Monosomies. Introduction. Mechanisms. Advanced article

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1 Monosomies Jean-Pierre Fryns, Centre for Human Genetics, Leuven, Belgium Tshilobo Prosper Lukusa, Centre for Human Genetics, Leuven, Belgium Errors in meiosis result in gametes with abnormal numbers of chromosomes and production, after fertilization, of an aneuploid conceptus. The genetic imbalance resulting from the loss of an entire chromosome in individuals with deletion-type aneuploidy is generally lethal, except for the full X chromosome monosomy. Most survivable partial monosomies are associated with significant dysmorphism and mental retardation. Advanced article Article contents Introduction Mechanisms Sex Chromosome Monosomies Autosomal Monosomies doi: /npg.els Introduction In a chromosomally normal human individual, each nucleus in a somatic cell receives at every mitosis two sets of 23 different chromosomes, the members of a pair of chromosomes being referred to as homologs. This diploid (2 6 23) number of chromosomes is halved when the gametes are formed during meiosis in such a way that each nucleus in the mature germ cell contains only a set of 23 chromosomes (haploid number). The 23 pairs of chromosomes include one set of chromosomes concerned with sex determination, which are referred to as sex chromosomes (chromosomes X and Y), and the remaining 22 pairs of chromosomes which look alike and are referred to as autosomes. The term monosomy refers to cytogenetic abnormalities in which one member of a pair of homologous chromosomes has been lost. The monosomy is said to be full when a whole chromosome has been lost, or partial when the loss concerns a portion of a chromosome. It can be pure, free, with the presence of only one cell line, or in mosaicism, with other cell lines present in the same or in other tissues. In theory, a monosomy resulting from meiotic errors is expected to be present in every cell in the resulting pregnancy, whereas postzygotic (postconception) mitotic errors will produce a mosaic state. Phenotypic features related to partial monosomies or to mosaic forms are less severe than when the same chromosome is totally lost. The abnormality can involve sex chromosomes or autosomes. Apart from the full monosomy X, which represents the well-known survivable Turner syndrome, reports of well-documented full monosomy in a liveborn human individual are extremely rare. Probably, even the very small autosomes carry so many important genes that the loss of such a chromosome is lethal, whereas X chromosome monosomy, full or partial, appears to have a much less deleterious effect. It is thought that a partially successful buffering mechanism exists in which the deficiency in one X chromosome is counteracted by X material being randomly inactivated, selectively inactivated or not inactivated at all, so that the potential deleterious effect may be minimal. On the other hand, partial autosomal monosomies involving various chromosomes have been described in several patients, producing a phenotype of widespread dysmorphogenesis with various congenital abnormalities, the most specific abnormalities being found in the craniofacial shape. Mental retardation is an almost invariable feature, and behavioral disorders are often associated. In some cases, a specific clinical syndrome has been recognized. We review the constitutional monosomies that have been observed in live-borns. Lethal forms and other categories of acquired monosomies such as those related to cancer are not included. Mechanisms Constitutional monosomies are invariably due to accidents during cell division, with the great majority of them originating from meiotic errors resulting in gametes that lack a given chromosome and produce therefore, after fertilization, a monosomic zygote (conceptus). During a person s lifetime, cells have to divide many times. Despite the processes of meiosis and mitosis being extremely well regulated, the high frequency of divisions leaves some room for rare but significant accidents. The error most commonly resulting in full monosomy is the so-called nondisjunction that can occur either during meiosis I (Angell, 1997), involving two homologous chromosomes (Figure 1), or meiosis II, involving sister chromatids (Figure 2) of one of the normally segregated homologous chromosomes. Normally, the two homologous chromosomes of each pair and, later on, the sister chromatids of each homolog should segregate at anaphase, but occasionally they may fail to separate for a given chromosome and migrate together into the nucleus of one daughter ENCYCLOPEDIA OF LIFE SCIENCES & 2005, John Wiley & Sons, Ltd. 1

