Congenital cytogenetic abnormalities

INTRODUCTION — Chromosomal aberrations are due to a change in the normal chromosome number or a change in the structure of a chromosome. They may involve one, two, or more chromosomes and may involve only part of a chromosome or the whole chromosome. Congenital anomalies, growth deficiency, and intellectual disability are among the findings observed in persons with chromosome abnormalities, although some cytogenetic aberrations have little to no clinical effect (approximately 1:500 healthy people have a balanced chromosome rearrangement [1]). Advances in human cytogenetics are continuously demonstrating a causal relationship between various chromosomal abnormalities and their phenotypic manifestations. In addition, the specific chromosomal etiologies of a wide variety of syndromes have been established. (See "Chromosomal translocations, deletions, and inversions" and "Genomic disorders: An overview".)

This topic reviews the most common chromosomal abnormalities and discusses when to refer a patient/parent for a genetic evaluation. Diseases caused by point mutations and other small genetic defects are discussed elsewhere. (See "Microdeletion syndromes (chromosomes 1 to 11)" and "Microdeletion syndromes (chromosomes 12 to 22)" and "Microduplication syndromes" and "Sex chromosome abnormalities" and "Down syndrome: Clinical features and diagnosis".)

INCIDENCE — Fifteen percent of clinically recognized pregnancies result in fetal death [2]. Cytogenetic abnormalities are more common in spontaneous abortions (50 percent of fetal deaths <20 weeks) than in stillbirths (6 to 13 percent of fetal deaths ≥20 weeks). A multicenter survey of 103,069 live births in the United States identified major chromosomal abnormalities in 1 in 140 live births [3]. However, the incidence of chromosomal abnormalities is dependent upon the tissue type evaluated, the population studied, and the type of diagnostic testing methodology used. As an example, the incidence of chromosomal abnormalities is lower among live births than among abortuses, second trimester fetuses, or stillbirths. Chromosome microarray (CMA) methodology detects more chromosome aberrations than standard karyotyping, however, misses balanced chromosome rearrangements [4,5].

Diagnosis of chromosomal abnormalities by conventional karyotyping has several limitations compared with a subsequently developed technique based upon microarray analysis [2,6,7]. As an example, analysis of macerated fetuses and nonviable tissues from spontaneous abortions and stillbirths has low yield by karyotype. In addition, chromosome banding techniques can only detect major structural abnormalities. CMA can detect smaller copy number variations (eg, DNA gains and losses) and has a higher yield when performed on fetal tissue from pregnancy losses, including formalin fixed (FFPE) tissues. Thus, CMA has become the preferred type of testing to analyze fetal loss. The use of CMA in prenatal diagnosis of chromosomal abnormalities and postnatal evaluation of pregnancy loss is discussed in detail separately. (See "Prenatal diagnosis of chromosomal imbalance: Chromosomal microarray" and "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Detecting cytogenetic abnormalities' and "Genomic disorders: An overview".)

Total versus live-birth prevalence — Estimates of total and live-birth prevalence of trisomy 21 (Down syndrome) and other trisomies vary depending upon demographics, race, year of data collection, regional differences in prenatal screening and pregnancy termination, and maternal age (see "Effects of advanced maternal age on pregnancy"). The maternal age-specific rate of trisomy 21, as well as other chromosomal abnormalities, is approximately 30 percent higher when diagnosed in the early second trimester by amniocenteses than when diagnosed after birth. These differences can be explained, in part, by spontaneous fetal loss (after the early second trimester) for fetuses with chromosomal abnormalities [8,9].

A European study of 21 population-based registries for the epidemiologic surveillance of congenital anomalies (EUROCAT) that included 6.1 million births from 1990 to 2009 revealed an increase in total prevalence of trisomy 21 over time to 22 in 10,000 (1 in 455) [10]. This change was attributed to an increase in the proportion of births to mothers aged 35 years and older from 13 percent in 1990 to 19 percent in 2009. At the same time, the live-birth prevalence of trisomies 13, 18, and 21 remained stable overall (1 in 20,830 for trisomy 13, 1 in 9614 for trisomy 18, and 1 in 890 for trisomy 21). The stable live-birth prevalence compared with the rise in total prevalence is most likely due to an increase in fetal loss rate in trisomy pregnancies with advancing maternal age [11] rather than to increased prenatal screening, such as cell-free fetal DNA testing, and pregnancy termination [10]. A review of several studies observed no increase in pregnancy terminations attributable to increased cell-free fetal DNA testing [12].

Trisomy 21 (Down syndrome) remains the most common chromosomal abnormality among liveborn infants [13-15]. However, the exact number of trisomy 21 live births in the United States is unknown. Data from the United States Centers for Disease Control and Prevention indicated an increase of trisomy 21 live births by 24 percent, from 1 in 1053 during the period from 1979 to 1983 to 1 in 847 from the years 1999 to 2003. In comparison, a decrease in trisomy 21 live births, from 1 in 900 in 1989 to 1 in 1070 in 2006, was seen in data based upon birth certificates from the National Center for Health Statistics (NCHS) [16]. The highest prevalence reported was from the 1998 multicenter United States survey, with a rate of 1 in 730 live births [3].

Data from spontaneous abortuses — Approximately one-half of spontaneous abortions have an abnormal chromosomal complement (on Giemsa [G] banded karyotyping), which is the probable etiology of the pregnancy loss. Autosomal trisomies are strongly correlated with maternal age and account, in part, for the higher rate of spontaneous abortion in women over 40 years [17,18]. (See "Effects of advanced maternal age on pregnancy".)

