Clinical Genetics 1978: 14: 98-104
Abnormalities resulting from a familial pericentric inversion of chromosome 18 M. K. KUKOLICH, B. W. ALTHAUS, J . W. SEARS, C . B. MANKIWNAND R. C . LEWANWWSKI Texas Department of Mental Health and Mental Retardation, Genetics Screening and Counseling Service, Denton, Texas, U S A . A female infant is reported with duplicationldeficiency of chromosome number 18 due to a familial pericentric inversion of chromosome 18. This patient had many of the classical findings of trisomy 18. Received I 1 January, accepted for publication 28 March 1978 K e y words: Arches; chromosome 18; duplication/deficiency; failure to thrive; inversion;
pericentric.
Familial pericentric inversions of many of the autosomal chromosomes have been reported (Ferguson-Smith 1977). There is little information, however, concerning pericentric inversion of chromosome 18 or the risk for recombinant chromosomes in the offspring of carriers of an inversion (ViannaMorgante et al. 1976, Vigi et al. 1977). A female infant with failure to thrive and multiple abnormalities on physical examination was referred to the Genetics Screening and Counseling Service as a possible trisomy 18. Chromosome analysis revealed a pericentric inversion of a chromosome 18 in the mother and a recombinant chromosome 18 in the infant. Case Report
The proposita (Fig. 1) was the first child born to a G-11, P-0, AB-I, 27-year-old woman and her nonconsanguinous 29-year-
old husband. There was a history of miscarriages and stillbirths in the maternal family (Fig. 2). T h e couple’s first pregnancy terminated in a spontaneous abortion at approximately 5 months of gestation. No information was available concerning the fetus. The second pregnancy was complicated by polyhydramnios. Delivery was at term and the amount of amniotic fluid was estimated to be 6000 cc. T h e infant weighed 2700 g, length was 48 cm, and head circumference was 36.8 cm. T h e infant had an initial Apgar Score of 4 and required intermittent oxygen. She was noted to be edematous a t birth and was kept in a n isolette for 3 days. Weight at discharge was 2270 g. Initial examination was at 3 months of age. T h e weight was 3380 g and length was 48 cm. T h e head circumference was 39.5 c m and the occiput was prominent. T h e hair was fine in texture with a large posterior hair whorl. The forehead was hirsute. Ab-
PERICENTRIC INVERSION OF CHROMOSOME 18
99
Fig. 1. Patient with partial duplication/deficiency of chromosome 18 at 3 months. Note abnormal facies with low-set ears, pectus excavatum, and lack of subcutaneous tissue.
normal facial characteristics included upslanting palpebral fissures, redundant skin folds of the eyelids, depressed nasal bridge, and upturned, bulbous nose. The palate was arched with a prominent midline ridge. The ears were low-set and posteriorly rotated. The remainder of the examination revealed a prominent pectus excavatum, hypoplastic nipples, minimal subcutaneous tissue, hypoplasia of the nails of the hands and feet, sacral dimple, and hypertonia. Since this initial examination, the child has progressed very slowly and at 1 year of age, height and weight were below the 3rd percentile, and head circumference was at approximately the 3rd percentile. Using the Denver Developmental Screening Test, she had only reached the developmental milestones expected of a 3-month old.
Dermatogly p hics The dermatoglyphics of the proposita, her parents, and maternal grandmother were studied (Table 1). The digital patterns of the proposita show 10 arches with a total finger ridge count of 0 and, the palms show a distal axial triradius with elevated atd angles, bilaterally. These findings are similar to findings in individuals with trisomy 18. The mother, an inversion carrier, shows an increased number of arches, with a total of five, and a low ridge count on the remaining ulnar loops, resulting in a reduced total finger ridge count of 20. Her palms were unremarkable. The maternal grandmother, also an inversion carrier, does not show an increased number of arches or low total finger ridge count. It was not possible to examine the
KUKOLICH
100
ET AL
h
r‘l
46 ,xx,rec ( 1 8 ) ,dup q inv ( 1 E l ( p l l . Z q f l .1)mat. ~
CARRIER PERICENTRIC INVERSION 16,Xx or XY.invllB1 (p11.2q21.1)
@ STILLBORN WITH CONGENITAL ANOUALIES
+& TESTED
N O W
@ STILLBIRTH,SEX
UNKNW
MISCARRIAGE
@ 6EX.NUHBER
VNKNDVN
Fig. 2. Family pedigree.
