573
Deletions within chromosome 22q11 in familial congenital heart disease
Because a locus on chromosome 22q1 1 is deleted in most individuals with DiGeorge and Shprintzen syndromes—conditions in which heart abnormalities are an important feature—we have looked for deletions in nine families with recurrent outflow-tract heart defects. In five families, chromosome 22 deletions were detected in all the living affected individuals studied and also in the clinically normal father of three affected children. The deletion was transmitted from parents to offspring and was associated with an increase in the severity of cardiac defects. No deletions were found in four families in which the parents were normal and affected siblings had anatomically identical defects. We propose that deletions within band q1 1 of chromosome 22 are an important cause of familial heart defects. Lancet 1992; 340: 573-75.
Introduction
People with congenital heart disease now often live to adulthood and have children of their own. The risk that their offspring will have heart disease is between 3 and 16% depending on the type of lesion and, possibly, parental origin.l-4 It is not possible to identify before the event those patients who have a high risk of disease unless they have additional features that lead to a syndrome diagnosis. Chromosome 22 deletions are found in most individuals with DiGeorge syndrome and Shprintzen syndrome,5-7 conditions in which heart malformations are an important feature. DiGeorge syndrome consists of outflow-tract defects of the heart, thymic hypoplasia or aplasia, hypoparathyroidism, and a dysmorphic appearance.8 Shprintzen syndrome consists of overt or submucous clefts of the palate, hypemasal speech secondary to facial dysmorphic velopharyngeal incompetence, appearance, and congenital heart disease.9 We have documented one family, 10 ascertained through our study of DiGeorge syndrome, in which an interstitial deletion within chromosome 22q11was found in a sibling with isolated coarctation of the aorta and in a sibling with a ventricular septal defect (VSD). This fmding prompted us to investigate chromosome 22ql1 in families with recurrence of congenital heart disease.
Subjects and
methods
Families were found by inviting members of the British Paediatric Association, paediatric cardiologists, and clinical geneticists to refer families with more than one member affected by a cardiac defect. Every affected family member had been
arteriosus, hypocalcaemia shortly after birth, and died aged 5 weeks. Her second child had pulmonary atresia and a VSD. The mother of family 3 had a heart defect detected as a young child and she had follow-up until the age of 15 years; however, her childhood medical records have been destroyed. Clinical examination and echocardiography at 45 years old were normal. Her second child had pulmonary atresia and a VSD. In family 4, the father had a right aortic arch, a small VSD, and an anomalous left subclavian artery. His first child was a girl with dextrocardia, an absent pulmonary valve, and a VSD, who died aged 11 days. His second child was a girl who had tetralogy of Fallot and died aged 2-5 years, his third child was normal, and his fourth also had tetralogy of Fallot. The parents of family 5 were both well. Their first and third children were normal but their second, a boy, had a patent arterial duct and slight developmental delay. He had symptomless hypocalcaemia shortly after birth, although serum calcium was normal by 1 year of age. The fourth child had an interrupted aortic arch, a VSD, and a right subclavian artery arising from the right pulmonary artery. She died at 2 days of age and necropsy revealed thymus aplasia. The fifth child had tetralogy of Fallot. In the remaining four families, the parents were normal but siblings in every family had anatomically identical cardiac lesions: double-outlet right ventricle in family 6, pulmonary atresia/VSD in family 7, pulmonary atresia and intact ventricular septum in family 8, and tetralogy of Fallot (identical twins) in family 9. Blood samples were obtained from surviving members of the families for high-resolution chromosome analysis and DNA analysis. Chromosome analysis was done on metaphase preparations with more than 850 bands per haploid set.11 This analysis was not done in family 4. DNA and densitometric analyses were done as described previously." Filters were prepared by Southern blotting and hybridised with the DNA probe HP500 and a rhodopsin gene control probe (RHO). HP500 is a subclone of KI-182 (D22S134) and is deleted in most children with DiGeorge syndrome.s The DNA analysis of every family was done in triplicate. Autoradiographs were analysed with a densitometer. truncus
Results In family 1, chromosome analysis of the mother was normal (46,XX) but did not achieve a resolution of greater than 850 bands per haploid set despite repeat sampling, and thus a microdeletion could not be excluded. High-resolution analysis was achieved in her son with pulmonary atresia/VSD and an interstitial deletion from chromosome 22 was detected [46,XY,del(22)(qll.21qll.23)]. Chromosome analyses of the other families (except family 4) revealed apparently normal karyotypes ( > 850 bands). DNA analysis by Southern blotting demonstrated a deletion from within 22q11 in every surviving affected member of families 1,2,3, and 4 (fig 2). A submicroscopic deletion was also detected in the unaffected father of family 5 and in his child with a patent arterial duct and neonatal hypocalcaemia; DNA analysis of the youngest child in this family, who has tetralogy of Fallot, has not yet been done. No deletions were found by DNA analysis of families 6, 7, 8, and 9.
