INTRODUCTION — DiGeorge syndrome (DGS) is a constellation of signs and symptoms associated with defective development of the pharyngeal pouch system. The classic triad of features of DGS on presentation is conotruncal cardiac anomalies, hypoplastic thymus, and hypocalcemia (resulting from parathyroid hypoplasia). Deletions in chromosome 22q11.2 are present in most patients with DGS, as well as in patients with other similar syndromes, such as velocardiofacial syndrome (VCFS, also called Shprintzen syndrome). These conditions are grouped together under the term chromosome 22q11.2 deletion syndrome (22qDS).
Infants with DGS or 22qDS may have some or all features of the classic triad, in addition to other associated congenital anomalies, listed with percent of individuals affected in the table (table 1). A broad spectrum characterizes the presence and severity of individual features. The severity of each feature appears to be independent of other features. Thus, an infant may have a severe conotruncal cardiac defect but normal calcium and only mild T cell lymphocytopenia or, alternatively, no heart disease but significant hypocalcemia and absent T cells. It is important to establish the presence and extent of abnormalities upon diagnosis and then to manage each one in collaboration with appropriate specialists.
This topic reviews the management and prognosis of patients with DGS and 22qDS, with particular emphasis on immunologic aspects of the disease. Transplantation options for complete DGS are discussed. The epidemiology, pathogenesis, clinical manifestations, and diagnosis of DGS and 22qDS are presented separately. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis" and "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis" and "Syndromes with craniofacial abnormalities", section on 'Velocardiofacial (Shprintzen) syndrome'.)
REFERRAL — The early childhood care of patients with DGS is generally best performed by a multidisciplinary team with specialists in the following fields in attendance: otolaryngology, plastic surgery, oral and maxillofacial surgery, immunology, cardiology, neurology, social work, dietary, speech pathology, genetics, and endocrinology. An initial evaluation by each specialist team is recommended to establish care, determine the degree of specific organ system involvement, and outline necessary surveillance monitoring and follow-up care. As patients with DGS get older, other associated medical conditions may emerge, such as behavioral and psychiatric conditions, requiring referral to appropriate specialists. Patients with DGS have individualized and often complex medical care needs. The best approach for optimizing quality of life in these patients requires a medical home model that is flexible and adept at facilitating specialized complex care and transitions of care from pediatrics to internal medicine [1].
ACUTE MANAGEMENT IN INFANTS — The acute management of neonates suspected of having DGS or 22qDS is focused upon evaluation and management of possible hypocalcemia and significant congenital cardiac defects and identification and treatment of infants with complete DGS, a form of severe combined immunodeficiency (SCID) [2].
Cardiac emergencies — Neonates with DGS may require emergent cardiothoracic surgery for conotruncal cardiac defects. The types and presenting features of cardiac defects seen in patients with DGS are reviewed separately. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis", section on 'Cardiac anomalies'.)
The most common causes of cyanotic heart disease of the newborn in neonates with DGS are as follows, and management of each of these disorders is reviewed separately:
●Interrupted aortic arch (see "Management of coarctation of the aorta")
●Truncus arteriosus (see "Truncus arteriosus")
●Tetralogy of Fallot (see "Management and outcome of tetralogy of Fallot")
The general evaluation and initial management of congenital heart disease is also reviewed in detail separately. (See "Identifying newborns with critical congenital heart disease" and "Cardiac causes of cyanosis in the newborn" and "Diagnosis and initial management of cyanotic heart disease in the newborn" and "Suspected heart disease in infants and children: Criteria for referral" and "Heart failure in children: Etiology, clinical manifestations, and diagnosis".)
Hypocalcemia — Early and aggressive management of hypocalcemia may help stabilize the myocardium and improve heart failure [3]. The management of hypocalcemia in the newborn is discussed in detail separately. (See "Neonatal hypocalcemia", section on 'Symptomatic infants' and "Neonatal hypocalcemia".)
Feeding and swallowing issues — Feeding and swallowing problems (eg, inadequate intake, poor weight gain, reflux, aspiration) may be critical issues in the first days and weeks of life, depending upon the palatal and gastrointestinal defects present. These problems are also seen in critically ill infants or those with cardiac lesions. Patients are typically evaluated and managed by a multidisciplinary team consisting of the patient's primary care clinician, health care providers with expertise in swallowing (speech and occupational therapists), and selected pediatric subspecialists depending upon the etiology (eg, neonatologist, cardiologist, otolaryngologist, oral and maxillofacial surgeon, gastroenterologist, neurologist). Management of neonatal sucking and swallowing disorders and correction of the underlying defects are discussed in detail separately. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis", section on 'Craniofacial abnormalities' and "Suspected heart disease in infants and children: Criteria for referral", section on 'Poor feeding' and "Aspiration due to swallowing dysfunction in children", section on 'Management' and "Neonatal oral feeding difficulties due to sucking and swallowing disorders".)