dermatoglyphics of the maternal grandfather to determine a high familial incidence of arches. The father’s prints are unremarkable. Cytogenetics
Both conventional 72-hour and synchronous lymphocyte cultures were established in RPMI-1640 (GIBCO) media from peripheral blood specimens of the proposita and her relatives. Following terminal 1-hour exposure to Colcemid, the cultures were harvested in the usual fashion and the cell pellets preserved by fixation. Slides were air dried prior to treatment by multiple banding
procedures that were employed using various standard technical protocols. A minimum of 30 cells were photomicrographed and individually analyzed for each individual. Karyotype analyses of C - , G-, Q-, and R-banded late prophase and early metaphase chromosome spreads of the proposita revealed normal chromosome morphology in all pairs of chromosomes except the number 18’s. One chromosome 18 was of increased length; it had a considerably enlarged p-arm bearing two conspicuous large, moderately fluorescent bands (Fig. 3). The parents were studied in order to determine the source of the additional mat-
PERICENTRIC INVERSION OF CHROMOSOME 18
101
Table 1
Subject:
I
Digital patterns 11 111 IV
Proposita Right Left
A A
A A
A A
A A
A A
Mother Right Left
L" A
A A
A A
L" L"
Father Right Left
A: L": Lr:
a-b ridge
ATD angle
Palmar formula
0
24 27
45 63
9.'.7.5".13' 9.'.5'.4.13'
L"
20
37 36
36 38
11-9.9.7.V.13' 9-9.x.5'.4.13'
L"
Lp
w\
L"
w
W1 L"
WIl' L"
145
L"
36 37
38 41
11.9.7.4.13 9.x.5".4.13
L" L!,
w'
L" W'"
W' L"
L" L"
137
27 37
34 35
11.9.7.5'.13' 11.x.7.5'.13'
W*
Maternal grandmother Right Left
V
Total ridge
WY
Arch Ulnar loop Radial loop
Wy: Wcp:
W'":
Spiral whorl Central pocket whorl Double loop whorl Not determined
erial on the number 18 p-arm. Analysis of the father's Q- and R-banded karyotypes revealed that all chromosomal pairs were normal, except for the Y chromosome which was nearly metacentric as a result of a pericentric inversion within the non-fluo-
Fig. 3. Partial karyotypes of proposita's chromosomes. Upper row - Q-banded E-group chromosomes with the recombinant no. 18 placed at the far right. Lower row G-banded no. 18's on the left and a pair of 0banded 18's from another cell on the right. In both cases, the recombinant no. 18 is placed to the right.
-
Fig. 4. Partial karyotypes of the mother's chromosomes. Upper row - Q-banded E-group with the inverted no. 18 chromosome placed at the far right. Lower row - G-, C-, R-, and Q-banded pairs of no. 18 chromosomes with the inverted no. 18 placed to the right of each pair.
I02
K U K O L I C H ET AL.
P 0
0
0
NORMAL 18
INVERSION 18
2
RECOMB INANT 18
Fig. 5. Schematic diagram of the no. 18 chromosomes seen in the mother and proposita. The break points involved in the formation of the original pericentric inversion are shown with arrows on the normal 18. The p-arm bands are stippled for identification. The point of crossing over within the inverted region between the inverted 18 and the normal homologous chromosome during meiosis I is shown with the arrow on the inverted 18 chromosome. The recombinant 18 has a portion of the inverted 18 on the top (shown shaded), and a portion of the paired homologous normal 18 (shown non-shaded), resulting in both a duplication of bands q21-qZZ and a deficiency of band p11.3.
