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velocardiofacial syndrome
Ltimmune cytopenias in two patients with
/velocardiofacial syndrome ~lO, Eli./14. Laurie, AID,Brian W. Berman, AID,Nathaniel H. Robin, MD, Arthur B. Zinn, MD, PbD, and Robert W. Hostoffer, DO
We describe two patients with clinical and cytogenetic findings consistent with DiGeorge/vetoeardiofaeiat syndrome who had recurrent cytopenias at presentation. Our observations suggest that recurrent eytopenias may be part of the clinical spectrum of deletion 22q11.2. We also suggest that the diagnosis of DG/VCF syndrome be considered in patients with unexplained recurrent immune cytopenias in association with cardiac lesions, subtle craniofacial dysmorphisms, and/or learning or behavioral impairments. (d Pediatr 1997; 131:484-6)
Monosomie deletion of chromosomal segment 22ql 1.2 is associated with a broad clinical spectrum, which includes DiGeorge syndrome, velocardiofacial syndrome, and isolated conotruneal heart defect.l-3 Patients with DG syndrome have aortic root defects, craniofacial dysmorphisms, hypoca]cemia, and T-cell deficiencies. 4 VCF syndrome includes cleft palate, conotruncal heart malformations, variable facial dysmorphisms, and learning disabilities, a We here report the first description of VCF syndrome associated with recurrent immune cympenias. We suggest that these autoimmune occurrences may be part of the spectrum of DG/VCF syndromes and that the diagnosis of DG/VCF syndrome be entertained in patients with unexplained recurrent immune cytopenias. From Lhe Department of Pediatrics, Rainbo~ Babies and Childreas Hospital, Cleveland, Ohio, and the Centerfor Human Genetics, Department of Genetics, Case Western Reserve University and University Hospitals of Cleveland, Clevelang Ohio.
Submitted for publication Aug. 28, 1996;accepted Nov. 18, 1996. Reprint requests: Robert W. Hostoffer, DO, Rainbow Babies and Childrens Hospital, Department of Pediatrics, 11100 Euclid Ave., Cleveland, OH 44106-5000. Copyright9 1997by Mosby-YearBook,Inc. 0022-3476/97/$5.00 + 0 9/22/79374
484
mia (positive result on antiglobulin [Coombs] test). Variable but generally well compensated hemolysis, immune thrombocytopenia, and neutropenla have persisted since then, with severe, acute ex-
CASE REPORT Patient 1 is a 15-year-old boy with cleft palate, sensorineural deafness, scoliosis, recurrent otitis media, splenomegaly, and learning disabilities. The family history is unremarkable; however, the father was not available for interview or examination. The patient was initially seen at age 4 years with autoimmune hemolytic aneTable L
Immunologic profiles
aeerbations of hemolysis (positive result on antiglobu]in test) noted at age 10 and 12 years and one episode of severe pancytopenia occurring at 15 years of age. IT was clinically determined in this patient by low numbers of large platelets, adequate bone marrow megakaryocytes, and a positive response to intravenously administered IgG with prednisone. The pa-
THE JOURNAL OF PEDIATRICS
DEPIERO ET AL.
Volume 131, Number 3 tient's immunologic profiles are noted in Table I. Mitogen and antigen stimulation studies showed a decreased proliferativ response (Table II). The patient's a ~ pearance and c]inical presentation were similar to those of other patients with VCF (Figure, A and B). Chromosome analysis was performed, and the patient was shown to have a deletion at 22ql 1.2, detected by fluorescent in situ hybridization using a probe (D22S75) specific for that region (the DiGeorge critical region). Patient 2 is a 1S-year-old girl with repaired tetralogy of Fallot, vitiligo, and submucosal cleft palate (Figure, C and D). A paternal grandmother had recurrent episodes of hemoly6c anemia. The patient was first seen at 10 years of age with two episodes of IT, with recurrence at age 15 years. IT was diagnosed by criteria similar to those used for patient 1. A bout of A I H A (positive result on antiglobulin test) occurred a* age 11 years. The patient's immunologic profile is noted in Table I. Results of lymphocyte studies performed at age 13 years were normal, but studies performed at age 11 years showed decreased T-cell numbers. The patient was lost to follow-up; hence mitogen and antigen proliferation studies were not performed. The clinical findings suggested DG/VCF syndrome and prompted chromosomal studies, which showed deletion 22ql 1.2.
