Hum. Genet. 39, 243--250 (1977) © by Springer-Verlag 1977
18p-- Syndrome Resulting from 14q/18q 'Dicentric' Fusion Translocation Steve J. Funderburk*, Robert S. Sparkes, and Ivana Klisak U.C.L.A. of Division of Medical Genetics, Departments of Psychiatry, Medicine, and Pediatrics, Los Angeles, CA, USA
Summary. A child with nasal hypoplasia, growth and developmental delay, and 18p-- due to 14q/18q apparent dicentric fusion is reported. Review o f t e n previously reported patients with 18p-- due to fusion translocations involving the long arm of chromosome 18 reveals clinical features ranging from arrhinencephaly to minimal dysmorphic changes and mild retardation. T h i s spectrum of clinical expression is similar to that seen in patients with partial 18p deletions. Since the same range of clinical features is observed whether there is partial or apparent total deletion of 18p, it is suggested that only a distal segment of the short arm of chromosome 18 may be etiologically related to the clinical phenotype in the 18p-- syndrome.
The 18p--syndrome includes a spectrum of phenotypic features, from arrhinencephaly and cebocephaly on the one extreme to simple hypertelorism and mild mental retardation on the other (Lurie and Lazjuk,1972; Schinzel et al., 1974; Faust et al., 1976). More than 80 patients have been reportedl most often with de novo deletion of a varying portion of the short arm of chromosome 18. Following is a report of a child with growth and developmental delay, nasal hypoplasia, and apparent total deletion of 18p-- due to 14q/18q fusion translocation.
Clinical Report G. F., a black male, was born on February 26, 1974, to healthy parents; the mother was 31 years old and the father 32 years old. The father and two of the proband's three older siblings had rudimentary sixth digits on the ulnar aspect of the fifth fingers. Preconceptionally and in the first trimester the mother took an occasional Triaxin (Mayrand) tablet. Delivery was ~it term and birth weight was 2760 g, head circumference 34.5 cm, and length 51 cm. Labor was prolonged and the amniotic fluid was meconium stained. Nasal hyp0plasia, paramedial palatal grooving, and a vestigial sixth digit on the ulnar aspect of the left hand were noted during the * Address offprint requests to : S. Funderburk, M.D., Neuropsychiatric Institute, 760 Westwood Plaza, Los Angeles, CA 90024, USA
244
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Fig. 1. G. F. at age 26 months. Note the nasal hypoplasia and low-set, posteriorly rotated ears
Fig. 2. One full karyotype by trypsin-Giemsa banding. Arrows indicate the 14q/18q fusion translocation and the missing chromosome 18
newborn examination. On the first day, the infant had respiratory distress due to hypoplastic nasal passages. Nasal catheterization and gavage feedings were required during the neonatal period. Delayed development and small stature were noted at 26 months of age. Head circumference was 46 cm, height 75 cm, arm span 70 cm, and weight 9.1 kg, all far beolw - - 2 SD. There were marked nasal and maxillary hypoplasia, micrognathia, and the ears were low set and posteriorly rotated (Fig. 1). Thirteen deciduous teeth were fully erupted and the midline left
Dicentric Fusion in the 18p- Syndrome
245
Fig. 3. Partial karyotype of the D and E groups by C-banding. Arrows indicate the 14q/18q fusion and the missing chromosome 18. Very little of 14p or 18p appears to be included in the translocation Fig. 4. Absence of ammoniacal silver staining immediately above the primary constriction of the 14q/18q fusion translocation (arrow), indicating nearly complete absence of 14p, tentative karyotype 45,XY,-14,-18,+t(14;18)(14qter- c e n - 14pll : : 18pll - c e n - 18qter)
upper incisor was missing (at 28 months). Dermatoglyphic examination of the proband revealed proximal axial palmar triradii and a digital pattern of three whorls and seven ulnar loops; the mother had proximal axial palmar triradii with six ulnar loops and four whorls, and the father had proximal axial palmar triradii with eight ulnar loops and two arches. The proband had moderate generalized hypotonia; deep tendon reflexes were present and the plantar responses were extensor. Cardiac catheterization, done because of a heart murmur and cardiomegaly, revealed a large secundum type atrial septal defect. Both kidneys were visualized during this procedure. Left hand and wrist X-ray at 27 months of age revealed a skeletal age of no more than 6 months. Quantitative immunoglobulin assay at 28 months of age was as follows: IgG 2090 m g / dl, IgM 53 mg/dl (both in the normal range), and IgA 25 mg/dl (below the normal range). Growth hormone assay obtained 90 min after onset of sleep was 6.8 ng/ml (> 5 ng/ml is normal responce to stimulation). Serum thyroxine was 4.9 mg%, in the normal range, at 20 months.
