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Complete trisomy 4 is a lethal abnormality and occurs in 2-3% of all chromosomally abnormal pregnancy losses. It does not seem that the chance of trisomy 4 increases strikingly with advancing maternal age (Marion et al, 1990), possibly since this trisomy may often be of post-zygotic as well as meiotic origin.

Trisomy 4 mosaicism is presumed to be very rare as it has not been reported in any of the large studies on CVS mosaicism and only rarely on amniocentesis Outcome has ranged from normal to multiple congenital anomalies and/or intrauterine death. Diagnosis of trisomy 4 on amniocentesis should be followed up with serial ultrasound. Some cases of trisomy 4 were present in th fetus but not in peripheral blood (Hsu, 1997; Chen et al. 2004).

Uniparental disomy for chromosome 4 has been reported in one case associated with placental trisomy 4 and intrauterine death (Kuchinka et al. 2000). However, the poor outcome in this case might well have been simply a consequence of the high levels of trisomy 4 in the placental trophoblast.

Trisomy 4 detected on CVS

Trisomy 4 conceptions have not been observed in the large case studies of chromosomal mosaicism discovered during chorionic villus sampling, however two cases ascertained through CVS diagnosis were reported by Kuchinka et al. (2000). One was found to have UPD4 in addition and resulted in an in utero death at 30 weeks gestation. It is unclear whether the outcome was a consequence of the UPD4 or placental trisomy. A second case showed only low levels of trisomy in the placenta and biparental inheritance of chromosome 4 in fetal tissues. This case had a normal outcome.

Trisomy 4 detected on amniocentesis

Hsu (1997) reviewed two reported cases of trisomy 4 mosaicism detected on amniocentesis. There was one normal outcome with 10% trisomy 4 cells detected on amniocentesis. The other case (Marion et al, 1990) with 31% trisomy 4 cells resulted in an abnormal outcome. This child was born with multiple congenital anomalies, facial dysmorphism, and congenital heart defect. There was no significant developmental delay by the age of one year. Another case of trisomy 4 detected in 3 of 36 AF cells resulted in a normal liveborn male (Zaslav et al. 2000).

Trisomy 4 was also detected in 100% of amniocytes analyzed subsequent to termination of an 18 week fetus with cyclopia, alobar holoprosencephaly, complex congenital heart defect, anal atresia, oligosyndactyly, cystic hygroma, skeletal abnormalities, and IUGR (Van Allen et al., 1993) .

Trisomy 4 was detected in 4 of 20 cells at amniocentesis in a case with tetralogy of Fallot detected on ultrasound (Chen et al. 2004). After termination, additional abnormalities were noted and trisomy 4 mosaicism was confirmed in amnion, liver, lungs, skin and umbillical cord; however only 46,XX cells were noted in cord blood. The trisomy was considered to be of paternal meiotic origin.

Trisomy 4 mosaicism may be another example of tissue-limited mosaicism given that, in serveal abnormal cases fetal blood sampling was falsely reassuring.

Uniparental Disomy (UPD 4)

One case of maternal UPD4 has been reported (Kuchinka et al. 2000). Ultrasound on this case was normal at 17 weeks but IUGR and oligohydramnious were detected at 29 weeks. Doppler blood flow studies showed "high impedence to flow in placental circulation and normal distribution of the fetal circulation". The baby died in utero in the 30th week. Fetal growth was normal and no external malformations were detected. Thus, while outcome was abnormal in this case, the features could easily be attributable to a placental cause as a consequence of the high level of trisomy 4 found in placental trophophoblast (15/15 cells showed the trisomy 4 on direct CVS analysis). Thus the possible effect of UPD4 should really be considered unknown.

There are no other reports at this time, although it should be noted that Carpenter et al. (Carpenter et al., 1982) reported a small, mildly dysmorphic child exhibiting developmental and language delay who was homozygous for a pericentric inversion of chromosome 4 found in heterozygous state in her normal mother. The father, who was not karyotyped, was assumed to also be a carrier of the inversion, but it has been subsequently suggested that the child could have had maternal UPD4 (Schinzel, 1993) .

Link to What is UPD?
Link to Maternal UPD 4
Link to Paternal UPD 4

Internet Links

  • HUGO Chromosome 4 - Chromosome 4 specific sites
  • uman Chromosome 4 - Provides links to gene maps, sequences, associated genetic disorders, nonhuman genetic models, identified genes, research efforts and laboratories, and other information as available. Links are very scientific.


Carpenter NJ, Say B, Barber ND. A homozygote for pericentric inversion of chromosome 4. J Med Genet. 1982 Dec;19(6):469-71.

Chen CP, Chern SR, Lee CC, Chang TY, Wang W, Tzen CY. Clinical, cytogenetic, and molecular findings of prenatally diagnosed mosaic trisomy 4. Prenat Diagn. 2004 Jan;24(1):38-44. Review. Pubmed

Hahnemann JM, Vejerslev LO. ( 1997) European collaborative research on mosaicism in CVS (EUCROMIC)--fetal and extrafetal cell lineages in 192 gestations with CVS mosaicism involving single autosomal trisomy. American Journal of Medical Genetics 70(2):179-87. PubMed

Hsu LY, Yu MT, Neu RL, Van Dyke DL, Benn PA, Bradshaw CL, Shaffer LG, Higgins RR, Khodr GS, Morton CC, Wang H, Brothman AR, Chadwick D, Disteche CM, Jenkins LS, Kalousek DK, Pantzar TJ, Wyatt P. (1997) Rare trisomy mosaicism diagnosed in amniocytes, involving an autosome other than chromosomes 13, 18, 20, and 21: karyotype/phenotype correlations. Prenatal Diagnosis 17(3):201-42. PubMed

Kuchinka BD, Barrett IJ, Moya G, Sanchez JM, Langlois S, Yong SL, Kalousek DK, Robinson WP.Two cases of confined placental mosaicism for chromosome 4, including one with maternal uniparental disomy. Prenatal Diagnosis 2001 Jan;21(1):36-9.

Ledbetter DH, Engel E. (1995) Uniparental disomy in humans: development of an imprinting map and its implications for prenatal diagnosis. Human Molecular Genetics 4:1757-1764 PubMed

Marion JP, Fernhoff PM, Korotkin J, Priest JH. (1990) Pre- and postnatal diagnosis of trisomy 4 mosaicism. American Journal Medical Genetics. 37(3):362-365. PubMed

Schinzel A. NICHD conference. Genomic imprinting: consequences of uniparental disomy for human disease. Am J Med Genet. 1993 Jul 1;46(6):683-4.

Van Allen MI, Ritchie S, Toi A, Fong K, Winsor E. Trisomy 4 in a fetus with cyclopia and other anomalies. Am J Med Genet. 1993 Apr 15;46(2):193-7.

Zaslav A-L, Blumenthal D, Willner JP, Pierno G, Jacob J, Fox JE Prenatal diagnosis of trisomy 4 mosaicism. Am J Med Genet 95:381-384.


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