Physical characteristics that are not themselves anomalies but that occur more commonly in fetuses with Down syndrome are calledsoft markers. The ratio of the prevalence of these markers in fetuses with Down syndrome to their prevalence in the normal population will result in a likelihood ratio that can be used to modify the a priori age or serum screening risk. This is the basis for ultrasound screening for Down syndrome.
For a marker to be useful for Down syndrome screening, it should be sensitive [i.e., present in a high proportion of fetuses with Down syndrome], specific [i.e., rarely seen in normal fetuses], easily imaged in standard ultrasound examinations, and present early enough in the second trimester that subsequent diagnostic testing by amniocentesis can be performed with the results available in time for pregnancy termination to be an option. Available markers and their likelihood ratios are listed inBox 32.2 andTable 32.8, respectively.
No soft marker is independently an indication for invasive testing; it should be part of a total risk analysis including the a priori risk determined by maternal age, the results of serum markers [first trimester or second trimester or both] or cell-free DNA aneuploid screening, and the presence or absence of other sonographic findings. Therefore it is wise to defer discussion of the impact of specific markers until the ultrasound examination has been completed, the results of serum screening are available, and a final adjusted risk is calculated. As biochemical and DNA screening tests have improved, the value of ultrasound soft markers in Down syndrome screening has become less significant.
Markers commonly sought to assess the risk for Down syndrome include the following:
1An increased nuchal fold [>6 mm] in the second trimester is the most distinctive marker. The fetal head is imaged in a transverse plane, the plane used to measure the biparietal diameter. The thalami and the upper portion of the cerebellum should be in the plane of the image. The distance between the external surface of the occipital bone and the external surface of the skin is then measured. About 35% of fetuses with Down syndrome, but only 0.7% of normal fetuses, have a nuchal skin fold measurement greater than 5 mm. This ratio yields a likelihood ratio of 50 but includes fetuses with more than one marker. When an increased nuchal fold is an isolated finding, the likelihood ratio is still strong at 20-fold. This high likelihood ratio is obtained because of the rarity of an increased nuchal fold in an unaffected population [i.e., high specificity]. For women with an a priori risk of less than 1 : 1600 [age-related risk for a 20-year-old], a 20-fold increase results in a risk estimate of at least 1 : 270. Thus the presence of an increased nuchal fold alone is an indication to offer further evaluation.92–95
2The fetal NB has been demonstrated to be hypoplastic or absent in up to 60% of Down syndrome pregnancies imaged in the second trimester and only about 1% to 2% of unaffected pregnancies. Complete absence occurs in about 37% of affected cases, and hypoplasia occurs in about 50%. In normal pregnancies, absence occurs in 0.9% of cases, and hypoplasia occurs in 2.4%. NB length can be converted to a likelihood ratio and used for Down syndrome risk assessment. When performed by experienced operators, NB evaluation may be the best single ultrasound marker for second-trimester risk assessment; however, as discussed in the earlier section on first-trimester NB screening, ethnic variation can occur.25
3Fetuses with Down syndrome in the second trimester may have short proximal extremities [humerus and femur] relative to the expected length for their biparietal diameter. This can be used to identify at-risk pregnancies by calculating a ratio of observed-to-expected femur length based on the biparietal diameter of the fetus. An observed-to-expected ratio of less than 0.91 or a biparietal diameter-to-femur ratio of more than 1.5 has a reported likelihood ratio of 1.5 to 2.7 when present as an isolated finding. A short humerus is more strongly related to Down syndrome, with reported likelihood ratios of 2.5 to 7.5. Bahado-Singh and coworkers combined humerus length with nuchal skin fold to estimate Down syndrome risk and calculated the likelihood ratios for various measurements to adjust estimated Down syndrome risk for each patient.96
4Echogenic intracardiac foci occur in up to 5% of normal pregnancies and in approximately 13% to 18% of Down syndrome pregnancies. The likelihood ratio for Down syndrome when an echogenic focus is present as an isolated marker is 1.8 to 2.8 but may be lower in an Asian population, where the frequency in unaffected pregnancies may be higher.97 The risk does not seem to vary if the focus is in the right or left ventricle or if it is unilateral or bilateral.
5Increased echogenicity of the fetal bowel, when brighter than the surrounding bone, has a likelihood ratio for Down syndrome of 5.5 to 6.7.98 This finding can also be seen with fetal cystic fibrosis [CF], congenital cytomegalovirus infection, swallowed bloody amniotic fluid, and severe IUGR or placental insufficiency. Therefore if amniocentesis is performed for this finding, testing for the other potential etiologies should be considered.