246
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When last examined at 28 months of age, the child had been walking without support for about two months. He was gesturing and using approximately five single words. He had been using a spoon for feeding from one year of age. Psychological testing revealed severe delay in language development but only mild delay in motor, adaptive, and social development.
Cytogenetic Studies Trypsin-Giemsa banding of peripheral blood lymphocytes revealed an apparent fusion translocation between the short arms of a chromosome 14 and 18 (Fig. 2). C-banding (Arrighi and Hsu, 1971) revealed two blocks of heterochromatin in the translocation, suggesting two centromeres, and nearly complete absence of the short arms of the chromosomes 14 and 18 (Fig. 3). Although both centromeres may be present in this fusion translocation, only a single primary constriction was observed, suggesting one functioning centromere. Absence of ammoniacal silver staining (Howell and Denton, 1975) immediately above the primary constriction (Fig. 4) indicated absence of the stalk region of chromosome 14. Karyotypes of both parents were normal.
Comment The clinical features of our patient and those previously reported with centric fusion translocations of the long arm of chromosome 18 are summarized in Table 1. Although one might assume a more severe phenotypic effect from complete absence of the short arm of chromosome 18, the same spectrum of clinical features as seen in Table 1 has been observed in patients with only partial deletions of the short arm (Faust et al., 1976). These observations suggest that the etiologically important portion of the short arm of chromosome 18 may be limited to a small terminal segment. This explanation would be consistent with the relatively small total R-band regions (proposed genetically functional regions) observed in chromosome 18 (Hoehn, 1975), and may be analogous to the evidence that Down Syndrome results from trisomy of a single band in the long arm of chromosome 21 (Niebuhr, 1974). Robertsonian translocations, i.e. long arm fusions between acrocentric chromosomes, have recently been shown to include both centromeres (Daniel and Lam-Po-Tang, 1976). To the authors' knowledge, none of the long arm 18 fusions previously reported (Table 1) have been shown to be dicentric. Whether one or both centromeres have altered function is not known for the Robertsonian translocations nor for the apparent dicentric fusion reported in our patient. A disproportionate delay in language development has been previously reported in the 18p-- syndrome (Schinzel et al., 1974; Faust et al., 1976). Similarly, our patient showed marked delay in language development with only mild delay in motor, adative, and social development. Growth hormone, as well as immunoglobulin A deficiency, have been reported in the 18p-- syndrome (Schinzel et al., 1974). The growth hormone deficiency was not responsive to replacement therapy in one patient (Leisti et al., 1974). One previously reported patient with IgA deficiency and 18p-- had
Dicentric Fusion in the 18p- Syndrome
249
c h r o n i c skin infections ( G i l g e n k r a n t z et al., 1974) b u t others, i n c l u d i n g the b o y r e p o r t e d here, a p p a r e n t l y have n o t h a d an increased incidence o f infections. The r e p o r t o f one p a t i e n t w h o d e v e l o p e d b e t a cell deficiency at age 5 years, a n d t h y r o i d deficiency with high t h y r o i d a n t i b o d y levels at age 9 years ( K i s t e n m a c h e r et al., 1974), e m p h a s i z e s the need for c o n t i n u e d e v a l u a t i o n o f e n d o c r i n e status in patients with the 1 8 p - - s y n d r o m e . In s u m m a r y , p a r t i a l o r n e a r l y c o m p l e t e absence o f the s h o r t a r m o f a c h r o m o s o m e 18 is a s s o c i a t e d with a range o f clinical features, f r o m a r r h i n e n c e p h a l y o r h o l o p r o s e n c e p h a l y a n d p e r i n a t a l d e a t h on the one extreme, t h r o u g h nasal h y p o p l a s i a a n d m i d f a c e r e t r a c t i o n as seen in the p a t i e n t r e p o r t e d here, to the o t h e r e x t r e m e o f o n l y m i n i m a l craniofacial changes a n d m i l d r e t a r d a t i o n . The severity o f clinical features does n o t a p p e a r to correlate with the a m o u n t o f m a t e r i a l missing f r o m the s h o r t a r m o f the 18 c h r o m o s o m e . Acknowledgement, We are grateful to Inge Lysdal for her assistance in preparation of the manuscript. This research supported in part by the U.C.L.A. Mental Retardation/Child Psychiatry Program; and N.I.H. grants MCH-927, HD-04612, HD-05615, and HD-06576.
