Cytogenetic anomalies should be considered in individuals with multiple congenital anomalies. DNA methylation analysis is the most sensitive initial test in evaluating for Prader-Willi and Angelman syndromes. The timely identification of cytogenetic anomalies allows for prompt initiation of early intervention services to maximize the potential of every individual as they grow older. Although many of these conditions are rare, keeping them in mind can have a profound impact on the clinical course of affected individuals. This article reviews some of the more common genetic syndromes.
Key points
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Cytogenetic anomalies should be considered in individuals with multiple congenital anomalies.
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DNA methylation analysis is the most sensitive initial test in evaluating for Prader-Willi and Angelman syndromes.
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The timely identification of cytogenetic anomalies allows for prompt initiation of early intervention services to maximize the potential of every individual as they grow older.
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Although many of these conditions are rare, keeping them in mind can have a profound impact on the clinical course of affected individuals.
Newborns with large genomic anomalies tend to have a pattern of malformations. If an isolated anomaly is noted, it is less likely a large genomic anomaly but could still be related to single gene mutations. There are exceptions as in the case of Turner syndrome; the only presenting sign at birth in some cases is lymphedema. The common large-scale chromosomal and genomic anomalies are reviewed.
Large-scale genomic anomalies
Down Syndrome
Down syndrome is one of the most common large-scale genomic anomalies with a prevalence of approximately 1 in 700 births. Infants born with Down syndrome are typically hypotonic and consequently have feeding difficulties. Cardiac anomalies are present in approximately 40% of individuals with Down syndrome. Most commonly, an atrioventricular canal or endocardial cushion defect is noted; however, isolated ventricular septal defects, auricular septal defect, and aberrant subclavian arteries have also been noted less frequently. Additional findings include the following:
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Low-set ears
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Up-slanting palpebral fissures
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Brushfield spots
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Flat facial profile
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Short neck
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Hypotonia/poor Moro reflex
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Mental retardation ( Figs. 1–4 )
Fig. 1
Single transverse palmar crease noted in trisomy 21.
( Courtesy of D. Clark, MD, Albany, NY.)
Fig. 2
Brachydactyly with single transverse palmar creases in Down syndrome.
Fig. 3
Wide space between first and second toes in Down syndrome.
Fig. 4
( A ). Typical facial features in Down syndrome with bilateral epicanthal folds, small mouth and depressed nasal root. ( B ). Brushfield spots, seen most often in individuals with lighter eye pigment in Down syndrome.
([ A ] Courtesy of D. Clark, MD, Albany, NY.)
Early intervention services can be beneficial and can help maximize potential. An increased risk of leukemia and Alzheimer disease has been noted in older individuals.
Trisomy 13 (Patau Syndrome)
Trisomy 13 has a prevalence of approximately 1 in 7000 births. This condition can present on the holoprosencephaly spectrum, with some individuals having severe midline anomalies of the brain and other structures including a single nostril and pronounced hypotelorism (closely set eyes). Additional findings are as follows ( Figs. 5 and 6 ):
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Cutis aplasia (usually of posterior scalp)
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Polydactyly
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Microphthalmia, coloboma of iris
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Cleft lip and/or palate
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Abnormal ears that are low set
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Cardiac anomalies
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Severe neurologic involvement
Life span is typically limited to weeks or months; however, there have been cases that have been described with individuals living years. Individuals with mosaicism can have milder manifestations and live much longer.
Trisomy 18 (Edwards Syndrome)
Trisomy 18 has a prevalence of approximately 1 in 4500 births. Individuals with this syndrome have a characteristic clenched hand appearance with a tendency for overlapping of the index finger over the third digit and the fifth finger over the fourth digit. Additional findings include the following:
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Short sternum
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Low-set malformed ears
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Micrognathia
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Clenched hands with overlapping fingers ( Fig. 7 )
Fig. 7
Typical overlapping fingers in trisomy 18.