investigated by echocardiography with
or without cardiac catheterisation. Nine families were identified and the pedigrees of five are shown in fig 1. In family 1, the mother had tetralogy of Fallot. Her first child was normal but her second had pulmonary atresia and a VSD. The mother of family 2 had a right aortic arch and had had a patent arterial duct that was ligated at the age of 4 years. Her first child had
ADDRESSES: Division of Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne NE24AA, UK (D. I. Wilson, MRCP, J. A Goodship, MD, Prof J. Burn, MD, I E Cross, BSc); and Department of Biochemistry and Molecular Genetics, St Mary’s Hospital Medical School, London (P. J. Scambler, MD)
Correspondence to
Dr D. I. Wilson
574
Fig 1-Pedigree of five families with familial cardiac defects. VSD=ventricular septal defect, PDA=patent arterial duct, !AA= interrupted aortic arch, RAA=right aortic arch, AnRSA=anomalous nght subclavian artery, AnLSA=anomalous left subclavian artery, AbPV=absent pulmonary value, Dextroc=dextrocardia. =affected male, 0 unaffected female,Ø deceased female. =
=
Furthermore, in every family the parents tend to have mild
Discussion Chromosome 22 deletions were detected in five of the nine families investigated because of recurrent heart defects. In four of the five families in which a deletion was found, one of the parents had a cardiac abnormality, but in the fifth family both parents were clinically normal. Three of five offspring in this family had a congenital heart defect with two offspring having additional features of DiGeorge syndrome. A chromosome 22 deletion was identified in the three affected children in family 5 and in their apparently normal father. This family is similar to one we reported previously,10 in which a chromosome 22 deletion was found in the apparently normal mother of a child with DiGeorge syndrome and in two children with isolated congenital heart defects. In every one of these families with a deletion there is phenotypic variation in the cardiac defect within the family. 1 2
3
31’g
5µg 7µg 9µg 44
5
6
Fig 2-Autoradiograph of a Southern blot from the DNA analysis of families 2 and 3. The 4 middle lanes are controls.and loaded with 3 I-1g, 5 µg, 7 µg, and 9 µg of DNA from normal individuals DNA from the affected mother, affected daughter, unaffected father, and unaffected maternal grandmother from family 2 are in lanes 1, 2, 3, and 4, respectively. DNA from the mother and affected daughter of family 3 are in lanes 5 and 6, respectively Intensity of the 3.5kb band detected by H P500 in lanes 1, 2, 5, and 6 is reduced compared with matched control lanes-ie, a control lane with equal intensity of the 72 kb control band RHO; analysis by densitometer shows that intensity is reduced by 50%.
