American J o u r n a l of Medical G e n e t i c s 4: 323-332 (1979)

Familial, Balanced Insertional Translocation of Chromosome 7 Leading to Offspring With Deletion and Duplication of the Inserted Segment, 7p15 + 7p21

Marvin Miller, Genevieve Kaufman, George Reed, Robert Bilenker, and Albert Sch inzel Department of Medicine, Division of Medical Genetics and Center for Inherited Diseases, University of Washington, Seattle (M.M.); Department of Pathology (G. K., G. R.), and Department of Pediatrics, Comprehensive Care Unit (R. B.), Case Western Reserve University School of Medicine at Cleveland Metropolitan General Hospital, Cleveland; and Dysmorphology Unit, University of Washington, Seattle (A.S.)

We report an uncle and niece with duplication and deletion, respectively, of segment 7p15 + 7p2 1 originating from a balanced, intrachrornosornal insertion in their mothers. The proposita had prenatal and postnatal growth deficiency, retarded psychomotor development, rnicrocephaly, wide cranial sutures, ocular hypertelorisrn, small palpebral fissures, apparently low-set and malformed ears, cleft palate, congenital heart defect, hypoplasia of the distal phalanx of first fingers, rocker-bottom feet, persistent cloaca, and imperforate anus. She died at three months. Her maternal uncle has duplication of this segment and is alive at 3 2 years. H e has severe mental deficiency, but normal growth; corn- municating hydrocephalus was diagnosed a t three months.

Key words: translocation, insertional balanced, chromosome 7, craniostenosis

INTRODUCTION

Banding techniques have made it possible to identify specific regions involved in chromosome aberrations and t o distinguish between terminal and interstitial rearrangements. We report a family in which three persons have a balanced intrachromosomal rearrange- ment of a chromosonie 7, leading to offspring with deletion as well as duplication of an interstitial segment of the short arm of chromosome 7.

Received for publication November 20, 1978; revision received March 22, 1979.

Albert Schinzel is now at the Division of Medical Genetics, Department of Pediatrics, University of Zurich, CH 8032, Zurich, Switzerland.

Address reprint requests t o Marvin Miller, MD, Division of Medical Gcnetics, University of Washington, Seattle, WA 98195.

0148-7299/79/0404-0323$02.00 0 1979 Alan R. Liss, Inc.

324 Miller et a1

REPORT OF PATIENTS

Patient 1

The proposita (111-3, Fig. 1 ; RW 040676) was born at 4 2 weeks t o a 19-year-old black primigravida. The father was 2 0 years old at the time of birth. The pregnancy was complicated by a urinary tract infection during the third month; it was treated with ampicillin for 10 days. The only other medication taken during pregnancy was iron and vitamins.

Following spontaneous onset of labor, the patient was born by precipitous, vaginal delivery. The amniotic fluid was meconium-stained, and there was only one umbilical artery. Apgar score at one minute was 4, and resuscitation was immediately started in the newborn intensive care unit. She responded t o oxygen and by 15 minutes the vital signs were stable. Birthweight was 2,260 gm (< 3rd %), length was 48 cm (3rd %), and OFC Head circumference 3 1.5 cm (< 3rd %).

microcephalic, with a widely spaced sagittal suture measuring 6 cm between the two parietal bones. The other cranial sutures were normal, The palpebral fissures were hori- zontal and measured 1.3 cm. The inner canthal distance was 3.0 cm. The ears were apparently low-set, posteriorly rotated, and malformed. The right nostril was flattened, and the nasal bridge was depressed. The mouth was normal except for hyperplastic alveolar ridges. There was a midline cleft of the soft palate. On examination the lungs and heart were normal. Abdomen was unremarkable. There was an enlarged clitoris with an imperforate anus and passage of meconiuin through the vagina. The patient’s fingers were distally tapered with hypoplasia of the distal phalanx and nail hypoplasia of both first fingers; she had rocker- bottom feet. Neurologic examination showed absence of a Moro reflex with no focal neurologic signs.

Intravenous pyelogram showed bilateral hydronephrosis, and retrograde injection through the vagina revealed a cloaca1 abnormality. Skeletal radiographs showed under- development of the tibia1 epiphyses and poor ossification of the membranous bones of

Examination at birth revealed numerous congenital anomalies (Fig. 2). The head was

the skull.

