- Email: [email protected]
The significance of cystic hygroma in fetuses
The Significance of Cystic Hygroma in Fetuses JULIANNE BYRNE, PhD,*·t WILLIAM A BLANC, MD,* DOROTHY WARBURTON, PhD,* AND JOACHIM WIGGER, MD* Cystic hygroma of the neck was observed in seven spontaneously aborted, severely autolyzed female fetuses. Four of five karyotyped cases had the 45,XO karyotype; one was a normal female, 46,XX. Diagnostic features associated with monosomy X in fetuses, which were observed in six of these cases, include large cystic hygromas, generalized edema, edematous chorionic villi with scalloped borders and trophoblastic inclusions, and, possibly, a small heart. In contrast, the single euploid fetus in this series had a small cystic hygroma, no hydrops, and chorionic villi of normal size. These features may differentiate cystic hygromas associated with the XO karyotype, which are not associated with recurrence risk, from those associated with a familial syndrome. HUM PATHOL 15:61-67, 1984.
There is increasing evidence that at least one feature widely considered pathognomonic for the XO karyotype in fetuses, namely, the presence of cystic hygromas, may be a feature of other malformation syndromes as well, some of which carry a recurrence risk. Two reports of such cases have been published: Bieber et al.! described a fetus with nuchal cystic hygroma and ascites, apparently part of a familial syndrome, and Cowchock et al. 2 described two fetuses with nuchal cystic hygroma and cleft palate from a single sibship. The relationship of cystic hygroma and Turner's syndrome has been the subject of some discussion in the Iiteratures-". Although most cases of cystic hygroma probably do occur in association with the XO karyotype in fetuses, more detailed investigation of the phenotypic characteristics may help differentiate cases of cystic hygroma with the XO karyotype, for which there is no increased risk of recurrence, and cases that may be part of other syndromes. We report here the results of our morphologic and karyotypic investigations of seven fetuses with cystic hygromas, one of which had the normal female karyotype. METHODS Seven fetuses with cystic hygromas of the neck were observed over the past six years as part of an on-going study of the pathology of early fetal loss; Received December 28, 1982, Accepted for publication]anuary 10, 1983. Supported in part by grants I-ROI-HD-08838, 1ROl-HD-12207, 5-ROI-DA-02090, and 5-T32-HD-07040 from the National Institutesof Health. it' Division of Developmental Pathology, Columbia University College of Physicians and Surgeons, New York, New York. t New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York. t Department of Human Genetics and Development, Columbia University College of Physicians and Surgeons. Address correspondence and reprint requests to Dr. Byrne: Division of Developmental Pathology, BHA-T22, Columbia University. 630 West 168th St, New York, NY 10032.
five were part of a collaborative pathologic, epidemiologic, and cytogenetic study of miscarriagess: two were examined since that collaboration ceased. In six of seven cases,' autopsies were performed, according to a standard protocol, either by Dr. Byrne or by specially trained assistants; one of the fetuses (case 5) received a more cursory examination. External and internal measurements were evaluated by use of fetal growth charts prepared from this abortus population. All organs were examined in situ and sectioned after fixation. Because of the extreme autolysis of the fetuses, tissue cultures for karyotyping were set up from the placenta (amnion, chorion, villi) in all cases except case 2, in which the placenta was received fixed. In this case fetal muscle was set up in culture but failed to grow. Sex chromatin examinations were made on sections of placental villi. RESULTS The incidence of fetuses with cystic hygroma in the large series of 3,500 miscarriages Byrne, unpublished data) was about 1 in 875, or about 1 in 200 miscarried fetuses greater than 3 em in crown-rump length (CRL). All seven cases of cystic hygroma occurred in severely autolyzed female fetuses. All but one, case 7, also showed generalized edema of the trunk and swelling of the extremities, with narrowing at major joints-elbows, wrists, knees, and anklesgiving the characteristic outline (fig. 1, left). In case 7 the lymphangiomas were smaller and no generalized hydrops was present (fig. 1, right). Perhaps significantly, the size of the heart in case 7 was within normal limits (fig. 2, toP), whereas in the other cases in which the heart was examined, it was markedly small according to fetal heart growth curves (fig. 2, bottom). The neck masses were symmetric in all cases, extending posteriorly and laterally to the shoulder, and they were restricted to the neck region. They consisted of multiple cystic structures that did not communicate with one another; these were filled with a dark brown, cloudy fluid. Sections through the tumors showed large cavities containing proteinaceous material and occasional lymphocytes. The fine wall structure was largely effaced because of autolysis. The endothelium had disappeared, leaving only a thin basement membrane. In contrast, adjacent blood vessels within the tumor lining already had a muscular media and contained blood cells. Blood vessels and nerves were observed within the thin septa separating the cysts. The tissues lining the cysts were massively edematous, but distinct lymphatic channels were observed in only two cases. These histologic fea-
a.