Immunologic management of complete DGS — Complete DiGeorge, a form of SCID secondary to congenital athymia, is uniformly fatal in early childhood, with nearly all patients dying in the first two years of life. Infants with possible complete DGS must be placed in protective isolation. If blood products are needed (eg, in infants undergoing heart surgery), they should be leukocyte depleted, cytomegalovirus (CMV) negative, and irradiated. If the patient has received unirradiated blood transfusions, then tests for CMV and lymphoid chimerism should be done prior to transplantation, which is the treatment of choice for confirmed complete DGS. Other general management issues for SCID are presented elsewhere. (See "Primary immunodeficiency: Overview of management" and "Severe combined immunodeficiency (SCID): An overview", section on 'Protective measures'.)
While most infants with DGS affecting thymic development have some degree of T cell lymphopenia, only a small subset have complete DGS (approximately 0.5 to 1.5 percent of all patients with DGS). The advent of widespread newborn screening for SCID with the T cell receptor excision circle (TREC) test in the United States has resulted in recognition of the infants with complete DGS and partial DGS accompanied by a significant degree of T cell lymphopenia [4,5]. Most infants with partial DGS will develop adequate T and B cell immunity over time but require monitoring. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis" and "Newborn screening for primary immunodeficiencies", section on 'Screening for SCID and other T cell defects' and 'Immunologic management of partial DGS' below.)
The only potential curative therapies for complete DGS require immediate protection with strict isolation, infusions of intravenous immune globulin, and antiinfective prophylaxis, followed by thymic or hematopoietic cell transplantation (HCT). Human leukocyte antigen (HLA) typing should be undertaken to identify an HLA-identical donor, and referral to a center participating in thymic transplantation should be explored in all patients [6]. In many cases, stable infants are observed for several weeks to monitor for possible development of T cells [7]. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Initial management' and "Hematopoietic cell transplantation for severe combined immunodeficiencies".)
The life expectancy for infants with complete DGS who do not undergo a transplantation procedure is less than one year [8]. Ideally, patients should be transplanted before the onset of significant infections to optimize their chances for successful engraftment and survival. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies".)
Choice of procedure — In infants with DGS and 22qDS, the bone marrow appears to be normal, but the maturation of hematopoietic precursors into T cells is prevented by lack of thymic tissue. Thymic tissue transplant, therefore, is the logical choice for curative treatment but has limited availability. HCT, using bone marrow or peripheral blood sources, has also been performed with success [9]. (See "Sources of hematopoietic stem cells".)
Cultured thymic transplant — Cultured postnatal thymic transplant is the preferred treatment for infants with complete DGS because it can result in the constitution of a fully functional T cell population [10-13]. Slices of thymic tissue procured during infant cardiac surgery are cultured ex vivo to remove mature T cells and then implanted in the quadriceps muscle of the patient. Few centers perform this procedure [6,14].
An allogeneic processed thymus tissue product for treatment of congenital athymia was approved by the US Food and Drug Administration (FDA) in 2021 [15]. Cultured postnatal thymic surgical transplantation was performed with this product in 95 treatment-naïve children, median age 9 months (range 1 to 36 months), with congenital athymia in 10 single-arm, open-label studies [16]. Nearly all deaths occurred in the first year posttransplant (23/29). Estimated survival was 77 percent (95% CI 0.67-0.84) at one year and 76 percent (0.66-0.83) at two years, with 94 percent of patients who survived the first year alive at a median follow-up of 10.7 years. The most common cause of death was infection, followed by cardiopulmonary complications. Sufficient T cell reconstitution was typically established 6 to 12 months after treatment with sustained increase through year 2 demonstrated in all surviving patients. The infection rates declined starting six months after treatment in surviving patients. The most commonly reported adverse effects were hypertension, cytokine release syndrome (related to antithymocyte globulin treatment), hypomagnesemia, rash, kidney impairment, autoimmune disorders (including cytopenias, anemia, proteinuria, and alopecia), and graft-versus-host disease (GVHD). Despite the US FDA approval, this therapy is not yet widely available.
