Case of the Week # 514

Case of the Week # 514

Javier Cortejoso
 on 03/19/2023
 on Sunday, March 19th, 2023
The ultrasound images demonstrate the following:
• Images 1-4: There appears to be a large head compared to the body. An abnormal posterior fossa is seen in the sagittal section, with an anechoic image at this level. The nuchal translucency is normal (1.54 mm) and nasal bone is identified. The placenta, located on the anterior wall, is homogeneous and small in size.
• Image 5: the orthogonal mode of a 3D volume of the head shows a dilated fourth ventricle
• Image 6: in the 3D surface mode of the fetus, the small size of the body with respect to the head is demonstrated (relative macrocephaly with small body).

Triploidy is a lethal chromosome abnormality caused by the presence of a complete extra set of chromosomes. Although it is the most common chromosomal abnormality at the time of conception (1–2% of all conceptions), most triploid fetuses will die before 20 weeks, thus the incidence is about 1 in 10,000 live births. Triploidy occurs sporadically, and in contrast to trisomy, its rate does not increase with advancing maternal age. Unlike other chromosomal abnormalities, triploidy may also affect the mother with varying degrees of preeclampsia or persistent trophoblastic disease.

The joining of one haploid spermatozoon and one haploid oocyte produces a normal diploid cell count of 46 chromosomes. Proper meiosis ensures that gametes are haploid in number before fusion. Triploidy can arise from:
(1) Fertilization of one egg by two spermatozoa, referred to as dispermy
(2) Fertilization of one oocyte by a diploid sperm, referred to as diandry
(3) Fertilization of a diploid oocyte by one sperm, referred to as digyny.
In the last two situations, the diploid state of the gamete results from unequal separation during the first or second meiotic division. When two haploid sperm or a diploid sperm fertilizes a normal haploid oocyte, the karyotype can be XXX, XXY, or XYY. This is type I triploidy and is paternally derived. Type II triploidy is maternally derived and results from the fertilization of a diploid oocyte by a haploid sperm, resulting in XXX or XXY karyotypes. The distribution of karyotypes seen in triploid conceptuses is 69,XXY (60%), 69,XXX (37%), and 69,XYY (3%). Maternal origin appears to be more common in pregnancies that persist beyond the embryonic period.

The phenotype of a triploid fetus depends on the parental origin of the extra chromosome set. In type I, a relatively well-grown fetus has a normal head size or microcephaly and a large, cystic placenta. In type II, a growth-restricted fetus has a disproportionately large head and a normal-appearing but small placenta.

The majority of triploid pregnancies are spontaneously aborted during the first trimester. In cases where this does not happen, there is a wide variation in the sonographic features associated with triploidy, ranging from a normal phenotype to multiple major birth defects. On the first trimester ultrasound, it should be suspected in any pregnancy with an enlarged, cystic placenta and living embryo or in the setting of severe asymmetric IUGR, even if placenta is normal. In the second and third trimesters, 85% have one or more anomalies, but no single anomaly is pathognomonic of triploidy. Abnormalities have been described in the head (ventriculomegaly, agenesis of corpus callosum, holoprosencephaly, Dandy-Walker malformation, dilation of fourth ventricle), spine (myelomeningocele), face and neck (hypertelorism, microphthalmia, micrognathia, cleft lip/palate, increased nuchal thickening, cystic hygroma), heart (ventricular and atrial septal defects), abdomen (omphalocele, hydronephrosis, renal dysplasia), genitalia (ambiguous genitalia, hypospadias, and cryptorchidism), extremities (syndactyly of third and fourth digits, clubbed feet), and amniotic fluid (oligohydramnios). Ventriculomegaly and syndactyly is a suggestive combination, but syndactyly is a difficult prenatal diagnosis. Posterior fossa abnormalities are also common.

Combined maternal serum screening and ultrasound has been used to identify fetuses with chromosomal alterations. In diandric triploidy, fetal nuchal translucency is increased as well serum total hCG and free b-hCG with mildly decreased PAPP-A, presenting as trisomy 21. In contrast, the digynic type is characterized by a normal fetal nuchal translucency with markedly decreased serum total hCG, free b-hCG and PAPP-A, presenting as trisomy 18. Currently, the majority of clinically available methods for cell-free DNA testing are counting methods, so the triploidy cases will escape diagnosis. An approach using a single-nucleotide polymorphism (SNP)-based method can theoretically resolve this problem. Nicolaides et al use this method and determine that it can effectively identify diandric triploidy, but fails to detect digynic triploidy due to the small size of the placenta, which may be contributing to low cfDNA fraction.

The differential diagnosis for triploidy includes syndromes associated with early onset IUGR and fetal anomalies. Among them are trisomies 18 and 9, Wolf-Hirschhorn syndrome, Neu-Laxova syndrome, Russell-Silver syndrome, Seckel syndrome, and maternal infections.

Suggested readings:
• Benacerraf BR. Intrauterine growth retardation in the first trimester associated with triploidy. J Ultrasound Med. 1988;7(3):153–154.
• Fleischer J, Shenoy A, Goetzinger K, et al. Digynic triploidy: utility and challenges of noninvasive prenatal testing. Clin Case Rep. 2015;3(6):406–410.
• Gainer JA. Triploidy. In: Copel JA, ed. Obstetric Imaging. Fetal diagnosis and care, 2nd ed. Elsevier, Philadelphia, PA, 2018; pages 598-602.e1
• Loureiro T, Ferreira AF, Ushakov F, et al. Dilated fourth ventricle in fetuses with trisomy 18, trisomy 13 and triploidy at 11-13 weeks' gestation. Fetal Diagn Ther. 2012;32(3):186–189.
• Lugthart MA, Horenblas J, Kleinrouweler CE, et al. Prenatal sonographic features can accurately determine parental origin in triploid pregnancies. Prenat Diagn. 2020 May;40(6):705-714.
• Massalska D, Bijok J, Ilnicka A, et al. Triploidy - variability of sonographic phenotypes. Prenat Diagn. 2017;37(8):774–780.
• McFadden DE, Kalousek DK. Two different phenotypes of fetuses with chromosomal triploidy: correlation with parental origin of the extra haploid set. Am J Med Genet. 1991;38(4):535–538.
• Nicolaides KH, Syngelaki A, del Mar Gil M, et al. Prenatal detection of fetal triploidy from cell-free DNA testing in maternal blood. Fetal Diagn Ther. 2014;35(3):212–217.
• Pan M, Yang D, He Y, et al. Early prenatal detection of triploidy: a 9-year experience in mainland China [published online ahead of print, 2019 Dec 18]. J Matern Fetal Neonatal Med. 2019;1–5.
• Zalel Y, Shapiro I, Weissmann-Brenner A, et al. Prenatal sonographic features of triploidy at 12-16 weeks. Prenat Diagn. 2016;36(7):650–655.

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