rescent region of the Y chromosome. The of the normal number 18 and in the homofather’s karyotype was judged to be 46,X, logous band located within the inverted inv(Y) ( p l l q l l ) according to the Paris Con- segment on the rearranged p-arm of the abference (1970, Supplement (1975). normal number 18. The recombinant numStudy of the mother’s G - , Q-, and R- ber 18, therefore, carries a duplication of banded karyotypes revealed a normal com- bands q21 through q22 and a deficiency of plement of chromosomes, except for one band p11.3 (Fig. 5). The proposita’s karyonumber 18 which was normal in length, but type is designated as 46,XX,rec(18),dup metacentric in appearance. Sequential fine- q,inv(l8) (pl1.2q21.l)mat. band analysis of the abnormal number 18 revealed a pericentric inversion (Fig. 4). The Discussion break-points were found to be at or near the interface of bands 11.2 and 11.3 in the p- The proposita has a partial trisomy for a arm and in the distal region of band 21 of segment of the long arm and a partial mothe q-arm. The mother’s karyotype was nosomy for a segment of the short arm of designated as 46,XX,inv(l8)(~11.2q21). chromosome 18. She shows many of the Crossing over within the inverted region features of trisomy 18 and a few of the of the abnormal number 18 apparently findings of the 18p- syndrome (Table 2). occurred in the mother between it and the Patients trisomic for only the distal portion normal homologous chromosome during of the long arm of chromosome 18 have meiosis I, giving rise to the recombinant also been reported (Steele et al. 1974, Neu number 18 chromosome found in the pro- et al. 1976), As expected, these patients have several features in common with the posita. As best as can be determined, the points proposita and are included in the table for of crossing over were just proximal to the comparison. The proposita’s chromosomal abnormality centromere at band 11 or 12.1 of the q-arm
103
P E R I C E N T R I C I N V E R S I O N OF C H R O M O S O M E 18
is apparently due to meiotic crossing over in the region of the pericentric inversion of a chromosome 18. The father of the proposita was found to have a pericentric inversion of the Y chromosome, but this does not appear to be involved in the chromosome imbalance seen in this case. Karyotypic study of other family members indicated that the inversion of chromosome 18 has been passed down through several generations (Fig. 2). The dermatoglyphic finding of a low dermal ridge count in the proposita is consistent with trisomy 18. The finding of a similar abnormality in the mother, who is an inversion carrier, is unusual. The possibility that this was due to the inversion was considered. However, the maternal grandmother, also an inversion carrier, did not show this pattern, and it has not been possible to study the maternal grandfather to evaluate the possibility of a high familial incidence of arches as contributing to the
dermatoglyphic abnormalities in the proposita and her mother. An estimate of the risk of recombination is necessary for genetic counseling in this family. Pericentric inversions of several of the autosomes in man have been reported. There is a great deal of variation in the estimates of the risks of recombinants occurring. Inversions involving a small portion of certain chromosomes, such as number 9, occur with a frequency of approximately 1 % (de la Chapelle et al. 1974) and may be inherited without apparent risk for recombination (Sutherland et al. 1976). However, in families with a positive history for previous recombinants, there is a significant recurrence risk. This risk has been estimated to be 5 % for male and 10 % for female inversion carriers to produce a chromosomally abnormal child (Sutherland et al. 1976, Vigi et al. 1977). Of particular significance to this case is a review of pericentric inversions involving t h e p l l q l 2 region of chro-
Table 2 Summary of findings in specific duplication or deficiency syndromes involving chromosome 18 Trisomy 18
Short arm partial deletion
Long arm partial trisomy
~
Polyhydramnios Developmental & growth retardation Microcephaly Prominent occiput Low-set, malformed ears Short palpebral fissures Micrognathia Narrow palate arch Short sternum Pectus excavatum Congenital heart Cryptorchidism Clenched hand Hypoplastic nails Low dermal ridge pattern on six or more digits Hypertonia Hypotonia ~~~
~
~~
u: unknown; nla: not applicable.
+
+ +
+ +
+ + + + + +
+ +
+ +
U
818 U
518 4/8
-
518 518 317
z2
a7 A14 618 U
516
-
w3
Our case
104
KUKOLICH ET AL.
mosome 18 (Vigi et al. 1977). T h e risk for a carrier of an inversion in this region to produce an offspring with duplication/deficiency was calculated to be 10 %. When a reasonable recurrence risk has been established, the possibility of amniocentesis for prenatal diagnosis must be considered. Although large recombination errors such as that seen in the proposita should be identifiable, smaller errors may prove difficult to recognize. I t is not clear what physical or developmental abnormalities would result from these smaller chromosomal imbalances. T h e families at risk must be informed concerning the difficulties with prenatal diagnosis and the possibility of not identifying a child with a small duplication/deficiency who might have significant physical or developmental handicaps. Acknowledgments
The authors thank M. Garcia and D. Hale for their technical assistance in the study of this case and manuscript preparation. The opinions or assertions contained herein are the private ones of the authors and are not to be interpreted as necessarily official or reflecting the view of the Texas Department of Mental Health and Mental Retardation. References
Ferguson-Smith, M. A. (1977). Human pericentric inversions; their behavior in meiosis and implications for genetic counseling. Excerpt. Med. 426, 31.