61
HUMAN PATHOLOGY
Volume 15, No.1 (Januory 1984)
FIGURE 1. Left case 2. Fetuswith cystic hygroma, generalized edema, and narrowing at major Joints; the crown-rump length (CRL) was 190 mm. Right case 7. Fetus with a small. opened cystic hygroma and no generalized edema: the CRL was 142 mrn.
tures contrast with those observed in lymphangiomas removed from infants and children, in which lymphoid follicles and bundles of smooth muscle are regularly found in the wall. Grossly, the placentas had no characteristic lesions. Particularly striking was the absence of Breus mole, reported to be associated with XO abortuses.f However, microscopic examination of the placentas showed characteristic changes consisting of hypoplasia of peripheral villi with severe edema causing a scalloped appearance of the villous margins. Trophoblastic inclusions secondary to the proliferation of the trophoblasts were observed. The scalloping pattern varied in degree, from minimal in case 6 (fig. 3e) to severe in cases 1 and 5 (fig. 3, a and d). Trophoblastic inclusions also varied in frequency. Superimposed on these features were variable degrees of intervillous fibrin deposition and fibrosis secondary to uterine retention of the dead fetus for various periods of time. In contrast, the placenta of case 7 (fig. 3j), which had the normal chromosome complement, showed neither villous edema nor trophoblastic inclusions, but only those changes due to retention-vascular obliteration and stromal proliferation. Vernix granulomas, also found in XO abortuses, were seen in three of the four cases in which the amnion was examined, including case 7. In all seven cases the ovaries were normal in size and in histologic structure. Chromosome studies, which were attempted in all cases, were successful in five; four cases yielded the 45,XO karyotype: case 7 was karyotyped as a
normal female, 46,XX. Fetuses with cystic hygroma and the XO karyotype represent only a small proportion (5.8 per cent) of all the XO abortuses in the large study Byrne, unpublished data).
a.
REPORT OF SEVEN CASES Case 1. A severely autolyzed 346-g female fetus had cystic hygroma and generalized edema. The CRL was 165 mm, and the crown-heel length (CHL) was 220 mm. The gestational age was 16 weeks; the developmental age corresponded to 18 weeks. A simian crease on the right hand was observed. Both lungs and heart were small (1.5 and 1.4 g, respectively). Coarctation of the aorta between the point of exit of the two carotid arteries was observed. There were no abnormalities in the abdominal cavity. The placenta was thin, measuring 90 x 90 x 2 mm. Tissue culture was established from the placenta; seven cells were counted and all were missing an X chromosome. This was the first pregnancy of a 17-year-old woman who afterwards delivered a live 1,570-g male infant at 31 weeks. Case 2. A severely autolyzed 538-g female fetus had bilateral cystic hygromas and generalized edema, with a CRL of 190 mm and a CHL of 270 mm (fig. 1, left). The gestational age was 23 weeks, and the developmental age was 21 weeks. Hypoplastic nails were observed on both hands and feet. Within the thorax, both heart and lungs were remarkably small (1.7 and 0.9 g, respectively). Coarctation of the aorta between the point of exit of the subclavian artery and the ductus arteriosus was observed. There was a persistent left superior vena cava with absence of the innominate vein (fig. 2, bottom). No abdominal abnormalities were observed. The placenta, received fixed in formalin, measured 110 x 110 x 15 rom and was completely
62
FETAl cysnc HYGROMA (Byrne et aJ.)
Top, case 7. Opened thorax showsa heart of normal size, small lungs, and coarctation (arro""1. Bottom, case 2. Opened thorax shows small heart, hypoplastic lungs (small arrows), and persistent left superior vena cava (large arrow) , FIGURE 2.
circumvallate. Tissue cultures were set up from fetal muscle but were unsuccessful. Sex chromatin find ings were negative. No maternal history was available. Case 3 . A severely autolyzed 570-g female fetus had bilateral cystic hygromas and generalized edema. The CRL was 195 mm and the CHL was 265 rnrn. The gestational age was 26 weeks and the developmental age corresponded to 21 weeks. Within the thorax the lungs were hypoplastic. The heart had a persistent left superior vena cava with absence of the innominate vein, a swiss-cheese-type of muscular ventricular septal defect, and tubular coarctation. The subclavian artery exited from the aorta distal to, rather than proximal to, the entrance of the ductus. Partial malrotation of the gut (no right-sided attachment) and a horseshoe kidney (fig. 4) were also observed. The placenta measured 130 X 105 x 10 mm and weighed 124 g. The cord had only two vessels. Sex chromatin findings were negative. The 25-year-old mother had had a previous normal
term delivery and subsequently had a normal term child. The parents were first cousins. Tissue cultures were set up from the placenta; at least eight cells were counted and all were lacking the second X chromosome. Case 4. A severely autolyzed 275-g female fetus had bilateral cystic hygromas and generalized edema. The CRL was 134 mm and the CHL was 190 mm. The gestational age was 26 weeks and the developmental age was 18 weeks. Both heart and lungs were markedly small (0.5 and 0.9 g, respectively), Tubular coarctation of the aorta and partial malrotation of the gut (failure of right-sided attachment) were observed. The placenta measured 122 x 86 X 9 mm and weighed 99 g. The cord had three vessels. Tissue culture, set up from the placenta, was successful; 15 cells were counted and all lacked the second X chromosome. Sex chromatin findings were negative. The mother was 23 years old and had a history of toxoplasmosis. She had had one previous elective abortion
63
HUIVIAN PATHOLOGY
Volume 15, No.1 (January 1984)
Placental villi, MOWS Indicate trophoblastic Inclusions, see text for details. 0, Case 1. b, Case 2. c Case 3, Legend con-
FIGURE 3.