DISCUSSION
A
C
D
Figure.
Front and lateral facial photographs of patients with recurrent c~openias and microdeletion of 22q I 1.2.A and B, Patient I. Note the classicfacial findings of velocardiofacial syndrome, including the elongated face, squared-off nasal root, bulbous nasaltip, malar underdevelopment, and mildly sinai/ mandible. C and D, Patient 2.Though the facial characteristicsoFVCF syndrome are more subtle, malar flattening, squared-off nasal root, bulbous nasaltip, and small jaw are evident.
Ta~/~ H. Mitogen and antigen stimulation studies of patient I
In 1965, DiGeorge 5 described the association of recurrent infection, absent thymus, and hypoparathyroidism. It was later shown that some of these were also associated with a cellular immunodeficiency, congenital heart disease, and abnormal facies, a'6-8 NIost cases of D G syndrome have been associated with a microdeletion of chromosome 22ql 1.2, although recently a new gene locus involving a deletion of chromosome 10p has been found in some patients with D G N C E 1'9 These deletions have also been found in patients with a broader spectrum of clinical phenotypes, including
485
DEPIERO ETAL.
VCF syndrome and isolated eonotruncal heart defects. 2'9'10 The clinical spectrum has been referred to as the DG/VCF syndrome. The T-cell defect found in patients with D G syndrome is the result of a small or absent thymus gland. 11 There has been speculation that this T-cell deficiency may predispose the patient to immunodysregulation, in which case autoimmune phenomena may occur. 12 In fact, Graves disease has been observed in long-term surviving patients with D G / V C F syndrome. I3 Shetty et al.14 reported in abstract form a patient with "partial" D G syndrome who had IT in infancy, followed by A I H A at 7 years of age. Pinchas-Hamel et al. is described a 5year-old patient with D G syndrome who had multiple episodes of A I H A and IT. This patient also had an undefined chronic, persistent hepatitis. Chromosomal analysis for the 22q11.2 deletion was not performed in either patient. The two patients we describe have subtle clinical findings consistent with DG/VCF syndrome and the characteristic microdeletion of chromosome 22ql 1.2. They also demonstrate a propensity for autoimmunity and thus have the first reported cases of V C F syndrome with recurrent cytopenias and with documented microdeletions of chromosome 22ql 1.2. O u r observations and those individual cases reported in the literature suggest that recurrent immune cytopenias may be part of the clinical spectrum associated with D G / V C F syndrome.
486
THE JOURNAL OF PEDIATmCS SEP-rENBER 1997 Because of the subtle clinical features of our patients, it took several years to establish the correct diagnosis. We recommend that the diagnosis of D G / V C F syndrome be considered in patients with unexplained recurrent immune eytopenias, particularly in association with aortic root or conotruneal cardiac lesions, subtle craniofacial dysmorphism, and/or learning or behavioral impairments. High-resolution karyotype performed in combination with fluorescent in Situ hybridization for chromosomal segment 22qI 1.2 is the most expeditious way of establishing this diagnosis.
REFERENCES 1. Driscoll D, Budarf M, Emanuel B. A genetic etiologyfor DiGeorge syndrome: consistent deletions and microdeletions of 22ql 1. Am J Hum Genet 1992;50:924-33. 2. Driscoll D, Spinner N, Budarf L, McDonald-McGinn DM, Zackai EH, Goldberg RB, et al. Deletions and microdelefionsof 22ql 1.2 in velo-cardio-facial syndi'ome.Am J Hum Genet 1992;44:261-8. 3. Goldgerg R, Motzkin B, Marion R, Scambler PJ, Shprintzen RJ. Velo-cardiofacial syndrome: a review of 120 patients. Am J Hum Genet 1993;45:313-9. 4. Barrett D, Ammann A, Wara D, Cowan T, Stiem R. Clinical and immunologic spectrum of the DiGeorge syndrome. J Ctin Lab ImmunoI 1981;6:1-6. 5. DiGeorge A. A new concept of the cellular basis of immunity [discussion]. J Pediatr
1965;67:907-8. 6. Lischner H, DiGeorge A. Role of the thymus in humoral immunity: observations in
7.
