- Email: [email protected]
DiGeorge Syndrome
DiGeorge Syndrome SD Bamforth and J Burn, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
© 2013 Elsevier Inc. All rights reserved.
This article is a revision of the previous edition article by J Goodship and J Burn, volume 1, pp 533–535, © 2001, Elsevier Inc.
Glossary Inner canthi The inner corner of the eye, where the upper and lower lids meet. Neural crest cells A group of embryonic cells that emerge from the neural tube and migrate to give several different lineages of adult cells, for example, the spinal and autonomic ganglia, the glial cells of the peripheral nervous system, and non-neuronal cells, such as chromaffin cells of the adrenal glands and melanocytes in the skin. Neural crest cells also contribute to the development of the aortic arch arteries and the outflow tract of the heart. Palpebral fissures The longitudinal opening between the eyelids.
DiGeorge syndrome is the most common microdeletion syndrome in humans, with a prevalence of 1 in 4000 live births. The syndrome is known by several names including velo-cardio-facial syndrome (VCFS), Shprintzen syndrome and conotruncal anomaly face syndrome. Another term, the acronym CATCH 22 (cardiac, abnormality, abnormal facies, T-cell deficiencies due to thymic hypoplasia, cleft palate/palatal dysfunction and hypocalcemia, deletion on chromosome 22) has fallen out of favor due to its association with the no-win situation in the Joseph Heller novel of the same name. However, the one common element to the syn drome is its cause: a microdeletion on chromosome 22, band q11.2, giving the syndrome another label, 22q11.2 deletion syndrome.
Clinical Features Associated with DiGeorge Syndrome The dysmorphic facial features associated with the deletion can be very subtle and as with many syndromes the facial appear ance changes with age (Figures 1 and 2). In young children the mouth is small. The palpebral fissures may be short and narrow with lateral placement of the inner canthi. The ears have a round appearance because of a deficient upper helix and small lobe. The root and bridge of the nose are wide, and this feature is most obvious in the older child and adult. Affected individuals are often constitutionally small. Although the children DiGeorge originally described had abnormalities of the thymus and parathyroids, it is unusual for these to cause the presenting features in children with the deletion. Severe immunodeficiency is very unusual, occurring in less than 1% of individuals with the deletion, but T lympho cyte numbers are often low, and this is largely due to low CD4 counts. However, most patients generate good antibody responses following immunization; so, routine vaccinations are not a problem. Clinically, it is important to check the
Brenner’s Encyclopedia of Genetics, 2nd edition, Volume 2
Second heart field An area of splanchnic mesoderm located caudal to the pharynx that is the source of cells destined for the outflow tract. Syntenic Conserved gene order along the chromosomes of different species. Tetralogy of Fallot A syndrome of congenital heart defects that includes a ventricular septal defect, an overriding aorta, narrowing of the pulmonary valve, and a thickened right ventricle. Velopharyngeal insufficiency The improper closing of the velopharyngeal sphincter (soft palate muscle) during speech characterized by an acute nasal quality of the voice.
calcium levels to prevent hypocalcemia seizures but hypocalce mia responds well to oral supplements. Congenital cardiovascular defects are present in 75% of DiGeorge syndrome patients. The heart defects most com monly seen are tetralogy of Fallot, pulmonary atresia with ventricular septal defect, ventricular septal defect, right-sided aortic arch, interrupted aortic arch type B, and common arterial trunk (also known as truncus arteriosus). As the first three of these are relatively common, and right-sided aortic arch may even be asymptomatic, the chance of a child with these heart defects having the deletion is small. However, almost half of all children presenting with type B interrupted aortic arch or trun cus arteriosus have the 22q11.2 deletion. Both of these defects carry a significant mortality. A third of patients have velopharyngeal insufficiency, which presents either in the neonatal period with drinks regurgitating through the nose or later with nasal speech. Overt clefting of the palate occurs in 10% of cases. A wide range of genitourinary abnormalities has been reported including renal agenesis and dysplasia. The majority of affected individuals have an intelli gence quotient less than 100, with almost half having a score of less than 70, resulting in most of these patients classed as having intellectual disability. Psychiatric disorders are more common in adults and children with the deletion compared with the general population. These disorders include schizo phrenia, attention-deficit hyperactivity disorder (ADHD), bipolar disorder, and autism spectrum disorders. The phenotype seen in DiGeorge syndrome patients is highly variable, ranging from practically asymptomatic to life-threatening abnormalities. Of the many clinical features identified in DiGeorge syndrome patients, no single one is found in all cases, and no patient will ever present with all of the described features. Moreover, identical twins with the same deletion may have different clinical features, and a parent with minor features may have a child with severe cardiovascular defects. As the phenotype is so variable, the diagnosis of
doi:10.1016/B978-0-12-374984-0.00402-2
319
320
DiGeorge Syndrome
Figure 1 Facial features associated with DiGeorge syndrome (side view). Note the prominent nose with a large tip.