tinues on facing page,
and, subsequent to this pregnancy, had a normal term female child. Case 5. A severely autolyzed 79-g female fetus had cystic hygromas and generalized edema. The CRL was 115 mm and the CHL was 150 mm. The gestational age was 22 weeks and the developmental age corresponded to 13 weeks. The heart and lungs were not examined. The pelvic organs were normal. The placenta measured 70 X 60 X 15 mm and weighed 58 g. Sex chromatin findings were negative. All ten karyotyped cells, obtained from placental tissue culture, were missing an X chromosome. The 24-year-old mother had had asthma as a child and syphilis and pyelonephritis ten years previously. She had delivered three liveborn children by cesarian sections. Case 6. A severely autolyzed 288-g female fetus had bilateral cystic hygromas and generalized edema. The CRL
was 150 mm and the CHL was 210 mm. The gestational age was 23 weeks; the developmental age corresponded to 17 weeks. The heart and lungs were markedly small (1.1 and 2.8 g, respectively). Coarctation of the ascending aorta was observed along with a bicuspid aortic valve. The subclavian artery exited Iowan the descending aorta, opposite the entry of the ductus. There was partial malrotation of the gut. The placenta measured 135 X 125 X 10 mm and weighed 94 g. The cord was inserted velamentausly and had three vessels. The 33-year-old mother had had two normal children. Tissue cultures, set up from placenta, developed yeast contamination and were discarded. Sex chromatin findings were negative. Case 7. A severely autolyzed 166-g female fetus had small cystic hygromas but no generalized edema. The CRL was 142 mm and the CHL was 200 mm (fig. 1, right). The
64
FETAL CYSTIC HYGROMA (Byrne et of.)
,
I
:. ~ ~
•
FIGURE 3 (continued), a Case 5, e, Case 6. f, Case 7, (All, hematoxylln-eosln stain. x 40.)
gestational age was 25 weeks; the developmental age corresponded to 16 weeks. Although the lungs were small, 2.6 g together, the heart was normal in size (2.0 g) in comparison with the rest of the body (fig. 2, top). Tubular coarctation of the aorta was observed together with a membranous ventricular septal defect and a large atrial septal defect. Many malformations of the abdominal cavity were seen-situs inversus abdominalis, malrotation of the gut, a small 4-mm spleen, and three accessory spleens. two measuring I mm and one measuring 2 mm (anisopolysplenia). The placenta was crescent-shaped, measured 143 X 106 x 17 mm, and weighed 157 g. A large S-shaped Breus mole was observed along with complete circummargination. The cord had three vessels. About 20 per cent of the cells examined were positive for sex chromatin, The karyotype, based on a harvest of three analyzable meta phases, was 46,XX.
The 19-year-old mother had had a previous normal delivery of a male child and a subsequent elective abortion. The father was an insulin-dependent diabetic. As indicated by the heart defects, the situs inversus, and the malrotation of the gut, the fetus had many features characteristic of the polysplenia syndrome.v The presence of cystic hygromas is not a usual concomitant of the condition and is more suggestive of the Noonan syndrome.w However, the lack of pulmonic stenosis and the absence of a familial pattern argue against this condition.
DISCUSSION In this series, seven cases of cystic hygroma were observed. Four of five karyotyped fetuses had the
65
HUMANPATHOLOGY
Volume 15, No.1 (January 1984)
FIGURE 4. Case 3. Opened abdomen shows horseshoe kldney and single umbilical artery. Ovorles have been removed.
