Partial duplication/deletion as a result of structural rearrangement is discussed in Chapter 9. Only those partial autosomal aneuploidies that result from the presence of a supernumerary chromosome will be presented in this chapter.
Tetrasomy 5p [47,XX or XY,+i(5)(p10)] resulting from the presence of a supernumerary isochromosome for the entire short arm of chromosome 5 is rare and has been reported in only three liveborns, all of whom are mosaics with both normal and abnormal cell lines (205). The abnormal cell line was found in lymphocytes, skin fibroblasts, and chondrocytes. The phenotype appears to be similar to that of trisomy 5p. This includes hypotonia, seizures/abnormal electroencephalogram (EEG), psychomotor retardation, macrocephaly, facial dysmorphism, and respiratory difficulties. Skin hyper-pigmentation was observed in one patient. Survival was variable; one patient died at 6 months and one was 5 years old at the time of reporting.
Tetrasomy 8p [47,XX or XY,+i(8)(p10)] usually results from the presence of a supernumerary isochromosome for the entire short arm of chromosome 8. All cases reported are mosaics, with both normal and abnormal cell lines. The abnormal cell line was found in lymphocytes and skin fibro-blasts. In some cases, the origin of the abnormal isochromosome was confirmed by molecular cyto-genetic (FISH) studies (206-208). At least 11 cases have been reported (reviewed in ref. 208,209). A few patients died before the first year of life, but survival beyond 5 years was not uncommon. Weight and head circumference were normal at birth. The most frequently observed phenotypic features include mental retardation, speech and motor delay, dilatation of cerebral ventricles, mild facial dysmorphism (depressed nasal bridge, short nose, upturned nares, low-set and posteriorly rotated ears), and vertebral abnormalities. Agenesis of the corpus callosum was noted in six patients and cardiac defects in five. Deep palmar and plantar creases have also been reported. The phenotype resembles, to some degree, that of mosaic trisomy 8.
Tetrasomy 9p [47,XX or XY,+i(9)(p10)], resulting from the presence of a supernumerary isochromosome, has been reported in more than 20 liveborns (reviewed in ref. 210,211-213). The isochromosome consists of either the entire short arm of chromosome 9 as described above, the entire short arm and part of the heterochromatic region of the long arm, or the entire short arm and part of the long arm extending to the euchromatic region. No consistent phenotypic differences have been observed among the three types. Both mosaic and apparently nonmosaic patients have been reported. The tetrasomy 9p cells were seen in both lymphocytes and skin fibroblasts. In contrast to tetrasomy 12p (described later), the 9p isochromosomes were present only in lymphocytes in five patients (210,211,214,215) and in fibroblasts at a much lower percentage than in lymphocytes in two others (216,217). The mechanism for this observed tissue-limited mosaicism for different chromosomes is not clear.
Survival is variable, ranging from a few hours to beyond 10 years. The most frequent phenotypic abnormalities include low birth weight, growth and developmental delay, craniofacial anomalies (microphthalmia, low-set malformed ears, bulbous tip of the nose, cleft lip/palate, micrognathia), short neck, skeletal anomalies, joint contracture, nail hypoplasia, and urogenital anomalies. Cardiac defects are present in over 50% of patients. Overall, nonmosaic patients are more severely affected. One patient who had the i(9p) present in 75% of lymphocytes but not in skin fibroblasts had only mild developmental delay and minor anomalies (210).