DiGeorge syndrome in populations. For example, in the north of England, a population cohort of consecutive newborn babies was assessed for congenital heart defects over a 5-year period, and 200 cases were identified from 40 000 births per year. During 1 year, 10 cases of 22q11.2 deletion were detected, thereby suggesting a minimum prevalence of 1 in 4000. DiGeorge syndrome maybe inherited from a mildly affected or undiagnosed parent in an autosomal-dominant manner, but the majority of cases are de novo mutations, that is, not inher ited from either parent. A European population study of 558 cases of DiGeorge syndrome revealed that, of the 285 parents that had also been tested, 28% of the cases were inherited from one parent, predominantly the mother. Seventy-five percent of cases presented with a clinically significant cardiovascular defect, with the majority of these showing tetralogy of Fallot, ventricular septal defect, interrupted aortic arch, pulmonary atresia, and common arterial trunk/persistent truncus arterio sus. Severe cardiovascular defects caused the death of 8% of patients, with half of these dying within 1 month of birth. It is possible that an immune deficiency may have been a factor in causing this early lethality. Calcium measurements, where available, showed that 60% of cases had low levels. Other relevant characteristics of DiGeorge syndrome, which are reported in a third of cases, include short stature, renal mal formation, and learning disabilities.
Genetics of DiGeorge Syndrome
Figure 2 Facial features associated with DiGeorge syndrome (frontal view). The eye, nose and mouth phenotypic features can be seen.
DiGeorge syndrome must be based on identifying the deletion of the critical region on chromosome 22.
Prevalence of Detection The standard method of detecting a 22q11.2 deletion is by fluorescent in situ hybridization (FISH). This involves the bind ing of DNA fragments from chromosome 22q11.2 labeled with fluorescent molecules to chromosomes prepared from a patient. Various studies have described the prevalence of
The genetic cause of DiGeorge syndrome was found in 1992, when the microdeletion on chromosome 22 was identified. DiGeorge syndrome is caused by a hemizygous � 3-Mb microdeletion on chromosome 22q11.2 in 90% of patients, with the remainder having a smaller deletion of � 1.5–2 Mb. The q11.2 band on chromosome 22 has been shown to have identical low copy repeats flanking the 3.0-Mb deleted region; recombina tion between repeats results in an intra-chromosomal deletion on one copy of the chromosome. In this region, more than 35 genes have been deleted, each of which is a possible candi date for causing one or more of the associated developmental defects in DiGeorge syndrome patients. The most likely candi date is believed to be the transcription factor TBX1, particularly for the cardiovascular abnormalities. Studies have revealed that patients presenting with the DiGeorge syndrome phenotype, but without the chromosomal deletion, have mutations in TBX1. These mutations can be missense, where a change in the DNA code causes a different codon to be translated, thereby causing the gene to function abnormally, or deletion of a base pair, which causes a frameshift in the translated DNA resulting in a truncated protein. Mouse models have been created that either lack the syntenic region deleted in humans or are speci fically mutated for Tbx1. Mice homozygous null (i.e., have had both copies of the gene removed) for Tbx1 die at birth with common arterial trunk, interrupted aortic arch (type B), double aortic arch, right-sided aortic arch, retro-esophageal right sub clavian artery, absent thymus and parathyroid glands, and craniofacial and vertebral abnormalities. Embryos heterozy gous (i.e., have had only one copy of the gene removed) for Tbx1 have 4th pharyngeal arch artery defects including inter rupted aortic arch and retro-esophageal right subclavian artery, indicating that Tbx1 gene dosage is critical. Indeed, transgenic
