Continuing Education Activity

DiGeorge syndrome (DGS) is a congenital disorder with a broad phenotypic presentation, which results predominantly from the microdeletion of chromosome 22 at a location known as 22q11.2. This mutation results in the failure of appropriate development of the pharyngeal pouches, which are responsible for the embryologic development of the middle and external ear, maxilla, mandible, palatine tonsils, thyroid, parathyroids, thymus, aortic arch, and cardiac outflow tract. Features of DGS include cardiac anomalies, recurrent infections, abnormal facies, thymic hypoplasia or aplasia, cleft palate, developmental delay, and hypocalcemia. This activity outlines the diagnosis, evaluation, treatment, and management of patients with DGS, and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

Summarize the etiology of DiGeorge syndrome and its broad phenotypic presentation.

Review the evaluation of patients with DiGeorge syndrome.

Explain the treatment and management options available for DiGeorge syndrome.

Outline interprofessional team strategies for improving care coordination and communication to advance the care of patients with DiGeorge syndrome and improve outcomes.

DiGeorge Syndrome (DGS) is a combination of signs and symptoms caused bydefects in the development of structures derived from the pharyngeal archesduring embryogenesis. Features of DGSwere first described in 1828 but properly reported by Dr. Angelo DiGeorge in 1965, as a clinical trialthat included immunodeficiency, hypoparathyroidism, and congenital heart disease.[1]

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 phenotypeshas 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.[2] Current literature supports the use of the names of these syndromes interchangeably.

Features ofDGSincludean 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, becausethisis 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 cellspecializingin certain immune functions: destroying cells that are infected or malignant,existing as an integralpart of the innate immune system by killing viruses (e.g., Killer T-cells), helping B-cells matureto produce immunoglobulins for strongeradaptive immunity (e.g. helper T-cells), etc. The degree of immunodeficiency of patients with DGS can present differently depending onthe extent of thymic hypoplasia.

Somepatients 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.[3] 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.[1] 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 isT-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.[4][5]

Microdeletion of 22q11.2 is the most common microdeletion syndrome, affecting approximately 0.1% of fetuses.[6]The rate of 22q11.2 microdeletion in live births occurs at an estimated rate of 1 in 4000 to 6000.[1][7] 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 produceembryonically 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 notundergo 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.[8]

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 developmentof the pharyngeal pouches, which is driven by TBX1, leads to absence or hypoplasia of the thymus and parathyroid glands.Mouse and zebrafishTBX1 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.[9]Moreover, zebrafish knockouts have demonstrated defects in the thymus and pharyngeal arches as well as malformation of the ears and thymus.[10]

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.[11][12]These findings, as well as the neuromicrovascular pathology found in TBX1 knockout mice, suggest a molecular basis for the psychiatric pathologies associated with DGS.[4][5]Of note, individuals affected bythissyndrome 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 theprenatal and pediatric periods, diagnosis can also occur in adulthood.Delay in motor development is a common presenting feature first recognized by parentswho notice delays in rolling over, sitting up, or other infant milestones.[13]These findings can be associated with delayed speech developmentand learning disabilities. Later in life, abnormal behavior in the setting of poor developmental history may be thechief presenting symptom of DGS.[1]

A detailed history mayrevealthefollowing:

Family history of diagnosed or suspected DGS

Abnormalgenetic testing results of family members

Delays in the achievement of developmental milestones

Behavioral disturbance

Cyanosis, exercise intolerance, or symptoms

Recurrent infections secondary to T-cell deficiency

Speech difficulty

Difficulty feeding and/or failure to thrive

Muscle spasms, twitching, tetany, seizure

An examination can reveal findings consistent with severalfeatures of DGS:

A complete cardiopulmonary evaluation can reveal murmurs, cyanosis, clubbing, or edema consistent withaortic arch anomalies, conotruncal defects (e.g., tetralogy of Fallot, truncus arteriosus, pulmonary atresia with ventricular septal defect, transposition of the great vessels, interrupted aortic arch), or tricuspid atresia.

A craniofacial examination may demonstrate abnormalities such as cleft palate, hypertelorism, ear anomalies, short down slanting palpebral fissures, short philtrum, and hypoplasia of the maxilla or mandible.

Recurrent sinopulmonary infections due to T cell deficiency as a result of thymic hypoplasia

Signs of hypocalcemia, including twitching and muscle spasm, may be evident as a result of parathyroid hypoplasia. Chvostek's and Trousseau's signs may be positive.

Delayed development, unusual behavior, or signs of psychiatric disorders may be observable.

A clinician makes a definitive diagnosis of DGS in individuals with amicrodeletion 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 testsshould merit consideration:

Echocardiogram to evaluateconotruncal abnormalities

Complete blood count with differential

T and B Lymphocyte subset panels

Flow cytometry to assess T cell repertoire

Immunoglobulin levels

Vaccine titers for evaluation of response to vaccines

Serum ionized calcium and phosphorus levels

Parathyroid hormone level

Chest x-ray for thymic shadow evaluation

Renal ultrasound for possible renal and genitourinary defects

Serum creatinine

TSH

Testing for growth hormone deficiency

It is important to note that the broad spectrum of disease severity makesthe evaluationofDGS particularlychallenging. 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 medicinemay assist in more effective diagnosis and evaluation of DGS patients.[14]

Treatment and management of DGS require intensive interprofessional care:

Fortunately, many patients with DGS have minor immunodeficiency, with preservation of T cell function despite decreased T cell production. Frequent follow-up with an immunologist experienced in treating primary immunodeficiencies is advisable. Immunodeficiency in neonates with complete DGS (cDGS) requires management with isolation, intravenous IgG,antibioticprophylaxis, and either thymic or hematopoietic cell transplant (HSCT).

