Clinical Genetics 1978: 14: 105-1 14
Mosaicism and the trisomy 8 syndrome A. C. BERRY,D. E. MUTTONAND D. G. M. LEWIS~
Paediatric Research Unit, Prince Philip Research Laboratories, Guy’s Hospital Medical School, London and 1 St. Mary’s General Hospital, Portsmouth, England Three new cases of trisomy 8 mosaicism are presented; two have features corresponding with those usually found in this syndrome, whereas one is highly atypical. In view of the almost universal mosaicism of these patients, the literature is reviewed with an emphasis on the patterns of mosaicism found. There is little correlation between degree of mosaicism and extent of clinical abnormality. The degree of mosaicism differs in different tissues, fibroblasts being more informative of aneuploidy than lymphocytes, and there is some evidence that the degree of mosaicism varies with time. The reasons for these findings are discussed, with particular reference to the raised paternal age found in a proportion of the reported cases. Received 5 January, accepted f o r prihlicatian I0 March 1978 K e y words: Clinical variation; mosaicism; paternal age; trisomy 8.
Since the advent of chromosome banding techniques, it has been possible to identify the various C-group abnormalities specifically. Trisomy 8 has now been reported a number of times, the majority of cases being mosaic. Certain characteristic clinical features are well recognised and have been described in detail by Pfeiffer (1977). They include: 1. Mild to moderate mental retardation. 2. Various skeletal abnormalities, in particular vertebral anomalies, joint movement restriction, absent patellae, camptodactyly and long, narrow chest. 3. Typical long, narrow facies, with deepset eyes, strabismus, abnormal ears and neck webbing. 4. Renal abnormalities. 5 . Deep plantar furrows in the newborn. Cassidy et al. (1975) suggested that trisomy 8 syndrome could now b e said to be a well-recognised clinical entity, and a review of the literature supports this con-
clusion. At intervals, however, patients with highly atypical clinical features a r e reported, the most extreme example being patient 3 of Caspersson et al. (1972), w h o presented on account of her history of miscarriages. This report presents three new cases, two of whom conform to the typical clinical picture, and one of whom shows few of these specific features. Possible reasons for this great variability in expression are discussed in the light of the frequent mosaicism found in these patients and the varying degrees of mosaicism found when different tissues are examined. Case Reports
Case 1: PRU 3717/5811 T h e patient was presented when aged about 1 year, with wry-neck and inability to sit unsupported. He was born in hospital in 1965 at 43 weeks of gestation (birthweight: 3.7 kg). During the first trimester, the
I06
BERRY, MUTTON AND LEWIS
mother is reported to have had a possible viral illness associated with diarrhoea. The patient required tube feeding after birth and his parents noted his distended abdomen at an early age. H e had a “kidney infection” treated during his first year. Family History. The father (born 1922) and mother (born 1922) are not blood relations and are phenotypically normal, as are his three older sibs. Otherwise, the family history contains nothing relevant. Examination at age 14 months (Dr. D. J. Mantle). The following were noted: head asymmetrical, low-set ears with high pointed pinnae; nose - broad base; lips - thick and dry; geographic tongue; three upper teeth and six lower teeth; left external jugular vein running across the sterno-mastoid and into the thorax on the right side; chest widely spaced nipples, long narrow chest with undulating lower ribs; lumbar kyphosis; elbows - not capable of full extension (they have a reverse carrying angle); fingers - only extensible t o about 75”; toes - about 10” flexion deformity; knees small, and patellae absent; abdomen - protuberant with low-set umbilicus; liver edge could be felt; spleen - tip was palpable; mass present in the right side of the abdomen extending down the right flank; genitalia - small penis; and testes - not definitely felt. E.C.G.: Probably some left ventricular hypertrophy but within normal limits. X-ray of the spine: Dorsal scoliosis convex to the left, and minor congenital anomalies of the upper dorsal vertebrae. Abnormalities of development and segmentation seen in the lumbar spine with partial hemivertebrae and fusions, particularly posteriorly. Development of the pelvis slightly abnormal, with small wings of innominate bones. 1.V.P.: Gross bilateral hydronephrosis and hydroureters.