Hematopoietic cell transplantation — HCT is a suitable, technically easier, and more readily available alternative to thymic transplantation in the patient with complete DGS who has an HLA-identical donor. Transplantation of hematopoietic stem cells (long-term, self-renewing, pluripotent progenitors) only, rather than stem cells and memory T cells, is not recommended in patients with DGS, since donor-derived T cells cannot develop from lymphoid progenitor cells in the absence of thymic tissue. The increase in T cell numbers following HCT in patients with DGS is secondary to expansion of donor memory T cells and not generation of naïve T cells (as would be expected in the absence of a thymus) [9,17-19]. Thus, HCT does not restore a full T cell repertoire, although it appears to provide adequate immune function. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies".)
An international survey identified 17 patients with complete DGS (eight with 22q11.2 deletion, five with a chromodomain helicase DNA-binding protein 7 [CHD7] mutation, four unknown) who underwent HCT from 1995 to 2006 [9]. Donors included HLA-identical relatives, a haploidentical parent (with T cell depletion), and matched, unrelated donors (bone marrow or peripheral blood), and one cord blood source. Pretransplant conditioning was used in five patients, and GVHD prophylaxis was used in 11 patients. GVHD developed in nine of the patients and may be more severe in this subset of SCID patients compared with SCID patients with thymic tissue. The overall survival rate was 41 percent (7 of 17), with a median follow-up of 5.8 years (range, 4 to 11.5 years), and only two patients did not experience serious adverse events. Among the 10 patients who did not survive, death occurred at a median of seven months posttransplant (range, 2 to 18 months). Survival was higher (five of seven, 71 percent) in patients with an HLA-identical sibling donor. The most common causes of death were due to problems related to the underlying disorder and complications from HCT. Five additional patients who underwent HCT are reported in the literature [8,17,18,20,21]. Among these patients, one had died, two were well two years posttransplant, and two were in their 20s at the time of publication.
LONG-TERM MANAGEMENT — Optimal management of patients with confirmed chromosome 22qDS requires a multidisciplinary team. Ideally, this would include a cardiologist, endocrinologist, otolaryngologist or oral and maxillofacial surgeon, speech/language pathologist, developmental pediatric specialist, and an immunologist, although the need for these subspecialists depends upon the patient's phenotype. Suggestions for monitoring patients with 22qDS have been published [2,22].
Monitoring — Patients with DGS must be monitored for the development of the many disorders associated with the condition (table 1) [2].
●Children should be evaluated for hearing difficulties, especially those with deletions in chromosome 10p [23]. (See "Hearing loss in children: Screening and evaluation" and "Hearing loss in children: Treatment".)
●Speech problems occur in the majority of patients and can be due to phonation difficulties, as well as the more general issues of cognitive disability and delays in language acquisition [7]. Regular evaluation of speech and language is recommended, and speech therapy is tailored to the needs of the individual patient. (See "Evaluation and treatment of speech and language disorders in children".)
●Growth should be monitored as it may be slowed by hypothyroidism or growth hormone deficiency [24]. (See "Clinical features and detection of congenital hypothyroidism" and "Treatment and prognosis of congenital hypothyroidism" and "Diagnosis of growth hormone deficiency in children" and "Treatment of growth hormone deficiency in children".)
●Learning, developmental, and behavioral difficulties are frequent in children with 22qDS [7]. Clinicians following patients with 22qDS should be vigilant for these problems and proactive with early intervention programs and other supportive services [25]. Most children with DGS can attend regular school classes. (See "Specific learning disabilities in children: Clinical features", section on 'Clinical features' and "Developmental-behavioral surveillance and screening in primary care".)
●Schizoaffective disorder, schizophrenia, and major depression can be observed in adolescents and adults with 22qDS [22]. (See "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis" and "Unipolar major depression in adults: Choosing initial treatment".)
Genetic counseling — Although 90 percent of chromosome 22q11.2 deletions are believed to occur spontaneously, it is still important to have parents tested and to offer genetic counseling, if appropriate. If a parent is found to have the same mutation, then the risk of future children being affected is 50 percent. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis".)
Correction of palatal defects — Chromosome 22qDS is a leading cause of palatal defects [26]. In addition to anatomic dysfunction, palatal anomalies can predispose patients to recurrent sinopulmonary and ear infections (independent of immune status), and surgical correction is often required. Removal of the tonsils and adenoids may be contraindicated in some types of palatal defects since these structures assist in velopharyngeal closure. Collaboration with an otolaryngologist or oral and maxillofacial surgeon experienced in palatal defects is recommended [27]. (See "Syndromes with craniofacial abnormalities", section on 'Management of VCFS'.)