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Fig. 1. Pedigree of family studied in this report. a - carrier of balanced intrachromosomal insertion: 46,XX,ins(7)(pl500p2104q22); - partial duplication 7p: 46,XY,rec(7)dup(pl5OOp2104)ins(7) (p1500p2104q22)mat; 3 - partial deletion 7p: 46,XX,rec(7)del(pl500p2104)ins(7)(pl500p2104q22) mat; - normal karyotype; a - spontaneous abortion; @ - multiple malformations, early infant death, no chromosome examination; 0 - phenotypically normal, no chromosome examination.

7p Deletion, Duplication 325

Fig. 2. The proposita at one month. Note hypertelorism and short palpebral fissures.

The baby had a stormy neonatal course with congestive heart failure, sepsis, and evidence of severe neurologic deficit and lack of growth, and she died at 3 months. Post- mortem examination showed a weight of 2,550 gm, length of 5 1 cm and OFC of 3 2 cm; all are below the third centile for age and sex. The following abnormalities were noted at autopsy: 1) tetralogy of Fallot with infundibular pulmonic stenosis, small (<0.5 cm) membranous ventricular septa1 defect, probe-patent foramen ovale, and widely patent ductus arteriosus (0.7-cm diameter): 2) eventration of the left diaphragm; 3) bilateral hydronephrosis with osmotic nephrosis of tubules; 4) small uterus, small Fallopian tubes, and small, histologically unremarkable ovaries; 5 ) imperforate anus with rectovaginal fistula; 6) intimal thickening of the intralobular arteries of the kidneys; hypoplasia of left hypogastric artery; 7) normal bone marrow elements with a defect in bone maturation; 8) absence of the falx cerebri and absence of the superior sagittal sinus with unfused sagittal suture and 7-cm distance between the two parietal bones; 9) brain of weight 420 gm showing no gross abnormalities when sectioned; histologic changes of anoxic encephalopathy.

Patient 2

The maternal uncle (11-7, Fig. 1 ; WM 121646) was born to a 27-year-old mother at 36 weeks gestation. It was not possible to examine him and little clinical information is available. Birthweight was reportedly normal. Communicating hydrocephalus was noted at 3 months. Growth was normal but he has severe mental deficiency. At 32 years, he is institutionalized, has n o intelligible speech, but is able t o perform self-help skills.

FAMILY HISTORY

Of the 15 pregnancies of the maternal grandmother (1-2, Fig. I) ofpat ient I , five ended in spontaneous abortion, and two in live-born children who died in early infancy. 11-4 died at 2 hours and reportedly had birth defects, but no records are available and no autopsy was done. 11-10 died at 4 months and on autopsy the following abnormalities were

326 Miller et a1

noted: 2-3 bilateral syndactyly of fingers and toes; a malformed nail on right hallux; an open posterior fontanel which measured 8 X 6 cm, and a 3.5-cm-wide sagittal suture. No gross or microscopic abnormalities of the brain were reported.

111-1 was stillborn at term with several malformations. The autopsy report noted marked widening of the sagittal suture, the parietal bones being 7 cm apart, tapering of the fingers with “deformities” of the digits, patent ductus arteriosus, large patent foramen ovale, but no other congenital heart defects, and bilateral hip dislocation.

Except for Patient 2, the remaining eight children of I-2 are apparently healthy.

CYTOG E N ET IC STUD I ES

We examined the G-banded karyotypes of the proposita, her parents, maternal grand- parents, and of two of her mother’s sibs. Patients I and 2 had different structural abnorm- alities of one chromosome 7. Patient 1 had a shortened short arm of chromosome 7 (Fig. 3b), and in Patient 2 it was noted that an additional segment was inserted in the long arm of chromosome 7 (Fig. 3c). The mother of the proposita had a balanced insertional trans- location of a segment of 7p into 7q (Fig. 3a). The long arm of the rearranged chromosome

Fig. 3 . G banding of the normal (left) and abnormal (right) number 7 chromosomes from (a) the mother (11-1 5) o f the proposita with the balanced insertional translocation: 46,XX,ins(7)(pISOOp2 104q22); (b) the prooosita (111-3), who is rnonosomic for 7plSOOp2104; and (c) the maternal uncle (11-7) of the proposita, who is trisomic for the same segment of 713. Note the identical short arms of the rearranged (right) number 7 chromosomes in (a) and (b) and the identical long arms of (a) and (c). Also note the slightly shorter subterminal G band of the short arm of the rearranged number 7 chromosomes in (a) and (b) compared to the normal homologue.

7p Deletion, Duplication 327

was identical to the long arm of the abnormal chromosome 7 in Patient 2, each containing an additional dark G band between the two normal-sized major bands and some additional G-light-staining material. The short arm of the balanced, rearranged chromosome was identical to the short arm of chromosome 7 in Patient 1.

