American Journal of Medical Genetics 42:404-413 (1992)
DISTAL LIMB DEFICIENCY FOLLOWING CHORIONIC VILLUS SAMPLING?
Rudiger SchWoo, Peter Miny, Wolfgang Holzgreve, Jurgen Horst, Widukind Lenz Department of Human Genetics, Department of Gynecology, Universitatsklinik Munster, Germany We have reviewed the follow-up of almost 3000 completed pregnancies in the Munster CVS Program and identified 4 children with distal limb deficiencies. Two cases involved only minor anomalies of distal digital phalanges. One child had a Hanhart anomaly (hypoglossia hypodactylia) We also reviewed 2 4 cases of limb defects following CVS reported previously. With the exception of a single series, neither the overall incidence of affected children nor cases reported from larger series provide unambiguous evidence of an increased risk of distal limb deficiency caused by CVS.
.
KEY W0RDS:chorionic villus sampling, distal limb deficiency, review INTRODUCTION Firth et al. (1991a,b) drew attention to a possible causal relationship of chorionic villus sampling (CVS) at 56-66 days of gestation and limb abnormalities of the fetus. Some kind of vascular insult was the suspected pathogenesis in 5 cases of severe Received for publication August 16, 1991; revision accepted November 18, 1991.
Address
reprint requests to R. Institut fur Humangenetik, Vesaliusweg 12-14, 4400 Munster, FRG Schloo,
0 1992 Wiley-Liss, Inc.
Obstetrics and
limb deficiency encountered in a series of 539 procedures. Shepard et (1991) proposed alternative al. mechanisms following accidental amniotic puncture during CVS, i. e. formation of amniotic bands, loss of amniotic fluid, or entrapment of distal limbs in the 'exocoelomic gel'. Subsequently other investigators reviewed their experience and reported disturbing (Hsieh et al., 1991; Mastroiacovo and Cavalcanti, 1991; Monni et al., 1991), but also for some of the larger series, reassuring data (Mahoney, 1991; Jackson et al., 1991; Miny et al., 1991; MRC Working Party on the Evaluation of Chorion Villus Sampling, 1991). Since CVS performed either transcervically or transabdominally may theoretically lead to vascular complications such as thrombosis of the mesenchymal core vessels of villi with subsequent embolism, the need for a careful risk assessment is obvious. Mastroiacovo and Cavalcanti (1991) have already addressed the possible involvement of other body areas in local hypoperfusion such as the brain. We present in detail 4 limb deficiencies observed in our series of almost 3000 completed pregnancies
Limb Defects Following CVS?
after transabdominal and transcervical CVS in the first trimester of pregnancy, and we also include data on the frequency of other structural defects of the Furthermore, we analysed fetus previously reported cases in an attempt to correlate the severity of limb defects with the gestational age at CVS or other procedure related criteria.
.
PATIENTS AND METHODS Between January 1, 1985 and June 30, 1991, a total of 2537 transcervical (TC) and 763 transabdominal (TA) procedures was carried out in the first trimester and 548 transabdominal placental biopsies in the second and third trimesters. Chorionic tissue was aspirated transabdominally with a 20 gauge spinal needle and transcervically by a polyethylene catheter with an external diameter of 1.7 mm (Holzgreve and Miny, 1987). Eighty-five TA and 551 TC procedures were done at 66 days or earlier. At the time of preparing this report, information on pregnancy 2836 outcome was available on pregnancies after CVS in the first trimester and 137 pregnancies ended in spontaneous abortions before 28 weeks of pregnancy. Follow-upinformation was available on nearly all patients and was collected from written reports of the obstetricians and additional phone interviews with the mothers. RESULTS Anatomical defects were recorded in a total of 16 newborn infants (5 heart defects, 4 isolated cleft lip/palate, 4 limb defects, 1 hypospadia, 1 gastroschisis, and 1 case with multiple malformations including cleft palate, hypertelorism, and agenesis of corpus callosum).
405
The children with limb defects of differing severity were examined between age 7 weeks and 2 years. There was no family history of limb abnormalities in 2 families. However, 2 maternal uncles of case C444/88 reportedly also had limb defects. In one uncle a ray of the right hand was absent. The other uncle had a duplication of the right thumb and a cleft lip and palate. Both were otherwise normal. Hands and feet were normal in the patient's mother. The mother of case I046/89 had bilateral camptodactyly. Case 1 (C037/85): At age 11 month he had classical Hanhart syndrome (Figs. 1-3, 5, 6 ) . Psychomotor development was adequate for age. CVS had been performed at 9 weeks of gestation (59 menstrual days, Table I). A radiological examination was performed at age 10 months (Figs. 4, 7). Case 2 (1046/89): The patient was seen at age 19 months. The examination showed minor anomalies (Figs. 8 , 9 ) . No radiological examination was performed. The patient's mother had bilateral camptodactyly and symphalangism (Fig. 10). Case 3 (I204/90) : Transcervical 10 weeks (2 CVS failed at insertions) and was instead performed transabdominally at 13 weeks (1 insertion). The clinical examination at age 7 weeks showed shortness of the distal phalanges of digits 3, 4 and 5 with absent nails on the left hand. No radiological examination was performed (Fig. 11). Case 4 (C444/88) : The examination at age 2 years showed only 4 rays in the right hand in an otherwise normal infant (Figs. 12, 13). See above for family history. A radiological examination was performed at age 5 months (Fig. 14). Details of CVS in cases 1-4 are shown in Table I.