45,XO chromosome complement and one had 46,XX. The single gross anatomic feature distinguishing the 46,XX fetus from the others was lack of generalized edema. In all other respects, particularly in the presence of coarctation, heart defects, and hypoplastic lungs, the features of this case mimicked the phenotypic characteristics of XO fetuses, i.e., cystic hygromas, generalized edema, and normal female genitalia. lO •ll In addition, coarctation of the aorta, hypoplastic lungs, and kidney malformations are common. 3 , l l - 13 Although mosaicism cannot be ruled out in case 7 (the Barr body count was lower than expected, and the karyotype was based on only three cells), it is interesting that neither previously reported case of familial cystic hygroma had generalized edema. In the case reported by Bieber et al.;' the well-preserved fetus clearly did not have hydrops, despite the presence of ascites. Hydrops also could not be detected in either of the cases, both autolyzed, from the second affected sibship reported by Cowchock et a1. 2 No familial pattern was apparent in our case of cystic hygroma with normal chromosomes. Rather, this case seems to represent a variant of the polysplenia syndrome in that in addition to the cystic hygroma, there were four spleens of unequal sizes, a heart defect, small lungs, situs inversus, and malrotation of the gut. In their detailed description of placental morphology and chromosome anomalies, Honore et al. 14 do not allude to the association of villous edema and trophoblastic inclusions with XO abortuses, which was observed here. It may be that the villous changes in XO conceptuses aborted earlier differ from those observed in more mature placentas. It may be instructive, in light of our findings, to speculate on the anatomic anomalies in children with Turner's syndrome born at term. While lungs as small as those observed here may not be incompatible with intrauterine life, they would be incompatible
with life after birth. We are not aware of any reports of infants with Turner's syndrome who had respiratory distress and succumbed in the neonatal period. It may be that phenotypic expression is variable, related perhaps to mosaicisrn.U with less severely affected fetuses surviving to term. Presumably, the severity of effect is related to the degree of hygroma development and concomitant hydrops, perhaps causing poor heart and lung growth. The exact mechanism of intrauterine death is unknown but may be related to excess fluid volume in the body coupled with heart failure or, perhaps, kidney failure. In a detailed anatomic study of the lymphatic system in female fetuses with cystic hygromas and generalized edema, van del' Putte-f reported great variability in the histologic features, but a common finding was hypoplasia of the main lymphatic trunks with accumulation of fluid in the intercellular spaces of the subcutaneous connective tissue. One explanation for the condition might lie in generalized hypoplasia and partial agenesis of the lymphatic system with failure of peripheral extension in the embryonic period. These speculations await confirmation from further anatomic studies of fetuses with cystic hygromas and from autopsy studies of neonates with Turner's syndrome. We suggest that an absence of hydrops in a female fetus with cystic hygromas and other anomalies associated with the XO karyotype may be a valid and reliable indicator of the normal chromosome complement. The proportion of such cases associated with a familial syndrome or other malformation syndromes remains to be seen. However, this combination of phenotypic and karyotypic features in an aborted fetus may warrant investigation of the family for other indicators of a familial malformation syndrome. These observations suggest that the use of the term "Turner-like phenotype" as a synonym for cystic hygroma is not always valid and should be confined
66
FETAL CYSTIC HYGROMA (Byrne et 01.)
to cases diagnosed on the basis of chromosomal or sex-chromatin findings . Addendum. Chervenak et al. recently reported 15 cases of nuchal cystic hygroma diagnosed by ultrasound in phenotypically female fe tuses. Ka ryotypes we re 45 ,XO in nine cases, 45 ,X0146 ,XX in three, and 46 ,XY in one. Amnion cells were sex- chromatin-negative in one case.l? Acknowledgments. The authors thank Dr. Zena Stein, Dr. Jennie Kline, and Dr. Mervyn Susser, co-principal investigators (with D.W.) of the Spontaneous Abortion Study; Diane Baker, Phoebe Kussin, Debra Zillmer, and Diana Andrews, research assistants in pathology; and Richard Weed of the NYS Institute for Basic Research in Developmental Disabilities for photographic assistance.
6.
7. 8. 9. 10. II. 12. 13.
REFERENCES 1. Bieber FR, Petres RE, Bieber M, et al: Prenatal detection of a familial nuchal bleb simulating encephalocele. Birth Defects 15:51, 1979 2. Cowchock ES, Wapner R], Kurtz A, et al: Not all cystic hygromas OCcur in the Ullrich-Turner syndrome. Am] Med Genet 12:327, 1982 3. Poland B], Dill F, Paradice B: A Turner-like phenotype in the aborted fetus. Teratology 21:361, 1980 4. Bieber FR: Comments on "A Turner-like phenotype in the aborted fetus." T eratology 21:418, 1980 5. Poland B], Dill F, Paradice B: Response to comments on "A
14. 15.
16. 17.