De La Chapelle, A. S., J. Schroder, K. Stenstrand, J. Fellman, R. Herva, M. Saarni, 1. Anitolainen, I. Tallia, L. Tervila, L. Husa, G. Tallqvist, E. B. Robson, P. J . L. Cook & R. Sanger (1974). Pericentric inversions of human chromosomes 9 and 10. Anier. J . hum. Genet. 28, 746-766. Neu, R. L., C. C . Ortega, G. A. Barg, W. Pinto, L. 1. Garddner, W. M. Howell & T. E. Denton (1976). Inclusion of satellites in an 18/21 translocation chromosome shown by ammonical-silver staining (set-banding) in the case of partial trisomy 18. J . med. Genet. 13, 5 20-5 22. Steele, M. W., S. Pan, J. Mickell & V. Senders (1974). Trisomy for the distal half of the long arm of chromosome no. 18. J . Pediat. 85, 827-829. Sutherland, G. R., A. J. Gardiner & R. F. Carter (1976). Familial pericentric inversion of chromosome 19, inv(l9) (p13q13) with a note on genetic counseling of pericentric inversion carriers. Clin. Genet. 10, 54-59. Vianna-Morgante, A. M., M. J. Nozaki, C. C. Ortega, V. Coates & Y . Yamamura (1976). Partial monosomy and partial trisomy 18 in two offspring of a carrier of pericentric inversion of chromosome 18. J . med. Genet. 13, 366-370. Vigi, V., P. Maraschio, G. Bosi, P. Guerini & M. Fraccaro (1977). Risk for recombinants in pericentric inversions of the (pllq12) region of chromosome 18. Hum. Genet. 37, 1-5.
Address: Mary K . Kukolich, M . D . Medical Geneticist TDMHMR Genetics Screening and Counseling Service 404 W . Oak Street Denton, Texas 76201 U.S.A.
Abnormalities resulting from a familial pericentric inversion of chromosome 18 M. K. KUKOLICH, B. W. ALTHAUS, J . W. SEARS, C . B. MANKIWNAND R. C . LEWANWWSKI Texas Department of Mental Health and Mental Retardation, Genetics Screening and Counseling Service, Denton, Texas, U S A . A female infant is reported with duplicationldeficiency of chromosome number 18 due to a familial pericentric inversion of chromosome 18. This patient had many of the classical findings of trisomy 18. Received I 1 January, accepted for publication 28 March 1978 K e y words: Arches; chromosome 18; duplication/deficiency; failure to thrive; inversion;
pericentric.
Familial pericentric inversions of many of the autosomal chromosomes have been reported (Ferguson-Smith 1977). There is little information, however, concerning pericentric inversion of chromosome 18 or the risk for recombinant chromosomes in the offspring of carriers of an inversion (ViannaMorgante et al. 1976, Vigi et al. 1977). A female infant with failure to thrive and multiple abnormalities on physical examination was referred to the Genetics Screening and Counseling Service as a possible trisomy 18. Chromosome analysis revealed a pericentric inversion of a chromosome 18 in the mother and a recombinant chromosome 18 in the infant. Case Report
The proposita (Fig. 1) was the first child born to a G-11, P-0, AB-I, 27-year-old woman and her nonconsanguinous 29-year-
old husband. There was a history of miscarriages and stillbirths in the maternal family (Fig. 2). T h e couple’s first pregnancy terminated in a spontaneous abortion at approximately 5 months of gestation. No information was available concerning the fetus. The second pregnancy was complicated by polyhydramnios. Delivery was at term and the amount of amniotic fluid was estimated to be 6000 cc. T h e infant weighed 2700 g, length was 48 cm, and head circumference was 36.8 cm. T h e infant had an initial Apgar Score of 4 and required intermittent oxygen. She was noted to be edematous a t birth and was kept in a n isolette for 3 days. Weight at discharge was 2270 g. Initial examination was at 3 months of age. T h e weight was 3380 g and length was 48 cm. T h e head circumference was 39.5 c m and the occiput was prominent. T h e hair was fine in texture with a large posterior hair whorl. The forehead was hirsute. Ab-
PERICENTRIC INVERSION OF CHROMOSOME 18
99
Fig. 1. Patient with partial duplication/deficiency of chromosome 18 at 3 months. Note abnormal facies with low-set ears, pectus excavatum, and lack of subcutaneous tissue.