DiGeorge Syndrome mice engineered to express varying levels of Tbx1 messenger RNA (mRNA) revealed that the penetrance of different DiGeorge syndrome features became more severe as the Tbx1 mRNA levels reduced. Moreover, cardiovascular defects became more severe when Tbx1 mRNA levels were reduced to a fifth of normal levels, indicating that a certain threshold level of the gene is required for normal development. This level of gene expression is probably associated with an environmental effect, which together can cause an increase in developmental defects. In the developing mouse, Tbx1 is expressed throughout the pharyngeal region. This is a segmented structure known as the pharyngeal (or branchial) arches, comprised of different tissue layers, the endoderm (inside), mesoderm (middle), and ecto derm (outside). Mesenchyme is contained within the ectoderm and endoderm and partly comprises neural crest cell-derived tissue. The first two pharyngeal arches develop into craniofacial structures (such as the jaw) and the caudal three pharyngeal arches give rise to glands such as the thymus and parathyroid, and contain the major arteries that transport blood away from the heart (the aorta, ductus arteriosus, carotid, and subclavian arteries). Tbx1 is not expressed in the neural crest, but it is expressed in the non-neural crest-derived mesenchyme, as well as in mesoderm, endoderm, and ectoderm. Transgenic mouse models have been created that can selectively delete Tbx1 from specific tissues during development. Such studies have shown that the Tbx1 transcription factor regulates the cardiac progenitor cells of the second heart field that contribute to the heart outflow tract. Studies have also shown that Tbx1 expression within the mesoderm, and/or endoderm and ecto derm, is vital for correct aortic arch artery development. The highly variable phenotype seen in DiGeorge syndrome is thought to be due to genetic modifiers in the genome. Indeed, several genes outside of the DiGeorge syndrome critical region on chromosome 22q11.2 have been implicated
321
in modulating the severity and penetrance of the phenotype in transgenic mice, for example, Vegf, Shh, Chordin, Raldh2, Tgfβ, and Fgf8. Tbx1 has also been shown to genetically interact with Fgf8, a growth factor important for embryonic development.
See also: Chromosome; Cleft Lip and Cleft Palate.
Further Reading Burn J and Goodship J (2007) Congenital heart disease. In: Rimoin DL, Connor JM, Pyeritz RE, and Korf BR (eds.) Principles and Practice of Medical Genetics. 5th edn., vol. 2., pp. 1083–1159. Philadelphia, PA: Elsevier. Momma K (2010) Cardiovascular anomalies associated with chromosome 22q11.2 deletion syndrome. American Journal of Cardiology 105: 1617–1624. Murphy KC and Scambler PJ (eds.) (2005) Velo-Cardio-Facial Syndrome. A Model for Understanding Microdeletion Disorders. Cambridge, UK: Cambridge University Press. Ryan AK, Goodship JA, Wilson DI, et al. (1997) Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: A European collaborative study. Journal of Medical Genetics 34: 798–804. Scambler PJ (2010) 22q11 deletion syndrome: A role for TBX1 in pharyngeal and cardiovascular development. Pediatric Cardiology 31: 378–390. Shprintzen RJ (2008) Velo-cardio-facial syndrome: 30 years of study. Developmental Disabilities Research Reviews 14: 3–10. Wurdak H, Ittner LM, and Sommer L (2006) DiGeorge syndrome and pharyngeal apparatus development. BioEssays 28: 1078–1086. Zhang Z and Baldini A (2007) In vivo response to high-resolution variation of Tbx1 mRNA dosage. Human Molecular Genetics 17: 150–157.
Relevant Websites http://www.maxappeal.org.uk – A website run by parents of children with DiGeorge syndrome. http://www.22q.org – The international 22q11.2 deletion syndrome foundation. http://www.vcfsef.org – The velo-cardio-facial syndrome education foundation.