defects
compared with those of their children. This finding alternatively, to mutations changing when transmitted from one generation to the next, which can lead to an extremely variable phenotype. The latter possibility is not unreasonable in the light of recent developments in understanding of the fragile X and myotonic dystrophy loci.12 No deletions were may be due to ascertainment bias or,
identified in four families. In these families the parents were normal and sibling pairs had identical heart defects. We cannot exclude the possibility that these four families have a stable mutation within the same gene that is deleted in the other families. The cardiac defects found in DiGeorge syndrome include interrupted aortic arch, truncus arteriosus, tetralogy of Fallot, and right-sided aortic arch. It is of note that of the three families in which the structural abnormality in the parent was known, two had right-sided aortic arch in association with other abnormalities and one had tetralogy of Fallot. Offspring studies have nearly all been done with survivors of cardiac surgery. No figures are available for risk of heart disease in offspring of individuals with right-sided aortic arch because this abnormality is not an indication for surgery. The risk of congential heart disease in offspring of patients with corrected tetralogy of Fallot is about 3%." Since one chromosome from each pair is transmitted from parent to offspring, there is a one in two chance of a chromosome deletion being passed on to offspring. Thus, if chromosome 22 deletions were to account for all cases of congenital heart disease in offspring of individuals with tetralogy of Fallot, about 6% of individuals with the disorder would be expected to have this deletion. We have done a preliminary prospective study of 40 individuals with tetralogy of Fallot and 40 clinically normal individuals, and found submicroscopic chromosome 22qll deletions in 2 (5%) of the Fallot’s group14 and none of the normal group (unpublished observations). This result is consistent with
575
the view that interstitial deletions of chromosome 22 account for most cases of congenital heart disease in the offspring of patients with tetralogy of Fallot. We have reported a wide spectrum of defects associated with chromosome 22q111 deletions and it is possible that such deletions also account for a proportion of affected offspring from parents with heart defects other than tetralogy of Fallot. Nasal speech due to velopharyngeal insufficiency is very characteristic and its presence in a patient with congenital heart disease makes the diagnosis of Shprintzen syndrome likely, thus allowing clinical identification of some patients at high risk of having offspring with congenital heart disease. Dysmorphic features are less useful in identifying at-risk patients. No individual in the five families with chromosome 22 deletions was identified as being dysmorphic by referring cardiologists, although, in retrospect, several did have subtle dysmorphic features. The fact that these features were not noted before genetic investigation shows that they are not useful in helping to identify the subgroup of patients in a routine cardiology clinic that are at high risk. The results reported here confirm our earlier finding that deletions within chromosome 22q11can cause isolated congenital heart disease and that the spectrum of cardiac abnormalities is wide, including interrupted aortic arch,
tetralogy of Fallot, truncus arteriosus, VSD, patent arterial duct, right aortic arch, and aberrant right subclavian artery. Rapid, reliable methods of screening for this deletion are clearly necessary to identify the subgroup of patients who have a 50% risk of affected offspring. We thank Dr H. H. Bain, Dr E. M. Thompson, Dr B. C. Davison, Dr P. Jardine, Dr J. Patterson, Dr J. M. Bridson, and Dr D. M. Cook for referring
affected families. We also thank all the families involved in this study for their help and cooperation, Mrs M. Van Altaan, Dr J. O’Sullivan, Dr E. A. Shineboume, Dr L. Allan, Dr D. F. Dickinson, Dr R. A. Emmott, Dr S. M. Amin, and Dr Meakin for their help, and Dr J. Nathans who kindly provided the rhodopsin probe used as the control. D. 1. W. is supported by the British Heart Foundation and Borwick Trust, and P. J. S. by the British Heart Foundation, Action Research, the Dunhill Medical Research Trust, and the Medical Research Council.