normal facial characteristics included upslanting palpebral fissures, redundant skin folds of the eyelids, depressed nasal bridge, and upturned, bulbous nose. The palate was arched with a prominent midline ridge. The ears were low-set and posteriorly rotated. The remainder of the examination revealed a prominent pectus excavatum, hypoplastic nipples, minimal subcutaneous tissue, hypoplasia of the nails of the hands and feet, sacral dimple, and hypertonia. Since this initial examination, the child has progressed very slowly and at 1 year of age, height and weight were below the 3rd percentile, and head circumference was at approximately the 3rd percentile. Using the Denver Developmental Screening Test, she had only reached the developmental milestones expected of a 3-month old.
Dermatogly p hics The dermatoglyphics of the proposita, her parents, and maternal grandmother were studied (Table 1). The digital patterns of the proposita show 10 arches with a total finger ridge count of 0 and, the palms show a distal axial triradius with elevated atd angles, bilaterally. These findings are similar to findings in individuals with trisomy 18. The mother, an inversion carrier, shows an increased number of arches, with a total of five, and a low ridge count on the remaining ulnar loops, resulting in a reduced total finger ridge count of 20. Her palms were unremarkable. The maternal grandmother, also an inversion carrier, does not show an increased number of arches or low total finger ridge count. It was not possible to examine the
KUKOLICH
100
ET AL
h
r‘l
46 ,xx,rec ( 1 8 ) ,dup q inv ( 1 E l ( p l l . Z q f l .1)mat. ~
CARRIER PERICENTRIC INVERSION 16,Xx or XY.invllB1 (p11.2q21.1)
@ STILLBORN WITH CONGENITAL ANOUALIES
+& TESTED
N O W
@ STILLBIRTH,SEX
UNKNW
MISCARRIAGE
@ 6EX.NUHBER
VNKNDVN
Fig. 2. Family pedigree.
dermatoglyphics of the maternal grandfather to determine a high familial incidence of arches. The father’s prints are unremarkable. Cytogenetics
Both conventional 72-hour and synchronous lymphocyte cultures were established in RPMI-1640 (GIBCO) media from peripheral blood specimens of the proposita and her relatives. Following terminal 1-hour exposure to Colcemid, the cultures were harvested in the usual fashion and the cell pellets preserved by fixation. Slides were air dried prior to treatment by multiple banding
procedures that were employed using various standard technical protocols. A minimum of 30 cells were photomicrographed and individually analyzed for each individual. Karyotype analyses of C - , G-, Q-, and R-banded late prophase and early metaphase chromosome spreads of the proposita revealed normal chromosome morphology in all pairs of chromosomes except the number 18’s. One chromosome 18 was of increased length; it had a considerably enlarged p-arm bearing two conspicuous large, moderately fluorescent bands (Fig. 3). The parents were studied in order to determine the source of the additional mat-
PERICENTRIC INVERSION OF CHROMOSOME 18
101
Table 1
Subject:
I
Digital patterns 11 111 IV
Proposita Right Left
A A
A A
A A
A A
A A
Mother Right Left
L" A
A A
A A
L" L"
Father Right Left
A: L": Lr:
a-b ridge
ATD angle
Palmar formula
0
24 27
45 63
9.'.7.5".13' 9.'.5'.4.13'
L"
20
37 36
36 38
11-9.9.7.V.13' 9-9.x.5'.4.13'
L"
Lp
w\
L"
w
W1 L"
WIl' L"
145
L"
36 37
38 41
11.9.7.4.13 9.x.5".4.13
L" L!,
w'
L" W'"
W' L"
L" L"
137
27 37
34 35
11.9.7.5'.13' 11.x.7.5'.13'
W*
Maternal grandmother Right Left
V
Total ridge
WY
Arch Ulnar loop Radial loop
Wy: Wcp:
W'":
Spiral whorl Central pocket whorl Double loop whorl Not determined
erial on the number 18 p-arm. Analysis of the father's Q- and R-banded karyotypes revealed that all chromosomal pairs were normal, except for the Y chromosome which was nearly metacentric as a result of a pericentric inversion within the non-fluo-
Fig. 3. Partial karyotypes of proposita's chromosomes. Upper row - Q-banded E-group chromosomes with the recombinant no. 18 placed at the far right. Lower row G-banded no. 18's on the left and a pair of 0banded 18's from another cell on the right. In both cases, the recombinant no. 18 is placed to the right.
