DiGeorge Syndrome (DGS) is a combination of signs and symptoms caused by defects in the development of structures derived from the pharyngeal arches during embryogenesis. Features of DGS were first described in 1828 but properly reported by Dr. Angelo DiGeorge in 1965, as a clinical trial that included immunodeficiency, hypoparathyroidism, and congenital heart disease.
DGS is one of several syndromes that has historically grouped under a bigger umbrella called 22q11 deletion syndromes, which include Shprintzen-Goldberg syndrome, velocardiofacial syndrome, Cayler cardiofacial syndrome, Sedlackova syndrome, conotruncal anomaly face syndrome, and DGS. Although the genetic etiology of these syndromes may be the same, varying phenotypes has supported the use of different nomenclature in the past, which has led to confusion in diagnosing patients with DGS, which causes potentially catastrophic delays in diagnosis. Current literature supports the use of the names of these syndromes interchangeably.
Features of DGS include an absent or hypoplastic thymus, cardiac abnormalities, hypocalcemia, and parathyroid hypoplasia (See "History and Physical" below). Perhaps, the most concerning characteristic of DGS is the lack of thymic tissue, because this is the organ responsible for T lymphocyte development. A complete absence of the thymus, though very rare and affecting less than 1% of patients with DGS, is associated with a form of severe combined immunodeficiency (SCID). T-cells are a differentiated type of white blood cell specializing in certain immune functions: destroying cells that are infected or malignant, existing as an integral part of the innate immune system by killing viruses (e.g., Killer T-cells), helping B-cells mature to produce immunoglobulins for stronger adaptive immunity (e.g. helper T-cells), etc. The degree of immunodeficiency of patients with DGS can present differently depending on the extent of thymic hypoplasia.
Some patients may have a mild to moderate immune deficiency, and the majority of patients have cardiac anomalies. Other features include palatal, renal, ocular, and gastrointestinal anomalies. Skeletal defects, psychiatric disease, and developmental delay are also of concern. There are different opinions about syndrome-related alterations in cognitive development, and a cognitive decline rather than an early onset intellectual disability is observable. The particularities of the clinical presentation requires observation on an individual basis, with careful evaluation and interprofessional treatment throughout the patient's life.
About 90% of DGS cases are a result of a deletion in chromosome 22, more specifically on the long arm (q) at the 11.2 locus (22q11.2). Most of these mutations arise de novo with no genetic abnormalities noted in the genome of the parents of children with DGS. Researchers have identified over 90 different genes at this locus, some of which they have studied in mouse models. The most studied of these genes is T-box transcription factor 1 (TBX1), which correlates with severe defects in the development of the heart, thymus, and parathyroid glands of mouse models. TBX1 also correlates with neuromicrovascular anomalies, which may be responsible for the behavioral and developmental abnormalities seen in DGS.
Microdeletion of 22q11.2 is the most common microdeletion syndrome, affecting approximately 0.1% of fetuses. The rate of 22q11.2 microdeletion in live births occurs at an estimated rate of 1 in 4000 to 6000. There are several explanations for the variance in fetal versus live birth prevalence. Firstly, current evidence may not comprise a large enough population. Secondly, 22q11.2 microdeletions may produce embryonically lethal phenotypes, which was observable in animal studies.
The prevalence of 22q11.2 microdeletion may be more common than supported in literature due to several factors. Firstly, not every patient with this microdeletion presents with several craniofacial abnormalities and hence does not undergo genetic testing. African-American children, for example, may not have the craniofacial abnormalities characteristic of DGS in other races. Secondly, access to healthcare, specifically genetic testing, is not available to every individual that might have the microdeletion, regardless of the severity of craniofacial dysmorphism. Further population studies are therefore needed to fully understand the extent and spectrum of 22q11.2 microdeletions in different populations.
DGS results from microdeletion of 22q11.2, which encodes over 90 genes. Patients with DGS display a broad array of phenotypes, and the most common findings include cardiac anomalies, hypocalcemia, and hypoplastic thymus.
On a genetic basis, TBX1 has correlations with the most prominent phenotypes characteristic of DGS. Failure in embryologic development of the pharyngeal pouches, which is driven by TBX1, leads to absence or hypoplasia of the thymus and parathyroid glands. Mouse and zebrafish TBX1 knockout models have been studied to understand the embryologic basis of this disease. In mice, for instance, the absence of TBX1 causes severe pharyngeal, cardiac, thymic, and parathyroid defects as well as a behavioral disturbance. Moreover, zebrafish knockouts have demonstrated defects in the thymus and pharyngeal arches as well as malformation of the ears and thymus.
A 22q11.2 knockout mouse model has also been studied, with findings pertinent for molecular and behavioral changes seen in Parkinson's disease, autism spectrum disorder, attention deficit hyperactivity disorder, and schizophrenia. These findings, as well as the neuromicrovascular pathology found in TBX1 knockout mice, suggest a molecular basis for the psychiatric pathologies associated with DGS. Of note, individuals affected by this syndrome have a 30-fold increased risk of developing schizophrenia.