REFERENCES 1. Whittemore R, Hobbins EJ, Engle MA. Pregnancy and its outcome in women with and without surgical treatment of congenital heart disease. Am J Cardiol 1982; 50: 641-57. 2. Czeizel A, Porno A, Peterffy E, Tarcal E. Studies of children of parents operated on for congenital cardio-vascular malformations. Br Heart J 1982; 47: 290-94. 3. Dennis NR, Warren J. Risks to the offspring of patients with some common congenital heart defects. J Med Genet 1981; 18: 8-16. 4. Zellers TM, Driscoll DJ, Michels VV. Prevalence of significant congenital heart defects in children of parents with Fallot’s tetralogy. Am J Cardiol 1990; 65: 523-26. 5. Carey AH, Kelly D, Halford S, et al. Molecular genetic study of the frequency of monosomy 22q1 1 in DiGeorge syndrome. Am J Hum
Genet (in press). 6. Scambler PJ, Kelly D, Lindsay E, et al. Velo-cardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus. Lancet 1992; 339: 1138-39. 7. Dnscoll AD, Budarf ML, Emanuel BS. A genetic etiology for DiGeorge syndrome: consistent deletions and microdeletions of 22q11. Am J Hum Genet 1992; 50: 924-33. 8. Conley ME, Beckwith JB, Mancer JFK, Tenckhoff L. The spectrum of the DiGeorge syndrome. J Pediatr 1979; 94: 883-90. 9. Lipson AH, Yuille D, Angel M, Thompson PG, Vandervoord JG, Beckenham EJ. Velocardiofacial (Shprintzen) syndrome: an important syndrome for the dysmorphologist to recognise. J Med Genet 1991; 28: 596-604. 10 Wilson DI, Cross IE, Goodship JA, et al. DiGeorge syndrome with isolated aortic coarctation and isolated ventricular septal defect in three sibs with a 22q11 deletion of maternal origin. Br Heart J 1991; 66: 308-12.
on Human Cytogenetic Nomenclature. An international system for human cytogenetic nomenclature (1985). Basel: S. Karger, 1985. 12. Sutherland GR, Haan EA, Kremer E, et al. Hereditary unstable DNA: a new explanation for some old genetic questions? Lancet 1991; 338: 289-92. 13. Burn J, Coffey R, Little J, et al. Recurrence risks in the offspring of adults born with major heart defects; first results of a British collaborative study. Am J Hum Genet 1990; 47: A121. 14. Wilson DI, Scambler PJ, Goodship JA, Burn J. Deletion within chromosome 22q11 is a major cause of isolated heart defects and most causes of DiGeorge and velocardiofacial syndromes (abstr P16). Proceedings of the British Paediatric Association Meeting; 1992 April 7-10; Warwick, UK.
11.
Standing Committee
SHORT REPORTS Splenic lymphoma with villous lymphocytes in tropical West Africa
Splenic lymphoma with villous lymphocytes (SLVL) is a monoclonal B-lymphoproliferative disorder characterised by splenomegaly and distinctive villous lymphocytes in the peripheral blood. It has not previously been reported from Africa, but we describe ten Ghanaian patients with SLVL seen at one hospital during a 4-year period. The clinical presentation is similar in Africa and in temperate regions, though the lymphocyte count is higher in African patients and the disorder predominantly affects middle-aged women rather than elderly men. It is likely that SLVL has previously been classified as splenic chronic lymphocytic leukaemia or hyper-reactive malarial splenomegaly.
In temperate areas, splenic lymphoma with villous lymphocytes (SLVL) is predominantly a disease of elderly men, which presents as splenomegaly, tiredness, and malaise. Paraproteins are found in serum or urine in more than 50% of patients. SLVL can be diagnosed in patients with peripheral-blood lymphocyte counts above 10 x 109/1 when at least 30% of these cells have a characteristic villous appearance.! The cytoplasm of villous lymphocytes is basophilic and there are characteristic short cytoplasmic villi unevenly distributed at one or both poles of the celU The cellular phenotype differs from that in hairy-cell leukaemia; CD25, CD lie, and tartrate-resistant acid-phosphatase markers are usually lacking. If the membrane markers are suggestive, SLVL may be diagnosed in patients with lymphocyte counts below 10 x 109/1.