Fig.1: Case 1: Hanhart syndrome: severe micrognathia
Fig.5: Case 1: Hanhart syndrome: normal appearing right foot.
Fig.2: Case 1: Hanhart syndrome: right hand.
Fig.6: Case 1: Hanhart syndrome: transversal defect of the left foot.
Fig.3: Case 1: Hanhart syndrome: left hand.
Fig.7: Case 1: Hanhart syndrome: X-ray of left and right foot.
Fig.4: Case 1: Hanhart syndrome: X-ray of left and right hand.
Fig.8: Case 2: at age 19 month: hypoplastic and tapering left index finger.
Fig.9: Case 2: short digits 1 and 2 in the left foot, zygodactyly, small nail in digit 1, missing nail in digit 2 .
Fig.10: Mother of Case 2: Bilateral camptodactyly of digits 5, poorly developed distal flexion creases of digits 4 . -
Fig.11: Case 3 : Absent or hypoplastic phalanges of digits 3 , 4 , 5 of the left hand.
Fig.12: Case 4: syndactyly of digits 2 and 3 of the right hand.
Fig.13: Case 4: partial cutaneous syndactyly 4 and 5 of the right hand.
Fig.14: Case
4:
X-ray of both hands.
C37/85
maternal age 35 years TC
8+1 8+3 1 15
retroverted anterior 46,XY
ethambutol therapy 40 3160
50 35
ID
Indication
Mode of sampling*
Gestational age at CVS** calculated by scan
Insertions
Estimated sample weight (mg)
Uterus position
Placental localization
Karyotype
Pregnancy history
Gestational age at Delivery (wk)
Birth weight (gr)
Length (cm)
Head circumference (cm)
30
1
12+6 12+5
2. TA
33.5
50
2920
33.5
52
3370
42
bleeding
--40
46,XX
46 ,XY
46 ,XX
34,5
52
3200
42
---
posterior
anteverted
35
1
10+5 10+5
TC
maternal age 37 years
C4 44/88
4
posterior/fundus
retroverted
0
2
10+0 9+5
1. TC
maternal age 36 years
I204/90
3
posterior/ lateral
anteverted
30
2
10+2 10+5
TA
maternal age 38 years
I46/89
2
* TC = transcervical, TA = transabdominal; ** completed menstrual weeks + days
1
Details of CVS in 4 Cases with Limb Defects.
Case
TABLE I:
Limb Defects Following CVS? DISCUSSION According to recent issues of the CVS-Newsletter (Jackson, 1991), more than 78000 transcervical and transabdominal procedures have been performed by now. The total number (n=28, Table 11) of distal limb deficiencies reported after CVS from centers giving their total number of procedures does not exceed the expected range (Froster-Iskenius and Baird, 1989; Bod et al., 1983) if one assumes nearly comp1ete ascertainment. There is also no clear evidence for an increased risk in the reports from some larger series (Jackson et al., 1991; Mahoney, 1991; Monni et al., 1991; Rhoads et al., 1989; Canadian Collaborative CVS Amniocentesis Clinical Trial Group, 1989; MRC Working Party on the Evaluation of 1991) Chorion Villus Sampling, (Table 111). At first sight the incidence of limb defects in our series appears to be increased (Table 111). However, at a closer look it seems doubtful whether all these cases are attributable to CVS. Case 4 (C444/88) has a positive family history of limb defects with a presumably similar malformation in at least one maternal uncle, who, unfortunately, could not be examined. Furthermore, syndactyly as in case 4 is believed to occur before 8 weeks of gestation and should therefore not be attributable to CVS. There is also a positive family history in case 2 (146/89). Finger anomalies as observed here have been reported in families with symphalangism (Poush, 1991). Only in the series reported by Firth et al. (1991a) distal limb deficiencies have appeared to be more frequent than expected. Furthermore, a total of 7 cases from different series with the so-called oromandibular-limb hypogenesissyndrome including 4 cases of Hanhart syndrome were taken as evidence of an increased risk of malformations attributable to CVS
409
(Firth et al., 1991b). Some authors consider local hypoperfusion as the pathogenetic mechanism in the socalled oromandibular-limb hypogenesis-syndromes (Firth et al., 1991b; Flannery, 1990). As discussed by Firth et al. (1991b), the insertion of a catheter or needle into the chorion frondosum with subsequent application of vacuum to aspirate villi of sometimes considerable volume may be easily imagined to cause thrombotic vascular occlusions, which in turn may become the source of emboli occluding fetal peripheral vessels and thus cause distal limb deficiencies (Scott, 1991; H o p e et 1982). Earlier studies, al., however, come to the conclusion that the so-called