8.
9.
10.
11.
12.
13.
14.
15.
complete or partial congenital absence of the thymus. Lancet 1969;2:1044-9. Bastian J, Law S, Vogler L, Lawton A, Herrod H, Anderson S, et al. Prediction of persistent immunodeficiency in the DiGeorge anomaly. J Pediatr 1989;115: 391-6. Kretschmer R, Say B, Brown D, Rosen F. Congenital aptasia of the thymus gland (DiGeorge's syndrome). N EngI J Med 1968;279:1295-301. Daw SCM, Taylor C, Kraman M, Call K, Moo J, Schuffenhauer S, et al. A common region of 10p deleted in DiGeorge and velocardiofacial syndromes. Nat Genet 1996;15:458-60. W'dson D, Goodship J, Burn J, Cross I, Scambler R Deletions within chromosome 22ql 1 in s congenital heart disease. Lancet 1992;340:573-5. Borzy M, Schulte-Wissermann H, Gilbert E, Horowitz S, Pellett J, Hong R. Thymic morphology in immunodeficiencydiseases: results of thymic biopsies. Clin Immunol Immunopathol 1979;12:31-51. Etzioni A, Pollack S. Autoimmune phenomena in DiGeorge syndrome [letter; comment]. Isr J Med Sci 1994;30:853. Ham Pong A, Cavallo A, Holman G, Goldman A. DiGeorge syndrome: longterm survival complicated by Graves' disease. J Pediatr 1985;106:61%20. Shetty R, Nelson R, Good R. Associationof immune thrombocytopenia and autoimmune hemolytic anemia in DiGeorge syndrome [abstract]. Pediatr Res 1990;27: 162A. Pinehas-Hamel O, Mandel M, Engelberg S, Passwell JH. Immune hemolyticanemia, thrombocytopenia and liver disease in a patient with DiGeorge syndrome. Isr J Med Sci 1994;30:530-2.
/velocardiofacial syndrome ~lO, Eli./14. Laurie, AID,Brian W. Berman, AID,Nathaniel H. Robin, MD, Arthur B. Zinn, MD, PbD, and Robert W. Hostoffer, DO
We describe two patients with clinical and cytogenetic findings consistent with DiGeorge/vetoeardiofaeiat syndrome who had recurrent cytopenias at presentation. Our observations suggest that recurrent eytopenias may be part of the clinical spectrum of deletion 22q11.2. We also suggest that the diagnosis of DG/VCF syndrome be considered in patients with unexplained recurrent immune cytopenias in association with cardiac lesions, subtle craniofacial dysmorphisms, and/or learning or behavioral impairments. (d Pediatr 1997; 131:484-6)
Monosomie deletion of chromosomal segment 22ql 1.2 is associated with a broad clinical spectrum, which includes DiGeorge syndrome, velocardiofacial syndrome, and isolated conotruneal heart defect.l-3 Patients with DG syndrome have aortic root defects, craniofacial dysmorphisms, hypoca]cemia, and T-cell deficiencies. 4 VCF syndrome includes cleft palate, conotruncal heart malformations, variable facial dysmorphisms, and learning disabilities, a We here report the first description of VCF syndrome associated with recurrent immune cympenias. We suggest that these autoimmune occurrences may be part of the spectrum of DG/VCF syndromes and that the diagnosis of DG/VCF syndrome be entertained in patients with unexplained recurrent immune cytopenias. From Lhe Department of Pediatrics, Rainbo~ Babies and Childreas Hospital, Cleveland, Ohio, and the Centerfor Human Genetics, Department of Genetics, Case Western Reserve University and University Hospitals of Cleveland, Clevelang Ohio.