Deletions within chromosome 22q11 in familial congenital heart disease
Because a locus on chromosome 22q1 1 is deleted in most individuals with DiGeorge and Shprintzen syndromes—conditions in which heart abnormalities are an important feature—we have looked for deletions in nine families with recurrent outflow-tract heart defects. In five families, chromosome 22 deletions were detected in all the living affected individuals studied and also in the clinically normal father of three affected children. The deletion was transmitted from parents to offspring and was associated with an increase in the severity of cardiac defects. No deletions were found in four families in which the parents were normal and affected siblings had anatomically identical defects. We propose that deletions within band q1 1 of chromosome 22 are an important cause of familial heart defects. Lancet 1992; 340: 573-75.
Introduction
People with congenital heart disease now often live to adulthood and have children of their own. The risk that their offspring will have heart disease is between 3 and 16% depending on the type of lesion and, possibly, parental origin.l-4 It is not possible to identify before the event those patients who have a high risk of disease unless they have additional features that lead to a syndrome diagnosis. Chromosome 22 deletions are found in most individuals with DiGeorge syndrome and Shprintzen syndrome,5-7 conditions in which heart malformations are an important feature. DiGeorge syndrome consists of outflow-tract defects of the heart, thymic hypoplasia or aplasia, hypoparathyroidism, and a dysmorphic appearance.8 Shprintzen syndrome consists of overt or submucous clefts of the palate, hypemasal speech secondary to facial dysmorphic velopharyngeal incompetence, appearance, and congenital heart disease.9 We have documented one family, 10 ascertained through our study of DiGeorge syndrome, in which an interstitial deletion within chromosome 22q11was found in a sibling with isolated coarctation of the aorta and in a sibling with a ventricular septal defect (VSD). This fmding prompted us to investigate chromosome 22ql1 in families with recurrence of congenital heart disease.
Subjects and
methods
Families were found by inviting members of the British Paediatric Association, paediatric cardiologists, and clinical geneticists to refer families with more than one member affected by a cardiac defect. Every affected family member had been
arteriosus, hypocalcaemia shortly after birth, and died aged 5 weeks. Her second child had pulmonary atresia and a VSD. The mother of family 3 had a heart defect detected as a young child and she had follow-up until the age of 15 years; however, her childhood medical records have been destroyed. Clinical examination and echocardiography at 45 years old were normal. Her second child had pulmonary atresia and a VSD. In family 4, the father had a right aortic arch, a small VSD, and an anomalous left subclavian artery. His first child was a girl with dextrocardia, an absent pulmonary valve, and a VSD, who died aged 11 days. His second child was a girl who had tetralogy of Fallot and died aged 2-5 years, his third child was normal, and his fourth also had tetralogy of Fallot. The parents of family 5 were both well. Their first and third children were normal but their second, a boy, had a patent arterial duct and slight developmental delay. He had symptomless hypocalcaemia shortly after birth, although serum calcium was normal by 1 year of age. The fourth child had an interrupted aortic arch, a VSD, and a right subclavian artery arising from the right pulmonary artery. She died at 2 days of age and necropsy revealed thymus aplasia. The fifth child had tetralogy of Fallot. In the remaining four families, the parents were normal but siblings in every family had anatomically identical cardiac lesions: double-outlet right ventricle in family 6, pulmonary atresia/VSD in family 7, pulmonary atresia and intact ventricular septum in family 8, and tetralogy of Fallot (identical twins) in family 9. Blood samples were obtained from surviving members of the families for high-resolution chromosome analysis and DNA analysis. Chromosome analysis was done on metaphase preparations with more than 850 bands per haploid set.11 This analysis was not done in family 4. DNA and densitometric analyses were done as described previously." Filters were prepared by Southern blotting and hybridised with the DNA probe HP500 and a rhodopsin gene control probe (RHO). HP500 is a subclone of KI-182 (D22S134) and is deleted in most children with DiGeorge syndrome.s The DNA analysis of every family was done in triplicate. Autoradiographs were analysed with a densitometer. truncus
Results In family 1, chromosome analysis of the mother was normal (46,XX) but did not achieve a resolution of greater than 850 bands per haploid set despite repeat sampling, and thus a microdeletion could not be excluded. High-resolution analysis was achieved in her son with pulmonary atresia/VSD and an interstitial deletion from chromosome 22 was detected [46,XY,del(22)(qll.21qll.23)]. Chromosome analyses of the other families (except family 4) revealed apparently normal karyotypes ( > 850 bands). DNA analysis by Southern blotting demonstrated a deletion from within 22q11 in every surviving affected member of families 1,2,3, and 4 (fig 2). A submicroscopic deletion was also detected in the unaffected father of family 5 and in his child with a patent arterial duct and neonatal hypocalcaemia; DNA analysis of the youngest child in this family, who has tetralogy of Fallot, has not yet been done. No deletions were found by DNA analysis of families 6, 7, 8, and 9.