oromandibular-limb hypogenesis-syndromes are caused by disturbances in ectodermal mesodermal interaction beginning at about the fourth week of development (Bersu et al., 1976; Herrmann et al., 1976). With regard to this hypothesis a causal influence of CVS remains doubtful. Advanced maternal age was the indication for CVS in most if not all cases of limb deficiencies. It remains to be examined if advanced parental ag,e may account for an increased incidence of so-called oromandibular-limb hypogenesissyndromes as proposed by Firth et al. (1991b). We are not aware of any available data. Considering our own experience we recommend a detailed family history and careful physical examinations of the propositi and their parents in every case. According to Table 11, only minor abnormalities involving distal finger phalanges were observed in 8 out of 28 cases. Anomalies such as these may well remain undiagnosed in surveys of newborn infants (FrosterIskenius and Baird, 1989; Bod et al., 1983), which is important to consider when the incidence of distal limb defects is estimated (Mahoney, 1991) (Table 11). Minor anomalies were observed exclusively after CVS at 68 days or later while
7
20
G spinal needle 2 0 G spinal needle
'Throphocan catheter' out. diameter 1,5 mm Polyurethan catheter Ext. diameter 2,2 mm int. diameter 1,5 mm 2 0 G spinal needle Polyethylen catheter out. diameter 1,7 mm / 2 0 G spinal needle 2 0 / 21 G spinal needle Polyethylen catheter out. diameter 1,5 mm
TC TC TC
TC
TC
TC
TA TA
TC
TC
TA
TC/TA
TA
TC
56-63
59
62
63
63 63
64
67
68
68/89
69
70
56-63
Polyethylen catheter out. diameter 1,7 mm Polyethylen catheter out. diameter 1,5 mm
? ?
3
7
spinal needle spinal needle
56-63
56-63
20 G
20 G
TA TA TC
Equipment
56 56-63
Menstrual days TA/TC
Christiaens et al. (1989) Mahoney (1991)
Annular constriction R prox. humerus Transverse defect secondary to amniotic bands all digits L hand Shortness distal phalanges digits 3, 4 , 5 L hand
Both absent thumbs, absent R radius, hypoplastic distal L radius
Bilateral agenesis of two fingers and hypoplasia R root
Jackson et al. (1991)
Mahoney ( 1991)
Jackson et al. (1991)
Miny et al. (1991)
Firth et al. (1991a) Firth et al. (1991a)
Boyd et al. (1990)
Mahoney ( 1991)
Miny et al. (1991)
Hsieh et al. (1991) Hsieh et al. (1991) Hsieh et al. (1991)
Firth et al. (1991a) Firth et al. (1991a) Hsieh et al. (1991)
Author
Absent L ulna, absent digits 4 and 5, humeroradial fusion Half its normal length R forearm , no digits Hanhart syndrome Micrognathia, cleft of soft palate, single palmar crease L hand , absent L foot from midtarsus, brain stem infarct Bilateral aplasia of thumbs
Hanhart syndrome Mobius-syndrome Absence of both forearms, amputation R leg, apodia L leg Amelia R leg , acheira R hand Amelia R leg Transverse reduction both forearms Hanhart syndrome
Abnormalities
TABLE I1 : Limb Defects of Unknown Cause Following CVS.
Polyethylen catheter out. diameter 1,5 mm
20 G spinal needle
Polyethylen catheter Polyethylen catheter out. diameter 1,5 mm
20 G spinal needle
Polyethylen catheter out. diameter 1,5 mm
'Chorionscope'
20 / 2 1 G spinal needle 19 G spinal needle
TC
TA
TC TC
TA
TC
TC
TA TA
73
75
75 76
77
77
78
89 98 ~~
Polyethylen catheter out. diameter 1,5 mm
TC
73
R = right, L = left
19 G spinal needle
TA
Equipment
71
Menstrua1 days TA/TC
~
~
~
Missing distal phalanx of fourth and fifth digits each hand, artial cutaneous syndactyly getween R toes 4 and 5 At mid-metacarpal level transverse defect R hand with wrist intact and 5 digits vestigial, epicanthal folds, broad nasal bridge, prominent philtrum Minor hypoplasia of digits 2, 3, and 4 of both feet and webbing between these toes, toenails absent,only a sinqle interphalangeal joint in these toes H poplastic nail digit 1 and axsent nail digit 2 L foot, short distal phalanx digit 2 L hand Syndactyly 2-3 R hand Transverse defect at metacarpophalanqeal level L hand with a nubbin-like thumb and no other digit Absence of little finger phalanges Transverse defect limited to distal two phalanges of third finger L hand Hypoplasia and absent two distal phalanges of digits 4 and 5 R hand, syndactyly of digits 3,4,5 R hand Absent L hand Absent distal phalanges on 2 fingers L hand
Abnormalities
TABLE I1 (Continued): Limb Defects of Unknown Cause Following CVS.