Immunologic management of partial DGS — The observation in some DGS patients of immunologic changes over time, including a diminished T cell repertoire, diminution of the naïve T cell pool, and static thymic output, suggests that these patients may be at risk for increasing frequency of infections with age [28]. An increased frequency of infections in DGS/22qDS may be due to poor B cell maturation [29]. A report from European and United States registries found that 3 percent of patients with 22qDS were receiving gammaglobulin therapy for hypogammaglobulinemia [30]. The mechanism(s) for increased infections are likely varied, and additional studies are necessary to fully understand the immune defects in patients with DGS/22qDS.
In one prospective longitudinal study, children with lower numbers of naive CD4+ T cells (CD45RA+) and CD3+CD8+ T cells could be categorized as high risk. This subset of patients with DGS was at higher risk for lethal infections, autoimmune phenomena, and Epstein-Barr virus (EBV)-associated lymphoproliferative disease [31]. These data suggest that patients with DGS can be stratified based upon T cell phenotypic enumeration, allowing for better prognostication. Further studies are necessary to confirm this observation since the subject number was small and potential confounders may exist, such as postinterventional chylothorax.
Monitoring of immune function — We monitor the immune function of all patients with DGS every 6 to 12 months during their early years. Specifically, we perform flow cytometry for immune cell enumeration, in vitro proliferation assays to assess T cell function, and measure total immunoglobulin levels and specific antibody titers. Patients whose protective titers are waning may require more frequent booster vaccinations [32]. (See "Laboratory evaluation of the immune system" and "Flow cytometry for the diagnosis of primary immunodeficiencies".)
Infections — T cell function is largely intact in the majority of DGS patients based upon available functional assays. Thus, prophylaxis against opportunistic infections is usually not required. (See "Primary immunodeficiency: Overview of management", section on 'Prophylactic antimicrobial therapy'.)
Sinopulmonary infections are common and should be treated aggressively with antibiotics when indicated. Recurrent respiratory infections suggest subtle immunodeficiencies and/or swallowing problems. The management of patients with identified disorders of antibody production or function is similar to other patients with humoral immunodeficiencies. (See "Immune globulin therapy in primary immunodeficiency" and "Primary immunodeficiency: Overview of management" and "Primary humoral immunodeficiencies: An overview".)
Treatment with specialized immune globulins after exposure to an infectious organism to which the patient has not been immunized, such as varicella zoster virus, is reviewed separately. (See 'Vaccination' below and "Primary immunodeficiency: Overview of management", section on 'Specialized immune globulins'.)
Vaccination — The administration of live vaccines (eg, measles-mumps-rubella [MMR], intranasal influenza, Bacillus Calmette-Guérin [BCG], rotavirus, and oral polio virus vaccines) to patients with T cell abnormalities is contraindicated, and this was previously applied to DGS patients as well. However, the appropriateness of avoidance of live vaccines has been questioned since the risk of natural infection continues to exist, and there is increasing evidence that T cell function is normal in most patients with DGS. Thus, the decision to administer live vaccines to patients with DGS is made on a case-by-case basis, following a discussion of the risks and benefits with the patient or caregivers. Prospective studies are necessary to formally define the threshold for safe administration of live-virus vaccines in patients with DGS. (See "Immunizations in patients with primary immunodeficiency", section on 'Live vaccines'.)
Several retrospective studies have examined the safety and efficacy of administration of live vaccines in patients with 22qDS [32-38]. As examples:
●In two of these studies (32 and 82 patients, respectively), the incidence of adverse events after administration of varicella or MMR vaccines (given only before the patients were diagnosed with DGS in one study) was comparable with that in the general population [32,34].
●In the second of these two studies, 85 percent of patients with DGS had robust seroconversion during the first year after administration of MMR. However, the maintenance of protective titers was significantly diminished in the patients with DGS compared with control subjects two or more years after vaccine administration, suggesting that reimmunization may be required in some patients [32].
●In another retrospective analysis of 93 patients with DGS, the majority of patients had sustained and normal cellular responses to tetanus antigen, including patients with CD3+ T cell numbers below the 10th percentile of normal values [33]. A small subset of fully immunized patients had poor cellular responses to tetanus that correlated with initial low CD3+ T cell numbers. However, they received live vaccines without adverse reactions.