References Arrighi, F. E., Hsu, T. C.: Localization of heterochromatin in human chromosomes. Cytogenetics 10, 81--86 (1971) Cohen, M. M., Putnam, T. I.: An 18q21q translocation in a patient with presumptive "monosomy G". Am. J. Dis. Child. 124, 908--910 (1972) Daniel, A., Lam-Po-Tang, P. R.L.C.: Structure and inheritance of some heterozygous Robertsonian translocations in man. J. Med. Genet. 13, 381--388 (1976) Faust, J., Habedank, M., Nieuwenhuijsen, C.: The 18p- syndrome; Report of four cases. Eur. J. Pediatr. 123, 59--66 (1976) Fraccaro, M., Herin, P., Hult6n, M., Ivemark, B. I., Jonasson, J., Lindsten, J., Tiepolo, L., Zetterqvist, P,: Structural abnormalities of chromosome 18. III. Two G/18 translocations, one identified as 22/18. Ann. G6n~t. 15, 93--98 (1972) Gilgenkrantz, S., Charles, J.-M., Cabrol, C., Mauuary, G., Vigneron, C.: D616tion due bras court du 18 par translocation t(22-, 18p+) avee d6flcit en IgA. Etude cytog6n6tique avec autoradiographic et fluorescence. Ann. G~n6t. 15, 275--281 (1972) Hoehn, H.: Functional implications of differential chromosome banding. Am. J. Hum. Genet. 27, 676--686 (1975) Howell, W. M., Denton, T. E., Diamond, J. R.: Differential staining of the satellite regions of human acrocentric chromosomes. Experientia (Basel) 31, 260--262 (1975) Kistenmacher, M. L., DiGeorge, A. M., Punnett, H. H.: 45,XX,-13,-18,t(18q13c0+ and autoimmune disorders. Am. J. Hum. genet. 26, 49A (1974) Leisti, J., Leisti, S., Perheentupa, J., Savilahti, E., Aula, P.: Absence of IgA and growth hormone deficiency associated with short arm deletion of chromosome 18. Arch. Dis. Child. 48, 320--322 (1973) Lurie, I. W., Lazjuk, G. I.: Partial monosomies 18; Review of cytogenetical and phenotypical variants. Humangenetik 15, 203--222 (1972) Malpuech, G., Raynaud, E. J., Belin, J., Godeneche, P., Grouchy, J. de: D616tion du bras court du 18 par translocation t(G-; 18p+). Une 6tude en fluorescence par la moutarde de quinacrine. Ann. Genet. 14, 213--218 (1971) Miller, J. Q., Selden, R. F., Meisner, L. F.: D/E translocation in a young girl. Sth. Med. J. (Bgham, Ala.) 63, 368--370 (1970)
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Niebuhr, E.: Down's Syndrome: the possibilityofa pathogenetic segment on chromosome no. 21. Humangenetik 21, 99--101 (1974) Pfeiffer, R. A.: Sporadische autosomale defizienz (45, XX, D2-, 18-, t[D218]) bei einem 5j~ihrigen M~tdchen. Helv. Paediatr. Acta 24, 167--173 (1969) Schinzel, A., Schmid, W., Luscher, U., Nater, M., Brook, C., Steinmann, B.: Structural aberrations of chromosome 18. I. The 18p- syndrome. Arch. Genet. (Zur.) 47, 1--15 (1974)
Received April 8, 1977 / June 20, 1977
18p-- Syndrome Resulting from 14q/18q 'Dicentric' Fusion Translocation Steve J. Funderburk*, Robert S. Sparkes, and Ivana Klisak U.C.L.A. of Division of Medical Genetics, Departments of Psychiatry, Medicine, and Pediatrics, Los Angeles, CA, USA
Summary. A child with nasal hypoplasia, growth and developmental delay, and 18p-- due to 14q/18q apparent dicentric fusion is reported. Review o f t e n previously reported patients with 18p-- due to fusion translocations involving the long arm of chromosome 18 reveals clinical features ranging from arrhinencephaly to minimal dysmorphic changes and mild retardation. T h i s spectrum of clinical expression is similar to that seen in patients with partial 18p deletions. Since the same range of clinical features is observed whether there is partial or apparent total deletion of 18p, it is suggested that only a distal segment of the short arm of chromosome 18 may be etiologically related to the clinical phenotype in the 18p-- syndrome.