Jackson et al. (1991) Monni et al. (1991)
Ghirardini and Camurri (1991)
Mahoney (1991)
Monni et al. (1991)
Miny et al. (1991) Mahoney (1991)
Miny et al. (1991)
Mahoney (1991)
Mahoney (1991)
Mahoney (1991)
Author
412
Schloo et al.
TABLE 111: Incidence of Limb Deficiencies in CVS Series (a) and Population Surveys (b). Author
Limb Defects/Procedures
%
99 % Confidence
Interval
Firth et al. (1991a) Jackson et al. (1991) Mahoney (1991) Monni et al. (1991) present series
Froster-Iskenius and Baird (1989) Bod et al. (1983)
*
5/539 5/12863 819588 2/2752 4/2836
0.928 0.039 0.083 0.073 0.141
0.96 3.61 5.42 0.79 1.69
-
13.94 25.54 27.25 12.12 15.33
659/1213913 274/561915
0.054 0.049
640.09 262.44
-
864.46 412.35
only series with a specified total number of procedures were considered. There is some overlap in the series of Jackson et al. (1991) and Mahoney (1991)
the more severe defects predominate after CVS at earlier stages of pregnancy, but were also observed as late as 89 days gestation. Limb defects have been observed after transabdominal as well as transcervical procedures without any obvious correlation to their extent or to the equipment applied. Due to lack of specific data, further correlations to procedure related criteria (e.g. number of insertions, sample weight) are not possible at present and therefore further careful follow-up of children born after CVS is required.
ACKNOWLEDGMENTS The CVS Program Munster was supported by grants from the Bundesminister fur Forschung und Technologie. The helpful comments of the distinguished reviewers are greatly appreciated.
REFERENCES Bersu ET, Petersen JC, Charboneau WJ, Opitz JM (1976): Studies of malformation syndromes in man XXXXI A: Anatomical studies in the Hanhart syndrome: A pathogenetic hypothesis. Eur J Pediatr 122:l17.
Bod M, Czeizel A, Lenz W (1983): Incidence at birth of different types of 1imb reduction abnormalities in Hungary 1975-77. Hum Genet 65:27-33. Boyd PA, Keeling JW, Selinger M, MacKenzie IZ (1990): Limb reduction and chorion villus sampling. Prenat Diagn 10:437-441. Canadian Collaborative cvs Amniocentesis Clinical Trial Group (1989): Multicentre randomised clinical trial of chorion villus sampling and amniocentesis. First report. Lancet 1:l-6. Christiaens GCM, van Baarlen J, Huber J, Leschot NJ (1989): Fetal limb constriction: A possible complication of CVS. Prenat Diagn 9 :67-71.
Firth HV, Boyd PA, Chamberlain P, MacKenzie IZ, Lindenbaum RH, Huson
Limb Defects Following CVS?
SM (1991a): Severe 1imb abnormalities after chorion villus sampling at 56-66 days’ gestation. Lancet 1:762-763. Firth H V , Boyd PA, Chamberlain P, MacKenzie 12, Lindenbaum RH, Huson SM (1991b): Limb abnormalities and chorion villus sampling. Lancet 2:51.
Flannery DB (1990): Hypoglossiahypodactylia. In Buyse ML (Ed): Birth Defects Encyclopedia.In Dover: Center for Birth Defects Information Services, Inc., pp 920-92 1.
Froster-Iskenius UG, Baird PA (1989): Limb reduction defects in over one million consecutive livebirths. Teratology 39:127-135. Ghirardini G, Camurri L (1991): Exocoelomic space, limb reduction, and CVS. Lancet 2:695. Herrmann J, Pallister PD, Gilbert EF, Viseskul C, Bersu E, Pettersen JC, Opitz JM (1976): Studies of malformation syndromes of man XXXXI B: Nosologic studies in the Hanhart and the Mobius syndrome. Eur J Pediatr 122:19-55. Holzgreve W, Miny P (1987): Chorionic villi sampling with an echogenic catheter: Experiences with the first 500 cases. J Perinat Med 15:244-249. Hoyme HE, Jones KL, van Allen MI, Saunders BS, Benirschke K (1982): Vascular pathogenesis of transverse limb reduction defects. J Pediatr 101:839-843. Hsieh FJ, Chen D, Tseng LH, Lee CN, KO TM, Chuang SM, Chen HY (1991): Letter to the editor: Limbreduction defects and chorion villus sampling. Lancet 1:1092. Jackson LG (1991): nnCVSnewsletternn. No. 31.