67
Turner-like phenotype in the aborted fetus ." Teratology 21:419, 1980 Kline], Stein Z, Susser M, et al: Environmental influences on early reproductive loss in a current New York City study. In Porter I, Hook EB (eds): Human Embryonic and Fetal Death. New York, Academic Press, 19BO Byrne]: Fetal pathology laboratory manual. Birth Defects 19:2, 1982 Philippe E: Histcpathclogie Placentaire. Paris, Masson, 1974 Van Mierop LHS: Polysplenia syndrome. In Bergsma D (ed): Birth Defects Compendium, 2nd edition. New York, Alan R. Liss, 1979 McKusick VA: Mendelian Inheritance in Man, 5th edition. Baltimore, The Johns Hopkins Uni versity Press, 1978 Rushton DI, Faed MJW, Richards SEM, et al: The fetal manifestations oEthe XO karyotype.] Obstet Gynecol Br Commonwealth 76:266 , 1969 Singh RP, Carr DH: The anatomy and histology ofXO human embryos and fetuses. Anat Rec 155:369, 1969 Matthies F, MacDiarmid WD, Rallison ML, etal: Renal anomalies in Turner's syndrome. Clin Pediatr 10:561, 1971 Honore LH , Dill F], Poland Bj. Placental morphology in spontaneous human abortuses with normal and abnormal karyotypes. Teratology 14:151,1976 Hook EB, Warburton D: The distribution of chromosomal genotypes associated with Turner's syndrome : livebirth prevalence rates and evid ence for diminished fetal mortality and severity in genotype associated with structural X abnormalities or mosaicism. Hum Genet 64:24, 1983 van der Putte SCJ: Lymphatic malformation in human fetuses . Virchows Arch [Pathol Anat] 376:233, 1977 Chervenak FA, Isaacson G, Blakemore K], et al: Fetal cystic hygroma: cause and natural history. N Engl] Med 309:822, 1983
There is increasing evidence that at least one feature widely considered pathognomonic for the XO karyotype in fetuses, namely, the presence of cystic hygromas, may be a feature of other malformation syndromes as well, some of which carry a recurrence risk. Two reports of such cases have been published: Bieber et al.! described a fetus with nuchal cystic hygroma and ascites, apparently part of a familial syndrome, and Cowchock et al. 2 described two fetuses with nuchal cystic hygroma and cleft palate from a single sibship. The relationship of cystic hygroma and Turner's syndrome has been the subject of some discussion in the Iiteratures-". Although most cases of cystic hygroma probably do occur in association with the XO karyotype in fetuses, more detailed investigation of the phenotypic characteristics may help differentiate cases of cystic hygroma with the XO karyotype, for which there is no increased risk of recurrence, and cases that may be part of other syndromes. We report here the results of our morphologic and karyotypic investigations of seven fetuses with cystic hygromas, one of which had the normal female karyotype. METHODS Seven fetuses with cystic hygromas of the neck were observed over the past six years as part of an on-going study of the pathology of early fetal loss; Received December 28, 1982, Accepted for publication]anuary 10, 1983. Supported in part by grants I-ROI-HD-08838, 1ROl-HD-12207, 5-ROI-DA-02090, and 5-T32-HD-07040 from the National Institutesof Health. it' Division of Developmental Pathology, Columbia University College of Physicians and Surgeons, New York, New York. t New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York. t Department of Human Genetics and Development, Columbia University College of Physicians and Surgeons. Address correspondence and reprint requests to Dr. Byrne: Division of Developmental Pathology, BHA-T22, Columbia University. 630 West 168th St, New York, NY 10032.
five were part of a collaborative pathologic, epidemiologic, and cytogenetic study of miscarriagess: two were examined since that collaboration ceased. In six of seven cases,' autopsies were performed, according to a standard protocol, either by Dr. Byrne or by specially trained assistants; one of the fetuses (case 5) received a more cursory examination. External and internal measurements were evaluated by use of fetal growth charts prepared from this abortus population. All organs were examined in situ and sectioned after fixation. Because of the extreme autolysis of the fetuses, tissue cultures for karyotyping were set up from the placenta (amnion, chorion, villi) in all cases except case 2, in which the placenta was received fixed. In this case fetal muscle was set up in culture but failed to grow. Sex chromatin examinations were made on sections of placental villi. RESULTS The incidence of fetuses with cystic hygroma in the large series of 3,500 miscarriages Byrne, unpublished data) was about 1 in 875, or about 1 in 200 miscarried fetuses greater than 3 em in crown-rump length (CRL). All seven cases of cystic hygroma occurred in severely autolyzed female fetuses. All but one, case 7, also showed generalized edema of the trunk and swelling of the extremities, with narrowing at major joints-elbows, wrists, knees, and anklesgiving the characteristic outline (fig. 1, left). In case 7 the lymphangiomas were smaller and no generalized hydrops was present (fig. 1, right). Perhaps significantly, the size of the heart in case 7 was within normal limits (fig. 2, toP), whereas in the other cases in which the heart was examined, it was markedly small according to fetal heart growth curves (fig. 2, bottom). The neck masses were symmetric in all cases, extending posteriorly and laterally to the shoulder, and they were restricted to the neck region. They consisted of multiple cystic structures that did not communicate with one another; these were filled with a dark brown, cloudy fluid. Sections through the tumors showed large cavities containing proteinaceous material and occasional lymphocytes. The fine wall structure was largely effaced because of autolysis. The endothelium had disappeared, leaving only a thin basement membrane. In contrast, adjacent blood vessels within the tumor lining already had a muscular media and contained blood cells. Blood vessels and nerves were observed within the thin septa separating the cysts. The tissues lining the cysts were massively edematous, but distinct lymphatic channels were observed in only two cases. These histologic fea-
a.