A review of 8841 spontaneous abortions found that 41 percent had chromosomal abnormalities visible on G-banded karyotyping [3]. The most frequent types of abnormalities detected were:

●Autosomal trisomies – 52 percent

●Polyploidies – 22 percent

●Monosomy X – 19 percent

●Other – 7 percent

Trisomy 16, with an incidence of approximately 1.5 percent in clinically recognized pregnancies, is the most common trisomy among abortuses and is never encountered in live births [19,20]. The cause of trisomy 16 in almost all zygotes is nondisjunction in maternal meiosis I [21]. Embryos with full trisomy 16 are spontaneously aborted or have arrested development between 8 to 15 weeks' gestational age. Some survive beyond this gestational age and are diagnosed prenatally by chorionic villus sampling (CVS) or amniocentesis. These surviving fetuses are virtually always mosaic as a result of trisomy rescue, a process in which one of the trisomic chromosomes is lost during mitotic cell division [22].

CMA provides an increased diagnostic yield over standard karyotyping for identifying pathogenic variants in spontaneous abortus specimens. CMA can detect aneuploidies as well as microdeletions/duplications. Arrays that asses for single nucleotide polymorphisms (SNP chips) can also detect maternal cell contaminations that would be undetectable in a karyotype from a female fetus. However, rates of detection of the most common trisomies/monosomies do not differ from karyotype findings [23].

Data from stillbirths and neonatal deaths — Stillbirth in the United States is defined as a fetal loss at a gestational age greater than 20 weeks, whereas neonatal death refers to death occurring within the first four weeks after a live birth.

In one series, karyotyping of a combined group of 823 stillbirths and neonatal deaths found a major chromosomal abnormality in 6.3 percent [3]. The frequency of abnormal karyotype in macerated stillbirths (deaths occurring during pregnancy), nonmacerated or fresh stillbirths (deaths occurring during labor or delivery), and neonatal deaths was approximately 12, 4, and 6 percent, respectively. The abnormalities reported were mostly comprised of trisomies 18, 13, or 21; sex chromosome aneuploidy; or unbalanced translocations. The frequency of chromosomal abnormality in this combined group was approximately 10-fold higher than the incidence of 0.7 percent observed in live births. In another series of 750 intrauterine fetal deaths, chromosomal abnormalities visible on G-banded karyotyping were identified in 38 and 5 percent of fetuses with and without morphologic abnormalities, respectively [24].

In fresh stillbirths with chromosomal abnormalities, sex chromosome abnormalities were observed in 20 percent, autosomal trisomies in 70 percent, and balanced structural rearrangements in 10 percent. In neonatal deaths, the type and frequency of chromosomal abnormalities were broader: monosomy X (7 percent), other sex chromosomal abnormalities (10 percent), autosomal trisomies (55 percent), triploidy (3 percent), balanced structural rearrangement (7 percent), unbalanced structural rearrangement (16 percent), and other unspecified chromosome abnormality (3 percent) [25].

Fetuses with congenital anomalies — The prevalence of chromosomal abnormalities visible by G-banded karyotyping in fetuses with congenital anomalies ranges from 2 to 35 percent, with the highest rate in fetuses with multiple anomalies as opposed to an isolated anomaly [26]. The risk of chromosomal abnormality also varies according to the type of isolated anomaly. As an example, duodenal atresia is associated with a relatively high rate of abnormal karyotype; approximately 30 percent of liveborn infants with duodenal atresia are diagnosed with trisomy 21 (Down syndrome), whereas an isolated urinary tract anomaly carries a low rate of chromosomal abnormality.

A systematic comparison of CMA to karyotyping in the evaluation of stillbirths showed an increased rate of test success using CMA technology as well as increased diagnostic yield of pathogenic variants in both structurally normal and abnormal fetuses [27], reinforcing the recommendation that CMA should be used over karyotype in cases of miscarriage or stillbirth. (See "Prenatal diagnosis of chromosomal imbalance: Chromosomal microarray".)

WHEN TO REFER FOR GENETIC EVALUATION — A cytogenetic abnormality may be identified during prenatal screening, or it may be suspected prenatally based upon ultrasound findings or postnatally due to congenital anomalies, growth failure, intellectual disability with or without dysmorphic features, developmental delay, and/or autism. Studies used to detect cytogenetic abnormalities are discussed in detail separately. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Detecting cytogenetic abnormalities' and "Prenatal screening for common aneuploidies using cell-free DNA".)

All cases of stillbirth and neonatal death should be investigated to provide adequate counseling for parents regarding the cause of death and risk of recurrence in future pregnancy. The cytogenetic evaluation is an important component of perinatal necroscopy and is discussed in detail separately [28]. (See "Stillbirth: Incidence, risk factors, etiology, and prevention" and "Stillbirth: Maternal and fetal evaluation" and "Prenatal diagnosis of chromosomal imbalance: Chromosomal microarray", section on 'Fetal demise'.)

Indications for prenatal genetic counseling and general and specific prenatal screening are discussed in detail separately. (See "Prenatal care: Initial assessment" and "Sonographic findings associated with fetal aneuploidy" and "Chorionic villus sampling" and "Diagnostic amniocentesis", section on 'Prenatal diagnosis' and "Down syndrome: Overview of prenatal screening".)

Indications for postnatal genetic counseling and testing in general for certain specific disorders are also discussed separately. (See "Genetic testing" and "Birth defects: Approach to evaluation", section on 'Laboratory studies' and "Down syndrome: Clinical features and diagnosis" and "Autism spectrum disorder: Evaluation and diagnosis", section on 'Genetic testing' and "Intellectual disability in children: Evaluation for a cause", section on 'Chromosomal abnormalities'.)

