need interventions to improve the function of many organ systems.

Prognosis

  • Prognosis depends markedly on the degree of involvement/impairment of cardiac and immune system function.
  • In a large European collaborative study, 558 patients with deletions within the DiGeorge syndrome critical region of chromosome 22q11 were evaluated by questionnaire.27 Eight percent of the patients died; more than half of the deaths occurred within the first month of life, and the majority occurred within 6 months of birth. Of the patients who survived, 62% had only mild learning problems or were developmentally normal. All but one of the deaths were attributable to congenital heart disease. Other clinical features varied as follows:
    • Cleft palate, 9%
    • Velopharyngeal insufficiency, 32%
    • Hypocalcemia, 60%
    • Cardiac problems, 75%
    • Renal abnormality, 36% (of patients who had abdominal ultrasound)
    • Small size (36% were <3rd percentile for either height or weight)

Miscellaneous

Medicolegal Pitfalls

  • The utmost care must be taken to avoid nonirradiated blood products.
  • Live vaccines are typically contraindicated in patients with DiGeorge anomaly and in household members of such patients because of the risk of shedding of live organisms; however, 2 recent studies show that live viral vaccines (LVVs) may be safe in select populations affected by DiGeorge anomaly.
    • Azzari et al recently evaluated the safety and immunogenicity of measles-mumps-rubella (MMR) vaccine in children with congenital T-cell defect (DiGeorge anomaly).28 No severe adverse reactions were reported in the 14 patients included in the study. Patients and control subjects experienced the same frequency of seroconversion for measles and rubella. The mean titers of antimeasles or antirubella antibodies were the same in patients and controls, and no decrease in CD4 cells was detected after immunization.
    • Moylett et al recently reviewed patients with partial DiGeorge syndrome at Texas Children's Hospital (Baylor College of Medicine).29 Forty-seven percent of the patients with partial DiGeorge syndrome received an LLV. No significant adverse events were recorded in association with administration of LVVs. At initial presentation, the difference between the cellular immune function of patients who received LVVs and of those who did not receive LVVs was not statistically significant. Adequate cellular immune function was documented for 15 of the 25 LVV recipients at the time of vaccine administration without significant change from baseline.

Special Concerns

  • The neurological and psychiatric manifestations of 22q11DS require careful monitoring by experts as part of the multidisciplinary team approach to care.
  • Psychiatric disorders are common in all patients with developmental delay; however, the association is stronger in patients with chromosome 22q11.2 deletion.
  • The behavioral aspects of chromosome 22q11.2 deletion syndromes include attention deficit hyperactivity disorder, poor social interaction skills, impulsivity, and bland affect. Bipolar disorder, autistic spectrum disorder, schizophrenia, and schizoaffective disorder are reported in 10–30% of teenagers and adults.

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Keywords

DiGeorge syndrome, DiGeorge anomaly, DGA, thymic hypoplasia, thymic aplasia, third and fourth pouch syndrome, third and fourth arch syndrome, cellular immunodeficiency, hypoparathyroidism, 22q11 deletion syndromes, 22q11.2 deletion syndromes, 22q11DS, CH22qD syndrome, velocardiofacial syndrome, VCFS, Shprintzen syndrome, conotruncal anomaly face syndrome, Cayler syndrome, Opitz-GBBB syndrome, CHARGE syndrome, coloboma, heart anomalies, atresia of choanae, choanal atresia, retardation, genital hypoplasia, ear anomalies, hypocalcemia, fetal alcohol syndrome, FAS, FISH, FISH technique, fluorescent in situ hybridization, multiplex ligation-dependent probe amplification, MLPA

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