-
Fig. 4. Partial karyotypes of the mother's chromosomes. Upper row - Q-banded E-group with the inverted no. 18 chromosome placed at the far right. Lower row - G-, C-, R-, and Q-banded pairs of no. 18 chromosomes with the inverted no. 18 placed to the right of each pair.
I02
K U K O L I C H ET AL.
P 0
0
0
NORMAL 18
INVERSION 18
2
RECOMB INANT 18
Fig. 5. Schematic diagram of the no. 18 chromosomes seen in the mother and proposita. The break points involved in the formation of the original pericentric inversion are shown with arrows on the normal 18. The p-arm bands are stippled for identification. The point of crossing over within the inverted region between the inverted 18 and the normal homologous chromosome during meiosis I is shown with the arrow on the inverted 18 chromosome. The recombinant 18 has a portion of the inverted 18 on the top (shown shaded), and a portion of the paired homologous normal 18 (shown non-shaded), resulting in both a duplication of bands q21-qZZ and a deficiency of band p11.3.
rescent region of the Y chromosome. The of the normal number 18 and in the homofather’s karyotype was judged to be 46,X, logous band located within the inverted inv(Y) ( p l l q l l ) according to the Paris Con- segment on the rearranged p-arm of the abference (1970, Supplement (1975). normal number 18. The recombinant numStudy of the mother’s G - , Q-, and R- ber 18, therefore, carries a duplication of banded karyotypes revealed a normal com- bands q21 through q22 and a deficiency of plement of chromosomes, except for one band p11.3 (Fig. 5). The proposita’s karyonumber 18 which was normal in length, but type is designated as 46,XX,rec(18),dup metacentric in appearance. Sequential fine- q,inv(l8) (pl1.2q21.l)mat. band analysis of the abnormal number 18 revealed a pericentric inversion (Fig. 4). The Discussion break-points were found to be at or near the interface of bands 11.2 and 11.3 in the p- The proposita has a partial trisomy for a arm and in the distal region of band 21 of segment of the long arm and a partial mothe q-arm. The mother’s karyotype was nosomy for a segment of the short arm of designated as 46,XX,inv(l8)(~11.2q21). chromosome 18. She shows many of the Crossing over within the inverted region features of trisomy 18 and a few of the of the abnormal number 18 apparently findings of the 18p- syndrome (Table 2). occurred in the mother between it and the Patients trisomic for only the distal portion normal homologous chromosome during of the long arm of chromosome 18 have meiosis I, giving rise to the recombinant also been reported (Steele et al. 1974, Neu number 18 chromosome found in the pro- et al. 1976), As expected, these patients have several features in common with the posita. As best as can be determined, the points proposita and are included in the table for of crossing over were just proximal to the comparison. The proposita’s chromosomal abnormality centromere at band 11 or 12.1 of the q-arm
103
P E R I C E N T R I C I N V E R S I O N OF C H R O M O S O M E 18
is apparently due to meiotic crossing over in the region of the pericentric inversion of a chromosome 18. The father of the proposita was found to have a pericentric inversion of the Y chromosome, but this does not appear to be involved in the chromosome imbalance seen in this case. Karyotypic study of other family members indicated that the inversion of chromosome 18 has been passed down through several generations (Fig. 2). The dermatoglyphic finding of a low dermal ridge count in the proposita is consistent with trisomy 18. The finding of a similar abnormality in the mother, who is an inversion carrier, is unusual. The possibility that this was due to the inversion was considered. However, the maternal grandmother, also an inversion carrier, did not show this pattern, and it has not been possible to study the maternal grandfather to evaluate the possibility of a high familial incidence of arches as contributing to the
dermatoglyphic abnormalities in the proposita and her mother. An estimate of the risk of recombination is necessary for genetic counseling in this family. Pericentric inversions of several of the autosomes in man have been reported. There is a great deal of variation in the estimates of the risks of recombinants occurring. Inversions involving a small portion of certain chromosomes, such as number 9, occur with a frequency of approximately 1 % (de la Chapelle et al. 1974) and may be inherited without apparent risk for recombination (Sutherland et al. 1976). However, in families with a positive history for previous recombinants, there is a significant recurrence risk. This risk has been estimated to be 5 % for male and 10 % for female inversion carriers to produce a chromosomally abnormal child (Sutherland et al. 1976, Vigi et al. 1977). Of particular significance to this case is a review of pericentric inversions involving t h e p l l q l 2 region of chro-
Table 2 Summary of findings in specific duplication or deficiency syndromes involving chromosome 18 Trisomy 18
Short arm partial deletion
Long arm partial trisomy
~
Polyhydramnios Developmental & growth retardation Microcephaly Prominent occiput Low-set, malformed ears Short palpebral fissures Micrognathia Narrow palate arch Short sternum Pectus excavatum Congenital heart Cryptorchidism Clenched hand Hypoplastic nails Low dermal ridge pattern on six or more digits Hypertonia Hypotonia ~~~
~
~~
u: unknown; nla: not applicable.