2 I II III A B Figure 1 Example of the mechanism of chromosomal nondisjunction: (A) normal meiosis; (B) meiosis with chromosomal nondisjunction visible in II. I: metaphase I; II: telophase I metaphase II showing nondisjunction in (B) (left cell); III: telophase II showing in (B), for chromosome 19, two disomic and two nullisomic daughter cells. I II III A B Figure 2 Example of the mechanism of nondisjunction of chromatids: (A) normal meiosis; (B) meiosis with nondisjunction of chromatids visible in III. I: metaphase I; II: telophase I metaphase II with normal chromosomal disjunction in A and B; III: telophase II showing in B one disomic daughter cell resulting from nondisjunction of the sister chromatids of chromosome 19, one subsequent nullisomic cell and two normal cells. 2

3 cell leaving the second nucleus devoid of the given chromosome. When the gamete with the latter nucleus unites with a normal one, the result will be a zygote that is monosomic for the chromosome considered. The loss of a chromosome through anaphase lag and the formation of a micronucleus have also been proposed as a mechanism in some cases. Mosaic offspring can arise from nondisjunction occurring later on in the mitotic divisions of a developing zygote or embryo and generate, in addition to the normal cell line, monosomic and trisomic cell lines. One of the latter cell lines would be nonviable and subsequently disappear. It has been postulated that maternal age might predispose to nondisjunction in ova (Dailey et al., 1996). Possible genetic control has also been proposed in some cases. Partial monosomies can represent de novo rearrangements or be inherited as unbalanced products of a reciprocal translocation in one parent. Possible mechanisms of de novo origin include either deletion from a break event during meiosis or formation before or during early meiosis of a balanced translocation, followed by malsegregation at anaphase, producing daughter germ cells with lack and/or excess of chromosomal segments. Meiotic chromosomal malsegregation is also at the origin of partial monosomies arising as an unbalanced product of an autosomal reciprocal balanced translocation in a clinically normal parent. In normal human cells, the 23 sets of homologous chromosomes align themselves during metaphase I, optimally pairing their homologous regions in a linear fashion to form 23 bivalents that later separate and migrate to daughter cells. In cells with a reciprocal translocation, the pairing of shared regions of the two pairs of derivative chromosomes involved in the translocation can be disturbed. To match these regions, the four chromosomes must form a structure with a complex quadrivalent configuration. Chromosome malsegregation can then occur, resulting in a variety of unbalanced gametocytes and, later on, of mature gametes with partial absence and/or excess of genetic material (Figure 3). Generally, the absence of chromosomal material is more deleterious than the presence of extra chromosomal material, and in the presence of both lack and excess of chromosome material, the deletion is predominantly clinically expressed. The carrier parent s risk of producing a live-born child with an unbalanced karyotype is dependent on the breakpoints, on the size and on the genetic material present in the segment involved in the translocation. In general, the smaller the extent of the imbalance, the more likely the survival. 