NUMERIC ABNORMALITIES — Individuals with numerical chromosome abnormalities (aneuploidies) may have multiple congenital malformations that can involve one or more organ systems. Intellectual disability and small stature are the two most constant features; low birth weight, dysmorphic features, and failure to thrive are other frequently observed problems. The presence of mosaicism can lead to variability in the phenotype, as well as the survival. Trisomies are the most common aneuploidies seen. Autosomal aneuploidies are reviewed here. Sex chromosome aneuploidies are reviewed separately. (See "Sex chromosome abnormalities", section on 'Numeric abnormalities (aneuploidies)'.)

Trisomy 21 (Down syndrome) — Trisomy 21 (MIM #190685) is the most common chromosome abnormality among live births (1 in 730 live births) and the most frequent form of intellectual disability caused by a microscopically demonstrable chromosomal aberration [29-32].

The three main types of cytogenetic abnormalities that result in the Down syndrome phenotype and their relative proportions are:

●Trisomy 21 (47,+21) – Approximately 95 percent.

●Robertsonian translocation involving chromosome 21 (figure 1) – 3 to 4 percent. (See "Chromosomal translocations, deletions, and inversions", section on 'Robertsonian translocations'.)

●Trisomy 21 mosaicism (47,+21/46) – 1 to 2 percent. Mosaicism results when two populations of cells are present: one with the normal 46 chromosomes and the other with 47,+21. The percentage of normal/abnormal cells is estimated in the tissue tested (peripheral blood, for example) based upon karyotype or chromosome microarray (CMA) analysis. However, this testing does not help determine the percentage of normal/abnormal cells in other relevant tissues such as the brain.

Most individuals with Down syndrome have free trisomy 21 (47,+21) [29]. Meiotic nondisjunction error is the cause in 95 percent of cases, and the error occurs at mitosis in somatic cells in the remaining 5 percent of cases [33]. In approximately 90 percent of cases, the extra chromosome 21 originates from the mother. This explains, in part, why the risk of this type of Down syndrome increases with advancing maternal age (table 1). The recurrence rate is approximately 1 percent in younger women; the maternal age-related risk is used if it is greater than 1 percent [34]. Studies of infants with trisomy 21 identified paternal trisomy in 7 percent of cases [35,36]. A slightly higher rate (approximately 11 percent) of a paternally derived extra copy of chromosome 21 is seen in cases of trisomy 21 diagnosed prenatally [37].

In Down syndrome patients with an unbalanced Robertsonian translocation, the entire long arm of one chromosome 21 is translocated to the long arm of an acrocentric chromosome (ie, chromosome 13, 14, 15, 21, or 22) [29]. The most common form of this translocation involves chromosomes 14 and 21 [46,der(14;21)(q10;q10),+21]. These individuals have 46 chromosomes, but one chromosome 14 contains the long arms of both chromosomes 14 and 21. Therefore, they actually have three copies of the long arm of chromosome 21 (two normal chromosome 21s and a third long arm translocated to chromosome 14), which results in Down syndrome. Trisomy 21 resulting from a Robertsonian translocation is not related to maternal age.

A case of free trisomy 21 versus Robertsonian translocation-derived trisomy 21 can only be determined by karyotype, not CMA. CMA is able to determine chromosome number but not structure. This distinction is crucial since a Robertsonian derived +21 may be inherited. Thus, a distinct recurrence risk exists.

A parent carrier of a balanced Robertsonian translocation involving chromosome 21, eg, 45,der(14;21)(q10;q10), has an observed risk as high as 15 percent of having an offspring born with an unbalanced translocation resulting in Down syndrome (figure 1). The risk is highest if the mother, rather than the father, is the translocation carrier (10 to 15 versus 2 to 5 percent). However, the majority of translocations resulting in Down syndrome occur de novo, with only 3 to 4 percent having a familial etiology. (See "Chromosomal translocations, deletions, and inversions".)

Duplication of the long (q) arm of chromosome 21 [dup(21q)] represents a rare form of Down syndrome with an estimated incidence of approximately 1 in 45,000 live births. Approximately 95 percent of dup(21q) are de novo. DNA polymorphism studies indicate that the majority of the de novo dup(21q) chromosomes are isochromosomes [i(21q)]. However, Robertsonian translocations [t(21q;21q)] have also been detected [38]. Interstitial duplication of the critical region 21q22.13-q22.2, resulting in "partial trisomy 21," is another uncommon cause of Down syndrome [39-41].

Prenatal screening and diagnosis of Down syndrome and the clinical manifestations and management of the disorder are discussed in detail separately. (See "Down syndrome: Overview of prenatal screening" and "Down syndrome: Clinical features and diagnosis" and "Down syndrome: Management".)

Trisomy 18 syndrome — The three main types of trisomy 18 (also called Edwards syndrome [42]) are:

●Trisomy 18 (47,+18) – 90 percent of cases of trisomy 18 are the result of meiotic nondisjunction.

●Translocation involving chromosome 18.

●Trisomy 18 mosaicism (47,+18/46).

Trisomy 18 is the second most common autosomal trisomy observed in live births (1 in 5500 live births) [29,43]. As with trisomy 21, there is a relationship between advanced maternal age and the occurrence of trisomy 18 in offspring due to meiotic nondisjunction. There is a 3:1 female-to-male ratio among affected infants.

The clinical spectrum of trisomy 18 may involve any organ system [29,44-46]. The major phenotypic features include intrauterine growth restriction (IUGR), hypertonia, prominent occiput, small mouth, micrognathia, pointy ears, short sternum, horseshoe kidney, and flexed fingers, with the index finger overlapping the third finger and the fifth finger overlapping the fourth. Congenital heart disease occurs in greater than 50 percent of affected individuals with common valvular involvement. Ventricular septal defects and patent duct arteriosus are the most common defects. The gastrointestinal system is involved in approximately 75 percent of cases. Meckel diverticulum and malrotation are the predominant abnormalities. Omphalocele is relatively common prenatally.