Tetrasomy 12p (Pallister-Killian syndrome) results from the presence of a supernumerary isochromosome for the entire short arm of chromosome 12 [i(12)(p10) or i(12p)] (see Fig. 10). The syndrome was first described in 1977 by Pallister et al. in two adults, a 37-year-old man and a 19-year-old woman (218). In 1981, Killian and Teschler-Nicola reported a 3-year-old girl with similar clinical manifestations (219). Subsequently, more than 60 cases have been reported (reviewed in ref. 220, 221), and many more have been observed but not reported in the literature. All cases were mosaics, with a normal cell line in addition to cells containing i(12p). Maternal age for reported cases has been shown to be significantly higher than that for the general population (222). This observation has been taken to suggest that the isochromosome arises from a meiotic error and that the normal cell line results from subsequent loss of the i(12p) from some cells. In six of seven cases studied by molecular analysis, the meiotic error was determined to be maternal (223,224). Tissue specificity and both the in vivo and in vitro age dependencies of the i(12p) have been well demonstrated (reviewed in ref. 225). The i(12p) is found in a high percentage of skin fibroblasts and amniocytes, but it is rarely seen in blood lymphocytes. The percentage of cells containing the isochromosome also decreases with age. The presence of tetrasomy 12p in 100% of bone marrow cells has been reported in at least two newborn infants (226,227) and in only 6% of marrow cells in a 3-year-old child (228). In lymphocytes, it has been found in fetal blood (225,229), but has never been seen beyond childhood. In a case reported by Ward et al., the i(12p) was present in 10% of lymphocytes initially, but was not seen in these cells when the patient was 2 months old (226). The isochromosome is more stable in skin fibroblasts and can be found in adults, usually at a lower percentage than in younger patients. When fibroblast cultures were examined, the percentage of cells containing the isochromosome decreased with increasing numbers of cell passages (223,225-227,230). One study using FISH showed that in lymphocytes, the i(12p) was present in a significantly higher proportion of interphase nuclei than in
metaphase cells (231). These authors proposed that lymphocytes containing i(12p) might fail to divide upon PHA stimulation. These observations suggest that tissue-limited mosaicism in Pallister-Killian syndrome could result from differential selection against cells containing i(12p) in different tissues and that this selection can occur both in vivo and in vitro.
Many patients die shortly after birth, but survival to adulthood is possible. Clinically, a distinct pattern of anomalies is observed in these patients. Growth parameters at birth are usually normal. Profound hypotonia is present in the newborn period, whereas contractures develop later in life. Sparse scalp hair, especially bitemporally, is observed in infancy, with coarsening of facial features over time. Craniofacial dysmorphism includes prominent forehead, large malformed ears, hyper-telorism, epicanthal folds, broad flat nasal bridge, short nose, upturned nares, long philtrum, thin upper lip, and high arched palate. Most patients have a generalized pigmentary dysplasia with areas of hyperpigmentation and hypopigmentation. Other abnormalities include short neck, macroglossia, micrognathia progressing to prognathia, accessory nipples, umbilical and inguinal hernias, and urogenital abnormalities. Severe mental retardation and seizure are seen in those who survive.
All cases are sporadic. The recurrence risk is probably negligible.
Tetrasomy 18p [47, XX or XY,+i(18)(p10)] results from the presence of a supernumerary isochromosome for the entire short arm of chromosome 18. The syndrome was first described by Froland et al. in 1963 (232), although identification of the marker as an i(18p) was not made until after the introduction of banding techniques in 1970. Confirmation of the origin of the marker has been possible in recent years by FISH studies. Of interest is the finding of a loss of approximately 80% of chromosome 18 a-satellite DNA in the i(18p) in one case (233).
At least 50 cases have been reported (234-238). Most are nonmosaics. The i(18p) is usually readily detectable in lymphocytes. Its presence in amniocytes (239) and cultured chorionic villus cells (233) has also been reported.
The most frequent clinical features include low birth weight, microcephaly, feeding problems, various degrees of psychomotor retardation, spasticity, seizures, craniofacial characteristics (oval-shaped face, arched eyebrows, strabismus, low-set dysplastic ears, small pinched nose, small triangular mouth, high arched palate, micrognathia), narrow shoulders and thorax, small iliac wings, scoliosis, camptodactyly, and simian creases. Cardiac defects including ASDs, VSDs, and PDA have been observed in some cases. Urogenital anomalies, including horseshoe kidneys, double ureter, and cryptorchidism have occasionally been seen.