6Mild fetal pyelectasis [a renal pelvis anterior-posterior diameter >4 mm] has been suggested as a potential marker for Down syndrome. As an isolated marker, the likelihood ratio is 1.5 to 1.9 [seeTable 32.8]. However, Snijders and coworkers found that mild renal pyelectasis is not significantly more frequent in Down syndrome pregnancies than in normal pregnancies.98a
7Other markers described include a hypoplastic fifth middle phalanx of the hand, short ears, a sandal gap between the first and second toes, an abnormal iliac wing angle, an altered foot-to-femur ratio, an altered frontomaxillary angle,99,100 and increased prenasal thickness.101,102 These markers are inconsistently used because of the time and expertise required to obtain them.
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Down Syndrome
D.J. Fidler, in Encyclopedia of Infant and Early Childhood Development, 2008
Introduction
Down syndrome is a genetic syndrome, occurring in from 1 in 650 to 1 in 1000 live births. In 95% of cases, Down syndrome is caused by nondisjunction during cell division, resulting in an extra chromosome 21 [trisomy 21]. Most cases of Down syndrome involve a nondisjunction during the first meiotic cell division, with mothers contributing the extra chromosome in 85% of cases. When nondisjunction occurs after fertilization, this leads to mosaic Down syndrome, where one line of cells in the developing fetus contains the extra copy of chromosome 21 and a second line of cells in the developing fetus does not. In a small percentage of cases, Down syndrome is caused by a translocation of genetic material on chromosome 21. Risk for Down syndrome is associated with maternal age. The pathways from genotype to phenotype in Down syndrome are currently not well characterized. However, current studies aim to identify how the additional chromosomal material on chromosome 21 impacts upon the developmental process.
Down syndrome was first described in the 1860s by John Langdon Down, who observed the clustering of specific physical and psychological features in a subgroup of individuals with cognitive impairments in medical settings. At that time, an unfortunate association was made between the craniofacial appearance of individuals with this clustering of symptoms and the physical features of specific ethnic groups. Modern genetic research has completely dispelled any a link between ethnic origin and Down syndrome. The discovery of the chromosomal cause of Down syndrome [trisomy 21] was made in 1959 by Jerome LeJeune. Since then, many notable advances have been made in this population, including increases in the life expectancy of individuals with Down syndrome [average life expectancy in the late 50s], as well as improvements in developmental outcomes and quality of life.
Though Down syndrome can be diagnosed clinically, a chromosome analysis is still considered necessary in order to confirm the clinical impression and to identify the underlying type of chromosome disorder. Common physical features associated with Down syndrome include a distinctive craniofacial structure, brachycephaly [abnormally wide head shape], short neck, congenital heart defects, anomalies of the extremities, muscular hypotonia, and musculoskeletal hyperflexibility. Most individuals with Down syndrome are born with a unique craniofacial appearance that includes palpebral fissures, epicanthal folds, Brushfield spots, flat nasal bridge, dysplastic ear, and a high arched palate.
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Down Syndrome
Fred F. Ferri MD, FACP, in Ferri's Clinical Advisor 2022, 2022
Physical Findings & Clinical Presentation
[Fig. E1]
FIG. E1. Individual with Down syndrome. Note depressed nasal bridge, epicanthal folds, upward slanting eyes, low-set ears, and large tongue.
Physical features:
•Microcephaly/brachycephaly
•3 fontanels, delayed fontanel closure
•Flattened occiput and flat facial profile
•Midface hypoplasia
•Upward slanting eyes with epicanthal folds
•Brushfield spots on iris
•Small nose, flat nasal bridge
•Open mouth, protruding tongue [relative macroglossia]
Small, dysplastic ears
•Broad, short neck with excessive nuchal skin [in infancy]
•Small feet, hands, digits
•Wide gap between first and second toes [sandal gap]
•Clinodactyly of fifth digit
•Single palmar crease
•Hypotonia [improves with age]
•Poor Moro reflex [in infancy]
•Short stature
Organ system involvement:
•Cardiac: Congenital heart disease [40% to 50% incidence] including complete AV canal defect, VSD, ASD, tetralogy of Fallot and PDA, pulmonary hypertension, valvular disease in adolescence [i.e., mitral valve prolapse, aortic regurgitation], hyperlipidemiaPulmonary: Anatomic airway anomalies, pulmonary hypertension, obstructive sleep apnea, frequent infections [sinusitis, nasopharyngitis, pneumonia]
•ENT: Stenotic ear canals, congenital or acquired hearing loss [conductive and/or sensorineural], serous or acute otitis media, chronic rhinorrhea/sinusitis
•Gastrointestinal: Structural malformations [duodenal atresia, annular pancreas, tracheoesophageal fistula, Hirschsprung disease, imperforate anus], celiac disease, GERD, constipation
•Endocrine: Congenital or acquired hypothyroidism, hyperthyroidism, diabetes mellitus [type 1 and type 2], obesity, infertility in males, potential fertility in females
•Musculoskeletal: Joint hypermobility, cervical spine instability [atlantoaxial and atlanto-occipital], scoliosis, hip dysplasia, recurrent joint dislocations [shoulder, knee, elbow, thumb], juvenile idiopathic arthritis, arthropathy, osteopenia
•Hematology/oncology: Transient myeloproliferative syndrome [in infancy], acute lymphocytic leukemia, acute myelogenous leukemia, acute megakaryoblastic leukemia, decreased risk for solid tumors [except retinoblastoma, germ cell], macrocytosis
•Ophthalmology: Refractive errors [myopia], congenital or acquired cataracts, nystagmus, strabismus, glaucoma, dacryostenosis
•Neurology: Seizures [infantile spasms in infancy, complex partial, tonic-clonic in adulthood], Moyamoya disease, early onset Alzheimer disease
Developmental: Delayed milestones in gross/fine motor skills, coordination, receptive and expressive language. IQ range of 20 to 70. Social performance is often better than expected relative to other skills, though dual diagnosis of autism spectrum disorder occurs in 7% to 16%.