The 18p--syndrome includes a spectrum of phenotypic features, from arrhinencephaly and cebocephaly on the one extreme to simple hypertelorism and mild mental retardation on the other (Lurie and Lazjuk,1972; Schinzel et al., 1974; Faust et al., 1976). More than 80 patients have been reportedl most often with de novo deletion of a varying portion of the short arm of chromosome 18. Following is a report of a child with growth and developmental delay, nasal hypoplasia, and apparent total deletion of 18p-- due to 14q/18q fusion translocation.
Clinical Report G. F., a black male, was born on February 26, 1974, to healthy parents; the mother was 31 years old and the father 32 years old. The father and two of the proband's three older siblings had rudimentary sixth digits on the ulnar aspect of the fifth fingers. Preconceptionally and in the first trimester the mother took an occasional Triaxin (Mayrand) tablet. Delivery was ~it term and birth weight was 2760 g, head circumference 34.5 cm, and length 51 cm. Labor was prolonged and the amniotic fluid was meconium stained. Nasal hyp0plasia, paramedial palatal grooving, and a vestigial sixth digit on the ulnar aspect of the left hand were noted during the * Address offprint requests to : S. Funderburk, M.D., Neuropsychiatric Institute, 760 Westwood Plaza, Los Angeles, CA 90024, USA
244
St. J. Funderburk et al.
Fig. 1. G. F. at age 26 months. Note the nasal hypoplasia and low-set, posteriorly rotated ears
Fig. 2. One full karyotype by trypsin-Giemsa banding. Arrows indicate the 14q/18q fusion translocation and the missing chromosome 18
newborn examination. On the first day, the infant had respiratory distress due to hypoplastic nasal passages. Nasal catheterization and gavage feedings were required during the neonatal period. Delayed development and small stature were noted at 26 months of age. Head circumference was 46 cm, height 75 cm, arm span 70 cm, and weight 9.1 kg, all far beolw - - 2 SD. There were marked nasal and maxillary hypoplasia, micrognathia, and the ears were low set and posteriorly rotated (Fig. 1). Thirteen deciduous teeth were fully erupted and the midline left
Dicentric Fusion in the 18p- Syndrome
245
Fig. 3. Partial karyotype of the D and E groups by C-banding. Arrows indicate the 14q/18q fusion and the missing chromosome 18. Very little of 14p or 18p appears to be included in the translocation Fig. 4. Absence of ammoniacal silver staining immediately above the primary constriction of the 14q/18q fusion translocation (arrow), indicating nearly complete absence of 14p, tentative karyotype 45,XY,-14,-18,+t(14;18)(14qter- c e n - 14pll : : 18pll - c e n - 18qter)
upper incisor was missing (at 28 months). Dermatoglyphic examination of the proband revealed proximal axial palmar triradii and a digital pattern of three whorls and seven ulnar loops; the mother had proximal axial palmar triradii with six ulnar loops and four whorls, and the father had proximal axial palmar triradii with eight ulnar loops and two arches. The proband had moderate generalized hypotonia; deep tendon reflexes were present and the plantar responses were extensor. Cardiac catheterization, done because of a heart murmur and cardiomegaly, revealed a large secundum type atrial septal defect. Both kidneys were visualized during this procedure. Left hand and wrist X-ray at 27 months of age revealed a skeletal age of no more than 6 months. Quantitative immunoglobulin assay at 28 months of age was as follows: IgG 2090 m g / dl, IgM 53 mg/dl (both in the normal range), and IgA 25 mg/dl (below the normal range). Growth hormone assay obtained 90 min after onset of sleep was 6.8 ng/ml (> 5 ng/ml is normal responce to stimulation). Serum thyroxine was 4.9 mg%, in the normal range, at 20 months.