The prenatal sonographic findings of trisomy 18 correspond to the physical abnormalities. IUGR associated with polyhydramnios, especially in a fetus with abnormal hand positioning ("clenched hands"), is suggestive of this disorder. Choroid plexus cysts are common. (See "Sonographic findings associated with fetal aneuploidy".)

The majority of prenatally diagnosed cases of trisomy 18 die in utero [34,47]. In a series of 23 pregnancies with diagnosed fetal trisomy 18, 14 fetuses died in utero, and the remainder died within 48 hours of birth [48]. In general, 50 percent of affected infants die within the first two weeks of life, and only 5 to 10 percent survive the first year [29,46,49,50]. However, survival into the school-age years is possible [51]. Severe intellectual disability is apparent in survivors over one year of age.

A "noninterventional paradigm" of withdrawal of intensive treatment has been recommended for trisomy 18 because of the lethality of the disorder, the severe intellectual disability in those that survive beyond one year of age, and the lack of a cure, although acceptance of this paradigm is not universal [43,51].

Despite this recommendation, retroactive assessment of hospitalization data on 10,939 patients collected from the nationally representative United States Kids Inpatient Databases for the years 1997, 2000, 2003, 2006, and 2009 demonstrated that children with trisomy 13 and trisomy 18 received significant inpatient medical care (eg, over 2500 major therapeutic procedures) [51]. Longer-term survivors made up a sizable proportion of this group, with over one-third older than one year of age and approximately 10 percent over eight years of age. A study using the Society of Thoracic Surgeons database that includes data from nearly all US pediatric heart centers found that preoperative mechanical ventilation was associated with a more than eightfold increased risk of postoperative mortality in children with trisomy 18 or 13 [52]. In a Canadian cohort study of 254 children with trisomy 18, mean 1-year survival was 12.6 percent, and 10-year survival was 9.8 percent [53]. Most deaths occurred in the first six months of life. Twenty-three of the 35 children who underwent surgeries ranging from simple interventions such as myringotomy to complex cardiac repairs survived for at least one year after the first surgery. Data on intensive treatment of 24 Japanese patients with trisomy 18 that included corrective surgery for gastrointestinal malformations but not surgery for congenital heart defects showed a survival rate of 25 percent at one year of age (median survival time 152.5 days) [43]. These studies suggest a role for alternative approaches to care.

Treatment and medical intervention depend upon the presence and type of major or life-threatening abnormalities in the patient. Therapeutic interventions may include gastrointestinal tract, cardiac, orthopedic, and pharynx/facial/sinus procedures, as well as tracheostomy. A multidisciplinary team including obstetrics, genetic counseling, pediatricians, surgeons, and social workers are important in providing information on availability of post-hospitalization care, educational programs, and support organizations.

Trisomy 13 syndrome — Trisomy 13 syndrome is a severe chromosomal disorder caused by an extra copy of chromosome 13. The three etiologies of trisomy 13 (also called Patau syndrome [54,55]) are:

●Trisomy 13 (47,+13), with three copies of chromosome 13 in each cell of the body as a result of meiotic error. This form is associated with advanced maternal age.

●Unbalanced Robertsonian translocation, with two normal copies of chromosome 13 and an extra copy of the long arm of chromosome 13 translocated to one of the other acrocentric chromosomes (ie, 14, 15, 21, 22) resulting in full trisomy 13. This type of trisomy 13 is not related to advanced maternal age. Although a balanced Robertsonian translocation involving chromosome 13 and 14 (ie, 45,t(13;14)(q10;q10)) is relatively common, there is a low risk for the carrier to bear offspring with an unbalanced chromosome complement because the high rate (98 to 99 percent) of early embryonic death [3,56].

●Trisomy 13 mosaicism (47,+13/46), with three copies of chromosome 13 in some cells and two copies in others. This form is caused by a mitotic nondisjunction error and is not related to maternal age.

Trisomy 13 syndrome is characterized by severe, multiple congenital anomalies. The classic triad is micro/anophthalmia, cleft lip and/or palate, and postaxial polydactyly, but the clinical presentation in patients with trisomy 13 can be quite variable [54,57].

Abnormalities observed in ≥50 percent of trisomy 13 patients [58] include:

●Central nervous system (CNS) – Holoprosencephaly with incomplete development of forebrain and olfactory and optic nerves, severe intellectual disability, deafness

●Craniofacial – Abnormal auricles, microphthalmia/anophthalmia, colobomata, sloping forehead (fissure or cleft of the iris, ciliary body, or choroid)

●Skin and limbs – Capillary hemangiomata, simian crease, hyperconvex narrow fingernails, polydactyly of hands and sometimes feet, prominent heel

●Cardiac – Found in approximately 80 percent of patients; includes ventricular septal defect (VSD), patent ductus arteriosus (PDA), atrial septal defect (ASD), and dextroposition

●Genitalia – Cryptorchidism in males; bicornuate uterus in females

Other abnormalities observed in less than 50 percent of patients include [57,58]:

●Growth – Prenatal growth deficiency

●CNS – Hyper- or hypotonia, agenesis of corpus callosum, cerebral hypoplasia

●Eyes – Hypo- or hypertelorism, cyclopia, upslanting palpebral fissures

●Nose, mouth, mandible – Absent philtrum, narrow palate, micrognathia

●Hands and feet – Retroflexible thumb, syndactyly, cleft between first and second toes, hypoplastic toenails, radial aplasia

●Abdomen – Omphalocele, incomplete rotation of colon, Meckel diverticulum

●Kidney – Polycystic kidney, hydronephrosis, horseshoe kidney

Prenatal sonographic findings of the characteristic CNS defects are the most common fetal signs suggestive of this diagnosis. (See "Sonographic findings associated with fetal aneuploidy" and "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly".)