•Psychiatric: Disruptive behaviors [ADHD, ODD, aggression], depression, anxiety, obsessive compulsive behaviors
•Dental: Delayed tooth eruption, periodontal disease
•Dermatology: Cutis marmorata, hyperkeratosis, seborrhea, eczema, alopecia areata, folliculitis, vitiligo
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Down Syndrome
A. Salehi, ... B. Pohlman, in Encyclopedia of Neuroscience, 2009
Down syndrome [DS], an important cause of intellectual disability [‘mental retardation’], results from the presence of three copies of human chromosome 21. The trisomy, affecting more than 300 genes, is associated with a variety of manifestations, including cardiac anomalies, thyroid dysfunction, leukemia, digestive disorders, and intellectual disabilities. DS significantly impacts the lives of those with the disorder as well as their families and the society in which they live, causing both human suffering and economic burden. Since the discovery of the genetic basis of DS, the possibility of linking individual genes to particular manifestations of DS has been an intensive focus of research. These efforts are especially relevant to the goal of understanding and treating cognitive disability and decline in people with DS. Due to developments in neurobiology and genetics, especially the Human Genome Project, the goal of linking specific genes to neurological phenotypes is now much closer to realization. Mouse models of DS have greatly helped to define and explore relevant phenotypes. In recent studies increased dosage of the gene [App] for the amyloid precursor protein was shown to be linked to cholinergic neurodegeneration in a mouse model of DS. In the future, it may be possible to define many more such linkages, thus enhancing opportunities both for understanding the genetic and cellular mechanisms of nervous system dysfunction in people with DS and for treating them effectively.
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Down syndrome
Karen L. Kelminson MD, ... Edward Goldson MD, in Berman's Pediatric Decision Making [Fifth Edition], 2011
Down syndrome is the most common chromosomal abnormality. It results from the presence of extra genetic material from chromosome 21. This extra chromosomal material can come about in three ways: [1] trisomy 21, which occurs in 95% of children with Down syndrome; [2] translocation between chromosome 21 and another acrocentric chromosome, which occurs in 3% to 4% of children with Down syndrome; and [3] mosaicism, the presence of both normal and trisomy 21 cell lines, which occurs in the remaining 1% to 2% of children. The prevalence rate of Down syndrome is 1 per 770 live births. It is important to recognize the considerable range in the phenotypic characteristics, associated conditions, and degree of intellectual and cognitive disability, with mosaicism at the mildest end of the spectrum.
A.Initial Counseling: The primary counseling visit with the parents of a child diagnosed with Down syndrome occurs before or soon after the infant’s delivery. Although it is important in this initial meeting not to overwhelm parents with information, the provider should clarify misunderstandings or misinformation regarding Down syndrome. The provider should also begin to prepare the family for issues and problems that may occur, especially during the child’s first months and years. It may be necessary to meet with the family on several occasions early on to adequately answer questions and address concerns. During these meetings, the provider should explain how the diagnosis of Down syndrome is made using karyotype information and other studies. It is important to review the risk for recurrences in subsequent pregnancies; the recurrence risk for trisomy 21 is 1 in 100, plus the risk of maternal age. The provider should inquire about other family members with Down syndrome or other developmental disabilities. Families with translocations or mosaicism should be referred for genetic counseling to discuss the mechanism of occurrence and recurrence risk in these cases.
B.Associated Conditions: Medical services should address the early identification and treatment of a wide range of conditions associated with Down syndrome [Figure 1]. These conditions include congenital heart disease [44%]; gastrointestinal anomalies [5%], including atresias and Hirschsprung disease; atlantoaxial instability or subluxation [15%]; eye disease, such as cataracts, strabismus, nystagmus, and visual impairment [60%]; ear disease and hearing impairment [75%]; hypothyroidism [15%]; celiac disease [5%–10%]; and leukemia [