1 Sex Chromosome Monosomies The most important and unique full sex chromosome monosomy syndrome reported in live-born individuals is the X monosomic Turner syndrome. Patients with either partial deletion of various segments of the Y chromosome, or Y isochromosomes, or ring Y chromosomes, have been described with variable clinical manifestations ranging from phenotypic males with or without azoospermia to phenotypic females with features of Turner syndrome. Monosomy X 3 More than 50% of classical cases of Turner syndrome result from full monosomy of chromosome X. Variants with mosaicism for 45,X and another cell line or with partial X monosomy Xp deletion, Xq deletion, isochromosome X or ring chromosome X are also seen. It is believed that presence of one or more genes on the X chromosome in a haploid state early in embryogenesis is probably the cause of the clinical syndrome. Haploinsufficiency of the short stature homeobox (SHOX) gene is currently considered and and and Figure 3 Expected segregation of the chromosomes within a quadrivalent in a 2 : 2 model. Each daughter cell receives two of the chromosomes of the quadrivalent in three ways: 1 and 2, adjacent I (1) and adjacent II (2) segregation two chromosomes with adjacent centromeres migrate together yielding chromosomal imbalance; 3, alternating segregation two chromosomes with alternate centromeres migrate together yielding normal or chromosomally balanced daughter cells. Other models (3 : 1 or 4: 1 segregation) can occur, but they appear to be much rarer. 3

4 as responsible for short stature and some additional somatic stigmata (Clement-Jones et al., 2000). The origin of the single X chromosome is maternal in approximately 75% of cases, and it has been found that it is usually the inactive X chromosome that is missing in X monosomic cells. A wellconducted study by Guttenbach et al. (1995) that looked at sex chromosome loss and aging failed to find any distinct age correlation before the maternal age of 51 years. The general risk estimate varies according to whether live birth or spontaneous abortion data are analyzed. It is estimated that approximately 1 : 2000 to 1 : 5000 (Powell, 1999) live female births are affected. The in utero lethality of 45,X embryos is very high, with spontaneous abortions occurring in 75% (Hook, 1983) to 99% (Powell, 1999) of 45,X cases detected by amniocentesis, and it has been speculated that all conceptions that survive to term have some degree of undetected mosaicism for a normal cell line. The clinical features of the classical Turner syndrome include short stature, congenital lymphedema of hands and feet, sexual infantilism with streak gonads, premature ovarian failure and variable dysmorphic features comprising prominent auricles, low posterior hairline, webbed neck, broad chest with widely spaced nipples, cubitus valgus, short fourth metacarpals and/or metatarsals and narrow, hyperconvex and/or deep-set nails. Cardiovascular defects, especially bicuspid aortic valve or coarctation of the aorta, and structural renal anomalies like horseshoe kidney or cleft renal pelvis are common.the main IQ is around 90, but there may be problems in visuospacial and/or perceptual abilities. The social cognition is affected and is more reduced in patients with maternally inherited X chromosome than in those with paternally inherited X (Donnelly et al., 2000). The great majority of women with Turner syndrome are infertile and their oocytes completely disappear by the age of 2 years. However, spontaneous menstruation has been reported in some cases, and a small proportion of 45,X women with spontaneous menses have been found to be fertile for a short-lived period. Patients with mosaicism or with only a partial X monosomy generally display a lesser degree of clinical manifestations. Hormonal supplementation is generally needed and it is recommended that Turner syndrome patients be followed by endocrinologists familiar with their specific problems. Autosomal Monosomies Full autosomal monosomies are extremely rare both in live-borns and abortuses. It is likely that most of them are so deleterious that they are lethal very early during development and thus result in unrecognized spontaneous abortions. The only full and free autosomal monosomy that has been reported is monosomy 21, although undetected mosaicism or partial monosomy resulting from subtle translocation cannot be completely excluded. In contrast, reports of partial autosomal