Submitted for publication Aug. 28, 1996;accepted Nov. 18, 1996. Reprint requests: Robert W. Hostoffer, DO, Rainbow Babies and Childrens Hospital, Department of Pediatrics, 11100 Euclid Ave., Cleveland, OH 44106-5000. Copyright9 1997by Mosby-YearBook,Inc. 0022-3476/97/$5.00 + 0 9/22/79374
484
mia (positive result on antiglobulin [Coombs] test). Variable but generally well compensated hemolysis, immune thrombocytopenia, and neutropenla have persisted since then, with severe, acute ex-
CASE REPORT Patient 1 is a 15-year-old boy with cleft palate, sensorineural deafness, scoliosis, recurrent otitis media, splenomegaly, and learning disabilities. The family history is unremarkable; however, the father was not available for interview or examination. The patient was initially seen at age 4 years with autoimmune hemolytic aneTable L
Immunologic profiles
aeerbations of hemolysis (positive result on antiglobu]in test) noted at age 10 and 12 years and one episode of severe pancytopenia occurring at 15 years of age. IT was clinically determined in this patient by low numbers of large platelets, adequate bone marrow megakaryocytes, and a positive response to intravenously administered IgG with prednisone. The pa-
THE JOURNAL OF PEDIATRICS
DEPIERO ET AL.
Volume 131, Number 3 tient's immunologic profiles are noted in Table I. Mitogen and antigen stimulation studies showed a decreased proliferativ response (Table II). The patient's a ~ pearance and c]inical presentation were similar to those of other patients with VCF (Figure, A and B). Chromosome analysis was performed, and the patient was shown to have a deletion at 22ql 1.2, detected by fluorescent in situ hybridization using a probe (D22S75) specific for that region (the DiGeorge critical region). Patient 2 is a 1S-year-old girl with repaired tetralogy of Fallot, vitiligo, and submucosal cleft palate (Figure, C and D). A paternal grandmother had recurrent episodes of hemoly6c anemia. The patient was first seen at 10 years of age with two episodes of IT, with recurrence at age 15 years. IT was diagnosed by criteria similar to those used for patient 1. A bout of A I H A (positive result on antiglobulin test) occurred a* age 11 years. The patient's immunologic profile is noted in Table I. Results of lymphocyte studies performed at age 13 years were normal, but studies performed at age 11 years showed decreased T-cell numbers. The patient was lost to follow-up; hence mitogen and antigen proliferation studies were not performed. The clinical findings suggested DG/VCF syndrome and prompted chromosomal studies, which showed deletion 22ql 1.2.
DISCUSSION
A
C
D
Figure.
Front and lateral facial photographs of patients with recurrent c~openias and microdeletion of 22q I 1.2.A and B, Patient I. Note the classicfacial findings of velocardiofacial syndrome, including the elongated face, squared-off nasal root, bulbous nasaltip, malar underdevelopment, and mildly sinai/ mandible. C and D, Patient 2.Though the facial characteristicsoFVCF syndrome are more subtle, malar flattening, squared-off nasal root, bulbous nasaltip, and small jaw are evident.
Ta~/~ H. Mitogen and antigen stimulation studies of patient I
In 1965, DiGeorge 5 described the association of recurrent infection, absent thymus, and hypoparathyroidism. It was later shown that some of these were also associated with a cellular immunodeficiency, congenital heart disease, and abnormal facies, a'6-8 NIost cases of D G syndrome have been associated with a microdeletion of chromosome 22ql 1.2, although recently a new gene locus involving a deletion of chromosome 10p has been found in some patients with D G N C E 1'9 These deletions have also been found in patients with a broader spectrum of clinical phenotypes, including
485
DEPIERO ETAL.
VCF syndrome and isolated eonotruncal heart defects. 2'9'10 The clinical spectrum has been referred to as the DG/VCF syndrome. The T-cell defect found in patients with D G syndrome is the result of a small or absent thymus gland. 11 There has been speculation that this T-cell deficiency may predispose the patient to immunodysregulation, in which case autoimmune phenomena may occur. 12 In fact, Graves disease has been observed in long-term surviving patients with D G / V C F syndrome. I3 Shetty et al.14 reported in abstract form a patient with "partial" D G syndrome who had IT in infancy, followed by A I H A at 7 years of age. Pinchas-Hamel et al. is described a 5year-old patient with D G syndrome who had multiple episodes of A I H A and IT. This patient also had an undefined chronic, persistent hepatitis. Chromosomal analysis for the 22q11.2 deletion was not performed in either patient. The two patients we describe have subtle clinical findings consistent with DG/VCF syndrome and the characteristic microdeletion of chromosome 22ql 1.2. They also demonstrate a propensity for autoimmunity and thus have the first reported cases of V C F syndrome with recurrent cytopenias and with documented microdeletions of chromosome 22ql 1.2. O u r observations and those individual cases reported in the literature suggest that recurrent immune cytopenias may be part of the clinical spectrum associated with D G / V C F syndrome.
