Kilic SS. DiGeorge
syndrome. Recent Advances in Pediatrics,†
Jaypee Brothers Medical Publishers,
DGS is a common congenital disorder characterized by neural-crest-related developmental defects. The genetic pathways regulating cardiac neural crest development are reviewed and the evidence implicating TBX1 gene on chromosome 22q11 in the pathogenesis of DiGeorge syndrome is summarized. DiGeorge Syndrome (DGS) was first documented ( DiGeorge 1965), (1) , with thymic hypoplasia and hypoparathyroidism. In 1981, de la Chapelle (2)†† reported a chromosome 22 translocation in four affected family members.† DGS can be associated with a broad phenotype, but the most characteristic features are congenital heart disease, especially defects of the aortic arch and cardiac outflow tract and thymic and parathyroid aplasia or hypoplasia, which may cause T cell immune deficiencies and hypocalcemia, respectively. The acknowledgement of similarities and phenotypic overlap with other disorders including velocardiofacial syndrome (VCFS) and conotruncal anomaly face syndrome (CTAFS) as well as the association of all of these disorders with the 22q11 deletion has led to an expanded phenotype which includes palatal and speech abnormalities and cognitive, neurologic, and psychiatric difficulties. DGS is an autosomal dominant disorder with estimated frequency of 1/4 000 live births. The overwhelming majority of patients with DGS (80-95%) have microdeletion in chromosome 22q11.2. Some of the patients are hemizygous for chromosome 10 p13 (3-5). The immunodeficiency that occurs secondary to the thymic hypoplasia is variable but usually characterized by defects in T cell production. Diminished T cell counts in the peripheral blood are common in patients with chromosome 22q11.2 deletion syndrome (6). Velocardiofacial syndrome (VCFS) and conotruncal anomaly face syndrome (CTAFS) as well as the association of all of these disorders with the 22q11 deletion (Del22q11.2) showed some clinical overlap with features of DGS including palatal and speech abnormalities and cognitive, neurologic, and psychiatric difficulties (7).†
The major candidate
gene (TBX1) for the wide range of developmental anomalies in the heart, glands
and facial structures has been recently identified (8). Tbx1, which encodes a
transcription factor of the T-box family, lies in the 22q11.2 locus. The majority
of DiGeorge syndrome (DGS) patients have a 1.5 Mb hemizygous deletion
of a 30-gene region of chromosome
22 and usually display interruption of the left fourth
aortic arch (interrupted aortic arch Type B), aberrant
right subclavian artery, persistence of the right fourth
aortic arch or the right
dorsal aorta, truncus arteriosus, tetralogy of Fallot, branch pulmonary artery atresia, or isolated
ventricular septal defects (9). Mice mutant for the T-box gene displayed a
wide range of developmental anomalies encompassing almost all of the common DGS
features, including hypoplasia of the thymus and
parathyroid glands, cardiac outflow tract abnormalities, abnormal facial
structures, abnormal vertebrae and cleft palate. The outflow†† tract shows truncus arteriosus
, another anomaly that is typically compatible with full term gestation
in humans. On the basis of this phenotype in
mice, it is proposed that TBX1 in humans is a key gene in the etiology of DGS (10).
Gene searches have been successful in identifying more than 30 genes in the deleted segment.
†A DGS patient with a 22q11 deletion has a 50% chance of transmitting the deletion-bearing chromosome to his or her offspring. The phenotype may range from complete DGS to mild facial dysmorphia and learning difficulties. Antenatal knowledge of the deletion status provides couples and clinicians with an accurate diagnosis, prognostic information, and recurrence risk, which may assist couples with their reproductive decisions (11).
The pathophysiology involves an embryologic defect in the 3rd and 4th pharyngeal pouch development from which† thymus and the parathyroid glands evolve. The embryologic defect may affect not only 3rd and 4th pharyngeal pouch but also 4th,† 5th and 6th branchial arches, thereby resulting in a contiguous field defect such as esophageal atresia and distal tracheo-esophageal fistula (12). Disruption of pharyngeal arch development in humans underlies many of the craniofacial defects observed in the 22q11.2 deletion syndrome.
Histopathology of Thymus:
Thymic tissue, when found, does contain Hassallís corpuscles and a normal density of thymocytes; corticomedullary distinction is present. Lymphoid follicles are usually present, but lymph node paracortical areas and thymus-dependent regions of the spleen show variable degrees of depletion (13).