Estimated developmental age: At 16 months estimated developmental age was 6 months. Oral smear: X chromatin negative. Chromosome analysis: Karyotype 46,XY/ 47,XY,+C (in 1967). In 1974, cells were recovered from the cell bank, and using Giemsa banding the additional C-group chromosome was shown to be a No. 8. For details, see Table 1. Case 2: PRU 1202/3569 (previously included as mosaic 46,XY/47,XY,+C in Table 3 of Polani 1969) The patient was born in August, 1961, after a full-term normal pregnancy. He presented with neck webbing, hypertonus and mental retardation when aged a few months. The birth-weight was 2.8 kg, and there were n o neonatal problems. Family History. The father (born 1920) and mother (born (1932) are unrelated and apparently healthy. The mother had had two first trimester miscarriages and two previous full-term pregnancies. The older two sibs are healthy. Physical examination at 2 years. The following features were present: eyes - deeply set, internal squint; ears - large with prominent helices; neck - slight webbing, and axillary webbing; chest - slightly funnelled, with hypoplastic nipples; scalp and posterior hairlines - normal; skin - obviously mottled; fingers - flexion deformity of the terminal phalanges; nails - well shaped but deeply set; some diminished extensibility of elbows; left foot long; big toe turns axially; other toes - deviated to tibia1 side; flexion deformities of mid-phalangeal joints; nails small and deeply embedded; right foot flexion deformity of toes, calcaneus prominent; sole of foot shows three deep furrows, corresponding to lst, 3rd and 4th interdigital spaces; genitalia - normal, but right testis not palpable; right inguinal hernia;
MOSAICISM AND THE TRISOMY 8 SYNDROME
deep dimples over sacro-coccygeal region; I.Q. (aged 5) = 56 (Terman and Merrill). Progress. In 1965, he had a right inguinal herniorraphy and right orchidectomy, as it was impossible to bring the testis into the scrotum. By age 13, his left testis had become retractile and there were no signs of puberty. He has had several orthopaedic operations to straighten his toes and has also had his strabismus surgically corrected. At age 15, he required a brace because of increasing spinal curvature. Further cardiac evaluation (Dr. M. Joseph) revealed a split second sound but no murmur, suggesting mild pulmonary hypertension not warranting further investigation. X-ray of the spine: In the cervical region there are hemivertebrae, and there is congenital fusion of the appendages posteriorly between L.3 and L.4, there being six lumbar vertebrae. Similarly, both ilia, particularly the left, are underdeveloped. E.C.G.: At the age of 10 years, ECG showed the axis to the right of normal with slightly peaked P-waves. Testis histology (in 1972): Examination showed testis histology to be immature but with fairly large tubules and little interstitial space (testis age: 8 + years). There were no Leydig cells, and slight thickening of the basement membrane was noted. Numerous rnultilayered cells occupied the tubular wall space and somewhat filled the lumen. All nuclei were small and compact, probably of Sertoli cells. There was no definite germinal element of any type (Professor P. E. Polani). Orul smear: X chromatin negative. Chromosome analysis (1 964). Two cell lines were identified, one 46,XY and one 47,XY, +C. In 1974, using Giemsa banding, the extra C-group chromosome was identified as a No. 8. For details, see Table 1. The mother and father had normal fe-
107
male and male chromosome complements, respectively. Case 3: PRU 4410/10907 The patient was born in 1972 after a fullterm, normal delivery. He was transferred to the special care unit owing to cyanotic attacks after feeds, and a feeble cry. The only abnormal finding on clinical examination was mild hypospadias. Full investigation revealed no cause for the cyanotic attacks, and these later ceased. By 5 months he was developmentally retarded, slow to gain weight and had marked hypotonia. His bone age at 6 months was only 3 months. Chromosome analysis by Dr. M. Seabright showed trisomy 8 mosaicism, and the patient was referred to the Paediatric Research Unit at the parents’ request for confirmation of this diagnosis. Family History. The father and mother (both born in 1945) are not blood relatives and are phenotypically normal, as is one elder brother. The father’s first cousin had a son who died aged a few hours with translocation D trisomy and Patau’s syndrome, the result of a D-centric fusion (46,XY,-D, t(DqDq)). Since both parents of this child had normal karyotypes, the translocation seems to have arisen de novo.
