Triploidy:  Variation of Phenotype

Abstract

Objectives: Triploidy (69, XXX; 69, XXY; 69, XYY) accounts for 1% of conceptions, but the affected fetus often does not survive past the first trimester. Fetal development in triploidy is rare. A consecutive series was used to describe the fetal and placental phenotypes and compare them with previous publications.

Methods: Fifty-four triploid fetuses were identified in the Active Malformations Surveillance Program between 1972 and 2012 at Brigham and Women’s Hospital in Boston. The phenotype was described from prenatal imaging and autopsy findings.

Results: The diagnosis was confirmed by chromosome analysis in 53 of the 54 fetuses. Twenty-seven (50%) of the affected fetuses were identified during pregnancy. The abnormalities identified by prenatal ultrasound included renal malformations, heart defects, hydrocephalus, holoprosencephaly, and myelomeningocele. At autopsy, syndactyly, usually between fingers 3 and 4, was identified in 37 (69%) of the fetuses. Thirteen (24%) of the infants had the histologic features of a partial hydatidiform mole in the placenta.

Conclusions: The presence of major malformations and growth restriction during pregnancy makes triploidy a potential diagnosis. There are no obligate clinical features in triploidy. Syndactyly, especially 3-4 syndactyly of the hands, is a distinctive feature. Cystic changes in the placenta can be seen by ultrasound during pregnancy. There was no difference in the phenotype between triploid infants associated with partial moles and those with nonmolar placentas.

Triploidy, a rare chromosomal abnormality, occurs in approximately 1% of conceptions.¹ Many triploid conceptions are aborted spontaneously in the first trimester; triploidy was present in 20% of spontaneous abortions in one series.² Triploidy associated with fetal development and survival beyond the first trimester is rare. The prevalence of triploidy at 16 to 20 weeks of pregnancy has been estimated to be 1 in 5,000.³

Many malformations have been reported in affected fetuses, including holoprosencephaly with median cleft lip, gastroschisis, encephalocele, myelomeningocele, syndactyly, clubfeet, heart defects, and renal agenesis.⁴ The most common of the associated malformations has been syndactyly, which was present in 65% of the infants in one study,⁵ most often complete syndactyly of the third and fourth fingers.^2,6,7

Placental molar changes were present in nine (47%) of 19 of the affected fetuses in one case series.⁵ In a review of 100 triploid spontaneous abortions, 86% were associated with partial hydatidiform moles.⁸ The diagnostic placental changes in partial molar placentas include syncytiotrophoblastic hyperplasia, villous edema leading to cistern formation, scalloped outline of villi, frequent “trophoblastic inclusion” formation,⁸ and an atypical pattern of trophoblastic hyperplasia.⁹ The distinctive changes in the placenta that can be identified prenatally in ultrasound imaging are cystic changes, an irregular appearance, and areas of increased echogenicity in the tissue surrounding the gestational sac.¹⁰

We reviewed our cases of triploidy with fetal development to describe the fetal and placental pathology and to refine the triploidy phenotype. We have compared our findings with those in previous publications.

Materials and Methods

Fetuses with triploidy were identified by the staff of the Active Malformations Surveillance Program at the Brigham and Women’s Hospital between February 16, 1972, and October 1, 2012.¹¹ This project was carried out 6 days a week, including holidays, except for the interval from February 15, 1975, through December 31, 1978, when the surveillance program was discontinued because of the loss of office space. The definition of a malformation used was a structural abnormality with surgical, medical, or cosmetic importance. The surveillance process by the research assistant included reading each newborn infant’s medical record, pathology reports, chromosome analyses, autopsy reports, and consultations reports. None of the fetuses with triploidy were identified after 2000 when, due to a change in personnel, the hospital significantly decreased most elective terminations of pregnancies.¹²

The infants were classified as live births, stillbirths (20 weeks or greater gestational age), or elective terminations. Neonatal deaths were infants who died within 28 days of birth. Spontaneous abortions that occurred before 20 weeks of gestation were excluded, since ascertainment was incomplete. The race of each fetus or infant was established by asking the mother to select a racial designation for her infant from a list of all possibilities.