deletions are somewhat more common, with some of them being recognized as specific clinical syndromes. Generally, large deletions have a more significant impact on phenotype with limited survival. Monosomy 21 A number of cases of survivable full monosomy 21 have been reported. Most of them died in early infancy. The most prominent clinical features included pre- and postnatal growth retardation, hypertonia, mental delay, microcephaly, facial dysmorphism with hypertelorism, downward-slanting palpebral fissures, prominent nose, cleft lip/palate, micrognathia and large low-set ears. Congenital heart defects were present in some cases. Findings in recent studies suggest that most, if not all, of these cases may represent only partial monosomies, with the presence of chromosome 21 material on another chromosome resulting from cryptic unbalanced translocations. Partial autosomal monosomies Partial monosomies are often referred to as deletions. Autosomal deletions that can be cytogenetically detected are generally associated with significant pathology, with the exception of loss of material from some heterochromatic regions or from the short arm of acrocentric chromosomes involved in Robertsonian translocations which can have no impact on phenotype. On the other hand, a new class of very small deletions, often at or below the resolution of microscopic analysis and associated with distinct clinical phenotypes, has been identified by using fluorescence in situ hybridization (FISH) and molecular techniques, and are referred to as microdeletion syndromes. Table 1 summarizes features of the main clinically recognized deletion and microdeletion syndromes. Although most phenotypic findings are nonspecific, their constellation in a given pattern of malformations should allow for suspicion of a given deletion syndrome. The great majority of the cases represent de novo deletions, with the deleted chromosome being most frequently of paternal origin. In a few examples, one of the parents, most frequently the mother, is a balanced translocation carrier. 4

5 Table 1 Main partial autosomal deletion syndromes Syndrome Deletion Phenotypic features 3p deletion 3p25!pter, > 90% de novo Growth and mental retardation, microcephaly, triangular face, synophrys, blepharoptosis, epicanthal folds, broad nasal bridge, upturned nostrils, long philtrum, thin upper lip, micrognathia, down-turned mouth, high-arched palate, malformed ears, cryptorchidism, anteriorly placed anus, postaxial polydactyly, heart/renal defects Wolf Hirschhorn syndrome 4p16.3, 87% de novo Growth and mental retardation, hypotonia, seizures, microcephaly, hypertelorism, epicanthal folds, strabismus, broad nasal bridge, beaked nose, cleft lip/palate, short philtrum, down-turned mouth, micrognathia, simple ear plus preauricular tag/pit, cryptorchidism, hypospadias, talipes equinovarus, scoliosis, hyperconvex fingernails, atrial septal defects 4q deletion 4q31!qter, > 90% de novo Growth and mental deficiency, hypotonia, seizures, early respiratory difficulties, asymmetric face, hypertelorism, broad nasal bridge, short nose, anteverted nares, cleft lip/palate, micrognathia, low-set abnormal ears, fifth finger/fingernail abnormalities, abnormal thumb/hallux implantation, overlapping toes, cardiac/genitourinary defects, abnormal behavior Cri du chat syndrome 5p15, 85% de novo Growth and developmental retardation, hypotonia, cat-like cry, microcephaly, round face, down-slanting palpebral fissures, strabismus, hypertelorism, epicanthal folds, broad nasal bridge, micrognathia, poorly formed pinnae and, in adulthood, long face, macrostomia, scoliosis, behavior problems Terminal 6q deletion 6q25!qter, mostly de novo Mental retardation, short stature, hypotonia, microcephaly, cerebral atrophy with hydrocephaly, seizures, strabismus, retinal abnormalities, epicanthal folds, broad nasal tip, prominent nose/nasal bridge, long philtrum, high/cleft palate, ear anomalies, micrognathia, short neck, limb abnormalities, cryptorchidism, genital hypoplasia, congenital heart defect Williams syndrome a 7q11.23, mostly de novo Growth and developmental delay, early feeding difficulties, hoarse voice, friendly