investigated by echocardiography with
or without cardiac catheterisation. Nine families were identified and the pedigrees of five are shown in fig 1. In family 1, the mother had tetralogy of Fallot. Her first child was normal but her second had pulmonary atresia and a VSD. The mother of family 2 had a right aortic arch and had had a patent arterial duct that was ligated at the age of 4 years. Her first child had
ADDRESSES: Division of Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne NE24AA, UK (D. I. Wilson, MRCP, J. A Goodship, MD, Prof J. Burn, MD, I E Cross, BSc); and Department of Biochemistry and Molecular Genetics, St Mary’s Hospital Medical School, London (P. J. Scambler, MD)
Correspondence to
Dr D. I. Wilson
574
Fig 1-Pedigree of five families with familial cardiac defects. VSD=ventricular septal defect, PDA=patent arterial duct, !AA= interrupted aortic arch, RAA=right aortic arch, AnRSA=anomalous nght subclavian artery, AnLSA=anomalous left subclavian artery, AbPV=absent pulmonary value, Dextroc=dextrocardia. =affected male, 0 unaffected female,Ø deceased female. =
=
Furthermore, in every family the parents tend to have mild
Discussion Chromosome 22 deletions were detected in five of the nine families investigated because of recurrent heart defects. In four of the five families in which a deletion was found, one of the parents had a cardiac abnormality, but in the fifth family both parents were clinically normal. Three of five offspring in this family had a congenital heart defect with two offspring having additional features of DiGeorge syndrome. A chromosome 22 deletion was identified in the three affected children in family 5 and in their apparently normal father. This family is similar to one we reported previously,10 in which a chromosome 22 deletion was found in the apparently normal mother of a child with DiGeorge syndrome and in two children with isolated congenital heart defects. In every one of these families with a deletion there is phenotypic variation in the cardiac defect within the family. 1 2
3
31’g
5µg 7µg 9µg 44
5
6
Fig 2-Autoradiograph of a Southern blot from the DNA analysis of families 2 and 3. The 4 middle lanes are controls.and loaded with 3 I-1g, 5 µg, 7 µg, and 9 µg of DNA from normal individuals DNA from the affected mother, affected daughter, unaffected father, and unaffected maternal grandmother from family 2 are in lanes 1, 2, 3, and 4, respectively. DNA from the mother and affected daughter of family 3 are in lanes 5 and 6, respectively Intensity of the 3.5kb band detected by H P500 in lanes 1, 2, 5, and 6 is reduced compared with matched control lanes-ie, a control lane with equal intensity of the 72 kb control band RHO; analysis by densitometer shows that intensity is reduced by 50%.