61
HUMAN PATHOLOGY
Volume 15, No.1 (Januory 1984)
FIGURE 1. Left case 2. Fetuswith cystic hygroma, generalized edema, and narrowing at major Joints; the crown-rump length (CRL) was 190 mm. Right case 7. Fetus with a small. opened cystic hygroma and no generalized edema: the CRL was 142 mrn.
tures contrast with those observed in lymphangiomas removed from infants and children, in which lymphoid follicles and bundles of smooth muscle are regularly found in the wall. Grossly, the placentas had no characteristic lesions. Particularly striking was the absence of Breus mole, reported to be associated with XO abortuses.f However, microscopic examination of the placentas showed characteristic changes consisting of hypoplasia of peripheral villi with severe edema causing a scalloped appearance of the villous margins. Trophoblastic inclusions secondary to the proliferation of the trophoblasts were observed. The scalloping pattern varied in degree, from minimal in case 6 (fig. 3e) to severe in cases 1 and 5 (fig. 3, a and d). Trophoblastic inclusions also varied in frequency. Superimposed on these features were variable degrees of intervillous fibrin deposition and fibrosis secondary to uterine retention of the dead fetus for various periods of time. In contrast, the placenta of case 7 (fig. 3j), which had the normal chromosome complement, showed neither villous edema nor trophoblastic inclusions, but only those changes due to retention-vascular obliteration and stromal proliferation. Vernix granulomas, also found in XO abortuses, were seen in three of the four cases in which the amnion was examined, including case 7. In all seven cases the ovaries were normal in size and in histologic structure. Chromosome studies, which were attempted in all cases, were successful in five; four cases yielded the 45,XO karyotype: case 7 was karyotyped as a
normal female, 46,XX. Fetuses with cystic hygroma and the XO karyotype represent only a small proportion (5.8 per cent) of all the XO abortuses in the large study Byrne, unpublished data).
a.
REPORT OF SEVEN CASES Case 1. A severely autolyzed 346-g female fetus had cystic hygroma and generalized edema. The CRL was 165 mm, and the crown-heel length (CHL) was 220 mm. The gestational age was 16 weeks; the developmental age corresponded to 18 weeks. A simian crease on the right hand was observed. Both lungs and heart were small (1.5 and 1.4 g, respectively). Coarctation of the aorta between the point of exit of the two carotid arteries was observed. There were no abnormalities in the abdominal cavity. The placenta was thin, measuring 90 x 90 x 2 mm. Tissue culture was established from the placenta; seven cells were counted and all were missing an X chromosome. This was the first pregnancy of a 17-year-old woman who afterwards delivered a live 1,570-g male infant at 31 weeks. Case 2. A severely autolyzed 538-g female fetus had bilateral cystic hygromas and generalized edema, with a CRL of 190 mm and a CHL of 270 mm (fig. 1, left). The gestational age was 23 weeks, and the developmental age was 21 weeks. Hypoplastic nails were observed on both hands and feet. Within the thorax, both heart and lungs were remarkably small (1.7 and 0.9 g, respectively). Coarctation of the aorta between the point of exit of the subclavian artery and the ductus arteriosus was observed. There was a persistent left superior vena cava with absence of the innominate vein (fig. 2, bottom). No abdominal abnormalities were observed. The placenta, received fixed in formalin, measured 110 x 110 x 15 rom and was completely
62
FETAl cysnc HYGROMA (Byrne et aJ.)
Top, case 7. Opened thorax showsa heart of normal size, small lungs, and coarctation (arro""1. Bottom, case 2. Opened thorax shows small heart, hypoplastic lungs (small arrows), and persistent left superior vena cava (large arrow) , FIGURE 2.
circumvallate. Tissue cultures were set up from fetal muscle but were unsuccessful. Sex chromatin find ings were negative. No maternal history was available. Case 3 . A severely autolyzed 570-g female fetus had bilateral cystic hygromas and generalized edema. The CRL was 195 mm and the CHL was 265 rnrn. The gestational age was 26 weeks and the developmental age corresponded to 21 weeks. Within the thorax the lungs were hypoplastic. The heart had a persistent left superior vena cava with absence of the innominate vein, a swiss-cheese-type of muscular ventricular septal defect, and tubular coarctation. The subclavian artery exited from the aorta distal to, rather than proximal to, the entrance of the ductus. Partial malrotation of the gut (no right-sided attachment) and a horseshoe kidney (fig. 4) were also observed. The placenta measured 130 X 105 x 10 mm and weighed 124 g. The cord had only two vessels. Sex chromatin findings were negative. The 25-year-old mother had had a previous normal
term delivery and subsequently had a normal term child. The parents were first cousins. Tissue cultures were set up from the placenta; at least eight cells were counted and all were lacking the second X chromosome. Case 4. A severely autolyzed 275-g female fetus had bilateral cystic hygromas and generalized edema. The CRL was 134 mm and the CHL was 190 mm. The gestational age was 26 weeks and the developmental age was 18 weeks. Both heart and lungs were markedly small (0.5 and 0.9 g, respectively), Tubular coarctation of the aorta and partial malrotation of the gut (failure of right-sided attachment) were observed. The placenta measured 122 x 86 X 9 mm and weighed 99 g. The cord had three vessels. Tissue culture, set up from the placenta, was successful; 15 cells were counted and all lacked the second X chromosome. Sex chromatin findings were negative. The mother was 23 years old and had a history of toxoplasmosis. She had had one previous elective abortion
63
HUIVIAN PATHOLOGY
Volume 15, No.1 (January 1984)
Placental villi, MOWS Indicate trophoblastic Inclusions, see text for details. 0, Case 1. b, Case 2. c Case 3, Legend con-
FIGURE 3.