246
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When last examined at 28 months of age, the child had been walking without support for about two months. He was gesturing and using approximately five single words. He had been using a spoon for feeding from one year of age. Psychological testing revealed severe delay in language development but only mild delay in motor, adaptive, and social development.
Cytogenetic Studies Trypsin-Giemsa banding of peripheral blood lymphocytes revealed an apparent fusion translocation between the short arms of a chromosome 14 and 18 (Fig. 2). C-banding (Arrighi and Hsu, 1971) revealed two blocks of heterochromatin in the translocation, suggesting two centromeres, and nearly complete absence of the short arms of the chromosomes 14 and 18 (Fig. 3). Although both centromeres may be present in this fusion translocation, only a single primary constriction was observed, suggesting one functioning centromere. Absence of ammoniacal silver staining (Howell and Denton, 1975) immediately above the primary constriction (Fig. 4) indicated absence of the stalk region of chromosome 14. Karyotypes of both parents were normal.
Comment The clinical features of our patient and those previously reported with centric fusion translocations of the long arm of chromosome 18 are summarized in Table 1. Although one might assume a more severe phenotypic effect from complete absence of the short arm of chromosome 18, the same spectrum of clinical features as seen in Table 1 has been observed in patients with only partial deletions of the short arm (Faust et al., 1976). These observations suggest that the etiologically important portion of the short arm of chromosome 18 may be limited to a small terminal segment. This explanation would be consistent with the relatively small total R-band regions (proposed genetically functional regions) observed in chromosome 18 (Hoehn, 1975), and may be analogous to the evidence that Down Syndrome results from trisomy of a single band in the long arm of chromosome 21 (Niebuhr, 1974). Robertsonian translocations, i.e. long arm fusions between acrocentric chromosomes, have recently been shown to include both centromeres (Daniel and Lam-Po-Tang, 1976). To the authors' knowledge, none of the long arm 18 fusions previously reported (Table 1) have been shown to be dicentric. Whether one or both centromeres have altered function is not known for the Robertsonian translocations nor for the apparent dicentric fusion reported in our patient. A disproportionate delay in language development has been previously reported in the 18p-- syndrome (Schinzel et al., 1974; Faust et al., 1976). Similarly, our patient showed marked delay in language development with only mild delay in motor, adative, and social development. Growth hormone, as well as immunoglobulin A deficiency, have been reported in the 18p-- syndrome (Schinzel et al., 1974). The growth hormone deficiency was not responsive to replacement therapy in one patient (Leisti et al., 1974). One previously reported patient with IgA deficiency and 18p-- had
Dicentric Fusion in the 18p- Syndrome
249