486
THE JOURNAL OF PEDIATmCS SEP-rENBER 1997 Because of the subtle clinical features of our patients, it took several years to establish the correct diagnosis. We recommend that the diagnosis of D G / V C F syndrome be considered in patients with unexplained recurrent immune eytopenias, particularly in association with aortic root or conotruneal cardiac lesions, subtle craniofacial dysmorphism, and/or learning or behavioral impairments. High-resolution karyotype performed in combination with fluorescent in Situ hybridization for chromosomal segment 22qI 1.2 is the most expeditious way of establishing this diagnosis.
REFERENCES 1. Driscoll D, Budarf M, Emanuel B. A genetic etiologyfor DiGeorge syndrome: consistent deletions and microdeletions of 22ql 1. Am J Hum Genet 1992;50:924-33. 2. Driscoll D, Spinner N, Budarf L, McDonald-McGinn DM, Zackai EH, Goldberg RB, et al. Deletions and microdelefionsof 22ql 1.2 in velo-cardio-facial syndi'ome.Am J Hum Genet 1992;44:261-8. 3. Goldgerg R, Motzkin B, Marion R, Scambler PJ, Shprintzen RJ. Velo-cardiofacial syndrome: a review of 120 patients. Am J Hum Genet 1993;45:313-9. 4. Barrett D, Ammann A, Wara D, Cowan T, Stiem R. Clinical and immunologic spectrum of the DiGeorge syndrome. J Ctin Lab ImmunoI 1981;6:1-6. 5. DiGeorge A. A new concept of the cellular basis of immunity [discussion]. J Pediatr
1965;67:907-8. 6. Lischner H, DiGeorge A. Role of the thymus in humoral immunity: observations in
7.
8.
9.
10.
11.
12.
13.
14.
15.
complete or partial congenital absence of the thymus. Lancet 1969;2:1044-9. Bastian J, Law S, Vogler L, Lawton A, Herrod H, Anderson S, et al. Prediction of persistent immunodeficiency in the DiGeorge anomaly. J Pediatr 1989;115: 391-6. Kretschmer R, Say B, Brown D, Rosen F. Congenital aptasia of the thymus gland (DiGeorge's syndrome). N EngI J Med 1968;279:1295-301. Daw SCM, Taylor C, Kraman M, Call K, Moo J, Schuffenhauer S, et al. A common region of 10p deleted in DiGeorge and velocardiofacial syndromes. Nat Genet 1996;15:458-60. W'dson D, Goodship J, Burn J, Cross I, Scambler R Deletions within chromosome 22ql 1 in s congenital heart disease. Lancet 1992;340:573-5. Borzy M, Schulte-Wissermann H, Gilbert E, Horowitz S, Pellett J, Hong R. Thymic morphology in immunodeficiencydiseases: results of thymic biopsies. Clin Immunol Immunopathol 1979;12:31-51. Etzioni A, Pollack S. Autoimmune phenomena in DiGeorge syndrome [letter; comment]. Isr J Med Sci 1994;30:853. Ham Pong A, Cavallo A, Holman G, Goldman A. DiGeorge syndrome: longterm survival complicated by Graves' disease. J Pediatr 1985;106:61%20. Shetty R, Nelson R, Good R. Associationof immune thrombocytopenia and autoimmune hemolytic anemia in DiGeorge syndrome [abstract]. Pediatr Res 1990;27: 162A. Pinehas-Hamel O, Mandel M, Engelberg S, Passwell JH. Immune hemolyticanemia, thrombocytopenia and liver disease in a patient with DiGeorge syndrome. Isr J Med Sci 1994;30:530-2.