Patients with DiGeorge syndrome are heterogeneous with respect to immune, cardiac, parathyroid, and other findings.The abnormalities that are already known to be associated with 22q11 deletion affect multiple body systems and include the characteristic craniofacial, otolaryngeal and cardiovascular features along with irregularities of the genitourinary, musculoskelatal, endocrinologic, neurologic and immunologic systems (14). In terms of structural defects, approximately 75% of patients had significant cardiovascular abnormalities, most often tetralogy of Fallot , ventricular septal defect, and outflow tract abnormalities; nearly 49% had otolaryngeal abnormalities and 36% had genitourinary anomalies. Hypocalcemia can present in the neonatal period as tetany, or at any state throughout infancy or into adulthood (15).
DiGeorge syndrome (DGS) is characterized by typical facial features including a short philtrum of the upper lip, hypertelorism, an antimongoloid slant to the eyes, mandibular hypoplasia, and low-set, often notched ears (Figure 1), conotruncal defects of the heart, parathroid glands, and thymus. Craniofacial findings include auricular abnormalities, nasal abnormalities, and "hooded eyelids." However, the presence of these features as well as other facial findings, such as a long face and malar flatness, is variable (3,4).
The structural airway anomalies which also have been described in DGS: tracheoesophageal fistula, short trachea with reduced numbers of tracheal rings, laryngomalacia, tracheomalacia, bronchomalacia, and abnormal thyroid cartilage (16). We had reported before one of our patients† with Del22q11.2 who had severe combined immunodeficiency and tracheo-esophageal fistula (TEF) (Figure 2), (12). Appropriate interactions between the epithelium and adjacent neural crest-derived mesenchyme are necessary for normal pharyngeal arch development. Disruption of pharyngeal arch development in humans underlies many of the craniofacial defects observed in the 22q11.2 deletion syndrome (17). TBX1 is also required for the development of pharyngeal arches and pouches, as predicted by the DGS clinical phenotype. Tbx1 transcripts have been found to be localized to the pharyngeal endoderm and the mesodermal core of the pharyngeal arches (8). Early feeding difficulties such as caughing, sputtering and failure to thrive are often manifestations of dysphagia, or difficulty swallowing. In infants, dysphagia can result from anotomic anomalies affecting the oropharyngeal structures (18).
The immunodeficiency that occurs secondary to the thymic hypoplasia is variable but usually characterized by defects in T cell production. Diminished T cell counts in the peripheral blood are common in patients with chromosome 22q11.2 deletion syndrome. Most patients have some thymic function. They may be born with low T-cell numbers but have significant proliferative responses to mitogens and antigens and normal antibody responses to immunization. T-cell numbers and function usually increase in these patients in the first years of life. It is rare for patients to have complete absence of the thymus. These patients have ďcomplete DiGeorge syndromeĒ and do not recover spontaneously (6,19). †Approximately †††5% of DGS patients have severely decreased T cell numbers and function as a result of thymic aplasia, these patients might require bone marrow transplantation or thymus transplantation . Fifteen percent of patients have impaired humoral immunity. The presence and severity of immune defects in children with chromosome 22q11 deletion syndrome vary and do not correlate with other phenotypic features .The spectrum of immune defects in DGS is broad but must often includes decreased CD3+ T cells (<1.500 cells/mm3 ), a CD4 T cells count of less than 1.000 cells/mm3 , and mildly impaired cellular immunity. †Approximately †††5% of DGS patients have severely decreased T cell numbers and function as a result of thymic aplasia, these patients might require bone marrow transplantation or thymus transplantation (20-22) . Fifteen percent of patients also have impaired humoral immunity. The presence and severity of immune defects in children with chromosome 22q11 deletion syndrome vary and do not correlate with other phenotypic features.
Autoimmune disorders associated with 22q11.2 deletion syndrome include: juvenile rheumatoid arthritis, idiopathic thrombocytopenia, hyperthyroidism (Grave's disease), hypothyroidism, vitiligo, hemolytic anemia, and celiac disease (23).