We interpret the rearrangement as an intrachromosomal translocation (Fig. 4a, b): most of band 7p21 and the adjacent light-staining band 7p15 (tentatively from 7 ~ 2 1 0 4 to 7 ~ 1 5 0 0 , according to the Paris Chromosome Conference, 1971, Supplement, 1975) have been inserted into the long arm of the same chromosome, The rest of band 7p2 1 fused with band 7p14 (which actually is smaller than is depicted in the diagram of the Paris Chromosome Conference, 1971, Supplement 1975). An exact determination of the break point on the long arm of chromosome 7 within band 7q22 is not possible, because it is unclear whether the insertion is noninverted with respect to the centromere (in which case it would be approximately 7q2202) or is inverted (in which case it would be approximately 7q2208). The former situation is diagrammed in Figure 4b.

Individuals 1-2 and 11-2 had the same intrachromosomal rearrangement. The karyotype of The karyotype of the proposita's mother is therefore 46,XX,ins(7)(pI 500p2104;q22).

-R cen I

a b C d e Fig. 4. Diagram of the balanced and unbalanced rearrangements of chromosome 7 in the present family. a: Normal number 7 (according to the Paris Chromosome Conference 1971, Supplement 1975). b: Noninverted insertional translocation of approximately 7p1500-7p2104 into 7q22. c: Meiotic pairing of the two homologous chromosomes a and b with the formation of two inversion loops in the normal lioniologue. C r o s h g over a t any point within the large loop (between 7 ~ 1 5 0 0 and 7q22) results in the two unbalanced daughter chromosomes d and e. Chromosome d contains the long arm of the normal 7 chromosome a and the short arm of the rearranged 7 chromosome b and is thus deficient for 7p1500-7p2104. Chromosome e contains the short arm of the normal 7 chromosome a and the long arm of the rearranged 7 chromosome b with duplication of 7~1500-72104. If crossover occurs in the region distal to the two break points (outside both loops), the resulting meiotic products will be similar to the chromosomes at the onset of meiosis, a normal number 7 chromosome and one with a balanced insertional translocation. If a crossover occurs within the smaller loop, which contains the inserted segment, then the resulting meiotic products will also be unbalanced, but different from those when crossover occurs within the larger loop. In the former, one chromosome will be deficient for the segment p2104-tpter and disoniic for the segment 7q22-+7qter, and the latter the situation is just the opposite.

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the proposita is 46,XX,rec(7)del(pl500p2104),ins(7)(pl5OOp2104;q22) mat, and that of Patient 2 is 46,XY,rec(7)dup(pl5OOp2 104),ins(7)(pl5OOp2 104q22) mat. The unbalanced rearrangements in the patients can be explained through meiotic crossing over between the breakpoints 7 ~ 1 5 0 0 and 7q22 (Fig. 4c). The normal homologue (a) formed two inversion loops, one loop containing the segment mentioned above and the other loop consisting of the translocated segment 7p1500-7p2104. Such a crossover results in two recombinant number 7 chromosomes (Fig. 4d,e), one being deficient in the segment 7pl500-7p2104 (Patient I), the other having a duplication of the same segment (Patient 2).

DISCUSSION

Balanced interchromosome and intrachromosome insertions which lead to viable offspring with an unbalanced chromosome constitution were not reported prior to the era of chromosome banding, since it was not possible to distinguish these two situations from balanced reciprocal translocations and pericentric inversions, respectively. At least one family with a balanced intrachromosome insertion analogous to that of the present family has been reported. Garver et a1 [ l ] , and Pan et a1 [2] described a large family in which there was a balanced insertional translocation of a segment of the short arm of chromosome 1 into the long arm of the same chromosome. This led to both types of unbalanced gametes (deletions and duplications of the inserted segment of chromosome 1) following meiotic crossing over. In that case and the present one, the two proximal break points on the opposite sides of the involved chromosome were relatively far from the centromere. Consequently, there was a high probability of meiotic recombination between these two break points, thus giving unbalanced recombinants (see Fig. 4c).

described by Therkelsen et a1 [3]. However, the correlation between phenotype and karyotype in the malformed patient is not clear, since he shows the same apparently balanced insertional translocation as his unaffected father.