© 2013 Elsevier Inc. All rights reserved.
This article is a revision of the previous edition article by J Goodship and J Burn, volume 1, pp 533–535, © 2001, Elsevier Inc.
Glossary Inner canthi The inner corner of the eye, where the upper and lower lids meet. Neural crest cells A group of embryonic cells that emerge from the neural tube and migrate to give several different lineages of adult cells, for example, the spinal and autonomic ganglia, the glial cells of the peripheral nervous system, and non-neuronal cells, such as chromaffin cells of the adrenal glands and melanocytes in the skin. Neural crest cells also contribute to the development of the aortic arch arteries and the outflow tract of the heart. Palpebral fissures The longitudinal opening between the eyelids.
DiGeorge syndrome is the most common microdeletion syndrome in humans, with a prevalence of 1 in 4000 live births. The syndrome is known by several names including velo-cardio-facial syndrome (VCFS), Shprintzen syndrome and conotruncal anomaly face syndrome. Another term, the acronym CATCH 22 (cardiac, abnormality, abnormal facies, T-cell deficiencies due to thymic hypoplasia, cleft palate/palatal dysfunction and hypocalcemia, deletion on chromosome 22) has fallen out of favor due to its association with the no-win situation in the Joseph Heller novel of the same name. However, the one common element to the syn drome is its cause: a microdeletion on chromosome 22, band q11.2, giving the syndrome another label, 22q11.2 deletion syndrome.
Clinical Features Associated with DiGeorge Syndrome The dysmorphic facial features associated with the deletion can be very subtle and as with many syndromes the facial appear ance changes with age (Figures 1 and 2). In young children the mouth is small. The palpebral fissures may be short and narrow with lateral placement of the inner canthi. The ears have a round appearance because of a deficient upper helix and small lobe. The root and bridge of the nose are wide, and this feature is most obvious in the older child and adult. Affected individuals are often constitutionally small. Although the children DiGeorge originally described had abnormalities of the thymus and parathyroids, it is unusual for these to cause the presenting features in children with the deletion. Severe immunodeficiency is very unusual, occurring in less than 1% of individuals with the deletion, but T lympho cyte numbers are often low, and this is largely due to low CD4 counts. However, most patients generate good antibody responses following immunization; so, routine vaccinations are not a problem. Clinically, it is important to check the
Brenner’s Encyclopedia of Genetics, 2nd edition, Volume 2
Second heart field An area of splanchnic mesoderm located caudal to the pharynx that is the source of cells destined for the outflow tract. Syntenic Conserved gene order along the chromosomes of different species. Tetralogy of Fallot A syndrome of congenital heart defects that includes a ventricular septal defect, an overriding aorta, narrowing of the pulmonary valve, and a thickened right ventricle. Velopharyngeal insufficiency The improper closing of the velopharyngeal sphincter (soft palate muscle) during speech characterized by an acute nasal quality of the voice.
calcium levels to prevent hypocalcemia seizures but hypocalce mia responds well to oral supplements. Congenital cardiovascular defects are present in 75% of DiGeorge syndrome patients. The heart defects most com monly seen are tetralogy of Fallot, pulmonary atresia with ventricular septal defect, ventricular septal defect, right-sided aortic arch, interrupted aortic arch type B, and common arterial trunk (also known as truncus arteriosus). As the first three of these are relatively common, and right-sided aortic arch may even be asymptomatic, the chance of a child with these heart defects having the deletion is small. However, almost half of all children presenting with type B interrupted aortic arch or trun cus arteriosus have the 22q11.2 deletion. Both of these defects carry a significant mortality. A third of patients have velopharyngeal insufficiency, which presents either in the neonatal period with drinks regurgitating through the nose or later with nasal speech. Overt clefting of the palate occurs in 10% of cases. A wide range of genitourinary abnormalities has been reported including renal agenesis and dysplasia. The majority of affected individuals have an intelli gence quotient less than 100, with almost half having a score of less than 70, resulting in most of these patients classed as having intellectual disability. Psychiatric disorders are more common in adults and children with the deletion compared with the general population. These disorders include schizo phrenia, attention-deficit hyperactivity disorder (ADHD), bipolar disorder, and autism spectrum disorders. The phenotype seen in DiGeorge syndrome patients is highly variable, ranging from practically asymptomatic to life-threatening abnormalities. Of the many clinical features identified in DiGeorge syndrome patients, no single one is found in all cases, and no patient will ever present with all of the described features. Moreover, identical twins with the same deletion may have different clinical features, and a parent with minor features may have a child with severe cardiovascular defects. As the phenotype is so variable, the diagnosis of
doi:10.1016/B978-0-12-374984-0.00402-2
319
320
DiGeorge Syndrome
Figure 1 Facial features associated with DiGeorge syndrome (side view). Note the prominent nose with a large tip.