413
Jackson LG, Wapner RJ, Brambati B (1991): Limb abnormalities and chorionic villus sampling. Lancet 1: 1423.
Mahoney MJ (1991): Limb abnormalities and chorionic villus sampling. Lancet 1:1422-1423. Mastroiacovo P, Cavalcanti DP (1991): Letter to the editor: Limb-reduction defects and chorion villus sampling. Lancet 1:1091. Miny P, Holzgreve W, Horst J, Lenz W (1991): Limb abnormalities and chorionic villus sampling. Lancet 1: 1423-1424.
Monni G, Ibba RM, Lai R, Olla G, Cao A (1991): Letter to the editor: Limb-reduction defects and chorion villus sampling. Lancet 1:1091. MRC Working Party on the Evaluation of Chorion Villus Sampling (1991): Medical Research Council European Trial of chorion villus sampling. Lancet 1:1491-1499. Poush JR (1991): Distal symphalangism: A report of two families. J Hered 82:233-238. Rhoads GG, Jackson LG, Schlesselmann SE, de la Cruz FF, Desnick RJ, Golbus MS, Ledbetter DH, Lubs HA, Mahoney MJ, Pergament E, Simpson RJ, Elias S, JL, Carpenter Ginsberg NA, Goldberg JD, Hobbins JC, Lynch L, Shiono PH, Wapner RJ, Zachary JM (1989): The safety and efficacy of chorionic villus sampling for early prenatal diagnosis of cytogenetic Engl J Med abnormalities. N 320:609-617. (1991): Limb abnormalities
Scott R after Lancet Shepard
chorionic villus sampling. 1:1038-1039.
TH, Kapur RP, Fantel AG (1991): Letter to the editor: Limb-reduction defects and chorion villus sampling. Lancet 1:1092.
DISTAL LIMB DEFICIENCY FOLLOWING CHORIONIC VILLUS SAMPLING?
Rudiger SchWoo, Peter Miny, Wolfgang Holzgreve, Jurgen Horst, Widukind Lenz Department of Human Genetics, Department of Gynecology, Universitatsklinik Munster, Germany We have reviewed the follow-up of almost 3000 completed pregnancies in the Munster CVS Program and identified 4 children with distal limb deficiencies. Two cases involved only minor anomalies of distal digital phalanges. One child had a Hanhart anomaly (hypoglossia hypodactylia) We also reviewed 2 4 cases of limb defects following CVS reported previously. With the exception of a single series, neither the overall incidence of affected children nor cases reported from larger series provide unambiguous evidence of an increased risk of distal limb deficiency caused by CVS.
.
KEY W0RDS:chorionic villus sampling, distal limb deficiency, review INTRODUCTION Firth et al. (1991a,b) drew attention to a possible causal relationship of chorionic villus sampling (CVS) at 56-66 days of gestation and limb abnormalities of the fetus. Some kind of vascular insult was the suspected pathogenesis in 5 cases of severe Received for publication August 16, 1991; revision accepted November 18, 1991.
Address
reprint requests to R. Institut fur Humangenetik, Vesaliusweg 12-14, 4400 Munster, FRG Schloo,
0 1992 Wiley-Liss, Inc.
Obstetrics and
limb deficiency encountered in a series of 539 procedures. Shepard et (1991) proposed alternative al. mechanisms following accidental amniotic puncture during CVS, i. e. formation of amniotic bands, loss of amniotic fluid, or entrapment of distal limbs in the 'exocoelomic gel'. Subsequently other investigators reviewed their experience and reported disturbing (Hsieh et al., 1991; Mastroiacovo and Cavalcanti, 1991; Monni et al., 1991), but also for some of the larger series, reassuring data (Mahoney, 1991; Jackson et al., 1991; Miny et al., 1991; MRC Working Party on the Evaluation of Chorion Villus Sampling, 1991). Since CVS performed either transcervically or transabdominally may theoretically lead to vascular complications such as thrombosis of the mesenchymal core vessels of villi with subsequent embolism, the need for a careful risk assessment is obvious. Mastroiacovo and Cavalcanti (1991) have already addressed the possible involvement of other body areas in local hypoperfusion such as the brain. We present in detail 4 limb deficiencies observed in our series of almost 3000 completed pregnancies
Limb Defects Following CVS?
after transabdominal and transcervical CVS in the first trimester of pregnancy, and we also include data on the frequency of other structural defects of the Furthermore, we analysed fetus previously reported cases in an attempt to correlate the severity of limb defects with the gestational age at CVS or other procedure related criteria.
.