A detailed history and physical is vital in the diagnosis and assessment of DiGeorge syndrome. A broad spectrum of disease severity exists, and suspicion of DGS from history and physical can prompt further evaluation. Although most cases get diagnosed in the prenatal and pediatric periods, diagnosis can also occur in adulthood. Delay in motor development is a common presenting feature first recognized by parents who notice delays in rolling over, sitting up, or other infant milestones. These findings can be associated with delayed speech development and learning disabilities. Later in life, abnormal behavior in the setting of poor developmental history may be the chief presenting symptom of DGS.
A detailed history may reveal the following:
An examination can reveal findings consistent with several features of DGS:
A clinician makes a definitive diagnosis of DGS in individuals with a microdeletion of chromosome 22 at the 22q11.2 locus. Classic evaluations of genetic abnormalities, such as trisomies, including the Giemsa banding technique, are incapable of revealing microdeletions. Microdeletions responsible for DGS are therefore detected by fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), single nucleotide polymorphism (SNP) array, comparative genomic hybridization (CGH) microarray, or quantitative polymerase chain reaction (qPCR). The availability and cost of these techniques can delay diagnosis, particularly in resource-poor settings.
Patients diagnosed with or suspected of having DGS should undergo extensive evaluation, particularly if life-threatening cardiac or immunologic deficits are present. The following tests should merit consideration:
It is important to note that the broad spectrum of disease severity makes the evaluation of DGS particularly challenging. Cases involving significant cardiac, thymic, and craniofacial deficits are more easily recognizable than those lacking severe features. Implementation of advancing genomic studies and facial recognition technology in modern medicine may assist in more effective diagnosis and evaluation of DGS patients.
Treatment and management of DGS require intensive interprofessional care:
Advanced approaches for the management of children with complete DiGeorge anomaly
In the cDGS featuring no thymus function and bone marrow stem cells can not develop into T cells, children usually die by age 2 years due to severe infections. In this setting, the proposal is to T cell–replete HSCT. Nevertheless, because of the absence of thymus, this strategy can only obtain engraftment of post thymic T cells. A multicenter survey on the outcome of HSCT showed a survival rate of 33% after matched unrelated donors and 60% in the case of matched sibling transplantations. Recently, the FDA approved the thymus transplantation as standard care. This approach focuses on producing naive T cells with a broad T-cell receptor set. The procedure takes place using general anesthesia, and thymus tissue usually gets transplanted into the recipient subject's quadriceps. Studies indicate up to 75% of long-term survival but have described frequent autoimmune sequelae (e.g., autoimmune hemolysis, thyroiditis, thrombocytopenia, enteropathy, and neutropenia) in survivors.
Treatment and management of DGS require intensive interprofessional care:
Less than 1% of patients with 22q11.2 microdeletion have complete DGS, the most severe subtype of DGS with a very poor prognosis. Without thymic or hematopoietic cell transplantation, these patients die by 12 months of age. Even with a transplant, however, prognosis remains poor. In a study of 50 infants who received a thymic transplant for complete DGS, only 36 survived to two years.
Patients with partial DGS do not have a defined prognosis, as this depends on the severity of the pathologies associated with the disease. While some do not survive infancy due to severe cardiac anomalies, many survive into adulthood. DGS may be vastly underdiagnosed, and many undiagnosed adults with DGS thrive in the community with undetectable congenital anomalies and minor intellectual and/or social impairment. Improvements in genetic diagnostics will hopefully improve understanding of DGS in the future.
Cardiac and craniofacial anomalies associated with DGS may require surgical repair. As with any surgical procedure, the possibility of complications, including bleeding, infection, and prolonged hospitalization, exists. These risks are particularly dangerous for DGS patients with significant immunocompromise.
Consistent follow-up of patients with DGS is necessary to evaluate for possible complications: severe recurrent infections, autoimmune diseases, and hematologic malignancies.
Parents of children with DGS should receive patient education as it pertains to the severity of their child's condition. Discussion topics may include the following:
DiGeorge syndrome is easy to remember using the "CATCH-22" mnemonic:
Conotruncal cardiac anomalies
Management of DGS requires an interprofessional approach by a team of healthcare professionals. Obstetricians and genetic counselors can assist in diagnosis and management prenatally. Neonatologists, primary care pediatricians, family medicine physicians, immunologists, cardiothoracic surgeons, pediatricians, craniofacial surgeons, and other medical specialties may be involved in the care of patients with DGS. Collaboration with nurses, pharmacists, psychologists, speech therapists, and other healthcare professionals is paramount. Pharmacists can verify agent selection and dosing with medications to address the endocrine aspects of the disease. Nursing can counsel parents and monitor treatment progress. Psychological professionals can assist with developmental difficulties, as well as work with family members. Patients with DGS require lifelong, consistent follow-up. Because numerous organs are involved, close follow up with each specialist is necessary. Open communication and collaboration between all members of the interprofessional healthcare team are vital to ensure good outcomes. [Level 5]
Diagnosis and management can be challenging, and the interprofessional team can provide a collaborative effort to reduce morbidity and mortality associated with DGS. Current evidence regarding the management of DGS reflects level 5 evidence, and treatment options require a tailored approach around the individual patient's disease manifestations.
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