In children and young adults, the 22q11DS has also been associated with high rates of a neuropsychiatric disorder , attention deficit hyperactivity disorder , autistic spectrum disorders, and mental retardation, with test profiles suggestive of nonverbal learning disorders.While the psychiatric dysfunction among those with 22q11 DS is as varied as the phenotypic presentation, several common temperamental features have been described in studies of children and adolescents with velocardiofacial syndrome (VCFS), including poor social interaction skills, high levels of anxiety, behavioral excitation, exaggerated response to threatening stimuli,† and irritability (24)
The specific fluorescence in situ hybridisation (FISH) test for this chromosome deletion is a standard method for diagnosis (Figure 3). Chromosome 22q11 deletion is a relatively common condition and is a readily diagnosed by FISH. Wide availability of commercial fluorescence in situ hybridization probes have increased capabilities to rapidly diagnose and care for affected children (25,26). Two probes are commercially available for 22q11.2 FISH analysis (TUPLE1 and N25).
Routine cytogenetic analysis continues to be important for the detection of other chromosomal† rearrangements, such as translocations, which may involve chromosomes other than 22. Due to the highlight the importance of recognising of all the associated features of chromosome 22q11 deletion, FISH 22 q11deletion analysis should be performed on patients with hypocalcemia and congenital cardiac malformations .†
Depending on the age and presenting problems of the individual with the 22q11.2 deletion syndrome, a multidisciplinary evaluation involving healthcare providers from the following specialties is often necessary: medical genetics, plastic surgery, speech pathology, otolaryngology, audiology, dentistry, cardiology, immunology, child development, child psychology, neurology, and general pediatrics (14).
About 30% of
individuals have confirmed hypocalcemia. Calcium
homeostasis typically normalizes with age, although recurrence of hypocalcemia in later childhood has been reported. In rare
instances, children receiving ongoing care for infantile hypocalcemia
may not be diagnosed with the 22q11.2 deletion syndrome until school age. A baseline cardiac
evaluation is recommended for all individuals diagnosed with the 22q11.2 deletion syndrome. Early
educational intervention and speech therapy are recommended beginning at age
one year because of the high incidence of speech and language delay. Speech and
language assessment may aid in diagnosis of a palatal abnormality or VPI.
Referral to a craniofacial team for management is recommended (4).
It is necessary to measure absolute lymphocyte count. A low absolute lymphocyte count necessitates evaluation of T and B cell subsets and referral to an immunologist. Infants with lymphocyte abnormalities should not be immunized with live vaccines (i.e., oral polio, MMR). No immunologic treatment is needed for the partial form (6). Patients with† complete DiGeorge syndrome have been experienced immunologic reconstitution after unfractionated HLA-identical bone marrow transplantation (20). Transplantation of cultured, mature thymic epithelial explants has successfully reconstituted the immune function of several infants with the complete DiGeorge syndrome (21,22). Antigen-specific T-cell responses were developed, and B-cell function also normalized in these DiGeorge patients. This management strategy appears to offer a real advantage over fetal thymus and BMT for effective treatment of complete DiGeorge syndrome patients. In 1999, Markert et al. (21) corrected additional patients with the most complete form of DiGeorge thymic aplasia by transplantation of MHC-matched thymus grafts from unrelated donors, obtained at surgery for congenital heart disease .
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions.
DiGeorge Syndrome (DGS) is a common congenital disorder characterized by neural-crest-related developmental defects and characterized by typical facial features, and conotruncal defects of the heart, parathroid glands, and thymus. The phenotypic spectrum of† Del22q11.2 syndromes includes a wide variety of malformations and abnormalities occuring in different combinations and severity. The major candidate gene (TBX1) for the wide range of developmental anomalies in the heart, glands and facial structures has been recently identified. The typical clinical picture is characterized† by congenital cardiac defects, recurrent infections and velopharyngeal insufficiency. In terms of structural defects, approximately 75% of patients had significant cardiovascular abnormalities, nearly 49% had otolaryngeal abnormalities and 36% had genitourinary anomalies . Nearly, 70% of patients was ascertained through the outpatient clinic of pediatric cardiology. The most typical heart defects associated with Del22q11.2 syndrome are conotruncal heart defects included tetralogy of Fallot , truncus arteriosus and interrupted aortic arch 8.† Hypocalcemia can present in the neonatal period as tetany, or at any state throughout infancy or into adulthood. †Any infant with a chromosome 22q11.2 deletion and difficulty feeding should receive an early evaluation, which should investigate not only cardiac and palatal status but also structure and function of airway and gastrointestinal tract.
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Figure 1.† Facial appearance of the patient with DGS.
Figure 2. Radiologic examination showed esophageal atresia and distal tracheo-esophageal fistula.
Fig 3: FISH analysis revealed a chromosome 22q11 deletion.