tinues on facing page,
and, subsequent to this pregnancy, had a normal term female child. Case 5. A severely autolyzed 79-g female fetus had cystic hygromas and generalized edema. The CRL was 115 mm and the CHL was 150 mm. The gestational age was 22 weeks and the developmental age corresponded to 13 weeks. The heart and lungs were not examined. The pelvic organs were normal. The placenta measured 70 X 60 X 15 mm and weighed 58 g. Sex chromatin findings were negative. All ten karyotyped cells, obtained from placental tissue culture, were missing an X chromosome. The 24-year-old mother had had asthma as a child and syphilis and pyelonephritis ten years previously. She had delivered three liveborn children by cesarian sections. Case 6. A severely autolyzed 288-g female fetus had bilateral cystic hygromas and generalized edema. The CRL
was 150 mm and the CHL was 210 mm. The gestational age was 23 weeks; the developmental age corresponded to 17 weeks. The heart and lungs were markedly small (1.1 and 2.8 g, respectively). Coarctation of the ascending aorta was observed along with a bicuspid aortic valve. The subclavian artery exited Iowan the descending aorta, opposite the entry of the ductus. There was partial malrotation of the gut. The placenta measured 135 X 125 X 10 mm and weighed 94 g. The cord was inserted velamentausly and had three vessels. The 33-year-old mother had had two normal children. Tissue cultures, set up from placenta, developed yeast contamination and were discarded. Sex chromatin findings were negative. Case 7. A severely autolyzed 166-g female fetus had small cystic hygromas but no generalized edema. The CRL was 142 mm and the CHL was 200 mm (fig. 1, right). The
64
FETAL CYSTIC HYGROMA (Byrne et of.)
,
I
:. ~ ~
•
FIGURE 3 (continued), a Case 5, e, Case 6. f, Case 7, (All, hematoxylln-eosln stain. x 40.)
gestational age was 25 weeks; the developmental age corresponded to 16 weeks. Although the lungs were small, 2.6 g together, the heart was normal in size (2.0 g) in comparison with the rest of the body (fig. 2, top). Tubular coarctation of the aorta was observed together with a membranous ventricular septal defect and a large atrial septal defect. Many malformations of the abdominal cavity were seen-situs inversus abdominalis, malrotation of the gut, a small 4-mm spleen, and three accessory spleens. two measuring I mm and one measuring 2 mm (anisopolysplenia). The placenta was crescent-shaped, measured 143 X 106 x 17 mm, and weighed 157 g. A large S-shaped Breus mole was observed along with complete circummargination. The cord had three vessels. About 20 per cent of the cells examined were positive for sex chromatin, The karyotype, based on a harvest of three analyzable meta phases, was 46,XX.
The 19-year-old mother had had a previous normal delivery of a male child and a subsequent elective abortion. The father was an insulin-dependent diabetic. As indicated by the heart defects, the situs inversus, and the malrotation of the gut, the fetus had many features characteristic of the polysplenia syndrome.v The presence of cystic hygromas is not a usual concomitant of the condition and is more suggestive of the Noonan syndrome.w However, the lack of pulmonic stenosis and the absence of a familial pattern argue against this condition.
DISCUSSION In this series, seven cases of cystic hygroma were observed. Four of five karyotyped fetuses had the
65
HUMANPATHOLOGY
Volume 15, No.1 (January 1984)
FIGURE 4. Case 3. Opened abdomen shows horseshoe kldney and single umbilical artery. Ovorles have been removed.
45,XO chromosome complement and one had 46,XX. The single gross anatomic feature distinguishing the 46,XX fetus from the others was lack of generalized edema. In all other respects, particularly in the presence of coarctation, heart defects, and hypoplastic lungs, the features of this case mimicked the phenotypic characteristics of XO fetuses, i.e., cystic hygromas, generalized edema, and normal female genitalia. lO •ll In addition, coarctation of the aorta, hypoplastic lungs, and kidney malformations are common. 3 , l l - 13 Although mosaicism cannot be ruled out in case 7 (the Barr body count was lower than expected, and the karyotype was based on only three cells), it is interesting that neither previously reported case of familial cystic hygroma had generalized edema. In the case reported by Bieber et al.;' the well-preserved fetus clearly did not have hydrops, despite the presence of ascites. Hydrops also could not be detected in either of the cases, both autolyzed, from the second affected sibship reported by Cowchock et a1. 2 No familial pattern was apparent in our case of cystic hygroma with normal chromosomes. Rather, this case seems to represent a variant of the polysplenia syndrome in that in addition to the cystic hygroma, there were four spleens of unequal sizes, a heart defect, small lungs, situs inversus, and malrotation of the gut. In their detailed description of placental morphology and chromosome anomalies, Honore et al. 14 do not allude to the association of villous edema and trophoblastic inclusions with XO abortuses, which was observed here. It may be that the villous changes in XO conceptuses aborted earlier differ from those observed in more mature placentas. It may be instructive, in light of our findings, to speculate on the anatomic anomalies in children with Turner's syndrome born at term. While lungs as small as those observed here may not be incompatible with intrauterine life, they would be incompatible
