Down Syndrome is a genetic disorder caused by an additional copy of chromosome to the 21^st chromosome during cell division in the fetus during the 10^th-22^nd week of pregnancy. During cell division (Meiosis-1 and Meiosis-2), sperm or egg may come with an error that is an extra copy of chromosome by which when the gamete fuses with a normal gamete, the zygote forms with three copies of chromosome 21, it is called nondisjunction [1-3].

Another reason is Robertsonian Translocation. In this scenario, 3-4% of cases of birth take place with trisomy-21 by genetic carriage, which means parents may be having the Trisomy-21. Actually, a part of chromosome 21 is sometimes associated with another chromosome as chromosome 14 usually. This translocation is inherited from parents who are balanced carriers [1-3].

The next reason is Mosaicism, in which some cells consist of three copies of chromosome 21, whereas others typically have two. This may lead to carrying milder features of Down Syndrome (Trisomy-21) as many proportion of cells with the extra chromosome. This can be seen in 1-2% of cases [1-3].

Last but not the least is chromosomal impact, in which the additional copy of chromosome 21 exhibits overexpression of genes joined to this chromosome. It can intervene with the normal regulatory process and lead to physiological and developmental abnormalities [1-3].

Down Syndrome cases have reached 1,579,784 (95% UI 1,251,955-1,962,089) in 2019 from 1,257,110 (95% UI 989,416-1,573,671) in 1990 [4].

An individual with Down syndrome has some characteristics by which we can identify visually as follows:

1. Facial characteristics: Flattened face, slant-up eyes, protruding tongue, small ears, and short neck (Figure 1).
2. Slow growth rate and shorter stature.
3. Short fingers, wide gap between the first and second toes, deep palmar crease.
4. Intellectual disabilities: They have mild to moderate intellectual disability with IQ ranges from 30 to 70.
5. Slow cognitive development, slow in speech and motor skills. Therefore, they require some practicing of skills in routine to improve cognitive skills.
6. Cardiac: Congenital defects in the heart for example, ventricular septal defects, and atrioventricular septal defects occur in approximately 50% of cases.
7. Gastrointestinal problem: duodenal atresia and Hirschsprung’s disease.
8. Immunologic: Higher susceptibility to infections because of immune system anomalies.
9. Hematologic: Higher risk of leukemia, especially acute lymphoblastic leukemia (ALL).
10. Endocrine: Hypothyroidism and thyroid dysfunctions.
11. Neurological: Higher risk of early-onset Alzheimer’s disease and seizures.

Figure 1: Physical characteristics of a child with Down Syndrome [25].

For assurance of a fetus with Down Syndrome, we prefer several screening tests (prenatal diagnosis) during the first trimester and second trimester- blood tests and ultrasound images to measure the thickness of amniotic fluid (Nuchal Translucency). NIPT (Non-invasive prenatal testing) provides cell-free fetal DNA analysis from maternal blood. Another test is a diagnostic test (part of prenatal diagnosis), i.e. CVS (Chorionic villus sampling). Amniocentesis gives a definitive diagnosis by an analysis of the fetus chromosome. As a postnatal diagnosis, we consider physical examination and karyotype analysis. Physical examination provides physical characteristics, and karyotype analysis makes assurance of the extra chromosome. An individual with Down syndrome needs extra care from the age of pregnancy to adulthood, and that care varies according to the age and the individual’s interests. Those cares include occupational therapy, physical therapy, and speech therapy to address delays in development. They also need specialized edutainment (education + entertainment) programs to enhance their skills [1-3].

They need regular medical check-ups to monitor their health-related issues like heart defects, vision and hearing problems, and thyroid dysfunction. For these issues, they are required to get medications like treatment for hypothyroidism and managing congenital heart anomalies. Apart from the mentioned care, they deserve family support, everyday counseling, programs for developing their social skill, and community involvement [1-3].

1. Genetic Research- Gene expression study: Understanding the combination and expression of genes on the 21^st chromosome and their impact on health and development.
2. Genetic Research-Therapeutic Approaches: Research on highly efficient and capable gene therapies and other cures to reduce the effects of the additional chromosome.
3. Biomedical Research- Neuro-development: Studies on brain growth in Trisomy-21 (Down Syndrome) to make interventions for cognitive development.
4. Biomedical Research-Pharmacological Treatments: Drug trial for making improvements in cognitive functions and other symptoms of Down Syndrome.

In this study, we reviewed various methods for detecting the fetus or birth with Down Syndrome or Trisomy-21. We found that a blood test of maternal blood helps to find a fetus whether having any chromosomal abnormality or not. Blood tests in the first-trimester help to measure proteins made by PAPP-A, placenta beta, HCG [5], and blood tests in the second trimester help to triple and quadruple measures and AFP (Alpha-Fetoproteins) test. Another method for testing the risk of Down Syndrome is an Ultrasound image that is safe and non-invasive. In this review, we found-

1. a technique i.e., Wavelet Analysis used to sharpen the edge of the boundary of nuchal translucency, and in this way, features are extracted from the image and give classification with 97.4% accuracy [6].
2. Hierarchical structural models to detect nuchal translucency-used techniques are SVM classifier, Dynamic programming, and distance [7].
3. Three-dimensional ultrasound measurement of nuchal translucency-used technique is a dynamic programming [8].
4. Using ultrasound video stream to measure the nuchal translucency of the fetus-done by experts [9].
5. Variation of nuchal translucency with increasing crown-lump length and gestational age in normal singleton pregnancies-used technique is linear regression [10].
6. Nasal bone detection from ultrasound image [11].
7. Nasal bone detection in first-trimester screening using an artificial neural network- used techniques are BPNN (back propagation neural network), DCT (Discrete cosine transform), and wavelet transform [12].
8. Screening test to detect trisomy-21 [13].
9. Nasal bone identification to detect Down Syndrome at an early stage- used technique is BPNN, DCT, wavelet transform, and Otsu thresholding [12].
10. Map matching method for finding nasal bone [14].
11. Fetal nasal bone length using Euclidean distance, morphological process, and Otsu thresholding [15].
12. Cross-correlation techniques for nasal bone segmentation [16].
13. Considering mid-second trimester for detection of hypoplasia [17]. Used techniques are mean shift analysis and canny operator [18].
14. Classification of image features to detect Down Syndrome using Haralick features- used technique is GLCM (Gray-level co-occurrence matrix), Lee & frost filter, and SVM classifier. Obtained accuracy is 94.4% [19].

Extracting features from an ultrasound image of the fetus is a very crucial task as we see in the above list of works because it comes under a non-invasive technique for visualizing amniotic fluid thickness, i.e., nuchal translucency. We apply many deep learning approaches for classification, and before the classification, we need to provide segmented images in the deep learning algorithms [11,20-23]. It is expected to enhance the accuracy for getting better results and extraction of features like nuchal translucency, nasal bone, CRL, etc. In account of accuracy enhancement and false detection challenges in trisomy-21 diagnosis, it is suggested to recognize and exhibit all relevant screenings which have the FMF (Frontomaxillary facial), FHR (fetal heart rate), bowels shine, swelling, crow’s feet, an augmented nuchal translucency, dilated brain ventricles, little bit kidney damage or swelling.

We observed the highest accuracy of 97.4% for nuchal translucency [6], 97.34% for facial difference [24], and 96.26% for nasal bone [16].