defects
compared with those of their children. This finding alternatively, to mutations changing when transmitted from one generation to the next, which can lead to an extremely variable phenotype. The latter possibility is not unreasonable in the light of recent developments in understanding of the fragile X and myotonic dystrophy loci.12 No deletions were may be due to ascertainment bias or,
identified in four families. In these families the parents were normal and sibling pairs had identical heart defects. We cannot exclude the possibility that these four families have a stable mutation within the same gene that is deleted in the other families. The cardiac defects found in DiGeorge syndrome include interrupted aortic arch, truncus arteriosus, tetralogy of Fallot, and right-sided aortic arch. It is of note that of the three families in which the structural abnormality in the parent was known, two had right-sided aortic arch in association with other abnormalities and one had tetralogy of Fallot. Offspring studies have nearly all been done with survivors of cardiac surgery. No figures are available for risk of heart disease in offspring of individuals with right-sided aortic arch because this abnormality is not an indication for surgery. The risk of congential heart disease in offspring of patients with corrected tetralogy of Fallot is about 3%." Since one chromosome from each pair is transmitted from parent to offspring, there is a one in two chance of a chromosome deletion being passed on to offspring. Thus, if chromosome 22 deletions were to account for all cases of congenital heart disease in offspring of individuals with tetralogy of Fallot, about 6% of individuals with the disorder would be expected to have this deletion. We have done a preliminary prospective study of 40 individuals with tetralogy of Fallot and 40 clinically normal individuals, and found submicroscopic chromosome 22qll deletions in 2 (5%) of the Fallot’s group14 and none of the normal group (unpublished observations). This result is consistent with
575
the view that interstitial deletions of chromosome 22 account for most cases of congenital heart disease in the offspring of patients with tetralogy of Fallot. We have reported a wide spectrum of defects associated with chromosome 22q111 deletions and it is possible that such deletions also account for a proportion of affected offspring from parents with heart defects other than tetralogy of Fallot. Nasal speech due to velopharyngeal insufficiency is very characteristic and its presence in a patient with congenital heart disease makes the diagnosis of Shprintzen syndrome likely, thus allowing clinical identification of some patients at high risk of having offspring with congenital heart disease. Dysmorphic features are less useful in identifying at-risk patients. No individual in the five families with chromosome 22 deletions was identified as being dysmorphic by referring cardiologists, although, in retrospect, several did have subtle dysmorphic features. The fact that these features were not noted before genetic investigation shows that they are not useful in helping to identify the subgroup of patients in a routine cardiology clinic that are at high risk. The results reported here confirm our earlier finding that deletions within chromosome 22q11can cause isolated congenital heart disease and that the spectrum of cardiac abnormalities is wide, including interrupted aortic arch,
tetralogy of Fallot, truncus arteriosus, VSD, patent arterial duct, right aortic arch, and aberrant right subclavian artery. Rapid, reliable methods of screening for this deletion are clearly necessary to identify the subgroup of patients who have a 50% risk of affected offspring. We thank Dr H. H. Bain, Dr E. M. Thompson, Dr B. C. Davison, Dr P. Jardine, Dr J. Patterson, Dr J. M. Bridson, and Dr D. M. Cook for referring
affected families. We also thank all the families involved in this study for their help and cooperation, Mrs M. Van Altaan, Dr J. O’Sullivan, Dr E. A. Shineboume, Dr L. Allan, Dr D. F. Dickinson, Dr R. A. Emmott, Dr S. M. Amin, and Dr Meakin for their help, and Dr J. Nathans who kindly provided the rhodopsin probe used as the control. D. 1. W. is supported by the British Heart Foundation and Borwick Trust, and P. J. S. by the British Heart Foundation, Action Research, the Dunhill Medical Research Trust, and the Medical Research Council.