with life after birth. We are not aware of any reports of infants with Turner's syndrome who had respiratory distress and succumbed in the neonatal period. It may be that phenotypic expression is variable, related perhaps to mosaicisrn.U with less severely affected fetuses surviving to term. Presumably, the severity of effect is related to the degree of hygroma development and concomitant hydrops, perhaps causing poor heart and lung growth. The exact mechanism of intrauterine death is unknown but may be related to excess fluid volume in the body coupled with heart failure or, perhaps, kidney failure. In a detailed anatomic study of the lymphatic system in female fetuses with cystic hygromas and generalized edema, van del' Putte-f reported great variability in the histologic features, but a common finding was hypoplasia of the main lymphatic trunks with accumulation of fluid in the intercellular spaces of the subcutaneous connective tissue. One explanation for the condition might lie in generalized hypoplasia and partial agenesis of the lymphatic system with failure of peripheral extension in the embryonic period. These speculations await confirmation from further anatomic studies of fetuses with cystic hygromas and from autopsy studies of neonates with Turner's syndrome. We suggest that an absence of hydrops in a female fetus with cystic hygromas and other anomalies associated with the XO karyotype may be a valid and reliable indicator of the normal chromosome complement. The proportion of such cases associated with a familial syndrome or other malformation syndromes remains to be seen. However, this combination of phenotypic and karyotypic features in an aborted fetus may warrant investigation of the family for other indicators of a familial malformation syndrome. These observations suggest that the use of the term "Turner-like phenotype" as a synonym for cystic hygroma is not always valid and should be confined
66
FETAL CYSTIC HYGROMA (Byrne et 01.)
to cases diagnosed on the basis of chromosomal or sex-chromatin findings . Addendum. Chervenak et al. recently reported 15 cases of nuchal cystic hygroma diagnosed by ultrasound in phenotypically female fe tuses. Ka ryotypes we re 45 ,XO in nine cases, 45 ,X0146 ,XX in three, and 46 ,XY in one. Amnion cells were sex- chromatin-negative in one case.l? Acknowledgments. The authors thank Dr. Zena Stein, Dr. Jennie Kline, and Dr. Mervyn Susser, co-principal investigators (with D.W.) of the Spontaneous Abortion Study; Diane Baker, Phoebe Kussin, Debra Zillmer, and Diana Andrews, research assistants in pathology; and Richard Weed of the NYS Institute for Basic Research in Developmental Disabilities for photographic assistance.
6.
7. 8. 9. 10. II. 12. 13.
REFERENCES 1. Bieber FR, Petres RE, Bieber M, et al: Prenatal detection of a familial nuchal bleb simulating encephalocele. Birth Defects 15:51, 1979 2. Cowchock ES, Wapner R], Kurtz A, et al: Not all cystic hygromas OCcur in the Ullrich-Turner syndrome. Am] Med Genet 12:327, 1982 3. Poland B], Dill F, Paradice B: A Turner-like phenotype in the aborted fetus. Teratology 21:361, 1980 4. Bieber FR: Comments on "A Turner-like phenotype in the aborted fetus." T eratology 21:418, 1980 5. Poland B], Dill F, Paradice B: Response to comments on "A
14. 15.
16. 17.
67
Turner-like phenotype in the aborted fetus ." Teratology 21:419, 1980 Kline], Stein Z, Susser M, et al: Environmental influences on early reproductive loss in a current New York City study. In Porter I, Hook EB (eds): Human Embryonic and Fetal Death. New York, Academic Press, 19BO Byrne]: Fetal pathology laboratory manual. Birth Defects 19:2, 1982 Philippe E: Histcpathclogie Placentaire. Paris, Masson, 1974 Van Mierop LHS: Polysplenia syndrome. In Bergsma D (ed): Birth Defects Compendium, 2nd edition. New York, Alan R. Liss, 1979 McKusick VA: Mendelian Inheritance in Man, 5th edition. Baltimore, The Johns Hopkins Uni versity Press, 1978 Rushton DI, Faed MJW, Richards SEM, et al: The fetal manifestations oEthe XO karyotype.] Obstet Gynecol Br Commonwealth 76:266 , 1969 Singh RP, Carr DH: The anatomy and histology ofXO human embryos and fetuses. Anat Rec 155:369, 1969 Matthies F, MacDiarmid WD, Rallison ML, etal: Renal anomalies in Turner's syndrome. Clin Pediatr 10:561, 1971 Honore LH , Dill F], Poland Bj. Placental morphology in spontaneous human abortuses with normal and abnormal karyotypes. Teratology 14:151,1976 Hook EB, Warburton D: The distribution of chromosomal genotypes associated with Turner's syndrome : livebirth prevalence rates and evid ence for diminished fetal mortality and severity in genotype associated with structural X abnormalities or mosaicism. Hum Genet 64:24, 1983 van der Putte SCJ: Lymphatic malformation in human fetuses . Virchows Arch [Pathol Anat] 376:233, 1977 Chervenak FA, Isaacson G, Blakemore K], et al: Fetal cystic hygroma: cause and natural history. N Engl] Med 309:822, 1983