Results

Of the 54 fetuses with triploidy identified, 40 (74.1%) were white, one (1.8%) was black, one (1.8%) was Asian, one (1.9%) was Hispanic, and 11 (20.4%) were of an unknown racial group. For 46 (85.2%) fetuses, the pregnancy was terminated electively; four (7.4%) affected infants died within days after birth; and four (7.4%) fetuses were stillborn.

The diagnosis of triploidy was established for 53 (98.1%) of 54 affected fetuses by chromosome analysis. Of these fetuses, 26 (49%) had abnormalities on prenatal ultrasound; the diagnosis was then confirmed by chromosome analysis from cultured tissue removed at autopsy after terminating the pregnancies. In the other 27 fetuses, the chromosome abnormality was identified in several ways: 20 (37.7%) were diagnosed by chromosome analysis from amniotic fluid removed during pregnancy by amniocentesis, four (7.5%) by amniocentesis with the diagnosis confirmed after delivery by chromosome analysis from cultured tissue, two (3.7%) by percutaneous ultrasound-guided blood sampling, and one (1.8%) by chorionic villus sampling and confirmed by chromosome analysis from cultured tissue after birth.

The presence of triploidy was not confirmed by chromosome analysis in one fetus, whose phenotypic features were myelomeningocele on prenatal ultrasound, syndactyly of digits 3 to 4 in the right hand, and the presence of partial hydatidiform molar pathology of the placenta.

The chromosome abnormalities identified were as follows: 69, XXX in 35 (64.8%) and 69, XXY in eight (14.8%). Three (5.6%) had triploid/diploid mosaicism: one 69, XXX/46, XX and two 69, XXY/46, XX. These three fetuses with triploid/diploid mosaicism were attributed to maternal cell contamination. Of the affected fetuses, eight (15%) were diagnosed as having triploidy by verbal reports from outside laboratories; the full karyotype was not available.

The abnormalities identified by prenatal ultrasound were intrauterine growth restriction (31.5%; n = 17), oligohydramnios (18.5%; n = 10), hydrocephalus (18.5%; n = 10), ventricular septal defect (9.3%; n = 5), holoprosencephaly (5.5%; n = 3), multicystic kidneys (3.7%; n = 2), renal agenesis/dysgenesis (9.3%; n = 5), horseshoe kidney (3.7%; n = 2), hydronephrosis (3.7%; n = 2), posterior fossa cyst (11.1%; n = 6), myelomeningocele (9.3%; n = 5), cystic hygroma (3.7%; n = 2), and hemivertebrae (3.7%; n = 2) Table 1. At autopsy, additional anomalies were identified, including syndactyly (69%; n = 37), anophthalmia (1.8%; n = 1), coloboma (1.8%; n = 1), hypospadias (1.8%; n = 1), clubfoot deformity (7.5%; n = 4), and calcification of the cardiac papillary muscle (3.7%; n = 2) Table 2.

Syndactyly of the fingers or toes was present in 37 (69%) of the 54 fetuses and infants. In particular, bilateral syndactyly of fingers 3 to 4 was the most common and distinctive anomaly in fetuses with triploidy Image 1 and Image 2; this syndactyly was present in 14 (37.8%) of the 37 fetuses with syndactyly Table 3. Bilateral syndactyly of toes 2 to 3 was present in seven (18.9%) of the 37 fetuses and was the second most common type of syndactyly. While syndactyly of fingers 3 to 4 was the most common pattern, the variation in the fingers and toes affected was extensive. For example, more extensive syndactyly of fingers 1 to 5 was present in one fetus and of toes 2 to 3, 4 to 5, and 2 to 4 in two other fetuses. In addition, one fetus had a bifid first toe, as well as syndactyly of fingers 3 to 4 and toes 2 to 3.

