polyploidy

DEFINITION: Euploid state with extra complete haploid sets of chromosomes (3n = triploidy, 4n = tetraploidy). Distinct from aneuploidy (gain/loss of individual chromosomes, e.g., trisomy 21, monosomy X), which is not a multiple of n.

MECHANISMS: - Triploidy (69 chromosomes): (1) Dispermy: two sperm fertilize one egg (~2/3 of cases, paternal origin) or a diploid sperm fertilizes a normal egg (failure of meiosis in the sperm). (2) Digyny: a diploid egg (failure of meiosis in the oocyte) is fertilized by a normal sperm (maternal origin). - Tetraploidy (92 chromosomes): failure of the first zygotic cleavage division (mitosis completes DNA replication without cytokinesis/division). Usually incompatible with life.

PARENT-OF-ORIGIN (IMPRINTING) EFFECTS (high-yield): - Extra paternal set (diandric triploidy, 69,XXY/XXX/XYY): partial hydatidiform mole. Features: large, hydropic, cystic placenta with marked trophoblastic overgrowth and a small, poorly developed/nonviable fetus (or fetal parts present). Fetal parts and an embryo may be seen; hCG is only modestly elevated; low risk of choriocarcinoma (much lower than complete mole). - Extra maternal set (digynic triploidy): small, fibrotic placenta, severe asymmetric intrauterine growth restriction, and a relatively large head. - Contrast with complete mole: 46,XX (or rarely 46,XY), entirely paternal (an empty egg fertilized by one sperm that duplicates, or two sperm); no fetal parts; "snowstorm" or "cluster of grapes" appearance on ultrasound; markedly elevated hCG; ~15–20% risk of malignant transformation (choriocarcinoma); p57 (CDKN1C) negative on immunostaining (maternally expressed gene), whereas p57 is positive in partial mole.

CLINICAL SIGNIFICANCE: - Triploidy accounts for a notable fraction of first-trimester spontaneous abortions; rare live births do not survive long (die within days). Anomalies include syndactyly (3rd/4th fingers), growth restriction, and cardiac, neural tube, and other defects. - Most common chromosomal abnormalities in spontaneous abortions overall: monosomy X (45,X) is the most common single abnormality, trisomy 16 is the most common trisomy, and polyploidy (mostly triploidy) is another significant category. - Diagnosis: karyotype/flow cytometry (shows 3n DNA content in partial moles), ultrasound (thickened cystic placenta with an abnormal fetus), and p57 immunostaining.

NORMAL/PHYSIOLOGIC POLYPLOIDY (somatic): Occurs in certain tissues, including hepatocytes (often 4n), megakaryocytes (endomitosis, up to 64n), and cardiac myocytes. Cancer cells also frequently show polyploidy/whole-genome doubling, which is associated with genomic instability and p53 loss. Plants commonly tolerate polyploidy (e.g., wheat, bananas, seedless watermelon), a distinction often noted in genetics.

BOARD PEARLS: - Polyploidy = multiples of the haploid number (euploid); aneuploidy = not a multiple. - Triploidy is the most common polyploidy seen in humans and usually results in miscarriage. - Partial mole = 69,XXX/XXY/XYY (two paternal sets + one maternal set); complete mole = 46,XX (all paternal). - Mechanisms: dispermy, nondisjunction of whole sets in meiosis (diploid gamete), failure of cleavage.