personality, periorbital fullness, short palpebral fissures, blue eyes, stellate pattern in the iris, upturned nostrils, long philtrum, open mouth, full lips, hypoplastic nails, joint limitations, supravalvular or valvular stenoses, renal anomalies, hypercalcemia Distal 8p deletion Langer Giedion (trichorhino-phalangeal) syndrome a 8p23.1!pter, mostly de novo 8q24.11 q24.13, mostly de novo Growth and mild mental retardation, microcephaly, narrow/high forehead, epicanthal folds, ear anomalies, short neck, broad chest, wide-set nipples, congenital heart defect, hypogenitalism, hyperactive/impulsive behavior Growth and mental retardation, microcephaly, sparse scalp hair, heavy eyebrows, deep-set eyes, bulbous nose, broad nasal bridge, simple, prominent and elongated philtrum, protruding ears, loose redundant skin in infancy, cone-shaped epiphyses, metaphyseal hooking, poor funnelization at proximal ends of phalanges, multiple exostoses (type 2) 9p deletion 9p22!pter, 2/3 de novo Mental retardation, trigonocephaly, flat occiput, highly arched eyebrows, prominent eyes, epicanthal folds, upslanting palpebral fissures, depressed nasal bridge, short nose, upturned nostrils, long philtrum, small mouth, poorly formed ears, short/broad neck, widely spaced nipples, hernias, hypogenitalism, long middle phalanges of the fingers, ductus arteriosus Monosomy 10qter 10q25/26!qter, mostly de novo Growth and mental retardation, microcephaly, triangular face, strabismus, hypertelorism, prominent nasal bridge, beaked or prominent nose, low-set dysplastic ears, various congenital heart defects, cryptorchidism, other anogenital anomalies, defect of hands/feet, limb contractures, abnormal behavior with hyperactivity, attention deficit, destructive tendency Aniridia Wilms tumor (WAGR) a 11p13, mostly de novo Wilms tumor, gonadoblastoma plus aniridia, cataracts, glaucoma, nystagmus, ptosis, blindness plus genital anomalies (cryptorchidism, hypospadias, micropenis) plus mental retardation; growth deficiency, microcephaly, poorly formed ears 5

6 Table 1 Continued Syndrome Deletion Phenotypic features Jacobsen syndrome 11q23!qter, > 90% de novo Growth and mental retardation, trigonocephaly, blepharoptosis, strabismus, hypertelorism, epicanthal folds, depressed nasal bridge, upturned nasal tip, carp-shaped mouth, micrognathia, ear dysplasia, digital anomalies, cardiac defects 13q deletion 13q14!qter, mostly de novo Growth and mental retardation, micro/trigonocephaly, ptosis, microphthalmia, colobomata, retinoblastoma (most 13q14), hypertelorism, epicanthal folds, prominent nasal bridge, prominent maxilla, micrognathia, low-set prominent ears, short neck, webbing, small/absent thumbs, short big toes, fused metacarpal bones 4 and 5, clinodactyly V, talipes equinovarus, hypospadias, cryptorchidism, imperforate anus, cardiac defects, holoprosencephaly-type anomalies Prader Willi syndrome a Angelman syndrome a 15q11 q13, paternal 15q, mostly de novo 15q11 q13, maternal 15q, mostly de novo Mental and growth retardation, decreased fetal activity, early hypotonia and tube feeding, obesity, excessive appetite, narrow bifrontal diameter, almond-shaped eyes, strabismus, small hands/ feet, hypogenitalism/hypogonadism, diabetes mellitus, scoliosis, skin picking, stubbornness, food-seeking behavior Mental and growth retardation, paroxysms of laughter, seizures, ataxia, jerky arm movements, microbrachycephaly, blond hair, blue eyes, deep-set eyes, strabismus, maxillary hypoplasia, large mouth, tongue protrusion, widely spaced teeth, prognathism, cerebral atrophy Rubinstein Taybi syndrome a 16p13.3, mostly de novo Mental retardation, hypotonia, broad thumbs with radial angulation, broad great toes, microcephaly, strabismus, long eyelashes, heavy eyebrows, strabismus, downslanting palpebral fissures, prominent/beaked nose, hypoplastic maxilla, narrow palate, grimacing smile, low-set/malformed auricles, cryptorchidism, early feeding difficulties and regurgitations, behavioral problems in some Smith Magenis syndrome a 17p11.2, de novo Mental retardation, hyperactivity, sleep disturbance, decreased pain sensitivity, self-destructive behavior, short stature, brachycephaly, midface