+
Exumination at the age of 18 months. The patient was not able to sit unaided, nor to crawl or lift his head when in a supine position. He had a relatively immobile face with ptosis of the eyelids, and narrow palpebral fissures. H e also had a small jaw; low-set, somewhat elfin-like ears; dolichocephaly with bilateral parietal bossing; and a narrow forehead. The following features were also noted: laryngeal stridor; no evidence of congenital heart disease or abdominal masses; diastasis of abdominal muscles; genitalia normal;
BERRY, MUTTON AND i E W l S
108
Table 1 Proportion of mosaic cell line with chromosome complement 47,XX or X Y , f S Age of patient (y)
Authot
Riccardi et al. 1970 Atkins et al. 1974 de Grouchy et al. 1971 Laurent et at. 1971 Caspersson et al. 1972
Eijlsma et al. 1972
Case 1 Case 2
10 -
Case Cass Case Case Case Case
-
adult 6 -
1 2
Schinzel et al. 1974
Walravens et al. 1974 Crandall et al. 1974
4'12
1 2 3 4
Malpeuch et al. 1972 Kakati et al. 1973
Jacobsen et al. 1974
4'11 10
Case 1 Case 2
c
Case 1 Case 2
adult
3 1
Tuncbilek et al 1974 Rutzler et al. 1974 Moore & Scott 1975 Gorlin et al. 1975 Aller et al. 1075 Fineman et al. 1975 Giraud et al. 1975
10
3'14
-
Mosaicism and the trisomy 8 syndrome A. C. BERRY,D. E. MUTTONAND D. G. M. LEWIS~
Paediatric Research Unit, Prince Philip Research Laboratories, Guy’s Hospital Medical School, London and 1 St. Mary’s General Hospital, Portsmouth, England Three new cases of trisomy 8 mosaicism are presented; two have features corresponding with those usually found in this syndrome, whereas one is highly atypical. In view of the almost universal mosaicism of these patients, the literature is reviewed with an emphasis on the patterns of mosaicism found. There is little correlation between degree of mosaicism and extent of clinical abnormality. The degree of mosaicism differs in different tissues, fibroblasts being more informative of aneuploidy than lymphocytes, and there is some evidence that the degree of mosaicism varies with time. The reasons for these findings are discussed, with particular reference to the raised paternal age found in a proportion of the reported cases. Received 5 January, accepted f o r prihlicatian I0 March 1978 K e y words: Clinical variation; mosaicism; paternal age; trisomy 8.
