Autosomal Trisomies

A trisomy (the presence of three homologous chromosomes instead of the usual two) arises prezygotically during meiosis due to faulty distribution (nondisjunction) of a chromosome pair. Itmay also arise after fertilization (postzygotic) during somatic cell division (mitosis); in this case, trisomy is present in a certain proportion of cells (chromosomal mosaicism). Trisomy leads to a phenotype characteristic for the particular chromosome, although in humans most trisomies are lethal in early embryonic development.

• Trisomy in jimsonweed (Datura stramonium)
  
  In 1922, Blakeslee observed that triploid and tetraploid jimsonweed plants (Datura stramonium) differ little in phenotype. However, when plants contained three copies of only one of the 12 chromosomes (trisomy), and two each of the others, a characteristic appearance resulted for each of the trisomies (from Blakeslee, 1922).
  
• Trisomies in the mouse
  
  During the 1970s, A. Gropp and co-workers investigated the effect of trisomies on the development of the mouse. Trisomic mice, resulting from the segregation of translocations, had a developmental profile and certain morphological changes characteristic for each trisomy (1). Embryos with a chromosome missing (monosomies) died very early in gestation. (Figure fromA. Gropp, 1982). Amouse embryo with trisomy 12 shows an open skull cap and other malformations on the 14th day of development (2), unlike other embryos of the same age (H.Winking, Lübeck, 1991; Boué et al., 1985). Only trisomy 19 is compatible with survival until birth (day 21), but the brain is too small (3). These animals die shortly after birth.
  
• Autosomal trisomies in man
  
  Of the 22 autosomes in man, only three occur regularly as trisomies in live-born infants: trisomy 21, trisomy 18, and trisomy 13. They differ in phenotype and course of disease. Other trisomies are not observed in live-born infants because they are lethal in early embryonic life, and not compatible with life at birth (see p. 402). Trisomy 21 causes the clinical picture of Down syndrome (formerly called mongolism).
  
• Nondisjunction as a cause of trisomy
  
  Especially in trisomy 21, the frequency of nondisjunction depends on the age of the mother at the time of conception (1). The age of the father has very little or no influence. Nondisjunction may occur during the first or the second maturation division (meiosis I or meiosis II, p. 116) (2). The difference can be established by appropriate chromosomal markers. If nondisjunction occurs in meiosis I, the three chromosomes will be different (1 + 1 + 1), whereas if nondisjunction occurs during meiosis II, two of the three chromosomes will be identical (2 + 1). In humans, about 70% of nondisjunctions occur in meiosis I, and 30% in meiosis II.
  
• References
  
  Antonarakis, S. E.: Down syndrome, pp. 1069–
  1078, In: Jameson, J.L., ed., Principles of
  Molecular Medicine. Humana Press, Totowa,
  New Jersey, 1998.
  Blakeslee, A.F.: Variation in Datura due to
  changes in chromosome number. Am. Naturalist
  56:16–31, 1922.
  Boué, A., Gropp, A., Boué, J.: Cytogenetics of
  pregnancy wastage. Adv. Hum. Genet.
  14:1–57, 1985.
  Epstein, C.J.: Down syndrome (trisomy 21), pp.
  749–794. In: C.R. Scriver, et al., eds., The
  Metabolic and Molecular Bases of Inherited
  Disease. 7th ed. McGraw-Hill, New York,
  1995.
  Gropp, A.: Value of an animal model for trisomy,
  Virchows Arch. Pathol. Anat. 395:117–131,
  1982.
  Therman, E., Susman, M.: Human Chromosomes.
  Structure, Behavior, Effects. 3rd ed.
  Springer Verlag, Heidelberg, 1993.
  Traut, W.: Chromosomen. Klassische und
  Molekulare Cytogenetik. Springer Verlag,
  Heidelberg, 1991.
  

• Triploidy
  
  Triploidy is one of the most frequent chromosomal aberrations in man (1). Possible causes include a diploid spermatocyte, a diploid oocyte, or fertilization of an egg cell by two spermatozoa (dispermy, p. 196). Triploidy usually leads to spontaneous miscarriage within the first four months of pregnancy. The fetus shows numerous severe malformations (2), such as cardiac defects, cleft lip and palate, skeletal defects, and others. The additional chromosome setmay be of either maternal or paternal origin, with different clinical consequences.
  
• Monosomy X (Turner syndrome)
  
  Monosomy X (karyotype 45,XO) is a frequent chromosomal aberration, representing about 5% of those in humans at conception. However, of 40 zygotes with monosomy X, only one will develop to birth. The phenotypic spectrum is very wide. During the fetal stage, (1) lymphedema of the head and neck result in cystic hygroma, large multilocular thin-walled lymphatic cysts. Congenital cardiovascular defects, especially involving the aorta, and kidney malformations are frequent. An important component of the disease is the absence of ovaries, which develop only as connective tissue (streak gonads). Small stature is always a feature (average adult height about 150 cm). In newborns, webbing of the neck (pterygium colli) may be present as a residual of the lymphedema (clinical picture of Ullrich–Turner syndrome). On the other hand, the manifestations may bemild (2). Very frequently, pure monosomy is not present, but rather chromosomal mosaicism with normal cells (45,XO/46,XX) or a structurally altered X chromosome (deletion of the short arm, isochromosome of the long or short arm, ring chromosome, or other).
  