It has been proposed that live vaccines can be safely given to patients older than one year of age who demonstrate all of the following [7,32]:
●The presence of antibodies to killed vaccine antigens
●Normal or near-normal proliferative responses to mitogens and recall antigens (ie, tetanus toxoid)
●A CD8+ T cell count >300 cells/mm3
●A CD4+ T cell count >500 cells/mm3
Periodic assessment of antibody titers (every 6 to 12 months) and reimmunization may be required because long-term maintenance of protective antibody levels may be diminished in patients with DGS [32].
Live-attenuated rotavirus vaccination is recommended for infants as young as six weeks to two months of age. However, due to reports of vaccine-acquired diarrheal illness in infants with severe combined immunodeficiency (SCID) [39], avoidance of rotavirus vaccine is prudent for all infants with complete DGS and infants with partial DGS who have T cell numbers significantly below normal ranges for age.
PROGNOSIS — The life expectancy for infants with complete DGS who do not undergo transplantation is less than one year. A small number of patients have been transplanted, most since the mid-1990s. Most deaths in transplanted patients occur in the first year after transplant. Survival rates are similar (72 percent) for thymic transplant and hematopoietic cell transplantation (HCT) with a human leukocyte antigen (HLA)-identical sibling donor. The median survival time for those who do not die in the first year after transplant is approximately five years. The oldest reported survivors are in their 20s. Survival rates are lower for HCT with other donor types [9,13]. (See 'Cultured thymic transplant' above and 'Hematopoietic cell transplantation' above.)
The prognosis for partial DGS patients and for complete DGS patients who survive transplantation is largely dependent upon the severity of the cardiac defect, degree of hypoparathyroidism, and intellectual development. The overall mortality was found to be 8 percent in a large survey of 558 DGS patients [40]. In most cases, death occurred in the first six months of life and was secondary to cardiac-related complications.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)
SUMMARY AND RECOMMENDATIONS
●Acute management in all neonates and infants with suspected DiGeorge syndrome (DGS)/22q11.2 deletion syndrome (22qDS) – The acute management of neonates suspected of having DGS or 22qDS is focused upon evaluation and management of possible hypocalcemia and congenital heart disease and identification of infants with complete DGS, a form of severe combined immunodeficiency (SCID). (See 'Acute management in infants' above.)
●Management in infants with complete DGS
•Infants suspected of having complete DGS should only receive blood products that are leukocyte depleted, cytomegalovirus (CMV) negative, and irradiated. (See 'Immunologic management of complete DGS' above and "Primary immunodeficiency: Overview of management" and "Severe combined immunodeficiency (SCID): An overview", section on 'Protective measures'.)
•We recommend that infants with complete DGS undergo definitive therapy with thymic transplantation or hematopoietic cell transplantation (HCT) (Grade 1A). Thymic transplantation is preferred but is not widely available. If thymic transplantation is not possible, HCT should be performed with a human leukocyte antigen (HLA) identical donor and without T cell depletion of the donor tissue. The life expectancy for infants with complete DGS who do not undergo transplantation is less than one year. The median survival of patients who have undergone successful transplantation is approximately five years, with survival into the third decade reported. (See 'Immunologic management of complete DGS' above and 'Prognosis' above.)
●Long-term management
•Monitoring for associated disorders – Optimal long-term management of patients with DGS or 22qDS requires a multidisciplinary team, as well as monitoring for the many disorders associated with this syndrome (table 1). (See 'Monitoring' above.)
•Correction of palatal defects – Palatal anomalies can predispose patients to recurrent sinopulmonary and ear infections (independent of immune status), and surgical correction is often required. (See 'Correction of palatal defects' above.)
•Immunologic management of patients with partial DGS – Most patients with partial DGS are not significantly immunosuppressed. However, they should be followed for waning immune function. Prophylaxis against opportunistic infections is usually not required, and live vaccines may be safely given if certain immunologic criteria are met. (See 'Immunologic management of partial DGS' above.)
●Genetic counseling – Parents of affected children should be offered genetic testing. If a parent is found to have the same mutation, then the risk of future children being affected is 50 percent. (See 'Genetic counseling' above.)
●Prognosis – The life expectancy for infants with complete DGS who do not undergo transplantation is less than one year. In contrast, overall mortality rate for patients with partial DGS or 22qDS has been estimated to be less than 10 percent. (See 'Prognosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.