Since the advent of chromosome banding techniques, it has been possible to identify the various C-group abnormalities specifically. Trisomy 8 has now been reported a number of times, the majority of cases being mosaic. Certain characteristic clinical features are well recognised and have been described in detail by Pfeiffer (1977). They include: 1. Mild to moderate mental retardation. 2. Various skeletal abnormalities, in particular vertebral anomalies, joint movement restriction, absent patellae, camptodactyly and long, narrow chest. 3. Typical long, narrow facies, with deepset eyes, strabismus, abnormal ears and neck webbing. 4. Renal abnormalities. 5 . Deep plantar furrows in the newborn. Cassidy et al. (1975) suggested that trisomy 8 syndrome could now b e said to be a well-recognised clinical entity, and a review of the literature supports this con-
clusion. At intervals, however, patients with highly atypical clinical features a r e reported, the most extreme example being patient 3 of Caspersson et al. (1972), w h o presented on account of her history of miscarriages. This report presents three new cases, two of whom conform to the typical clinical picture, and one of whom shows few of these specific features. Possible reasons for this great variability in expression are discussed in the light of the frequent mosaicism found in these patients and the varying degrees of mosaicism found when different tissues are examined. Case Reports
Case 1: PRU 3717/5811 T h e patient was presented when aged about 1 year, with wry-neck and inability to sit unsupported. He was born in hospital in 1965 at 43 weeks of gestation (birthweight: 3.7 kg). During the first trimester, the
I06
BERRY, MUTTON AND LEWIS
mother is reported to have had a possible viral illness associated with diarrhoea. The patient required tube feeding after birth and his parents noted his distended abdomen at an early age. H e had a “kidney infection” treated during his first year. Family History. The father (born 1922) and mother (born 1922) are not blood relations and are phenotypically normal, as are his three older sibs. Otherwise, the family history contains nothing relevant. Examination at age 14 months (Dr. D. J. Mantle). The following were noted: head asymmetrical, low-set ears with high pointed pinnae; nose - broad base; lips - thick and dry; geographic tongue; three upper teeth and six lower teeth; left external jugular vein running across the sterno-mastoid and into the thorax on the right side; chest widely spaced nipples, long narrow chest with undulating lower ribs; lumbar kyphosis; elbows - not capable of full extension (they have a reverse carrying angle); fingers - only extensible t o about 75”; toes - about 10” flexion deformity; knees small, and patellae absent; abdomen - protuberant with low-set umbilicus; liver edge could be felt; spleen - tip was palpable; mass present in the right side of the abdomen extending down the right flank; genitalia - small penis; and testes - not definitely felt. E.C.G.: Probably some left ventricular hypertrophy but within normal limits. X-ray of the spine: Dorsal scoliosis convex to the left, and minor congenital anomalies of the upper dorsal vertebrae. Abnormalities of development and segmentation seen in the lumbar spine with partial hemivertebrae and fusions, particularly posteriorly. Development of the pelvis slightly abnormal, with small wings of innominate bones. 1.V.P.: Gross bilateral hydronephrosis and hydroureters.
Estimated developmental age: At 16 months estimated developmental age was 6 months. Oral smear: X chromatin negative. Chromosome analysis: Karyotype 46,XY/ 47,XY,+C (in 1967). In 1974, cells were recovered from the cell bank, and using Giemsa banding the additional C-group chromosome was shown to be a No. 8. For details, see Table 1. Case 2: PRU 1202/3569 (previously included as mosaic 46,XY/47,XY,+C in Table 3 of Polani 1969) The patient was born in August, 1961, after a full-term normal pregnancy. He presented with neck webbing, hypertonus and mental retardation when aged a few months. The birth-weight was 2.8 kg, and there were n o neonatal problems. Family History. The father (born 1920) and mother (born (1932) are unrelated and apparently healthy. The mother had had two first trimester miscarriages and two previous full-term pregnancies. The older two sibs are healthy. Physical examination at 2 years. The following features were present: eyes - deeply set, internal squint; ears - large with prominent helices; neck - slight webbing, and axillary webbing; chest - slightly funnelled, with hypoplastic nipples; scalp and posterior hairlines - normal; skin - obviously mottled; fingers - flexion deformity of the terminal phalanges; nails - well shaped but deeply set; some diminished extensibility of elbows; left foot long; big toe turns axially; other toes - deviated to tibia1 side; flexion deformities of mid-phalangeal joints; nails small and deeply embedded; right foot flexion deformity of toes, calcaneus prominent; sole of foot shows three deep furrows, corresponding to lst, 3rd and 4th interdigital spaces; genitalia - normal, but right testis not palpable; right inguinal hernia;