It is not clear whether patients with tetrasomy 18p are born to mothers of increased age. Most of the reported cases are sporadic. The presence of i(18p) in maternal lymphocytes has been reported in three families. In two families, the mothers had an abnormal chromosome 18 with deletion of the short arm and a supernumerary i(18p) and, thus, were trisomic for 18p. The offspring inherited the normal chromosome 18 and the i(18p) and were, therefore, tetrasomic for 18p (240,241). In the third family, the mother had low-level mosaicism for a supernumerary i(18p) and was mildly affected clinically. The child apparently had nonmosaic tetrasomy 18p and had the full clinical presentation of the syndrome (242). In another recent report, the presence of an i(18p) in two maternal half-siblings was observed. No i(18p) was found in the mother's lymphocytes or fibroblasts, raising the possibility of gonadal mosaicism (238). The recurrence risk in such families will be high.
Other Partial Autosomal Aneuploidies
In addition to the tetrasomies described above, partial autosomal aneuploidies can result from the presence of small supernumerary marker chromosomes of cytogenetically indeterminate origin. The frequency of such markers is approximately 0.7 per 1000 in newborns (243) and 0.8-1.5 per 1000 in prenatal specimens (244-246). Because their cytogenetic origins are not initially known, these markers might represent autosomal aneuploidy. Identification of such markers is now typically achieved using FISH; this is covered in Chapter 17.
These supernumerary markers are often classified as satellited or nonsatellited and are frequently present in mosaic form. They are a heterogeneous group and the clinical significance of a marker depends on its origin and characteristics. Markers that contain only heterochromatin and/or the short arms of acrocentric chromosomes are typically of no phenotypic consequence. On the other hand, markers that contain euchromatin are generally not benign and can result in phenotypic abnormalities. Among these are the dicentric bisatellited markers that contain variable amounts of long-arm euchromatin of an acrocentric chromosome.
Markers derived from all autosomes have been reported (reviewed in ref. 247,248-250). The most common marker is the so-called inverted duplication of chromosome 15, inv dup(15). This is an archaic misnomer that dates from an incorrect assessment of the mechanism of formation of such chromosomes and represents a heterogeneous group of small markers consisting of two copies of the short arm of chromosome 15, with or without variable amounts of long-arm material. These account for approximately 40% of all marker chromosomes (249,251). The amount of long-arm euchromatin present in the marker dictates its phenotypic significance. A direct correlation has been observed between the presence of the Prader-Willi/Angelman syndrome regions (located at 15q11.2) on the marker and mental retardation or developmental delay (252-254). Of particular interest is the observation of a few patients with this type of marker who present clinically with Prader-Willi syndrome (253,255-258) or Angelman syndrome (258,259). Molecular studies performed on some of these patients indicate that the abnormal phenotype results not from the presence of the marker, but from either uniparental disomy of the two normal chromosomes 15 (253,258) or a deletion of 15q11-q13 on one of the apparently cytogenetically normal 15s (259).
Another type of marker chromosome that results in a clinically recognizable multiple congenital anomaly syndrome is the supernumerary bisatellited dicentric marker derived from chromosome 22.
This marker contains two copies of a small segment of proximal long-arm euchromatin (22q11.2), thus resulting in tetrasomy for 22q11.2. Clinically, these patients usually present with cat-eye syndrome (260-262). Characteristic features include craniofacial anomalies (vertical coloboma of the iris, which gives the syndrome its name, coloboma of the choroid or optic nerve, preauricular skin tags/pits, down-slanting palpebral fissures), and anal atresia with rectovestibular fistula. Cardiac defects are present in more than one-third of cases. Renal malformations include unilateral agenesis, unilateral or bilateral hypoplasia, or dysplasia. Other less frequent findings include microphthalmia, microtia, atresia of the external auditory canal, biliary atresia, and malrotation of the gut. Intelligence is usually low normal to mildly deficient.
Other types of supernumerary marker, such as ring chromosomes derived from chromosome 22 resulting in either trisomy or tetrasomy for 22q11.2, can also cause various features of the cat-eye syndrome. The critical region of this syndrome has been shown to lie within a 2.1-Mb DNA segment defined distally by locus D22S57 and containing the ATP6E (the E subunit of vacuolar H-ATPase) gene (263).
Clinically definable entities have not been observed for other markers, as each is typically unique. However, this could change as data concerning the composition of marker chromosomes accumulates through the use of FISH and other molecular technologies.
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