DiGeorge syndrome in populations. For example, in the north of England, a population cohort of consecutive newborn babies was assessed for congenital heart defects over a 5-year period, and 200 cases were identified from 40 000 births per year. During 1 year, 10 cases of 22q11.2 deletion were detected, thereby suggesting a minimum prevalence of 1 in 4000. DiGeorge syndrome maybe inherited from a mildly affected or undiagnosed parent in an autosomal-dominant manner, but the majority of cases are de novo mutations, that is, not inher ited from either parent. A European population study of 558 cases of DiGeorge syndrome revealed that, of the 285 parents that had also been tested, 28% of the cases were inherited from one parent, predominantly the mother. Seventy-five percent of cases presented with a clinically significant cardiovascular defect, with the majority of these showing tetralogy of Fallot, ventricular septal defect, interrupted aortic arch, pulmonary atresia, and common arterial trunk/persistent truncus arterio sus. Severe cardiovascular defects caused the death of 8% of patients, with half of these dying within 1 month of birth. It is possible that an immune deficiency may have been a factor in causing this early lethality. Calcium measurements, where available, showed that 60% of cases had low levels. Other relevant characteristics of DiGeorge syndrome, which are reported in a third of cases, include short stature, renal mal formation, and learning disabilities.
Genetics of DiGeorge Syndrome
Figure 2 Facial features associated with DiGeorge syndrome (frontal view). The eye, nose and mouth phenotypic features can be seen.
DiGeorge syndrome must be based on identifying the deletion of the critical region on chromosome 22.
Prevalence of Detection The standard method of detecting a 22q11.2 deletion is by fluorescent in situ hybridization (FISH). This involves the bind ing of DNA fragments from chromosome 22q11.2 labeled with fluorescent molecules to chromosomes prepared from a patient. Various studies have described the prevalence of
The genetic cause of DiGeorge syndrome was found in 1992, when the microdeletion on chromosome 22 was identified. DiGeorge syndrome is caused by a hemizygous � 3-Mb microdeletion on chromosome 22q11.2 in 90% of patients, with the remainder having a smaller deletion of � 1.5–2 Mb. The q11.2 band on chromosome 22 has been shown to have identical low copy repeats flanking the 3.0-Mb deleted region; recombina tion between repeats results in an intra-chromosomal deletion on one copy of the chromosome. In this region, more than 35 genes have been deleted, each of which is a possible candi date for causing one or more of the associated developmental defects in DiGeorge syndrome patients. The most likely candi date is believed to be the transcription factor TBX1, particularly for the cardiovascular abnormalities. Studies have revealed that patients presenting with the DiGeorge syndrome phenotype, but without the chromosomal deletion, have mutations in TBX1. These mutations can be missense, where a change in the DNA code causes a different codon to be translated, thereby causing the gene to function abnormally, or deletion of a base pair, which causes a frameshift in the translated DNA resulting in a truncated protein. Mouse models have been created that either lack the syntenic region deleted in humans or are speci fically mutated for Tbx1. Mice homozygous null (i.e., have had both copies of the gene removed) for Tbx1 die at birth with common arterial trunk, interrupted aortic arch (type B), double aortic arch, right-sided aortic arch, retro-esophageal right sub clavian artery, absent thymus and parathyroid glands, and craniofacial and vertebral abnormalities. Embryos heterozy gous (i.e., have had only one copy of the gene removed) for Tbx1 have 4th pharyngeal arch artery defects including inter rupted aortic arch and retro-esophageal right subclavian artery, indicating that Tbx1 gene dosage is critical. Indeed, transgenic