Familial balanced interchromosomal insertions are more common than intra- chromosomal insertions. At least nine families with balanced interchromosomal insertions have been described in which there have been unbalanced offspring. Interestingly, in only one of the nine families was there an unbalanced offspring due to meiotic crossing over between the normal and balanced chromosome, thus leading to partial trisomy of the inserted segment [4]. In the eight other families the unbalanced offspring resulted from the random segregation of the chromosomes involved in the rearrangement [5-121 . The likely explanation of this is that the inserted segments are usually short, reducing the probability of crossing over within them. In interchromosomal, insertional translocations unbalanced gametes will result only if the crossing over occurs within the inserted segment. This must be contrasted with the situation involving an intrachromosomal insertional translocation, where unbalanced gametes will result if crossing over occurs between the two proximal break points and is not dependent on the length of the insertional segment.

resulted from different cytogenetic events: 1) probable de novo terminal deletions [ 13, 141 , 2) de novo unbalanced translocation [15] , 3) probable insertional deletion [16], 4) ring formations [17], and 5 ) unbalanced familial pericentric inversions [I81 . No two cases have had exactly the same deletion, and the ring chromosome cases were also deficient for a terminal segment of 7q. Thus there has been considerable cytogenetic heterogeneity among these reported cases, and it cannot be expected that a common clinical syndrome would

Another family with a balanced insertional translocation within chromosome 2 was

Several cases of deletions of the short arm of chromosome 7 have been reported that

7p Deletion, Duplication 33 1

emerge from these cytogenetically different cases. However, an association between deletions of 7p and craniostenosis has been mentioned [ 13, 14, 16, 171 . The remainder of the clinical features of these cases have little similarity. Table I summarizes the cytogenetic and clinical features in eight individuals monosomic for part of 7p.

The patient reported by Wilson et a1 [13] more likely has a balanced 7/13 transloca- tion than a terminal deletion. In the ring chromosome cases [16] the clinical findings could be due to deletions of the terminal segment of 7p, 7q, or both. In the cases of Nakagome et a1 [ 151 , Winsor et a1 [ 181 , and our proposita, none of whom had craniostenosis, evidence of a partial deletion of 7p is stronger than in the two other cases with craniostenosis, which were de novo deletions of 7p [13, 151. In the latter two cases a hidden balanced or unbalanced rearrangement cannot be completely ruled out. In the case of Nakagome et a1 [15] the centromere of the translocated chromosome 15 was demonstrated by C banding, thus providing strong evidence of a loss of a terminal segment of 7p (probably 7p22 and a distal portion of 7 ~ 2 1 ) . Winsor et a1 [8] described two cousins who showed deletions of 7p22-pter and duplications for 7q32-qter resulting from a familial pericentric inversion in their respective mothers. Both had mental deficiency, and one had plagiocephaly but no craniostenosis. In the present case the balanced re- arrangement in the mother demonstrated a deletion of 7p15 and a part of 7p21 in the proband.

suture abnormalities. Of 8 cases with 7p- listed in Table I, 6 had microcephaly, 4 cranio- stenosis, 2 widely spaced sutures, and one plagiocephaly. Since none of the 8 had identical 7p chromosome loss, except perhaps the ring chromosome cases, it is of interest that cranial bone and suture abnormalities can occur over such a wide and variable spectrum of monosomy for different portions of chromosome 7. Craniostenosis has been noted in several other chromosome syndromes - duplication 5p [21] , 13q- [22], trisomy 13 and triploidy [23] - while broad sutures have been seen in duplication 7q [24] . However, we believe that craniostenosis may not be as consistent a feature of the 7p- syndrome as was originally thought.

abortions, two children who died early in infancy (11-4 and 11-10), and a stillbirth (111-1). It is possible that most of these conceptuses iepresent unbalanced rearrangements that were spontaneously aborted. Widely spaced sutures and early postnatal death in cases 11-10 and 111-1 may indicate that both of these individuals had deletion of 7p, since both of these manifestations characterized the proposita, who had partial monosomy for 7p. These two unbalanced chromosome constitutions once again demonstrate that deletions of an auto- soma1 segment are, as a rule, less viable and lead to more severe disturbance of prenatal development than duplications of the identical segment [25] .

Thus, a common clinical feature of 7p- syndrome appears t o be cranial bone and

Generations I1 and I11 contain one malformed, living individual (11-7), five spontaneous

ACKNOWLEDGMENTS

This study was supported by Department of Health, Education, and Welfare/US Public Health Service grant GM15253 from the National Institute of General Medical Sciences.

The authors would like to thank Dr. Holger Hoehn and his staff for help in the preparation and photography of some of the karyotypes, Dr. Arno G. Motulsky for review- ing the manuscript, and Dorothy Van Winkle for help in the preparation of the manuscript.

332 Miller et a1

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Edited by Uta Francke