The classification of each affected fetus or infant as a partial hydatidiform mole or as a non-molar pregnancy was made by an experienced perinatal pathologist (D.J.R.) from a review of the pathology reports. The original slides and tissue blocks were not available. Thirteen (24%) of the 54 triploid fetuses had the features of a partial hydatidiform mole, and 41 (67%) were non-molar. Abnormalities were identified in 12 (92%) of 13 cases in the partial mole group and 35 (85%) of 41 cases in the non-molar group. The associated abnormalities in the two groups were similar Table 4. A detailed description of the internal and external malformations, as well as the growth parameters of each fetus, is presented in Table 5 and Table 6.

Partial hydatidiform moles were present in 13 (24%) of cases Image 3. The most distinctive features in the placenta of the partial mole group (n = 13) were hydrops (eight; 61.5%) and trophoblastic inclusions (two; 15.4%). In the non-molar placenta group (n = 41), 40 fetuses showed normal placental features, and one fetus had placental mesenchymal dysplasia diagnosed at autopsy. The absence of trophoblastic hyperplasia negated the diagnosis of a partial hydatidiform mole in that fetus.

Discussion

The strength of this study is in the detailed anatomic analysis of 54 affected fetuses. This analysis provided a description of the spectrum of structural abnormalities that occurred in association with triploidy. The pathologists’ detailed descriptions of the digits make it possible to describe the pattern of syndactyly beyond the often reported and distinctive syndactyly of fingers 3 and 4. The findings identified by prenatal imaging with ultrasound emphasize the importance of additional diagnostic testing, such as amniocentesis, whenever anomalies (eg, myelomeningocele and holoprosencephaly) and growth restriction are identified, since these abnormalities are commonly present in fetuses with triploidy.

One weakness of this review of consecutive cases is the fact that the screening by prenatal ultrasound was not carried out very often in the 1970s, and the technology was evolving in the 1980s. Therefore, the detection by prenatal ultrasound imaging varied and improved between 1972 and 2000, when the last affected infant was identified. Chromosome analysis based on amniocytes or tissue culture postmortem was the most reliable testing. Chromosomal microarray, which became available in the past decade, has not detected triploidy.¹³

The noninvasive prenatal testing for fetal aneuploidies, using cell-free fetal (cff) DNA, was able to detect the presence of additional fetal haplotypes associated with dizygotic twins and triploidy in one study.¹⁴ This method does not distinguish between these possibilities. Hence, ultrasound examination is warranted to distinguish between an ongoing twin and a singleton pregnancy and may reveal the presence of a vanished twin. In the case of a confirmed singleton pregnancy with additional haplotypes, a follow-up invasive diagnostic testing (i.e., amniocentesis) is still recommended to establish a final diagnosis. Therefore, the conventional screening tests are recommended, and suspected cases should have amniocentesis or chorionic villous sampling until the accuracy of cff DNA testing has been determined.

Two of the most common prenatal findings identified by ultrasound were intrauterine growth restriction (IUGR) and oligohydramnios, present in 17 (32%) of 54 and 10 (19%) of 54 affected fetuses, respectively. By comparison, in two other studies,^5,15 these findings were reported in 11 (55%) of 20 and 65.3% for IUGR and 10 (19%) of 54 and 12 (60%) of 20 for oligohydramnios.

The types of abnormalities identified in the 54 affected fetuses we report and those reported by Mittal et al⁵ were similar (Tables 1 and 2). This comparison shows that growth restriction, oligohydramnios, hydrocephalus, myelomeningocele, holoprosencephaly, heart defects, and a variety of renal malformations were the most common findings in both series.

One cardiac finding in the non-molar placenta group (n = 41) was papillary muscle calcification. In our cohort, papillary muscle calcification was demonstrated in two (3.7%) of 54 non-molar pregnancy triploid fetuses. By comparison,¹⁶ papillary muscle calcification was present in 14 (16%) of 85 fetuses with trisomy 21 and in seven (39%) of 18 with trisomy 13.

In an analysis of 85 cases of single umbilical artery and multiple fetal defects,¹⁷ 37 had chromosomal abnormalities, of which five were triploidy. Single umbilical artery was demonstrated in six (15%) of 41 cases in the non-molar triploid gestations. The presence of enlarged villi (≥3-4 mm) is one of four major histologic diagnostic features of partial mole.¹⁸ In our cohort, villi were enlarged in seven (53.8%) of 13 cases, and the diameter range was 1 to 15 mm.