REFERENCES 1. Whittemore R, Hobbins EJ, Engle MA. Pregnancy and its outcome in women with and without surgical treatment of congenital heart disease. Am J Cardiol 1982; 50: 641-57. 2. Czeizel A, Porno A, Peterffy E, Tarcal E. Studies of children of parents operated on for congenital cardio-vascular malformations. Br Heart J 1982; 47: 290-94. 3. Dennis NR, Warren J. Risks to the offspring of patients with some common congenital heart defects. J Med Genet 1981; 18: 8-16. 4. Zellers TM, Driscoll DJ, Michels VV. Prevalence of significant congenital heart defects in children of parents with Fallot’s tetralogy. Am J Cardiol 1990; 65: 523-26. 5. Carey AH, Kelly D, Halford S, et al. Molecular genetic study of the frequency of monosomy 22q1 1 in DiGeorge syndrome. Am J Hum
Genet (in press). 6. Scambler PJ, Kelly D, Lindsay E, et al. Velo-cardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus. Lancet 1992; 339: 1138-39. 7. Dnscoll AD, Budarf ML, Emanuel BS. A genetic etiology for DiGeorge syndrome: consistent deletions and microdeletions of 22q11. Am J Hum Genet 1992; 50: 924-33. 8. Conley ME, Beckwith JB, Mancer JFK, Tenckhoff L. The spectrum of the DiGeorge syndrome. J Pediatr 1979; 94: 883-90. 9. Lipson AH, Yuille D, Angel M, Thompson PG, Vandervoord JG, Beckenham EJ. Velocardiofacial (Shprintzen) syndrome: an important syndrome for the dysmorphologist to recognise. J Med Genet 1991; 28: 596-604. 10 Wilson DI, Cross IE, Goodship JA, et al. DiGeorge syndrome with isolated aortic coarctation and isolated ventricular septal defect in three sibs with a 22q11 deletion of maternal origin. Br Heart J 1991; 66: 308-12.
on Human Cytogenetic Nomenclature. An international system for human cytogenetic nomenclature (1985). Basel: S. Karger, 1985. 12. Sutherland GR, Haan EA, Kremer E, et al. Hereditary unstable DNA: a new explanation for some old genetic questions? Lancet 1991; 338: 289-92. 13. Burn J, Coffey R, Little J, et al. Recurrence risks in the offspring of adults born with major heart defects; first results of a British collaborative study. Am J Hum Genet 1990; 47: A121. 14. Wilson DI, Scambler PJ, Goodship JA, Burn J. Deletion within chromosome 22q11 is a major cause of isolated heart defects and most causes of DiGeorge and velocardiofacial syndromes (abstr P16). Proceedings of the British Paediatric Association Meeting; 1992 April 7-10; Warwick, UK.
11.
Standing Committee
SHORT REPORTS Splenic lymphoma with villous lymphocytes in tropical West Africa
Splenic lymphoma with villous lymphocytes (SLVL) is a monoclonal B-lymphoproliferative disorder characterised by splenomegaly and distinctive villous lymphocytes in the peripheral blood. It has not previously been reported from Africa, but we describe ten Ghanaian patients with SLVL seen at one hospital during a 4-year period. The clinical presentation is similar in Africa and in temperate regions, though the lymphocyte count is higher in African patients and the disorder predominantly affects middle-aged women rather than elderly men. It is likely that SLVL has previously been classified as splenic chronic lymphocytic leukaemia or hyper-reactive malarial splenomegaly.
In temperate areas, splenic lymphoma with villous lymphocytes (SLVL) is predominantly a disease of elderly men, which presents as splenomegaly, tiredness, and malaise. Paraproteins are found in serum or urine in more than 50% of patients. SLVL can be diagnosed in patients with peripheral-blood lymphocyte counts above 10 x 109/1 when at least 30% of these cells have a characteristic villous appearance.! The cytoplasm of villous lymphocytes is basophilic and there are characteristic short cytoplasmic villi unevenly distributed at one or both poles of the celU The cellular phenotype differs from that in hairy-cell leukaemia; CD25, CD lie, and tartrate-resistant acid-phosphatase markers are usually lacking. If the membrane markers are suggestive, SLVL may be diagnosed in patients with lymphocyte counts below 10 x 109/1.