PATIENTS AND METHODS Between January 1, 1985 and June 30, 1991, a total of 2537 transcervical (TC) and 763 transabdominal (TA) procedures was carried out in the first trimester and 548 transabdominal placental biopsies in the second and third trimesters. Chorionic tissue was aspirated transabdominally with a 20 gauge spinal needle and transcervically by a polyethylene catheter with an external diameter of 1.7 mm (Holzgreve and Miny, 1987). Eighty-five TA and 551 TC procedures were done at 66 days or earlier. At the time of preparing this report, information on pregnancy 2836 outcome was available on pregnancies after CVS in the first trimester and 137 pregnancies ended in spontaneous abortions before 28 weeks of pregnancy. Follow-upinformation was available on nearly all patients and was collected from written reports of the obstetricians and additional phone interviews with the mothers. RESULTS Anatomical defects were recorded in a total of 16 newborn infants (5 heart defects, 4 isolated cleft lip/palate, 4 limb defects, 1 hypospadia, 1 gastroschisis, and 1 case with multiple malformations including cleft palate, hypertelorism, and agenesis of corpus callosum).
405
The children with limb defects of differing severity were examined between age 7 weeks and 2 years. There was no family history of limb abnormalities in 2 families. However, 2 maternal uncles of case C444/88 reportedly also had limb defects. In one uncle a ray of the right hand was absent. The other uncle had a duplication of the right thumb and a cleft lip and palate. Both were otherwise normal. Hands and feet were normal in the patient's mother. The mother of case I046/89 had bilateral camptodactyly. Case 1 (C037/85): At age 11 month he had classical Hanhart syndrome (Figs. 1-3, 5, 6 ) . Psychomotor development was adequate for age. CVS had been performed at 9 weeks of gestation (59 menstrual days, Table I). A radiological examination was performed at age 10 months (Figs. 4, 7). Case 2 (1046/89): The patient was seen at age 19 months. The examination showed minor anomalies (Figs. 8 , 9 ) . No radiological examination was performed. The patient's mother had bilateral camptodactyly and symphalangism (Fig. 10). Case 3 (I204/90) : Transcervical 10 weeks (2 CVS failed at insertions) and was instead performed transabdominally at 13 weeks (1 insertion). The clinical examination at age 7 weeks showed shortness of the distal phalanges of digits 3, 4 and 5 with absent nails on the left hand. No radiological examination was performed (Fig. 11). Case 4 (C444/88) : The examination at age 2 years showed only 4 rays in the right hand in an otherwise normal infant (Figs. 12, 13). See above for family history. A radiological examination was performed at age 5 months (Fig. 14). Details of CVS in cases 1-4 are shown in Table I.
Fig.1: Case 1: Hanhart syndrome: severe micrognathia
Fig.5: Case 1: Hanhart syndrome: normal appearing right foot.
Fig.2: Case 1: Hanhart syndrome: right hand.
Fig.6: Case 1: Hanhart syndrome: transversal defect of the left foot.
Fig.3: Case 1: Hanhart syndrome: left hand.
Fig.7: Case 1: Hanhart syndrome: X-ray of left and right foot.
Fig.4: Case 1: Hanhart syndrome: X-ray of left and right hand.
Fig.8: Case 2: at age 19 month: hypoplastic and tapering left index finger.
Fig.9: Case 2: short digits 1 and 2 in the left foot, zygodactyly, small nail in digit 1, missing nail in digit 2 .
Fig.10: Mother of Case 2: Bilateral camptodactyly of digits 5, poorly developed distal flexion creases of digits 4 . -
Fig.11: Case 3 : Absent or hypoplastic phalanges of digits 3 , 4 , 5 of the left hand.
Fig.12: Case 4: syndactyly of digits 2 and 3 of the right hand.
Fig.13: Case 4: partial cutaneous syndactyly 4 and 5 of the right hand.
Fig.14: Case
4:
X-ray of both hands.
C37/85
maternal age 35 years TC
8+1 8+3 1 15
retroverted anterior 46,XY
ethambutol therapy 40 3160
50 35
ID
Indication
Mode of sampling*
Gestational age at CVS** calculated by scan
Insertions
Estimated sample weight (mg)
Uterus position
Placental localization
Karyotype
Pregnancy history
Gestational age at Delivery (wk)
Birth weight (gr)
Length (cm)
Head circumference (cm)
30
1
12+6 12+5
2. TA
33.5
50
2920
33.5
52
3370
42
bleeding
--40
46,XX
46 ,XY
46 ,XX
34,5
52
3200
42
---
posterior
anteverted
35
1
10+5 10+5
TC
maternal age 37 years
C4 44/88
4
posterior/fundus
retroverted
0
2
10+0 9+5
1. TC
maternal age 36 years
I204/90
3
posterior/ lateral
anteverted
30
2
10+2 10+5
TA
maternal age 38 years
I46/89
2
* TC = transcervical, TA = transabdominal; ** completed menstrual weeks + days
1
Details of CVS in 4 Cases with Limb Defects.