hypoplasia, prognathism, fetal pads, hoarse voice Miller Dieker (lissencephaly) syndrome 17p13.3, either de novo or inherited Developmental/mental retardation, failure to thrive, initial feeding problems and hypotonia, later on spasticity, seizures, lissencephaly, microcephaly, bitemporal narrowing, upslanting palpebral fissures, small nose with anteverted nostrils, long philtrum, protuberant upper lip, micrognathia, low-set dysplastic ears, cryptorchidism, clinodactyly 18p deletion 18p, 2/3 de novo Growth and mental deficiency, hypotonia, mild microcephaly, rounded facies, ptosis, epicanthal folds, strabismus, low nasal bridge, hypertelorism, wide/down-turned mouth, dental caries, protruding ears, pectus excavatum, various genital anomalies, short hands and feet with various digit anomalies, holoprosencephaly, restlessness, poor concentration 18q deletion 18q21.3!qter, 80% de novo Growth and mental retardation, hypotonia, seizures, microcephaly, midfacial hypoplasia, deep-set eyes with various anomalies, carp-shaped mouth, narrow palate, prominent antihelix/antitragus, narrow/atretic external canal, deafness, long hands, tapering fingers, abnormal implantation of toes, hypogenitalism, skin dimples, cardiac defects, obnoxious or autistic behavior Shprintzen a, velocardiofacial a, DiGeorge syndrome a 22q11.2, 485% de novo Short stature, learning disabilities, early hypotonia, feeding and respiratory problems, microcephaly, long face, short palpebral fissures, prominent nose with squared nasal root and narrow alar base, short philtrum, ear anomalies with decreased hearing, patent or submucous cleft palate with hypernasal speech and velopharyngeal incompetence, micrognathia, slender limbs with hyperextensible hands/ fingers, tetralogy of Fallot, ventricular septal defects and outflow tract abnormalities, thymus and parathyroid hypoplasia/aplasia, T-cell immunodeficiency, hypocalcemia, early seizures, and mental retardation (25%), esophageal atresia, imperforate anus, diaphragmatic hernia, genitourinary anomalies, psychiatric disorders a Microdeletion syndrome. 6

7 See also Fetal Wastage: Molecular Basis Microdeletion Syndromes Trisomy Turner Syndrome References Angell RR (1997) First-meiotic-division nondisjunction in human oocytes. American Journal of Human Genetics 61: Clement-Jones M, Schiller S, Rao E, et al. (2000) The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome. Human Molecular Genetics 9: Dailey T, Dale B, Cohen J and Munne S (1996) Association between nondisjunction and maternal age in meiosis-ii human oo cytes. American Journal of Human Genetics 59: Donnelly SL, Wolpert CM, Menold MM, et al. (2000) Female with autistic disorder and monosomy X (Turner syndrome): parentof-origin effect of the X chromosome. American Journal of Medical Genetics 96: Guttenbach M, Koschorz B, Bernthaler U, Grimm T and Schmid M (1995) Sex chromosome loss and aging: in situ hybridization studies on human interphase nuclei. American Journal of Human Genetics 57: Hook EB (1983) Chromosome abnormalities and spontaneous fetal death following amniocentesis: further data and association with maternal age. American Journal of Human Genetics 35: Powell CM (1999) Sex chromosomes and sex chromosome abnormalities. In: Gersen SL and Keagle MB (eds.) The Principles of Clinical Cytogenetics, pp Totowa, NJ: Humana Press. Further Reading Claeys I, Holvoet M, Eyskens B, et al. (1997) A recognisable behavioural phenotype associated with terminal deletions of the short arm of chromosome 8. American Journal of Medical Genetics 74: Devriendt K, Matthijs G, Van Dael R, et al. (1999) Delineation of the critical deletion region for congenital heart defects, on chromosome 8p23.1. American Journal of Human Genetics 64: Hsu YF (1994) Phenotype/karyotype correlation of Y chromosome aneuploidy with emphasis on structural aberrations in postnatally diagnosed cases. American Journal of Medical Genetics 53: Lukusa T, Devriendt K and Fryns JP (1999) A 3p deletion syndrome in a child with both del(3)(p25?pter) and dup(17)(q23?qter). Annales de Génétique 42: Web Links Short stature homeobox (SHOX); Locus ID: LocusLink: Short stature homeobox (SHOX); MIM number OMIM: dispmim?