The original pathology was diagnosed at an institution with a strong academic foundation in gynecology and perinatal pathology staffed by experienced perinatal pathologists. In addition, for this article, the pathology reports were re-reviewed by an experienced perinatal pathologist (D.J.R.). The diagnosis of partial hydatidiform mole was made in 13 (24%) of 54, in contrast to 47.3% in one study⁵ of 20 fetuses and 86% in another⁸ study of 100 cases of spontaneous abortions. Our data suggest that partial hydatidiform mole is not common in triploid gestations associated with fetal development beyond 20 weeks gestational age. An explanation of this difference could be that triploid conceptions associated with partial moles abort spontaneously before 20 weeks of gestation. These 54 affected fetuses were identified in our study as fetuses older than 20 weeks of gestational age; stillborn and live born infants were enrolled.

We found syndactyly to be a characteristic phenotype of triploidy, whether associated with partial hydatidiform mole or not. Although characteristic, it is not pathognomonic. Syndactyly of fingers 3 and 4 occurs in phenotypes other than triploidy. In the Active Malformations Surveillance Program carried out at Brigham and Women’s Hospital from 1972 to 2012, syndactyly of fingers 3 to 4 was identified in four other phenotypes: trisomy 21, trisomy 18, urethral atresia, and amniotic band syndrome.¹¹ Syndactyly of fingers 3 and 4 is rare. Therefore, if identified at autopsy or by antenatal diagnostics, triploidy should be considered the most likely diagnosis.

Three of the karyotypes on these 54 affected fetuses and infants were reported as triploid/diploid mosaics: 69, XXY or 69, XXX/46, XX. The cytogeneticists analyzing the chromosome karyotypes in 1984, 1990, and 1994 interpreted the presence of 46, XX cells as maternal cell contamination. Laboratory testing to confirm that interpretation was not available at that time. However, true mosaicism 69, XXX/46, XX has been reported recently in two individuals.^19,20 Jewell et al¹⁹ reported a 29-year-old woman with true mosaicism: 69, XXX (47%)/46, XX (53%). She was born at 38 weeks’ gestation, following induction for IUGR. As an infant, she had low birth weight and height, poor feeding, and hypotonia. She was developmentally delayed and had chronic tonic-clonic seizures, anxiety, depression, and obsessive behavior. At age 29 years, she had learning difficulties, seizures, short stature, truncal obesity, scoliosis, asymmetry of her legs, and syndactyly of fingers 3 to 4 on her left hand and between fingers 2 and 5 on her right hand, as well as between toes 2 and 4 on her left foot and toes 2 and 3 on her right foot. Boonen et al²⁰ reported a 14-year-old girl with mosaicism, 69, XXX (86%) and 46, XX (14%), who was born at 42 + 3 weeks with growth restriction. Her medical problems included hypotonia, bilateral conductive hearing loss, and psychomotor development delay. At age 14 years, she was described as having kyphoscoliosis, truncal obesity, and asymmetric extremities. Her hands and feet were small with hyperextension of the fingers. The thumbs were proximally placed; there was clinodactyly of the fifth fingers. Her first toes were short; there was increased space between toes 1 and 2 and syndactyly between toes 2 and 3. In comparison to non-mosaic triploidy, diploid/triploid mosacisim appears to be a more infrequent and a less severe condition.

Conclusions

Triploidy is a common chromosome abnormality that occurs most often as a spontaneous abortion or stillbirth but rarely as a live-born infant. There are no obligate clinical features in triploidy. It is typically a surprise diagnosis in the studies offered to the pregnant woman whose unborn fetus has been found to have major malformations, growth restriction, and/or distinctive changes seen by ultrasound in the placenta. In this series of 54 consecutive affected fetuses or newborns identified by a malformations surveillance program, a wide spectrum of malformations was identified. Syndactyly of fingers 3 to 4 was a common finding, but in this series, the syndactyly was more varied in pattern. This detailed description of the phenotype of triploidy is meant to facilitate the diagnosis of triploidy for ultrasonographers and pathologists.

References