The prevalence of trisomy 13 in newborns is 1 in 5000 [58,59]. The majority of prenatally diagnosed cases of trisomy 13 die in utero [34,47]. The median survival for liveborn children is seven days, and 91 percent die within the first year, with the majority (approximately 80 percent) dying within the first month of life [29,47,56,58]. There are several published cases of patients with trisomy 13 who are over five years of age [60]. Cardiac anomalies were reported in only 46 percent of the long-lived survivors, in contrast to the much higher frequency (up to 80 percent) reported in all trisomy 13 cases. This finding suggests that the lower frequency of heart defects may contribute to the longer survival [60]. Intensive treatments, including resuscitation and surgical procedures, may prolong survival. As an example, a retrospective study from 1989 to 2010 that included 16 Japanese patients with trisomy 13 who had received intensive treatment showed a median survival time of 24 months [61]. Severe intellectual disability, seizures, and failure to thrive are common in survivors over one year of age [29,56,62].

As with trisomy 18, a "noninterventional paradigm" of providing supportive, but not intensive, treatment has been recommended for trisomy 13 because of the high mortality of the disorder, the severe intellectual disability in those that survive beyond one year of age, and the lack of a cure [43,51]. However, acceptance of this paradigm is not universal, because survival beyond infancy is possible, particularly in those who receive intensive treatment. In a Canadian cohort of 174 children with trisomy 13, mean 1-year survival was 19.8 percent, and 10-year survival was 12.9 percent [53]. Most deaths occurred in the first three months of life. Twenty-nine of the 41 children who underwent surgeries ranging from simple interventions such as myringotomy to complex cardiac repairs survived for at least one year after the first surgery. Options for management of trisomy 13 are similar to that for trisomy 18. (See 'Trisomy 18 syndrome' above.)

Trisomy 8 syndrome — Full trisomy 8 is estimated to occur in 0.1 percent of all clinically recognized pregnancies and is usually prenatal lethal [63]. In liveborn infants, trisomy 8 is almost always a mosaic (47,+8/46). The estimated frequency of mosaic trisomy 8 in liveborn infants is 1 in 25,000 to 1 in 50,000 [64]. A skewed sex ratio (3:1 male:female) is observed in mosaic cases [65,66]. If the prenatal testing was performed on a chorionic villus sample (CVS), one should keep in mind that the incidence of confined placental mosaicism is high, and oftentimes the fetus is not affected. In these cases, a follow-up amniocentesis is recommended [67].

Ultrasonographic detection of agenesis of the corpus callosum and ventriculomegaly should alert to the possibility of mosaic trisomy 8 [68]. In addition, mosaic trisomy 8 is sometimes associated with an elevated maternal serum alpha-fetoprotein. A diagnosis of mosaic trisomy 8 can be difficult to establish and can be missed at amniocentesis [69]. A normal chromosome constitution in lymphocyte culture does not exclude trisomy 8 mosaicism, since abnormal cell lines are far more likely to be detected in fibroblast cultures (eg, skin biopsy, or other tissues) than in lymphocytes [70], making the condition difficult to diagnose.

Trisomy 8 mosaicism is also difficult to diagnose postnatally due to great phenotypic variation [29,63,64,71,72]. The severity of the phenotype does not appear to correlate with the level (ie, percentage) and distribution of the trisomic cells in tissue types [73]. Characteristic phenotypic features include agenesis of corpus callosum, ventriculomegaly, skeletal and joint abnormalities, congenital heart defects, deep palmar and plantar creases, facial dysmorphism, and moderate to severe intellectual disability. The growth of children with trisomy 8 is variable, ranging from small to tall stature. Life expectancy is usually normal [63].

Molecular studies revealed that trisomy 8 mosaicism in live-born infants almost always originates from postzygotic mitotic error [65,74]. Parental ages of liveborn infants with trisomy 8 mosaicism are usually not increased [75], and cases with uniparental disomy (UPD) 8 are rare because they can only originate from a meiotic nondisjunction error.

Genetic counseling is difficult due to great phenotypic variability. Prognosis, management, and treatment depend upon the specific clinical abnormalities in the patient (eg, repair of cleft palate or heart defects, surgical intervention for hydronephrosis). Patients and their parents/caregivers should be made aware of a possible association with malignancy [76]. Early assessment for intellectual disability is recommended for additional assistance in providing special education programs.

Trisomy 9 syndrome — Full trisomy 9 occurs in approximately 0.1 percent of conceptions and is almost always prenatal lethal [77]. The phenotype appears to be similar in the several liveborn infants described so far and consists of severe growth restriction, characteristic facial appearance (eg, micrognathia, bulbous nose, low-set ears), cleft palate, skeletal abnormalities (eg, dislocated joins), heart abnormalities (eg, ventricular septal defect), hypoplastic genitalia, and kidney and brain abnormalities. The survival time after birth varies between minutes to nine months [78-80].

The majority of liveborn individuals with trisomy 9 have a mosaic karyotype (47,+9/46) that may be detected in amniocytes or a peripheral blood sample [70,71,78,79]. Mosaic trisomy 9 observed in a CVS specimen should be interpreted with caution due the possibility of mosaicism confined to the placenta (see 'Trisomy 8 syndrome' above). The constellation of phenotypic abnormalities of trisomy 9 mosaicism is similar to that seen in liveborn infants with full trisomy 9 described above [29,70,71,78,79,81]. Failure to thrive, severe intellectual and motor deficiency, cryptorchidism in males, and renal cysts are common. Death typically occurs at less than one year of age, although longer survival intervals have been reported [79,82,83].