• Additional X or Y chromosomes
  
  An additional X chromosome in males (47,XXY) leads to the clinical picture of Klinefelter syndrome after puberty when untreated (1). This includes tall stature, absent or decreased development of male secondary sex characteristics, and infertility due to absent spermatogenesis. With an additional Y chromosome (47,XYY) no unusual phenotype results (2). Girls with three X chromosomes (47,XXX) are also physically unremarkable (3). However, learning disorders and delayed speech development have been observed in some of these children.
  
• Wide spectrum of chromosomal aberrations in human fetuses
  
  The relative proportions of the various trisomies observed in fetuses after spontaneous abortion differ. The most frequent is trisomy 16, which accounts for about 5% of all autosomal trisomies. Autosomal monosomies lead to death of the embryo within the first days or weeks. (Data after Lauritsen, 1982).
  
  
• References
  
  DeGrouchy, J., Turleau, C.: Clinical Atlas of
  Human Chromosomes. 2nd ed. John Wiley &
  Sons, New York, 1984.
  Lauritsen, J.G.: The cytogenetics of spontaneous
  abortion. Res. Reproduct. 14:3–4, 1982.
  Schinzel, A.: Catalogue of Unbalanced Chromosome
  Aberrations in Man. W. de Gruyter,
  Berlin, 1984.

• Deletion 5p–: Cri-du-chat syndrome
  
  In 1963, Lejeune and his co-workers in Paris described children with a partial deletion of the short arm of a chromosome 5 (5p–) and retarded mental and physical development. About 15% of the parents show a translocation of chromosome 5. In these cases, the risk of recurrence of the disorder is increased. Affected infants have prolonged, high-pitched crying resembling that of a kitten (cri-du-chat, cat cry).
  
  
• Deletion 4p–:Wolf–Hirschhorn syndrome
  
  Described in 1964 independently by U. Wolf in Freiburg and K. Hirschhorn in New York and their co-workers, this is a characteristic phenotype resulting from a partial deletion of chromosomal material of the short arm of a chromosome 4. Variable but considerable mental and statomotoric retardation is associated with characteristic facial features (1, 2) and with midline defects (cleft palate, hypospadias), coloboma of the iris, congenital heart defects, and other malformations. In some patients the deletion can only be detected by FISH. The simplified map of 4p16 (3) shows the critical chromosomal region (WHSCR, Wolf–Hirschhorn critical region). (Figure adapted from Wright et al., 1999).
  
  
• Microdeletion syndromes
  
  Of the more than 20 different microdeletion syndromes (for review see Spinner and Emanuel, 1996; Budarf and Emanuel, 1997) three are presented here. The Williams–Beuren syndrome (1, McKusick 194050, 130160) usually presents with characteristic facial features (“elfinlike”), infantile hypercalcemia, supravalvular aortic stenosis, growth retardation, and impaired mental development. The underlying deletion involves the long arm of chromosome 7 at q11.23. The gene for elastin (ELN) is lost most frequently. Deletion of 22q11 leads to a group of clinically different but overlapping disorders (DiGeorge syndrome, McKusick 188400), characterized by absence or hypoplasia of the thymus and the parathyroid glands and malformations of the aortic arch; velocardiofacial syndrome, McKusick 192430; conotruncal cardiac defects, McKusick 217095; and others (2). The Rubinstein–Taybi syndrome (McKusick 180849) is characterized by typical facial features (3), broad thumbs and toes, and their associated radiological changes, mental retardation, and other features. A deletion of 16p13.3 is detectable in about 12% of patients. Point mutations in the CREB-binding gene (CBP gene) cause this disorder.
  
  
• Phenotype of duplication 5q at different ages
  
  A unique duplication illustrates the similar facial phenotypes at different ages: in a fetus at 22 weeks gestation (1), in a 5-month-old infant (2), and in an 8-year-old child. The affected individuals are siblings in one family. The partial duplication 5q33-qter resulted from a paternal reciprocal translation (Passarge et al., 1982). A number of other duplications are associated with characteristic phenotypes.
  
  
• References
  
  Budarf, M.L., Emanuel, B.S. : Progress in the autosomal
  segmental aneusomy syndromes
  (SASs): single or multi-locus disorders?
  Hum. Mol. Genet. 6:1657–1665, 1997.
  Meng, X., et al.: Complete physical map of the
  common deletion region in Williams syndrome
  and identification and characterization
  of three novel genes. Hum. Genet. 103:
  590–599, 1998.
  Passarge, E., et al.: Fetalmanifestation of a chromosomal
  disorder: partial duplication of
  the long arm of chromosome 5 (5q33-qter).
  Teratology 25:221–225, 1982.
  Petrij, F., et al.: Diagnostic analysis of the Rubinstein-
  Taybi syndrome: five cosmids should
  be used for microdeletion detection and low
  number of protein truncating mutations. J.
  Med. Genet. 37:168–176, 2000.
  Wright, T.J., et al.: Comparative analysis of a
  novel gene from the Wolf-Hirschhorn/Pitt-
  Rogers-Danks syndrome critical region.
  Genomics 59:203–212, 1999.