DiGeorge Syndrome mice engineered to express varying levels of Tbx1 messenger RNA (mRNA) revealed that the penetrance of different DiGeorge syndrome features became more severe as the Tbx1 mRNA levels reduced. Moreover, cardiovascular defects became more severe when Tbx1 mRNA levels were reduced to a fifth of normal levels, indicating that a certain threshold level of the gene is required for normal development. This level of gene expression is probably associated with an environmental effect, which together can cause an increase in developmental defects. In the developing mouse, Tbx1 is expressed throughout the pharyngeal region. This is a segmented structure known as the pharyngeal (or branchial) arches, comprised of different tissue layers, the endoderm (inside), mesoderm (middle), and ecto derm (outside). Mesenchyme is contained within the ectoderm and endoderm and partly comprises neural crest cell-derived tissue. The first two pharyngeal arches develop into craniofacial structures (such as the jaw) and the caudal three pharyngeal arches give rise to glands such as the thymus and parathyroid, and contain the major arteries that transport blood away from the heart (the aorta, ductus arteriosus, carotid, and subclavian arteries). Tbx1 is not expressed in the neural crest, but it is expressed in the non-neural crest-derived mesenchyme, as well as in mesoderm, endoderm, and ectoderm. Transgenic mouse models have been created that can selectively delete Tbx1 from specific tissues during development. Such studies have shown that the Tbx1 transcription factor regulates the cardiac progenitor cells of the second heart field that contribute to the heart outflow tract. Studies have also shown that Tbx1 expression within the mesoderm, and/or endoderm and ecto derm, is vital for correct aortic arch artery development. The highly variable phenotype seen in DiGeorge syndrome is thought to be due to genetic modifiers in the genome. Indeed, several genes outside of the DiGeorge syndrome critical region on chromosome 22q11.2 have been implicated
321
in modulating the severity and penetrance of the phenotype in transgenic mice, for example, Vegf, Shh, Chordin, Raldh2, Tgfβ, and Fgf8. Tbx1 has also been shown to genetically interact with Fgf8, a growth factor important for embryonic development.
See also: Chromosome; Cleft Lip and Cleft Palate.
Further Reading Burn J and Goodship J (2007) Congenital heart disease. In: Rimoin DL, Connor JM, Pyeritz RE, and Korf BR (eds.) Principles and Practice of Medical Genetics. 5th edn., vol. 2., pp. 1083–1159. Philadelphia, PA: Elsevier. Momma K (2010) Cardiovascular anomalies associated with chromosome 22q11.2 deletion syndrome. American Journal of Cardiology 105: 1617–1624. Murphy KC and Scambler PJ (eds.) (2005) Velo-Cardio-Facial Syndrome. A Model for Understanding Microdeletion Disorders. Cambridge, UK: Cambridge University Press. Ryan AK, Goodship JA, Wilson DI, et al. (1997) Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: A European collaborative study. Journal of Medical Genetics 34: 798–804. Scambler PJ (2010) 22q11 deletion syndrome: A role for TBX1 in pharyngeal and cardiovascular development. Pediatric Cardiology 31: 378–390. Shprintzen RJ (2008) Velo-cardio-facial syndrome: 30 years of study. Developmental Disabilities Research Reviews 14: 3–10. Wurdak H, Ittner LM, and Sommer L (2006) DiGeorge syndrome and pharyngeal apparatus development. BioEssays 28: 1078–1086. Zhang Z and Baldini A (2007) In vivo response to high-resolution variation of Tbx1 mRNA dosage. Human Molecular Genetics 17: 150–157.
Relevant Websites http://www.maxappeal.org.uk – A website run by parents of children with DiGeorge syndrome. http://www.22q.org – The international 22q11.2 deletion syndrome foundation. http://www.vcfsef.org – The velo-cardio-facial syndrome education foundation.