Case
TABLE I:
Limb Defects Following CVS? DISCUSSION According to recent issues of the CVS-Newsletter (Jackson, 1991), more than 78000 transcervical and transabdominal procedures have been performed by now. The total number (n=28, Table 11) of distal limb deficiencies reported after CVS from centers giving their total number of procedures does not exceed the expected range (Froster-Iskenius and Baird, 1989; Bod et al., 1983) if one assumes nearly comp1ete ascertainment. There is also no clear evidence for an increased risk in the reports from some larger series (Jackson et al., 1991; Mahoney, 1991; Monni et al., 1991; Rhoads et al., 1989; Canadian Collaborative CVS Amniocentesis Clinical Trial Group, 1989; MRC Working Party on the Evaluation of 1991) Chorion Villus Sampling, (Table 111). At first sight the incidence of limb defects in our series appears to be increased (Table 111). However, at a closer look it seems doubtful whether all these cases are attributable to CVS. Case 4 (C444/88) has a positive family history of limb defects with a presumably similar malformation in at least one maternal uncle, who, unfortunately, could not be examined. Furthermore, syndactyly as in case 4 is believed to occur before 8 weeks of gestation and should therefore not be attributable to CVS. There is also a positive family history in case 2 (146/89). Finger anomalies as observed here have been reported in families with symphalangism (Poush, 1991). Only in the series reported by Firth et al. (1991a) distal limb deficiencies have appeared to be more frequent than expected. Furthermore, a total of 7 cases from different series with the so-called oromandibular-limb hypogenesissyndrome including 4 cases of Hanhart syndrome were taken as evidence of an increased risk of malformations attributable to CVS
409
(Firth et al., 1991b). Some authors consider local hypoperfusion as the pathogenetic mechanism in the socalled oromandibular-limb hypogenesis-syndromes (Firth et al., 1991b; Flannery, 1990). As discussed by Firth et al. (1991b), the insertion of a catheter or needle into the chorion frondosum with subsequent application of vacuum to aspirate villi of sometimes considerable volume may be easily imagined to cause thrombotic vascular occlusions, which in turn may become the source of emboli occluding fetal peripheral vessels and thus cause distal limb deficiencies (Scott, 1991; H o p e et 1982). Earlier studies, al., however, come to the conclusion that the so-called oromandibular-limb hypogenesis-syndromes are caused by disturbances in ectodermal mesodermal interaction beginning at about the fourth week of development (Bersu et al., 1976; Herrmann et al., 1976). With regard to this hypothesis a causal influence of CVS remains doubtful. Advanced maternal age was the indication for CVS in most if not all cases of limb deficiencies. It remains to be examined if advanced parental ag,e may account for an increased incidence of so-called oromandibular-limb hypogenesissyndromes as proposed by Firth et al. (1991b). We are not aware of any available data. Considering our own experience we recommend a detailed family history and careful physical examinations of the propositi and their parents in every case. According to Table 11, only minor abnormalities involving distal finger phalanges were observed in 8 out of 28 cases. Anomalies such as these may well remain undiagnosed in surveys of newborn infants (FrosterIskenius and Baird, 1989; Bod et al., 1983), which is important to consider when the incidence of distal limb defects is estimated (Mahoney, 1991) (Table 11). Minor anomalies were observed exclusively after CVS at 68 days or later while
7
20
G spinal needle 2 0 G spinal needle
'Throphocan catheter' out. diameter 1,5 mm Polyurethan catheter Ext. diameter 2,2 mm int. diameter 1,5 mm 2 0 G spinal needle Polyethylen catheter out. diameter 1,7 mm / 2 0 G spinal needle 2 0 / 21 G spinal needle Polyethylen catheter out. diameter 1,5 mm
TC TC TC
TC
TC
TC
TA TA
TC
TC
TA
TC/TA
TA
TC
56-63
59
62
63
63 63
64
67
68
68/89
69
70
56-63
Polyethylen catheter out. diameter 1,7 mm Polyethylen catheter out. diameter 1,5 mm
? ?
3
7
spinal needle spinal needle
56-63
56-63
20 G
20 G
TA TA TC
Equipment
56 56-63
Menstrual days TA/TC
Christiaens et al. (1989) Mahoney (1991)
Annular constriction R prox. humerus Transverse defect secondary to amniotic bands all digits L hand Shortness distal phalanges digits 3, 4 , 5 L hand
Both absent thumbs, absent R radius, hypoplastic distal L radius
Bilateral agenesis of two fingers and hypoplasia R root
Jackson et al. (1991)
Mahoney ( 1991)
Jackson et al. (1991)
Miny et al. (1991)
Firth et al. (1991a) Firth et al. (1991a)
Boyd et al. (1990)
Mahoney ( 1991)
Miny et al. (1991)
Hsieh et al. (1991) Hsieh et al. (1991) Hsieh et al. (1991)
Firth et al. (1991a) Firth et al. (1991a) Hsieh et al. (1991)
Author
Absent L ulna, absent digits 4 and 5, humeroradial fusion Half its normal length R forearm , no digits Hanhart syndrome Micrognathia, cleft of soft palate, single palmar crease L hand , absent L foot from midtarsus, brain stem infarct Bilateral aplasia of thumbs
Hanhart syndrome Mobius-syndrome Absence of both forearms, amputation R leg, apodia L leg Amelia R leg , acheira R hand Amelia R leg Transverse reduction both forearms Hanhart syndrome
Abnormalities
TABLE I1 : Limb Defects of Unknown Cause Following CVS.