Based upon molecular studies, it appears that trisomy 9 is caused by a meiotic error, and subsequent trisomy rescue leads to mosaicism in surviving embryos. In some cases, UPD has been documented in the diploid cell line [84]. Association with advanced maternal age is observed, similar to other trisomy syndromes [79]. (See "Genetics: Glossary of terms".)

The percentage of mosaicism appears not to correlate with clinical manifestations and does not help to predict survival. Medical intervention depends upon the presence and severity of abnormalities. Genetic counseling and early assessment are recommended to provide any necessary special medical/educational assistance.

Other rare autosomal trisomies — Other autosomal trisomies are rare and have been described largely in case reports. Most of these individuals have a mosaic karyotype. Mosaic trisomy 7 is often associated with maternal UPD 7, leading to Silver-Russell syndrome [85,86]. Mosaic trisomy 14 is associated with growth and intellectual disability, congenital heart defects (especially tetralogy of Fallot and septal defects), and body and/or facial asymmetry [70,87-90]. Trisomy 22 can occur as a mosaic or full trisomy [91-97]. The major clinical features are IUGR, microcephaly, abnormal ears, ear tags, webbed neck/redundant skin, congenital heart defects, kidney abnormalities, and long fingers. Nonmosaic trisomy 22 usually ends in miscarriage; survival beyond the early neonatal period is rare but has been reported.

The risk level of having documented malformations associated with a given trisomic mosaicism, based upon cases diagnosed prenatally through amniocentesis and assessed at birth or at pregnancy termination, is as follows [70]:

●Trisomic mosaicism of chromosome 2, 16, or 22 – Greater than 60 percent

●Trisomic mosaicism of chromosome 5, 9, 14, or 15 – 40 to 59 percent

●Trisomy 12 mosaicism – 26 percent

●Trisomy 7 mosaicism – Up to 19 percent

●Trisomy 17 mosaicism – Low

The prognoses of the remaining rare trisomies have not been determined due to insufficient data [70].

Triploidy syndrome — Triploidy occurs in 1 to 3 percent of clinically recognized pregnancies and accounts for approximately 20 percent of spontaneous abortions [98]. The frequency in liveborn infants is estimated at 1 in 10,000 [99]. Triploid fetuses that survive to the third trimester usually have severe IUGR [29].

Triploidy refers to a complete extra set of haploid chromosomes derived from the mother (digynic) or the father (diandric). Digynic triploidy can result from fertilization of a diploid ovum due to an error at either the first or second meiotic division. Diandric triploidy may occur through fertilization of a normal ovum by a diploid sperm or by two sperm (dispermy/double fertilization) and is more common than digynic triploidy (90 versus 10 percent) [29].

Two distinct phenotypes have been noted due to an imprinting effect that depends upon the origin of the extra haploid set of chromosomes [100,101] (see "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Parent-of-origin effects (imprinting)'). When the triploid is diandric, the placenta is enlarged, and the histology is consistent with a partial hydatidiform mole (see "Gestational trophoblastic disease: Pathology"). The fetus is mildly growth restricted, with either head size proportionate to the trunk size or mild microcephaly. By comparison, a digynic triploid is associated with severe fetal growth restriction, relative macrocephaly, and a small, noncystic placenta. The digynic triploid fetus tends to survive longer than the diandric triploid, although there is 100 percent mortality (usually intrauterine, rarely within a few months of birth). Fetuses with triploid mosaicism may be viable.

Supernumerary marker chromosome — The term supernumerary marker chromosome (SMC; also sometimes called an extra structurally abnormal chromosome [ESAC]) refers to any extra, small, structurally altered chromosome in addition to the normal diploid cell line. SMCs were often uncharacterized by conventional cytogenetic methods due to insufficient banding pattern. Modern molecular technologies, such as fluorescence in situ hybridization (FISH) and CMA, have allowed determination of marker chromosomes deriving from all 46 chromosomes.

The overall incidence of SMC is similar at amniocentesis and in newborns, 0.6 to 1.5 and 0.72 per 1000, respectively [102-105]. A study performed on 143,000 consecutive prenatal samples, including 44,786 CVS and 98,214 amniotic fluid (AF) samples, revealed an overall frequency of 0.073 percent for a de novo SMC. The overall frequency differed between CVS (ie, 0.103 percent) and AF (ie, 0.059 percent) samples [106]. The difference between karyotype in placental versus fetal tissue most likely reflects a confined placental mosaicism (CPM).

For the de novo markers, the overall risk for abnormal phenotype has been estimated between 14 and 30 percent. However, the risk for abnormal phenotype is lower (ie, 7 percent) when the marker is derived from an acrocentric chromosome (13, 14, 21, 22), except for chromosome 15. There is an approximate 28 percent overall risk for abnormalities in carriers of SMC derived from nonacrocentric chromosomes. However, the risk may decrease to 18 percent in cases with no congenital abnormalities detected by high-level ultrasound [107]. Thus, identification of the origin and genetic makeup of a marker is crucial for risk calculation and genetic counseling.

Various cytogenetic and molecular methods can be applied to identify markers, including karyotyping, FISH, and CMA. Applying genomewide microarray is an efficient method to identify and characterize markers, as well as to detect any additional potential abnormality/imbalance in the genome [108]. There are technical limitations for each method; for example, neocentromeric markers cannot be identified by FISH with centromeric alpha satellite DNA probes, and CMA does not detect minute markers that do not contain euchromatin or cases with a low level of mosaicism (<10 percent).

The four most common SMCs are discussed below. The terms "pter" and "qter" refer to the terminal parts of the short and long arms of a chromosome, respectively.