c h r o n i c skin infections ( G i l g e n k r a n t z et al., 1974) b u t others, i n c l u d i n g the b o y r e p o r t e d here, a p p a r e n t l y have n o t h a d an increased incidence o f infections. The r e p o r t o f one p a t i e n t w h o d e v e l o p e d b e t a cell deficiency at age 5 years, a n d t h y r o i d deficiency with high t h y r o i d a n t i b o d y levels at age 9 years ( K i s t e n m a c h e r et al., 1974), e m p h a s i z e s the need for c o n t i n u e d e v a l u a t i o n o f e n d o c r i n e status in patients with the 1 8 p - - s y n d r o m e . In s u m m a r y , p a r t i a l o r n e a r l y c o m p l e t e absence o f the s h o r t a r m o f a c h r o m o s o m e 18 is a s s o c i a t e d with a range o f clinical features, f r o m a r r h i n e n c e p h a l y o r h o l o p r o s e n c e p h a l y a n d p e r i n a t a l d e a t h on the one extreme, t h r o u g h nasal h y p o p l a s i a a n d m i d f a c e r e t r a c t i o n as seen in the p a t i e n t r e p o r t e d here, to the o t h e r e x t r e m e o f o n l y m i n i m a l craniofacial changes a n d m i l d r e t a r d a t i o n . The severity o f clinical features does n o t a p p e a r to correlate with the a m o u n t o f m a t e r i a l missing f r o m the s h o r t a r m o f the 18 c h r o m o s o m e . Acknowledgement, We are grateful to Inge Lysdal for her assistance in preparation of the manuscript. This research supported in part by the U.C.L.A. Mental Retardation/Child Psychiatry Program; and N.I.H. grants MCH-927, HD-04612, HD-05615, and HD-06576.
References Arrighi, F. E., Hsu, T. C.: Localization of heterochromatin in human chromosomes. Cytogenetics 10, 81--86 (1971) Cohen, M. M., Putnam, T. I.: An 18q21q translocation in a patient with presumptive "monosomy G". Am. J. Dis. Child. 124, 908--910 (1972) Daniel, A., Lam-Po-Tang, P. R.L.C.: Structure and inheritance of some heterozygous Robertsonian translocations in man. J. Med. Genet. 13, 381--388 (1976) Faust, J., Habedank, M., Nieuwenhuijsen, C.: The 18p- syndrome; Report of four cases. Eur. J. Pediatr. 123, 59--66 (1976) Fraccaro, M., Herin, P., Hult6n, M., Ivemark, B. I., Jonasson, J., Lindsten, J., Tiepolo, L., Zetterqvist, P,: Structural abnormalities of chromosome 18. III. Two G/18 translocations, one identified as 22/18. Ann. G6n~t. 15, 93--98 (1972) Gilgenkrantz, S., Charles, J.-M., Cabrol, C., Mauuary, G., Vigneron, C.: D616tion due bras court du 18 par translocation t(22-, 18p+) avee d6flcit en IgA. Etude cytog6n6tique avec autoradiographic et fluorescence. Ann. G~n6t. 15, 275--281 (1972) Hoehn, H.: Functional implications of differential chromosome banding. Am. J. Hum. Genet. 27, 676--686 (1975) Howell, W. M., Denton, T. E., Diamond, J. R.: Differential staining of the satellite regions of human acrocentric chromosomes. Experientia (Basel) 31, 260--262 (1975) Kistenmacher, M. L., DiGeorge, A. M., Punnett, H. H.: 45,XX,-13,-18,t(18q13c0+ and autoimmune disorders. Am. J. Hum. genet. 26, 49A (1974) Leisti, J., Leisti, S., Perheentupa, J., Savilahti, E., Aula, P.: Absence of IgA and growth hormone deficiency associated with short arm deletion of chromosome 18. Arch. Dis. Child. 48, 320--322 (1973) Lurie, I. W., Lazjuk, G. I.: Partial monosomies 18; Review of cytogenetical and phenotypical variants. Humangenetik 15, 203--222 (1972) Malpuech, G., Raynaud, E. J., Belin, J., Godeneche, P., Grouchy, J. de: D616tion du bras court du 18 par translocation t(G-; 18p+). Une 6tude en fluorescence par la moutarde de quinacrine. Ann. Genet. 14, 213--218 (1971) Miller, J. Q., Selden, R. F., Meisner, L. F.: D/E translocation in a young girl. Sth. Med. J. (Bgham, Ala.) 63, 368--370 (1970)
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Received April 8, 1977 / June 20, 1977