( Courtesy of D. Clark, MD, Albany, NY.)
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Short sternum
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Cardiac anomalies
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Severe mental retardation and neurologic dysfunction
Like trisomy 13, life span is typically limited to weeks or months; however, there have been cases that have been described with individuals living years. Individuals with mosaicism can have milder manifestations and live much longer.
Turner Syndrome
Turner syndrome has a prevalence of approximately 1 in 3500 births. The development of a cystic hygroma during fetal development can be pronounced. In many cases, the cystic hygroma interferes with the development of head and neck structures to such a degree that it results in a miscarriage. The fetuses that survive the cystic hygroma have the characteristic neck webbing seen in many individuals with Turner syndrome. Additional findings are as follows ( Fig. 8 ):
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Lymphedema in the newborn period
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Neck webbing
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Short stature
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Subtle cognitive issues
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Shield chest
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Wide-spaced nipples
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Coarctation of the aorta
Individuals with Turner syndrome can have mild difficulties in school. Many are picked up when being evaluated for delayed menarche. Life span is normal. If a mosaic state is noted with some 46, XY cells, streak gonads may be present, which must be addressed immediately because of the high risk of gonadoblastoma formation.
Klinefelter Syndrome
Individuals with Klinefelter syndrome do not have any clinical findings in the newborn period. They tend to present with infertility and gynecomastia. Typical findings include the following:
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Hypogonadism
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Small testes
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Azoospermia
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Oligospermia
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Hyalinization and fibrosis of the seminiferous tubules
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Gynecomastia in late puberty
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Psychosocial problems
Endocrinologic findings include the following:
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Low serum testosterone levels
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High luteinizing hormone and follicle-stimulating hormone levels
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Frequently elevated estradiol levels
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Progressive decline in testosterone production during the life span, and not all men suffer from hypogonadism
Large-scale genomic anomalies
Down Syndrome
Down syndrome is one of the most common large-scale genomic anomalies with a prevalence of approximately 1 in 700 births. Infants born with Down syndrome are typically hypotonic and consequently have feeding difficulties. Cardiac anomalies are present in approximately 40% of individuals with Down syndrome. Most commonly, an atrioventricular canal or endocardial cushion defect is noted; however, isolated ventricular septal defects, auricular septal defect, and aberrant subclavian arteries have also been noted less frequently. Additional findings include the following:
- •
Low-set ears
- •
Up-slanting palpebral fissures
- •
Brushfield spots
- •
Flat facial profile
- •
Short neck
- •
Hypotonia/poor Moro reflex
- •
Mental retardation ( Figs. 1–4 )
Fig. 1
Single transverse palmar crease noted in trisomy 21.
( Courtesy of D. Clark, MD, Albany, NY.)
Fig. 2
Brachydactyly with single transverse palmar creases in Down syndrome.
Fig. 3
Wide space between first and second toes in Down syndrome.
Fig. 4
( A ). Typical facial features in Down syndrome with bilateral epicanthal folds, small mouth and depressed nasal root. ( B ). Brushfield spots, seen most often in individuals with lighter eye pigment in Down syndrome.
([ A ] Courtesy of D. Clark, MD, Albany, NY.)
Early intervention services can be beneficial and can help maximize potential. An increased risk of leukemia and Alzheimer disease has been noted in older individuals.
Trisomy 13 (Patau Syndrome)
Trisomy 13 has a prevalence of approximately 1 in 7000 births. This condition can present on the holoprosencephaly spectrum, with some individuals having severe midline anomalies of the brain and other structures including a single nostril and pronounced hypotelorism (closely set eyes). Additional findings are as follows ( Figs. 5 and 6 ):
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Cutis aplasia (usually of posterior scalp)
- •
Polydactyly
- •
Microphthalmia, coloboma of iris
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Cleft lip and/or palate
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Abnormal ears that are low set
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Cardiac anomalies
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Severe neurologic involvement