47,+inv dup(15) — This SMC is formed by inverted duplication of the proximal part of chromosome 15. It is the most common marker found at prenatal testing. The inv dup(15) markers are classified as two subtypes based upon breakpoint on the long (q) arm: a small inv dup(15) with the break at 15q11 and a large inv dup(15) containing the Prader-Willi/Angelman critical region (PWACR), with the break at 15q12 or q13. The small inv dup (15)(q11) can be inherited or de novo. In two large studies, the inv dup(15) accounted for 57 and 25 percent of all markers detected in 39,105 and 100,000 prenatal diagnoses, respectively [104,105].

The majority of carriers of a small dup(15) have a normal phenotype [109], with some exceptions [110]. There are rare cases of Angelman or Prader-Willi syndrome due to UPD 15 [111]. Postnatal studies have demonstrated a correlation among the large inv dup(15)(q12 or q13), (PW/ACR+) marker, and distinctive clinical findings that include intellectual disability, developmental delay, early central hypotonia, seizures, and autistic behavior [102,111-114].

In the majority of cases, the inv dup(15)(q12 or q13) is derived from maternal chromosomes at meiosis, is associated with advanced maternal age at conception, and is almost always de novo [113,115]. Thus, it is essential to determine whether the 47,+inv dup(15) marker chromosome contains the PWACR when the SMC is prenatally identified as a de novo inv dup(15). The inv dup(15) markers can be detected by standard chromosome analysis and FISH with probes specific to centromere of chromosome 15 and to the PW/AS locus or by array comparative genomic hybridization (aCGH) to detect and to determine the extent of the duplication. Methylation study and/or microsatellite analysis should also be performed to determine the origin of chromosome 15 in the proband. (See "Prader-Willi syndrome: Clinical features and diagnosis" and "Prader-Willi syndrome: Management" and "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 maternal deletion syndrome (Angelman syndrome)' and "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 paternal deletion syndrome (Prader-Willi syndrome)'.)

47,+i(18p) — This supernumerary marker chromosome is an isochromosome consisting of two identical copies of the entire short (p) arm of chromosome 18, i(18p), in the presence of two normal copies of chromosome 18, resulting in tetrasomy of 18p. It is one of the most commonly observed isochromosomes [116], with a frequency of approximately 1 in 625,000 births [117]. In the majority of cases, nondisjunction of chromosome 18 occurs in maternal meiosis II, followed by centromeric misdivision [118].

Isochromosome 18p is associated with a distinctive syndrome that results from tetrasomy 18p. The most common clinical features include growth retardation, neonatal hypotonia and feeding problems, microcephaly, facial dysmorphism [119], cardiac abnormalities (eg, patent ductus arteriosus, ventricular septal defect, atrial septal defect), cryptorchidism, talipes equinovarus (clubfoot), congenital hip dysplasia, and mild to moderate intellectual disability and developmental delay [120]. Autistic characteristics are common.

Most cases of tetrasomy 18p are sporadic, although familial cases have been reported [121,122]. Parental chromosome analysis is recommended for a recurrence risk evaluation.

Evaluations for patients with tetrasomy 18p depend upon the clinical features present and may include evaluations by ophthalmology, otolaryngology and audiology, cardiology, orthopedics, neurology, endocrinology, and gastroenterology. Patients may also benefit from referral for developmental services and specific medical treatment for congenital anomalies. Specific management guidelines are available [123].

47,+i(12p) — This supernumerary marker is an isochromosome consisting of two copies of the short (p) arm of chromosome 12 in the presence of two normal copies of chromosome 12, resulting in tetrasomy of 12p, also called Pallister-Killian syndrome (MIM #601803). Mosaicism with a normal cell line frequently occurs [124,125].

The exact prevalence of Pallister-Killian syndrome is unknown, but the estimate is approximately 1 in 200,000 [126]. It may be underdiagnosed because of broad phenotype variability. The major clinical manifestations are severe intellectual disability, seizures, hypotonia with subsequent contractures, coarse and dysmorphic facies, large and abnormal ears, short neck, and sparse hair [29,127,128].

Prenatally, the ultrasound findings most often seen in cases of Pallister-Killian syndrome are polyhydramnios and congenital diaphragmatic hernia [126].

Chromosome analysis (ie, karyotype, FISH, CMA) is recommended in suspected cases of Pallister-Killian syndrome. Cells with 47,+i(12p) are tissue specific in mosaic cases and are more likely to be detected in skin fibroblasts than in peripheral blood lymphocyte cultures or amniocytes [102]. Thus, different types of tissue (eg, skin biopsy and/or buccal smears) should be submitted for testing when Pallister-Killian syndrome is suspected.

Early evaluation for abnormalities requiring surgical intervention is recommended. Some patients will require multiple corrective surgeries. Enrollment in special education programs should be considered for patients with milder developmental delay.

47,+inv dup(22)(q11) — This supernumerary bisatellited marker is derived from an inverted duplication of the short arm (p) and proximal long arm (q) of chromosome 22 (ie, inv dup 22pter—22q11.2), resulting in tetrasomy of this region of chromosome 22. This defect is associated with cat-eye syndrome, a developmental disorder characterized by a highly variable phenotype [129,130]. Cat-eye syndrome can be the result of trisomy or tetrasomy 22q. The name is derived from the presence of vertical iris coloboma. Characteristic clinical features include preauricular tags and/or pits, iris coloboma, congenital heart disease (total anomalous pulmonary venous return [TAPVR] is the characteristic defect associated with this condition), anal anomalies, kidney malformation, skeletal abnormalities, and intellectual disability. The clinical manifestation may vary from very mild to a full pattern and lethal outcome [131-133]. Chromosome analysis of parents is recommended in children in whom the inv dup(22)(q11) chromosome is detected by cytogenetic analysis due to the significant phenotypic variability of the disease.

Patients with cat-eye syndrome should be assessed at birth for presence of heart, biliary, and anorectal abnormalities. Early intervention and treatment can prevent possible future complications, including patient death.