MOSAICISM AND THE TRISOMY 8 SYNDROME
deep dimples over sacro-coccygeal region; I.Q. (aged 5) = 56 (Terman and Merrill). Progress. In 1965, he had a right inguinal herniorraphy and right orchidectomy, as it was impossible to bring the testis into the scrotum. By age 13, his left testis had become retractile and there were no signs of puberty. He has had several orthopaedic operations to straighten his toes and has also had his strabismus surgically corrected. At age 15, he required a brace because of increasing spinal curvature. Further cardiac evaluation (Dr. M. Joseph) revealed a split second sound but no murmur, suggesting mild pulmonary hypertension not warranting further investigation. X-ray of the spine: In the cervical region there are hemivertebrae, and there is congenital fusion of the appendages posteriorly between L.3 and L.4, there being six lumbar vertebrae. Similarly, both ilia, particularly the left, are underdeveloped. E.C.G.: At the age of 10 years, ECG showed the axis to the right of normal with slightly peaked P-waves. Testis histology (in 1972): Examination showed testis histology to be immature but with fairly large tubules and little interstitial space (testis age: 8 + years). There were no Leydig cells, and slight thickening of the basement membrane was noted. Numerous rnultilayered cells occupied the tubular wall space and somewhat filled the lumen. All nuclei were small and compact, probably of Sertoli cells. There was no definite germinal element of any type (Professor P. E. Polani). Orul smear: X chromatin negative. Chromosome analysis (1 964). Two cell lines were identified, one 46,XY and one 47,XY, +C. In 1974, using Giemsa banding, the extra C-group chromosome was identified as a No. 8. For details, see Table 1. The mother and father had normal fe-
107
male and male chromosome complements, respectively. Case 3: PRU 4410/10907 The patient was born in 1972 after a fullterm, normal delivery. He was transferred to the special care unit owing to cyanotic attacks after feeds, and a feeble cry. The only abnormal finding on clinical examination was mild hypospadias. Full investigation revealed no cause for the cyanotic attacks, and these later ceased. By 5 months he was developmentally retarded, slow to gain weight and had marked hypotonia. His bone age at 6 months was only 3 months. Chromosome analysis by Dr. M. Seabright showed trisomy 8 mosaicism, and the patient was referred to the Paediatric Research Unit at the parents’ request for confirmation of this diagnosis. Family History. The father and mother (both born in 1945) are not blood relatives and are phenotypically normal, as is one elder brother. The father’s first cousin had a son who died aged a few hours with translocation D trisomy and Patau’s syndrome, the result of a D-centric fusion (46,XY,-D, t(DqDq)). Since both parents of this child had normal karyotypes, the translocation seems to have arisen de novo.
+
Exumination at the age of 18 months. The patient was not able to sit unaided, nor to crawl or lift his head when in a supine position. He had a relatively immobile face with ptosis of the eyelids, and narrow palpebral fissures. H e also had a small jaw; low-set, somewhat elfin-like ears; dolichocephaly with bilateral parietal bossing; and a narrow forehead. The following features were also noted: laryngeal stridor; no evidence of congenital heart disease or abdominal masses; diastasis of abdominal muscles; genitalia normal;
BERRY, MUTTON AND i E W l S
108
Table 1 Proportion of mosaic cell line with chromosome complement 47,XX or X Y , f S Age of patient (y)
Authot
Riccardi et al. 1970 Atkins et al. 1974 de Grouchy et al. 1971 Laurent et at. 1971 Caspersson et al. 1972
Eijlsma et al. 1972
Case 1 Case 2
10 -
Case Cass Case Case Case Case
-
adult 6 -
1 2
Schinzel et al. 1974
Walravens et al. 1974 Crandall et al. 1974
4'12
1 2 3 4
Malpeuch et al. 1972 Kakati et al. 1973
Jacobsen et al. 1974
4'11 10
Case 1 Case 2
c
Case 1 Case 2
adult
3 1
Tuncbilek et al 1974 Rutzler et al. 1974 Moore & Scott 1975 Gorlin et al. 1975 Aller et al. 1075 Fineman et al. 1975 Giraud et al. 1975
10
3'14
-