Polyethylen catheter out. diameter 1,5 mm
20 G spinal needle
Polyethylen catheter Polyethylen catheter out. diameter 1,5 mm
20 G spinal needle
Polyethylen catheter out. diameter 1,5 mm
'Chorionscope'
20 / 2 1 G spinal needle 19 G spinal needle
TC
TA
TC TC
TA
TC
TC
TA TA
73
75
75 76
77
77
78
89 98 ~~
Polyethylen catheter out. diameter 1,5 mm
TC
73
R = right, L = left
19 G spinal needle
TA
Equipment
71
Menstrua1 days TA/TC
~
~
~
Missing distal phalanx of fourth and fifth digits each hand, artial cutaneous syndactyly getween R toes 4 and 5 At mid-metacarpal level transverse defect R hand with wrist intact and 5 digits vestigial, epicanthal folds, broad nasal bridge, prominent philtrum Minor hypoplasia of digits 2, 3, and 4 of both feet and webbing between these toes, toenails absent,only a sinqle interphalangeal joint in these toes H poplastic nail digit 1 and axsent nail digit 2 L foot, short distal phalanx digit 2 L hand Syndactyly 2-3 R hand Transverse defect at metacarpophalanqeal level L hand with a nubbin-like thumb and no other digit Absence of little finger phalanges Transverse defect limited to distal two phalanges of third finger L hand Hypoplasia and absent two distal phalanges of digits 4 and 5 R hand, syndactyly of digits 3,4,5 R hand Absent L hand Absent distal phalanges on 2 fingers L hand
Abnormalities
TABLE I1 (Continued): Limb Defects of Unknown Cause Following CVS.
Jackson et al. (1991) Monni et al. (1991)
Ghirardini and Camurri (1991)
Mahoney (1991)
Monni et al. (1991)
Miny et al. (1991) Mahoney (1991)
Miny et al. (1991)
Mahoney (1991)
Mahoney (1991)
Mahoney (1991)
Author
412
Schloo et al.
TABLE 111: Incidence of Limb Deficiencies in CVS Series (a) and Population Surveys (b). Author
Limb Defects/Procedures
%
99 % Confidence
Interval
Firth et al. (1991a) Jackson et al. (1991) Mahoney (1991) Monni et al. (1991) present series
Froster-Iskenius and Baird (1989) Bod et al. (1983)
*
5/539 5/12863 819588 2/2752 4/2836
0.928 0.039 0.083 0.073 0.141
0.96 3.61 5.42 0.79 1.69
-
13.94 25.54 27.25 12.12 15.33
659/1213913 274/561915
0.054 0.049
640.09 262.44
-
864.46 412.35
only series with a specified total number of procedures were considered. There is some overlap in the series of Jackson et al. (1991) and Mahoney (1991)
the more severe defects predominate after CVS at earlier stages of pregnancy, but were also observed as late as 89 days gestation. Limb defects have been observed after transabdominal as well as transcervical procedures without any obvious correlation to their extent or to the equipment applied. Due to lack of specific data, further correlations to procedure related criteria (e.g. number of insertions, sample weight) are not possible at present and therefore further careful follow-up of children born after CVS is required.
ACKNOWLEDGMENTS The CVS Program Munster was supported by grants from the Bundesminister fur Forschung und Technologie. The helpful comments of the distinguished reviewers are greatly appreciated.
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Bod M, Czeizel A, Lenz W (1983): Incidence at birth of different types of 1imb reduction abnormalities in Hungary 1975-77. Hum Genet 65:27-33. Boyd PA, Keeling JW, Selinger M, MacKenzie IZ (1990): Limb reduction and chorion villus sampling. Prenat Diagn 10:437-441. Canadian Collaborative cvs Amniocentesis Clinical Trial Group (1989): Multicentre randomised clinical trial of chorion villus sampling and amniocentesis. First report. Lancet 1:l-6. Christiaens GCM, van Baarlen J, Huber J, Leschot NJ (1989): Fetal limb constriction: A possible complication of CVS. Prenat Diagn 9 :67-71.
Firth HV, Boyd PA, Chamberlain P, MacKenzie IZ, Lindenbaum RH, Huson
Limb Defects Following CVS?
SM (1991a): Severe 1imb abnormalities after chorion villus sampling at 56-66 days’ gestation. Lancet 1:762-763. Firth H V , Boyd PA, Chamberlain P, MacKenzie 12, Lindenbaum RH, Huson SM (1991b): Limb abnormalities and chorion villus sampling. Lancet 2:51.
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