STRUCTURAL DEFECTS — Structural chromosomal defects include deletions, duplications, translocations, and inversions. Cytogenetically detectable autosomal deletions are present in 1 in 7000 live births [134]. The incidence of autosomal duplications is unknown. The more common autosomal deletion and duplication syndromes that are primarily caused by macrodeletions or duplications (deletions or duplications detectable on chromosomal banding with light microscopy) are discussed below. Syndromes that are typically caused by submicroscopic deletions or duplications (microdeletions or microduplications) are reviewed in detail elsewhere. Structural defects of the sex chromosomes are also covered elsewhere. The mechanisms for structural chromosomal defects are discussed separately. (See "Microdeletion syndromes (chromosomes 1 to 11)" and "Microdeletion syndromes (chromosomes 12 to 22)" and "Microduplication syndromes" and "Sex chromosome abnormalities" and "Genomic disorders: An overview" and "Chromosomal translocations, deletions, and inversions".)

5p deletion syndrome (cri-du-chat syndrome) — Cri-du-chat (cat cry; MIM #123450) is a deletion syndrome, with an incidence of approximately 1 in 45,000 liveborn infants [135,136]. Approximately 85 percent of cases result from a de novo partial deletion of the short arm of chromosome 5 (the deleted chromosome is of paternal origin in 80 percent) [29]. The remaining cases derive from a parental translocation involving 5p. The critical region for the high-pitched, cat-like crying is 5p15.3, while the remaining clinical features of this syndrome are mapped to a smaller region within 5p15.2 (figure 2) [137-139].

Patients with cri-du-chat or cat cry syndrome have a mew-like cry early on in life that quickly resolves (apparently related to vocal cord abnormalities) and low birth weight, failure to thrive, hypotonia, psychomotor delay, intellectual disability, microcephaly, hypertelorism, round face, downslanting palpebral fissures, broad nasal bridge, and low-set and/or malformed ears [29,136,140,141]. Genotype-phenotype correlation in one series of 62 patients with terminal deletions showed progressive severity of clinical features (eg, degree of microcephaly) and psychomotor retardation according to the size of the deletion [141]. With advancing age, the clinical manifestations become less striking, making diagnosis more difficult [142]. Most children, but not all, have low weight for age and, to a lesser extent, shortened height for age [143].

18q deletions — This group of conditions is technically not a syndrome, because it may involve any size deletion from any region of the long arm of chromosome 18 (MIM #601808). The frequency of all 18q deletions is approximately 1 in 55,000 births [117]. Ninety-four percent are de novo events as opposed to inherited from a parent with a balanced translocation. With regard to location of the deletion, there are two nonoverlapping regions thereby creating two groups: proximal 18q- and distal 18q-.

Proximal 18q- (18q11.2-q21.1) — Proximal 18q- involves an interstitial deletion within the region between 20 and 45.7 Mbp, a region that includes 80 genes [123]. However, there is no common region of overlap for these deletions, and most persons have deletions between 5 and 15 Mb in size. Persons whose deletions include the SET-binding protein 1 (SETBP1) gene have significant expressive speech delay [144,145]. The most common problems include developmental delay, hypotonia, cardiac abnormalities, hydronephrosis, and vision problems.

Distal 18q- (18q21.1–q23) — Distal 18q- involves an interstitial or terminal deletion occurring between 46.7 Mb and the end of the chromosome, a region that includes 103 genes. The size and the location of the deletion vary between affected persons and can involve between 1 and all 103 genes. There is no commonly deleted region for persons with a distal 18q deletion, although 83 percent have terminal deletions [146]. Several genes and small regions are associated with specific clinical manifestations. Thus, knowledge of a patient's molecular-based deletion is essential to providing personalized care.

The transcription factor 4 (TCF4) gene has a dramatic effect on development. Persons whose deletion includes TCF4 have more serious developmental and medical issues, with a constellation of clinical features called Pitt-Hopkins syndrome [147]. For persons whose deletion does not include the TCF4 gene, the most common clinical manifestations include delayed development, hearing and vision problems, foot deformities, and growth hormone deficiency. Anxiety and depression are common. Patients should be monitored for hypothyroidism and autoimmune disorders. Approximately half of these patients are classified as having intellectual disability, although all require some level of special support as adults.

Specific management guidelines and directions for determining an individualized management plan are available [123].

SUMMARY

●Incidence – A major chromosomal abnormality is found in approximately 1 in 140 live births. Trisomy 21 (Down syndrome) is the most common congenital cytogenetic abnormality. (See 'Incidence' above.)

●Numeric abnormalities – Persons with unbalanced autosomal aberrations may have congenital abnormalities that can involve one or more organ systems. Intellectual disability and small stature are the two most constant features. Low birth weight and failure to thrive are other frequently observed problems. (See 'Numeric abnormalities' above.)

•Trisomies – Trisomies are the most common aneuploidies seen. Autosomal trisomies, with the exception of trisomy 21 (Down syndrome), are almost always lethal. Mosaicism alters survivorship for some autosomal trisomies. Survival can be prolonged by application of intensive medical intervention. (See 'Numeric abnormalities' above.)

•Supernumerary marker chromosome – The term "supernumerary marker chromosome" (SMC) refers to any extra, small, structurally altered chromosome in addition to the normal diploid cell line. Identification and characterization of marker chromosomes have diagnostic and prognostic value and may provide information for a more accurate estimation of recurrence risk. (See 'Supernumerary marker chromosome' above.)

●Structural defects – Structural chromosomal defects include deletions, duplications, translocations, and inversions. Cri-du-chat (cat cry) syndrome is one of the most common human deletion syndromes. (See 'Structural defects' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Stanislawa Weremowicz, PhD, who contributed to earlier versions of this topic review.