+
+ +
+ +
+ + + + + +
+ +
+ +
U
818 U
518 4/8
-
518 518 317
z2
a7 A14 618 U
516
-
w3
Our case
104
KUKOLICH ET AL.
mosome 18 (Vigi et al. 1977). T h e risk for a carrier of an inversion in this region to produce an offspring with duplication/deficiency was calculated to be 10 %. When a reasonable recurrence risk has been established, the possibility of amniocentesis for prenatal diagnosis must be considered. Although large recombination errors such as that seen in the proposita should be identifiable, smaller errors may prove difficult to recognize. I t is not clear what physical or developmental abnormalities would result from these smaller chromosomal imbalances. T h e families at risk must be informed concerning the difficulties with prenatal diagnosis and the possibility of not identifying a child with a small duplication/deficiency who might have significant physical or developmental handicaps. Acknowledgments
The authors thank M. Garcia and D. Hale for their technical assistance in the study of this case and manuscript preparation. The opinions or assertions contained herein are the private ones of the authors and are not to be interpreted as necessarily official or reflecting the view of the Texas Department of Mental Health and Mental Retardation. References
Ferguson-Smith, M. A. (1977). Human pericentric inversions; their behavior in meiosis and implications for genetic counseling. Excerpt. Med. 426, 31.
De La Chapelle, A. S., J. Schroder, K. Stenstrand, J. Fellman, R. Herva, M. Saarni, 1. Anitolainen, I. Tallia, L. Tervila, L. Husa, G. Tallqvist, E. B. Robson, P. J . L. Cook & R. Sanger (1974). Pericentric inversions of human chromosomes 9 and 10. Anier. J . hum. Genet. 28, 746-766. Neu, R. L., C. C . Ortega, G. A. Barg, W. Pinto, L. 1. Garddner, W. M. Howell & T. E. Denton (1976). Inclusion of satellites in an 18/21 translocation chromosome shown by ammonical-silver staining (set-banding) in the case of partial trisomy 18. J . med. Genet. 13, 5 20-5 22. Steele, M. W., S. Pan, J. Mickell & V. Senders (1974). Trisomy for the distal half of the long arm of chromosome no. 18. J . Pediat. 85, 827-829. Sutherland, G. R., A. J. Gardiner & R. F. Carter (1976). Familial pericentric inversion of chromosome 19, inv(l9) (p13q13) with a note on genetic counseling of pericentric inversion carriers. Clin. Genet. 10, 54-59. Vianna-Morgante, A. M., M. J. Nozaki, C. C. Ortega, V. Coates & Y . Yamamura (1976). Partial monosomy and partial trisomy 18 in two offspring of a carrier of pericentric inversion of chromosome 18. J . med. Genet. 13, 366-370. Vigi, V., P. Maraschio, G. Bosi, P. Guerini & M. Fraccaro (1977). Risk for recombinants in pericentric inversions of the (pllq12) region of chromosome 18. Hum. Genet. 37, 1-5.
Address: Mary K . Kukolich, M . D . Medical Geneticist TDMHMR Genetics Screening and Counseling Service 404 W . Oak Street Denton, Texas 76201 U.S.A.