Cardiac anomalies, if not diagnosed during the fetal ultrasound, may present shortly after birth as life-threatening cyanotic heart disease. Pediatric cardiothoracic surgery evaluation may be urgently required. Blood products, if necessary, should be irradiated, CMV negative, and leukocyte reduced to prevent transfusion-associated graft-versus-host disease. These measures also aim to reduce lung injury, particularly in surgical cases requiring cardiopulmonary bypass.

Cleft palate cases require evaluation by an otolaryngologist, plastic surgeon, or oral & maxillofacial surgeon with experience in surgical correction of palatal defects. Repair ofa cleft palate can improve feeding ability, speech, and reduce the incidence of sinopulmonary infections.

Hypocalcemia is manageable with calcium and vitamin D supplementation. Recombinant human PTH is an option in DGS patients refractory to standard therapy.

Autoimmune diseases are common in DGS patients, includingimmune thrombocytopenia(ITP), rheumatoid arthritis, autoimmune hemolytic anemia, Graves disease, and Hashimoto thyroiditis. DGS patientsshould be evaluated carefully for autoimmune symptoms regularly.

Audiologic evaluationis necessary for DGS patients experiencing difficulty with hearing. Children too young to express difficulty with hearing need assessment, particularly with a delay in cognitive and behavioral development.

Early intervention services arebeneficial for children with impaired cognitive and behavioral development.

Speech therapy isnecessary for difficulty with language secondary to craniofacial anomalies and/or cognitive impairment.

Genetic counseling is a reasonable consideration for parents of a child with DGS who desire more children, as well as for patients with DGS who may want to become parents. If a parent has the same mutation as an affected child, there is a 50% chance a new baby will also have DGS.

Advanced approaches for the management of children withcomplete DiGeorge anomaly

In the cDGS featuring no thymus function andbone marrow stem cells can not develop into T cells, childrenusually die by age 2 years due to severe infections. In this setting, the proposal is to T cellreplete HSCT. Nevertheless, because of the absence of thymus, thisstrategy can only obtain engraftment of post thymic T cells.[17]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.[18] Recently, the FDA approved the thymus transplantation as standard care. This approach focuses on producingnaive T cellswith 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 indicateup to 75% of long-term survival but have described frequent autoimmune sequelae (e.g., autoimmune hemolysis, thyroiditis, thrombocytopenia, enteropathy, and neutropenia) in survivors.[19]

All patient findings that are part ofDiGeorge syndrome can also be present as isolatedanomalies in an otherwise normal individual.

The following conditions present with overlapping features:

Smith-Lemli-Opitz syndrome - (polydactyly and cleft palate are common findings).

Oculo-auriculo vertebral (Goldenhar) syndrome (OAVS) - (ear anomalies, heart disease, vertebral defects,and renalanomalies are present). OAVS often demonstrates a sporadic presentation.

Alagille syndrome - (butterfly vertebrae,congenital heart disease, and posterior embryotoxon arecommon to both conditions).

VATER association (heart disease, vertebral, renal, and limb anomalies present in both conditions). VATER association is a diagnosis of exclusion for which an established etiology to date remains unknown.

CHARGE syndrome - (any combination ofcongenital heart disease, palatal differences, atresia choanae, coloboma, renal, growth deficiency, ear anomalies/hearing loss, facial palsy, developmental differences,genitourinary anomalies, and immunodeficiency are present in both syndromes).

Genetic consult is essential along with the complete clinical picture to make an accurate diagnosis of DiGeorge syndrome.

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.[20]

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 possiblecomplications: 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:

Early signs and symptoms of infection

Signs of hypocalcemia

Safe use of medications

Surgical intervention options

Immune therapy options

Genetic counseling

Speech therapy for feeding or language difficulty

Developmental milestones and warning signs of developmental delay

Benefits of early intervention programs

Signs and symptoms of psychiatric disorders

DiGeorge syndrome is easy to remember using the "CATCH-22" mnemonic:

Conotruncal cardiac anomalies

Abnormal facies

Thymic hypoplasia

Cleft palate

Hypocalcemia

22q11.2 microdeletion

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 othermedical 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.

DiGeorge syndrome. Contributed by Professor Victor Grech (CC By=S.A. 3.0 https://creativecommons.org/licenses/by-sa/3.0/) Image courtesy: https://en.wikipedia.org/wiki/DiGeorge_syndrome#/media/File:DiGeorge_syndrome1.jpg

DiGeorge syndrome karyotype. Image courtesy O Chaigasame

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DiGeorge Syndrome - StatPearls - NCBI Bookshelf

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